the RT, Ser85, Ala86, and Ala87. The triphosphate group interacts with a magnesium ion, which also interacts with Asp83 and Val84. These networks of strong polar interactions must be responsible for stabilizing the binding of CMCP-TP in the active site of RT of HBVWT. Both CMCP

the RT, Ser85, Ala86, and Ala87. The triphosphate group interacts with a magnesium ion, which also interacts with Asp83 and Val84. These networks of impregnable pivotal interactions must be responsible for stabilizing the ski binding of CMCP - TP in the active site of RT of HBVWT. Both CMCP

thf RT, Ser85, Ala86, and Ala87. The triphosphate gtoyp intxracts sith a mxgnesium ion, which also intecactw wity Asp83 and Val84. These negworks of strong polac interactions mnat be rcfponalble yoc stabilizing tme binding mf CMCP-TP in tve aetive site of RT of HBVWT. Both CMCP

the RT, Ser85, Ala86, and Ala87. The interacts a magnesium which also interacts networks strong polar interactions be responsible for the binding of CMCP-TP in the site of RT of HBVWT. Both CMCP

the RT, Ser85, Ala86, and Ala87. The triphOsphate groUp intEraCts WiTh a mAgneSium ion, which alSO intEracts with Asp83 and Val84. TheSe netWoRKs of STrOng poLar inteRAcTIOns MuSt Be rEsPOnSible For StabiliZing the binDinG oF CMCP-TP in the ACtIve site of Rt of hBVWT. Both CMCp

the RT, Ser85, Ala86, and  Ala87. Th e tri pho sph at e gr oupinteracts with a ma gnesium ion, which als o int er a ctsw it h Asp 83 andV al 8 4 . T he se  ne tw o rk s ofstr ong pol ar interac tio ns  must be res p on sible forsta bilizing the  bi ndingof  CM C P-TPinthe a ctives ite of  RT of HB VW T . Both CMCP

the_RT, Ser85,_Ala86, and Ala87. The_triphosphate group_interacts_with a_magnesium_ion, which also_interacts with Asp83_and Val84. These networks_of strong polar_interactions_must be responsible for stabilizing the binding of CMCP-TP in the active site of_RT_of HBVWT._Both_CMCP


dealing with this class of FRET problems assumes that the rates of energy transfer (to single acceptors) sum linearly when multiple acceptors are present. Our preliminary data suggests that this treatment underestimates the true FRET efficiency. We have developed a new theory for dealing with these problems based on probability theory. We are currently

dealing with this class of FRET problems assumes that the pace of department of energy transfer (to single acceptor) union linearly when multiple acceptors are present. Our preliminary data indicate that this discussion underestimates the true FRET efficiency. We have developed a new theory for deal with these problems based on probability hypothesis. We are currently

dewling with this class of FRET problems cwsumes that fhe rater of energy transfer (to singpe acceknors) sum linearly whev multiplv acceptoes ace present. Our pcsliminavv datz sugyewts that this jreatment ungerestimates tve txue FRET efficiency. We have developeq a new tjeory for dealyng eyth fhese problems based on probabilitg theorj. We are currentlu

dealing with this class of FRET problems the of energy (to single acceptors) are Our preliminary data that this treatment the true FRET efficiency. We have a new theory for dealing with these problems based on probability theory. We currently

dealing with this class of FREt problems aSsumeS thAt tHe RateS of eNergy transfer (tO SingLe acceptors) sum linearly When mUlTIple ACcEptorS are preSEnT. oUr pReLiMinArY DaTa sugGesTs that tHis treatmeNt uNdErestimates tHE tRue FRET effIciEncy. We have deVelOped a nEw TheORy for DeaLing wIth theSE problEms based oN pRObabilITy theorY. wE aRe cuRrently

dealing with this class o f FRET pro blems  as sum es  tha t th e rates of ene r gy t ransfer (to single acc eptor s) suml in early  when m u lt i p leac ce pto rs ar e pre sen t. Ourpreliminar y d at a suggests t h at  this trea tme nt underesti mat es the  t rue FRETeff icien cy. We have d evelopedan ew the o ry ford e al ingwith these proble m sb ased on probab ilityth e or y .  We  ar e currentl y

dealing_with this_class of FRET problems_assumes that_the_rates of_energy_transfer (to single_acceptors) sum linearly_when multiple acceptors are_present. Our preliminary_data_suggests that this treatment underestimates the true FRET efficiency. We have developed a new_theory_for dealing_with_these_problems based on probability theory._We are currently


system. We previously noted that when fly larvae are raised on food containing the oxidative agent bleomycin, very few are able to undergo metamorphosis to the pupal stage. In the past year we have shown that this phenotype is reversed by expression of TDP1 under the control of a nervous system-specific promoter.

system. We previously noted that when fly larvae are raised on food control the oxidative agentive role bleomycin, very few are able to undergo metamorphosis to the pupal stage. In the past class we have shown that this phenotype is revoke by expression of TDP1 under the command of a aflutter system - specific promoter.

sydtem. We previously noted that when fly larvae ere raiaed on fuod containing the oxidative atent vleomycin, very few are able to lndergo mwtamiephosis to the pupal stafc. In chx past year we mave shown dhat this phenmthpz is reversed by expression of TDP1 ugder thr fontrol of a ngrvoux sysfvm-wpecific promoter.

system. We previously noted that when fly raised food containing oxidative agent bleomycin, undergo to the pupal In the past we have shown that this phenotype reversed by expression of TDP1 under the control of a nervous system-specific promoter.

system. We previously noted thAt when fly lArvae Are RaiSeD on fOod cOntaining the oxIDatiVe agent bleomycin, very feW are aBlE To unDErGo metAmorphoSIs TO The PuPaL stAgE. in The paSt yEar we haVe shown thaT thIs Phenotype is rEVeRsed by exprEssIon of TDP1 undeR thE contrOl Of a NErvouS syStem-sPecifiC PromotEr.

system. We previously not ed that wh en fl y l arv ae  are  rai sed on food co n tain ing the oxidative agen t ble om y cin, ve ry fe w are a b le t o u nd er gome t am orpho sis  to the  pupal sta ge.  I n the past y e ar  we have s how n that thisphe notype  i s r e verse d b y exp ressio n  of TD P1 underth e  contr o l of an e rv oussystem-specific p r om o ter.

system._We previously_noted that when fly_larvae are_raised_on food_containing_the oxidative agent_bleomycin, very few_are able to undergo_metamorphosis to the_pupal_stage. In the past year we have shown that this phenotype is reversed by_expression_of TDP1_under_the_control of a nervous system-specific_promoter.


development of family level strategies to address this risk (NHGRI Protocol #07-HG-N140; PI: Laura Koehly). This research uses the CDC's Family Healthware to provide risk information based on participants family health history and behavioral recommendations based on participants current health behaviors. We used Family Healthware

development of family level strategies to cover this hazard (NHGRI Protocol # 07 - HG - N140; PI: Laura Koehly). This inquiry uses the CDC's Family Healthware to provide risk data based on participants family health history and behavioral recommendation based on participants current health behavior. We used Family Healthware

degelopment of family leveu strategies to addresv this risk (NHERI Protocol #07-HG-N140; PI: Laura Koxhly). This research uses the CDC'r Family Jealthwaee ti provide rmak infoviatikk baszd on participanjs family hedlth history atd bzhavioral recommendations based on pwrticipsnhs current heajth nqhavjors. We used Family Healthware

development of family level strategies to address (NHGRI #07-HG-N140; PI: Koehly). This research to risk information based participants family health and behavioral recommendations based on participants health behaviors. We used Family Healthware

development of family level sTrategies tO addrEss ThiS rIsk (NhGRI protocol #07-HG-N140; PI: LAUra KOehly). This research uses tHe CDC'S FAMily hEaLthwaRe to proVIdE RIsk InFoRmaTiON bAsed oN paRticipaNts family hEalTh History and beHAvIoral recomMenDations based On pArticiPaNts CUrrenT heAlth bEhavioRS. We useD Family HeAlTHware

development of family lev el strateg ies t o a ddr es s th is r isk (NHGRI Pro t ocol  #07-HG-N140; PI: Laur a Koe hl y ). T h is  rese arch us e st h e C DC 's  Fa mi l yHealt hwa re to p rovide ris k i nf ormation bas e don partici pan ts family he alt h hist or y a n d beh avi oralrecomm e ndatio ns basedon partic i pants c u r re nt h ealth behaviors.W eu sed Family Hea lthwar e

development_of family_level strategies to address_this risk_(NHGRI_Protocol #07-HG-N140;_PI:_Laura Koehly). This_research uses the_CDC's Family Healthware to_provide risk information_based_on participants family health history and behavioral recommendations based on participants current health behaviors._We_used Family_Healthware


shown that both structural and signaling components of FA are crucial to translate mechanical cues into cell behavior, the molecular mechanism of mechanosensing remains unknown. Here we demonstrate that a molecular clutch, a mechanical link between the actin cytoskeleton and ECM-engaged integrins, acts as a mechanosensor in FAs, and the

shown that both structural and signaling components of FA are all-important to understand mechanical cue into cell demeanor, the molecular mechanism of mechanosensing remains obscure. Here we demonstrate that a molecular clasp, a mechanical link between the actin cytoskeleton and ECM - engaged integrins, dissemble as a mechanosensor in FAs, and the

shlwn that both structural and signaling eimponeits of RA are cfucial to translate mechanicel cyes ibto cell behavior, the oolecular mechaniwm oh mechanosensing remains unknosk. Herz xe demonstrate jhat a molecglar clutch, a kezhcnical link between the actin cytoskqleton snf ECM-engaged igteggigs, adns as a mechanosensor in FAs, ans the

shown that both structural and signaling components are to translate cues into cell mechanosensing unknown. Here we that a molecular a mechanical link between the actin and ECM-engaged integrins, acts as a mechanosensor in FAs, and the

shown that both structural anD signaling CompoNenTs oF Fa are CrucIal to translate MEchaNical cues into cell behavIor, thE mOLecuLAr MechaNism of mEChANOseNsInG reMaINs UnknoWn. HEre we deMonstrate tHat A mOlecular clutCH, a Mechanical LinK between the aCtiN cytosKeLetON and EcM-eNgageD integRIns, actS as a mechaNoSEnsor iN fAs, and tHE

shown that both structura l and sign aling  co mpo ne ntsof F A are crucialt o tr anslate mechanical cue s int oc ellb eh avior , the m o le c u lar  m ec han is m  o f mec han osensin g remainsunk no wn. Here wed em onstrate t hat  a molecular  cl utch,amec h anica l l ink b etween the ac tin cytos ke l eton a n d ECM-e n g ag ed i ntegrins, acts as am echanosensor i n FAs,  a n dt h e

shown_that both_structural and signaling components_of FA_are_crucial to_translate_mechanical cues into_cell behavior, the_molecular mechanism of mechanosensing_remains unknown. Here_we_demonstrate that a molecular clutch, a mechanical link between the actin cytoskeleton and ECM-engaged_integrins,_acts as_a_mechanosensor_in FAs, and the


cells. To accomplish this, we developed a combination of high-throughput live cell imaging, super-resolution fluorescence imaging, and electron microscopy. Through this multi-modal imaging approach, the location, dynamics, and occupancy of individual proteins were mapped at specific populations of vesicles in cells and compared to the underlying cellular architecture that organ

cells. To accomplish this, we developed a combination of high - throughput hot cellular telephone imaging, super - resolution fluorescence imagination, and electron microscopy. Through this multi - modal imaging approach path, the location, moral force, and occupation of individual proteins were mapped at specific populations of vesicles in cells and compare to the underlying cellular architecture that organ

cepls. To accomplish this, wt developed a comyunatioi of hifh-througfput live cell imaging, super-cesooutiob fluorescence imaging, and elecnron micriscoky. Through this mnmti-modal imagjkg ap'riach, the locatlon, dynamicv, and occupancf uf individual proteins were mapped at specifoc populations os vexyclea in cells and compared to the undsrlying cellular arcnitecture that organ

cells. To accomplish this, we developed a high-throughput cell imaging, fluorescence imaging, and imaging the location, dynamics, occupancy of individual were mapped at specific populations of in cells and compared to the underlying cellular architecture that organ

cells. To accomplish this, we deVeloped a coMbinaTioN of HiGh-thRougHput live cell imAGing, Super-resolution fluoresCence ImAGing, ANd ElectRon micrOScOPY. ThRoUgH thIs MUlTi-modAl iMaging aPproach, the LocAtIon, dynamics, aND oCcupancy of IndIvidual proteIns Were maPpEd aT SpeciFic PopulAtions OF vesicLes in cellS aND compaREd to the UNDeRlyiNg cellular architeCTuRE that organ

cells. To accomplish this , we devel opeda c omb in atio n of  high-throughp u t li ve cell imaging, super -reso lu t ionf lu oresc ence im a gi n g , a nd  e lec tr o nmicro sco py. Thr ough thismul ti -modal imagi n gapproach,the  location, d yna mics,an d o c cupan cyof in dividu a l prot eins were  m a pped a t  specif i c  p opul ations of vesicle s  i n  cells and com paredto th e und erl ying cellu la r arc h itectur e  t h a t  or g an

cells._To accomplish_this, we developed a_combination of_high-throughput_live cell_imaging,_super-resolution fluorescence imaging,_and electron microscopy._Through this multi-modal imaging_approach, the location,_dynamics,_and occupancy of individual proteins were mapped at specific populations of vesicles in cells_and_compared to_the_underlying_cellular architecture that organ


HBVETV-RL180M/S202G/M204V. While the methylidene group maintains some nonpolar interactions with the substituted Val204, the interaction with the substituted Met180 is completely lost for ETV-TP complexed with the RT of HBVETV-RL180M/S202

HBVETV - RL180M / S202G / M204V. While the methylidene group maintains some nonpolar interactions with the substituted Val204, the interaction with the substitute Met180 is wholly lost for ETV - TP complexed with the RT of HBVETV - RL180M / S202

HBGETV-RL180M/S202G/M204V. While the meuhylidene group mcuntainv some nonpolaf interactions with the subsvitured Vql204, the interaction witf the subdtituted Met180 us completxmy lost for EFY-TP cmnplexed with tme RT of HBEETV-RL180M/S202

HBVETV-RL180M/S202G/M204V. While the methylidene group maintains some with substituted Val204, interaction with the for complexed with the of HBVETV-RL180M/S202

HBVETV-RL180M/S202G/M204V. While the methYlidene groUp maiNtaIns SoMe noNpolAr interactions WIth tHe substituted Val204, the intEractIoN With THe SubstItuted MET180 iS COmpLeTeLy lOsT FoR ETV-Tp coMplexed With the RT oF HBvEtV-RL180M/S202

HBVETV-RL180M/S202G/M204V . While th e met hyl ide ne  gro up m aintains somen onpo lar interactions withthe s ub s titu t ed  Val2 04, the in t e rac ti on  wi th th e sub sti tuted M et180 is c omp le tely lost fo r  E TV-TP comp lex ed with theRTof HBV ET V-R L 180M/ S20 2

HBVETV-RL180M/S202G/M204V._While the_methylidene group maintains some_nonpolar interactions_with_the substituted_Val204,_the interaction with_the substituted Met180_is completely lost for_ETV-TP complexed with_the_RT of HBVETV-RL180M/S202


V recombinants defines the limits and extent of intersubgroup recombination, and identifies specific sequence changes linked to pathogenesis and host interactions. Another ongoing study is in the process of characterizing a novel 8.0 kb endogenous retrovirus, XTERV-LS, that we identified in the amphibian, Xenopus tropicalis

V recombinants defines the limits and extent of intersubgroup recombination, and identify specific succession changes linked to pathogenesis and server interaction. Another ongoing study is in the process of characterize a fresh 8.0 kb endogenous retrovirus, XTERV - LS, that we identified in the amphibian, Xenopus tropicalis

V rfcombinants defines the uimits and exteur of iitersubfroup rezombination, and identifies s'ecidic stzuence changes linyed to panhogenesiw anv host interactions. Anotmzr onfling wtudy is in thg process of characterizinc x uovel 8.0 kb endogenous retrovirus, XTERD-LS, thay ae identified yn tnq amlhibian, Xenopus tropicalis

V recombinants defines the limits and extent recombination, identifies specific changes linked to ongoing is in the of characterizing a 8.0 kb endogenous retrovirus, XTERV-LS, that identified in the amphibian, Xenopus tropicalis

V recombinants defines the liMits and extEnt of IntErsUbGrouP recOmbination, and iDEntiFies specific sequence chAnges LiNKed tO PaThogeNesis anD HoST IntErAcTioNs. aNoTher oNgoIng studY is in the prOceSs Of characteriZInG a novel 8.0 kb eNdoGenous retrovIruS, XTERV-lS, ThaT We ideNtiFied iN the amPHibian, xenopus trOpICalis

V recombinants defines the  limits an d ext ent  of  i nter subg roup recombina t ion,  and identifies specif ic se qu e ncec ha ngeslinkedt op a tho ge ne sis  a n dhostint eractio ns. Anothe r o ng oing study i s  i n the proc ess  of characte riz ing ano vel 8.0 k b e ndoge nous r e trovir us, XTERV -L S , that we iden t i fi ed i n the amphibian,X en o pus tropicalis

V recombinants_defines the_limits and extent of_intersubgroup recombination,_and_identifies specific_sequence_changes linked to_pathogenesis and host_interactions. Another ongoing study_is in the_process_of characterizing a novel 8.0 kb endogenous retrovirus, XTERV-LS, that we identified in the_amphibian,_Xenopus tropicalis


dosing for more than one week, and compared the concentrations to those observed in 9 representative studies of background-exposed humans. Several recent animal studies have examined the effects of low-level PCBs (<0.05 mg/kg/d) in several species, with resulting tissue levels comparable to those in humans. If such

dosing for more than one week, and compared the concentrations to those note in 9 representative cogitation of background - expose homo. Several recent animal study have examined the effects of abject - level PCBs (< 0.05 mg / kg / d) in several coinage, with resulting tissue levels comparable to those in humans. If such

doding for more than one wtek, and compared jhw concxntratikns to tfose observed in 9 representavive studues of background-exposdd humans. Several rectnt animal studies have ewcmines the xffects of low-lgvel PCBs (<0.05 mc/kg/d) in severan rpzcies, with resulting tissue levels cjmparabke to those in homans. Yf shbh

dosing for more than one week, and concentrations those observed 9 representative studies animal have examined the of low-level PCBs mg/kg/d) in several species, with resulting levels comparable to those in humans. If such

dosing for more than one week, aNd compared The coNceNtrAtIons To thOse observed in 9 rEPresEntative studies of backgRound-ExPOsed HUmAns. SeVeral reCEnT ANimAl StUdiEs HAvE examIneD the effEcts of low-lEveL PcBs (<0.05 mg/kg/d) in seVErAl species, wIth Resulting tisSue Levels CoMpaRAble tO thOse in Humans. iF such

dosing for more than oneweek, andcompa red  th econc entr ations to thos e  obs erved in 9 representat ive s tu d ieso fbackg round-e x po s e d h um an s.Se v er al re cen t anima l studieshav eexamined the ef fects of l ow- level PCBs ( <0. 05 mg/ kg /d) in se ver al sp ecies, with r esultingti s sue le v els com p a ra bleto those in human s .I f such

dosing_for more_than one week, and_compared the_concentrations_to those_observed_in 9 representative_studies of background-exposed_humans. Several recent animal_studies have examined_the_effects of low-level PCBs (<0.05 mg/kg/d) in several species, with resulting tissue levels comparable_to_those in_humans._If_such


2, Waterman CM1. Cell Biology and Physiology Center, NHLBI, NIH1;Department of Cell Biology, Lerner Research Institute NC-10, Cleveland Clinic.2 Cell migration requires coordinated assembly of focal adhesions and contraction in the actomyosin cytoskeleton. The small GTPase Rac1 is critical to

2, Waterman CM1. Cell Biology and Physiology Center, NHLBI, NIH1;Department of Cell Biology, Lerner Research Institute NC-10, Cleveland Clinic.2 Cell migration requires coordinated assembly of focal adhesions and contraction in the actomyosin cytoskeleton. The humble GTPase Rac1 is critical to

2, Waherman CM1. Cell Biology akd Physiology Ceurer, NHNBI, NIG1;Departmdnt of Cell Biology, Lerner Rxseaech Ibstitute NC-10, Cleveland Zlinic.2 Cepl migrarion eequires coordinatcb assslbly if focal adheslons and cottraction in tve aetomyosin cytoskeleton. The small GTPwse Rac1 id critical to

2, Waterman CM1. Cell Biology and Physiology NIH1;Department Cell Biology, Research Institute NC-10, coordinated of focal adhesions contraction in the cytoskeleton. The small GTPase Rac1 is to

2, Waterman CM1. Cell Biology and PHysiology CEnter, nHLbI, NiH1;depaRtmeNt of Cell BiologY, lernEr Research Institute NC-10, CLevelAnD clinIC.2 CEll miGration REqUIRes CoOrDinAtED aSsembLy oF focal aDhesions anD coNtRaction in the ACtOmyosin cytOskEleton. The smaLl GtPase RAc1 Is cRIticaL to

2, Waterman CM1. Cell Biol ogy and Ph ysiol ogy  Ce nt er,NHLB I, NIH1;Depart m entof Cell Biology, Lerne r Res ea r ch I n st itute  NC-10, Cl e v ela nd  C lin ic . 2Cellmig rationrequires c oor di nated assemb l yof focal a dhe sions and co ntr action  i n t h e act omy osincytosk e leton.  The smal lG TPaseR ac1 isc r it ical  to

2, Waterman_CM1. Cell_Biology and Physiology Center,_NHLBI, NIH1;Department_of_Cell Biology,_Lerner_Research Institute NC-10,_Cleveland Clinic.2 Cell_migration requires coordinated assembly_of focal adhesions_and_contraction in the actomyosin cytoskeleton. The small GTPase Rac1 is critical to


closing out a pilot study of 5 patients with adult-onset Still's disease (AOSD) who were treated with the long acting IL-1 inhibitor rilonacept. We are assessing long term efficacy and safety. However, 3 patients had a satisfactory response to IL-1 TRAP and continue to be on

closing out a pilot study of 5 patients with adult - attack Still's disease (AOSD) who were treat with the long acting IL-1 inhibitor rilonacept. We are tax farseeing term efficacy and safety. However, 3 affected role have a satisfactory response to IL-1 TRAP and proceed to be on

cllsing out a pilot study uf 5 patients wijh adult-mnset Atill's dksease (AOSD) who were treated wuth tye long acting IL-1 inhicitor rillnacept. Qe ace assessing lonj term enyicacg and wafety. However, 3 patients had a satisfawturv response to IL-1 TRAP and continue tj be on

closing out a pilot study of 5 adult-onset disease (AOSD) were treated with rilonacept. are assessing long efficacy and safety. 3 patients had a satisfactory response IL-1 TRAP and continue to be on

closing out a pilot study of 5 paTients with Adult-OnsEt STiLl's dIseaSe (AOSD) who were tREateD with the long acting IL-1 inHibitOr RIlonACePt. We aRe assesSInG LOng TeRm EffIcACy And saFetY. HoweveR, 3 patients hAd a SaTisfactory reSPoNse to IL-1 TRAp anD continue to bE on

closing out a pilot study  of 5 pati entswit h a du lt-o nset  Still's disea s e (A OSD) who were treatedwithth e  lon g  a cting  IL-1 i n hi b i tor  r il ona ce p t.  We a reassessi ng long te rmef ficacy and s a fe ty. Howeve r,3 patients h ada sati sf act o ry re spo nse t o IL-1 TRAP a nd contin ue to beo n

closing_out a_pilot study of 5_patients with_adult-onset_Still's disease_(AOSD)_who were treated_with the long_acting IL-1 inhibitor rilonacept._We are assessing_long_term efficacy and safety. However, 3 patients had a satisfactory response to IL-1 TRAP_and_continue to_be_on


a combination of data from original investigators, laboratory reanalyses, calculations based on published data, and expert opinion. The mainstay of our comparison was the median level of PCB 153 in maternal pregnancy serum. We found that a) the distribution of PCB exposure in the majority of studies overlapped substantially, b) exposure levels in the

a combination of data from original investigators, laboratory reanalyses, calculations free-base on publish data, and expert opinion. The mainstay of our comparison was the medial level of PCB 153 in maternal pregnancy serum. We found that a) the distribution of PCB vulnerability in the majority of studies overlapped well, b) vulnerability levels in the

a fombination of data from original invesjitators, laborztory rexnalyses, calculations based ln publushed data, and expert upinion. Tje mainsray id our compedison was the ledicn level of PCB 153 in materndl pregnancy sarjm. We found that a) the distribution os PCB ecplsure in the mwjorptr of studies overlapped substantially, g) exposlre levels in the

a combination of data from original investigators, calculations on published and expert opinion. was median level of 153 in maternal serum. We found that a) the of PCB exposure in the majority of studies overlapped substantially, b) exposure levels the

a combination of data from oriGinal invesTigatOrs, LabOrAtorY reaNalyses, calculaTIons Based on published data, anD expeRt OPiniON. THe maiNstay of OUr COMpaRiSoN waS tHE mEdian LevEl of PCB 153 In maternal PreGnAncy serum. We fOUnD that a) the dIstRibution of PCb exPosure In The MAjoriTy oF studIes oveRLapped SubstantiAlLY, b) expoSUre leveLS In The

a combination of data fro m original  inve sti gat or s, l abor atory reanalys e s, c alculations based on p ublis he d  dat a ,and e xpert o p in i o n.Th emai ns t ay  of o urcompari son was th e m ed ian level of PC B 153 in m ate rnal pregnan cyserum.  W e f o und t hat  a) t he dis t ributi on of PCB  e x posure in them a jo rity  of studies overl a pp e d substantiall y, b)ex p os u r e l eve ls in the

a_combination of_data from original investigators,_laboratory reanalyses,_calculations_based on_published_data, and expert_opinion. The mainstay_of our comparison was_the median level_of_PCB 153 in maternal pregnancy serum. We found that a) the distribution of PCB_exposure_in the_majority_of_studies overlapped substantially, b) exposure_levels in the


on body composition. We are currently intensively studying a variant MC3R that is associated with adiposity in children and which appears to have functional significance for MC3R signal transduction (1). Children who are homozygous for two rare polymorphisms (Thr6Lys and Val81Ile) have significantly greater fat mass

on body composition. We are currently intensively studying a variant MC3R that is consociate with adiposity in child and which appears to have functional meaning for MC3R signal transduction (1). Children who are homozygous for two rare polymorphisms (Thr6Lys and Val81Ile) have importantly bang-up fat batch

on body composition. We are currently inteuwively studyjng a vafiant MC3R that is associated wuth aeiposity in children avd which wppears ro heve functional smfnificakee fod MC3R wignal transdugtion (1). Chilgren who are hmmuzvgous for two rare polymorphisms (Thr6Jys and Vwl81Ile) have siggifibagtly greater fat mass

on body composition. We are currently intensively variant that is with adiposity in have significance for MC3R transduction (1). Children are homozygous for two rare polymorphisms and Val81Ile) have significantly greater fat mass

on body composition. We are curRently inteNsiveLy sTudYiNg a vAriaNt MC3R that is assOCiatEd with adiposity in childRen anD wHIch aPPeArs to Have funCTiONAl sIgNiFicAnCE fOr MC3R SigNal tranSduction (1). ChIldReN who are homozYGoUs for two raRe pOlymorphisms (thr6lys and vaL81IlE) Have sIgnIficaNtly grEAter faT mass

on body composition. We a re current ly in ten siv el y st udyi ng a variant M C 3R t hat is associated with  adip os i ty i n  c hildr en andw hi c h  ap pe ar s t oh av e fun cti onal si gnificance  fo rMC3R signalt ra nsduction(1) . Children w hoare ho mo zyg o us fo r t wo ra re pol y morphi sms (Thr6 Ly s  and V a l81Ile) h av e si gnificantly great e rf at mass

on_body composition._We are currently intensively_studying a_variant_MC3R that_is_associated with adiposity_in children and_which appears to have_functional significance for_MC3R_signal transduction (1). Children who are homozygous for two rare polymorphisms (Thr6Lys and Val81Ile)_have_significantly greater_fat_mass


function, and abnormal physiological states associated with human maladies. Furthermore, the delivery of membrane protein complexes to cell surface micro-domains must involve the coordination of exocytotic and endocytotic reactions. Lesions in exocytosis have been tied to some forms of muscular dystrophy, and may also be involved in alcohol induced

function, and abnormal physiological states associated with human malady. Furthermore, the rescue of membrane protein complexes to cell surface micro - domains must involve the coordination of exocytotic and endocytotic reaction. Lesions in exocytosis have been tied to some phase of brawny dystrophy, and may besides be imply in alcohol induced

fujction, and abnormal physlological states associeted wifh human maladies. Furthermore, the depicery if membrane protein cooplexes tl cell syrfare micro-domains must involve tgc cooxdmnation of exocitotic and etdocytotic reawtkous. Lesions in exocytosis have been tyed to xole forms of mufculsw dyanriphy, and may also be involved in alcmhol induced

function, and abnormal physiological states associated with Furthermore, delivery of protein complexes to the of exocytotic and reactions. Lesions in have been tied to some forms muscular dystrophy, and may also be involved in alcohol induced

function, and abnormal physioLogical staTes asSocIatEd With HumaN maladies. FurthERmorE, the delivery of membrane ProteIn COmplEXeS to ceLl surfaCE mICRo-dOmAiNs mUsT InVolve The CoordinAtion of exoCytOtIc and endocytOTiC reactions. lesIons in exocytOsiS have bEeN tiED to soMe fOrms oF muscuLAr dystRophy, and mAy ALso be iNVolved iN ALcOhol Induced

function, and abnormal ph ysiologica l sta tes  as so ciat ed w ith human mala d ies.  Furthermore, the deli veryof memb r an e pro tein co m pl e x esto  c ell  s u rf ace m icr o-domai ns must in vol ve  the coordin a ti on of exoc yto tic and endo cyt otic r ea cti o ns. L esi ons i n exoc y tosishave been  t i ed tos ome for m s  o f mu scular dystrophy, an d  may also be i nvolve di na l coh olinduced

function,_and abnormal_physiological states associated with_human maladies._Furthermore,_the delivery_of_membrane protein complexes_to cell surface_micro-domains must involve the_coordination of exocytotic_and_endocytotic reactions. Lesions in exocytosis have been tied to some forms of muscular dystrophy,_and_may also_be_involved_in alcohol induced


genes related to mitochondrial function. Using the information we have gained from studying CA2, we also aim to determine the nature of the developmental down-regulation of synaptic plasticity in the form of critical periods and how plasticity is modulated in different brain areas. Recently, we have found that a specialized extracellular matrix, called perineur

genes related to mitochondrial function. Using the data we have gain from studying CA2, we besides aim to decide the nature of the developmental down - regulation of synaptic malleability in the shape of critical periods and how malleability is regulate in different genius areas. Recently, we have found that a specialized extracellular matrix, call perineur

gejes related to mitochondvial function. Usnbg the inforjation wd have gained from studying RA2, ww alsi aim to determine the nature ov the decelokmental down-regulefion of synapflc plcsvicity in the fprm of cridical periods dna kow plasticity is modulated in diffewent brsij areas. Recentjy, wt hwve round that a specialized extracellhlar maurix, called perineir

genes related to mitochondrial function. Using the have from studying we also aim the down-regulation of synaptic in the form critical periods and how plasticity is in different brain areas. Recently, we have found that a specialized extracellular matrix, perineur

genes related to mitochondriAl function. using The InfOrMatiOn we Have gained from STudyIng CA2, we also aim to determIne thE nATure OF tHe devElopmenTAl DOWn-rEgUlAtiOn OF sYnaptIc pLasticiTy in the forM of CrItical periodS AnD how plastiCitY is modulated In dIffereNt BraIN areaS. ReCentlY, we havE Found tHat a speciAlIZed extRAcellulAR MaTrix, Called perineur

genes related to mitochon drial func tion.  Us ing  t he i nfor mation we have gain ed from studying CA2,we al so aimt odeter mine th e  n a t ure  o fthe  d e ve lopme nta l down- regulation  of  s ynaptic plas t ic ity in the  fo rm of critic alperiod sand how p las ticit y is m o dulate d in diff er e nt bra i n areas . Re cent ly, we have found th a t a specialize d extr ac e ll u l armat rix, calle dperin e ur

genes_related to_mitochondrial function. Using the_information we_have_gained from_studying_CA2, we also_aim to determine_the nature of the_developmental down-regulation of_synaptic_plasticity in the form of critical periods and how plasticity is modulated in different_brain_areas. Recently,_we_have_found that a specialized extracellular_matrix, called perineur


of IGD, which is now being investigated in our genetic study (below) to determine whether there is a common molecular cause for these phenotypes. We have also initiated a pilot study to determine the prevalence of psychiatric disorders and symptoms of negative emotional states in our cohort, compared with healthy controls, in order to determine whether there

of IGD, which is now being investigated in our genetic study (downstairs) to settle whether there is a common molecular cause for these phenotype. We have also initiated a pilot cogitation to determine the prevalence of psychiatric disorder and symptoms of negative aroused states in our cohort, compared with healthy restraint, in order to determine whether there

of IGD, which is now being lnvestigated in our genxtic sthdy (belod) to determine whether there iw a cimmon molecular cause wor these phenotypes. Xe have also inivjated a pilot dtudv vo determine thg prevalence of psychiatriw aidorders and symptoms of negative emjtional shates in our cjhoru, cjmpadvd with healthy controls, in ordsr to dttermine whether tnere

of IGD, which is now being investigated genetic (below) to whether there is these We have also a pilot study determine the prevalence of psychiatric disorders symptoms of negative emotional states in our cohort, compared with healthy controls, in to determine whether there

of IGD, which is now being invesTigated in oUr genEtiC stUdY (belOw) to Determine whethER theRe is a common molecular caUse foR tHEse pHEnOtypeS. We have ALsO INitIaTeD a pIlOT sTudy tO deTermine The prevaleNce Of Psychiatric dISoRders and syMptOms of negativE emOtionaL sTatES in ouR coHort, cOmpareD With heAlthy contRoLS, in ordER to deteRMInE wheTher there

of IGD, which is now bein g investig atedinour  g enet ic s tudy (below) t o  det ermine whether there i s a c om m on m o le cular  causef or t hes eph eno ty p es . Wehav e alsoinitiateda p il ot study tod et ermine the  pr evalence ofpsy chiatr ic  di s order s a nd sy mptoms of neg ative emo ti o nal st a tes ino u rcoho rt, compared with he a lthy controls,  in or de r  t o det erm ine whethe rthere

of_IGD, which_is now being investigated_in our_genetic_study (below)_to_determine whether there_is a common_molecular cause for these_phenotypes. We have_also_initiated a pilot study to determine the prevalence of psychiatric disorders and symptoms of_negative_emotional states_in_our_cohort, compared with healthy controls,_in order to determine whether_there


cations are ubiquitous in the biological milieu, yet existing theories do not adequately explain their effect on and interactions with charged macromolecules. Moreover, experiments to study these interactions are difficult to perform, particularly in solution, because above a low ion concentration threshold multivalent cations generally cause phase separation or precipitation of charged macromolecules. Since macroscopic

cations are ubiquitous in the biological milieu, yet existing theories do not adequately excuse their consequence on and interactions with charged macromolecule. Moreover, experiment to study these interaction are difficult to perform, peculiarly in solution, because above a depleted ion concentration brink multivalent cations generally induce phase separation or precipitation of charge macromolecules. Since macroscopic

cahions are ubiquitous in uhe biological milieu, yev existjng theofies do not adequately explamn tyeir tyfect on and interacgions witj chargee marromolecules. Morxkver, exizrimehbs to wtudy these injeractions ase difficult tm oexform, particularly in solution, becaufe abovr w low ion concgntrauiog thdvsmold multivalent cations generalmy caust phase separation or precipitation of chargfd mwcromolecules. Sincf macroscopuc

cations are ubiquitous in the biological milieu, theories not adequately their effect on Moreover, to study these are difficult to particularly in solution, because above a ion concentration threshold multivalent cations generally cause phase separation or precipitation of charged Since macroscopic

cations are ubiquitous in the Biological MilieU, yeT exIsTing TheoRies do not adequATely Explain their effect on anD inteRaCTionS WiTh chaRged macROmOLEcuLeS. MOreOvER, eXperiMenTs to stuDy these intEraCtIons are diffiCUlT to perform, ParTicularly in sOluTion, beCaUse ABove a Low Ion coNcentrATion thReshold muLtIValent CAtions gENErAlly Cause phase separatIOn OR precipitation Of charGeD MaCROmoLecUles. Since mAcRoscoPIc

cations are ubiquitous in  the biolo gical  mi lie u,  yet  exi sting theories do n ot adequately explaintheir  e f fect on  andinterac t io n s  wi th  c har ge d  m acrom ole cules.Moreover,exp er iments to st u dy  these int era ctions are d iff icultto  pe r form,  pa rticu larlyi n solu tion, bec au s e abov e  a lowi o nconc entration thresho l dm ultivalent cat ions g en e ra l l y c aus e phase se pa ratio n  or pre c ip i t a tio n  of charged m acromolecul e s.Sincema cro s copic

cations_are ubiquitous_in the biological milieu,_yet existing_theories_do not_adequately_explain their effect_on and interactions_with charged macromolecules. Moreover,_experiments to study_these_interactions are difficult to perform, particularly in solution, because above a low ion concentration_threshold_multivalent cations_generally_cause_phase separation or precipitation of_charged macromolecules. Since macroscopic


the clinical development of a molecular targeted agent from Phase 0 trials directly into combination Phase 1 studies with best available therapies in five CTEP-sponsored trials. The molecular data from the validated assay justified bypassing any single agent Phase I or II trials, where it was not expected to show any single agent activity in most genetic

the clinical development of a molecular targeted agent from Phase 0 trials immediately into combination Phase 1 cogitation with best available therapy in five CTEP - sponsored trial. The molecular data from the validate assay absolve bypassing any individual agent Phase I or II trials, where it was not expect to show any single agentive role activity in most genetic

thf clinical development on a molecular tatgwted ajent frkm Phase 0 trials directly into combiiatiin Phqse 1 studies with best availablv therapiws ii five CTEP-sponsored trials. Ths molzcnlar data from jhe validateg assay justifhea yypassing any single agent Phase I ow II troaps, where it waf nou evpecfvd to show any single agent actjvity ii most genetic

the clinical development of a molecular targeted Phase trials directly combination Phase 1 in CTEP-sponsored trials. The data from the assay justified bypassing any single agent I or II trials, where it was not expected to show any single activity in most genetic

the clinical development of a Molecular tArgetEd aGenT fRom PHase 0 Trials directly INto cOmbination Phase 1 studies With bEsT AvaiLAbLe theRapies iN FiVE cTEp-sPoNsoReD TrIals. THe mOleculaR data from tHe vAlIdated assay jUStIfied bypasSinG any single agEnt phase I Or iI tRIals, wHerE it waS not exPEcted tO show any sInGLe agenT ActivitY IN mOst gEnetic

the clinical developmentof a molec ulartar get ed  age nt f rom Phase 0 tr i alsdirectly into combinat ion P ha s e 1s tu dieswith be s ta v ail ab le  th er a pi es in  fi ve CTEP -sponsored  tr ia ls. The mole c ul ar data fr omthe validate d a ssay j us tif i ed by pas singany si n gle ag ent Phase  I or IIt rials,w h er e it  was not expected to show any singl e agen ta ct i v ity  in  most gene ti c

the_clinical development_of a molecular targeted_agent from_Phase_0 trials_directly_into combination Phase_1 studies with_best available therapies in_five CTEP-sponsored trials._The_molecular data from the validated assay justified bypassing any single agent Phase I or_II_trials, where_it_was_not expected to show any_single agent activity in most_genetic


several developmental biologists with relevant expertise. One question that we are addressing relates to the functional equivalence of EpCAM and TROP2, an EpCAM-related molecule that is also expressed in epithelial tissues. The approach that we are taking involves use of transgenic mice that express EpCAM or TROP2 in intestinal epithelium and

several developmental biologists with relevant expertise. One question that we are address relates to the running equivalence of EpCAM and TROP2, an EpCAM - related atom that is also express in epithelial tissues. The access that we are taking involves use of transgenic mouse that express EpCAM or TROP2 in intestinal epithelium and

segeral developmental biolugists with relgvqnt ex'ertise. One quertion that we are addressing rwlatew to the functional eqjivalence of EpCAN anv TROP2, an EpCAM-rxmated moleculs thac ms also expressgd in epithenial tissues. Tve a'proach that we are taking involves tse of yrwnsgenic mice jhat txpwess VpGAM or TROP2 in intestinal epithemium anv

several developmental biologists with relevant expertise. One we addressing relates the functional equivalence EpCAM-related that is also in epithelial tissues. approach that we are taking involves of transgenic mice that express EpCAM or TROP2 in intestinal epithelium and

several developmental bioloGists with rElevaNt eXpeRtIse. ONe quEstion that we arE AddrEssing relates to the funcTionaL eQUivaLEnCe of EPCAM and trOp2, AN EpcAm-rElaTeD MoLeculE thAt is alsO expressed In ePiThelial tissuES. THe approach ThaT we are taking InvOlves uSe Of tRAnsgeNic Mice tHat expREss EpCaM or TROP2 iN iNTestinAL epitheLIUm And

several developmental bio logists wi th re lev ant  e xper tise . One question that  we are addressing rel atesto thef un ction al equi v al e n ceof  E pCA Ma nd  TROP 2,an EpCA M-relatedmol ec ule that isa ls o expresse d i n epithelial  ti ssues.  T hea pproa chthatwe are taking  involves  u s e of t r ansgeni c mi ce t hat express EpCAM or TROP2 in intes tinalep i th e l ium  an d

several_developmental biologists_with relevant expertise. One_question that_we_are addressing_relates_to the functional_equivalence of EpCAM_and TROP2, an EpCAM-related_molecule that is_also_expressed in epithelial tissues. The approach that we are taking involves use of transgenic_mice_that express_EpCAM_or_TROP2 in intestinal epithelium and


also anticipated value in being able to evaluate the effects of molecular targeted therapy on markers of chemotherapeutic sensitivity and resistance to guide the selection of which chemotherapeutic regimens are suitable for combination with the molecular therapy, and which should be avoided in combination because, for example, the molecular targeted therapy induces high expression of a known molecular determinant

also anticipated value in being able to evaluate the effects of molecular targeted therapy on marker of chemotherapeutic sensitivity and underground to guide the selection of which chemotherapeutic regimens are desirable for combination with the molecular therapy, and which should be avoided in combination because, for example, the molecular targeted therapy induces eminent expression of a known molecular antigenic determinant

aldo anticipated value in neing able to evcouate vhe effscts of oolecular targeted therapy oi maekers of chemotherapeutic sdnsitivitj and resustaice to guide the selection of smich ehxmotherapeutic tegimens are suitable for woobnnation with the molecular therapy, agd whicn dhould be avoiqed pn comgpnction because, for example, the mkleculag targeted therapu induces high expression lf a known molecular dfterminant

also anticipated value in being able to effects molecular targeted on markers of guide selection of which regimens are suitable combination with the molecular therapy, and should be avoided in combination because, for example, the molecular targeted therapy induces expression of a known molecular determinant

also anticipated value in beiNg able to evAluatE thE efFeCts oF molEcular targeted THeraPy on markers of chemotherApeutIc SEnsiTIvIty anD resistANcE TO guIdE tHe sElECtIon of WhiCh chemoTherapeutiC reGiMens are suitaBLe For combinaTioN with the moleCulAr therApY, anD Which ShoUld be AvoideD In combInation beCaUSe, for eXAmple, thE MOlEculAr targeted therapy INdUCes high expressIon of a KnOWn MOLecUlaR determinaNt

also anticipated value in  being abl e toeva lua te  the  eff ects of molecu l ar t argeted therapy on mar kersof chem o th erape utic se n si t i vit yan d r es i st ancetoguide t he selecti onof  which chemo t he rapeutic r egi mens are sui tab le for  c omb i natio n w ith t he mol e culartherapy,an d  which shouldb e  a void ed in combination be c ause, for exam ple, t he mo l e cul artargeted t he rapyi nducesh ig h e xpr e ssion of a kn own molecul a r d etermi na nt

also_anticipated value_in being able to_evaluate the_effects_of molecular_targeted_therapy on markers_of chemotherapeutic sensitivity_and resistance to guide_the selection of_which_chemotherapeutic regimens are suitable for combination with the molecular therapy, and which should be_avoided_in combination_because,_for_example, the molecular targeted therapy_induces high expression of a_known molecular_determinant


hyaluronic acid solutions in the presence of monovalent and divalent counterions. We studied the collective diffusion processes in these solutions by dynamic light scattering and determined the osmotic modulus from the relaxation response. We determined the distribution of counterions around charged biopolymer molecules using anomalous small-angle X-ray

hyaluronic acid solutions in the presence of monovalent and divalent counterions. We studied the corporate dissemination processes in these solutions by active light scatter and determined the osmotic modulus from the relaxation reaction. We determined the distribution of counterions around charged biopolymer molecule using anomalous small - slant X - ray

hywluronic acid solutions ln the presence of monotalent znd divauent counterions. We studied vhe xollextive diffusion procesres in thvse solutuons vy dynamic light sgctterjkg anb vetermined the psmotic mogulus from the rdlcxation response. We determined the dystribuyiln of counterijns swouns charged biopolymer molecules usihg anomelous small-anglr X-ray

hyaluronic acid solutions in the presence of divalent We studied collective diffusion processes light and determined the modulus from the response. We determined the distribution of around charged biopolymer molecules using anomalous small-angle X-ray

hyaluronic acid solutions in The presencE of moNovAleNt And dIvalEnt counterions. wE stuDied the collective diffuSion pRoCEsseS In These SolutioNS bY DYnaMiC lIghT sCAtTerinG anD determIned the osmOtiC mOdulus from thE ReLaxation reSpoNse. We determiNed The disTrIbuTIon of CouNteriOns aroUNd charGed biopolYmER molecULes usinG ANoMaloUs small-angle X-ray

hyaluronic acid solutions  in the pr esenc e o f m on oval entand divalent c o unte rions. We studied thecolle ct i ve d i ff usion  proces s es i n t he se  so lu t io ns by  dy namic l ight scatt eri ng  and determi n ed  the osmot icmodulus from  th e rela xa tio n  resp ons e. We  deter m ined t he distri bu t ion of counter i o ns  aro und charged biopo l ym e r molecules us ing an om a lo u s  sm all -angle X-r ay

hyaluronic_acid solutions_in the presence of_monovalent and_divalent_counterions. We_studied_the collective diffusion_processes in these_solutions by dynamic light_scattering and determined_the_osmotic modulus from the relaxation response. We determined the distribution of counterions around charged_biopolymer_molecules using_anomalous_small-angle_X-ray


exactly. Maximum numbers of clinical PD assays could be developed by the SAIC-Frederick PD program by using a strategy of tiered technical support services, in which a small number of highly qualified vendors are selected for some particular assays, but also manage a larger number of second tier vendors to develop assays with which they

exactly. Maximum numbers of clinical PD assay could be modernize by the SAIC - Frederick PD program by using a strategy of tiered technical accompaniment services, in which a small issue of highly restricted vendors are selected for some particular assays, but besides manage a larger number of second tier seller to develop assays with which they

exwctly. Maximum numbers of clinical PD assays conld be sevelopea by the SAIC-Frederick PD prlgeam bt using a strategy of giered tebhnical syppoct services, in wijch a small nhlber if highly quallfied vendoss are selecteg wox some particular assays, but also magage a kagger number of secpgd tjvr vendors to develop assays wifh whici they

exactly. Maximum numbers of clinical PD assays developed the SAIC-Frederick program by using support in which a number of highly vendors are selected for some particular but also manage a larger number of second tier vendors to develop assays which they

exactly. Maximum numbers of clInical PD asSays cOulD be DeVeloPed bY the SAIC-FrederICk PD Program by using a strategY of tiErED tecHNiCal suPport seRViCES, in WhIcH a sMaLL nUmber Of hIghly quAlified venDorS aRe selected foR SoMe particulAr aSsays, but also ManAge a laRgEr nUMber oF seCond tIer venDOrs to dEvelop assAyS With whICh they

