{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:57:02Z","timestamp":1791363422480,"version":"4.3.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1012374","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T00:00:00Z","timestamp":1742256000000}}],"reference-count":105,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T00:00:00Z","timestamp":1741305600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R24 GM137787"],"award-info":[{"award-number":["R24 GM137787"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Intestinal mucosal block is the transient reduction in iron absorption ability of intestinal epithelial cells (enterocytes) in response to previous iron exposures that occur at the cell scale. The block characteristics have been shown to depend both on iron exposure magnitude and temporality, and understanding block control will enable deeper understanding of how intestinal iron absorption contributes to pathological iron states. Three biochemical mechanisms implicated in driving the block behavior are divalent metal transporter 1 endocytosis, ferritin iron sequestration, and iron regulatory protein regulation of iron related protein expression. In this work, a model of enterocyte iron metabolism is built based on published experimental data that is capable of reproducing the mucosal block phenomena. The model is then used to estimate the quantitative contribution of each of the three mechanisms on the properties of the mucosal block. Analysis reveals that ferritin and iron regulatory proteins are the main intracellular mechanisms contributing to the mucosal block, findings congruent with experimental predictions. Lastly, DMT1 endocytosis is shown to play a role in limiting total iron uptake by enterocytes but does not contribute to the decrease in total iron transfer across their basal membrane seen in the mucosal block.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012374","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T18:23:11Z","timestamp":1741371791000},"page":"e1012374","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mathematical modeling reveals ferritin as the strongest cellular driver of dietary iron transfer block in 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Muckenthaler","year":"2017","journal-title":"Cell"},{"issue":"2","key":"pcbi.1012374.ref011","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1681\/ASN.2006070802","article-title":"Molecular control of iron transport","volume":"18","author":"T Ganz","year":"2007","journal-title":"J Am Soc Nephrol"},{"issue":"9","key":"pcbi.1012374.ref012","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1172\/JCI200420945","article-title":"IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin","volume":"113","author":"E Nemeth","year":"2004","journal-title":"J Clin Invest"},{"issue":"1","key":"pcbi.1012374.ref013","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/jcp.1041580104","article-title":"Iron absorption by CaCo 2 cells cultivated in serum-free medium as in vitro model of the human intestinal epithelial barrier","volume":"158","author":"C Halleux","year":"1994","journal-title":"J Cell 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Masison","year":"2023","journal-title":"PLoS One"},{"key":"pcbi.1012374.ref023","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41540-019-0114-3","article-title":"ModelBricks-modules for reproducible modeling improving model annotation and provenance","volume":"5","author":"AE Cowan","year":"2019","journal-title":"NPJ Syst Biol Appl"},{"key":"pcbi.1012374.ref024","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.jbiotec.2017.06.1200","article-title":"COPASI and its applications in biotechnology","volume":"261","author":"FT Bergmann","year":"2017","journal-title":"J Biotechnol"},{"issue":"24","key":"pcbi.1012374.ref025","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1093\/bioinformatics\/btl485","article-title":"COPASI--a COmplex PAthway SImulator","volume":"22","author":"S Hoops","year":"2006","journal-title":"Bioinformatics"},{"issue":"5","key":"pcbi.1012374.ref026","first-page":"563","article-title":"GEPASI: a software package for modelling 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Arch"},{"issue":"2","key":"pcbi.1012374.ref036","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/0014-5793(88)80775-0","article-title":"How do external parameters control fluxes and concentrations of metabolites? An additional relationship in the theory of metabolic control","volume":"232","author":"BN