. First, a HITI donor template bearing a CMV promoter-driven copGFP reporter gene flanked by 20-nt ITGB2-specific sgRNA target sequences (designated ITGB2-ts) was constructed and packaged within recombinant adeno-associated virus serotype 6 (rAAV6) caps

. First, a HITI donor template bearing a CMV promoter - driven copGFP reporter gene flank by 20 - national trust ITGB2 - specific sgRNA aim sequences (indicate ITGB2 - ts) was manufacture and packaged within recombinant adeno - associated virus serotype 6 (rAAV6) cap

. Figst, a HITI donor templatt bearing a CMV ptonoter-dciven ckpGFP reoorter gene flanked by 20-nt ITJB2-spwcifix sgRNA target sequencds (designwted ITGV2-ts) xas constructed ehd packaged wjbhin xerombinant adeno-sssociated virus serotypa 6 (rCAV6) caps

. First, a HITI donor template bearing promoter-driven reporter gene by 20-nt ITGB2-specific was and packaged within adeno-associated virus serotype (rAAV6) caps

. First, a HITI donor template beAring a CMV pRomotEr-dRivEn CopGfP rePorter gene flanKEd by 20-Nt ITGB2-specific sgRNA tarGet seQuENces (DEsIgnatEd ITGB2-tS) WaS COnsTrUcTed AnD PaCkageD wiThin recOmbinant adEno-AsSociated viruS SeRotype 6 (rAAV6) CapS

. First, a HITI donor temp late beari ng aCMV  pr om oter -dri ven copGFP rep o rter  gene flanked by 20-nt  ITGB 2- s peci f ic  sgRN A targe t  s e q uen ce s(de si g na ted I TGB 2-ts) w as constru cte dand packaged wi thin recom bin ant adeno-as soc iatedvi rus serot ype  6 (r AAV6)c aps

. First,_a HITI_donor template bearing a_CMV promoter-driven_copGFP_reporter gene_flanked_by 20-nt ITGB2-specific_sgRNA target sequences_(designated ITGB2-ts) was constructed_and packaged within_recombinant_adeno-associated virus serotype 6 (rAAV6) caps


rites, and N-nitroso compounds, and higher serum levels of polychlorinated biphenyls have been associated with increased risk. With respect to type 2 diabetes, data on arsenic and TCDD in relation to risk were suggestive of a direct association. The occupational data suggested that more data on exposure to

rites, and N - nitroso compounds, and higher serum levels of polychlorinated biphenyls have been consociate with increase risk. With respect to type 2 diabetes, data on arsenic and TCDD in relative to risk were suggestive of a lineal association. The occupational data suggested that more datum on vulnerability to

ritfs, and N-nitroso compoundr, and higher setun levens of lolychlofinated biphenyls have been essoxiatee with increased risk. Dith respvct to type 2 viabetes, data on arsenic and TDFD iu celation to risl were sugcestive of a dhrdcc association. The occupational data fuggestrd that more datw on qxpoalrt to

rites, and N-nitroso compounds, and higher serum polychlorinated have been with increased risk. diabetes, on arsenic and in relation to were suggestive of a direct association. occupational data suggested that more data on exposure to

rites, and N-nitroso compounds, And higher sErum lEveLs oF pOlycHlorInated biphenylS Have Been associated with incrEased RiSK. WitH ReSpect To type 2 dIAbETEs, dAtA oN arSeNIc And TCdD iN relatiOn to risk weRe sUgGestive of a diREcT associatiOn. THe occupationAl dAta sugGeSteD That mOre Data oN exposURe to

rites, and N-nitroso compo unds, andhighe r s eru mleve ls o f polychlorina t ed b iphenyls have been ass ociat ed with in creas ed risk .  W i t h r es pe ctto ty pe 2dia betes,data on ar sen ic  and TCDD in re lation toris k were sugge sti ve ofadir e ct as soc iatio n. The occupa tional da ta sugges t ed that m or e da ta on exposure to

rites, and_N-nitroso compounds,_and higher serum levels_of polychlorinated_biphenyls_have been_associated_with increased risk._With respect to_type 2 diabetes, data_on arsenic and_TCDD_in relation to risk were suggestive of a direct association. The occupational data suggested_that_more data_on_exposure_to


PP, and we are using next-generation sequencing to identify causative variants in known and novel candidate genes. Examining the genetic characteristics of subjects with pubertal disorders will reveal insights into the mechanisms underlying the reawakening of the hypothalamic-pituitary-gonadal axis at puberty. This will provide

PP, and we are using next - generation sequencing to name causative random variable in known and novel campaigner genes. examine the genetic characteristic of topic with pubertal disorders will uncover insights into the mechanisms underlie the reawakening of the hypothalamic - pituitary - gonadal axis at puberty. This will provide

PP, wnd we are using next-gentration sequenciny to idxntify dausativd variants in known and novep xandieate genes. Examining tfe genetib charactwrisuics of subjects xjth pubcxtal slsordzrw will reveal lnsights indo the mechanivmr bnderlying the reawakening of the hy[othalakif-pituitary-gonaqal svis zn kuberty. This will provide

PP, and we are using next-generation sequencing causative in known novel candidate genes. subjects pubertal disorders will insights into the underlying the reawakening of the hypothalamic-pituitary-gonadal at puberty. This will provide

PP, and we are using next-generaTion sequenCing tO idEntIfY cauSatiVe variants in knOWn anD novel candidate genes. ExAminiNg THe geNEtIc chaRacteriSTiCS Of sUbJeCts WiTH pUbertAl dIsorderS will reveaL inSiGhts into the mEChAnisms undeRlyIng the reawakEniNg of thE hYpoTHalamIc-pItuitAry-gonADal axiS at pubertY. THIs will PRovide

PP, and we are using next- generation  sequ enc ing  t o id enti fy causative v a rian ts in known and novelcandi da t e ge n es . Exa miningt he g ene ti ccha ra c te risti csof subj ects withpub er tal disorder s  w ill reveal  in sights intothe  mecha ni sms under lyi ng th e reaw a kening  of the h yp o thalam i c-pitui t a ry -gon adal axis at pube r ty .  This will pro vide

PP, and_we are_using next-generation sequencing to_identify causative_variants_in known_and_novel candidate genes._Examining the genetic_characteristics of subjects with_pubertal disorders will_reveal_insights into the mechanisms underlying the reawakening of the hypothalamic-pituitary-gonadal axis at puberty. This_will_provide


demonstrable in many cell types. Reconstitution with exogenous Gαi2 or other isoforms did not significantly rectify the chemotaxis defect. Unlike Nef induced loss, siRNA mediated Gαi2 KD did not diminish CXCL12 dependent signaling or alter CXCR4 expression. By degrading

demonstrable in many cell types. Reconstitution with exogenous Gαi2 or other isoforms did not significantly correct the chemotaxis blemish. Unlike Nef induced loss, siRNA intercede Gαi2 KD did not decrease CXCL12 dependent signaling or alter CXCR4 saying. By degrading

delonstrable in many cell uypes. Reconstitutnin witi exogehous Gαi2 ur other isoforms did not sijnifucantoy rectify the chemotabis defecn. Unlike Bef mnduced loss, siRIZ mediabzd Gαi2 ND dnd not diminish GXCL12 dependant signaling mr apter CXCR4 expression. By degrading

demonstrable in many cell types. Reconstitution with or isoforms did significantly rectify the loss, mediated Gαi2 KD not diminish CXCL12 signaling or alter CXCR4 expression. By

demonstrable in many cell typEs. ReconstiTutioN wiTh eXoGenoUs Gαi2 Or other isoformS Did nOt significantly rectify The chEmOTaxiS DeFect. UNlike NeF InDUCed LoSs, SiRnA MEdIated gαi2 Kd did not Diminish CXcL12 dEpEndent signalINg Or alter CXCr4 exPression. By deGraDing

demonstrable in many cell  types. Re const itu tio nwith  exo genous Gα i 2 or  other isoforms did no t sig ni f ican t ly  rect ify the ch e m ota xi sdef ec t .Unlik e N ef indu ced loss,siR NA  mediated G& # 94 5;i2 KD di d n ot diminishCXC L12 de pe nde n t sig nal ing o r alte r  CXCR4  expressi on .  By de g rading

demonstrable_in many_cell types. Reconstitution with_exogenous Gαi2_or_other isoforms_did_not significantly rectify_the chemotaxis defect._Unlike Nef induced loss,_siRNA mediated Gαi2_KD_did not diminish CXCL12 dependent signaling or alter CXCR4 expression. By degrading


patients have contracted T(CM) compartments and a defect in effector cell development, defects that persist even following clearance of infection. The fact that these global changes in memory and effector cell compartments do not yet occur in infected children makes early treatment of LF even more crucial. Beyond the APC dysfunction, T cells from patients with patent

patients have contracted T(CM) compartments and a defect in effecter cellular telephone exploitation, defects that prevail even postdate clearance of infection. The fact that these ball-shaped changes in memory and effector cell compartment do not yet occur in infect children makes early discussion of LF even more crucial. Beyond the APC dysfunction, T cells from patients with patent

pahients have contracted T(GM) compartments cbd a dxfect ih effectur cell development, defects vhat persust even following clexrance of infectiin. Tie fact that these global chanfcs in nemory and effgctor cell cmmpartments do nut yet occur in infected children makqs earlu hreatment of LS evtn iore brmcial. Beyond the APC dysfunction, T cellv from patienys with patent

patients have contracted T(CM) compartments and a effector development, defects persist even following that global changes in and effector cell do not yet occur in infected makes early treatment of LF even more crucial. Beyond the APC dysfunction, T from patients with patent

patients have contracted T(CM) CompartmenTs and A deFecT iN effEctoR cell developmeNT, defEcts that persist even folLowinG cLEaraNCe Of infEction. THE fACT thAt ThEse GlOBaL chanGes In memorY and effectOr cElL compartmentS Do Not yet occuR in Infected chilDreN makes EaRly TReatmEnt Of LF eVen morE CruciaL. Beyond thE Apc dysfuNCtion, T cELLs From Patients with patenT

patients have contractedT(CM) comp artme nts  an da de fect  in effector c e ll d evelopment, defects th at pe rs i st e v en  foll owing c l ea r a nce  o finf ec t io n. Th e f act tha t these gl oba lchanges in m e mo ry and eff ect or cell comp art mentsdo  no t  yetocc ur in  infec t ed chi ldren mak es earlyt reatmen t of  LFeven more crucial .  B e yond the APC d ysfunc ti o n, T  ce lls  from pati en ts wi t h paten t

patients_have contracted_T(CM) compartments and a_defect in_effector_cell development,_defects_that persist even_following clearance of_infection. The fact that_these global changes_in_memory and effector cell compartments do not yet occur in infected children makes early_treatment_of LF_even_more_crucial. Beyond the APC dysfunction,_T cells from patients with_patent


significantly lower compared to that in ETV-receiving mice (p0.0001). We finally analyzed the structural interactions of ETV-TP and CMCP-TP with reverse transcriptase (RT) of HBVWT. There are multiple strong polar interactions between CMCP-TP and the reverse transcriptase. The amino

significantly lower compared to that in ETV - receiving mouse (p0.0001). We ultimately analyzed the structural interactions of ETV - TP and CMCP - TP with inverse transcriptase (RT) of HBVWT. There are multiple strong diametric interactions between CMCP - TP and the reverse transcriptase. The amino

sihnificantly lower compartd to that in ETV-texeivinj mice (l0.0001). We finxlly analyzed the structural ibteraxtions of ETV-TP and CMZP-TP with reverse traiscriptase (RT) of HBVWT. Tmzre adc mulci'le strong polat interactiots between CMC[-TO cnd the reverse transcriptase. The amyno

significantly lower compared to that in ETV-receiving We analyzed the interactions of ETV-TP (RT) HBVWT. There are strong polar interactions CMCP-TP and the reverse transcriptase. The

significantly lower compareD to that in EtV-recEivIng MiCe (p0.0001). WE finAlly analyzed thE StruCtural interactions of ETv-TP anD CmcP-TP WItH reveRse tranSCrIPTasE (Rt) oF HBvWt. thEre arE muLtiple sTrong polar IntErActions betweEN CmCP-TP and thE reVerse transcrIptAse. The AmIno

significantly lower compa red to tha t inETV -re ce ivin g mi ce (p0.0001).W e fi nally analyzed the str uctur al inte r ac tions  of ETV - TP a ndCM CP -TP  w i th  reve rse  transc riptase (R T)of  HBVWT. Ther e  a re multipl e s trong polarint eracti on s b e tween  CM CP-TP  and t h e reve rse trans cr i ptase. The ami n o

significantly_lower compared_to that in ETV-receiving_mice (p0.0001)._We_finally analyzed_the_structural interactions of_ETV-TP and CMCP-TP_with reverse transcriptase (RT)_of HBVWT. There_are_multiple strong polar interactions between CMCP-TP and the reverse transcriptase. The amino


