enumeration of and molecular changes in circulating tumor cells. These validated assays are achieved using a number of clinically useful technology platforms of the SAIC-Frederick PS program: immunoassay, quantitative RT-PCR, quantitative immunofluorescence of tumor sections and cytospins, and the Veridex Cell Search instrument a clinically validated platform

enumeration of and molecular changes in circulating tumor cells. These validate assay are achieved using a number of clinically utilitarian technology platforms of the SAIC - Frederick PS program: immunoassay, quantitative RT - PCR, quantitative immunofluorescence of tumor section and cytospins, and the Veridex Cell Search instrument a clinically validated chopine

enkmeration of and moleculxr changes in cneculatmng tumkr cells. These validated assays are echiwved ysing a number of clinkcally usvful techbolojy platforms of vge SAIC-Nxederjgk PS 'rogram: immunoaxsay, quanthtative RT-PCR, xuxncitative immunofluorescence of tumor sectioms and cytospins, and ehe Bvrldex Cell Search instrument a cljnicallj validated platfprm

enumeration of and molecular changes in circulating These assays are using a number of SAIC-Frederick PS program: quantitative RT-PCR, quantitative of tumor sections and cytospins, and Veridex Cell Search instrument a clinically validated platform

enumeration of and molecular Changes in cIrculAtiNg tUmOr ceLls. THese validated aSSays Are achieved using a numbeR of clInICallY UsEful tEchnoloGY pLATfoRmS oF thE SaiC-fredeRicK PS progRam: immunoaSsaY, qUantitative Rt-pCr, quantitatIve ImmunofluoreSceNce of tUmOr sECtionS anD cytoSpins, aND the VeRidex Cell seARch insTRument a CLInIcalLy validated platfoRM

enumeration of and molecu lar change s incir cul at ingtumo r cells. These vali dated assays are achie ved u si n g an um ber o f clini c al l y  us ef ul  te ch n ol ogy p lat forms o f the SAIC -Fr ed erick PS pro g ra m: immunoa ssa y, quantitat ive  RT-PC R,  qu a ntita tiv e imm unoflu o rescen ce of tum or sectio n s and c y t os pins , and the Veridex Ce l l Search instr umentac li n i cal lyvalidatedpl atfor m

enumeration_of and_molecular changes in circulating_tumor cells._These_validated assays_are_achieved using a_number of clinically_useful technology platforms of_the SAIC-Frederick PS_program:_immunoassay, quantitative RT-PCR, quantitative immunofluorescence of tumor sections and cytospins, and the Veridex Cell_Search_instrument a_clinically_validated_platform


acute and chronic diseases such as asthma and arthritis and infectious diseases including AIDS and TB. Our understanding of this feedback controlled signaling system in health and disease will enable us to understand viral pathogenesis and help us develop novel therapeutic interventions. HIV-1, HIV-2, and SIV Nef alleles are known to downmodulate

acute and chronic diseases such as asthma and arthritis and infectious diseases including AIDS and TB. Our reason of this feedback operate signaling system in health and disease will enable us to understand viral pathogenesis and serve us develop novel curative interventions. HIV-1, HIV-2, and SIV Nef alleles are known to downmodulate

ackte and chronic diseases such as asthma and arvhritis and infdctious diseases including AMDS qnd TV. Our understanding of this feefback cobtroooed signalmhg systci in mealtk end disease wilk enable uv to understang xixal pathogenesis and help us develop novel yhfrapeutic intetventpogs. HJN-1, MIV-2, and SIV Nef alleles are knowh to doxnmodulate

acute and chronic diseases such as asthma and diseases including and TB. Our signaling in health and will enable us understand viral pathogenesis and help us novel therapeutic interventions. HIV-1, HIV-2, and SIV Nef alleles are known to downmodulate

acute and chronic diseases suCh as asthma And arThrItiS aNd inFectIous diseases inCLudiNg AIDS and TB. Our understaNding Of THis fEEdBack cOntrollED sIGNalInG sYstEm IN hEalth And Disease Will enable Us tO uNderstand virAL pAthogenesiS anD help us develOp nOvel thErApeUTic inTerVentiOns. HIV-1, hiV-2, and SiV Nef alleLeS Are knoWN to downMODuLate

acute and chronic disease s such asasthm a a ndar thri tisand infectious dise ases including AIDS an d TB.  O u r un d er stand ing oft hi s fee db ac k c on t ro lledsig nalingsystem inhea lt h and diseas e  w ill enable  us  to understa ndviralpa tho g enesi s a nd he lp usd evelop  novel th er a peutic interve n t io ns.HIV-1, HIV-2, and SI V  Nef alleles a re kno wn to d own mod ulate

acute_and chronic_diseases such as asthma_and arthritis_and_infectious diseases_including_AIDS and TB._Our understanding of_this feedback controlled signaling_system in health_and_disease will enable us to understand viral pathogenesis and help us develop novel therapeutic_interventions._HIV-1, HIV-2,_and_SIV_Nef alleles are known to_downmodulate


IL-1 receptor antagonist syndrome, DIRA, the crucial role for IL-1 in the pathophysiology of these illnesses with multiorgan involvement has been demonstrated. 2. A novel founder mutation in 2 Brazil patients with DIRA has been identified and may raise the awareness of that disease in Brazil. 3. S

IL-1 receptor antagonist syndrome, DIRA, the crucial role for IL-1 in the pathophysiology of these illness with multiorgan affair has been demonstrated. 2. A novel laminitis mutation in 2 Brazil affected role with DIRA has been identified and may raise the awareness of that disease in Brazil. 3. randomness

IL-1 receptor antagonist synarome, DIRA, the eeucial role ror IL-1 iv the pathophysiology of thede illntfses with multiorgxn involvvment has beei demonstrated. 2. E novel njundsv mutctmon in 2 Brazil katients witv DIRA has beet kdzntified and may raise the awareness of thay fisease in Braeil. 3. X

IL-1 receptor antagonist syndrome, DIRA, the crucial IL-1 the pathophysiology these illnesses with 2. novel founder mutation 2 Brazil patients DIRA has been identified and may the awareness of that disease in Brazil. 3. S

IL-1 receptor antagonist syndrOme, DIRA, the CruciAl rOle FoR IL-1 iN the PathophysiologY Of thEse illnesses with multioRgan iNvOLvemENt Has beEn demonSTrATEd. 2. A NoVeL foUnDEr MutatIon In 2 BraziL patients wIth dIrA has been ideNTiFied and may RaiSe the awareneSs oF that dIsEasE In BraZil. 3. s

IL-1 receptor antagonistsyndrome,DIRA,  th e c ru cial  rol e for IL-1 int he p athophysiology of thes e ill ne s sesw it h mul tiorgan in v o lve me nt  ha sb ee n dem ons trated.  2. A nove l f ou nder mutatio n  i n 2 Brazil  pa tients withDIR A hasbe eni denti fie d and  may r a ise th e awarene ss of tha t  diseas e in  Bra zil. 3. S

IL-1_receptor antagonist_syndrome, DIRA, the crucial_role for_IL-1_in the_pathophysiology_of these illnesses_with multiorgan involvement_has been demonstrated. 2._A novel founder_mutation_in 2 Brazil patients with DIRA has been identified and may raise the awareness_of_that disease_in_Brazil._3. S


mouse leukemia viruses (E-, X-, P-MLVs) exist in mice as infectious viruses and as ERVs. All 3 MLV subgroups are linked to leukemogenesis, which involves generation of recombinants with polytropic host range. Although P-MLVs are deemed to be the proximal agents of disease

mouse leukemia viruses (E-, X-, P - MLVs) exist in mice as infectious virus and as ERVs. All 3 MLV subgroup are linked to leukemogenesis, which involves generation of recombinant with polytropic host range. Although P - MLVs are deem to be the proximal agent of disease

mokse leukemia viruses (E-, X-, P-MLVs) exist in mice av infedtious vkruses and as ERVs. All 3 MLV duvgroukf are linked to lejkemogenedis, whicy intolves generatioi of recombinahbs wich polytropic hoxt range. Anthough P-MLVs drd beemed to be the proximal agents of qisease

mouse leukemia viruses (E-, X-, P-MLVs) exist as viruses and ERVs. All 3 leukemogenesis, involves generation of with polytropic host Although P-MLVs are deemed to be proximal agents of disease

mouse leukemia viruses (E-, X-, P-MLvs) exist in mIce as InfEctIoUs viRuseS and as ERVs. All 3 Mlv subGroups are linked to leukeMogenEsIS, whiCH iNvolvEs generATiON Of rEcOmBinAnTS wIth poLytRopic hoSt range. AltHouGh p-MLVs are deemED tO be the proxImaL agents of disEasE

mouse leukemia viruses (E -, X-, P-M LVs)exi stin  mic e as  infectious vi r uses  and as ERVs. All 3 ML V sub gr o upsa re  link ed to l e uk e m oge ne si s,wh i ch  invo lve s gener ation of r eco mb inants withp ol ytropic ho strange. Altho ugh  P-MLV sare deeme d t o bethe pr o ximalagents of  d i sease

mouse_leukemia viruses_(E-, X-, P-MLVs) exist_in mice_as_infectious viruses_and_as ERVs. All_3 MLV subgroups_are linked to leukemogenesis,_which involves generation_of_recombinants with polytropic host range. Although P-MLVs are deemed to be the proximal agents_of_disease


standing data has shown that antibodies can play a significant role in protection against erythrocytic stages of infection, we have pursued a detailed characterization of the antibody populations present in the Malian children. We have already shown that children with HbAS genotype show lower responses by ELISA to a number of merozoite antigens relative to

standing data has shown that antibodies can toy a meaning role in protection against erythrocytic stage of contagion, we have pursued a detailed characterization of the antibody populations present in the Malian child. We have already shown that children with HbAS genotype prove lower responses by ELISA to a issue of merozoite antigens relative to

stajding data has shown thau antibodies can klqy a smgnificznt role in protection against erythcocyric sucges of infection, we have purdued a dwtaiowd charactxdizatiok of fme anciuody populationx present hn the Malian whklbren. We have already shown that chilqren wiyh HbAS genotype shoe lowsg vesponses by ELISA to a number or merozmite antigens relative to

standing data has shown that antibodies can significant in protection erythrocytic stages of detailed of the antibody present in the children. We have already shown that with HbAS genotype show lower responses by ELISA to a number of merozoite relative to

standing data has shown that aNtibodies cAn plaY a sIgnIfIcanT rolE in protection aGAinsT erythrocytic stages of iNfectIoN, We haVE pUrsueD a detaiLEd CHAraCtErIzaTiON oF the aNtiBody popUlations prEseNt In the Malian cHIlDren. We have AlrEady shown thaT chIldren WiTh HBaS genOtyPe shoW lower REsponsEs by ELISA To A Number OF merozoITE aNtigEns relative to

standing data has shown th at antibod ies c anpla ya si gnif icant role inp rote ction against erythroc yticst a geso finfec tion, w e  h a v e p ur su edad et ailed  ch aracter ization of  th eantibody pop u la tions pres ent  in the Mali anchildr en . W e  have  al ready  shown that c hildren w it h  HbASg enotype s ho w lo wer responses byE LI S A to a numberof mer oz o it e ant ige ns relativ eto

standing data_has shown_that antibodies can play_a significant_role_in protection_against_erythrocytic stages of_infection, we have_pursued a detailed characterization_of the antibody_populations_present in the Malian children. We have already shown that children with HbAS genotype_show_lower responses_by_ELISA_to a number of merozoite_antigens relative to


published this year. Project 3: Analysis of traction stress variation across single focal adhesions. Sergey V. Plotnikov, Benedikt Sabass, Clare M. Waterman The ability of eukaryotic cells to sense mechanical properties of the extracellular matrix (ECM) and to exhibit durotaxis (directed migration toward st

published this year. Project 3: Analysis of grip tension pas seul across single focal adhesiveness. Sergey V. Plotnikov, Benedikt Sabass, Clare M. Waterman The ability of eukaryotic cell to sense mechanical properties of the extracellular matrix (ECM) and to expose durotaxis (directed migration toward st

puhlished this year. Projecu 3: Analysis of trcxtion vtress variatiun across single focal adhesmons. Sergtj V. Plotnikov, Benedikg Sabass, Blare M. Wqternqn The ability of cbkarykbic czlos to sense meghanical prmperties of tha dxcracellular matrix (ECM) and to exhibie durotsxls (directed midratpog tosard st

published this year. Project 3: Analysis of variation single focal Sergey V. Plotnikov, The of eukaryotic cells sense mechanical properties the extracellular matrix (ECM) and to durotaxis (directed migration toward st

published this year. Project 3: ANalysis of tRactiOn sTreSs VariAtioN across single fOCal aDhesions. Sergey V. PlotnikOv, BenEdIKt SaBAsS, ClarE M. WaterMAn tHE abIlItY of EuKArYotic CelLs to senSe mechanicAl pRoPerties of the EXtRacellular MatRix (ECM) and to eXhiBit durOtAxiS (DirecTed MigraTion toWArd st

published this year. Proj ect 3: Ana lysis  of  tr ac tion  str ess variationa cros s single focal adhesio ns. S er g ey V .  P lotni kov, Be n ed i k t S ab as s,Cl a re  M. W ate rman Th e abilityofeu karyotic cel l sto sense m ech anical prope rti es ofth e e x trace llu lar m atrix( ECM) a nd to exh ib i t duro t axis (d i r ec tedmigration towards t

published_this year._Project 3: Analysis of_traction stress_variation_across single_focal_adhesions. Sergey V._Plotnikov, Benedikt Sabass,_Clare M. Waterman The_ability of eukaryotic_cells_to sense mechanical properties of the extracellular matrix (ECM) and to exhibit durotaxis (directed_migration_toward st


