{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T22:26:29Z","timestamp":1783635989597,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1011907","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T00:00:00Z","timestamp":1710115200000}}],"reference-count":83,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T00:00:00Z","timestamp":1708905600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010446","name":"Institute for Basic Science","doi-asserted-by":"publisher","award":["IBS-R029-C3"],"award-info":[{"award-number":["IBS-R029-C3"]}],"id":[{"id":"10.13039\/501100010446","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Strong circadian (~24h) rhythms in heart rate (HR) are critical for flexible regulation of cardiac pacemaking function throughout the day. While this circadian flexibility in HR is sustained in diverse conditions, it declines with age, accompanied by reduced maximal HR performance. The intricate regulation of circadian HR involves the orchestration of the autonomic nervous system (ANS), circadian rhythms of body temperature (CRBT), and local circadian rhythmicity (LCR), which has not been fully understood. Here, we developed a mathematical model describing ANS, CRBT, and LCR in sinoatrial nodal cells (SANC) that accurately captures distinct circadian patterns in adult and aged mice. Our model underscores how the alliance among ANS, CRBT, and LCR achieves circadian flexibility to cover a wide range of firing rates in SANC, performance to achieve maximal firing rates, while preserving robustness to generate rhythmic firing patterns irrespective of external conditions. Specifically, while ANS dominates in promoting SANC flexibility and performance, CRBT and LCR act as primary and secondary boosters, respectively, to further enhance SANC flexibility and performance. Disruption of this alliance with age results in impaired SANC flexibility and performance, but not robustness. This unexpected outcome is primarily attributed to the age-related reduction in parasympathetic activities, which maintains SANC robustness while compromising flexibility. Our work sheds light on the critical alliance of ANS, CRBT, and LCR in regulating time-of-day cardiac pacemaking function and dysfunction, offering insights into novel therapeutic targets for the prevention and treatment of cardiac arrhythmias.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011907","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T18:42:56Z","timestamp":1708972976000},"page":"e1011907","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Circadian regulation of sinoatrial nodal cell pacemaking function: Dissecting the roles of autonomic control, body temperature, and local circadian rhythmicity"],"prefix":"10.1371","volume":"20","author":[{"given":"Pan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7842-2172","authenticated-orcid":true,"given":"Jae Kyoung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,2,26]]},"reference":[{"issue":"4","key":"pcbi.1011907.ref001","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1161\/CIRCRESAHA.109.209957","article-title":"The cardiomyocyte circadian clock: emerging roles in health and disease","volume":"106","author":"DJ Durgan","year":"2010","journal-title":"Circulation research"},{"issue":"2","key":"pcbi.1011907.ref002","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.hrthm.2018.08.026","article-title":"Circadian rhythm of cardiac electrophysiology, arrhythmogenesis, and the underlying mechanisms","volume":"16","author":"N Black","year":"2019","journal-title":"Heart rhythm"},{"key":"pcbi.1011907.ref003","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/978-1-4939-3450-8_8","volume-title":"Circadian Clocks: Role in Health and Disease","author":"FJ Alibhai","year":"2016"},{"issue":"9","key":"pcbi.1011907.ref004","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1113\/JP282402","article-title":"The role of the cardiomyocyte circadian clocks in ion channel regulation and cardiac electrophysiology","volume":"600","author":"EA Schroder","year":"2022","journal-title":"The Journal of