, several rare phenotypic categories have been described in men with IGD, including adult-onset IHH (Nachtigall, LB, et al, N Engl J Med, 1997) and reversal of the disorder after a period of treatment (Raivio, T, et al, N Engl J Med

, several rare phenotypic categories have been described in serviceman with IGD, include adult - onset IHH (Nachtigall, LB, et al, N Engl J Med, 1997) and reversal of the disorder after a menstruation of treatment (Raivio, T, et al, N Engl J Med

, segeral rare phenotypic cauegories have beeu descrmbed in men witf IGD, including adult-onset IIH (Nqchtitall, LB, et al, N Engl J Med, 1997) and reversao of rhe disordxd after a perjld oy vreatment (Raivip, T, et al, T Engl J Med

, several rare phenotypic categories have been men IGD, including IHH (Nachtigall, LB, Med, and reversal of disorder after a of treatment (Raivio, T, et al, Engl J Med

, several rare phenotypic cateGories have Been dEscRibEd In meN witH IGD, including aDUlt-oNset IHH (Nachtigall, LB, et aL, N EngL J mEd, 1997) anD ReVersaL of the dISoRDEr aFtEr A peRiOD oF treaTmeNt (RaiviO, T, et al, N EngL J MEd

, several rare phenotypiccategories  have  be ende scri bedin men with IG D , in cluding adult-onset IH H (Na ch t igal l ,LB, e t al, N En g l  JMe d,  19 97 )  a nd re ver sal ofthe disord eraf ter a period of  treatment  (R aivio, T, et  al , N En gl  JM ed

, several_rare phenotypic_categories have been described_in men_with_IGD, including_adult-onset_IHH (Nachtigall, LB,_et al, N_Engl J Med, 1997)_and reversal of_the_disorder after a period of treatment (Raivio, T, et al, N Engl J Med


cells (T(EFF)) than did ENs giving significantly smaller T(EFF):T(EM) ratios. These contracted T(CM) and T(EFF) populations were still evident in patients previously mf+ who had cleared their infection (CLInf). These data indicate that filarial-infected

cells (T(EFF) ) than did ENs giving importantly small T(EFF):T(EM) ratios. These compress T(CM) and T(EFF) population were still evident in affected role previously mf+ who had clear their infection (CLInf). These datum bespeak that filarial - infected

cepls (T(EFF)) than did ENs giying significantly smalner T(ERF):T(EM) ragios. These contracted T(CM) anv T(EDF) pokllations were still exident in patientw prtviously mf+ who hes clearcb thejv infzcvion (CLInf). Thesg data indicdte that filarhau-iufected

cells (T(EFF)) than did ENs giving significantly ratios. contracted T(CM) T(EFF) populations were mf+ had cleared their (CLInf). These data that filarial-infected

cells (T(EFF)) than did ENs giving SignificanTly smAllEr T(eFf):T(EM) RatiOs. These contracTEd T(Cm) and T(EFF) populations werE stilL eVIdenT In PatieNts prevIOuSLY mf+ WhO hAd cLeAReD theiR inFection (cLInf). These DatA iNdicate that fILaRial-infectEd

cells (T(EFF)) than did E Ns givingsigni fic ant ly  sma ller  T(EFF):T(EM)r atio s. These contracted T( CM) a nd T(EF F )popul ationsw er e sti ll  e vid en t  i n pat ien ts prev iously mf+  wh ohad clearedt he ir infecti on(CLInf). The sedata i nd ica t e tha t f ilari al-inf e cted

cells_(T(EFF)) than_did ENs giving significantly_smaller T(EFF):T(EM)_ratios._These contracted_T(CM)_and T(EFF) populations_were still evident_in patients previously mf+_who had cleared_their_infection (CLInf). These data indicate that filarial-infected


whether improving basic cognition aided in maintaining functional independence in elders. As to be reported in JAMA (11/12/02), Phase I found strong, broad and durable cognitive ability-specific training effects. The effect sizes were comparable to or greater than the amount of cognitive decline observed in other longitudinal studies, suggesting that the

whether improving basic cognition aided in maintaining functional independence in elder. As to be report in JAMA (11/12/02), Phase I found strong, broad and durable cognitive ability - specific education effects. The effect sizes were comparable to or capital than the amount of cognitive decline observe in other longitudinal studies, indicate that the

whfther improving basic connition aided in maintamning fhnctionau independence in elders. As vo bw repirted in JAMA (11/12/02), Phase I found stgong, broae anv durable cognitmbe abillcy-spedlfic creining effects. Jhe effect shzes were compdrxbpe to or greater than the amount of cognitovf decline obsetved pn othsg oongitudinal studies, suggestihg that the

whether improving basic cognition aided in maintaining in As to reported in JAMA broad durable cognitive ability-specific effects. The effect were comparable to or greater than amount of cognitive decline observed in other longitudinal studies, suggesting that the

whether improving basic cognItion aided In maiNtaIniNg FuncTionAl independence IN eldErs. As to be reported in JAMa (11/12/02), PhasE I FOund STrOng, brOad and dURaBLE coGnItIve AbILiTy-speCifIc trainIng effects. the EfFect sizes werE CoMparable to Or gReater than thE amOunt of CoGniTIve deCliNe obsErved iN Other lOngitudinAl STudies, SUggestiNG ThAt thE

whether improving basic c ognition a idedinmai nt aini ng f unctional inde p ende nce in elders. As to b e rep or t ed i n  J AMA ( 11/12/0 2 ), P has eIfou nd st rong,  br oad and  durable c ogn it ive ability- s pe cific trai nin g effects. T heeffect  s ize s  were  co mpara ble to or gre ater than  t h e amou n t of co g n it ivedecline observedi no ther longitudi nal st ud i es , sug ges ting thatth e

whether_improving basic_cognition aided in maintaining_functional independence_in_elders. As_to_be reported in_JAMA (11/12/02), Phase_I found strong, broad_and durable cognitive_ability-specific_training effects. The effect sizes were comparable to or greater than the amount of_cognitive_decline observed_in_other_longitudinal studies, suggesting that the


are previously unidentified psychological features in need of further investigation. Preliminary results from this pilot study suggest that there is an increase in both anxiety and depression symptoms in the IGD group, and that this can be ascertained by online surveys to improve recruitment. As a result of the phenotyping efforts pioneered by our collaborators at MGH

are previously unidentified psychological features in need of further investigation. Preliminary result from this pilot burner study suggest that there is an addition in both anxiety and depression symptoms in the IGD group, and that this can be ascertained by on-line surveys to improve recruitment. As a consequence of the phenotyping efforts pioneered by our collaborator at MGH

arf previously unidentifiea psychological featurxs in nsed of fjrther investigation. Prelimiiary resuots from this pilot stjdy suggedt that rhert is an increase mh both anxietg and vepression sympjoms in the HGD group, and dhxt this can be ascertained by online furveys tl improve recroitmeme. As a result of the phenotyping efforfs piontered by our collanorators at MGH

are previously unidentified psychological features in need investigation. results from pilot study suggest in anxiety and depression in the IGD and that this can be ascertained online surveys to improve recruitment. As a result of the phenotyping efforts pioneered our collaborators at MGH

are previously unidentified PsychologiCal feAtuRes In Need Of fuRther investigaTIon. PReliminary results from tHis piLoT StudY SuGgest That theRE iS AN inCrEaSe iN bOTh AnxieTy aNd depreSsion symptOms In The IGD group, aND tHat this can Be aScertained by OnlIne surVeYs tO ImproVe rEcruiTment. AS A resulT of the pheNoTYping eFForts piONEeRed bY our collaborators AT Mgh

are previously unidentifi ed psychol ogica l f eat ur es i n ne ed of furtheri nves tigation. Preliminaryresul ts from th is pi lot stu d ys u gge st  t hat  t h er e isanincreas e in bothanx ie ty and depre s si on symptom s i n the IGD gr oup , andth att his c anbe as certai n ed byonline su rv e ys toi mprover e cr uitm ent. As a resulto ft he phenotyping  effor ts pi o n eer edby our col la borat o rs at M G H

are_previously unidentified_psychological features in need_of further_investigation._Preliminary results_from_this pilot study_suggest that there_is an increase in_both anxiety and_depression_symptoms in the IGD group, and that this can be ascertained by online surveys_to_improve recruitment._As_a_result of the phenotyping efforts_pioneered by our collaborators at_MGH


infection have induced pathways that in concert prevent Th1-type T cell activation. We have recently shown that the filarial infection at homeostasis is associated with an expansion of IL-10 producing adaptive Tregs as well as nTregs and that these are associated with the suppression of parasite-antigen induced pro-inflammatory Th

infection have induced pathways that in concert prevent Th1 - type metric ton cellular telephone activation. We have recently shown that the filarial contagion at homeostasis is associated with an expansion of IL-10 produce adaptive Tregs as well as nTregs and that these are associate with the suppression of parasite - antigen induce pro - inflammatory Th

invection have induced patmways that in couxert pcevent Fh1-type T cell activation. We have recxntlt shoqn that the filarial ivfection wt homeowtasms is associated with an expanalon oy ML-10 producing adsptive Trecs as well as tTfeys and that these are associated witr the siporession of patasitt-aneigeh induced pro-inflammatory Th

infection have induced pathways that in concert T activation. We recently shown that is with an expansion IL-10 producing adaptive as well as nTregs and that are associated with the suppression of parasite-antigen induced pro-inflammatory Th

infection have induced pathwAys that in cOncerT prEveNt th1-tyPe T cEll activation. WE Have Recently shown that the fiLariaL iNFectIOn At homEostasiS Is ASSocIaTeD wiTh AN eXpansIon Of IL-10 proDucing adapTivE TRegs as well as NtrEgs and that TheSe are associaTed With thE sUppREssioN of ParasIte-antIGen indUced pro-inFlAMmatorY th

infection have induced pa thways tha t incon cer tprev entTh1-type T cel l  act ivation. We have recen tly s ho w n th a tthe f ilarial in f e cti on  a t h om e os tasis  is  associ ated withanex pansion of I L -1 0 producin g a daptive Treg s a s well  a s n T regsand  that  these are as sociatedwi t h thes uppress i o nof p arasite-antigen i n du c ed pro-inflamm atoryTh

infection_have induced_pathways that in concert_prevent Th1-type_T_cell activation._We_have recently shown_that the filarial_infection at homeostasis is_associated with an_expansion_of IL-10 producing adaptive Tregs as well as nTregs and that these are associated_with_the suppression_of_parasite-antigen_induced pro-inflammatory Th


they have little intrinsic market value. So, investigators must obtain the key reagents of the assay from R&D suppliers that do not adhere to quality assurance measures required of manufacturers of diagnostic tests that are critical for achieving consistent lot-to-lot content and performance. The SAIC-Frederick clinical PD support program has

they have little intrinsic market value. So, detective must receive the key reagents of the assay from R&D suppliers that do not stand by to quality assurance measures want of manufacturer of diagnostic tests that are critical for achieve reproducible lot - to - draw content and performance. The SAIC - Frederick clinical PD accompaniment platform has

thfy have little intrinsic market value. So, invesvigatora must octain the key reagents of thx asway feom R&D suppliers that ao not adjere to wualmty assurance meeaures rczuirsf of nanufacturers pf diagnosdic tests that afe critical for achieving consistent jot-to-loy fontent and petformsgce. Fhe SAIC-Frederick clinical PD suppkrt projram has

they have little intrinsic market value. So, obtain key reagents the assay from adhere quality assurance measures of manufacturers of tests that are critical for achieving lot-to-lot content and performance. The SAIC-Frederick clinical PD support program has

they have little intrinsic maRket value. SO, inveStiGatOrS musT obtAin the key reageNTs of The assay from R&D supplierS that Do NOt adHErE to quAlity asSUrANCe mEaSuRes ReQUiRed of ManUfacturErs of diagnOstIc Tests that are CRiTical for acHieVing consisteNt lOt-to-loT cOntENt and PerFormaNce. The saIC-FreDerick cliNiCAl PD suPPort proGRAm Has

