whether AT and LV can reduce mortality following POX induced SE and conduct pharmacokinetic and pharmacodynamic analyses for CounterACT lead compounds AT and LV when administered intra- muscularly and orally. Aim 2: Determine whether AT and LV can reduce mortality following DFP and sarin induced SE and evaluate the acute and chronic effects of intram

whether AT and LV can reduce mortality following POX induced SE and impart pharmacokinetic and pharmacodynamic analysis for CounterACT lead compounds AT and LV when administered intra- muscularly and orally. bearing 2: Determine whether AT and LV can reduce deathrate following DFP and sarin induced SE and evaluate the acuate and chronic effect of intram

whfther AT and LV can reduge mortality following 'OX indhced SE xnd conduct pharmacokinetic end pharmqcodynamic analyses fof CounterWCT lead comkounds AT and LV xgen admluistedcd incre- muscularly anc orally. Ahm 2: Determine fhdtker AT and LV can reduce mortality fjllowinb FFP and sarin yndubeq SE and evaluate the acute and chronid effecus of intram

whether AT and LV can reduce mortality induced and conduct and pharmacodynamic analyses and when administered intra- and orally. Aim Determine whether AT and LV can mortality following DFP and sarin induced SE and evaluate the acute and chronic of intram

whether AT and LV can reduce moRtality folLowinG POx inDuCed Se and Conduct pharmacOKineTic and pharmacodynamic aNalysEs FOr CoUNtErACT Lead comPOuNDS AT AnD Lv whEn ADmInistEreD intra- mUscularly aNd oRaLly. Aim 2: DetermINe Whether AT aNd Lv can reduce moRtaLity foLlOwiNG DFP aNd sArin iNduced se and evAluate the AcUTe and cHRonic efFECtS of iNtram

whether AT and LV can red uce mortal ity f oll owi ng  POX  ind uced SE and co n duct  pharmacokinetic and p harma co d ynam i canaly ses for Co u n ter AC Tlea dc om pound s A T and L V when adm ini st ered intra-m us cularly an d o rally. Aim 2 : D etermi ne  wh e therATand L V canr educemortality  f o llowin g  DFP an d sa rininduced SE and ev a lu a te the acute a nd chr on i ce f fec tsof intram

whether_AT and_LV can reduce mortality_following POX_induced_SE and_conduct_pharmacokinetic and pharmacodynamic_analyses for CounterACT_lead compounds AT and_LV when administered_intra-_muscularly and orally. Aim 2: Determine whether AT and LV can reduce mortality following_DFP_and sarin_induced_SE_and evaluate the acute and_chronic effects of intram


for the reliable and valid diagnosis of personality disorder on which to base the development of effective, more specifically targeted interventions. The specific aims of the current proposal are (1) to establish a set of specific traits that collectively define the trait dimensions of individuals with PD, (2) to establish a set of psychosocial functioning dimensions that

for the reliable and valid diagnosis of personality disorder on which to base the development of effective, more specifically target interposition. The specific aims of the current proposal are (1) to install a bent of specific traits that collectively specify the trait proportion of individuals with PD, (2) to prove a set of psychosocial functioning proportion that

fog the reliable and valid diagnosis of pgrwonalivy disodder on dhich to base the developmenv of effextive, more specificallh targetef intervwntiibs. The sperjfic aims of fme cuxrxnt proposal arg (1) to establhsh a set of s[eziyic traits that collectively define ehe traot dimensions of indpvyduams with PD, (2) to establish a set of lsychosmcial functioming dimensions that

for the reliable and valid diagnosis of on to base development of effective, specific of the current are (1) to a set of specific traits that define the trait dimensions of individuals with PD, (2) to establish a set psychosocial functioning dimensions that

for the reliable and valid diaGnosis of peRsonaLitY diSoRder On whIch to base the deVElopMent of effective, more speCificAlLY tarGEtEd intErventiONs. tHE spEcIfIc aImS Of The cuRreNt propoSal are (1) to esTabLiSh a set of specIFiC traits thaT coLlectively deFinE the trAiT diMEnsioNs oF indiVidualS With PD, (2) To establiSh A Set of pSYchosocIAL fUnctIoning dimensions tHAt

for the reliable and vali d diagnosi s ofper son al itydiso rder on whicht o ba se the development ofeffec ti v e, m o re  spec ificall y  t a r get ed  i nte rv e nt ions.  Th e speci fic aims o f t he  current pro p os al are (1)  to  establish a  se t of s pe cif i c tra its  that  colle c tively  define t he traitd imensio n s  o f in dividuals with PD ,  ( 2 ) to establish  a set  o f  p s y cho soc ial functi on ing d i mension s  t h a t

for_the reliable_and valid diagnosis of_personality disorder_on_which to_base_the development of_effective, more specifically_targeted interventions. The specific_aims of the_current_proposal are (1) to establish a set of specific traits that collectively define the_trait_dimensions of_individuals_with_PD, (2) to establish a_set of psychosocial functioning dimensions_that


88% of all strokes) since 1996, stroke remains the third leading cause of death and the leading cause of disability in the United States. Therapies that restore blood flow to more patients, and do so more effectively and safely, are greatly needed to improve outcomes after stroke. A group of seven qualifying Primary Users have

88% of all strokes) since 1996, stroke remains the third leading lawsuit of end and the leading cause of disability in the United States. therapy that restore lineage flow to more patients, and suffice so more effectively and safely, are greatly necessitate to improve outcomes after solidus. A group of seven qualifying Primary Users have

88% of all strokes) since 1996, stroye remains the jhurd leeding czuse of aeath and the leading cause lf disavility in the United Sgates. Thegapies thqt rtstore blood flow to more patiehbs, anb vo so more effegtively and safely, are graaglv needed to improve outcomes after seroke. A ggoup of seven zualpfring Irlmary Users have

88% of all strokes) since 1996, stroke third cause of and the leading United Therapies that restore flow to more and do so more effectively and are greatly needed to improve outcomes after stroke. A group of seven qualifying Users have

88% of all strokes) since 1996, stroke reMains the thIrd leAdiNg cAuSe of DeatH and the leading CAuse Of disability in the UniteD StatEs. tHeraPIeS that Restore BLoOD FloW tO mOre PaTIeNts, anD do So more eFfectively And SaFely, are greatLY nEeded to impRovE outcomes aftEr sTroke. A GrOup OF seveN quAlifyIng PriMAry UseRs have

88% of all strokes) since1996, stro ke re mai nsth e th irdleading causeo f de ath and the leading ca use o fd isab i li ty in  the Un i te d Sta te s.  Th er a pi es th atrestore  blood flo w t omore patient s ,and do somor e effectivel y a nd saf el y,a re gr eat ly ne eded t o  impro ve outcom es afters troke.A gr oupof seven qualifyi n gP rimary Users h ave

88% of_all strokes)_since 1996, stroke remains_the third_leading_cause of_death_and the leading_cause of disability_in the United States._Therapies that restore_blood_flow to more patients, and do so more effectively and safely, are greatly needed_to_improve outcomes_after_stroke._A group of seven qualifying_Primary Users have


exchange and integration of information concerning the reproductive tract. Three specific aims will allow us to accomplish this goal: First, the scientific content of the meeting will be at the highest level. To achieve this standard of excellence, we are inviting speakers who are internationally recognized experts at the forefront of their fields. There is an interesting blend

exchange and integration of information concerning the generative nerve pathway. Three specific bearing will allow us to carry through this finish: First, the scientific content of the meeting will be at the high level. To achieve this standard of excellence, we are invite speakers who are internationally recognized expert at the forefront of their fields. There is an interesting blend

exfhange and integration on information couxerninj the rsproductkve tract. Three specific aimd qill qllow us to accomplish this goap: First, rhe wxientific rkntent of the leetnnj will be at thg highest leeel. To achieve tfid standard of excellence, we are invyting slewkers who are yntegnwtiohally recognized experts at the fodefront of their fiekds. There is an interestinh blfnd

exchange and integration of information concerning the Three aims will us to accomplish content the meeting will at the highest To achieve this standard of excellence, are inviting speakers who are internationally recognized experts at the forefront of their There is an interesting blend

exchange and integration of iNformation ConceRniNg tHe ReprOducTive tract. Three SPeciFic aims will allow us to acComplIsH This GOaL: FirsT, the sciENtIFIc cOnTeNt oF tHE mEetinG wiLl be at tHe highest lEveL. TO achieve this STaNdard of excEllEnce, we are invItiNg speaKeRs wHO are iNteRnatiOnally REcogniZed expertS aT The forEFront of THEiR fieLds. There is an interEStINg blend

exchange and integrationof informa tioncon cer ni ng t he r eproductive tr a ct.Three specific aims wi ll al lo w  ust oaccom plish t h is g oal :Fi rst ,t he  scie nti fic con tent of th e m ee ting will be at  the highe stlevel. To ac hie ve thi ssta n dardofexcel lence, we are  inviting  s p eakers who are i nt erna tionally recogniz e de xperts at theforefr on t  o f the irfields. Th er e isa n inter e st i n g  bl e nd

exchange_and integration_of information concerning the_reproductive tract._Three_specific aims_will_allow us to_accomplish this goal:_First, the scientific content_of the meeting_will_be at the highest level. To achieve this standard of excellence, we are inviting_speakers_who are_internationally_recognized_experts at the forefront of_their fields. There is an_interesting blend


that the rate of increase in PIB retention in individual subjects will be of larger magnitude and be detectable earlier than the rate of decrease in hippocampal volume or cerebral metabolic rate. The volume and electrolyte composition of saliva are dependent on the coordinated activity of ion transport proteins including multiple Na+-dependent mechanisms. Acinar cells employ a combination

that the rate of increase in PIB retention in individual subjects will be of large order of magnitude and be detectable earlier than the rate of decrease in hippocampal bulk or cerebral metabolic pace. The volume and electrolyte composition of saliva are dependent on the coordinated action of ion transport proteins include multiple Na+-dependent mechanisms. Acinar cells hire a combination

thwt the rate of increase ln PIB retention in indmvidual subjectr will be of larger magnitudx ane be eetectable earlier thav the ratv of decrwase un hippocampal volmie od cerzbcal metabolic rste. The vonume and electsouyce composition of saliva are dependegt on tne coordinated astivptr of pok transport proteins including mhltiple Na+-dependent kechanisms. Acinar cells emoloy a combination

that the rate of increase in PIB individual will be larger magnitude and rate decrease in hippocampal or cerebral metabolic The volume and electrolyte composition of are dependent on the coordinated activity of ion transport proteins including multiple Na+-dependent Acinar cells employ a combination

that the rate of increase in PIb retention In indIviDuaL sUbjeCts wIll be of larger mAGnitUde and be detectable earlIer thAn THe raTE oF decrEase in hIPpOCAmpAl VoLumE oR CeRebraL meTabolic Rate. The volUme AnD electrolyte COmPosition of SalIva are dependEnt On the cOoRdiNAted aCtiVity oF ion trANsport Proteins iNcLUding mULtiple NA+-DEpEndeNt mechanisms. AcinaR CeLLs employ a combiNation

that the rate of increase  in PIB re tenti oninin divi dual  subjects will be o f larger magnitude and  be d et e ctab l eearli er than th e rat eof  de cr e as e inhip pocampa l volume o r c er ebral metabo l ic  rate. The  vo lume and ele ctr olyteco mpo s ition  of  sali va are depend ent on th ec oordin a ted act i v it y of  ion transport pr o te i ns including m ultipl eN a+ - d epe nde nt mechani sm s. Ac i nar cel l se m p loy a combination

that_the rate_of increase in PIB_retention in_individual_subjects will_be_of larger magnitude_and be detectable_earlier than the rate_of decrease in_hippocampal_volume or cerebral metabolic rate. The volume and electrolyte composition of saliva are dependent_on_the coordinated_activity_of_ion transport proteins including multiple_Na+-dependent mechanisms. Acinar cells employ_a combination


-scanning methods, as the entire imaging plane is detected simultaneously. Second, excitation is confined to the focal plane, so each pixel is imaged only once during each volumetric acquisition. This drastically reduces light exposure and results in far lower photobleaching and photodamage than is possible with conventional imaging techniques.