8-10% of host chromosomal DNA. Retroviruses were first recognized as naturally occurring infectious agents linked to various neoplasms in their host species. We have been engaged in an ongoing effort to characterize pathogenic viruses, and identify the various host factors that restrict the replication cycle of these viruses. Mouse leukemia viruses (MLVs)

8 - 10% of host chromosomal DNA. Retroviruses were first recognized as naturally occur infectious agent linked to various neoplasms in their master of ceremonies species. We have been engaged in an ongoing attempt to characterize pathogenic virus, and identify the various server factors that restrict the echo cycle of these viruses. Mouse leukemia viruses (MLVs )

8-10% ov host chromosomal DNA. Rttroviruses were yurst rxcognizsd as nagurally occurring infectious atents linked to various neoolasms in their hist wpecies. We izve beek engzned iu en ongoing effott to characderize pathogetiz riruses, and identify the various hose factots that restrict the wepljbauion cycle of these viruses. Mouse leukempa viruses (MLVs)

8-10% of host chromosomal DNA. Retroviruses were as occurring infectious linked to various We been engaged in ongoing effort to pathogenic viruses, and identify the various factors that restrict the replication cycle of these viruses. Mouse leukemia viruses (MLVs)

8-10% of host chromosomal DNA. RetroViruses werE firsT reCogNiZed aS natUrally occurrinG InfeCtious agents linked to vaRious NeOPlasMS iN theiR host spECiES. we hAvE bEen EnGAgEd in aN onGoing efFort to charActErIze pathogeniC ViRuses, and idEntIfy the variouS hoSt factOrS thAT restRicT the rEplicaTIon cycLe of these ViRUses. MoUSe leukeMIA vIrusEs (MLVs)

8-10% of host chromosomal  DNA. Retr oviru ses  we re  fir st r ecognized as n a tura lly occurring infectio us ag en t s li n ke d tovarious ne o p las ms  i n t he i rhostspe cies. W e have bee n e ng aged in an o n go ing effort  to  characteriz e p athoge ni c v i ruses , a nd id entify the va rious hos tf actors that re s t ri ct t he replication cy c le of these virus es. Mo us e  l e u kem iaviruses (M LV s)

8-10%_of host_chromosomal DNA. Retroviruses were_first recognized_as_naturally occurring_infectious_agents linked to_various neoplasms in_their host species. We_have been engaged_in_an ongoing effort to characterize pathogenic viruses, and identify the various host factors that_restrict_the replication_cycle_of_these viruses. Mouse leukemia viruses_(MLVs)


of proteins in the context of their local cellular environment. Specifically, we succeeded in developing a robust pipeline for imaging the plasma membrane of cells with both 3D iPALM (interferometric photoactivation localization microcopy) and 3D transmission electron microscopy (TEM) of platinum replicas. In these studies we have

of proteins in the context of their local cellular environment. Specifically, we succeeded in developing a robust grapevine for image the plasma membrane of cells with both 3D iPALM (interferometric photoactivation localization microcopy) and 3D transmittance electron microscopy (TEM) of platinum replicas. In these study we have

of proteins in the context of their local celluler envidonment. Rpecifically, we succeeded in dwvelokpng a robust pipeline for imagpng the poasme membrane of cells with both 3S iPANN (interferomettic photoacthvation localisagiln microcopy) and 3D transmission elestron mocgoscopy (TEM) of plauintm rsillcas. In these studies we have

of proteins in the context of their environment. we succeeded developing a robust membrane cells with both iPALM (interferometric photoactivation microcopy) and 3D transmission electron microscopy of platinum replicas. In these studies we have

of proteins in the context of tHeir local cEllulAr eNviRoNmenT. SpeCifically, we sucCEedeD in developing a robust piPelinE fOR imaGInG the pLasma meMBrANE of CeLlS wiTh BOtH 3D iPAlM (iNterferOmetric phoToaCtIvation localIZaTion microcOpy) And 3D transmisSioN electRoN miCRoscoPy (TeM) of pLatinuM ReplicAs. In these StUDies we HAve

of proteins in the contex t of their  loca l c ell ul ar e nvir onment. Specif i call y, we succeeded in dev elopi ng a ro b us t pip eline f o ri m agi ng  t hepl a sm a mem bra ne of c ells withbot h3D iPALM (in t er ferometric  ph otoactivatio n l ocaliz at ion micro cop y) an d 3D t r ansmis sion elec tr o n micr o scopy ( T E M)  ofplatinum replicas .  I n  these studies  we ha ve

of_proteins in_the context of their_local cellular_environment._Specifically, we_succeeded_in developing a_robust pipeline for_imaging the plasma membrane_of cells with_both_3D iPALM (interferometric photoactivation localization microcopy) and 3D transmission electron microscopy (TEM) of platinum_replicas._In these_studies_we_have


a cohort of individuals with delayed pubertal development and Chiari type 1 malformations whose genomic DNA will soon be sent for ES, based on discoveries made through our phenotyping protocol. Analysis of these data has the potential to identify new non-reproductive features of IGD, as well as novel molecular pathways involved in

a cohort of individuals with delayed pubertal development and Chiari type 1 deformity whose genomic DNA will soon be mail for ES, based on discoveries made through our phenotyping protocol. psychoanalysis of these data has the potential to name modern non - reproductive feature of IGD, as well as novel molecular pathway involved in

a fohort of individuals wiuh delayed pubertco devenopmenf and Chkari type 1 malformations whode genonic DNA will soon be sdnt for ED, based in dmscoveries made vgrough our phskotypnnj protocol. Analisis of thesa data has the putzntial to identify new non-reproductide featirfs of IGD, as wgll ax novsl molecular pathways involved in

a cohort of individuals with delayed pubertal Chiari 1 malformations genomic DNA will based discoveries made through phenotyping protocol. Analysis these data has the potential to new non-reproductive features of IGD, as well as novel molecular pathways involved in

a cohort of individuals with dElayed pubeRtal dEveLopMeNt anD ChiAri type 1 malformATionS whose genomic DNA will soOn be sEnT For Es, BaSed on DiscoveRIeS MAde ThRoUgh OuR PhEnotyPinG protocOl. Analysis Of tHeSe data has the POtEntial to idEntIfy new non-repRodUctive FeAtuREs of IgD, aS well As noveL MolecuLar pathwaYs INvolveD In

a cohort of individuals w ith delaye d pub ert alde velo pmen t and Chiari t y pe 1  malformations whose g enomi cD NA w i ll  soon  be sen t  f o r  ES ,ba sed  o n  d iscov eri es made  through o urph enotyping pr o to col. Analy sis  of these da tahas th epot e ntial  to  iden tify n e w non- reproduct iv e  featu r es of I G D ,as w ell as novel mole c ul a r pathways inv olvedin

a_cohort of_individuals with delayed pubertal_development and_Chiari_type 1_malformations_whose genomic DNA_will soon be_sent for ES, based_on discoveries made_through_our phenotyping protocol. Analysis of these data has the potential to identify new non-reproductive_features_of IGD,_as_well_as novel molecular pathways involved_in


of normal cognition. Prior to our work on synaptic plasticity in area CA2, few groups had appreciated that the area was in fact a distinct region of the hippocampus and as a result, nothing was known about the how neurons in area CA2 function during even the simplest of behaviors such as exploration of an open field. We

of normal cognition. Prior to our work on synaptic plasticity in area CA2, few groups had prize that the sphere was in fact a distinct region of the hippocampus and as a resultant role, nothing was know about the how neurons in area CA2 officiate during even the childlike of behaviors such as exploration of an exposed field. We

of normal cognition. Prior uo our work on syuqptic 'lasticjty in afea CA2, few groups had apprecmatee thau the area was in fxct a disninct reguon id the hippocampus and as w revnlt, nothing was known abogt the how neusovs in area CA2 function during even thq simplrsh of behaviors sucn as sqpooration of an open field. We

of normal cognition. Prior to our work plasticity area CA2, groups had appreciated fact distinct region of hippocampus and as result, nothing was known about the neurons in area CA2 function during even the simplest of behaviors such as of an open field. We

of normal cognition. Prior to oUr work on syNaptiC plAstIcIty iN areA CA2, few groups haD ApprEciated that the area was iN fact A dIStinCT rEgion Of the hiPPoCAMpuS aNd As a ReSUlT, nothIng Was knowN about the hOw nEuRons in area CA2 FUnCtion durinG evEn the simplesT of BehaviOrS suCH as exPloRatioN of an oPEn fielD. We

of normal cognition. Prio r to our w ork o n s yna pt ic p last icity in areaC A2,few groups had appreci atedth a t th e  a rea w as in f a ct a  di st in ctre g io n ofthe  hippoc ampus andasaresult, noth i ng  was known  ab out the howneu rons i nare a  CA2fun ction  durin g  eventhe simpl es t  of be h aviorss u ch  asexploration of an op e n field. We

of_normal cognition._Prior to our work_on synaptic_plasticity_in area_CA2,_few groups had_appreciated that the_area was in fact_a distinct region_of_the hippocampus and as a result, nothing was known about the how neurons in_area_CA2 function_during_even_the simplest of behaviors such_as exploration of an open_field. We


receptors that serve as TNF binding proteins. The specific aim of this project is to identify new mechanisms by which the release of soluble TNF receptors are regulated. We hypothesized that the mechanism of TNFR1 shedding might involve interactions with regulatory proteins. Utilizing a yeast two-hybrid approach, we identified ARTS-1 (A

receptors that serve as TNF binding proteins. The specific purpose of this undertaking is to identify new mechanism by which the handout of soluble TNF receptors are regulated. We speculate that the mechanism of TNFR1 shedding might involve interactions with regulative protein. Utilizing a yeast two - hybrid overture, we identified ARTS-1 (A

refeptors that serve as TNN binding proteiuw. The vpecifjc aim ow this project is to identifb neq mecyanisms by which the rdlease of soluble TNF eeceptors ede regulated. Sc hypmvhesized that tme mechanisk of TNFR1 shedgivg might involve interactions with redulatoru oroteins. Utilieing s yeaan uwo-hybrid approach, we identified ZRTS-1 (A

receptors that serve as TNF binding proteins. aim this project to identify new of TNF receptors are We hypothesized that mechanism of TNFR1 shedding might involve with regulatory proteins. Utilizing a yeast two-hybrid approach, we identified ARTS-1 (A

receptors that serve as TNF biNding proteIns. ThE spEciFiC aim Of thIs project is to iDEntiFy new mechanisms by which The reLeASe of SOlUble TnF recepTOrS ARe rEgUlAteD. WE HyPotheSizEd that tHe mechanisM of tNfR1 shedding miGHt Involve intEraCtions with reGulAtory pRoTeiNS. UtilIziNg a yeAst two-HYbrid aPproach, we IdENtifieD aRTS-1 (A

receptors that serve as T NF binding  prot ein s.Th e sp ecif ic aim of this proj ect is to identify new  mech an i smsb ywhich  the re l ea s e  of  s ol ubl eT NF  rece pto rs areregulated.  We  h ypothesizedt ha t the mech ani sm of TNFR1she ddingmi ght invol veinter action s  withregulator yp rotein s . Utili z i ng  a y east two-hybrid a p pr o ach, we identi fied A RT S -1 ( A

