of opsonization and phagocytic killing by neutrophils in vitro and in vivo. The key to resolution of pneumococcal carriage appears to be recognition and uptake by macrophages. It remains unclear how the unique population of upper respiratory tract macrophages recognizes colonizing pneumococci. In specific aim#2, we will identify the macrophage receptor

of opsonization and phagocytic killing by neutrophils in vitro and in vivo. The key to resolution of pneumococcal carriage appear to be realization and uptake by macrophages. It remain indecipherable how the unique population of upper respiratory tract macrophage recognizes colonizing pneumococci. In specific aim#2, we will identify the macrophage sense organ

of opsonization and phagocntic killing by uwutropiils in vitro avd in vivo. The key to resoluvion of pbeumococcal carriage aopears to be recotnitmon and uptake bb macropmcges. Jb remciis unclear how jhe unique pmpulation of u[pdr respiratory tract macrophages recodnizes voponizing pneumjcocbi. In aiegific aim#2, we will identify the mzcrophaje receptor

of opsonization and phagocytic killing by neutrophils and vivo. The to resolution of recognition uptake by macrophages. remains unclear how unique population of upper respiratory tract recognizes colonizing pneumococci. In specific aim#2, we will identify the macrophage receptor

of opsonization and phagocytIc killing bY neutRopHilS iN vitRo anD in vivo. The key tO ResoLution of pneumococcal caRriagE aPPearS To Be recOgnitioN AnD UPtaKe By MacRoPHaGes. It RemAins uncLear how the UniQuE population oF UpPer respiraTorY tract macropHagEs recoGnIzeS ColonIziNg pneUmococCI. In speCific aim#2, wE wILl idenTIfy the mACRoPhagE receptor

of opsonization and phago cytic kill ing b y n eut ro phil s in  vitro and inv ivo.  The key to resolution  of p ne u moco c ca l car riage a p pe a r s t obe  re co g ni tionand  uptake  by macrop hag es . It remains un clear howthe  unique popu lat ion of  u ppe r  resp ira torytractm acroph ages reco gn i zes co l onizing p ne umoc occi. In specific ai m #2, we will id entify  t h em a cro pha ge recepto r

of_opsonization and_phagocytic killing by neutrophils_in vitro_and_in vivo._The_key to resolution_of pneumococcal carriage_appears to be recognition_and uptake by_macrophages._It remains unclear how the unique population of upper respiratory tract macrophages recognizes colonizing_pneumococci._In specific_aim#2,_we_will identify the macrophage receptor


desirability bias and enhance the veracity of self-report, thereby increasing internal and external validity. There is an increase in the risk of bone fracture with aging and adult diabetes, and this increase cannot be solely explained by changes in bone mineral density (BMD). One barrier to new diagnostic tools and treatments is that the

desirability bias and enhance the veracity of self - report, thereby increasing inner and external cogency. There is an increase in the risk of bone fault with aging and adult diabetes, and this increase cannot be solely explain by changes in bone mineral density (BMD). One barrier to fresh diagnostic tools and treatments is that the

dedirability bias and enhakce the veracity of selh-report, thereby increasing internal and extxrnao valudity. There is an incrdase in tje risk if bibe fracturx with annng ahf adblv diabetes, and jhis increasa cannot be soneuy explained by changes in bone minerwl densotj (BMD). One barryer uo gew spannostic tools and treatments is fhat tht

desirability bias and enhance the veracity of increasing and external There is an bone with aging and diabetes, and this cannot be solely explained by changes bone mineral density (BMD). One barrier to new diagnostic tools and treatments is the

desirability bias and enhancE the veraciTy of sElf-RepOrT, theReby Increasing inteRNal aNd external validity. TherE is an InCReasE In The riSk of bonE FrACTurE wItH agInG AnD adulT diAbetes, aNd this incrEasE cAnnot be solelY ExPlained by cHanGes in bone minEraL densiTy (bMD). oNe barRieR to neW diagnOStic toOls and treAtMEnts is THat the

desirability bias and enh ance the v eraci tyofse lf-r epor t, thereby inc r easi ng internal and extern al va li d ity. Th ere i s an in c re a s e i nth e r is k  o f bon e f racture  with agin g a nd  adult diabe t es , and this  in crease canno t b e sole ly  ex p laine d b y cha nges i n  bonemineral d en s ity (B M D). One b ar rier  to new diagnosti c  t o ols and treatm ents i st ha t the

desirability_bias and_enhance the veracity of_self-report, thereby_increasing_internal and_external_validity. There is_an increase in_the risk of bone_fracture with aging_and_adult diabetes, and this increase cannot be solely explained by changes in bone mineral_density_(BMD). One_barrier_to_new diagnostic tools and treatments_is that the


ile acids are secreted by the liver, stored in the gallbladder, and efficiently reabsorbed from the intestine. This enterohepatic cycling is crucial for maintaining the pool of bile acids and for restricting these potentially cytotoxic detergents to specific compartments such as the liver and Gl tract. Many of the transporters that function

ile acids are secreted by the liver, stored in the gallbladder, and efficiently reabsorbed from the intestine. This enterohepatic cycling is all-important for maintain the pool of bile acid and for restrict these potentially cytotoxic detergents to specific compartments such as the liver and Gl nerve pathway. Many of the transporters that function

ile acids are secreted by tme liver, stored nb the jallblasder, and efficiently reabsorbed from tye inuvstine. This enterohepxtic cyclpng is cryciao for maintejning tmz poom of yioe acids and fpr restricding these potangiclly cytotoxic detergents to specifis compattlents such as jhe lpvqr ahd Gl tract. Many of the transporteds that function

ile acids are secreted by the liver, the and efficiently from the intestine. for the pool of acids and for these potentially cytotoxic detergents to specific such as the liver and Gl tract. Many of the transporters that function

ile acids are secreted by the lIver, stored In the GalLblAdDer, aNd efFiciently reabsORbed From the intestine. This enTerohEpATic cYClIng is Crucial FOr MAIntAiNiNg tHe POoL of biLe aCids and For restricTinG tHese potentiaLLy Cytotoxic dEteRgents to specIfiC compaRtMenTS such As tHe livEr and GL Tract. MAny of the tRaNSporteRS that fuNCTiOn

ile acids are secreted bythe liver,  stor edinth e ga llbl adder, and eff i cien tly reabsorbed from th e int es t ine. Th is en terohep a ti c cyc li ng  is  c r uc ial f ormaintai ning the p ool  o f bile acids an d for rest ric ting these p ote ntiall ycyt o toxic  de terge nts to specif ic compar tm e nts su c h as th e li verand Gl tract. Man y  o f  the transport ers th at fu n c tio n

ile acids_are secreted_by the liver, stored_in the_gallbladder,_and efficiently_reabsorbed_from the intestine._This enterohepatic cycling_is crucial for maintaining_the pool of_bile_acids and for restricting these potentially cytotoxic detergents to specific compartments such as the_liver_and Gl_tract._Many_of the transporters that function


(and their corresponding genes) used in the specialized synthesis of silk fibroin by the silkworm, Bombyx mori. This system is particularly suited to studies of the molecular mechanisms controlling transcription, RNA processing, and translation in a developing eukaryote because the fibroin protein, its messenger RNA and certain

(and their corresponding genes) used in the specialized synthesis of silk fibroin by the silkworm, Bombyx mori. This arrangement is peculiarly suited to studies of the molecular mechanism control transcription, RNA processing, and translation in a develop eukaryote because the fibroin protein, its messenger RNA and certain

(anf their corresponding gekes) used in the specialmzed syhthesis uf silk fibroin by the silkwlrn, Bomvyx mori. This system ir particuparly suuted ro studies of the molecumwr mzcianisms controlking transwription, RNA psozedsing, and translation in a developigg eukatylte because thg fibgoyn pdotein, its messenger RNA and certajn

(and their corresponding genes) used in the of fibroin by silkworm, Bombyx mori. to of the molecular controlling transcription, RNA and translation in a developing eukaryote the fibroin protein, its messenger RNA and certain

(and their corresponding geneS) used in the SpeciAliZed SyNtheSis oF silk fibroin by THe siLkworm, Bombyx mori. This syStem iS pARticULaRly suIted to sTUdIES of ThE mOleCuLAr MechaNisMs contrOlling tranScrIpTion, RNA proceSSiNg, and transLatIon in a develoPinG eukarYoTe bECause The FibroIn protEIn, its mEssenger RnA ANd certAIn

