Early childhood mathematics 2. ed Edition Sperry Smith
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LISTOFCONTRIBUTORS
C.FredBrewer, DepartmentofMolecularPharmacology,Microbiologyand Immunology,AlbertEinsteinCollegeofMedicine,Bronx,NewYork,10461,USA
KlausBuchholz, DepartmentofTechnicalChemistry,TechnicalUniversity, Braunschweig,D-38106,Germany
YoannM.Chabre, DepartmentofChemistry,Universite ´ duQue ´ beca ` Montre ´ al, Montre ´ al,Que ´ bec,H3C3P8,Canada
TarunK.Dam, DepartmentofMolecularPharmacology,AlbertEinsteinCollegeof Medicine,Bronx,NewYork,10461,USA
R.ColinHughes, NationalInstituteforMedicalResearch,MillHill,London,UK
LennartKenne, DepartmentofChemistry,SwedishUniversityofAgricultural Sciences,Uppsala,Sweden
OlleLarm, ExTheraAB,KarolinskaSciencePark,Stockholm,Sweden
AlfLindberg, DepartmentofClinicalBacteriology,KarolinskaInstitutet,Huddinge UniversityHospital,Huddinge,Sweden
SusanaD.Lucas, CentrodeQuı´micaeBioquı´mica/DepartamentodeQuı´mica eBioquı´mica,FaculdadedeCie ˆ nciasdaUniversidadedeLisboa,Ed.C8,5○ Piso, CampoGrande,1749-016,Lisboa,Portugal
Ame ´ liaP.Rauter, CentrodeQuı´micaeBioquı´mica/DepartamentodeQuı´mica eBioquı´mica,FaculdadedeCie ˆ nciasdaUniversidadedeLisboa,Ed.C8,5○ Piso, CampoGrande,1749-016,Lisboa,Portugal
Rene ´ Roy, DepartmentofChemistry,Universite ´ duQue ´ beca ` Montre ´ al,Montre ´ al, Que ´ bec,H3C3P8,Canada
MiguelSantos, CentrodeQuı´micaeBioquı´mica/DepartamentodeQuı´micae Bioquı´mica,FaculdadedeCie ˆ nciasdaUniversidadedeLisboa,Ed.C8,5○ Piso, CampoGrande,1749-016,Lisboa,Portugal
x LISTOFCONTRIBUTORS
Ju ¨ rgenSeibel, InstituteofOrganicChemistry,UniversityofWurzburg,AmHubland, D-97074,Wu ¨ rzburg,Germany
NathanSharon, WeizmannInstituteofScience,BiologicalChemistryDepartment, Rehovot,Israel
NunoM.Xavier, CentrodeQuı´micaeBioquı´mica/DepartamentodeQuı´micaeBioquı´mica,FaculdadedeCie ˆ nciasdaUniversidadedeLisboa,Ed.C8,5○ Piso,Campo Grande,1749-016,Lisboa,Portugal
PREFACE
Synthesishasbeenasustainedareaofmajorinterestincarbohydratescience,andthe precedingVolume62ofthisseriesfeaturedthreechaptersfocusingindetailonthe constructionofglycosidiclinkages.Manyestablishedsyntheticmethodspermitthe elaborationofcomplextargetmolecules,butfrequentlyinvolvetheuseoftedious protection–deprotectionsequencesandexpensiveorhazardousreagents.Thiscurrent Volume63of Advances presentstwoarticlesthatofferpromiseofusefulmethodologiesforsimplifiedproceduresamenabletolow-costlarge-scaleapplications,using mildconditionsandenvironmentallyfriendlymaterials.
RauterandhercoauthorsXavier,Lucas,andSantos(Lisbon)presentherea detailedoverviewofthepotentialforheterogeneouscatalystsinusefulsynthetic transformationsofcarbohydrates.Suchsilicon-basedcatalystsaszeolitesareeasy tohandleandrecover,arenontoxic,andcanofferinterestingpossibilitiesforexercisingstereo-andregio-controlinmanyestablishedcarbohydratetransformations.
Inthemidstofwide-rangingresearchontheroleofcomplexoligosaccharidesin biologicalrecognitionprocesses,andtheattendantfocusonsynthesisofsuchmolecules,theimportantroleofoligosaccharidesinlarge-scalecommercialapplicationsis oftenoverlooked.ThecontributionbySeibelandBuchholz(WurzburgandBraunschweig)inthisvolumeaddressesindetailthosetoolsofparticularvalueforpreparation ofoligosaccharidesthatserveneedsinthefood,pharmaceutical,andcosmetic industries.Majoremphasisisdevotedtotheuseofreadilyavailableenzymes(glycosidases,glycosynthases,glucansucrases,fructansucrases)andabundantcarbohydratesubstrates,especiallysucrose,andtheapplicationsofenzymeandsubstrate engineering.Particularattentionisgiventothoselarge-scaleapplicationsofoligosaccharidesthatserveassweeteners,aswellaspromisingnewmedicalapplications.
Twocomplementarytreatmentsdealwithdifferentaspectsoftheintensecurrent interestinthebiologicalrecognitionphenomenabetweencarbohydratesandproteins. DamandBrewer(NewYork)examineindetailtheenergeticsandmechanismsof bindingbetweenlectins(carbohydrate-bindingproteins)andthemultivalentglycoproteinreceptorsonthesurfaceofnormalandtransformedcells,aswellasothertypes ofcarbohydratereceptors,includinglinearglycoproteins(mucins).Theauthors postulateacommon‘‘bind-and-jump’’mechanismthatinvolvesenhancedentropic effectswhichfacilitatebindingandsubsequentcomplexformation.
Inanextensiveandcomprehensivesurvey,ChabreandRoy(Montreal)revisitthe subjectofneoglycoconjugatesintroducedthreedecadesagobyStowellandLeein Volume37ofthisSeries.Itwasthenanascenttopic,andtheMontrealauthorsnow bringtogetherinasinglelargearticlethevastnewliteraturebasethathas
subsequentlyevolvedinthefieldofthe‘‘glycosideclustereffect.’’Theyearshave witnessedmuchcreativityinthedesignandstrategiesofsynthesisthathaveafforded awidearrayofnovelcarbohydratestructures,andreflecttheongoingdynamic activityinthisrapidlyevolvingarea,evensincetherecentarticlebytheNicotra groupinVolume61ofthisseries.Elaboratenanostructures,nowtermedglycoclusters andglycodendrimers,featurearraysofcarbohydrateepitopesjoinedvialigandsonto avarietyofscaffolds,includingcalixarenes,porphyrins,andsuchcarbonnanostructuresasfullerenesandnanotubes.Theirsynthesisandcharacterizationisaddressedin detailalongwithevaluationviasuchtechniquesasmicroarraysandothermodern analyticaltechniques,fortheirpotentialinapplicationtobiologicalsystems.