receptors_that serve_as TNF binding proteins._The specific_aim_of this_project_is to identify_new mechanisms by_which the release of_soluble TNF receptors_are_regulated. We hypothesized that the mechanism of TNFR1 shedding might involve interactions with regulatory_proteins._Utilizing a_yeast_two-hybrid_approach, we identified ARTS-1 (A


pu is species-specific. However, in collaboration with Malcolm Martins lab we recently identified several primary Vpu isolates, such as DH12, capable of antagonizing both human and rhesus BST-2. We subsequently found that while Vpu interacts with human BST-2 primarily through their respective transmembrane domains

pu is species - specific. However, in collaboration with Malcolm Martins lab we recently identified several primary Vpu isolates, such as DH12, adequate to of antagonize both human and rhesus BST-2. We subsequently found that while Vpu interacts with human BST-2 primarily through their respective transmembrane domain

pu ls species-specific. Howevtr, in collaboration with Malcomm Martivs lab we recently identifiev seceral primary Vpu isolates, ruch as DJ12, capablw of qntagoniziif both mbman zkd rhzsns BST-2. We subseauently fognd that while Vou interacts with human BST-2 primarily througn hheir respectide tgagsmejbrane domains

pu is species-specific. However, in collaboration with lab recently identified primary Vpu isolates, antagonizing human and rhesus We subsequently found while Vpu interacts with human BST-2 through their respective transmembrane domains

pu is species-specific. HoweveR, in collaboRatioN wiTh MAlColm martIns lab we recentLY ideNtified several primary VPu isoLaTEs, suCH aS DH12, caPable of ANtAGOniZiNg BotH hUMaN and rHesUs BST-2. We SubsequentLy fOuNd that while VPU iNteracts wiTh hUman BST-2 primaRilY throuGh TheIR respEctIve trAnsmemBRane doMains

pu is species-specific. Ho wever, incolla bor ati on  wit h Ma lcolm Martinsl ab w e recently identifiedsever al prim a ry  Vpuisolate s ,s u chas  D H12 ,c ap ableofantagon izing both  hu ma n and rhesus BS T-2. We su bse quently foun d t hat wh il e V p u int era cts w ith hu m an BST -2 primar il y  throu g h their r es pect ive transmembrane do m ains

pu is_species-specific. However,_in collaboration with Malcolm_Martins lab_we_recently identified_several_primary Vpu isolates,_such as DH12,_capable of antagonizing both_human and rhesus_BST-2._We subsequently found that while Vpu interacts with human BST-2 primarily through their respective_transmembrane_domains


series of highly specific intermediates. We identified residues of Tf1 RT that recognize specific intermediates of cDNA by screening large numbers of RT mutants. A combination of genetic assays and physical analyses identified a set of 35 mutations that inhibited integration without reducing reverse transcription. Our experiments focused on a cluster of mutations in ribonuclease H (

series of highly specific intermediates. We identified residues of Tf1 RT that accredit specific intermediate of cDNA by screening big number of RT mutants. A combination of genetic assay and forcible analyses identified a set of 35 mutations that inhibited consolidation without reducing reverse transcription. Our experiments focus on a cluster of mutation in ribonuclease H (

segies of highly specific lntermediates. We identihied reaidues ow Tf1 RT that recognize specihic unternediates of cDNA by scfeening lwrge numvers if RT mutaifs. A combinatjln oy jenetic assays snd physicdl analyses idangiyied a set of 35 mutations that inhibieed intrggation without redlcyng dvvtrse transcription. Our experimenta focustd on a cluster of mutations in ribonuclease H (

series of highly specific intermediates. We identified Tf1 that recognize intermediates of cDNA RT A combination of assays and physical identified a set of 35 mutations inhibited integration without reducing reverse transcription. Our experiments focused on a cluster of in ribonuclease H (

series of highly specific intErmediates. we ideNtiFieD rEsidUes oF Tf1 RT that recogNIze sPecific intermediates of CDNA bY sCReenINg Large Numbers OF Rt MUtaNtS. A ComBiNAtIon of GenEtic assAys and physIcaL aNalyses identIFiEd a set of 35 muTatIons that inhiBitEd inteGrAtiON withOut ReducIng revERse traNscriptioN. OUR experIMents foCUSeD on a Cluster of mutationS In RIbonuclease H (

series of highly specific  intermedi ates.  We  id en tifi ed r esidues of Tf1 RT t hat recognize specific  inte rm e diat e sof cD NA by s c re e n ing  l ar genu m be rs of  RT  mutant s. A combi nat io n of genetic as says and p hys ical analyse s i dentif ie d a set o f 3 5 mut ations that i nhibitedin t egrati o n witho u t  r educ ing reverse trans c ri p tion. Our expe riment sf oc u s edona clusterof  muta t ions in ri b o n ucl e ase H (

series_of highly_specific intermediates. We identified_residues of_Tf1_RT that_recognize_specific intermediates of_cDNA by screening_large numbers of RT_mutants. A combination_of_genetic assays and physical analyses identified a set of 35 mutations that inhibited integration_without_reducing reverse_transcription._Our_experiments focused on a cluster_of mutations in ribonuclease H_(


how neuronal activity can induce lasting modifications in neurons, we use a diverse collection of molecular, biochemical, electrophysiological, and imaging techniques. We use the hippocampal slice preparation from neonate and adult mice. The relatively simple laminar structure of the hippocampus, which itself plays an important role in learning and memory, allows electrophysiological

how neuronal activity can induce lasting modifications in nerve cell, we practice a divers collection of molecular, biochemical, electrophysiological, and imaging techniques. We practice the hippocampal slice preparation from neonate and adult mice. The relatively elementary laminar structure of the hippocampus, which itself plays an significant role in learning and memory, allow electrophysiological

hoa neuronal activity can lnduce lasting modificavions ih neuronr, we use a diverse collectioi of molexular, biochemical, elecgrophysiopogical, qnd mmaging techniquxa. We usc the mippoeanpal slice prekaration frok neonate and ddjlc mice. The relatively simple laminar structirf of the hipposampls, whidh itself plays an important role jn leariing and memory, allows electrophysiologicwl

how neuronal activity can induce lasting modifications we a diverse of molecular, biochemical, use hippocampal slice preparation neonate and adult The relatively simple laminar structure of hippocampus, which itself plays an important role in learning and memory, allows electrophysiological

how neuronal activity can indUce lasting ModifIcaTioNs In neUronS, we use a diverse COlleCtion of molecular, biocheMical, ElECtroPHySioloGical, anD ImAGIng TeChNiqUeS. we Use thE hiPpocampAl slice preParAtIon from neonaTE aNd adult micE. ThE relatively sImpLe lamiNaR stRUcturE of The hiPpocamPUs, whicH itself plAyS An impoRTant rolE IN lEarnIng and memory, allowS ElECtrophysiologiCal

how neuronal activity can  induce la sting  mo dif ic atio ns i n neurons, weu se a  diverse collection of  mole cu l ar,b io chemi cal, el e ct r o phy si ol ogi ca l ,and i mag ing tec hniques. W e u se  the hippoca m pa l slice pr epa ration fromneo nate a nd  ad u lt mi ce.  Therelati v ely si mple lami na r  struc t ure oft h ehipp ocampus, which it s el f  plays an impo rtantro l ei n  le arn ing and me mo ry, a l lows el e ct r o p hys i ological

how_neuronal activity_can induce lasting modifications_in neurons,_we_use a_diverse_collection of molecular,_biochemical, electrophysiological, and_imaging techniques. We use_the hippocampal slice_preparation_from neonate and adult mice. The relatively simple laminar structure of the hippocampus, which_itself_plays an_important_role_in learning and memory, allows_electrophysiological


and functional characteristics were compared with those of monocytes exposed to factors known to generate either alternatively (interleukin-4 IL-4) or classically (macrophage colony-stimulating factor MCSF) activated MΦ. IL-4 upregulated mRNA expression of CCL13, CCL15, CCL17

and functional characteristics were compared with those of monocytes expose to divisor known to generate either alternatively (interleukin-4 IL-4) or classically (macrophage colony - stimulating divisor MCSF) activated MΦ . IL-4 upregulated mRNA expression of CCL13, CCL15, CCL17

anf functional characterisuics were compareb with vhose or monocyges exposed to factors known ti gentgate either alternatixely (integleukin-4 IO-4) or xlassicallb (macropmcge ckpony-vvimulating factpr MCSF) acdivated MΦ. IL-4 u[rdgblated mRNA expression of CCL13, CCL15, CCJ17

and functional characteristics were compared with those exposed factors known generate either alternatively colony-stimulating MCSF) activated MΦ. upregulated mRNA expression CCL13, CCL15, CCL17

and functional characteristIcs were comPared WitH thOsE of mOnocYtes exposed to fACtorS known to generate either AlterNaTIvelY (InTerleUkin-4 IL-4) oR ClASSicAlLy (MacRoPHaGe colOny-StimulaTing factor mCSf) aCtivated MΦ. IL-4 uPReGulated mRNa exPression of CCl13, CCl15, CCL17

and functional characteri stics were  comp are d w it h th oseof monocytes e x pose d to factors known togener at e  eit h er  alte rnative l y( i nte rl eu kin -4 IL -4) o r c lassica lly (macro pha ge  colony-stim u la ting facto r M CSF) activat edM&#934 ;.  IL - 4 upr egu lated  mRNAe xpress ion of CC L1 3 , CCL1 5 , CCL17

and_functional characteristics_were compared with those_of monocytes_exposed_to factors_known_to generate either_alternatively (interleukin-4 IL-4)_or classically (macrophage colony-stimulating_factor MCSF) activated_MΦ._IL-4 upregulated mRNA expression of CCL13, CCL15, CCL17


hWT) MSCs. MC3R(hDM/hDM) impacted nutrient partitioning to generate increased adipose tissue that appeared metabolically healthy. These data confirmed the importance of MC3R signaling in human metabolism and suggested a previously-unrecognized role for the MC3R in adipose tissue development. Current studies are seeking

hWT) MSCs. MC3R(hDM / hDM) impacted nutrient partitioning to render increase adipose tissue that appeared metabolically healthy. These data confirm the importance of MC3R signaling in human metabolism and indicate a previously - unrecognized character for the MC3R in adipose tissue development. Current studies are seeking

hWT) MSCs. MC3R(hDM/hDM) impacted nutrient partijiining vo genedate incfeased adipose tissue that a'peaeed mtnabolically healthy. Tfese data confirmwd tie importance of MC3R sigkcling ln huken metabolism akd suggesteg a previously-gnfeeognized role for the MC3R in adipose tissue dfvelopment. Curtent xeudiss are seeking

hWT) MSCs. MC3R(hDM/hDM) impacted nutrient partitioning to adipose that appeared healthy. These data signaling human metabolism and a previously-unrecognized role the MC3R in adipose tissue development. studies are seeking

hWT) MSCs. MC3R(hDM/hDM) impacted nUtrient parTitioNinG to GeNeraTe inCreased adipose TIssuE that appeared metabolicAlly hEaLThy. THEsE data ConfirmED tHE ImpOrTaNce Of mc3R SignaLinG in humaN metabolisM anD sUggested a preVIoUsly-unrecoGniZed role for thE MC3r in adiPoSe tISsue dEveLopmeNt. CurrENt studIes are seeKiNG

hWT) MSCs. MC3R(hDM/hDM) i mpacted nu trien t p art it ioni ng t o generate inc r ease d adipose tissue thatappea re d  met a bo lical ly heal t hy . The se  d ata  c o nf irmed  th e impor tance of M C3R  s ignaling inh um an metabol ism  and suggest eda prev io usl y -unre cog nized  rolef or the  MC3R inad i pose t i ssue de v e lo pmen t. Current studie s  a r e seeking

hWT) MSCs._MC3R(hDM/hDM) impacted_nutrient partitioning to generate_increased adipose_tissue_that appeared_metabolically_healthy. These data_confirmed the importance_of MC3R signaling in_human metabolism and_suggested_a previously-unrecognized role for the MC3R in adipose tissue development. Current studies are seeking


membrane-associated ARTS-1, decreased soluble TNFR1 release and increased membrane-associated TNFR1. ARTS-1 neither bound to TNFR2 nor altered its shedding, suggesting specificity for TNFR1. Although a GST-ARTS-1 fusion protein demonstrated selective aminopeptidase activity towards non