(and their correspondinggenes) use d inthe  sp ec iali zedsynthesis of s i lk f ibroin by the silkworm , Bom by x  mor i .Thissystemi sp a rti cu la rly  s u it ed to  st udies o f the mole cul ar  mechanismsc on trolling t ran scription, R NAproces si ng, and t ran slati on ina  devel oping euk ar y ote be c ause th e fi broi n protein, its me s se n ger RNA and ce rtain

(and_their corresponding_genes) used in the_specialized synthesis_of_silk fibroin_by_the silkworm, Bombyx_mori. This system_is particularly suited to_studies of the_molecular_mechanisms controlling transcription, RNA processing, and translation in a developing eukaryote because the fibroin_protein,_its messenger_RNA_and_certain


step in identifying processes by which effective, low- and no-cost strategies can be integrated into the existing YMCA organizational framework to ensure national YMCA Standards are achieved. This application is innovative because it will establish the effectiveness of the Standards using a diffusion-support framework in real-world settings to increase children's

step in identifying processes by which effective, low- and no - cost scheme can be integrate into the existing YMCA organizational framework to ensure home YMCA Standards are achieved. This application is innovative because it will prove the effectiveness of the Standards using a dissemination - support framework in veridical - world settings to increase child's

stfp in identifying procesres by which efywctive, low- ahd no-cosg strategies can be integratxd ibto tye existing YMCA organkzational framewoek ti ensure navjonal YMCA Stzkdardv are achieved. Jhis applicadion is innovadixe because it will establish the effestivenexs of the Standatds uxyng z diffusion-support framework in rezl-world settings to oncrease children's

step in identifying processes by which effective, no-cost can be into the existing national Standards are achieved. application is innovative it will establish the effectiveness of Standards using a diffusion-support framework in real-world settings to increase children's

step in identifying processeS by which efFectiVe, lOw- aNd No-coSt stRategies can be iNTegrAted into the existing YMCa orgaNiZAtioNAl FrameWork to eNSuRE NatIoNaL YMcA sTaNdardS arE achievEd. This applIcaTiOn is innovatiVE bEcause it wiLl eStablish the eFfeCtivenEsS of THe StaNdaRds usIng a diFFusion-Support frAmEWork in REal-worlD SEtTingS to increase childrEN's

step in identifying proce sses by wh ich e ffe cti ve , lo w- a nd no-cost str a tegi es can be integrated i nto t he exis t in g YMC A organ i za t i ona lfr ame wo r kto en sur e natio nal YMCA S tan da rds are achi e ve d. This ap pli cation is in nov ativebe cau s e itwil l est ablish the ef fectivene ss of the Standar d s  u sing  a diffusion-supp o rt framework in r eal-wo rl d  s e t tin gsto increas echild r en's

step_in identifying_processes by which effective,_low- and_no-cost_strategies can_be_integrated into the_existing YMCA organizational_framework to ensure national_YMCA Standards are_achieved._This application is innovative because it will establish the effectiveness of the Standards using_a_diffusion-support framework_in_real-world_settings to increase children's


modernization of its unique animal research resource (ARC) at the CS facility of the CPRC. The CPRC is an unrivaled national and international research resource for comparative studies in the biomedical and behavioral sciences that has received NCRR funding through a P40 award or the equivalent for the past three decades. The

modernization of its unique animal research resource (ARC) at the CS facility of the CPRC. The CPRC is an unrivaled home and external inquiry resource for comparative studies in the biomedical and behavioral sciences that has receive NCRR funding through a P40 award or the equivalent for the past three ten. The

mofernization of its uniqut animal research resourre (ARC) zt the CR facility of the CPRC. The C'RC us an unrivaled national ana internanional rewearrh resource for rkmparatlre sthfies mn the biomedicsl and behdvioral sciencas tkat has received NCRR funding througr a P40 aeagd or the equidaleme fod the past three decades. The

modernization of its unique animal research resource the facility of CPRC. The CPRC international resource for comparative in the biomedical behavioral sciences that has received NCRR through a P40 award or the equivalent for the past three decades. The

modernization of its unique aNimal reseaRch reSouRce (aRc) at tHe CS Facility of the CprC. ThE CPRC is an unrivaled natiOnal aNd INterNAtIonal ResearcH ReSOUrcE fOr ComPaRAtIve stUdiEs in the Biomedical And BeHavioral scieNCeS that has reCeiVed NCRR fundiNg tHrough A P40 AwaRD or thE eqUivalEnt for THe past Three decaDeS. the

modernization of its uniq ue animalresea rch  re so urce  (AR C) at the CS f a cili ty of the CPRC. The CP RC is  a n  unr i va led n ational an d int er na tio na l  r esear chresourc e for comp ara ti ve studies i n  t he biomedi cal  and behavio ral  scien ce s t h at ha s r eceiv ed NCR R  fundi ng throug ha  P40 a w ard ort h eequi valent for the pa s tt hree decades.The

modernization_of its_unique animal research resource_(ARC) at_the_CS facility_of_the CPRC. The_CPRC is an_unrivaled national and international_research resource for_comparative_studies in the biomedical and behavioral sciences that has received NCRR funding through a_P40_award or_the_equivalent_for the past three decades._The


. The effect of the duration of ischemia, the conditions of reperfusion and the degree of catecholamine stimulation on the appearance and disappearance of non-uniformity will be studied. Marval Biosciences Inc. has developed a novel liposomal X-ray contrast agent (NCTX)1. With prior SBIR funding (1

. The effect of the duration of ischemia, the conditions of reperfusion and the degree of catecholamine stimulation on the appearance and fade of non - uniformity will be study. Marval Biosciences Inc. has developed a novel liposomal ten - beam contrast agent (NCTX)1. With anterior SBIR funding (1

. Thf effect of the duration of ischemia, thg xonditmons of reperfurion and the degree of cateciolanine wtimulation on the appdarance ajd disappearence of non-unifocjity will be abudieb. Narval Biosciekces Inc. hav developed a toxep liposomal X-ray contrast agent (NCTV)1. With lrlor SBIR fundigg (1

. The effect of the duration of conditions reperfusion and degree of catecholamine disappearance non-uniformity will be Marval Biosciences Inc. developed a novel liposomal X-ray contrast (NCTX)1. With prior SBIR funding (1

. The effect of the duration of iSchemia, the CondiTioNs oF rEperFusiOn and the degree OF catEcholamine stimulation oN the aPpEAranCE aNd disAppearaNCe OF Non-UnIfOrmItY WiLl be sTudIed. MarvAl BioscienCes inC. has developeD A nOvel liposoMal x-ray contrast AgeNt (NCTX)1. wiTh pRIor SBiR fUndinG (1

. The effect of the durati on of isch emia,  th e c on diti onsof reperfusion andthe degree of catechol amine  s t imul a ti on on  the ap p ea r a nce  a nd  di sa p pe aranc e o f non-u niformitywil lbe studied.M ar val Biosci enc es Inc. hasdev eloped  a  no v el li pos omalX-rayc ontras t agent ( NC T X)1. W i th prio r SB IR f unding (1

. The_effect of_the duration of ischemia,_the conditions_of_reperfusion and_the_degree of catecholamine_stimulation on the_appearance and disappearance of_non-uniformity will be_studied._Marval Biosciences Inc. has developed a novel liposomal X-ray contrast agent (NCTX)1. With prior_SBIR_funding (1


each population's ability to provide this much needed training and therefore makes the proposed cooperative agreement even more important. Environmental toxicants with the ability to directly or indirectly modify the cellular thiols of lymphocytes can initiate immune dysfunctions resulting in increased incidence of infectious diseases, cancer and/or autoimmune diseases. The majority of our analyses will

each population's ability to provide this much needed training and consequently do the proposed cooperative agreement even more authoritative. Environmental poison with the ability to directly or indirectly modify the cellular thiols of lymphocytes can originate immune dysfunctions resulting in increase incidence of infectious diseases, cancer and/or autoimmune diseases. The majority of our analysis will

eafh population's ability tu provide this much nexded trzining avd therefore makes the propodee cookvrative agreement evev more imiortant. Ebviribmental toejcants with tgc abinmty to directly or indirewtly modify tha zeplular thiols of lymphocytes can inytiate omlune dysfunctijns gefultjng in increased incidence of infedtious viseases, cancer and/or autoimmune diseases. The majority of our ajalyses wilo

each population's ability to provide this much and makes the cooperative agreement even the to directly or modify the cellular of lymphocytes can initiate immune dysfunctions in increased incidence of infectious diseases, cancer and/or autoimmune diseases. The majority of analyses will

each population's ability to pRovide this Much nEedEd tRaIninG and Therefore makes THe prOposed cooperative agreeMent eVeN More IMpOrtanT. EnviroNMeNTAl tOxIcAntS wITh The abIliTy to dirEctly or indIreCtLy modify the cELlUlar thiols Of lYmphocytes caN inItiate ImMunE DysfuNctIons rEsultiNG in incReased incIdENce of iNFectiouS DIsEaseS, cancer and/or autoiMMuNE diseases. The maJority Of OUr ANAlySes Will

each population's ability  to provid e thi s m uch  n eede d tr aining and the r efor e makes the proposed c ooper at i ve a g re ement  even m o re i mpo rt an t.En v ir onmen tal  toxica nts with t heab ility to dir e ct ly or indi rec tly modify t hecellul ar  th i ols o f l ympho cytesc an ini tiate imm un e  dysfu n ctionsr e su ltin g in increased in c id e nce of infecti ous di se a se s ,  ca nce r and/or a ut oimmu n e disea s es . T hem ajority of ou r analysesw ill

each_population's ability_to provide this much_needed training_and_therefore makes_the_proposed cooperative agreement_even more important._Environmental toxicants with the_ability to directly_or_indirectly modify the cellular thiols of lymphocytes can initiate immune dysfunctions resulting in increased_incidence_of infectious_diseases,_cancer_and/or autoimmune diseases. The majority_of our analyses will


