{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T22:39:10Z","timestamp":1785796750460,"version":"3.56.0"},"reference-count":55,"publisher":"Elsevier BV","issue":"1","license":[{"start":{"date-parts":[[2011,5,1]],"date-time":"2011-05-01T00:00:00Z","timestamp":1304208000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Mathematical Biosciences"],"published-print":{"date-parts":[[2011,5]]},"DOI":"10.1016\/j.mbs.2011.03.008","type":"journal-article","created":{"date-parts":[[2011,3,16]],"date-time":"2011-03-16T04:33:50Z","timestamp":1300250030000},"page":"19-38","source":"Crossref","is-referenced-by-count":23,"title":["Design of the lac gene circuit revisited"],"prefix":"10.1016","volume":"231","author":[{"given":"Michael A.","family":"Savageau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.mbs.2011.03.008_b0005","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S0022-2836(61)80072-7","article-title":"Genetic regulatory mechanisms in the synthesis of proteins","volume":"3","author":"Jacob","year":"1961","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.mbs.2011.03.008_b0010","series-title":"The Lactose Operon, Cold Spring Harbor Laboratory","year":"1970"},{"key":"10.1016\/j.mbs.2011.03.008_b0015","series-title":"The Operon, Cold Spring Harbor Laboratory","year":"1980"},{"key":"10.1016\/j.mbs.2011.03.008_b0020","series-title":"The Lac Operon: A Short History of a Genetic Paradigm","author":"M\u00fcller-Hill","year":"1996"},{"key":"10.1016\/j.mbs.2011.03.008_b0025","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1073\/pnas.71.6.2453","article-title":"Genetic regulatory mechanisms and the ecological niche of Escherichia coli","volume":"71","author":"Savageau","year":"1974","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.mbs.2011.03.008_b0030","series-title":"Theoretical Biology \u2013 Epigenetic and Evolutionary Order","first-page":"42","article-title":"Are there rules governing patterns of gene regulation?","author":"Savageau","year":"1989"},{"key":"10.1016\/j.mbs.2011.03.008_b0035","doi-asserted-by":"crossref","first-page":"3999","DOI":"10.1073\/pnas.0506610103","article-title":"Rules for biological regulation based on error minimization","volume":"103","author":"Shinar","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.mbs.2011.03.008_b0040","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1006\/jmbi.1995.0257","article-title":"Subunit structure of regulator proteins influences the design of gene circuitry: analysis of perfectly coupled and completely uncoupled circuits","volume":"248","author":"Hlavacek","year":"1995","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.mbs.2011.03.008_b0045","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1006\/jmbi.1996.0011","article-title":"Rules for coupled expression of regulator and effector genes in inducible circuits","volume":"255","author":"Hlavacek","year":"1996","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.mbs.2011.03.008_b0050","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/nrg1244","article-title":"Design of gene circuits: lessons from bacteria","volume":"5","author":"Wall","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"10.1016\/j.mbs.2011.03.008_b0055","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1073\/pnas.43.7.553","article-title":"Enzyme induction as an all-or-none phenomenon","volume":"43","author":"Novick","year":"1957","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.mbs.2011.03.008_b0060","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/0022-5193(68)90190-2","article-title":"Mathematics of cellular control processes II: Positive feedback to one gene","volume":"20","author":"Griffith","year":"1968","journal-title":"J. Theor. Biol."},{"key":"10.1016\/j.mbs.2011.03.008_b0065","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/0014-5793(72)80317-X","article-title":"Chemical instabilities of \u2018all-or-none\u2019 type in \u03b2-galactosidase induction and active transport","volume":"23","author":"Babloyantz","year":"1972","journal-title":"FEBS Lett."