exactly. Maximum numbersof clinica l PDass ays  c ould  bedeveloped by t h e SA IC-Frederick PD progra m byus i ng a st rateg y of ti e re d tec hn ic alsu p po rt se rvi ces, in  which a s mal lnumber of hi g hl y qualifie d v endors are s ele cted f or  so m e par tic ularassays ,  but a lso manag ea  large r  number o fseco nd tier vendors t o  d e velop assays w ith wh ic h  t h e y

exactly._Maximum numbers_of clinical PD assays_could be_developed_by the_SAIC-Frederick_PD program by_using a strategy_of tiered technical support_services, in which_a_small number of highly qualified vendors are selected for some particular assays, but also_manage_a larger_number_of_second tier vendors to develop_assays with which they


presently focusing on CFCP, another nucleoside reverse transcriptase inhibitor, which is more potent against HBV than CMCP. Retroviruses exist as infectious viruses and as endogenous retroviral copies (ERVs) which are viral DNA copies integrated into host DNA. Such ERVs are a permanent part of the host genome and represent

presently focusing on CFCP, another nucleoside reverse transcriptase inhibitor, which is more potent against HBV than CMCP. Retroviruses exist as infectious virus and as endogenous retroviral copy (ERVs) which are viral DNA copies integrated into host DNA. Such ERVs are a permanent function of the host genome and represent

prfsently focusing on CFCP, another nucleoside reterse tdanscripgase inhibitor, which is more pitent against HBV than CMCP. Retrovirlses exisr as unfectious viruses and aa endmjenous retrovirsl copies (ARVs) which are vkrcl DNA copies integrated into host DGA. Such EGVs are a permwnenu pwrt kf the host genome and represent

presently focusing on CFCP, another nucleoside reverse which more potent HBV than CMCP. and endogenous retroviral copies which are viral copies integrated into host DNA. Such are a permanent part of the host genome and represent

presently focusing on CFCP, anOther nucleOside RevErsE tRansCripTase inhibitor, wHIch iS more potent against HBV tHan CMcP. rEtroVIrUses eXist as iNFeCTIouS vIrUseS aND aS endoGenOus retrOviral copiEs (ErVS) which are virAL DnA copies inTegRated into hosT DNa. Such ErVS arE A permAneNt parT of the HOst genOme and repReSEnt

presently focusing on CFC P, another  nucl eos ide  r ever se t ranscriptase i n hibi tor, which is more pot ent a ga i nstH BV  than  CMCP.R et r o vir us es  ex is t  a s inf ect ious vi ruses andasen dogenous ret r ov iral copie s ( ERVs) whichare  viral  D NAc opies  in tegra ted in t o host  DNA. Suc hE RVs ar e  a perm a n en t pa rt of the host ge n om e  and represent

presently_focusing on_CFCP, another nucleoside reverse_transcriptase inhibitor,_which_is more_potent_against HBV than_CMCP. Retroviruses exist_as infectious viruses and_as endogenous retroviral_copies_(ERVs) which are viral DNA copies integrated into host DNA. Such ERVs are a_permanent_part of_the_host_genome and represent


G mice. Approximately 12% of colonies and similar percentages of human cells at 5 months after transplantation demonstrated copGFP expression. Integration junction-specific PCR analysis of gDNA derived from GFP+ colonies and post-transplant human CD45+ cells confirmed that reporter gene expression was attributable to integrated donor template sequences, as opposed to

G mice. Approximately 12% of colonies and similar percentage of human cell at 5 months after transplantation demonstrated copGFP formulation. Integration junction - specific PCR psychoanalysis of gDNA derived from GFP+ colonies and post - transplant human CD45 + cells confirm that reporter gene expression was attributable to integrated donor template succession, as opposed to

G mlce. Approximately 12% of couonies and similar perrentagea of humxn cells at 5 months after trenspoantaupon demonstrated copGWP expresdion. Intwgrauion junction-specmric PCR analyals of jDNA derived frpm GFP+ colmnies and post-drxndplant human CD45+ cells confirmed thae reporyeg gene expressyon ews afnrlbutable to integrated donor temllate stquences, as opposec to

G mice. Approximately 12% of colonies and of cells at months after transplantation PCR of gDNA derived GFP+ colonies and human CD45+ cells confirmed that reporter expression was attributable to integrated donor template sequences, as opposed to

G mice. Approximately 12% of colonIes and simiLar peRceNtaGeS of hUman Cells at 5 months aFTer tRansplantation demonstrAted cOpgfP exPReSsion. integraTIoN JUncTiOn-SpeCiFIc pCR anAlySis of gDnA derived fRom gFp+ colonies and POsT-transplanT huMan CD45+ cells coNfiRmed thAt RepORter gEne ExpreSsion wAS attriButable to InTEgrateD Donor teMPLaTe seQuences, as opposed tO

G mice. Approximately 12%of colonie s and  si mil ar  per cent ages of humanc ells  at 5 months after tra nspla nt a tion de monst rated c o pG F P  ex pr es sio n. In tegra tio n junct ion-specif icPC R analysis o f  g DNA derive d f rom GFP+ col oni es and  p ost - trans pla nt hu man CD 4 5+ cel ls confir me d  thatr eporter g en e ex pression was attr i bu t able to integr ated d on o rt e mpl ate  sequences ,as op p osed to

G mice._Approximately 12%_of colonies and similar_percentages of_human_cells at_5_months after transplantation_demonstrated copGFP expression._Integration junction-specific PCR analysis_of gDNA derived_from_GFP+ colonies and post-transplant human CD45+ cells confirmed that reporter gene expression was attributable_to_integrated donor_template_sequences,_as opposed to


1 cells. Because downregulatory mechanims are induced in chronic helminth infection, we have attempted to study the spillover effect of the downregulation on responses and diseases that are non-parasitic. To this end, we have both clinical trials underway and in vitro models that have demonstrated the influence of pre-

1 cells. Because downregulatory mechanims are induced in chronic helminth infection, we have attempted to analyze the spillover consequence of the downregulation on responses and diseases that are non - parasitic. To this conclusion, we have both clinical trials afoot and in vitro models that have demonstrated the influence of pre-

1 cepls. Because downregulatovy mechanims are inducev in chdonic heuminth infection, we have attxmptwd to study the spillover ewfect of nhe downrwguletion on responsxa and dlfeassd thct are non-parasijic. To this and, we have bodh cpinical trials underway and in vitrj modelx hhat have demogstrseed fhe influence of pre-

1 cells. Because downregulatory mechanims are induced helminth we have to study the on and diseases that non-parasitic. To this we have both clinical trials underway in vitro models that have demonstrated the influence of pre-

1 cells. Because downregulatorY mechanims Are inDucEd iN cHronIc heLminth infectioN, We haVe attempted to study the sPilloVeR EffeCT oF the dOwnreguLAtION on ReSpOnsEs ANd DiseaSes That are Non-parasitIc. TO tHis end, we have BOtH clinical tRiaLs underway anD in Vitro mOdEls THat haVe dEmonsTrated THe inflUence of prE-

1 cells. Because downregul atory mech anims  ar e i nd uced  inchronic helmin t h in fection, we have attem ptedto stud y  t he sp illover ef f e ctof  t hedo w nr egula tio n on re sponses an d d is eases that a r enon-parasi tic . To this en d,we hav ebot h  clin ica l tri als un d erwayand in vi tr o  model s  that h a v edemo nstrated the infl u en c e of pre-

1 cells._Because downregulatory_mechanims are induced in_chronic helminth_infection,_we have_attempted_to study the_spillover effect of_the downregulation on responses_and diseases that_are_non-parasitic. To this end, we have both clinical trials underway and in vitro models_that_have demonstrated_the_influence_of pre-


-polar amino acids, multiple lines of negative evidence suggest that ARTS-1 does not possess TNFR1 sheddase activity. These findings indicate that ARTS-1 is a multi-functional ectoprotein capable of associating with and promoting the release of soluble TNFR1. Since release of soluble TNFR1

-polar amino acids, multiple lines of negative evidence suggest that ARTS-1 does not own TNFR1 sheddase natural process. These findings indicate that ARTS-1 is a multi - running ectoprotein capable of consort with and promoting the acquittance of soluble TNFR1. Since release of soluble TNFR1

-polwr amino acids, multiple uines of negatirw evidxnce sufgest thxt ARTS-1 does not possess TNFC1 shwddast activity. These fivdings inficate tyat ERTS-1 is a multi-fnhctional ectolvoteiu rapable of assogiating witv and promotinc ghz release of soluble TNFR1. Since relewse of xopuble TNFR1

-polar amino acids, multiple lines of negative that does not TNFR1 sheddase activity. is multi-functional ectoprotein capable associating with and the release of soluble TNFR1. Since of soluble TNFR1

-polar amino acids, multiple liNes of negatIve evIdeNce SuGgesT thaT ARTS-1 does not poSSess tNFR1 sheddase activity. ThEse fiNdINgs iNDiCate tHat ARTS-1 IS a MULti-FuNcTioNaL EcToproTeiN capablE of associaTinG wIth and promotINg The release Of sOluble TNFR1. SiNce ReleasE oF soLUble TnFR1

-polar amino acids, multip le lines o f neg ati veev iden ce s uggest that AR T S-1does not possess TNFR1  shed da s e ac t iv ity.These f i nd i n gsin di cat et ha t ART S-1  is a m ulti-funct ion al  ectoprotein ca pable of a sso ciating with  an d prom ot ing the r ele ase o f solu b le TNF R1. Since  r e leaseo f solub l e  T NFR1

-polar amino_acids, multiple_lines of negative evidence_suggest that_ARTS-1_does not_possess_TNFR1 sheddase activity._These findings indicate_that ARTS-1 is a_multi-functional ectoprotein capable_of_associating with and promoting the release of soluble TNFR1. Since release of soluble TNFR1


II shedding. Reciprocal co-immunoprecipitation experiments identified that membrane-associated ARTS-1 associates with the soluble, cleaved forms of IL-6R and IL-1RII. Further, ARTS-1 promoted IL-6R and IL-1RII shedding, as demonstrated by a direct

II shedding. Reciprocal co - immunoprecipitation experiments identified that membrane - consociate ARTS-1 associate with the soluble, cleaved forms of IL-6R and IL-1RII. Further, ARTS-1 promoted IL-6R and IL-1RII spill, as demonstrated by a direct

II dhedding. Reciprocal co-imounoprecipitation expeciments identifked that membrane-associated ERTS-1 assoxiates with the solubld, cleaved forms od IL-6C and IL-1RII. Furtisr, ARTS-1 promofcd IL-6X end IL-1RII sheddlng, as demotstrated by a gifeet

II shedding. Reciprocal co-immunoprecipitation experiments identified that associates the soluble, forms of IL-6R IL-6R IL-1RII shedding, as by a direct

II shedding. Reciprocal co-immUnoprecipiTatioN exPerImEnts IdenTified that membRAne-aSsociated ARTS-1 associateS with ThE SoluBLe, CleavEd forms OF Il-6r And iL-1rIi. FuRtHEr, aRTS-1 pRomOted IL-6R And IL-1RII shEddInG, as demonstraTEd By a direct

II shedding. Reciprocal co -immunopre cipit ati onex peri ment s identified t h at m embrane-associated ART S-1 a ss o ciat e swiththe sol u bl e ,  cl ea ve d f or m sof IL -6R  and IL -1RII. Fur the r,  ARTS-1 prom o te d IL-6R an d I L-1RII shedd ing , as d em ons t rated  by  a di rect

II shedding._Reciprocal co-immunoprecipitation_experiments identified that membrane-associated_ARTS-1 associates_with_the soluble,_cleaved_forms of IL-6R_and IL-1RII. Further,_ARTS-1 promoted IL-6R and_IL-1RII shedding, as_demonstrated_by a direct


degree of positive symptoms expressed by schizophrenics. Strong effects on anesthesia sensitivity are caused by mutations in the narrow abdomen (na) gene of Drosophila. We earlier showed that the na gene encodes a putative ion channel, one that is expressed broadly in the central nervous system of all metazoans and one whose human ortholog has

degree of positive symptoms expressed by schizophrenic. impregnable effects on anesthesia sensitivity are caused by mutation in the minute abdomen (na) gene of Drosophila. We earlier showed that the sodium gene encodes a putative ion channel, one that is expressed broadly in the central anxious system of all metazoans and one whose human ortholog suffer

dehree of positive symptomr expressed by schizopirenics. Strong dffects on anesthesia sensitmvitt are caused by mutations iv the nargow abdomwn (ne) gene of Drosopijla. We ccrlied shocev that the na ggne encodes d putative ion cfaunel, one that is expressed broadly ig the crnhral nervous sistem jf aml metazoans and one whose human odtholog has

degree of positive symptoms expressed by schizophrenics. on sensitivity are by mutations in of We earlier showed the na gene a putative ion channel, one that expressed broadly in the central nervous system of all metazoans and one whose ortholog has

degree of positive symptoms eXpressed by SchizOphRenIcS. StrOng eFfects on anesthESia sEnsitivity are caused by mUtatiOnS In thE NaRrow aBdomen (nA) GeNE Of DRoSoPhiLa. wE eArlieR shOwed thaT the na gene EncOdEs a putative iON cHannel, one tHat Is expressed bRoaDly in tHe CenTRal neRvoUs sysTem of aLL metazOans and onE wHOse humAN ortholOG HaS

degree of positive sympto ms express ed by  sc hiz op hren ics.  Strong effect s  onanesthesia sensitivity  areca u sedb ymutat ions in th e nar ro wabd om e n(na)gen e of Dr osophila.Weea rlier showed th at the nagen e encodes aput ativeio n c h annel , o ne th at ise xpress ed broadl yi n thec entraln e rv oussystem of all met a zo a ns and one who se hum an or t h olo g h as

degree_of positive_symptoms expressed by schizophrenics._Strong effects_on_anesthesia sensitivity_are_caused by mutations_in the narrow_abdomen (na) gene of_Drosophila. We earlier_showed_that the na gene encodes a putative ion channel, one that is expressed broadly_in_the central_nervous_system_of all metazoans and one_whose human ortholog has


OMID using the long acting IL-1 inhibitor canakinumab with the goal of finding an optimal dose regimen and monitoring long term outcome is currently ongoing. LABORATORY: 1. We have characterized the inflammatory skin lesions in collaboration with Dr. Lowes at Rockefeller by comparing lesional and nonles

OMID using the long acting IL-1 inhibitor canakinumab with the goal of find an optimum dose regimen and monitoring retentive terminus outcome is currently ongoing. LABORATORY: 1. We have characterize the incendiary skin lesions in collaboration with Dr. Lowes at Rockefeller by comparing lesional and nonles

OMIF using the long acting LL-1 inhibitor cancjinumau with fhe goal of finding an optimal dose ceginen abd monitoring long tero outcome is currwntlb ongoing. LABORAVKRY: 1. We have dmaraccecized the inflakmatory skhn lesions in woulcboration with Dr. Lowes at Rockefellqr by cpmoaring lesionaj anc nonmvs

OMID using the long acting IL-1 inhibitor the of finding optimal dose regimen is ongoing. LABORATORY: 1. have characterized the skin lesions in collaboration with Dr. at Rockefeller by comparing lesional and nonles

OMID using the long acting IL-1 iNhibitor caNakinUmaB wiTh The gOal oF finding an optiMAl doSe regimen and monitoring Long tErM OutcOMe Is curRently oNGoING. LAbOrAtORy: 1. WE HaVe chaRacTerized The inflammAtoRy Skin lesions iN CoLlaboratioN wiTh Dr. Lowes at ROckEfelleR bY coMParinG leSionaL and noNLes

OMID using the long acting  IL-1 inhi bitor  ca nak in umab  wit h the goal off indi ng an optimal dose reg imenan d  mon i to ringlong te r mo u tco me  i s c ur r en tly o ngo ing. LA BORATORY:1.We  have charac t er ized the i nfl ammatory ski n l esions  i n c o llabo rat ion w ith Dr .  Lowes  at Rocke fe l ler by compari n g  l esio nal and nonles

OMID using_the long_acting IL-1 inhibitor canakinumab_with the_goal_of finding_an_optimal dose regimen_and monitoring long_term outcome is currently_ongoing. LABORATORY: 1._We_have characterized the inflammatory skin lesions in collaboration with Dr. Lowes at Rockefeller by_comparing_lesional and_nonles


complexes of CMCP-TP and ETV-TP with the RT of HBVETV-RL180M/S202G/M204V, it is most likely that the difference in the interactions of CMCP-TP over ETV-TP with the RT of HBVETV-RL180M/S

complexes of CMCP - TP and ETV - TP with the RT of HBVETV - RL180M / S202G / M204V, it is most likely that the difference in the interaction of CMCP - TP over ETV - TP with the RT of HBVETV - RL180M / S

colplexes of CMCP-TP and ETY-TP with the RT of HBVEVV-RL180M/S202G/J204V, it is most likely that the differxnce in tye interactions of CMCO-TP over VTV-TP wity tht RT of HBVETV-RL180M/S

complexes of CMCP-TP and ETV-TP with the HBVETV-RL180M/S202G/M204V, is most that the difference over with the RT HBVETV-RL180M/S

complexes of CMCP-TP and ETV-TP With the RT oF HBVEtV-Rl180M/S202g/M204v, it iS mosT likely that the DIffeRence in the interactions Of CMCp-Tp Over etV-tP witH the RT oF hBvetV-Rl180M/s

complexes of CMCP-TP andETV-TP wit h the  RT  of  H BVET V-RL 180M/S202G/M20 4 V, i t is most likely thatthe d if f eren c ein th e inter a ct i o nsof  C MCP -T P  o ver E TV- TP with  the RT of  HB VE TV-RL180M/S

complexes_of CMCP-TP_and ETV-TP with the_RT of_HBVETV-RL180M/S202G/M204V,_it is_most_likely that the_difference in the_interactions of CMCP-TP over_ETV-TP with the_RT_of HBVETV-RL180M/S


position these cleavages would alter the sequences at the 3' end of the minus strand and as a result have a drastic impact on the ability of IN to catalyze strand transfer. The sequence from the 3? ends of the minus strand cDNA from Tf1 particles was determined using ligation mediated PCR. The mutations clearly

position these cleavages would alter the sequences at the 3' goal of the minus strand and as a resultant role have a drastic impact on the ability of IN to catalyze strand transmit. The sequence from the 3? ends of the subtraction strand cDNA from Tf1 particles was determined using ligation intercede PCR. The mutations clearly

podition these cleavages wuuld alter the sequencxs at tge 3' end uf the minus strand and as a rwsult have a drastic impact on the ahility od IN ro catalyzx strand transrcr. Thz wequence from jhe 3? ends of the minus strdna eDNA from Tf1 particles was determineq using llgation mediatgd PCG. Ehe jltctions clearly

position these cleavages would alter the sequences 3' of the strand and as impact the ability of to catalyze strand The sequence from the 3? ends the minus strand cDNA from Tf1 particles was determined using ligation mediated PCR. mutations clearly

position these cleavages wouLd alter the SequeNceS at ThE 3' end Of thE minus strand anD As a rEsult have a drastic impacT on thE aBIlitY Of iN to cAtalyze STrAND trAnSfEr. THe SEqUence FroM the 3? endS of the minuS stRaNd cDNA from Tf1 PArTicles was dEteRmined using lIgaTion meDiAteD pCR. ThE muTatioNs cleaRLy

position these cleavageswould alte r the  se que nc es a t th e 3' end of th e  min us strand and as a res ult h av e  a d r as tic i mpact o n  t h e  ab il it y o fI Nto ca tal yze str and transf er.  T he sequencef ro m the 3? e nds  of the minu s s trandcD NAf rom T f1parti cles w a s dete rmined us in g  ligat i on medi a t ed  PCR . The mutations c l ea r ly

position_these cleavages_would alter the sequences_at the_3'_end of_the_minus strand and_as a result_have a drastic impact_on the ability_of_IN to catalyze strand transfer. The sequence from the 3? ends of the minus_strand_cDNA from_Tf1_particles_was determined using ligation mediated_PCR. The mutations clearly


(e.g., osmotic and mechanical properties, state of hydration, charge density) must be characterized on distance scales below 100 nm. Understanding the interaction of polyelectrolytes with ions is critical to clarifying the basic physics of ion binding as well as physical mechanisms affecting a large number of biological processes. To determine

(e.g., osmotic and mechanical properties, state of hydration, charge concentration) must be qualify on distance scales below 100 nm. understand the interaction of polyelectrolyte with ions is critical to clarifying the basic physics of ion tie down as well as physical mechanism affecting a large issue of biological processes. To determine

(e.g., osmotic and mechanical kroperties, state of hydretion, cgarge devsity) must be characterized ln distqnce scales below 100 nm. Jnderstanfing the inttraction of polyelectrolybzs wifm ionv is critical tp clarifyitg the basic pvyries of ion binding as well as physicaj mechamidms affecting w laggq nujber of biological processes. To defermine

(e.g., osmotic and mechanical properties, state of density) be characterized distance scales below of with ions is to clarifying the physics of ion binding as well physical mechanisms affecting a large number of biological processes. To determine

(e.g., osmotic and mechanical proPerties, staTe of hYdrAtiOn, CharGe deNsity) must be chaRActeRized on distance scales bElow 100 nM. UNDersTAnDing tHe interACtION of PoLyEleCtROlYtes wIth Ions is cRitical to cLarIfYing the basic PHySics of ion bIndIng as well as pHysIcal meChAniSMs affEctIng a lArge nuMBer of bIological PrOCesses. tO determINE

(e.g., osmotic and mechan ical prope rties , s tat eof h ydra tion, charge d e nsit y) must be characteriz ed on  d i stan c escale s below 10 0 nm.  U nd ers ta n di ng th e i nteract ion of pol yel ec trolytes wit h  i ons is cri tic al to clarif yin g theba sic physi csof io n bind i ng aswell as p hy s ical m e chanism s af fect ing a large numbe r  o f  biological pr ocesse s. To d ete rmi ne

(e.g.,_osmotic and_mechanical properties, state of_hydration, charge_density)_must be_characterized_on distance scales_below 100 nm._Understanding the interaction of_polyelectrolytes with ions_is_critical to clarifying the basic physics of ion binding as well as physical mechanisms_affecting_a large_number_of_biological processes. To determine


al sex steroids during normal brain development. The final analysis of this data is being completed with a manuscript in preparation. The Molecular Basis of Inherited Reproductive Disorders Human and animal models have identified a number of genes responsible for IGD, but more than half of patients with clinical evidence of the disorder do not

al sex steroids during normal brain development. The concluding psychoanalysis of this datum is being completed with a manuscript in preparation. The Molecular Basis of Inherited Reproductive Disorders Human and animal models have name a number of genes creditworthy for IGD, but more than half of patients with clinical evidence of the disorder make not

al dex steroids during normxl brain develokmwnt. Thx final analysir of this data is being comppered wuth a manuscript in prdparation. The Molwculer Basis of Inhecjted Reixoducflve Dnsirders Human akd animal mmdels have idettkfned a number of genes responsible fow IGD, bit more than hals of [atisnts with clinical evidence of the disordtr do not

al sex steroids during normal brain development. analysis this data being completed with Molecular of Inherited Reproductive Human and animal have identified a number of genes for IGD, but more than half of patients with clinical evidence of the do not

al sex steroids during normal Brain develOpmenT. ThE fiNaL anaLysiS of this data is bEIng cOmpleted with a manuscripT in prEpARatiON. THe MolEcular BASiS OF InHeRiTed rePRoDuctiVe DIsorderS Human and aNimAl Models have idENtIfied a numbEr oF genes responSibLe for IgD, But MOre thAn hAlf of PatienTS with cLinical evIdENce of tHE disordER Do Not

al sex steroids during nor mal braindevel opm ent .Thefina l analysis oft hisdata is being complete d wit ha  man u sc riptin prep a ra t i on.  T he  Mo le c ul ar Ba sis  of Inh erited Rep rod uc tive Disorde r sHuman andani mal models h ave  ident if ied a num ber  of g enes r e sponsi ble for I GD ,  but m o re than h al f of  patients with cl i ni c al evidence of  the d is o rd e r  do  no t

al sex_steroids during_normal brain development. The_final analysis_of_this data_is_being completed with_a manuscript in_preparation. The Molecular Basis_of Inherited Reproductive_Disorders_Human and animal models have identified a number of genes responsible for IGD, but_more_than half_of_patients_with clinical evidence of the_disorder do not


, 2007). We found that subjects with confirmed reversal, or recovery from HH with sustained endogenous LH pulsatility, are responsive to IV bolus infusions of kisspeptin, a neuropeptide known to be a key stimulus of GnRH release in the human. On the other hand, subjects who relapse from their

, 2007). We found that subjects with confirmed reversal, or recovery from HH with free burning endogenous LH pulsatility, are reactive to IV bolus infusion of kisspeptin, a neuropeptide known to be a cardinal stimulus of GnRH passing in the human. On the early hand, subjects who relapse from their

, 2007). Wf found that subjects wiuh confirmed revetsql, or cecoverg from HF with sustained endogenous PH pulsqtility, are responsive to IV bopus infuwionw of kisspe'fin, a ncbropelbide niown to be a kei stimulus ox GnRH release iv che human. On the other hand, subjects who rekaose from their

, 2007). We found that subjects with or from HH sustained endogenous LH bolus of kisspeptin, a known to be key stimulus of GnRH release in human. On the other hand, subjects who relapse from their

, 2007). We found that subjects with coNfirmed revErsal, Or rEcoVeRy frOm HH With sustained eNDogeNous LH pulsatility, are reSponsIvE To IV BOlUs infUsions oF KiSSPepTiN, a NeuRoPEpTide kNowN to be a kEy stimulus Of GNRh release in thE HuMan. On the otHer Hand, subjects Who RelapsE fRom THeir

, 2007). We found that sub jects with  conf irm edre vers al,or recovery fr o m HH  with sustained endoge nousLH puls a ti lity,  are re s po n s ive  t oIVbo l us  infu sio ns of k isspeptin,  ane uropeptide k n ow n to be akey  stimulus of  Gn RH rel ea sei n the  hu man.On the otherhand, sub je c ts who relapse f ro m th eir

, 2007)._We found_that subjects with confirmed_reversal, or_recovery_from HH_with_sustained endogenous LH_pulsatility, are responsive_to IV bolus infusions_of kisspeptin, a_neuropeptide_known to be a key stimulus of GnRH release in the human. On the_other_hand, subjects_who_relapse_from their


TLR4 form homo- or hetero-dimers, which can recognize various bacterial lipopeptides. These TLRs on the cell surface of leukocytes regulate chemotaxis, phagocytosis, and immune activation. TLR ligand LPS at 0.02 ng/ml over 15 min inhibited chemotactic response of CCR2, CXCR4

TLR4 form homo- or hetero - dimers, which can recognize various bacterial lipopeptides. These TLRs on the cell open of leukocyte regulate chemotaxis, phagocytosis, and immune activation. TLR ligand LPS at 0.02 nanogram / ml over 15 min inhibit chemotactic response of CCR2, CXCR4

TLG4 form homo- or hetero-dimtrs, which can recognize tarious bacterixl lipopeptides. These TLRs oi thw celo surface of leukocyter regulatv chemotazis, khagocytosis, and mjmune agcivatjln. TNC ligand LPS at 0.02 ng/ml oves 15 min inhibitad ckemotactic response of CCR2, CXCR4

TLR4 form homo- or hetero-dimers, which can bacterial These TLRs the cell surface and activation. TLR ligand at 0.02 ng/ml 15 min inhibited chemotactic response of CXCR4

TLR4 form homo- or hetero-dimers, Which can reCogniZe vAriOuS bacTeriAl lipopeptides. tHese tLRs on the cell surface of LeukoCyTEs reGUlAte chEmotaxiS, PhAGOcyToSiS, anD iMMuNe actIvaTion. TLR Ligand LPS aT 0.02 ng/Ml Over 15 min inhibITeD chemotactIc rEsponse of CCR2, cXCr4

TLR4 form homo- or hetero -dimers, w hichcan  re co gniz e va rious bacteria l  lip opeptides. These TLRson th ec ells ur faceof leuk o cy t e s r eg ul ate  c h em otaxi s,phagocy tosis, and  im mu ne activatio n .TLR ligand  LP S at 0.02 ng /ml  over15  mi n  inhi bit ed ch emotac t ic res ponse ofCC R 2, CXC R 4

TLR4_form homo-_or hetero-dimers, which can_recognize various_bacterial_lipopeptides. These_TLRs_on the cell_surface of leukocytes_regulate chemotaxis, phagocytosis, and_immune activation. TLR_ligand_LPS at 0.02 ng/ml over 15 min inhibited chemotactic response of CCR2, CXCR4


of drug resistance. The DCTD envisions using extending the proven principles of assay development, validation and clinical implementation to develop and validate clinical PD assays for known chemotherapeutic markers, and then to deploy these in the Phase 0 trial setting under the FDA's Exploratory IND Guidance in order to not only confirm the

of drug resistance. The DCTD envisions using extending the proven principle of assay growth, validation and clinical implementation to develop and validate clinical palladium assays for known chemotherapeutic markers, and then to deploy these in the Phase 0 test setting under the FDA's Exploratory IND Guidance in order to not merely confirm the

of drug resistance. The DCTA envisions usiut exteiding tge provev principles of assay develo'menr, valudation and clinical ioplementanion to dwvelip and valivzte clikncal LF asveys for known cmemotherapegtic markers, atd tken to deploy these in the Phase 0 tryal setyijg under the FQA's Txpjorafory IND Guidance in order to not knly coifirm the

of drug resistance. The DCTD envisions using proven of assay validation and clinical clinical assays for known markers, and then deploy these in the Phase 0 setting under the FDA's Exploratory IND Guidance in order to not only confirm

of drug resistance. The DCTD enVisions usiNg extEndIng ThE proVen pRinciples of assAY devElopment, validation and cLinicAl IMpleMEnTatioN to deveLOp AND vaLiDaTe cLiNIcAl PD aSsaYs for knOwn chemothEraPeUtic markers, aND tHen to deploY thEse in the PhasE 0 trIal setTiNg uNDer thE FDa's ExpLoratoRY IND GuIdance in oRdER to not ONly confIRM tHe

of drug resistance. The D CTD envisi ons u sin g e xt endi ng t he proven prin c iple s of assay development , val id a tion an d cli nical i m pl e m ent at io n t od ev elopand  valida te clinica l P Dassays for k n ow n chemothe rap eutic marker s,and th en  to deplo y t hesein the Phase0 trial s et t ing un d er theF D A' s Ex ploratory IND Gui d an c e in order tonot on ly co n f irm  th e

of_drug resistance._The DCTD envisions using_extending the_proven_principles of_assay_development, validation and_clinical implementation to_develop and validate clinical_PD assays for_known_chemotherapeutic markers, and then to deploy these in the Phase 0 trial setting under_the_FDA's Exploratory_IND_Guidance_in order to not only_confirm the


factors that place children at-risk for undue weight gain (2-14). We have recently examined how obesity and thyroid hormone (4) are interrelated as well as how leptin impacts bone in children (2) Two recent initiatives target insulin resistance. One trial studied the role of depressive symptoms in childrens insulin resistance.

factors that place children at - risk for excessive system of weights gain (2 - 14). We have recently examined how fleshiness and thyroid hormone (4) are interrelate as well as how leptin impacts bone in child (2) Two recent initiatives target insulin electric resistance. One trial studied the function of depressive symptoms in childrens insulin resistance.

faftors that place childrek at-risk for undoe weighv gain (2-14). We have recently examined how obesivy abd thtroid hormone (4) are intdrrelated as well as iow leptin impacva bone lu chimfren (2) Two recent inltiatives tdrget insulin seridtance. One trial studied the role os deprexslve symptoms ig chplqrena insulin resistance.

factors that place children at-risk for undue (2-14). have recently how obesity and as as how leptin bone in children Two recent initiatives target insulin resistance. trial studied the role of depressive symptoms in childrens insulin resistance.

factors that place children aT-risk for unDue weIghT gaIn (2-14). we haVe reCently examined HOw obEsity and thyroid hormone (4) Are inTeRRelaTEd As welL as how lEPtIN ImpAcTs BonE iN ChIldreN (2) TwO recent InitiativeS taRgEt insulin resIStAnce. One triAl sTudied the rolE of DepresSiVe sYMptomS in ChildRens inSUlin reSistance.

factors that place childr en at-risk  forund uewe ight  gai n (2-14). We h a ve r ecently examined how o besit ya nd t h yr oid h ormone( 4) a rein te rre la t ed  as w ell  as how  leptin im pac ts  bone in chi l dr en (2) Two  re cent initiat ive s targ et  in s ulinres istan ce. On e  trial  studiedth e  roleo f depre s s iv e sy mptoms in childre n si nsulin resista nce.

factors_that place_children at-risk for undue_weight gain_(2-14)._We have_recently_examined how obesity_and thyroid hormone_(4) are interrelated as_well as how_leptin_impacts bone in children (2) Two recent initiatives target insulin resistance. One trial studied_the_role of_depressive_symptoms_in childrens insulin resistance.


G/M204V. This is because of the lack of the 4'-cyano group in ETV compared to CMCP. Thus, from the observation that the interactions of the RT of HBVETV-RL180M/S202G/M204V with M204V and D205 persist in both

G / M204V. This is because of the lack of the 4'-cyano group in ETV compared to CMCP. Thus, from the observation that the interactions of the RT of HBVETV - RL180M / S202G / M204V with M204V and D205 prevail in both

G/M204V. This is because of the uack of the 4'-cyaui grou' in ETB compardd to CMCP. Thus, from the obsxrvarion ukat the interactions of the RN of HBVERV-RL180N/W202G/M204V with M204V and D205 persiab in yovh

G/M204V. This is because of the lack 4'-cyano in ETV to CMCP. Thus, interactions the RT of with M204V and persist in both

G/M204V. This is because of the lack Of the 4'-cyano Group In EtV cOmPareD to CmCP. Thus, from the OBserVation that the interactiOns of ThE rT of hbVeTV-RL180m/S202G/M204V wiTH M204v ANd D205 PeRsIst In BOtH

G/M204V. This is because o f the lack  of t he4'- cy anogrou p in ETV compa r ed t o CMCP. Thus, from the  obse rv a tion th at th e inter a ct i o nsof  t heRT of  HBVE TV- RL180M/ S202G/M204 V w it h M204V andD 20 5 persistinboth

G/M204V. This_is because_of the lack of_the 4'-cyano_group_in ETV_compared_to CMCP. Thus,_from the observation_that the interactions of_the RT of_HBVETV-RL180M/S202G/M204V_with M204V and D205 persist in both


. Other allelic variations we found in DAOA and COMT genes interact to increase risk for SZ and impaired DLPFC information processing. This again, demonstrated a functional yet statistically significant interaction between risk alleles in DAOA and COMT which may play a role in glutaminergic and dopaminergic dysregulation. Lastly a variant

. Other allelic variations we found in DAOA and COMT genes interact to increase hazard for SZ and afflicted DLPFC data processing. This again, demonstrated a functional yet statistically significant interaction between hazard alleles in DAOA and COMT which may play a role in glutaminergic and dopaminergic dysregulation. last a version

. Otjer allelic variations wt found in DAOA aue COMT genes interacg to increase risk for SZ anv impairee DLPFC information prucessing. Nhis agaib, deninstrated e functional ysb staciwtically signinicant intesaction betweet fidk alleles in DAOA and COMT which mwy play a role in glutaiineggyc ahd dopaminergic dysregulation. Lastmy a vagiant

. Other allelic variations we found in COMT interact to risk for SZ This demonstrated a functional statistically significant interaction risk alleles in DAOA and COMT may play a role in glutaminergic and dopaminergic dysregulation. Lastly a variant

. Other allelic variations we fOund in DAOA And COmT gEneS iNterAct tO increase risk fOR SZ aNd impaired DLPFC informaTion pRoCEssiNG. THis agAin, demoNStRATed A fUnCtiOnAL yEt staTisTically SignificanT inTeRaction betweEN rIsk alleles In DaOA and COMT whIch May plaY a RolE In gluTamInergIc and dOPamineRgic dysreGuLAtion. LAStly a vaRIAnT

. Other allelic variations  we foundin DA OAand  C OMTgene s interact toi ncre ase risk for SZ and im paire dD LPFC in forma tion pr o ce s s ing .Th isag a in , dem ons trateda function alye t statistica l ly  significa ntinteractionbet ween r is k a l leles  in  DAOA  and C O MT whi ch may pl ay a role in glut a m in ergi c and dopaminergi c  d y sregulation. L astlyav ar i a nt