Thecontributionsoftwooftheworld’sleadingcarbohydrateinnovatorsarerecognizedinthisissue.TheworkofRogerJeanlozevolvedfromaclassicalbackgroundin synthesisandstructureelucidationtowideapplicationsinthebiologicalareawhich haveledhimtobeconsideredasthefatherofthesubjectnowknownasglycobiology. Hecontributedextensivelytothese Advances,witharticlesinVolumes6,11,13,and43 oftheseries,andhislifeandscientificworkisthesubjectoftheobituaryarticleby Sharon(Israel)andHughes(London).ThearticlebyKenne,Larm,andAlfLindberg (Stockholm)surveysthecareerofBengtLindberg,andespeciallynotesLindberg’s developmentofthemethodologyformicroscaleanalysisofcarbohydratestructuresthat haspermitteddeterminationofthesequencestructureofminutesamplesofoligo-and poly-saccharidesfrombiologicalsourcesandhasenabledtheexplosivegrowthof modernresearchinglycobiology.Lindbergwasalsoanotablecontributortothisseries, witharticlesinVolumes15,31,33,and48thatdocumentinLindberg’sclassicterse styletheevolutionofstructuralmethodologyfromearlybeginningstosophisticated applications,inparticularforbacterialpolysaccharides.
ThedeathonOctober8,2009ofAntonioGo ´ mezSa ´ nchezisnotedwithregret.He wasoneofthesuccessorsoftheSevillecarbohydrateschoolbuiltupbyFrancisco Garcı´aGonza ´ lez,withwhomhecoauthoredinVolume20achapteronthereactionof aminosugarswith1,3-dicarbonylcompounds,asubjectthatwasamajorthemeof Go ´ mezSa ´ nchez’sresearch.
SincerethanksareexpressedtoProfessorsStephenAngyalandJ.GrantBuchanan fortheirmanyyearsofadviceandsupportasmembersoftheBoardofAdvisors. WelcomedasanewmemberoftheBoardisProfessorToddLowary.
DEREK HORTON
Washington,DC November,2009
ROGERW.JEANLOZ
1917–2007
RogerWilliamJeanloz,whopassedawayonSeptember12,2007,6weeksshortof his90thbirthday,wasamongtheearliestpioneersinthefieldnowknownas Glycobiology.Hemadeseminalcontributionstothesubject,andtrainedanumber ofleadersinthefield.Hewasoneoftheprimeorganizersinthe1950softhe Glycosaminoglycan,Glycoprotein,andGlycolipidGroup(knownasthe4Gs), laternamedtheSocietyofComplexCarbohydrates,andeventuallytheSocietyfor Glycobiology,ofwhichheservedasPresidentin1974.
FromGlycogenandDeoxySugarstoComplexCarbohydrates
JeanlozwasbornonNovember3,1917inBerne,Switzerland,toaFrenchmother andaSwiss–Germanfather.HewasbroughtupinFrench-speakingGenevawherehe pursuedclassicalstudiesemphasizingGreekandLatinatCollegeCalvin.In1936,he wasawardedtheB.S.degreefromthisCollegeandin1941aDiplomainChemical EngineeringfromtheUniversityofGeneva,wherehestudiedorganicchemistryand biochemistry.Hiskeeninterestinscienceandresearchbeganin1941whenKurtH. Meyer,wellknownforhispioneeringstudiesoncelluloseandstarch,acceptedhimas adoctoralstudent.InMeyer’slaboratory,Jeanlozinvestigatedtheenzymaticdegradationofstarch1 andthenthestructureofmuscleglycogen.2 Thelatterstudieswere thesubjectofhisD.Sc.thesis,completedin1943.Atthesametimeheservedashead instructorfororganicchemistry.
In1943,afterbeingawardedtheD.Sc.degree,JeanlozwasappointedasResearch Associate,firstwithMeyerandthenwithTadeuszReichstein,NobelLaureateforhis workonsteroidhormones.WithReichsteinhestudiedthechemistryofdeoxysugars, someofwhichareconstituentsofthesehormones,anddeveloped3 anewmethodfor theassayofthesesugars.In1946–1947hespent1yearinCanadaasResearch AssociateattheUniversityofMontreal,wherehecollaboratedwithD.A.Prins fromtheResearchDivision,ClevelandClinic,Cleveland,OH,inthepreparationof
ISBN:978-0-12-380856-1
DOI:10.1016/S0065-2318(10)63001-6.
4
NATHANSHARONANDR.COLINHUGHES
areviewofthechemistryofcarbohydrates4 fortheprestigious AnnualReviewsof Biochemistry,thefirstofmanyimportantoneshewroteduringhisscientificcareer. HethenmovedtotheUnitedStates,whereheworkedfor1yearasaSeniorResearch FellowintheNationalInstitutesofHealthlaboratoryofthenotedcarbohydrate chemist,ClaudeS.Hudson,wherehebecameinvolvedinthestudyofriboseandits derivatives5–7,andhecontributedwithHewittFletcherfromthesamelaboratorya review8 onthechemistryofriboseinthefledgling AdvancesinCarbohydrate Chemistry.Thefollowing3yearswerespentattheWorcesterFoundationfor ExperimentalBiology,thenunderthedirectionofthenotedendocrinologistGregory Pincus,workingonsteroidhormones,asubjectonwhichhecontinuedtocollaborate withthePincusgroupforseveralyearsthereafter.9–14
In1951,JeanlozwasinvitedbyDr.WalterBauer,ChiefoftheMedicalServices andoftheArthritisUnitattheMassachusettsGeneralHospital,tobecomeamember oftheRobertW.LovettMemorialGroupfortheStudyofCripplingDiseases,andto organizealaboratoryforthestudyofthechemicalstructureofthepolysaccharidesof connectivetissueandofrelatedbiochemicalproblems.Tenyearslater,hewas appointedastheHeadofthenewlyformedLaboratoryforCarbohydrateResearch oftheLovettGroup,andin1969asProfessorofBiologicalChemistryandMolecular PharmacologyatHarvardMedicalSchool.Heheldthesepositionsuntilhisretirement,andcontinuedtobeactiveinresearchandteachingthereafter.Itwasinthe CarbohydrateResearchlaboratorythatJeanloz,duringhalfacentury,mademajor contributionstoourknowledgeofthestructure,biosynthesis,andfunctionofcomplex carbohydrates,anareathatnowfallsunderthesubjectofglycobiology.Indeed,he maybeconsideredasoneoftheearlyglycobiologists.