physiology"},{"issue":"5","key":"pcbi.1011907.ref005","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.yjmcc.2011.07.028","article-title":"A full range of mouse sinoatrial node AP firing rates requires protein kinase A-dependent calcium signaling","volume":"51","author":"J Liu","year":"2011","journal-title":"Journal of molecular and cellular cardiology"},{"key":"pcbi.1011907.ref006","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3389\/fphys.2016.00419","article-title":"The autonomic nervous system regulates the heart rate through cAMP-PKA dependent and independent coupled-clock pacemaker cell mechanisms","volume":"7","author":"J Behar","year":"2016","journal-title":"Frontiers in physiology"},{"issue":"6","key":"pcbi.1011907.ref007","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/0031-9384(94)90392-1","article-title":"The suprachiasmatic nucleus controls the circadian rhythm of heart rate via the sympathetic nervous system","volume":"55","author":"WS Warren","year":"1994","journal-title":"Physiology & behavior"},{"issue":"4","key":"pcbi.1011907.ref008","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1080\/23328940.2020.1743605","article-title":"Circadian rhythmicity of body temperature and metabolism","volume":"7","author":"R. Refinetti","year":"2020","journal-title":"Temperature"},{"key":"pcbi.1011907.ref009","doi-asserted-by":"crossref","first-page":"109127","DOI":"10.1016\/j.ecolmodel.2020.109127","article-title":"and its applications in biological systems: Beyond the Arrhenius theory","volume":"431","author":"KC Mundim","year":"2020","journal-title":"Ecological Modelling"},{"issue":"4","key":"pcbi.1011907.ref010","doi-asserted-by":"crossref","first-page":"042717","DOI":"10.1103\/PhysRevE.87.042717","article-title":"Role of temperature on nonlinear cardiac dynamics","volume":"87","author":"FH Fenton","year":"2013","journal-title":"Physical Review E"},{"issue":"4","key":"pcbi.1011907.ref011","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1529\/biophysj.105.067074","article-title":"Temperature dependence and thermodynamic properties of Ca2+ sparks in rat cardiomyocytes","volume":"89","author":"Y Fu","year":"2005","journal-title":"Biophysical journal"},{"issue":"1","key":"pcbi.1011907.ref012","doi-asserted-by":"crossref","first-page":"H397","DOI":"10.1152\/ajpheart.2000.279.1.H397","article-title":"Mathematical models of action potentials in the periphery and center of the rabbit sinoatrial node","volume":"279","author":"H Zhang","year":"2000","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"issue":"5","key":"pcbi.1011907.ref013","doi-asserted-by":"crossref","first-page":"H2074","DOI":"10.1152\/ajpheart.00900.2001","article-title":"Dynamical description of sinoatrial node pacemaking: improved mathematical model for primary pacemaker cell","volume":"283","author":"Y Kurata","year":"2002","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"issue":"4","key":"pcbi.1011907.ref014","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1152\/ajplegacy.1969.217.4.1139","article-title":"Heart rate and its neural regulation with rising body temperature in anesthetized rats","volume":"217","author":"R. Walsh","year":"1969","journal-title":"American Journal of Physiology-Legacy Content"},{"key":"pcbi.1011907.ref015","article-title":"HCN channels sense temperature and determine heart rate responses to heat","author":"Y Wu","year":"2023","journal-title":"bioRxiv"},{"issue":"3","key":"pcbi.1011907.ref016","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.cbpb.2010.07.004","article-title":"Thermogenesis in CD-1 mice after combined chronic hypoxia and cold acclimation. Comparative Biochemistry and Physiology Part B","volume":"157","author":"JL Beaudry","year":"2010","journal-title":"Biochemistry and Molecular Biology"},{"key":"pcbi.1011907.ref017","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s11357-010-9164-6","article-title":"Sex-and age-specific differences in core body temperature of C57Bl\/6 mice.","volume":"33","author":"M Sanchez-Alavez","year":"2011","journal-title":"Age."},{"issue":"1","key":"pcbi.1011907.ref018","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3390\/biology10010065","article-title":"A tangled threesome: circadian rhythm, body temperature variations, and the immune system","volume":"10","author":"B Coiffard","year":"2021","journal-title":"Biology"},{"issue":"5","key":"pcbi.1011907.ref019","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.hrthm.2020.11.026","article-title":"A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate","volume":"18","author":"A D\u2019souza","year":"2021","journal-title":"Heart Rhythm"},{"issue":"3","key":"pcbi.1011907.ref020","doi-asserted-by":"crossref","first-page":"H1391","DOI":"10.1152\/ajpheart.2001.280.3.H1391","article-title":"Physiological and anatomic evidence for regulation of the heart by suprachiasmatic nucleus in rats","volume":"280","author":"F Scheer","year":"2001","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"issue":"4","key":"pcbi.1011907.ref021","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1080\/09291016.2012.704801","article-title":"Circadian expressions of cardiac ion channel genes in mouse might be associated with the central clock in the SCN but not the peripheral clock in the heart","volume":"44","author":"M Tong","year":"2013","journal-title":"Biological Rhythm Research"},{"issue":"1","key":"pcbi.1011907.ref022","doi-asserted-by":"crossref","first-page":"e13707","DOI":"10.1111\/apha.13707","article-title":"Prolonged QT intervals in mice with cardiomyocyte-specific deficiency of the molecular clock.","volume":"233","author":"LA Gottlieb","year":"2021","journal-title":"Acta Physiologica"},{"issue":"1","key":"pcbi.1011907.ref023","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1038\/s41467-021-22788-8","article-title":"Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia","volume":"12","author":"EA Hayter","year":"2021","journal-title":"Nature communications"},{"key":"pcbi.1011907.ref024","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.yjmcc.2015.02.003","article-title":"Sick sinus syndrome and atrial fibrillation in older persons\u2014a view from the sinoatrial nodal myocyte","volume":"83","author":"O Monfredi","year":"2015","journal-title":"Journal of molecular and cellular cardiology"},{"issue":"44","key":"pcbi.1011907.ref025","doi-asserted-by":"crossref","first-page":"18011","DOI":"10.1073\/pnas.1308477110","article-title":"St. Clair JR, Sumner WA, Bannister RA, Proenza C. Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate","volume":"110","author":"ED Larson","year":"2013","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"pcbi.1011907.ref026","doi-asserted-by":"crossref","first-page":"617698","DOI":"10.3389\/fnins.2021.617698","article-title":"Age-related changes in cardiac autonomic modulation and heart rate variability in mice","volume":"15","author":"C Piantoni","year":"2021","journal-title":"Frontiers in neuroscience"},{"issue":"2","key":"pcbi.1011907.ref027","doi-asserted-by":"crossref","first-page":"e1439","DOI":"10.1002\/wsbm.1439","article-title":"Mathematical modeling of circadian rhythms. Wiley Interdisciplinary Reviews","volume":"11","author":"A Asgari-Targhi","year":"2019","journal-title":"Systems Biology and Medicine"},{"issue":"1","key":"pcbi.1011907.ref028","doi-asserted-by":"crossref","first-page":"4652","DOI":"10.1038\/s41467-022-32326-9","article-title":"Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals","volume":"13","author":"YO Abe","year":"2022","journal-title":"Nature Communications"},{"issue":"8","key":"pcbi.1011907.ref029","doi-asserted-by":"crossref","first-page":"e2113403119","DOI":"10.1073\/pnas.2113403119","article-title":"Systematic modeling-driven experiments identify distinct molecular clockworks underlying hierarchically organized pacemaker neurons","volume":"119","author":"EM Jeong","year":"2022","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"1","key":"pcbi.1011907.ref030","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/msb.2012.62","article-title":"A mechanism for robust circadian timekeeping via stoichiometric balance","volume":"8","author":"JK Kim","year":"2012","journal-title":"Molecular systems biology"},{"key":"pcbi.1011907.ref031","first-page":"55","volume-title":"Mathematical Modeling in Circadian Rhythmicity. Circadian Regulation: Methods and Protocols","author":"S Grabe","year":"2021"},{"issue":"1","key":"pcbi.1011907.ref032","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1161\/CIRCRESAHA.110.223578","article-title":"Integrative systems models of cardiac excitation\u2013contraction coupling","volume":"108","author":"JL Greenstein","year":"2011","journal-title":"Circulation research"},{"key":"pcbi.1011907.ref033","first-page":"20","article-title":"Mathematical models of cardiac pacemaking function","volume":"1","author":"P Li","year":"2013","journal-title":"Frontiers in Physics"},{"issue":"1","key":"pcbi.1011907.ref034","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1177\/0748730412469499","article-title":"Modeling the effects of the circadian clock on cardiac electrophysiology","volume":"28","author":"P Fotiadis","year":"2013","journal-title":"Journal of Biological Rhythms"},{"key":"pcbi.1011907.ref035","volume-title":"When the clock strikes: Modeling the relation between circadian rhythms and cardiac arrhythmias. Journal of Physics: Conference Series","author":"P Seenivasan","year":"2016"},{"issue":"2","key":"pcbi.1011907.ref036","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.bpj.2020.11.2264","article-title":"Circadian rhythms of early afterdepolarizations and ventricular arrhythmias in a cardiomyocyte model","volume":"120","author":"CO Diekman","year":"2021","journal-title":"Biophysical Journal"},{"issue":"3","key":"pcbi.1011907.ref037","doi-asserted-by":"crossref","first-page":"H594","DOI":"10.1152\/ajpheart.01118.2008","article-title":"Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model","volume":"296","author":"VA Maltsev","year":"2009","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"pcbi.1011907.ref038","doi-asserted-by":"crossref","first-page":"692247","DOI":"10.3389\/fphys.2021.692247","article-title":"Dissecting the roles of the autonomic nervous system and physical activity on circadian heart rate fluctuations in mice","volume":"12","author":"N Barazi","year":"2021","journal-title":"Frontiers in physiology"},{"issue":"11","key":"pcbi.1011907.ref039","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1113\/expphysiol.2011.057752","article-title":"Ageing-dependent remodelling of ion channel and Ca2+ clock genes underlying sino-atrial node pacemaking","volume":"96","author":"JO Tellez","year":"2011","journal-title":"Experimental physiology"},{"issue":"10","key":"pcbi.1011907.ref040","doi-asserted-by":"crossref","first-page":"H1385","DOI":"10.1152\/ajpheart.00088.2014","article-title":"Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca2+ signaling","volume":"306","author":"J Liu","year":"2014","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"issue":"3","key":"pcbi.1011907.ref041","first-page":"126","article-title":"Age-related attenuation of parasympathetic control of the heart in mice","volume":"7","author":"JL Freeling","year":"2015","journal-title":"International journal of physiology, pathophysiology and pharmacology."},{"issue":"5","key":"pcbi.1011907.ref042","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1161\/01.RES.29.5.437","article-title":"Brief reviews: sympathetic-parasympathetic interactions in the heart","volume":"29","author":"MN Levy","year":"1971","journal-title":"Circulation research"},{"key":"pcbi.1011907.ref043","first-page":"69","article-title":"Parasympathetic control of the heart","author":"M. Levy","year":"1984","journal-title":"Nervous control of cardiovascular function"},{"issue":"17","key":"pcbi.1011907.ref044","doi-asserted-by":"crossref","first-page":"4073","DOI":"10.1113\/jphysiol.2013.257758","article-title":"Myths and realities of the cardiac vagus","volume":"591","author":"JH Coote","year":"2013","journal-title":"The Journal of physiology"},{"issue":"9","key":"pcbi.1011907.ref045","doi-asserted-by":"crossref","DOI":"10.1063\/1.5000710","article-title":"Temperature, geometry, and bifurcations in the numerical modeling of the cardiac mechano-electric feedback","volume":"27","author":"A Collet","year":"2017","journal-title":"Chaos: An Interdisciplinary Journal of Nonlinear