membrane - associated ARTS-1, decreased soluble TNFR1 release and increased membrane - consociate TNFR1. ARTS-1 neither tie to TNFR2 nor altered its shedding, suggesting specificity for TNFR1. Although a GST - ARTS-1 coalition protein demonstrated selective aminopeptidase activity towards non

melbrane-associated ARTS-1, degreased soluble JNDR1 relxase ans increared membrane-associated TNFR1. ERTS-1 neityer bound to TNFR2 nor xltered ins sheddibg, snggesting specifmdity fov TNFD1. Altkongh a GST-ARTS-1 fosion proteit demonstrated sdlzctive aminopeptidase activity towarqs non

membrane-associated ARTS-1, decreased soluble TNFR1 release and TNFR1. neither bound TNFR2 nor altered TNFR1. a GST-ARTS-1 fusion demonstrated selective aminopeptidase towards non

membrane-associated ARTS-1, decReased soluBle TNfR1 rEleAsE and IncrEased membrane-aSSociAted TNFR1. ARTS-1 neither bouNd to TnFr2 Nor aLTeRed itS sheddiNG, sUGGesTiNg SpeCiFIcIty foR TNfR1. AlthoUgh a GST-ARTs-1 fuSiOn protein demONsTrated seleCtiVe aminopeptiDasE activItY toWArds nOn

membrane-associated ARTS- 1, decreas ed so lub leTN FR1rele ase and increa s ed m embrane-associated TNF R1. A RT S -1 n e it her b ound to TN F R 2 n or  a lte re d  i ts sh edd ing, su ggesting s pec if icity for TN F R1 . Although  aGST-ARTS-1 f usi on pro te ind emons tra ted s electi v e amin opeptidas ea ctivit y  toward s no n

membrane-associated_ARTS-1, decreased_soluble TNFR1 release and_increased membrane-associated_TNFR1._ARTS-1 neither_bound_to TNFR2 nor_altered its shedding,_suggesting specificity for TNFR1._Although a GST-ARTS-1_fusion_protein demonstrated selective aminopeptidase activity towards non


/stops progression of hearing loss and vision loss. 5. The phenotypic difference between NOMID and DIRA (no CNS, eye and ear inflammation in DIRA, compared to NOMID) and difference in skin manifestations, urticaria-like versus pustulosis, allow us to study

/stops progression of hearing loss and vision personnel casualty. 5. The phenotypical difference between NOMID and DIRA (no CNS, eye and ear excitement in DIRA, compare to NOMID) and difference in skin expression, urticaria - comparable versus pustulosis, allow us to analyze

/stoos progression of hearinn loss and visiou loss. 5. The pgenotypiz difference between NOMID aid DURA (ni CNS, eye and ear inflxmmation pn DIRA, cimpaced to NOMID) and differekee in dkin nanifestations, urticaria-nike versus puvtjllsis, allow us to study

/stops progression of hearing loss and vision The difference between and DIRA (no in compared to NOMID) difference in skin urticaria-like versus pustulosis, allow us to

/stops progression of hearing Loss and visIon loSs. 5. THe pHeNotyPic dIfference betweEN NOMiD and DIRA (no CNS, eye and eaR inflAmMAtioN In dIRA, cOmpared TO NomiD) aNd DiFfeReNCe In skiN maNifestaTions, urticAriA-lIke versus pusTUlOsis, allow uS to Study

/stops progression of hear ing loss a nd vi sio n l os s. 5 . Th e phenotypic d i ffer ence between NOMID and  DIRA  ( n o CN S ,eye a nd eari nf l a mma ti on  in  D I RA , com par ed to N OMID) anddif fe rence in ski n  m anifestati ons , urticaria- lik e vers us  pu s tulos is,  allo w us t o  study

/stops progression_of hearing_loss and vision loss._5. The_phenotypic_difference between_NOMID_and DIRA (no_CNS, eye and_ear inflammation in DIRA,_compared to NOMID)_and_difference in skin manifestations, urticaria-like versus pustulosis, allow us to study


, CCL18, CCL22, CLEC10A, MRC1, CADH1, CD274, and CD273 associated with alternative activation of MΦ but not arginase 1. IL-4-cultured monocytes had a diminished ability to promote proliferation of both CD4(+) and CD

, CCL18, CCL22, CLEC10A, MRC1, CADH1, CD274, and CD273 associated with alternative activation of MΦ but not arginase 1. IL-4 - cultured monocyte have a diminished ability to promote proliferation of both CD4(+) and certificate of deposit

, CCP18, CCL22, CLEC10A, MRC1, CADH1, CD274, xnd CD273 associatgd with elternafive actkvation of MΦ but not arginasx 1. IO-4-cultyred monocytes had a dkminished ability to kromote proliferavjon of njth DF4(+) anb RD

, CCL18, CCL22, CLEC10A, MRC1, CADH1, CD274, associated alternative activation MΦ but not a ability to promote of both CD4(+) CD

, CCL18, CCL22, CLEC10A, MRC1, CADH1, CD274, and CD273 Associated With aLteRnaTiVe acTivaTion of MΦ but not aRGinaSe 1. IL-4-cultured monocytes hAd a diMiNIsheD AbIlity To promoTE pROLifErAtIon Of BOtH CD4(+) anD CD

, CCL18, CCL22, CLEC10A, M RC1, CADH1 , CD2 74,  an dCD27 3 as sociated witha lter native activation of M &#934 ;b ut n o targin ase 1.I L- 4 - cul tu re d m on o cy tes h ada dimin ished abil ity  t o promote pr o li feration o f b oth CD4(+) a ndCD

, CCL18,_CCL22, CLEC10A,_MRC1, CADH1, CD274, and_CD273 associated_with_alternative activation_of_MΦ but not_arginase 1. IL-4-cultured_monocytes had a diminished_ability to promote_proliferation_of both CD4(+) and CD


binding and entry. We are currently working on the XPR1 receptor for the xenotropic/polytropic MLVs (XP-MLVs). We have determined that, in mouse populations exposed to infectious virus, virus resistance is mediated by polymorphisms of the cell surface receptor. We have identified a total of six XPR

binding and entry. We are currently working on the XPR1 sense organ for the xenotropic / polytropic MLVs (XP - MLVs). We have determine that, in mouse populations expose to infectious virus, virus immunity is mediated by polymorphisms of the cellular telephone surface receptor. We have identified a sum of six XPR

bijding and entry. We are cmrrently working on the XPR1 rsceptor wor the xenotropic/polytropic MOVs (XK-ILVs). We have deteroined than, in mousw pokulations exposed to infegcious yirus, tirus resistancg is mediateg by polymorphhsos of the cell surface receptor. We hade idenyivied a total os siq VPR

binding and entry. We are currently working XPR1 for the MLVs (XP-MLVs). We populations to infectious virus, resistance is mediated polymorphisms of the cell surface receptor. have identified a total of six XPR

binding and entry. We are curreNtly workinG on thE XPr1 reCePtor For tHe xenotropic/poLYtroPic MLVs (XP-MLVs). We have detErminEd THat, iN MoUse poPulatioNS eXPOseD tO iNfeCtIOuS viruS, viRus resiStance is meDiaTeD by polymorphISmS of the cell SurFace receptor. we hAve ideNtIfiED a totAl oF six XpR

binding and entry. We are  currently  work ing  on  t he X PR1receptor for t h e xe notropic/polytropic ML Vs (X P- M LVs) .  W e hav e deter m in e d  th at ,inmo u se  popu lat ions ex posed to i nfe ct ious virus,v ir us resista nce  is mediated  by  polym or phi s ms of  th e cel l surf a ce rec eptor. We  h a ve ide n tifieda to talof six XPR

binding_and entry._We are currently working_on the_XPR1_receptor for_the_xenotropic/polytropic MLVs (XP-MLVs)._We have determined_that, in mouse populations_exposed to infectious_virus,_virus resistance is mediated by polymorphisms of the cell surface receptor. We have identified_a_total of_six_XPR


of EpCAM as Langerhans cell surface marker and have extended our earlier studies and demonstrated that EpCAM expression, in conjunction with other surface markers, differentiates Langerhance cells from all other dendritic cells, including several recently described novel cutaneous dendritic cell subsets. In an effort to elucidate important aspects of EpCAM

of EpCAM as Langerhans cell surface marker and have extended our earlier report and attest that EpCAM expression, in conjunction with other airfoil markers, differentiates Langerhance cell from all early dendritic cells, including several recently described novel cutaneous dendritic cellular telephone subsets. In an effort to elucidate important aspect of EpCAM

of EpCAM as Langerhans celu surface market qnd hate extehded our earlier studies and demonstcatee thau EpCAM expression, kn conjunbtion wity otier surface markxds, diffcxentizbes Lcnjerhance cells nrom all otver dendritic weuld, including several recently descrifed novrl cutaneous denqritpc celm subsets. In an effort to elucidats imporuant aspects of EpVAM

of EpCAM as Langerhans cell surface marker extended earlier studies demonstrated that EpCAM surface differentiates Langerhance cells all other dendritic including several recently described novel cutaneous cell subsets. In an effort to elucidate important aspects of EpCAM

of EpCAM as Langerhans cell suRface markeR and hAve ExtEnDed oUr eaRlier studies anD DemoNstrated that EpCAM expreSsion, In COnjuNCtIon wiTh other SUrFACe mArKeRs, dIfFErEntiaTes langerhAnce cells fRom AlL other dendriTIc Cells, incluDinG several receNtlY descrIbEd nOVel cuTanEous dEndritIC cell sUbsets. In aN eFFort to ELucidatE IMpOrtaNt aspects of EpCAM

of EpCAM as Langerhans ce ll surface  mark erand  h aveexte nded our earli e r st udies and demonstrated  that  E p CAMe xp ressi on, inc on j u nct io nwit ho th er su rfa ce mark ers, diffe ren ti ates Langerh a nc e cells fr omall other de ndr itic c el ls, inclu din g sev eral r e cently  describe dn ovel c u taneous d en drit ic cell subsets.I na n effort to el ucidat ei mp o r tan t a spects ofEp CAM

of_EpCAM as_Langerhans cell surface marker_and have_extended_our earlier_studies_and demonstrated that_EpCAM expression, in_conjunction with other surface_markers, differentiates Langerhance_cells_from all other dendritic cells, including several recently described novel cutaneous dendritic cell subsets._In_an effort_to_elucidate_important aspects of EpCAM


atal PCB Exposure: We examined the association between fetal loss in previous pregnancies and DDE levels that were in a range where effects had been seen in two other studies. Complete data were available for 2,380 subjects, of whom 361 were born preterm and 221 were small-for-gestational age. We examined maternal D

atal PCB Exposure: We examined the association between fetal loss in former pregnancy and DDE floor that were in a range where effect had been understand in two other studies. arrant datum were available for 2,380 subjects, of whom 361 were born preterm and 221 were small - for - gestational age. We examined enate D

atap PCB Exposure: We examintd the associatiou betwexn fetam loss iv previous pregnancies and DVE lwvels that were in a range dhere effvcts had veen ween in two other studiea. Com'lxte data were ayailable fos 2,380 subjects, of wfol 361 were born preterm and 221 were smalj-for-gesyahional age. We gxamimqd mznevnal D

atal PCB Exposure: We examined the association loss previous pregnancies DDE levels that effects been seen in other studies. Complete were available for 2,380 subjects, of 361 were born preterm and 221 were small-for-gestational age. We examined maternal D

atal PCB Exposure: We examined The associaTion bEtwEen FeTal lOss iN previous pregnANcieS and DDE levels that were iN a ranGe WHere EFfEcts hAd been sEEn IN Two OtHeR stUdIEs. complEte Data werE available For 2,380 SuBjects, of whom 361 WErE born preteRm aNd 221 were small-fOr-gEstatiOnAl aGE. We exAmiNed maTernal d

atal PCB Exposure: We exam ined the a ssoci ati onbe twee n fe tal loss in pr e viou s pregnancies and DDElevel st hatw er e ina range wh e r e e ff ec tsha d  b een s een  in two  other stu die s.  Complete da t awere avail abl e for 2,380sub jects,  o f w h om 36 1 w ere b orn pr e term a nd 221 we re small- f or-gest a t io nalage. We examinedm at e rnal D

atal PCB_Exposure: We_examined the association between_fetal loss_in_previous pregnancies_and_DDE levels that_were in a_range where effects had_been seen in_two_other studies. Complete data were available for 2,380 subjects, of whom 361 were born_preterm_and 221_were_small-for-gestational_age. We examined maternal D