Mostprominentamonghiscontributionsweretheelucidationofglycosaminoglycan structures,chieflybymethylationanalysis;thesynthesisofrareaminosugars;establishmentofthestructureofthepolysaccharidebackboneofthebacterialcell-wallpeptidoglycan;providingthefoundationforstructuralstudiesofthecarbohydratemoietiesof N-andO-linkedglycoproteins;synthesisofmanyoftheglycopeptideconstituentsof glycoproteins;detailedstructuralanalysisaswellassynthesisofseveralofthedolichyl sugarphosphatesinvolvedinproteinglycosylation;characterizationofglycansaccumulatedinlysosomalstoragediseases,andtheactionpatternofcatabolicglycosidases. Inaddition,analysisofTA-3glycoproteininitiatedinhislaboratoryledtothemost detailedinvestigationofanytumor-relatedglycoproteinexaminedatthetime.Hiswork hashadimplicationsinmanyareasofbiology,amongthembiochemistryandbacteriology,immunology,andcancerresearch.Adominantfeatureofmuchofthethisworkwas Jeanloz’semphasisontheimportanceofchemicalsynthesisofcomponentpartsof complexglycoconjugatesinordertodistinguish,forexample, D or L enantiomers,ring
structuresand a or b anomers,intheoverallstructureofbiologicallyactive macromolecules.
ApplicationsofMethylationAnalysis
BeforejoiningtheLovettGroup,Jeanlozdevotedconsiderableefforttounderstandingtheperiodateoxidationreaction,startingwithanexaminationofitseffects onglucosamine.15 HeandEnricoForchiellithenusedittoexaminethestructureof hyaluronicacid15,16 andchitin.17 Itrapidlybecameevidenttohimthatthismethod,as wasthecaseinthesuccessfuldeterminationofthestructureofsimplerpolysaccharidessuchasglycogenorstarch,requiredsupplementationwithotherones,particularlythemethylationtechnique.Thelattertechniquehadalreadybeenattemptedin thefieldofglycosaminoglycans,butwithoutpositiveresults.Themaindifficulty residedinthefactthatdegradationofamethylatedheteropolysaccharide,madeupof repeatingunitsofhexosamineanduronicacidwithdifferentlinkages,couldgiverise toalargenumberofmono-di-andtri-O-methylatedmonosaccharides.Itwas thereforenecessarytosynthesizeallofthereferencesubstances,andtoseparate andidentifytheminartificialmixtures.Jeanlozwasencouragedinthislongand arduoustask,whichrequiredgramquantitiesofstartingmaterials,bytheknowledge thatifshowntobeefficient,themethodcouldbeappliednotonlytotheelucidationof thestructureoftheglycosaminoglycansbutalsotootherclassesofcomplex carbohydrates.
Inthecourseofthe1950sJeanlozsynthesized13methylatedderivativesof glucosamineandgalactosamine(reviewedin Ref.18).Theseincludedthe4-methyl19 and6-methyl20 ethersofglucosaminehydrochlorideandthe3,6-and4,6-dimethyl ethersofthishexosamine.21 Concurrentlythe3-22 4-,23 and6-24 monomethylethersof galactosaminehydrochloride,andits3,6-25 and4,6-26 dimethyletherswerealso prepared.Methylatedderivativesofothermonosaccharideswerealsosynthesized subsequently,amongthemthoseofmuramicacid,withHaroldFlowers27 and N-acetylmannosaminewithNasir-ud-Din.28
Themethylatedglucosamineandgalactosaminederivativesinparticularwerein suchdemandbyotherlaboratoriesasreferencecompoundsthatoneresearchassistant workedfulltimesolelytoreplenishsuppliesofthesecompounds.Inthissynthetic approach,whichtook10yearstoaccomplish,Jeanlozwashelpedbyseveralassociates,includinghiswifeDorothy,andPierreJ.Stoffynwhojoinedhisgroupin1953 andstayeduntil1961.Oneofthemanyresultsoftheirproductivecollaborationwas theStoffynandJeanlozmethod29 foridentificationofhexosaminesbyninhydrin degradationtothecorrespondingpentoses,whichisstillthesimplestmethodto distinguishbetweenglucosamineandgalactosamine.
NATHANSHARONANDR.COLINHUGHES
ConnectiveTissueGlycosaminoglycanStructure
ThemethylatedderivativesservedasthebasisofelegantstudiesinwhichJeanloz andhiscolleaguesunequivocallyestablishedthestructureofhyaluronan,dermatan sulfate,andthechondroitinsulfates.Theyalsoclarifiedmanyconfusingissues, includingthepositionofthesulfategroupsinthesepolymers.Inthecourseofthis work,theyprovedthatdermatansulfatecontained L-iduronicacid,asugarnotknown beforetooccurinnature.
Applicationofthemethylationtechniquetohyaluronanestablishedthelinkageat position3oftheglucosamineI moietyandthelinkageatposition4oftheglucuronic acidmoiety.30 Eventually,hyalobiouronicacid[b-GlcA-(1 ! 3)-GlcNAc],therepeatingunitofhyaluronanwassynthesized;itwasidenticalwithoneoftheaciddegradationproductsoftheparentpolysaccharide.31,32 Jeanlozandhiscolleaguesalso isolatedmethylderivativesofhyalobiouronicacidfromthemethylated polysaccharide.
MethylationanalysisofchondroitinsulfateAshowedthatthesulfateislocatedat position4ofthegalactosaminemoiety,thatthe N-acetyl-b-galactosamineresidueis locatedatposition4oftheglucuronicacidmoiety,andthatgalactosaminepossessesa pyranosestructure.Thismethodgavealsoadditionalevidencefora b-(1 ! 3)interglycosidiclinkagebetweenglucuronicacidand N-acetylgalactosamineresidues, consistentwitharepeatingdisaccharideunitof b-glucuronate-(1 ! 3)-4-sulfo-Nacetyl-b-galactosamine-(1 ! 4).Usingthesametechnique,Jeanlozalsoinvestigated thestructureofchondroitinsulfateC,andprovidedevidencethatchondroitinsulfate Cisanunbranchedpolysaccharidecomposedofalternateresiduesofglucuronicacid and N-acetylgalactosamine6-sulfateresidues b-glycosidicallylinkedatpositions (1 ! 3)and(1 ! 4),respectively(see Ref.33 forareview).
