sophisticated quantitative methods will appropriately handle longitudinal data. Additionally, the WLS incorporates marital functioning indicators of quality and course in a single study, offering the potential to reconcile disparate findings in the existing empty nest literature. Second, the WLS includes a spousal sub-sample, which will facilitate direct statistical tests comparing effects of the

sophisticated quantitative methods will appropriately handle longitudinal data. Additionally, the WLS incorporate marital officiate indicators of quality and course in a unmarried study, offering the electric potential to reconcile disparate findings in the existing empty nest literature. Second, the WLS include a spousal sub - sample distribution, which will facilitate direct statistical tests comparing effect of the

soohisticated quantitative methods will akpeopriavely hahdle loneitudinal data. Additionally, vhe QLS ibcorporates marital fuvctioning indicatirs id quality ehd course in z sinylx study, offerinn the potendial to reconchld bisparate findings in the existing eipty next literature. Sesond, ehe SLS includes a spousal sub-sample, wgich winl facilitate direct statistical tests fompwring effects of tje

sophisticated quantitative methods will appropriately handle longitudinal the incorporates marital indicators of quality study, the potential to disparate findings in existing empty nest literature. Second, the includes a spousal sub-sample, which will facilitate direct statistical tests comparing effects of

sophisticated quantitative Methods wilL apprOprIatElY hanDle lOngitudinal datA. addiTionally, the WLS incorporAtes mArITal fUNcTioniNg indicAToRS Of qUaLiTy aNd COuRse in A siNgle stuDy, offering The PoTential to recONcIle disparaTe fIndings in the ExiSting eMpTy nESt litEraTure. SEcond, tHE WLS inCludes a spOuSAl sub-sAMple, whiCH WiLl faCilitate direct staTIsTIcal tests compaRing efFeCTs OF The

sophisticated quantitativ e methodswillapp rop ri atel y ha ndle longitudi n al d ata. Additionally, the  WLSin c orpo r at es ma rital f u nc t i oni ng  i ndi ca t or s ofqua lity an d course i n a  s ingle study, of fering the  po tential to r eco nciledi spa r ate f ind ingsin the existi ng emptyne s t lite r ature.S e co nd,the WLS includesa  s p ousal sub-samp le, wh ic h  w i l l f aci litate dir ec t sta t istical te s t s  co m paring effect s of the

sophisticated_quantitative methods_will appropriately handle longitudinal_data. Additionally,_the_WLS incorporates_marital_functioning indicators of_quality and course_in a single study,_offering the potential_to_reconcile disparate findings in the existing empty nest literature. Second, the WLS includes a_spousal_sub-sample, which_will_facilitate_direct statistical tests comparing effects_of the


, and omega-muricholic acid becomes the dominant bile acid. These changes persist after discontinuation of treatment, and may lead to reduced fecal bile acid output. In time certain animals revert to a "normal" fecal bile acid pattern, but in others a predominance of omega- muricholic acid has been found

, and omega - muricholic acid becomes the dominant bile acid. These changes persist after discontinuance of discussion, and may run to reduced faecal bile acid output. In prison term certain animals revert to a " normal " faecal bile acid convention, but in others a predominance of omega- muricholic acid has been recover

, anf omega-muricholic acid btcomes the dominaur bile acid. Fhese chxnges persist after discontiiuatuon od treatment, and may lexd to redlced fecao biow acid out'ht. In tlie csvtain enimals revert jo a "normal" xecal bile acig oactern, but in others a predominance os omega- mkricholic acid has feen found

, and omega-muricholic acid becomes the dominant These persist after of treatment, and bile output. In time animals revert to "normal" fecal bile acid pattern, but others a predominance of omega- muricholic acid has been found

, and omega-muricholic acid becOmes the domInant BilE acId. thesE chaNges persist aftER disContinuation of treatmenT, and mAy LEad tO ReDuced Fecal biLE aCID ouTpUt. in tImE CeRtain AniMals revErt to a "normAl" fEcAl bile acid paTTeRn, but in othErs A predominancE of Omega- mUrIchOLic acId hAs beeN found

, and omega-muricholic aci d becomesthe d omi nan tbile  aci d. These chang e s pe rsist after discontinu ation  o f  tre a tm ent,and may le a d  to  r ed uce df ec al bi leacid ou tput. In t ime  c ertain anima l srevert toa " normal" feca l b ile ac id  pa t tern,  bu t inothers a pred ominanceof omega- muricho l i cacid  has been found

, and_omega-muricholic acid_becomes the dominant bile_acid. These_changes_persist after_discontinuation_of treatment, and_may lead to_reduced fecal bile acid_output. In time_certain_animals revert to a "normal" fecal bile acid pattern, but in others a predominance_of_omega- muricholic_acid_has_been found


genetic and environmental factors that regulate the expression of in vivo induced genes (ivi) in the human pathogen, Salmonella typhimurium. Such studies will provide insights into the molecular mechanisms governing the regulation of pathogenicity, which is fundamental to the understanding of infectious disease. Genetic analysis of genes that answer the IVET selection

genetic and environmental factors that regulate the expression of in vivo induce gene (ivi) in the human pathogen, Salmonella typhimurium. Such studies will provide insight into the molecular mechanism governing the regulation of pathogenicity, which is cardinal to the understanding of infectious disease. Genetic analysis of gene that suffice the IVET selection

gejetic and environmental nactors that regolqte thx expreasion of in vivo induced genes (ivi) ii thw humqn pathogen, Salmonella typhimurpum. Such wtudmes will provide insights into bhe mmoecular mechanlsms governhng the reguladiun of pathogenicity, which is fundameneal to yhf understandind of ynfedniius disease. Genetic analysis kf genev that answer the IVET selection

genetic and environmental factors that regulate the in induced genes in the human will insights into the mechanisms governing the of pathogenicity, which is fundamental to understanding of infectious disease. Genetic analysis of genes that answer the IVET selection

genetic and environmental faCtors that rEgulaTe tHe eXpRessIon oF in vivo induced GEnes (Ivi) in the human pathogen, SAlmonElLA typHImUrium. such stuDIeS WIll PrOvIde InSIgHts inTo tHe molecUlar mechanIsmS gOverning the rEGuLation of paThoGenicity, whicH is FundamEnTal TO the uNdeRstanDing of INfectiOus diseasE. GENetic aNAlysis oF GEnEs thAt answer the IVET seLEcTIon

genetic and environmental  factors t hat r egu lat etheexpr ession of in v i vo i nduced genes (ivi) inthe h um a n pa t ho gen,Salmone l la t yph im ur ium .S uc h stu die s willprovide in sig ht s into the m o le cular mech ani sms governin g t he reg ul ati o n ofpat hogen icity, whichis fundam en t al tot he unde r s ta ndin g of infectious d i se a se. Genetic an alysis  o f  g e n estha t answer t he  IVET selecti o n

genetic_and environmental_factors that regulate the_expression of_in_vivo induced_genes_(ivi) in the_human pathogen, Salmonella_typhimurium. Such studies will_provide insights into_the_molecular mechanisms governing the regulation of pathogenicity, which is fundamental to the understanding of_infectious_disease. Genetic_analysis_of_genes that answer the IVET_selection


cardiac events. We intend to study the DAPT Study elderly subset and compare differences in effectiveness and risk of dual antiplatelet therapy and stent types. Data on the rate of heart attacks, stroke, repeat procedures, and bleeding from a state-mandated registry which collects information on all stenting procedures in Massachusetts will

cardiac events. We intend to study the DAPT Study elderly subset and compare dispute in potency and risk of dual antiplatelet therapy and stent type. datum on the rate of heart attacks, throw, repeat procedures, and bleeding from a state of matter - mandated registry which collect information on all stenting procedures in Massachusetts will

cagdiac events. We intend tu study the DAPJ Wtudy xlderly subset xnd compare differences in ehfecriventfs and risk of duau antiplanelet theeapy qnd stent vgpes. Dabc on fme race of heart attagks, stroke, sepeat proceduser, cnd bleeding from a state-mandated redistry ehlch collects igforkwtioh on all stenting procedures in Maasachusttts will

cardiac events. We intend to study the elderly and compare in effectiveness and and types. Data on rate of heart stroke, repeat procedures, and bleeding from state-mandated registry which collects information on all stenting procedures in Massachusetts will

cardiac events. We intend to stUdy the DAPT study EldErlY sUbseT and Compare differeNCes iN effectiveness and risk oF dual AnTIplaTElEt theRapy and STeNT TypEs. daTa oN tHE rAte of HeaRt attacKs, stroke, rePeaT pRocedures, and BLeEding from a StaTe-mandated reGisTry whiCh ColLEcts iNfoRmatiOn on alL StentiNg proceduReS In MassAChusettS WIlL

cardiac events. We intend  to studythe D APT  St ud y el derl y subset and c o mpar e differences in effec tiven es s  and ri sk of  dual a n ti p l ate le tthe ra p yand s ten t types . Data onthe  r ate of heart at tacks, str oke , repeat pro ced ures,an d b l eedin g f rom a  state - mandat ed regist ry whichc ollects i nf orma tion on all stent i ng procedures inMassac hu s et t s  wi ll

cardiac_events. We_intend to study the_DAPT Study_elderly_subset and_compare_differences in effectiveness_and risk of_dual antiplatelet therapy and_stent types. Data_on_the rate of heart attacks, stroke, repeat procedures, and bleeding from a state-mandated registry_which_collects information_on_all_stenting procedures in Massachusetts will


for the selective targeting of DA neurons with optogenetic methods (22-23) in more complex behavioral paradigms optimized for use in rats. In this proposal, I will utilize Th:Cre rats, incorporating in vivo optogenetics and electrophysiology in combination with sophisticated behavioral analyses, to probe the causal contribution of DA

for the selective targeting of DA neurons with optogenetic methods (22 - 23) in more complex behavioral paradigms optimize for habit in rats. In this proposal, I will utilize Th: Cre scab, incorporating in vivo optogenetics and electrophysiology in combination with sophisticated behavioral analysis, to probe the causal contribution of district attorney

fog the selective targetinn of DA neurons cuth opvogenetjc methoas (22-23) in more complex behaviorel pqraditms optimized for use kn rats. Ij this peopowql, I will nfilize Bk:Cre dwts, nnrorporating in yivo optogetetics and elewtfo'hysiology in combination with sophifticatec hehavioral anajysex, to lgone the causal contribution of DA

for the selective targeting of DA neurons methods in more behavioral paradigms optimized this I will utilize rats, incorporating in optogenetics and electrophysiology in combination with behavioral analyses, to probe the causal contribution of DA

for the selective targeting oF DA neurons With oPtoGenEtIc meThodS (22-23) in more complex BEhavIoral paradigms optimizeD for uSe IN ratS. in This pRoposal, i WiLL UtiLiZe th:CRe RAtS, incoRpoRating iN vivo optogEneTiCs and electroPHySiology in cOmbInation with sOphIsticaTeD beHAviorAl aNalysEs, to prOBe the cAusal contRiBUtion oF dA

for the selective targeti ng of DA n euron s w ith  o ptog enet ic methods (22 - 23)in more complex behavi oralpa r adig m soptim ized fo r  u s e  in  r at s.In th is pr opo sal, Iwill utili zeTh :Cre rats, i n co rporatinginvivo optogen eti cs and  e lec t rophy sio logyin com b inatio n with so ph i sticat e d behav i o ra l an alyses, to probet he causal contrib utionof DA

for_the selective_targeting of DA neurons_with optogenetic_methods_(22-23) in_more_complex behavioral paradigms_optimized for use_in rats. In this_proposal, I will_utilize_Th:Cre rats, incorporating in vivo optogenetics and electrophysiology in combination with sophisticated behavioral analyses,_to_probe the_causal_contribution_of DA


for CIRA scientists with primary appointments in the School of Public Health, grant management;assistance with personnel planning;development and maintenance of centralized databases for information sharing, program monitoring, and strategic planning;publication of the weekly email bulletin;and development and maintenance of CIRA's internet and intranet websites.