severely overweight children (6-12y) who manifested hyperinsulinemia and insulin resistance. We concluded that metformin, added to a monthly behavioral program, significantly improved weight loss, insulin resistance, and cholesterol over a 6-month interval in severely overweight, insulin-resistant children. We recently reported how the pharmacokinetics of metformin

severely overweight children (6 - 12y) who manifested hyperinsulinemia and insulin underground. We conclude that metformin, added to a monthly behavioral program, significantly better weight loss, insulin resistor, and cholesterol over a 6 - calendar month interval in severely overweight, insulin - resistant children. We recently report how the pharmacokinetics of metformin

segerely overweight childrtn (6-12y) who manifestgd hypermnsulinsmia and insulin resistance. We conclnded that metformin, added to a oonthly bvhavioral projram, significantly improyzd wejnht lmws, insulin reslstance, and cholesterol oeef c 6-month interval in severely overweidht, insilln-resistant chyldrtn. Re rsbektly reported how the pharmacokihetics mf metformin

severely overweight children (6-12y) who manifested hyperinsulinemia resistance. concluded that added to a weight insulin resistance, and over a 6-month in severely overweight, insulin-resistant children. We reported how the pharmacokinetics of metformin

severely overweight childreN (6-12y) who manifEsted HypEriNsUlinEmia And insulin resiSTancE. We concluded that metforMin, adDeD To a mONtHly beHavioraL PrOGRam, SiGnIfiCaNTlY imprOveD weight Loss, insuliN reSiStance, and choLEsTerol over a 6-MonTh interval in SevErely oVeRweIGht, inSulIn-resIstant CHildreN. We recentLy REporteD How the pHARmAcokInetics of metformiN

severely overweight child ren (6-12y ) who  ma nif es tedhype rinsulinemia a n d in sulin resistance. We c onclu de d  tha t  m etfor min, ad d ed t o a  m on thl yb eh avior alprogram , signific ant ly  improved we i gh t loss, in sul in resistanc e,and ch ol est e rol o ver  a 6- monthi nterva l in seve re l y over w eight,i n su lin- resistant childre n .W e recently rep ortedho w  t h e  ph arm acokinetic sof me t formin

severely_overweight children_(6-12y) who manifested hyperinsulinemia_and insulin_resistance._We concluded_that_metformin, added to_a monthly behavioral_program, significantly improved weight_loss, insulin resistance,_and_cholesterol over a 6-month interval in severely overweight, insulin-resistant children. We recently reported how_the_pharmacokinetics of_metformin


ammaretrovirus genomes, many of which can produce infectious and pathogenic viruses. Second, there are also host factors that interfere directly with virus infection and replication, and we are particularly interested in those factors that inhibit virus entry and the early post-entry stages of the virus replicative cycle. These host factors affect different stages

ammaretrovirus genomes, many of which can produce infectious and pathogenic viruses. Second, there be besides host factors that intervene directly with virus contagion and replication, and we are particularly concerned in those factors that inhibit virus entry and the early post - entry phase of the virus replicative cycle. These host agent affect different stage

ammwretrovirus genomes, many of which can ptoeuce iifectiohs and pxthogenic viruses. Second, thece aee alwo host factors that ivterfere firectly witi virus infectioi and reijicaflon, aud we are particolarly interasted in those fxccors that inhibit virus entry and thq early plst-entry stagef of ehe bprms replicative cycle. These host ractors affect diffetent stages

ammaretrovirus genomes, many of which can produce pathogenic Second, there also host factors infection replication, and we particularly interested in factors that inhibit virus entry and early post-entry stages of the virus replicative cycle. These host factors affect different

ammaretrovirus genomes, many Of which can ProduCe iNfeCtIous And pAthogenic virusES. SecOnd, there are also host facTors tHaT InteRFeRe dirEctly wiTH vIRUs iNfEcTioN aND rEplicAtiOn, and we Are particuLarLy Interested in THoSe factors tHat Inhibit virus EntRy and tHe EarLY post-EntRy staGes of tHE virus ReplicatiVe CYcle. ThESe host fACToRs afFect different stagES

ammaretrovirus genomes, ma ny of whic h can  pr odu ce  inf ecti ous and pathog e nicviruses. Second, there  areal s o ho s tfacto rs that in t e rfe re  d ire ct l ywithvir us infe ction andrep li cation, andw eare partic ula rly interest edin tho se  fa c torstha t inh ibit v i rus en try and t he earlyp ost-ent r y  s tage s of the virus re p li c ative cycle. T hese h os t  f a c tor s a ffect diff er ent s t ages

ammaretrovirus genomes,_many of_which can produce infectious_and pathogenic_viruses._Second, there_are_also host factors_that interfere directly_with virus infection and_replication, and we_are_particularly interested in those factors that inhibit virus entry and the early post-entry stages_of_the virus_replicative_cycle._These host factors affect different_stages


of FRET standards to aid in the interpretation of FRET analysis. In the course of this study we have identified two important potential artifacts that can complicate the proper interpretation of FRET analysis. 2. We are also in the final data collection stage for a study describing the generation of Homo-FRET standards that

of FRET standards to aid in the interpretation of FRET analysis. In the path of this discipline we have identified two important potential artifact that can complicate the proper interpretation of FRET analysis. 2. We are also in the concluding datum collection stage for a study describing the generation of Homo - FRET standard that

of FRET standards to aid ik the interpretajiin of HRET anzlysis. Iv the course of this study wx hace idtutified two importang potentiwl artifqcts rhat can complicatc the iropex mnterpretation pf FRET andlysis. 2. We are ausl in the final data collection stagq for a shudy describind tht gqnerzniin of Homo-FRET standards that

of FRET standards to aid in the FRET In the of this study potential that can complicate proper interpretation of analysis. 2. We are also in final data collection stage for a study describing the generation of Homo-FRET standards

of FRET standards to aid in the InterpretaTion oF FReT aNaLysiS. In tHe course of this STudy We have identified two impOrtanT pOTentIAl ArtifActs thaT CaN COmpLiCaTe tHe PRoPer inTerPretatiOn of FRET anAlySiS. 2. We are also in THe Final data cOllEction stage fOr a Study dEsCriBIng thE geNeratIon of HOMo-FRET Standards ThAT

of FRET standards to aidin the int erpre tat ion  o f FR ET a nalysis. In th e  cou rse of this study we h ave i de n tifi e dtwo i mportan t  p o t ent ia lart if a ct s tha t c an comp licate the  pr op er interpret a ti on of FRET  an alysis. 2. W e a re als oint he fi nal  data  colle c tion s tage foras tudy d e scribin g th e ge neration of Homo- F RE T  standards tha t

of_FRET standards_to aid in the_interpretation of_FRET_analysis. In_the_course of this_study we have_identified two important potential_artifacts that can_complicate_the proper interpretation of FRET analysis. 2. We are also in the final data_collection_stage for_a_study_describing the generation of Homo-FRET_standards that


epistatic interactions with neurotrophic and dopaminergic processes that modulate AKT1 effects. AKT1 modulation via pharmaceuticals effected cognition and PF-MTL brain structure in SZ. Therefore, AKT1 and related neuroplasticity and developmental pathways may influence cognition and risk for SZ through effects that may be pharmacologically modifiable

epistatic interactions with neurotrophic and dopaminergic processes that modulate AKT1 effects. AKT1 transition via pharmaceutical effected cognition and PF - MTL brain social organization in SZ. Therefore, AKT1 and related neuroplasticity and developmental pathway may influence cognition and risk for SZ through effect that may be pharmacologically modifiable

eplstatic interactions witm neurotrophic aue dopakinergjc procerses that modulate AKT1 effecvs. AJT1 moeulation via pharmaceugicals efvected cigniuion and PF-MTL brejn strugcure jk SZ. Chxrefore, AKT1 and related nauroplasticity avd developmental pathways may influense cognotlon and risk fjr SE trroufh effects that may be pharmacologjcally kodifiable

epistatic interactions with neurotrophic and dopaminergic processes AKT1 AKT1 modulation pharmaceuticals effected cognition SZ. AKT1 and related and developmental pathways influence cognition and risk for SZ effects that may be pharmacologically modifiable

epistatic interactions with NeurotrophIc and DopAmiNeRgic ProcEsses that modulATe AKt1 effects. AKT1 modulation vIa phaRmACeutICaLs effEcted coGNiTIOn aNd pF-mTL BrAIn StrucTurE in SZ. ThErefore, AKT1 And ReLated neuroplAStIcity and deVelOpmental pathWayS may inFlUenCE cognItiOn and Risk foR sZ throUgh effectS tHAt may bE PharmacOLOgIcalLy modifiable

epistatic interactions wi th neurotr ophic  an d d op amin ergi c processes th a t mo dulate AKT1 effects. A KT1 m od u lati o nvia p harmace u ti c a lsef fe cte dc og nitio n a nd PF-M TL brain s tru ct ure in SZ. T h er efore, AKT 1 a nd related n eur oplast ic ity and d eve lopme ntal p a thways  may infl ue n ce cog n ition a n d  r iskfor SZ through ef f ec t s that may bepharma co l og i c all y m odifiable

epistatic_interactions with_neurotrophic and dopaminergic processes_that modulate_AKT1_effects. AKT1_modulation_via pharmaceuticals effected_cognition and PF-MTL_brain structure in SZ._Therefore, AKT1 and_related_neuroplasticity and developmental pathways may influence cognition and risk for SZ through effects that_may_be pharmacologically_modifiable


elevated levels of pro-fibrotic cytokinescharacterize filarial infection-induced lymphatic pathology. Filarial-induced CD4+ and CD8+ responses have been characterized fully (using microarray/quantitative RT-PCR) in both the generally more-responsive expatriate patients and the less responsive indigenous (with lifelong exposure)

elevated levels of pro - fibrotic cytokinescharacterize filarial infection - induced lymphatic pathology. Filarial - induce CD4 + and CD8 + answer have been characterized fully (using microarray / quantitative RT - PCR) in both the broadly more - responsive expatriate patients and the less reactive indigenous (with lifelong exposure )

elfvated levels of pro-fibrutic cytokinesckqractecize fimarial ivfection-induced lymphatic pavholigy. Fularial-induced CD4+ and ZD8+ respondes have beei characterized hhlly (uslug midvoarrcy/wuantitative RJ-PCR) in both the generally murz-responsive expatriate patients and ehe lesx gesponsive indygenpts (wjnh lifelong exposure)

elevated levels of pro-fibrotic cytokinescharacterize filarial infection-induced Filarial-induced and CD8+ have been characterized both generally more-responsive expatriate and the less indigenous (with lifelong exposure)

elevated levels of pro-fibrotIc cytokineScharActEriZe FilaRial Infection-inducED lymPhatic pathology. FilariaL-induCeD cD4+ anD cD8+ RespoNses havE BeEN ChaRaCtEriZeD FuLly (usIng MicroarRay/quantitAtiVe rT-PCR) in both tHE gEnerally moRe-rEsponsive expAtrIate paTiEntS And thE leSs resPonsivE IndigeNous (with lIfELong exPOsure)

elevated levels of pro-fi brotic cyt okine sch ara ct eriz e fi larial infecti o n-in duced lymphatic pathol ogy.Fi l aria l -i nduce d CD4+a nd C D8+  r es pon se s  h ave b een  charac terized fu lly  ( using microa r ra y/quantita tiv e RT-PCR) in  bo th the  g ene r allymor e-res ponsiv e  expat riate pat ie n ts and the les s re spon sive indigenous ( w it h  lifelong expo sure)

elevated_levels of_pro-fibrotic cytokinescharacterize filarial infection-induced_lymphatic pathology._Filarial-induced_CD4+ and_CD8+_responses have been_characterized fully (using_microarray/quantitative RT-PCR) in both_the generally more-responsive_expatriate_patients and the less responsive indigenous (with lifelong exposure)


compared with those in the neighboring regions. In addition, we have found that a regulator of G-protein signaling (RGS-14), and adenosine A1 receptors (A1Rs), which are highly enriched in CA2, are also negative regulators of plasticity in CA2. We have also found that the social ne

compared with those in the neighboring regions. In addition, we have found that a governor of deoxyguanosine monophosphate - protein signaling (RGS-14), and adenosine A1 receptors (A1Rs), which are highly enrich in CA2, are besides negative regulators of plasticity in CA2. We have besides discover that the social ne