Dermatansulfate,alsotermedchondroitinsulfateB,arelatedglycosaminoglycan constituentofconnectivetissue,wasknowntobecomposedofgalactosamineanda uronicacid,originallybelievedtobeglucuronicacidbutthenclaimedtobeiduronic acidbasedlargelyoncolorreactionsandpaperchromatography.However,the D or L-enantiomerstatusofthelattermonosaccharidewasnotclear.JeanlozandStoffyn unequivocallycharacterizedthemonosaccharideas L-iduronicacidbyconsecutive desulfation,reduction,andhydrolysisofthepolysaccharide,followedbyisolationof thecrystalline2,3,4-tri-O-acetyl-1,6-anhydro-b-L-idopyranose,whichwasshownto beidenticaltoanauthenticspecimensynthesizedfrom1,2-O-isopropylidene-b-Lidofuranose.34
IAllsugarsareofthe D configuration,unlessotherwisenoted.
R.W.JEANLOZ
Duringthiscarefulanalyticalworkonchondroitinanddermatansulfates,Jeanloz notedthatthestoichiometryofthepurifiedglycosaminoglycansindicatedsignificant heterogeneity,inparticularvariablesulfation.Itisnowknownthatsuchvariabilityin sulfationanduronicacidcontentsignificantlyimpactsontheabilityofconnectivetissuepolysaccharidestobindadiverserangeofbiologicallyactivemolecules, includinggrowthfactorsandproteaseinhibitors.
MammalianMembraneGlycolipids
Asearlyas1955,Jeanlozfeltthatthemethodsdevisedforthestudyofconnectivetissueglycosaminoglycanscouldbeappliedtootherclassesofglycoconjugates. TogetherwithSen-itiroHakomori,whocametotheLaboratoryforCarbohydrate ResearchfromtheUniversityofSendaiinJapan,heundertooktheoneroustaskof purifyingthesubstancesconferringhumanerythrocyteblood-typespecificity.ExtractionoferythrocytesofhumanAandBbloodtypeaffordedsmallamountsof glycolipids( 1mg/lofblood)possessingblood-groupactivity.Purificationwas obtainedbyadsorptiononactivatedaluminaandactivatedsilicagel,followedby partitionchromatographyoncellulose.Theactivesubstancesisolatedfromthetwo differentbloodtypesshowedgreatsimilarities.Partialhydrolysisshowedaresistant corecomposedoffattyacid,sphingosine,glucose,andgalactoseforthesubstances isolatedfrombothbloodtypes.Inbothsubstances,additionalresiduesofeither galactoseorgalactosamineconstituentswerelocatedat,ornear,theextremitiesof thecarbohydratechain,hintingatthepossibilitythatthesesugarswerepartofthe bloodtypeimmunodeterminants.35 Subsequently,theyisolatedfromhumancancerous tissueaglycolipidrichinfucose,36 andtogetherwithJerzyKoscielakandK.J.Bloch showedthatthisglycolipidcross-reactedimmunologicallywithhumanblood-group substances.37 Inaddition,thefirstdefinitiveevidenceoftheimmunogenicityof glycolipidswasobtainedbyimmunizingrabbitswithapurifiedglycolipid(globoside) withtheformationofaprecipitatingantiglobosideantibody.38 Theantibodyagglutinatedandhemolyzedhumanredcells,providedthattheywerepretreatedwithtrypsin.
BacterialCell-WallPeptidoglycan
Intheearly1960sJeanlozbecameintriguedbypeptidoglycan,therigidconstituent ofbacterialcellwallsthatendowsthesemicroorganismswiththeircharacteristic shape,whetherround(cocci)orelongated(bacilli).Atthetimeitwasbelievedthat thepolysaccharidebackboneofpeptidoglycanconsistsofarepeatingdisaccharidein which N-acetylglucosamineis b-(1 ! 6)linkedtomuramicacid(3-O-D-lactyl-Nacetylglucosamine),andthatlinkagebetweenthedisaccharideunitsinthebackbone is b-(1 ! 4).Toestablishunequivocallythestructureofthedisaccharide,the
8 NATHANSHARONANDR.COLINHUGHES
synthesisofmuramicacidanditsvariousderivatives,includingthedisaccharide bGlcNAc-(1 ! 6)-MurNAcwasperformedintheJeanlozlabbyHaroldFlowers39–41 andbyToshiakiOsawa.42 Theseincludedvariousmethylethers43 andglycosides,44 andacetylderivatives45 ofmuramicacidandits galacto46 and manno47 analogues, inthesynthesisofseveralofwhichPierreSinay ¨ wasinvolved.Additionally,muramic acid6-phosphatewassynthesized48 andtheabsoluteconfigurationofthecarboxyethyl(lactyl)side-chainofmuramicacidwasestablished.49 Inthecourseofthese studies,thepeptidoglycanpolysaccharidebackbonewasshowntocontainsome disaccharideunitshavingthe manno (ratherthan gluco)analogofmuramicacid.50 Methodsweredevelopedquiteearlyonforthelarge-scalepreparationofbacterialcell wallsfrom Micrococcuslysodeikticus (laterrenamed M.luteus)51 andfortheisolation ofthenaturaldisaccharidefromlysozymedigestsofthewalls.Comparisonofthe syntheticdisaccharidewiththenaturalonerevealedquitesurprisinglythatthetwo werenotidentical.Theconclusionwasthatthenaturaldisaccharideis b-(1 ! 4)linked,asisthepolysaccharidebackbonethroughout.52 Thiswasconfirmedby comparisonofthenaturaldisaccharidewithsynthetic b-GlcNAc-(1 ! 4)-MurNAc. Thebacterialpolysaccharideisthereforechemicallyhomologoustochitin.
Oneoftheminorbyproductsoftheisolationprocedureofthedisaccharidefrom lysozymedigestsofbacterialcellwallswasthetetrasaccharide b-GlcNAc-(1!4)b-MurNAc-(1!4)-b-GlcNAc-(1!4)-MurNAc.Thisstructureisreadilycleavedby lysozyme,andhasprovedtobeextremelyusefulinotherlaboratoriesforthestudyof themechanismofactionoftheenzyme.