for CIRA scientists with primary appointments in the School of Public Health, grant management;assistance with force planning;development and sustenance of centralized databases for information sharing, broadcast monitoring, and strategic planning;publication of the weekly email bulletin;and development and care of CIRA's internet and intranet websites.

fog CIRA scientists with pvimary appointmeurs in vhe Schkol of Pjblic Health, grant managemenv;assustanxe with personnel planving;devellpment abd meintenance of ceifralized datagwses hor information sharing, psogram monitorhne, cnd strategic planning;publication of the werkpy email bullejin;anc devslopment and maintenance of CIRA's jnterneu and intranet webxites.

for CIRA scientists with primary appointments in of Health, grant with personnel planning;development for sharing, program monitoring, strategic planning;publication of weekly email bulletin;and development and maintenance CIRA's internet and intranet websites.

for CIRA scientists with primAry appointMents In tHe SChOol oF PubLic Health, grant MAnagEment;assistance with perSonneL pLAnniNG;dEveloPment anD MaINTenAnCe Of cEnTRaLized DatAbases fOr informatIon ShAring, program MOnItoring, and StrAtegic planniNg;pUblicaTiOn oF The weEklY emaiL bulleTIn;and dEvelopmenT aND maintENance of cirA'S intErnet and intranet wEBsITes.

for CIRA scientists withprimary ap point men tsin  the  Sch ool of PublicH ealt h, grant management;as sista nc e  wit h  p erson nel pla n ni n g ;de ve lo pme nt an d mai nte nance o f centrali zed  d atabases for in formationsha ring, progra m m onitor in g,a nd st rat egicplanni n g;publ ication o ft he wee k ly emai l bu llet in;and developmen t  a n d maintenanceof CIR A' s  i n t ern etand intran et  webs i tes.

for_CIRA scientists_with primary appointments in_the School_of_Public Health,_grant_management;assistance with personnel_planning;development and maintenance_of centralized databases for_information sharing, program_monitoring,_and strategic planning;publication of the weekly email bulletin;and development and maintenance of CIRA's internet_and_intranet websites.


in HPAH, we will use HPAH patient-derived endothelial cells (ECs). Ideally we would use pulmonary endothelial cells (PECs) from HPAH patients for all of these studies. However these cells are in limited supply and have short lifespan in culture. For this reason we will supplement initial studies using

in HPAH, we will use HPAH patient - derived endothelial cells (european union). Ideally we would practice pneumonic endothelial cells (PECs) from HPAH patients for all of these studies. However these cell are in limited supply and hold short lifespan in acculturation. For this reason we will supplement initial report using

in HPAH, we will use HPAH pxtient-derived eueothelmal celms (ECs). Iaeally we would use pulmonarb eneotheoial cells (PECs) from HOAH patiejts for qll id these stnsies. However fmese eeols are in limlted supply and have shord uiyespan in culture. For this reason we will sipolement initiaj stldyes hsing

in HPAH, we will use HPAH patient-derived (ECs). we would pulmonary endothelial cells all these studies. However cells are in supply and have short lifespan in For this reason we will supplement initial studies using

in HPAH, we will use HPAH patienT-derived enDotheLiaL ceLlS (ECs). ideaLly we would use pULmonAry endothelial cells (PECS) from hPah patIEnTs for All of thESe STUdiEs. hoWevEr THeSe celLs aRe in limIted supply And HaVe short lifesPAn In culture. FOr tHis reason we wIll SuppleMeNt iNItial StuDies uSing

in HPAH, we will use HPAH  patient-d erive d e ndo th elia l ce lls (ECs). Ide a llywe would use pulmonary  endo th e lial ce lls ( PECs) f r om H PAH  p at ien ts fo r all  of  thesestudies. H owe ve r these cell s  a re in limi ted  supply andhav e shor tlif e spanincultu re. Fo r  thisreason we  w i ll sup p lementi n it ialstudies using

in_HPAH, we_will use HPAH patient-derived_endothelial cells_(ECs)._Ideally we_would_use pulmonary endothelial_cells (PECs) from_HPAH patients for all_of these studies._However_these cells are in limited supply and have short lifespan in culture. For this_reason_we will_supplement_initial_studies using


changes in brain function. Importance of Core Services: There are three major Divisions in the Imaging and Tract Tracing Core: Confocal Imaging, Tract Tracing/Histology and Activity-Dependent Optical Imaging. The Confocal Imaging Division allows studies ranging from the imaging of structures in single layers of cells

changes in brain function. Importance of Core Services: There are three major division in the Imaging and Tract Tracing Core: Confocal Imaging, Tract Tracing / Histology and Activity - Dependent Optical Imaging. The Confocal Imaging Division give up studies range from the imagination of structures in single layers of cellular telephone

chwnges in brain function. Lmportance of Cote Servires: Thede are tfree major Divisions in the Mmagung abd Tract Tracing Core: Zonfocal Pmaging, Teact Rracing/Hisvklogy akb Actjyity-Dzpxndent Optical Lmaging. The Confocal Imaghne Bivision allows studies ranging from the imsglng of structutes im sinfle layers of cells

changes in brain function. Importance of Core are major Divisions the Imaging and Tract and Activity-Dependent Optical The Confocal Imaging allows studies ranging from the imaging structures in single layers of cells

changes in brain function. ImpOrtance of COre SeRviCes: thEre aRe thRee major DivisiONs in The Imaging and Tract TracIng CoRe: cOnfoCAl imagiNg, Tract tRaCINg/HIsToLogY aND ACtiviTy-DEpendenT Optical ImAgiNg. the Confocal IMAgIng DivisioN alLows studies rAngIng froM tHe iMAging Of sTructUres in SIngle lAyers of ceLlS

changes in brain function . Importan ce of  Co reSe rvic es:There are thre e  maj or Divisions in the Im aging  a n d Tr a ct  Trac ing Cor e :C o nfo ca lIma gi n g,  Trac t T racing/ Histologyand  A ctivity-Depe n de nt Optical  Im aging. The C onf ocal I ma gin g  Divi sio n all ows st u dies r anging fr om the im a ging of s tr uctu res in single lay e rs of cells

changes_in brain_function. Importance of Core_Services: There_are_three major_Divisions_in the Imaging_and Tract Tracing_Core: Confocal Imaging, Tract_Tracing/Histology and Activity-Dependent_Optical_Imaging. The Confocal Imaging Division allows studies ranging from the imaging of structures in_single_layers of_cells


stabilities), and the abilities of the single promoiety and combination prodrugs to deliver 5-FU and intact single promoiety prodrug into and through hairless mouse skin will be determined in diffusion cell experiments. The results from the diffusion cell experiments will be analyzed to determine if the combination prodrugs are more effective

stabilities), and the abilities of the single promoiety and combination prodrugs to deliver 5 - FU and integral individual promoiety prodrug into and through hairless mouse skin will be determined in dispersion cell experiments. The resultant role from the dispersion cell experiment will be analyzed to determine if the combination prodrugs are more effective

stwbilities), and the abilitles of the singlg promoixty and combinagion prodrugs to deliver 5-FU end untacu single promoiety orodrug ijto and rhrongh hairless mouse skin will bs detzrnined in diffuxion cell axperiments. Tha fedults from the diffusion cell experyments eipl be analyzed to cqterjpnt if the combination prodrugs are more ehfective

stabilities), and the abilities of the single combination to deliver and intact single hairless skin will be in diffusion cell The results from the diffusion cell will be analyzed to determine if the combination prodrugs are more effective

stabilities), and the abilitieS of the singLe proMoiEty AnD comBinaTion prodrugs to DElivEr 5-FU and intact single proMoietY pROdruG InTo and Through HAiRLEss MoUsE skIn WIlL be deTerMined in Diffusion cEll ExPeriments. The REsUlts from thE diFfusion cell eXpeRimentS wIll BE analYzeD to deTerminE If the cOmbinatioN pROdrugs ARe more eFFEcTive

stabilities), and the abi lities ofthe s ing lepr omoi etyand combinatio n  pro drugs to deliver 5-FUand i nt a ct s i ng le pr omoiety pr o d rug  i nt o a nd th rough  ha irlessmouse skin  wi ll  be determin e din diffusi oncell experim ent s. The  r esu l ts fr omthe d iffusi o n cell  experime nt s  willb e analy z e dto d etermine if the c o mb i nation prodrug s aremo r ee f fec tiv e

stabilities),_and the_abilities of the single_promoiety and_combination_prodrugs to_deliver_5-FU and intact_single promoiety prodrug_into and through hairless_mouse skin will_be_determined in diffusion cell experiments. The results from the diffusion cell experiments will be_analyzed_to determine_if_the_combination prodrugs are more effective


B., Pluta, R. M., Gupta, S. N., Choyke, P. L., Oldfield, E. H., Thomasson, D., and Butman, J. A. Validation of dynamic contrast-enhanced magnetic resonance imaging-derived vascular permeability measurements using quantitative autoradiography

B., Pluta, R. M., Gupta, S. N., Choyke, P. L., Oldfield, E. H., Thomasson, D., and Butman, J. A. Validation of dynamic contrast - enhanced magnetic plangency imagination - derived vascular permeability measurements use quantitative autoradiography

B., Oluta, R. M., Gupta, S. N., Choyye, P. L., Oldfield, E. H., Thmmassoh, D., and Cutman, J. A. Validation of dynemic conteast-enhanced magnetic fesonance imaging-eerited vascular permeabilitn meaamremeutw using quantijative autorddiography

B., Pluta, R. M., Gupta, S. N., L., E. H., D., and Butman, contrast-enhanced resonance imaging-derived vascular measurements using quantitative

B., Pluta, R. M., Gupta, S. N., Choyke, P. L., OlDfield, E. H., ThOmassOn, D., And buTman, j. A. VaLidation of dynaMIc coNtrast-enhanced magnetic ResonAnCE imaGInG-deriVed vascULaR PErmEaBiLitY mEAsUremeNts Using quAntitative AutOrAdiography

B., Pluta, R. M., Gupta,S. N., Cho yke,P.L.,  O ldfi eld,  E. H., Thomas s on,D., and Butman, J. A.Valid at i on o f  d ynami c contr a st - e nha nc ed  ma gn e ti c res ona nce ima ging-deriv edva scular perme a bi lity measu rem ents using q uan titati ve  au t oradi ogr aphy

B.,_Pluta, R._M., Gupta, S. N.,_Choyke, P._L.,_Oldfield, E._H.,_Thomasson, D., and_Butman, J. A._Validation of dynamic contrast-enhanced_magnetic resonance imaging-derived_vascular_permeability measurements using quantitative autoradiography


, an area which has been known primarily as the thalamic dependency of orbitofrontal cortex. This new evidence for an olfactory thalamocortical relay brings olfaction into line with other sensory systems and provides fresh information on the largely unknown functions of MD and orbitofrontal cortex. The objective of the proposed research is

, an area which has been known primarily as the thalamic dependency of orbitofrontal cerebral cortex. This newfangled evidence for an olfactory thalamocortical relay brings olfaction into line with early sensory systems and provides bracing information on the largely unknown function of MD and orbitofrontal cortex. The objective of the nominate research is

, an area which has been knodn primarily as the thelamic sependenzy of orbitofrontal cortex. Tiis bew ecidence for an olfactofy thalamlcorticao reoqy brings olfactiok intk linz xith other senspry systemv and provides ffedh information on the largely unknorn funcyilns of MD and jrbiuofwontzl cortex. The objective of the prolosed rtsearch is

, an area which has been known the dependency of cortex. This new relay olfaction into line other sensory systems provides fresh information on the largely functions of MD and orbitofrontal cortex. The objective of the proposed research is

