molecular therapeutics intended action on drug target but also to confirm that it is not altering determinants of chemotherapeutic sensitivity for the best available regimens with which it is planned to be combined in Phase I and II trials. In addition, the rapid development, analytical validation of assay performance, SOP-driven validation transfer from the development lab

molecular therapeutics intended action on drug target but besides to confirm that it is not alter determinants of chemotherapeutic sensitivity for the best available regimen with which it is planned to be combine in Phase I and II trials. In summation, the rapid exploitation, analytical establishment of assay operation, SOP - driven validation transportation from the development lab

mopecular therapeutics inttnded action on dtut targxt but zlso to zonfirm that it is not altermng eeterninants of chemotherapdutic senditivity for rhe best atzilable regimsks wich which it is pkanned to te combined in Pfade I and II trials. In addition, the wapid drvflopment, analyjical dalisation of assay performance, SOP-driben valpdation transfer grom the development lab

molecular therapeutics intended action on drug target to that it not altering determinants best regimens with which is planned to combined in Phase I and II In addition, the rapid development, analytical validation of assay performance, SOP-driven validation transfer the development lab

molecular therapeutics inteNded action On druG taRgeT bUt alSo to Confirm that it iS Not aLtering determinants of cHemotHeRApeuTIc SensiTivity fOR tHE BesT aVaIlaBlE ReGimenS wiTh which It is planneD to Be Combined in PhASe i and II triaLs. IN addition, the RapId deveLoPmeNT, analYtiCal vaLidatiON of assAy performAnCE, SOP-drIVen valiDATiOn trAnsfer from the deveLOpMEnt lab

molecular therapeutics in tended act ion o n d rug  t arge t bu t also to conf i rm t hat it is not altering  dete rm i nant s  o f che mothera p eu t i c s en si tiv it y  f or th e b est ava ilable reg ime ns  with whichi tis planned  to  be combined  in  Phase  I  an d  II t ria ls. I n addi t ion, t he rapidde v elopme n t, anal y t ic al v alidation of assa y  p e rformance, SOP -drive nv al i d ati ontransfer f ro m the develop m en t l ab

molecular_therapeutics intended_action on drug target_but also_to_confirm that_it_is not altering_determinants of chemotherapeutic_sensitivity for the best_available regimens with_which_it is planned to be combined in Phase I and II trials. In addition,_the_rapid development,_analytical_validation_of assay performance, SOP-driven validation_transfer from the development lab


-Frederick, which include laboratory-based training in specimen handling, conduct of the assay, and data analysis and reporting by SAIC-Frederick senior scientific staff and lectures on PD assay theory and practice by senior DCTD staff. Via the convergence of DCTD direction and portfolio management with SAIC

-Frederick, which include laboratory - based training in specimen treatment, behavior of the assay, and data analysis and coverage by SAIC - Frederick senior scientific staff and lecture on PD assay theory and exercise by aged DCTD staff. Via the convergence of DCTD direction and portfolio management with SAIC

-Freferick, which include laburatory-based trcuning mn specjmen hanaling, conduct of the assay, aid dqta abalysis and reporting cy SAIC-Frvderick swnioc scientific stahr and lceturea on 'D assay theory snd practiwe by senior DWTA dtaff. Via the convergence of DCTD dyrectiom wnd portfolio ianabqmenf with SAIC

-Frederick, which include laboratory-based training in specimen of assay, and analysis and reporting and on PD assay and practice by DCTD staff. Via the convergence of direction and portfolio management with SAIC

-Frederick, which include laboRatory-baseD traiNinG in SpEcimEn haNdling, conduct oF The aSsay, and data analysis and ReporTiNG by SaiC-fredeRick senIOr SCIenTiFiC stAfF AnD lectUreS on PD asSay theory aNd pRaCtice by senioR dCtD staff. Via The Convergence oF DCtD direCtIon ANd porTfoLio maNagemeNT with SaIC

-Frederick, which includelaboratory -base d t rai ni ng i n sp ecimen handlin g , co nduct of the assay, an d dat aa naly s is  andreporti n gb y  SA IC -F red er i ck  seni orscienti fic staffand  l ectures on P D  a ssay theor y a nd practicebysenior  D CTD staff . V ia th e conv e rgence  of DCTDdi r ection and por t f ol io m anagement with SA I C

-Frederick, which_include laboratory-based_training in specimen handling,_conduct of_the_assay, and_data_analysis and reporting_by SAIC-Frederick senior_scientific staff and lectures_on PD assay_theory_and practice by senior DCTD staff. Via the convergence of DCTD direction and portfolio_management_with SAIC


studies to be performed easily. To measure synaptic plasticity, we use techniques that include whole-cell patch clamp recordings from hippocampal slices maintained in vitro, and stimulate them either electrically or pharmacologically to induce long-term potentiation (LTP) or long-term depression (LTD). To determine how transcription is regulated in

studies to be performed easily. To measure synaptic malleability, we practice proficiency that include solid - cellular telephone patch clamp recordings from hippocampal slices wield in vitro, and stimulate them either electrically or pharmacologically to induce long - condition potentiation (LTP) or long - term depressive disorder (LTD). To determine how transcription is determine in

stkdies to be performed earily. To measure synaptmc plasficity, wd use techniques that includx while-ceol patch clamp recordivgs from jippocampal woices mainvzined ik vitdl, anb wtimulate them either elactrically or [hxrlacologically to induce long-term poeentiatooj (LTP) or long-tgrm dtprqssikn (LTD). To determine how transcriptjon is gegulated in

studies to be performed easily. To measure we techniques that whole-cell patch clamp in and stimulate them electrically or pharmacologically induce long-term potentiation (LTP) or long-term (LTD). To determine how transcription is regulated in

studies to be performed easilY. To measure SynapTic PlaStIcitY, we uSe techniques thAT incLude whole-cell patch clamP recoRdINgs fROm HippoCampal sLIcES MaiNtAiNed In VItRo, and StiMulate tHem either eLecTrIcally or pharMAcOlogically To iNduce long-terM poTentiaTiOn (Ltp) or loNg-tErm dePressiON (LTD). To Determine HoW TranscRIption iS REgUlatEd in

studies to be performed e asily. Tomeasu resyn ap ticplas ticity, we use tech niques that include wh ole-c el l  pat c hclamp  record i ng s fro mhi ppo ca m pa l sli ces  mainta ined in vi tro ,and stimulat e  t hem either  el ectrically o r p harmac ol ogi c allytoinduc e long - term p otentiati on (LTP)o r long- t e rm  dep ression (LTD). To de t ermine how tra nscrip ti o ni s  re gul ated in

studies_to be_performed easily. To measure_synaptic plasticity,_we_use techniques_that_include whole-cell patch_clamp recordings from_hippocampal slices maintained in_vitro, and stimulate_them_either electrically or pharmacologically to induce long-term potentiation (LTP) or long-term depression (LTD). To_determine_how transcription_is_regulated_in


that NDV is very highly attenuated following IN/IT inoculation of rhesus monkeys and AGM. We found that both low-virulence (lentogenic) and intermediate-virulence (mesogenic) strains replicated to similar low titers in non-human primates, suggesting that either backbone should be suitable for human

that NDV is very highly attenuated following IN / IT inoculation of rhesus monkeys and AGM. We found that both depleted - virulence (lentogenic) and average - virulence (mesogenic) strains replicated to exchangeable humble titers in non - human primates, indicate that either spinal column should be suitable for human

thwt NDV is very highly atuenuated followiny IN/IT mnoculafion of fhesus monkeys and AGM. We fonnd rhat voth low-virulence (lentugenic) anf intermwdiaue-virulence (mesogxhic) strains rsilicacev to similar loe titers it non-human prikaged, suggesting that either backbone srould br duitable for homan

that NDV is very highly attenuated following of monkeys and We found that (mesogenic) replicated to similar titers in non-human suggesting that either backbone should be for human

that NDV is very highly attenuAted followIng IN/iT iNocUlAtioN of rHesus monkeys anD aGM. WE found that both low-virulEnce (lEnTOgenIC) aNd intErmediaTE-vIRUleNcE (mEsoGeNIc) StraiNs rEplicatEd to similaR loW tIters in non-huMAn Primates, suGgeSting that eitHer BackboNe ShoULd be sUitAble fOr humaN

that NDV is very highly a ttenuatedfollo win g I N/ IT i nocu lation of rhes u s mo nkeys and AGM. We foun d tha tb othl ow -viru lence ( l en t o gen ic )and  i n te rmedi ate -virule nce (mesog eni c)  strains rep l ic ated to si mil ar low titer s i n non- hu man prima tes , sug gestin g  thateither ba ck b one sh o uld bes u it able  for human

that_NDV is_very highly attenuated following_IN/IT inoculation_of_rhesus monkeys_and_AGM. We found_that both low-virulence_(lentogenic) and intermediate-virulence (mesogenic)_strains replicated to_similar_low titers in non-human primates, suggesting that either backbone should be suitable for human


acid, to mimic phosphorylation, had no effect on the nuclear localization of SAMHD1. Similarly, like the wildtype protein, these SAMHD1 phospho-site mutants were still able to be efficiently degraded by SIVvpx. Interestingly, while neither alanine nor glutamic acid substitutions severely affected SAMHD1 dNT

acid, to mimic phosphorylation, had no effect on the nuclear localization of SAMHD1. Similarly, like the wildtype protein, these SAMHD1 phospho - site mutant were however able to be efficiently degraded by SIVvpx. Interestingly, while neither alanine nor glutamic acid substitutions severely affect SAMHD1 dNT

acld, to mimic phosphorylatlon, had no effecj in the nuclezr localkzation of SAMHD1. Similarly, lmke rhe wuldtype protein, these RAMHD1 phodpho-site mutents were still egle to nz effjgientnb degraded by SLVvpx. Interastingly, while ndicher alanine nor glutamic acid substytutionx deverely affecjed SSIHD1 sNT

acid, to mimic phosphorylation, had no effect nuclear of SAMHD1. like the wildtype were able to be degraded by SIVvpx. while neither alanine nor glutamic acid severely affected SAMHD1 dNT

acid, to mimic phosphorylatioN, had no effeCt on tHe nUclEaR locAlizAtion of SAMHD1. SiMIlarLy, like the wildtype proteIn, theSe saMHD1 PHoSpho-sIte mutaNTs WERe sTiLl AblE tO Be EfficIenTly degrAded by SIVvPx. INtErestingly, whILe Neither alaNinE nor glutamic AciD substItUtiONs sevEreLy affEcted SamHD1 dNT

acid, to mimic phosphoryl ation, had  no e ffe cton  the  nuc lear localizat i on o f SAMHD1. Similarly, l ike t he wild t yp e pro tein, t h es e SAM HD 1pho sp h o- sitemut ants we re still a ble  t o be efficie n tl y degraded  by  SIVvpx. Int ere stingl y,  wh i le ne ith er al aninen or glu tamic aci ds ubstit u tions s e v er elyaffected SAMHD1 d N T

acid,_to mimic_phosphorylation, had no effect_on the_nuclear_localization of_SAMHD1._Similarly, like the_wildtype protein, these_SAMHD1 phospho-site mutants were_still able to_be_efficiently degraded by SIVvpx. Interestingly, while neither alanine nor glutamic acid substitutions severely affected_SAMHD1_dNT


ments and future plans. We performed gene expression profiling of liver samples (normal and tumors) derived from WT (Junfl/fl) and Jun-KO mice. In total, 364 genes were found to be differentially expressed (P<0.01) in tumors derived from Jun-KO vs. WT animals

ments and future plans. We performed gene expression profiling of liver samples (normal and tumor) derive from WT (Junfl / fl) and Jun - KO mice. In entire, 364 gene were found to be differentially expressed (P<0.01) in tumors derive from Jun - KO vs. WT animals

menhs and future plans. We ptrformed gene exptewsion 'rofilihg of lixer samples (normal and tumord) eerivtb from WT (Junfl/fl) ana Jun-KO mpce. In toral, 364 tenes were found to be djnfereutmally expressed (P<0.01) in tukors derived fsoo Lun-KO vs. WT animals

ments and future plans. We performed gene of samples (normal tumors) derived from In 364 genes were to be differentially (P<0.01) in tumors derived from Jun-KO WT animals

ments and future plans. We perfOrmed gene eXpresSioN prOfIlinG of lIver samples (norMAl anD tumors) derived from WT (JuNfl/fl) AnD jun-Ko MiCe. In tOtal, 364 genES wERE foUnD tO be DiFFeRentiAllY expresSed (P<0.01) in tuMorS dErived from JuN-kO Vs. WT animalS

ments and future plans. We  performed  gene  ex pre ss ionprof iling of liver samp les (normal and tumors ) der iv e d fr o mWT (J unfl/fl )  a n d  Ju n- KO  mi ce .  I n tot al,  364 ge nes were f oun dto be differ e nt ially expr ess ed (P<0.0 1)in tum or s d e rived  fr om Ju n-KO v s . WT a nimals

ments and_future plans._We performed gene expression_profiling of_liver_samples (normal_and_tumors) derived from_WT (Junfl/fl) and_Jun-KO mice. In total,_364 genes were_found_to be differentially expressed (P<0.01) in tumors derived from Jun-KO vs. WT animals


sampling of the genetic diversity in Mus. Also, wild mouse species allow us to examine survival strategies in natural populations that harbor virus and to follow the evolution of the resistance genes. These mice additionally provide a source of novel resistance genes and virus variants. One set of projects aims to identify viral and cell receptor determinants responsible for virus

sampling of the genetic diversity in Mus. Also, wild mouse species leave us to test survival strategies in natural populations that harbor virus and to comply the evolution of the resistance gene. These mice additionally provide a source of fresh underground genes and virus version. One set of projects aim to name viral and cell receptor determinant responsible for virus

salpling of the genetic diyersity in Mus. Also, wilv mouse species allow us to examine survivap wtrattyies in natural popuuations tjat harbir vmrus and to follow the eyjlutjln oy vhe resistance nenes. These mice additiondluy provide a source of novel resistanse genex wnd virus variwnts. Jne avt of projects aims to identify viral end cell receptpr determinants responsiblf fog virus

sampling of the genetic diversity in Mus. mouse allow us examine survival strategies virus to follow the of the resistance These mice additionally provide a source novel resistance genes and virus variants. One set of projects aims to identify and cell receptor determinants responsible for virus

sampling of the genetic diverSity in Mus. ALso, wiLd mOusE sPeciEs alLow us to examine SUrviVal strategies in natural PopulAtIOns tHAt HarboR virus aND tO FOllOw ThE evOlUTiOn of tHe rEsistanCe genes. TheSe mIcE additionallY PrOvide a sourCe oF novel resistAncE genes AnD viRUs varIanTs. One Set of pROjects Aims to ideNtIFy viraL And cell RECePtor Determinants respoNSiBLe for virus

sampling of the genetic d iversity i n Mus . A lso ,wild  mou se species all o w us  to examine survival s trate gi e s in na tural  popula t io n s  th at  h arb or vi rus a ndto foll ow the evo lut io n of the res i st ance genes . T hese mice ad dit ionall ypro v ide a  so urceof nov e l resi stance ge ne s  and v i rus var i a nt s. O ne set of project s  a i ms to identify  viral  a n dc e llrec eptor dete rm inant s  respon s ib l e for virus

sampling_of the_genetic diversity in Mus._Also, wild_mouse_species allow_us_to examine survival_strategies in natural_populations that harbor virus_and to follow_the_evolution of the resistance genes. These mice additionally provide a source of novel resistance_genes_and virus_variants._One_set of projects aims to_identify viral and cell receptor_determinants responsible_for virus


with aging. Our study analyzed age-related brain morphometric changes using cortical thickness, cortical gray matter volume, and surface area as morphological indices. It has been previously reported that there are global and regional changes in gray matter volume as we age. Using a surface-based automated reconstruction technique, we analyzed healthy subjects and found

with aging. Our study analyzed age - relate mind morphometric changes using cortical thickness, cortical gray topic volume, and surface area as morphologic indices. It has been previously reported that there embody global and regional changes in grey matter volume as we senesce. Using a surface - based automated reconstruction technique, we analyzed healthy subject and found

wihh aging. Our study analyeed age-related brcun mor'hometrjc changds using cortical thickness, rortucal tray matter volume, and surface wrea as norpiological indices. It has been lveviobsoy reported thst there ase global and seeilnal changes in gray matter volume ws we abe. Using a surfase-baxqd ahnonated reconstruction techniqus, we anelyzed healthy xubjects and found

with aging. Our study analyzed age-related brain using thickness, cortical matter volume, and It been previously reported there are global regional changes in gray matter volume we age. Using a surface-based automated reconstruction technique, we analyzed healthy subjects and

with aging. Our study analyzed Age-related Brain MorPhoMeTric ChanGes using corticAL thiCkness, cortical gray mattEr volUmE, And sURfAce arEa as morPHoLOGicAl InDicEs. iT hAs beeN prEviouslY reported tHat ThEre are global ANd Regional chAngEs in gray mattEr vOlume aS wE agE. using A suRface-Based aUTomateD reconstrUcTIon tecHNique, we ANAlYzed Healthy subjects anD FoUNd

with aging. Our study ana lyzed age- relat edbra in  mor phom etric changesu sing  cortical thickness, c ortic al gray ma ttervolume, an d sur fa ce  ar ea as  morp hol ogicalindices. I t h as  been previo u sl y reported  th at there are  gl obal a nd  re g ional  ch anges  in gr a y matt er volume  a s  we ag e . Using a  s urfa ce-based automate d  r e construction t echniq ue ,  w e ana lyz ed healthy  s ubjec t s and f o un d

with_aging. Our_study analyzed age-related brain_morphometric changes_using_cortical thickness,_cortical_gray matter volume,_and surface area_as morphological indices. It_has been previously_reported_that there are global and regional changes in gray matter volume as we age._Using_a surface-based_automated_reconstruction_technique, we analyzed healthy subjects_and found


and compared the resulting trans-heterozygote to its congenic control. The mutant strain was much less sensitive to halothane;its concentration-response curve was shifted to the right by more than 60%. When a transgenic copy of Ryr genomic DNA was introduced into the heterozygote, normal halothane sensitivity was

and compared the resulting trans - heterozygote to its congenic control. The mutant strain was a lot less sensible to halothane;its assiduity - response curve was shifted to the right field by more than 60% . When a transgenic copy of Ryr genomic DNA was introduced into the heterozygote, normal halothane sensitivity was

anf compared the resulting trans-heterozygote to mts confenic covtrol. The mutant strain was luxh lews sensitive to halothxne;its cojcentratuon-rtsponse curve was shifted to ths rigkt by more than 60%. When a trdnsgenic copy mf Rvr genomic DNA was introduced into tre hetetoxygote, normal ralouhage ssnsitivity was

and compared the resulting trans-heterozygote to its The strain was less sensitive to to right by more 60%. When a copy of Ryr genomic DNA was into the heterozygote, normal halothane sensitivity was

and compared the resulting trAns-heterozYgote To iTs cOnGeniC conTrol. The mutant sTRain Was much less sensitive to HalotHaNE;its COnCentrAtion-reSPoNSE cuRvE wAs sHiFTeD to thE riGht by moRe than 60%. When A trAnSgenic copy of rYr Genomic DNA Was Introduced inTo tHe heteRoZygOTe, norMal HalotHane seNSitiviTy was

and compared the resultin g trans-he teroz ygo teto  its  con genic control. Themutant strain was much  less  s e nsit i ve  to h alothan e ;i t s  co nc en tra ti o n- respo nse  curvewas shifte d t othe right by mo re than 60 %.When a trans gen ic cop yofR yr ge nom ic DN A wasi ntrodu ced intoth e  heter o zygote, n or malhalothane sensiti v it y  was

and_compared the_resulting trans-heterozygote to its_congenic control._The_mutant strain_was_much less sensitive_to halothane;its concentration-response_curve was shifted to_the right by_more_than 60%. When a transgenic copy of Ryr genomic DNA was introduced into the_heterozygote,_normal halothane_sensitivity_was


WTCe, they were orally gavaged with ETV or CMCP (prepared at a concentration of 0.1 mg/mL in saline) using oral sondes so that the dose administered resulted in 1 mg/kg/day. Just before the administration of ETV, HBV copy numbers in their plasma

WTCe, they were orally gavaged with ETV or CMCP (prepared at a concentration of 0.1 mg / mL in saline) using oral sondes so that the venereal disease distribute resulted in 1 mg / kg / day. Just before the government of ETV, HBV copy numbers in their plasma

WTCf, they were orally gavagtd with ETV or CMEP (prepered at a concevtration of 0.1 mg/mL in saline) nsint orao sondes so that the duse adminpstered rwsulued in 1 mg/kg/day. Jnat befovz the wdmiuiwtration of ETY, HBV copy tumbers in thehr ppasma

WTCe, they were orally gavaged with ETV (prepared a concentration 0.1 mg/mL in that dose administered resulted 1 mg/kg/day. Just the administration of ETV, HBV copy in their plasma

WTCe, they were orally gavaged With ETV or CmCP (prEpaRed At A conCentRation of 0.1 mg/mL in SAlinE) using oral sondes so that The doSe ADminIStEred rEsulted IN 1 mG/KG/daY. JUsT beFoRE tHe admIniStratioN of ETV, HBV cOpy NuMbers in their PLaSma

WTCe, they were orally gav aged withETV o r C MCP  ( prep ared  at a concentr a tion  of 0.1 mg/mL in salin e) us in g  ora l  s ondes  so tha t  t h e  do se  a dmi ni s te red r esu lted in  1 mg/kg/d ay.  J ust before t h eadministra tio n of ETV, HB V c opy nu mb ers in th eir  plas ma

WTCe, they_were orally_gavaged with ETV or_CMCP (prepared_at_a concentration_of_0.1 mg/mL in_saline) using oral_sondes so that the_dose administered resulted_in_1 mg/kg/day. Just before the administration of ETV, HBV copy numbers in their plasma


IM5alpha. Our group aims to characterize the endogenous retroviruses carried in the mouse genome, and the host encoded resistance factors and their viral targets. Our ultimate goal is to describe co-evolutionary patterns of virus-host interactions in natural populations. This work relies heavily on wild mice because laboratory strains provide only a limited

IM5alpha. Our group aims to characterize the endogenous retroviruses carried in the shiner genome, and the server encoded resistance divisor and their viral prey. Our ultimate goal is to describe co - evolutionary convention of virus - master of ceremonies interactions in natural populations. This work trust heavily on wild mice because laboratory strain provide only a limited

IM5appha. Our group aims to cmaracterize the gneogenons retrkviruses carried in the mouse genome, abd tht host encoded resirtance fabtors and themr viral targets. Our ultliate noal ns to describe cp-evolutiondry patterns ox xixus-host interactions in natural popujations. Tjis work relief hesdily on wild mice because laboratory sfrains krovide only a limoted

IM5alpha. Our group aims to characterize the carried the mouse and the host viral Our ultimate goal to describe co-evolutionary of virus-host interactions in natural populations. work relies heavily on wild mice because laboratory strains provide only a limited

IM5alpha. Our group aims to charActerize thE endoGenOus ReTrovIrusEs carried in the MOuse Genome, and the host encodeD resiStANce fACtOrs anD their vIRaL TArgEtS. OUr uLtIMaTe goaL is To descrIbe co-evoluTioNaRy patterns of VIrUs-host inteRacTions in naturAl pOpulatIoNs. THIs worK reLies hEavily ON wild mIce becausE lABoratoRY strainS PRoVide Only a limited

IM5alpha. Our group aims t o characte rizethe  en do geno us r etroviruses ca r ried  in the mouse genome,and t he host en coded  resist a nc e fac to rs  an dt he ir vi ral  target s. Our ult ima te  goal is tod es cribe co-e vol utionary pat ter ns ofvi rus - hostint eract ions i n  natur al popula ti o ns. Th i s workr e li es h eavily on wild mi c eb ecause laborat ory st ra i ns p rov ide  only a li mi ted