InvertebrateMatrixGlycoconjugates
Inthelate1960s,Jeanlozbegananextendedstudyoftheextracellularmatrixof invertebrates.Earlier,Jeanloz’scolleagueintheLovettUnit,JerryGross,hadpointed outthatinvertebratematricescontainedgreaterandmorevariedamountsofcarbohydratethanvertebratematrices.TheJeanlozlaboratory,inparticularRichardKatzman, togetherwithAndyKangoftheGrosslaboratory,setouttoidentifythesepoorly characterizedglycoconjugatesfromthreeinvertebratephyla,theseaanemone Metridiumdiocanthus,theseacucumber Thyonebriareus,andamarinesponge Hippospongiagossypina 53–55 Themajoroligosaccharidechainoftheinvertebratecollagens, presentinhigheramountsthaninvertebratecollagens,wasshowntobe a-glucopyranosyl-(1 ! 2)-b-galactopyranosyl-(1 ! 5)-L-lysine,similartothemajorglycanof vertebratecollagen.Asparagine-linked N-glycanscontainingglucosamine,fucose, andmannosewerealsopresent.Furtherstudiesshowedthepresenceinseacucumber matrixoftwomajoracidicglycosaminoglycans,namelyachondroitinsulfatesimilar instructuretovertebratechondroitins,andanovelpolyfucosesulfate.Thislatter
componentwasnamedthyonatanandcharacterizedasan a-(1 ! 2)-linkedpolyfucose-4-sulfatepolysaccharide.Theabsenceofanaminosugardistinguishesthyonatan fromallknownvertebrateconnective-tissueglycoconjugates.Chondroitinandthyonatanwerenotfoundinspongesandseaanemone,leadingtothespeculationthat acidicglycoconjugatesplaynocrucialroleincollagenfibrilformation,contrasting withtheprevailingideaatthetimethatregularlyspacedacidicgroupsmayactasa templateuponwhichcollagenfibrilsarebuiltup.Interestingly,arabinosewasisolated fromspongeconnectivetissue:itsidentitywasconfirmedbythepreparationofa crystallinederivativeofbenzyl-1-phenylhydrazine.56 Althougharabinoseisacommonsugarinplants,itisveryrareinanimals.Katzmanproposedthatthearabinofuranosylnucleosidesofuracilandthymidine,isolatedinthe1950sfromsponges,may serveinbiosynthesisofarabinose-containingpolysaccharidesintheseorganisms. Interestininvertebratematrixglycoconjugateshasrecentlyincreased.Someofthese matrices,forexampletheseacucumber,haveanabilitytoaltertheirstiffnessin responsetochangesinpHorionicconcentrations,creatingthepossibilityofderiving newdynamicneocompositesforbiomedicalapplications.
RareAminoSugars
ThesyntheticstudiesofJeanlozledtothesolutionofmanyotherquestionsin carbohydratechemistry,especiallythatofuncommonaminosugars.Resultingfrom thesestudieswasthesynthesis,mainlywithDorothyJeanlozandwithSoniaTarasiejskayaofseveralaminosugars,someofwhichforinstance,gulosamine,57,58 had beenshowntobeconstituentsofaminoglycosideantibiotics,suchasthestreptothricins,andothersthatatthetimewerenotknowntooccurinNature.Theseincluded allosamineandtalosamine,3-amino-3-deoxyidose,and3-amino-3-deoxygulose,as wellas2,4-diamino-2,4-dideoxyglucose.59–61 Bacillosamine(2,4-diamino-2,4,6-trideoxyglucose),anotherrareaminosugar,wasfirstisolatedintheJeanlozlaboratory byNathanSharonfromabacterialpolysaccharidethathepreparedattheWeizman Institute,Rehovot.62 Thisstructure,determinedlaterelsewhere,hasrecentlybeen identifiedasaconstituentofthecarbohydrate–peptidelinkinggroupofglycoproteins ofmanyeubacterialpathogens,andappearstoberequiredfortheirvirulence.Itis thereforeattractingconsiderablecurrentinterest.
StructuralAnalysisofProtein-BoundOligosaccharides
Anumberofthecentralthemesofcurrentglycoconjugateresearchcanbetraced backtostudiesbegunintheJeanlozlaboratory.Oneprominentexampleisthe elucidationofthesequencesofthecarbohydrateslinked N-or O-glycosylicallyto asparagineorserine/threonineresiduesrespectivelyinglycoproteins.Littlewas
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knownaboutthesestructuresatthetime:rapidmethodshavesubsequentlybeen developed,providinginformationthatiscrucialinglycomics,describingthevariety ofglycanstructuresindifferentorganismsandtissues.Workwasinitiatedinthelate 1950sbytheJeanlozlaboratoryontwoserumglycoproteins,alpha1-acidglycoproteinandfetuinbyEdEylarandRobertSpiro,respectively.63–66 Inthiswork,purified glycosidases,suchas Diplococcuspneumoniae neuraminidaseand b-N-acetylglucosaminidase,wereusedforthefirsttime.Sequentialremovalofsugarsfromthe nonreducingterminalsoftheglycansbytheglycosidasesledtorational,ifpartial, proposalsforoligosaccharidesequence.Additionalinformationwasobtainedbymild acidhydrolysisforfragmentsequencing,methylationanalysis,andsequentialperiodateoxidation(Smithdegradation).Forthefirsttime,thecommonpresenceof N-acetyllactosamineattheterminiofcomplex-typeasparagine-linkedglycanswas demonstratedandshownunequivocallybyanalysisofthecrystallinedisaccharide. Jeanlozalsosuggestedfromstudieswithalpha1-acidglycoproteinthattheinnercore, linkedtoasparaginedirectly,wascomposedoftwo N-acetylglucosamineandseveral mannoseresidues.AsadditionalproofoftheproposedstructuresJeanlozandhis colleagues,inparticularHariGarg,usedchemicalsynthesis.67 Thecarbodiimide couplingreagentwasemployedextensivelyforthesynthesisofasparagine-linked compoundssuchas b-GlcNAc-N-Asn.Syntheseswerealsodescribedofdisaccharide fragmentssuchas b-GlcNAc-(1 ! 4)-GlcNAcandtrisaccharidessuchas a-Man(1 ! 6)-b-GlcNAc-(1 ! 4)-GlcNAc.Thesewerecoupledtogivethecorresponding asparagine-linkedderivatives.Subsequently,methodsweredevelopedforthesynthesisofO-glycans,basedonthecorestructure a-GalNAc1-Ser.67