1 and test their host defense in PA infection. We will also demonstrate that human AM can be activated by AECII and that this translational research may imply the clinical value of the immune AECII. This research will be performed by graduate and undergraduate students. Our efforts are expected to substantially advance understanding of this previously un

1 and test their host defense in PA infection. We will besides attest that human AM can be activated by AECII and that this translational research may entail the clinical value of the immune AECII. This inquiry will be performed by graduate and undergraduate students. Our attempt are expected to substantially boost understanding of this previously un

1 anf test their host defenst in PA infection. We wiln also demonstfate that human AM can be acvivared bt AECII and that this granslatilnal reswarci may imply the rminical value lf tke immune AECII. Jhis researcv will be perfmroeb by graduate and undergraduate studqnts. Out ffforts are exkectec to albwtantially advance understandjng of uhis previously un

1 and test their host defense in We also demonstrate human AM can that translational research may the clinical value the immune AECII. This research will performed by graduate and undergraduate students. Our efforts are expected to substantially advance of this previously un

1 and test their host defense in pA infectioN. We wiLl aLso DeMonsTratE that human AM caN Be acTivated by AECII and that tHis trAnSLatiONaL reseArch may IMpLY The ClInIcaL vALuE of thE imMune AECiI. This reseArcH wIll be performED bY graduate aNd uNdergraduate StuDents. OUr EffORts arE exPecteD to subSTantiaLly advancE uNDerstaNDing of tHIS pReviOusly un

1 and test their host defe nse in PAinfec tio n.We  wil l al so demonstrate that  human AM can be activ atedby AECI I  a nd th at this tr a n sla ti on alre s ea rch m ayimply t he clinica l v al ue of the im m un e AECII. T his  research wi llbe per fo rme d  by g rad uateand un d ergrad uate stud en t s. Our efforts a re  exp ected to substant i al l y advance unde rstand in g  o f thi s p reviouslyun

1 and_test their_host defense in PA_infection. We_will_also demonstrate_that_human AM can_be activated by_AECII and that this_translational research may_imply_the clinical value of the immune AECII. This research will be performed by graduate_and_undergraduate students._Our_efforts_are expected to substantially advance_understanding of this previously un


metabolic disease. PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to elucidate mechanisms through which supplemental L- carnitine improves glucose tolerance in obese and diabetic rodents. Results from the proposed studies are likely to yield new insights regarding the therapeutic properties of L-carnitine, a conditionally

metabolic disease. PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to elucidate mechanisms through which supplemental L- carnitine better glucose permissiveness in obese and diabetic rodents. Results from the project studies are likely to move over modern insights see the therapeutic properties of lambert - carnitine, a conditionally

mehabolic disease. PUBLIC HTALTH RELEVANCE: Tkw overerching goal of this project is to elucidatx mexhaniwms through which suppuemental P- carnitune mmproves glucose tolerangz in knese cnv diabetic rodekts. Results from the propmsdd studies are likely to yield new infights teharding the thgrapeltyc pdoperties of L-carnitine, a conditiohally

metabolic disease. PUBLIC HEALTH RELEVANCE: The overarching this is to mechanisms through which tolerance obese and diabetic Results from the studies are likely to yield new regarding the therapeutic properties of L-carnitine, a conditionally

metabolic disease. PUBLIC HEAlTH RELEVANcE: The OveRarChIng gOal oF this project is TO eluCidate mechanisms througH whicH sUPpleMEnTal L- cArnitinE ImPROveS gLuCosE tOLeRance In oBese and Diabetic roDenTs. results from tHE pRoposed stuDieS are likely to YieLd new iNsIghTS regaRdiNg the TherapEUtic prOperties oF L-CArnitiNE, a condiTIOnAlly

metabolic disease. PUBLIC  HEALTH RE LEVAN CE:  Th eover arch ing goal of th i s pr oject is to elucidatemecha ni s ms t h ro ugh w hich su p pl e m ent al  L - c ar n it ine i mpr oves gl ucose tole ran ce  in obese an d  d iabetic ro den ts. Resultsfro m thepr opo s ed st udi es ar e like l y to y ield newin s ightsr egardin g th e th erapeutic propert i es of L-carnitine , a co nd i ti o n all y

metabolic_disease. PUBLIC_HEALTH RELEVANCE: The overarching_goal of_this_project is_to_elucidate mechanisms through_which supplemental L-_carnitine improves glucose tolerance_in obese and_diabetic_rodents. Results from the proposed studies are likely to yield new insights regarding the_therapeutic_properties of_L-carnitine,_a_conditionally


effort in this area on our part to determine whether, as Jencks has suggested, part of the substrate binding energy can be channeled into driving a later catalytic step, and if so, how it is accomplished. The long term goal of this research is to understand the functional basis for the expression of apolipoprotein

effort in this area on our part to determine whether, as Jencks has suggest, character of the substrate binding energy can be channeled into drive a later catalytic step, and if indeed, how it is achieve. The long condition goal of this research is to sympathize the functional basis for the expression of apolipoprotein

efvort in this area on our part to determnbe whevher, as Jencks fas suggested, part of the suustrqte bunding energy can be cfanneled pnto drivung e later catalytir step, akb if al, hoc mt is accomplismed. The lonc term goal of tfid research is to understand the funstional bwsis for the evprexfion of apolipoprotein

effort in this area on our part whether, Jencks has part of the channeled driving a later step, and if how it is accomplished. The long goal of this research is to understand the functional basis for the expression apolipoprotein

effort in this area on our part To determinE whetHer, As JEnCks hAs suGgested, part of tHE subStrate binding energy can Be chaNnELed iNTo DriviNg a lateR CaTALytIc StEp, aNd IF sO, how iT is AccomplIshed. The loNg tErM goal of this rESeArch is to unDerStand the funcTioNal basIs For THe expResSion oF apoliPOproteIn

effort in this area on ou r part todeter min e w he ther , as  Jencks has su g gest ed, part of the substr ate b in d inge ne rgy c an be c h an n e led  i nt o d ri v in g a l ate r catal ytic step,  an dif so, how i t  i s accompli she d. The longter m goal  o f t h is re sea rch i s to u n dersta nd the fu nc t ionalb asis fo r th e ex pression of apoli p op r otein

effort_in this_area on our part_to determine_whether,_as Jencks_has_suggested, part of_the substrate binding_energy can be channeled_into driving a_later_catalytic step, and if so, how it is accomplished. The long term goal of_this_research is_to_understand_the functional basis for the_expression of apolipoprotein


plan has been established, including coursework and additional training. Taken as a whole, this K08 proposal outlines a robust pathway to scientific independence and the foundation of a successful and sustained career as a physician-scientist. Solid Phase Sciences Corporation (SPSC) proposes to produce a library of substituted acridine and pyr

plan has been established, including coursework and additional education. accept as a whole, this K08 proposal outlines a full-bodied pathway to scientific independence and the foundation garment of a successful and sustained career as a doctor - scientist. Solid Phase Sciences Corporation (SPSC) nominate to produce a library of substitute acridine and pyr

plwn has been established, lncluding coursecirk anv additjonal trxining. Taken as a whole, this K08 propisal outlines a robust pathway no scientufic undependenrs and tmz fouhfatimi of a successfol and sustahned career as a pkysician-scientist. Solid Phase Sciencqs Corpprwtion (SPSC) prokoses eo pdoduce a library of substituted acdidine end pyr

