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簡(jiǎn)介：BIODRUGS20082213744NOVELTHERAPEUTICSTRATEGIES11738804/08/00010037/4800/0?2008ADISDATAINFORMATIONBVALLRIGHTSRESERVEDFIBROBLASTGROWTHFACTOR21ASATHERAPEUTICAGENTFORMETABOLICDISEASESALEXEIKHARITONENKOVANDARMENBSHANAFELTBIOTECHOLOGYDISCOVERYRESEARCH,LILLYRESEARCHLABORATORIES,LILLYCORPORATECENTER,INDIANAPOLIS,INDIANA,USACONTENTSABSTRACT371THEROLEOFFIBROBLASTGROWTHFACTORSFGFSINTHEREGULATIONOFMETABOLICPROCESSES372OVERVIEWOFFGF21ANDITSINVITROEFFECTS383FGF21INVIVOPHARMACOLOGY394INSIGHTSINTOFGF21MECHANISMOFACTION405CONCLUSION43FIBROBLASTGROWTHFACTORFGF21ISAUNIQUEMEMBEROFTHEFGFFAMILY,WITHSEVERALMOLECULARCHARACTERISABSTRACTTICSTHATDIFFERFROMCLASSICALFGFSANDEXHIBITINGAPHARMACOLOGICPROFILETHATINCLUDESAVARIETYOFMETABOLICRESPONSESINVITROANDWHENTESTEDINVIVOINANIMALMODELSFGF21REPRESENTSANOVELANDATTRACTIVETHERAPEUTICAGENTFORTYPE2DIABETESMELLITUS,BECAUSEOFITSABILITYTOMODULATEDISEASEPHENOTYPEINPRECLINICALSETTINGSWITHOUTINDUCINGANYAPPARENTADVERSEEFFECTSALTHOUGHFGF21WASDISCOVEREDRELATIVELYRECENTLY,THEUNDERSTANDINGOFITSBIOLOGYANDTHERAPEUTICUTILITYISRAPIDLYEVOLVINGANUMBEROFKEYMETABOLICALLYLINKEDMOLECULESANDPATHWAYSHAVEBEENSUGGESTEDTOBEINVOLVEDINTHEMECHANISMOFACTIONOFFGF21,DEPENDINGONTHESPECIFICTARGETTISSUE/ORGANFURTHERRESEARCHINTOTHESEMECHANISMSSHOULDLEADTOIMPORTANTADVANCESINTHEUNDERSTANDINGOFFGF21BIOLOGYANDPAVETHEWAYFORNOVELTHERAPEUTICSTRATEGIESTHESPECIFICSOFFGF21ACTIVITIESBOTHINCELLCULTUREANDINVIVO,ITSPOTENTIALASATARGETFORDIABETES,ANDINSIGHTSINTOTHEMOLECULARMECHANISMSOFFGF21METABOLICACTIONSWILLBEDISCUSSEDINTHISREVIEW1THEROLEOFFIBROBLASTGROWTHFACTORSFGFSINRODENTS,RESPECTIVELY8,9WHENTESTEDINMICE,FGF19PROVIDESTHEREGULATIONOFMETABOLICPROCESSESRESISTANCETOOBESITYANDINSULINDESENSITIZATION10,11ANOTHERMEMBEROFTHEFGFFAMILY,FGF23,ISAKEYPLAYERINTHEREGULAFIBROBLASTGROWTHFACTORSFGFSANDTHEIRCORRESPONDINGRETIONOFPHOSPHATEANDCALCIUMMETABOLISM12,13LIKEWISE,THECEPTORSFGFRSHAVEBEENPRIMARILYASSOCIATEDWITHTHEPROCESSESOFDEVELOPMENT,TRANSFORMATION,ANDANGIOGENESIS14HOWOVEREXPRESSIONOFADOMINANTNEGATIVEFORMOFFGFR1INPANCREEVER,OVERTHELASTDECADE,NEWDATAHAVEEMERGEDSHOWINGTHATATICΒCELLSLEADSTODIABETESMELLITUSINMICE14FGFR2APPEARSTOFGF/FGFRMEDIATEDPATHWAYSMAYPLAYIMPORTANTROLESINDEFINBEAKEYMOLECULEINTHEPROCESSOFPANCREATICDEVELOPMENT1517INGANDREGULATINGFUNCTIONSOFENDOCRINERELEVANTTISSUESANDFGFR3ISACRITICALPLAYERINBONE,18WHEREASFGFR4HASBEENORGANS,ASWELLASMODULATINGVARIOUSMETABOLICPROCESSESFORIMPLICATEDINCHOLESTEROLMETABOLISMANDBILEACIDSYNTHESIS19EXAMPLE,FGF10ANDFGF16PLAYIMPORTANTROLESINADIPOCYTEANDTHEMETABOLICROLESOFFGF/FGFRARESTILLNOTPRECISELYDEFINEDPANCREATICBIOLOGY,57ANDFGF19ANDITSMOUSEORTHOLOGFGF15,REGULATECHOLESTEROLANDBILEACIDMETABOLISMINHUMANSANDANDARECURRENTLYUNDERINTENSEINVESTIGATIONFGF21ANDMETABOLICDISEASES39INDUCESUPREGULATIONOFPPARΓPROTEINALTHOUGHITISCURRENTLYINCIDENCEOFHEPATOCELLULARCARCINOMASINFGF21TRANSGENICMICEUNCLEARWHATPARTICULARIMPACTEACHOFTHESEEFFECTSHASONGLUCOSEAT12MONTHSOFAGEWASSIMILARTOTHATINCONTROLANIMALSTHUS,IFTRANSPORT,THESEDATAREVEALPOTENTIALSYNERGYINTHEACTIONSBEFGF21NEGATIVELYREGULATESCHEMICALLYINDUCEDHEPATOCARCITWEENTHESETWOREGULATORSOFGLUCOSEHOMEOSTASIS,FGF21ANDNOGENESIS,ITISLIKELYTOINTERFEREWITHDISEASEPROGRESSIONATITSPPARΓ31EARLYSTAGES24RECENTLY,ANOTHERLINEOFFGF21TRANSGENICMICEONAC57BL/6JBACKGROUNDHASBEENDESCRIBED26THESEANIMALSHAD50–1503FGF21INVIVOPHARMACOLOGYTIMESHIGHERLEVELSOFFGF21MRNAINTHELIVERTHANCONTROLANIMALS,ANDHADLOWEREDLEVELSOFSERUMCHOLESTEROL,TRITHEINVIVOBIOACTIVITYOFFGF21HASBEENOBSERVEDUSINGGLYCERIDES,GLUCOSEANDINSULININDICATIVEOFTHEIMPROVEDLIPIDNUMEROUSBIOMARKERSTHATILLUSTRATETHEEFFECTSOFFGF21ACTIONSANDGLYCEMICMETABOLISM,ANDAMELIORATEDINSULINRESISTANCE,INABROADRANGEOFANIMALSTUDIESCOVERINGAVARIETYOFDISEASECONSISTENTWITHPREVIOUSLYPUBLISHEDDATA20FGF21TRANSGENICMODELS20,2326,35MICEWEREALSOFOUNDTOHAVEELEVATEDSERUMLEVELSOFΒHYDROXYTHECONSEQUENCESOFENFORCEDEXPRESSIONOFHUMAN20ANDBUTYRATE,SUGGESTINGTHEINDUCTIONOFKETOGENESIS,ASWELLASHAVMOUSEFGF2123,26HAVEBEENEVALUATEDINTRANSGENICMICE20,24,26INGADIPOCYTESOFSMALLERSIZE,INCREASEDLIPASEEXPRESSIONINWHITEFGF21TRANSGENICANIMALSAPPEARVIABLE,NORMALATBIRTH,ANDADIPOSETISSUEANDELEVATEDSERUMLEVELSOFFREEFATTYACIDS,ALLESSENTIALLYINDISTINGUISHABLEFROMTHEIRWILDTYPELITTERMATESNOEVOCATIVEOFTHEINDUCTIONOFLYPOLYSIS26IMPORTANTLY,ASURINETICEABLY,THEYDONOTPOSSESSSIGNSOFNEOPLASIA,TUMORS,ORANYCONCENTRATIONSOFADRENALINEANDNORADRENALINEWEREREDUCEDINOTHEROVERTABNORMALITIESTHROUGHOUTTHEIRLIFESPAN,ASDEMONSTRAFGF21TRANSGENICANIMALS,FGF21DOESNOTAPPEARTOSTIMULATETEDBYEXTENSIVEMORPHOLOGICANDHISTOLOGICANALYSES20,23THUS,LIPOLYSISTHROUGHASYSTEMICINCREASEINCATECHOLAMINES26SURPROLONGEDEXPOSUREOFMICETOFGF21DOESNOTLEADTOCARCINOGENPRISINGLY,THESEFGF21TRANSGENICMICEWEREALSOREPORTEDTOHAVEICEVENTSNEVERTHELESS,ASPECIFICPHENOTYPEOFFGF21TRANSGENIC1–2oCLOWERCOREBODYTEMPERATURES,REDUCEDLOCOMOTORACTIVITY,MICEWASREVEALEDUPONAVARIETYOFCHALLENGESANDENHANCEDTORPORDURING24HOURFASTINGCOMPAREDWITHTHEIRC57BL/6MICEOVEREXPRESSINGHUMANFGF21FROMTHELIVERCONTROLLITTERMATES26ALTHOUGHINTRIGUING,THELATTEROBSERVATIONSCIRCULATINGLEVELSOF70–150N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簡(jiǎn)介：CEFOSELISCFSL,AFOURTHGENERATIONPARENTERALCEPHALOSPORIN,HASBEENMARKETEDINJAPANSINCESEPTEMBER1998INDECEMBER1998,WARNINGSOFCENTRALNERVOUSSYSTEMCNSADVERSEEFFECTSSUCHASSEIZURESANDCONFUSIONALSTATESWEREADDEDTOTHELABELINGOFCFSLINMANYCASES,THESEADVERSEEFFECTSWEREOBSERVEDINPATIENTSWHOWEREELDERLYAND/ORHADRENALFAILURETHEREFORERENALFAILUREISCONSIDEREDASONEOFTHERISKFACTORSFORNEUROTOXICITYOFCFSLSINCECFSLISMAINLYELIMINATEDBYRENALEXCRETION,1RENALFAILUREWOULDBEASSOCIATEDWITHINCREASEDSERUMCONCENTRATIONSOFCFSLONTHEOTHERHAND,ITISSTILLUNKNOWNWHETHERRENALFAILURECANALTERTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESDRUGADMINISTRATIONCANBEDIVIDEDINTOTWOPHASESAPHARMACOKINETICPHASEINWHICHDOSE,DOSAGEFORM,FREQUENCY,ANDROUTEOFADMINISTRATIONARERELATEDTODRUGCONCENTRATION–TIMERELATIONSHIPSINTHEBODYANDAPHARMACODYNAMICPHASEINWHICHTHECONCENTRATIONOFDRUGATTHESITESOFACTIONISRELATEDTOTHEMAGNITUDESOFTHEEFFECTSPRODUCED2THEPATHOPHYSIOLOGICSTATUSOFPATIENTSCANAFFECTBOTHTHEPHARMACOKINETICSANDTHEPHARMACODYNAMICSOFADRUGOURKNOWLEDGEOFTHEEFFECTSOFDISEASEONTHEPHARMACOKINETICSOFADRUGCANNOTBEUSEDTOOPTIMIZETHEDRUGDOSAGEOFAPATIENTWITHOUTINFORMATIONONDISEASEEFFECTSONTHEPHARMACODYNAMICS3THEREFOREITISIMPORTANTTODISTINGUISHTHEEFFECTSOFDISEASEONTHEPHARMACOKINETICSFROMTHOSEONTHEPHARMACODYNAMICSDANHOFANDLEVY3REPORTEDANEXPERIMENTALSTRATEGYTOASSESSTHEEFFECTSOFDISEASEANDOTHERVARIABLESONTHEPHARMACODYNAMICSOFDRUGSWITHCNSACTIVITYTHEEFFECTSOFEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCNSSTIMULANTDRUGSSUCHASTHEOPHYLLINE,4PENTYLENTETRAZOLE,5ANDCIMETIDINE6WEREINVESTIGATEDPREVIOUSLYTHEREHAVEBEENCLINICALCASEREPORTSOFSEIZURESCAUSEDBYVARIOUSBLACTAMANTIBIOTICSSUCHASPENICILLIN,7CEFAZOLINE,8AMPICILLIN,9ANDIMIPENEM10HOWEVER,TOOURKNOWLEDGE,THEREHAVEBEENNOREPORTSTHATCLARIFIEDTHEEFFECTOFRENALFAILUREONTHEPHARMACODYNAMICSOFBLACTAMANTIBIOTICINDUCEDSEIZURESTOASSURESAFEANDEFFECTIVEANTIBIOTICDRUGTHERAPY,ITMUSTBEDETERMINEDIFRENALFAILURECANCHANGETHERELATIONSHIPBETWEENTHECONCENTRATIONANDINTENSITYOFPHARMACOLOGICACTIVITYOFDRUGSTHEPRESENTSTUDYWASDESIGNEDTODETERMINE1THESUITABILITYOFTHERATASANANIMALMODELOFCFSLINDUCEDSEIZURES2THESAMPLINGSITEWHERECFSLCONCENTRATIONSREFLECTTHEDRUGCONCENTRATIONATTHESITEOFNEUROTOXICACTIONAND3THEEFFECTOFRENALFAILUREONTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESMATERIALSANDMETHODSANIMALSMALEWISTARRATSWEIGHING240TO300GWEREUSEDINTHISINVESTIGATIONTHERATSHADANINDWELLINGCANNULAIMPLANTEDINTHELEFTJUGLARVEINUNDERLIGHTETHERANESTHESIAONEDAYBEFORETHEEXPERIMENTANDTHEYWEREFASTEDUNTILTHECFSLINFUSIONBEGANCHEMICALSCFSLSULFATEWINCEF?FORINFUSIONUSEDFORANIMALEXPERIMENTSWASOBTAINEDFROMFUJISAWAPHARMACEUTICALCO,LTDCEFPIROMESULFATEBROACT?INJECTIONUSEDASANINTERNALSTANDARDWASOBTAINEDFROMSHIONOGICO,LTDALLOTHERCHEMICALSWEREPURCHASEDFROMCOMMERCIALSOURCESANDUSEDWITHOUTFURTHERPURIFICATIONEFFECTOFINFUSIONRATEONTHECONCENTRATIONSOFCFSLINSERUM,BRAIN,ANDCSFATONSETOFMAXIMALSEIZURESCFSLWASINFUSEDTHROUGHTHECANNULAATONEOFTHREEDIFFERENTRATES14,29,OR58G/HINRATSTHEINFUSIONWASSTOPPEDIMMEDIATELYATTHEONSETOFMAXIMALSEIZURESTHERATSWERETHENLIGHTLYANESTHETIZEDWITHETHER,ANDSAMPLESOFCSF,BLOOD,ANDBRAINWEREOBTAINED,INTHATORDERCSFWASOBTAINEDBYCISTERNALPUNCTUREBLOODWASOBTAINEDFROMTHEABDOMINALAORTAANDCENTRIFUGEDTOOBTAINSERUMTHEWHOLEBRAINWASREMOVEDANDTHERIGHTHALFOFTHECEREBRUMWASUSEDFORDRUGASSAYSEPTEMBER2001BIOLPHARMBULL2491049105220011049?TOWHOMCORRESPONDENCESHOULDBEADDRESSEDEMAILYASUHARAMPHAMEDTMDACJP?2001PHARMACEUTICALSOCIETYOFJAPANEFFECTOFEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCEFOSELISINDUCEDSEIZURESINRATSMASASHINAGATAANDMASATOYASUHARADEPARTMENTOFHOSPITALPHARMACY,SCHOOLOFMEDICINE,TOKYOMEDICALANDDENTALUNIVERSITY,1–5–45YUSHIMA,BUNKYOKU,TOKYO113–8519,JAPANRECEIVEDAPRIL17,2001ACCEPTEDJUNE12,2001WEINVESTIGATEDTHEEFFECTOFINFUSIONRATEANDEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCEFOSELISCFSLINDUCEDSEIZURESASANANIMALMODELOFCFSLINDUCEDSEIZURES,MALEWISTARRATSRECEIVEDANINTRAVENOUSINFUSIONOFCFSLATONEOFTHREEDIFFERENTRATES1458G/H/RATUNTILTHEONSETOFMAXIMALSEIZURESWHICHOCCURREDAFTER80TO360MINOFINFUSIONSAMPLESOFCEREBROSPINALFLUIDCSF,BLOODFORSERUM,ANDBRAINWEREOBTAINEDIMMEDIATELYAFTERSTOPPINGINFUSIONOFCSFLTHESERUMCONCENTRATIONOFCFSLATTHEONSETOFSEIZURESINCREASEDWITHINCREASINGINFUSIONRATE,BUTBRAINANDCSFCONCENTRATIONSOFCFSLATTHEONSETOFSEIZURESWERENOTAFFECTEDBYTHEINFUSIONRATEURETERLIGATEDULANDCONTROLRATSRECEIVEDANINTRAVENOUSINFUSIONOFCFSLAT14G/H/RATUNTILTHEONSETOFSEIZURESTHENTHESAMEPROCEDUREASUSEDTODETERMINETHEEFFECTOFINFUSIONRATEONTHECONCENTRATIONSOFCFSLWASCARRIEDOUTRENALFAILUREWASASSOCIATEDWITHASIGNIFICANTDECREASEINTHEAMOUNTOFCFSLREQUIREDTOINDUCESEIZURESSERUM,BRAIN,ANDCSFCONCENTRATIONSOFCFSLINULRATSWERESIGNIFICANTLYLOWERTHANTHOSEINCONTROLRATSTHESERESULTSINDICATETHATTHEEXPERIMENTALSTRATEGYANDANIMALMODELINTHISINVESTIGATIONWOULDBEUSEFULTOASSESSTHEEFFECTSOFDISEASESANDOTHERVARIABLESONTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESANDTHATRENALFAILUREISONEOFTHERISKFACTORSFORNEUROTOXICITYOFCFSLKEYWORDSCEFOSELISRENALFAILURESEIZUREPHARMACODYNAMICSDISCUSSIONDRUGSTHATACTDIRECTLYANDREVERSIBLY,HAVENOPHARMACOLOGICALLYACTIVEMETABOLITES,ANDARENOTSUBJECTTOTHEDEVELOPMENTOFACUTETOLERANCEMAYBEEXPECTEDTOPRODUCETHEIRAPPARENTPHARMACOLOGICEFFECTSWHENTHEIRCONCENTRATIONSATTHESITEOFACTIONREACHANDEXCEEDTHEMINIMUMEFFECTIVECONCENTRATIONWENEEDTODETERMINETHESAMPLINGSITETHATREFLECTSDRUGCONCENTRATIONSINTHESITEOFACTIONBECAUSEITISTECHNICALLYIMPOSSIBLETOMEASUREDRUGCONCENTRATIONSINTHEIMMEDIATEENVIRONMENTOFTHESITEOFACTIONFORTHISPURPOSE,THEDRUGISADMINISTEREDBYCONSTANTRATEINTRAVENOUSINFUSIONATDIFFERENTRATESUNTILTHEONSETOFASUITABLEPHARMACOLOGICENDPOINTANDDRUGCONCENTRATIONINVARIOUSFLUIDSANDTISSUESSERUM,BRAIN,ANDCSFATTHATTIMEAREDETERMINEDSITESATWHICHTHEDRUGCONCENTRATIONATTHEONSETOFACTIONISDEPENDENTONINFUSIONRATETHECONCENTRATIONTENDSTOINCREASEWITHINCREASINGINFUSIONRATECANBECONSIDEREDTOBEINSLOWEQUILIBRIUMWITHTHESITEOFACTIONANYFLUIDORTISSUETHATYIELDSTHESAMEDRUGCONCENTRATIONATONSETOFACTION,INDEPENDENTOFTHERATEOFDRUGADMINISTRATION,MUSTBECONSIDEREDASBEINGIN“INSTANTANEOUS”DISTRIBUTIONEQUILIBRIUMWITHTHESITEOFACTION3THERESULTSOFTHISSTUDYSHOWTHATCFSLCONCENTRATIONINTHESERUMATTHEONSETOFMAXIMALSEIZURESISSIGNIFICANTLYAFFECTEDBYTHERATEOFDRUGINFUSION,WHEREASCFSLCONCENTRATIONSINTHEBRAINANDCSFATTHEPHARMACOLOGICENDPOINTAREINDEPENDENTOFINFUSIONRATETHESERESULTSSUGGESTTHATCFSLEQUILIBRATESSLOWLYBETWEENSERUMANDTHESITEOFACTION,ANDDRUGCONCENTRATIONSINTHEBRAINANDCSFAREMOREAPPROPRIATEINDICESOFTHEDRUGCONCENTRATIONINTHESITEOFACTIONWEALSOINVESTIGATEDTHEEFFECTOFEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESINRATSINTHEPRESENTSTUDY,RENALFAILUREWASASSOCIATEDWITHASIGNIFICANTDECREASEINTHEAMOUNTOFCFSLREQUIREDTOINDUCESEIZURESTHISRESULTSUGGESTSTHATRENALFAILUREISONEOFTHERISKFACTORSFORCFSLINDUCEDSEIZURES,ANDTHISISCONSISTENTWITHRECENTCLINICALFINDINGSOFAHIGHERINCIDENCEOFCFSLINDUCEDNEUROTOXICITYINPATIENTSWITHRENALFAILURE11INADDITION,SERUM,BRAIN,ANDCSFCONCENTRATIONSOFCFSLINULRATSWERESIGNIFICANTLYLOWERTHANTHOSEINCONTROLRATSTHISINDICATESTHATRENALFAILUREISASSOCIATEDWITHCHANGESINTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESRENALFAILURECOULDCHANGETHEPHARMACOKINETICSOFCFSLBECAUSECFSLISMAINLYELIMINATEDBYRENALEXCRETION1THEPERMEABILITYOFTHEBLOODCSFBARRIERMAYBEINCREASEDASREFLECTEDBYINCREASEDPROTEINCONCENTRATIONINTHECSFIFRENALFAILUREAFFECTEDONLYTHEPHARMACOKINETICSOFCFSLAND/ORTHEPERMEABILITYOFCFSLATTHEBLOODCSFBARRIER,THEREWOULDBENODIFFERENCESINTHECFSLCONCENTRATIONINTHEBRAINANDCSFATTHEONSETOFSEIZURESBETWEENCONTROLANDULRATSINTHISSTUDY,HOWEVER,ULRATSHADLOWERBRAINANDCSFCONCENTRATIONSOFCFSLATTHEONSETOFSEIZURESCOMPAREDWITHTHECORRESPONDINGRESULTSINCONTROLRATSTHISINDICATESTHATTHECAUSEOFTHECHANGEINDRUGEFFECTWITHRENALFAILUREISNOTONLYTHEDELAYINCFSLELIMINATIONANDTHEINCREASEDPERMEABILITYOFCFSLATTHEBLOODCSFBARRIERBUTALSOTHEINCREASEDCNSSENSITIVITYTOCFSLINDUCEDSEIZURESTHEEFFECTSOFEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFOTHERCNSACTIVEDRUGSWEREINVESTIGATEDPREVIOUSLY46,12,13RAMZANANDLEVY4REPORTEDTHATTHETHEOPHYLLINECONCENTRATIONSINTHESERUM,BRAIN,ANDCSFATTHEONSETOFMAXIMALSEIZURESINRATSWITHRENALFAILUREBYURETERLIGATIONWERELOWERTHANTHOSEINCONTROLRATSHOFFMANANDLEVY14REPORTEDTHATTHEPOTENTIATIONOFTHECONVULSIVEEFFECTOFTHEOPHYLINEINRATSWITHRENALFAILUREWASCOUNTERACTEDBYORALADMINISTRATIONOFACTIVATEDCHARCOALTHATPRESUMABLYINTERRUPTSTHECYCLINGOFTHEENDOGENOUSSUBSTANCESBETWEENBLOODANDTHEGASTROINTESTINALTRACTTHESEINDICATETHATCHANGESINDRUGEFFECTSUNDERRENALIMPAIRMENTMAYBEDUETO,ATLEASTINPART,ANINCREASEINLEVELSOFONEORMOREENDOGENOUSSUBSTANCESTHATALTERTHEPHARMACOLOGICALEFFECTSOFCERTAINDRUGSINUREMICRATSTHEUREMICBLOODAPPARENTLYCONTAINSELEVATEDCONCENTRATIONSOFONEORMOREENDOGENOUSSUBSTANCES,THESOCALLEDUREMICTOXINS,ANDTHESERETAINEDSUBSTANCESPROBABLYPLAYAMAJORROLEASTOXINSINTHEPATHOGENESISOFUREMIA,EITHERWORKINGSINGLYORINCOMBINATION15GUANIDINOCOMPOUNDSAREBELIEVEDTOBETOXICAGENTSINPATIENTSWITHRENALINSUFFICIENCYGAMMAGUANIDINOBUTYRICACIDWASSHOWNTOINDUCETONICANDCLONICSEIZURESFOLLOWINGINTRACISTERNALINJECTIONINRABBITS16DEDEYNETALREPORTEDTHATGUANIDINOCOMPOUNDSWEREFOUNDTOBEINCREASEDINTHESERUMANDCSFOFUREMICPATIENTS17ANDGUANIDINOSUCCINICACIDINDUCEDBEHAVIORALCONVULSIONSAFTERINTRAPERITONEALINJECTIONINMICE18INADDITION,FOURGUANIDINOCOMPOUNDSGUANIDINOSUCCINICACID,CREATININE,GUANIDINE,ANDMETHYLGUANIDINEWERESHOWNTOINHIBITGAMMAAMINOBUTYRICACIDANDGLYCINERESPONSESONMOUSENEURONSINCELLCULTURE19THESESUGGESTTHATGUANIDINOCOMPOUNDSCANCONTRIBUTETOINCREASEDNEUROTOXICACTIONOFCERTAINDRUGSINUREMIAWEUSEDULRATSASAMODELOFRENALFAILUREINTHISSTUDYRAMZANANDLEVY5REPORTEDTHATTHEEFFECTOFIMPAIREDRENALFUNCTIONONTHECONVULSANTACTIVITYOFPENTYLENTETRAZOLINULRATSWASDIFFERENTFROMTHATINURANYLNITRATETREATEDRATSFURTHERINVESTIGATIONUSINGMORETHANONEEXPERIMENTALMODELOFDISEASEISTHUSWARRANTEDINCONCLUSION,RENALFAILUREISASSOCIATEDWITHINCREASEDCNSSENSITIVITYTOCFSLINDUCEDSEIZURES,ANDTHEEXPERIMENTALSTRATEGYANDANIMALMODELINTHISINVESTIGATIONWOULDBEUSEFULTOASSESSTHEEFFECTSOFDISEASEANDOTHERVARIABLESONTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESACKNOWLEDGMENTTHISWORKWASSUPPORTEDINPARTBYAGRANTINAIDFORSCIENTIFICRESEARCHCFROMTHEJAPANSOCIETYFORTHEPROMOTIONOFSCIENCEREFERENCES1SAKAMOTOH,HATANOK,HIGASHIY,MINEY,NAKAMOTOS,TAWARAS,KAMIMURAT,JANTIBIOT,46,1201301

簡(jiǎn)介：中文中文2845字出處出處CONTROLENGINEERINGPRACTICE,2000,83253258畢業(yè)設(shè)計(jì)（論文）畢業(yè)設(shè)計(jì)（論文）譯文及原稿譯文題目基于接收機(jī)的一種新差分GPS修正原稿題目ANEWMETHODOFGENERATINGDIFFERENTIALGPSCORRECTIONS原稿出處WWWELSEVIERCOM/LOCATE/CONENGPRAC圖1圖2GPS提供經(jīng)度，緯度，高度，時(shí)間，航線，和速度。GPS的水平精度是近100米至156米高度，時(shí)間為340納秒在世界任何地方和任何天氣條件下。

簡(jiǎn)介：附錄附錄一外文原文TEMPERATURECONTROLUSINGAMICROCONTROLLERANINTERDISCIPLINARYUNDERGRADUATEENGINEERINGDESIGNPROJECTJAMESSMCDONALDDEPARTMENTOFENGINEERINGSCIENCETRINITYUNIVERSITYSANANTONIO,TX78212ABSTRACTTHISPAPERDESCRIBESANINTERDISCIPLINARYDESIGNPROJECTWHICHWASDONEUNDERTHEAUTHOR’SSUPERVISIONBYAGROUPOFFOURSENIORSTUDENTSINTHEDEPARTMENTOFENGINEERINGSCIENCEATTRINITYUNIVERSITYTHEOBJECTIVEOFTHEPROJECTWASTODEVELOPATEMPERATURECONTROLSYSTEMFORANAIRFILLEDCHAMBERTHESYSTEMWASTOALLOWENTRYOFADESIREDCHAMBERTEMPERATUREINAPRESCRIBEDRANGEANDTOEXHIBITOVERSHOOTANDSTEADYSTATETEMPERATUREERROROFLESSTHAN1DEGREEKELVININTHEACTUALCHAMBERTEMPERATURESTEPRESPONSETHEDETAILSOFTHEDESIGNDEVELOPEDBYTHISGROUPOFSTUDENTS,BASEDONAMOTOROLAMC68HC05FAMILYMICROCONTROLLER,AREDESCRIBEDTHEPEDAGOGICALVALUEOFTHEPROBLEMISALSODISCUSSEDTHROUGHADESCRIPTIONOFSOMEOFTHEKEYSTEPSINTHEDESIGNPROCESSITISSHOWNTHATTHESOLUTIONREQUIRESBROADKNOWLEDGEDRAWNFROMSEVERALENGINEERINGDISCIPLINESINCLUDINGELECTRICAL,MECHANICAL,ANDCONTROLSYSTEMSENGINEERING1INTRODUCTIONTHEDESIGNPROJECTWHICHISTHESUBJECTOFTHISPAPERORIGINATEDFROMAREALWORLDAPPLICATIONAPROTOTYPEOFAMICROSCOPESLIDEDRYERHADBEENDEVELOPEDAROUNDANOMEGATMMODELCN390TEMPERATURECONTROLLER,ANDTHEOBJECTIVEWASTODEVELOPACUSTOMTEMPERATURECONTROLSYSTEMTOREPLACETHEOMEGASYSTEMTHEMOTIVATIONWASTHATACUSTOMCONTROLLERTARGETEDSPECIFICALLYFORTHEAPPLICATIONSHOULDBEABLETO2PROBLEMSTATEMENTTHEBASICIDEAOFTHEPROJECTISTOREPLACETHERELEVANTPARTSOFTHEFUNCTIONALITYOFANOMEGACN390TEMPERATURECONTROLLERUSINGACUSTOMDESIGNEDSYSTEMTHEAPPLICATIONDICTATESTHATTEMPERATURESETTINGSAREUSUALLYKEPTCONSTANTFORLONGPERIODSOFTIME,BUTIT’SNONETHELESSIMPORTANTTHATSTEPCHANGESBETRACKEDINA“REASONABLE”MANNERTHUSTHEMAINREQUIREMENTSBOILDOWNTOALLOWINGACHAMBERTEMPERATURESETPOINTTOBEENTERED,DISPLAYINGBOTHSETPOINTANDACTUALTEMPERATURES,ANDTRACKINGSTEPCHANGESINSETPOINTTEMPERATUREWITHACCEPTABLERISETIME,STEADYSTATEERROR,ANDOVERSHOOTALTHOUGHNOTEXPLICITLYAPARTOFTHESPECIFICATIONSINTABLE1,ITWASCLEARTHATTHECUSTOMERDESIREDDIGITALDISPLAYSOFSETPOINTANDACTUALTEMPERATURES,ANDTHATSETPOINTTEMPERATUREENTRYSHOULDBEDIGITALASWELLASOPPOSEDTO,SAY,THROUGHAPOTENTIOMETERSETTING3SYSTEMDESIGNTHEREQUIREMENTSFORDIGITALTEMPERATUREDISPLAYSANDSETPOINTENTRYALONEAREENOUGHTODICTATETHATAMICROCONTROLLERBASEDDESIGNISLIKELYTHEMOSTAPPROPRIATEFIGURE2SHOWSABLOCKDIAGRAMOFTHESTUDENTS’DESIGN

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簡(jiǎn)介：畢業(yè)設(shè)計(jì)（論文）外文文獻(xiàn)譯文及原文學(xué)生生王波波王波波學(xué)號(hào)號(hào)200705010322200705010322院（系）（系）機(jī)電工程學(xué)院機(jī)電工程學(xué)院專業(yè)業(yè)機(jī)械設(shè)計(jì)制造及其自動(dòng)化機(jī)械設(shè)計(jì)制造及其自動(dòng)化指導(dǎo)教師指導(dǎo)教師周明貴周明貴2011年5月20日2SHIMBO報(bào)道,在典型的結(jié)構(gòu)成型工藝另一種微孔發(fā)泡過(guò)程中注塑機(jī)，使用了一個(gè)預(yù)塑式注塑機(jī)被用來(lái)塑化螺柱塞聚合物,是用來(lái)注入聚合物進(jìn)入模具腔,另一個(gè)替代方案泡沫注射成型工藝是在發(fā)達(dá)的德國(guó)亞琛的一個(gè)系統(tǒng),在這個(gè)系統(tǒng)中,氣體注射在一個(gè)特別設(shè)計(jì)的噴油嘴，它安裝在塑化單元之間的，可對(duì)噴嘴關(guān)閉的常規(guī)射出成型機(jī)。此外,它達(dá)到更好的分散性之氣,靜態(tài)混合元素被安裝之間的氣體噴油嘴和關(guān)閉噴嘴。這項(xiàng)技術(shù)后來(lái)為商業(yè)化專利。在2006年,有人提出了一個(gè)結(jié)構(gòu),經(jīng)過(guò)在先進(jìn)的高慶宇發(fā)泡成型技術(shù)的基礎(chǔ)上,預(yù)塑式注射機(jī)傳統(tǒng)的結(jié)構(gòu)發(fā)泡技術(shù)這樣就提高了注入氣體會(huì)完全溶解在聚合物。由一個(gè)強(qiáng)化技術(shù)的齒輪油泵及附加蓄能器使聚合物/氣體混合物形成一步連續(xù)不斷的成型操作。換句話說(shuō),更新的設(shè)計(jì)完全解耦,氣體溶解步驟的注塑操作使用一個(gè)主驅(qū)動(dòng)泵。這一先進(jìn)的結(jié)構(gòu)發(fā)泡的細(xì)節(jié)技術(shù)概述在下一節(jié)。3先進(jìn)的成型結(jié)構(gòu)先進(jìn)的成型機(jī)。經(jīng)過(guò)先進(jìn)的發(fā)泡成型機(jī)器這種技術(shù)促進(jìn)統(tǒng)一的氣體色散和完整或?qū)嵸|(zhì)溶解在聚合物熔體,盡管是穩(wěn)定成型工藝。但是它認(rèn)識(shí)到連續(xù)成型行為不可避免地引起不一致的氣體充填、這種結(jié)構(gòu)使得流動(dòng)但是聚合物熔體和天然氣是連續(xù)的即不停止在注射時(shí)期。圖1圖2