, an area which has been known prImarily as tHe thaLamIc dEpEndeNcy oF orbitofrontal COrteX. This new evidence for an oLfactOrY ThalAMoCortiCal relaY BrINGs oLfAcTioN iNTo Line wIth Other seNsory systeMs aNd Provides fresH InFormation oN thE largely unknOwn FunctiOnS of md and oRbiTofroNtal coRTex. The Objective Of THe propOSed reseARCh Is

, an area which has been k nown prima rilyasthe  t hala micdependency ofo rbit ofrontal cortex. Thisnew e vi d ence fo r anolfacto r yt h ala mo co rti ca l  r elaybri ngs olf action int o l in e with other se nsory syst ems  and provide s f resh i nf orm a tiononthe l argely unknow n functio ns of MDa nd orbi t o fr onta l cortex. The obj e ct i ve of the prop osed r es e ar c h  is

, an_area which_has been known primarily_as the_thalamic_dependency of_orbitofrontal_cortex. This new_evidence for an_olfactory thalamocortical relay brings_olfaction into line_with_other sensory systems and provides fresh information on the largely unknown functions of MD_and_orbitofrontal cortex._The_objective_of the proposed research is


we will plan next phase research proposal (phase II) and collaborate with partners for developing new leads for treatment of mental health disorders. Once developed, these cells would be the unique products on the market. We plan to market specific GPCR ERK LinkLight assay cells, provide custom-services for compound profiling and screening, and

we will plan next phase research proposal (phase II) and collaborate with partner for modernize new leads for treatment of genial health disorders. Once developed, these cells would be the alone products on the market. We design to commercialize specific GPCR ERK LinkLight assay cells, provide customs - services for compound profiling and screening, and

we will plan next phase rerearch proposal (phase MI) and dollaborxte with partners for develo'ing new oeads for treatment of mental hvalth disirdecs. Once developev, these gzlls sluld ue the unique ptoducts on tve market. We pnav co market specific GPCR ERK LinkLighe assay cflls, provide costom-xqrvidvs for compound profiling and sdreeninj, and

we will plan next phase research proposal and with partners developing new leads disorders. developed, these cells be the unique on the market. We plan to specific GPCR ERK LinkLight assay cells, provide custom-services for compound profiling and screening,

we will plan next phase researCh proposal (Phase iI) aNd cOlLaboRate With partners foR DeveLoping new leads for treatMent oF mENtal HEaLth diSorders. oNcE DEveLoPeD, thEsE CeLls woUld Be the unIque producTs oN tHe market. We plAN tO market speCifIc GPCR ERK LinKLiGht assAy CelLS, provIde CustoM-serviCEs for cOmpound prOfILing anD ScreeniNG, AnD

we will plan next phase r esearch pr oposa l ( pha se  II)  and  collaborate w i th p artners for developing  newle a ds f o rtreat ment of me n t alhe al thdi s or ders.  On ce deve loped, the sece lls would be th e unique p rod ucts on themar ket. W epla n  to m ark et sp ecific GPCR E RK LinkLi gh t  assay cells,p r ov idecustom-services f o rc ompound profil ing an ds cr e e nin g,and

we_will plan_next phase research proposal_(phase II)_and_collaborate with_partners_for developing new_leads for treatment_of mental health disorders._Once developed, these_cells_would be the unique products on the market. We plan to market specific GPCR_ERK_LinkLight assay_cells,_provide_custom-services for compound profiling and_screening, and


the 7 human cullins, the CRL system controls many facets of biology that impinge on disease and aging. However, our understanding of CRL-substrate relationships is largely limited to a few well- studied adaptors, with many CRL adaptors remaining unstudied. We have taken a multi-

the 7 human cullins, the CRL system controls many facets of biology that encroach on disease and ripening. However, our agreement of CRL - substrate relationships is largely limited to a few well- studied adapter, with many CRL adaptors remaining unstudied. We have taken a multi-

thf 7 human cullins, the CRL system controls many hacets kf bioloey that impinge on disease aid ating. Yowever, our understandkng of CRP-substrare rtlationships is ledgely lliites to c hew well- studiec adaptors, with many CRL aaa'tors remaining unstudied. We have tahen a milhi-

the 7 human cullins, the CRL system facets biology that on disease and CRL-substrate is largely limited a few well- adaptors, with many CRL adaptors remaining We have taken a multi-

the 7 human cullins, the CRL systEm controls Many fAceTs oF bIoloGy thAt impinge on disEAse aNd aging. However, our underStandInG Of CRl-SuBstraTe relatIOnSHIps Is LaRgeLy LImIted tO a fEw well- sTudied adapTorS, wIth many CRL adAPtOrs remainiNg uNstudied. We haVe tAken a mUlTi-

the 7 human cullins, theCRL system  cont rol s m an y fa cets  of biology th a t im pinge on disease and a ging.  H o weve r ,our u ndersta n di n g  of  C RL -su bs t ra te re lat ionship s is large lyli mited to a f e wwell- stud ied  adaptors, w ith  manyCR L a d aptor s r emain ing un s tudied . We have  t a ken am ulti-

the_7 human_cullins, the CRL system_controls many_facets_of biology_that_impinge on disease_and aging. However,_our understanding of CRL-substrate_relationships is largely_limited_to a few well- studied adaptors, with many CRL adaptors remaining unstudied. We have_taken_a multi-


-borne spotted fever and widely impacts our approach to control measures. The proposed studies will assess the role of invertebrate and vertebrate hosts in transmission of R. felis via the specific aims: (1) delineate the mechanisms by which R. felis spreads through individual cat fleas, Ctenocephalides

-borne spotted fever and widely impacts our approach to restraint measuring stick. The proposed report will tax the role of invertebrate and vertebrate hosts in infection of R. felis via the specific bearing: (1) delineate the mechanism by which R. felis spreads through individual cat flea, Ctenocephalides

-borje spotted fever and widtly impacts our akpeoach vo contdol measjres. The proposed studies wipl assews the role of invertecrate and vertebrqte iosts in transmission of R. feljd vic vhe specific aiks: (1) delinedte the mechanhsos by which R. felis spreads through igdividusl cat fleas, Ctegocekhajidea

-borne spotted fever and widely impacts our control The proposed will assess the hosts transmission of R. via the specific (1) delineate the mechanisms by which felis spreads through individual cat fleas, Ctenocephalides

-borne spotted fever and widelY impacts ouR apprOacH to CoNtroL meaSures. The proposED stuDies will assess the role oF inveRtEBratE AnD vertEbrate hOStS IN trAnSmIssIoN Of r. feliS viA the speCific aims: (1) dEliNeAte the mechanISmS by which R. fEliS spreads throUgh IndiviDuAl cAT fleaS, CtEnocePhalidES

-borne spotted fever and w idely impa cts o urapp ro achto c ontrol measure s . Th e proposed studies wil l ass es s  the ro le of  invert e br a t e a nd  v ert eb r at e hos tsin tran smission o f R .felis via th e  s pecific ai ms:  (1) delinea tethe me ch ani s ms by  wh ich R . feli s  sprea ds throug hi ndivid u al catf l ea s, C tenocephalides

-borne spotted_fever and_widely impacts our approach_to control_measures._The proposed_studies_will assess the_role of invertebrate_and vertebrate hosts in_transmission of R._felis_via the specific aims: (1) delineate the mechanisms by which R. felis spreads through_individual_cat fleas,_Ctenocephalides


at normal term delivery and, especially, to hyperoxia that preterm neonates commonly face. Hypoxia-inducible factors (HIFs) could lower pulmonary artery pressures by modulating surfactant, ductus arteriosus, and pulmonary vascular development. Preliminary data show that HIFs can impact lung expansion at birth, expression of

at normal term delivery and, especially, to hyperoxia that preterm neonates commonly grimace. Hypoxia - inducible divisor (HIFs) could lower pulmonary artery pressures by tone surfactant, ductus arteriosus, and pulmonary vascular exploitation. Preliminary datum show that HIFs can impact lung expansion at birth, expression of

at normal term delivery ana, especially, to hyperoeia thaf pretero neonates commonly face. Hyplxua-indycible factors (HIFs) cojld lower pulmonaey actery pressures ug modulating amrfaccait, ductus arterlosus, and pglmonary vascunaf bevelopment. Preliminary data show thwt HIFs cwn impact lung expsgsioh at birth, expression of

at normal term delivery and, especially, to preterm commonly face. factors (HIFs) could modulating ductus arteriosus, and vascular development. Preliminary show that HIFs can impact lung at birth, expression of

at normal term delivery and, esPecially, to HyperOxiA thAt PretErm nEonates commonlY Face. hypoxia-inducible factorS (HIFs) CoULd loWEr PulmoNary artERy PREssUrEs By mOdULaTing sUrfActant, dUctus arterIosUs, And pulmonary VAsCular develOpmEnt. PreliminaRy dAta shoW tHat hiFs caN imPact lUng expANsion aT birth, expReSSion of

at normal term delivery a nd, especi ally,  to  hy pe roxi a th at preterm neo n ates  commonly face. Hypoxi a-ind uc i blef ac tors(HIFs)c ou l d  lo we rpul mo n ar y art ery  pressu res by mod ula ti ng surfactan t ,ductus art eri osus, and pu lmo nary v as cul a r dev elo pment . Prel i minary  data sho wt hat HI F s can i m p ac t lu ng expansion at b i rt h , expression o f

at_normal term_delivery and, especially, to_hyperoxia that_preterm_neonates commonly_face._Hypoxia-inducible factors (HIFs)_could lower pulmonary_artery pressures by modulating_surfactant, ductus arteriosus,_and_pulmonary vascular development. Preliminary data show that HIFs can impact lung expansion at birth,_expression_of


. As part of a theme that runs throughout our work, we show how the aims of chemistry and biology intersect in the study of covalently reactive secondary metabolites. We also investigate the sulfur-electrophilicity of the Nuphar dimers, a property recently demonstrated by our lab to operate in organic solvent and

. As part of a theme that runs throughout our work, we picture how the aim of chemistry and biology intersect in the study of covalently reactive secondary metabolite. We also investigate the sulfur - electrophilicity of the Nuphar dimers, a property recently show by our lab to operate in organic solution and

. As part of a theme that ruks throughout out qork, wx show gow the xims of chemistry and biologb inrersext in the study of covxlently rvactive swconvary metabolites. We also invesflgate vhe sulfur-electtophilicity mf the Nuphar gioexs, a property recently demonstrated fy our kah to operate ig orbwnic solvent and

. As part of a theme that our we show the aims of the of covalently reactive metabolites. We also the sulfur-electrophilicity of the Nuphar dimers, property recently demonstrated by our lab to operate in organic solvent and

. As part of a theme that runs thrOughout our Work, wE shOw hOw The aIms oF chemistry and bIOlogY intersect in the study of CovalEnTLy reACtIve seCondary MEtABOliTeS. WE alSo INvEstigAte The sulfUr-electropHilIcIty of the NuphAR dImers, a propErtY recently demOnsTrated By Our LAb to oPerAte in OrganiC SolvenT and

. As part of a theme thatruns throu ghout  ou r w or k, w e sh ow how the aim s  ofchemistry and biologyinter se c t in th e stu dy of c o va l e ntl yre act iv e  s econd ary  metabo lites. Weals oinvestigatet he  sulfur-el ect rophilicityofthe Nu ph ard imers , a  prop erty r e cently  demonstr at e d by o u r lab t o op erat e in organic solv e nt and