Kholodenko","year":"1988","journal-title":"FEBS Lett"},{"issue":"3","key":"pcbi.1012374.ref037","first-page":"G417-22","article-title":"Iron Imports. V. Transport of iron through the intestinal epithelium","volume":"290","author":"Y Ma","year":"2006","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"6641","key":"pcbi.1012374.ref038","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/41343","article-title":"Cloning and characterization of a mammalian proton-coupled metal-ion transporter","volume":"388","author":"H Gunshin","year":"1997","journal-title":"Nature"},{"issue":"6","key":"pcbi.1012374.ref039","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/iub.1621","article-title":"Ferritin, cellular iron storage and regulation","volume":"69","author":"P Arosio","year":"2017","journal-title":"IUBMB Life"},{"issue":"2","key":"pcbi.1012374.ref040","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/S0022-2836(65)80196-6","article-title":"An x-ray scattering study of ferritin and apoferritin","volume":"14","author":"FA Fischbach","year":"1965","journal-title":"J Mol Biol"},{"issue":"7","key":"pcbi.1012374.ref041","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.bbagen.2008.09.004","article-title":"Ferritins: a family of molecules for iron storage, antioxidation and more","author":"P Arosio","year":"2009","journal-title":"Biochim Biophys Acta"},{"issue":"5","key":"pcbi.1012374.ref042","doi-asserted-by":"crossref","first-page":"mfab021","DOI":"10.1093\/mtomcs\/mfab021","article-title":"Chemistry and biology of ferritin","volume":"13","author":"M Plays","year":"2021","journal-title":"Metallomics"},{"issue":"23","key":"pcbi.1012374.ref043","doi-asserted-by":"crossref","first-page":"8557","DOI":"10.1073\/pnas.0401146101","article-title":"Ferritin reactions: direct identification of the site for the diferric peroxide reaction intermediate","volume":"101","author":"X Liu","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"35","key":"pcbi.1012374.ref044","doi-asserted-by":"crossref","first-page":"25160","DOI":"10.1016\/S0021-9258(19)74019-8","article-title":"Ferroxidase kinetics of horse spleen apoferritin","volume":"267","author":"S Sun","year":"1992","journal-title":"Journal of Biological Chemistry"},{"issue":"10","key":"pcbi.1012374.ref045","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.1021\/bi027357v","article-title":"Multiple pathways for mineral core formation in mammalian apoferritin. 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Narayanan","year":"2019","journal-title":"J Phys D: Appl Phys"},{"issue":"3","key":"pcbi.1012374.ref049","doi-asserted-by":"crossref","first-page":"C445-55","DOI":"10.1152\/ajpcell.00505.2005","article-title":"Release of iron from ferritin requires lysosomal activity","volume":"291","author":"TZ Kidane","year":"2006","journal-title":"Am J Physiol Cell Physiol"},{"issue":"4","key":"pcbi.1012374.ref050","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3390\/ph11040114","article-title":"The Role of NCOA4-Mediated Ferritinophagy in Health and Disease","volume":"11","author":"N Santana-Codina","year":"2018","journal-title":"Pharmaceuticals (Basel)"},{"key":"pcbi.1012374.ref051","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/1752-0509-4-92","article-title":"BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models","volume":"4","author":"C Li","year":"2010","journal-title":"BMC Syst Biol"},{"issue":"47","key":"pcbi.1012374.ref052","doi-asserted-by":"crossref","first-page":"18182","DOI":"10.1073\/pnas.0805083105","article-title":"The ferritin Fe2 site at the diiron catalytic center controls the reaction with O2 in the rapid mineralization pathway","volume":"105","author":"T Tosha","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"pcbi.1012374.ref053","doi-asserted-by":"crossref","first-page":"e1003299","DOI":"10.1371\/journal.pcbi.1003299","article-title":"A computational model of liver iron metabolism","volume":"9","author":"S Mitchell","year":"2013","journal-title":"PLoS Comput Biol"},{"issue":"43","key":"pcbi.1012374.ref054","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3001127","article-title":"Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis","volume":"2","author":"ZK Pinnix","year":"2010","journal-title":"Sci Transl Med"},{"issue":"19","key":"pcbi.1012374.ref055","doi-asserted-by":"crossref","first-page":"4758","DOI":"10.1182\/bloodadvances.2020001864","article-title":"Human ferroportin mediates proton-coupled active transport of iron","volume":"4","author":"S