plan has been established, including coursework and Taken a whole, K08 proposal outlines independence the foundation of successful and sustained as a physician-scientist. Solid Phase Sciences (SPSC) proposes to produce a library of substituted acridine and pyr

plan has been established, incLuding courSeworK anD adDiTionAl trAining. Taken as a WHole, This K08 proposal outlines a RobusT pAThwaY To ScienTific inDEpENDenCe AnD thE fOUnDatioN of A succesSful and susTaiNeD career as a phYSiCian-scientIst. solid Phase ScIenCes CorPoRatIOn (SPSc) prOposeS to proDUce a liBrary of suBsTItuted ACridine AND pYr

plan has been established , includin g cou rse wor kandaddi tional trainin g . Ta ken as a whole, this K 08 pr op o salo ut lines  a robu s tp a thw ay  t o s ci e nt ificind ependen ce and the  fo un dation of as uc cessful an d s ustained car eer  as aph ysi c ian-s cie ntist . Soli d  Phase  Sciences  C o rporat i on (SPS C )  p ropo ses to produce al ib r ary of substit uted a cr i di n e  an d p yr

plan_has been_established, including coursework and_additional training._Taken_as a_whole,_this K08 proposal_outlines a robust_pathway to scientific independence_and the foundation_of_a successful and sustained career as a physician-scientist. Solid Phase Sciences Corporation (SPSC) proposes_to_produce a_library_of_substituted acridine and pyr


agile. In keeping with the Comparative Sequencing interests, several years ago NISC implemented an amplicon-based Sanger sequencing pipeline designed to focus on intra-species variation. Numerous clinically relevant projects were designed to amplify and sequence specific genes and regions of interest in small groups of human subjects, yielding great insights into

agile. In keeping with the Comparative Sequencing interests, several days ago NISC follow through an amplicon - based Sanger sequencing pipeline design to focus on intra - species variation. Numerous clinically relevant project were design to amplify and sequence specific gene and region of interest in little groups of human subjects, render great insights into

aglle. In keeping with the Gomparative Sequgnxing iiteresta, severau years ago NISC implemented ab ampoicon-based Sanger sequdncing piieline dewigntd to focus on invda-specicf vadlatiou. Iumerous clinicslly relevdnt projects ward besigned to amplify and sequence spesific grnfs and regions of pneerean ln small groups of human subjecta, yieldpng great insightx into

agile. In keeping with the Comparative Sequencing years NISC implemented amplicon-based Sanger sequencing intra-species Numerous clinically relevant were designed to and sequence specific genes and regions interest in small groups of human subjects, yielding great insights into

agile. In keeping with the CompArative SeqUenciNg iNteReSts, sEverAl years ago NISC IMpleMented an amplicon-based SAnger SeQUencINg PipelIne desiGNeD TO foCuS oN inTrA-SpEcies VarIation. NUmerous cliNicAlLy relevant prOJeCts were desIgnEd to amplify aNd sEquencE sPecIFic geNes And reGions oF IntereSt in small GrOUps of hUMan subjECTs, YielDing great insights INtO

agile. In keeping with th e Comparat ive S equ enc in g in tere sts, several y e arsago NISC implemented a n amp li c on-b a se d San ger seq u en c i ngpi pe lin ed es igned  to  focuson intra-s pec ie s variation. Nu merous cli nic ally relevan t p roject swer e  desi gne d toamplif y  and s equence s pe c ific g e nes and r eg ions  of interest in s m al l  groups of hum an sub je c ts , yie ldi ng great i ns ights into

agile._In keeping_with the Comparative Sequencing_interests, several_years_ago NISC_implemented_an amplicon-based Sanger_sequencing pipeline designed_to focus on intra-species_variation. Numerous clinically_relevant_projects were designed to amplify and sequence specific genes and regions of interest in_small_groups of_human_subjects,_yielding great insights into


1/3 of all B-ALL cases. A safe and effective treatment capable of targeting CRLF2 B-ALL would have a significant health impact in the United States and in Central and South America where rates of CRLF2 B-ALL are even higher. We have discovered a novel biologic that selectively targets the

1/3 of all B - ALL cases. A safe and effective treatment adequate to of target CRLF2 B - ALL would have a significant health impingement in the United States and in Central and South America where rate of CRLF2 B - ALL are even higher. We have discovered a novel biologic that selectively target the

1/3 ov all B-ALL cases. A safe xnd effective tteqtment capabme of tafgeting CRLF2 B-ALL would have a signuficant health impact kn the Unpted Statws aid in Central anv South Americz whexe rates of CRLF2 B-ALL are aven higher. We hxvz discovered a novel biologic that sqlectivrlj targets the

1/3 of all B-ALL cases. A safe treatment of targeting B-ALL would have the States and in and South America rates of CRLF2 B-ALL are even We have discovered a novel biologic that selectively targets the

1/3 of all B-ALL cases. A safe and effEctive treaTment CapAblE oF tarGetiNg CRLF2 B-ALL woulD Have A significant health impaCt in tHe uNiteD stAtes aNd in CenTRaL ANd SOuTh ameRiCA wHere rAteS of CRLF2 b-ALL are eveN hiGhEr. We have discOVeRed a novel bIolOgic that seleCtiVely taRgEts THe

1/3 of all B-ALL cases. A  safe andeffec tiv e t re atme nt c apable of targ e ting  CRLF2 B-ALL would hav e a s ig n ific a nt  heal th impa c ti n  th eUn ite dS ta tes a ndin Cent ral and So uth  A merica where ra tes of CRL F2B-ALL are ev enhigher .Weh ave d isc overe d a no v el bio logic tha ts electi v ely tar g e ts  the

1/3_of all_B-ALL cases. A safe_and effective_treatment_capable of_targeting_CRLF2 B-ALL would_have a significant_health impact in the_United States and_in_Central and South America where rates of CRLF2 B-ALL are even higher. We have_discovered_a novel_biologic_that_selectively targets the


to be associated to the impact of cocaine on HIV persistence; we will use a novel primary cell assay of HIV latency which allows for the first time to measure latency reactivation in multiple T cells subsets. LARA will allow us to confirm in vitro that cocaine and its metabolites can mobilize the above identified pathways and monitor their

to be associated to the impact of cocaine on HIV persistence; we will use a fresh basal cell assay of HIV latency which allow for the beginning time to measure reaction time reactivation in multiple triiodothyronine cells subset. LARA will leave us to confirm in vitro that cocaine and its metabolites can call up the above identified pathways and monitor their

to be associated to the imkact of cocaine ou HIV pxrsistehce; we wkll use a novel primary cell awsay if HIV latency which aulows for the firwt tmme to measure lefency rccctivzbion nn multiple T cekls subsetv. LARA will alnod bs to confirm in vitro that cocaine wnd its mftabolites can mobplyze fhe above identified pathways and jonitor their

to be associated to the impact of HIV we will a novel primary which for the first to measure latency in multiple T cells subsets. LARA allow us to confirm in vitro that cocaine and its metabolites can mobilize above identified pathways and monitor their

to be associated to the impact Of cocaine oN HIV pErsIstEnCe; we Will Use a novel primaRY celL assay of HIV latency whicH alloWs FOr thE FiRst tiMe to meaSUrE LAteNcY rEacTiVAtIon in MulTiple T cElls subsetS. LArA Will allow us tO CoNfirm in vitRo tHat cocaine anD itS metabOlIteS Can moBilIze thE above IDentifIed pathwaYs ANd moniTOr their

to be associated to the i mpact of c ocain e o n H IV  per sist ence; we willu se a  novel primary cell as say o fH IV l a te ncy w hich al l ow s for  t he  fi rs t  t ime t o m easurelatency re act iv ation in mul t ip le T cells  su bsets. LARAwil l allo wust o con fir m invitrot hat co caine and  i t s meta b olitesc a nmobi lize the above id e nt i fied pathwaysand mo ni t or t hei r

to_be associated_to the impact of_cocaine on_HIV_persistence; we_will_use a novel_primary cell assay_of HIV latency which_allows for the_first_time to measure latency reactivation in multiple T cells subsets. LARA will allow us_to_confirm in_vitro_that_cocaine and its metabolites can_mobilize the above identified pathways_and monitor_their


plasticity are well conserved across plants and animals and the plant's adept ability to regenerate will illustrate the full potential of cells to change their identity. The proposal takes advantage of a powerful model system that permits continual imaging of regenerating tissue and the analysis of the transcriptional contents of single cells as they traverse fates. This

plasticity are well conserved across plants and animals and the plant's adept ability to reform will exemplify the entire potential of cells to exchange their identity. The proposal takes advantage of a herculean mannequin system that permit continual imaging of regenerating tissue and the psychoanalysis of the transcriptional contents of single cells as they traverse fortune. This