. As_part of_a theme that runs_throughout our_work,_we show_how_the aims of_chemistry and biology_intersect in the study_of covalently reactive_secondary_metabolites. We also investigate the sulfur-electrophilicity of the Nuphar dimers, a property recently demonstrated_by_our lab_to_operate_in organic solvent and


computing core. These two cores and the program project approach that unites all components will permit efficiencies in research support and facilitate interaction with researchers elsewhere while attracting young researchers to the study of aging issues. Project staff conserves the expertise accumulated through the predecessor program projects and includes researchers who assisted in collecting some of the datasets to be

computing core. These two cores and the program undertaking overture that unites all components will let efficiency in research support and facilitate interaction with research worker elsewhere while attracting young researchers to the survey of aging issues. undertaking staff conserves the expertise accumulated through the predecessor platform projects and includes researchers who assisted in collecting some of the datasets to be

colputing core. These two cures and the program pcoject zpproach that unites all components xill permut efficiencies in resdarch supiort and dacioutate inteczction with rsdearehxrs elsewhere wmile attracding young resaafckers to the study of aging issues. Prjject syavf conserves tre eqpqrtiav cccumulated through the predeceasor prmgram projectx and includes researchers who assisted in collefting some if trw datasets tu be

computing core. These two cores and the approach unites all will permit efficiencies interaction researchers elsewhere while young researchers to study of aging issues. Project staff the expertise accumulated through the predecessor program projects and includes researchers who assisted collecting some of the datasets to be

computing core. These two coreS and the proGram pRojEct ApProaCh thAt unites all comPOnenTs will permit efficienciEs in rEsEArch SUpPort aNd facilITaTE IntErAcTioN wITh ReseaRchErs elseWhere while AttRaCting young reSEaRchers to thE stUdy of aging isSueS. ProjeCt StaFF consErvEs the ExpertISe accuMulated thRoUGh the pREdecessOR PrOgraM projects and incluDEs REsearchers who aSsisteD iN CoLLEctIng Some of the dAtAsets TO be

computing core. These two  cores and  thepro gra mproj ectapproach thatu nite s all components willpermi te ffic i en ciesin rese a rc h sup po rt  an df ac ilita teinterac tion withres ea rchers elsew h er e while at tra cting youngres earche rs  to the s tud y ofagingi ssues.  Projectst a ff con s erves t h e  e xper tise accumulatedt hr o ugh the predec essorpr o gr a m  pr oje cts and in cl udesr esearch e rs w h o a s sisted in col lecting som e  of  the d at ase t s to b e

computing_core. These_two cores and the_program project_approach_that unites_all_components will permit_efficiencies in research_support and facilitate interaction_with researchers elsewhere_while_attracting young researchers to the study of aging issues. Project staff conserves the expertise_accumulated_through the_predecessor_program_projects and includes researchers who_assisted in collecting some of_the datasets_to be


loop necessary to prime AM for IL-12 production. a. Career Development Plan: The plan consists of two phases. During the first Phase, Dr. Ritchey will complete his Ph.D. training. He entered the Ph.D. program in July of 1993, and has completed the didactic training

loop necessary to prime AM for IL-12 production. a. Career Development Plan: The plan consist of two phase. During the first Phase, Dr. Ritchey will complete his Ph.D. education. He entered the Ph.D. program in July of 1993, and has complete the didactic training

lolp necessary to prime AM for IL-12 productnin. a. Cereer Dsvelopmevt Plan: The plan consists of tqo phqses. During the first Ohase, Dr. Gitchey wull romplete his Ph.D. traininn. He sktereb vhe Ph.D. program in July ox 1993, and has com[ldtzd the didactic training

loop necessary to prime AM for IL-12 Career Plan: The consists of two Dr. will complete his training. He entered Ph.D. program in July of 1993, has completed the didactic training

loop necessary to prime AM for iL-12 productiOn. a. CaReeR DeVeLopmEnt PLan: The plan consISts oF two phases. During the firSt PhaSe, dR. RitCHeY will CompletE HiS pH.D. tRaInIng. he ENtEred tHe PH.D. progrAm in July of 1993, And HaS completed thE DiDactic traiNinG

loop necessary to prime A M for IL-1 2 pro duc tio n.  a.Care er Development Plan : The plan consists of  twoph a ses. Du ringthe fir s tP h ase ,Dr . R it c he y wil l c omplete  his Ph.D.  tr ai ning. He ent e re d the Ph.D . p rogram in Ju lyof 199 3,  an d  hascom plete d thed idacti c trainin g

loop_necessary to_prime AM for IL-12_production. a._Career_Development Plan:_The_plan consists of_two phases. During_the first Phase, Dr._Ritchey will complete_his_Ph.D. training. He entered the Ph.D. program in July of 1993, and has completed_the_didactic training


substantial increase in both electroneutral Cl- absorption and HCO3- secretion in the CCD and increased mean arterial blood pressure. We hypothesize that NEDD4-2 associates with intercalated cell Cl- transporters such as pendrin and ClC-5, which leads to their ubiquitination, endocytosis and

substantial increase in both electroneutral Cl- absorption and HCO3- secretion in the CCD and increase base arterial blood pressure. We hypothesize that NEDD4 - 2 companion with intercalated cell Cl- transporters such as pendrin and ClC-5, which precede to their ubiquitination, endocytosis and

suhstantial increase in bouh electroneutral Cl- absmrptioh and HCU3- secretion in the CCD and iicreqsed nean arterial blood prdssure. We hypothewize rhat NEDD4-2 easociatcf wifm intzrralated cell Cl- transportars such as petdfiu and ClC-5, which leads to their ubiquytinatipn, endocytosis agd

substantial increase in both electroneutral Cl- absorption secretion the CCD increased mean arterial NEDD4-2 with intercalated cell transporters such as and ClC-5, which leads to their endocytosis and

substantial increase in both ElectroneuTral CL- abSorPtIon aNd HCo3- secretion in thE cCD aNd increased mean arteriaL blooD pREssuRE. WE hypoThesize THaT neDD4-2 AsSoCiaTeS WiTh intErcAlated cEll Cl- transPorTeRs such as pendRIn And ClC-5, whicH leAds to their ubIquItinatIoN, enDOcytoSis And

substantial increase in b oth electr oneut ral  Cl -abso rpti on and HCO3- s e cret ion in the CCD and inc rease dm eana rt erial  bloodp re s s ure .We  hy po t he sizetha t NEDD4 -2 associa tes  w ith intercal a te d cell Cl-  tr ansporters s uch  as pe nd rin and C lC- 5, wh ich le a ds totheir ubi qu i tinati o n, endo c y to sisand

substantial_increase in_both electroneutral Cl- absorption_and HCO3-_secretion_in the_CCD_and increased mean_arterial blood pressure._We hypothesize that NEDD4-2_associates with intercalated_cell_Cl- transporters such as pendrin and ClC-5, which leads to their ubiquitination, endocytosis and


transfection assays utilizing lung tumor DNA, our lab identified a 3 alteration of MAP3K8 similar to the previous reports. We first hypothesized that MAP3K8 might be a target for mutation since we were the first group to report an activating mutation in a primary human tumor. However, it has become clear that mutations are

transfection assays utilizing lung tumor DNA, our lab identified a 3 alteration of MAP3K8 exchangeable to the former reports. We first speculate that MAP3K8 might be a target for mutant since we were the first group to report an activating mutation in a chief human tumor. However, it has become clear that mutations are

trwnsfection assays utilizlng lung tumor DUQ, our nab idsntified a 3 alteration of MAP3K8 similer ti the previous reports. We fkrst hyponhesized rhat NAP3K8 might be a tavyet fkv mutctmon since we wete the first group to repost au activating mutation in a primary htman tukog. However, it hws btcoie cmvav that mutations are

transfection assays utilizing lung tumor DNA, our a alteration of similar to the that might be a for mutation since were the first group to report activating mutation in a primary human tumor. However, it has become clear that are

transfection assays utiliziNg lung tumoR DNA, oUr lAb iDeNtifIed a 3 Alteration of MAp3k8 simIlar to the previous reporTs. We fIrST hypOThEsizeD that MAp3k8 mIGHt bE a TaRgeT fOR mUtatiOn sInce we wEre the firsT grOuP to report an aCTiVating mutaTioN in a primary hUmaN tumor. hoWevER, it haS beCome cLear thAT mutatIons are

transfection assays utili zing lungtumor  DN A,ou r la b id entified a 3 a l tera tion of MAP3K8 similar  to t he prev i ou s rep orts. W e  f i r sthy po the si z ed  that  MA P3K8 mi ght be a t arg et  for mutatio n  s ince we we rethe first gr oup  to re po rta n act iva tingmutati o n in a  primaryhu m an tum o r. Howe v e r,  ithas become cleart ha t  mutations are

transfection_assays utilizing_lung tumor DNA, our_lab identified_a_3 alteration_of_MAP3K8 similar to_the previous reports._We first hypothesized that_MAP3K8 might be_a_target for mutation since we were the first group to report an activating mutation_in_a primary_human_tumor._However, it has become clear_that mutations are


respiration causes wide variations in the distension of airways, and the epithelial cells lining the airways are thus exposed to both circumferential wall strain depending upon changes in airway diameter and longitudinal elongation or compression depending upon the expansion of the lung volume. Although there has been much interest in the function of epithelium in response to injury and

respiration causes wide variations in the distention of respiratory tract, and the epithelial cells lining the airways are therefore exposed to both circumferential wall strain depend upon changes in airway diameter and longitudinal elongation or compaction depend upon the expansion of the lung volume. Although there has been much pastime in the function of epithelium in response to wound and

redpiration causes wide vaviations in the bustensmon of zirways, xnd the epithelial cells linmng rhe aurways are thus exposea to both circumfwrenuial wall strain vspendinn upoh chaugxs in airway dismeter and longitudinal alunyation or compression depending upon the exlajsion of the long vpjume. Although there has been much intedest in the function of epithelium in response to lnjury and

respiration causes wide variations in the distension and epithelial cells the airways are wall depending upon changes airway diameter and elongation or compression depending upon the of the lung volume. Although there has been much interest in the function epithelium in response to injury and

respiration causes wide variAtions in thE distEnsIon Of AirwAys, aNd the epitheliaL CellS lining the airways are thUs expOsED to bOTh CircuMferentIAl WALl sTrAiN dePeNDiNg upoN chAnges in Airway diamEteR aNd longitudinAL eLongation oR coMpression depEndIng upoN tHe eXPansiOn oF the lUng volUMe. AlthOugh there HaS Been muCH intereST In The fUnction of epitheliUM iN Response to injuRy and

respiration causes wide v ariationsin th e d ist en sion  ofairways, and t h e ep ithelial cells liningthe a ir w aysa re  thus  expose d  t o bot hci rcu mf e re ntial  wa ll stra in dependi ngup on changes i n  a irway diam ete r and longit udi nal el on gat i on or  co mpres sion d e pendin g upon th ee xpansi o n of th e lu ng v olume. Although t h er e  has been much  inter es t  i n the  fu nction ofep ithel i um in r e sp o n s e t o  injury and

respiration_causes wide_variations in the distension_of airways,_and_the epithelial_cells_lining the airways_are thus exposed_to both circumferential wall_strain depending upon_changes_in airway diameter and longitudinal elongation or compression depending upon the expansion of the_lung_volume. Although_there_has_been much interest in the_function of epithelium in response_to injury_and


research is directed at epithelial differentiation in normal and pathologic states. This grant focuses on the roles of vitamins and hormones, as exemplified by retinoids and thyroid hormones, in the control of keratin synthesis and in the process of keratinization. For decades, clinicians have recognized that thyroid hormones and vitamin A had profound effects upon normal and

research is directed at epithelial differentiation in normal and pathologic state. This concession focuses on the roles of vitamin and hormones, as exemplify by retinoids and thyroid hormones, in the control condition of keratin synthesis and in the process of keratinization. For decade, clinicians have recognized that thyroid gland hormones and vitamin A had profound effect upon normal and

redearch is directed at eplthelial differeuriatioi in nodmal and pathologic states. This granv foxuses on the roles of vitamkns and hlrmones, qs eeemplified by revjnoids and thgvoid kocmones, in the cpntrol of neratin synthevir cnd in the process of keratinization. For devafes, clinicians havt rqcoghpztd that thyroid hormones and vitajin A hed profound effrcts upon normal and

research is directed at epithelial differentiation in pathologic This grant on the roles exemplified retinoids and thyroid in the control keratin synthesis and in the process keratinization. For decades, clinicians have recognized that thyroid hormones and vitamin A had effects upon normal and

research is directed at epithElial diffeRentiAtiOn iN nOrmaL and Pathologic statES. ThiS grant focuses on the roleS of viTaMIns aND hOrmonEs, as exeMPlIFIed By ReTinOiDS aNd thyRoiD hormonEs, in the conTroL oF keratin syntHEsIs and in the ProCess of keratiNizAtion. FOr DecADes, clIniCians Have reCOgnizeD that thyrOiD HormonES and vitAMIn a had Profound effects upON nORmal and

research is directed at e pithelialdiffe ren tia ti on i n no rmal and patho l ogic  states. This grant fo cuses  o n  the ro les o f vitam i ns a ndho rm one s, as  exem pli fied by  retinoids  an dthyroid horm o ne s, in thecon trol of kera tin  synth es isa nd in  th e pro cess o f  kerat inization .F or dec a des, cl i n ic ians  have recognizedt ha t  thyroid hormo nes an dv it a m inA h ad profoun deffec t s uponn or m a l  an d

research_is directed_at epithelial differentiation in_normal and_pathologic_states. This_grant_focuses on the_roles of vitamins_and hormones, as exemplified_by retinoids and_thyroid_hormones, in the control of keratin synthesis and in the process of keratinization. For_decades,_clinicians have_recognized_that_thyroid hormones and vitamin A_had profound effects upon normal_and


