Graphical Approach to Model Reduction for Nonlinear Biochemical Networks 英文参考文献.docVIP

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Graphical Approach to Model Reduction for Nonlinear Biochemical Networks 英文参考文献.doc

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Graphical Approach to Model Reduction for Nonlinear Biochemical Networks 英文参考文献

GraphicalApproachtoModelReductionforNonlinear BiochemicalNetworks DavidO.Holland,NicholasC.Krainak,JeffreyJ.Saucerman* DepartmentofBiomedicalEngineering,RobertM.BerneCardiovascularResearchCenter,UniversityofVirginia,Charlottesville,Virginia,UnitedStatesofAmerica Abstract Modelreductionisacentralchallengetothedevelopmentandanalysisofmultiscalephysiologymodels.Advancesinmodel reduction are needed not only for computational feasibility but also for obtaining conceptual insights from complex systems.Here,weintroduceanintuitivegraphicalapproachtomodelreductionbasedonphaseplaneanalysis.Timescale separation is identified by the degree of hysteresis observed in phase-loops, which guides a ‘‘concentration-clamp’’ procedure for estimating explicit algebraic relationships between species equilibrating on fast timescales. The primary advantages of this approach over Jacobian-based timescale decomposition are that: 1) it incorporates nonlinear system dynamics,and2)itcanbeeasilyvisualized,evendirectlyfromexperimentaldata.Wetestedthisgraphicalmodelreduction approach using a25-variable model of cardiac b1-adrenergic signaling, obtaining 6- and4-variable reduced models that retaingoodpredictivecapabilitieseveninresponsetonewperturbations.These6signalingspeciesappeartobeoptimal ‘‘kineticbiomarkers’’oftheoverallb1-adrenergicpathway.The6-variablereducedmodeliswellsuitedforintegrationinto multiscalemodelsofheartfunction,andmoregenerally,thisgraphicalmodelreductionapproachisreadilyapplicabletoa varietyofothercomplexbiologicalsystems. Citation:HollandDO,KrainakNC,SaucermanJJ(2011)GraphicalApproachtoModelReductionforNonlinearBiochemicalNetworks.PLoSONE6(8):e23795. doi:10.1371/journal.pone.0023795 Editor:VladimirBrezina,MountSinaiSchoolofMedicine,UnitedStatesofAmerica ReceivedMarch23,2011;AcceptedJuly27,2011;PublishedAugust25,2011 Copyright: ? 2011 Holland et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestric