{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:43:48Z","timestamp":1779893028130,"version":"3.53.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1012564","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000}}],"reference-count":123,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014261","name":"National Institute for Health Care Management Foundation","doi-asserted-by":"publisher","award":["R01 DK073368"],"award-info":[{"award-number":["R01 DK073368"]}],"id":[{"id":"10.13039\/100014261","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006831","name":"U.S. Air Force","doi-asserted-by":"publisher","award":["FA9550-18-1-0051"],"award-info":[{"award-number":["FA9550-18-1-0051"]}],"id":[{"id":"10.13039\/100006831","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000183","name":"Army Research Office","doi-asserted-by":"publisher","award":["W911NF2310249"],"award-info":[{"award-number":["W911NF2310249"]}],"id":[{"id":"10.13039\/100000183","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The nanoscale organization of enzymes associated with the dynamics of second messengers is critical for ensuring compartmentation and localization of signaling molecules in cells. Specifically, the spatiotemporal orchestration of cAMP and Ca<jats:sup>2+<\/jats:sup> oscillations is critical for many cellular functions. Previous experimental studies have shown that the formation of nanodomains of A-kinase anchoring protein 79\/150 (AKAP150) and adenylyl cyclase 8 (AC8) on the surface of pancreatic MIN6 \u03b2 cells modulates the phase of Ca<jats:sup>2+<\/jats:sup>-cAMP oscillations from out-of-phase to in-phase. In this work, we develop computational models of the Ca<jats:sup>2+<\/jats:sup>\/cAMP pathway and AKAP\/AC nanodomain formation that give rise to the two important predictions: instead of an arbitrary phase difference, the out-of-phase Ca<jats:sup>2+<\/jats:sup>\/cAMP oscillation reaches Ca<jats:sup>2+<\/jats:sup> trough and cAMP peak simultaneously, which is defined as inversely out-of-phase; the in-phase and inversely out-of-phase oscillations associated with Ca<jats:sup>2+<\/jats:sup>-cAMP dynamics on and away from the nanodomains can be explained by an incoherent feedforward loop. Factors such as cellular surface-to-volume ratio, compartment size, and distance between nanodomains do not affect the existence of in-phase or inversely out-of-phase Ca<jats:sup>2+<\/jats:sup>\/cAMP oscillation, but cellular surface-to-volume ratio and compartment size can affect the time delay for the inversely out-of-phase Ca<jats:sup>2+<\/jats:sup>\/cAMP oscillation while the distance between two nanodomains does not. Finally, we predict that both the Turing pattern-generated nanodomains and experimentally measured nanodomains demonstrate the existence of in-phase and inversely out-of-phase Ca<jats:sup>2+<\/jats:sup>\/cAMP oscillation when the AC8 is at a low level, consistent with the behavior of an incoherent feedforward loop. These findings unveil the key circuit motif that governs cAMP and Ca<jats:sup>2+<\/jats:sup> oscillations and advance our understanding of how nanodomains can lead to spatial compartmentation of second messengers.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012564","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T17:47:31Z","timestamp":1730396851000},"page":"e1012564","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Spatiotemporal orchestration of calcium-cAMP oscillations on AKAP\/AC nanodomains is governed by an incoherent feedforward 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Berridge","year":"1998","journal-title":"Nature"},{"issue":"3","key":"pcbi.1012564.ref014","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.bbagen.2013.11.015","article-title":"Frequency decoding of calcium oscillations","volume":"1840","author":"E Smedler","year":"2014","journal-title":"Biochimica et Biophysica Acta (BBA)\u2014General Subjects"},{"issue":"6679","key":"pcbi.1012564.ref015","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/31960","article-title":"Calcium oscillations increase the efficiency and specificity of gene expression","volume":"392","author":"RE Dolmetsch","year":"1998","journal-title":"Nature"},{"issue":"1","key":"pcbi.1012564.ref016","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1124\/pharmrev.120.000086","article-title":"Subcellular Organization of the cAMP Signaling Pathway","volume":"73","author":"M Zaccolo","year":"2021","journal-title":"Pharmacological 