{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T09:13:29Z","timestamp":1778577209495,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1006121","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T00:00:00Z","timestamp":1525305600000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2018,4,23]],"date-time":"2018-04-23T00:00:00Z","timestamp":1524441600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000086","name":"Directorate for Mathematical and Physical Sciences","doi-asserted-by":"publisher","award":["1125174"],"award-info":[{"award-number":["1125174"]}],"id":[{"id":"10.13039\/100000086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000086","name":"Directorate for Mathematical and Physical Sciences","doi-asserted-by":"publisher","award":["1248071"],"award-info":[{"award-number":["1248071"]}],"id":[{"id":"10.13039\/100000086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000086","name":"Directorate for Mathematical and Physical Sciences","doi-asserted-by":"publisher","award":["1521771"],"award-info":[{"award-number":["1521771"]}],"id":[{"id":"10.13039\/100000086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000185","name":"Defense Advanced Research Projects Agency","doi-asserted-by":"publisher","award":["HR0011-16-2-0033"],"award-info":[{"award-number":["HR0011-16-2-0033"]}],"id":[{"id":"10.13039\/100000185","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000086","name":"Directorate for Mathematical and Physical Sciences","doi-asserted-by":"publisher","award":["1226113"],"award-info":[{"award-number":["1226113"]}],"id":[{"id":"10.13039\/100000086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000086","name":"Directorate for Mathematical and Physical Sciences","doi-asserted-by":"publisher","award":["1361240"],"award-info":[{"award-number":["1361240"]}],"id":[{"id":"10.13039\/100000086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000185","name":"Defense Advanced Research Projects Agency","doi-asserted-by":"publisher","award":["D12AP200025"],"award-info":[{"award-number":["D12AP200025"]}],"id":[{"id":"10.13039\/100000185","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01AG040020-01"],"award-info":[{"award-number":["1R01AG040020-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000199","name":"U.S. Department of Agriculture","doi-asserted-by":"publisher","award":["2015-51106-23970"],"award-info":[{"award-number":["2015-51106-23970"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000185","name":"Defense Advanced Research Projects Agency","doi-asserted-by":"publisher","award":["FA8750-17-C-0054"],"award-info":[{"award-number":["FA8750-17-C-0054"]}],"id":[{"id":"10.13039\/100000185","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM126555-01"],"award-info":[{"award-number":["R01 GM126555-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000185","name":"Defense Advanced Research Projects Agency","doi-asserted-by":"publisher","award":["FA8750-17-C-0054"],"award-info":[{"award-number":["FA8750-17-C-0054"]}],"id":[{"id":"10.13039\/100000185","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM126555-01"],"award-info":[{"award-number":["R01 GM126555-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1006121","type":"journal-article","created":{"date-parts":[[2018,4,23]],"date-time":"2018-04-23T13:36:55Z","timestamp":1524490615000},"page":"e1006121","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["Identifying robust hysteresis in networks"],"prefix":"10.1371","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5555-6741","authenticated-orcid":true,"given":"Tom\u00e1\u0161","family":"Gedeon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3097-5277","authenticated-orcid":true,"given":"Bree","family":"Cummins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaun","family":"Harker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantin","family":"Mischaikow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2018,4,23]]},"reference":[{"key":"ref1","article-title":"An introduction to systems biology","author":"U Alon","year":"2007"},{"issue":"4","key":"ref2","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.cell.2009.06.013","article-title":"Defining Network Topologies that Can Achieve Biochemical Adaptation","volume":"138","author":"W Ma","year":"2009","journal-title":"Cell"},{"issue":"6","key":"ref3","doi-asserted-by":"crossref","first-page":"e1002085","DOI":"10.1371\/journal.pcbi.1002085","article-title":"Robust Network Topologies for Generating Switch-Like Cellular Responses","volume":"7","author":"NA Shah","year":"2011","journal-title":"PLoS Comput Biol"},{"issue":"7","key":"ref4","article-title":"Origin of bistability underlying mammalian cell cycle entry","volume":"485","author":"G