},{"key":"10.1016\/j.mbs.2011.03.008_b0070","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0301-4622(76)85001-6","article-title":"Sustained oscillations and threshold phenomena in an operon control circuit","volume":"4","author":"Sanglier","year":"1976","journal-title":"Biophys. Chem."},{"key":"10.1016\/j.mbs.2011.03.008_b0075","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/0022-2836(72)90253-7","article-title":"lac Repressor\u2013operator interaction. VI. The natural inducer of the lac operon","volume":"69","author":"Jobe","year":"1972","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.mbs.2011.03.008_b0080","unstructured":"M.A. Savageau, Biochemical Systems Analysis: A Study of Function and Design in Molecular Biology, 40th Anniversary Edition, 2009. http:\/\/www.amazon.com\/Biochemical-Systems-Analysis-Function-Molecular\/dp\/1449590764\/ (a reprinting of the original edition published by Addison-Wesley, Reading, Mass., 1976)."},{"key":"10.1016\/j.mbs.2011.03.008_b0085","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1042\/bst0270264","article-title":"Design of gene circuitry by natural selection: analysis of the lactose catabolic system in E. coli","volume":"27","author":"Savageau","year":"1999","journal-title":"Biochem. Soc. Trans."},{"key":"10.1016\/j.mbs.2011.03.008_b0090","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0025-5564(02)00113-X","article-title":"Alternative designs for a genetic switch: analysis of switching times using the piece-wise power-law representation","volume":"180","author":"Savageau","year":"2002","journal-title":"Math. Biosci."},{"key":"10.1016\/j.mbs.2011.03.008_b0095","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1128\/MMBR.00024-06","article-title":"How phosphotransferase system-related protein phosphorylation regulates carbohydrate metabolism in bacteria","volume":"70","author":"Deutscher","year":"2006","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"10.1016\/j.mbs.2011.03.008_b0100","doi-asserted-by":"crossref","first-page":"6448","DOI":"10.1074\/jbc.M512672200","article-title":"In vitro reconstitution of catabolite repression in Escherichia coli","volume":"281","author":"Park","year":"2006","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.mbs.2011.03.008_b0105","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1021\/bi00654a029","article-title":"A quantitation of the factors which affect the hydrolase and transgalactosylase activities of \u03b2-galactosidase (E. coli) on lactose","volume":"15","author":"Huber","year":"1976","journal-title":"Biochemistry"},{"key":"10.1016\/j.mbs.2011.03.008_b0110","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1139\/m84-060","article-title":"Escherichia coli growth on lactose requires cycling of \u03b2-galactosidase products into the medium","volume":"30","author":"Huber","year":"1984","journal-title":"Can. J. Microbiol."},{"key":"10.1016\/j.mbs.2011.03.008_b0115","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1046\/j.1365-2958.1999.01321.x","article-title":"The identification of a new family of sugar efflux pumps in Escherichia coli","volume":"31","author":"Liu","year":"1999","journal-title":"Mol. Microbiol."},{"key":"10.1016\/j.mbs.2011.03.008_b0120","doi-asserted-by":"crossref","first-page":"22977","DOI":"10.1074\/jbc.274.33.22977","article-title":"Functional and biochemical characterization of Escherichia coli sugar efflux transporters","volume":"274","author":"Liu","year":"1999","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.mbs.2011.03.008_b0125","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1016\/0009-2509(95)00306-1","article-title":"On physiological multiplicity and population heterogeneity of biological systems","volume":"51","author":"Chung","year":"1996","journal-title":"Chem. Eng. Sci."},{"key":"10.1016\/j.mbs.2011.03.008_b0130","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1007\/s11538-007-9289-7","article-title":"Bistability of the lac operon during growth of Escherichia coli on lactose and lactose+glucose","volume":"70","author":"Narang","year":"2008","journal-title":"Bull. Math. Biol."},{"key":"10.1016\/j.mbs.2011.03.008_b0135","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1002\/j.1460-2075.1990.tb08199.x","article-title":"The three operators of the lac operon cooperate in repression","volume":"9","author":"Oehler","year":"1990","journal-title":"EMBO J."