Science"},{"key":"pcbi.1011907.ref046","doi-asserted-by":"crossref","first-page":"546508","DOI":"10.3389\/fphys.2020.546508","article-title":"Cardiac pacemaker dysfunction arising from different studies of ion channel remodeling in the aging rat heart","volume":"11","author":"AM Alghamdi","year":"2020","journal-title":"Frontiers in Physiology"},{"issue":"2\u20133","key":"pcbi.1011907.ref047","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.physbeh.2006.09.003","article-title":"The circadian rhythm of core temperature: effects of physical activity and aging","volume":"90","author":"D Weinert","year":"2007","journal-title":"Physiology & behavior"},{"key":"pcbi.1011907.ref048","doi-asserted-by":"crossref","first-page":"e77327","DOI":"10.7554\/eLife.77327","article-title":"A phenotype-based forward genetic screen identifies Dnajb6 as a sick sinus syndrome gene","volume":"11","author":"Y Ding","year":"2022","journal-title":"Elife"},{"issue":"1","key":"pcbi.1011907.ref049","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1161\/CIRCRESAHA.111.246512","article-title":"A model of canine purkinje cell electrophysiology and Ca2+ cycling: rate dependence, triggered activity, and comparison to ventricular myocytes","volume":"109","author":"P Li","year":"2011","journal-title":"Circulation research"},{"issue":"12","key":"pcbi.1011907.ref050","doi-asserted-by":"crossref","first-page":"2706","DOI":"10.1016\/j.bpj.2012.05.011","article-title":"Dynamics of early afterdepolarization-mediated triggered activity in cardiac monolayers","volume":"102","author":"MG Chang","year":"2012","journal-title":"Biophysical journal"},{"issue":"11","key":"pcbi.1011907.ref051","doi-asserted-by":"crossref","first-page":"5645","DOI":"10.3390\/ijms22115645","article-title":"Intracellular Na+ modulates pacemaking activity in murine sinoatrial node myocytes: An in silico analysis","volume":"22","author":"S Morotti","year":"2021","journal-title":"International journal of molecular sciences"},{"issue":"2","key":"pcbi.1011907.ref052","doi-asserted-by":"crossref","first-page":"H1036","DOI":"10.1152\/ajpheart.01291.2007","article-title":"Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression.","volume":"294","author":"MS Bray","year":"2008","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology."},{"issue":"10","key":"pcbi.1011907.ref053","doi-asserted-by":"crossref","first-page":"C954","DOI":"10.1152\/ajpcell.00383.2012","article-title":"The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility","volume":"304","author":"EA Schroder","year":"2013","journal-title":"American Journal of Physiology-Cell Physiology"},{"key":"pcbi.1011907.ref054","doi-asserted-by":"crossref","first-page":"605","DOI":"10.3389\/fphys.2022.845634","article-title":"Functional heterogeneity of cell populations increases robustness of pacemaker function in a numerical model of the sinoatrial node tissue","volume":"13","author":"AV Maltsev","year":"2022","journal-title":"Frontiers in physiology"},{"issue":"12","key":"pcbi.1011907.ref055","doi-asserted-by":"crossref","first-page":"677","DOI":"10.5483\/BMBRep.2015.48.12.061","article-title":"The end effector of circadian heart rate variation: the sinoatrial node pacemaker cell.","volume":"48","author":"Y Yaniv","year":"2015","journal-title":"BMB reports"},{"issue":"11","key":"pcbi.1011907.ref056","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nrg1471","article-title":"Biological robustness.","volume":"5","author":"H. Kitano","year":"2004","journal-title":"Nature Reviews Genetics"},{"issue":"6039","key":"pcbi.1011907.ref057","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1126\/science.1200705","article-title":"Glycolytic oscillations and limits on robust efficiency","volume":"333","author":"FA Chandra","year":"2011","journal-title":"science"},{"issue":"4","key":"pcbi.1011907.ref058","doi-asserted-by":"crossref","first-page":"H1017","DOI":"10.1152\/ajpheart.01216.2008","article-title":"Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium","volume":"296","author":"KF Decker","year":"2009","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"issue":"1","key":"pcbi.1011907.ref059","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1161\/CIRCRESAHA.122.321668","article-title":"Cardiac