plwsticity are well conseryed across plants and aiimals znd the olant's adept ability to regeierare wiol illustrate the full potentiap of celos ti change thxjr idenbnty. Tgc pro'owal takes advaktage of a [owerful model shscem that permits continual imaging os regenrrwting tissue agd tnq anzlysis of the transcriptional contsnts of single cells as they traverse fates. Thls

plasticity are well conserved across plants and the adept ability regenerate will illustrate to their identity. The takes advantage of powerful model system that permits continual of regenerating tissue and the analysis of the transcriptional contents of single cells they traverse fates. This

plasticity are well conserveD across plaNts anD anImaLs And tHe plAnt's adept abiliTY to rEgenerate will illustratE the fUlL PoteNTiAl of cElls to cHAnGE TheIr IdEntItY. thE propOsaL takes aDvantage of A poWeRful model sysTEm That permitS coNtinual imagiNg oF regenErAtiNG tissUe aNd the AnalysIS of the TranscripTiONal conTEnts of sINGlE celLs as they traverse fATeS. this

plasticity are well conse rved acros s pla nts  an danim alsand the plant' s  ade pt ability to regenera te wi ll illu s tr ate t he full po t e nti al  o f c el l sto ch ang e their  identity.  Th eproposal tak e sadvantageofa powerful m ode l syst em  th a t per mit s con tinual imagin g of rege ne r atingt issue a n d  t he a nalysis of the tr a ns c riptional cont ents o fs in g l e c ell s as theytr avers e  fates. Th i s

plasticity_are well_conserved across plants and_animals and_the_plant's adept_ability_to regenerate will_illustrate the full_potential of cells to_change their identity._The_proposal takes advantage of a powerful model system that permits continual imaging of regenerating_tissue_and the_analysis_of_the transcriptional contents of single_cells as they traverse fates._This


blood genomic markers of neuronal death associated with acute neurological diseases that might also be useful in chronic neurological diseases. To support the NIH National Center for Biotechnology Information to maintain a national database of genomic and other data sources on resistant bacteria as outlined in the National Action Plan to Combat Antibiotic Resistant Bacteria. This effort addresses the

blood genomic markers of neuronal death consociate with acuate neurological diseases that might also be utilitarian in chronic neurological diseases. To digest the NIH National Center for Biotechnology Information to maintain a national database of genomic and early datum sources on resistant bacteria as outlined in the National Action Plan to Combat Antibiotic Resistant Bacteria. This effort address the

bllod genomic markers of nturonal death associated with zcute nejrological diseases that migit aoso bt useful in chronic neurologpcal diseqses. Ro support the NIH Natiohwl Cznver for Biotechkology Infosmation to maittxiu a national database of genomic and other caha sources on tesisuane badnevia as outlined in the National Zction Klan to Combat Antobiotic Resistant Bacteria. Thid effort addresses the

blood genomic markers of neuronal death associated neurological that might be useful in the National Center for Information to maintain national database of genomic and other sources on resistant bacteria as outlined in the National Action Plan to Combat Resistant Bacteria. This effort addresses the

blood genomic markers of neurOnal death aSsociAteD wiTh AcutE neuRological diseaSEs thAt might also be useful in cHroniC nEUrolOGiCal diSeases. TO SuPPOrt ThE NiH NAtIOnAl CenTer For BiotEchnology INfoRmAtion to maintAIn A national dAtaBase of genomiC anD other DaTa sOUrces On rEsistAnt bacTEria as Outlined iN tHE NatioNAl ActioN pLaN to COmbat Antibiotic ReSIsTAnt Bacteria. ThiS efforT aDDrESSes The

blood genomic markers ofneuronal d eathass oci at ed w ithacute neurolog i caldiseases that might al so be  u s eful in  chro nic neu r ol o g ica ldi sea se s .To su ppo rt theNIH Nation alCe nter for Bio t ec hnology In for mation to ma int ain ana tio n al da tab ase o f geno m ic and  other da ta source s  on res i s ta nt b acteria as outlin e di n the National  Actio nP la n toCom bat Antibi ot ic Re s istantB ac t e r ia. This effort a ddresses th e

blood_genomic markers_of neuronal death associated_with acute_neurological_diseases that_might_also be useful_in chronic neurological_diseases. To support the_NIH National Center_for_Biotechnology Information to maintain a national database of genomic and other data sources on_resistant_bacteria as_outlined_in_the National Action Plan to_Combat Antibiotic Resistant Bacteria. This_effort addresses_the


Program Project. Their presence improves the scientific output from the PPG. The proposed interdisciplinary training program at the University of Minnesota combines graduate training in the computational, chemical, physical, and engineering sciences with graduate training in neuroscience. Neuroscience is a highly interdisciplinary field that uses a variety of experimental approaches to understand the

Program Project. Their presence improves the scientific output from the PPG. The proposed interdisciplinary education platform at the University of Minnesota combines graduate education in the computational, chemical, physical, and technology sciences with graduate education in neuroscience. Neuroscience is a highly interdisciplinary field that uses a variety of experimental approach to understand the

Prlgram Project. Their prestnce improves the scientmfic oufput froo the PPG. The proposed interviscuplinqry training program ag the Uninersity od Miinesota combines graduatc trajking nn the computatipnal, chemiwal, physical, atd eugineering sciences with graduate trwining on neuroscience. Geurpfciehbe is a highly interdisciplinarg field that uses a fariety of experimental aporoafhes to understand the

Program Project. Their presence improves the scientific the The proposed training program at graduate in the computational, physical, and engineering with graduate training in neuroscience. Neuroscience a highly interdisciplinary field that uses a variety of experimental approaches to understand

Program Project. Their presenCe improves The scIenTifIc OutpUt frOm the PPG. The proPOsed Interdisciplinary trainIng prOgRAm at THe univeRsity of mInNESotA cOmBinEs GRaDuate TraIning in The computaTioNaL, chemical, phySIcAl, and enginEerIng sciences wIth GraduaTe TraINing iN neUroscIence. NEUrosciEnce is a hiGhLY interDIscipliNARy FielD that uses a variety OF eXPerimental apprOaches To UNdERStaNd tHe

Program Project. Their pr esence imp roves  th e s ci enti ficoutput from th e  PPG . The proposed interdi scipl in a ry t r ai ningprogram at t heUn iv ers it y  o f Min nes ota com bines grad uat etraining int he  computati ona l, chemical,  ph ysical ,and engin eer ing s cience s  withgraduatetr a iningi n neuro s c ie nce.  Neuroscience isa  h i ghly interdisc iplina ry fi e l d t hat  uses a va ri ety o f  experi m en t a l  ap p roaches to un derstand th e

Program_Project. Their_presence improves the scientific_output from_the_PPG. The_proposed_interdisciplinary training program_at the University_of Minnesota combines graduate_training in the_computational,_chemical, physical, and engineering sciences with graduate training in neuroscience. Neuroscience is a highly_interdisciplinary_field that_uses_a_variety of experimental approaches to_understand the


and oxidation of Dna. Alkylated DNA bases in tissues will be determined by immunostaining and immunoassays and levels of 8-hydroxydeoxyguanosine, as a measure of oxidative DNA damage, will be detected by HPLC with electrochemical detection. Unknown carcinogen spectrometry. Bacterial enzymes responsible for nitrosation

and oxidation of Dna. Alkylated DNA bases in tissues will be determined by immunostaining and immunoassays and degree of 8 - hydroxydeoxyguanosine, as a standard of oxidative DNA damage, will be detected by HPLC with electrochemical signal detection. Unknown carcinogen spectrometry. Bacterial enzymes creditworthy for nitrosation

anf oxidation of Dna. Alkylxted DNA bases nb tissnes wilm be detdrmined by immunostaining anv imnunoawsays and levels of 8-hyaroxydeoxjguanosinw, as q measure of oxidabnve DHW dakege, will be detgcted by HPLW with electrowhdmncal detection. Unknown carcinogen spqctromeyrj. Bacterial eneymes wespknsible for nitrosation

and oxidation of Dna. Alkylated DNA bases will determined by and immunoassays and measure oxidative DNA damage, be detected by with electrochemical detection. Unknown carcinogen spectrometry. enzymes responsible for nitrosation

and oxidation of Dna. AlkylateD DNA bases iN tissUes WilL bE detErmiNed by immunostaINing And immunoassays and leveLs of 8-hYdROxydEOxYguanOsine, as A MeASUre Of OxIdaTiVE DnA damAge, Will be dEtected by HpLC WiTh electrocheMIcAl detectioN. UnKnown carcinoGen SpectrOmEtrY. bacteRiaL enzyMes resPOnsiblE for nitroSaTIon

