Quantitative Analysis of Mechanisms That Govern Red Blood Cell Age Structure and Dynamics during Anaemia 英文参考文献.docVIP

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Quantitative Analysis of Mechanisms That Govern Red Blood Cell Age Structure and Dynamics during Anaemia 英文参考文献.doc

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Quantitative Analysis of Mechanisms That Govern Red Blood Cell Age Structure and Dynamics during Anaemia 英文参考文献

QuantitativeAnalysisofMechanismsThatGovernRed BloodCellAgeStructureandDynamicsduringAnaemia NicholasJ.Savill1*,WilliamChadwick1,2,SarahE.Reece1,2 1CentreforInfectiousDiseases,InstituteofImmunologyandInfectionResearch,UniversityofEdinburgh,Edinburgh,UnitedKingdom,2InstituteofEvolutionaryBiology, UniversityofEdinburgh,Edinburgh,UnitedKingdom Abstract Mathematical modelling has proven an important tool in elucidating and quantifying mechanisms that govern the age structureandpopulationdynamicsofredbloodcells(RBCs).Herewesynthesiseideasfrompreviousexperimentaldataand themathematicalmodellingliteraturewithnewdatainordertotesthypothesesandgeneratenewpredictionsaboutthese mechanisms.Theresultisasetofcompetinghypothesesaboutthreeintrinsicmechanisms:thefeedbackfromcirculating RBCconcentrationtoproductionrateofimmatureRBCs(reticulocytes)inbonemarrow,thereleaseofreticulocytesfrom bonemarrow intothecirculation, andtheir subsequentageingandclearance.Inaddition weexaminetwomechanisms specific to our experimental system: the effect of phenylhydrazine (PHZ) and blood sampling on RBC dynamics. We performedasetofexperimentstoquantifythedynamicsofreticulocyteproportion,RBCconcentration,anderythropoietin concentration in PHZ-induced anaemic mice. By quantifying experimental error we are able to fit and assess each hypothesisagainstourdataandrecoverparameterestimatesusingMarkovchainMonteCarlobasedBayesianinference.We findthat,undernormalconditions,about3%ofreticulocytesarereleasedearlyfrombonemarrowanduponmaturationall cellsarereleasedimmediately.Inthecirculation,RBCsundergorandomclearancebuthaveamaximumlifespanofabout50 days.Underanaemicconditionsreticulocyteproductionrateislinearlycorrelatedwiththedifferencebetweennormaland anaemicRBCconcentrations,andtheirreleaserateisexponentiallycorrelatedwiththesame.PHZappearstoagerather thankillRBCs,andyoungerRBCsareaffectedmorethanolderRBCs.Bloodsamplingcausedshortaperiodicspikesinthe proportionofreticulocyteswhichappeartohaveadifferent