Li","year":"2020","journal-title":"Blood Adv"},{"issue":"3","key":"pcbi.1012374.ref056","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1042\/BJ20101825","article-title":"Regulation of cellular iron metabolism","volume":"434","author":"J Wang","year":"2011","journal-title":"Biochem J"},{"issue":"9","key":"pcbi.1012374.ref057","doi-asserted-by":"crossref","first-page":"4591","DOI":"10.3390\/ijms22094591","article-title":"On Iron Metabolism and Its Regulation","volume":"22","author":"A-CS Vogt","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"6","key":"pcbi.1012374.ref058","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.cmet.2012.03.018","article-title":"Hepcidin-induced endocytosis of ferroportin is 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IRP1","volume":"7","author":"MA Khan","year":"2017","journal-title":"Sci Rep"},{"issue":"4","key":"pcbi.1012374.ref062","first-page":"2300","article-title":"Modulation of iron regulatory protein functions. Further insights into the role of nitrogen- and oxygen-derived reactive species","volume":"271","author":"C Bouton","year":"1996","journal-title":"J Biol Chem"},{"issue":"Pt 3","key":"pcbi.1012374.ref063","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1107\/S1744309106004192","article-title":"Crystallization and preliminary X-ray diffraction analysis of iron regulatory protein 1 in complex with ferritin IRE RNA","volume":"62","author":"AI Selezneva","year":"2006","journal-title":"Acta Crystallogr Sect F Struct Biol Cryst Commun"},{"issue":"12","key":"pcbi.1012374.ref064","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1039\/D0MT00192A","article-title":"Differential translational control of 5\u2019 IRE-containing mRNA in response to dietary iron deficiency and acute iron overload","volume":"12","author":"KR Garza","year":"2020","journal-title":"Metallomics"},{"issue":"22","key":"pcbi.1012374.ref065","doi-asserted-by":"crossref","first-page":"8417","DOI":"10.1073\/pnas.1120045109","article-title":"Fe2+ binds iron responsive element-RNA, selectively changing protein-binding affinities and regulating mRNA repression and activation","volume":"109","author":"J Ma","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4833","key":"pcbi.1012374.ref066","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1126\/science.3685996","article-title":"Identification of the iron-responsive element for the translational regulation of human ferritin mRNA","volume":"238","author":"MW Hentze","year":"1987","journal-title":"Science"},{"issue":"2","key":"pcbi.1012374.ref067","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1097\/MOG.0b013e32831ef1f7","article-title":"Iron absorption and metabolism","volume":"25","author":"GJ Anderson","year":"2009","journal-title":"Curr Opin 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binding protein","volume":"4","author":"RD Klausner","year":"1993","journal-title":"Mol Biol Cell"},{"issue":"37","key":"pcbi.1012374.ref071","doi-asserted-by":"crossref","first-page":"21645","DOI":"10.1074\/jbc.270.37.21645","article-title":"Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome","volume":"270","author":"B Guo","year":"1995","journal-title":"J Biol Chem"},{"issue":"22","key":"pcbi.1012374.ref072","doi-asserted-by":"crossref","first-page":"eabg4302","DOI":"10.1126\/sciadv.abg4302","article-title":"Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5","volume":"7","author":"EM Terzi","year":"2021","journal-title":"Sci Adv"},{"issue":"1","key":"pcbi.1012374.ref073","doi-asserted-by":"crossref","first-page":"31-41.e5","DOI":"10.1016\/j.molcel.2020.02.011","article-title":"FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster","volume":"78","author":"H Wang","year":"2020","journal-title":"Mol Cell"},{"issue":"5","key":"pcbi.1012374.ref074","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1172\/JCI110900","article-title":"Iron binding proteins of iron-absorbing rat intestinal mucosa","volume":"71","author":"G Johnson","year":"1983","journal-title":"J Clin Invest"},{"issue":"1","key":"pcbi.1012374.ref075","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12918-017-0431-3","article-title":"Modeling the dynamics of mouse iron body distribution: hepcidin is necessary but not sufficient","volume":"11","author":"JH Parmar","year":"2017","journal-title":"BMC Syst Biol"},{"issue":"1","key":"pcbi.1012374.ref076","doi-asserted-by":"crossref","first-page":"e1006680","DOI":"10.1371\/journal.pcbi.1006680","article-title":"A computational model to understand mouse iron physiology and disease","volume":"15","author":"JH Parmar","year":"2019","journal-title":"PLoS Comput Biol"},{"issue":"6","key":"pcbi.1012374.ref077","doi-asserted-by":"crossref","first-page":"G930-6","DOI":"10.1152\/ajpgi.2000.278.6.G930","article-title":"Gene expression of divalent metal transporter 1 and transferrin receptor in duodenum of Belgrade rats","volume":"278","author":"PS Oates","year":"2000","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"6","key":"pcbi.1012374.ref078","doi-asserted-by":"crossref","first-page":"G981-6","DOI":"10.1152\/ajpgi.00363.2005","article-title":"Iron Imports. II. Iron uptake at the apical membrane in the intestine","volume":"289","author":"B Mackenzie","year":"2005","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"2","key":"pcbi.1012374.ref079","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.cmet.2008.12.012","article-title":"Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency","volume":"9","author":"YM Shah","year":"2009","journal-title":"Cell Metab"},{"issue":"6","key":"pcbi.1012374.ref080","doi-asserted-by":"crossref","first-page":"827","DOI":"10.3324\/haematol.2011.056119","article-title":"Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis","volume":"97","author":"M Mastrogiannaki","year":"2012","journal-title":"Haematologica"},{"issue":"19","key":"pcbi.1012374.ref081","doi-asserted-by":"crossref","first-page":"12345","DOI":"10.1073\/pnas.192423399","article-title":"Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function","volume":"99","author":"N Hubert","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"9","key":"pcbi.1012374.ref082","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1016\/j.febslet.2005.02.035","article-title":"Regulation of divalent metal transporter expression in human intestinal epithelial cells following exposure to non-haem iron","volume":"579","author":"DM Johnson","year":"2005","journal-title":"FEBS Lett"},{"issue":"6","key":"pcbi.1012374.ref083","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1053\/gast.2001.24033","article-title":"Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload","volume":"120","author":"H Zoller","year":"2001","journal-title":"Gastroenterology"},{"issue":"5","key":"pcbi.1012374.ref084","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.cmet.2009.03.006","article-title":"A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression","volume":"9","author":"D-L Zhang","year":"2009","journal-title":"Cell Metab"},{"issue":"2","key":"pcbi.1012374.ref085","first-page":"155","article-title":"Differential regulation of two related RNA-binding proteins, iron regulatory protein (IRP) and IRPB","volume":"1","author":"K Pantopoulos","year":"1995","journal-title":"RNA"},{"key":"pcbi.1012374.ref086","first-page":"124","article-title":"The physiological functions of iron regulatory proteins in iron homeostasis - an update","volume":"5","author":"D-L Zhang","year":"2014","journal-title":"Front Pharmacol"},{"issue":"34","key":"pcbi.1012374.ref087","doi-asserted-by":"crossref","first-page":"24650","DOI":"10.1074\/jbc.M703167200","article-title":"Excess capacity of the iron regulatory protein system","volume":"282","author":"W Wang","year":"2007","journal-title":"J Biol Chem"},{"issue":"2","key":"pcbi.1012374.ref088","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/sj.emboj.7600041","article-title":"Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis","volume":"23","author":"EG Meyron-Holtz","year":"2004","journal-title":"EMBO J"},{"issue":"7","key":"pcbi.1012374.ref089","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1182\/blood-2005-04-1365","article-title":"Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2)","volume":"106","author":"B Galy","year":"2005","journal-title":"Blood"},{"issue":"2","key":"pcbi.1012374.ref090","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/84859","article-title":"Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice","volume":"27","author":"T LaVaute","year":"2001","journal-title":"Nat Genet"},{"issue":"3","key":"pcbi.1012374.ref091","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1182\/blood-2004-12-4703","article-title":"Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2","volume":"106","author":"SS Cooperman","year":"2005","journal-title":"Blood"},{"issue":"18","key":"pcbi.1012374.ref092","doi-asserted-by":"crossref","first-page":"11098","DOI":"10.1016\/S0021-9258(17)44390-0","article-title":"The role of iron in the activation-inactivation of aconitase","volume":"258","author":"MC