Yao","year":"2011","journal-title":"Molecular Systems Biology"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1107c","DOI":"10.1126\/science.1099334","article-title":"Comment on Network Motifs: Simple Building Blocks of Complex Networks and Superfamilies of Evolved and Designed Networks","volume":"305","author":"Y Artzy-Randrup","year":"2004","journal-title":"Science"},{"issue":"108","key":"ref6","article-title":"Network motifs: structure does not determine function","volume":"7","author":"PJ Ingram","year":"2006","journal-title":"BMC Genomics"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.physd.2016.08.006","article-title":"Global Dynamics for Steep Sigmoidal Nonlinearities in Two Dimensions","volume":"339","author":"T Gedeon","year":"2017","journal-title":"Physica D"},{"issue":"4","key":"ref8","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1137\/15M1052743","article-title":"Combinatorial Representation of Parameter Space for Switching Systems","volume":"15","author":"B Cummins","year":"2016","journal-title":"SIAM J Appl Dyn Syst"},{"key":"ref9","article-title":"Model rejection and parameter reduction via time series","author":"B Cummins","journal-title":"to appear SIAM J Appl Dyn Sys"},{"issue":"4","key":"ref10","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s10208-004-0163-9","article-title":"An algorithmic approach to chain recurrence","volume":"5","author":"WD Kalies","year":"2005","journal-title":"Found Comput Math"},{"issue":"2","key":"ref11","article-title":"Lattice Structures for Attractors I","volume":"1","author":"W Kalies","year":"2014","journal-title":"J of Comp Dyn"},{"key":"ref12","article-title":"Lattice Structures for Attractors II","author":"WD Kalies","year":"2015","journal-title":"Found Comput Math"},{"issue":"3","key":"ref13","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1137\/080734935","article-title":"A database schema for the analysis of global dynamics of multiparameter systems","volume":"8","author":"Z Arai","year":"2009","journal-title":"SIAM J Appl Dyn Syst"},{"issue":"4","key":"ref14","doi-asserted-by":"crossref","DOI":"10.1063\/1.4767672","article-title":"Combinatorial-topological framework for the analysis of global dynamics","volume":"22","author":"J Bush","year":"2012","journal-title":"CHAOS"},{"issue":"6","key":"ref15","first-page":"3379","article-title":"Combinatorial-topological framework for the analysis of global dynamics","volume":"16","author":"J Bush","year":"2014","journal-title":"Entropy"},{"issue":"2","key":"ref16","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1137\/15M1017971","article-title":"Conley-Morse Databases for the Angular Dynamics of Newton\u2019s Method on the Plane","volume":"15","author":"J Bush","year":"2016","journal-title":"SIADS"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1073\/pnas.71.4.1286","article-title":"A restriction point for control of normal animal cell proliferation","volume":"71","author":"A Pardee","year":"1974","journal-title":"PNAS"},{"issue":"1","key":"ref18","doi-asserted-by":"crossref","first-page":"102","DOI":"10.4161\/cc.1.2.108","article-title":"The Restriction Point of the Cell Cycle","volume":"2","author":"MV Blagosklonny","year":"2002","journal-title":"Cell Cycle"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"11617","DOI":"10.1074\/jbc.R100063200","article-title":"Signaling networks that link cell proliferation and cell fate","volume":"277","author":"R Sears","year":"2002","journal-title":"J Biol Chem"},{"issue":"6976","key":"ref20","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/nature02298","article-title":"Multistability in the lactose utilization network of Escherichia coli","volume":"427","author":"E Ozbudak","year":"2004","journal-title":"Nature"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/ncb1711","article-title":"A bistable Rb-E2F switch underlies the restriction point","volume":"10","author":"G Yao","year":"2008","journal-title":"Nat Cell Biol"},{"issue":"9","key":"ref22","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nrc2399","article-title":"Cellular mechanisms of tumour suppression by the retinoblastoma gene","volume":"8","author":"D Burkhart","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/B978-0-12-380916-2.00005-X","article-title":"RB1, development, and cancer","volume":"94","author":"M Chinnam","year":"2011","journal-title":"Curr Top Dev Biol"},{"issue":"5","key":"ref24","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1242\/dmm.008060","article-title":"Newly identified aspects of tumor suppression by RB","volume":"4","author":"P Viatour","year":"2011","journal-title":"Dis Model Mech"},{"issue":"3","key":"ref25","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nrc3216","article-title":"RB: mitotic implications