LipidIntermediatesinGlycoproteinBiosynthesis
Long-chainisoprenoidalcohols,polyprenolsanddolichols,wereidentifiedinthe 1970sasintermediatesinbiosynthesisofbacterialpolysaccharidesaswellasinthe multistepprocessofproteinglycosylationinplantsandanimals.Thedonorthatinitiates N-linkedglycansynthesisisaGlc3Man9GlcNAc2 structureattachedtothelipiddolichol throughapyrophosphatelinkage.Theenzymesthatbuildupadolichylpyrophosphateintermediatecontainingtwo N-acetylglucosamineresiduesandthefirstfivemannose residuesutilizesugarnucleotidesdirectly.Transferofthelastfourmannoseresiduesand thethreeglucoseresiduesaremediatedbydolichylphosphate-linkedsugars.Progressin thisresearchwashamperedbythelowabundanceofthephosphorylateddolichol intermediatesincellextracts.Jeanlozandhiscolleagues,inparticularChrisWarren andAnnetteHercovicsandinitiallyinaveryproductivecollaborationwithJackStrominger’slaboratoryatHarvard,undertooktheunequivocalchemicalsynthesisofthese stillpoorlycharacterizedmolecules,andtheirutilizationinbiochemicalstudiesfor
R.W.JEANLOZ
comparisonwiththenaturalcompounds(seeforexample, Refs.68–70).Althoughthe workraisedmanydifficultproblems,anovelmethodologywasdevelopedforthefirst facilesynthesisofdolicholphosphateandpyrophosphate,andtheirsugarderivatives. Althoughitwasgenerallyassumedatthetimethatthelipidmoietyinthelipidintermediateswasdolichol,thishadnotbeenestablishedasinsufficientmaterialwasavailable forchemicalcharacterization:similarlytheanomericidentityofthesugarintermediates wasnotknown.Toaddressthesepoints,theradioactivelylabeledlipidintermediates formedintissuessuchascalfpancreasmicrosomeswerecharacterizedbycomparison withthesyntheticcompounds.Usingthisapproach,theformationintissueswas establishedofdolichyl-b-mannosylphosphate,dolichyl-b-glucosylphosphateand dolichyl-b-N-acetylglucosaminylpyrophosphate.Alipid-linkeddi-N-acetylchitobiose structureformedinthemicrosomalfractionwasshownunequivocallytobeidenticalto syntheticdi-N-acetylchitobiosyl-dolichylpyrophosphate.Inatechnical tourdeforce the pyrophosphate-linkedlipidintermediatecontainingasubstantialpartofthenatural Glc3Man9GlcNAc2 lipidintermediatewasprepared.71 Inthiswork,thesyntheticchemistryintheJeanlozlaboratorywenthandinhandwiththebiochemistry,andmadeamajor contributiontounderstandingofthemodeofassemblyoftheasparagine-linked carbohydrates.
LysosomalGlycosidaseDeficiencies
Inthelate1980s,JeanlozandChrisWarren,incollaborationwithBrianWinchester fromtheInstituteofChildHealth,UniversityofLondonandPeterDanielfromthe KennedySchriverofMentalRetardation,Boston,becameinterestedinthelysosomal storagediseasemannosidosis,aswellasinthetoxicosisinducedinsheepbyingestion offoodstuffscontainingthetoxinswainsonine,apowerfulmannosidaseinhibitor.72–75 Inpartthisinterestwaspromptedbytheneedforrelativelylargeamountsof mannose-richoligosaccharidesforchemicalsynthesisofdolicholintermediatesand glycopeptides.Urinefrompatientswithnoorlowlevelsoflysosomalmannosidases isaconvenientsourceofsucholigosaccharides.Theworkunexpectedlyrevealed someinterestingdataonthepatternsofglycancatabolism.Thestructuresofoligosaccharidesaccumulatedandexcretedbymannosidosispatients,aswellasfromcats andcattlegeneticallyaffectedbylossoflysosomalmannosidases,werecharacterized. Inallcases,thestructureswereconsistentwiththeincompletebreakdownofN-linked glycansorbiosyntheticintermediates.Therewereclearinterspeciesdifferences, however.Compoundscontainingacoreofdi-N-acetylchitobiose,insteadofasingle N-acetylglucosamineresiduewereisolatedfromcattleandcatsbutwereabsentin humanmannosidosis.Humantissuesalonecontainalysosomalendo-b-N-acetylglucosaminidase,accountingforthisdifference.Therewerealsomajordifferencesinthe
NATHANSHARONANDR.COLINHUGHES
structuresoftheexcretedoligomannosecompounds,presumablyreflectingdifferencesinsubstratespecificityoflysosomalmannosidasesinthethreespecies.In humanmannosidosis,wherethereisacompletedeficiencyofthemajorlysosomal mannosidase,thestructureandlevelsofthestoredoligosaccharidesappearedtoresult fromtheactionofaminorlysosomalmannosidasewithspecificityforan a-(1 ! 6) linkage.Infelinemannosidosis,aseveredeficiencyoflysosomalmannosidasesleads tostorageofintactMan9GlcNAc2 oligosaccharidesandtheundegradedMan3GlcNAc2 coreofcomplex-typeglycans.Infurtherstudies,thedetectionofabnormal catabolicproductsinplacentawasfoundtoofferapromisingearlydiagnosisof lysosomalmannosidasedeficiency.76
Tumor-CellGlycoproteins
Attheendofthe1960s,therewasconsiderableinterestinemergingevidencethat alteredcellsurfaceglycosylationappearedtobecommoninmalignantandpremalignantepithelialandsomenonepithelialcells.Thepresenceatcellsurfacesoflarge amountsofcarbohydrate-containingmacromoleculeshadpreviouslybeendemonstratedbyhistochemicalstaining.However,theidentityofthesecomponentsandtheir relevancetocarcinogenesiswaspoorlyunderstood.Atthistime,theJeanlozlaboratory,inparticularJohnCodington,beganworkontheglycoconjugatesoftumorcells incollaborationwithBarbaraSanfordoftheMGHPathologyDivision.77–80 Previous workhadshownthatsomesub-linesoftheTA3tumorcell,derivedfromaspontaneousmammaryadenocarcinomaofanA-strainmouse,haveasurfacemembrane enrichedincarbohydrate.Itwasalsoknownthatthesesub-lineshadloststrain specificityandweretransplantableintostrainsofallogeneicmice,thusevading immunologicalrejectionacrossmajorhistocompatibilitybarriers.Sanfordhad shownfurtherthatsuccessfultransplantationoftheTA3sub-linesintoallogeneic micewasmarkedlyreducedbytreatmentofthecellswithneuraminidase.The suggestionwasthatthesecellsescapethehostdefensesystemthroughcellsurface antigenmaskingbyhighlysialylatedcell-surfaceglycoconjugates.In1972,themajor sialylatedglycoconjugateofTA3cellswasisolatedintheJeanlozlaboratoryand calledepiglycanin.Asshownalittlelaterepiglycaninturnedouttobeasurface membrane-associatedmucincontainingatypicalserineandthreonine-richtandemrepeatsequence,atransmembranedomainandacytoplasmicdomain.TheextracellulardomainwasshownbyDirkvandenEijdenandCodingtontobeheavily substitutedwithO-glycans,basedonthecorestructure b-Gal-(1 ! 