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Nikolaev","year":"2010","journal-title":"Science"},{"issue":"2","key":"pcbi.1012564.ref026","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1093\/carcin\/bgl164","article-title":"The functional genetic variant Ile 646 Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer","volume":"28","author":"M Wirtenberger","year":"2007","journal-title":"Carcinogenesis"},{"issue":"5751","key":"pcbi.1012564.ref027","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1126\/science.1112915","article-title":"DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling","volume":"310","author":"JK Millar","year":"2005","journal-title":"Science"},{"issue":"20","key":"pcbi.1012564.ref028","doi-asserted-by":"crossref","first-page":"7817","DOI":"10.1523\/JNEUROSCI.17-20-07817.1997","article-title":"Intracellular Calcium Oscillations in Astrocytes: A Highly Plastic, Bidirectional Form of Communication between Neurons and Astrocytes In Situ","volume":"17","author":"L Pasti","year":"1997","journal-title":"Journal of Neuroscience"},{"issue":"9","key":"pcbi.1012564.ref029","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1038\/nn.2174","article-title":"Circadian oscillation of hippocampal MAPK activity and cAMP: implications for memory persistence","volume":"11","author":"KL Eckel-Mahan","year":"2008","journal-title":"Nature Neuroscience"},{"key":"pcbi.1012564.ref030","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.yjmcc.2013.04.004","article-title":"Optimization of direct fibroblast reprogramming to cardiomyocytes using calcium activity as a functional measure of success","volume":"60","author":"RC Addis","year":"2013","journal-title":"Journal of Molecular and Cellular Cardiology"},{"issue":"7074","key":"pcbi.1012564.ref031","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nature04410","article-title":"Oscillations of cyclic AMP in hormone-stimulated insulin-secreting \u03b2-cells","volume":"439","author":"O Dyachok","year":"2006","journal-title":"Nature"},{"key":"pcbi.1012564.ref032","doi-asserted-by":"crossref","first-page":"e55013","DOI":"10.7554\/eLife.55013","article-title":"Spatially compartmentalized phase regulation of a Ca2+-cAMP-PKA oscillatory circuit","volume":"9","author":"B Tenner","year":"2020","journal-title":"eLife"},{"issue":"10","key":"pcbi.1012564.ref033","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0007189","article-title":"Cross-Talk between Signaling Pathways Can Generate Robust Oscillations in Calcium and cAMP","volume":"4","author":"F Siso-Nadal","year":"2009","journal-title":"PLOS ONE"},{"issue":"3","key":"pcbi.1012564.ref034","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a004226","article-title":"Calcium Oscillations","volume":"3","author":"G Dupont","year":"2011","journal-title":"Cold Spring Harbor Perspectives in 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Qiao","year":"2022","journal-title":"eLife"},{"issue":"10","key":"pcbi.1012564.ref038","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1016\/j.bpj.2019.10.003","article-title":"Computational Modeling Reveals Frequency Modulation of calcium-cAMP\/PKA Pathway in Dendritic Spines","volume":"117","author":"D Ohadi","year":"2019","journal-title":"Biophysical Journal"},{"issue":"10","key":"pcbi.1012564.ref039","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1016\/j.bpj.2019.10.004","article-title":"Geometric Control of Frequency Modulation of cAMP Oscillations due to Calcium in Dendritic Spines","volume":"117","author":"D Ohadi","year":"2019","journal-title":"Biophysical Journal"},{"issue":"7","key":"pcbi.1012564.ref040","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0039722","article-title":"The Mitochondrial Ca2+ Uniporter MCU Is Essential for Glucose-Induced ATP Increases in Pancreatic Cells","volume":"7","author":"AI Tarasov","year":"2012","journal-title":"PLOS ONE"},{"issue":"6","key":"pcbi.1012564.ref041","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.cell.2012.02.010","article-title":"Diabetes Mellitus and the \u03b2 Cell: The Last Ten Years","volume":"148","author":"FM Ashcroft","year":"2012","journal-title":"Cell"},{"issue":"1","key":"pcbi.1012564.ref042","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1074\/jbc.271.1.270","article-title":"Amperometric Detection of Quantal Secretion from Patch-clamped Rat Pancreatic \u03b2-Cells","volume":"271","author":"Z Zhou","year":"1996","journal-title":"Journal of Biological Chemistry"},{"issue":"5","key":"pcbi.1012564.ref043","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/j.jmb.2019.08.009","article-title":"New Insights into \u03b2-Cell GLP-1 Receptor and cAMP Signaling","volume":"432","author":"A Tomas","year":"2020","journal-title":"Journal of Molecular 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incoherent feed\u2010forward loop can generate non\u2010monotonic input functions for genes","volume":"4","author":"S Kaplan","year":"2008","journal-title":"Molecular Systems Biology"},{"issue":"5","key":"pcbi.1012564.ref057","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.molcel.2009.11.018","article-title":"The Incoherent Feedforward Loop Can Provide Fold-Change Detection in Gene Regulation","volume":"36","author":"L Goentoro","year":"2009","journal-title":"Molecular Cell"},{"key":"pcbi.1012564.ref058","doi-asserted-by":"crossref","first-page":"e32323","DOI":"10.7554\/eLife.32323","article-title":"An incoherent feedforward loop facilitates adaptive tuning of gene expression","volume":"7","author":"J Hong","year":"2018","journal-title":"eLife"},{"issue":"3","key":"pcbi.1012564.ref059","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cels.2019.08.006","article-title":"Network topologies that can achieve dual function of adaptation and noise 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Rangamani","year":"2013","journal-title":"Cell"},{"issue":"6","key":"pcbi.1012564.ref063","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/j.cell.2014.02.007","article-title":"The Interdependence of Membrane Shape and Cellular Signal Processing","volume":"156","author":"M Schmick","year":"2014","journal-title":"Cell"},{"issue":"6","key":"pcbi.1012564.ref064","doi-asserted-by":"crossref","first-page":"jcs214015","DOI":"10.1242\/jcs.214015","article-title":"How cells sense their own shape\u2014mechanisms to probe cell geometry and their implications in cellular organization and function","volume":"131","author":"A Haupt","year":"2018","journal-title":"Journal of Cell Science"},{"issue":"4","key":"pcbi.1012564.ref065","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/nmeth.4221","article-title":"Genetically encoded biosensors for visualizing live-cell biochemical activity at super-resolution","volume":"14","author":"GC 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Varga","year":"2020","journal-title":"Biophysical Journal"},{"issue":"3","key":"pcbi.1012564.ref069","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pcbi.1006016","article-title":"Particle-based simulations of polarity establishment reveal stochastic promotion of Turing pattern formation","volume":"14","author":"M Pablo","year":"2018","journal-title":"PLOS Computational Biology"},{"issue":"9","key":"pcbi.1012564.ref070","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pcbi.1004407","article-title":"Dynamical Organization of Syntaxin-1A at the Presynaptic Active Zone","volume":"11","author":"A Ullrich","year":"2015","journal-title":"PLOS Computational Biology"},{"issue":"205","key":"pcbi.1012564.ref071","doi-asserted-by":"crossref","first-page":"ra2","DOI":"10.1126\/scisignal.2002413","article-title":"Incoherent Feedforward Control Governs Adaptation of Activated Ras in a Eukaryotic Chemotaxis Pathway","volume":"5","author":"K Takeda","year":"2012","journal-title":"Science Signaling"},{"issue":"5","key":"pcbi.1012564.ref072","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1042\/bst0310925","article-title":"Calcium oscillations in T-cells: mechanisms and consequences for gene expression","volume":"31","author":"RS Lewis","year":"2003","journal-title":"Biochemical Society Transactions"},{"issue":"4","key":"pcbi.1012564.ref073","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.neuron.2005.11.001","article-title":"Come Together, Right. Now: Synchronization of Rhythms in a Mammalian Circadian Clock","volume":"48","author":"SJ Aton","year":"2005","journal-title":"Neuron"},{"key":"pcbi.1012564.ref074","doi-asserted-by":"crossref","DOI":"10.3389\/fnhum.2012.00074","article-title":"Oscillatory power decreases and long-term memory: the information via desynchronization hypothesis","volume":"6","author":"S Hanslmayr","year":"2012","journal-title":"Frontiers in Human Neuroscience"},{"issue":"1","key":"pcbi.1012564.ref075","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.tins.2015.11.004","article-title":"Oscillations and Episodic Memory: Addressing the Synchronization\/Desynchronization Conundrum","volume":"39","author":"S Hanslmayr","year":"2016","journal-title":"Trends in Neurosciences"},{"issue":"5981","key":"pcbi.1012564.ref076","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1126\/science.1183415","article-title":"The