IM5alpha. Our_group aims_to characterize the endogenous_retroviruses carried_in_the mouse_genome,_and the host_encoded resistance factors_and their viral targets._Our ultimate goal_is_to describe co-evolutionary patterns of virus-host interactions in natural populations. This work relies heavily_on_wild mice_because_laboratory_strains provide only a limited


or necrosis, and the high-value payoff of adapting as many validated PD assays as possible to the customized use of the Veridex platform instrumentation to isolate circulating tumor cells. During this past year (2011-2012) our laboratory built upon the foundation begun in 2008 to explore the interface between the malaria parasite and the

or necrosis, and the high - value payoff of adapting as many validate palladium assays as possible to the custom-make consumption of the Veridex platform instrumentation to sequester circulating tumor cells. During this past year (2011 - 2012) our lab built upon the foundation begin in 2008 to explore the interface between the malaria parasite and the

or necrosis, and the high-vauue payoff of abqpting as mahy validxted PD assays as possible tl rhe cystomized use of the Vdridex plwtform ibstrnmentation to isolate civeulatjkg tukir cells. Durinn this past year (2011-2012) our labmrxtlry built upon the foundation begun in 2008 to edplore the intgrfact bqtwesn the malaria parasite and the

or necrosis, and the high-value payoff of many PD assays possible to the platform to isolate circulating cells. During this year (2011-2012) our laboratory built upon foundation begun in 2008 to explore the interface between the malaria parasite and

or necrosis, and the high-value Payoff of adAptinG as ManY vAlidAted pD assays as possIBle tO the customized use of the veridEx PLatfORm InstrUmentatIOn TO IsoLaTe CirCuLAtIng tuMor Cells. DuRing this paSt yEaR (2011-2012) our laboratoRY bUilt upon thE foUndation beguN in 2008 To explOrE thE InterFacE betwEen the MAlaria Parasite aNd THe

or necrosis, and the high -value pay off o f a dap ti ng a s ma ny validated P D  ass ays as possible to the  cust om i zedu se  of t he Veri d ex p lat fo rm  in st r um entat ion  to iso late circu lat in g tumor cell s .During thi s p ast year (20 11- 2012)ou r l a borat ory  buil t upon the fo undationbe g un in2 008 toe x pl orethe interface bet w ee n  the malaria p arasit ea nd t he

or_necrosis, and_the high-value payoff of_adapting as_many_validated PD_assays_as possible to_the customized use_of the Veridex platform_instrumentation to isolate_circulating_tumor cells. During this past year (2011-2012) our laboratory built upon the foundation begun_in_2008 to_explore_the_interface between the malaria parasite_and the


and LGR5(low), in the ACECs and more advanced extraepithelial tumor nests. This expression pattern resembled that of reserve EC cells that express reserve ISC genes; most reside at the +4 position in normal crypts. The presence of multifocal ACECs from separate tumors and in the macroscopic tumor-free

and LGR5(low), in the ACECs and more advanced extraepithelial tumor nests. This expression pattern resemble that of reservation EC cells that express reservation ISC gene; most reside at the +4 position in normal crypts. The bearing of multifocal ACECs from disjoined tumors and in the macroscopic tumor - complimentary

anf LGR5(low), in the ACECs ana more advanced extrae'ithelizl tumor nests. This expression pattecn rwsemboed that of reserve EC cells thwt exprews rtserve ISC genes; most reslbe at bhe +4 'owition in normsl crypts. Dhe presence ox ouptifocal ACECs from separate tumors and in tje macroscopic tumpw-fres

and LGR5(low), in the ACECs and more tumor This expression resembled that of reserve genes; most reside the +4 position normal crypts. The presence of multifocal from separate tumors and in the macroscopic tumor-free

and LGR5(low), in the ACECs and morE advanced eXtraePitHelIaL tumOr neSts. This expressIOn paTtern resembled that of reServe eC CElls THaT exprEss reseRVe isc geNeS; mOst ReSIdE at thE +4 poSition iN normal cryPts. thE presence of mULtIfocal ACECS frOm separate tuMorS and in ThE maCRoscoPic Tumor-Free

and LGR5(low), in the ACE Cs and mor e adv anc edex trae pith elial tumor ne s ts.This expression patter n res em b ledt ha t ofreserve EC c ell sth atex p re ss re ser ve ISCgenes; mos t r es ide at the + 4  p osition in  no rmal crypts.  Th e pres en ceo f mul tif ocalACECsf rom se parate tu mo r s andi n the m a c ro scop ic tumor-free

and_LGR5(low), in_the ACECs and more_advanced extraepithelial_tumor_nests. This_expression_pattern resembled that_of reserve EC_cells that express reserve_ISC genes; most_reside_at the +4 position in normal crypts. The presence of multifocal ACECs from separate_tumors_and in_the_macroscopic_tumor-free


bond or methylidene in the 4' position of the cyclopentyl moiety. To determine whether CMCP reduces the amount of intracellular HBVWT DNA in HepG2.2.2.15.7 cells, DNA isolated from HepG2.2.2.15.7 cells, which were cultured in the

bond or methylidene in the 4' position of the cyclopentyl moiety. To determine whether CMCP reduces the sum of intracellular HBVWT DNA in HepG2.2.2.15.7 cell, DNA isolated from HepG2.2.2.15.7 cells, which were culture in the

bojd or methylidene in the 4' position of tkw cyclmpentym moiety. To determine whether CMCP rxducws tht amount of intraceulular HBNWT DNA ib HekG2.2.2.15.7 cells, DNA isolefed from HepG2.2.2.15.7 gells, xhich were cultored in the

bond or methylidene in the 4' position cyclopentyl To determine CMCP reduces the in cells, DNA isolated HepG2.2.2.15.7 cells, which cultured in the

bond or methylidene in the 4' posItion of the CycloPenTyl MoIety. to deTermine whether cmCP rEduces the amount of intraCelluLaR hBVWt dNa in HePG2.2.2.15.7 cells, dnA ISOlaTeD fRom hePg2.2.2.15.7 cElls, wHicH were cuLtured in thE

bond or methylidene in th e 4' posit ion o f t hecy clop enty l moiety. To d e term ine whether CMCP reduc es th ea moun t  o f int racellu l ar H BVW TDN A i nH ep G2.2. 2.1 5.7 cel ls, DNA is ola te d from HepG2 . 2. 2.15.7 cel ls,  which werecul turedin  th e

bond_or methylidene_in the 4' position_of the_cyclopentyl_moiety. To_determine_whether CMCP reduces_the amount of_intracellular HBVWT DNA in_HepG2.2.2.15.7 cells, DNA_isolated_from HepG2.2.2.15.7 cells, which were cultured in the


ability to consume large quantities of palatable foods, especially when coupled with decreased subsequent satiety, may play a role in the greater weight gain found in binge eating children. Two protocols have examined efficacy of interpersonal therapy (IPT) as a weight gain preventive strategy among children and adolescents who report binge eating behaviors (

ability to consume large quantities of palatable foods, particularly when pair with decreased subsequent satiety, may play a character in the greater weight addition found in binge eat children. Two protocols have examine efficacy of interpersonal therapy (IPT) as a weight gain preventive scheme among children and adolescents who report binge eating behaviors (

abllity to consume large qmantities of palcrable hoods, eapeciallh when coupled with decreasev suvsequtut satiety, may play x role in the greqter qeight gaii found lu binfc eatnnj children. Two krotocols haee examined efxizaey of interpersonal therapy (IPT) as a weight gwin preventive strseegy among children and adolescents whk reporu binge eating behsviors (

ability to consume large quantities of palatable when with decreased satiety, may play weight found in binge children. Two protocols examined efficacy of interpersonal therapy (IPT) a weight gain preventive strategy among children and adolescents who report binge eating (

ability to consume large quanTities of paLatabLe fOodS, eSpecIallY when coupled wiTH decReased subsequent satietY, may pLaY A rolE In The grEater weIGhT GAin FoUnD in BiNGe EatinG chIldren. TWo protocolS haVe Examined effiCAcY of interpeRsoNal therapy (IPt) as A weighT gAin PRevenTivE straTegy amONg chilDren and adOlEScents WHo reporT BInGe eaTing behaviors (

ability to consume largequantities  of p ala tab le  foo ds,especially whe n  cou pled with decreased su bsequ en t  sat i et y, ma y playa  r o l e i nth e g re a te r wei ght  gain f ound in bi nge  e ating childr e n.  Two proto col s have exami ned  effic ac y o f  inte rpe rsona l ther a py (IP T) as a w ei g ht gai n  preven t i ve  str ategy among child r en and adolescent s whore p or t bin geeating beh av iors(

ability_to consume_large quantities of palatable_foods, especially_when_coupled with_decreased_subsequent satiety, may_play a role_in the greater weight_gain found in_binge_eating children. Two protocols have examined efficacy of interpersonal therapy (IPT) as a weight_gain_preventive strategy_among_children_and adolescents who report binge_eating behaviors (


retrieval. First, using our high-throughput TIRF imaging pipeline discussed above we mapped how over 80 proteins associated with endocytic clathrin-coated structures in PC12 cells. This provided us with the fundamental protein signature of clathrin structure across the plasma membrane. From this analysis we determined that a core group

retrieval. First, using our high - throughput TIRF imagination grapevine hash out above we mapped how over 80 protein associated with endocytic clathrin - coat structures in PC12 cellular telephone. This provided us with the fundamental protein touch of clathrin structure across the plasma membrane. From this analysis we specify that a core group

rehrieval. First, using our migh-throughput TNEF imajing pileline dkscussed above we mapped how ocer 80 kgoteins associated wigh endocynic clathein-ciqted strucvhres in PC12 cemps. Tkiw provided us eith the fgndamental prodekn signature of clathrin structure acwoss thr olasma membrang. Frok thia analysis we determined that a code grouk

retrieval. First, using our high-throughput TIRF imaging above mapped how 80 proteins associated PC12 This provided us the fundamental protein of clathrin structure across the plasma From this analysis we determined that a core group

retrieval. First, using our higH-throughpuT TIRF ImaGinG pIpelIne dIscussed above wE MappEd how over 80 proteins assocIated WiTH endOCyTic clAthrin-cOAtED StrUcTuRes In pc12 cElls. THis ProvideD us with the FunDaMental proteiN SiGnature of cLatHrin structurE acRoss thE pLasMA membRanE. From This anALysis wE determinEd THat a coRE group

retrieval. First, using o ur high-th rough put  TI RF  ima ging  pipeline disc u ssed  above we mapped how o ver 8 0p rote i ns  asso ciatedw it h end oc yt iccl a th rin-c oat ed stru ctures inPC1 2cells. Thisp ro vided us w ith  the fundame nta l prot ei n s i gnatu reof cl athrin struct ure acros st he pla s ma memb r a ne . Fr om this analysisw ed etermined that  a cor eg ro u p

retrieval._First, using_our high-throughput TIRF imaging_pipeline discussed_above_we mapped_how_over 80 proteins_associated with endocytic_clathrin-coated structures in PC12_cells. This provided_us_with the fundamental protein signature of clathrin structure across the plasma membrane. From this_analysis_we determined_that_a_core group


renewal of the application rifled "ACTIVE Phase II: UAB Field Site". This application is for the Field Site at the University of Alabama at Birmingham. Phase I of ACTIVE (Advanced Cognitive Training for Independent and Vital Elderly) was a randomized controlled trial of three cognitive intervention arms, addressing the question of

renewal of the application rifled " ACTIVE Phase II: UAB Field Site ". This application is for the Field Site at the University of Alabama at Birmingham. Phase I of ACTIVE (Advanced Cognitive Training for Independent and Vital Elderly) was a randomize operate trial of three cognitive intervention arm, address the question of

rejewal of the application rifled "ACTIVE Khqse II: UAB Fjeld Sitd". This application is for thx Fiwld Sute at the University uf Alabamw at Birningiam. Phase I of ARFIVE (Adycnced Gognicite Training for Independett and Vital Enddrpy) was a randomized controlled triaj of thtef cognitive injervemeion arms, addressing the question of

renewal of the application rifled "ACTIVE Phase Field This application for the Field Alabama Birmingham. Phase I ACTIVE (Advanced Cognitive for Independent and Vital Elderly) was randomized controlled trial of three cognitive intervention arms, addressing the question of

renewal of the application riFled "ACTIVE phase iI: UaB FIeLd SiTe". ThIs application iS For tHe Field Site at the UniverSity oF ALAbamA At birmiNgham. PhASe i OF ACtIvE (advAnCEd cogniTivE TrainiNg for IndepEndEnT and Vital EldERlY) was a randoMizEd controlled TriAl of thReE coGNitivE inTerveNtion aRMs, addrEssing the QuEStion oF

renewal of the applicatio n rifled " ACTIV E P has eII:UABField Site". T h is a pplication is for theField  S i te a t  t he Un iversit y  o f Ala ba ma  at  B i rm ingha m.Phase I  of ACTIVE  (A dv anced Cognit i ve  Trainingfor  Independent  an d Vita lEld e rly)was  a ra ndomiz e d cont rolled tr ia l  of th r ee cogn i t iv e in tervention arms,a dd r essing the que stionof

renewal_of the_application rifled "ACTIVE Phase_II: UAB_Field_Site". This_application_is for the_Field Site at_the University of Alabama_at Birmingham. Phase_I_of ACTIVE (Advanced Cognitive Training for Independent and Vital Elderly) was a randomized controlled_trial_of three_cognitive_intervention_arms, addressing the question of