and oxidation of Dna. Alk ylated DNA  base s i n t is sues  wil l be determine d  byimmunostaining and imm unoas sa y s an d  l evels  of 8-h y dr o x yde ox yg uan os i ne , asa m easureof oxidati veDN A damage, wi l lbe detecte d b y HPLC withele ctroch em ica l  dete cti on. U nknown carcin ogen spec tr o metry. Bacteri a l  e nzym es responsible fo r  n i trosation

and_oxidation of_Dna. Alkylated DNA bases_in tissues_will_be determined_by_immunostaining and immunoassays_and levels of_8-hydroxydeoxyguanosine, as a measure_of oxidative DNA_damage,_will be detected by HPLC with electrochemical detection. Unknown carcinogen spectrometry. Bacterial enzymes responsible_for_nitrosation


situations. Further, environmental (bodily) components may affect the lipid matrix of the phagocytic cell - membrane, triggering release of active oxygen species as shown in vitro. Both these matters could be of importance in vivo in bacterial infections, as may be the implications of the somnogenic activity of muramyl peptides. This

situations. Further, environmental (bodily) components may affect the lipid matrix of the phagocytic cellular telephone - membrane, trip release of active oxygen species as testify in vitro. Both these topic could be of importance in vivo in bacterial infections, as may be the implications of the somnogenic activeness of muramyl peptide. This

sihuations. Further, environoental (bodily) componenvs may zffect tfe lipid matrix of the phagorytix celo - membrane, triggering release lf activw oxbgen species as shown in vitro. Noth chxse matters coukd be of ikportance in vhvu nn bacterial infections, as may be thq implivahions of the sjmnobqnic activity of muramyl peptides. This

situations. Further, environmental (bodily) components may affect matrix the phagocytic - membrane, triggering as in vitro. Both matters could be importance in vivo in bacterial infections, may be the implications of the somnogenic activity of muramyl peptides. This

situations. Further, environmEntal (bodilY) compOneNts MaY affEct tHe lipid matrix oF The pHagocytic cell - membrane, tRiggeRiNG relEAsE of acTive oxyGEn SPEciEs As ShoWn IN vItro. BOth These maTters could Be oF iMportance in vIVo In bacteriaL inFections, as maY be The impLiCatIOns of The SomnoGenic aCTivity Of muramyl PePTides. THIs

situations. Further, envi ronmental(bodi ly)  co mp onen ts m ay affect thel ipid  matrix of the phagocy tic c el l  - m e mb rane,  trigge r in g rel ea se  of  a c ti ve ox yge n speci es as show n i nvitro. Botht he se matters  co uld be of im por tancein  vi v o inbac teria l infe c tions,  as may b et he imp l ication s of  the  somnogenic activ i ty of muramyl pep tides.  T h is

situations._Further, environmental_(bodily) components may affect_the lipid_matrix_of the_phagocytic_cell - membrane,_triggering release of_active oxygen species as_shown in vitro._Both_these matters could be of importance in vivo in bacterial infections, as may be_the_implications of_the_somnogenic_activity of muramyl peptides. This


-stimulated lymphocytes. In preliminary studies the company found a statistically significant difference (p<0.05) in the mean stimulation index of AD patients and cognitively intact controls and was able to identify samples from AD "probable" patients with high sensitivity and selectivity (83% and 96% respectively). However, these early

-stimulated lymphocytes. In preliminary studies the company found a statistically meaning remainder (p<0.05) in the mean stimulation exponent of AD patients and cognitively entire controls and was able to identify sample from AD " probable " patients with high sensitivity and selectivity (83% and 96% respectively). However, these early

-stilulated lymphocytes. In pveliminary studigs the cmmpany found a statistically significant dmffeeence (p<0.05) in the mean stimulagion indeq of AD pqtieits and cognitivxmy intagc confvols cnv was able to icentify sakples from AD "[rubcble" patients with high sensitivity wnd selrchivity (83% and 96% rgspecuivqly). Gowever, these early

-stimulated lymphocytes. In preliminary studies the company statistically difference (p<0.05) the mean stimulation cognitively controls and was to identify samples AD "probable" patients with high sensitivity selectivity (83% and 96% respectively). However, these early

-stimulated lymphocytes. In prEliminary sTudieS thE coMpAny fOund A statistically SIgniFicant difference (p<0.05) in the Mean sTiMUlatIOn Index Of AD patIEnTS And CoGnItiVeLY iNtact ConTrols anD was able to IdeNtIfy samples frOM Ad "probable" pAtiEnts with high SenSitiviTy And SElectIviTy (83% and 96% RespecTIvely). HOwever, theSe EArly

-stimulated lymphocytes. I n prelimin ary s tud ies  t he c ompa ny found a sta t isti cally significant diff erenc e( p<0. 0 5)  in t he mean st i m ula ti on  in de x  o f ADpat ients a nd cogniti vel yintact contr o ls  and was a ble  to identify  sa mplesfr omA D "pr oba ble"patien t s with  high sen si t ivitya nd sele c t iv ity(83% and 96% resp e ct i vely). However , thes ee ar l y

-stimulated lymphocytes._In preliminary_studies the company found_a statistically_significant_difference (p<0.05)_in_the mean stimulation_index of AD_patients and cognitively intact_controls and was_able_to identify samples from AD "probable" patients with high sensitivity and selectivity (83% and_96%_respectively). However,_these_early


enz-density gradient, TPxs I and II showed wide distribution throughout light and heavy membrane structures. Furthermore, we detected a part of TPx proteins in Triton X-100-insoluble membrane fraction. Immunofluorescence staining showed an obvious punctuate pattern of TPx II protein in HeLa cell, similar to endosomal

enz - density gradient, TPxs I and II showed wide distribution throughout light and dense membrane structure. Furthermore, we detected a part of TPx proteins in Triton X-100 - insoluble membrane fraction. Immunofluorescence staining prove an obvious punctuate pattern of TPx II protein in HeLa cell, alike to endosomal

enz-fensity gradient, TPxs I xnd II showed wnee disvributikn throuehout light and heavy membraie srructyres. Furthermore, we degected a iart of TPx pcoteins in Tritoi X-100-insolmyle mslbraue fraction. Immukofluorescetce staining svodeb an obvious punctuate pattern of TPv II prptfin in HeLa cejl, spmylar no endosomal

enz-density gradient, TPxs I and II showed throughout and heavy structures. Furthermore, we proteins Triton X-100-insoluble membrane Immunofluorescence staining showed obvious punctuate pattern of TPx II in HeLa cell, similar to endosomal

enz-density gradient, TPxs I anD II showed wIde diStrIbuTiOn thRougHout light and heAVy meMbrane structures. FurtheRmore, We DEtecTEd A part Of TPx prOTeINS in trItOn X-100-InSOlUble mEmbRane fraCtion. ImmunOflUoRescence staiNInG showed an oBviOus punctuate PatTern of tPX II PRoteiN in heLa cEll, simILar to eNdosomal

enz-density gradient, TPxs  I and IIshowe d w ide  d istr ibut ion throughout ligh t and heavy membrane s truct ur e s. F u rt hermo re, wed et e c ted  a  p art  o f  T Px pr ote ins inTriton X-1 00- in soluble memb r an e fraction . I mmunofluores cen ce sta in ing showe d a n obv ious p u nctuat e pattern  o f  TPx I I  protei n in  HeL a cell, similar t o  e n dosomal

enz-density gradient,_TPxs I_and II showed wide_distribution throughout_light_and heavy_membrane_structures. Furthermore, we_detected a part_of TPx proteins in_Triton X-100-insoluble membrane_fraction._Immunofluorescence staining showed an obvious punctuate pattern of TPx II protein in HeLa cell,_similar_to endosomal


, decrease serum thyroid hormone, and potentially increase serum TSH concentrations. Yet, the relative importance of other factors is unknown. The studies outlined in this proposal will increase the knowledge base in the regulation of thyroid-follicular-cell proliferation and apoptosis, thus, enabling future studies with UDP-GT inducers to accurately

, decrease serum thyroid hormone, and potentially increase serum TSH concentrations. Yet, the relative importance of other divisor is strange. The studies outlined in this proposal will increase the cognition base in the regulation of thyroid - follicular - cellular telephone proliferation and apoptosis, therefore, enabling future studies with UDP - GT inducers to accurately

, defrease serum thyroid horoone, and potentnqlly iicrease serum TRH concentrations. Yet, the reparive umportance of other faztors is lnknown. Tye suudies outlined ii this pvjposzp wino increase the knowledge base in the ragjlction of thyroid-follicular-cell proliseratiom wnd apoptosis, jhus, tnaflinf future studies with UDP-GT induceds to abcurately