alternans: From bedside to bench and back","volume":"132","author":"Z Qu","year":"2023","journal-title":"Circulation Research"},{"issue":"3","key":"pcbi.1011907.ref060","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S0006-3495(95)80271-7","article-title":"Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence","volume":"68","author":"J Zeng","year":"1995","journal-title":"Biophysical journal"},{"issue":"9852","key":"pcbi.1011907.ref061","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1016\/S0140-6736(12)61413-5","article-title":"Ventricular arrhythmias and sudden cardiac death","volume":"380","author":"RM John","year":"2012","journal-title":"The Lancet"},{"key":"pcbi.1011907.ref062","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.coisb.2020.07.007","article-title":"Wearable technology and systems modeling for personalized chronotherapy","volume":"21","author":"DW Kim","year":"2020","journal-title":"Current Opinion in Systems Biology"},{"issue":"6453","key":"pcbi.1011907.ref063","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1126\/science.aax7621","article-title":"Dosing time matters","volume":"365","author":"MD Ruben","year":"2019","journal-title":"Science"},{"issue":"Suppl 1","key":"pcbi.1011907.ref064","doi-asserted-by":"crossref","first-page":"S103","DOI":"10.21037\/jtd.2018.01.11","article-title":"Delayed sleep-wake phase disorder","volume":"10","author":"AD Nesbitt","year":"2018","journal-title":"Journal of thoracic disease"},{"issue":"2","key":"pcbi.1011907.ref065","article-title":"Chemotherapy delivery time affects treatment outcomes of female patients with diffuse large B cell lymphoma","volume":"8","author":"DW Kim","year":"2023","journal-title":"JCI insight"},{"key":"pcbi.1011907.ref066","first-page":"64","article-title":"Circadian Regulation of Drug Responses: Toward Sex-Specific and Personalized Chronotherapy","author":"A. L\u00e9vi F","year":"2024","journal-title":"Annual Review of Pharmacology and Toxicology"},{"key":"pcbi.1011907.ref067","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.coph.2020.10.014","article-title":"Chronotherapy of cardiac and vascular disease: timing medications to circadian rhythms to optimize treatment effects and outcomes","volume":"57","author":"MH Smolensky","year":"2021","journal-title":"Current Opinion in Pharmacology"},{"issue":"7","key":"pcbi.1011907.ref068","first-page":"1","article-title":"Modeling and validating chronic pharmacological manipulation of circadian rhythms","volume":"2","author":"JK Kim","year":"2013","journal-title":"CPT: pharmacometrics & systems pharmacology"},{"issue":"7","key":"pcbi.1011907.ref069","doi-asserted-by":"crossref","first-page":"e8838","DOI":"10.15252\/msb.20198838","article-title":"Systems approach reveals photosensitivity and PER 2 level as determinants of clock-modulator efficacy","volume":"15","author":"DW Kim","year":"2019","journal-title":"Molecular Systems Biology"},{"issue":"9","key":"pcbi.1011907.ref070","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1158\/1535-7163.MCT-15-0129","article-title":"Identification of circadian determinants of cancer chronotherapy through in vitro chronopharmacology and mathematical modeling","volume":"14","author":"S Dulong","year":"2015","journal-title":"Molecular cancer therapeutics"},{"issue":"1","key":"pcbi.1011907.ref071","doi-asserted-by":"crossref","first-page":"e1007218","DOI":"10.1371\/journal.pcbi.1007218","article-title":"Optimizing circadian drug infusion schedules towards personalized cancer chronotherapy","volume":"16","author":"RJ Hill","year":"2020","journal-title":"PLoS Computational Biology"},{"issue":"11","key":"pcbi.1011907.ref072","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.52586\/5025","article-title":"Circadian rhythms, cardiac arrhythmias and sudden death.","volume":"26","author":"L Vicent","year":"2021","journal-title":"Frontiers in Bioscience-Landmark"},{"issue":"1","key":"pcbi.1011907.ref073","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/cpt.896","article-title":"Mechanistic model-informed proarrhythmic risk assessment of drugs: review of the \u201cCiPA\u201d