they have little intrinsi c market v alue.  So , i nv esti gato rs must obtain thekey reagents of the as say f ro m  R&D su pplie rs that do n otad he reto qu ality  as surance  measuresreq ui red of manuf a ct urers of d iag nostic tests  th at are  c rit i cal f orachie ving c o nsiste nt lot-to -l o t cont e nt andp e rf orma nce. The SAIC-Fre d er i ck clinical PD  suppo rt pr o g ram  ha s

they_have little_intrinsic market value. So,_investigators must_obtain_the key_reagents_of the assay_from R&D suppliers_that do not adhere_to quality assurance_measures_required of manufacturers of diagnostic tests that are critical for achieving consistent lot-to-lot content_and_performance. The_SAIC-Frederick_clinical_PD support program has


potential roles at exocytic sites. Through this work we developed a universal map of the proteins that control exocytosis and provide a new global network level analysis of vesicle fusion. We were able to identify unique classes of key regulatory molecules that strongly associate with the vast majority of docked exocytic vesicles in endocrine chromaffin and beta

potential roles at exocytic sites. Through this work we develop a cosmopolitan map of the proteins that see exocytosis and put up a new global net level analysis of vesicle fusion. We were able to name alone classes of cardinal regulatory molecules that strongly associate with the huge majority of docked exocytic vesicles in hormone chromaffin and beta

pohential roles at exocytig sites. Through jhus worn we dsveloped a universal map of the protxins that control exocytosis ana provide a new goobao network lxbel analysis kn vesncoe fusion. We wgre able to hdentify uniqua zlcsses of key regulatory molecules thwt stromgpy associate wyth uhe vasf majority of docked exocytic vesidles in endocrine chtomaffin and beta

potential roles at exocytic sites. Through this developed universal map the proteins that new network level analysis vesicle fusion. We able to identify unique classes of regulatory molecules that strongly associate with the vast majority of docked exocytic vesicles endocrine chromaffin and beta

potential roles at exocytic sItes. ThrougH this WorK we DeVeloPed a Universal map of THe prOteins that control exocyTosis AnD ProvIDe A new gLobal neTWoRK LevEl AnAlySiS Of VesicLe fUsion. We Were able to IdeNtIfy unique claSSeS of key reguLatOry molecules ThaT stronGlY asSOciatE wiTh the Vast maJOrity oF docked exOcYTic vesICles in eNDOcRine Chromaffin and beta

potential roles at exocyt ic sites.Throu ghthi swork  wedeveloped a un i vers al map of the proteins  that  c o ntro l  e xocyt osis an d  p r o vid eanew  g l ob al ne two rk leve l analysis  of  v esicle fusio n .We were ab leto identifyuni que cl as ses of ke y r egula tory m o lecule s that st ro n gly as s ociatew i th  the  vast majority of do c ked exocytic v esicle si ne n doc rin e chromaff in  andb eta

potential_roles at_exocytic sites. Through this_work we_developed_a universal_map_of the proteins_that control exocytosis_and provide a new_global network level_analysis_of vesicle fusion. We were able to identify unique classes of key regulatory molecules_that_strongly associate_with_the_vast majority of docked exocytic_vesicles in endocrine chromaffin and_beta


of the pancreatic islets. Along with these studies we have developed a new super-resolution correlative light and electron microscopy method (CLEM). This CLEM method allows us to image the location of identified proteins in the nano-scale structural context of the cellular environment. Specifically, we have succeeded in developing a robust pipeline for

of the pancreatic islets. Along with these studies we have developed a new ace - settlement correlative light and electron microscopy method (CLEM). This CLEM method acting allows us to visualize the location of identified protein in the nano - scale structural context of the cellular environment. Specifically, we have succeeded in develop a robust pipeline for

of the pancreatic islets. Auong with these studiev we hzve deveuoped a new super-resolution rorrwlatice light and electron oicroscopj method (XLEM). Rhis CLEM method allows hd to mmage the locatlon of idendified proteinv kn the nano-scale structural context os the crlpular environmgnt. Skecyficzlly, we have succeeded in developihg a rouust pipeline fpr

of the pancreatic islets. Along with these have a new correlative light and CLEM allows us to the location of proteins in the nano-scale structural context the cellular environment. Specifically, we have succeeded in developing a robust pipeline for

of the pancreatic islets. AlonG with these StudiEs wE haVe DeveLopeD a new super-resoLUtioN correlative light and elEctroN mICrosCOpY methOd (CLEM). THIs cleM mEtHoD alLoWS uS to imAge The locaTion of idenTifIeD proteins in tHE nAno-scale stRucTural context Of tHe cellUlAr eNVironMenT. SpecIficalLY, we havE succeedeD iN DeveloPIng a robUST pIpelIne for

of the pancreatic islets.  Along wit h the sestu di es w e ha ve developed a newsuper-resolution corre lativ el ight an d ele ctron m i cr o s cop yme tho d( CL EM).Thi s CLEMmethod all ows  u s to image t h elocation o f i dentified pr ote ins in  t hen ano-s cal e str uctura l  conte xt of the  c e llular environ m e nt . Sp ecifically, we ha v es ucceeded in de velopi ng ar o bus t p ipeline fo r

of_the pancreatic_islets. Along with these_studies we_have_developed a_new_super-resolution correlative light_and electron microscopy_method (CLEM). This CLEM_method allows us_to_image the location of identified proteins in the nano-scale structural context of the cellular_environment._Specifically, we_have_succeeded_in developing a robust pipeline_for


of the polymer concentration and the calcium ion content, and is close to the value of the DNA double helix (10 A). This finding implies that bundle formation is negligible in the present DNA gels. The results of this study show that changes in the ionic environment offer a molecular level control of the interactions between DNA strands and allow

of the polymer concentration and the calcium ion content, and is close to the value of the DNA bivalent coil (10 ampere). This finding implies that bundle geological formation is negligible in the present DNA gels. The resultant role of this sketch show that deepen in the ionic environment offer a molecular level command of the interactions between DNA strand and admit

of the polymer concentratiun and the calcnym ion conteht, and ir close to the value of the VNA eoublt helix (10 A). This finaing implpes that vundow formatioi is negligibls in chx present DNA ggls. The resunts of this stgdh dhow that changes in the ionic enviwonment ovfer a moleculwr ltvej cohnril of the interactions betweeh DNA surands and allow

of the polymer concentration and the calcium and close to value of the This implies that bundle is negligible in present DNA gels. The results of study show that changes in the ionic environment offer a molecular level control the interactions between DNA strands and allow

of the polymer concentration And the calcIum ioN coNteNt, And iS cloSe to the value of THe DNa double helix (10 A). This findiNg impLiES thaT BuNdle fOrmatioN Is NEGliGiBlE in ThE PrEsent dNA Gels. The Results of tHis StUdy show that cHAnGes in the ioNic Environment oFfeR a moleCuLar LEvel cOntRol of The intERactioNs between dNa StrandS And alloW

of the polymer concentrat ion and th e cal ciu m i on  con tent , and is close to t he value of the DNA do ublehe l ix ( 1 0A). T his fin d in g imp li es  th at bu ndlefor mationis negligi ble  i n the presen t  D NA gels. T heresults of t his  study  s how thatcha ngesin the ionicenvironme nt offera  molecu l a rleve l control of thei nt e ractions betwe en DNA  s t ra n d s a ndallow

of_the polymer_concentration and the calcium_ion content,_and_is close_to_the value of_the DNA double_helix (10 A). This_finding implies that_bundle_formation is negligible in the present DNA gels. The results of this study show_that_changes in_the_ionic_environment offer a molecular level_control of the interactions between_DNA strands_and allow


segment of this region. As a further test, we subdivided the 540 kb ED4065 deletion and the 389 kb ED2247 deletion. In both cases, dosage sensitivity could be recapitulated by a 50 kb deletion. In each of these regions, is a single gene responsible for the anesthesia phenotype? Our test

segment of this region. As a further test, we subdivided the 540 kilobyte ED4065 omission and the 389 kb ED2247 deletion. In both lawsuit, dose sensitivity could be recapitulated by a 50 kb omission. In each of these regions, is a single gene responsible for the anesthesia phenotype? Our trial

sehment of this region. As x further test, cw subdmvided fhe 540 kb DD4065 deletion and the 389 kb ED2247 dxletuon. Ib both cases, dosage sevsitivity could bw rerapitulated by a 50 kb delccion. Jk eack if these regioks, is a sincle gene respotskbpe for the anesthesia phenotype? Our test

segment of this region. As a further subdivided 540 kb deletion and the both dosage sensitivity could recapitulated by a kb deletion. In each of these is a single gene responsible for the anesthesia phenotype? Our test

segment of this region. As a furTher test, we SubdiVidEd tHe 540 Kb ED4065 DeleTion and the 389 kb ED2247 DEletIon. In both cases, dosage seNsitiViTY couLD bE recaPitulatED bY A 50 Kb dElEtIon. in EAcH of thEse Regions, Is a single gEne ReSponsible for THe Anesthesia PheNotype? Our tesT

segment of this region. A s a furthe r tes t,wesu bdiv ided  the 540 kb ED 4 065deletion and the 389 k b ED2 24 7  del e ti on. I n bothc as e s , d os ag e s en s it ivity  co uld berecapitula ted  b y a 50 kb de l et ion. In ea chof these reg ion s, isasin g le ge nerespo nsible for th e anesthe si a  pheno t ype? Ou r te st

segment_of this_region. As a further_test, we_subdivided_the 540_kb_ED4065 deletion and_the 389 kb_ED2247 deletion. In both_cases, dosage sensitivity_could_be recapitulated by a 50 kb deletion. In each of these regions, is a_single_gene responsible_for_the_anesthesia phenotype? Our test


-NETs originate from a subset of EC cells (reserve EC cells that express reserve ISC genes) via multifocal and polyclonal processes. The epithelium of the small intestine renews itself every 3-5 days as a result of actively cycling intestinal stem cells ISCs residing at the crypt base. Most recently, we

-NETs originate from a subset of EC cells (reserve EC cells that express reservation ISC gene) via multifocal and polyclonal processes. The epithelium of the small intestine regenerate itself every 3 - 5 day as a result of actively cycling intestinal bow cell ISCs residing at the crypt foundation. Most recently, we

-NETd originate from a subseu of EC cells (resgrce EC rells tgat exprdss reserve ISC genes) via muptufocao and polyclonal procerses. The vpitheliun of rhe small mhtestinc rensas icsxlf every 3-5 days as a resunt of actively chcping intestinal stem cells ISCs resyding ay hhe crypt base. Mosu rqcenfly, we

-NETs originate from a subset of EC EC that express ISC genes) via epithelium the small intestine itself every 3-5 as a result of actively cycling stem cells ISCs residing at the crypt base. Most recently, we

-NETs originate from a subset oF EC cells (reServe eC cEllS tHat eXpreSs reserve ISC geNEs) viA multifocal and polyclonAl proCeSSes. THE ePitheLium of tHE sMALl iNtEsTinE rENeWs itsElf Every 3-5 daYs as a resulT of AcTively cyclinG InTestinal stEm cElls ISCs resiDinG at the CrYpt BAse. MoSt rEcentLy, we

-NETs originate from a sub set of ECcells  (r ese rv e EC  cel ls that expres s  res erve ISC genes) via mu ltifo ca l  and po lyclo nal pro c es s e s.Th eepi th e li um of  th e small  intestine  re ne ws itself ev e ry  3-5 daysasa result ofact ivelycy cli n g int est inalstem c e lls IS Cs residi ng at the crypt b a s e.  Mos t recently, we

-NETs originate_from a_subset of EC cells_(reserve EC_cells_that express_reserve_ISC genes) via_multifocal and polyclonal_processes. The epithelium of_the small intestine_renews_itself every 3-5 days as a result of actively cycling intestinal stem cells ISCs_residing_at the_crypt_base._Most recently, we


, and 23 nM to block HBV DNA synthesis in HepG2.2.2.15.7 cells for ETV, CdG, and CMCP, respectively. We further examined the effects of CMCP on cellular mitochondrial DNA (mtDNA), cell growth, and cell viability using MOLT-4 and D

, and 23 nM to block HBV DNA synthesis in HepG2.2.2.15.7 cells for ETV, CdG, and CMCP, respectively. We further probe the effect of CMCP on cellular mitochondrial DNA (mtDNA), cell growth, and cell viability use MOLT-4 and D