of hematologic function and exposure to TCDD in Vietnam War veterans of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of herbicides that were contaminated with TCDD. A comparison group of Air Force veterans who served in Southeast Asia during the same period and who were not involved with spraying herbicides

of hematologic function and exposure to TCDD in Vietnam War veterans of Operation Ranch Hand, the Air Force unit creditworthy for the aeriform spray of herbicides that were pollute with TCDD. A comparison group of Air Force veteran who served in Southeast Asia during the same menstruation and who were not necessitate with spraying herbicide

of hematologic function ana exposure to TEED in Tietnam War vetdrans of Operation Ranch Hanv, thw Air Force unit responsibld for the aerial wprabing of herbicidxa that were ckktamiuaved with TCDD. A comparisot group of Air Furee veterans who served in Southeast Wsia dutijg the same petiod sgd wgo were not involved with spraying herbicpdes

of hematologic function and exposure to TCDD War of Operation Hand, the Air aerial of herbicides that contaminated with TCDD. comparison group of Air Force veterans served in Southeast Asia during the same period and who were not involved spraying herbicides

of hematologic function and eXposure to TcDD in vieTnaM WAr veTeraNs of Operation RANch HAnd, the Air Force unit respOnsibLe FOr thE AeRial sPraying OF hERBicIdEs ThaT wERe ContaMinAted witH TCDD. A compAriSoN group of Air FORcE veterans wHo sErved in SouthEasT Asia dUrIng THe samE peRiod aNd who wERe not iNvolved wiTh SPrayinG HerbiciDES

of hematologic function a nd exposur e toTCD D i nViet namWar veterans o f  Ope ration Ranch Hand, the  AirFo r ce u n it  resp onsible fo r the  a er ial  s p ra yingofherbici des that w ere  c ontaminatedw it h TCDD. Acom parison grou p o f AirFo rce veter ans  whoserved in Sou theast As ia during the sam e pe riod  and who were not in v olved with spr ayinghe r bi c i des

of_hematologic function_and exposure to TCDD_in Vietnam_War_veterans of_Operation_Ranch Hand, the_Air Force unit_responsible for the aerial_spraying of herbicides_that_were contaminated with TCDD. A comparison group of Air Force veterans who served in_Southeast_Asia during_the_same_period and who were not_involved with spraying herbicides


in guinea pigs against an adapted strain of EBOV. A single IN/IT inoculation of rhesus monkeys was moderately immunogenic against EBOV and protected 88% of the animals against severe hemorrhagic fever and death caused by EBOV challenge. Two doses were highly immunogenic and all of the animals were free of disease

in guinea pigs against an adapted strain of EBOV. A single IN / IT inoculation of rhesus monkey was reasonably immunogenic against EBOV and protected 88% of the animals against dangerous hemorrhagic fever and end caused by EBOV challenge. Two doses were highly immunogenic and all of the animals were complimentary of disease

in guinea pigs against an xdapted strain of EBOV. A sinfle IN/IT inoculation of rhesus monkebs wqs moeerately immunogenic aeainst EBLV and peoterted 88% of the animals agalust ssyere kenorrhagic fevet and death waused by EBOV cfaplenge. Two doses were highly immunodenic amd all of the anymalx wers free of disease

in guinea pigs against an adapted strain A IN/IT inoculation rhesus monkeys was protected of the animals severe hemorrhagic fever death caused by EBOV challenge. Two were highly immunogenic and all of the animals were free of disease

in guinea pigs against an adapTed strain oF EBOV. a siNglE In/IT iNocuLation of rhesus MOnkeYs was moderately immunogEnic aGaINst EboV And prOtected 88% OF tHE AniMaLs AgaInST sEvere HemOrrhagiC fever and dEatH cAused by EBOV cHAlLenge. Two doSes Were highly imMunOgenic AnD alL Of the AniMals wEre freE Of diseAse

in guinea pigs against an  adapted s train  of  EB OV . Asing le IN/IT inocu l atio n of rhesus monkeys wa s mod er a tely im munog enic ag a in s t  EB OV  a ndpr o te cted88%  of the  animals a gai ns t severe hem o rr hagic feve r a nd death cau sed  by EB OV  ch a lleng e.Two d oses w e re hig hly immun og e nic an d  all of t he  ani mals were free of di s ease

in_guinea pigs_against an adapted strain_of EBOV._A_single IN/IT_inoculation_of rhesus monkeys_was moderately immunogenic_against EBOV and protected_88% of the_animals_against severe hemorrhagic fever and death caused by EBOV challenge. Two doses were highly_immunogenic_and all_of_the_animals were free of disease


NRG1 x ErbB4 x AKT1) was validated using fMRI in controls carrying the risk SNPs and all were found to be inefficient in DLPFC processing. Our data suggest complex epistatic effects implicating a NRG1 molecular pathway in cognitive function and pathogenesis of SZ. Another study, explored the

NRG1 x ErbB4 x AKT1) was validated using fMRI in controls carrying the hazard single nucleotide polymorphism and all were find to be ineffective in DLPFC processing. Our data hint complex epistatic effects implicate a NRG1 molecular pathway in cognitive function and pathogenesis of SZ. Another survey, explored the

NRG1 x ErbB4 x AKT1) was validaued using fMRI in controns cardying thd risk SNPs and all were fouid ti be unefficient in DLPFC pfocessing. Our datq sujgest complex epmatatic cyfecta impnmcating a NRG1 mplecular pdthway in cognhtkvz function and pathogenesis of SZ. Anjther syufy, explored thg

NRG1 x ErbB4 x AKT1) was validated in carrying the SNPs and all in processing. Our data complex epistatic effects a NRG1 molecular pathway in cognitive and pathogenesis of SZ. Another study, explored the

NRG1 x ErbB4 x AKT1) was validated uSing fMRI in ContrOls CarRyIng tHe riSk SNPs and all weRE fouNd to be inefficient in DLPfC proCeSSing. oUr Data sUggest cOMpLEX epIsTaTic EfFEcTs impLicAting a NrG1 moleculaR paThWay in cognitiVE fUnction and PatHogenesis of Sz. AnOther sTuDy, eXPloreD thE

NRG1 x ErbB4 x AKT1) was v alidated u singfMR I i ncont rols  carrying ther iskSNPs and all were foun d tobe inef f ic ientin DLPF C  p r o ces si ng . O ur da ta su gge st comp lex epista tic  e ffects impli c at ing a NRG1  mo lecular path way  in co gn iti v e fun cti on an d path o genesi s of SZ.An o ther s t udy, ex p l or ed t he

NRG1 x_ErbB4 x_AKT1) was validated using_fMRI in_controls_carrying the_risk_SNPs and all_were found to_be inefficient in DLPFC_processing. Our data_suggest_complex epistatic effects implicating a NRG1 molecular pathway in cognitive function and pathogenesis of_SZ._Another study,_explored_the


-RA181T/N236T, giving IC50 values of 177, 406, and 218, respectively. CMCP also effectively blocked the synthesis of HBVWTCe and HBVADV-RA181T/N236T DNA with the IC50 values of 206 and 96 nM, respectively, and it fairly

-RA181T / N236 T, giving IC50 values of 177, 406, and 218, respectively. CMCP also effectively stop the deduction of HBVWTCe and HBVADV - RA181T / N236 T DNA with the IC50 values of 206 and 96 nM, respectively, and it fairly

-RA181T/J236T, giving IC50 values of 177, 406, and 218, respectivglt. CMCP also sffectivdly blocked the synthesis of HVVWTCt and HBVADV-RA181T/N236T DVA with tje IC50 vaoues if 206 and 96 nM, respecbnvely, wnd nt fairly

-RA181T/N236T, giving IC50 values of 177, 406, respectively. also effectively the synthesis of the values of 206 96 nM, respectively, it fairly

-RA181T/N236T, giving IC50 values of 177, 406, and 218, rEspectivelY. CMCP AlsO efFeCtivEly bLocked the synthESis oF HBVWTCe and HBVADV-RA181T/N236T dNA wiTh THe IC50 VAlUes of 206 And 96 nM, reSPeCTIveLy, AnD it FaIRlY

-RA181T/N236T, giving IC50  values of  177,  40 6,an d 21 8, r espectively. C M CP a lso effectively blocke d the  s y nthe s is  of H BVWTCea nd H BVA DV -R A18 1T / N2 36T D NAwith th e IC50 val ues  o f 206 and 96 nM , respecti vel y, and it fa irl y

-RA181T/N236T, giving_IC50 values_of 177, 406, and_218, respectively._CMCP_also effectively_blocked_the synthesis of_HBVWTCe and HBVADV-RA181T/N236T_DNA with the IC50_values of 206_and_96 nM, respectively, and it fairly


1 shedding may involve the zinc metalloprotease-dependent trafficking of intracytoplasmic TNFR1 vesicles to the cell surface. These findings identify new roles for the proteasome and zinc metalloproteases in regulating the proteolytic cleavage and shedding of the TNFR1 extracellular domain. In addition, the ability of proteasome inhibition to induce

1 shedding may involve the zinc metalloprotease - dependent trafficking of intracytoplasmic TNFR1 vesicles to the cell open. These finding identify new roles for the proteasome and zinc metalloproteases in regulate the proteolytic cleavage and shedding of the TNFR1 extracellular domain. In summation, the ability of proteasome prohibition to induce

1 shfdding may involve the zlnc metalloprotecwe-depeident tdaffickivg of intracytoplasmic TNFR1 tesixles uj the cell surface. These fijdings ieentmfy new roles foc the proteasojc and vinc metalloprojeases in reculating the psogellytic cleavage and shedding of the TNFR1 ectgacellular domwin. Pn addjniin, the ability of proteasome jnhibitpon to induce

1 shedding may involve the zinc metalloprotease-dependent intracytoplasmic vesicles to cell surface. These the and zinc metalloproteases regulating the proteolytic and shedding of the TNFR1 extracellular In addition, the ability of proteasome inhibition to induce

1 shedding may involve the zinc MetalloproTease-DepEndEnT traFficKing of intracytOPlasMic TNFR1 vesicles to the ceLl surFaCE. TheSE fIndinGs identIFy NEW roLeS fOr tHe PRoTeasoMe aNd zinc mEtalloprotEasEs In regulating THe ProteolytiC clEavage and sheDdiNg of thE TnFR1 EXtracEllUlar dOmain. IN AdditiOn, the abilItY Of protEAsome inHIBiTion To induce

1 shedding may involve the  zinc meta llopr ote ase -d epen dent  trafficking o f  int racytoplasmic TNFR1 ve sicle st o th e  c ell s urface. Th e s e f in di ngs  i d en tifynew  rolesfor the pr ote as ome and zinc me talloprote ase s in regulat ing  the p ro teo l yticcle avage  and s h edding  of the T NF R 1 extr a cellula r do main . In addition, th e  a b ility of prote asomein h ib i t ion  to  induce

1 shedding_may involve_the zinc metalloprotease-dependent trafficking_of intracytoplasmic_TNFR1_vesicles to_the_cell surface. These_findings identify new_roles for the proteasome_and zinc metalloproteases_in_regulating the proteolytic cleavage and shedding of the TNFR1 extracellular domain. In addition, the_ability_of proteasome_inhibition_to_induce


turned up one (c522) that provides substantial rescue of the halothane phenotype, suggesting that arousal depends on localized circuitry. However, channel expression under the control of c522 fails to rescue the sevoflurane phenotypes of na mutants. This result not only proves that the halothane rescue is not the result

turned up one (c522) that provides substantial rescue of the halothane phenotype, suggesting that foreplay depend on localized circuitry. However, channel formula under the dominance of c522 fails to rescue the sevoflurane phenotypes of na mutant. This solution not only proves that the halothane rescue is not the result

tugned up one (c522) that proviaes substantial rescue of ths halothxne phenotype, suggesting thav ariusal depends on localized zircuitry. However, chainel expression nhder thc confvol oy r522 fails to rescoe the sevofnurane phenoty[er lf na mutants. This result not only [roves yhwt the halothage rtscte ia not the result

turned up one (c522) that provides substantial the phenotype, suggesting arousal depends on under control of c522 to rescue the phenotypes of na mutants. This result only proves that the halothane rescue is not the result

turned up one (c522) that provides sUbstantial RescuE of The HaLothAne pHenotype, suggesTIng tHat arousal depends on locAlizeD cIRcuiTRy. howevEr, channEL eXPResSiOn UndEr THe ContrOl oF c522 fails To rescue thE seVoFlurane phenoTYpEs of na mutaNts. this result noT onLy provEs ThaT The haLotHane rEscue iS Not the Result

turned up one (c522) that  providessubst ant ial  r escu e of  the halothane phen otype, suggesting that  arou sa l  dep e nd s onlocaliz e dc i rcu it ry . H ow e ve r, ch ann el expr ession und erth e control of c5 22 fails t o r escue the se vof lurane  p hen o types  of  na m utants .  Thisresult no to nly pr o ves tha t th e ha lothane rescue is no t  the result

turned_up one_(c522) that provides substantial_rescue of_the_halothane phenotype,_suggesting_that arousal depends_on localized circuitry._However, channel expression under_the control of_c522_fails to rescue the sevoflurane phenotypes of na mutants. This result not only proves_that_the halothane_rescue_is_not the result


proteins translated from alternatively spliced mRNAs. We have recently demonstrated that proteasome inhibition induces the proteolytic cleavage and shedding of soluble TNFR1 ectodomains from human pulmonary epithelial cells, which is associated with a reduction of intracytoplasmic TNFR1 vesicles and cell surface receptors. Furtherthemore, the mechanism of TNFR

proteins translated from alternatively spliced mRNAs. We have recently attest that proteasome prohibition induces the proteolytic cleavage and shedding of soluble TNFR1 ectodomains from human pneumonic epithelial cells, which is consort with a reduction of intracytoplasmic TNFR1 vesicle and cellular telephone surface receptors. Furtherthemore, the mechanism of TNFR

prlteins translated from auternatively spliced mCNAs. We have rezently demonstrated that proveasime ibhibition induces the oroteolytpc cleavate aid shedding of soluble TKYR1 ecfldomciis from human polmonary epidhelial cells, fhkck is associated with a reduction of yntracyyoolasmic TNFR1 vgsiclts wnd dvlo surface receptors. Furtherthsmore, tie mechanism of TNFR

proteins translated from alternatively spliced mRNAs. We demonstrated proteasome inhibition the proteolytic cleavage ectodomains human pulmonary epithelial which is associated a reduction of intracytoplasmic TNFR1 vesicles cell surface receptors. Furtherthemore, the mechanism of TNFR

proteins translated from altErnatively SplicEd mrNAS. WE havE recEntly demonstraTEd thAt proteasome inhibition InducEs THe prOTeOlytiC cleavaGE aND SheDdInG of SoLUbLe TNFr1 ecTodomaiNs from humaN puLmOnary epithelIAl Cells, which Is aSsociated witH a rEductiOn Of iNTracyTopLasmiC TNFR1 vESicles And cell suRfACe recePTors. FurTHErThemOre, the mechanism of tnFr

proteins translated fromalternativ ely s pli ced  m RNAs . We  have recently demo nstrated that proteaso me in hi b itio n  i nduce s the p r ot e o lyt ic  c lea va g eand s hed ding of  soluble T NFR 1ectodomainsf ro m human pu lmo nary epithel ial  cells ,whi c h isass ociat ed wit h  a red uction of  i n tracyt o plasmic T NF R1 v esicles and cells ur f ace receptors.  Furth er t he m o re,  th e mechanis mof TN F R

proteins_translated from_alternatively spliced mRNAs. We_have recently_demonstrated_that proteasome_inhibition_induces the proteolytic_cleavage and shedding_of soluble TNFR1 ectodomains_from human pulmonary_epithelial_cells, which is associated with a reduction of intracytoplasmic TNFR1 vesicles and cell surface_receptors._Furtherthemore, the_mechanism_of_TNFR


using approved therapeutics in the treatment of these children to obtain answers to the underlying immune dysregulatory defect. CONCLUSIONS AND SIGNIFICANCE 1. In now 2 severe autoinflammatory syndromes, cryopyrin associated periodic syndromes, CAPS (which includes FACS, MWS and NOMID), and deficiency of the

using approved therapeutics in the treatment of these child to receive answers to the underlying immune dysregulatory defect. conclusion AND SIGNIFICANCE 1. In now 2 hard autoinflammatory syndromes, cryopyrin associated periodic syndrome, CAPS (which includes FACS, MWS and NOMID), and deficiency of the

uslng approved therapeuticr in the treatmgnr of tiese chjldren tu obtain answers to the undeclyibg imnune dysregulatory defdct. CONCLLSIONS ANE SIJNIFICANCE 1. In now 2 sevevz autklnflaknatory syndromgs, cryopyrin associated pesiudnc syndromes, CAPS (which includes FACF, MWS amd NOMID), and defyciemsy or the

using approved therapeutics in the treatment of to answers to underlying immune dysregulatory In 2 severe autoinflammatory cryopyrin associated periodic CAPS (which includes FACS, MWS and and deficiency of the

using approved therapeutics In the treatMent oF thEse ChIldrEn to Obtain answers tO The uNderlying immune dysreguLatorY dEFect. coNcLUSIoNS AND SigNifiCAnCe 1. IN noW 2 sEVeRe autOinFlammatOry syndromEs, cRyOpyrin associATeD periodic sYndRomes, CAPS (whiCh iNcludeS FaCS, mwS and nOMiD), and DeficiENcy of tHe

using approved therapeuti cs in thetreat men t o fthes e ch ildren to obta i n an swers to the underlyin g imm un e  dys r eg ulato ry defe c t. C ONC LU SI ONS  A N DSIGNI FIC ANCE 1.  In now 2sev er e autoinflam m at ory syndro mes , cryopyrinass ociate dper i odicsyn drome s, CAP S  (whic h include sF ACS, M W S and N O M ID ), a nd deficiency oft he

using_approved therapeutics_in the treatment of_these children_to_obtain answers_to_the underlying immune_dysregulatory defect. CONCLUSIONS_AND SIGNIFICANCE 1. In_now 2 severe_autoinflammatory_syndromes, cryopyrin associated periodic syndromes, CAPS (which includes FACS, MWS and NOMID), and deficiency_of_the


, and Env products represent the main virion components, while Tat and Rev regulate intracellular transcriptional and post-transcriptional events for the controlled expression of viral genes. Of particular interest are the HIV accessory proteins Vif, Vpr, Vpu, Vpx, and Nef, which are unique to primate lentivir

, and Env products represent the main virion components, while Tat and Rev determine intracellular transcriptional and post - transcriptional event for the controlled expression of viral genes. Of finical interest are the HIV accessory proteins Vif, Vpr, Vpu, Vpx, and Nef, which are unique to primate lentivir

, anf Env products represent the main viriou compoients, wgile Tat and Rev regulate intracellupae trabscriptional and post-tfanscriptponal evebts hor the controllxs expression kn vircl genes. Of partlcular intesest are the HHV aecessory proteins Vif, Vpr, Vpu, Vpx, anq Nef, wnifh are unique jo prpmwte mvnuivir

, and Env products represent the main while and Rev intracellular transcriptional and expression viral genes. Of interest are the accessory proteins Vif, Vpr, Vpu, Vpx, Nef, which are unique to primate lentivir

, and Env products represent thE main virioN compOneNts, WhIle TAt anD Rev regulate inTRaceLlular transcriptional aNd posT-tRAnscRIpTionaL events FOr THE coNtRoLleD eXPrEssioN of Viral geNes. Of partiCulAr Interest are tHE HiV accessorY prOteins Vif, Vpr, vpu, vpx, and neF, whICh are UniQue to PrimatE LentivIr

, and Env products represe nt the mai n vir ion  co mp onen ts,while Tat andR ev r egulate intracellulartrans cr i ptio n al  andpost-tr a ns c r ipt io na l e ve n ts  forthe  contro lled expre ssi on  of viral ge n es . Of parti cul ar interestare  the H IV  ac c essor y p rotei ns Vif ,  Vpr,Vpu, Vpx,  a n d Nef, which a r e  u niqu e to primate lent i vi r

, and_Env products_represent the main virion_components, while_Tat_and Rev_regulate_intracellular transcriptional and_post-transcriptional events for_the controlled expression of_viral genes. Of_particular_interest are the HIV accessory proteins Vif, Vpr, Vpu, Vpx, and Nef, which are_unique_to primate_lentivir


is associated with increased risks of preterm birth and fetal loss. If these findings are replicated, they could affect vector control policies in other countries and help reduce the global burden of this persistent toxic substance. PCBs are resistant to chemical and biological breakdown and this contributed to their widespread commercial use in a variety of applications. Even though

is associated with increased risks of preterm birth and fetal personnel casualty. If these finding are replicated, they could affect vector control policy in other countries and help oneself reduce the global load of this persistent toxic substance. PCBs are repellent to chemical and biological breakdown and this contributed to their far-flung commercial use in a variety of applications. Even though

is associated with increastd risks of pretetm birth and fstal losr. If these findings are replmcatwd, thtj could affect vector control iolicies un ouher countries anv help rcbuce fme glmual burden of tmis persistant toxic subsdavcz. PCBs are resistant to chemical and biologocwl breakdown agd tnys ckntributed to their widespread comjercial use in a varoety of applications. Even hhouhh

is associated with increased risks of preterm fetal If these are replicated, they in countries and help the global burden this persistent toxic substance. PCBs are to chemical and biological breakdown and this contributed to their widespread commercial use a variety of applications. Even though

is associated with increased Risks of preTerm bIrtH anD fEtal Loss. if these findingS Are rEplicated, they could affeCt vecToR ContROl PolicIes in otHEr COUntRiEs And HeLP rEduce The Global bUrden of thiS peRsIstent toxic sUBsTance. PCBs aRe rEsistant to chEmiCal and BiOloGIcal bReaKdown And thiS ContriButed to thEiR WidespREad commERCiAl usE in a variety of applICaTIons. Even though

is associated with increa sed risksof pr ete rmbi rthandfetal loss. If thes e findings are replica ted,th e y co u ld  affe ct vect o rc o ntr ol  p oli ci e sin ot her  countr ies and he lpre duce the glo b al  burden of  th is persisten t t oxic s ub sta n ce. P CBs  areresist a nt tochemicalan d  biolo g ical br e a kd ownand this contribu t ed to their wides preadco m me r c ial  us e in a var ie ty of applica t io n s .  Ev e n though

is_associated with_increased risks of preterm_birth and_fetal_loss. If_these_findings are replicated,_they could affect_vector control policies in_other countries and_help_reduce the global burden of this persistent toxic substance. PCBs are resistant to chemical_and_biological breakdown_and_this_contributed to their widespread commercial_use in a variety of_applications. Even_though


epithelial stem cell survival an/or proliferation. We have also identified and characterized a novel proteolytic pathway that is a dominant regulator of EpCAM function. We are in the process of submitting publications that describe our results in detail. In an effort to explore EpCAM function in other tissues, we are involved in collaborations with

epithelial stem cell survival an / or proliferation. We have also identified and qualify a fresh proteolytic pathway that is a dominant governor of EpCAM function. We are in the summons of submitting publications that report our results in detail. In an attempt to explore EpCAM function in early tissues, we are involved in collaborations with

eplthelial stem cell surviyal an/or prolifetarion. Wx have zlso idevtified and characterized a ioveo prouvolytic pathway that ks a domijant regylatie of EpCAM functiok. We zve in vhe process of xubmitting publications dhxt describe our results in detail. In wn effott to explore EpSAM gtnctjon in other tissues, we are involvsd in cmllaborations with

epithelial stem cell survival an/or proliferation. We identified characterized a proteolytic pathway that EpCAM We are in process of submitting that describe our results in detail. an effort to explore EpCAM function in other tissues, we are involved in with

epithelial stem cell survivaL an/or proliFeratIon. we hAvE alsO ideNtified and charACterIzed a novel proteolytic pAthwaY tHAt is A DoMinanT regulaTOr OF epCaM FuNctIoN. we Are in The Process Of submittiNg pUbLications thaT DeScribe our rEsuLts in detail. IN an Effort To ExpLOre EpcAM FunctIon in oTHer tisSues, we are InVOlved iN CollaboRATiOns wIth

epithelial stem cell surv ival an/or  prol ife rat io n. W e ha ve also identi f iedand characterized a no vel p ro t eoly t ic  path way tha t  i s a d om in ant  r e gu lator  of  EpCAMfunction.Wear e in the pro c es s of submi tti ng publicati ons  thatde scr i be ou r r esult s in d e tail.In an eff or t  to ex p lore Ep C A Mfunc tion in other tis s ue s , we are invol ved in  c o ll a b ora tio ns with

epithelial_stem cell_survival an/or proliferation. We_have also_identified_and characterized_a_novel proteolytic pathway_that is a_dominant regulator of EpCAM_function. We are_in_the process of submitting publications that describe our results in detail. In an effort_to_explore EpCAM_function_in_other tissues, we are involved_in collaborations with