},{"key":"10.1016\/j.mbs.2011.03.008_b0140","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1093\/nar\/gkj453","article-title":"Induction of the lac promoter in the absence of DNA loops and the stoichiometry of induction","volume":"34","author":"Oehler","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.mbs.2011.03.008_b0145","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1529\/biophysj.105.077420","article-title":"In silico evolved lac operons exhibit bistability for artificial inducers, but not for lactose","volume":"91","author":"van Hoek","year":"2006","journal-title":"Biophys. J."},{"key":"10.1016\/j.mbs.2011.03.008_b0150","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1529\/biophysj.107.118026","article-title":"Bistable behavior in a model of the lac operon in Escherichia coli with variable growth rate","volume":"94","author":"Santill\u00e1n","year":"2008","journal-title":"Biophys. J."},{"key":"10.1016\/j.mbs.2011.03.008_b0155","doi-asserted-by":"crossref","first-page":"6435","DOI":"10.1073\/pnas.0809869106","article-title":"Phenotypes and tolerances in the design space of biochemical systems","volume":"106","author":"Savageau","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"issue":"3","key":"10.1016\/j.mbs.2011.03.008_b0160","doi-asserted-by":"crossref","first-page":"e1000319","DOI":"10.1371\/journal.pcbi.1000319","article-title":"Global tolerance of biochemical systems and the design of moiety-transfer cycles","volume":"5","author":"Coelho","year":"2009","journal-title":"PLOS Comput. Biol."},{"key":"10.1016\/j.mbs.2011.03.008_b0165","doi-asserted-by":"crossref","first-page":"3914","DOI":"10.1016\/j.febslet.2009.10.073","article-title":"Qualitatively distinct phenotypes in the design space of biochemical systems","volume":"583","author":"Savageau","year":"2009","journal-title":"FEBS Lett."},{"key":"10.1016\/j.mbs.2011.03.008_b0170","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1534\/genetics.109.111963","article-title":"Duplication frequency in a population of Salmonella enterica rapidly approaches steady state with or without recombination","volume":"184","author":"Reams","year":"2010","journal-title":"Genetics"},{"key":"10.1016\/j.mbs.2011.03.008_b0175","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/j.1365-2958.2010.07437.x","article-title":"Phenotypic repertoire of the FNR regulatory network in Escherichia coli","volume":"79","author":"Tolla","year":"2011","journal-title":"Mol. Microbiol."},{"key":"10.1016\/j.mbs.2011.03.008_b0180","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1093\/bioinformatics\/btq479","article-title":"Automatic construction and analysis of the design space of biochemical systems","volume":"26","author":"Fasani","year":"2010","journal-title":"Bioinformatics"},{"key":"10.1016\/j.mbs.2011.03.008_b0185","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1021\/bp970003o","article-title":"Mathematical model of the lac operon: inducer exclusion; catabolite repression and diauxic growth on glucose and lactose","volume":"13","author":"Wong","year":"1997","journal-title":"Biotechnol. Prog."},{"key":"10.1016\/j.mbs.2011.03.008_b0190","series-title":"Introduction to Applied Nonlinear Dynamical Systems and Chaos","author":"Wiggins","year":"1990"},{"key":"10.1016\/j.mbs.2011.03.008_b0195","series-title":"Catastrophe Theory","author":"Arnol\u2019d","year":"1992"},{"key":"10.1016\/j.mbs.2011.03.008_b0200","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1049\/iet-syb:20080095","article-title":"Determinants of bistability in induction of the Escherichia coli lac operon","volume":"2","author":"Dreisigmeyer","year":"2008","journal-title":"IET Systems Biology"},{"key":"10.1016\/j.mbs.2011.03.008_b0205","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":"Ozbudak","year":"2004","journal-title":"Nature"},{"key":"10.1016\/j.mbs.2011.03.008_b0210","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1126\/science.1188308","article-title":"Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells","volume":"329","author":"Taniguchi","year":"2010","journal-title":"Science"},{"key":"10.1016\/j.mbs.2011.03.008_b0215","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1063\/1.1349892","article-title":"Design principles for elementary gene circuits: elements, methods, and examples","volume":"11","author":"Savageau","year":"2001","journal-title":"Chaos"},{"key":"10.1016\/j.mbs.2011.03.008_b0220","series-title":"Temporal Organization in Cells","author":"Goodwin","year":"1963"},{"key":"10.1016\/j.mbs.2011.03.008_b0225","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.mib.2008.02.007","article-title":"The mechanisms of carbon catabolite repression in bacteria","volume":"11","author":"Deutscher","year":"2008","journal-title":"Curr. Opin. Microbiol."},{"key":"10.1016\/j.mbs.2011.03.008_b0230","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S1369-5274(02)00296-5","article-title":"Regulation of gene expression in the PTS in Escherichia coli: the role and interactions of Mlc","volume":"5","author":"Plumbridge","year":"2003","journal-title":"Curr. Opin. Microbiol."},{"key":"10.1016\/j.mbs.2011.03.008_b0235","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0022-2836(65)80255-8","article-title":"The properties of repressor and the kinetics of its action","volume":"12","author":"Sadler","year":"1965","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.mbs.2011.03.008_b0240","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/B978-0-12-152809-6.50013-5","article-title":"Quantitative aspects of protein induction","volume":"9","author":"Yagil","year":"1975","journal-title":"Curr. Top. Cell Regul."},{"issue":"9","key":"10.1016\/j.mbs.2011.03.008_b0245","doi-asserted-by":"crossref","first-page":"e13031","DOI":"10.1371\/journal.pone.0013031","article-title":"Relating genotype to phenotype via the quantitative behavior of the NADPH redox cycle in human erythrocytes: mutant analysis","volume":"5","author":"Coelho","year":"2010","journal-title":"PLOS One"},{"key":"10.1016\/j.mbs.2011.03.008_b0250","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1007\/s10439-010-0220-2","article-title":"System design space with applications to biomedical engineering","volume":"39","author":"Savageau","year":"2011","journal-title":"Annal Biomed. Engr."},{"key":"10.1016\/j.mbs.2011.03.008_b0255","doi-asserted-by":"crossref","first-page":"17642","DOI":"10.1073\/pnas.0505693102","article-title":"Inferring the in vivo looping properties of DNA","volume":"102","author":"Saiz","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.mbs.2011.03.008_b0260","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1086\/284168","article-title":"Escherichia coli habitats, cell types, and molecular mechanisms of gene control","volume":"122","author":"Savageau","year":"1983","journal-title":"Am. Naturalist"},{"key":"10.1016\/j.mbs.2011.03.008_b0265","first-page":"45","article-title":"A critique of the enzymologist\u2019s test tube","volume":"vol. 3A","author":"Savageau","year":"1992"},{"key":"10.1016\/j.mbs.2011.03.008_b0270","doi-asserted-by":"crossref","first-page":"273","DOI":"10.3354\/ame016273","article-title":"Use of high temperature catalytic oxidation (HTCO) to measure carbon content of microorganisms","volume":"16","author":"Pelegr\u0131\u00b4","year":"1999","journal-title":"Aquat. Microbiol. Ecol."},{"key":"10.1016\/j.mbs.2011.03.008_b0275","unstructured":"H.W. Bode, Network Analysis and Feedback Amplifier Design, Van Nostran, Princeton, New Jersey, 1945."}],"container-title":["Mathematical Biosciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0025556411000381?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0025556411000381?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2019,6,9]],"date-time":"2019-06-09T04:23:36Z","timestamp":1560054216000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0025556411000381"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,5]]},"references-count":55,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,5]]}},"alternative-id":["S0025556411000381"],"URL":"https:\/\/doi.org\/10.1016\/j.mbs.2011.03.008","relation":{},"ISSN":["0025-5564"],"issn-type":[{"value":"0025-5564","type":"print"}],"subject":[],"published":{"date-parts":[[2011,5]]}}}