, anf 23 nM to block HBV DNA snnthesis in HepG2.2.2.15.7 cells hor ETV, CdG, and CMCP, respectively. We furthec exqminee the effects of CMCP un cellulwr mitocyondcial DNA (mtDNA), cxml growbk, and gell riebility using MPLT-4 and D

, and 23 nM to block HBV in cells for CdG, and CMCP, effects CMCP on cellular DNA (mtDNA), cell and cell viability using MOLT-4 and

, and 23 nM to block HBV DNA synthesIs in HepG2.2.2.15.7 ceLls foR ETv, Cdg, aNd CMcP, reSpectively. We fuRTher Examined the effects of CMcP on cElLUlar MItOchonDrial DNa (Mtdna), ceLl GrOwtH, aND cEll viAbiLity usiNg MOLT-4 and D

, and 23 nM to block HBV D NA synthes is in  He pG2 .2 .2.1 5.7cells for ETV, CdG,  and CMCP, respectivel y. We  f u rthe r  e xamin ed thee ff e c tsof  C MCP  o n  c ellul armitocho ndrial DNA  (m tD NA), cell gr o wt h, and cel l v iability usi ngMOLT-4  a ndD

, and_23 nM_to block HBV DNA_synthesis in_HepG2.2.2.15.7_cells for_ETV,_CdG, and CMCP,_respectively. We further_examined the effects of_CMCP on cellular_mitochondrial_DNA (mtDNA), cell growth, and cell viability using MOLT-4 and D


it is highly likely that excellent hypotheses about human endocrine disruption will arise, and that the NCS should be designed to accommodate as many such possibilities as is feasible. We reviewed the epidemiologic data that addressed whether environmental contaminants might cause type 1 or type 2 diabetes. For type 1 diabetes, higher intake of nitrates, nit

it is highly likely that excellent hypotheses about human endocrine disruption will rebel, and that the NCS should be design to accommodate as many such possibilities as is feasible. We reviewed the epidemiologic datum that addressed whether environmental contaminants might cause character 1 or character 2 diabetes. For type 1 diabetes, higher intake of nitrates, nit

it is highly likely that ewcellent hypotheses abont humah endocrkne disruption will arise, anv thqt tht NCS should be deskgned to wccommodqte es many such possibiliticf as ls fecsmble. We reviewec the epidamiologic data tfac addressed whether environmental cogtaminamtd might cause jype 1 jr tgie 2 diabetes. For type 1 diabetes, higher intake of niyrates, nit

it is highly likely that excellent hypotheses endocrine will arise, that the NCS as such possibilities as feasible. We reviewed epidemiologic data that addressed whether environmental might cause type 1 or type 2 diabetes. For type 1 diabetes, higher of nitrates, nit

it is highly likely that excelLent hypothEses aBouT huMaN endOcriNe disruption wiLL ariSe, and that the NCS should bE desiGnED to aCCoMmodaTe as manY SuCH PosSiBiLitIeS As Is feaSibLe. We revIewed the epIdeMiOlogic data thAT aDdressed whEthEr environmenTal ContamInAntS Might CauSe typE 1 or typE 2 DiabetEs. For type 1 DiABetes, hIGher intAKE oF nitRates, nit

it is highly likely thatexcellenthypot hes esab outhuma n endocrine di s rupt ion will arise, and th at th eN CS s h ou ld be  design e dt o  ac co mm oda te as  many  su ch poss ibilitiesasis  feasible. W e  r eviewed th e e pidemiologic  da ta tha tadd r essed  wh ether  envir o nmenta l contami na n ts mig h t cause t yp e 1or type 2 diabete s .F or type 1 diab etes,hi g he r int ake  of nitrat es , nit

it_is highly_likely that excellent hypotheses_about human_endocrine_disruption will_arise,_and that the_NCS should be_designed to accommodate as_many such possibilities_as_is feasible. We reviewed the epidemiologic data that addressed whether environmental contaminants might cause_type_1 or_type_2_diabetes. For type 1 diabetes,_higher intake of nitrates, nit


revealed two characteristic length scales, the mesh size of the transient network, and the cross-sectional radius of the DNA double helix. In gels the mesh size is greater than in the corresponding solutions by approximately 50%, reflecting the increased heterogeneity of the crosslinked system. The cross-sectional radius of the DNA chain is practically independent

revealed two characteristic length scales, the mesh size of the transeunt net, and the cross - sectional radius of the DNA bivalent helix. In gelatin the mesh size is greater than in the match solutions by approximately 50% , reflecting the increase heterogeneity of the crosslinked system. The cross - sectional spoke of the DNA chain is practically independent

regealed two characteristig length scales, jhw mesh size kf the tfansient network, and the crods-wectiinal radius of the DNA double hvlix. In gwls uhe mesh size is jdeater bkan ih the rorresponding splutions bf approximatelf 50%, rzflecting the increased heterogeneitr of thr frosslinked syftem. Ehe dgows-sectional radius of the DNA chain ps practically incependent

revealed two characteristic length scales, the mesh the network, and cross-sectional radius of gels mesh size is than in the solutions by approximately 50%, reflecting the heterogeneity of the crosslinked system. The cross-sectional radius of the DNA chain is independent

revealed two characteristic Length scalEs, the MesH siZe Of thE traNsient network, aND the Cross-sectional radius of The DNa dOUble HElIx. In gEls the mESh SIZe iS gReAteR tHAn In the CorRespondIng solutioNs bY aPproximately 50%, REfLecting the IncReased heteroGenEity of ThE crOSslinKed SysteM. The crOSs-sectIonal radiUs OF the DNa Chain is PRAcTicaLly independent

revealed two characterist ic lengthscale s,the  m eshsize  of the transi e nt n etwork, and the cross- secti on a l ra d iu s ofthe DNA do u b lehe li x.In ge ls th e m esh siz e is great erth an in the co r re sponding s olu tions by app rox imatel y50% ,  refl ect ing t he inc r easedheterogen ei t y of t h e cross l i nk ed s ystem. The cross- s ec t ional radius o f theDN A  c h a inispracticall yindep e ndent

revealed_two characteristic_length scales, the mesh_size of_the_transient network,_and_the cross-sectional radius_of the DNA_double helix. In gels_the mesh size_is_greater than in the corresponding solutions by approximately 50%, reflecting the increased heterogeneity of_the_crosslinked system._The_cross-sectional_radius of the DNA chain_is practically independent


converting enzyme (TACE, ADAM17) cleaves membrane-associated cytokines and receptors and thereby regulates inflammatory and immune events, as well as lung development and mucin production. TACE is synthesized as a latent pro-enzyme that is retained in an inactive state via an interaction between its pro-domain and catalytic domain

converting enzyme (TACE, ADAM17) cleaves membrane - associated cytokines and receptors and thereby determine incendiary and immune events, as well as lung growth and mucin output. TACE is synthesized as a latent pro - enzyme that is retain in an dormant state via an interaction between its pro - domain and catalytic domain

cojverting enzyme (TACE, ADAO17) cleaves membrcbe-assoriated dytokiner and receptors and thereby ceguoates inflammatory and immuve events, as well as oyng develo'jent and mucih proburtion. TACE is sinthesized av a latent pro-anxyle that is retained in an inactive ftate voa an interactiog beuweqn ifs pro-domain and catalytic domain

converting enzyme (TACE, ADAM17) cleaves membrane-associated cytokines and regulates inflammatory immune events, as mucin TACE is synthesized a latent pro-enzyme is retained in an inactive state an interaction between its pro-domain and catalytic domain

converting enzyme (TACE, ADAM17) cLeaves membRane-aSsoCiaTeD cytOkinEs and receptors ANd thEreby regulates inflammaTory aNd IMmunE EvEnts, aS well as LUnG DEveLoPmEnt AnD MuCin prOduCtion. TAcE is syntheSizEd As a latent pro-ENzYme that is rEtaIned in an inacTivE state ViA an INteraCtiOn betWeen itS Pro-domAin and catAlYTic domAIn

converting enzyme (TACE,ADAM17) cl eaves  me mbr an e-as soci ated cytokines andreceptors and therebyregul at e s in f la mmato ry andi mm u n e e ve nt s,as we ll as  lu ng deve lopment an d m uc in productio n .TACE is sy nth esized as alat ent pr o- enz y me th atis re tained in aninactivest a te via an inte r a ct ionbetween its pro-d o ma i n and catalyti c doma in

converting_enzyme (TACE,_ADAM17) cleaves membrane-associated cytokines_and receptors_and_thereby regulates_inflammatory_and immune events,_as well as_lung development and mucin_production. TACE is_synthesized_as a latent pro-enzyme that is retained in an inactive state via an interaction_between_its pro-domain_and_catalytic_domain


extracts from parasitized erythrocytes, binding to immobilized aptamers, and identification of target molecules by mass spectrometry. However, we now have bands on SDS-PAGE gels and are confident we will have identification of target molecules. Using our standardized blood-stage parasite growth inhibition assay (GIA), we have collaborated with others in

extracts from parasitized erythrocytes, binding to immobilized aptamers, and identification of prey molecule by mass spectrometry. However, we now own bands on SDS - PAGE gelatin and are convinced we will have identification of target molecules. Using our exchangeable blood - stage parasite growth prohibition assay (GIA), we have collaborated with others in

exhracts from parasitized trythrocytes, bindnbg to mmmobiljzed aptxmers, and identification of vargwt mooecules by mass spectrumetry. Hoaever, we now yave bands on SDS-PAGE gemd anb ere confident wg will have hdentification ow carget molecules. Using our standardised blopd-dtage parasite groeeh ihhibition assay (GIA), we have collabkrated xith others in

extracts from parasitized erythrocytes, binding to immobilized identification target molecules mass spectrometry. However, SDS-PAGE and are confident will have identification target molecules. Using our standardized blood-stage growth inhibition assay (GIA), we have collaborated with others in

extracts from parasitized erYthrocytes, BindiNg tO imMoBiliZed aPtamers, and idenTIficAtion of target molecules By masS sPEctrOMeTry. HoWever, we NOw HAVe bAnDs On SdS-paGe gels And Are confIdent we wilL haVe IdentificatiON oF target molEcuLes. Using our sTanDardizEd BloOD-stagE paRasitE growtH InhibiTion assay (gIa), We have COllaborATEd With Others in

extracts from parasitized  erythrocy tes,bin din gto i mmob ilized aptamer s , an d identification of ta rgetmo l ecul e sby ma ss spec t ro m e try .Ho wev er ,  w e now  ha ve band s on SDS-P AGE  g els and arec on fident wewil l have ident ifi cation  o f t a rgetmol ecule s. Usi n g ourstandardi ze d  blood - stage p a r as itegrowth inhibition as s ay (GIA), we h ave co ll a bo r a ted  wi th othersin

extracts_from parasitized_erythrocytes, binding to immobilized_aptamers, and_identification_of target_molecules_by mass spectrometry._However, we now_have bands on SDS-PAGE_gels and are_confident_we will have identification of target molecules. Using our standardized blood-stage parasite growth inhibition_assay_(GIA), we_have_collaborated_with others in


antigenic and sequence analysis of these as a prelude to their evaluation for attenuation and safety in non-human primates as potential vectors. Complete sequences have been determined for representatives of APMV2, 3, 4, 7, 8, and 9. In some cases, complete sequences are available for more than one strain

antigenic and sequence analysis of these as a prelude to their evaluation for attenuation and safety in non - human archpriest as likely vectors. Complete sequence have been determine for representatives of APMV2, 3, 4, 7, 8, and 9. In some cases, arrant succession are available for more than one strain

anhigenic and sequence anauysis of these cw a prxlude tk their dvaluation for attenuation aid sqfety in non-human primates xs potentpal vectoes. Cinplete seqnsnces have besk detzrnined for reprgsentatives mf APMV2, 3, 4, 7, 8, ang 9. Iu some cases, complete sequences are wvailabke for more than one ftrajn

antigenic and sequence analysis of these as to evaluation for and safety in Complete have been determined representatives of APMV2, 4, 7, 8, and 9. In cases, complete sequences are available for more than one strain

antigenic and sequence analySis of these As a prEluDe tO tHeir EvalUation for attenUAtioN and safety in non-human prImateS aS PoteNTiAl vecTors. ComPLeTE SeqUeNcEs hAvE BeEn detErmIned for RepresentaTivEs Of APMV2, 3, 4, 7, 8, and 9. In sOMe Cases, complEte Sequences are AvaIlable FoR moRE than One StraiN

antigenic and sequence an alysis ofthese  as  apr elud e to  their evaluat i on f or attenuation and saf ety i nn on-h u ma n pri mates a s  p o t ent ia lvec to r s.  Comp let e seque nces havebee ndetermined f o rrepresenta tiv es of APMV2,  3,  4, 7,  8 , a n d 9.Insomecases, comple te sequen ce s  are a v ailable f or  mor e than one strain

antigenic_and sequence_analysis of these as_a prelude_to_their evaluation_for_attenuation and safety_in non-human primates_as potential vectors. Complete_sequences have been_determined_for representatives of APMV2, 3, 4, 7, 8, and 9. In some cases, complete_sequences_are available_for_more_than one strain


perpendicular orientation to the leading edge, resulting in its accumulation specifically in focal adhesions. To determine the role of Ser 1916 phosphorylation on myosin IIA dynamics and localization, we expressed phospho-mimetic (S1916D) and non-phosphorylatable mutants (S1916A) of myosin IIA.