of a tumour suppressor","volume":"12","author":"A Manning","year":"2012","journal-title":"Nat Rev Cancer"},{"issue":"6","key":"ref26","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.ceb.2013.07.012","article-title":"The multiple connections between pRB and cell metabolism","volume":"25","author":"BN Nicolay","year":"2013","journal-title":"Curr Opin Cell Biol"},{"issue":"8","key":"ref27","doi-asserted-by":"crossref","first-page":"e105833","DOI":"10.1371\/journal.pone.0105833","article-title":"Systematic Reverse Engineering of Network Topologies: A Case Study of Resettable Bistable Cellular Responses","volume":"9","author":"D Mondal","year":"2014","journal-title":"Plos One"},{"issue":"6767","key":"ref28","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/35002131","article-title":"Construction of a genetic toggle switch in Escherichia coli","volume":"403","author":"T Gardner","year":"2000","journal-title":"Nature"},{"issue":"9","key":"ref29","doi-asserted-by":"crossref","first-page":"e1000189","DOI":"10.1371\/journal.pbio.1000189","article-title":"Recruitment of Cln3 Cyclin to Promoters Controls Cell Cycle Entry via Histone Deacetylase and Other Targets","volume":"7","author":"H Wang","year":"2009","journal-title":"PLoS Biol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/nature07118","article-title":"Positive feedback of G1 cyclins ensures coherent cell cycle entry","volume":"454","author":"JM Skotheim","year":"2008","journal-title":"Nature"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"3532","DOI":"10.1098\/rstb.2011.0078","article-title":"Evolution of networks and sequences in eukaryotic cell cycle control","volume":"366","author":"FR Cross","year":"2011","journal-title":"Phil Trans R Soc B"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"110009","DOI":"10.1098\/rsob.110009","article-title":"Cell cycle commitment in budding yeast emerges from the cooperation of multiple bistable switches","volume":"1","author":"T Zhang","year":"2011","journal-title":"Open Biol"},{"key":"ref33","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms11372","article-title":"Whi5 phosphorylation embedded in the G1\/S network dynamically controls critical cell size and cell fate","volume":"7","author":"P Palumbo","year":"2016","journal-title":"Nature Comm"},{"key":"ref34","article-title":"The Cell: A molecular approach","author":"GM Cooper","year":"2015"},{"issue":"2","key":"ref35","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0022-5193(72)90157-9","article-title":"Co-operative components, spatial localization and oscillatory cellular dynamics","volume":"34","author":"L Glass","year":"1972","journal-title":"Journal of Theoretical Biology"},{"issue":"1","key":"ref36","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0022-5193(73)90208-7","article-title":"The logical analysis of continuous, non-linear biochemical control networks","volume":"39","author":"L Glass","year":"1973","journal-title":"Journal of Theoretical Biology"},{"issue":"2","key":"ref37","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.bulm.2003.08.010","article-title":"Qualitative simulation of genetic regulatory networks using piecewise-linear models","volume":"66","author":"HD Jong","year":"2004","journal-title":"Bull Math Biol"},{"issue":"2","key":"ref38","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.jtbi.2009.06.006","article-title":"Uncovering operational interactions in genetic networks using asynchronous Boolean dynamics","volume":"260","author":"L Tournier","year":"2009","journal-title":"J Theor Biol"},{"key":"ref39","first-page":"187","article-title":"Chaos in neural and gene networks with hard switching","volume":"9","author":"R Edwards","year":"2001","journal-title":"Diff Eq Dyn Sys"},{"key":"ref40","unstructured":"Harker S, Cummins B. Code Supplemental for \u201cIdentifying robust hysteresis in networks\u201d. GitHub repository. 2017;"},{"key":"ref41","unstructured":"Harker S. DSGRN Software. GitHub repository. 2017;"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1006121","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T00:00:00Z","timestamp":1525305600000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pcbi.1006121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,10,19]],"date-time":"2018-10-19T15:41:51Z","timestamp":1539963711000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1006121"}},"subtitle":[],"editor":[{"given":"Lingchong","family":"You","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2018,4,23]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,4,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1006121","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1006121","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,23]]}}}