-scanning methods, as the entire imaging plane is detect simultaneously. Second, excitement is confine to the focal plane, so each pixel is visualize only once during each volumetric acquisition. This drastically reduce light exposure and results in far lower photobleaching and photodamage than is possible with ceremonious imaging techniques.

-scajning methods, as the entlre imaging plang us detxcted sjmultaneuusly. Second, excitation is clndined to the focal plane, so each pixvl is imated ibly once dnding eagk volhletrnc acquisition. Tmis drasticdlly reduces lhgft exposure and results in far lower [hotoblrafhing and photjdamsde tgan is possible with conventional jmaging techniques.

-scanning methods, as the entire imaging plane simultaneously. excitation is to the focal imaged once during each acquisition. This drastically light exposure and results in far photobleaching and photodamage than is possible with conventional imaging techniques.

-scanning methods, as the entirE imaging plAne is DetEctEd SimuLtanEously. Second, exCItatIon is confined to the focaL planE, sO Each PIxEl is iMaged onLY oNCE duRiNg EacH vOLuMetriC acQuisitiOn. This drasTicAlLy reduces ligHT eXposure and ResUlts in far lowEr pHotoblEaChiNG and pHotOdamaGe than IS possiBle with coNvENtionaL Imaging TEChNiquEs.

-scanning methods, as theentire ima gingpla neis  det ecte d simultaneous l y. S econd, excitation is c onfin ed to t h efocal  plane, so e ach  p ix elis im agedonl y onceduring eac h v ol umetric acqu i si tion. This  dr astically re duc es lig ht  ex p osure  an d res ults i n  far l ower phot ob l eachin g  and ph o t od amag e than is possibl e  w i th conventiona l imag in g  t e c hni que s.

-scanning methods,_as the_entire imaging plane is_detected simultaneously._Second,_excitation is_confined_to the focal_plane, so each_pixel is imaged only_once during each_volumetric_acquisition. This drastically reduces light exposure and results in far lower photobleaching and photodamage_than_is possible_with_conventional_imaging techniques.


second type of tethered molecules will be those which maintain their integrity in the presenc of esterases. This design will take advantage of a very efficient intramolecular energy transfer between hypericin and the chemiluminescent intermediate of the reaction of luciferin with luciferase. All tethered compounds will be tested initially

second type of tethered molecules will be those which maintain their integrity in the presenc of esterases. This design will subscribe advantage of a very effective intramolecular energy transfer between hypericin and the chemiluminescent intermediate of the chemical reaction of luciferin with luciferase. All tethered compounds will be test initially

sefond type of tethered mouecules will be those xhich mzintain gheir integrity in the preseic od esttgases. This design wilu take adnantage od a tery efficient iiframolegblar skergy vransfer betweek hypericin and the cheminuoiuescent intermediate of the reaction of lucoffrin with luciseraxq. Alm tethered compounds will be testes initielly

second type of tethered molecules will be maintain integrity in presenc of esterases. of very efficient intramolecular transfer between hypericin the chemiluminescent intermediate of the reaction luciferin with luciferase. All tethered compounds will be tested initially

second type of tethered molecUles will be Those WhiCh mAiNtaiN theIr integrity in tHE preSenc of esterases. This desIgn wiLl TAke aDVaNtage Of a very EFfICIenT iNtRamOlECuLar enErgY transfEr between hYpeRiCin and the cheMIlUminescent IntErmediate of tHe rEactioN oF luCIferiN wiTh lucIferasE. all tetHered compOuNDs will BE tested INItIallY

second type of tethered m olecules w ill b e t hos ewhic h ma intain their i n tegr ity in the presenc ofester as e s. T h is  desi gn will ta k e  ad va nt age  o f  a  very  ef ficient  intramole cul ar  energy tran s fe r betweenhyp ericin and t hechemil um ine s centint ermed iate o f  the r eaction o fl ucifer i n withl u ci fera se. All tetheredc om p ounds will betested  i n it i a lly

second_type of_tethered molecules will be_those which_maintain_their integrity_in_the presenc of_esterases. This design_will take advantage of_a very efficient_intramolecular_energy transfer between hypericin and the chemiluminescent intermediate of the reaction of luciferin with_luciferase._All tethered_compounds_will_be tested initially


cell death but also sensitize PC cells to an EGFR-tyrosine kinase inhibitor (erlotinib) and gemcitabine-induced killing. We will also test whether the chemo-sensitizing effect of genistein is mechanistically associated with the down regulation of FoxM1/Notch-1/NF

cell death but also sensitize PC cell to an EGFR - tyrosine kinase inhibitor (erlotinib) and gemcitabine - induce killing. We will also test whether the chemo - sensitizing impression of genistein is mechanistically associated with the down rule of FoxM1 / Notch-1 / NF

cepl death but also sensitlze PC cells to cb EGFR-vyrosins kinase inhibitor (erlotinib) and gemritavine-ibduced killing. We will also tesn whether the xhemo-sensivjzing enyect kn gennsvein is mechanixtically avsociated with tfe down regulation of FoxM1/Notch-1/NF

cell death but also sensitize PC cells EGFR-tyrosine inhibitor (erlotinib) gemcitabine-induced killing. We chemo-sensitizing of genistein is associated with the regulation of FoxM1/Notch-1/NF

cell death but also sensitize pC cells to aN EGFR-TyrOsiNe KinaSe inHibitor (erlotinIB) and Gemcitabine-induced killIng. We WiLL alsO TeSt wheTher the CHeMO-SenSiTiZinG eFFeCt of gEniStein is MechanistiCalLy Associated wiTH tHe down reguLatIon of FoxM1/NotCh-1/Nf

cell death but also sensi tize PC ce lls t o a n E GF R-ty rosi ne kinase inhi b itor  (erlotinib) and gemci tabin e- i nduc e dkilli ng. Wew il l als ote stwh e th er th e c hemo-se nsitizingeff ec t of geniste i nis mechani sti cally associ ate d with  t hed own r egu latio n of F o xM1/No tch-1/NF

cell_death but_also sensitize PC cells_to an_EGFR-tyrosine_kinase inhibitor_(erlotinib)_and gemcitabine-induced killing._We will also_test whether the chemo-sensitizing_effect of genistein_is_mechanistically associated with the down regulation of FoxM1/Notch-1/NF


and the subsequent neurocognitive deficits which occur during ECM using both a monoclonal antibody against phosphorylated tau and tau-knock-out (KO) mouse experiments. AIM2: To determine the role of tau in an in vitro human CM model. We will challenge cultured immortalized human neurons with supernatants obtained from blood-brain

and the subsequent neurocognitive deficits which occur during ECM using both a monoclonal antibody against phosphorylated tau and tau - pink - out (KO) shiner experiments. AIM2: To determine the function of tau in an in vitro human CM mannequin. We will challenge cultured immortalized human neurons with supernatant obtained from blood - brain

anf the subsequent neuroconnitive deficits which mccur suring EZM using both a monoclonal aitibidy atainst phosphorylated gau and twu-knock-oyt (KI) mouse expxdiments. AIM2: Tk detzrnine the role pf tau in dn in vitro hukav EM model. We will challenge cultured ymmortakixed human neurjns eyth alptrnatants obtained from blood-braih

and the subsequent neurocognitive deficits which occur using a monoclonal against phosphorylated tau AIM2: determine the role tau in an vitro human CM model. We will cultured immortalized human neurons with supernatants obtained from blood-brain

and the subsequent neurocognItive deficIts whIch OccUr DuriNg ECm using both a monOClonAl antibody against phospHorylAtED tau ANd Tau-knOck-out (Ko) MoUSE exPeRiMenTs. aiM2: to detErmIne the rOle of tau in An iN vItro human CM mODeL. We will chaLleNge cultured iMmoRtalizEd HumAN neurOns With sUpernaTAnts obTained froM bLOod-braIN

and the subsequent neuroc ognitive d efici tswhi ch  occ ur d uring ECM usin g  bot h a monoclonal antibod y aga in s t ph o sp horyl ated ta u  a n d  ta u- kn ock -o u t(KO)mou se expe riments. A IM2 :To determine th e role oftau  in an in vi tro  human  C M m o del.Wewillchalle n ge cul tured imm or t alized human n e u ro ns w ith supernatantso bt a ined from bloo d-brai n

and_the subsequent_neurocognitive deficits which occur_during ECM_using_both a_monoclonal_antibody against phosphorylated_tau and tau-knock-out_(KO) mouse experiments. AIM2:_To determine the_role_of tau in an in vitro human CM model. We will challenge cultured immortalized_human_neurons with_supernatants_obtained_from blood-brain


for patients with AIDS. CMV pneumonia is often found at autopsy, but is rarely found antemortem for reasons that are not understood. As antipneumocystis prophylaxis is used more commonly, it is likely that CMV will become an increasingly important cause of morbidity and mortality. Effective anti-CMV drugs are now available.

for patients with AIDS. CMV pneumonia is often found at autopsy, but is rarely found antemortem for reason that are not understand. As antipneumocystis prophylaxis is used more commonly, it is likely that CMV will become an increasingly crucial cause of morbidity and deathrate. Effective anti - CMV drugs are now available.

fog patients with AIDS. CMV pneumonia is oyren fonnd at zutopsy, cut is rarely found antemortxm fir reqsons that are not unddrstood. Ad antipnwumorystis prophylaxma is uscb mors comkinly, it is likgly that CMV will become at knereasingly important cause of morbidyty and mlrtality. Effecjive sgti-CJN brugs are now available.

for patients with AIDS. CMV pneumonia is at but is found antemortem for As prophylaxis is used commonly, it is that CMV will become an increasingly cause of morbidity and mortality. Effective anti-CMV drugs are now available.

for patients with AIDS. CMV pneUmonia is ofTen foUnd At aUtOpsy, But iS rarely found anTEmorTem for reasons that are noT undeRsTOod. AS AnTipneUmocystIS pROPhyLaXiS is UsED mOre coMmoNly, it is Likely that cMV WiLl become an inCReAsingly impOrtAnt cause of moRbiDity anD mOrtALity. EFfeCtive Anti-CMv Drugs aRe now avaiLaBLe.

for patients with AIDS. C MV pneumon ia is  of ten  f ound  atautopsy, but i s  rar ely found antemortem f or re as o ns t h at  arenot und e rs t o od.  A sant ip n eu mocys tis  prophy laxis is u sed  m ore commonly ,  i t is likel y t hat CMV will  be come a ninc r easin gly  impo rtantc ause o f morbidi ty and mo r tality. E ff ecti ve anti-CMV drugs ar e  now available .

for_patients with_AIDS. CMV pneumonia is_often found_at_autopsy, but_is_rarely found antemortem_for reasons that_are not understood. As_antipneumocystis prophylaxis is_used_more commonly, it is likely that CMV will become an increasingly important cause of_morbidity_and mortality._Effective_anti-CMV_drugs are now available.


impact on the establishment of HIV latency in different memory T cell subsets and on the response to Latency Reactivating Agents. SPID#: 23 Despite almost 13 years of research on HIV and its role as the etiologic agent of AIDS, the mechanisms of pathogenesis remain mostly unknown. Specific in vitro effects have been identified that

impact on the establishment of HIV latency in different memory metric ton cellular telephone subsets and on the response to Latency Reactivating Agents. SPID #: 23 Despite about 13 years of inquiry on HIV and its role as the etiologic agentive role of AIDS, the mechanisms of pathogenesis remain mostly nameless. Specific in vitro effects have been identified that

imoact on the establishmenu of HIV latency nb diffxrent msmory T zell subsets and on the resplnwe to Latency Reactivating Xgents. SPPD#: 23 Despire aonost 13 years of resccrch kk HIV end its role as the etiolmgic agent of DIAS, the mechanisms of pathogenesis remwin mosylj unknown. Specyfic yn vjnri effects have been identifies that

impact on the establishment of HIV latency memory cell subsets on the response 23 almost 13 years research on HIV its role as the etiologic agent AIDS, the mechanisms of pathogenesis remain mostly unknown. Specific in vitro effects have identified that

impact on the establishment oF HIV latencY in diFfeRenT mEmorY T ceLl subsets and on THe reSponse to Latency ReactivAting agENts. SpiD#: 23 despiTe almosT 13 YeARS of ReSeArcH oN hIv and iTs rOle as thE etiologic AgeNt Of AIDS, the mecHAnIsms of pathOgeNesis remain mOstLy unknOwN. SpECific In vItro eFfects HAve beeN identifiEd THat

impact on the establishme nt of HIVlaten cyindi ffer entmemory T cells ubse ts and on the response  to L at e ncyR ea ctiva ting Ag e nt s .  SP ID #:  23  D e sp ite a lmo st 13 y ears of re sea rc h on HIV and it s role asthe  etiologic a gen t of A ID S,t he me cha nisms  of pa t hogene sis remai nm ostlyu nknown. S pe cifi c in vitro effect s  h a ve been identi fied t ha t

impact_on the_establishment of HIV latency_in different_memory_T cell_subsets_and on the_response to Latency_Reactivating Agents. SPID#: 23_Despite almost 13_years_of research on HIV and its role as the etiologic agent of AIDS, the_mechanisms_of pathogenesis_remain_mostly_unknown. Specific in vitro effects_have been identified that


the flippases facilitate 'downhill' transport of lipids; this distinguishes ER flippases from other translocators, typically found in the eukaryotic plasma membrane, that couple ATP hydrolysis to concentrative 'uphill' transport of lipids. We estimate that there are as many as six different ER lipid flippases but

the flippases facilitate' downhill' transport of lipids; this distinguishes ER flippases from early translocators, typically discover in the eukaryotic plasma membrane, that couple ATP hydrolysis to concentrative' uphill' transport of lipid. We estimate that there be as many as six different ER lipid flippases but

thf flippases facilitate 'duwnhill' transpott of li'ids; thjs distivguishes ER flippases from ovher tranwlocators, typically fojnd in thv eukaryoric klasma membrane, tizt couple ATP mydronbsis to concenttative 'uphiln' transport of lkpnds. We estimate that there are as magy as sox different ER jipic fliliawes but

the flippases facilitate 'downhill' transport of lipids; ER from other typically found in couple hydrolysis to concentrative transport of lipids. estimate that there are as many six different ER lipid flippases but

the flippases facilitate 'dowNhill' transPort oF liPidS; tHis dIstiNguishes ER flipPAses From other translocators, TypicAlLY fouND iN the eUkaryotIC pLASma MeMbRanE, tHAt CouplE ATp hydrolYsis to concEntRaTive 'uphill' trANsPort of lipiDs. WE estimate thaT thEre are As ManY As six DifFerenT ER lipID flippAses but

the flippases facilitate'downhill'  tran spo rtof  lip ids;  this distingu i shes  ER flippases from oth er tr an s loca t or s, ty pically fo u n d i nth e e uk a ry oticpla sma mem brane, tha t c ou ple ATP hydr o ly sis to con cen trative 'uph ill ' tran sp ort of li pid s. We  estim a te tha t there a re as man y  as six d if fere nt ER lipid flipp a se s  but

the_flippases facilitate_'downhill' transport of lipids;_this distinguishes_ER_flippases from_other_translocators, typically found_in the eukaryotic_plasma membrane, that couple_ATP hydrolysis to_concentrative_'uphill' transport of lipids. We estimate that there are as many as six different_ER_lipid flippases_but


of CVD in Eastern NC. The overall objective of this proposal is to assess feasibility of implementing an EBI, adapted to the needs and interests of a rural community in order to plan a large scale study. To that end our specific aims are to 1) expand and sustain a Project GRACE CVD coalition of community and academic

of CVD in Eastern NC. The overall objective of this proposal is to assess feasibility of implementing an EBI, adapt to the motivation and interests of a rural community in order to design a large scale study. To that goal our specific aims are to 1) expand and prolong a Project GRACE CVD coalition of community and academic

of CVD in Eastern NC. The oyerall objective of thiv propksal is go assess feasibility of imppenentibg an EBI, adapted to tfe needs wnd inteeestw of a rural communlcy in lrdex vo plan a large scale stugy. To that end ojr specific aims are to 1) expand and ststain s Oroject GRACE SVD bowlitjon of community and academic

of CVD in Eastern NC. The overall this is to feasibility of implementing needs interests of a community in order plan a large scale study. To end our specific aims are to 1) expand and sustain a Project GRACE coalition of community and academic

of CVD in Eastern NC. The overalL objective Of thiS prOpoSaL is tO assEss feasibility OF impLementing an EBI, adapted tO the nEeDS and INtErestS of a rurAL cOMMunItY iN orDeR To Plan a LarGe scale Study. To thaT enD oUr specific aiMS aRe to 1) expand And Sustain a ProjEct gRACE CvD CoaLItion Of cOmmunIty and ACademiC

of CVD in Eastern NC. The  overall o bject ive  of  t hisprop osal is to ass e ss f easibility of implemen tingan EBI, ad apted  to the ne e d s a nd  i nte re s ts  of a  ru ral com munity inord er  to plan a l a rg e scale st udy . To that en d o ur spe ci fic aimsare  to 1 ) expa n d andsustain a  P r ojectG RACE CV D co alit ion of communitya nd academic

of_CVD in_Eastern NC. The overall_objective of_this_proposal is_to_assess feasibility of_implementing an EBI,_adapted to the needs_and interests of_a_rural community in order to plan a large scale study. To that end our_specific_aims are_to_1)_expand and sustain a Project_GRACE CVD coalition of community_and academic


, often while the child is still asymptomatic. Such early detection and treatment can have a profound impact on the clinical severity of the condition in the affected child. If left undiagnosed and untreated, the consequences of the targeted disorders can be dire, many causing irreversible neurological damage, intellectual, developmental and physical disabilities, and

, often while the child is still asymptomatic. Such early detection and treatment can get a fundamental impact on the clinical severity of the condition in the moved child. If left undiagnosed and untreated, the consequences of the targeted disorder can be dire, many causing irreversible neurological price, intellectual, developmental and physical disability, and

, ofhen while the child is suill asymptomatic. Such eerly defection xnd treatment can have a prohoune impqct on the clinical sexerity of the coneitiib in the ahrected gkild. Jn lefc nndiagnosed and untreated, the consequenwer lf the targeted disorders can be diwe, many cwusing irreverfiblt nquromogical damage, intellectual, develolmental and physical disabilities, and

, often while the child is still early and treatment have a profound of condition in the child. If left and untreated, the consequences of the disorders can be dire, many causing irreversible neurological damage, intellectual, developmental and physical and

, often while the child is still AsymptomatIc. SucH eaRly DeTectIon aNd treatment can HAve a Profound impact on the cliNical SeVEritY Of The coNdition IN tHE AffEcTeD chIlD. if Left uNdiAgnosed And untreatEd, tHe Consequences OF tHe targeted DisOrders can be dIre, Many caUsIng IRreveRsiBle neUrologICal damAge, intellEcTUal, devELopmentAL AnD phySical disabilities, ANd

, often while the child is  still asy mptom ati c.Su ch e arly  detection and trea tment can have a profo und i mp a ct o n  t he cl inicals ev e r ity  o fthe  c o nd ition  in  the af fected chi ld.  I f left undia g no sed and un tre ated, the co nse quence soft he ta rge ted d isorde r s canbe dire,ma n y caus i ng irre v e rs ible  neurological dam a ge ,  intellectual,  devel op m en t a l a ndphysical d is abili t ies, an d

, often_while the_child is still asymptomatic._Such early_detection_and treatment_can_have a profound_impact on the_clinical severity of the_condition in the_affected_child. If left undiagnosed and untreated, the consequences of the targeted disorders can be_dire,_many causing_irreversible_neurological_damage, intellectual, developmental and physical_disabilities, and


ioxygenases will be purified and characterized and studies on the mechanism of enzymatic oxygen fixation will be initiated. The products formed by the action of these dioxygenases on a variety of aromatic hydrocarbons and their substituted derivatives will be isolated and characterized by conventional chemical techniques. Trichotillomania (TTM) is

ioxygenases will be purified and characterized and studies on the mechanism of enzymatic oxygen fixation will be initiate. The product formed by the action of these dioxygenases on a variety of aromatic hydrocarbon and their substituted derivatives will be isolated and characterized by ceremonious chemical proficiency. Trichotillomania (TTM) is

ioxjgenases will be purifiea and characternzed anv studiss on thd mechanism of enzymatic oxyjen dixatuon will be initiated. Ghe produbts formee by rhe action of thesc diosngenavxs on a variety of aromathc hydrocarbonv xnb their substituted derivatives will be isokahed and characjeriztd fy cknventional chemical techniques. Trjchotilnomania (TTM) ix

ioxygenases will be purified and characterized and the of enzymatic fixation will be the of these dioxygenases a variety of hydrocarbons and their substituted derivatives will isolated and characterized by conventional chemical techniques. Trichotillomania (TTM) is

ioxygenases will be purified And charactErizeD anD stUdIes oN the Mechanism of enzYMatiC oxygen fixation will be iNitiaTeD. the pROdUcts fOrmed by THe ACTioN oF tHesE dIOxYgenaSes On a variEty of aromaTic HyDrocarbons anD ThEir substitUteD derivatives WilL be isoLaTed ANd chaRacTerizEd by coNVentioNal chemicAl TEchniqUEs. TrichOTIlLomaNia (TTM) is

ioxygenases will be purifi ed and cha racte riz edan d st udie s on the mecha n ismof enzymatic oxygen fi xatio nw illb einiti ated. T h ep r odu ct sfor me d  b y the  ac tion of  these dio xyg en ases on a va r ie ty of arom ati c hydrocarbo nsand th ei r s u bstit ute d der ivativ e s will  be isola te d  and c h aracter i z ed  byconventional chem i ca l  techniques. T richot il l om a n ia(TT M) is

ioxygenases will_be purified_and characterized and studies_on the_mechanism_of enzymatic_oxygen_fixation will be_initiated. The products_formed by the action_of these dioxygenases_on_a variety of aromatic hydrocarbons and their substituted derivatives will be isolated and characterized_by_conventional chemical_techniques._Trichotillomania_(TTM) is


ing binding capacity and unbound bilirubin are not facile. However, all these parameters can be directly measured simply in a very small volume of whole blood with a special purpose fluorometer, the hematofluorometer, first described years ago, by making use of the natural fluorescence of bilirubin bound to albumin. This

ing binding capacity and unbound bilirubin are not facile. However, all these parameters can be immediately measure simply in a very small bulk of hale blood with a special determination fluorometer, the hematofluorometer, foremost described years ago, by making use of the natural fluorescence of bilirubin bind to albumin. This

ing binding capacity and unnound bilirubin cee not facils. Howevef, all these parameters can bx dieectlt measured simply in a very smapl volumw of qhole bloov with a specizp puxpise fluorometet, the hematoxluorometer, fissg bescribed years ago, by making use of the nayugal fluorescense og biljgunin bound to albumin. This

ing binding capacity and unbound bilirubin are However, these parameters be directly measured volume whole blood with special purpose fluorometer, hematofluorometer, first described years ago, by use of the natural fluorescence of bilirubin bound to albumin. This

ing binding capacity and unboUnd bilirubIn are Not FacIlE. HowEver, All these parameTErs cAn be directly measured siMply iN a VEry sMAlL voluMe of whoLE bLOOd wItH a SpeCiAL pUrposE flUorometEr, the hematOflUoRometer, first DEsCribed yearS agO, by making use Of tHe natuRaL flUOrescEncE of biLirubiN Bound tO albumin. THiS

ing binding capacity and u nbound bil irubi n a reno t fa cile . However, all thes e parameters can be di rectl ym easu r ed  simp ly in a ve r y  sm al lvol um e  o f who leblood w ith a spec ial  p urpose fluor o me ter, the h ema tofluoromete r,firstde scr i bed y ear s ago , by m a king u se of the  n a turalf luoresc e n ce  ofbilirubin bound t o  a l bumin. This

ing binding_capacity and_unbound bilirubin are not_facile. However,_all_these parameters_can_be directly measured_simply in a_very small volume of_whole blood with_a_special purpose fluorometer, the hematofluorometer, first described years ago, by making use of the_natural_fluorescence of_bilirubin_bound_to albumin. This


microscopic analysis, including partial denaturation and heteroduplex techniques, and cleavage of specific circular DNA classes with site-specific restriction endonucleases in order to determine the relationships between these molecules. DNA-DNA hybridization will also be employed as will sedimentation velocity procedures for characterization of these elements. Specific inhibitors will be employed

microscopic analysis, including partial denaturation and heteroduplex techniques, and cleavage of specific round deoxyribonucleic acid class with site - specific limitation endonucleases in club to determine the kinship between these atom. DNA - DNA hybridization will besides be use as will sedimentation velocity procedure for characterization of these elements. Specific inhibitor will be employed

mifroscopic analysis, incluaing partial deuqturatmon and heterodjplex techniques, and cleavagx of specufic circular DNA clasres with dite-specufic eestrictioi endonugjeassd in irder to deterkine the ralationships batdezn these molecules. DNA-DNA hybridizatyon wilk wlso be employgd as rill sedimentation velocity procedures for cheracterization pf these elements. Specific inhlbitors will be emoloyed

microscopic analysis, including partial denaturation and heteroduplex cleavage specific circular classes with site-specific determine relationships between these DNA-DNA hybridization will be employed as will sedimentation velocity for characterization of these elements. Specific inhibitors will be employed

microscopic analysis, includIng partial DenatUraTioN aNd heTeroDuplex techniquES, and Cleavage of specific circUlar DnA CLassES wIth siTe-speciFIc REStrIcTiOn eNdONuCleasEs iN order tO determine The ReLationships bETwEen these moLecUles. DNA-DNA hyBriDizatiOn WilL Also bE emPloyeD as wilL SedimeNtation veLoCIty proCEdures fOR ChAracTerization of these ELeMEnts. Specific inHibitoRs WIlL BE emPloYed

microscopic analysis, inc luding par tialden atu ra tion  and  heteroduplext echn iques, and cleavage of  spec if i c ci r cu lar D NA clas s es w ith  s it e-s pe c if ic re str ictionendonuclea ses  i n order to d e te rmine therel ationships b etw een th es e m o lecul es.  DNA- DNA hy b ridiza tion will  a l so bee mployed a swill  sedimentation ve l oc i ty proceduresfor ch ar a ct e r iza tio n of these  e lemen t s. Spec i fi c i nhi b itors will be  employed

microscopic_analysis, including_partial denaturation and heteroduplex_techniques, and_cleavage_of specific_circular_DNA classes with_site-specific restriction endonucleases_in order to determine_the relationships between_these_molecules. DNA-DNA hybridization will also be employed as will sedimentation velocity procedures for characterization_of_these elements._Specific_inhibitors_will be employed


: The transient exposure to Zeb produced differential cell density-depended responses in 5/7 tested HCC cell lines. In cell lines which were scored as Zeb-sensitive, a 3-day drug pre-treatment of LD cultures (LDZ) caused a remarkable increase in primary sphere formation. This effect persisted through

: The transient exposure to Zeb produced differential cell concentration - depend responses in 5/7 tested HCC cellular telephone lines. In cellular telephone lines which were scored as Zeb - sensible, a 3 - day drug pre - treatment of LD cultures (LDZ) cause a remarkable increase in basal sphere formation. This consequence persisted through

: Thf transient exposure to Eeb produced diffgrwntial cell sensity-ddpended responses in 5/7 tested HXC ceol lines. In cell lines which wege scored as Eeb-sensitive, a 3-dab drug pvz-treaflent if LD cultures (LDZ) causeg a remarkable ivcxease in primary sphere formation. Thys effevt persisted thrjugh

: The transient exposure to Zeb produced density-depended in 5/7 HCC cell lines. scored Zeb-sensitive, a 3-day pre-treatment of LD (LDZ) caused a remarkable increase in sphere formation. This effect persisted through

: The transient exposure to Zeb Produced diFfereNtiAl cElL denSity-Depended responSEs in 5/7 Tested HCC cell lines. In ceLl linEs WHich WErE scorEd as Zeb-SEnSITivE, a 3-DaY drUg PRe-TreatMenT of LD cuLtures (LDZ) cAusEd A remarkable iNCrEase in primAry Sphere formatIon. this efFeCt pERsistEd tHrougH

: The transient exposure t o Zeb prod uceddif fer en tial  cel l density-depe n dedresponses in 5/7 teste d HCC  c e ll l i ne s. In  cell l i ne s whi ch  w ere  s c or ed as  Ze b-sensi tive, a 3- day  d rug pre-trea t me nt of LD c ult ures (LDZ) c aus ed a r em ark a ble i ncr easein pri m ary sp here form at i on. Th i s effec t pe rsis ted through

: The_transient exposure_to Zeb produced differential_cell density-depended_responses_in 5/7_tested_HCC cell lines._In cell lines_which were scored as_Zeb-sensitive, a 3-day_drug_pre-treatment of LD cultures (LDZ) caused a remarkable increase in primary sphere formation. This_effect_persisted through


A-IV deletion mutants and phospholipid will be studied by physico-chemical techniques to examine the impact of protein structure on the properties and LCAT reactivity of apo A-IV/lipid complexes; 3) The interaction of CETP and HDL will be investigated using fluorescent labelled recombinant and native HDL to determine the

A - IV deletion mutants and phospholipid will be studied by physico - chemical technique to test the impact of protein structure on the properties and LCAT responsiveness of apo A - IV / lipid complexes; 3) The interaction of CETP and HDL will be investigated using fluorescent label recombinant and native HDL to determine the

A-IG deletion mutants and pmospholipid will be stuvied by physico-zhemical techniques to examiie tye imkcct of protein strucgure on tje propeetiew and LCAT csactivibv of zio A-IR/lmpid complexes; 3) The interdction of CETP avd HDL will be investigated using flujresceny pabelled recomfiname ans native HDL to determine the

A-IV deletion mutants and phospholipid will be physico-chemical to examine impact of protein LCAT of apo A-IV/lipid 3) The interaction CETP and HDL will be investigated fluorescent labelled recombinant and native HDL to determine the

A-IV deletion mutants and phosPholipid wiLl be sTudIed By PhysIco-cHemical techniqUEs to Examine the impact of protEin stRuCTure ON tHe proPerties ANd lcaT rEaCtIviTy OF aPo A-IV/LipId complExes; 3) The intEraCtIon of CETP and hdL Will be inveStiGated using flUorEscent LaBelLEd recOmbInant And natIVe HDL tO determinE tHE

A-IV deletion mutants and  phospholi pid w ill  be  s tudi ed b y physico-chem i caltechniques to examinethe i mp a ct o f  p rotei n struc t ur e onth epro pe r ti es an d L CAT rea ctivity of  ap oA-IV/lipid c o mp lexes; 3)The  interaction  of  CETPan d H D L wil l b e inv estiga t ed usi ng fluore sc e nt lab e lled re c o mb inan t and native HDLt od etermine the

A-IV_deletion mutants_and phospholipid will be_studied by_physico-chemical_techniques to_examine_the impact of_protein structure on_the properties and LCAT_reactivity of apo_A-IV/lipid_complexes; 3) The interaction of CETP and HDL will be investigated using fluorescent labelled_recombinant_and native_HDL_to_determine the


and the development of tests of etiological and prognostic value. PROJECT SUMMARY/ABSTRACT Juvenile myelomonocytic leukemia (JMML) is the most common myeloproliferative neoplasm (MPN) in childhood, and tends to occur in very young children less than 4 years of age. JM

and the development of tests of etiological and prognostic value. PROJECT SUMMARY / ABSTRACT Juvenile myelomonocytic leukemia (JMML) is the most coarse myeloproliferative tumor (MPN) in childhood, and tends to occur in very unseasoned child less than 4 years of age. JM

anf the development of tesus of etiological and prmgnostjc value. PROJECT SUMMARY/ABSTRACT Juvxnilw myeoomonocytic leukemia (JOML) is thv most conmon nyeloprolihsrative neoplzdm (M'N) in childhood, snd tends do occur in vesy ylung children less than 4 years of ade. JM

and the development of tests of etiological value. SUMMARY/ABSTRACT Juvenile leukemia (JMML) is (MPN) childhood, and tends occur in very children less than 4 years of JM

and the development of tests oF etiologicAl and ProGnoStIc vaLue. PrOJECT SUMMARY/AbsTRAcT Juvenile myelomonocytIc leuKeMIa (JMml) iS the mOst commON mYELopRoLiFerAtIVe NeoplAsm (mPN) in chIldhood, and TenDs To occur in verY YoUng childreN leSs than 4 years oF agE. JM

and the development of te sts of eti ologi cal  an dprog nost ic value. PROJ E CT S UMMARY/ABSTRACT Juveni le my el o mono c yt ic le ukemia( JM M L ) i sth e m os t  c ommon  my eloprol iferativeneo pl asm (MPN) in ch ildhood, a ndtends to occ urin ver yyou n g chi ldr en le ss tha n  4 yea rs of age .J M

and_the development_of tests of etiological_and prognostic_value._PROJECT SUMMARY/ABSTRACT_Juvenile_myelomonocytic leukemia (JMML)_is the most_common myeloproliferative neoplasm (MPN)_in childhood, and_tends_to occur in very young children less than 4 years of age. JM


able cancers is crucial. This fact is particularly important in this era in which tiny cancers are detected by imaging and more advanced techniques are needed for localizing tumors. This project may be able to decrease positive margins, local recurrence and possible cure of early stage cancers. Taste controls an animals food intake. For the past fifteen

able cancers is crucial. This fact is particularly important in this earned run average in which bantam cancer are detected by imaging and more advance techniques are needed for localizing tumor. This undertaking may be able to decrease positive margins, local recurrence and possible cure of early stage cancer. Taste controls an animals food inhalation. For the past fifteen

ablf cancers is crucial. Thir fact is partieylarly imporfant in ghis era in which tiny cancecs aee deuvcted by imaging and oore advajced tecyniqnes are needed for locallving fmmors. Vhis project mai be able to decrease posidixe margins, local recurrence and possifle curr lf early stage canbews. Tzste controls an animals food intaie. For uhe past fifteen

able cancers is crucial. This fact is in era in tiny cancers are advanced are needed for tumors. This project be able to decrease positive margins, recurrence and possible cure of early stage cancers. Taste controls an animals food For the past fifteen

able cancers is crucial. This fAct is partiCularLy iMpoRtAnt iN thiS era in which tinY CancErs are detected by imaginG and mOrE AdvaNCeD techNiques aRE nEEDed FoR lOcaLiZInG tumoRs. THis projEct may be abLe tO dEcrease positIVe Margins, locAl rEcurrence and PosSible cUrE of EArly sTagE cancErs. TasTE contrOls an animAlS Food inTAke. For tHE PaSt fiFteen

able cancers is crucial. T his fact i s par tic ula rl y im port ant in this er a  inwhich tiny cancers are  dete ct e d by im aging  and mo r ea d van ce dtec hn i qu es ar e n eeded f or localiz ing  t umors. Thisp ro ject may b e a ble to decre ase  posit iv e m a rgins , l ocalrecurr e nce an d possibl ec ure of early s t a ge  can cers. Taste contr o ls an animals foo d inta ke .  F o r  th e p ast fiftee n

able cancers_is crucial._This fact is particularly_important in_this_era in_which_tiny cancers are_detected by imaging_and more advanced techniques_are needed for_localizing_tumors. This project may be able to decrease positive margins, local recurrence and possible_cure_of early_stage_cancers._Taste controls an animals food_intake. For the past fifteen


is to test the hypothesis that expression and localization of specific subunits of the GABAAR are altered during postnatal development in a mouse model of FXS and that these changes are associated with functional deficits, including increased neuronal excitability and altered anxiety- related behavior. Specific Aim 1 will identify changes in the 12 subunit of the GABAAR

is to test the hypothesis that expression and localization of specific fractional monetary unit of the GABAAR are alter during postnatal development in a mouse exemplar of FXS and that these change are associated with functional deficit, admit increased neural excitability and alter anxiety- related behavior. Specific Aim 1 will name changes in the 12 subunit of the GABAAR

is to test the hypothesis uhat expression aue locanizatikn of spdcific subunits of the GABAAC arw alttged during postnatal aevelopmejt in a noust model of FXS anv that tmzse cgwngev are associatec with funwtional deficids, iucluding increased neuronal excitabijity anc wltered anxieti- relseed gvhcvior. Specific Aim 1 will identiry chanjes in the 12 subinit of the GABAAR

is to test the hypothesis that expression of subunits of GABAAR are altered mouse of FXS and these changes are with functional deficits, including increased neuronal and altered anxiety- related behavior. Specific Aim 1 will identify changes in the subunit of the GABAAR

is to test the hypothesis that Expression And loCalIzaTiOn of SpecIfic subunits of THe GAbAAR are altered during poStnatAl DEvelOPmEnt in A mouse mODeL OF FXs aNd ThaT tHEsE chanGes Are assoCiated with FunCtIonal deficitS, InCluding incReaSed neuronal eXciTabiliTy And ALtereD anXiety- RelateD BehaviOr. SpecifiC AIM 1 will iDEntify cHANgEs in The 12 subunit of the GAbaAr

is to test the hypothesis  that expr essio n a ndlo cali zati on of specific subu nits of the GABAAR are  alte re d  dur i ng  post natal d e ve l o pme nt  i n a  m o us e mod elof FXSand that t hes echanges area ss ociated wi thfunctional d efi cits,in clu d ing i ncr eased  neuro n al exc itability  a n d alte r ed anxi e t y-  rel ated behavior. Sp e ci f ic Aim 1 willidenti fy ch a n ges  in  the 12 su bu nit o f  the GA B AA R

is_to test_the hypothesis that expression_and localization_of_specific subunits_of_the GABAAR are_altered during postnatal_development in a mouse_model of FXS_and_that these changes are associated with functional deficits, including increased neuronal excitability and altered_anxiety-_related behavior._Specific_Aim_1 will identify changes in_the 12 subunit of the_GABAAR


the development of LE are not known. Therefore, the specific aims of this study, in a sample of patients following treatment for breast cancer, are to: determine genetic predictors of LE using a candidate gene approach and evaluate for epigenetic changes, as measured by DNA methylation and subsequent gene expression, in candidate genes associated with the diagnosis

the development of LE are not known. Therefore, the specific aims of this discipline, in a sample distribution of patients following discussion for breast cancer, are to: determine genic predictors of LE using a campaigner gene approach path and evaluate for epigenetic changes, as measured by DNA methylation and subsequent gene construction, in candidate genes consort with the diagnosis

thf development of LE are kot known. Therefore, the speciric aims of this study, in a sample oh parientw following treatment wor breasn cancer, qre uo: determine genevjc predletors lf LZ nsing a candidaje gene apprmach and evaludtd yor epigenetic changes, as measured br DNA mrtjylation and sobseqlegt gsne expression, in candidate genes zssociaued with the diagnpsis

the development of LE are not known. specific of this in a sample breast are to: determine predictors of LE a candidate gene approach and evaluate epigenetic changes, as measured by DNA methylation and subsequent gene expression, in candidate associated with the diagnosis

the development of LE are not kNown. TherefOre, thE spEciFiC aimS of tHis study, in a samPLe of Patients following treatMent fOr BReasT CaNcer, aRe to: detERmINE geNeTiC prEdICtOrs of lE uSing a caNdidate genE apPrOach and evaluATe For epigeneTic Changes, as meaSurEd by DNa mEthYLatioN anD subsEquent GEne expRession, in CaNDidate GEnes assOCIaTed wIth the diagnosis

the development of LE are  not known . The ref ore ,thespec ific aims of t h is s tudy, in a sample of p atien ts foll o wi ng tr eatment fo r bre as tcan ce r ,are t o:determi ne genetic  pr ed ictors of LE us ing a cand ida te gene appr oac h andev alu a te fo r e pigen etic c h anges,  as measu re d  by DN A  methyl a t io n an d subsequent gene ex p ression, in ca ndidat eg en e s  as soc iated with  t he di a gnosis

the_development of_LE are not known._Therefore, the_specific_aims of_this_study, in a_sample of patients_following treatment for breast_cancer, are to:_determine_genetic predictors of LE using a candidate gene approach and evaluate for epigenetic changes,_as_measured by_DNA_methylation_and subsequent gene expression, in_candidate genes associated with the_diagnosis


long time goal of our studies is to delineate the molecular mechanism that regulates the immune defense against invading pathogens. The study proposed is focused on the role of the family transcription factors of interferon regulatory factors (IRF) in the innate and acquired responses to viral infection. These factors were shown to participate not only in the induction

long time goal of our studies is to trace the molecular mechanism that determine the immune defense against invading pathogens. The report proposed is focused on the function of the family transcription factor of interferon regulatory factors (IRF) in the congenital and acquired responses to viral contagion. These factors were shown to enter not only in the evocation

lojg time goal of our studles is to delinecre the molechlar mecfanism that regulates the imlube dedense against invading pathogend. The stydy kroposed is focusxs on thc rols of chx family transctiption factmrs of interfesov xegulatory factors (IRF) in the innate and acaulred responses to niwal jnfection. These factors were shown to paruicipate not only on the induction

long time goal of our studies is the mechanism that the immune defense proposed focused on the of the family factors of interferon regulatory factors (IRF) the innate and acquired responses to viral infection. These factors were shown to not only in the induction

long time goal of our studies iS to delineaTe the MolEcuLaR mecHaniSm that regulateS The iMmune defense against invAding PaTHogeNS. THe stuDy propoSEd IS FocUsEd On tHe ROlE of thE faMily traNscription FacToRs of interferON rEgulatory fActOrs (IRF) in the iNnaTe and aCqUirED respOnsEs to vIral inFEction. these factOrS Were shOWn to parTICiPate Not only in the inducTIoN

long time goal of our stu dies is to  deli nea teth e mo lecu lar mechanismt hatregulates the immune d efens ea gain s tinvad ing pat h og e n s.Th estu dy pr opose d i s focus ed on therol eof the famil y  t ranscripti onfactors of i nte rferon  r egu l atory  fa ctors  (IRF) in the  innate a nd acquir e d respo n s es  toviral infection.T he s e factors were  shown  t o  p a r tic ipa te not onl yin th e  induct i on

long_time goal_of our studies is_to delineate_the_molecular mechanism_that_regulates the immune_defense against invading_pathogens. The study proposed_is focused on_the_role of the family transcription factors of interferon regulatory factors (IRF) in the innate_and_acquired responses_to_viral_infection. These factors were shown_to participate not only in_the induction


. These ongoing studies give rise to an overarching hypothesis to be tested in four interrelated sub-projects in this SCR requiring a highly integrated approach. The SCR overall novel hypothesis addressed is: Periodontal disease (oral inflammation and tissue injury), certain microbes, surgical anesthesia, and other widely used drugs impact recently uncovered

. These ongoing studies give rise to an overarching hypothesis to be quiz in four interconnected sub - projects in this SCR command a highly desegregate approach. The SCR overall novel guess addressed is: Periodontal disease (oral inflammation and tissue wound), sealed microbes, surgical anesthesia, and other wide used drugs shock recently uncover

. Thfse ongoing studies give rise to an ovetaeching hypotgesis to be tested in four interrelaved wub-prijects in this SCR reqjiring a jighly ibtegcated approach. Tis SCR oyzrall kovel iypothesis addrgssed is: Perhodontal diseave (oxal inflammation and tissue injury), cqrtain kifrobes, surgicaj antstresiz, and other widely used drugs impadt receitly uncovered

. These ongoing studies give rise to hypothesis be tested four interrelated sub-projects highly approach. The SCR novel hypothesis addressed Periodontal disease (oral inflammation and tissue certain microbes, surgical anesthesia, and other widely used drugs impact recently uncovered

. These ongoing studies give riSe to an overArchiNg hYpoThEsis To be Tested in four inTErreLated sub-projects in this sCR reQuIRing A HiGhly iNtegratED aPPRoaCh. thE SCr oVErAll noVel HypotheSis addressEd iS: PEriodontal diSEaSe (oral inflAmmAtion and tissUe iNjury), cErTaiN MicroBes, SurgiCal aneSThesia, And other wIdELy used DRugs impACT rEcenTly uncovered

. These ongoing studies gi ve rise to  an o ver arc hi ng h ypot hesis to be te s tedin four interrelated s ub-pr oj e ctsi nthisSCR req u ir i n g a  h ig hly  i n te grate d a pproach . The SCRove ra ll novel hyp o th esis addre sse d is: Period ont al dis ea se( oralinf lamma tion a n d tiss ue injury ), certai n  microb e s ,surg ical anesthesia,a nd other widely u sed dr ug s  i m p act  re cently unc ov ered

. These_ongoing studies_give rise to an_overarching hypothesis_to_be tested_in_four interrelated sub-projects_in this SCR_requiring a highly integrated_approach. The SCR_overall_novel hypothesis addressed is: Periodontal disease (oral inflammation and tissue injury), certain microbes, surgical_anesthesia,_and other_widely_used_drugs impact recently uncovered


ically treated with sildenafil. Male and female subjects, age 18 and above with sickle cell disease or thalassemia were eligible for Stage I of the study. Stage I evaluated 25 subjects and included pulmonary function testing, chest x-rays, VQ scan, 6-minute walk, sleep study

ically treated with sildenafil. Male and female subjects, age 18 and above with sickle cell disease or thalassemia were eligible for Stage I of the discipline. stagecoach I evaluated 25 subjects and included pneumonic function testing, chest ten - rays, VQ scan, 6 - minute base on balls, sleep study

icaply treated with sildenanil. Male and femcoe suboects, afe 18 and xbove with sickle cell diseade or tyalassemia were eligibue for Stwge I of the wtudy. Stagx I evalmcted 25 dubjzcvs and included pulmonary function testhne, ehest x-rays, VQ scan, 6-minute walk, slee[ study

ically treated with sildenafil. Male and female 18 above with cell disease or I the study. Stage evaluated 25 subjects included pulmonary function testing, chest x-rays, scan, 6-minute walk, sleep study

ically treated with sildenafIl. Male and fEmale SubJecTs, Age 18 aNd abOve with sickle cELl diSease or thalassemia were EligiBlE For STAgE I of tHe study. sTaGE i evAlUaTed 25 SuBJeCts anD inCluded pUlmonary fuNctIoN testing, chesT X-rAys, VQ scan, 6-mInuTe walk, sleep sTudY

ically treated with silden afil. Male  andfem ale  s ubje cts,  age 18 and ab o ve w ith sickle cell diseas e orth a lass e mi a wer e eligi b le f orSt ag e I  o f  t he st udy . Stage  I evaluat ed25  subjects an d  i ncluded pu lmo nary functio n t esting ,che s t x-r ays , VQscan,6 -minut e walk, s le e p stud y

ically treated_with sildenafil._Male and female subjects,_age 18_and_above with_sickle_cell disease or_thalassemia were eligible_for Stage I of_the study. Stage_I_evaluated 25 subjects and included pulmonary function testing, chest x-rays, VQ scan, 6-minute walk,_sleep_study


and by providing leadership in the scientific and administrative efforts of CCG. During the first three years of the last grant period, 1989,1990 and 1991, two hundred-forty-eight patients were entered onto therapeutic studies, 181 onto epidemiology and late effects studies, and 36 onto biology studies. At the end of 1991

and by providing leadership in the scientific and administrative efforts of CCG. During the first three years of the final concession period, 1989,1990 and 1991, two hundred - forty - eight patients were enroll onto curative studies, 181 onto epidemiology and late effects study, and 36 onto biology studies. At the goal of 1991

anf by providing leadershik in the scientifnx and edminisfrative dfforts of CCG. During the ficst rhree years of the last gravt period, 1989,1990 and 1991, tqo hnndred-forty-eight patients were cnterzd onto therapeujic studies, 181 onto epidemionoey and late effects studies, and 36 onto biologu dtudies. At the end jf 1991

and by providing leadership in the scientific efforts CCG. During first three years 1989,1990 1991, two hundred-forty-eight were entered onto studies, 181 onto epidemiology and late studies, and 36 onto biology studies. At the end of 1991

and by providing leadership iN the scientIfic aNd aDmiNiStraTive Efforts of CCG. DuRIng tHe first three years of the Last gRaNT perIOd, 1989,1990 And 1991, twO hundreD-FoRTY-eiGhT pAtiEnTS wEre enTerEd onto tHerapeutic StuDiEs, 181 onto epidemIOlOgy and late EffEcts studies, aNd 36 oNto bioLoGy sTUdies. at tHe end Of 1991

and by providing leadersh ip in thescien tif ican d ad mini strative effor t s of  CCG. During the first  thre ey ears of  thelast gr a nt p eri od ,198 9, 1 99 0 and  19 91, two  hundred-f ort y- eight patien t swere enter edonto therape uti c stud ie s,1 81 on toepide miolog y  and l ate effec ts studie s , and 3 6 on to b iology studies. A t  t h e end of 1991

and_by providing_leadership in the scientific_and administrative_efforts_of CCG._During_the first three_years of the_last grant period, 1989,1990_and 1991, two_hundred-forty-eight_patients were entered onto therapeutic studies, 181 onto epidemiology and late effects studies, and_36_onto biology_studies._At_the end of 1991


rat liver cells pre-treated to make only their plasma membranes permeable to solutes. Having already documented joint steady-state regulation of ambient (Ca2 ion) by mitochondria plus microsomes at values approximating those of liver cell cytosol, this project will investigate 1) inter-organellar effects on Ca2 ion

rat liver cells pre - treated to make merely their plasma membrane permeable to solutes. Having already documented joint steady - country regulation of ambient (Ca2 ion) by mitochondria plus microsomes at value estimate those of liver cell cytosol, this undertaking will investigate 1) inter - organellar effect on Ca2 ion

rah liver cells pre-treated to make only tkwir plesma mejbranes oermeable to solutes. Having elreqdy dicumented joint steady-rtate regllation od amuient (Ca2 ion) by mitochondria pmms mierisomes at valugs approximading those of nixex cell cytosol, this project will invqstigatr 1) inter-organellwr egsecta on Ca2 ion

rat liver cells pre-treated to make only membranes to solutes. already documented joint ion) mitochondria plus microsomes values approximating those liver cell cytosol, this project will 1) inter-organellar effects on Ca2 ion

rat liver cells pre-treated to Make only thEir plAsmA meMbRaneS perMeable to soluteS. haviNg already documented joiNt steAdY-StatE ReGulatIon of amBIeNT (ca2 iOn) By MitOcHOnDria pLus MicrosoMes at valueS apPrOximating thoSE oF liver cell CytOsol, this projEct Will inVeStiGAte 1) inTer-OrganEllar eFFects oN Ca2 ion

rat liver cells pre-treat ed to make  only  th eir  p lasm a me mbranes permea b le t o solutes. Having alre ady d oc u ment e djoint  steady - st a t e r eg ul ati on of  ambi ent  (Ca2 i on) by mit och on dria plus mi c ro somes at v alu es approxima tin g thos eofl ivercel l cyt osol,t his pr oject wil li nvesti g ate 1)i n te r-or ganellar effectso nC a2 ion

rat_liver cells_pre-treated to make only_their plasma_membranes_permeable to_solutes._Having already documented_joint steady-state regulation_of ambient (Ca2 ion)_by mitochondria plus_microsomes_at values approximating those of liver cell cytosol, this project will investigate 1) inter-organellar_effects_on Ca2_ion


methodological expertise in the study of family demography, with an emphasis on contextual influences on family formation for lesbian and gay parents. The second goal is to increase my knowledge and expertise in using established national datasets such as the U.S. Census and the American Community survey to conduct secondary data analyses pertinent to the study of LG

methodological expertise in the study of family demography, with an emphasis on contextual influence on syndicate formation for lesbian and gay parents. The second finish is to increase my knowledge and expertise in using establish national datasets such as the U.S. Census and the American Community survey to behave secondary data analysis pertinent to the study of LG

mehhodological expertise ik the study of fcnily dxmograpgy, with xn emphasis on contextual inhluebces in family formation fof lesbian and gay partnts. The second goal is to incrswse kb knowledge and expertise in using estatlksked national datasets such as the U.S. Census ajd the Americag Cokiunifj wurvey to conduct secondary dzta ananyses pertinemt to the study of LG

methodological expertise in the study of family an on contextual on family formation The goal is to my knowledge and in using established national datasets such the U.S. Census and the American Community survey to conduct secondary data analyses to the study of LG

methodological expertise in The study of FamilY deMogRaPhy, wIth aN emphasis on conTExtuAl influences on family foRmatiOn FOr leSBiAn and Gay pareNTs. tHE seCoNd GoaL iS To IncreAse My knowlEdge and expErtIsE in using estaBLiShed nationAl dAtasets such aS thE U.S. CenSuS anD The AmEriCan CoMmunitY Survey To conduct SeCOndary DAta analYSEs PertInent to the study of lg

methodological expertisein the stu dy of  fa mil ydemo grap hy, with an em p hasi s on contextual influe nceson fami l yforma tion fo r  l e s bia nan d g ay pa rents . T he seco nd goal is  to  i ncrease my k n ow ledge andexp ertise in us ing  estab li she d  nati ona l dat asetss uch as  the U.S.  C e nsus a n d the A m e ri canCommunity surveyt oc onduct seconda ry dat aa na l y ses  pe rtinent to  t he st u dy of L G

methodological_expertise in_the study of family_demography, with_an_emphasis on_contextual_influences on family_formation for lesbian_and gay parents. The_second goal is_to_increase my knowledge and expertise in using established national datasets such as the U.S._Census_and the_American_Community_survey to conduct secondary data_analyses pertinent to the study_of LG


) nd increase in both serum ALT and prednisone requirements was found in AIH patients from the US and from Japan. Based on these results, the K08 proposal will define a key mechanistic role for MIF in the immunoregulation of AIH, enabling new strategies for therapy and disease management. To accomplish this

) nd increase in both serum ALT and prednisone requirements was found in AIH patients from the US and from Japan. Based on these result, the K08 marriage proposal will define a key mechanistic function for MIF in the immunoregulation of AIH, enable new strategies for therapy and disease management. To accomplish this

) nd increase in both serum XLT and prednisone reqniremenfs was fuund in AIH patients from thx US and drom Japan. Based on thdse resulns, the K08 propiwal will dxrine a key medmaniscir role for MIF ln the immutoregulation ox XIK, enabling new strategies for therapr and dosfase managemenj. To sscomllish this

) nd increase in both serum ALT requirements found in patients from the on results, the K08 will define a mechanistic role for MIF in the of AIH, enabling new strategies for therapy and disease management. To accomplish this

) nd increase in both serum ALT aNd prednisoNe reqUirEmeNtS was FounD in AIH patients FRom tHe US and from Japan. Based oN thesE rESultS, ThE K08 proPosal wiLL dEFIne A kEy MecHaNIsTic roLe fOr MIF in The immunorEguLaTion of AIH, enaBLiNg new stratEgiEs for therapy And DiseasE mAnaGEment. to aCcompLish thIS

) nd increase in both seru m ALT andpredn iso nere quir emen ts was found i n  AIH  patients from the USand f ro m  Jap a n.  Base d on th e se r esu lt s,  th eK 08  prop osa l willdefine a k eyme chanistic ro l efor MIF in  th e immunoregu lat ion of  A IH, enabl ing  newstrate g ies fo r therapy  a n d dise a se mana g e me nt.To accomplish thi s

) nd_increase in_both serum ALT and_prednisone requirements_was_found in_AIH_patients from the_US and from_Japan. Based on these_results, the K08_proposal_will define a key mechanistic role for MIF in the immunoregulation of AIH, enabling_new_strategies for_therapy_and_disease management. To accomplish this


throughput cDNA expression screen for regulators of this splicing switch. This screen identified the epithelial cell type specific splicing regulators ESRP1 and ESRP2 demonstrating the feasibility of cell-based splicing assays in high throughput, array-based screens. An extensive set of ESRP-regulated exons switch splicing during the EMT, indicating that global

throughput cDNA expression screen for regulators of this splice substitution. This screen door identified the epithelial cellular telephone type specific splice regulators ESRP1 and ESRP2 demonstrating the feasibility of cellular telephone - based splicing assays in eminent throughput, array - based screens. An across-the-board set of ESRP - regulated exons switch splice during the EMT, indicating that global

thgoughput cDNA expression screen for regolqtors mf thia splicivg switch. This screen identihied the tiithelial cell type soecific silicing rwguletors ESRP1 and ESRP2 demokftraflng tke feasibility on cell-based splicing assafs iu high throughput, array-based screens. An extrndive set of ESTP-regllwted vxins switch splicing during ths EMT, iidicating that blobal

throughput cDNA expression screen for regulators of switch. screen identified epithelial cell type ESRP2 the feasibility of splicing assays in throughput, array-based screens. An extensive set ESRP-regulated exons switch splicing during the EMT, indicating that global

throughput cDNA expression sCreen for reGulatOrs Of tHiS splIcinG switch. This scrEEn idEntified the epithelial cEll tyPe SPeciFIc SplicIng reguLAtORS ESrP1 AnD ESrP2 DEmOnstrAtiNg the feAsibility oF ceLl-Based splicinG AsSays in high ThrOughput, array-BasEd screEnS. An EXtensIve Set of eSRP-reGUlated Exons switCh SPlicinG During tHE eMt, indIcating that global

throughput cDNA expressio n screen f or re gul ato rs  ofthis  splicing swit c h. T his screen identifiedthe e pi t heli a lcelltype sp e ci f i c s pl ic ing  r e gu lator s E SRP1 an d ESRP2 de mon st rating the f e as ibility of  ce ll-based spl ici ng ass ay s i n  high  th rough put, a r ray-ba sed scree ns .  An ex t ensives e tof E SRP-regulated exo n ss witch splicing  durin gt he E MT,  in dicating t ha t glo b al

throughput_cDNA expression_screen for regulators of_this splicing_switch._This screen_identified_the epithelial cell_type specific splicing_regulators ESRP1 and ESRP2_demonstrating the feasibility_of_cell-based splicing assays in high throughput, array-based screens. An extensive set of ESRP-regulated exons_switch_splicing during_the_EMT,_indicating that global


, and academic instruction; 4) to publish joint research publications; 5) to incorporate team-based projects that will generate a steady pipeline of students to continue advanced studies in the nation's top graduate institutions; and 6) to create competitive minority scientists that are successful in receiving funding for addressing cancer health disparities. [unreadable]

, and academic instruction; 4) to publish joint research publications; 5) to integrate team - free-base projects that will generate a regular grapevine of students to continue advanced study in the nation's top graduate institution; and 6) to create competitive minority scientists that are successful in receive funding for addressing cancer health disparity. [ unreadable ]

, anf academic instruction; 4) uo publish joint tewearch publidations; 5) to incorporate team-based prljwcts ukat will generate a rteady piieline of stuvents to continux advanccb stusles iu vhe nation's top graduate hnstitutions; atd 6) co create competitive minority scieneists tnah are successfol in wecejnikg funding for addressing cancer health disparities. [inreadable]

, and academic instruction; 4) to publish publications; to incorporate projects that will students continue advanced studies the nation's top institutions; and 6) to create competitive scientists that are successful in receiving funding for addressing cancer health disparities. [unreadable]

, and academic instruction; 4) to pUblish joinT reseArcH puBlIcatIons; 5) To incorporate tEAm-baSed projects that will genErate A sTEady PIpEline Of studeNTs TO ConTiNuE adVaNCeD studIes In the naTion's top grAduAtE institutionS; AnD 6) to create cOmpEtitive minorIty ScientIsTs tHAt are SucCessfUl in reCEiving Funding foR aDDressiNG cancer HEAlTh diSparities. [unreadabLE]

, and academic instruction ; 4) to pu blish  jo int  r esea rchpublications;5 ) to  incorporate team-base d pro je c ts t h at  will  genera t ea ste ad ypip el i ne  of s tud ents to  continueadv an ced studiesi nthe nation 'stop graduate  in stitut io ns; and 6 ) t o cre ate co m petiti ve minori ty scient i sts tha t ar e su ccessful in recei v in g  funding for a ddress in g  c a n cer  he alth dispa ri ties. [unread a bl e ]

, and_academic instruction;_4) to publish joint_research publications;_5)_to incorporate_team-based_projects that will_generate a steady_pipeline of students to_continue advanced studies_in_the nation's top graduate institutions; and 6) to create competitive minority scientists that are_successful_in receiving_funding_for_addressing cancer health disparities. [unreadable]


1 (HIF1), a critical transcription factor for VEGF gene regulation. Our recent data and other published studies suggest that OSM may promote angiogenesis, tumor progression, and metastasis in vivo. In this grant, we propose to determine the multiple mechanisms by which OSM promotes VEGF expression in human breast cancer. To accomplish this

1 (HIF1), a critical transcription factor for VEGF gene regulation. Our recent datum and early print studies suggest that OSM may advertise angiogenesis, tumor progression, and metastasis in vivo. In this grant, we propose to specify the multiple mechanisms by which OSM promotes VEGF saying in human breast cancer. To accomplish this

1 (HLF1), a critical transcriptlon factor for VGGD gene regulztion. Ouf recent data and other publmshee stueies suggest that OSM oay promone angiogwnesms, tumor progression, and metasfwsis mn vivo. In this grant, we [ropose to detaroiue the multiple mechanisms by which JSM prokohes VEGF exprefsiom in glmcn breast cancer. To accomplish fhis

1 (HIF1), a critical transcription factor for regulation. recent data other published studies angiogenesis, progression, and metastasis vivo. In this we propose to determine the multiple by which OSM promotes VEGF expression in human breast cancer. To accomplish this

1 (HIF1), a critical transcription Factor for VeGF geNe rEguLaTion. our rEcent data and otHEr puBlished studies suggest tHat OSm mAY proMOtE angiOgenesiS, TuMOR prOgReSsiOn, ANd MetasTasIs in vivO. In this graNt, wE pRopose to deteRMiNe the multiPle Mechanisms by WhiCh OSM pRoMotES VEGF ExpRessiOn in huMAn breaSt cancer. TO aCCompliSH this

1 (HIF1), a critical tran scriptionfacto r f orVE GF g eneregulation. Ou r  rec ent data and other pub lishe ds tudi e ssugge st that OS M may  p ro mot ea ng iogen esi s, tumo r progress ion ,and metastas i sin vivo. I n t his grant, w e p ropose  t o d e termi nethe m ultipl e  mecha nisms bywh i ch OSM promote s VE GF e xpression in huma n  b r east cancer. T o acco mp l is h thi s

1_(HIF1), a_critical transcription factor for_VEGF gene_regulation._Our recent_data_and other published_studies suggest that_OSM may promote angiogenesis,_tumor progression, and_metastasis_in vivo. In this grant, we propose to determine the multiple mechanisms by which_OSM_promotes VEGF_expression_in_human breast cancer. To accomplish_this


TAF)60 and TAF110 and RNA pol II subunits] as well as factors that modulate transcription through their affects on chromatin structure [Trithorax group (TRX-G) genes, RPD3, and SIN3]. Additional mutations have been identified that may also encode transcriptional regulators. Phenotypic

TAF)60 and TAF110 and RNA pol II subunits ] as well as factors that tone arrangement through their affects on chromatin structure [ Trithorax group (TRX - G) gene, RPD3, and SIN3 ]. Additional mutations have been identified that may besides encode transcriptional regulator. Phenotypic

TAF)60 and TAF110 and RNA pol II rubunits] as well as fartors tgat moduuate transcription through tieir affexts on chromatin strucgure [Tritjorax griup (URX-G) genes, RPD3, anv SIN3]. Additionzp mucavions have been identifieg that may alsm dneode transcriptional regulators. Phenjtypic

TAF)60 and TAF110 and RNA pol II well factors that transcription through their group genes, RPD3, and Additional mutations have identified that may also encode transcriptional Phenotypic

TAF)60 and TAF110 and RNA pol II subunIts] as well aS factOrs ThaT mOdulAte tRanscription thROugh Their affects on chromatiN struCtURe [TrIThOrax gRoup (TRX-g) GeNES, RPd3, aNd sIN3]. adDItIonal MutAtions hAve been ideNtiFiEd that may alsO EnCode transcRipTional regulaTorS. PhenoTyPic

TAF)60 and TAF110 and RNApol II sub units ] a s w el l as  fac tors that modu l atetranscription throughtheir  a f fect s  o n chr omatins tr u c tur e[T rit ho r ax  grou p ( TRX-G)genes, RPD 3,an d SIN3]. Add i ti onal mutat ion s have beenide ntifie dtha t  mayals o enc ode tr a nscrip tional re gu l ators. Phenoty p i c

TAF)60 and_TAF110 and_RNA pol II subunits]_as well_as_factors that_modulate_transcription through their_affects on chromatin_structure [Trithorax group (TRX-G)_genes, RPD3, and_SIN3]._Additional mutations have been identified that may also encode transcriptional regulators. Phenotypic


.2. Gscl may contribute to the development of these syndromes. Therefore, we have generated Gscl-null mice that will serve as important resources to determine the role of Gscl in the DGS/VCFS. Finally, defects are not observed in all Gsc-expressing tissues of G

.2. Gscl may contribute to the development of these syndromes. Therefore, we have generate Gscl - null mouse that will serve as important resources to decide the role of Gscl in the DGS / VCFS. Finally, blemish are not observe in all Gsc - express tissues of G

.2. Gsfl may contribute to the development of these vyndrojes. Therdfore, we have generated Gscl-iull mice that will serve as imoortant rvsources ro dttermine the role of Gscl in ths DGS/RCHS. Finally, defegts are not observed in anl Gdc-expressing tissues of G

.2. Gscl may contribute to the development syndromes. we have Gscl-null mice that to the role of in the DGS/VCFS. defects are not observed in all tissues of G

.2. Gscl may contribute to the devElopment of These SynDroMeS. TheRefoRe, we have generaTEd GsCl-null mice that will servE as imPoRTant REsOurceS to deteRMiNE The RoLe Of GScL In The DGs/VCfS. FinalLy, defects aRe nOt Observed in alL gsC-expressinG tiSsues of G

.2. Gscl may contribute to  the devel opmen t o f t he se s yndr omes. Therefor e , we  have generated Gscl-n ull m ic e  tha t  w ill s erve as im p o rta nt  r eso ur c es  to d ete rmine t he role of  Gs cl  in the DGS/ V CF S. Finally , d efects are n otobserv ed  in all G sc- expre ssingt issues  of G

.2. Gscl_may contribute_to the development of_these syndromes._Therefore,_we have_generated_Gscl-null mice that_will serve as_important resources to determine_the role of_Gscl_in the DGS/VCFS. Finally, defects are not observed in all Gsc-expressing tissues of G


positional information needed for the establishment of the correct set of limb cartilages and bones. Gene targeting in mouse embryo-derived stem cells provides the means for generating mice with disruptions in each of these genes. The goal of this grant is to use gene targeting to undertake a systematic analysis of this gene complex and thereby directly

positional information needed for the establishment of the correct hardening of arm cartilages and bones. Gene target in mouse embryo - derive stem cell put up the means for generate mice with disruptions in each of these gene. The goal of this grant is to use gene targeting to contract a systematic analysis of this gene building complex and thereby directly

poditional information neeaed for the estcvlishmxnt of fhe corrdct set of limb cartilages aid bines. Tene targeting in mousd embryo-dvrived stwm ctlls provides the means for gensvatiny nice with disroptions in edch of these gands. The goal of this grant is to use gqne tarbehing to undertwke s sysfvmctic analysis of this gene compmex and thereby direvtly

positional information needed for the establishment of set limb cartilages bones. Gene targeting provides means for generating with disruptions in of these genes. The goal of grant is to use gene targeting to undertake a systematic analysis of this complex and thereby directly

positional information needEd for the esTabliShmEnt Of The cOrreCt set of limb carTIlagEs and bones. Gene targetinG in moUsE EmbrYO-dEriveD stem ceLLs PROviDeS tHe mEaNS fOr genEraTing micE with disruPtiOnS in each of theSE gEnes. The goaL of This grant is tO usE gene tArGetINg to uNdeRtake A systeMAtic anAlysis of tHiS Gene coMPlex and THErEby dIrectly

positional information ne eded for t he es tab lis hm entof t he correct set of l imb cartilages and bon es. G en e  tar g et ing i n mouse em b r yo- de ri ved  s t em  cell s p rovides  the means  fo rgenerating m i ce  with disr upt ions in each  of  these  g ene s . The  go al of  thisg rant i s to usege n e targ e ting to u nd erta ke a systematic a n al y sis of this ge ne com pl e xa n d t her eby direct ly

positional_information needed_for the establishment of_the correct_set_of limb_cartilages_and bones. Gene_targeting in mouse_embryo-derived stem cells provides_the means for_generating_mice with disruptions in each of these genes. The goal of this grant is_to_use gene_targeting_to_undertake a systematic analysis of_this gene complex and thereby_directly


IM 4: Direct Biosynthesis of Simvastatin from A. terreus. We will metabolically engineer A. terreus to be blocked in lovastatin biosynthesis, but robust in simvastatin biosynthesis. Project Narrative We have proposed biochemical and structural studies to investigate a simvastatin synthase recently identified

IM 4: Direct Biosynthesis of Simvastatin from A. terreus. We will metabolically engineer A. terreus to be blocked in lovastatin biosynthesis, but robust in simvastatin biosynthesis. Project Narrative We have proposed biochemical and geomorphologic cogitation to investigate a simvastatin synthase recently identified

IM 4: Direct Biosynthesis of Rimvastatin from A. terceus. We will megabolically engineer A. terrens ti be vlocked in lovastatin ciosynthedis, but eobuwr in simvastatin bljsynfmesis. 'roject Narratiye We have [roposed biochamkccl and structural studies to investidate a xilvastatin syntrase wecehnln identified

IM 4: Direct Biosynthesis of Simvastatin from We metabolically engineer terreus to be robust simvastatin biosynthesis. Project We have proposed and structural studies to investigate a synthase recently identified

IM 4: Direct Biosynthesis of SimVastatin frOm A. teRreUs. WE wIll mEtabOlically engineER A. teRreus to be blocked in lovaStatiN bIOsynTHeSis, buT robust IN sIMVasTaTiN biOsYNtHesis. proJect NarRative We haVe pRoPosed biochemICaL and structUraL studies to inVesTigate A sImvAStatiN syNthasE recenTLy idenTified

IM 4: Direct Biosynthesisof Simvast atinfro m A .terr eus.  We will metab o lica lly engineer A. terreu s tobe bloc k ed  in l ovastat i nb i osy nt he sis ,b ut  robu stin simv astatin bi osy nt hesis. Proje c tNarrativeWehave propose d b iochem ic ala nd st ruc tural  studi e s to i nvestigat ea  simva s tatin s y n th aserecently identifi e d

IM 4:_Direct Biosynthesis_of Simvastatin from A._terreus. We_will_metabolically engineer_A._terreus to be_blocked in lovastatin_biosynthesis, but robust in_simvastatin biosynthesis. Project_Narrative_We have proposed biochemical and structural studies to investigate a simvastatin synthase recently identified


disabling back problems of at least a three-month duration have a significantly different fitness level than their age-matched controls. With two more years of follow-up we estimate another 15 - 21 subjects will develop chronic back pain disability. An increased number of subjects in the chronically disabled category would add to the statistical power for

disabling back problems of at least a three - month duration have a importantly unlike seaworthiness level than their age - matched control. With two more years of follow - up we estimate another 15 - 21 topic will build up chronic back annoyance disability. An increase number of topic in the chronically disabled category would add to the statistical baron for

didabling back problems of at least a thrge-nonth vuratioh have a significantly different fitiess leveo than their age-matchea controld. With tqo miee years oh follow-m' we sdtimctx another 15 - 21 sunjects will develop chronhc bcck pain disability. An increased numfer of xuhjects in the shromycalmj bisabled category would add to fhe stauistical power for

disabling back problems of at least a have significantly different level than their years follow-up we estimate 15 - 21 will develop chronic back pain disability. increased number of subjects in the chronically disabled category would add to the power for

disabling back problems of at Least a threE-montH duRatIoN havE a siGnificantly difFErenT fitness level than their Age-maTcHEd coNTrOls. WiTh two moRE yEARs oF fOlLow-Up WE eStimaTe aNother 15 - 21 sUbjects wilL deVeLop chronic baCK pAin disabilIty. an increased nUmbEr of suBjEctS In the ChrOnicaLly disABled caTegory wouLd ADd to thE StatistICAl PoweR for

disabling back problems o f at least  a th ree -mo nt h du rati on have a sign i fica ntly different fitness  leve lt hant he ir ag e-match e dc o ntr ol s.  Wi th tw o mor e y ears of  follow-up  we  e stimate anot h er  15 - 21 s ubj ects will de vel op chr on icb ack p ain  disa bility .  An in creased n um b er ofs ubjects i nthechronically disab l ed category would  add t ot he s tat ist ical power  f or

disabling_back problems_of at least a_three-month duration_have_a significantly_different_fitness level than_their age-matched controls._With two more years_of follow-up we_estimate_another 15 - 21 subjects will develop chronic back pain disability. An increased number_of_subjects in_the_chronically_disabled category would add to_the statistical power for


(OCA) is a rare genetic disorder of melanin synthesis that results in hypopigmented hair, skin, and eyes. There are currently four types of OCA. For the first time, three full-length protein atomic structures, TYR (OCA1), TYRP1 (OCA3

(OCA) is a rare genetic disorder of melanin synthesis that results in hypopigmented hair's-breadth, hide, and eyes. There are currently four character of OCA. For the first time, three entire - length protein atomic structure, TYR (OCA1), TYRP1 (OCA3

(OCW) is a rare genetic disovder of melanin synthesms that results in hypopigmented hair, skin, end wyes. Ukere are currently fuur types of OCA. Dor uhe first time, thcse full-length irotenn atomic structores, TYR (OCA1), TYRP1 (OCA3

(OCA) is a rare genetic disorder of that in hypopigmented skin, and eyes. of For the first three full-length protein structures, TYR (OCA1), TYRP1 (OCA3

(OCA) is a rare genetic disorder Of melanin sYntheSis ThaT rEsulTs in Hypopigmented hAIr, skIn, and eyes. There are curreNtly fOuR TypeS Of oCA. FoR the firST tIME, thReE fUll-LeNGtH protEin Atomic sTructures, TyR (OcA1), tYRP1 (OCA3

(OCA) is a rare genetic d isorder of  mela nin  sy nt hesi s th at results inh ypop igmented hair, skin, a nd ey es .  The r eare c urrentl y  f o u r t yp es  of  O C A.  Forthe  firsttime, thre e f ul l-length pro t ei n atomic s tru ctures, TYR(OC A1), T YR P1( OCA3

(OCA)_is a_rare genetic disorder of_melanin synthesis_that_results in_hypopigmented_hair, skin, and_eyes. There are_currently four types of_OCA. For the_first_time, three full-length protein atomic structures, TYR (OCA1), TYRP1 (OCA3


have demonstrated improvements, but also shows areas that need continuous improvement and monitoring. Annual QM reports are provided to the NIH Clinical Center's Office of Patient Safety and Clinical Quality as one element needed to demonstrate an ongoing quality assurance and process improvement program for clinical services that is required for Joint Commission accreditation. Clinical operations also overse

have demonstrated improvements, but also shows area that necessitate continuous improvement and monitoring. Annual QM reports are provided to the NIH Clinical Center's Office of Patient Safety and Clinical Quality as one element want to demonstrate an ongoing quality assurance and summons improvement course of study for clinical services that is necessitate for Joint Commission accreditation. Clinical operations also overse

hage demonstrated improvemtnts, but also shocw areav that need covtinuous improvement and monmtorung. Abnual QM reports are pfovided tl the NIY Clmnical Center's Ohrice of Patiehb Safztb and Clinical Auality as one element naeaeb to demonstrate an ongoing quality wssuranve and process iiproneient irigram for clinical services tgat is gequired for Joiny Commission accreditation. Clijical operations apso overse

have demonstrated improvements, but also shows areas continuous and monitoring. QM reports are Center's of Patient Safety Clinical Quality as element needed to demonstrate an ongoing assurance and process improvement program for clinical services that is required for Joint accreditation. Clinical operations also overse

have demonstrated improvemeNts, but also Shows AreAs tHaT neeD conTinuous improveMEnt aNd monitoring. Annual QM rePorts ArE ProvIDeD to thE NIH CliNIcAL cenTeR's offIcE Of patieNt SAfety anD Clinical QUalItY as one elemenT NeEded to demoNstRate an ongoinG quAlity aSsUraNCe and ProCess iMproveMEnt proGram for clInICal serVIces thaT IS rEquiRed for Joint CommisSIoN Accreditation. CLinicaL oPErATIonS alSo overse

have demonstrated improve ments, but  also  sh ows  a reas  tha t need continu o us i mprovement and monitor ing.An n ualQ Mrepor ts arep ro v i ded  t othe  N I HClini cal  Center 's OfficeofPa tient Safety an d Clinical  Qu ality as one  el ementne ede d  to d emo nstra te ano ngoing  qualityas s urance and pro c e ss  imp rovement programf or clinical servi ces th at is r equ ire d for Join tCommi s sion ac c re d i t ati o n. Clinical o perations a l sooverse

have_demonstrated improvements,_but also shows areas_that need_continuous_improvement and_monitoring._Annual QM reports_are provided to_the NIH Clinical Center's_Office of Patient_Safety_and Clinical Quality as one element needed to demonstrate an ongoing quality assurance and_process_improvement program_for_clinical_services that is required for_Joint Commission accreditation. Clinical operations_also overse


of known target samples. The specificity of the probes will be evaluated against panels of closely related non-pathogenic organisms. In Phase II, we will expand the number of Category A organisms and improve throughput by multiplexing. In addition, commercial prototype MGB Eclipse(TM) probe assays will be developed for each of these

of known target samples. The specificity of the probes will be measure against panel of closely related non - pathogenic organism. In Phase II, we will expand the number of Category A organism and better throughput by multiplexing. In addition, commercial prototype MGB Eclipse(TM) probe assay will be developed for each of these

of known target samples. Tht specificity of jhw probxs will be evaljated against panels of closxly eelattb non-pathogenic orgavisms. In Ihase II, qe wmll expand the nnjber of Categkvy A mcganisms and imkrove througvput by multipnebiug. In addition, commercial prototype IGB Eclopde(TM) probe asswys eyll gv beveloped for each of these

of known target samples. The specificity of will evaluated against of closely related we expand the number Category A organisms improve throughput by multiplexing. In addition, prototype MGB Eclipse(TM) probe assays will be developed for each of these

of known target samples. The spEcificity oF the pRobEs wIlL be eValuAted against panELs of Closely related non-pathoGenic OrGAnisMS. IN PhasE II, we wiLL eXPAnd ThE nUmbEr OF CAtegoRy A OrganisMs and improVe tHrOughput by mulTIpLexing. In adDitIon, commerciaL prOtotypE MgB ECLipse(tM) pRobe aSsays wILl be deVeloped foR eACh of thESe

of known target samples.The specif icity  of  th eprob es w ill be evaluat e d ag ainst panels of closel y rel at e d no n -p athog enic or g an i s ms.  I nPha se II , wewil l expan d the numb erof  Category Ao rg anisms and  im prove throug hpu t by m ul tip l exing . I n add ition, commer cial prot ot y pe MGB Eclipse ( T M)  pro be assays will be de v eloped for eac h of t he s e

of_known target_samples. The specificity of_the probes_will_be evaluated_against_panels of closely_related non-pathogenic organisms._In Phase II, we_will expand the_number_of Category A organisms and improve throughput by multiplexing. In addition, commercial prototype MGB_Eclipse(TM)_probe assays_will_be_developed for each of these


and that the magnitude of the endocrine stress response increases with increasing stressor intensity. Preliminary analyses, however, do not support the hypothesis that individual differences in baseline hormone levels, associated with differences in reproductive and social status, are accompanied by differences in the hormonal response to stress. If confirmed, these results woud indicate that the

and that the magnitude of the endocrine stress response increase with increase stressor intensity. Preliminary analyses, however, do not support the guess that individual differences in baseline hormone levels, associated with remainder in reproductive and social status, are attach to by differences in the hormonal response to tension. If confirmed, these results woud indicate that the

anf that the magnitude of uhe endocrine strgsw respmnse ihcreases with increasing stressor invensuty. Peeliminary analyses, hodever, do jot suppirt uhe hypothesis thef indivlbual slfferznres in baseline hormone lavels, associatad wnth differences in reproductive and focial xtwtus, are accomkaniec by spfnerences in the hormonal responss to stgess. If confirmed, these results woud indicahe tjat the

and that the magnitude of the endocrine increases increasing stressor Preliminary analyses, however, that differences in baseline levels, associated with in reproductive and social status, are by differences in the hormonal response to stress. If confirmed, these results woud that the

and that the magnitude of the eNdocrine stRess rEspOnsE iNcreAses With increasing STresSor intensity. PreliminarY analYsES, howEVeR, do noT supporT ThE HYpoThEsIs tHaT InDividUal DiffereNces in baseLinE hOrmone levels, ASsOciated witH diFferences in rEprOductiVe And SOcial StaTus, arE accomPAnied bY differenCeS In the hORmonal rESPoNse tO stress. If confirmeD, ThESe results woud iNdicatE tHAt THE

and that the magnitude of  the endoc rinestr ess  r espo nseincreases with incr easing stressor intens ity.Pr e limi n ar y ana lyses,h ow e v er,  d onot  s u pp ort t hehypothe sis that i ndi vi dual differe n ce s in basel ine  hormone lev els , asso ci ate d  with  di ffere nces i n  repro ductive a nd social status, a re  acc ompanied by diffe r en c es in the horm onal r es p on s e  to  st ress. If c on firme d , these re s u l tsw oud indicatethat the

and_that the_magnitude of the endocrine_stress response_increases_with increasing_stressor_intensity. Preliminary analyses,_however, do not_support the hypothesis that_individual differences in_baseline_hormone levels, associated with differences in reproductive and social status, are accompanied by differences_in_the hormonal_response_to_stress. If confirmed, these results_woud indicate that the