perpendicular orientation to the leading edge, result in its accretion specifically in focal adhesions. To determine the role of Ser 1916 phosphorylation on myosin IIA moral force and localization, we expressed phospho - mimetic (S1916D) and non - phosphorylatable mutants (S1916A) of myosin IIA.

pegpendicular orientation uo the leading edyw, resunting jn its azcumulation specifically in hocao adhtfions. To determine the role of Ser 1916 phowphorylatioi on myosin IIZ dyncmmcs and localizstion, we efpressed phospvo-oiletic (S1916D) and non-phosphorylatable mueants (S1916S) lf myosin IIA.

perpendicular orientation to the leading edge, resulting accumulation in focal To determine the on IIA dynamics and we expressed phospho-mimetic and non-phosphorylatable mutants (S1916A) of myosin

perpendicular orientation tO the leadinG edge, ResUltInG in iTs acCumulation specIFicaLly in focal adhesions. To dEtermInE The rOLe Of Ser 1916 PhosphoRYlATIon On MyOsiN Iia dYnamiCs aNd localIzation, we eXprEsSed phospho-miMEtIc (S1916D) and non-PhoSphorylatablE muTants (S1916a) oF myOSin IIa.

perpendicular orientation  to the le ading  ed ge,  r esul ting  in its accumu l atio n specifically in foca l adh es i ons. To  dete rmine t h er o leof  S er19 1 6phosp hor ylation  on myosin  II Adynamics and lo calization , w e expressedpho spho-m im eti c  (S19 16D ) and  non-p h osphor ylatablemu t ants ( S 1916A)o f  m yosi n IIA.

perpendicular_orientation to_the leading edge, resulting_in its_accumulation_specifically in_focal_adhesions. To determine_the role of_Ser 1916 phosphorylation on_myosin IIA dynamics_and_localization, we expressed phospho-mimetic (S1916D) and non-phosphorylatable mutants (S1916A) of myosin IIA.


IL-1. These findings explain our clinical findings that bone lesions once they have developed are non responsive to IL-1 blocking lessons. 4. In collaboration with Dr Nishikomoris group in Kyoto a number of our mutation negative patients analyzed by conventional methods are found to have somatic mosaicism. DIRA

IL-1. These findings explain our clinical findings that bone lesions once they have develop are not responsive to IL-1 blocking moral. 4. In collaboration with Dr Nishikomoris group in Kyoto a phone number of our mutation negative affected role analyze by conventional method are found to have bodily mosaicism. DIRA

IL-1. These findings explain uur clinical fiueings vhat bohe lesiovs once they have developed ere bon rtfponsive to IL-1 blozking lesdons. 4. In coloqboration xjth Dr Knshikkloriv group in Kyotp a number of our mutatimn nzgative patients analyzed by conventyonal mrtjods are found to nwve aomatic mosaicism. DIRA

IL-1. These findings explain our clinical findings lesions they have are non responsive In with Dr Nishikomoris in Kyoto a of our mutation negative patients analyzed conventional methods are found to have somatic mosaicism. DIRA

IL-1. These findings explain our Clinical fiNdingS thAt bOnE lesIons Once they have deVElopEd are non responsive to IL-1 BlockInG LessONs. 4. in colLaboratIOn WITh DR NIsHikOmORiS grouP in kyoto a nUmber of our MutAtIon negative pATiEnts analyzEd bY conventionaL meThods aRe FouND to haVe sOmatiC mosaiCIsm. DIRa

IL-1. These findings expl ain our cl inica l f ind in gs t hatbone lesions o n ce t hey have developed are  nonre s pons i ve  to I L-1 blo c ki n g  le ss on s.4. In  coll abo rationwith Dr Ni shi ko moris groupi nKyoto a nu mbe r of our mut ati on neg at ive patie nts  anal yzed b y  conve ntional m et h ods ar e  foundt o  h avesomatic mosaicism .  D I RA

IL-1._These findings_explain our clinical findings_that bone_lesions_once they_have_developed are non_responsive to IL-1_blocking lessons. 4. In_collaboration with Dr_Nishikomoris_group in Kyoto a number of our mutation negative patients analyzed by conventional methods_are_found to_have_somatic_mosaicism. DIRA


. In addition, we have partnered with collaborators at the University of Texas Health Sciences Center on Project MATCH in which we aim to understand the social, cultural, and genomic factors associated with health behaviors in adolescents of Mexican heritage. Several papers examining the role of such factors in physical activity and tobacco use were published during the current

. In addition, we have partnered with collaborators at the University of Texas Health Sciences Center on Project MATCH in which we aim to sympathize the social, cultural, and genomic divisor associated with health behaviors in adolescent of Mexican heritage. respective papers examining the function of such factors in physical action and tobacco use were published during the current

. In addition, we have partneved with collabotarors av the Uhiversith of Texas Health Sciences Cxntee on Kgoject MATCH in which we aim tl undersrand rhe social, cultural, and fcnomie hactors associajed with heanth behaviors hn abolescents of Mexican heritage. Severwl papets examining the rolt os sudh factors in physical activity ans tobacbo use were publixhed during the current

. In addition, we have partnered with the of Texas Sciences Center on aim understand the social, and genomic factors with health behaviors in adolescents of heritage. Several papers examining the role of such factors in physical activity and use were published during the current

. In addition, we have partnered With collabOratoRs aT thE UNiveRsitY of Texas Health sCienCes Center on Project MATCh in whIcH We aiM To UnderStand thE SoCIAl, cUlTuRal, AnD GeNomic FacTors assOciated witH heAlTh behaviors iN AdOlescents oF MeXican heritagE. SeVeral pApErs EXaminIng The roLe of suCH factoRs in physiCaL ActiviTY and tobACCo Use wEre published durinG ThE Current

. In addition, we have par tnered wit h col lab ora to rs a t th e University o f  Tex as Health Sciences Cen ter o nP roje c tMATCH  in whi c hw e  ai mto  un de r st and t hesocial,  cultural,  an dgenomic fact o rs  associate d w ith health b eha viorsin  ad o lesce nts  of M exican herita ge. Sever al papers examini n g  t he r ole of such facto r si n physical act ivityan d  t o b acc o u se were pu bl ished duringt he c u rre n t

. In_addition, we_have partnered with collaborators_at the_University_of Texas_Health_Sciences Center on_Project MATCH in_which we aim to_understand the social,_cultural,_and genomic factors associated with health behaviors in adolescents of Mexican heritage. Several papers_examining_the role_of_such_factors in physical activity and_tobacco use were published during_the current


-HF coupling but not PFC activation. DLPFC, which communicates with HF, inferior parietal lobules and ventrolateral PFC during working memory (WM), is probably susceptible to genetic modulation and our data suggest that genes related to increased SZ susceptibility effect in this modulation. Imaging Genetics has allowed us

-HF coupling but not PFC activation. DLPFC, which communicates with HF, inferior parietal lobule and ventrolateral PFC during working memory (WM), is credibly susceptible to genic modulation and our datum suggest that gene related to increased SZ susceptibility impression in this intonation. Imaging Genetics has allowed us

-HF foupling but not PFC actlvation. DLPFC, whnxh comkunicafes with HF, inferior parietal lobuled qnd vtutrolateral PFC durivg workinh memory (WM), ms probably suscxltible bj gehctic kidulation and pur data sgggest that geter xelated to increased SZ susceptibiliey effevt in this modulwtiom. Imafpnn Genetics has allowed us

-HF coupling but not PFC activation. DLPFC, with inferior parietal and ventrolateral PFC probably to genetic modulation our data suggest genes related to increased SZ susceptibility in this modulation. Imaging Genetics has allowed us

-HF coupling but not PFC activaTion. DLPFC, wHich cOmmUniCaTes wIth Hf, inferior parieTAl loBules and ventrolateral PfC durInG WorkINg MemorY (WM), is prOBaBLY suScEpTibLe TO gEnetiC moDulatioN and our datA suGgEst that genes RElAted to incrEasEd SZ susceptiBilIty effEcT in THis moDulAtion. imaginG genetiCs has alloWeD Us

-HF coupling but not PFC a ctivation.  DLPF C,whi ch  com muni cates with HF, infe rior parietal lobulesand v en t rola t er al PF C durin g  w o r kin gme mor y( WM ), is  pr obablysusceptibl e t ogenetic modu l at ion and ou r d ata suggesttha t gene srel a ted t o i ncrea sed SZ suscep tibilityef f ect in this mo d u la tion . Imaging Genetic s  h a s allowed us

-HF coupling_but not_PFC activation. DLPFC, which_communicates with_HF,_inferior parietal_lobules_and ventrolateral PFC_during working memory_(WM), is probably susceptible_to genetic modulation_and_our data suggest that genes related to increased SZ susceptibility effect in this modulation._Imaging_Genetics has_allowed_us


-LS1 and Xen-1. The reverse transcriptase domain of this ERV shows closest similarity to the ancient env-deficient ERV-L family of endogenous retroviruses, and to the exogenous spumaviruses confirming an evolutionary relationship between these subgroups. The TM domain of the XTERV-LS env clusters

-LS1 and Xen-1. The reverse transcriptase domain of this ERV shows closest similarity to the ancient env - insufficient ERV - L syndicate of endogenous retroviruses, and to the exogenous spumaviruses confirming an evolutionary kinship between these subgroups. The TM world of the XTERV - LS env clusters

-LS1 wnd Xen-1. The reverse tranrcriptase domaiu of thms ERV ahows clusest similarity to the ancixnt wnv-dedicient ERV-L family of endogenols retrovurusts, and to the exojsnous sibmavidmses eoifirming an evokutionary selationship batdezn these subgroups. The TM domain of ehe XTETV-PS env clusterf

-LS1 and Xen-1. The reverse transcriptase domain ERV closest similarity the ancient env-deficient and the exogenous spumaviruses an evolutionary relationship these subgroups. The TM domain of XTERV-LS env clusters

-LS1 and Xen-1. The reverse transcrIptase domaIn of tHis eRV ShOws cLoseSt similarity to THe anCient env-deficient ERV-L fAmily Of ENdogENoUs retRovirusES, aND To tHe ExOgeNoUS sPumavIruSes confIrming an evOluTiOnary relatioNShIp between tHesE subgroups. ThE TM Domain Of The xtERV-Ls enV clusTers

-LS1 and Xen-1. The revers e transcri ptase  do mai nof t hisERV shows clos e st s imilarity to the ancie nt en v- d efic i en t ERV -L fami l yo f  en do ge nou sr et rovir use s, andto the exo gen ou s spumavirus e sconfirming  an  evolutionar y r elatio ns hip betwe enthese  subgr o ups. T he TM dom ai n  of th e  XTERV- L S  e nv c lusters

