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Thepersonalitytraitofneuroticismreferstorelativelystabletendenciestorespondwithnegativeemotionstothreat,frustration,orloss.Individualsinthepopulationvarymarkedlyonthistrait,rangingfromfrequentandintenseemotionalreactionstominorchallengestolittleemotionalreactioneveninthefaceofsignificantdifficulties.Althoughnotwidelyappreciated,thereisgrowingevidencethatneuroticismisapsychologicaltraitofprofoundpublichealthsignificance.Neuroticismisarobustcorrelateandpredictorofmanydifferentmentalandphysicaldisorders,comorbidityamongthem,andthefrequencyofmentalandgeneralhealthserviceuse.Indeed,neuroticismapparentlyisapredictorofthequalityandlongevityofourlives.Achievingafullunderstandingofthenatureandoriginsofneuroticism,andthemechanismsthroughwhichneuroticismislinkedtomentalandphysicaldisorders,shouldbeatoppriorityforresearch.Knowingwhyneuroticismpredictssuchawidevarietyofseeminglydiverseoutcomesshouldleadtoimprovedunderstandingofcommonalitiesamongthoseoutcomesandimprovedstrategiesforpreventingthem.
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Intelligenttransportationsystems—Enablingtechnologies
MathematicalandComputerModelling,Volume22,Issues4-7,August-October1995,Pages11-81
A.Garcí
a-Ortiz,S.M.Amin,J.R.Wootton
Abstract
Intelligenttransportationprogramstakemanydifferentnamesthroughouttheworld;
intheUnitedStatesitisITS,inEuropeitisPrometheus,andinJapanitisAMTICSandRACS.Allofthemshareverysimilarobjectives,i.e.,thedevelopmentofadvancedTrafficManagementSystems,TravelerInformationSystems,VehicleControlSystems,CommercialVehicleOperations,PublicTransportationSystems,andRuralTransportationSystems.Severalkeytechnologiesstandtoservethesynthesisofeachandeveryoneoftheseobjectives.Thesetechnologiesare:
DigitalMaps,Computers,PathPlanning,HumanFactors,Sensors,Communications,VehicleControl,andTrafficControl.Thispaperdiscusseseachoneofthesesubjectsinenoughdetailtoprovidethereaderwithanintroductiontoboththetechnologyanditsstate-of-the-art.Inaddition,thepaperdiscussessocio-politico-economicissuesassociatedwiththeimplementationofthevariousprograms.Webelievethatthishighlyneglectedsubjectwillservetotemperthedevelopmentanddeploymentoftheseprograms.
ArticleOutline
•References
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Methodsofinvitrotoxicology
ReviewArticle
FoodandChemicalToxicology,Volume40,Issues2-3,February-March2002,Pages193-236
GEisenbrand,BPool-Zobel,VBaker,MBalls,B.JBlaauboer,ABoobis,ACarere,SKevekordes,J.-CLhuguenot,RPieters,JKleiner
AbstractAbstract|Figures/TablesFigures/Tables|ReferencesReferences
Invitromethodsarecommonandwidelyusedforscreeningandrankingchemicals,andhavealsobeentakenintoaccountsporadicallyforriskassessmentpurposesinthecaseoffoodadditives.However,therangeoffood-associatedcompoundsamenabletoinvitrotoxicologyisconsideredmuchbroader,comprisingnotonlynaturalingredients,includingthosefromfoodpreparation,butalsocompoundsformedendogenouslyafterexposure,permissible/authorisedchemicalsincludingadditives,residues,supplements,chemicalsfromprocessingandpackagingandcontaminants.Amajorpromiseofinvitrosystemsistoobtainmechanism-derivedinformationthatisconsideredpivotalforadequateriskassessment.Thispapercriticallyreviewstheentireprocessofriskassessmentbyinvitrotoxicology,encompassingongoingandfuturedevelopments,withmajoremphasisoncytotoxicity,cellularresponses,toxicokinetics,modelling,metabolism,cancer-relatedendpoints,developmentaltoxicity,predictionofallergenicity,andfinally,developmentandapplicationofbiomarkers.Itdescribesindepththeuseofinvitromethodsinstrategiesforcharacterisingandpredictinghazardstothehuman.Majorweaknessesandstrengthsoftheseassaysystemsareaddressed,togetherwithsomekeyissuesconcerningmajorresearchprioritiestoimprovehazardidentificationandcharacterisationoffood-associatedchemicals.