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簡(jiǎn)介：1本科畢業(yè)論文外文翻譯外文題目EXPORTSOFHIGHTECHNOLOGYPRODUCTSFROMDEVELOPINGCOUNTRIESISITREALORASTATISTICALARTIFACT出處2000UNU/INTECH,DISCUSSIONPAPERS作者SUNILMANI原文EXPORTSOFHIGHTECHNOLOGYPRODUCTSFROMDEVELOPINGCOUNTRIESISITREALORASTATISTICALARTIFACTSUNILMANIMAY2000ABSTRACTTHISPAPERFIRSTDEVELOPSACONSISTENTTIMESERIESDATAONTHEEXPORTSOFHIGHTECHNOLOGYPRODUCTSFROMESSENTIALLYTHEDEVELOPINGCOUNTRIESANANALYSISOFTHEDATASHOWSTHATDEVELOPINGCOUNTRIESAREINCREASINGLYBECOMINGEXPORTERSOFMANUFACTUREDPRODUCTSASAGAINSTPRIMARYPRODUCTSINTHEPASTSECONDTHEWORLDTRADEISINCREASINGLYBECOMINGATRADEINHIGHTECHPRODUCTSWHATISMORESTRIKINGISTHESIGNIFICANTINCREASEOFTHETECHNOLOGYCONTENTOFEXPORTSBYDEVELOPINGCOUNTRIESVERYNEARLYAQUARTEROFTHEEXPORTSFROMDEVELOPINGCOUNTRIESISNOWINHIGHTECHPRODUCTSTHIRD,THESHAREOFDEVELOPINGCOUNTRIESINHIGHTECHEXPORTSHAVESHOWNDRAMATICINCREASESITHASINCREASEDFROMABOUT8PERCENTIN1988TOABOUT23PERCENTBY1997BUTTHEREISCONSIDERABLECONCENTRATIONOFITINAFEWCOUNTRIESTHEPAPERTHENSEEKSTOEXPLAINWHETHERTHESEDEVELOPINGCOUNTRIESAREREALEXPORTERSOFHIGHTECHPRODUCTSORNOTTHISISACCOMPLISHEDBYACAREFULEXAMINATIONOFTHEDEGREEOFPRODUCTSPECIALISATIONBYBOTHDEVELOPEDANDDEVELOPINGCOUNTRIES,BYEXAMININGTHEIRRECORDWITHRESPECTTOPATENTINGANDFINALLYBYANALYSINGCERTAININDICATORSOFHIGHTECHCOMPETITIVENESSTHEPAPERCONCLUDESBYPRESENTINGACASESTUDYOFALEADINGHIGHTECHEXPORTERFROMTHEDEVELOPINGWORLD1DEFINITIONOFHIGHTECHNOLOGYECONOMISTSHAVEBEENATTEMPTINGTOMEASURETHETECHNOLOGYCONTENTOFWORLDTRADETHISISACCOMPLISHEDINTERMSOFTHETECHNOLOGYEMBODIEDINPRODUCTSTHATAREEXPORTEDFROMACOUNTRYADMITTEDLYITISADIFFICULTEXERCISEANDNOMETHODISFOOLPROOFANDPERFECTTHEGREATESTDIFFICULTYISINCLASSIFYINGPRODUCTSACCORDINGTOTHETECHNOLOGYCONTENTEMBODIEDINITSEVERALATTEMPTSINTHISDIRECTIONHAVEBEENMADEINTHEPASTINTHEFOLLOWINGIUNDERTAKEAQUICKREVIEWOFTHEMETHODOLOGIESTHISISESSENTIAL,ASIWILLATTEMPTTOSHOWTHATDEPENDINGONTHEDEFINITIONOFHIGHTECHNOLOGYTHATISEMPLOYED,ITISPOSSIBLETOGETSIGNIFICANTLYDIFFERENTRESULTSTHEFIRSTSYSTEMATICEFFORTINTHISDIRECTIONWASBYDAVIS1982HEDEFINEDHIGHTECHNOLOGY3ALLTHECOUNTRIESACCORDINGTOTHEIRHIGHTECHEXPORTINTENSITY,ANDTHENTHERANKINGISENTIRELYDIFFERENTTABLE8TABLE7CONCENTRATIONINEXPORTSOFHIGHTECHPRODUCTSBASEDONABSOLUTEVALUESSHAREOFTHETOP10HIGHTECHEXPORTINGCOUNTRIESINPERCENTCONCENTRATIONWITHINEACHCATEGORYINPERCENTSHAREOFTOP5DEVELOPEDCOUNTRIESSHAREOFTOP5DEVELOPINGCOUNTRIES19886866871989777687199075748619917878821992787685199377768619947775861995767387199674728219977572851998777295NOTETHETOP5DEVELOPEDCOUNTRIESARETHEUS,JAPAN,GERMANY,UKANDFRANCEANDTHETOP5DEVELOPINGCOUNTRIESARESINGAPORE,KOREA,MALAYSIA,CHINAANDMEXICOSOURCEINTECH2000TABLE8RANKINGOFDEVELOPEDANDDEVELOPINGCOUNTRIESACCORDINGTOHIGHTECHEXPORTINTENSITYDEVELOPEDCOUNTRIESDEVELOPINGCOUNTRIESRANKNAMEAVERAGEEXPORTINTENSITYRANKNAMEAVERAGEEXPORTINTENSITY1IRELAND42821SINGAPORE49782USA3192MALAYSIA43133JAPAN25113PHILIPPINES38334UK24964THAILAND22795NETHERLANDS21715KOREA2162NOTESAVERAGEDURINGTHEPERIOD198898MALTA,WHICHHASANAVERAGEEXPORTINTENSITYOF5572PERCENT,ISTHEHIGHESTINTHEWORLDFORTHETIMEBEING,THISHASBEENEXCLUDEDSOURCEINTECH2000ITMAYWELLBETHATSOMEOFTHESECOUNTRIESANDESPECIALLYTHOSEFROMTHEDEVELOPINGWORLDANDPERHAPSIRELANDFROMTHEDEVELOPEDWORLDARENOREALMANUFACTURERSOFHIGHTECHPRODUCTSTHISPOINTWILLBEEXAMINEDINSOMEDETAILINTHELASTSECTION22THECATCHINGUPOFDEVELOPINGCOUNTRIESINHIGHTECHEXPORTS

簡(jiǎn)介：ABSTRACTHONDAHASDEVELOPEDAPOWERTRAINFOR2013SUBCOMPACTCLASSEVSTHISPOWERTRAINHASBOTHHIGHPOWERANDLOWLOSSINORDERTOPROVIDETHEEVWITHBETTERMARKETABILITYTHANEXISTINGEVS,WITHTHEWORLDBESTENERGYEFFICIENCYANDCLASSEXCEEDINGDYNAMICPERFORMANCETOACHIEVETHEENERGYEFFICIENCY,THISPOWERTRAINALSOHASAFUNCTIONOFCOOPERATIVECONTROLWITHANEWLYDEVELOPEDELECTRICALLYOPERATEDSERVOBRAKESYSTEMTOACHIEVETHEHIGHDYNAMICPERFORMANCE,ANEWROTORSHAPEHASBEENINTRODUCEDTOTHEELECTRICMOTOR,ANDTHEPOWERCONTROLUNITPCUISEQUIPPEDWITHAHIGHTHERMALCONDUCTIVITYHEATSINKTHEBATTERYSYSTEMALLOWSHIGHOUTPUTPOWERINACOMPACTSTRUCTUREBECAUSEOFATRIPLEPARALLELMODULEGROUPCONFIGURATIONANDANAIRCOOLINGSYSTEMASARESULTOFTHESEINNOVATIONSINTHEPOWERTRAIN,THEVEHICLEATTAINS82MILESOFDRIVINGRANGEWHILEACHIEVINGWORLDLEADINGENERGYEFFICIENCYOF29KWH/100MILESITALSOHASTHEACCELERATIONPERFORMANCEEQUIVALENTTOATWOLITERGASOLINEDRIVENVEHICLEINTRODUCTIONINRECENTYEARS,ELECTRICVEHICLESHAVEBEENGATHERINGINCREASEDATTENTIONASAMEANSOFELIMINATINGEXHAUSTGASEMISSIONSFROMVEHICLESANDREDUCINGDEPENDENCEONOILINRESPONSETOTHESENEEDS,HONDARELEASED100ELECTRICPOWEREDVEHICLESINCLUDINGTHEEVPLUSELECTRICVEHICLEIN1997ANDTHEFCXCLARITYFUELCELLVEHICLEIN2009,BASEDONTHEEFFORTSOFDEVELOPINGHIGHEFFICIENCYENVIRONMENTALLYFRIENDLYPOWERTRAINSTHEAUTHORSDEVELOPEDAPOWERTRAINFORSUBCOMPACTCLASSEVTHATENABLESTHEVEHICLETOHAVEEXCELLENTENERGYEFFICIENCYANDSUPERIORDYNAMICPERFORMANCE,BYLEVERAGINGHONDASEXPERTISEOFELECTRICPOWERTRAINSANDENERGYMANAGEMENTTECHNOLOGYWITHTHEAIMOFREDUCINGCARBONDIOXIDEEMISSIONANDEFFECTIVELYUSINGALTERNATIVEENERGYSOURCESTHISPAPERPRESENTSADETAILEDEXPLANATIONOFTHELOWLOSSTECHNOLOGYAPPLIEDTOTHISVEHICLECOMPONENTANDPERCENTAGEOFEACHENERGYLOSSFIGURE1SHOWSENERGYLOSSESOFTHEPREVIOUSMODELEVTHELOSSESINCLUDEACCELERATIONRESISTANCE,DRIVINGRESISTANCE,LOSSESFROMSYSTEMCOMPONENTSINCLUDINGTHEMOTORANDTHECHARGER,ANDLOSSESOFBATTERYCHARGINGANDDISCHARGINGINTHISDEVELOPMENT,IMPROVEMENTSHAVEBEENMADEWITHTHEAIMOFREDUCINGOVERALLLOSSESBY40THEFOLLOWINGSECTIONSEXPLAININDETAILTHEIMPROVEMENTSMADETOREDUCELOSSOFEACHTYPEFIGURE1LOSSESINPREVIOUSMODELEVDEVELOPMENTOFANEWPOWERTRAINFORSUBCOMPACTELECTRICVEHICLES2013011478PUBLISHED04/08/2013AKIRAKABASAWA,KENICHIROKIMURA,TAKESHITAGUCHIANDAKIHIROANEKAWAHONDARDCO,LTDCOPYRIGHT?2013SAEINTERNATIONALDOI104271/2013011478DOWNLOADEDFROMSAEINTERNATIONALBYNORTHCAROLINAATUNIVERSITY,THURSDAY,JUNE08,2017LIMITEDTHEDEVELOPEDMODELRAPIDLYANDACCURATELYCOORDINATESTHEBRAKINGTORQUEPRODUCEDBYBOTHTHEHYDRAULICBRAKESANDREGENERATIVEBRAKES,ALLOWINGMOREEFFICIENTUSEOFREGENERATIVEENERGYFIGURE5SHOWSASCHEMATICDIAGRAMDEPICTINGTHEOPERATIONOFTHEELECTRICALLYOPERATEDSERVOBRAKESYSTEMFIGURE5SCHEMATICDIAGRAMOFELECTRICSERVOBRAKESYSTEMFIGURE6EFFECTOFELECTRICBRAKESERVOSYSTEMINTHISSYSTEM,THEOPERATIONOFTHEPEDALANDTHEMECHANISMFORAPPLYINGTHEBRAKEAREINDEPENDENTWHENTHEDRIVERSTEPSONTHEPEDAL,ASTROKESENSORPRODUCESASIGNAL,THESERVOMOTORROTATESINRESPONSETOTHESIGNALANDDRIVESABALLSCREW,PRODUCINGTHESAMESTROKEASTHEDRIVERSPEDALMOVEMENTABRUSHLESSMOTORASTHESERVOMOTORANDABALLSCREWACHIEVEHIGHLYPRECISEFLUIDPRESSURECONTROLANDAFASTRESPONSETHROUGHTHISMECHANISM,THEBRAKEISABLETOREGENERATEMOREENERGYOVERACOURSEOFDRIVINGTHANTHEPREVIOUSMECHANISMS,FROMTHEINSTANTTHEDRIVERPRESSESTHEBRAKEPEDALRIGHTUPTOTHEINSTANTTHEVEHICLESTOPSTHISINCREASESREGENERATIVEENERGYBYAPPROXIMATELY8FIGURE6SHOWSTHEEFFECTOFTHISSYSTEMREDUCTIONOFDRIVINGRESISTANCEFORREDUCINGTHEDRIVINGRESISTANCE,THEAERODYNAMICPERFORMANCEWASIMPROVEDINCOMPARISONWITHTHEBASEMODELWITHANINTERNALCOMBUSTIONENGINE,ANEVREQUIRESMUCHLOWERCOOLINGPERFORMANCEOFITSPOWERTRAINTHEREFORE,REDUCTIONOFAIRRESISTANCEWASENABLEDBYREDUCINGTHEAIRINTAKEBY30FURTHERMORE,ABATTERYPACKFORMINGAFLATUNDERBODYREDUCEDANAERODYNAMICRESISTANCESINCEANEVNOLONGERREQUIRESANEXHAUSTPIPEFIGURE7SHOWSTHEPARTTHATHASBEENMODIFIEDFROMTHEBASEMODELWITHANINTERNALCOMBUSTIONENGINETHUSWEWEREABLETOIMPROVE15TOAIRRESISTANCECOEFFICIENTFIGURE7IMPROVEMENTINAERODYNAMICRESISTANCEREDUCTIONOFBATTERYLOSSTHOUGHTHEPREVIOUSMODELUSEDNICKELMETALHYDRIDEBATTERIES,THEDEVELOPEDMODELADOPTSTHELITHIUMIONBATTERIESBECAUSEOFTHEHIGHERENERGYDENSITYANDHIGHERCHARGE/DISCHARGEEFFICIENCYINSPITEOFTHEENERGYDENSITYANDTHEEFFICIENCY,BATTERYCAPACITYFADEHASTOBETAKENINTOACCOUNTWHENUSINGLITHIUMIONBATTERIESASAVEHICLEENERGYSOURCEIMPROVEMENTOFDURABILITYOFTHELITHIUMIONBATTERYISDESCRIBEDBELOWIMPROVEMENTOFBATTERYDURABILITYONEOFTHEFACTORSTHATALITHIUMIONBATTERYDEGRADESISTHEDEPOSITIONOFMETALLICLITHIUMONTHENEGATIVEELECTRODEPOTENTIALDIFFERENCEBETWEENAPOSITIVEELECTRODEANDACARBONNEGATIVEELECTRODEOFALITHIUMIONBATTERYISNEAR42V,ANDDOWNLOADEDFROMSAEINTERNATIONALBYNORTHCAROLINAATUNIVERSITY,THURSDAY,JUNE08,2017

簡(jiǎn)介：ULTRAWIDEBANDSAMPLINGDOWNCONVERTERWITHSAMPLINGPHASEDETECTORALEXANDERREISENZAHN,STUDENTMEMBER,IEEE,STEFANMATZINGER,THOMASBUCHEGGER,STUDENTMEMBER,IEEE,SEBASTIANHANTSCHER,CHRISTIANGDISKUS,SENIORMEMBER,IEEEAREISENZAHN,SMATZINGER,SHANTSCHER,CGDISKUSAREWITHTHEINSTITUTEFORMICROELECTRONICSATTHEJOHANNESKEPLERUNIVERSITY,ALTENBERGERSTRASSE69,LINZ,4040,AUSTRIA,EMAILALEXANDERREISENZAHNJKUATTBUCHEGGERISWITHTHELINZCENTEROFCOMPETENCEINMECHATRONICS,ALTENBERGERSTRASSE69,LINZ,4040,AUSTRIAABSTRACTULTRAWIDEBANDRADARISANEXCELLENTTOOLFORNONDESTRUCTIVEEXAMINATIONOFWALLSANDHIGHWAYSTRUCTURESTHEREFOREOFTENSTEEPEDGEDNARROWPULSESWITHRISE,FALLTIMESINTHERANGEOF100PSAREUSEDFORDIGITIZINGOFTHEREFLECTEDPULSESADOWNCONVERSIONHASTOBEACCOMPLISHEDANEWLOWCOSTSAMPLINGDOWNCONVERTERWITHASAMPLINGPHASEDETECTORFORUSEINULTRAWIDEBANDRADARAPPLICATIONSISPRESENTEDKEYWORDSULTRAWIDEBAND,SAMPLINGPHASEDETECTOR,SAMPLINGDOWNCONVERTER,SAMPLINGCIRCUITIINTRODUCTIONULTRAWIDEBANDUWBPULSESAREVERYATTRACTIVEFORRADARAPPLICATIONSADVANTAGESAREAHIGHERRANGEMEASUREMENTACCURACYANDRANGESOLUTIONDUETOTHESHORTPULSEDURATION,IMMUNITYTOPASSIVEINTERFERERSANDMANYOTHERSTHESPECTRUMSTARTSATVERYLOWFREQUENCIESANDEXTENDSTOVERYHIGHFREQUENCIESTHEFEDERALCOMMUNICATIONSCOMMISSIONFCCALLOCATESAFREQUENCYRANGEOF75GHZFROM31GHZUPTO106GHZFORUNLICENSEDUSEINCOMMUNICATIONORRADARAPPLICATIONSANDFROM2GHZTO106GHZFORTHROUGHWALLIMAGING1THEFORMOFTHEREFLECTEDPULSEYIELDSTHETARGETINFORMATIONTOENABLEANINTERPRETATIONOFTHESIGNALANANALOGTODIGITALCONVERSIONISNECESSARYTODAYADIRECTCONVERSIONOFPULSESINTHESUBNANOSECONDREGIONISIMPOSSIBLETHEREFOREASAMPLINGDOWNCONVERTERISNECESSARY,WHICHISUSEDFOREXAMPLEINSAMPLINGOSCILLOSCOPESANDRADARAPPLICATIONSTHEDISCUSSEDSAMPLINGDOWNCONVERTERSHOULDBEUSEFULFORLOWCOSTUWBRADARAPPLICATIONSLIKEDETECTINGHIDDENINCLUSIONSINWALLSTHEFUNCTIONPRINCIPLEOFASAMPLINGDOWNCONVERTERISEXPLAINEDINTHEFOLLOWINGPULSESWITHAPULSEREPETITIONTIMETPRARESENTBYATRANSMITTERFIG1SHOWSTHEREFLECTEDPULSESTHESEPULSESHAVEADURATIONTPLOFSOMEHUNDREDPICOSECONDSTHESAMPLERHASTOBETURNEDONAFTERALITTLELONGERTIMETHANTHEPULSEREPETITIONTIMETPRTHISCANBEACCOMPLISHEDFOREXAMPLEWITHASLIGHTLYHIGHERFREQUENCYFPR30MHZ,FSAMPLE30000001MHZORTHESAMPLINGCLOCKISPHASESHIFTEDWITHADIRECTDIGITALSYNTHESIZERDDSATEACHREFLECTEDPULSEASAMPLEISTAKEN,MARKEDBYTHEDOTSTHEACCUMULATEDSAMPLESFORMTHEDOWNCONVERTEDPULSESTIMEAMPLITUDETPRTPLTSAMPLEFIGURE1PRINCIPLEOFSAMPLINGDOWNCONVERSIONIISAMPLINGPHASEDETECTORINPREVIOUSPUBLICATIONS2,3THESAMPLINGDOWNCONVERTERHASBEENBUILTOFDISCRETEELEMENTSINTHEPRESENTEDCIRCUITRYTHESAMPLINGPHASEDETECTORSPDCONTAINSALLNECESSARYPARTSINONEPACKAGEUPTONOWSPDSHAVEBEENUSEDFORTHEPHASELOCKOFAVOLTAGECONTROLLEDOSCILLATORINTHEVHF,UHFANDMICROWAVERANGEINCOMMUNICATIONANDRADARAPPLICATION4,5ANDFORSYNCHRONIZATIONINPULSEBASEDUWBTRANSMISSIONSYSTEMS6ASPDCONSISTSOFASTEPRECOVERYDIODESRD,TWOCAPACITORSANDASERIESPAIROFSCHOTTKYDIODESASSHOWNINFIG2SPDLOINRFINIFOUTFIGURE2CIRCUITRYOFTHESAMPLINGPHASEDETECTORTHESRDISASPECIALDIODEWITHANEXTREMELYFASTRECOVERYTIMEINTHERANGEOFPICOSECONDSCHARGEISSTOREDDURINGTHEPOSITIVEHALFFROMASINUSOIDALSIGNALANDEXTRACTEDDURINGTHENEGATIVEHALFCYCLETOGENERATEACURRENTPULSEWITHARISETIMEEQUIVALENTTOTHERECOVERYTIMETHEREFORETHESRDGENERATESSTEPFUNCTIONSOFADIFFERENTIALSINUSOIDALLOINPUTSIGNALWHICHAREDIFFERENTIATEDTOPULSES078039433X/05/2000?2005IEEEAPMC2005PROCEEDINGSFIGURE5DOWNCONVERTEDUWBRADARPULSETHEPULSESHAPEAGREESMUCHBETTERWITHTHEORIGINALPULSEIFADDSISUSEDFORPHASESHIFTTHERESULTISDEPICTEDINFIG6THEPULSEREPETITIONFREQUENCYINTHISCASEWAS125MHZINONEPERIOD212SAMPLESARETAKENEVERYSAMPLEPOINTISAVERAGED640TIMESWHICHCAUSESAREDUCTIONOFTHEJITTERDUETOTHEPHASENOISEOFTHELOCALOSCILLATORTHISCIRCUITRYWASASSEMBLEDONROGERSDUROIDRT6010SUBSTRATEFIGURE6DOWNCONVERTEDUWBRADARPULSE,PHASESHIFTWITHDDSTHEMEASUREDCONVERSIONGAINWITHA3DBMSINUSOIDALRFINPUTSIGNALATDIFFERENTFREQUENCIESCANBESEENINFIG7THESCHOTTKYDIODESAREUNBIASEDINTHISCASE,REVERSEBIASINGWOULDINCREASETHEBANDWIDTHTHE3DBCUTOFFFREQUENCYISABOUT64GHZTHERESULTCONFIRMSTHATTHEASSUMPTIONSTHATHAVEBEENTAKENAGREEQUITEWELLWITHTHEREALITYTHEFLATCHARACTERISTICOFTHECONVERSIONGAINARISESFROMTHELARGERFINPUTBANDWIDTHOFTHEUSEDSPDTHEBREAKINSAT42GHZANDAT53GHZAREPROBABLYCAUSEDBYTHEUSEDSMACONNECTORSFIGURE7CONVERSIONGAINOFTHESAMPLINGDOWNCONVERTERVCONCLUSIONANEWLOWCOSTSAMPLINGDOWNCONVERTERFORULTRAWIDEBANDRADARAPPLICATIONSWITHLOWSAMPLINGRATESUSINGASAMPLINGPHASEDETECTORISPRESENTEDTHECIRCUITDISPLAYSACONVERSIONGAINOF8DBFORA64GHZRFBANDWIDTHWITHOUTBIASINGTHESCHOTTKYDIODESTHEIMPULSEGENERATORWASREALIZEDWITHANEWLOFEEDUSINGADIFFERENTIALOPERATIONALAMPLIFIER,WHICHISPOSSIBLEUPTOSOMEHUNDREDMEGASAMPLESPERSECONDTHELOSIGNALISTRANSFORMEDFROMSINGLEENDEDTOBALANCEDBEFOREGENERATINGTHESAMPLINGPULSESTHISTRANSFORMATIONINFRONTOFTHESRDMAKESABROADBANDHYBRIDJUNCTIONUNNECESSARYTHEUSEOFTHESPDFORASAMPLINGDOWNCONVERTERISNEWTHESPDCONTAINSALLNECESSARYPARTSFORPULSEGENERATIONANDSAMPLINGINONEPACKAGEANDTHEREFOREALLOWSACOMPACT,LOWCOSTANDSIMPLETOMANUFACTURECIRCUITACKNOWLEDGMENTTHISWORKWASCARRIEDOUTATTHEINSTITUTEFORMICROELECTRONICSIME,JOHANNESKEPLERUNIVERSITY,LINZWEWOULDLIKETOACKNOWLEDGEBERNHARDMAY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簡(jiǎn)介：THEMEDSECTIONVECTORDESIGNANDDRUGDELIVERYREVIEWTWENTYYEARSOFCELLPENETRATINGPEPTIDESFROMMOLECULARMECHANISMSTOTHERAPEUTICSFREDERICHEITZ,MAYCATHERINEMORRISANDGILLESDIVITACENTREDERECHERCHESDEBIOCHIMIEMACROMOLéCULAIRE,UMR5237,CNRS,UM1,UM2,CRBMDEPARTMENTOFMOLECULARBIOPHYSICSANDTHERAPEUTICS,1919ROUTEDEMENDE,MONTPELLIER,FRANCETHERECENTDISCOVERYOFNEWPOTENTTHERAPEUTICMOLECULESTHATDONOTREACHTHECLINICDUETOPOORDELIVERYANDLOWBIOAVAILABILITYHAVEMADEOFDELIVERYAKEYSTONEINTHERAPEUTICDEVELOPMENTSEVERALTECHNOLOGIESHAVEBEENDESIGNEDTOIMPROVECELLULARUPTAKEOFTHERAPEUTICMOLECULES,INCLUDINGCELLPENETRATINGPEPTIDESCPPSCPPSWEREFIRSTDISCOVEREDBASEDONTHEPOTENCYOFSEVERALPROTEINSTOENTERCELLSNUMEROUSCPPSHAVEBEENDESCRIBEDSOFAR,WHICHCANBEGROUPEDINTOTWOMAJORCLASSES,THEFIRSTREQUIRINGCHEMICALLINKAGEWITHTHEDRUGFORCELLULARINTERNALIZATIONANDTHESECONDINVOLVINGFORMATIONOFSTABLE,NONCOVALENTCOMPLEXESWITHDRUGSNOWADAYS,CPPSCONSTITUTEVERYPROMISINGTOOLSFORNONINVASIVECELLULARIMPORTOFCARGOANDHAVEBEENSUCCESSFULLYAPPLIEDFORINVITROANDINVIVODELIVERYOFTHERAPEUTICMOLECULESVARYINGFROMSMALLCHEMICALMOLECULE,NUCLEICACIDS,PROTEINS,PEPTIDES,LIPOSOMESANDPARTICLESTHISREVIEWWILLFOCUSONTHESTRUCTURE/FUNCTIONANDCELLULARUPTAKEMECHANISMOFCPPSINTHEGENERALCONTEXTOFDRUGDELIVERYWEWILLALSOHIGHLIGHTTHEAPPLICATIONOFPEPTIDECARRIERSFORTHEDELIVERYOFTHERAPEUTICMOLECULESANDPROVIDEANUPDATEOFTHEIRCLINICALEVALUATIONBRITISHJOURNALOFPHARMACOLOGY2009157,195–206DOI101111/J14765381200800057XPUBLISHEDONLINE20MARCH2009THISARTICLEISPARTOFATHEMEDSECTIONONVECTORDESIGNANDDRUGDELIVERYFORALISTOFALLARTICLESINTHISSECTIONSEETHEENDOFTHISPAPER,ORVISITHTTP//WWW3INTERSCIENCEWILEYCOM/JOURNAL/121548564/ISSUEYEARYEAR2009KEYWORDSCELLPENETRATINGPEPTIDENONCOVALENTDELIVERYSYSTEMSIRNANANOPARTICLEDRUGDELIVERYMOLECULARMECHANISMSTHERAPEUTICSABBREVIATIONSCPP,CELLPENETRATINGPEPTIDEGAG,GLUCOSAMINOGLYCANNLS,NUCLEARLOCALIZATIONSEQUENCEPMO,PHOSPHORODIAMIDATEMORPHOLINOOLIGOMERPNA,PEPTIDENUCLEICACIDPTD,PROTEINTRANSDUCTIONDOMAINSINTRODUCTIONCHALLENGESINDRUGDELIVERYOVERTHEPAST10YEARS,INORDERTOCIRCUMVENTLIMITATIONSOFSMALLMOLECULEANDGENEBASEDTHERAPIES,WEHAVEWITNESSEDADRAMATICACCELERATIONINTHEPRODUCTIONOFNEWLARGETHERAPEUTICMOLECULES,WHICHDONOTFOLLOWLIPINSKI’SRULES,SUCHASPROTEINS,PEPTIDESANDNUCLEICACIDTHERAPEUTICSHOWEVER,THEIRDEVELOPMENTISRESTRICTEDBYVERYSPECIFICISSUESINCLUDINGPOORSTABILITYINVIVO,LACKOFCELLULARUPTAKEANDINSUFFICIENTCAPABILITYTOREACHTARGETSTHISISASSOCIATEDWITHTHECOMPLETELOSSOFPHARMACEUTICALPOTENCYORATLEASTWITHTHEREQUIREMENTFORHIGHDOSESANDRISKOFMAJORSIDEEFFECTSTHEREFORE,DELIVERYCONSTITUTESAMAJORPIECEOFTHETHERAPEUTICPUZZLE,ANDTHEREISAREALDEMANDFORNEWANDMOREEFFICIENTDRUGDELIVERYSYSTEMSMAJORRULESHAVETOBESATISFIED,INPARTICULARIDELIVERYEFFICIENCYINDIFFERENTANDCHALLENGINGCELLLINESIIRAPIDENDOSOMALRELEASEIIIABILITYTOREACHTHETARGETIVACTIVITYATLOWDOSESVLACKOFTOXICITYANDVIFACILITYOFTHERAPEUTICAPPLICATIONSUBSTANTIALPROGRESSHASBEENMADEINTHEDESIGNOFNEWTECHNOLOGIESTOIMPROVECELLULARUPTAKEOFTHERAPEUTICCOMPOUNDSOPALINSKAANDGEWIRTZ,2002J?RVERANDLANGEL,2004GLOVERETAL,2005TORCHILIN,2005DEFOUGEROLLESETAL,2007KONGANDMOONEY,2007ANUMBEROFNONVIRALSTRATEGIESHAVEBEENPROPOSEDINCLUDINGLIPID,POLYCATIONIC,NANOPARTICLEANDPEPTIDEBASEDFORMULATIONSASREPORTEDINTHISSPECIALISSUEMORRISETAL,2000OGRISANDWAGNER,2002J?RVERANDLANGEL,2004TORCHILIN,2005,BUTONLYASUBSETOFTHESETECHNOLOGIESAREEFFICIENTLYAPPLIEDINVIVOATEITHERPRECLINICALORCLINICALLEVELSPROTEINTRANSDUCTIONDOMAINSPTDSORCELLPENETRATINGPEPTIDESCPPSCORRESPONDTOSHORT30RESIDUESYNTHETICPEPTIDESANDAREPARTOFTHEMOSTPROMISINGSTRATEGYTOOVERCOMEBOTHEXTRACELLULARANDINTRACELLULARLIMITATIONSOFVARIOUSBIOMOLECULESOFINCLUDINGPLASMIDDNA,CORRESPONDENCEGILLESDIVITA,CENTREDERECHERCHESDEBIOCHIMIEMACROMOLéCULAIRE,UMR5237,CNRS,UM1,UM2,CRBMDEPARTMENTOFMOLECULARBIOPHYSICSANDTHERAPEUTICS,1919ROUTEDEMENDE,34293MONTPELLIER,FRANCEEMAILGILLESDIVITACRBMCNRSFRRECEIVED14JULY2008REVISED7OCTOBER2008ACCEPTED20OCTOBER2008BRITISHJOURNALOFPHARMACOLOGY2009,157,195–206?2009THEAUTHORSJOURNALCOMPILATION?2009THEBRITISHPHARMACOLOGICALSOCIETYALLRIGHTSRESERVED00071188/09WWWBRJPHARMACOLORGCOVALENTSTRATEGYCELLPENETRATINGPEPTIDEBASEDTECHNOLOGIESDESCRIBEDSOFARMAINLYINVOLVETHEFORMATIONOFACOVALENTCONJUGATEBETWEENTHECARGOANDTHECARRIERPEPTIDE,WHICHISACHIEVEDBYCHEMICALCROSSLINKINGORBYCLONINGFOLLOWEDBYEXPRESSIONOFACPPFUSIONPROTEINNAGAHARAETAL,1998GAIT,2003MOULTONANDMOULTON,2004ZATSEPINETAL,2005MOSTOFTHEWORKHASBEENREPORTEDFORPEPTIDESDERIVEDFROMTATFAWELLETAL,1994VIVESETAL,1997FRANKELANDPABO,1988,PENETRATINDEROSSIETAL,1994,POLYARGININEPEPTIDEARG8SEQUENCEWENDERETAL,2000FUTAKIETAL,2001ANDTRANSPORTAN,POOGAETAL,1998OTHERPROTEINDERIVEDPEPTIDESSUCHASVP22PROTEINFROMHERPESSIMPLEXVIRUSELLIOTTANDO’HARE,1997,PVECELMQUISTETAL,2001,CALCITONINDERIVEDPEPTIDESSCHMIDTETAL,1998KRAUSSETAL,2004,ANTIMICROBIALPEPTIDESBUFORINIANDSYNBPARKETAL,1998PARKETAL,2000,ASWELLASPOLYPROLINESWEETARROWPEPTIDEPUJALSETAL,2006HAVEALSOBEENSUCCESSFULLYUSEDTOIMPROVETHEDELIVERYOFCOVALENTLYLINKEDCARGOSJOLIOTANDPROCHIANTZ,2004ELANDALOUSSIETAL,2005MURRIELANDDOWDY,2006MORERECENTLY,NEWGENERATIONSOFCPPS,COMBININ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簡(jiǎn)介：IEEETRANSACTIONSONEVOLUTIONARYCOMPUTATION,VOL1,NO1,APRIL199753ANTCOLONYSYSTEMACOOPERATIVELEARNINGAPPROACHTOTHETRAVELINGSALESMANPROBLEMMARCODORIGO,SENIORMEMBER,IEEE,ANDLUCAMARIAGAMBARDELLA,MEMBER,IEEEABSTRACTTHISPAPERINTRODUCESTHEANTCOLONYSYSTEMACS,ADISTRIBUTEDALGORITHMTHATISAPPLIEDTOTHETRAVELINGSALESMANPROBLEMTSPINTHEACS,ASETOFCOOPERATINGAGENTSCALLEDANTSCOOPERATETOFINDGOODSOLUTIONSTOTSP’SANTSCOOPERATEUSINGANINDIRECTFORMOFCOMMUNICATIONMEDIATEDBYAPHEROMONETHEYDEPOSITONTHEEDGESOFTHETSPGRAPHWHILEBUILDINGSOLUTIONSWESTUDYTHEACSBYRUNNINGEXPERIMENTSTOUNDERSTANDITSOPERATIONTHERESULTSSHOWTHATTHEACSOUTPERFORMSOTHERNATUREINSPIREDALGORITHMSSUCHASSIMULATEDANNEALINGANDEVOLUTIONARYCOMPUTATION,ANDWECONCLUDECOMPARINGACS3OPT,AVERSIONOFTHEACSAUGMENTEDWITHALOCALSEARCHPROCEDURE,TOSOMEOFTHEBESTPERFORMINGALGORITHMSFORSYMMETRICANDASYMMETRICTSP’SINDEXTERMSADAPTIVEBEHAVIOR,ANTCOLONY,EMERGENTBEHAVIOR,TRAVELINGSALESMANPROBLEMIINTRODUCTIONTHENATURALMETAPHORONWHICHANTALGORITHMSAREBASEDISTHATOFANTCOLONIESREALANTSARECAPABLEOFFINDINGTHESHORTESTPATHFROMAFOODSOURCETOTHEIRNEST3,22WITHOUTUSINGVISUALCUES24BYEXPLOITINGPHEROMONEINFORMATIONWHILEWALKING,ANTSDEPOSITPHEROMONEONTHEGROUNDANDFOLLOW,INPROBABILITY,PHEROMONEPREVIOUSLYDEPOSITEDBYOTHERANTSINFIG1,WESHOWAWAYANTSEXPLOITPHEROMONETOFINDASHORTESTPATHBETWEENTWOPOINTSCONSIDERFIG1AANTSARRIVEATADECISIONPOINTINWHICHTHEYHAVETODECIDEWHETHERTOTURNLEFTORRIGHTSINCETHEYHAVENOCLUEABOUTWHICHISTHEBESTCHOICE,THEYCHOOSERANDOMLYITCANBEEXPECTEDTHAT,ONAVERAGE,HALFOFTHEANTSDECIDETOTURNLEFTANDTHEOTHERHALFTOTURNRIGHTTHISHAPPENSBOTHTOANTSMOVINGFROMLEFTTORIGHTTHOSEWHOSENAMEBEGINSWITHANLANDTOTHOSEMOVINGFROMRIGHTTOLEFTNAMEBEGINSWITHANRFIG1BANDCSHOWSWHATHAPPENSINTHEIMMEDIATELYFOLLOWINGINSTANTS,SUPPOSINGTHATALLANTSWALKATAPPROXIMATELYTHESAMESPEEDTHENUMBEROFDASHEDLINESISROUGHLYPROPORTIONALTOTHEAMOUNTOFPHEROMONETHATTHEANTSHAVEDEPOSITEDONTHEGROUNDSINCETHELOWERPATHISSHORTERTHANTHEUPPERONE,MOREANTSWILLVISITITONAVERAGE,ANDTHEREFOREPHEROMONEACCUMULATESFASTERAFTERASHORTTRANSITORYPERIODTHEDIFFERENCEINTHEAMOUNTOFPHEROMONEONTHETWOPATHSISSUFFICIENTLYLARGESOASTOINFLUENCETHEDECISIONOFNEWANTSCOMINGINTOTHESYSTEMTHISISSHOWNBYMANUSCRIPTRECEIVEDOCTOBER7,1996REVISEDJANUARY18,1997ANDFEBRUARY3,1997THISWORKWASSUPPORTEDBYTHESWISSNATIONALSCIENCEFUNDCONTRACT214565395MDORIGOISWITHIRIDIA,UNIVERSITELIBREDEBRUXELLES,1050BRUXELLES,BELGIUMEMAILMDORIGOULBACBELMGAMBARDELLAISWITHIDSIA,6900LUGANO,SWITZERLANDPUBLISHERITEMIDENTIFIERS1089778X97033031FIG1DFROMNOWON,NEWANTSWILLPREFERINPROBABILITYTOCHOOSETHELOWERPATH,SINCEATTHEDECISIONPOINTTHEYPERCEIVEAGREATERAMOUNTOFPHEROMONEONTHELOWERPATHTHISINTURNINCREASES,WITHAPOSITIVEFEEDBACKEFFECT,THENUMBEROFANTSCHOOSINGTHELOWER,ANDSHORTER,PATHVERYSOONALLANTSWILLBEUSINGTHESHORTERPATHTHEABOVEBEHAVIOROFREALANTSHASINSPIREDANTSYSTEM,ANALGORITHMINWHICHASETOFARTIFICIALANTSCOOPERATETOTHESOLUTIONOFAPROBLEMBYEXCHANGINGINFORMATIONVIAPHEROMONEDEPOSITEDONGRAPHEDGESTHEANTSYSTEMHASBEENAPPLIEDTOCOMBINATORIALOPTIMIZATIONPROBLEMSSUCHASTHETRAVELINGSALESMANPROBLEMTSP7,8,10,12ANDTHEQUADRATICASSIGNMENTPROBLEM32,42THEANTCOLONYSYSTEMACS,THEALGORITHMPRESENTEDINTHISARTICLE,BUILDSONTHEPREVIOUSANTSYSTEMINTHEDIRECTIONOFIMPROVINGEFFICIENCYWHENAPPLIEDTOSYMMETRICANDASYMMETRICTSP’STHEMAINIDEAISTHATOFHAVINGASETOFAGENTS,CALLEDANTS,SEARCHINPARALLELFORGOODSOLUTIONSTOTHETSPANDCOOPERATETHROUGHPHEROMONEMEDIATEDINDIRECTANDGLOBALCOMMUNICATIONINFORMALLY,EACHANTCONSTRUCTSATSPSOLUTIONINANITERATIVEWAYITADDSNEWCITIESTOAPARTIALSOLUTIONBYEXPLOITINGBOTHINFORMATIONGAINEDFROMPASTEXPERIENCEANDAGREEDYHEURISTICMEMORYTAKESTHEFORMOFPHEROMONEDEPOSITEDBYANTSONTSPEDGES,WHILEHEURISTICINFORMATIONISSIMPLYGIVENBYTHEEDGE’SLENGTHTHEMAINNOVELIDEAINTRODUCEDBYANTALGORITHMS,WHICHWILLBEDISCUSSEDINTHEREMAINDEROFTHEPAPER,ISTHESYNERGISTICUSEOFCOOPERATIONAMONGMANYRELATIVELYSIMPLEAGENTSWHICHCOMMUNICATEBYDISTRIBUTEDMEMORYIMPLEMENTEDASPHEROMONEDEPOSITEDONEDGESOFAGRAPHTHISPAPERISORGANIZEDASFOLLOWSSECTIONIIPUTSTHEACSINCONTEXTBYDESCRIBINGANTSYSTEM,THEPROGENITOROFTHEACSSECTIONIIIINTRODUCESTHEACSSECTIONIVISDEDICATEDTOTHESTUDYOFSOMECHARACTERISTICSOFTHEACSWESTUDYHOWPHEROMONECHANGESATRUNTIME,ESTIMATETHEOPTIMALNUMBEROFANTSTOBEUSED,OBSERVETHEEFFECTSOFPHEROMONEMEDIATEDCOOPERATION,ANDEVALUATETHEROLETHATPHEROMONEANDTHEGREEDYHEURISTICHAVEINACSPERFORMANCESECTIONVPROVIDESANOVERVIEWOFRESULTSONASETOFSTANDARDTESTPROBLEMSANDCOMPARISONSOFTHEACSWITHWELLKNOWNGENERALPURPOSEALGORITHMSLIKEEVOLUTIONARYCOMPUTATIONANDSIMULATEDANNEALINGINSECTIONVIWEADDLOCALOPTIMIZATIONTOTHEACS,OBTAININGANEWALGORITHMCALLEDACS3OPTTHISALGORITHMISCOMPAREDFAVORABLYWITHTHEWINNEROFTHEFIRSTINTERNATIONALCONTESTONEVOLUTIONARYOPTIMIZATION5ONASYMMETRICTSPATSPPROBLEMSSEEFIG2,WHILEITYIELDSASLIGHTLYWORSEPERFORMANCEONTSPPROBLEMSSECTIONVIIIS1089–778X/971000?1997IEEEDORIGOANDGAMBARDELLAANTCOLONYSYSTEM55FIG3THEACSALGORITHMPROBABILITYWITHWHICHANTINCITYCHOOSESTOMOVETOTHECITYIFOTHERWISE1WHEREISTHEPHEROMONE,ISTHEINVERSEOFTHEDISTANCE,ISTHESETOFCITIESTHATREMAINTOBEVISITEDBYANTPOSITIONEDONCITYTOMAKETHESOLUTIONFEASIBLE,ANDISAPARAMETERWHICHDETERMINESTHERELATIVEIMPORTAN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簡(jiǎn)介：CHAPTER13THEDILEMMAOFPERFORMANCEAPPRAISALPETERPROWSEANDJULIEPROWSEABSTRACTTHISPAPERDEALSWITHTHEDILEMMAOFMANAGINGPERFORMANCEUSINGPERFORMANCEAPPRAISALTHEAUTHORSWILLEVALUATETHEHISTORICALDEVELOPMENTOFAPPRAISALSANDARGUETHATTHECRITICALAREAOFLINEMANAGEMENTDEVELOPMENTTHATWASBEENIDENTIFIEDASACRITICALSUCCESSFACTORINAPPRAISALSHASBEENIGNOREDINTHELATERLITERATUREEVALUATINGTHEEFFECTIVENESSOFPERFORMANCETHROUGHAPPRAISALSTHISPAPERWILLEVALUATETHEAIMSANDMETHODSOFAPPRAISAL,THEDIFFICULTIESENCOUNTEREDINTHEAPPRAISALPROCESSITALSOREEVALUATESTHELACKOFTHEORETICALDEVELOPMENTINAPPRAISALANDMOVESFROMTHEPSYCHOLOGICALAPPROACHESOFANALYSISTOAMORECRITICALREALISATIONOFAPPROACHESBEFOREREEVALUATINGTHECHALLENGETOREMOVESUBJECTIVITYANDBIASINJUDGEMENTOFAPPRAISAL131INTRODUCTIONTHISPAPERWILLDEFINEANDOUTLINEPERFORMANCEMANAGEMENTANDAPPRAISALITWILLSTARTBYEVALUATINGWHATFORMOFPERFORMANCEISEVALUATED,THENDEVELOPLINKSTOTHEDEVELOPMENTOFDIFFERENTPERFORMANCETRADITIONSPSYCHOLOGICALTRADITION,MANAGEMENTBYOBJECTIVES,MOTIVATIONANDDEVELOPMENTITWILLOUTLINETHEHISTORICALDEVELOPMENTOFPERFORMANCEMANAGEMENTTHENEVALUATEHIGHPERFORMANCESTRATEGIESUSINGPERFORMANCEAPPRAISALITWILLEVALUATETHECONTINUINGISSUEOFSUBJECTIVITYANDETHICALDILEMMASREGARDINGMEASUREMENTANDASSESSMENTOFPERFORMANCETHEPAPERWILLTHENEXAMINEHOWORGANISATIONSMEASUREPERFORMANCEBEFOREEVALUATIONOFRESEARCHONSOMERECENTTRENDSINPERFORMANCEAPPRAISALTHISCHAPTERWILLEVALUATETHEHISTORICALDEVELOPMENTOFPERFORMANCEAPPRAISALFROMMANAGEMENTBYOBJECTIVESMBOLITERATUREBEFOREEVALUATINGTHEDEBATESBETWEENLINKAGESBETWEENPERFORMANCEMANAGEMENTANDAPPRAISALITWILLOUTLINEPPROWSEBUNIVERSITYOFBRADFORD,BRADFORD,ENGLAND,UKEMAILPJPROWSEBRADFORDACUK195PTATICCHIED,BUSINESSPERFORMANCEMEASUREMENTANDMANAGEMENT,DOI101007/9783642048005_13,C?SPRINGERVERLAGBERLINHEIDELBERG201013THEDILEMMAOFPERFORMANCEAPPRAISAL197APPRAISALFEEDBACKBEYONDPERFORMANCEFORPROFESSIONALSANDMANAGERSTONEARLY95OFWORKPLACESINTHE2004WERSSURVEYSEETABLE131CLEARLYTHEUSEOFAPPRAISALSHASBEENTHEDEVELOPMENTANDEXTENSIONOFAPPRAISALSTOCOVERALARGEPROPORTIONOFTHEUKWORKFORCEANDTHECOVERAGEOFNONMANAGERIALOCCUPATIONSANDTHEEXTENDEDUSEINPRIVATEANDPUBLICSECTORS1322THEPURPOSEOFAPPRAISALSTHECRITICALISSUEISWHATISTHEPURPOSEOFAPPRAISALSANDHOWEFFECTIVEISITRESEARCHEDANDUSEDINPRACTICETHROUGHOUTORGANIZATIONSTHEPURPOSEOFAPPRAISALSNEEDSTOBECLEARLYIDENTIFIEDFIRSTLYTHEIRPURPOSERANDELL1994STATESTHEYAREASYSTEMATICEVALUATIONOFINDIVIDUALPERFORMANCELINKEDTOWORKPLACEBEHAVIOURAND/ORSPECIFICCRITERIAAPPRAISALSOFTENTAKETHEFORMOFANAPPRAISALINTERVIEW,USUALLYANNUAL,SUPPORTEDBYSTANDARDISEDFORMS/PAPERWORKTHEKEYOBJECTIVEOFAPPRAISALISTOPROVIDEFEEDBACKFORPERFORMANCEISPROVIDEDBYTHELINEMANAGERTHETHREEKEYQUESTIONSFORQUALITYOFFEEDBACK1WHATANDHOWAREOBSERVATIONSONPERFORMANCEMADE2WHYANDHOWARETHEYDISCUSSED3WHATDETERMINESTHELEVELOFPERFORMANCEINTHEJOBITHASBEENARGUEDBYONESCHOOLOFTHOUGHTTHATTHESEPROCESSCANNOTBEPERFORMEDEFFECTIVELYUNLESSTHELINEMANAGEROFPERSONPROVIDINGFEEDBACKHASTHEINTERPERSONALINTERVIEWINGSKILLSTOPROVIDETHATFEEDBACKTOPEOPLEBEINGAPPRAISEDTHISHASBEENDEFINEDASTHE“BRADFORDAPPROACH”WHICHPLACESAHIGHPRIORITYONAPPRAISALSKILLSDEVELOPMENTRANDELL,1994THISAPPROACHISOUTLINEDINFIG131WHICHIDENTIFIESTHELINKAGESBETWEENINVOLVING,DEVELOPING,REWARDINGANDVALUINGPEOPLEATWORK1323HISTORICALDEVELOPMENTOFAPPRAISALTHEHISTORICALDEVELOPMENTOFPERFORMANCEFEEDBACKHASDEVELOPEDFROMARANGEOFAPPROACHESFORMALOBSERVATIONOFINDIVIDUALWORKPERFORMANCEWASREPORTEDINROBERTOWENS’SSCOTTISHFACTORYINNEWLANARKINTHEEARLY1800SCOLE,1925OWENHUNGOVERMACHINESAPIECEOFCOLOUREDWOODOVERMACHINESTOINDICATETHESUPERINTENDENT’SASSESSMENTOFTHEPREVIOUSDAY’SCONDUCTWHITEFOREXCELLENT,YELLOW,BLUEANDTHENBLACKFORPOORPERFORMANCETHETWENTIETHCENTURYLEDTOFWTAYLORANDHISMEASUREDPERFORMANCEANDTHESCIENTIFICMANAGEMENTMOVEMENTTAYLOR,1964THE1930STRAITSAPPROACHESIDENTIFIEDPERSONALITYANDPERFORMANCEANDUSEDFEEDBACKUSINGGRAPHICRATINGSCALES,AMIXEDSTANDARDOFPERFORMANCESCALESNOTINGBEHAVIOURINLIKERTSCALERATINGSTHISWASUSEDTORECRUITANDIDENTIFY

簡(jiǎn)介：焦?fàn)t煤氣在活性碳作用下干燥重整合成甲醇焦?fàn)t煤氣在活性碳作用下干燥重整合成甲醇摘要摘要焦?fàn)t煤氣在以活性炭為催化劑進(jìn)行干燥重整已經(jīng)被研究用來(lái)生產(chǎn)合適的甲醇合成氣，這項(xiàng)工作的主要目的是研究焦?fàn)t煤氣中氫數(shù)量對(duì)焦?fàn)t煤氣干燥重整的影響，以及其它條件的影響，利如溫度和體積空速的影響。結(jié)果發(fā)現(xiàn)，反向水煤氣變換（RWGS）反應(yīng)的發(fā)生是由于焦?fàn)t煤氣中氫的存在，而且它對(duì)反應(yīng)的影響隨著溫度的降低過(guò)程而增加。這種情可能引起的焦?fàn)t煤氣中的氫組成的變化，并由此預(yù)計(jì)。這種反應(yīng)可以在約1000度的高溫下生產(chǎn)適合用于合成甲醇的合成氣。結(jié)果還發(fā)現(xiàn)，空速的增加對(duì)水煤氣變換反應(yīng)有利。此外，活性炭被證明是最適合焦?fàn)t煤氣生產(chǎn)合成甲醇的合成氣的催化劑。關(guān)鍵詞關(guān)鍵詞焦?fàn)t煤氣焦?fàn)t煤氣干重整，合成氣，甲醇干重整，合成氣，甲醇1簡(jiǎn)介合成氣是大多數(shù)氫產(chǎn)品和各種有機(jī)物的生產(chǎn)原料，它主要由氫氣和一氧化碳組成，它基本上產(chǎn)自天然氣和石油，但有限的化石燃料的供應(yīng)和應(yīng)對(duì)氣候變化以及溫室氣體（GHG）的排放，加強(qiáng)了對(duì)生產(chǎn)的替代工藝，如生物質(zhì)氣化1或沼氣重整研究3。焦?fàn)t氣體（焦?fàn)t煤氣），它可以被認(rèn)為是焦化廠的副產(chǎn)品，主要由氫氣（5560％），甲烷（2327％），一氧化碳（58％）和N2（35％），以及其他碳?xì)浠衔?，其中硫化氫和氨的比例小。這種氣體大部分是用作煉焦?fàn)t和鋼鐵廠的燃料，但往往對(duì)過(guò)剩焦?fàn)t煤氣的使用不能使用這種方式，所以通常放散燃燒，這也引起了環(huán)境污染的問(wèn)題和如何解決環(huán)境的問(wèn)題49。對(duì)于多余的焦?fàn)t煤氣如何處理，我們可以通過(guò)氫分離手段加以利用或通過(guò)部分氧化8,10,11蒸汽重整7,12,14,15或干燥重整4,5,16來(lái)生產(chǎn)合成氣12,13，生。這樣生產(chǎn)的合成氣可以反過(guò)來(lái)用于不同其他有機(jī)合成產(chǎn)品，主要是甲醇。雖然大多數(shù)研究者都集中在焦?fàn)t煤氣水蒸汽轉(zhuǎn)化法的研究，在過(guò)去的幾年焦?fàn)t煤氣干燥重整也已經(jīng)被深入的研究4,5,16。由于它提供了比水蒸汽重整更理想的反應(yīng)條件和環(huán)境，如二氧化碳消耗的能源或節(jié)能，有著許多優(yōu)勢(shì)。另一個(gè)重要的優(yōu)勢(shì)在于焦?fàn)t煤氣干燥重整的好處是獲得了氫氣和一氧化碳的比率約2的合成氣，這是一個(gè)理想中合成甲醇的合成氣的比率17,18圖中所示只有一個(gè)步是提供甲烷和二氧化碳反應(yīng)時(shí)的化學(xué)計(jì)量條件。從圖1中可以看出，這個(gè)過(guò)程可以被視為一種方法，即二氧化碳的部分再偱環(huán)、部分參加反應(yīng)“，在理論上甲醇燃燒時(shí)會(huì)產(chǎn)生一半的二氧化碳。這項(xiàng)技術(shù)的研究的前景是深遠(yuǎn)的，由于汽車燃料對(duì)甲醇的需求，和氫燃料電池或生物柴油的原料量的迅速增加19。這項(xiàng)工作主要目的是對(duì)焦?fàn)t煤氣的干燥重整的研究，以生產(chǎn)合適的原料氣H2/CO作為合成甲醇的合成氣。焦?fàn)t煤氣干燥重整中的活性炭，已被證明是一個(gè)對(duì)甲烷干燥重整有效的催化劑。氫氣數(shù)量是影響焦?fàn)t煤氣干燥重整和其它反應(yīng)條件，如溫度或空速度，是目前研究重心。甲烷和從甲烷干重整造成二氧化碳轉(zhuǎn)換的變化。正如圖3所示，甲烷轉(zhuǎn)化降至40％以下開(kāi)始的反應(yīng)，反應(yīng)6小時(shí)后達(dá)到20％左右。仔細(xì)的觀察，在減少可能由于初始不穩(wěn)定的第一分鐘。此外，二氧化碳轉(zhuǎn)化率比在干燥的甲烷重整（圖2），這表明RWGS比對(duì)的平衡轉(zhuǎn)移效應(yīng)的影響更大。在冷凝器收集的大量水，約占8VOL％反應(yīng)的產(chǎn)品，這個(gè)也是由其他研究者報(bào)告的建議16。除了降低氫氣的產(chǎn)量和改變H2/CO比，水也會(huì)阻礙甲醇合成，因?yàn)樗鼤?huì)使銅催化劑的失能的影響23。31．溫度的影響圖4顯示了在900℃時(shí)的三元混合氣體干燥重組反應(yīng)?？梢钥闯觯藭r(shí)甲烷轉(zhuǎn)化率大于50％，在整個(gè)反應(yīng)實(shí)驗(yàn)中可以看出，這個(gè)轉(zhuǎn)化率是800℃時(shí)測(cè)試所達(dá)不到的，CO2的轉(zhuǎn)化率也高于它在800℃的。由于RWGS反應(yīng)（反應(yīng)2）小于甲烷干重整（反應(yīng)1）吸熱，反應(yīng)溫度的增加提高了干燥改革吸熱，便出現(xiàn)了較高的甲烷轉(zhuǎn)化率，因此，會(huì)產(chǎn)生更多的氫，而水則會(huì)減少。實(shí)際上，隨著CO2轉(zhuǎn)化率的增加，會(huì)使干燥重整反應(yīng)增強(qiáng)，而不是RWGS反應(yīng)，因?yàn)榉磻?yīng)所需的水量，在近3次的實(shí)驗(yàn)明中顯低于800℃時(shí)的。其他可能的解釋是甲烷水蒸在高溫度下進(jìn)行重整（反應(yīng)3）。但是，這個(gè)機(jī)制似乎不太可能，因?yàn)樗鼤?huì)導(dǎo)致甲烷和二氧化碳的轉(zhuǎn)換而沒(méi)有發(fā)生類似的增量，在圖4中可以看到。然而，RWGS反應(yīng)（反應(yīng)2）和蒸汽重整反應(yīng)（反應(yīng)3）引起的干重整反應(yīng)（反應(yīng)1），這使得難以區(qū)分此種反應(yīng)遵循什么樣的規(guī)律。圖5顯示了在1000℃時(shí)所進(jìn)行的測(cè)試的轉(zhuǎn)換結(jié)果。反應(yīng)溫度的增加同時(shí)也增加了轉(zhuǎn)換結(jié)果，多達(dá)80％的甲烷和95％的二氧化碳的實(shí)驗(yàn)后6小時(shí)。此外，在1000℃時(shí)沒(méi)有水的生產(chǎn)。所以，在此溫度下工作，它有可能避免水煤氣變換的發(fā)生，最大限度地利用氫。32空速的影響的體積空速在900℃和1000℃研究空速對(duì)反應(yīng)過(guò)程的影響。在800℃溫度，因?yàn)樵诳账僭黾佣鴮?dǎo)致轉(zhuǎn)換物的進(jìn)一步減少20和水的形成，這將使它很難研究的空速變化和對(duì)反應(yīng)進(jìn)程的影響。三元混合氣體在900℃時(shí)采用三種不同的空速（分別是075，1，15LGH小時(shí)下進(jìn)行干燥重整反應(yīng)，圖6所示反應(yīng)的結(jié)果?？梢钥闯觯淄楹投??1?化碳的轉(zhuǎn)換是受空速變化的影響。因此，轉(zhuǎn)換率的影響在于空速變化，轉(zhuǎn)換率隨著空速增加而降低。隨著水煤氣變換反應(yīng)空速增加。反應(yīng)器中二氧化碳濃度的也增加。由于存在較高氫氣的含量，二氧化碳可能是限制水煤氣變換反應(yīng)的物種。因此，二氧化碳的轉(zhuǎn)換應(yīng)避免高的轉(zhuǎn)換，以防止水煤氣變換的副反應(yīng)。圖7顯示了通過(guò)在1000℃和075LGH和150LGH時(shí)兩次測(cè)試，出1?1?1?1?現(xiàn)了兩種不同的結(jié)果。正如上文所述，在反應(yīng)條件為075LGH1000℃時(shí)不1?1?產(chǎn)生水。當(dāng)空速增加到150LGH小時(shí)，則會(huì)產(chǎn)生一些水，由于干重整反應(yīng)1?1?