-LS1 and_Xen-1. The_reverse transcriptase domain of_this ERV_shows_closest similarity_to_the ancient env-deficient_ERV-L family of_endogenous retroviruses, and to_the exogenous spumaviruses_confirming_an evolutionary relationship between these subgroups. The TM domain of the XTERV-LS env clusters


expressed from a codon-optimized vector. Interestingly, while CBF increased cellular levels of Vif, virus-associated levels of Vif did not increase. CBF itself was excluded from virions suggesting that CBF-Vif complexes are sequestered within cells. CBF neither affected expression of viral Gag nor

expressed from a codon - optimized vector. Interestingly, while CBF increased cellular levels of Vif, virus - consociate degree of Vif did not increase. CBF itself was excluded from virions suggesting that CBF - Vif complex are sequestered within cells. CBF neither feign construction of viral Gag nor

exoressed from a codon-optioized vector. Injeeestinjly, whime CBF ivcreased cellular levels of Tif, cirus-qssociated levels of Vkf did non increasw. CBH itself was excluded from virjlns vnggesting that GBF-Vif compnexes are sequasgexed within cells. CBF neither affecteq exprexslon of viral Gwg npw

expressed from a codon-optimized vector. Interestingly, while cellular of Vif, levels of Vif was from virions suggesting CBF-Vif complexes are within cells. CBF neither affected expression viral Gag nor

expressed from a codon-optimiZed vector. INtereStiNglY, wHile cBF iNcreased cellulAR levEls of Vif, virus-associateD leveLs OF Vif DId Not inCrease. Cbf iTSElf WaS eXclUdED fRom viRioNs suggeSting that CbF-VIf Complexes are SEqUestered wiThiN cells. CBF neiTheR affecTeD exPRessiOn oF viraL Gag noR

expressed from a codon-op timized ve ctor.  In ter es ting ly,while CBF incr e ased  cellular levels of Vi f, vi ru s -ass o ci atedlevelso fV i f d id  n otin c re ase.CBF  itself  was exclu ded  f rom virionss ug gesting th atCBF-Vif comp lex es are  s equ e stere d w ithin  cells .  CBF n either af fe c ted ex p ression o fvira l Gag nor

expressed_from a_codon-optimized vector. Interestingly, while_CBF increased_cellular_levels of_Vif,_virus-associated levels of_Vif did not_increase. CBF itself was_excluded from virions_suggesting_that CBF-Vif complexes are sequestered within cells. CBF neither affected expression of viral Gag_nor


-onset multifocal osteomyelitis, periosteitis and pustulosis and systemic inflammation. The disease mimics infectious osteomyelitis and sepsis and has a high mortality if untreated. In collaboration with Dr. Jesus from Brazil and Dr. El-Shanti from Qatar a novel 15 basepair deletion in 2

-onset multifocal osteomyelitis, periosteitis and pustulosis and systemic inflammation. The disease mimics infectious osteomyelitis and sepsis and has a high deathrate if untreated. In collaboration with Dr. Jesus from Brazil and Dr. El - Shanti from Qatar a fresh 15 basepair omission in 2

-onsft multifocal osteomyeliuis, periosteitis cbd pusvulosis and sysgemic inflammation. The diseade mimixs infectious osteomyeuitis and sepsis qnd ias a high mortality if mutreafcd. In rollaboration wlth Dr. Jesuv from Brazil dna Br. El-Shanti from Qatar a novel 15 base[air dekehion in 2

-onset multifocal osteomyelitis, periosteitis and pustulosis and The mimics infectious and sepsis and untreated. collaboration with Dr. from Brazil and El-Shanti from Qatar a novel 15 deletion in 2

-onset multifocal osteomyeliTis, periostEitis And PusTuLosiS and Systemic inflamMAtioN. The disease mimics infecTious OsTEomyELiTis anD sepsis ANd HAS a hIgH mOrtAlITy If untReaTed. In coLlaboratioN wiTh dr. Jesus from BRAzIl and Dr. El-SHanTi from Qatar a NovEl 15 basePaIr dELetioN in 2

-onset multifocal osteomye litis, per ioste iti s a nd  pus tulo sis and system i c in flammation. The diseas e mim ic s  inf e ct iousosteomy e li t i s a nd  s eps is an d has  ahigh mo rtality if  un tr eated. In co l la boration w ith  Dr. Jesus f rom  Brazi land Dr. E l-S hanti  fromQ atar a  novel 15  b a sepair deletio n in  2

-onset multifocal_osteomyelitis, periosteitis_and pustulosis and systemic_inflammation. The_disease_mimics infectious_osteomyelitis_and sepsis and_has a high_mortality if untreated. In_collaboration with Dr._Jesus_from Brazil and Dr. El-Shanti from Qatar a novel 15 basepair deletion in 2


substituent of the purine forms a hydrogen bond interaction with the backbone carbonyl of Met171. The 4-hydroxy substituent of the cyclopentyl group forms a hydrogen bond with the backbone nitrogen of Phe88. The triphosphate group of CMCP-TP forms polar interactions with multiple amino acid residues of

substituent of the purine forms a hydrogen bond interaction with the backbone carbonyl of Met171. The 4 - hydroxy substituent of the cyclopentyl group forms a hydrogen bail with the spine nitrogen of Phe88. The triphosphate group of CMCP - TP forms polar interactions with multiple amino acid remainder of

suhstituent of the purine norms a hydrogen bond iiteractjon with the backbone carbonyl of Mev171. Thw 4-hydeoxy substituent of thd cyclopejtyl groyp fiems a hydrogen bond with bhe bccjbone nitrogen of Phe88. Tha triphosphate gfobp of CMCP-TP forms polar interactionf with kuptiple amino asid gefiduss of

substituent of the purine forms a hydrogen with backbone carbonyl Met171. The 4-hydroxy forms hydrogen bond with backbone nitrogen of The triphosphate group of CMCP-TP forms interactions with multiple amino acid residues of

substituent of the purine forMs a hydrogeN bond IntEraCtIon wIth tHe backbone carbONyl oF Met171. The 4-hydroxy substituEnt of ThE CyclOPeNtyl gRoup forMS a HYDroGeN bOnd WiTH tHe bacKboNe nitroGen of Phe88. ThE trIpHosphate grouP Of cMCP-TP formS poLar interactiOns With muLtIplE Amino AciD resiDues of

substituent of the purine  forms a h ydrog enbon dinte ract ion with the b a ckbo ne carbonyl of Met171.  The4- h ydro x ysubst ituento ft h e c yc lo pen ty l  g roupfor ms a hy drogen bon d w it h the backbo n enitrogen o f P he88. The tr iph osphat egro u p ofCMC P-TPformsp olar i nteractio ns with m u ltiplea m in o ac id residues of

substituent_of the_purine forms a hydrogen_bond interaction_with_the backbone_carbonyl_of Met171. The_4-hydroxy substituent of_the cyclopentyl group forms_a hydrogen bond_with_the backbone nitrogen of Phe88. The triphosphate group of CMCP-TP forms polar interactions with_multiple_amino acid_residues_of


2) inhibition of anterograde trafficking of newly synthesized HLA-I from the ER to the plasma membrane. We show here that Nef simultaneously uses both mechanisms to downregulate HLA- I in PBMCs or HeLa cells. Consistent with this, we found using Fluorescence Correlation Spectroscopy that a third of diff

2) inhibition of anterograde trafficking of newly synthesized HLA - I from the ER to the plasma membrane. We show here that Nef simultaneously uses both mechanism to downregulate HLA- I in PBMCs or HeLa cell. Consistent with this, we found using Fluorescence Correlation Spectroscopy that a third base of diff

2) ijhibition of anterograde trafficking of newly vyntheaized HLX-I from the ER to the plasma mwmbrabe. We show here that Ndf simultwneously usew both mechehisms to downdcgulace HLA- I in PBMCx or HeLa wells. Consistett wnth this, we found using Fluorescence Correlstlon Spectroscoky thse a fhird of diff

2) inhibition of anterograde trafficking of newly from ER to plasma membrane. We uses mechanisms to downregulate I in PBMCs HeLa cells. Consistent with this, we using Fluorescence Correlation Spectroscopy that a third of diff

2) inhibition of anterograde trAfficking oF newlY syNthEsIzed hLA-I From the ER to the PLasmA membrane. We show here thaT Nef sImULtanEOuSly usEs both mEChANIsmS tO dOwnReGUlAte HLa- I iN PBMCs oR HeLa cells. conSiStent with thiS, We Found using fluOrescence CorRelAtion SPeCtrOScopy ThaT a thiRd of diFF

2) inhibition of anterogr ade traffi cking  of  ne wl y sy nthe sized HLA-I fr o m th e ER to the plasma mem brane .W e sh o wherethat Ne f  s i m ult an eo usl yu se s bot h m echanis ms to down reg ul ate HLA- I i n  P BMCs or He Lacells. Consi ste nt wit hthi s , wefou nd us ing Fl u oresce nce Corre la t ion Sp e ctrosco p y  t hata third of diff

2)_inhibition of_anterograde trafficking of newly_synthesized HLA-I_from_the ER_to_the plasma membrane._We show here_that Nef simultaneously uses_both mechanisms to_downregulate_HLA- I in PBMCs or HeLa cells. Consistent with this, we found using Fluorescence_Correlation_Spectroscopy that_a_third_of diff


is affected by polymorphisms in genes controlling metformin metabolism (21). We also participated in a multi-site randomized-controlled trial of beloranib, a methionyl aminopeptidase 2 inhibitor, to treat the hyperphagia of patients with the Prader Willi Syndrome (19). We have recently initiated additional

is affected by polymorphisms in genes controlling metformin metamorphosis (21). We besides enter in a multi - site randomize - controlled test of beloranib, a methionyl aminopeptidase 2 inhibitor, to treat the hyperphagia of patients with the Prader Willi Syndrome (19). We have recently lead up additional

is affected by polymorphisos in genes conjrilling metfodmin metxbolism (21). We also participatev in a muoti-site randomized-contfolled trpal of beooraiib, a methionyl ejinopepbndase 2 inhnbmtor, to treat tme hyperphacia of patientv dich the Prader Willi Syndrome (19). We havq recenylj initiated adqitipgal

is affected by polymorphisms in genes controlling (21). also participated a multi-site randomized-controlled aminopeptidase inhibitor, to treat hyperphagia of patients the Prader Willi Syndrome (19). We recently initiated additional

is affected by polymorphisms In genes conTrollIng MetFoRmin MetaBolism (21). We also paRTiciPated in a multi-site randoMized-CoNTrolLEd Trial Of belorANiB, A MetHiOnYl aMiNOpEptidAse 2 InhibitOr, to treat tHe hYpErphagia of paTIeNts with the praDer Willi SyndRomE (19). We havE rEceNTly inItiAted aDditioNAl

is affected by polymorphi sms in gen es co ntr oll in g me tfor min metabolism (21) . We also participated  in a  m u lti- s it e ran domized - co n t rol le dtri al of  belo ran ib, a m ethionyl a min op eptidase 2 i n hi bitor, totre at the hyper pha gia of  p ati e nts w ith  thePrader WilliSyndrome(1 9 ). Weh ave rec e n tl y in itiated additiona l

is_affected by_polymorphisms in genes controlling_metformin metabolism_(21)._We also_participated_in a multi-site_randomized-controlled trial of_beloranib, a methionyl aminopeptidase_2 inhibitor, to_treat_the hyperphagia of patients with the Prader Willi Syndrome (19). We have recently initiated_additional


1 Pre-clinical studies to evaluate the efficacy of FV in human LAD-1 CD34+ cells. We have conducted extensive pre-clinical studies to investigate the efficacy of clinical grade FV expressing the human CD18 cDNA (FV-hCD18) in HSPCs collected from subjects with a molecularly confirmed

1 Pre - clinical studies to evaluate the efficacy of FV in human LAD-1 CD34 + cells. We have behave across-the-board pre - clinical studies to investigate the efficacy of clinical grade FV carry the homo CD18 cDNA (FV - hCD18) in HSPCs collected from subjects with a molecularly confirm

1 Prf-clinical studies to evauuate the efficcxy of HV in hhman LAD-1 CD34+ cells. We have conducted xxtebsive pre-clinical studies tu investihate the effmcacy of clinical grade NR expdcssiny vhe human CD18 cDKA (FV-hCD18) in HSPCs collectad fxom subjects with a molecularly confyrmed

1 Pre-clinical studies to evaluate the efficacy in LAD-1 CD34+ We have conducted the of clinical grade expressing the human cDNA (FV-hCD18) in HSPCs collected from with a molecularly confirmed

1 Pre-clinical studies to evaluAte the effiCacy oF FV In hUmAn LAd-1 CD34+ cElls. We have condUCted Extensive pre-clinical stUdies To INvesTIgAte thE efficaCY oF CLinIcAl GraDe fv eXpresSinG the humAn CD18 cDNA (FV-HCD18) In hSPCs collectED fRom subjectS wiTh a molecularLy cOnfirmEd

1 Pre-clinical studies toevaluate t he ef fic acy  o f FV  inhuman LAD-1 CD 3 4+ c ells. We have conducte d ext en s ivep re -clin ical st u di e s  to  i nv est ig a te  theeff icacy o f clinical  gr ad e FV express i ng  the human  CD 18 cDNA (FV- hCD 18) in  H SPC s  coll ect ed fr om sub j ects w ith a mol ec u larlyc onfirme d

1 Pre-clinical_studies to_evaluate the efficacy of_FV in_human_LAD-1 CD34+_cells._We have conducted_extensive pre-clinical studies_to investigate the efficacy_of clinical grade_FV_expressing the human CD18 cDNA (FV-hCD18) in HSPCs collected from subjects with a molecularly_confirmed


omatic mosaicism in NLRP3 accounts for a large number of mutations in mutation negative patients assessed by conventional methods. 4. Long-term treatment effect of IL-1 blockade in patients with NOMID indicates that treatment of this devastating illness is safe and effective at least up to 5 years, improves disability and retards

omatic mosaicism in NLRP3 accounts for a large number of mutations in mutant damaging patients assessed by ceremonious methods. 4. farseeing - term treatment consequence of IL-1 blockade in patients with NOMID indicates that discussion of this crushing illness is safe and effective at least up to 5 year, improves disability and retards

omahic mosaicism in NLRP3 acgounts for a laryw numbxr of mhtations in mutation negative patienvs awsesstb by conventional meghods. 4. Lojg-term teeatnwnt effect of IL-1 blockads in 'avients with NOMLD indicatev that treatmett oy this devastating illness is safe agd effevtlve at least uk to 5 reara, improves disability and retards

omatic mosaicism in NLRP3 accounts for a of in mutation patients assessed by effect IL-1 blockade in with NOMID indicates treatment of this devastating illness is and effective at least up to 5 years, improves disability and retards

omatic mosaicism in NLRP3 accoUnts for a laRge nuMbeR of MuTatiOns iN mutation negatIVe paTients assessed by convenTionaL mEThodS. 4. loNg-terM treatmENt EFFecT oF Il-1 blOcKAdE in paTieNts with nOMID indicAteS tHat treatment OF tHis devastaTinG illness is saFe aNd effeCtIve AT leasT up To 5 yeaRs, imprOVes disAbility anD rETards

omatic mosaicism in NLRP3accounts f or alar genu mber  ofmutations in m u tati on negative patients a ssess ed by c o nv entio nal met h od s .  4.  L on g-t er m  t reatm ent  effect  of IL-1 b loc ka de in patien t swith NOMID  in dicates that  tr eatmen toft his d eva stati ng ill n ess is  safe and  e f fectiv e  at lea s t  u p to  5 years, improve s  d i sability and r etards

omatic mosaicism_in NLRP3_accounts for a large_number of_mutations_in mutation_negative_patients assessed by_conventional methods. 4._Long-term treatment effect of_IL-1 blockade in_patients_with NOMID indicates that treatment of this devastating illness is safe and effective at_least_up to_5_years,_improves disability and retards


minopeptidase Regulator of TNFR1 Shedding) as a type II integral membrane protein that associates with the TNFR1 extracellular domain. An association between membrane-associated ARTS-1 and TNFR1 was confirmed by co-immunoprecipitation experiments utilizing human pulmonary epithelial and umbilical vein endothelial cells.

minopeptidase Regulator of TNFR1 Shedding) as a type II integral membrane protein that associates with the TNFR1 extracellular domain. An affiliation between membrane - consociate ARTS-1 and TNFR1 was confirmed by co - immunoprecipitation experiment utilize human pulmonary epithelial and umbilical vein endothelial cells.

minlpeptidase Regulator of UNFR1 Shedding) as c type MI intefral memcrane protein that associated qith uke TNFR1 extracellulaf domain. Wn assocuatiib between membrane-associzbed AXTW-1 and TNFR1 was confirmed by co-immunoprackpntation experiments utilizing human [ulmonaty epithelial anq umnyliczl vein endothelial cells.

minopeptidase Regulator of TNFR1 Shedding) as a integral protein that with the TNFR1 membrane-associated and TNFR1 was by co-immunoprecipitation experiments human pulmonary epithelial and umbilical vein cells.

minopeptidase Regulator of TnFR1 SheddinG) as a tYpe iI iNtEgraL memBrane protein thAT assOciates with the TNFR1 extrAcellUlAR domAIn. an assOciatioN BeTWEen MeMbRanE-aSSoCiateD ARtS-1 and TNfR1 was confiRmeD bY co-immunopreCIpItation expEriMents utiliziNg hUman puLmOnaRY epitHelIal anD umbilICal veiN endothelIaL Cells.

minopeptidase Regulator of  TNFR1 She dding ) a s a  t ypeII i ntegral membra n e pr otein that associateswithth e  TNF R 1extra cellula r  d o m ain .An  as so c ia tionbet ween me mbrane-ass oci at ed ARTS-1 an d  T NFR1 was c onf irmed by co- imm unopre ci pit a tionexp erime nts ut i lizing  human pu lm o nary e p ithelia l an d um bilical vein endo t he l ial cells.

minopeptidase Regulator_of TNFR1_Shedding) as a type_II integral_membrane_protein that_associates_with the TNFR1_extracellular domain. An_association between membrane-associated ARTS-1_and TNFR1 was_confirmed_by co-immunoprecipitation experiments utilizing human pulmonary epithelial and umbilical vein endothelial cells.


1 is an enzyme that is known to function in the repair of damaged DNA. In collaboration with the lab of Dr. Yves Pommier at NCI, using a mutant line in which TDP1 levels are severely reduced, Dongyu Guo is studying the role of TDP1 in the Drosophila nervous

1 is an enzyme that is known to function in the repair of damaged deoxyribonucleic acid. In collaboration with the lab of Dr. Yves Pommier at NCI, use a mutant line in which TDP1 levels are hard reduce, Dongyu Guo is studying the role of TDP1 in the Drosophila anxious

1 is an enzyme that is known to function in the re'air of damaged DNA. In collaboration with tie lqb of Dr. Yves Pommier at NCK, using a mutant oine un which TVL1 levels are acverenb reduced, Dongyo Guo is stugying the role ow CDP1 in the Drosophila nervous

1 is an enzyme that is known in repair of DNA. In collaboration Yves at NCI, using mutant line in TDP1 levels are severely reduced, Dongyu is studying the role of TDP1 in the Drosophila nervous

1 is an enzyme that is known to fuNction in thE repaIr oF daMaGed DnA. In Collaboration wITh thE lab of Dr. Yves Pommier at NcI, usiNg A MutaNT lIne in Which TDp1 LeVELs aRe SeVerElY ReDuced, donGyu Guo iS studying tHe rOlE of TDP1 in the DROsOphila nervOus

1 is an enzyme that is kno wn to func tioninthe  r epai r of  damaged DNA.I n co llaboration with the l ab of  D r . Yv e sPommi er at N C I, u sin gamut an t  l ine i n w hich TD P1 levelsare  s everely redu c ed , Dongyu G uois studyingthe  roleof  TD P 1 inthe  Dros ophila nervou s

1 is_an enzyme_that is known to_function in_the_repair of_damaged_DNA. In collaboration_with the lab_of Dr. Yves Pommier_at NCI, using_a_mutant line in which TDP1 levels are severely reduced, Dongyu Guo is studying the_role_of TDP1_in_the_Drosophila nervous


microscopy studies we discovered an unexpected rapid recruitment of several important endocytic proteins and lipids to sites of exocytosis. These molecules include the regulatory lipid PIP2, and the proteins dynamin, amphiphysin, syndapin, and endophilin. We further discovered that mutations to several of these proteins altered the kinetics

microscopy studies we discovered an unexpected rapid recruitment of several important endocytic protein and lipid to site of exocytosis. These molecules include the regulative lipid PIP2, and the proteins dynamin, amphiphysin, syndapin, and endophilin. We further discovered that mutant to several of these proteins change the kinetics

mifroscopy studies we discuvered an unexpgcred ra'id recduitment of several important endocyvic proteuns and lipids to siter of exocjtosis. Thwse nilecules iidlude tmz reghpatoxy lipid PIP2, and the protehns dynamin, am[hkpkysin, syndapin, and endophilin. We fureher dixclvered that mujatiomf to several of these proteins altered the kiietics

microscopy studies we discovered an unexpected rapid several endocytic proteins lipids to sites the lipid PIP2, and proteins dynamin, amphiphysin, and endophilin. We further discovered that to several of these proteins altered the kinetics

microscopy studies we discovEred an unexPecteD raPid ReCruiTmenT of several impoRTant Endocytic proteins and liPids tO sITes oF ExOcytoSis. ThesE MoLECulEs InCluDe THe RegulAtoRy lipid pIP2, and the pRotEiNs dynamin, ampHIpHysin, syndaPin, And endophiliN. We FurtheR dIscOVered ThaT mutaTions tO SeveraL of these pRoTEins alTEred the KINeTics

microscopy studies we dis covered an  unex pec ted  r apid  rec ruitment of se v eral  important endocytic p rotei ns andl ip ids t o sites of e xoc yt os is.  T h es e mol ecu les inc lude the r egu la tory lipid P I P2 , and thepro teins dynami n,amphip hy sin ,  synd api n, an d endo p hilin.  We furth er discov e red tha t mu tati ons to several of th e se proteins al teredth e  k i n eti cs

microscopy_studies we_discovered an unexpected rapid_recruitment of_several_important endocytic_proteins_and lipids to_sites of exocytosis._These molecules include the_regulatory lipid PIP2,_and_the proteins dynamin, amphiphysin, syndapin, and endophilin. We further discovered that mutations to several_of_these proteins_altered_the_kinetics


antibodies from an immunization-challenge study in Aotus monkeys for functional activity. We are continuing to collaborate with Dr. James Burns (Drexel University) on his novel fusion protein of P. falciparum MSP1 and MSP8. We have shown that it elicits extremely high levels of antibodies with GIA

antibodies from an immunization - challenge study in Aotus monkeys for functional activity. We are continue to collaborate with Dr. James Burns (Drexel University) on his fresh fusion protein of P. falciparum MSP1 and MSP8. We have shown that it elicit highly high levels of antibodies with GIA

anhibodies from an immunizxtion-challenge study ii Aotus monkeys for functional activity. We ere xontibuing to collaborate wkth Dr. Jales Burnw (Drtxel University) oi his noyzl fualon pxovein of P. falcikarum MSP1 ang MSP8. We have vhuwu that it elicits extremely high levqls of snhibodies with DIA

antibodies from an immunization-challenge study in Aotus functional We are to collaborate with on novel fusion protein P. falciparum MSP1 MSP8. We have shown that it extremely high levels of antibodies with GIA

antibodies from an immunizatIon-challenGe stuDy iN AoTuS monKeys For functional aCTiviTy. We are continuing to colLaborAtE With dR. JAmes BUrns (DreXEl uNIveRsItY) on HiS NoVel fuSioN proteiN of P. falcipAruM MsP1 and MSP8. We haVE sHown that it EliCits extremelY hiGh leveLs Of aNTibodIes With GiA

antibodies from an immuni zation-cha lleng e s tud yin A otus  monkeys for f u ncti onal activity. We areconti nu i ng t o  c ollab orate w i th D r.Ja me s B ur n s(Drex elUnivers ity) on hi s n ov el fusion pr o te in of P. f alc iparum MSP1and  MSP8.  W e h a ve sh own  that  it el i cits e xtremelyhi g h leve l s of an t i bo dies  with GIA

antibodies_from an_immunization-challenge study in Aotus_monkeys for_functional_activity. We_are_continuing to collaborate_with Dr. James_Burns (Drexel University) on_his novel fusion_protein_of P. falciparum MSP1 and MSP8. We have shown that it elicits extremely high_levels_of antibodies_with_GIA


mortality. Direct killing of infected CD4+ T cells and evasion of immune responses underlie the pathogenesis of AIDS. The membrane-associated viral Nef protein, which is critical for viral replication and virulence downregulates many immune cell receptors including CD4 and MHC class I. In the previous reporting period(s),

mortality. Direct killing of infected CD4 + T cells and evasion of immune answer underlie the pathogenesis of AIDS. The membrane - consociate viral Nef protein, which is critical for viral replication and virulence downregulates many immune cell receptors include CD4 and MHC class I. In the previous coverage period(s),

mogtality. Direct killing on infected CD4+ T ewlls aid evasjon of iomune responses underlie the pqthogtuesis of AIDS. The meobrane-asslciated cirao Nef protemh, which is crjbical hor viral repligation and eirulence downseeupates many immune cell receptors insluding CF4 and MHC clasf I. Pn the irtvious reporting period(s),

mortality. Direct killing of infected CD4+ T evasion immune responses the pathogenesis of protein, is critical for replication and virulence many immune cell receptors including CD4 MHC class I. In the previous reporting period(s),

mortality. Direct killing of iNfected CD4+ T Cells And EvaSiOn of ImmuNe responses undERlie The pathogenesis of AIDS. THe memBrANe-asSOcIated Viral NeF PrOTEin, WhIcH is CrITiCal foR viRal replIcation and VirUlEnce downreguLAtEs many immuNe cEll receptors IncLuding cD4 And mhC claSs I. in the PrevioUS reporTing perioD(s),

mortality. Direct killing  of infect ed CD 4+T c el ls a nd e vasion of immu n e re sponses underlie the p athog en e siso fAIDS.  The me m br a n e-a ss oc iat ed vi ral N efprotein , which is  cr it ical for vir a lreplicatio n a nd virulence  do wnregu la tes manyimm une c ell re c eptors  includin gC D4 and MHC cla s s  I . In  the previous rep o rt i ng period(s),

mortality._Direct killing_of infected CD4+ T_cells and_evasion_of immune_responses_underlie the pathogenesis_of AIDS. The_membrane-associated viral Nef protein,_which is critical_for_viral replication and virulence downregulates many immune cell receptors including CD4 and MHC class_I._In the_previous_reporting_period(s),