1.Introduction
2.Invitroassessmentofgeneraltoxicity
2.1.Cytotoxicity
2.1.1.Introduction
2.1.2.Stateoftheart
2.1.2.1.Theuseofcytotoxicitydataasapredictorofacutesystemictoxicity
2.1.2.2.Relevantendpoints
2.1.3.Newdevelopmentsandresearchgaps
2.2.Cellularresponses
2.2.1.Genomics,transcriptomicsandproteomics
2.2.1.1.Introduction
2.2.1.2.Stateoftheart—thetechnologiesofgenomics,transcriptomics,proteomicsandbioinformatics
2.2.1.2.1.Genomicsandtranscriptomics
2.2.1.2.2.DNA/oligonucleotidemicroarrays
2.2.1.2.3.Proteomics
2.2.1.2.4.Bioinformatics
2.2.1.3.Applicationsoftranscriptomicsandproteomicstohazardidentification
2.2.1.3.1.Transcriptomicsappliedtotoxicologicalhazardidentification
2.2.1.3.2.Proteomicsappliedtotoxicologicalhazardidentification
2.2.1.3.3.Transcriptomicsandproteomics—acombinedapproach
2.2.1.4.Challengesandresearchgaps
2.2.1.4.1.Microarraytechnologyandexperimentalprocedures
2.2.1.4.2.Proteomictechnology
2.2.1.4.3.Datahandlingandinterpretation—bioinformatics
2.2.1.4.4.Buildingreferencedatasetsandcorrelationwithclassicendpointsoftoxicity
2.2.1.5.Conclusionsandfuturepriorities
2.2.2.Functionalresponses
2.2.2.1.Introduction
2.2.2.2.Stateoftheart—cellularresponsesasearlymarkersoftoxicity
2.2.2.2.1.Genotoxicity(seesection3.1.2,Genotoxicity)
2.2.2.2.2.Oxidativestressandglutathionehomeostasis
2.2.2.2.3.Calciumregulationandtheendoplasmicreticulum
2.2.2.2.4.Heatshockproteins
2.2.2.2.5.Stress-activatedproteinkinases(SAPKs)
2.2.2.2.6.Metallothioneins
2.2.2.2.7.Adaptiveresponses
2.2.2.3.Conclusionsandfuturepriorities
2.2.3.Perspectivesforusinginvitromethodstoevaluatechronictoxicityofcompounds
2.3.Toxicokineticmodellingandmetabolism
2.3.1.Extrapolationofkineticbehaviourfromtheinvitrototheinvivosituation
2.3.2.Obtainingcompound-specificparametersforPB-TKmodellingfrominvitrostudiesorothernon-animalmodels
2.3.2.1.Absorption
2.3.2.1.1.Tissue–bloodpartitioning
2.3.2.2.Metabolism
3.Theuseofinvitromethodsinstrategiesforcharacterisingandpredictinghazardstothehuman
3.1.Parallelogramapproach
3.2.Integratedteststrategy
3.2.1.Anticipatedexposurelevels
3.2.2.Existingtoxicologicalknowledge
3.2.3.Applicationofdataonphysicochemicalproperties
3.2.4.Toxicokinetics
3.2.5.Basalcytotoxicity
3.2.6.Specifictoxicity
3.2.7.Specificrequirements
4.Endpointsofinvitrotoxicologysystems
4.1.Cancer-relatedendpoints
4.1.1.Introduction
4.1.2.Genotoxicity
4.1.2.1.Introduction
4.1.2.2.Stateoftheart
4.1.2.3.Testingstrategy
4.1.2.4.Testmethods
4.1.2.5.Noveldevelopments
4.1.3.Non-genotoxiccancerendpoints
4.1.3.1.Stateoftheart
4.1.3.1.1.Persistentcytotoxicityaccompaniedbyproliferativeregeneration.
4.1.3.1.2.Chronicinflammation
4.1.3.1.3.Hormones
4.1.3.1.4.Ligandsforxenobioticinductionreceptors
4.1.3.1.5.DNAmethylation
4.1.3.2.Limitations
4.1.3.3.Noveldevelopments
4.1.3.3.1.Developmentofinvitrosystemstodetectcompoundsactingbythemajormechanismsinvolvedinnon-genotoxiccarcinogenesis
4.1.3.4.Conclusion
4.2.Developmentaltoxicity
4.2.1.Introduction
4.2.2.Celllinesandembryonicstemcells
4.2.3.Aggregateandmicromasscultures
4.2.4.Embryosoflowerorderspecies
4.2.5.Avianandmammalianwholeembryoculture
4.2.6.Validation
4.2.7.Futuredevelopments
4.3.Predictionofallergenicity
4.3.1.Introduction
4.3.1.1.BasicsofTcellsensitisation
4.3.2.Stateoftheart
4.3.2.1.Applicabilityandlimitationsofinvitrotesting
4.3.2.2.DetectionofsensitisingpotentialofHMWCinthefood
4.3.3.Futureprospectsforthepremarkethazardidentification
5.Invitroapproachesfordevelopmentofbiomarkers
5.1.Introduction
5.2.Stateoftheartandpotentialroleofinvitrotests
5.2.1.Definitionandrole
5.3.Typesofbiomarkers
5.3.1.Biomarkersofexposure
5.3.1.1.Challengeassaystoassessimpactsofbodyfluidsinmodelcellcultures
5.3.2.Biomarkersofeffect
5.3.2.1.Humantissuesastargetsforbiomarkersandtoidentifynewparametersofeffect
5.3.3.Susceptibilitybiomarkers
5.3.3.1.Studyingtheimpactofhazardouschemicalsonthebasisofsusceptibilityfactors
5.4.Conclusion
6.Generalsummaryandconclusions
6.1.Weaknesses
6.2.Strengths
6.3.Keyfeaturesofinvitrosystems
6.4.Priorityresearchneeds
References
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