colpared with those in the neighboring reyuons. Ii additjon, we hxve found that a regulator oh G-peoteib signaling (RGS-14), and addnosine A1 receptoes (A1Cs), which are higimy enrigked ih CA2, crx also negative regulatorv of plasticitf kn CA2. We have also found that the socyal ne

compared with those in the neighboring regions. we found that regulator of G-protein receptors which are highly in CA2, are negative regulators of plasticity in CA2. have also found that the social ne

compared with those in the neiGhboring reGions. in aDdiTiOn, we Have Found that a reguLAtor Of G-protein signaling (RGS-14), And adEnOSine a1 ReCeptoRs (A1Rs), whICh ARE hiGhLy EnrIcHEd In CA2, aRe aLso negaTive regulaTorS oF plasticity iN cA2. we have also FouNd that the socIal Ne

compared with those in th e neighbor ing r egi ons .In a ddit ion, we have f o undthat a regulator of G- prote in sign a li ng (R GS-14), an d ade no si neA1 re cepto rs(A1Rs),  which are  hi gh ly enrichedi nCA2, are a lso  negative re gul atorsof  pl a stici tyin CA 2. Weh ave al so foundth a t thes ocial n e

compared_with those_in the neighboring regions._In addition,_we_have found_that_a regulator of_G-protein signaling (RGS-14),_and adenosine A1 receptors_(A1Rs), which are_highly_enriched in CA2, are also negative regulators of plasticity in CA2. We have also_found_that the_social_ne


its ability to maintain TACE in an inactive state, independent of a cysteine switch mechanism. We synthesized a 37-amino acid peptide, corresponding to TACE amino acids 18 to 54 (N-TACE18-54), and assessed whether it possessed TACE inhibitory activity. The N-TACE18-54 amino

its ability to maintain TACE in an inactive state, independent of a cysteine substitution mechanism. We synthesize a 37 - amino acid peptide, corresponding to TACE amino acids 18 to 54 (N - TACE18 - 54), and tax whether it own TACE inhibitory activity. The N - TACE18 - 54 amino

itd ability to maintain TAGE in an inactivg wtate, mndepensent of x cysteine switch mechanism. Xe stnthewized a 37-amino acid pepgide, corrvsponding to UACE amino acids 18 to 54 (N-TAGZ18-54), and wssevwed whether it possessed TACE inhibitosy aetivity. The N-TACE18-54 amino

its ability to maintain TACE in an independent a cysteine mechanism. We synthesized to amino acids 18 54 (N-TACE18-54), and whether it possessed TACE inhibitory activity. N-TACE18-54 amino

its ability to maintain TACE iN an inactivE statE, inDepEnDent Of a cYsteine switch mEChanIsm. We synthesized a 37-amino Acid pEpTIde, cORrEsponDing to TacE AMIno AcIdS 18 to 54 (n-TacE18-54), And asSesSed whetHer it posseSseD TaCE inhibitorY AcTivity. The N-tACe18-54 amino

its ability to maintain T ACE in aninact ive  st at e, i ndep endent of a cy s tein e switch mechanism. We  synt he s ized a37-am ino aci d  p e p tid e,  c orr es p on dingtoTACE am ino acids18to  54 (N-TACE1 8 -5 4), and as ses sed whetheritposses se d T A CE in hib itory  activ i ty. Th e N-TACE1 8- 5 4 amin o

its_ability to_maintain TACE in an_inactive state,_independent_of a_cysteine_switch mechanism. We_synthesized a 37-amino_acid peptide, corresponding to_TACE amino acids_18_to 54 (N-TACE18-54), and assessed whether it possessed TACE inhibitory activity. The N-TACE18-54 amino


distribution of the molecular assemblies control the phenotypes of the cells. We demonstrated that enzyme instructed self-assembly makes it possible to modulate the spatiotemporal profiles of small molecules in a cellular environment. Objective 1: Develop a FV-based gene therapy approach for the treatment of subjects with LAD-1. 1.

distribution of the molecular assemblies control the phenotypes of the cells. We attest that enzyme instruct self - assembly makes it possible to regulate the spatiotemporal profiles of small atom in a cellular environment. Objective 1: build up a FV - based gene therapy access for the treatment of subjects with LAD-1. 1.

didtribution of the molecuuar assemblies eintrol the pgenotyper of the cells. We demonstratxd tyat ebzyme instructed self-arsembly mwkes it possmble to modulate the spabnotemllral 'rofiles of smakl moleculas in a celluldr euvironment. Objective 1: Develop a FV-bafed genr hherapy approash fpw ths treatment of subjects with LAD-1. 1.

distribution of the molecular assemblies control the the We demonstrated enzyme instructed self-assembly the profiles of small in a cellular Objective 1: Develop a FV-based gene approach for the treatment of subjects with LAD-1. 1.

distribution of the moleculaR assemblieS contRol The PhEnotYpes Of the cells. We deMOnstRated that enzyme instrucTed seLf-ASsemBLy Makes It possiBLe TO ModUlAtE thE sPAtIotemPorAl profiLes of small MolEcUles in a celluLAr EnvironmenT. ObJective 1: DevelOp a fV-baseD gEne THerapY apProacH for thE TreatmEnt of subjEcTS with Lad-1. 1.

distribution of the molec ular assem blies  co ntr ol  the  phe notypes of the cell s. We demonstrated tha t enz ym e  ins t ru ctedself-as s em b l y m ak es  it  p o ss ibletomodulat e the spat iot em poral profil e sof small m ole cules in a c ell ular e nv iro n ment.  Ob jecti ve 1:D evelop  a FV-bas ed gene t h erapy a p p ro achfor the treatment of subjects withLAD-1.  1 .

distribution_of the_molecular assemblies control the_phenotypes of_the_cells. We_demonstrated_that enzyme instructed_self-assembly makes it_possible to modulate the_spatiotemporal profiles of_small_molecules in a cellular environment. Objective 1: Develop a FV-based gene therapy approach for_the_treatment of_subjects_with_LAD-1. 1.


als interactions with Leu180 of RT of HBVWT. This Leu180 interaction is also present in the complex of RT of HBVETV-RL180M/S202G/M204V. However, there is a distinct difference in the non-polar interactions of ETV-TP with the RT of

als interactions with Leu180 of RT of HBVWT. This Leu180 interaction is also present in the complex of RT of HBVETV - RL180M / S202G / M204V. However, there is a discrete remainder in the non - polar interactions of ETV - TP with the RT of

als interactions with Leu180 on RT of HBVWT. Thnw Leu180 mnteracfion is xlso present in the complex lf RT od HBVETV-RL180M/S202G/M204V. Howevef, there id a distunct eifference in the kjn-pomwr iutxractions of ETY-TP with tha RT of

als interactions with Leu180 of RT of Leu180 is also in the complex there a distinct difference the non-polar interactions ETV-TP with the RT of

als interactions with Leu180 of Rt of HBVWT. ThIs Leu180 IntEraCtIon iS alsO present in the cOMpleX of RT of HBVETV-RL180M/S202G/M204V. HoWever, ThERe is A DiStincT differENcE IN thE nOn-PolAr INtEractIonS of ETV-Tp with the RT Of

als interactions with Leu1 80 of RT o f HBV WT.  Th is  Leu 180interaction is also  present in the comple x ofRT of H B VE TV-RL 180M/S2 0 2G / M 204 V.  H owe ve r ,there  is  a dist inct diffe ren ce  in the non- p ol ar interac tio ns of ETV-TP  wi th the  R T o f

als interactions_with Leu180_of RT of HBVWT._This Leu180_interaction_is also_present_in the complex_of RT of_HBVETV-RL180M/S202G/M204V. However, there is_a distinct difference_in_the non-polar interactions of ETV-TP with the RT of


based approach to Cas9-mediated transgene knock-in, known as HITI, to achieve robust site-specific transgene integration within human CD34+ HSPCs. As proof-of-concept, a copGFP expression cassette was targeted to the genetic locus ITGB2 encoding the beta-2 integrin subunit CD18

based approach to Cas9 - mediated transgene knock - in, known as HITI, to achieve full-bodied web site - specific transgene consolidation within human CD34 + HSPCs. As proof - of - concept, a copGFP expression cassette was targeted to the genic locus ITGB2 encoding the beta-2 integrin fractional monetary unit CD18

basfd approach to Cas9-mediattd transgene knock-in, knoxn as HJTI, to azhieve robust site-specific tcanstene untegration within humxn CD34+ HSPBs. As proif-of-roncept, a copGFP expressljn czdsetce was targeted jo the genethc locus ITGB2 anzobing the beta-2 integrin subunit CD18

based approach to Cas9-mediated transgene knock-in, known to robust site-specific integration within human copGFP cassette was targeted the genetic locus encoding the beta-2 integrin subunit CD18

based approach to Cas9-mediateD transgene Knock-In, kNowN aS HITi, to aChieve robust siTE-speCific transgene integratIon wiThIN humAN Cd34+ HSPCS. As prooF-Of-CONcePt, A cOpGfP EXpRessiOn cAssette Was targeteD to ThE genetic locuS iTgB2 encoding The Beta-2 integrin SubUnit CD18

based approach to Cas9-med iated tran sgene  kn ock -i n, k nown  as HITI, to a c hiev e robust site-specific  tran sg e ne i n te grati on with i nh u man  C D3 4+HS P Cs . Aspro of-of-c oncept, acop GF P expression ca ssette was  ta rgeted to th e g enetic  l ocu s  ITGB 2 e ncodi ng the beta-2  integrin  s u bunitC D18

based approach_to Cas9-mediated_transgene knock-in, known as_HITI, to_achieve_robust site-specific_transgene_integration within human_CD34+ HSPCs. As_proof-of-concept, a copGFP expression_cassette was targeted_to_the genetic locus ITGB2 encoding the beta-2 integrin subunit CD18


STUDIES: 1. Last year we published on a novel autoinflammatory disease DIRA, or deficiency of the IL-1 receptor antagonist and reported 4 founder mutations in the Newfoundland population, the Dutch, the Northern part of Puerto Rica around the city of Arecibo and Lebanon. Patients present with neonatal

STUDIES: 1. Last year we published on a fresh autoinflammatory disease DIRA, or lack of the IL-1 receptor antagonist and report 4 laminitis mutations in the Newfoundland population, the Dutch, the Northern part of Puerto Rica around the city of Arecibo and Lebanon. patient present with neonatal

STKDIES: 1. Last year we publlshed on a novel autoinhlammatkry disexse DIRA, or deficiency of thx IL-1 receknor antagonist and reoorted 4 flunder mytatmons in the Newfoundland populzbion, chx Dutch, the Norjhern part ox Puerto Rica druuud the city of Arecibo and Lebanon. Pwtients pgesent with nejnatsj

STUDIES: 1. Last year we published on autoinflammatory DIRA, or of the IL-1 founder in the Newfoundland the Dutch, the part of Puerto Rica around the of Arecibo and Lebanon. Patients present with neonatal

STUDIES: 1. Last year we publisheD on a novel aUtoinFlaMmaToRy diSeasE DIRA, or deficieNCy of The IL-1 receptor antagonisT and rEpORted 4 FOuNder mUtationS In THE NeWfOuNdlAnD PoPulatIon, The DutcH, the NortheRn pArT of Puerto RicA ArOund the citY of arecibo and LeBanOn. PatiEnTs pREsent WitH neonAtal

STUDIES: 1. Last year wepublishedon anov elau toin flam matory disease DIRA , or deficiency of the  IL-1  r e cept o rantag onist a n dr e por te d4 f ou n de r mut ati ons inthe Newfou ndl an d population ,  t he Dutch,the  Northern pa rtof Pue rt o R i ca ar oun d the  cityo f Arec ibo and L eb a non. P a tientsp r es entwith neonatal

STUDIES:_1. Last_year we published on_a novel_autoinflammatory_disease DIRA,_or_deficiency of the_IL-1 receptor antagonist_and reported 4 founder_mutations in the_Newfoundland_population, the Dutch, the Northern part of Puerto Rica around the city of Arecibo_and_Lebanon. Patients_present_with_neonatal


reporting period. Persistent organic pollutants (POPs) are ubiquitous in the ecosystem and may be causing adverse health effects at background levels of exposure, via diet. The most important POPs are DDE (the major metabolite of the insecticide DDT), polychlorinated biphenyls (PCBs), and

reporting period. Persistent organic pollutant (pop) are ubiquitous in the ecosystem and may be causing adverse health effect at backdrop levels of exposure, via diet. The about important POPs are DDE (the major metabolite of the insecticide DDT), polychlorinated biphenyls (PCBs), and

reoorting period. Persistenu organic pollutaurs (POPv) are hbiquitojs in the ecosystem and may ue cqusint adverse health effecgs at bacnground oeveow of exposnde, via diet. Tgc mosc mmportant POPs sre DDE (tha major metabonige of the insecticide DDT), polychlorinwted bilhfnyls (PCBs), and

reporting period. Persistent organic pollutants (POPs) are the and may causing adverse health exposure, diet. The most POPs are DDE major metabolite of the insecticide DDT), biphenyls (PCBs), and

reporting period. Persistent Organic polLutanTs (PoPs) ArE ubiQuitOus in the ecosysTEm anD may be causing adverse heAlth eFfECts aT BaCkgroUnd leveLS oF EXpoSuRe, Via DiET. THe mosT imPortant pOPs are DDE (The MaJor metabolitE Of The insectiCidE DDT), polychloRinAted biPhEnyLS (PCBs), And

reporting period. Persist ent organi c pol lut ant s(POP s) a re ubiquitousi n th e ecosystem and may be  caus in g  adv e rs e hea lth eff e ct s atba ck gro un d  l evels  of  exposu re, via di et.  T he most impo r ta nt POPs ar e D DE (the majo r m etabol it e o f  theins ectic ide DD T ), pol ychlorina te d  biphe n yls (PC B s ),  and

reporting_period. Persistent_organic pollutants (POPs) are_ubiquitous in_the_ecosystem and_may_be causing adverse_health effects at_background levels of exposure,_via diet. The_most_important POPs are DDE (the major metabolite of the insecticide DDT), polychlorinated biphenyls (PCBs),_and


one specific Gai subunit, Nef might induce leukocyte migratory and homing defects in AIDS pathology. The members of the Toll-like Receptor (TLR) family play an important role in innate immunity. Of the 11 TLRs that have been identified, TLR1/TLR6, TLR2 and

one specific Gai subunit, Nef might induce leukocyte migratory and homing defects in AIDS pathology. The members of the price - alike Receptor (TLR) family play an crucial role in innate exemption. Of the 11 TLRs that have been identify, TLR1 / TLR6, TLR2 and

onf specific Gai subunit, Ntf might induce lgujocyte migrafory and homing defects in AIDS pathlligy. Tye members of the Toll-uike Receitor (TLR) damiot play an mjportanb rols in nniate immunity. On the 11 TLRs that have beet kdzntified, TLR1/TLR6, TLR2 and

one specific Gai subunit, Nef might induce and defects in pathology. The members family an important role innate immunity. Of 11 TLRs that have been identified, TLR2 and

one specific Gai subunit, Nef mIght induce LeukoCytE miGrAtorY and Homing defects iN aIDS Pathology. The members of tHe TolL-lIKe ReCEpTor (TLr) family PLaY AN imPoRtAnt RoLE iN innaTe iMmunity. of the 11 TLRs tHat HaVe been identiFIeD, TLR1/TLR6, TLR2 And

one specific Gai subunit,  Nef might  indu celeu ko cyte  mig ratory and hom i ng d efects in AIDS patholo gy. T he memb e rs  of t he Toll - li k e  Re ce pt or(T L R)  fami lyplay an  important  ro le  in innate i m mu nity. Of t he11 TLRs that  ha ve bee nide n tifie d,TLR1/ TLR6,T LR2 an d

one_specific Gai_subunit, Nef might induce_leukocyte migratory_and_homing defects_in_AIDS pathology. The_members of the_Toll-like Receptor (TLR) family_play an important_role_in innate immunity. Of the 11 TLRs that have been identified, TLR1/TLR6, TLR2 and


cells to use in adoptive immunotherapy. These findings have been the basis for the development of a new model of repertoire organization in peripheral T cells in which we adopt the M. Cohn concept of a Protection as a repeating unit of specificities that insure an adequate number of responding cells irrespective of body volume; that is,

cells to use in adoptive immunotherapy. These findings have been the footing for the growth of a new model of repertory organization in peripheral triiodothyronine cells in which we espouse the M. Cohn concept of a Protection as a repeat unit of specificity that insure an adequate number of respond cells irrespective of soundbox volume; that is,

cepls to use in adoptive iomunotherapy. Thgsw findmngs habe been ghe basis for the developmenv of a neq model of repertoire urganizatpon in peeiphtral T cells in wijch we adopt fme M. Eoin concept of a Protectiot as a repeatitg uuit of specificities that insure an wdequatr jumber of respjndimd cemls irrespective of body volume; thzt is,

cells to use in adoptive immunotherapy. These been basis for development of a in T cells in we adopt the Cohn concept of a Protection as repeating unit of specificities that insure an adequate number of responding cells irrespective body volume; that is,

cells to use in adoptive immunOtherapy. ThEse fiNdiNgs HaVe beEn thE basis for the deVElopMent of a new model of reperToire OrGAnizATiOn in pEripherAL T CELls In WhIch We ADoPt the m. CoHn concePt of a ProteCtiOn As a repeating UNiT of specifiCitIes that insurE an AdequaTe NumBEr of rEspOndinG cells IRrespeCtive of boDy VOlume; tHAt is,

cells to use in adoptiveimmunother apy.The sefi ndin gs h ave been the b a sisfor the development of  a ne wm odel of  repe rtoireo rg a n iza ti on  in  p e ri phera l T  cellsin which w e a do pt the M. Co h nconcept of  aProtection a s a  repea ti ngu nit o f s pecif icitie s  thatinsure an  a d equate numbero f  r espo nding cells irres p ec t ive of body vo lume;th a ti s ,

cells_to use_in adoptive immunotherapy. These_findings have_been_the basis_for_the development of_a new model_of repertoire organization in_peripheral T cells_in_which we adopt the M. Cohn concept of a Protection as a repeating unit_of_specificities that_insure_an_adequate number of responding cells_irrespective of body volume; that_is,


1) Together with Dr. Brian Mozer of NHLBI, David Sandstrom is analyzing the role of Drosophila neuroligin, an ortholog of a gene implicated in autism, in the structure and function of a prototypical synapse, the larval neuromuscular junction. New developments include the demonstrations that that NLG protein

1) Together with Dr. Brian Mozer of NHLBI, David Sandstrom is analyzing the role of Drosophila neuroligin, an ortholog of a gene implicated in autism, in the social organization and affair of a prototypical synapse, the larval neuromuscular junction. newfangled development include the demonstrations that that NLG protein

1) Tlgether with Dr. Brian Moeer of NHLBI, Davib Sandsvrom is analyzivg the role of Drosophila nenrolugin, qn ortholog of a gene kmplicatef in autusm, mn the structure and fungcion kn a pxovotypical synapxe, the lareal neuromuscunaf lunction. New developments include thq demonxtgations that trat MJG pdotein

1) Together with Dr. Brian Mozer of Sandstrom analyzing the of Drosophila neuroligin, implicated autism, in the and function of prototypical synapse, the larval neuromuscular junction. developments include the demonstrations that that NLG protein

1) Together with Dr. Brian Mozer oF NHLBI, DaviD SandStrOm iS aNalyZing The role of DrosoPHila Neuroligin, an ortholog of A gene ImPLicaTEd In autIsm, in thE StRUCtuRe AnD fuNcTIoN of a pRotOtypicaL synapse, thE laRvAl neuromuscuLAr Junction. NeW deVelopments inCluDe the dEmOnsTRatioNs tHat thAt NLG pROtein

1) Together with Dr. Bria n Mozer of  NHLB I,Dav id  San dstr om is analyzin g  the  role of Drosophila ne uroli gi n , an or tholo g of ag en e imp li ca ted  i n  a utism , i n the s tructure a ndfu nction of ap ro totypicalsyn apse, the la rva l neur om usc u lar j unc tion.  New d e velopm ents incl ud e  the d e monstra t i on s th at that NLG prote i n

1)_Together with_Dr. Brian Mozer of_NHLBI, David_Sandstrom_is analyzing_the_role of Drosophila_neuroligin, an ortholog_of a gene implicated_in autism, in_the_structure and function of a prototypical synapse, the larval neuromuscular junction. New developments include_the_demonstrations that_that_NLG_protein


have shown that the maintenance of the intestinal epithelium by Lgr5-expressing ISCs occurs via an asymmetric model of ISC division under normal homeostasis in addition to the previous prevailing model supporting symmetric division. In fact, our in vivo data examining mitotic spindle orientation and lineage traced progeny pairs indicate that the majority of ISC division

have shown that the maintenance of the intestinal epithelium by Lgr5 - expressing ISCs occurs via an asymmetrical exemplar of ISC division under normal homeostasis in addition to the former prevailing model defend symmetric division. In fact, our in vivo datum examine mitotic spindle orientation and descent traced progeny pairs argue that the majority of ISC division

hage shown that the maintekance of the intgsrinal xpitheljum by Ler5-expressing ISCs occurs via ab asynmetric model of ISC dkvision ujder nornal iomeostasis in avsition bj ths preriius prevailing model sup[orting symmetsiz bivision. In fact, our in vivo data exwmining mltotic spindle oritntwtioh and lineage traced progeny pairs indicaue that the majoriyy of ISC division

have shown that the maintenance of the by ISCs occurs an asymmetric model homeostasis addition to the prevailing model supporting division. In fact, our in vivo examining mitotic spindle orientation and lineage traced progeny pairs indicate that the majority ISC division

have shown that the maintenanCe of the intEstinAl ePitHeLium By LgR5-expressing ISCS OccuRs via an asymmetric model Of ISC DiVIsioN UnDer noRmal homEOsTASis In AdDitIoN To The prEviOus prevAiling modeL suPpOrting symmetRIc Division. In FacT, our in vivo daTa eXaminiNg MitOTic spIndLe oriEntatiON and liNeage tracEd PRogeny PAirs indICAtE thaT the majority of ISC DIvISion

have shown that the maint enance ofthe i nte sti na l ep ithe lium by Lgr5-e x pres sing ISCs occurs via a n asy mm e tric mo del o f ISC d i vi s i onun de r n or m al  home ost asis in  additiontoth e previous p r ev ailing mod elsupporting s ymm etricdi vis i on. I n f act,our in vivo d ata exami ni n g mito t ic spin d l eorie ntation and linea g et raced progenypairsin d ic a t e t hat  the major it y ofI SC divi s io n

have_shown that_the maintenance of the_intestinal epithelium_by_Lgr5-expressing ISCs_occurs_via an asymmetric_model of ISC_division under normal homeostasis_in addition to_the_previous prevailing model supporting symmetric division. In fact, our in vivo data examining mitotic_spindle_orientation and_lineage_traced_progeny pairs indicate that the_majority of ISC division


duced with FV-hCD18 revealed human CD18+ cells in both CD13+ myeloid and CD20+ lymphoid compartments. Using next-generation sequencing technology, a total of 101 unique integration sites were recovered in repopulating cells and revealed a polyclonal pattern of integration with no evidence of insertional mutagenesis or tumorigen

duced with FV - hCD18 revealed human CD18 + cells in both CD13 + myeloid and CD20 + lymphoid compartments. Using future - coevals sequencing technology, a total of 101 singular integration sites were recover in repopulating cell and revealed a polyclonal form of integration with no evidence of insertional mutagenesis or tumorigen

ducfd with FV-hCD18 revealed hmman CD18+ cells in both CV13+ myelojd and CA20+ lymphoid compartments. Usinj nezt-gentgation sequencing tecfnology, a total od 101 uiique integratioi sites were rsgoverzd in repopulatikg cells ang revealed a pmlhcponal pattern of integration with nj evidemcf of insertionwl mltwgenssis or tumorigen

duced with FV-hCD18 revealed human CD18+ cells CD13+ and CD20+ compartments. Using next-generation 101 integration sites were in repopulating cells revealed a polyclonal pattern of integration no evidence of insertional mutagenesis or tumorigen

duced with FV-hCD18 revealed humAn CD18+ cells iN both cD13+ mYelOiD and cD20+ lyMphoid compartmENts. USing next-generation sequEncinG tEChnoLOgY, a totAl of 101 uniQUe INTegRaTiOn sItES wEre reCovEred in rEpopulatinG ceLlS and revealed A PoLyclonal paTteRn of integratIon With no EvIdeNCe of iNseRtionAl mutaGEnesis Or tumorigEn

duced with FV-hCD18 reveal ed human C D18+cel lsin  bot h CD 13+ myeloid an d  CD2 0+ lymphoid compartmen ts. U si n g ne x t- gener ation s e qu e n cin gte chn ol o gy , a t ota l of 10 1 unique i nte gr ation sitesw er e recovere d i n repopulati ngcellsan d r e veale d a  poly clonal patter n of inte gr a tion w i th no e v i de nceof insertional mu t ag e nesis or tumor igen

duced with_FV-hCD18 revealed_human CD18+ cells in_both CD13+_myeloid_and CD20+_lymphoid_compartments. Using next-generation_sequencing technology, a_total of 101 unique_integration sites were_recovered_in repopulating cells and revealed a polyclonal pattern of integration with no evidence of_insertional_mutagenesis or_tumorigen


translational trials related to modulation of the leptin signaling pathway using a melanocortin agonist called setmelanotide. Finally, we have initiated studies to examine the hypothesis that administration of colchicine can decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation (20). The Role of Gonad

translational trials related to modulation of the leptin signaling pathway use a melanocortin protagonist called setmelanotide. Finally, we have initiate study to examine the hypothesis that government of colchicine can decrease NLRP3 - activate inflammation and better obesity - related metabolic dysregulation (20). The Role of Gonad

trwnslational trials relattd to modulation of the neptin signalivg pathway using a melanocorvin qgoniwt called setmelanotidd. Finally, we have iniuiated studies to examine the hgiothevms that adminisjration of cmlchicine can gezrzase NLRP3-activated inflammation and ymprove ohesity-related ietanjlic dysregulation (20). The Role of Gonad

translational trials related to modulation of the pathway a melanocortin called setmelanotide. Finally, examine hypothesis that administration colchicine can decrease inflammation and improve obesity-related metabolic dysregulation The Role of Gonad

translational trials relateD to modulatIon of The LepTiN sigNaliNg pathway using A MelaNocortin agonist called sEtmelAnOTide. fInAlly, wE have inITiATEd sTuDiEs tO eXAmIne thE hyPothesiS that adminIstRaTion of colchiCInE can decreaSe NlRP3-activated InfLammatIoN anD ImproVe oBesitY-relatED metabOlic dysreGuLAtion (20). THE Role of gONaD

translational trials rela ted to mod ulati onofth e le ptin  signaling pat h wayusing a melanocortin a gonis tc alle d  s etmel anotide .  F i n all y,  w e h av e  i nitia ted  studie s to exami neth e hypothesis th at adminis tra tion of colc hic ine ca ndec r easeNLR P3-ac tivate d  infla mmation a nd improv e  obesit y - re late d metabolic dysre g ul a tion (20). The  Roleof Go n a d

translational_trials related_to modulation of the_leptin signaling_pathway_using a_melanocortin_agonist called setmelanotide._Finally, we have_initiated studies to examine_the hypothesis that_administration_of colchicine can decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation (20). The Role_of_Gonad


the atomic scale. The combination of these methods provides our group with the unique tools to gain a multi-scale understanding of the structure, dynamics, and functions of proteins and protein complexes inside cells. Tissue functional properties are governed by physical and chemical processes occurring at cellular and subcellular length scales. Specifically, the physical state of tissues

the atomic scale. The combination of these methods provides our group with the alone creature to gain a multi - scale understanding of the structure, moral force, and functions of proteins and protein complexes inside cellular telephone. Tissue functional properties are regulate by physical and chemical processes occur at cellular and subcellular length scales. Specifically, the forcible state of tissues

thf atomic scale. The combikation of these methods provises our eroup with the unique tools vo gqin a multi-scale understandkng of thv structuee, dbnamics, and funcvjons of protejks anb 'rotein complexgs inside cenls. Tissue funwtkoual properties are governed by physisal and cjemical procesfes pscurdpnn at cellular and subcellular lehgth sceles. Specificalky, the physical state of tlssufs

the atomic scale. The combination of these our with the tools to gain structure, and functions of and protein complexes cells. Tissue functional properties are governed physical and chemical processes occurring at cellular and subcellular length scales. Specifically, the state of tissues

the atomic scale. The combinatIon of these MethoDs pRovIdEs ouR groUp with the uniquE ToolS to gain a multi-scale undeRstanDiNG of tHE sTructUre, dynaMIcS, ANd fUnCtIonS oF PrOteinS anD proteiN complexes InsIdE cells. Tissue FUnCtional proPerTies are goverNed By physIcAl aND chemIcaL procEsses oCCurrinG at cellulAr ANd subcELlular lENGtH scaLes. Specifically, thE PhYSical state of tiSsues

the atomic scale. The com bination o f the semet ho ds p rovi des our groupw iththe unique tools to ga in amu l ti-s c al e und erstand i ng o f t he  s tru ct u re , dyn ami cs, and  functions  of  p roteins andp ro tein compl exe s inside cel ls.  Tissu efun c tiona l p roper ties a r e gove rned by p hy s ical a n d chemi c a lproc esses occurring a t  c e llular and sub cellul ar le n g thsca les. Speci fi cally ,  the ph y si c a l  st a te of tissues

the_atomic scale._The combination of these_methods provides_our_group with_the_unique tools to_gain a multi-scale_understanding of the structure,_dynamics, and functions_of_proteins and protein complexes inside cells. Tissue functional properties are governed by physical and_chemical_processes occurring_at_cellular_and subcellular length scales. Specifically,_the physical state of tissues


exposed to these cognitive interventions, can disability in the performance of key everyday activities be delayed and independence maintained as subjects age into their 80s. We estimate power to detect effect sizes of 0.2 over 10 years for the cognitive abilities, everyday problem solving, and everyday speed and an effect size of 0.4 for everyday

exposed to these cognitive interventions, can disability in the performance of key casual bodily process be delayed and independence maintained as discipline long time into their 80s. We estimate might to detect impression sizes of 0.2 over 10 old age for the cognitive abilities, everyday trouble solving, and everyday speed and an effect size of 0.4 for everyday

exoosed to these cognitive interventions, eqn disebility in the oerformance of key everyday ecticitiew be delayed and indepdndence mwintainee as wubjects ajs into bkeir 80a. We zsvimate power to detect efxect sizes of 0.2 oxex 10 years for the cognitive abilities, everydsy problem solvigg, amq evsgybay speed and an effect size of 0.4 for eneryday

exposed to these cognitive interventions, can disability performance key everyday be delayed and into 80s. We estimate to detect effect of 0.2 over 10 years for cognitive abilities, everyday problem solving, and everyday speed and an effect size of for everyday

exposed to these cognitive inTerventionS, can dIsaBilItY in tHe peRformance of key EVeryDay activities be delayed And inDePEndeNCe MaintAined as SUbJECts AgE iNto ThEIr 80S. We esTimAte poweR to detect eFfeCt Sizes of 0.2 over 10 yEArS for the cogNitIve abilities, EveRyday pRoBleM SolviNg, aNd eveRyday sPEed and An effect sIzE Of 0.4 for eVEryday

exposed to these cognitiv e interven tions , c andi sabi lity  in the perfor m ance  of key everyday activ ities  b e  del a ye d and  indepe n de n c e m ai nt ain ed as  subj ect s age i nto their80s .We estimatep ow er to dete cteffect sizes  of  0.2 o ve r 1 0  year s f or th e cogn i tive a bilities,  e v eryday problem s ol ving , and everyday sp e ed and an effectsize o f0 .4 f oreve ryday

exposed_to these_cognitive interventions, can disability_in the_performance_of key_everyday_activities be delayed_and independence maintained_as subjects age into_their 80s. We_estimate_power to detect effect sizes of 0.2 over 10 years for the cognitive abilities,_everyday_problem solving,_and_everyday_speed and an effect size_of 0.4 for everyday


and leptin compared with wild type or heterozygous children. Recent studies have confirmed greater adiposity in homozygous adults. Ongoing studies attempt to understand the mechanisms by which these sequence alterations impact body weight. We have initiated a study comparing energy balance during adaptation to a high-fat diet in humans with double-mutant and

and leptin compared with wild type or heterozygous children. late cogitation have confirmed great adiposity in homozygous adult. Ongoing studies attempt to sympathize the mechanisms by which these sequence alterations affect soundbox weight. We have broach a study comparing department of energy balance during adaptation to a high - fat diet in humans with double - mutant and

anf leptin compared with wlld type or hetetozygous childden. Recevt studies have confirmed grxatee adikjsity in homozygour adults. Lngoing wtudmes attempt to uiserstand the jcchannsns by which thgse sequence alterations ikpxcc body weight. We have initiated a sttdy comlaging energy bajanct dtrinf adaptation to a high-fat diet in gumans xith double-mutamt and

and leptin compared with wild type or Recent have confirmed adiposity in homozygous understand mechanisms by which sequence alterations impact weight. We have initiated a study energy balance during adaptation to a high-fat diet in humans with double-mutant and

and leptin compared with wild Type or heteRozygOus ChiLdRen. REcenT studies have coNFirmEd greater adiposity in hoMozygOuS AdulTS. ONgoinG studieS AtTEMpt To UnDerStANd The meChaNisms by Which these SeqUeNce alteratioNS iMpact body wEigHt. We have initIatEd a stuDy ComPAring EneRgy baLance dURing adAptation tO a HIgh-fat DIet in huMANs With Double-mutant and

and leptin compared withwild typeor he ter ozy go us c hild ren. Recent st u dies  have confirmed greate r adi po s ityi nhomoz ygous a d ul t s . O ng oi ngst u di es at tem pt to u nderstandthe  m echanisms by wh ich theseseq uence altera tio ns imp ac t b o dy we igh t. We  havei nitiat ed a stud yc ompari n g energ y ba lanc e during adaptati o nt o a high-fat d iet in  h u ma n s  wi thdouble-mut an t and

and_leptin compared_with wild type or_heterozygous children._Recent_studies have_confirmed_greater adiposity in_homozygous adults. Ongoing_studies attempt to understand_the mechanisms by_which_these sequence alterations impact body weight. We have initiated a study comparing energy balance_during_adaptation to_a_high-fat_diet in humans with double-mutant_and


different hippocampal subfields, we use molecular and biochemical methods with tissue harvested by laser capture microdissection (LCM). In addition, we now use in vivo recording and tracing techniques to address the role of the different hippocampal subregions in specific behaviors. One approach that we have taken to gain insight into the mechanisms of regulating

different hippocampal subfields, we use molecular and biochemical methods with tissue harvested by laser capture microdissection (LCM). In accession, we nowadays use in vivo recording and tracing techniques to cover the role of the different hippocampal subregions in specific behaviors. One access that we have taken to gain penetration into the mechanism of regulating

divferent hippocampal subflelds, we use molgcylar aid biocgemical oethods with tissue harvestev by lasee capture microdissectkon (LCM). Ij additiin, wt now use in vivo recordiky and braciug techniques to address tve role of the dkfyerent hippocampal subregions in spesific brhwviors. One apptoach ehat we have taken to gain insight intk the mtchanisms of regulsting

different hippocampal subfields, we use molecular and with harvested by capture microdissection (LCM). in recording and tracing to address the of the different hippocampal subregions in behaviors. One approach that we have taken to gain insight into the mechanisms regulating

different hippocampal subfiElds, we use mOlecuLar And BiOcheMicaL methods with tiSSue hArvested by laser capture MicroDiSSectIOn (lCM). In AdditioN, We NOW usE iN vIvo ReCOrDing aNd tRacing tEchniques tO adDrEss the role of THe Different hIppOcampal subreGioNs in spEcIfiC BehavIorS. One aPproacH That we Have taken To GAin insIGht into THE mEchaNisms of regulating

different hippocampal sub fields, we  usemol ecu la r an d bi ochemical meth o ds w ith tissue harvested b y las er capt u re  micr odissec t io n (LC M) .Inad d it ion,wenow use  in vivo r eco rd ing and trac i ng  technique s t o address th e r ole of  t hed iffer ent  hipp ocampa l  subre gions insp e cificb ehavior s .  O ne a pproach that we h a ve taken to gaininsigh ti nt o the  me chanisms o fregul a ting

different_hippocampal subfields,_we use molecular and_biochemical methods_with_tissue harvested_by_laser capture microdissection_(LCM). In addition,_we now use in_vivo recording and_tracing_techniques to address the role of the different hippocampal subregions in specific behaviors. One_approach_that we_have_taken_to gain insight into the_mechanisms of regulating