Onset of Collective Behavior in Social Amoebae","volume":"328","author":"T Gregor","year":"2010","journal-title":"Science"},{"issue":"7279","key":"pcbi.1012564.ref077","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/nature08753","article-title":"A synchronized quorum of genetic clocks","volume":"463","author":"T Danino","year":"2010","journal-title":"Nature"},{"issue":"1","key":"pcbi.1012564.ref078","doi-asserted-by":"crossref","first-page":"17866","DOI":"10.1038\/s41598-020-74700-x","article-title":"Cell shape regulates subcellular organelle location to control early Ca2+ signal dynamics in vascular smooth muscle cells","volume":"10","author":"RC Calizo","year":"2020","journal-title":"Scientific Reports"},{"issue":"15","key":"pcbi.1012564.ref079","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.1113\/JP283407","article-title":"Spatiotemporal modelling reveals geometric dependence of AMPAR dynamics on dendritic spine morphology","volume":"601","author":"MK Bell","year":"2023","journal-title":"The Journal of 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Baschieri","year":"2018","journal-title":"Nature Communications"},{"issue":"32","key":"pcbi.1012564.ref083","doi-asserted-by":"crossref","first-page":"13204","DOI":"10.1523\/JNEUROSCI.2381-12.2013","article-title":"Super-Resolution Imaging Reveals That AMPA Receptors Inside Synapses Are Dynamically Organized in Nanodomains Regulated by PSD95","volume":"33","author":"D Nair","year":"2013","journal-title":"Journal of Neuroscience"},{"issue":"6","key":"pcbi.1012564.ref084","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.cell.2020.07.043","article-title":"Phase Separation of a PKA Regulatory Subunit Controls cAMP Compartmentation and Oncogenic Signaling","volume":"182","author":"JZ Zhang","year":"2020","journal-title":"Cell"},{"issue":"49","key":"pcbi.1012564.ref085","doi-asserted-by":"crossref","first-page":"19333","DOI":"10.1073\/pnas.0707054104","article-title":"Essential role of Epac2\/Rap1 signaling in regulation of insulin granule dynamics by cAMP","volume":"104","author":"T Shibasaki","year":"2007","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"Pt 1","key":"pcbi.1012564.ref086","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1469-7793.1997.105bl.x","article-title":"Protein kinase A-dependent and-independent stimulation of exocytosis by cAMP in mouse pancreatic B-cells","volume":"502","author":"E Renstr\u00f6m","year":"1997","journal-title":"The Journal of physiology"},{"issue":"3","key":"pcbi.1012564.ref087","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1085\/jgp.20028707","article-title":"SUR1 Regulates PKA-independent cAMP-induced Granule Priming in Mouse Pancreatic B-cells","volume":"121","author":"L Eliasson","year":"2003","journal-title":"Journal of General Physiology"},{"issue":"3","key":"pcbi.1012564.ref088","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.cmet.2011.02.002","article-title":"Snapin Mediates Incretin Action and Augments Glucose-Dependent Insulin Secretion","volume":"13","author":"WJ Song","year":"2011","journal-title":"Cell Metabolism"},{"issue":"2","key":"pcbi.1012564.ref089","doi-asserted-by":"crossref","first-page":"E452","DOI":"10.1152\/ajpendo.90585.2008","article-title":"Truncation of SNAP-25 reduces the stimulatory action of cAMP on rapid exocytosis in insulin-secreting cells","volume":"297","author":"J Vikman","year":"2009","journal-title":"American Journal of Physiology-Endocrinology and Metabolism"},{"issue":"6","key":"pcbi.1012564.ref090","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1085\/jgp.200409082","article-title":"Protein Kinase Activation Increases Insulin Secretion by Sensitizing the Secretory Machinery to Ca2+","volume":"124","author":"QF Wan","year":"2004","journal-title":"Journal of General Physiology"},{"issue":"S1","key":"pcbi.1012564.ref091","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/dom.12993","article-title":"cAMP signalling in insulin and glucagon secretion","volume":"19","author":"A Tengholm","year":"2017","journal-title":"Diabetes, Obesity and Metabolism"},{"issue":"3","key":"pcbi.1012564.ref092","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1177\/1073858410384740","article-title":"AKAP Signaling Complexes in Regulation of Excitatory Synaptic Plasticity","volume":"17","author":"JL Sanderson","year":"2011","journal-title":"The Neuroscientist"},{"issue":"10","key":"pcbi.1012564.ref093","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1016\/j.cellsig.2008.05.001","article-title":"Neuronal AKAP150 coordinates PKA and Epac-mediated PKB\/Akt phosphorylation","volume":"20","author":"IM Nijholt","year":"2008","journal-title":"Cellular Signalling"},{"issue":"4","key":"pcbi.1012564.ref094","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/s41568-022-00444-7","article-title":"Liquid\u2013liquid phase separation drives cellular function and dysfunction in cancer","volume":"22","author":"S Mehta","year":"2022","journal-title":"Nature Reviews Cancer"},{"issue":"2","key":"pcbi.1012564.ref095","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.ccell.2020.12.003","article-title":"Biomolecular Condensates and Cancer","volume":"39","author":"A Boija","year":"2021","journal-title":"Cancer Cell"},{"key":"pcbi.1012564.ref096","doi-asserted-by":"crossref","first-page":"e60264","DOI":"10.7554\/eLife.60264","article-title":"Protein phase separation and its role in tumorigenesis","volume":"9","author":"S Jiang","year":"2020","journal-title":"eLife"},{"issue":"7","key":"pcbi.1012564.ref097","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.tibs.2021.01.002","article-title":"Biomolecular Condensates and Their Links to Cancer Progression","volume":"46","author":"D Cai","year":"2021","journal-title":"Trends in Biochemical Sciences"},{"issue":"15","key":"pcbi.1012564.ref098","doi-asserted-by":"crossref","first-page":"7734","DOI":"10.1093\/nar\/gkz634","article-title":"DAXX in cancer: phenomena, processes, mechanisms and regulation","volume":"47","author":"I Mahmud","year":"2019","journal-title":"Nucleic Acids Research"},{"issue":"1","key":"pcbi.1012564.ref099","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.molcel.2018.08.027","article-title":"Cancer Mutations of the Tumor Suppressor SPOP Disrupt the Formation of Active, Phase-Separated Compartments","volume":"72","author":"JJ Bouchard","year":"2018","journal-title":"Molecular Cell"},{"issue":"7","key":"pcbi.1012564.ref100","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1016\/j.cell.2016.11.035","article-title":"Mutant KRAS Enhances Tumor Cell Fitness by Upregulating Stress Granules","volume":"167","author":"E Grabocka","year":"2016","journal-title":"Cell"},{"issue":"7","key":"pcbi.1012564.ref101","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1083\/jcb.201411047","article-title":"YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1","volume":"208","author":"SP Somasekharan","year":"2015","journal-title":"Journal of Cell Biology"},{"issue":"6","key":"pcbi.1012564.ref102","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/nrm.2016.43","article-title":"Stop pulling my strings\u2014what telomeres taught us about the DNA damage response","volume":"17","author":"E Lazzerini-Denchi","year":"2016","journal-title":"Nature Reviews Molecular Cell Biology"},{"issue":"2","key":"pcbi.1012564.ref103","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.trecan.2015.07.007","article-title":"ALTernative Telomere Maintenance and Cancer","volume":"1","author":"RL Dilley","year":"2015","journal-title":"Trends in Cancer"},{"issue":"5999","key":"pcbi.1012564.ref104","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1126\/science.1179047","article-title":"Reaction-Diffusion Model as a Framework for Understanding Biological Pattern Formation","volume":"329","author":"S Kondo","year":"2010","journal-title":"Science"},{"issue":"5804","key":"pcbi.1012564.ref105","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1126\/science.1130088","article-title":"WNT and DKK Determine Hair Follicle Spacing through a Reaction-Diffusion Mechanism","volume":"314","author":"S Sick","journal-title":"Science"},{"issue":"6196","key":"pcbi.1012564.ref106","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1126\/science.1252960","article-title":"Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients","volume":"345","author":"J Raspopovic","year":"2014","journal-title":"Science"},{"issue":"3","key":"pcbi.1012564.ref107","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/jb\/mvu087","article-title":"Models of lung branching morphogenesis","volume":"157","author":"T Miura","year":"2015","journal-title":"The Journal of Biochemistry"},{"issue":"11","key":"pcbi.1012564.ref108","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pbio.3002391","article-title":"A simple Turing reaction\u2013diffusion model explains how PLK4 breaks symmetry during centriole duplication and assembly","volume":"21","author":"ZM Wilmott","year":"2023","journal-title":"PLOS Biology"},{"issue":"26","key":"pcbi.1012564.ref109","doi-asserted-by":"crossref","first-page":"6572","DOI":"10.1073\/pnas.1720770115","article-title":"Stochastic