wild type MC3R. We have also successfully bred and studied novel knock-in mice expressing the human wild type MC3R(hWT/hWT) and human double-mutant MC3R(hDM/hDM). MC3R(hDM/hDM) have greater weight and fat

wild type MC3R. We have also successfully bred and study fresh knock - in mice expressing the human raving mad character MC3R(hWT / hWT) and human double - mutant MC3R(hDM / hDM). MC3R(hDM / hDM) have greater system of weights and fat

wipd type MC3R. We have also successfully btee and vtudies novel ynock-in mice expressing the iumab wile type MC3R(hWT/hWT) and hjman doubpe-mutant MC3R(iDM/hDM). MC3R(hDM/hDM) have grccter scight end fat

wild type MC3R. We have also successfully studied knock-in mice the human wild MC3R(hDM/hDM). have greater weight fat

wild type MC3R. We have also succEssfully brEd and StuDieD nOvel KnocK-in mice expressINg thE human wild type MC3R(hWT/hWt) and hUmAN douBLe-MutanT MC3R(hDM/HdM). mc3r(hDm/hdM) HavE gREaTer weIghT and fat

wild type MC3R. We have a lso succes sfull y b red  a nd s tudi ed novel knock - in m ice expressing the hum an wi ld type MC 3R(hW T/hWT)a nd h uma ndo ubl e- m ut ant M C3R (hDM/hD M). MC3R(h DM/ hD M) have grea t er  weight an d f at

wild_type MC3R._We have also successfully_bred and_studied_novel knock-in_mice_expressing the human_wild type MC3R(hWT/hWT)_and human double-mutant MC3R(hDM/hDM)._MC3R(hDM/hDM) have greater_weight_and fat


for enumerating circulating tumor cells. The steps of PD assay development, clinical implementation including SOP-based specimen handling, analytical validation and transfer to a recipient clinical lab have been formalized into milestones and metrics by the SAIC-Frederick PD support program, and rigorously achieving each milestone in the process is

for enumerating circulating tumor cells. The steps of PD assay growth, clinical execution including SOP - based specimen treatment, analytical establishment and transfer to a recipient clinical lab have been formalized into milestone and system of measurement by the SAIC - Frederick PD support plan, and rigorously achieving each milestone in the process is

fog enumerating circulatinn tumor cells. Thg wteps mf PD zssay dexelopment, clinical implementetiob incouding SOP-based specimdn handlijg, analyricao validatioi and transfer bo a xeripient clinicak lab have been formalizad iuto milestones and metrics by the SAYC-Fredetifk PD support krogrsi, ans rigorously achieving each milestkne in uhe process is

for enumerating circulating tumor cells. The steps assay clinical implementation SOP-based specimen handling, a clinical lab have formalized into milestones metrics by the SAIC-Frederick PD support and rigorously achieving each milestone in the process is

for enumerating circulating Tumor cells. the stEps Of Pd aSsay DeveLopment, clinicaL ImplEmentation including SOP-Based SpECimeN HaNdlinG, analytICaL VAliDaTiOn aNd TRaNsfer To a RecipieNt clinical Lab HaVe been formalIZeD into milesTonEs and metrics By tHe SAIC-frEdeRIck PD SupPort pRogram, ANd rigoRously achIeVIng eacH MilestoNE In The pRocess is

for enumerating circulati ng tumor c ells.  Th e s te ps o f PD  assay develop m ent,  clinical implementati on in cl u ding SO P-bas ed spec i me n han dl in g,an a ly tical  va lidatio n and tran sfe rto a recipie n tclinical l abhave been fo rma lizedin tom ilest one s and  metri c s by t he SAIC-F re d erickP D suppo r t  p rogr am, and rigorousl y  a c hieving each m ilesto ne in t hepro cess is

for_enumerating circulating_tumor cells. The steps_of PD_assay_development, clinical_implementation_including SOP-based specimen_handling, analytical validation_and transfer to a_recipient clinical lab_have_been formalized into milestones and metrics by the SAIC-Frederick PD support program, and rigorously_achieving_each milestone_in_the_process is


WGS library preparation and high-throughput sequencing. We employed somatic variant calling algorithms to identify de novo insertions/deletions (indel) mutations, single nucleotide variants (SNVs) and structural variants (SVs) captured within the WGS datasets for each treatment group relative to the un-treated, bulk HSP

WGS library preparation and high - throughput sequencing. We employed somatic random variable call algorithms to identify de novo insertions / deletion (indel) mutations, single nucleotide version (SNVs) and morphologic variants (SVs) capture within the WGS datasets for each treatment group relative to the un - cover, bulk HSP

WGD library preparation ana high-throughpuj wequenring. We employea somatic variant calling aljorirhms uj identify de novo insertiojs/deletiins (mndel) mutations, single nmeleotjfe vcrmants (SNVs) and xtructural variants (SVs) waotbred within the WGS datasets for eacr treatkejt group relatyve uo ehe hn-treated, bulk HSP

WGS library preparation and high-throughput sequencing. We variant algorithms to de novo insertions/deletions (SNVs) structural variants (SVs) within the WGS for each treatment group relative to un-treated, bulk HSP

WGS library preparation and hIgh-throughPut seQueNciNg. we emPloyEd somatic variaNT calLing algorithms to identiFy de nOvO InseRTiOns/deLetions (INdEL) MutAtIoNs, sInGLe NucleOtiDe variaNts (SNVs) and StrUcTural variantS (sVS) captured wIthIn the WGS dataSetS for eaCh TreATment GroUp relAtive tO The un-tReated, bulK Hsp

WGS library preparation a nd high-th rough put  se qu enci ng.We employed so m atic  variant calling algor ithms  t o  ide n ti fy de  novo i n se r t ion s/ de let io n s(inde l)mutatio ns, single  nu cl eotide varia n ts  (SNVs) an d s tructural va ria nts (S Vs ) c a pture d w ithin  the W G S data sets forea c h trea t ment gr o u prela tive to the un-tr e at e d, bulk HSP

WGS_library preparation_and high-throughput sequencing. We_employed somatic_variant_calling algorithms_to_identify de novo_insertions/deletions (indel) mutations,_single nucleotide variants (SNVs)_and structural variants_(SVs)_captured within the WGS datasets for each treatment group relative to the un-treated, bulk_HSP


pathogen-like particles having a size (70 300 nm) and shape resembling spherical viruses that naturally evolved to deliver nucleic acids to the cells. They contain the pDNA in the interior surrounded by synthetic polymer bearing sugar residues on the surface recognized by the M cells and dendritic cells as pathogens. Because we can control the stability and

pathogen - like particles having a size (70 300 nm) and condition resemble spherical viruses that naturally develop to rescue nucleic acids to the cells. They check the pDNA in the inside surrounded by synthetic polymer bearing sugar remainder on the surface recognized by the M cell and dendritic cell as pathogens. Because we can control the stability and

pahhogen-like particles havlng a size (70 300 nm) cbd sha'e resejbling soherical viruses that naturaplt evooved to deliver nucleiz acids tl the ceols. Uhey contain the 'SNA in bke infcrior wurrounded by xynthetic [olymer bearinc ruyar residues on the surface recognizqd by tne M cells and dgndriuic celms as pathogens. Because we can confrol tht stability and

pathogen-like particles having a size (70 300 shape spherical viruses naturally evolved to cells. contain the pDNA the interior surrounded synthetic polymer bearing sugar residues on surface recognized by the M cells and dendritic cells as pathogens. Because we control the stability and

pathogen-like particles haviNg a size (70 300 nm) aNd shaPe rEseMbLing SpheRical viruses thAT natUrally evolved to deliver NucleIc ACids TO tHe celLs. They cONtAIN thE pdNa in ThE InTerioR suRroundeD by synthetIc pOlYmer bearing sUGaR residues oN thE surface recoGniZed by tHe m ceLLs and DenDritiC cells AS pathoGens. BecauSe WE can coNTrol the STAbIlitY and

pathogen-like particles h aving a si ze (7 0 3 00nm ) an d sh ape resembling sphe rical viruses that nat urall ye volv e dto de liver n u cl e i c a ci ds  to  t h ecells . T hey con tain the p DNA  i n the interi o rsurrounded  by  synthetic p oly mer be ar ing sugar  re sidue s on t h e surf ace recog ni z ed byt he M ce l l sanddendritic cells a s  p a thogens. Becau se weca n  c o n tro l t he stabili ty  and

pathogen-like_particles having_a size (70 300_nm) and_shape_resembling spherical_viruses_that naturally evolved_to deliver nucleic_acids to the cells._They contain the_pDNA_in the interior surrounded by synthetic polymer bearing sugar residues on the surface recognized_by_the M_cells_and_dendritic cells as pathogens. Because_we can control the stability_and


-MPL antibodies conjugated to immunotoxin. In collaboration with Dr. Zhirui Wang and Dr. Diogo Magnani, proof-of-concept experiments have been initiated in non-human primates (NHP). Construction of anti-c-MPL monomeric and dimeric single-chain variable fragment (scFv

-MPL antibodies conjugated to immunotoxin. In collaboration with Dr. Zhirui Wang and Dr. Diogo Magnani, proof - of - concept experiments have been initiated in non - human archpriest (NHP). structure of anti - c - MPL monomeric and dimeric single - range variable shard (scFv

-MPL antibodies conjugated tu immunotoxin. Iu collauoratioh with Df. Zhirui Wang and Dr. Diogo Megnabi, priof-of-concept experimengs have bven initiqted un non-humai primatcf (NHL). Convvruction of antl-c-MPL monomaric and dimerhc snngle-chain variable fragment (scFv

-MPL antibodies conjugated to immunotoxin. In collaboration Zhirui and Dr. Magnani, proof-of-concept experiments primates Construction of anti-c-MPL and dimeric single-chain fragment (scFv

-MPL antibodies conjugated to ImmunotoxiN. In coLlaBorAtIon wIth DR. Zhirui Wang and dR. DioGo Magnani, proof-of-concepT expeRiMEnts HAvE been InitiatED iN NOn-hUmAn PriMaTEs (nHP). CoNstRuction Of anti-c-MPL MonOmEric and dimerIC sIngle-chain VarIable fragmenT (scfv

-MPL antibodies conjugated  to immuno toxin . I n c ol labo rati on with Dr. Zh i ruiWang and Dr. Diogo Mag nani,  p r oof- o f- conce pt expe r im e n tsha ve  be en in itiat edin non- human prim ate s(NHP). Const r uc tion of an ti- c-MPL monome ric  and d im eri c  sing le- chain  varia b le fra gment (sc Fv

-MPL antibodies_conjugated to_immunotoxin. In collaboration with_Dr. Zhirui_Wang_and Dr._Diogo_Magnani, proof-of-concept experiments_have been initiated_in non-human primates (NHP)._Construction of anti-c-MPL_monomeric_and dimeric single-chain variable fragment (scFv


RNase H) that included a region with five single amino acid substitutions in a five?amino acid segment. Surprisingly, these mutations in RNase H did not reduce the levels of full-length double stranded cDNA. Crystallographic studies by Dr. Edward Arnold and colleagues indicated that the corresponding residues of HIV-1 RT interact

RNase H) that included a region with five single amino acid substitutions in a five?amino acid section. amazingly, these mutant in RNase H did not reduce the levels of broad - length double maroon cDNA. Crystallographic studies by Dr. Edward Arnold and colleague indicated that the corresponding remainder of HIV-1 RT interact

RNade H) that included a reglon with five siutle ammno acis substigutions in a five?amino acid detment. Surprisingly, these mugations ij RNase Y div not reduce the levels of fulm-pengch double strandgd cDNA. Crysdallographic sduaizs by Dr. Edward Arnold and colleaguef indicstfd that the cotresppgdinf residues of HIV-1 RT interact

RNase H) that included a region with amino substitutions in five?amino acid segment. H not reduce the of full-length double cDNA. Crystallographic studies by Dr. Edward and colleagues indicated that the corresponding residues of HIV-1 RT interact

RNase H) that included a region With five siNgle aMinO acId SubsTituTions in a five?amINo acId segment. Surprisingly, tHese mUtATionS In rNase h did not REdUCE thE lEvEls Of FUlL-lengTh dOuble stRanded cDNA. cryStAllographic sTUdIes by Dr. EdwArd arnold and colLeaGues inDiCatED that The CorreSpondiNG residUes of HIV-1 Rt iNTeract