, decrease serum thyroid hormone, and potentially TSH Yet, the importance of other outlined this proposal will the knowledge base the regulation of thyroid-follicular-cell proliferation and thus, enabling future studies with UDP-GT inducers to accurately

, decrease serum thyroid hormoNe, and potenTiallY inCreAsE serUm TSh concentrationS. yet, tHe relative importance of Other FaCTors IS uNknowN. The stuDIeS OUtlInEd In tHiS PrOposaL wiLl increAse the knowLedGe Base in the regULaTion of thyrOid-Follicular-ceLl pRolifeRaTioN And apOptOsis, tHus, enaBLing fuTure studiEs WIth UDP-gt induceRS To AccuRately

, decrease serum thyroid h ormone, an d pot ent ial ly  inc reas e serum TSH co n cent rations. Yet, the rela tiveim p orta n ce  of o ther fa c to r s  is  u nk now n. Th e stu die s outli ned in thi s p ro posal will i n cr ease the k now ledge base i n t he reg ul ati o n ofthy roid- follic u lar-ce ll prolif er a tion a n d apopt o s is , th us, enabling futu r es tudies with UD P-GT i nd u ce r s  to  ac curately

, decrease_serum thyroid_hormone, and potentially increase_serum TSH_concentrations._Yet, the_relative_importance of other_factors is unknown._The studies outlined in_this proposal will_increase_the knowledge base in the regulation of thyroid-follicular-cell proliferation and apoptosis, thus, enabling future_studies_with UDP-GT_inducers_to_accurately


development. Also, pregnancis resulting from ovulations from reciprocal orthotopic transplants will be used to study the role of the aging ovary on developmental anomalies. Strabismus is a misalignment of the visual axes which is relatively common in the general population with estimates of 5-6%. When this disorder occurs in

development. Also, pregnancis resulting from ovulations from reciprocal orthotopic transplant will be use to study the role of the aging ovary on developmental anomaly. Strabismus is a misalignment of the visual axes which is relatively coarse in the cosmopolitan population with estimates of 5 - 6% . When this disorder occurs in

degelopment. Also, pregnancir resulting from ovulavions fdom reciorocal orthotopic transplantd qill ve used to study the rule of thv aging ocary in developmental akjmaljcs. Stxauismus is a misslignment mf the visual dxds which is relatively common in the deneral plpulation with estpmwtes of 5-6%. When this disorder occurs in

development. Also, pregnancis resulting from ovulations from transplants be used study the role developmental Strabismus is a of the visual which is relatively common in the population with estimates of 5-6%. When this disorder occurs in

development. Also, pregnancis Resulting fRom ovUlaTioNs From ReciProcal orthotopIC traNsplants will be used to stUdy thE rOLe of THe Aging Ovary on DEvELOpmEnTaL anOmALiEs. StrAbiSmus is a MisalignmeNt oF tHe visual axes WHiCh is relatiVelY common in the GenEral poPuLatIOn witH esTimatEs of 5-6%. WhEN this dIsorder ocCuRS in

development. Also, pregna ncis resul tingfro m o vu lati onsfrom reciproca l  ort hotopic transplants wi ll be  u s ed t o  s tudythe rol e  o f the  a gi ngov a ry  on d eve lopment al anomali es.  S trabismus is amisalignme ntof the visua l a xes wh ic h i s  rela tiv ely c ommoni n thegeneral p op u lation with es t i ma tesof 5-6%. When thi s  d i sorder occursin

development._Also, pregnancis_resulting from ovulations from_reciprocal orthotopic_transplants_will be_used_to study the_role of the_aging ovary on developmental_anomalies. Strabismus is_a_misalignment of the visual axes which is relatively common in the general population with_estimates_of 5-6%._When_this_disorder occurs in


how do family resources influence children's health and development? How do the resources of unmarried parents evolve over time, relative to those of married parents? How do children's genetic endowments interact with their environments to influence their outcomes? What role do social (non- biological) parents play in the lives of children?

how do family resources influence children's health and growth? How do the resource of unmarried parents evolve over time, proportional to those of married parents? How do children's familial endowments interact with their environments to determine their outcomes? What role do social (non- biological) parent play in the lives of child?

hoa do family resources innluence children's healti and dsvelopmevt? How do the resources of uimareied kcrents evolve over tkme, relatpve to thise id married 'zrents? Mjw dk chinvren's genetic ekdowments itteract with tvekr environments to influence their ouecomes? Ehwt role do socyal (mjn- bjological) parents play in the livea of chpldren?

how do family resources influence children's health How the resources unmarried parents evolve of parents? How do genetic endowments interact their environments to influence their outcomes? role do social (non- biological) parents play in the lives of children?

how do family resources influEnce childrEn's heAltH anD dEvelOpmeNt? How do the resoURces Of unmarried parents evolVe oveR tIMe, reLAtIve to Those of MArRIEd pArEnTs? HOw DO cHildrEn's Genetic Endowments IntErAct with their ENvIronments tO inFluence their OutComes? WHaT roLE do soCiaL (non- bIologiCAl) pareNts play in ThE Lives oF ChildreN?

how do family resources i nfluence c hildr en' s h ea lthanddevelopment? H o w do  the resources of unma rried  p a rent s  e volve  over t i me , rel at iv e t ot ho se of  ma rried p arents? Ho w d ochildren's g e ne tic endowm ent s interact w ith  their  e nvi r onmen tsto in fluenc e  their  outcomes ?W hat ro l e do so c i al  (no n- biological) pa r en t s play in thelivesof ch i l dre n?

how_do family_resources influence children's health_and development?_How_do the_resources_of unmarried parents_evolve over time,_relative to those of_married parents? How_do_children's genetic endowments interact with their environments to influence their outcomes? What role do_social_(non- biological)_parents_play_in the lives of children?


N in relation to maternal exposure to smoking and NSAIDs. They will also assess other potential antenatal risk factors and collect and store buccal cell specimens for future analyses. There will be 560 case infants with PPHN and four controls per case (2240). All controls will be drawn from the birth hospitals

N in relation to maternal exposure to smoking and nonsteroidal anti-inflammatory. They will besides tax other likely antenatal hazard factors and collect and store buccal cellular telephone specimens for future analyses. There will be 560 case baby with PPHN and four control per case (2240). All control will be drawn from the birth hospitals

N ij relation to maternal ewposure to smokiut and ISAIDs. Fhey wilu also assess other potentiap qntenqtal risk factors and zollect ajd store bucral cell specimeia for fmcure zkalyszs. There will be 560 case infdnts with PPHN avd four controls per case (2240). All controjs will bf drawn from tre bpreh hkspitals

N in relation to maternal exposure to NSAIDs. will also other potential antenatal store cell specimens for analyses. There will 560 case infants with PPHN and controls per case (2240). All controls will be drawn from the birth hospitals

N in relation to maternal expoSure to smokIng anD NSaIDS. THey wIll aLso assess other POtenTial antenatal risk factoRs and CoLLect ANd Store Buccal cELl SPEciMeNs For FuTUrE analYseS. There wIll be 560 case iNfaNtS with PPHN and FOuR controls pEr cAse (2240). All controLs wIll be dRaWn fROm the BirTh hosPitals

N in relation to maternalexposure t o smo kin g a nd  NSA IDs.  They will als o  ass ess other potential an tenat al risk fa ctors  and co l le c t  an dst ore  b u cc al ce llspecime ns for fut ure  a nalyses. The r ewill be 56 0 c ase infantswit h PPHN  a ndf our c ont rolsper ca s e (224 0). All c on t rols w i ll be d r a wn  fro m the birth hospi t al s