Turing patterns in a synthetic bacterial population","volume":"115","author":"D Karig","year":"2018","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"pcbi.1012564.ref110","doi-asserted-by":"crossref","first-page":"e56159","DOI":"10.7554\/eLife.56159","article-title":"Dynamic metastable long-living droplets formed by sticker-spacer proteins","volume":"9","author":"S Ranganathan","year":"2020","journal-title":"eLife"},{"key":"pcbi.1012564.ref111","doi-asserted-by":"crossref","first-page":"218101","DOI":"10.1103\/PhysRevLett.101.218101","article-title":"Self-Organized Periodicity of Protein Clusters in Growing Bacteria","volume":"101","author":"H Wang","year":"2008","journal-title":"Phys Rev Lett"},{"issue":"29","key":"pcbi.1012564.ref112","doi-asserted-by":"crossref","first-page":"11905","DOI":"10.1073\/pnas.1222339110","article-title":"Phase separation explains a new class of self-organized spatial patterns in ecological systems","volume":"110","author":"QX Liu","year":"2013","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"12","key":"pcbi.1012564.ref113","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s11538-020-00823-x","article-title":"Modeling the Mechanisms by Which Coexisting Biomolecular RNA\u2013Protein Condensates Form","volume":"82","author":"K Gasior","year":"2020","journal-title":"Bulletin of Mathematical Biology"},{"key":"pcbi.1012564.ref114","doi-asserted-by":"crossref","first-page":"8373","DOI":"10.1039\/D1SM00502B","article-title":"Curvature-driven feedback on aggregation\u2013diffusion of proteins in lipid bilayers","volume":"17","author":"A Mahapatra","year":"2021","journal-title":"Soft Matter"},{"key":"pcbi.1012564.ref115","article-title":"Spine apparatus modulates Ca2+ in spines through spatial localization of sources and sinks","author":"MH Mesa","year":"2023","journal-title":"bioRxiv"},{"key":"pcbi.1012564.ref116","unstructured":"Qiao L, Khalilimeybodi A, Linden-Santangeli NJ, Rangamani P. The evolution of systems biology and systems medicine: From mechanistic models to uncertainty quantification. arXiv. 2024;."},{"key":"pcbi.1012564.ref117","article-title":"Increasing certainty in systems biology models using Bayesian multimodel inference","author":"N Linden-Santangeli","year":"2024","journal-title":"bioRxiv"},{"issue":"10","key":"pcbi.1012564.ref118","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pcbi.1010651","article-title":"Bayesian parameter estimation for dynamical models in systems biology","volume":"18","author":"NJ Linden","year":"2022","journal-title":"PLOS Computational Biology"},{"issue":"8","key":"pcbi.1012564.ref119","doi-asserted-by":"crossref","first-page":"e202112980","DOI":"10.1085\/jgp.202112980","article-title":"Dendritic spine morphology regulates calcium-dependent synaptic weight change","volume":"154","author":"MK Bell","year":"2022","journal-title":"Journal of General Physiology"},{"issue":"1","key":"pcbi.1012564.ref120","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1186\/1471-2202-7-S1-S10","article-title":"Mathematical modeling of intracellular signaling pathways","volume":"7","author":"E Klipp","year":"2006","journal-title":"BMC Neuroscience"},{"issue":"5760","key":"pcbi.1012564.ref121","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/285073a0","article-title":"Calmodulin\u2014an intracellular calcium receptor","volume":"285","author":"AR Means","year":"1980","journal-title":"Nature"},{"key":"pcbi.1012564.ref122","unstructured":"Finkston B. Mean Shift Clustering; 2024. https:\/\/www.mathworks.com\/matlabcentral\/fileexchange\/10161-mean-shift-clustering."},{"issue":"5","key":"pcbi.1012564.ref123","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1109\/34.1000236","article-title":"Mean shift: a robust approach toward feature space analysis","volume":"24","author":"D Comaniciu","year":"2002","journal-title":"IEEE Transactions on Pattern Analysis and Machine Intelligence"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1012564","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012564","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T18:39:28Z","timestamp":1731436768000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012564"}},"subtitle":[],"editor":[{"given":"Marc R","family":"Birtwistle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,10,31]]},"references-count":123,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1012564","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1012564","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,31]]}}}