RNase H) that included a r egion with  five  si ngl eamin o ac id substitutio n s in  a five?amino acid seg ment.  S u rpri s in gly,these m u ta t i ons  i nRNa se Hdid n otreducethe levels  of  f ull-length d o ub le strande d c DNA. Crystal log raphic  s tud i es by  Dr . Edw ard Ar n old an d colleag ue s  indic a ted tha t th e co rresponding resid u es of HIV-1 RT in teract

RNase H)_that included_a region with five_single amino_acid_substitutions in_a_five?amino acid segment._Surprisingly, these mutations_in RNase H did_not reduce the_levels_of full-length double stranded cDNA. Crystallographic studies by Dr. Edward Arnold and colleagues indicated_that_the corresponding_residues_of_HIV-1 RT interact


is localized to the synapse and that reduction in neurotransmitter release in nlg mutants is paralleled by reduction in the number of synaptic boutons. Further evidence that nlg regulates synaptic structure is: a)mutations in nlg and its trans-synaptic partner neurexin alter the amplitude distributions of spontaneous

is localized to the synapse and that reduction in neurotransmitter release in nlg mutants is twin by decrease in the number of synaptic boutons. Further evidence that nlg regulates synaptic social organization is: a)mutations in nlg and its trans - synaptic partner neurexin change the amplitude distributions of ad-lib

is localized to the synapst and that reductnin in ieurotrznsmittef release in nlg mutants is 'araolelee by reduction in the vumber of synaptix bontons. Further evmsence tmct nlf regbletes synaptic sjructure is: d)mutations in tle cnd its trans-synaptic partner neurexyn altet hhe amplitude qistgifutikns of spontaneous

is localized to the synapse and that neurotransmitter in nlg is paralleled by synaptic Further evidence that regulates synaptic structure a)mutations in nlg and its trans-synaptic neurexin alter the amplitude distributions of spontaneous

is localized to the synapse anD that reducTion iN neUroTrAnsmItteR release in nlg mUTantS is paralleled by reductiOn in tHe NUmbeR Of SynapTic boutONs. fURthEr EvIdeNcE ThAt nlg RegUlates sYnaptic strUctUrE is: a)mutationS In Nlg and its tRanS-synaptic parTneR neureXiN alTEr the AmpLitudE distrIButionS of spontaNeOUs

is localized to the synap se and tha t red uct ion  i n ne urot ransmitter rel e asein nlg mutants is para llele db y re d uc tionin then um b e r o fsy nap ti c  b outon s.Further  evidencetha tnlg regulate s  s ynaptic st ruc ture is: a)m uta tionsin  nl g  andits  tran s-syna p tic pa rtner neu re x in alt e r the a m p li tude  distributions of sp o ntaneous

is_localized to_the synapse and that_reduction in_neurotransmitter_release in_nlg_mutants is paralleled_by reduction in_the number of synaptic_boutons. Further evidence_that_nlg regulates synaptic structure is: a)mutations in nlg and its trans-synaptic partner neurexin alter_the_amplitude distributions_of_spontaneous


% CI -6.08, -0.70, Cohen's d =.79) and less odds of LOC-eating (95% CI -3.93, -0.03, Cohen's d =.38) than FB-HE. Family-based approaches that address interpersonal and emotional underp

% CI -6.08, -0.70, Cohen's d = .79) and less odds of LOC - eating (95% CI -3.93, -0.03, Cohen's d = .38) than FB - HE. Family - based access that cover interpersonal and emotional underp

% CI -6.08, -0.70, Cohen's d =.79) and less odas of LOC-eating (95% CI -3.93, -0.03, Rohen's s =.38) than WB-HE. Family-based approaches vhat addrtfs interpersonal avd emotiojal undeep

% CI -6.08, -0.70, Cohen's d =.79) odds LOC-eating (95% -3.93, -0.03, Cohen's approaches address interpersonal and underp

% CI -6.08, -0.70, Cohen's d =.79) and less odds of LOC-Eating (95% CI -3.93, -0.03, CoHen's d =.38) ThaN FB-hE. famiLy-baSed approaches tHAt adDress interpersonal and eMotioNaL UndeRP

% CI -6.08, -0.70, Cohen's  d =.79) a nd le ssodd sof L OC-e ating (95% CI- 3.93 , -0.03, Cohen's d =.3 8) th an FB-H E .Famil y-based ap p r oac he stha ta dd ressint erperso nal and em oti on al underp

% CI_-6.08, -0.70,_Cohen's d =.79) and_less odds_of_LOC-eating (95%_CI_-3.93, -0.03, Cohen's_d =.38) than_FB-HE. Family-based approaches that_address interpersonal and_emotional_underp


of a serotype, namely APMV2 (2 strains), APMV3 (2 strains), and APMV8 (2 strains). Sequences already were available for two strains of APMV6: we have analyzed 2 more in addition. Also, sequencing of APMV5 is almost complete. The purpose in analyzing

of a serotype, namely APMV2 (2 strains), APMV3 (2 strains), and APMV8 (2 strains). Sequences already were available for two tune of APMV6: we have analyze 2 more in addition. Also, sequencing of APMV5 is about complete. The purpose in analyzing

of a serotype, namely APMV2 (2 strains), APMV3 (2 strains), and ALMV8 (2 strxins). Sequences already were evaioable for two strains of APOV6: we havv analyzee 2 miee in addivjon. Also, sequskcing if APMV5 is almpst complede. The purpose iv cnalyzing

of a serotype, namely APMV2 (2 strains), strains), APMV8 (2 Sequences already were APMV6: have analyzed 2 in addition. Also, of APMV5 is almost complete. The in analyzing

of a serotype, namely APMV2 (2 straIns), APMV3 (2 strAins), aNd ApMV8 (2 StRainS). SeqUences already wERe avAilable for two strains of aPMV6: wE hAVe anALyZed 2 moRe in addITiON. alsO, sEqUenCiNG oF APMV5 Is aLmost coMplete. The pUrpOsE in analyzing

of a serotype, namely APM V2 (2 stra ins),  AP MV3  ( 2 st rain s), and APMV8( 2 st rains). Sequences alre ady w er e  ava i la ble f or twos tr a i nsof  A PMV 6: we  have  an alyzed2 more inadd it ion. Also, s e qu encing ofAPM V5 is almost  co mplete .The purpo sein an alyzin g

of_a serotype,_namely APMV2 (2 strains),_APMV3 (2_strains),_and APMV8_(2_strains). Sequences already_were available for_two strains of APMV6:_we have analyzed_2_more in addition. Also, sequencing of APMV5 is almost complete. The purpose in analyzing


and vertebrates, the same complex is found in post-mitotic neurons, where it appears to play a role in microtubule organization. Further study of this gene is likely to be relevant to the mission of NIMH since the human ortholog of another origin complex subunit, ORC3, has been implicated in determining the

and vertebrates, the same complex is found in post - mitotic nerve cell, where it appear to play a role in microtubule constitution. Further report of this gene is likely to be relevant to the mission of NIMH since the human ortholog of another lineage complex fractional monetary unit, ORC3, has been implicated in determining the

anf vertebrates, the same cumplex is found in posv-mitotid neuronr, where it appears to play a rile ib microtubule organizagion. Furtjer studt of rhis gene ma likeln to gc relzvent to the misslon of NIMH since the humdn oxtholog of another origin complex sufunit, OTC3, has been implycattd yn dsnevmining the

and vertebrates, the same complex is found neurons, it appears play a role of gene is likely be relevant to mission of NIMH since the human of another origin complex subunit, ORC3, has been implicated in determining the

and vertebrates, the same compLex is found In posT-miTotIc NeurOns, wHere it appears tO Play A role in microtubule orgaNizatIoN. furtHEr Study Of this gENe IS LikElY tO be ReLEvAnt to The Mission Of NIMH sincE thE hUman ortholog OF aNother origIn cOmplex subuniT, ORc3, has beEn ImpLIcateD in DeterMining THe

and vertebrates, the same  complex i s fou ndinpo st-m itot ic neurons, wh e re i t appears to play a ro le in  m i crot u bu le or ganizat i on . Fur th er  st ud y  o f thi s g ene islikely tobere levant to th e  m ission ofNIM H since thehum an ort ho log of an oth er or igin c o mplexsubunit,OR C 3, has been im p l ic ated  in determining t h e

and_vertebrates, the_same complex is found_in post-mitotic_neurons,_where it_appears_to play a_role in microtubule_organization. Further study of_this gene is_likely_to be relevant to the mission of NIMH since the human ortholog of another_origin_complex subunit,_ORC3,_has_been implicated in determining the


The Section on Cellular Biophotonics, of the Laboratory of Molecular Physiology, NIAAA, was established in April 2003. The principle aim of this section is to use imaging techniques to study how protein complexes, with special emphasis on complexes comprised of integral membrane proteins, are formed and maintained in living cells. Membrane

The Section on Cellular Biophotonics, of the Laboratory of Molecular Physiology, NIAAA, was established in April 2003. The principle aim of this section is to use image technique to study how protein complexes, with special stress on complexes comprised of built-in membrane proteins, are formed and maintained in life cells. Membrane

The Section on Cellular Biokhotonics, of the Laboratmry of Moleculxr Physiology, NIAAA, was estaulisyed ib April 2003. The principle aim of tjis sectuon ms to use imaginj techniques tk stuby how protein cpmplexes, whth special em[hxsns on complexes comprised of integraj membrsnf proteins, are forkqd ahd maintained in living cells. Membdane

The Section on Cellular Biophotonics, of the Molecular NIAAA, was in April 2003. section to use imaging to study how complexes, with special emphasis on complexes of integral membrane proteins, are formed and maintained in living cells. Membrane

The Section on Cellular BiophOtonics, of tHe LabOraTorY oF MolEculAr Physiology, NIaaA, waS established in April 2003. The PrincIpLE aim OF tHis seCtion is TO uSE ImaGiNg TecHnIQuEs to sTudY how proTein compleXes, WiTh special empHAsIs on compleXes Comprised of iNteGral meMbRanE ProteIns, Are foRmed anD MaintaIned in livInG Cells. MEMbrane

The Section on Cellular Bi ophotonics , ofthe  La bo rato ry o f Molecular Ph y siol ogy, NIAAA, was establ ished  i n  Apr i l2003.  The pr i nc i p leai mofth i ssecti onis to u se imaging  te ch niques to st u dy  how prote incomplexes, w ith  speci al  em p hasis  on  comp lexesc ompris ed of int eg r al mem b rane pr o t ei ns,are formed and ma i nt a ined in living  cells .M em b r ane

The Section_on Cellular_Biophotonics, of the Laboratory_of Molecular_Physiology,_NIAAA, was_established_in April 2003._The principle aim_of this section is_to use imaging_techniques_to study how protein complexes, with special emphasis on complexes comprised of integral membrane_proteins,_are formed_and_maintained_in living cells. Membrane


proteins that influence the development of tissue fibrosis. They are regulated by another family of proteins called tissue inhibitors of metalloproteinases. The interplay between these proteins governs tissue fibrosis in a variety of conditions. In addition, certain cytokines are known to promote pro-fibrotic events. We have attempted to elucidate the role of the above

proteins that influence the development of tissue fibrosis. They are regulated by another syndicate of protein called tissue inhibitors of metalloproteinases. The interplay between these protein governs weave fibrosis in a variety of conditions. In summation, sealed cytokines are known to promote pro - fibrotic events. We have attempted to clear the role of the above

prlteins that influence tht development of jiwsue fmbrosis. They ard regulated by another familb of prottpns called tissue inhkbitors ov metalliproueinases. The intecllay bebceen fmese 'riteins governs tissue fitrosis in a vasidtv of conditions. In addition, certain sytokinrs are known to kromoue [ro-fjbrotic events. We have attempted tk elucivate the role og the above

proteins that influence the development of tissue are by another of proteins called interplay these proteins governs fibrosis in a of conditions. In addition, certain cytokines known to promote pro-fibrotic events. We have attempted to elucidate the role of above

proteins that influence the dEvelopment Of tisSue FibRoSis. THey aRe regulated by aNOtheR family of proteins calleD tissUe INhibIToRs of mEtallopROtEINasEs. thE inTeRPlAy betWeeN these pRoteins govErnS tIssue fibrosiS In A variety of ConDitions. In addItiOn, certAiN cyTOkineS arE knowN to proMOte pro-Fibrotic eVeNTs. We haVE attempTED tO eluCidate the role of thE AbOVe

proteins that influence t he develop mentoftis su e fi bros is. They are r e gula ted by another familyof pr ot e insc al led t issue i n hi b i tor sof  me ta l lo prote ina ses. Th e interpla y b et ween these p r ot eins gover nstissue fibro sis  in ava rie t y ofcon ditio ns. In additi on, certa in cytoki n es arek n ow n to  promote pro-fibr o ti c  events. We ha ve att em p te d toelu cidate the  r ole o f  the ab o ve

proteins_that influence_the development of tissue_fibrosis. They_are_regulated by_another_family of proteins_called tissue inhibitors_of metalloproteinases. The interplay_between these proteins_governs_tissue fibrosis in a variety of conditions. In addition, certain cytokines are known to_promote_pro-fibrotic events._We_have_attempted to elucidate the role_of the above


4 (which lack classical motifs for endocytosis) are downregulated more profoundly than wt receptors. Nef induced ubiquitination of CXCR4 through recruitment of E3 ligase, AIP4 followed by a dynamin dependent endocytosis into MVBs for proteolyis. These mechanisms were confirmed by interaction between Nef, A

4 (which lack classical motifs for endocytosis) are downregulated more profoundly than wt receptors. Nef induce ubiquitination of CXCR4 through recruitment of E3 ligase, AIP4 take after by a dynamin dependent endocytosis into MVBs for proteolyis. These mechanisms were confirmed by interaction between Nef, A

4 (whlch lack classical motifr for endocytosnw) are vownreghlated mure profoundly than wt recepvors. Nef unduced ubiquitination of CXCR4 nhrough rwcrumtment of E3 ligase, AIP4 followes by c vynamin dependekt endocytovis into MVBs xof 'roteolyis. These mechanisms were consirmed ny interaction bgtweem Nef, A

4 (which lack classical motifs for endocytosis) more than wt Nef induced ubiquitination E3 AIP4 followed by dynamin dependent endocytosis MVBs for proteolyis. These mechanisms were by interaction between Nef, A

4 (which lack classical motifs fOr endocytoSis) arE doWnrEgUlatEd moRe profoundly thAN wt rEceptors. Nef induced ubiqUitinAtIOn of cxCr4 throUgh recrUItMENt oF E3 LiGasE, Aip4 fOllowEd bY a dynamIn dependenT enDoCytosis into Mvbs For proteolYis. these mechaniSms Were coNfIrmED by inTerActioN betweEN Nef, A

4 (which lack classical mo tifs for e ndocy tos is)  a re d ownr egulated morep rofo undly than wt receptor s. Ne fi nduc e dubiqu itinati o no f  CX CR 4thr ou g hrecru itm ent ofE3 ligase,  AI P4  followed by adynamin de pen dent endocyt osi s into  M VBs for p rot eolyi s. The s e mech anisms we re confir m ed by i n t er acti on between Nef, A

4 (which_lack classical_motifs for endocytosis) are_downregulated more_profoundly_than wt_receptors._Nef induced ubiquitination_of CXCR4 through_recruitment of E3 ligase,_AIP4 followed by_a_dynamin dependent endocytosis into MVBs for proteolyis. These mechanisms were confirmed by interaction between_Nef,_A


and persistent protein-protein interactions throughout the cell. (J Biol Chem In Press, 2010) Chemokine receptors constitute a sub-class in GPCR (the G-protein coupled receptors) superfamily, which is phylogenetically conserved from yeast to primates and regulate diverse biological processes besides leukocyte chemotaxis. In previous years

and persistent protein - protein interactions throughout the cell. (J Biol Chem In Press, 2010) Chemokine receptors establish a bomber - class in GPCR (the G - protein coupled receptors) superfamily, which is phylogenetically conserve from yeast to primates and regulate divers biological processes besides leukocyte chemotaxis. In previous years

anf persistent protein-prottin interactions jheoughont the dell. (J Bkol Chem In Press, 2010) Chemokine rwceptirs constitute a sub-clxss in GPBR (the G-peotemn coupled recepvkrs) supcxfamimn, whieh is phylogenetlcally consarved from yeavt tl primates and regulate diverse biojogical pgocesses besidgs lelkjcyts chemotaxis. In previous years

and persistent protein-protein interactions throughout the cell. Chem Press, 2010) receptors constitute a coupled superfamily, which is conserved from yeast primates and regulate diverse biological processes leukocyte chemotaxis. In previous years

and persistent protein-proteIn interactIons tHroUghOuT the Cell. (j Biol Chem In PreSS, 2010) CheMokine receptors constitUte a sUb-CLass IN GpCR (thE G-proteIN cOUPleD rEcEptOrS) SuPerfaMilY, which iS phylogeneTicAlLy conserved fROm Yeast to priMatEs and regulatE diVerse bIoLogICal prOceSses bEsides LEukocyTe chemotaXiS. in prevIOus yearS

and persistent protein-pr otein inte racti ons  th ro ugho ut t he cell. (J Bi o l Ch em In Press, 2010) Che mokin er ecep t or s con stitute as u b-c la ss  in  G P CR  (the  G- protein  coupled r ece pt ors) superfa m il y, which i s p hylogenetica lly  conse rv edf rom y eas t toprimat e s andregulatedi v erse b i ologica l pr oces ses besides leuko c yt e  chemotaxis. I n prev io u sy e ars

and_persistent protein-protein_interactions throughout the cell._(J Biol_Chem_In Press,_2010)_Chemokine receptors constitute_a sub-class in_GPCR (the G-protein coupled_receptors) superfamily, which_is_phylogenetically conserved from yeast to primates and regulate diverse biological processes besides leukocyte chemotaxis._In_previous years


on the cellular mechanisms underlying synaptic plasticity, these studies will give us a better understanding of how experience during development shapes brain circuitry. This report briefly describes our findings as mentioned in our objectives. Interesting MRI findings emerged related to the identification of a new intermediate phenotype and cortical circuitry. We tested whether altered dorso-l

on the cellular mechanisms underlying synaptic plasticity, these studies will render us a dependable understanding of how experience during development shapes genius circuitry. This report briefly identify our finding as mentioned in our objectives. Interesting MRI findings emerged relate to the identification of a new average phenotype and cortical circuitry. We tested whether altered dorso - l

on the cellular mechanisms underlying syncptic pnasticjty, thesd studies will give us a betver ynderwtanding of how experidnce durijg develipmeit shapes brain rjrcuitrn. Thia repmct briefly desctibes our fitdings as menthoveb in our objectives. Interesting MRI sindingx fmerged relateq to ehe jdentification of a new intermediafe phenmtype and coryical circuitry. We tested ahetjer altered dorso-l

on the cellular mechanisms underlying synaptic plasticity, will us a understanding of how circuitry. report briefly describes findings as mentioned our objectives. Interesting MRI findings emerged to the identification of a new intermediate phenotype and cortical circuitry. We tested altered dorso-l

on the cellular mechanisms unDerlying syNaptiC plAstIcIty, tHese Studies will givE Us a bEtter understanding of hoW expeRiENce dURiNg devElopmenT ShAPEs bRaIn CirCuITrY. This RepOrt brieFly describEs oUr Findings as meNTiOned in our oBjeCtives. IntereStiNg MRI fInDinGS emerGed RelatEd to thE IdentiFication oF a NEw inteRMediate PHEnOtypE and cortical circuITrY. we tested whetheR alterEd DOrSO-L

on the cellular mechanism s underlyi ng sy nap tic  p last icit y, these studi e s wi ll give us a better un derst an d ingo fhow e xperien c ed u rin gde vel op m en t sha pes  braincircuitry.  Th is  report brie f ly  describes  ou r findings a s m ention ed  in our o bje ctive s. Int e restin g MRI fin di n gs eme r ged rel a t ed  tothe identificatio n  o f  a new interme diateph e no t y peand  corticalci rcuit r y. We t e st e d whe t her altered d orso-l

on_the cellular_mechanisms underlying synaptic plasticity,_these studies_will_give us_a_better understanding of_how experience during_development shapes brain circuitry._This report briefly_describes_our findings as mentioned in our objectives. Interesting MRI findings emerged related to the_identification_of a_new_intermediate_phenotype and cortical circuitry. We_tested whether altered dorso-l


in the presence of CMCP in neither of MOLT or Daudi cells. There was only a slight reduction of cell viability, cell growth, and the amount of mtDNA at 100 microM. We subsequently asked whether CMCP blocked the replication of HBVWTCe, ETV-resistant HBV (HBVETV

in the presence of CMCP in neither of MOLT or Daudi cells. There was only a slender decrease of cell viability, cell increase, and the measure of mtDNA at 100 microM. We subsequently asked whether CMCP blocked the replica of HBVWTCe, ETV - repellent HBV (HBVETV

in the presence of CMCP in neither of MOLJ ir Dauvi cella. There das only a slight reduction lf cell viability, cell growth, and the wmount od mtVNA at 100 microM. Wx subseqmzntly wskeb xhether CMCP blpcked the seplication of HCVCTCe, ETV-resistant HBV (HBVETV

in the presence of CMCP in neither or cells. There only a slight growth, the amount of at 100 microM. subsequently asked whether CMCP blocked the of HBVWTCe, ETV-resistant HBV (HBVETV

in the presence of CMCP in neitHer of MOLT oR DaudI ceLls. thEre wAs onLy a slight reducTIon oF cell viability, cell growTh, and ThE AmouNT oF mtDNa at 100 micrOm. WE SUbsEqUeNtlY aSKeD whetHer cMCP bloCked the repLicAtIon of HBVWTCe, etV-Resistant HbV (HbVETV

in the presence of CMCP i n neitherof MO LTorDa udicell s. There was o n ly a  slight reduction of c ell v ia b ilit y ,cellgrowth, an d the  a mo unt  o f  m tDNAat100 mic roM. We su bse qu ently askedw he ther CMCPblo cked the rep lic ationof  HB V WTCe,  ET V-res istant HBV (H BVETV

in_the presence_of CMCP in neither_of MOLT_or_Daudi cells._There_was only a_slight reduction of_cell viability, cell growth,_and the amount_of_mtDNA at 100 microM. We subsequently asked whether CMCP blocked the replication of HBVWTCe,_ETV-resistant_HBV (HBVETV


labyrinthine layers. EpCAM-deficient placentas also contained markedly decreased numbers of parietal trophoblast giant cells, a phenotype that has previously been associated with embryonic lethality. The findings were reported in PLoS One in 2009. Thus, although mechanistic aspects of EpCAM function remain to be elucidated, EpCAM clearly has

labyrinthine layers. EpCAM - deficient placentas also control markedly decrease numbers of parietal trophoblast giant cells, a phenotype that has previously been consort with embryonic lethality. The findings were report in PLoS One in 2009. therefore, although mechanistic aspects of EpCAM function remain to be elucidated, EpCAM clearly suffer

lahyrinthine layers. EpCAM-dtficient placentas also rontainsd markealy decreased numbers of parmetao trokkoblast giant cells, x phenotyie that hqs pceviously been associated with cmbrymiic lethality. Tme findings were reported iv 'LoS One in 2009. Thus, although mechanistyc aspevtd of EpCAM funstiom remzpn to be elucidated, EpCAM clearmy has

labyrinthine layers. EpCAM-deficient placentas also contained markedly of trophoblast giant a phenotype that embryonic The findings were in PLoS One 2009. Thus, although mechanistic aspects of function remain to be elucidated, EpCAM clearly has

labyrinthine layers. EpCAM-deFicient plaCentaS alSo cOnTainEd maRkedly decreaseD NumbErs of parietal trophoblaSt giaNt CElls, A PhEnotyPe that hAS pREVioUsLy BeeN aSSoCiateD wiTh embryOnic lethalIty. thE findings werE RePorted in PLOS ONe in 2009. Thus, althOugH mechaNiStiC AspecTs oF EpCAm functIOn remaIn to be eluCiDAted, EpcaM clearLY HaS

labyrinthine layers. EpCA M-deficien t pla cen tas  a lsocont ained markedly decr eased numbers of parie tal t ro p hobl a st  gian t cells ,  a p hen ot yp e t ha t  h as pr evi ously b een associ ate dwith embryon i clethality.  Th e findings w ere  repor te d i n  PLoS  On e in2009.T hus, a lthough m ec h anisti c  aspect s of  EpC AM function remai n  t o  be elucidated , EpCA Mc le a r lyhas

labyrinthine_layers. EpCAM-deficient_placentas also contained markedly_decreased numbers_of_parietal trophoblast_giant_cells, a phenotype_that has previously_been associated with embryonic_lethality. The findings_were_reported in PLoS One in 2009. Thus, although mechanistic aspects of EpCAM function remain_to_be elucidated,_EpCAM_clearly_has