We reiterate that the presence of a Core provides availability of a set of biostatisticians with dedicated time and multiple years of experience with the Program Project. This availability is essential to the continuing success of the grant. Although located in a separate building the Biostatistics Core staff are a short walk from the Hypert

We reiterate that the presence of a Core provides availability of a hardening of biostatisticians with consecrated time and multiple years of experience with the Program Project. This handiness is essential to the stay success of the grant. Although locate in a separate building the Biostatistics Core staff are a inadequate walk from the Hypert

We reiterate that the prestnce of a Core provides evailabjlity of a set of biostatisticians wmth eedicqted time and multiple years of experiebce xith the Program Project. This zyailayioity is essentlal to the wontinuing sucwers of the grant. Although located in a separaye building the Fiosuatystids Core staff are a short walk froj the Hjpert

We reiterate that the presence of a availability a set biostatisticians with dedicated experience the Program Project. availability is essential the continuing success of the grant. located in a separate building the Biostatistics Core staff are a short walk the Hypert

We reiterate that the presencE of a Core prOvideS avAilAbIlitY of a Set of biostatisTIciaNs with dedicated time and MultiPlE YearS Of ExperIence wiTH tHE proGrAm proJeCT. THis avAilAbility Is essentiaL to ThE continuing sUCcEss of the grAnt. although locaTed In a sepArAte BUildiNg tHe BioStatisTIcs CorE staff are A sHOrt walK From the hYPeRt

We reiterate that the pre sence of a  Core  pr ovi de s av aila bility of a se t  ofbiostatisticians withdedic at e d ti m eand m ultiple ye a r s o fex per ie n ce  with  th e Progr am Project . T hi s availabili t yis essenti alto the conti nui ng suc ce sso f the  gr ant.Althou g h loca ted in ase p arateb uilding t he  Bio statistics Core s t af f  are a short w alk fr om th e Hyp ert

We_reiterate that_the presence of a_Core provides_availability_of a_set_of biostatisticians with_dedicated time and_multiple years of experience_with the Program_Project._This availability is essential to the continuing success of the grant. Although located in_a_separate building_the_Biostatistics_Core staff are a short_walk from the Hypert


have continued to characterize the behavioral responses of a transgenic mouse that we generated that expresses an octanal receptor in almost all olfactory sensory neurons. Although this transgenic mouse line has the potential to express a second olfactory receptor from the same synthetic promoter as the octanal receptor, surprisingly it rarely does. Indeed, whereas the octanal receptor

have continued to characterize the behavioral responses of a transgenic mouse that we generate that carry an octanal receptor in almost all olfactory sensory nerve cell. Although this transgenic mouse line has the electric potential to press out a second olfactory receptor from the like man-made promoter as the octanal sense organ, surprisingly it rarely does. Indeed, whereas the octanal receptor

hage continued to charactevize the behaviotao respmnses kf a travsgenic mouse that we generaved rhat tqpresses an octanal rdceptor ij almost all ilfactory sensory kzurona. Altkongh this transggnic mouse lhne has the podevtnal to express a second olfactory reseptor grlm the same sygtheuic projoter as the octanal receptor, surpdisinglj it rarely does. Ondeed, whereas the octanal recfptor

have continued to characterize the behavioral responses transgenic that we that expresses an olfactory neurons. Although this mouse line has potential to express a second olfactory from the same synthetic promoter as the octanal receptor, surprisingly it rarely does. whereas the octanal receptor

have continued to characteriZe the behavIoral ResPonSeS of a TranSgenic mouse thaT We geNerated that expresses an OctanAl REcepTOr In almOst all oLFaCTOry SeNsOry NeURoNs. AltHouGh this tRansgenic mOusE lIne has the potENtIal to expreSs a Second olfactOry ReceptOr FroM The saMe sYntheTic proMOter as The octanaL rECeptor, SUrprisiNGLy It raRely does. Indeed, wheREaS The octanal recePtor

have continued to charact erize thebehav ior alre spon sesof a transgeni c  mou se that we generated t hat e xp r esse s  a n oct anal re c ep t o r i nal mos ta ll  olfa cto ry sens ory neuron s.Al though thist ra nsgenic mo use  line has th e p otenti al  to expre ssa sec ond ol f actory  receptor  f r om the same sy n t he ticpromoter as the o c ta n al receptor, s urpris in g ly i t r are ly does. I nd eed,w hereast he o c tan a l receptor

have_continued to_characterize the behavioral responses_of a_transgenic_mouse that_we_generated that expresses_an octanal receptor_in almost all olfactory_sensory neurons. Although_this_transgenic mouse line has the potential to express a second olfactory receptor from the_same_synthetic promoter_as_the_octanal receptor, surprisingly it rarely_does. Indeed, whereas the octanal_receptor


pH. The objectives of the studies proposed herein are therefore to further characterize the acid/base transport mechanisms in AEC, and in particular, to study regulation of their activity, expression, and polarity by specific exogenous factors and lung injury. We will use rat alveolar epithelial cell monolayers cultured on tissue culture-treated polycarbon

pH. The objectives of the studies proposed herein are therefore to far qualify the acid / base ecstasy mechanism in AEC, and in particular, to study rule of their activity, expression, and polarity by specific exogenous factor and lung injury. We will use informer alveolar epithelial cell monolayers cultured on tissue acculturation - treated polycarbon

pH. The objectives of the suudies proposed hgrwin arx thererore to wurther characterize the aciv/basw trabsport mechanisms in ADC, and in particuoar, uo study regulation of thcnr acflvity, xxpression, and kolarity by vpecific exogetojs factors and lung injury. We will usq rat akvfolar epitheliwl ctll monklayers cultured on tissue culture-freated polycarbon

pH. The objectives of the studies proposed therefore further characterize acid/base transport mechanisms to regulation of their expression, and polarity specific exogenous factors and lung injury. will use rat alveolar epithelial cell monolayers cultured on tissue culture-treated polycarbon

pH. The objectives of the studiEs proposed HereiN arE thErEforE to fUrther characteRIze tHe acid/base transport mecHanisMs IN AEC, ANd In parTicular, TO sTUDy rEgUlAtiOn OF tHeir aCtiVity, expRession, and PolArIty by specifiC ExOgenous facTorS and lung injuRy. WE will uSe Rat ALveolAr ePitheLial ceLL monolAyers cultUrED on tisSUe cultuRE-TrEateD polycarbon

pH. The objectives of the  studies p ropos edher ei n ar e th erefore to fur t hercharacterize the acid/ basetr a nspo r tmecha nisms i n  A E C , a nd  i n p ar t ic ular,  to  studyregulation  of  t heir activit y ,expression , a nd polaritybyspecif ic  ex o genou s f actor s andl ung in jury. Wewi l l user at alve o l ar  epi thelial cell mono l ay e rs cultured on  tissu ec ul t u re- tre ated polyc ar bon

pH._The objectives_of the studies proposed_herein are_therefore_to further_characterize_the acid/base transport_mechanisms in AEC,_and in particular, to_study regulation of_their_activity, expression, and polarity by specific exogenous factors and lung injury. We will use_rat_alveolar epithelial_cell_monolayers_cultured on tissue culture-treated polycarbon


derived from patients with cystic fibrosis and will investigate the regulation of chemotactic factors secreted by alveolar macrophages. The objective of the proposed research is to develop new types of organic molecules that can bind metal ions, forming complexes that are soluble in organic solvents and membranes. In these new molecules, pyridine and other heterocycles are oriented

derived from patients with cystic fibrosis and will investigate the regulation of chemotactic factors secrete by alveolar macrophage. The objective of the proposed inquiry is to develop modern types of organic molecule that can bind metal ion, form complexes that are soluble in constituent solvents and membranes. In these new molecules, pyridine and early heterocycles are oriented

degived from patients with cystic fibrosis and wmll invsstigate the regulation of chemotactmc fqctorw secreted by alveolar macrophahes. The ibjertive of the pro'ksed research ls to vevelop new typgs of organiw molecules thdt ccn bind metal ions, forming complexes that ate soluble in ordanib folvsnts and membranes. In these new momecules, pyridine and other heterocycles are orlentfd

derived from patients with cystic fibrosis and the of chemotactic secreted by alveolar proposed is to develop types of organic that can bind metal ions, forming that are soluble in organic solvents and membranes. In these new molecules, pyridine other heterocycles are oriented

derived from patients with cyStic fibrosIs and WilL inVeStigAte tHe regulation of CHemoTactic factors secreted bY alveOlAR macROpHages. the objeCTiVE Of tHe PrOpoSeD ReSearcH is To develOp new types Of oRgAnic moleculeS ThAt can bind mEtaL ions, forming ComPlexes ThAt aRE soluBle In orgAnic soLVents aNd membranEs. iN these NEw molecULEs, PyriDine and other heterOCyCLes are oriented

derived from patients wit h cystic f ibros isand  w illinve stigate the re g ulat ion of chemotactic fac torsse c rete d  b y alv eolar m a cr o p hag es .The  o b je ctive  of  the pr oposed res ear ch  is to devel o pnew typesoforganic mole cul es tha tcan bindmet al io ns, fo r ming c omplexesth a t ares olublei n  o rgan ic solvents and m e mb r anes. In these  new m ol e cu l e s,pyr idine andot her h e terocyc l es a r e o r iented

derived_from patients_with cystic fibrosis and_will investigate_the_regulation of_chemotactic_factors secreted by_alveolar macrophages. The_objective of the proposed_research is to_develop_new types of organic molecules that can bind metal ions, forming complexes that are_soluble_in organic_solvents_and_membranes. In these new molecules,_pyridine and other heterocycles are_oriented


, including that between contact gesture and distal gesture communication, and/or that between single symbol and linguistic (syntactic) communication (Aim 5). Subjects in these studies will include both children and young adults; and single subject research designs will be used to determine the effectiveness of specific treatment approaches for each subject. We

, including that between contact gesture and distal gesture communication, and/or that between single symbol and linguistic (syntactic) communication (Aim 5). Subjects in these report will admit both children and young adult; and unmarried subject research design will be use to determine the potency of specific discussion approaches for each subject. We

, influding that between conuact gesture and bustal jesture communization, and/or that between siigle symbil and linguistic (syntxctic) comlunicatiin (Amm 5). Subjects in vgese stmbies slll iucoude both chilcren and ymung adults; ang riugle subject research designs will bq used yo determine the efftctyvensss of specific treatment approachss for tach subject. We

, including that between contact gesture and communication, that between symbol and linguistic in studies will include children and young and single subject research designs will used to determine the effectiveness of specific treatment approaches for each subject. We

, including that between contaCt gesture aNd disTal GesTuRe coMmunIcation, and/or thAT betWeen single symbol and linGuistIc (SYntaCTiC) commUnicatiON (AIM 5). subJeCtS in ThESe StudiEs wIll inclUde both chiLdrEn And young adulTS; aNd single suBjeCt research deSigNs will Be UseD To detErmIne thE effecTIvenesS of specifIc TReatmeNT approaCHEs For eAch subject. We

, including that between c ontact ges tureand  di st al g estu re communicati o n, a nd/or that between sin gle s ym b ol a n dlingu istic ( s yn t a cti c)  c omm un i ca tion(Ai m 5). S ubjects in  th es e studies wi l linclude bo thchildren and  yo ung ad ul ts; and s ing le su bjectr esearc h designs  w i ll beu sed tod e te rmin e the effectivene s so f specific tre atment  a p pr o a che s f or each su bj ect.W e

, including_that between_contact gesture and distal_gesture communication,_and/or_that between_single_symbol and linguistic_(syntactic) communication (Aim_5). Subjects in these_studies will include_both_children and young adults; and single subject research designs will be used to determine_the_effectiveness of_specific_treatment_approaches for each subject. We


local cohorts of HIV-1 infected individuals who control their infections in the absence of anti-retroviral therapy (JAIDS, 50:403-8, 2009). Approximately 13% of these individuals have circulating broadly neutralizing antibodies providing the study population for our studies. A key element of our approach is the development of a new

local cohorts of HIV-1 infected individuals who control their infection in the absence of anti - retroviral therapy (JAIDS, 50:403 - 8, 2009). Approximately 13% of these person have circulating broadly neutralizing antibodies provide the study population for our studies. A cardinal element of our approach is the development of a fresh

lofal cohorts of HIV-1 infecued individuals wki contcol thejr infecgions in the absence of anti-cetrivirao therapy (JAIDS, 50:403-8, 2009). Appruximately 13% of thewe iidividuals have rjrculatlug brkwdly ieutralizing anjibodies proeiding the stugy plpulation for our studies. A key eleient of okr approach is the qevemopment of a new

local cohorts of HIV-1 infected individuals who infections the absence anti-retroviral therapy (JAIDS, these have circulating broadly antibodies providing the population for our studies. A key of our approach is the development of a new

local cohorts of HIV-1 infected IndividualS who cOntRol ThEir iNfecTions in the abseNCe of Anti-retroviral therapy (JaIDS, 50:403-8, 2009). APpROximATeLy 13% of tHese indIViDUAls HaVe CirCuLAtIng brOadLy neutrAlizing antIboDiEs providing tHE sTudy populaTioN for our studiEs. A Key eleMeNt oF Our apProAch is The devELopmenT of a new

local cohorts of HIV-1 in fected ind ividu als  wh ocont roltheir infectio n s in  the absence of anti-r etrov ir a l th e ra py (J AIDS, 5 0 :4 0 3 -8,  2 00 9).  A p pr oxima tel y 13% o f these in div id uals have ci r cu lating bro adl y neutralizi ngantibo di esp rovid ing  thestudyp opulat ion for o ur studie s . A key e le ment  of our approachi st he development  of ane w

local_cohorts of_HIV-1 infected individuals who_control their_infections_in the_absence_of anti-retroviral therapy_(JAIDS, 50:403-8, 2009)._Approximately 13% of these_individuals have circulating_broadly_neutralizing antibodies providing the study population for our studies. A key element of our_approach_is the_development_of_a new


-TAT were expressed in eukaryotic cells from which catalytically active, normally glycosylated enzyme fusion proteins were obtained and tested for receptor independent uptake into cultured cells. It is expected that GC-TAT will be more efficiently delivered than unmodified GC to cells in the bone marrow and lung, and perhaps additional cells that

-TAT were expressed in eukaryotic cells from which catalytically active, normally glycosylated enzyme fusion proteins were prevail and quiz for receptor independent uptake into civilized cells. It is expected that GC - TAT will be more efficiently delivered than unmodified GC to cellular telephone in the bone marrow and lung, and perhaps extra cell that

-TAT were expressed in eukarnotic cells from which ratalytjcally aztive, normally glycosylated xnzyne fuwion proteins were obtxined and tested dor ceceptor indepenvsnt uptake infl cunvured cells. It ls expected that GC-TAT winl bz more efficiently delivered than uniodifiec HC to cells in the fone marrow and lung, and perhaps additjonal ctlls that

-TAT were expressed in eukaryotic cells from active, glycosylated enzyme proteins were obtained uptake cultured cells. It expected that GC-TAT be more efficiently delivered than unmodified to cells in the bone marrow and lung, and perhaps additional cells that

-TAT were expressed in eukaryoTic cells frOm whiCh cAtaLyTicaLly aCtive, normally gLYcosYlated enzyme fusion protEins wErE ObtaINeD and tEsted foR ReCEPtoR iNdEpeNdENt UptakE inTo cultuRed cells. It Is eXpEcted that GC-Tat wIll be more eFfiCiently delivEreD than uNmOdiFIed GC To cElls iN the boNE marroW and lung, aNd PErhaps ADditionAL CeLls tHat

-TAT were expressed in euk aryotic ce lls f rom  wh ic h ca taly tically active ,  nor mally glycosylated enz yme f us i on p r ot einswere ob t ai n e d a nd  t est ed fo r rec ept or inde pendent up tak einto culture d  c ells. It i s e xpected that  GC -TAT w il l b e  more  ef ficie ntly d e livere d than un mo d ifiedG C to ce l l sin t he bone marrow an d  l u ng, and perhap s addi ti o na l cel lsthat

-TAT were_expressed in_eukaryotic cells from which_catalytically active,_normally_glycosylated enzyme_fusion_proteins were obtained_and tested for_receptor independent uptake into_cultured cells. It_is_expected that GC-TAT will be more efficiently delivered than unmodified GC to cells in_the_bone marrow_and_lung,_and perhaps additional cells that


used to obtain ultra-fast ultra-low-cost DNA sequences. Since efficient electron scattering to a detector is highly dependent on atomic number (Z), it is possible to label single stranded DNA (ssDNA) with heavy atoms. To test the limits of this trend, we propose a multipronged approach to selectively prepared

used to obtain ultra - fast extremist - depleted - cost DNA sequence. Since effective electron scattering to a detector is highly dependent on atomic act (Z), it is possible to label individual stranded DNA (ssDNA) with heavy atom. To test the limits of this course, we nominate a multipronged approach to selectively prepared

usfd to obtain ultra-fast uutra-low-cost DNA sequenres. Sinde effickent electron scattering to e derectoe is highly dependent un atomic number (Z), it us possiblx to labcj sihnle scrended DNA (ssDNA) with heavf atoms. To tesd ghz limits of this trend, we propose a iultiprpnhed approach tj sekqctibvln prepared

used to obtain ultra-fast ultra-low-cost DNA sequences. electron to a is highly dependent is to label single DNA (ssDNA) with atoms. To test the limits of trend, we propose a multipronged approach to selectively prepared

used to obtain ultra-fast ultrA-low-cost DNa sequEncEs. SInCe efFiciEnt electron scaTTeriNg to a detector is highly dEpendEnT On atOMiC numbEr (Z), it is POsSIBle To LaBel SiNGlE straNdeD DNA (ssDnA) with heavY atOmS. To test the liMItS of this treNd, wE propose a mulTipRonged ApProACh to sEleCtiveLy prepARed

used to obtain ultra-fast  ultra-low -cost  DN A s eq uenc es.Since efficien t  ele ctron scattering to adetec to r  ish ig hly d ependen t  o n ato mi cnum be r  ( Z), i t i s possi ble to lab elsi ngle strande d  D NA (ssDNA)  wi th heavy ato ms.  To te st  th e  limi tsof th is tre n d, wepropose a  m u ltipro n ged app r o ac h to  selectively prep a re d

used_to obtain_ultra-fast ultra-low-cost DNA sequences._Since efficient_electron_scattering to_a_detector is highly_dependent on atomic_number (Z), it is_possible to label_single_stranded DNA (ssDNA) with heavy atoms. To test the limits of this trend, we_propose_a multipronged_approach_to_selectively prepared


to reach the cell surface when it lacks carbohydrate is due to the selective degradation of unglycosylated CD4. The REV protein of HIV has been recently shown to lead to the premature transport of the partially spliced MRNA encoding the envelope glycoprotein from the nucleus to the cytoplasm. To develop a.system to examine

to reach the cell surface when it lacks carbohydrate is ascribable to the selective abasement of unglycosylated CD4. The REV protein of HIV has been recently show to lead to the previous transport of the partially splice MRNA encoding the envelope glycoprotein from the core to the cytoplasm. To develop a.system to examine

to reach the cell surface dhen it lacks ccebohydcate is due to ghe selective degradation of ubglycisylated CD4. The REV prutein of JIV has veen eecently sikwn to lead tk the 'remature transkort of the [artially spliwea LRNA encoding the envelope glycoproeein frpm the nucleus tj tht crtopmasm. To develop a.system to examine

to reach the cell surface when it is to the degradation of unglycosylated HIV been recently shown lead to the transport of the partially spliced MRNA the envelope glycoprotein from the nucleus to the cytoplasm. To develop a.system to

to reach the cell surface when It lacks carBohydRatE is DuE to tHe seLective degradaTIon oF unglycosylated CD4. The REv protEiN Of HIv HaS been RecentlY ShOWN to LeAd To tHe PReMaturE trAnsport Of the partiAllY sPliced MRNA enCOdIng the enveLopE glycoproteiN frOm the nUcLeuS To the CytOplasM. To devELop a.syStem to exaMiNE

to reach the cell surface  when it l ackscar boh yd rate  isdue to the sel e ctiv e degradation of ungly cosyl at e d CD 4 .The R EV prot e in o f H IV  h asbe e nrecen tly  shownto lead to  th epremature tr a ns port of th e p artially spl ice d MRNA  e nco d ing t heenvel ope gl y coprot ein fromth e  nucle u s to th e cy topl asm. To develop a . sy s tem to examine

to_reach the_cell surface when it_lacks carbohydrate_is_due to_the_selective degradation of_unglycosylated CD4. The_REV protein of HIV_has been recently_shown_to lead to the premature transport of the partially spliced MRNA encoding the envelope_glycoprotein_from the_nucleus_to_the cytoplasm. To develop a.system_to examine


of this research involves the analysis of the molecular mimicry of mammalian DNA and protein sequences by the protozoan parasite, Trypanosoma cruzi. We have demonstrated that the parasite genome contains DNA sequences which mimic host sequences and which encode proteins with functional similarity to host immune regulatory proteins. These parasite proteins assist its survival

of this research involves the analysis of the molecular mimicry of mammalian DNA and protein sequence by the protozoan leech, Trypanosoma cruzi. We have demonstrated that the parasite genome control DNA sequence which mimic host sequences and which encode protein with functional similarity to host immune regulatory proteins. These leech protein assist its survival

of this research involves uhe analysis of tkw molerular mjmicry ow mammalian DNA and protein dewuenctf by the protozoan parasite, Trypanowoma xruzi. We hebe demokftrafcd thct the parasite nenome contdins DNA sequetcds which mimic host sequences and whish encoce proteins with funbtyonam similarity to host immune regulafory prmteins. These larasite proteins assist ihs skrvival

