o-osmotic stress, and that increased cardiac FAK activity is observed in vivo in hypertrophic hearts. The idea that FAK activation plays a direct role in the development of cardiomyocyte hypertrophy is evident from our seminal findings that the activation of FAK is required for PE-stimulated hypertrophy of cultured cells and similar

o - osmotic stress, and that increased cardiac FAK activity is observed in vivo in hypertrophic heart. The theme that FAK activation plays a direct character in the development of cardiomyocyte hypertrophy is evident from our germinal findings that the activation of FAK is required for PE - stimulate hypertrophy of cultured cells and exchangeable

o-oslotic stress, and that ingreased cardiac YQK actmvity ia observdd in vivo in hypertrophic hxartw. The idea that FAK activatkon plays a direcr roow in the dxbelopmekc of dwrdimnyocyte hyperttophy is evigent from our veoiual findings that the activation of SAK is teeuired for PE-sjimulseed gjptrtrophy of cultured cells and sijilar

o-osmotic stress, and that increased cardiac FAK observed vivo in hearts. The idea direct in the development cardiomyocyte hypertrophy is from our seminal findings that the of FAK is required for PE-stimulated hypertrophy of cultured cells and similar

o-osmotic stress, and that incrEased cardiAc FAK ActIviTy Is obServEd in vivo in hypeRTropHic hearts. The idea that FAk actiVaTIon pLAyS a dirEct role IN tHE DevElOpMenT oF CaRdiomYocYte hypeRtrophy is eVidEnT from our semiNAl Findings thAt tHe activation Of FaK is reQuIreD For PE-StiMulatEd hypeRTrophy Of cultureD cELls and SImilar

o-osmotic stress, and that  increased  card iac  FA Kacti vity  is observed i n  viv o in hypertrophic hear ts. T he idea th at FA K activ a ti o n  pl ay sa d ir e ct  role  in  the de velopmentofca rdiomyocyteh yp ertrophy i s e vident fromour  semin al  fi n dings  th at th e acti v ationof FAK is  r e quired for PE- s t im ulat ed hypertrophy of cu l tured cells an d simi la r

o-osmotic stress,_and that_increased cardiac FAK activity_is observed_in_vivo in_hypertrophic_hearts. The idea_that FAK activation_plays a direct role_in the development_of_cardiomyocyte hypertrophy is evident from our seminal findings that the activation of FAK is_required_for PE-stimulated_hypertrophy_of_cultured cells and similar


. A hallmark of immunity is its longevity, manifested by the durability of memory B cells (Bmem ) and plasma cells (PC).Through the analysis and isolation of extremely rare antigen-specific Bmem populations, we have scrutinized their functional responsiveness and their transcriptome. Such genetic analyses and functional studies in vivo have opened up

. A hallmark of immunity is its longevity, manifested by the durability of memory boron cell (Bmem) and plasma cells (PC).Through the analysis and isolation of extremely rare antigen - specific Bmem population, we have scrutinized their functional responsiveness and their transcriptome. Such genic analysis and functional study in vivo have opened up

. A jallmark of immunity is lts longevity, mauufestev by ths durabiuity of memory B cells (Bmem ) abd plqsma cells (PC).Through tfe analysps and isilatmon of extremely rare anbngen-slccifie Umem populationx, we have vcrutinized thaif yunctional responsiveness and their eranscrophome. Such genejic amwlysss and functional studies in vivo gave optned up

. A hallmark of immunity is its by durability of B cells (Bmem the and isolation of rare antigen-specific Bmem we have scrutinized their functional responsiveness their transcriptome. Such genetic analyses and functional studies in vivo have opened up

. A hallmark of immunity is its lOngevity, maNifesTed By tHe DuraBiliTy of memory B celLS (BmeM ) and plasma cells (PC).ThrouGh the AnALysiS AnD isolAtion of EXtREMelY rArE anTiGEn-SpeciFic bmem popUlations, we HavE sCrutinized thEIr Functional ResPonsiveness aNd tHeir trAnScrIPtome. sucH geneTic anaLYses anD functionAl STudies IN vivo haVE OpEned Up

. A hallmark of immunity i s its long evity , m ani fe sted  bythe durability of m emory B cells (Bmem )and p la s ma c e ll s (PC ).Throu g ht h e a na ly sis  a n disola tio n of ex tremely ra rean tigen-specif i cBmem popul ati ons, we have  sc rutini ze d t h eir f unc tiona l resp o nsiven ess and t he i r tran s criptom e .  S uchgenetic analysesa nd functional stu dies i nv iv o hav e o pened up

. A_hallmark of_immunity is its longevity,_manifested by_the_durability of_memory_B cells (Bmem_) and plasma_cells (PC).Through the analysis_and isolation of_extremely_rare antigen-specific Bmem populations, we have scrutinized their functional responsiveness and their transcriptome. Such_genetic_analyses and_functional_studies_in vivo have opened up


use in the purification of 8-hydroxy-5-deazaflavin-dependent enzymes was synthesized. Successful development of a vaccine against HIV will likely require the induction of both antibody and/or cellular immune responses sufficient to prevent infection or disease respectively following infectious challenge. While the induction of antibody responses for a variety of

use in the purification of 8 - hydroxy-5 - deazaflavin - dependent enzymes was synthesize. Successful growth of a vaccine against HIV will likely require the induction of both antibody and/or cellular immune reaction sufficient to prevent infection or disease respectively following infectious challenge. While the trigger of antibody reception for a variety of

usf in the purification of 8-hydroxy-5-deazaflccin-depxndent snzymes das synthesized. Successful dxvelipmenu of a vaccine agaivst HIV wpll likelt rewyire the iisuction of bofm antnbidy and/or cellolar immune sesponses suffhckeut to prevent infection or disease rqspectifepy following igfecuiots cgallenge. While the induction of anfibody gesponses for a vsriety of

use in the purification of 8-hydroxy-5-deazaflavin-dependent enzymes Successful of a against HIV will both and/or cellular immune sufficient to prevent or disease respectively following infectious challenge. the induction of antibody responses for a variety of

use in the purification of 8-hydRoxy-5-deazafLavin-DepEndEnT enzYmes Was synthesized. sUcceSsful development of a vacCine aGaINst Hiv wIll liKely reqUIrE THe iNdUcTioN oF BoTh antIboDy and/or Cellular imMunE rEsponses suffICiEnt to preveNt iNfection or diSeaSe respEcTivELy folLowIng inFectioUS challEnge. While ThE InductIOn of antIBOdY resPonses for a variety OF

use in the purification o f 8-hydrox y-5-d eaz afl av in-d epen dent enzymes w a s sy nthesized. Successfuldevel op m ento fa vac cine ag a in s t  HI Vwi llli k el y req uir e the i nduction o f b ot h antibody a n d/ or cellula r i mmune respon ses  suffi ci ent to pr eve nt in fectio n  or di sease res pe c tively followi n g  i nfec tious challenge.W hi l e the inductio n of a nt i bo d y  re spo nses for a  v ariet y  of

use_in the_purification of 8-hydroxy-5-deazaflavin-dependent enzymes_was synthesized._Successful_development of_a_vaccine against HIV_will likely require_the induction of both_antibody and/or cellular_immune_responses sufficient to prevent infection or disease respectively following infectious challenge. While the induction_of_antibody responses_for_a_variety of


. While not within the scope of the present proposal, we anticipate that therapeutic interventions that abrogate hypoxia-induced blood flow decreases and changes in markers of vascular damage detected in these human models will decrease frequency of crisis and lessen the degree of end-organ damage if tested in larger clinical trials. In this project, mechanisms

. While not within the scope of the present proposal, we anticipate that therapeutic interposition that abrogate hypoxia - induce blood flow decreases and change in markers of vascular damage detect in these human models will decrease frequency of crisis and lessen the degree of goal - organ damage if test in larger clinical trials. In this undertaking, mechanisms

. Whlle not within the scope of the present proposel, we ahticipatd that therapeutic interventmons that abrogate hypoxia-inducdd blood vlow deceeasts and changes in markers of vaagular vamage detected in these vuman models whlu becrease frequency of crisis and lesfen the dfgree of end-ordan cwmags if tested in larger clinical trizls. In uhis project, mechamisms

. While not within the scope of proposal, anticipate that interventions that abrogate changes markers of vascular detected in these models will decrease frequency of crisis lessen the degree of end-organ damage if tested in larger clinical trials. In project, mechanisms

. While not within the scope of tHe present pRoposAl, wE anTiCipaTe thAt therapeutic iNTervEntions that abrogate hypOxia-iNdUCed bLOoD flow DecreasES aND ChaNgEs In mArKErS of vaScuLar damaGe detected In tHeSe human modelS WiLl decrease FreQuency of crisIs aNd lessEn The DEgree Of eNd-orgAn damaGE if tesTed in largEr CLinicaL Trials. IN THiS proJect, mechanisms

. While not within the sco pe of theprese ntpro po sal,  weanticipate tha t  the rapeutic interventions  that  a b roga t ehypox ia-indu c ed b loo dfl owde c re asesand  change s in marke rsof  vascular da m ag e detected  in  these human  mo dels w il l d e creas e f reque ncy of crisis  and less en the de g ree ofe n d- orga n damage if teste d  i n  larger clinic al tri al s .I n  th isproject, m ec hanis m s

. While_not within_the scope of the_present proposal,_we_anticipate that_therapeutic_interventions that abrogate_hypoxia-induced blood flow_decreases and changes in_markers of vascular_damage_detected in these human models will decrease frequency of crisis and lessen the degree_of_end-organ damage_if_tested_in larger clinical trials. In_this project, mechanisms


an autoinhibitory domain that interacts with the IAD, burying key residues required for IRF dimerization and preventing IRF nuclear accumulation. C-terminal phosphorylation induces charge repulsions, causing the autoinhibitory domain to unmask the IAD, allowing formation of transcriptionally active IRF dimers. To identify

an autoinhibitory domain that interacts with the IAD, burying key residue command for IRF dimerization and preventing IRF nuclear accumulation. C - concluding phosphorylation induces charge repulsions, cause the autoinhibitory domain to unmask the IAD, allowing constitution of transcriptionally active IRF dimers. To identify

an autoinhibitory domain tmat interacts wijh the IED, buryjng key fesidues required for IRF dileeizatuon and preventing IRF nuclear wccumularion. X-terminal 'gosphornjatikk indbcxs charge repulxions, caushng the autoinvicicory domain to unmask the IAD, allowigg formstlon of transcryptipgallg active IRF dimers. To identify

an autoinhibitory domain that interacts with the key required for dimerization and preventing induces repulsions, causing the domain to unmask IAD, allowing formation of transcriptionally active dimers. To identify

an autoinhibitory domain thaT interacts With tHe IaD, bUrYing Key rEsidues requireD For IrF dimerization and preveNting iRf NuclEAr AccumUlation. c-TeRMInaL pHoSphOrYLaTion iNduCes charGe repulsioNs, cAuSing the autoiNHiBitory domaIn tO unmask the IAd, alLowing FoRmaTIon of TraNscriPtionaLLy actiVe IRF dimeRs. tO identIFy

an autoinhibitory domainthat inter actswit h t he  IAD , bu rying key resi d uesrequired for IRF dimer izati on andp re venti ng IRFn uc l e arac cu mul at i on . C-t erm inal ph osphorylat ion  i nduces charg e  r epulsions,  ca using the au toi nhibit or y d o maintounmas k theI AD, al lowing fo rm a tion o f  transc r i pt iona lly active IRF di m er s . To identify

an_autoinhibitory domain_that interacts with the_IAD, burying_key_residues required_for_IRF dimerization and_preventing IRF nuclear_accumulation. C-terminal phosphorylation induces_charge repulsions, causing_the_autoinhibitory domain to unmask the IAD, allowing formation of transcriptionally active IRF dimers. To_identify


will guide our methods development using data from 500,000 samples from the UK Biobank, and will work closely with the Haplotype Reference Consortium (see letters of support). Our aim is to understand chemotactic migration in cells from a biochemical standpoint. To this end we have investigated this process in both phagocytic cells

will guide our methods development using datum from 500,000 sample from the UK Biobank, and will work closely with the Haplotype Reference Consortium (visualize letter of support). Our aim is to sympathize chemotactic migration in cells from a biochemical standpoint. To this end we have investigate this process in both phagocytic cells

wipl guide our methods devtlopment using daja from 500,000 samplss from ghe UK Biobank, and will work cooselt with the Haplotype Rdference Bonsortiun (set letters of support). Our aim is bo unbecstand chemotacjic migratiot in cells frok x yiochemical standpoint. To this end wq have ongestigated thif prpsess pn both phagocytic cells

will guide our methods development using data samples the UK and will work Consortium letters of support). aim is to chemotactic migration in cells from a standpoint. To this end we have investigated this process in both phagocytic cells

will guide our methods develoPment using Data fRom 500,000 SamPlEs frOm thE UK Biobank, and wILl woRk closely with the HaplotYpe ReFeREnce cOnSortiUm (see leTTeRS Of sUpPoRt). OUr AIm Is to uNdeRstand cHemotactic MigRaTion in cells fROm A biochemicAl sTandpoint. To tHis End we hAvE inVEstigAteD this ProcesS In both PhagocytiC cELls

will guide our methods de velopmentusing  da tafr om 5 00,0 00 samples fro m  the  UK Biobank, and willworkcl o sely wi th th e Haplo t yp e Ref er en ceCo n so rtium  (s ee lett ers of sup por t) . Our aim is to  understan d c hemotactic m igr ationin  ce l ls fr oma bio chemic a l stan dpoint. T ot his en d  we hav e in vest igated this proce s si n both phagocy tic ce ll s

will_guide our_methods development using data_from 500,000_samples_from the_UK_Biobank, and will_work closely with_the Haplotype Reference Consortium_(see letters of_support)._Our aim is to understand chemotactic migration in cells from a biochemical standpoint. To_this_end we_have_investigated_this process in both phagocytic_cells


we propose to: (1) study their relationship to the activity and vascular complications in RA and SLE, (2) analyze those features, such as complement fixing ability, that could account for their phlogogenic capacity, (3) determine their ability to influence lymphocyte function (especially lymphocyte-mediated cytotoxicity) and, finally

we propose to: (1) study their relationship to the activity and vascular complication in RA and SLE, (2) analyze those feature, such as complement fixing ability, that could account for their phlogogenic capacity, (3) decide their ability to influence lymphocyte function (specially lymphocyte - mediate cytotoxicity) and, finally

we propose to: (1) study their relationship to the artivity and vaszular complications in RA anv SLW, (2) anqlyze those features, sjch as colplement fixmng ability, that could ageount nor tkemr phlogogenic gapacity, (3) datermine their acipity to influence lymphocyte functijn (espeviwlly lymphocytg-mediseed djtitoxicity) and, finally

we propose to: (1) study their relationship activity vascular complications RA and SLE, as fixing ability, that account for their capacity, (3) determine their ability to lymphocyte function (especially lymphocyte-mediated cytotoxicity) and, finally

we propose to: (1) study their relaTionship to The acTivIty AnD vasCulaR complications IN RA aNd SLE, (2) analyze those featuRes, suCh AS comPLeMent fIxing abILiTY, ThaT cOuLd aCcOUnT for tHeiR phlogoGenic capacIty, (3) DeTermine their ABiLity to inflUenCe lymphocyte FunCtion (eSpEciALly lyMphOcyte-MediatED cytotOxicity) anD, fINally

we propose to: (1) studytheir rela tions hip  to  t he a ctiv ity and vascul a r co mplications in RA andSLE,(2 )  ana l yz e tho se feat u re s ,  su ch  a s c om p le mentfix ing abi lity, that  co ul d account fo r  t heir phlog oge nic capacity , ( 3) det er min e  thei r a bilit y to i n fluenc e lymphoc yt e  funct i on (esp e c ia llylymphocyte-mediat e dc ytotoxicity) a nd, fi na l ly

we_propose to:_(1) study their relationship_to the_activity_and vascular_complications_in RA and_SLE, (2) analyze_those features, such as_complement fixing ability,_that_could account for their phlogogenic capacity, (3) determine their ability to influence lymphocyte function_(especially_lymphocyte-mediated cytotoxicity)_and,_finally


physician scientists at Johns Hopkins including Drs. Cynthia Sears and David Huso. All of these individuals have committed their time, resources, and expertise to facilitate Dr. Guerrerio's career development and research goals. In addition, the candidate will acquire additional skills and training through didactic coursework at the highly regarded

physician scientists at Johns Hopkins including Drs. Cynthia Sears and David Huso. All of these individuals have commit their meter, resources, and expertise to facilitate Dr. Guerrerio's career exploitation and research goals. In summation, the campaigner will acquire additional skills and training through didactic coursework at the highly regarded

phjsician scientists at Jomns Hopkins inclodung Drv. Cyntgia Searr and David Huso. All of thesx ineividyals have committed thdir time, gesources, and wxpertise vk facillcate Sv. Guexrxrio's career deyelopment atd research godlr. Nn addition, the candidate will acquiwe addiyilnal skills anq trsyninf through didactic coursework at tge highny regarded

physician scientists at Johns Hopkins including Drs. and Huso. All these individuals have expertise facilitate Dr. Guerrerio's development and research In addition, the candidate will acquire skills and training through didactic coursework at the highly regarded

physician scientists at JohnS Hopkins inCludiNg DRs. CYnThia searS and David Huso. ALL of tHese individuals have comMitteD tHEir tIMe, ResouRces, and EXpERTisE tO fAciLiTAtE Dr. GuErrErio's caReer develoPmeNt And research gOAlS. In additioN, thE candidate wiLl aCquire AdDitIOnal sKilLs and TrainiNG throuGh didactiC cOUrsewoRK at the hIGHlY regArded

physician scientists at J ohns Hopki ns in clu din gDrs.  Cyn thia Sears and Davi d Huso. All of these i ndivi du a ls h a ve  comm itted t h ei r tim e,  r eso ur c es , and  ex pertise  to facili tat eDr. Guerreri o 's  career de vel opment and r ese arch g oa ls. In ad dit ion,the ca n didate  will acq ui r e addi t ional s k i ll s an d training throug h  d i dactic coursew ork at  t h eh i ghl y r egarded

physician_scientists at_Johns Hopkins including Drs._Cynthia Sears_and_David Huso._All_of these individuals_have committed their_time, resources, and expertise_to facilitate Dr._Guerrerio's_career development and research goals. In addition, the candidate will acquire additional skills and_training_through didactic_coursework_at_the highly regarded


iplegia due to damage in the brain in both the pediatric and adult populations stems not only from the loss of neurons killed by the vascular insult but also from the loss of function in viable but dormant neurons in the affected hemisphere. The latter problem may be avoidable and, to a certain extent, correctable. The

iplegia due to damage in the brain in both the pediatric and adult populations stems not merely from the personnel casualty of neurons killed by the vascular insult but besides from the loss of function in viable but abeyant nerve cell in the affected hemisphere. The latter problem may be avoidable and, to a certain extent, correctable. The

iplfgia due to damage in tht brain in both tkw pedietric ahd adult populations stems not only hrom the ooss of neurons killed by the vwscular unsuor but also from thc losa of yuiction in viablg but dormand neurons in tve ayfected hemisphere. The latter problei may br wvoidable and, jo a bewtaih extent, correctable. The

iplegia due to damage in the brain the and adult stems not only killed the vascular insult also from the of function in viable but dormant in the affected hemisphere. The latter problem may be avoidable and, to a extent, correctable. The

iplegia due to damage in the brAin in both tHe pedIatRic AnD aduLt poPulations stems NOt onLy from the loss of neurons KilleD bY The vAScUlar iNsult buT AlSO FroM tHe LosS oF FuNctioN in Viable bUt dormant nEurOnS in the affectED hEmisphere. THe lAtter problem May Be avoiDaBle ANd, to a CerTain eXtent, cORrectaBle. The

iplegia due to damage in t he brain i n bot h t hepe diat ricand adult popu l atio ns stems not only from  thelo s s of ne urons  killed by t heva sc ula ri ns ult b utalso fr om the los s o ffunction inv ia ble but do rma nt neurons i n t he aff ec ted hemis phe re. T he lat t er pro blem maybe avoida b le and, t oa ce rtain extent, cor r ec t able. The

iplegia due_to damage_in the brain in_both the_pediatric_and adult_populations_stems not only_from the loss_of neurons killed by_the vascular insult_but_also from the loss of function in viable but dormant neurons in the affected_hemisphere._The latter_problem_may_be avoidable and, to a_certain extent, correctable. The


PE) as coating substrates. Here the positively-charged PEs encourage spheroid formation and ELP encourages stable surface-tethering of spheroids. We will systematically investigate the effect of charge content and chemistry on 3-D spheroid organization. Our overarching hypothesis is that we will achieve superior adip

PE) as coating substrates. Here the positively - charged PEs encourage spheroid constitution and ELP encourage stable surface - tethering of spheroids. We will systematically investigate the impression of charge content and chemistry on 3 - five hundred spheroid organization. Our overarching hypothesis is that we will achieve superscript adip

PE) ws coating substrates. Heve the positiveli-cyarged PEs ehcourage spheroid formation and ELP xncoyragew stable surface-tetherkng of spjeroids. Qe wmll systematically invesbngate bhe eyfxct of charge cpntent and chemistry on 3-G rpkeroid organization. Our overarching rypothexid is that we wyll sshiebv wuperior adip

PE) as coating substrates. Here the positively-charged spheroid and ELP stable surface-tethering of the of charge content chemistry on 3-D organization. Our overarching hypothesis is that will achieve superior adip

PE) as coating substrates. Here The positivEly-chArgEd Pes EncoUragE spheroid formaTIon aNd ELP encourages stable sUrfacE-tETherINg Of sphEroids. WE WiLL SysTeMaTicAlLY iNvestIgaTe the efFect of charGe cOnTent and chemiSTrY on 3-D spheroId oRganization. OUr oVerarcHiNg hYPotheSis Is thaT we wilL AchievE superior AdIP

PE) as coating substrates.  Here theposit ive ly- ch arge d PE s encourage sp h eroi d formation and ELP en coura ge s  sta b le  surf ace-tet h er i n g o fsp her oi d s.  We w ill  system atically i nve st igate the ef f ec t of charg e c ontent and c hem istryon  3- D  sphe roi d org anizat i on. Ou r overarc hi n g hypo t hesis i s th at w e will achieve su p er i or adip

PE) as_coating substrates._Here the positively-charged PEs_encourage spheroid_formation_and ELP_encourages_stable surface-tethering of_spheroids. We will_systematically investigate the effect_of charge content_and_chemistry on 3-D spheroid organization. Our overarching hypothesis is that we will achieve superior_adip


premise of Arp5 as the?gatekeeper? regulating DNA traversing through the center of nucleosomes with wild type INO80 and mutant Arp5 in which either its histone or nucleosome binding regions have been deleted or mutated. We will also test whether the Arp8 module regulates Arp5 interactions with

premise of Arp5 as the?gatekeeper? regulating DNA traversing through the center of nucleosomes with wild character INO80 and mutant Arp5 in which either its histone or nucleosome tie regions have been edit or mutate. We will also test whether the Arp8 module regulate Arp5 interactions with

prfmise of Arp5 as the?gatekteper? regulating BBA tratersing through the center of nucleosomes wmth qild ujpe INO80 and mutant Aro5 in whicj either its yistone or nucleosome bihfing cegions have begn deleted os mutated. We whlu clso test whether the Arp8 module regtlates Sro5 interactions witn

premise of Arp5 as the?gatekeeper? regulating DNA the of nucleosomes wild type INO80 either histone or nucleosome regions have been or mutated. We will also test the Arp8 module regulates Arp5 interactions with

premise of Arp5 as the?gatekeepEr? regulatiNg DNA TraVerSiNg thRougH the center of nuCLeosOmes with wild type INO80 and MutanT ARP5 in wHIcH eithEr its hiSToNE Or nUcLeOsoMe BInDing rEgiOns have Been deleteD or MuTated. We will aLSo Test whetheR thE Arp8 module reGulAtes ArP5 iNteRActioNs wIth

premise of Arp5 as the?ga tekeeper?regul ati ngDN A tr aver sing through t h e ce nter of nucleosomes wi th wi ld type IN O80 a nd muta n tA r p5in  w hic he it her i tshistone  or nucleo som ebinding regi o ns  have been  de leted or mut ate d. Wewi lla lso t est  whet her th e  Arp8module re gu l ates A r p5 inte r a ct ions  with

premise_of Arp5_as the?gatekeeper? regulating DNA_traversing through_the_center of_nucleosomes_with wild type_INO80 and mutant_Arp5 in which either_its histone or_nucleosome_binding regions have been deleted or mutated. We will also test whether the Arp8_module_regulates Arp5_interactions_with


as well as monocyte progenitors to release enhanced amounts of cytokine in response to bacterial endotoxin. Using both tissue macrophage and those derived from bone marrow progenitors, cytokine responses to endotoxin as well as phagocytosis and chemotaxis will be determined in mice with denervated compared to neural intact bone marrow. Having established the role of

as well as monocyte progenitors to release enhanced amounts of cytokine in reception to bacterial endotoxin. use both tissue macrophage and those derived from bone marrow progenitors, cytokine reaction to endotoxin as well as phagocytosis and chemotaxis will be determined in mouse with denervated compare to neural integral bone marrow. Having established the function of

as well as monocyte progenltors to release enhancxd amouhts of chtokine in response to bactecial endoujxin. Using both tirsue macrlphage abd tiose derived from bone marrow lvogenntirs, cytokine rgsponses to andotoxin as walu cs phagocytosis and chemotaxis will fe detetmlned in mice wyth cqnerbated compared to neural intact bohe marrmw. Having estsblished the role of

as well as monocyte progenitors to release of in response bacterial endotoxin. Using derived bone marrow progenitors, responses to endotoxin well as phagocytosis and chemotaxis will determined in mice with denervated compared to neural intact bone marrow. Having established role of

as well as monocyte progenitoRs to releasE enhaNceD amOuNts oF cytOkine in responsE To baCterial endotoxin. Using bOth tiSsUE macROpHage aNd those DErIVEd fRoM bOne MaRRoW progEniTors, cytOkine respoNseS tO endotoxin as WElL as phagocyTosIs and chemotaXis Will be DeTerMIned iN miCe witH denerVAted coMpared to nEuRAl intaCT bone maRROw. haviNg established the rOLe OF

as well as monocyte proge nitors torelea seenh an cedamou nts of cytokin e  inresponse to bacterialendot ox i n. U s in g bot h tissu e  m a c rop ha ge  an dt ho se de riv ed from  bone marr owpr ogenitors, c y to kine respo nse s to endotox inas wel lasp hagoc yto sis a nd che m otaxis  will bede t ermine d  in mic e wi th d enervated compare d  t o  neural intact  bonema r ro w .  Ha vin g establis he d the role of

as_well as_monocyte progenitors to release_enhanced amounts_of_cytokine in_response_to bacterial endotoxin._Using both tissue_macrophage and those derived_from bone marrow_progenitors,_cytokine responses to endotoxin as well as phagocytosis and chemotaxis will be determined in_mice_with denervated_compared_to_neural intact bone marrow. Having_established the role of


-dependent gene expression. This study aims to address two fundamental questions relating to Gcn5 and its role in RA-mediated forebrain development. First, I will investigate patterning and differentiation in the forebrains of Gcn5hat mutants to determine the exact role of Gcn5 in forebrain development. More specifically,

-dependent gene expression. This study aims to address two cardinal question relating to Gcn5 and its role in RA - intercede forebrain exploitation. First, I will investigate patterning and differentiation in the forebrain of Gcn5hat mutants to determine the exact function of Gcn5 in forebrain development. More specifically,

-depfndent gene expression. Tmis study aims to addrevs two fundamevtal questions relating to Grn5 abd itw role in RA-mediated furebrain fevelopmwnt. Hirst, I will invxatigate pattedking cnv differentiatipn in the xorebrains of Ccv5hct mutants to determine the exact roje of Gvn5 in forebrain qevekjpmehn. Nore specifically,

-dependent gene expression. This study aims to fundamental relating to and its role I investigate patterning and in the forebrains Gcn5hat mutants to determine the exact of Gcn5 in forebrain development. More specifically,

-dependent gene expression. ThIs study aimS to adDreSs tWo FundAmenTal questions reLAtinG to Gcn5 and its role in RA-meDiateD fORebrAIn DevelOpment. FIRsT, i WilL iNvEstIgATe PatteRniNg and diFferentiatIon In The forebrainS Of gcn5hat mutaNts To determine tHe eXact roLe Of GCN5 in foRebRain dEvelopMEnt. MorE specificAlLY,

-dependent gene expression . This stu dy ai mstoad dres s tw o fundamentalq uest ions relating to Gcn5and i ts role in  RA-m ediated fo r e bra in  d eve lo p me nt. F irs t, I wi ll investi gat epatterning a n ddifferenti ati on in the fo reb rainsof  Gc n 5hatmut antsto det e rminethe exact  r o le ofG cn5 inf o re brai n development. Mo r es pecifically,

-dependent gene_expression. This_study aims to address_two fundamental_questions_relating to_Gcn5_and its role_in RA-mediated forebrain_development. First, I will_investigate patterning and_differentiation_in the forebrains of Gcn5hat mutants to determine the exact role of Gcn5 in_forebrain_development. More_specifically,


of nasal macrophages. The proposed studies provide a mechanistic understanding of i) its ability to inhibit uptake and killing by neutrophils, ii) its recognition by macrophages, and iii) the role of its capsule type in these interactions with phagocytes. Experimental autoimmune thyroiditis in mice is a very useful model of autoimmune disease since it shows

of nasal macrophages. The proposed studies leave a mechanistic reason of i) its ability to inhibit uptake and kill by neutrophils, ii) its recognition by macrophage, and iii) the role of its capsule type in these interactions with phagocyte. Experimental autoimmune thyroiditis in mouse is a very useful mannequin of autoimmune disease since it shows

of nasal macrophages. The pvoposed studies krivide e mechahistic uvderstanding of i) its abilitb to inhivit uptake and killing by neutrlphils, iu) itw recognition by magxophafcs, anb mii) the role of its capsune type in theve iuteractions with phagocytes. Experimegtal auyolmmune thyroidytis yn mjbe is a very useful model of aufoimmunt disease since it shows

of nasal macrophages. The proposed studies provide understanding i) its to inhibit uptake its by macrophages, and the role of capsule type in these interactions with Experimental autoimmune thyroiditis in mice is a very useful model of autoimmune disease it shows

of nasal macrophages. The propOsed studieS provIde A meChAnisTic uNderstanding of I) Its aBility to inhibit uptake aNd kilLiNG by nEUtRophiLs, ii) its REcOGNitIoN bY maCrOPhAges, aNd iIi) the roLe of its capSulE tYpe in these inTErActions witH phAgocytes. ExpeRimEntal aUtOimMUne thYroIditiS in micE Is a verY useful moDeL Of autoIMmune diSEAsE sinCe it shows

of nasal macrophages. The  proposedstudi espro vi de a  mec hanistic under s tand ing of i) its abilityto in hi b it u p ta ke an d killi n gb y  ne ut ro phi ls ,  i i) it s r ecognit ion by mac rop ha ges, and iii )  t he role of  it s capsule ty pein the se  in t eract ion s wit h phag o cytes.  Experime nt a l auto i mmune t h y ro idit is in mice is a v e ry useful model o f auto im m un e dis eas e since it  s hows

of_nasal macrophages._The proposed studies provide_a mechanistic_understanding_of i)_its_ability to inhibit_uptake and killing_by neutrophils, ii) its_recognition by macrophages,_and_iii) the role of its capsule type in these interactions with phagocytes. Experimental autoimmune_thyroiditis_in mice_is_a_very useful model of autoimmune_disease since it shows


augments parasympathetic and/or reduces cardiac sympathetic activity and thereby protects against VF. Specific Aim #1 will test the hypothesis that exercise training alters cardiac autonomic balance in animals susceptible and resistant to VF. Specifically, cardiac autonomic balance will be evaluated in animals either resistant or susceptible to VF before, during and

augments parasympathetic and/or reduces cardiac sympathetic activity and thereby protect against VF. Specific Aim # 1 will screen the hypothesis that exercise training alters cardiac autonomic remainder in animals susceptible and resistant to VF. Specifically, cardiac autonomic libra will be evaluate in animals either immune or susceptible to VF before, during and

auhments parasympathetic akd/or reduces carbuac sykpathefic actixity and thereby protects ageinsr VF. Wpecific Aim #1 will tesg the hyplthesis rhat wxercise tczining alters gardicc autonomic balsnce in anhmals susceptitld cnd resistant to VF. Specifically, carqiac auyojomic balance rill fe ebaluated in animals either resistaht or slsceptible to VF nefore, during and

augments parasympathetic and/or reduces cardiac sympathetic activity protects VF. Specific #1 will test alters autonomic balance in susceptible and resistant VF. Specifically, cardiac autonomic balance will evaluated in animals either resistant or susceptible to VF before, during and

augments parasympathetic anD/or reduces CardiAc sYmpAtHetiC actIvity and therebY ProtEcts against VF. Specific AIm #1 wilL tESt thE HyPotheSis that EXeRCIse TrAiNinG aLTeRs carDiaC autonoMic balance In aNiMals susceptiBLe And resistaNt tO VF. SpecificaLly, CardiaC aUtoNOmic bAlaNce wiLl be evALuated In animals EiTHer resIStant or SUScEptiBle to VF before, duriNG aND

augments parasympatheticand/or red ucescar dia csymp athe tic activity a n d th ereby protects against  VF.Sp e cifi c  A im #1  will t e st t hehy po the si s  t hat e xer cise tr aining alt ers  c ardiac auton o mi c balanceinanimals susc ept ible a nd  re s istan t t o VF.  Speci f ically , cardiac  a u tonomi c  balanc e wi ll b e evaluated in an i ma l s either resis tant o rs us c e pti ble  to VF bef or e, du r ing and

augments_parasympathetic and/or_reduces cardiac sympathetic activity_and thereby_protects_against VF._Specific_Aim #1 will_test the hypothesis_that exercise training alters_cardiac autonomic balance_in_animals susceptible and resistant to VF. Specifically, cardiac autonomic balance will be evaluated in_animals_either resistant_or_susceptible_to VF before, during and


term changes mediated by neural activity are dependent on calcium-activated transcription of new gene products. Thus, calcium-activated transcription factors provide a mechanism for linking extrinsic signals with genetic programs of neural development. NeuroD2 is a basic helix-loop-helix transcription factor previously isolated in our lab, using a screen for novel

term changes mediated by neural natural process are pendent on calcium - activated transcription of new gene product. Thus, calcium - activated recording agent provide a mechanism for associate extrinsic signals with genetic platform of neural development. NeuroD2 is a basic coil - loop - helix transcription factor previously isolated in our lab, using a screen for novel

terl changes mediated by nemral activity arg eependxnt on dalcium-aztivated transcription of nex gebe priducts. Thus, calcium-actkvated trwnscriptuon hactors provide e mechanlfm fkv linnmng extrinsic slgnals with genetic progrdmr lf neural development. NeuroD2 is a bwsic hekid-loop-helix tragscrppeion factor previously isolated in our lab, uspng a screen for movel

term changes mediated by neural activity are calcium-activated of new products. Thus, calcium-activated for extrinsic signals with programs of neural NeuroD2 is a basic helix-loop-helix transcription previously isolated in our lab, using a screen for novel

term changes mediated by neurAl activity Are dePenDenT oN calCium-Activated transCRiptIon of new gene products. ThUs, calCiUM-actIVaTed trAnscripTIoN FActOrS pRovIdE A mEchanIsm For linkIng extrinsIc sIgNals with geneTIc Programs of NeuRal developmeNt. NEuroD2 iS a BasIC heliX-loOp-helIx tranSCriptiOn factor pReVIously ISolated IN OuR lab, Using a screen for noVEl

term changes mediated by n eural acti vityare  de pe nden t on  calcium-activ a tedtranscription of new g ene p ro d ucts .  T hus,calcium - ac t i vat ed  t ran sc r ip tionfac tors pr ovide a me cha ni sm for linki n gextrinsicsig nals with ge net ic pro gr ams of ne ura l dev elopme n t. Neu roD2 is a  b a sic he l ix-loop - h el ix t ranscription fact o rp reviously isol ated i no ur l ab,  us ing a scre en  forn ovel

term changes_mediated by_neural activity are dependent_on calcium-activated_transcription_of new_gene_products. Thus, calcium-activated_transcription factors provide_a mechanism for linking_extrinsic signals with_genetic_programs of neural development. NeuroD2 is a basic helix-loop-helix transcription factor previously isolated in_our_lab, using_a_screen_for novel


model of inflammatory pain and hyperalgesia. The investigators will use their well-characterized model if inflammation to examine the effects of these active components on pain and hyperalgesia that persists for hours or days. This model will also distinguish between analgesic and antihyperalgesic activity. The second aim is to

model of inflammatory pain and hyperalgesia. The investigators will practice their well - qualify model if inflammation to test the impression of these active components on pain and hyperalgesia that prevail for hours or days. This exemplar will also distinguish between analgesic and antihyperalgesic activeness. The second aim is to

mofel of inflammatory pain and hyperalgesnq. The mnvestifators wkll use their well-characterived nodel if inflammation to exxmine the effects of uhese active components ok paih and iyperalgesia thst persistv for hours or dxyd. This model will also distinguish fetween ajalgesic and agtihjpqralfvslc activity. The second aim is to

model of inflammatory pain and hyperalgesia. The use well-characterized model inflammation to examine components pain and hyperalgesia persists for hours days. This model will also distinguish analgesic and antihyperalgesic activity. The second aim is to

model of inflammatory pain anD hyperalgeSia. ThE inVesTiGatoRs wiLl use their well-CHaraCterized model if inflammAtion To EXamiNE tHe effEcts of tHEsE ACtiVe CoMpoNeNTs On paiN anD hyperaLgesia that PerSiSts for hours oR DaYs. This modeL wiLl also distinGuiSh betwEeN anALgesiC anD antiHyperaLGesic aCtivity. ThE sECond aiM Is to

model of inflammatory pai n and hype ralge sia . T he  inv esti gators will us e  the ir well-characterizedmodel  i f  inf l am matio n to ex a mi n e  th eef fec ts of  thes e a ctive c omponentsonpa in and hyper a lg esia thatper sists for ho urs  or da ys . T h is mo del  will  alsod isting uish betw ee n  analg e sic and a nt ihyp eralgesic activit y .T he second aimis to

model_of inflammatory_pain and hyperalgesia. The_investigators will_use_their well-characterized_model_if inflammation to_examine the effects_of these active components_on pain and_hyperalgesia_that persists for hours or days. This model will also distinguish between analgesic and_antihyperalgesic_activity. The_second_aim_is to


microsphere-derived flows using an acute canine model of stenosis. The ability of deformation and differential deformation derived from 4D stress echocardiography to detect new myocardial tissue at-risk in the presence of existing infarction will then be determined in a hybrid acute/chronic canine model of infarction with superimposed ischemia. The technique will be translated

microsphere - derived flows using an acute canine exemplar of stenosis. The ability of distortion and differential deformation derived from 4D stress echocardiography to detect raw myocardial tissue at - risk in the presence of exist infarct will then be determined in a hybrid acute / chronic canine model of infarction with superimposed ischemia. The proficiency will be translated

mifrosphere-derived flows uring an acute ccbine mmdel or stenosks. The ability of deformatioi ane difderential deformation aerived fgom 4D strwss tchocardiography vk detecb new lyoccrvial tissue at-rlsk in the [resence of exhsgiug infarction will then be determineq in a nyhrid acute/chrogic bagine model of infarction with superimpksed isbhemia. The techniaue will be translated

microsphere-derived flows using an acute canine model The of deformation differential deformation derived detect myocardial tissue at-risk the presence of infarction will then be determined in hybrid acute/chronic canine model of infarction with superimposed ischemia. The technique will be

microsphere-derived flows usIng an acute CaninE moDel Of StenOsis. the ability of deFOrmaTion and differential defOrmatIoN DeriVEd From 4D Stress eCHoCARdiOgRaPhy To DEtEct neW myOcardiaL tissue at-rIsk In The presence oF ExIsting infaRctIon will then bE deTerminEd In a HYbrid AcuTe/chrOnic caNIne modEl of infarCtIOn with SUperimpOSEd IschEmia. The technique wILl BE translated

microsphere-derived flows  using anacute  ca nin emode l of  stenosis. The abil ity of deformation and  diff er e ntia l  d eform ation d e ri v e d f ro m4Dst r es s ech oca rdiogra phy to det ect  n ew myocardia l  t issue at-r isk  in the pres enc e of e xi sti n g inf arc tionwill t h en bedetermine di n a hy b rid acu t e /c hron ic canine model o f  i n farction withsuperi mp o se d isc hem ia. The te ch nique will be tr a n s lat e d

microsphere-derived_flows using_an acute canine model_of stenosis._The_ability of_deformation_and differential deformation_derived from 4D_stress echocardiography to detect_new myocardial tissue_at-risk_in the presence of existing infarction will then be determined in a hybrid acute/chronic_canine_model of_infarction_with_superimposed ischemia. The technique will_be translated


the first time. The ultimate objective is to develop predictive models for deposition using both theory and experimentally derived coefficients, including models that account for the pronounced nonuniformity of epithelial depositions on the airways. We propose to make single path hollow airway casts of human and dog tracheobronchial airways, including a

the first time. The ultimate objective is to develop predictive model for deposit using both theory and experimentally derive coefficient, including models that account for the pronounce nonuniformity of epithelial depositions on the airways. We project to make single way hollow airway casts of human and dog tracheobronchial respiratory tract, including a

thf first time. The ultimatt objective is to develo' predidtive moaels for deposition using bovh tyeory and experimentally defived coevficientw, inrluding models tizt accomut fod the 'ronounced nonukiformity ox epithelial dapusntions on the airways. We propose to iake simgpe path hollow airewy czsts of human and dog tracheobroncgial aigways, including a

the first time. The ultimate objective is predictive for deposition both theory and that for the pronounced of epithelial depositions the airways. We propose to make path hollow airway casts of human and dog tracheobronchial airways, including a

the first time. The ultimate obJective is tO deveLop PreDiCtivE modEls for depositiON usiNg both theory and experimEntalLy DErivED cOeffiCients, iNClUDIng MoDeLs tHaT AcCount For The pronOunced nonuNifOrMity of epitheLIaL depositioNs oN the airways. WE prOpose tO mAke SIngle PatH hollOw airwAY casts Of human anD dOG trachEObronchIAL aIrwaYs, including a

the first time. The ultim ate object ive i s t o d ev elop  pre dictive models fordeposition using boththeor ya nd e x pe rimen tally d e ri v e d c oe ff ici en t s,  incl udi ng mode ls that ac cou nt  for the pro n ou nced nonun ifo rmity of epi the lial d ep osi t ionsonthe a irways .  We pr opose toma k e sing l e pathh o ll ow a irway casts of hu m an and dog trache obronc hi a la i rwa ys,  including  a

the_first time._The ultimate objective is_to develop_predictive_models for_deposition_using both theory_and experimentally derived_coefficients, including models that_account for the_pronounced_nonuniformity of epithelial depositions on the airways. We propose to make single path hollow_airway_casts of_human_and_dog tracheobronchial airways, including a


might be developed to interact specifically with helical biomolecules, such as proteins and nucleotides. All complexes will be studied spectroscopically and crystallographically to improve fundamental understanding of the interactions of metals with biomolecules. The new complexing agents will be tested as ionophores in ion-selective electrodes for analysis of metals in biological fluids.

might be developed to interact specifically with helical biomolecules, such as proteins and nucleotides. All complex will be study spectroscopically and crystallographically to improve fundamental understanding of the interaction of metals with biomolecules. The new complexing agent will be test as ionophores in ion - selective electrodes for psychoanalysis of metallic element in biological fluids.

mihht be developed to intevact specificalli qith hxlical giomolecjles, such as proteins and nurleorides. All complexes will be studied dpectrosxopirally and crystallographleally bo im'rive fundamentak understatding of the ittdrcctions of metals with biomolecules. Ehe new clmplexing agenjs wikj be newted as ionophores in ion-seledtive enectrodes for analysis of metals in biopogifal fluids.

might be developed to interact specifically with such proteins and All complexes will to fundamental understanding of interactions of metals biomolecules. The new complexing agents will tested as ionophores in ion-selective electrodes for analysis of metals in biological fluids.

might be developed to interacT specificaLly wiTh hEliCaL bioMoleCules, such as proTEins And nucleotides. All complExes wIlL Be stUDiEd speCtroscoPIcALLy aNd CrYstAlLOgRaphiCalLy to impRove fundamEntAl UnderstandinG Of The interacTioNs of metals wiTh bIomoleCuLes. tHe new ComPlexiNg agenTS will bE tested as IoNOphoreS In ion-seLECtIve eLectrodes for analySIs OF metals in bioloGical fLuIDs.

might be developed to int eract spec ifica lly  wi th  hel ical  biomolecules, such  as proteins and nucle otide s. Allc om plexe s willb es t udi ed  s pec tr o sc opica lly  and cr ystallogra phi ca lly to impro v efundamenta l u nderstanding  of  the i nt era c tions  of  meta ls wit h  biomo lecules.Th e  new c o mplexin g ag ents  will be tested a s  i o nophores in io n-sele ct i ve e lec tro des for an al ysiso f metal s  i n b iol o gical fluids.

might_be developed_to interact specifically with_helical biomolecules,_such_as proteins_and_nucleotides. All complexes_will be studied_spectroscopically and crystallographically to_improve fundamental understanding_of_the interactions of metals with biomolecules. The new complexing agents will be tested as_ionophores_in ion-selective_electrodes_for_analysis of metals in biological_fluids.


infected brains of rhesus monkeys for biomarker discovery using transcriptomics (gene array) and metabolomics (mass spectrometry) based technologies. For this project, we will perform hypothesis-based studies building on the wealth of data generated in functional proteomics at the University of Nebraska Medical Center (UNMC, Drs. Howard

infected brains of rhesus monkeys for biomarker discovery using transcriptomics (gene array) and metabolomics (mass spectroscopy) free-base technologies. For this project, we will do hypothesis - base studies build on the wealth of data generated in running proteomics at the University of Nebraska Medical Center (UNMC, Drs. Howard

invected brains of rhesus oonkeys for biomarker viscovedy using transcriptomics (gene array) end netabilomics (mass spectromegry) based technoligiew. For this 'doject, we wilm peryocm hypothesis-baxed studiev building on dhd cealth of data generated in functionwl protrolics at the Unyverxyty kf Nebraska Medical Center (UNMC, Dra. Howarv

infected brains of rhesus monkeys for biomarker transcriptomics array) and (mass spectrometry) based will hypothesis-based studies building the wealth of generated in functional proteomics at the of Nebraska Medical Center (UNMC, Drs. Howard

infected brains of rhesus monKeys for bioMarkeR diScoVeRy usIng tRanscriptomics (GEne aRray) and metabolomics (masS specTrOMetrY) BaSed teChnologIEs. fOR thIs PrOjeCt, WE wIll peRfoRm hypotHesis-based StuDiEs building on THe Wealth of daTa gEnerated in fuNctIonal pRoTeoMIcs at The univeRsity oF nebrasKa Medical ceNTer (UNMc, drs. HowaRD

infected brains of rhesus  monkeys f or bi oma rke rdisc over y using transc r ipto mics (gene array) andmetab ol o mics (m ass s pectrom e tr y )  ba se dtec hn o lo gies.  Fo r thisproject, w e w il l perform hy p ot hesis-base d s tudies build ing  on th ewea l th of  da ta ge nerate d  in fu nctionalpr o teomic s  at the U ni vers ity of Nebraska M e di c al Center (UNM C, Drs .H ow a r d

infected_brains of_rhesus monkeys for biomarker_discovery using_transcriptomics_(gene array)_and_metabolomics (mass spectrometry)_based technologies. For_this project, we will_perform hypothesis-based studies_building_on the wealth of data generated in functional proteomics at the University of Nebraska_Medical_Center (UNMC,_Drs._Howard


enriched in the plasma membranes and nuclear fractions in proliferating cells and appear to modify specific proteins in the membrane fractions. The aim of this RO3 proposal is to examine the ability of cyclin D1 and other cell cycle regulatory proteins to promote hepatocyte proliferation in culture and in vivo. Mature hepatocytes retain the ability to function

enriched in the plasma membranes and nuclear fractions in proliferating cell and look to modify specific proteins in the membrane fraction. The bearing of this RO3 proposal is to examine the ability of cyclin D1 and early cell cycle regulatory protein to advertise hepatocyte proliferation in culture and in vivo. Mature hepatocytes retain the ability to function

engiched in the plasma memnranes and nuclece fracvions ih prolifdrating cells and appear to loeify wpecific proteins in tfe membraje fractuons. Rhe aim of this RO3 propoawl iv to examine thg ability of cyclin D1 and mtfex cell cycle regulatory proteins to [romote hfpatocyte prolyferseion pn culture and in vivo. Mature hspatocyues retain the abikity to function

enriched in the plasma membranes and nuclear proliferating and appear modify specific proteins aim this RO3 proposal to examine the of cyclin D1 and other cell regulatory proteins to promote hepatocyte proliferation in culture and in vivo. Mature hepatocytes the ability to function

enriched in the plasma membraNes and nuclEar frActIonS iN proLifeRating cells and APpeaR to modify specific proteIns in ThE MembRAnE fracTions. ThE AiM OF thIs rO3 ProPoSAl Is to eXamIne the aBility of cyCliN D1 And other cell CYcLe regulatoRy pRoteins to proMotE hepatOcYte PRolifEraTion iN cultuRE and in Vivo. MaturE hEPatocyTEs retaiN THe AbilIty to function

enriched in the plasma me mbranes an d nuc lea r f ra ctio ns i n proliferatin g  cel ls and appear to modif y spe ci f ic p r ot einsin them em b r ane  f ra cti on s .The a imof this  RO3 propo sal  i s to examine th e abilityofcyclin D1 an d o ther c el l c y cle r egu lator y prot e ins to  promotehe p atocyt e  prolif e r at ionin culture and in vi v o. Mature hepa tocyte sr et a i n t heability to  f uncti o n

enriched_in the_plasma membranes and nuclear_fractions in_proliferating_cells and_appear_to modify specific_proteins in the_membrane fractions. The aim_of this RO3_proposal_is to examine the ability of cyclin D1 and other cell cycle regulatory proteins_to_promote hepatocyte_proliferation_in_culture and in vivo. Mature_hepatocytes retain the ability to_function


this study is to determine the role of caveolae in airway remodeling in asthma. This chronic inflammatory disease of the airways affects an estimated 15 million people in the United States and 100-150 million people worldwide. Among this population at risk, a subset of subjects will develop irreversible remodeling and airway obstruction. Airway remodeling

this study is to determine the role of caveolae in airway remodel in asthma. This chronic incendiary disease of the airways affects an estimated 15 million citizenry in the United States and 100 - 150 million multitude worldwide. Among this population at risk, a subset of subjects will build up irreversible remodeling and airline obstruction. air passage remodeling

thls study is to determine the role of carwolae mn airwzy remoddling in asthma. This chronic ibflamnatory disease of the xirways avfects ab esuimated 15 million 'sople ik the Mniteb Wtates and 100-150 miklion peopne worldwide. Akovg this population at risk, a subset os subjevtd will develop irrtvewsibmv vemodeling and airway obstructioh. Airwaj remodeling

this study is to determine the role in remodeling in This chronic inflammatory an 15 million people the United States 100-150 million people worldwide. Among this at risk, a subset of subjects will develop irreversible remodeling and airway obstruction. remodeling

this study is to determine the Role of caveOlae iN aiRwaY rEmodElinG in asthma. This cHRoniC inflammatory disease of The aiRwAYs afFEcTs an eStimateD 15 MiLLIon PeOpLe iN tHE UNited staTes and 100-150 mIllion peopLe wOrLdwide. Among tHIs Population At rIsk, a subset of SubJects wIlL deVElop iRreVersiBle remODeling And airway ObSTructiON. Airway REMoDeliNg

this study is to determin e the role  of c ave ola ein a irwa y remodeling i n  ast hma. This chronic infl ammat or y  dis e as e ofthe air w ay s aff ec ts  an  e s ti mated  15  millio n people i n t he  United Stat e sand 100-15 0 m illion peopl e w orldwi de . A m ong t his  popu lation at ris k, a subs et of sub j ects wi l l  d evel op irreversible r e mo d eling and airw ay obs tr u ct i o n.Air way remode li ng

this_study is_to determine the role_of caveolae_in_airway remodeling_in_asthma. This chronic_inflammatory disease of_the airways affects an_estimated 15 million_people_in the United States and 100-150 million people worldwide. Among this population at risk,_a_subset of_subjects_will_develop irreversible remodeling and airway_obstruction. Airway remodeling


distinction of patients with and without prior alloimmunization is critical because of their different immunological behavior in response to blood transfusions. Prior sensitization will be determined by conventional cytotoxicity and by flow cytometry. for the first objective, non-alloimmunized patients with newly diagnosed acute non-lymphocytic leukemia will be randomized into

distinction of patients with and without prior alloimmunization is critical because of their different immunological demeanor in reception to blood transfusions. anterior sensitization will be determine by conventional cytotoxicity and by flow cytometry. for the inaugural objective, non - alloimmunized patients with newly diagnose acute non - lymphocytic leukemia will be randomized into

didtinction of patients wiuh and without prnir allmimmunjzation ks critical because of their duffertut immunological behxvior in gesponse ro boiod transfnaions. Pvnor ssksitivavion will be dejermined by wonventional cftutlxicity and by flow cytometry. for tre firsy lbjective, non-ajloikiuniavd patients with newly diagnoses acute non-lymphocytoc leukemia will be randomlzed into

distinction of patients with and without prior critical of their immunological behavior in sensitization be determined by cytotoxicity and by cytometry. for the first objective, non-alloimmunized with newly diagnosed acute non-lymphocytic leukemia will be randomized into

distinction of patients with And without Prior AllOimMuNizaTion Is critical becaUSe of Their different immunoloGical BeHAvioR In RespoNse to blOOd TRAnsFuSiOns. prIOr SensiTizAtion wiLl be determIneD bY conventionaL CyTotoxicity And By flow cytomeTry. For the FiRst OBjectIve, Non-alLoimmuNIzed paTients witH nEWly diaGNosed acUTE nOn-lyMphocytic leukemia WIlL Be randomized inTo

distinction of patients w ith and wi thout  pr ior  a lloi mmun ization is cri t ical  because of their diff erent  i m muno l og icalbehavio r  i n res po ns e t ob lo od tr ans fusions . Prior se nsi ti zation willb edetermined  by  conventiona l c ytotox ic ity and b y f low c ytomet r y. for  the firs to bjecti v e, non- a l lo immu nized patients wi t hn ewly diagnosed  acute  n o n- l y mph ocy tic leukem ia  will be rand o mi z e d  in t o

distinction_of patients_with and without prior_alloimmunization is_critical_because of_their_different immunological behavior_in response to_blood transfusions. Prior sensitization_will be determined_by_conventional cytotoxicity and by flow cytometry. for the first objective, non-alloimmunized patients with newly_diagnosed_acute non-lymphocytic_leukemia_will_be randomized into


relationship to smoking-relevant variables will be examined, including its relationship to nicotine dependence, withdrawal, motivation to quit, abstinence self-efficacy, negative affect, and smoking expectancies. We hypothesize that the SAQ will have significant relationships with each of these variables, thereby providing evidence for its construct validity. The proposed study

relationship to smoking - relevant variables will be examined, include its kinship to nicotine dependence, withdrawal, motivation to depart, abstinence self - efficacy, minus affect, and smoking expectancies. We speculate that the SAQ will have significant relationships with each of these variable, thereby providing evidence for its construct robustness. The proposed study

repationship to smoking-reltvant variables wnol be xxamines, includkng its relationship to nicovine depebdence, withdrawal, motixation to quit, abwtintnce self-efficacy, negativc affsgt, anb wmoking expectsncies. We vypothesize thdt tke SAQ will have significant relatiogships eihh each of thefe vswiabmvs, thereby providing evidence fkr its bonstruct validitu. The proposed study

relationship to smoking-relevant variables will be examined, relationship nicotine dependence, motivation to quit, smoking We hypothesize that SAQ will have relationships with each of these variables, providing evidence for its construct validity. The proposed study

relationship to smoking-releVant variabLes wiLl bE exAmIned, InclUding its relatiONshiP to nicotine dependence, wIthdrAwAL, motIVaTion tO quit, abSTiNENce SeLf-EffIcACy, NegatIve Affect, aNd smoking eXpeCtAncies. We hypoTHeSize that thE SAq will have sigNifIcant rElAtiONshipS wiTh eacH of theSE variaBles, thereBy PRovidiNG evidenCE FoR its Construct validity. tHe PRoposed study

relationship to smoking-r elevant va riabl eswil lbe e xami ned, including itsrelationship to nicoti ne de pe n denc e ,withd rawal,m ot i v ati on  t o q ui t ,absti nen ce self -efficacy,  ne ga tive affect, an d smokingexp ectancies. W e h ypothe si zet hat t heSAQ w ill ha v e sign ificant r el a tionsh i ps with e ac h of  these variables, th e reby providing  evide nc e  f o r  it s c onstruct v al idity .  The pr o po s e d  st u dy

relationship_to smoking-relevant_variables will be examined,_including its_relationship_to nicotine_dependence,_withdrawal, motivation to_quit, abstinence self-efficacy,_negative affect, and smoking_expectancies. We hypothesize_that_the SAQ will have significant relationships with each of these variables, thereby providing evidence_for_its construct_validity._The_proposed study


promoter specificities. We also identified the vulnerabilities of drug candidates to the evolution of drug resistance by using PACE to evolve proteases that are resistant to HCV protease inhibitors currently used in human clinical trials. In addition, we developed important PACE capabilities beyond basic positive selection, including small- molecule modulation of selection stringency and negative

promoter specificities. We also identified the vulnerability of drug campaigner to the evolution of drug resistance by using PACE to develop proteases that are resistant to HCV protease inhibitors presently use in human clinical trials. In accession, we developed important PACE capability beyond basic positive selection, include small- molecule modulation of selection stringency and negative

prlmoter specificities. We xlso identified the vunnerabjlities uf drug candidates to the evllytion of drug resistance by using PABE to evoove kroteases that arx resistant to MCV pxovease inhibitorx currentlf used in humat zlnnical trials. In addition, we developqd impottwnt PACE capabylitpef begond basic positive selection, inclhding skall- molecule modulation of selection shrinhency and negative

promoter specificities. We also identified the vulnerabilities candidates the evolution drug resistance by that resistant to HCV inhibitors currently used human clinical trials. In addition, we important PACE capabilities beyond basic positive selection, including small- molecule modulation of selection and negative

promoter specificities. We alSo identifiEd the VulNerAbIlitIes oF drug candidateS To thE evolution of drug resistAnce bY uSIng PacE To evoLve protEAsES ThaT aRe ResIsTAnT to HCv prOtease iNhibitors cUrrEnTly used in humAN cLinical triAls. in addition, we DevEloped ImPorTAnt PAcE cApabiLities BEyond bAsic positIvE SelectIOn, incluDINg SmalL- molecule modulatiON oF Selection strinGency aNd NEgATIve

promoter specificities. W e also ide ntifi edthe  v ulne rabi lities of drug cand idates to the evolutio n ofdr u g re s is tance  by usi n gP A CEto  e vol ve pr oteas esthat ar e resistan t t oHCV protease in hibitors c urr ently used i n h uman c li nic a l tri als . Inadditi o n, wedeveloped  i m portan t  PACE c a p ab ilit ies beyond basicp os i tive selection , incl ud i ng s mal l-molecule m od ulati o n of se l ec t i o n s t ringency andnegative

promoter_specificities. We_also identified the vulnerabilities_of drug_candidates_to the_evolution_of drug resistance_by using PACE_to evolve proteases that_are resistant to_HCV_protease inhibitors currently used in human clinical trials. In addition, we developed important PACE_capabilities_beyond basic_positive_selection,_including small- molecule modulation of_selection stringency and negative


real-life setting, the project will provide integrated results that would complement existing population-level data and inform science-driven regulation of cigarette packaging that balances constitutional law and public health interest. This proposal is aimed at continuing our ongoing efforts to identify and characterize novel AD genes involved in presenilin-related pathways. AD candidate

real - life setting, the project will leave integrate results that would complement existing population - level datum and inform science - driven regulation of cigarette promotion that balance constitutional jurisprudence and public health interest. This proposal is calculate at continuing our ongoing efforts to name and characterize novel AD genes involved in presenilin - related pathways. AD candidate

rewl-life setting, the projegt will provide nbtegraved reshlts thag would complement existing 'opuoatiob-level data and inform science-dgiven regylatmon of cigarette packagiky thaf balcnres constitutiokal law and public health ivtzrest. This proposal is aimed at contynuing pug ongoing effotts tp idehniny and characterize novel AD genss invonved in presemilin-related pathways. AD cwndifate

real-life setting, the project will provide integrated would existing population-level and inform science-driven balances law and public interest. This proposal aimed at continuing our ongoing efforts identify and characterize novel AD genes involved in presenilin-related pathways. AD candidate

real-life setting, the project Will providE inteGraTed ReSultS thaT would complemeNT exiSting population-level daTa and InFOrm sCIeNce-drIven regULaTIOn oF cIgAreTtE PaCkagiNg tHat balaNces constiTutIoNal law and pubLIc Health inteResT. This proposaL is Aimed aT cOntINuing Our OngoiNg effoRTs to idEntify and ChARacterIZe novel ad GeNes iNvolved in presenilIN-rELated pathways. Ad candiDaTE

real-life setting, the pr oject will  prov ide  in te grat ed r esults that wo u ld c omplement existing pop ulati on - leve l  d ata a nd info r ms c ien ce -d riv en re gulat ion  of cig arette pac kag in g that balan c es  constitut ion al law and p ubl ic hea lt h i n teres t.Thispropos a l is a imed at c on t inuing our ong o i ng  eff orts to identifya nd characterize n ovel A Dg en e s  in vol ved in pre se nilin - related pa t h w ays .  AD candidate

real-life_setting, the_project will provide integrated_results that_would_complement existing_population-level_data and inform_science-driven regulation of_cigarette packaging that balances_constitutional law and_public_health interest. This proposal is aimed at continuing our ongoing efforts to identify and_characterize_novel AD_genes_involved_in presenilin-related pathways. AD candidate


underlying the high frequency of mutation and chromosome rearrangements in Giardia lamblia, and its variable gene expression. The Core components include: (a) ICIDR administration, (b) a Visiting Investigator Program, (c) Microbiology, (d) Giardia lamblia Serology, (

underlying the high frequency of mutation and chromosome rearrangements in Giardia lamblia, and its varying gene formula. The Core components include: (a) ICIDR presidency, (b) a Visiting Investigator Program, (c) Microbiology, (d) Giardia lamblia Serology, (

unferlying the high frequekcy of mutation cbd chrmmosoms rearravgements in Giardia lamblia, end uts vqriable gene expressiov. The Corv componebts mnclude: (a) ICIDR esministvction, (n) a Vnsmting Investigajor Program, (w) Microbiology, (d) Gnardia lamblia Serology, (

underlying the high frequency of mutation and in lamblia, and variable gene expression. ICIDR (b) a Visiting Program, (c) Microbiology, Giardia lamblia Serology, (

underlying the high frequencY of mutatioN and cHroMosOmE reaRranGements in GiardIA lamBlia, and its variable gene ExpreSsIOn. ThE coRe comPonents INcLUDe: (a) iCiDr adMiNIsTratiOn, (b) A VisitiNg InvestigAtoR PRogram, (c) MicroBIoLogy, (d) GiardIa lAmblia SeroloGy, (

underlying the high frequ ency of mu tatio n a ndch romo some  rearrangement s  inGiardia lamblia, and i ts va ri a bleg en e exp ression .  T h e  Co re  c omp on e nt s inc lud e: (a)ICIDR admi nis tr ation, (b) a Vi siting Inv est igator Progr am,  (c) M ic rob i ology , ( d) Gi ardial amblia  Serology ,(

underlying_the high_frequency of mutation and_chromosome rearrangements_in_Giardia lamblia,_and_its variable gene_expression. The Core_components include: (a) ICIDR_administration, (b) a_Visiting_Investigator Program, (c) Microbiology, (d) Giardia lamblia Serology, (


) determining if the drug-induced changes in 13C pyruvate to 130 lactate conversion that parallel target inhibition and drug sensitivity in vitro also do so in xenografts in vivo, and 4) determining if treatment-induced alterations in pyruvate metabolism detected by hyperpolarized 130 MRSI can be used alone, or in combination with

) determining if the drug - induced changes in 13C pyruvate to 130 lactate conversion that parallel target prohibition and drug sensitivity in vitro besides dress so in heterograft in vivo, and 4) determining if discussion - induced alterations in pyruvate metamorphosis detected by hyperpolarized 130 MRSI can be used alone, or in combination with

) dehermining if the drug-indmced changes in 13E pyruvete to 130 lactate conversion that parallel tacget inhivition and drug sensitkvity in nitro alsi do wo in xenojdafts ik vivk, and 4) determining in treatment-hnduced alteradiund in pyruvate metabolism detected br hyperloparized 130 MRSI san nq ussd alone, or in combination with

) determining if the drug-induced changes in to lactate conversion parallel target inhibition also so in xenografts vivo, and 4) if treatment-induced alterations in pyruvate metabolism by hyperpolarized 130 MRSI can be used alone, or in combination with

) determining if the drug-inducEd changes iN 13C pyrUvaTe tO 130 lActaTe coNversion that paRAlleL target inhibition and drUg senSiTIvitY In Vitro Also do sO In XENogRaFtS in ViVO, aNd 4) detErmIning if Treatment-iNduCeD alterations IN pYruvate metAboLism detected By hYperpoLaRizED 130 MRSI Can Be useD alone, OR in comBination wItH

) determining if the drug- induced ch anges  in  13 Cpyru vate  to 130 lactat e  con version that paralleltarge ti nhib i ti on an d drugs en s i tiv it yinvi t ro  also  do  so inxenografts  in  v ivo, and 4)d et ermining i f t reatment-ind uce d alte ra tio n s inpyr uvate  metab o lism d etected b yh yperpo l arized1 3 0MRSI  can be used alon e ,o r in combinati on wit h

) determining_if the_drug-induced changes in 13C_pyruvate to_130_lactate conversion_that_parallel target inhibition_and drug sensitivity_in vitro also do_so in xenografts_in_vivo, and 4) determining if treatment-induced alterations in pyruvate metabolism detected by hyperpolarized 130_MRSI_can be_used_alone,_or in combination with


huge financial burden and generated serious public and personal crises in the United States. To date, evidence-based treatment for TBI recovery is not yet available. Considering the fact that TBI Veterans are currently in the chronic phase of the disease, there is a critical need to develop neurorestorative strategies for brain repair in the chronic

huge financial burden and generated serious public and personal crisis in the United States. To date, evidence - free-base treatment for TBI recovery is not yet available. study the fact that TBI Veterans are currently in the chronic phase of the disease, there is a critical indigence to build up neurorestorative strategies for mind repair in the chronic

huhe financial burden and nenerated serious publir and psrsonal zrises in the United States. Vo dqte, ecidence-based treatment for TBI gecovery us nir yet available. Cokfidedlng tke fact that TBI Veterans dre currently hn tke chronic phase of the disease, therq is a vrltical need to devtlo[ nehgovestorative strategies for brain repair in the chronoc

huge financial burden and generated serious public crises the United To date, evidence-based not available. Considering the that TBI Veterans currently in the chronic phase of disease, there is a critical need to develop neurorestorative strategies for brain repair the chronic

huge financial burden and genErated seriOus puBliC anD pErsoNal cRises in the UnitED StaTes. To date, evidence-based TreatMeNT for tbI RecovEry is noT YeT AVaiLaBlE. CoNsIDeRing tHe fAct that tBI VeteranS arE cUrrently in thE ChRonic phase Of tHe disease, theRe iS a critIcAl nEEd to dEveLop neUroresTOrativE strategiEs FOr braiN Repair iN THe ChroNic

huge financial burden and  generated  seri ous  pu bl ic a nd p ersonal crises in t he United States. To d ate,ev i denc e -b asedtreatme n tf o r T BI  r eco ve r yis no t y et avai lable. Con sid er ing the fact th at TBI Vet era ns are curre ntl y in t he  ch r onicpha se of  the d i sease,  there is  a critic a l needt o  d evel op neurorestorati v es trategies forbrainre p ai r inthe  chronic

huge_financial burden_and generated serious public_and personal_crises_in the_United_States. To date,_evidence-based treatment for_TBI recovery is not_yet available. Considering_the_fact that TBI Veterans are currently in the chronic phase of the disease, there_is_a critical_need_to_develop neurorestorative strategies for brain_repair in the chronic


expand our current processes to assure they are applicable to AAV serotypes 1, 2 and 5. We will also address the significant problem of AAV aggregation. Finally, we will conduct an in vivo mouse study to determine the correlation between purity, biological activity and safety through the evaluation of immune and histopathological responses to the vector

expand our current processes to assure they are applicable to AAV serotypes 1, 2 and 5. We will also cover the meaning trouble of AAV aggregation. Finally, we will conduct an in vivo shiner study to determine the correlation between honor, biological activeness and safety through the evaluation of immune and histopathological response to the vector

exoand our current processts to assure they are ap'licabls to AAV serotypes 1, 2 and 5. We will aldo addrtfs the significant problem lf AAV atgrejation. Finally, wx will conduct wn iu tivo mouse studi to determite the correladiun between purity, biological activity and sagehy through the evaktatikn of immune and histopathological responves to the vevtor

expand our current processes to assure they to serotypes 1, and 5. We problem AAV aggregation. Finally, will conduct an vivo mouse study to determine the between purity, biological activity and safety through the evaluation of immune and histopathological to the vector

expand our current processes To assure thEy are AppLicAbLe to aAV sErotypes 1, 2 and 5. We wILl alSo address the significanT probLeM Of AAv AgGregaTion. FinALlY, WE wiLl CoNduCt AN iN vivo MouSe study To determinE thE cOrrelation beTWeEn purity, biOloGical activitY anD safetY tHroUGh the EvaLuatiOn of imMUne and HistopathOlOGical rESponses TO ThE vecTor

expand our current proces ses to ass ure t hey  ar eappl icab le to AAV sero t ypes  1, 2 and 5. We will a lso a dd r esst he  sign ificant pr o b lem  o fAAV  a g gr egati on.  Finall y, we will  co nd uct an in vi v omouse stud y t o determinethe  corre la tio n  betw een  puri ty, bi o logica l activit ya nd saf e ty thro u g htheevaluation of imm u ne and histopatho logica lr es p o nse s t o the vect or

expand_our current_processes to assure they_are applicable_to_AAV serotypes_1,_2 and 5._We will also_address the significant problem_of AAV aggregation._Finally,_we will conduct an in vivo mouse study to determine the correlation between purity,_biological_activity and_safety_through_the evaluation of immune and_histopathological responses to the vector


a single local inflammation of a handpaw lasting for approximately 24 hours can result in significant changes in future withdrawal responses to noxious stimulation in the affected animals. However, the specific parameters of the "window(s) of vulnerability" of the developing nociceptive circuitry to such short- lasting inflammation, as well

a single local inflammation of a handpaw lasting for approximately 24 hours can leave in meaning change in future withdrawal answer to noxious foreplay in the affected animals. However, the specific parameters of the " window(s) of vulnerability " of the develop nociceptive circuitry to such short- lasting inflammation, equally well

a dingle local inflammatiok of a handpaw lcwting hor appdoximateuy 24 hours can result in signmficqnt cyanges in future withdfawal resionses to noxmous stimulation in the affectsf annmels. However, the specific [arameters of dhd "cindow(s) of vulnerability" of the devejoping moficeptive circoitry eo shbh short- lasting inflammation, aa well

a single local inflammation of a handpaw approximately hours can in significant changes noxious in the affected However, the specific of the "window(s) of vulnerability" of developing nociceptive circuitry to such short- lasting inflammation, as well

a single local inflammation oF a handpaw lAstinG foR apPrOximAtelY 24 hours can resulT In siGnificant changes in futuRe witHdRAwal REsPonseS to noxiOUs STImuLaTiOn iN tHE aFfectEd aNimals. HOwever, the sPecIfIc parameters OF tHe "window(s) oF vuLnerability" oF thE develOpIng NOcicePtiVe cirCuitry TO such sHort- lastiNg INflammATion, as wELL

a single local inflammati on of a ha ndpaw  la sti ng  for  app roximately 24h ours  can result in signifi cantch a nges in  futu re with d ra w a l r es po nse st onoxio usstimula tion in th e a ff ected animal s .However, t hespecific par ame ters o fthe "wind ow( s) of  vulne r abilit y" of the  d e velopi n g nocic e p ti ve c ircuitry to suchs ho r t- lasting inf lammat io n ,a s  we ll

a_single local_inflammation of a handpaw_lasting for_approximately_24 hours_can_result in significant_changes in future_withdrawal responses to noxious_stimulation in the_affected_animals. However, the specific parameters of the "window(s) of vulnerability" of the developing nociceptive_circuitry_to such_short-_lasting_inflammation, as well


medication effects. Side effects will be carefully monitored with standard instruments. Plasma levels of risperidone plus 9-OH-risperidone will be monitored throughout the treatment period and related to treatment response and side effects. Pre- and post-treatment serotonin platelet will be assessed and related to treatment response. The study will advance

medication effects. Side effects will be cautiously monitor with standard instruments. Plasma levels of risperidone plus 9 - ohio - risperidone will be monitored throughout the discussion period and related to discussion response and side effects. Pre- and post - treatment serotonin platelet will be measure and related to treatment reply. The study will advance

mefication effects. Side efnects will be catedully konitoded with standard instruments. Plasma lwvels of risperidone plus 9-OF-risperidlne will be ninitored tidoughoub the breatkxnt period and telated to tseatment respotsd cnd side effects. Pre- and post-treatmegt seroyojin platelet wyll nq asavswed and related to treatment desponst. The study will acvance

medication effects. Side effects will be carefully standard Plasma levels risperidone plus 9-OH-risperidone treatment and related to response and side Pre- and post-treatment serotonin platelet will assessed and related to treatment response. The study will advance

medication effects. Side effeCts will be cArefuLly MonItOred With Standard instruMEnts. plasma levels of risperidOne plUs 9-oh-risPErIdone Will be mONiTORed ThRoUghOuT ThE treaTmeNt perioD and relateD to TrEatment respoNSe And side effEctS. Pre- and post-tReaTment sErOtoNIn plaTelEt wilL be assESsed anD related tO tREatmenT ResponsE. tHe StudY will advance

medication effects. Sideeffects wi ll be  ca ref ul ly m onit ored with stan d ardinstruments. Plasma le velsof risp e ri doneplus 9- O H- r i spe ri do newi l lbe mo nit ored th roughout t hetr eatment peri o dand relate d t o treatmentres ponsean d s i de ef fec ts. P re- an d  post- treatment  s e rotoni n  platel e t  w illbe assessed and r e la t ed to treatmen t resp on s e. T hestu dy will ad va nce

medication_effects. Side_effects will be carefully_monitored with_standard_instruments. Plasma_levels_of risperidone plus_9-OH-risperidone will be_monitored throughout the treatment_period and related_to_treatment response and side effects. Pre- and post-treatment serotonin platelet will be assessed and_related_to treatment_response._The_study will advance


education and the necessary histological material is available. Increased sophistication will be achieved through (l) the use of high end computer graphic hardware and software (2) use of a professional science writer to develop textual materials and (3) a scientific advisory board including teachers, clinicians and textbook authors. The materials developed in phase II

education and the necessary histological material is available. Increased sophistication will be achieve through (lambert) the use of high goal calculator graphic hardware and software (2) use of a professional science writer to develop textual material and (3) a scientific advisory board including teacher, clinicians and textbook authors. The material developed in phase II

edkcation and the necessarn histological mcrerial is avzilable. Kncreased sophistication wilp ve acyieved through (l) the ure of higj end conputtr graphic hardwacs and softwars (2) usz if a professiokal science writer to devalup textual materials and (3) a scientifis advisprj board includyng ueashera, clinicians and textbook authors. Fhe mattrials developed im phase II

education and the necessary histological material is sophistication be achieved (l) the use hardware software (2) use a professional science to develop textual materials and (3) scientific advisory board including teachers, clinicians and textbook authors. The materials developed in II

education and the necessary hIstologicaL mateRiaL is AvAilaBle. INcreased sophisTIcatIon will be achieved throuGh (l) thE uSE of hIGh End coMputer gRApHIC haRdWaRe aNd SOfTware (2) Use Of a profEssional scIenCe Writer to deveLOp Textual matEriAls and (3) a scienTifIc adviSoRy bOArd inCluDing tEacherS, ClinicIans and teXtBOok autHOrs. The mATErIals Developed in phase Ii

education and the necessa ry histolo gical  ma ter ia l is  ava ilable. Increa s ed s ophistication will beachie ve d  thr o ug h (l)  the us e  o f hig hen d c om p ut er gr aph ic hard ware and s oft wa re (2) use o f  a  professio nal  science wri ter  to de ve lop textu almater ials a n d (3)a scienti fi c  advis o ry boar d in clud ing teachers, cli n ic i ans and textbo ok aut ho r s. T hemat erials dev el opedi n phase II

education_and the_necessary histological material is_available. Increased_sophistication_will be_achieved_through (l) the_use of high_end computer graphic hardware_and software (2)_use_of a professional science writer to develop textual materials and (3) a scientific advisory_board_including teachers,_clinicians_and_textbook authors. The materials developed_in phase II


1 line this year. Searching for optimal freezing conditions is in progress. Bovine Visual Arrestin: The arrestin crystals diffract to 3.0[unreadable] resolution using synchrotron radiation (NSLS X-25 beamline and MacCHESS A-1 beamline). We have collected complete native

1 line this year. Searching for optimal freeze condition is in progress. Bovine Visual Arrestin: The arrestin crystal diffract to 3.0[unreadable ] resoluteness using synchrotron radiation (NSLS X-25 beamline and MacCHESS A-1 beamline). We have collect arrant native

1 lije this year. Searching fur optimal freeeibg convitions is in pfogress. Bovine Visual Arrestmn: Tye areestin crystals diffrazt to 3.0[unrvadable] rwsolntion using syncidotron vcdiatjln (NVOS X-25 beamline snd MacCHEVS A-1 beamline). Fe hcve collected complete native

1 line this year. Searching for optimal is progress. Bovine Arrestin: The arrestin using radiation (NSLS X-25 and MacCHESS A-1 We have collected complete native

1 line this year. Searching for oPtimal freeZing cOndItiOnS is iN proGress. Bovine VisUAl ArRestin: The arrestin crystAls diFfRAct tO 3.0[UnReadaBle] resoLUtION usInG sYncHrOTrOn radIatIon (NSLS x-25 beamline aNd MAccHESS A-1 beamliNE). WE have colleCteD complete natIve

1 line this year. Searchin g for opti mal f ree zin gcond itio ns is in progr e ss.Bovine Visual Arrestin : The  a r rest i ncryst als dif f ra c t  to  3 .0 [un re a da ble]res olution  using syn chr ot ron radiatio n  ( NSLS X-25bea mline and Ma cCH ESS A- 1bea m line) . W e hav e coll e cted c omplete n at i ve

1 line_this year._Searching for optimal freezing_conditions is_in_progress. Bovine_Visual_Arrestin: The arrestin_crystals diffract to_3.0[unreadable] resolution using synchrotron_radiation (NSLS X-25_beamline_and MacCHESS A-1 beamline). We have collected complete native


that RSV, the major cause of respiratory problems in young children worldwide, induced p53 protein activation, resulting in the expression of several A3 genes in a p53-dependent manner and influencing negatively the virus replication. A SNP in TLR8 regulatory region creates a p53 responsive sequence that renders responsiveness and transcriptional control of this

that RSV, the major cause of respiratory problems in young children worldwide, induce p53 protein energizing, resulting in the expression of respective A3 genes in a p53 - subject manner and influencing negatively the virus replication. A SNP in TLR8 regulative area creates a p53 responsive sequence that renders responsiveness and transcriptional control of this

thwt RSV, the major cause on respiratory problems mn younf childrdn worldwide, induced p53 protemn axtivaupon, resulting in the dxpressioj of sevwral Q3 genes in a p53-depekbent jwnnex end influencing negativelf the virus re[lkcction. A SNP in TLR8 regulatory region createx w p53 responsive seqlegce fhat renders responsiveness and trznscripuional control of yhis

that RSV, the major cause of respiratory young worldwide, induced protein activation, resulting A3 in a p53-dependent and influencing negatively virus replication. A SNP in TLR8 region creates a p53 responsive sequence that renders responsiveness and transcriptional control of

that RSV, the major cause of resPiratory prOblemS in YouNg ChilDren Worldwide, inducED p53 prOtein activation, resultiNg in tHe EXpreSSiOn of sEveral A3 GEnES In a P53-dEpEndEnT MaNner aNd iNfluencIng negativEly ThE virus replicATiOn. A SNP in TLr8 reGulatory regiOn cReates A p53 ResPOnsivE seQuencE that rENders rEsponsiveNeSS and trANscriptIONaL conTrol of this

that RSV, the major cause  of respir atory  pr obl em s in  you ng children wo r ldwi de, induced p53 protei n act iv a tion ,  r esult ing int he e xpr es si onof se veral  A3  genesin a p53-d epe nd ent manner a n dinfluencin g n egatively th e v irus r ep lic a tion.  ASNP i n TLR8 regula tory regi on create s  a p53r e sp onsi ve sequence thatr en d ers responsive ness a nd tr a n scr ipt ional cont ro l oft his

that_RSV, the_major cause of respiratory_problems in_young_children worldwide,_induced_p53 protein activation,_resulting in the_expression of several A3_genes in a_p53-dependent_manner and influencing negatively the virus replication. A SNP in TLR8 regulatory region creates_a_p53 responsive_sequence_that_renders responsiveness and transcriptional control_of this


contractility. Finally, airway inflammation enhances BDNF signaling, leading to an overall enhancement of [Ca2+]i and force. In this proposal, we will use human ASM and the ovalbumin (OVA) mouse model to examine the relative role of the BDNF receptors (high affinity TrkB vs.

contractility. Finally, airway inflammation enhances BDNF signaling, lead to an overall enhancement of [ Ca2+]i and power. In this proposal, we will use human ASM and the ovalbumin (OVA) shiner model to examine the relative function of the BDNF receptors (high affinity TrkB vs.

cojtractility. Finally, airwxy inflammation enhancxs BDNF signalivg, leading to an overall enhencenent if [Ca2+]i and force. In thks proposwl, we wiol uww human ASM and thc ovamnumin (IVA) mouse modek to examite the relativa fope of the BDNF receptors (high affinyty TrkN gs.

contractility. Finally, airway inflammation enhances BDNF signaling, an enhancement of and force. In human and the ovalbumin mouse model to the relative role of the BDNF (high affinity TrkB vs.

contractility. Finally, airwaY inflammatIon enHanCes bDnF siGnalIng, leading to an OVeraLl enhancement of [Ca2+]i and fOrce. IN tHIs prOPoSal, we Will use HUmAN aSM AnD tHe oVaLBuMin (OVa) moUse modeL to examine The ReLative role of THe bDNF receptOrs (High affinity trkb vs.

contractility. Finally, a irway infl ammat ion  en ha nces  BDN F signaling, l e adin g to an overall enhanc ement  o f  [Ca 2 +] i and  force. In t his  p ro pos al ,  w e wil l u se huma n ASM andthe  o valbumin (OV A )mouse mode l t o examine th e r elativ erol e  of t heBDNFrecept o rs (hi gh affini ty TrkB v s .

contractility._Finally, airway_inflammation enhances BDNF signaling,_leading to_an_overall enhancement_of_[Ca2+]i and force._In this proposal,_we will use human_ASM and the_ovalbumin_(OVA) mouse model to examine the relative role of the BDNF receptors (high affinity_TrkB_vs.


regulation of neurons and its indirect effects via bone marrow-derived monocytes/macrophages (BMDM). Using the approaches of live brain imaging, transgenic mice and targeted knockout mice, neurobehavioral assessments, and cell signaling, the central hypothesis will be tested and the objective of this application wil be achieved by accomplishing

regulation of neurons and its indirect effects via bone kernel - derive monocytes / macrophages (BMDM). use the approach of live brain imagination, transgenic mice and targeted knockout mouse, neurobehavioral assessments, and cell signal, the central hypothesis will be tested and the objective of this lotion wil be achieved by accomplishing

rehulation of neurons and lts indirect effgcrs via bone jarrow-defived monocytes/macrophages (BLDN). Usibg the approaches of lkve brain imaging, traisgenic mice and targeted knocilut kmce, neurobehavipral assesvments, and celn riynaling, the central hypothesis will fe testrd and the objecjive ps thjs application wil be achieved by zccomplpshing

regulation of neurons and its indirect effects marrow-derived (BMDM). Using approaches of live targeted mice, neurobehavioral assessments, cell signaling, the hypothesis will be tested and the of this application wil be achieved by accomplishing

regulation of neurons and its Indirect efFects Via BonE mArroW-derIved monocytes/mACropHages (BMDM). Using the approAches Of LIve bRAiN imagIng, tranSGeNIC miCe AnD taRgETeD knocKouT mice, neUrobehavioRal AsSessments, and CElL signaling, The Central hypotHesIs will Be TesTEd and The ObjecTive of THis appLication wIl BE achieVEd by accOMPlIshiNg

regulation of neurons and  its indir ect e ffe cts  v ia b onemarrow-derived mono cytes/macrophages (BMD M). U si n g th e  a pproa ches of li v e  br ai nima gi n g,  tran sge nic mic e and targ ete dknockout mic e ,neurobehav ior al assessmen ts,  and c el l s i gnali ng,  thecentra l  hypot hesis wil lb e test e d and t h e  o bjec tive of this appl i ca t ion wil be ach ievedby ac c o mpl ish ing

regulation_of neurons_and its indirect effects_via bone_marrow-derived_monocytes/macrophages (BMDM)._Using_the approaches of_live brain imaging,_transgenic mice and targeted_knockout mice, neurobehavioral_assessments,_and cell signaling, the central hypothesis will be tested and the objective of this_application_wil be_achieved_by_accomplishing


. Studies proposed here will leverage our recent advances, including identification of lead candidate human monoclonal antibodies (huMAbs) that neutralize LASV infectivity and protect guinea pigs against fatal disease induced by LASV. Zalgen's exclusive technology for rapid development (<3 months) of high yield antibody expressing stable cell

. Studies proposed here will leverage our recent advances, include designation of lead candidate human monoclonal antibodies (huMAbs) that neutralize LASV infectivity and protect guinea fowl pigs against fatal disease induce by LASV. Zalgen's single technology for rapid development (<3 months) of high yield antibody express stable cell

. Stkdies proposed here will leverage our rgcwnt adtances, jncludine identification of lead canvidare hunan monoclonal antibodkes (huMAbd) that nwutrelize LASV infecvjvity akb profcct gbiiea pigs againsj fatal disedse induced by LXSR. Zalgen's exclusive technology for rwpid defepopment (<3 monthf) of righ jitld antibody expressing stable ceml

. Studies proposed here will leverage our including of lead human monoclonal antibodies and guinea pigs against disease induced by Zalgen's exclusive technology for rapid development months) of high yield antibody expressing stable cell

. Studies proposed here will leVerage our rEcent AdvAncEs, InclUdinG identificatioN Of leAd candidate human monoclOnal aNtIBodiES (hUMAbs) That neuTRaLIZe LaSv iNfeCtIViTy and ProTect guiNea pigs agaInsT fAtal disease iNDuCed by LASV. ZAlgEn's exclusive TecHnologY fOr rAPid deVelOpmenT (<3 monthS) Of high Yield antiBoDY expreSSing staBLE cEll

. Studies proposed here wi ll leverag e our  re cen tadva nces , including id e ntif ication of lead candid ate h um a n mo n oc lonal  antibo d ie s (hu MA bs ) t ha t  n eutra liz e LASVinfectivit y a nd  protect gui n ea  pigs agai nst  fatal disea seinduce dbyL ASV.Zal gen's  exclu s ive te chnologyfo r  rapid develop m e nt  (<3  months) of highy ie l d antibody exp ressin gs ta b l e c ell

. Studies_proposed here_will leverage our recent_advances, including_identification_of lead_candidate_human monoclonal antibodies_(huMAbs) that neutralize_LASV infectivity and protect_guinea pigs against_fatal_disease induced by LASV. Zalgen's exclusive technology for rapid development (<3 months) of high_yield_antibody expressing_stable_cell


extracellular portion of L-R results in the activation of Janus kinase 2 (JAK2) that is constitutively bound on the intracellular regions of the receptor. Leptin-instigated JAK2 signaling in hypothalamic nuclei reduces food intake and stimulates energy expenditure, while functional defects in either leptin or L-R

extracellular portion of L - R results in the energizing of Janus kinase 2 (JAK2) that is constitutively tie on the intracellular regions of the receptor. Leptin - incite JAK2 bespeak in hypothalamic nuclei reduces food inhalation and stimulate energy outgo, while functional defects in either leptin or lambert - R

exhracellular portion of L-V results in the activavion of Janus kknase 2 (JAK2) that is constitutmvelt boubd on the intracellulaf regions of the eecektor. Leptin-instigefed JAK2 signamlng iu iypothalamic nuglei reducev food intake dna dtimulates energy expenditure, while functipnwl defects in githeg jeptjn or L-R

extracellular portion of L-R results in the Janus 2 (JAK2) is constitutively bound the Leptin-instigated JAK2 signaling hypothalamic nuclei reduces intake and stimulates energy expenditure, while defects in either leptin or L-R

extracellular portion of L-R rEsults in thE actiVatIon Of januS kinAse 2 (JAK2) that is coNStitUtively bound on the intraCelluLaR RegiONs Of the ReceptoR. lePTIn-iNsTiGatEd jaK2 SignaLinG in hypoThalamic nuCleI rEduces food inTAkE and stimulAteS energy expenDitUre, whiLe FunCTionaL deFects In eithER leptiN or L-R

extracellular portion ofL-R result s inthe  ac ti vati on o f Janus kinase 2 (J AK2) that is constitut ively  b o undo nthe i ntracel l ul a r  re gi on s o ft he  rece pto r. Lept in-instiga ted  J AK2 signalin g  i n hypothal ami c nuclei red uce s food  i nta k e and  st imula tes en e rgy ex penditure ,w hile f u nctiona l de fect s in either lepti n  o r  L-R

extracellular_portion of_L-R results in the_activation of_Janus_kinase 2_(JAK2)_that is constitutively_bound on the_intracellular regions of the_receptor. Leptin-instigated JAK2_signaling_in hypothalamic nuclei reduces food intake and stimulates energy expenditure, while functional defects in_either_leptin or_L-R


an understanding of the molecular basis of LT gene activation by antigen. The objective of this project is to elucidate the catalytic mechanism of CO dehydrogenase (a.k.a. acetyl-CoA synthase - ACS), emphasizing the structure and function of the unique Ni-Fe-S clusters contained therein. The enzyme is an alpha-

an understanding of the molecular basis of LT gene activation by antigen. The objective of this undertaking is to clarify the catalytic mechanism of CO dehydrogenase (a.k.a. acetyl - CoA synthase - ACS), emphasizing the structure and affair of the singular Ni - Fe - S clusters contained therein. The enzyme is an alpha-

an understanding of the mouecular basis oy LT geie actibation bh antigen. The objective of tiis projext is to elucidate the catalytib mechaniwm oh CO dehydrogenase (a.k.a. agztyl-CkW syutiase - ACS), emphaxizing the structure and fjnetion of the unique Ni-Fe-S clusters cjntainec hherein. The eneyme ps an zlpha-

an understanding of the molecular basis of activation antigen. The of this project mechanism CO dehydrogenase (a.k.a. synthase - ACS), the structure and function of the Ni-Fe-S clusters contained therein. The enzyme is an alpha-

an understanding of the molecUlar basis oF LT geNe aCtiVaTion By anTigen. The objectIVe of This project is to elucidaTe the CaTAlytIC mEchanIsm of CO DEhYDRogEnAsE (a.k.A. aCEtYl-CoA SynThase - ACs), emphasiziNg tHe Structure and FUnCtion of the UniQue Ni-Fe-S clusTerS contaInEd tHErein. the EnzymE is an aLPha-

an understanding of the m olecular b asisofLTge ne a ctiv ation by antig e n. T he objective of this p rojec ti s to el ucida te thec at a l yti cme cha ni s mof CO  de hydroge nase (a.k. a.ac etyl-CoA syn t ha se - ACS),  em phasizing th e s tructu re  an d  func tio n ofthe un i que Ni -Fe-S clu st e rs con t ained t h e re in.The enzyme is ana lp h a-

an_understanding of_the molecular basis of_LT gene_activation_by antigen._The_objective of this_project is to_elucidate the catalytic mechanism_of CO dehydrogenase_(a.k.a._acetyl-CoA synthase - ACS), emphasizing the structure and function of the unique Ni-Fe-S clusters_contained_therein. The_enzyme_is_an alpha-