Kennedy","year":"1983","journal-title":"Journal of Biological Chemistry"},{"issue":"44","key":"pcbi.1012374.ref093","doi-asserted-by":"crossref","first-page":"30122","DOI":"10.1074\/jbc.M109.041061","article-title":"Direct Fe2+ sensing by iron-responsive messenger RNA:repressor complexes weakens binding","volume":"284","author":"MA Khan","year":"2009","journal-title":"J Biol Chem"},{"issue":"49","key":"pcbi.1012374.ref094","doi-asserted-by":"crossref","first-page":"15704","DOI":"10.1021\/bi960653l","article-title":"Expression and biochemical characterization of iron regulatory proteins 1 and 2 in Saccharomyces cerevisiae","volume":"35","author":"JD Phillips","year":"1996","journal-title":"Biochemistry"},{"issue":"21","key":"pcbi.1012374.ref095","first-page":"16227","article-title":"The aconitase function of iron regulatory protein 1. Genetic studies in yeast implicate its role in iron-mediated redox regulation","volume":"275","author":"J Narahari","year":"2000","journal-title":"J Biol Chem"},{"issue":"1","key":"pcbi.1012374.ref096","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1261\/rna.1857210","article-title":"Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy","volume":"16","author":"JB Goforth","year":"2010","journal-title":"RNA"},{"issue":"12","key":"pcbi.1012374.ref097","doi-asserted-by":"crossref","first-page":"7000","DOI":"10.1016\/S0021-9258(19)39250-6","article-title":"Determinants of the interaction between the iron-responsive element-binding protein and its binding site in rat L-ferritin mRNA","volume":"265","author":"HA Barton","year":"1990","journal-title":"Journal of Biological Chemistry"},{"issue":"90","key":"pcbi.1012374.ref098","doi-asserted-by":"crossref","first-page":"5553","DOI":"10.21105\/joss.05553","article-title":"BASICO: A simplified Python interface to COPASI","volume":"8","author":"FT Bergmann","year":"2023","journal-title":"JOSS"},{"issue":"5","key":"pcbi.1012374.ref099","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S1478-5382(03)02370-9","article-title":"CellDesigner: a process diagram editor for gene-regulatory and biochemical networks","volume":"1","author":"A Funahashi","year":"2003","journal-title":"BIOSILICO"},{"issue":"8","key":"pcbi.1012374.ref100","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/nbt.1558","article-title":"The Systems Biology Graphical Notation","volume":"27","author":"NL Nov\u00e8re","year":"2009","journal-title":"Nat Biotechnol"},{"issue":"2","key":"pcbi.1012374.ref101","doi-asserted-by":"crossref","first-page":"20190022","DOI":"10.1515\/jib-2019-0022","article-title":"Systems Biology Graphical Notation: Process Description language Level 1 Version 2.0","volume":"16","author":"A Rougny","year":"2019","journal-title":"J Integr Bioinform"},{"issue":"2","key":"pcbi.1012374.ref102","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/5979","article-title":"Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse","volume":"21","author":"CD Vulpe","year":"1999","journal-title":"Nat Genet"},{"issue":"5","key":"pcbi.1012374.ref103","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1182\/blood-2003-02-0347","article-title":"Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency","volume":"102","author":"H Chen","year":"2003","journal-title":"Blood"},{"issue":"4","key":"pcbi.1012374.ref104","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s004249900193","article-title":"Structural and cellular adaptation of duodenal iron uptake in rats maintained on an iron-deficient diet","volume":"439","author":"MW Smith","year":"2000","journal-title":"Pflugers Arch"},{"key":"pcbi.1012374.ref105","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/1752-0509-4-147","article-title":"Mathematical modeling of the dynamic storage of iron in ferritin","volume":"4","author":"JC Salgado","year":"2010","journal-title":"BMC Syst Biol"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1012374","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T00:00:00Z","timestamp":1742256000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012374","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T17:54:15Z","timestamp":1742320455000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012374"}},"subtitle":[],"editor":[{"given":"Stacey D.","family":"Finley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,3,7]]},"references-count":105,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1012374","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1012374","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,7]]}}}