. Other_allelic variations_we found in DAOA_and COMT_genes_interact to_increase_risk for SZ_and impaired DLPFC_information processing. This again,_demonstrated a functional_yet_statistically significant interaction between risk alleles in DAOA and COMT which may play a_role_in glutaminergic_and_dopaminergic_dysregulation. Lastly a variant


, combined with the strategic decisions of its dedicated SAIC-Frederick support program to use only assay technologies that have proven clinical applicability and to apply diagnostic assay expertise and developmental principles to PD assays, have already yielded validated assays for several molecular targets since the program's inception in mid-2005. One of these assays accelerated

, combined with the strategic decisions of its dedicated SAIC - Frederick support platform to practice only assay technology that have prove clinical applicability and to apply diagnostic assay expertise and developmental principle to PD assay, have already yielded validate assays for several molecular target since the program's inception in mid-2005. One of these assay accelerate

, colbined with the strategig decisions of ijs dediceted SAJC-Frederkck support program to use oily qssay technologies that havd proven blinical qpplmcability and to apply dlcgnosflc asvey expertise anc developmantal principlas tl PD assays, have already yielded vajidated adsays for sevetal mpjecumar targets since the program's incsption pn mid-2005. One of thexe assays accelerated

, combined with the strategic decisions of SAIC-Frederick program to only assay technologies and apply diagnostic assay and developmental principles PD assays, have already yielded validated for several molecular targets since the program's inception in mid-2005. One of these accelerated

, combined with the strategic dEcisions of Its deDicAteD SaIC-FRedeRick support proGRam tO use only assay technologIes thAt HAve pROvEn cliNical apPLiCABilItY aNd tO aPPlY diagNosTic assaY expertise And DeVelopmental pRInCiples to PD AssAys, have alreaDy yIelded VaLidATed asSayS for sEveral MOleculAr targets SiNCe the pROgram's iNCEpTion In mid-2005. One of these asSAyS Accelerated

, combined with the strate gic decisi ons o f i tsde dica tedSAIC-Frederick supp ort program to use onl y ass ay tech n ol ogies  that h a ve p rov en  c lin ic a lappli cab ility a nd to appl y d ia gnostic assa y  e xpertise a nddevelopmenta l p rincip le s t o  PD a ssa ys, h ave al r eady y ielded va li d ated a s says fo r se vera l molecular targe t ss ince the progr am's i nc e pt i o n i n m id-2005. O ne  of t h ese ass a ys a c cel e rated

, combined_with the_strategic decisions of its_dedicated SAIC-Frederick_support_program to_use_only assay technologies_that have proven_clinical applicability and to_apply diagnostic assay_expertise_and developmental principles to PD assays, have already yielded validated assays for several molecular_targets_since the_program's_inception_in mid-2005. One of these_assays accelerated


slices with an enzyme that disrupts PNNs enables synaptic potentiation in CA2 pyramidal neurons. CA2 and its surrounding regions are anatomically and molecularly very similar, and as such, these findings may therefore lead to identification of other critical molecular components in the pathways necessary for developmental changes in synaptic plasticity and development

slices with an enzyme that disrupts PNNs enables synaptic potentiation in CA2 pyramidal neurons. CA2 and its besiege region are anatomically and molecularly very similar, and as such, these findings may therefore run to identification of other critical molecular component in the pathways necessary for developmental changes in synaptic malleability and growth

sllces with an enzyme that disrupts PNNs gnqbles vynaptjc potengiation in CA2 pyramidal neurlnw. CA2 qnd its surrounding reeions are anatomixallb and molecularlb very sliilad, and es such, these flndings may therefore leag go identification of other critical mjleculat fomponents in jhe psehwags necessary for developmental chahges in synaptic plaxticity and development

slices with an enzyme that disrupts PNNs potentiation CA2 pyramidal CA2 and its molecularly similar, and as these findings may lead to identification of other critical components in the pathways necessary for developmental changes in synaptic plasticity and development

slices with an enzyme that disRupts PNNs eNableS syNapTiC potEntiAtion in CA2 pyramIDal nEurons. CA2 and its surroundIng reGiONs arE AnAtomiCally anD MoLECulArLy VerY sIMiLar, anD as Such, theSe findings May ThErefore lead tO IdEntificatiOn oF other criticAl mOleculAr ComPOnentS in The paThways NEcessaRy for deveLoPMental CHanges iN SYnAptiC plasticity and devELoPMent

slices with an enzyme tha t disrupts  PNNs  en abl es  syn apti c potentiation in C A2 pyramidal neurons.CA2 a nd itss ur round ing reg i on s are  a na tom ic a ll y and  mo lecular ly very si mil ar , and as suc h ,these find ing s may theref ore  leadto  id e ntifi cat ion o f othe r  criti cal molec ul a r comp o nents i n th e pa thways necessaryf or developmentalchange si ns y nap tic  plasticit yand d e velopme n t

slices_with an_enzyme that disrupts PNNs_enables synaptic_potentiation_in CA2_pyramidal_neurons. CA2 and_its surrounding regions_are anatomically and molecularly_very similar, and_as_such, these findings may therefore lead to identification of other critical molecular components in_the_pathways necessary_for_developmental_changes in synaptic plasticity and_development


IP4 and CXCR4 and by reversal of Nef effect through siRNA knockdown of AIP4 or by a small molecular weight inhibitor of dynamin. Nef has been shown to inhibit agonist driven chemotaxis through CXCR4 and CCR5 receptors by subverting chemotactic signaling at multiple steps. We show that although Nef

IP4 and CXCR4 and by reversal of Nef effect through siRNA knockdown of AIP4 or by a small molecular weight inhibitor of dynamin. Nef has been testify to suppress agonist driven chemotaxis through CXCR4 and CCR5 receptors by sabotage chemotactic signal at multiple steps. We show that although Nef

IP4 wnd CXCR4 and by reversal of Nef effect jheough viRNA inockdowv of AIP4 or by a small molecnlar weigyt inhibitor of dynamiv. Nef has been shiwn uo inhibit agonisv driven chemofwxis vhrough CXCR4 anc CCR5 rece[tors by subvestkny chemotactic signaling at multiple fteps. Wr dhow that althjugh Gef

IP4 and CXCR4 and by reversal of through knockdown of or by a dynamin. has been shown inhibit agonist driven through CXCR4 and CCR5 receptors by chemotactic signaling at multiple steps. We show that although Nef

IP4 and CXCR4 and by reversal of NEf effect thRough SiRnA kNoCkdoWn of aIP4 or by a small mOLecuLar weight inhibitor of dyNamin. neF Has bEEn Shown To inhibIT aGONisT dRiVen ChEMoTaxis ThrOugh CXCr4 and CCR5 recEptOrS by subvertinG ChEmotactic sIgnAling at multiPle Steps. WE sHow THat alThoUgh NeF

IP4 and CXCR4 and by rever sal of Nef  effe ctthr ou gh s iRNA  knockdown ofA IP4or by a small molecula r wei gh t  inh i bi tor o f dynam i n. N efha sbee ns ho wn to  in hibit a gonist dri ven  c hemotaxis th r ou gh CXCR4 a ndCCR5 recepto rsby sub ve rti n g che mot actic  signa l ing at  multiple  s t eps. W e  show t h a talth ough Nef

IP4 and_CXCR4 and_by reversal of Nef_effect through_siRNA_knockdown of_AIP4_or by a_small molecular weight_inhibitor of dynamin. Nef_has been shown_to_inhibit agonist driven chemotaxis through CXCR4 and CCR5 receptors by subverting chemotactic signaling at_multiple_steps. We_show_that_although Nef


C reference sequence. Consistent with previous studies investigating CRISPR-Cas9 off-target activity in mouse embryos and human iPSCs, our WGS-based analysis of potential Cas9 RNP-associated off-target mutational events in primary human CD34+ HSPCs suggests that genome-editing utilizing electroporated

C reference sequence. Consistent with former cogitation investigating CRISPR - Cas9 off - prey bodily process in mouse embryos and human iPSCs, our WGS - establish analysis of potential Cas9 RNP - associate off - target mutational events in basal human CD34 + HSPCs suggests that genome - editing use electroporated

C rfference sequence. Consisuent with previous studixs inveatigatine CRISPR-Cas9 off-target activivy ib mouwe embryos and human iOSCs, our AGS-based anaotsis of povsntial Gcs9 RNL-wssoeieted off-target kutational events in prikafy human CD34+ HSPCs suggests that genomq-editinb ktilizing elecjropogaeed

C reference sequence. Consistent with previous studies off-target in mouse and human iPSCs, Cas9 off-target mutational events primary human CD34+ suggests that genome-editing utilizing electroporated

C reference sequence. ConsistEnt with preVious StuDieS iNvesTigaTing CRISPR-Cas9 oFF-tarGet activity in mouse embrYos anD hUMan ipsCS, our WgS-based ANaLYSis Of PoTenTiAL CAs9 RNP-AssOciated Off-target mUtaTiOnal events in PRiMary human Cd34+ HSpCs suggests tHat Genome-EdItiNG utilIziNg eleCtropoRAted

C reference sequence. Cons istent wit h pre vio usst udie s in vestigating CR I SPR- Cas9 off-target activi ty in  m o usee mb ryosand hum a ni P SCs ,ou r W GS - ba sed a nal ysis of  potential  Ca s9  RNP-associa t ed  off-targe t m utational ev ent s in p ri mar y  huma n C D34+HSPCss uggest s that ge no m e-edit i ng util i z in g el ectroporated

C reference_sequence. Consistent_with previous studies investigating_CRISPR-Cas9 off-target_activity_in mouse_embryos_and human iPSCs,_our WGS-based analysis_of potential Cas9 RNP-associated_off-target mutational events_in_primary human CD34+ HSPCs suggests that genome-editing utilizing electroporated


Since paxillin phosphorylation on tyrosine residues 31 and 118 mediates vinculin recruitment into FAs, we demonstrated that vinculin and the paxillin-vinculin interaction are essential to strengthen the molecular clutch and to enable mechanosensing over a wide range of ECM compliances. We demonstrated the physiological importance of

Since paxillin phosphorylation on tyrosine residues 31 and 118 mediates vinculin recruitment into FAs, we demonstrated that vinculin and the paxillin - vinculin interaction are essential to tone the molecular clutch bag and to enable mechanosensing over a wide range of ECM submission. We prove the physiological importance of

Sijce paxillin phosphorylauion on tyrosine tewidues 31 and 118 mediater vinculin recruitment into HAs, qe denonstrated that vinculkn and thv paxillib-vinrulin interactioi are essentiam to vvrengthen the mplecular cnutch and to etaclz mechanosensing over a wide range os ECM cpmoliances. We deionsuraeed fhe physiological importance of

Since paxillin phosphorylation on tyrosine residues 31 mediates recruitment into we demonstrated that are to strengthen the clutch and to mechanosensing over a wide range of compliances. We demonstrated the physiological importance of

Since paxillin phosphorylatIon on tyrosIne reSidUes 31 AnD 118 medIateS vinculin recruITmenT into FAs, we demonstrated That vInCUlin ANd The paXillin-vINcULIn iNtErActIoN ArE esseNtiAl to strEngthen the MolEcUlar clutch anD To Enable mechAnoSensing over a WidE range Of eCM COmpliAncEs. We dEmonstRAted thE physioloGiCAl impoRTance of

Since paxillin phosphoryl ation on t yrosi neres id ues31 a nd 118 mediate s  vin culin recruitment into  FAs,  w e  dem o ns trate d thatv in c u lin  a nd  th ep ax illin -vi nculininteractio n a re  essential t o  s trengthenthe  molecular c lut ch and  t o e n ablemec hanos ensing over a  wide ran ge of ECM complia n c es . We  demonstrated the ph y siological imp ortanc eo f

Since_paxillin phosphorylation_on tyrosine residues 31_and 118_mediates_vinculin recruitment_into_FAs, we demonstrated_that vinculin and_the paxillin-vinculin interaction are_essential to strengthen_the_molecular clutch and to enable mechanosensing over a wide range of ECM compliances. We_demonstrated_the physiological_importance_of