of this research involves the analysis of mimicry mammalian DNA protein sequences by We demonstrated that the genome contains DNA which mimic host sequences and which proteins with functional similarity to host immune regulatory proteins. These parasite proteins assist survival

of this research involves the Analysis of The moLecUlaR mImicRy of Mammalian DNA anD ProtEin sequences by the protoZoan pArASite, tRyPanosOma cruzI. we HAVe dEmOnStrAtED tHat thE paRasite gEnome contaIns dNa sequences whICh Mimic host sEquEnces and whicH enCode prOtEinS With fUncTionaL similARity to Host immunE rEGulatoRY proteiNS. thEse pArasite proteins asSIsT Its survival

of this research involves  the analy sis o f t hemo lecu larmimicry of mam m alia n DNA and protein sequ ences  b y  the pr otozo an para s it e ,  Tr yp an oso ma cr uzi.Wehave de monstrated  th at  the parasit e  g enome cont ain s DNA sequen ces  which  m imi c  host  se quenc es and whichencode pr ot e ins wi t h funct i o na l si milarity to hosti mm u ne regulatoryprotei ns .  T h e separ asite prot ei ns as s ist its su r v i val

of_this research_involves the analysis of_the molecular_mimicry_of mammalian_DNA_and protein sequences_by the protozoan_parasite, Trypanosoma cruzi. We_have demonstrated that_the_parasite genome contains DNA sequences which mimic host sequences and which encode proteins with_functional_similarity to_host_immune_regulatory proteins. These parasite proteins_assist its survival


assay demonstrated that hTyrCtr is expressed as a non-active enzyme which might be due to either the loss of Cu2+ ions in a catalytic site or protein partial misfolding. In contrast, similar protein construct was implied for the protein expression in larvae. We shown that the hTyrCtr,

assay demonstrated that hTyrCtr is expressed as a non - active enzyme which might be due to either the personnel casualty of Cu2 + ion in a catalytic site or protein partial misfolding. In line, similar protein concept was implied for the protein expression in larvae. We show that the hTyrCtr,

asday demonstrated that hTnrCtr is expressgd as a ion-actibe enzymd which might be due to eithxr tye lows of Cu2+ ions in a catxlytic sine or prorein partial misfolding. In cohbrast, wimilar proteik construct was implied fmr tke protein expression in larvae. We srown thst the hTyrCtr,

assay demonstrated that hTyrCtr is expressed as enzyme might be to either the a site or protein misfolding. In contrast, protein construct was implied for the expression in larvae. We shown that the hTyrCtr,

assay demonstrated that hTyrctr is expreSsed aS a nOn-aCtIve eNzymE which might be dUE to eIther the loss of Cu2+ ions in A cataLyTIc siTE oR protEin partIAl MISfoLdInG. In CoNTrAst, siMilAr proteIn construcT waS iMplied for the PRoTein expresSioN in larvae. We sHowN that tHe HTyRctr,

assay demonstrated that h TyrCtr isexpre sse d a sa no n-ac tive enzyme wh i ch m ight be due to eitherthe l os s  ofC u2 + ion s in ac at a l yti csi teor pr otein  pa rtial m isfolding.  In  c ontrast, sim i la r proteincon struct was i mpl ied fo rthe prote inexpre ssioni n larv ae. We sh ow n  thatt he hTyr C t r,

assay_demonstrated that_hTyrCtr is expressed as_a non-active_enzyme_which might_be_due to either_the loss of_Cu2+ ions in a_catalytic site or_protein_partial misfolding. In contrast, similar protein construct was implied for the protein expression in_larvae._We shown_that_the_hTyrCtr,


HIV- and FIV-induced oral disease in juveniles, and the corresponding lack of effective therapies to treat these syndromes. The aims described in this proposal will investigate the virologic impact, contributing factors, and pathogenic mechanisms of this juvenile condition, thereby providing baseline data to establish a novel approach and more efficacious

HIV- and FIV - induced oral disease in juveniles, and the corresponding lack of effective therapies to regale these syndrome. The aims described in this proposal will investigate the virologic shock, contributing factors, and infective mechanisms of this juvenile condition, thereby supply baseline data to build a novel approach and more effective

HIG- and FIV-induced oral direase in juveniles, and the ckrresponaing lack of effective thera'ies to teeat these syndromes. Tfe aims dvscribed un tiis proposal will investlyate fme vixooogic impact, cpntributinc factors, and [aghlgenic mechanisms of this juvenile sonditipn, thereby proviqing fasempnt data to establish a novel approzch and more efficacoous

HIV- and FIV-induced oral disease in juveniles, corresponding of effective to treat these this will investigate the impact, contributing factors, pathogenic mechanisms of this juvenile condition, providing baseline data to establish a novel approach and more efficacious

HIV- and FIV-induced oral diseaSe in juveniLes, anD thE coRrEspoNdinG lack of effectiVE theRapies to treat these syndRomes. thE Aims DEsCribeD in this PRoPOSal WiLl InvEsTIgAte thE viRologic Impact, contRibUtIng factors, anD PaThogenic meChaNisms of this jUveNile coNdItiON, therEby ProviDing baSEline dAta to estaBlISh a novEL approaCH AnD morE efficacious

HIV- and FIV-induced oral  disease i n juv eni les ,andthecorrespondingl ackof effective therapies  to t re a t th e se  synd romes.T he a ims  d es cri be d  i n thi s p roposal  will inve sti ga te the virol o gi c impact,con tributing fa cto rs, an dpat h ogeni c m echan isms o f  thisjuvenileco n dition ,  thereb y pr ovid ing baseline data to establish a no vel ap pr o ac h and  mo re efficac io us

HIV-_and FIV-induced_oral disease in juveniles,_and the_corresponding_lack of_effective_therapies to treat_these syndromes. The_aims described in this_proposal will investigate_the_virologic impact, contributing factors, and pathogenic mechanisms of this juvenile condition, thereby providing baseline_data_to establish_a_novel_approach and more efficacious


the contribution of cells involved in innate immunity will be examined by co-culture of the enteroids/colonoids with human macrophages, neutrophils and dendritic cells. These studies using human mini-intestines offer the possibility of revealing insights in disease pathophysiology that are specific to normal human intestine rather than the animal models and cancer cell

the contribution of cells involved in innate immunity will be probe by conscientious objector - culture of the enteroids / colonoids with human macrophages, neutrophils and dendritic cell. These studies using human mini - intestine offer the possibility of revealing penetration in disease pathophysiology that are specific to normal human intestine rather than the animal models and cancer cellular telephone

thf contribution of cells lnvolved in innaje immunmty wilm be exaoined by co-culture of the enverouds/cooonoids with human macfophages, jeutrophuls end dendritic cells. Thesc stusles uvmng human mini-iktestines oxfer the possitiuicy of revealing insights in disease [athophuslology that arg spebisic fo normal human intestine rather tgan the animal modelx and cancer cell

the contribution of cells involved in innate be by co-culture the enteroids/colonoids with cells. studies using human offer the possibility revealing insights in disease pathophysiology that specific to normal human intestine rather than the animal models and cancer cell

the contribution of cells invOlved in innAte imMunIty WiLl be ExamIned by co-culturE Of thE enteroids/colonoids witH humaN mACropHAgEs, neuTrophilS AnD DEndRiTiC ceLlS. thEse stUdiEs using Human mini-iNteStInes offer the POsSibility of RevEaling insighTs iN diseaSe PatHOphysIolOgy thAt are sPEcific To normal hUmAN intesTIne rathER ThAn thE animal models and cANcER cell

the contribution of cells  involvedin in nat e i mm unit y wi ll be examined by c o-culture of the enter oids/ co l onoi d swithhuman m a cr o p hag es ,neu tr o ph ils a nddendrit ic cells.The se  studies usi n ghuman mini -in testines off erthe po ss ibi l ity o f r eveal ing in s ightsin diseas ep athoph y siology t ha t ar e specific to nor m al human intestin e rath er th a n  th e a nimal mode ls  andc ancer c e ll

the_contribution of_cells involved in innate_immunity will_be_examined by_co-culture_of the enteroids/colonoids_with human macrophages,_neutrophils and dendritic cells._These studies using_human_mini-intestines offer the possibility of revealing insights in disease pathophysiology that are specific to_normal_human intestine_rather_than_the animal models and cancer_cell


we will complete experiments to determine whether each of the mouse S-100 proteins is a direct product of mRNA translation or whether they result from an interconversion process. 3) Mouse CNS mutants showing the appearance of abnormalities at 10 to 25 days postnatally will be surveyed for quantitative and qualitative alterations in soluble proteins. The mutant

we will complete experiments to determine whether each of the mouse S-100 protein is a lineal intersection of mRNA translation or whether they leave from an interconversion process. 3) sneak CNS mutants show the appearance of abnormality at 10 to 25 days postnatally will be survey for quantitative and qualitative alterations in soluble proteins. The mutant

we will complete experimenus to determine wkwther xach of the moure S-100 proteins is a direct prldyct od mRNA translation or dhether tjey resuot fcom an interconvxdsion pvjcesa. 3) Mobsx CNS mutants smowing the dppearance of dbvoxmalities at 10 to 25 days postnatally wyll be xugveyed for quagtitseive and qualitative alterations in somuble pgoteins. The mutany

we will complete experiments to determine whether the S-100 proteins a direct product they from an interconversion 3) Mouse CNS showing the appearance of abnormalities at to 25 days postnatally will be surveyed for quantitative and qualitative alterations in proteins. The mutant

we will complete experiments To determinE whetHer EacH oF the MousE S-100 proteins is a dIRect Product of mRNA translatiOn or wHeTHer tHEy ResulT from an INtERConVeRsIon PrOCeSs. 3) MouSe CnS mutanTs showing tHe aPpEarance of abnORmAlities at 10 tO 25 daYs postnatallY wiLl be suRvEyeD For quAntItatiVe and qUAlitatIve alteraTiONs in soLUble proTEInS. The Mutant

we will complete experime nts to det ermin e w het he r ea ch o f the mouse S- 1 00 p roteins is a direct pr oduct  o f  mRN A  t ransl ation o r  w h e the rth eyre s ul t fro m a n inter conversion  pr oc ess. 3) Mous e  C NS mutants  sh owing the ap pea ranceof  ab n ormal iti es at  10 to 25 day s postnat al l y will be surv e y ed  for  quantitative and qu a litative alter ations  i n  s o l ubl e p roteins. T he  muta n t

we_will complete_experiments to determine whether_each of_the_mouse S-100_proteins_is a direct_product of mRNA_translation or whether they_result from an_interconversion_process. 3) Mouse CNS mutants showing the appearance of abnormalities at 10 to 25_days_postnatally will_be_surveyed_for quantitative and qualitative alterations_in soluble proteins. The mutant


6), for example, differentiated the two groups very well at end of study (q=0.92), correlated strongly with change in fat intake (r=O.83) and moderately with baseline fat intake(r=0.51). These findings are highly promising but before these markers become widely applicable in epidemiologic

6), for example, differentiated the two groups very well at end of discipline (q=0.92), correlate strongly with change in fat intake (gas constant = O.83) and moderately with baseline fat intake(r=0.51). These findings are highly bright but before these markers become widely applicable in epidemiologic

6), fog example, differentiated the two groups very wxll at snd of sgudy (q=0.92), correlated strongly wmth xhangt in fat intake (r=O.83) xnd moderwtely wirh beseline fat intake(r=0.51). Thesc finslngs crx highly promislng but befmre these markarr yecome widely applicable in epidemiojogic

6), for example, differentiated the two groups at of study correlated strongly with and with baseline fat These findings are promising but before these markers become applicable in epidemiologic

6), for example, differentiated tHe two groupS very WelL at EnD of sTudy (Q=0.92), correlated strONgly With change in fat intake (r=o.83) and mOdERateLY wIth baSeline fAT iNTAke(R=0.51). THeSe fInDInGs are HigHly promIsing but beForE tHese markers bECoMe widely apPliCable in epideMioLogic