3)-GalNAc attachedtoserineorthreonineresidues,heavilysubstitutedwithsialylresidues. ImmunoelectronmicroscopyshowedthatepiglycanincoverstheTA3cellsurface withanextendedfilamentouscoat.Crucially,thisglycoproteinwasfoundnottobe
present,orpresentinlowamounts,inTA3tumorsublinesthatcannotgrowin allogeneichosts,offeringstrongcorroborationoftheideathatcellsurfaceepiglycanin stericallyhinderscytotoxicT-cellsfrommountinganimmuneresponseagainstthe tumor.Manytypesofcancercellsarenowknowntopossesslargeconcentrationsof mucin-likesubstancesattheircellsurface.These,likeepiglycanin,arecharacterized bythepresenceofmultiple O-glycosylically-linkedglycansandextendedrod-like conformations.Theevidenceindicatesthatthesestructures,likeepiglycanin,play rolesinhinderingimmunesurveillancemechanismsandincreasingmetastaticpotential.Recently,thehumanorthologueofepiglycaninhasbeenclonedandnamed Muc21.Itisexpressedinmanymalignanttissues,includinglungadenocarcinomas andbreastcancers,andisofmuchcurrentinterest.
Editor,SymposiaOrganizer,andExpertonCarbohydrateNomenclature
TheproductivityofJeanlozisexemplifiedbyhisbibliographyofmorethan400 publications.Heauthoredmanyreviews,whichareoutstandingfortheirclarity, concisestyle,andinterpretation.Healsoeditedseveralbooks,themostnotableof whichis TheAminoSugars,athree-volumetreatisecoeditedwithEndreBalazs.81 He wasparticularlyconcernedwiththenomenclatureofcarbohydratesandwasinstrumentalinresolvingkeyissuesandintroducingmanynewandwell-definedtermssuch ashyaluronanandglycosaminoglycan.82,83 Inhispublications,hewasalwayscareful inusingthefullchemicalnomenclatureofcarbohydrates.Thus,hefavoredtheterm 2-amino-2-deoxy-D-glucosefor N-acetylglucosamine,andalmostcompletelyavoided theuseoftheabbreviation‘‘GlcN.’’Inadditiontohisresearchandteachingactivities atHarvardandelsewherethroughouttheworld,Jeanlozservedonnumerouscommitteesandeditorialboards;amongothers,hewasoneofthefoundersintheearly 1960softhejournal CarbohydrateResearch,thefirstofitskinddevotedtothe subject.
Thecommunityofcarbohydratescientistsisespeciallyindebtedtohimasacentral figureinthesettingupandorganizationoftheInternationalSymposiaonGlycoconjugates.ThefirstoftheseSymposiawasconvenedin1965inSwampscottwith JeanlozasCo-Chairman.HewasalsotheprimemoverinencouraginghisEuropean colleaguestoorganizethesecondandthirdmeetingsinLillein1973andinBrighton in1975,respectively,andwasactiveintheorganizationofthe4thSymposiumon GlycoconjugatesheldatWood’sHole.TogetherwithJohnGregoryheeditedthetwovolumeproceedingsofthisSymposium.84 In1974–1975,Jeanlozwaspresidentofthe NationalSocietyofComplexCarbohydrates.Hewasalsoactiveformanyyearsinthe DivisionofCarbohydrateChemistryoftheAmericanChemicalSociety,ofwhichhe servedasChairman.Hisnumerousachievementshavebroughthimmanynational
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andinternationalhonors.TheseincludetheMedaloftheSocie ´ te ´ deChimieBiologiquedeFrance;MedaloftheUniversitydeLie ´ ge;PrixJaubert,UniversityofGeneva; ClaudeS.HudsonAward,AmericanChemicalSociety;DocteurHonorisCausa, UniversityofParis;andrecentlytheAlexandervonHumboldtAward,Germany’s mostprestigiousscientificaward.Posthumously,thesecondeditionof Essentialsin Glycobiology,editedbyAjitVarki etal.andpublishedin2008,isdedicatedtohis memoryandthatofRosalindKornfeld‘‘pioneersintheelucidationofglycan structureandfunction.’’
DedicatedTeacher,AvidSportsman,andInveterateTraveler
ThescopeofJeanloz’sactivities,andtheknowledgeandenthusiasmthathe impartedtohiscolleagues,allcombinedtoinspirehismanystudents.Hewasfor manyyearsatutorwiththeFacultyofArtsandSciencesofHarvardUniversity, retiringfromthisactivityonlyafewmonthsbeforehisdeath.Becauseofhisqualities, hewasabletoattractandinmanycaseskeepableassociatestohislaboratoryand frequentlycontinuedcollaborationswiththemaftertheyleft.Theexcellenttraining theyreceivedfromJeanlozandthecontactsandfriendshipsmadeinhislaboratory exerciseddecisiveinfluenceontheircareers.Hisdemonstrationoftheimportanceof applyingtherigoroustechniquesoforganicchemistrytothesolutionofbiochemical problemswasthemostcrucialpointofthistraining.
TheuniquelycongenialatmosphereintheJeanlozlaboratorythatisremembered withaffectionbythosewhoworkedwithhimwasaidedgreatlybythepresenceofhis charmingwife,Dorothea,anorganicchemist,whocollaboratedwithhimformany years.Inspiteoftheirbusyschedules,DorotheaandRogeralwaystookgreatinterest inthewell-beingoftheirassociates.Jeanloz’spersonalqualitiesandbonvivant characterendearedhimtoallofhiscolleagues.