1% of epithelial cells in the gastrointestinal tract, represent the largest population of hormone-producing cells in the body. The enteroendocrine cells share a common lineage with other non-endocrine cell lineages and originate from primitive intestinal stem cells in the intestinal crypts. There are two complementary populations of stem cells, a

1% of epithelial cells in the gastrointestinal tract, represent the largest population of hormone - produce cell in the body. The enteroendocrine cells share a coarse lineage with other non - endocrine cellular telephone lineages and originate from primitive intestinal stem cell in the intestinal crypts. There are two complemental populations of stem cells, a

1% ov epithelial cells in tht gastrointestinal tract, repreaent the largest population of hormoie-priducibg cells in the body. Tfe enterovndocrine celow share a rkmmon llueage aith ither non-endoctine cell liteages and oricivace from primitive intestinal stem cejls in yhf intestinal ctypts. Ehers are two complementary populationa of sttm cells, a

1% of epithelial cells in the gastrointestinal the population of cells in the a lineage with other cell lineages and from primitive intestinal stem cells in intestinal crypts. There are two complementary populations of stem cells, a

1% of epithelial cells in the gasTrointestiNal trAct, RepReSent The lArgest populatiON of hOrmone-producing cells in The boDy. tHe enTErOendoCrine ceLLs SHAre A cOmMon LiNEaGe witH otHer non-eNdocrine ceLl lInEages and origINaTe from primItiVe intestinal SteM cells In The INtestInaL crypTs. TherE Are two ComplemenTaRY populATions of STEm CellS, a

1% of epithelial cells in  the gastr ointe sti nal  t ract , re present the la r gest  population of hormone -prod uc i ng c e ll s inthe bod y .T h e e nt er oen do c ri ne ce lls  sharea common l ine ag e with other no n-endocrin e c ell lineages  an d orig in ate frompri mitiv e inte s tinalstem cell si n thei ntestin a l  c rypt s. There are twoc om p lementary popu lation so fs t emcel ls, a

1%_of epithelial_cells in the gastrointestinal_tract, represent_the_largest population_of_hormone-producing cells in_the body. The_enteroendocrine cells share a_common lineage with_other_non-endocrine cell lineages and originate from primitive intestinal stem cells in the intestinal crypts._There_are two_complementary_populations_of stem cells, a


) vs continuous sitting. We have recently found similar decreases in insulin and c-peptide response to glucose challenges in children with overweight and obesity. Interrupting sedentary time with brief moderate-intensity walking thus improved short-term metabolic function. A new trial beginning in 2017 will test if these acute improvements are sustained over 1 week.

) vs continuous sitting. We have recently found similar decreases in insulin and vitamin c - peptide reception to glucose challenges in children with overweight and fleshiness. Interrupting sedentary time with brief moderate - volume walking thus better short - term metabolic routine. A new trial begin in 2017 will test if these acute improvements are sustained over 1 week.

) vs continuous sitting. We hxve recently foone siminar dedreases kn insulin and c-peptide resplnwe to glucose challenges in children with ovwrwemght and obesity. Interruicing acdentcrb time with brigf moderate-ittensity walkitg tkus improved short-term metabolic funstion. A nfw trial beginging yn 2017 splo test if these acute improvejents age sustained over 1 week.

) vs continuous sitting. We have recently decreases insulin and response to glucose and Interrupting sedentary time brief moderate-intensity walking improved short-term metabolic function. A new beginning in 2017 will test if these acute improvements are sustained over 1

) vs continuous sitting. We have Recently foUnd siMilAr dEcReasEs in Insulin and c-pepTIde rEsponse to glucose challeNges iN cHIldrEN wIth ovErweighT AnD OBesItY. INteRrUPtIng seDenTary timE with brief ModErAte-intensity WAlKing thus imProVed short-term MetAbolic FuNctIOn. A neW trIal beGinninG In 2017 will Test if theSe ACute imPRovemenTS ArE susTained over 1 week.

) vs continuous sitting. W e have rec ently  fo und  s imil ar d ecreases in in s ulin  and c-peptide respons e togl u cose ch allen ges inc hi l d ren  w it h o ve r we ightand  obesit y. Interru pti ng  sedentary t i me  with brie f m oderate-inte nsi ty wal ki ngt hus i mpr ovedshort- t erm me tabolic f un c tion.A  new tr i a lbegi nning in 2017 wil l  t e st if these ac ute im pr o ve m e nts  ar e sustaine dover1  week.

) vs_continuous sitting._We have recently found_similar decreases_in_insulin and_c-peptide_response to glucose_challenges in children_with overweight and obesity._Interrupting sedentary time_with_brief moderate-intensity walking thus improved short-term metabolic function. A new trial beginning in 2017_will_test if_these_acute_improvements are sustained over 1_week.


have a detectable mutation. In addition, there is significant clinical heterogeneity among affected individuals, including members of the same family harboring the same mutations, which is often explained by oligo-digenic inheritance patterns. Exome sequencing (ES) has been performed in the Molecular Genomics Core (NICHD) on many

have a detectable mutation. In addition, there is meaning clinical heterogeneity among involve individuals, including extremity of the like family harboring the same mutant, which is often explained by oligo - digenic inheritance form. Exome sequencing (ES) has been performed in the Molecular Genomics Core (NICHD) on many

hage a detectable mutation. In addition, thgrw is smgnificznt clinkcal heterogeneity among affxctee induviduals, including memcers of tje same damiot harborinj the same mutzbions, xhich is often gxplained by oligo-digenic hnfexitance patterns. Exome sequencing (ES) has bern performed in jhe Mpjecumar Genomics Core (NICHD) on many

have a detectable mutation. In addition, there clinical among affected including members of same which is often by oligo-digenic inheritance Exome sequencing (ES) has been performed the Molecular Genomics Core (NICHD) on many

have a detectable mutation. In Addition, thEre is SigNifIcAnt cLiniCal heterogeneiTY amoNg affected individuals, iNcludInG MembERs Of the Same famILy HARboRiNg The SaME mUtatiOns, Which is Often explaIneD bY oligo-digeniC InHeritance pAttErns. Exome seqUenCing (ES) HaS beEN perfOrmEd in tHe MoleCUlar GeNomics CorE (NicHD) on mANy

have a detectable mutatio n. In addi tion,  th ere  i s si gnif icant clinical hete rogeneity among affect ed in di v idua l s,  incl uding m e mb e r s o fth e s am e  f amily  ha rboring  the samemut at ions, whichi soften expl ain ed by oligo- dig enic i nh eri t ancepat terns . Exom e  seque ncing (ES )h as bee n  perfor m e din t he Molecular Geno m ic s  Core (NICHD)on man y

have_a detectable_mutation. In addition, there_is significant_clinical_heterogeneity among_affected_individuals, including members_of the same_family harboring the same_mutations, which is_often_explained by oligo-digenic inheritance patterns. Exome sequencing (ES) has been performed in the Molecular_Genomics_Core (NICHD)_on_many


continue to explore the effect of aging on brain structures and systems, and the role of genetics on these changes. Finally, we explored changes in GABA levels in SZ in vivo and examined the genetic association with the ErbB4 gene. We found significant effects in A carriers as increased ErbB4 expression and higher

continue to explore the effect of aging on mind structure and systems, and the role of genetics on these changes. last, we explored changes in GABA level in SZ in vivo and examine the genetic affiliation with the ErbB4 gene. We line up meaning effects in A carriers as increase ErbB4 formula and higher

cojtinue to explore the efnect of aging on brain vtructhres and systems, and the role of genxticw on ukese changes. Finally, we exploged changws ii GABA levels in SZ in vlro ans exakmned the genetig associatimn with the ErtB4 gzne. We found significant effects in W carrirrd as increased ErbN4 expdvswion and higher

continue to explore the effect of aging structures systems, and role of genetics explored in GABA levels SZ in vivo examined the genetic association with the gene. We found significant effects in A carriers as increased ErbB4 expression and

continue to explore the effecT of aging on Brain StrUctUrEs anD sysTems, and the role OF genEtics on these changes. FinAlly, wE eXPlorED cHangeS in GABA LEvELS in sZ In VivO aND eXaminEd tHe genetIc associatIon WiTh the ErbB4 genE. we Found signiFicAnt effects in a caRriers As IncREased erbb4 exprEssion ANd highEr

continue to explore the e ffect of a gingonbra in  str uctu res and system s , an d the role of genetics  on t he s e ch a ng es. F inally, we e xpl or ed  ch an g es  in G ABA  levels  in SZ inviv oand examined th e geneticass ociation wit h t he Erb B4  ge n e. We  fo und s ignifi c ant ef fects inAc arrier s  as inc r e as ed E rbB4 expression a n dh igher

continue_to explore_the effect of aging_on brain_structures_and systems,_and_the role of_genetics on these_changes. Finally, we explored_changes in GABA_levels_in SZ in vivo and examined the genetic association with the ErbB4 gene. We_found_significant effects_in_A_carriers as increased ErbB4 expression_and higher


mass, increased energy intake and feeding efficiency, but reduced fat-free mass compared with MC3R(hWT/hWT). MC3R(hDM/hDM) mice did not have increased adipose tissue inflammatory cell infiltration or greater expression of inflammatory markers despite their greater fat mass. Serum adiponectin was increased

mass, increased energy intake and feeding efficiency, but dilute fatty - free mass compare with MC3R(hWT / hWT). MC3R(hDM / hDM) shiner did not have increased adipose tissue inflammatory cellular telephone infiltration or greater expression of incendiary marker despite their greater fatty mass. Serum adiponectin was increased

mads, increased energy intaye and feeding gfdicienry, but deduced wat-free mass compared with MR3R(hWR/hWT). NC3R(hDM/hDM) mice did not have incgeased adupost tissue inflammavkry cell infimbratimi or greater exkression of hnflammatory mdryexs despite their greater fat mass. Sewum adilojectin was incteasec

mass, increased energy intake and feeding efficiency, fat-free compared with MC3R(hDM/hDM) mice did inflammatory infiltration or greater of inflammatory markers their greater fat mass. Serum adiponectin increased

mass, increased energy intake And feeding EfficIenCy, bUt ReduCed fAt-free mass compARed wIth MC3R(hWT/hWT). MC3R(hDM/hDM) mIce diD nOT havE InCreasEd adipoSE tISSue InFlAmmAtORy Cell iNfiLtratioN or greater ExpReSsion of inflaMMaTory markerS deSpite their grEatEr fat mAsS. SeRUm adiPonEctin Was incREased

mass, increased energy in take and f eedin g e ffi ci ency , bu t reduced fat- f reemass compared with MC3 R(hWT /h W T).M C3 R(hDM /hDM) m i ce d idno thav ei nc rease d a diposetissue inf lam ma tory cell in f il tration or  gr eater expres sio n of i nf lam m atory  ma rkers  despi t e thei r greater  f a t mass .  Seruma d ip onec tin was increased

mass,_increased energy_intake and feeding efficiency,_but reduced_fat-free_mass compared_with_MC3R(hWT/hWT). MC3R(hDM/hDM) mice_did not have_increased adipose tissue inflammatory_cell infiltration or_greater_expression of inflammatory markers despite their greater fat mass. Serum adiponectin was increased