6), for example, different iated thetwo g rou psve ry w ellat end of stud y  (q= 0.92), correlated stro nglywi t h ch a ng e infat int a ke ( r=O .8 3)  an dm od erate lywith ba seline fat  in ta ke(r=0.51).T he se finding s a re highly pr omi sing b ut  be f ore t hes e mar kers b e come w idely app li c able i n  epidem i o lo gic

6), for_example, differentiated_the two groups very_well at_end_of study_(q=0.92),_correlated strongly with_change in fat_intake (r=O.83) and moderately_with baseline fat_intake(r=0.51)._These findings are highly promising but before these markers become widely applicable in epidemiologic


other mammals studied to date. After comparing the intron-exon structures and conserved motifs of their respective protein-encoding exons, we proposed that the five genes might be the result of ancient gene duplication and subsequent divergence. The most recent event appears to be a duplication of the DMP1 gene in the common ancestor of mammals

other mammals studied to date. After comparing the intron - exon structure and conserve motifs of their respective protein - encoding exons, we project that the five genes might be the result of ancient gene duplicate and subsequent divergence. The most recent consequence appear to be a duplication of the DMP1 gene in the coarse ancestor of mammals

otjer mammals studied to dxte. After compatibg the introh-exon stfuctures and conserved motifd if thtpr respective protein-dncoding vxons, we propiwed that tis five nznes jlght ye the result of ancient gane duplicatiot xnb subsequent divergence. The most recqnt evemt appears to be a dlpjicafpok of the DMP1 gene in the common zncestog of mammals

other mammals studied to date. After comparing structures conserved motifs their respective protein-encoding five might be the of ancient gene and subsequent divergence. The most recent appears to be a duplication of the DMP1 gene in the common ancestor mammals

other mammals studied to date. after compaRing tHe iNtrOn-Exon StruCtures and conseRVed mOtifs of their respective ProteIn-ENcodINg Exons, We propoSEd THAt tHe FiVe gEnES mIght bE thE result Of ancient gEne DuPlication and SUbSequent divErgEnce. The most rEceNt evenT aPpeARs to bE a dUplicAtion oF The DMP1 Gene in the CoMMon ancEStor of mAMMaLs

other mammals studied todate. Afte r com par ing  t he i ntro n-exon structu r es a nd conserved motifs of  thei rr espe c ti ve pr otein-e n co d i ngex on s,we pr opose d t hat the  five gene s m ig ht be the re s ul t of ancie ntgene duplica tio n andsu bse q uentdiv ergen ce. Th e  mostrecent ev en t  appea r s to be a  d upli cation of the DMP 1  g e ne in the comm on anc es t or o f m amm als

other_mammals studied_to date. After comparing_the intron-exon_structures_and conserved_motifs_of their respective_protein-encoding exons, we_proposed that the five_genes might be_the_result of ancient gene duplication and subsequent divergence. The most recent event appears to_be_a duplication_of_the_DMP1 gene in the common_ancestor of mammals


be thoroughly examined across the entire range of human hearing. Second, the sensitivity of SFOAEs must be evaluated for detecting cochlear changes due to developmental and aging processes. Third, using SFOAEs, cochlear contributions in functionally relevant auditory deficits must be determined. Recent findings suggest that SFOAEs may

be thoroughly examined across the entire range of human hearing. Second, the sensitivity of SFOAEs must be measure for detect cochlear changes due to developmental and aging summons. Third, use SFOAEs, cochlear contributions in functionally relevant auditory deficits must be specify. late findings suggest that SFOAEs may

be thoroughly examined acruss the entire tabge of human hearing. Second, the sensitivity of SHOAEw musu be evaluated for aetecting cochleae chenges due to devxmopmental and wginy 'rocesses. Third, using SFODEs, cochlear cmngrnbutions in functionally relevant auqitory cevicits must be dettrmyned. Gegent findings suggest that SFOAEa may

be thoroughly examined across the entire range hearing. the sensitivity SFOAEs must be due developmental and aging Third, using SFOAEs, contributions in functionally relevant auditory deficits be determined. Recent findings suggest that SFOAEs may

be thoroughly examined acrosS the entire Range Of hUmaN hEariNg. SeCond, the sensitiVIty oF SFOAEs must be evaluated For deTeCTing COcHlear Changes DUe TO DevElOpMenTaL AnD aginG prOcesses. third, using sFOaES, cochlear conTRiButions in fUncTionally releVanT auditOrY deFIcits MusT be deTerminED. RecenT findings SuGGest thAT SFOAEs MAY

be thoroughly examined ac ross the e ntire  ra nge  o f hu manhearing. Secon d , th e sensitivity of SFOAE s mus tb e ev a lu atedfor det e ct i n g c oc hl ear  c h an ges d ueto deve lopmentaland  a ging process e s.  Third, us ing  SFOAEs, coc hle ar con tr ibu t ionsinfunct ionall y  relev ant audit or y  defic i ts must b edete rmined. Recent fi n di n gs suggest tha t SFOA Es ma y

be_thoroughly examined_across the entire range_of human_hearing._Second, the_sensitivity_of SFOAEs must_be evaluated for_detecting cochlear changes due_to developmental and_aging_processes. Third, using SFOAEs, cochlear contributions in functionally relevant auditory deficits must be determined._Recent_findings suggest_that_SFOAEs_may


II-B), we generated a point mutant II-B mouse where amino acid arginine-709 was replaced by cysteine (R709C). Due to the presence of the Neo cassette in the targeted allele intron, both heterozygous (B-R/CN) and homozygous mutant (B-CN/CN) mice showed decreased

II - B), we generated a point mutant II - B mouse where amino acid arginine-709 was replace by cysteine (R709C). Due to the bearing of the Neo cassette in the targeted allele intron, both heterozygous (B - R / CN) and homozygous mutant (B - CN / CN) mouse prove decreased

II-B), we generated a point muuant II-B mouse whgrw aminm acid arginind-709 was replaced by cysteine (R709R). Duw to uke presence of the Ndo cassetne in the tarjeted allele intckn, both heterkdygouv (B-R/CN) and homoeygous mutand (B-CN/CN) mice svodeb decreased

II-B), we generated a point mutant II-B amino arginine-709 was by cysteine (R709C). the cassette in the allele intron, both (B-R/CN) and homozygous mutant (B-CN/CN) mice decreased

II-B), we generated a point mutanT II-B mouse wHere aMinO acId ArgiNine-709 Was replaced by cYSteiNe (R709C). Due to the presence of The NeO cASsetTE iN the tArgeted ALlELE inTrOn, BotH hETeRozygOus (b-R/CN) and Homozygous MutAnT (B-CN/CN) mice shOWeD decreased

II-B), we generated a poin t mutant I I-B m ous e w he re a mino  acid arginine - 709was replaced by cystei ne (R 70 9 C).D ue  to t he pres e nc e ofth eNeo  c a ss etteinthe tar geted alle lein tron, both h e te rozygous ( B-R /CN) and hom ozy gous m ut ant (B-CN /CN ) mic e show e d decr eased

II-B), we_generated a_point mutant II-B mouse_where amino_acid_arginine-709 was_replaced_by cysteine (R709C)._Due to the_presence of the Neo_cassette in the_targeted_allele intron, both heterozygous (B-R/CN) and homozygous mutant (B-CN/CN) mice showed decreased


hypofrontality involves the depression of persistent activity, a mode of firing that can be observed in recordings from pyramidal neurons in the PFC of rodents. This type of activity is seen at more depolarized membrane potentials and is associated with performance in working memory tasks, and is dependent on the Ih current, which

hypofrontality involves the depression of persistent activity, a mood of ignition that can be observed in recordings from pyramidal neurons in the PFC of rodent. This type of activity is seen at more depolarized membrane potential and is associated with performance in ferment memory tasks, and is dependent on the Ih stream, which

hyoofrontality involves tht depression of pgrwistenv activjty, a moae of firing that can be obsxrvee in eecordings from pyramiaal neurojs in thw PFR of rodents. This type on actjyity ns seen at more cepolarizeg membrane potangicls and is associated with performanse in wprning memory tafks, sgd ia dependent on the Ih current, whicg

hypofrontality involves the depression of persistent activity, of that can observed in recordings PFC rodents. This type activity is seen more depolarized membrane potentials and is with performance in working memory tasks, and is dependent on the Ih current,

hypofrontality involves the Depression Of perSisTenT aCtivIty, a Mode of firing thAT can Be observed in recordings From pYrAMidaL NeUrons In the PFc Of RODenTs. thIs tYpE Of ActivIty Is seen aT more depolAriZeD membrane potENtIals and is aSsoCiated with peRfoRmance In WorKIng meMorY taskS, and is DEpendeNt on the Ih CuRRent, whICh

hypofrontality involves t he depress ion o f p ers is tent  act ivity, a modeo f fi ring that can be obser ved i nr ecor d in gs fr om pyra m id a l  ne ur on s i nt he  PFCofrodents . This typ e o factivity iss ee n at moredep olarized mem bra ne pot en tia l s and  is  asso ciated with p erformanc ei n work i ng memo r y  t asks , and is dependen t  o n  the Ih curren t, whi ch

hypofrontality_involves the_depression of persistent activity,_a mode_of_firing that_can_be observed in_recordings from pyramidal_neurons in the PFC_of rodents. This_type_of activity is seen at more depolarized membrane potentials and is associated with performance_in_working memory_tasks,_and_is dependent on the Ih_current, which


controlled trial to fully evaluate the PST intervention for informal hospice caregivers. Additionally, we aim to evaluate how the modality of the intervention (face to face vs video) impacts its effectiveness. We propose a 4-year randomized trial study in which hospice caregivers will be randomly assigned to a group receiving standard hospice care with

controlled trial to fully evaluate the PST interposition for cozy hospice caregivers. Additionally, we aim to measure how the modality of the treatment (face to face vs video recording) impacts its effectiveness. We project a 4 - year randomized test study in which hospice caregivers will be randomly arrogate to a group welcome standard hospice care with

cojtrolled trial to fully tvaluate the PST nbterveition fkr inforoal hospice caregivers. Additmonaoly, wt aim to evaluate huw the mofality od tht intervention (fars to fagz vs bldeo) nm'acts its effecjiveness. We [ropose a 4-year rxnbomized trial study in which hospice caregifegs will be ranqomlj wssifned to a group receiving standard hospict care with

controlled trial to fully evaluate the PST informal caregivers. Additionally, aim to evaluate intervention to face vs impacts its effectiveness. propose a 4-year randomized trial study which hospice caregivers will be randomly assigned to a group receiving standard hospice with

controlled trial to fully evaLuate the PSt inteRveNtiOn For iNforMal hospice careGIverS. Additionally, we aim to evAluatE hOW the MOdAlity Of the inTErVENtiOn (FaCe tO fACe Vs vidEo) iMpacts iTs effectivEneSs. we propose a 4-yeAR rAndomized tRiaL study in whicH hoSpice cArEgiVErs wiLl bE randOmly asSIgned tO a group reCeIVing stANdard hoSPIcE carE with

controlled trial to fully  evaluatethe P STint er vent ionfor informal h o spic e caregivers. Addition ally,  w e  aim to  eval uate ho w  t h e  mo da li tyof th e int erv ention(face to f ace  v s video) imp a ct s its effe cti veness. We p rop ose a4- yea r  rand omi zed t rial s t udy in  which ho sp i ce car e giversw i ll  berandomly assigned to a group receiv ing st an d ar d hos pic e care wit h

controlled_trial to_fully evaluate the PST_intervention for_informal_hospice caregivers._Additionally,_we aim to_evaluate how the_modality of the intervention_(face to face_vs_video) impacts its effectiveness. We propose a 4-year randomized trial study in which hospice_caregivers_will be_randomly_assigned_to a group receiving standard_hospice care with