Jeanlozwasaninveteratetraveler,whotaughtstudentsfromaboutasmany countriesashehadvisited,atotaldifficulttotallyinanycategory.Inhisyounger yearshewasaskilledalpinist,andmademanyoftheclassicalclimbsintheSwiss FrenchAlps.Hewasalsoanexpertskier,asporthecontinuedtoenjoyintohismore advancedyears,oftenaccompaniedbyhisgrandchildren.Jeanlozwasaloverof classicalmusic,andanenthusiasticgardener.Hisloveforplantscameearlyinhislife whenhebroughtbouquetsofalpineflowersfrommountainexpeditions.Hisinterest insportscanbetracedtohischildhood.Attheageof12,hestartedplayingbasketball, asportthathadbeenintroducedintoSwitzerlandbytheAmericanYMCA.Hewasa memberoftheGenevateamthatwasselectedtorepresentSwitzerlandininternationalgames.Laterhebecameakeentennisplayer,andwasafamiliarfigureonthe tenniscourtsoftheMGH,andintheLongwoodCricketClubnearthefamilyhomein
Newton,Massachusetts,wheretheyraisedtheirfourchildrenDanielle,Sylvie,Raymond,andClaude.FormanyofthelateryearsRogerandDorothyenjoyedtimein theirdelightfulsecondhomeinTourettes-sur-LoupinthesouthofFrance,wherethey wereoftengeneroushoststofriendsandcolleagues.
In1986,aSymposiumwasheldtohonorRogerJeanlozaspartofthe8thInternationalSymposiumonGlycoconjugatesinHouston,Texas.Forthisoccasionthe eminentBritishscientistAlbertNeubergerwrote:‘‘His(Jeanloz’s)workischaracterizedbyamasteryofallchemicalandbiologicalmethods,byreliabilityoftheresults obtained,andbycarefulandbalancedinterpretation.Thereishardlyanytopicinthis widefield,whichhehasnottouched,andwhichhasnotbenefitedfromhisresearch. RogerJeanlozhasmadehislaboratoryoneofthefewoutstandingcentersinthefield ofcomplexcarbohydrates.Hiscombinationofsupremechemicalcompetenceand biologicalunderstandingarethehallmarkofhiscareer.’’
RogerJeanlozwillberememberedwithgreataffectionandutmostrespectbyhis manyfriends,colleagues,anddiscipleswherevertheyare.
ListofassociateswhoworkedwithJeanlozattheLaboratoryofCarbohydrate Research:
E.Alpert,J.Alroy,C.Augi,L.SAzaroff,J.Badet,N.Baggett,E.A.Balasz, M.Beppu,A.K.Bhattacharaya,A.Bhattacharyya,V.P.Bhavanandan,P.Biely,K. C.Blieszner,G.Blix,D.J.Bloch,K.J.Bloch,K.J.BlochSr.,C.H.Bolton,A.A. Bothner,M.C.Brown,B.Bugge,R.A.Byrn,G.F.Cahill,M.S.Choudhary,A.-M. Close,J.F.Codington,A.G.Cooper,T.Dalianis,P.F.Daniel,D.Daniels,D.M. Darby,H.R.Das,E.A.Davidson,P.Degand,M.R.Dick,F.DuBois,D.vanden Ejnden,J.V.Ellard,N.A.Evans,E.H.Eylar,N.E.Fayaz-ud-Din,H.M.Flowers,R. Fricke,D.M.Frim,T.C.Fuller,C.Gansser,H.G.Garg,J.DeGasperi,M.C.Glick, D.Gminsky,A.M.Golovchenko,Y.Goussault,P.H.Gross,M.Gut,M.A.Gvalambor,P.Gyorgy,S.Hakomori,H.vanHalbeeck,A.M.Halford,M.D.A.Halford, M.H.Halford,A.Hallen,V.B.Hatcher,F.Heatley,A.Herscovics,O.Hoshino,S.A. Houssain,R.C.Hughes,M.R.Jahnke,L.F.James,D.Jeanloz,A.Jimbo,M.Z.Jones, R.Kaifu,R.L.Katzman,R.D.Kilker,W.Klaffke,G.Klein,E.H.Kolodny,Y. Konami,J.Koscielak,J.J.Lamar,G.Lamblin,L.A.Lampert,D.W.Laske,R.D. Lasky,M.L.Laver,M.M.Lee,N.Lee,C.Levrat,M.Lhermitte,K.B.Linsley,E. Lisowska,C.M.Liu,I.Y.Liu,T.Matsumoto,M.D.Maxfield,J.W.McArthur,D. Medrek,C.Merser,M.-L.Milat,D.K.Miller,S.C.Miller,T.Mitvedt,KMiyai,Y. Mizuno,J.D.Moore,J.H.G.M.Mutsaers,S.Nakabayashi,T.E.Nash,E.Salomon, R.Naves,N.Nikrui,H.VonNocolai,T.Osawa,P.D.Palmer,M.Parquet,P. Perchfelides,J.M.Petit,J.R.Poortmans,D.Power,E.S.Rachaman,S.S.Raghavan, A.M.C.Rapin,E.J.SRathke,V.N.Reinhold,G.P.Roberts,A.A.Rossini,S.W.
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Rostad,P.Roussel,S.Sadeh,M.M.ElSadek,B.H.Sanford,S.Santikarn,W.Sasak, D.M.Schmid,K.Schmid,A.S.Schmit,D.Schwarzenbach,G.O.H.Schwarzmann,J. F.Scott,M.Shaban,M.Shalev,N.Sharon,C.Silber,P.Sinay ¨ ,H.S.Slayte,M.Spinola, R.G.Spiro,G.F.Springer,D.K.Stearns,R.L.Stephens,P.F.Stoffyn,G.Strecker,S. Suzuki,Z.Tarasiejska-Glazer,P.Thoma,J.S.Tkacz,M.Tomoda,M.Tre ´ me ` ege,R.B. Trimble,B.Tuttle,Nasir-ud-Din,J.R.Vercellotti,A.Veyrie ` res,J.F.G.Vliegenthart,R. Vrba,E.Walker,C.D.Warren,H.Wecyer,J.F.Wedgwood,N.R.Williams,B. Winchester,J.K.Wold,I.Yamashina,T.Yamazaki,J.Yoshikawa,N.Zamchek,U. Zehavi,F.Zilliken.
Theworkofonlyafewofthemorethantwohundredcolleaguesandcollaborators ofJeanlozlistedherecouldbedetailedwithinthescopeofthistribute.
NathanSharon R.ColinHughes
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