initiative and design of a prospective clinical validation study.","volume":"103","author":"J Vicente","year":"2018","journal-title":"Clinical Pharmacology & Therapeutics"},{"key":"pcbi.1011907.ref074","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s11357-019-00126-7","article-title":"Acclimation to a thermoneutral environment abolishes age-associated alterations in heart rate and heart rate variability in conscious, unrestrained mice.","volume":"42","author":"JE Axsom","year":"2020","journal-title":"Geroscience"},{"issue":"3","key":"pcbi.1011907.ref075","doi-asserted-by":"crossref","first-page":"H945","DOI":"10.1152\/ajpheart.00143.2010","article-title":"A mathematical model of action potentials of mouse sinoatrial node cells with molecular bases","volume":"301","author":"S Kharche","year":"2011","journal-title":"American Journal of Physiology-Heart and circulatory physiology"},{"issue":"2","key":"pcbi.1011907.ref076","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1074\/jbc.M209241200","article-title":"Ca2+\/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock.","volume":"278","author":"SA Tischkau","year":"2003","journal-title":"Journal of Biological Chemistry"},{"key":"pcbi.1011907.ref077","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12872-019-1164-6","article-title":"Functional aging in health and heart failure: the COmPLETE Study","volume":"19","author":"J Wagner","year":"2019","journal-title":"BMC cardiovascular disorders"},{"key":"pcbi.1011907.ref078","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1007\/s11940-010-0090-9","article-title":"Treatment of shift work disorder and jet lag","volume":"12","author":"PC Zee","year":"2010","journal-title":"Current treatment options in neurology"},{"issue":"2","key":"pcbi.1011907.ref079","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1113\/jphysiol.1994.sp020130","article-title":"Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms","volume":"476","author":"J Bassani","year":"1994","journal-title":"The Journal of physiology"},{"issue":"2","key":"pcbi.1011907.ref080","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0163-7258(03)00032-9","article-title":"Regulation of muscarinic acetylcholine receptor signaling","volume":"98","author":"CJ van Koppen","year":"2003","journal-title":"Pharmacology & therapeutics"},{"issue":"11","key":"pcbi.1011907.ref081","doi-asserted-by":"crossref","first-page":"7949","DOI":"10.1016\/S0021-9258(18)53050-7","article-title":"Cross-talk between m1 muscarinic acetylcholine and beta 2-adrenergic receptors. cAMP and the third intracellular loop of m1 muscarinic receptors confer heterologous regulation","volume":"268","author":"N Lee","year":"1993","journal-title":"Journal of Biological Chemistry"},{"issue":"11","key":"pcbi.1011907.ref082","doi-asserted-by":"crossref","first-page":"H2285","DOI":"10.1152\/ajpheart.00221.2011","article-title":"Roles of sarcoplasmic reticulum Ca2+ cycling and Na+\/Ca2+ exchanger in sinoatrial node pacemaking: insights from bifurcation analysis of mathematical models","volume":"302","author":"Y Kurata","year":"2012","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"pcbi.1011907.ref083","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1007\/s00424-014-1482-6","article-title":"T-type channels in the sino-atrial and atrioventricular pacemaker mechanism","volume":"466","author":"P Mesirca","year":"2014","journal-title":"Pfl\u00fcgers Archiv-European Journal of Physiology"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1011907","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T00:00:00Z","timestamp":1710115200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011907","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T17:47:53Z","timestamp":1710179273000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011907"}},"subtitle":[],"editor":[{"given":"Christian I.","family":"Hong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,2,26]]},"references-count":83,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1011907","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1011907","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,26]]}}}