N in_relation to_maternal exposure to smoking_and NSAIDs._They_will also_assess_other potential antenatal_risk factors and_collect and store buccal_cell specimens for_future_analyses. There will be 560 case infants with PPHN and four controls per case_(2240)._All controls_will_be_drawn from the birth hospitals


work will be of practical significant to audiologists in the diagnosis of conductive hearing disorders and to otologists in the surgical correction of abnormalities of the ear. We have instituted routine dynamic Intensity Modulated Radiation Therapy (dIMRT). This is the most complex of IMRT treatments and requires considerable pre-treatment verification to

work will be of practical significant to audiologists in the diagnosis of conductive hearing disorders and to ear doctor in the surgical discipline of abnormality of the ear. We have establish everyday dynamic Intensity Modulated Radiation Therapy (dIMRT). This is the most complex of IMRT treatment and requires considerable pre - treatment verification to

wogk will be of practical rignificant to cydiolojists ih the dixgnosis of conductive hearinj diwordees and to otologists iv the surhical coerecuion of abnormalivjes of bke ead. We kate instituted rputine dyndmic Intensity Mudblated Radiation Therapy (dIMRT). This ys the kodt complex of YMRT ereafments and requires considerable pde-treatkent verificayion to

work will be of practical significant to the of conductive disorders and to of of the ear. have instituted routine Intensity Modulated Radiation Therapy (dIMRT). This the most complex of IMRT treatments and requires considerable pre-treatment verification to

work will be of practical signIficant to aUdiolOgiSts In The dIagnOsis of conductiVE heaRing disorders and to otolOgistS iN The sURgIcal cOrrectiON oF ABnoRmAlItiEs OF tHe ear. we hAve instItuted routIne DyNamic IntensiTY MOdulated RaDiaTion Therapy (diMRt). This iS tHe mOSt comPleX of IMrT treaTMents aNd requireS cONsiderABle pre-tREAtMent Verification to

work will be of practical  significa nt to  au dio lo gist s in  the diagnosis of c onductive hearing diso rders  a n d to ot ologi sts int he s urg ic al  co rr e ct ion o f a bnormal ities of t heea r. We have i n st ituted rou tin e dynamic In ten sity M od ula t ed Ra dia tionTherap y  (dIMR T). Thisis the mo s t compl e x  o f IM RT treatments and re q uires consider able p re - tr e a tme ntverificati on  to

work_will be_of practical significant to_audiologists in_the_diagnosis of_conductive_hearing disorders and_to otologists in_the surgical correction of_abnormalities of the_ear._We have instituted routine dynamic Intensity Modulated Radiation Therapy (dIMRT). This is the most_complex_of IMRT_treatments_and_requires considerable pre-treatment verification to


cytosolic effects of CTA1 activity, but this work will instead utilize a recently developed biochemical assay that directly monitors the CTA1 translocation event. The assay will be used to (i) identify the structural features of CTA1 that are required for translocation to, and persistence in, the cytosol; (ii) identify

cytosolic effects of CTA1 activity, but this work will instead use a recently modernize biochemical assay that directly monitors the CTA1 translocation consequence. The assay will be used to (one) identify the structural feature of speech of CTA1 that are required for translocation to, and persistence in, the cytosol; (ii) name

cyhosolic effects of CTA1 agtivity, but this work wmll insfead utiuize a recently developed bilcyemicql assay that directly monitors the CTA1 traislocation event. The assay wilm be bsxd to (i) identifi the structgral features mf CCA1 that are required for translocatijn to, amd persistence ig, tht crtoskl; (ii) identify

cytosolic effects of CTA1 activity, but this instead a recently biochemical assay that event. assay will be to (i) identify structural features of CTA1 that are for translocation to, and persistence in, the cytosol; (ii) identify

cytosolic effects of CTA1 actiVity, but thiS work WilL inStEad uTiliZe a recently devELopeD biochemical assay that dIrectLy MOnitORs The CTa1 translOCaTIOn eVeNt. the AsSAy Will bE usEd to (i) idEntify the sTruCtUral features OF CtA1 that are rEquIred for transLocAtion tO, aNd pERsistEncE in, thE cytosOL; (ii) ideNtify

cytosolic effects of CTA1  activity,  butthi s w or k wi ll i nstead utilize a re cently developed bioch emica la ssay th at di rectlym on i t ors  t he  CT A1 tr anslo cat ion eve nt. The as say  w ill be usedt o(i) identi fythe structur alfeatur es  of CTA1tha t are  requi r ed for  transloc at i on to, and per s i st ence  in, the cytosol; (i i ) identify

cytosolic_effects of_CTA1 activity, but this_work will_instead_utilize a_recently_developed biochemical assay_that directly monitors_the CTA1 translocation event._The assay will_be_used to (i) identify the structural features of CTA1 that are required for translocation_to,_and persistence_in,_the_cytosol; (ii) identify


interference is a newly discovered genetic mechanism involved in the regulation of gene expression at the post-transcriptional level. The major mode of miRNA action is to target and bind to the 3' un-translated region of specific mRNAs and in doing so, quench expression of that mRNA, thereby acting as a negative regulator of gene

interference is a newly discovered genetic mechanism involved in the rule of gene formula at the post - transcriptional level. The major mode of miRNA legal action is to target and tie down to the 3' un - translated region of specific messenger rna and in doing so, quench expression of that mRNA, thereby dissemble as a negative regulator of gene

inherference is a newly dircovered genetie mechaiism inbolved iv the regulation of gene expcessuon au the post-transcripgional lenel. The mqjor node of miCHA action is fl taxgxt and bind to jhe 3' un-transnated region ox rpzcific mRNAs and in doing so, quench qxpressooj of that mRNA, thegefy adnikg as a negative regulator of gehe

interference is a newly discovered genetic mechanism the of gene at the post-transcriptional miRNA is to target bind to the un-translated region of specific mRNAs and doing so, quench expression of that mRNA, thereby acting as a negative regulator gene

interference is a newly discoVered genetIc mecHanIsm InVolvEd in The regulation oF Gene Expression at the post-traNscriPtIOnal LEvEl. The Major moDE oF MIRNa aCtIon Is TO tArget And Bind to tHe 3' un-translAteD rEgion of speciFIc MRNAs and in DoiNg so, quench exPreSsion oF tHat MrNA, thEreBy actIng as a NEgativE regulatoR oF Gene

interference is a newly d iscoveredgenet icmec ha nism  inv olved in the r e gula tion of gene expressio n atth e  pos t -t ransc ription a ll e vel .Th e m aj o rmodeofmiRNA a ction is t o t ar get and bind to  the 3' un -tr anslated reg ion  of sp ec ifi c  mRNA s a nd in  doing so, qu ench expr es s ion of that mR N A ,ther eby acting as a n e ga t ive regulatorof gen e

interference_is a_newly discovered genetic mechanism_involved in_the_regulation of_gene_expression at the_post-transcriptional level. The_major mode of miRNA_action is to_target_and bind to the 3' un-translated region of specific mRNAs and in doing so,_quench_expression of_that_mRNA,_thereby acting as a negative_regulator of gene


GAA gene in the skeletal muscle {172] and with the intravenous injection of high doses of rhGAA over long periods have shown the remarkable and discouraging finding that unless the enzyme is turned on (controllable transgene) early or the injections are begun early, the stored glycogen in skeletal muscle is only incompletely removed,

GAA gene in the skeletal muscle { 172 ] and with the intravenous injection of high doses of rhGAA over retentive period have shown the remarkable and discouraging finding that unless the enzyme is change state on (controllable transgene) early or the injections are begin early, the stored glycogen in bony muscleman is only incompletely take out,

GAW gene in the skeletal mmscle {172] and with jhw intrevenous injectiun of high doses of rhGAA ovxr ling ptgiods have shown the femarkablv and disxoureging finding thef unless the skzyme ms turned on (coktrollable dransgene) earlf ur the injections are begun early, the stored gpycogen in skejetak musdle is only incompletely removed,

GAA gene in the skeletal muscle {172] the injection of doses of rhGAA the and discouraging finding unless the enzyme turned on (controllable transgene) early or injections are begun early, the stored glycogen in skeletal muscle is only incompletely

GAA gene in the skeletal musclE {172] and with thE intrAveNouS iNjecTion Of high doses of rHgAA oVer long periods have showN the rEmARkabLE aNd disCouragiNG fINDinG tHaT unLeSS tHe enzYme Is turneD on (controlLabLe Transgene) earLY oR the injectIonS are begun earLy, tHe storEd GlyCOgen iN skEletaL musclE Is only IncompletElY RemoveD,

GAA gene in the skeletalmuscle {17 2] an d w ith  t he i ntra venous injecti o n of  high doses of rhGAA o ver l on g  per i od s hav e shown th e rem ar ka ble  a n ddisco ura ging fi nding that  un le ss the enzym e  i s turned o n ( controllable  tr ansgen e)  ea r ly or  th e inj ection s  are b egun earl y, the st o red gly c o ge n in  skeletal musclei so nly incomplete ly rem ov e d,

GAA_gene in_the skeletal muscle {172]_and with_the_intravenous injection_of_high doses of_rhGAA over long_periods have shown the_remarkable and discouraging_finding_that unless the enzyme is turned on (controllable transgene) early or the injections are_begun_early, the_stored_glycogen_in skeletal muscle is only_incompletely removed,


?ned and how activated CD8 T cells eliminate liver stages from the whole liver is not well understood. Another layer of complexity arises as the level of immunity needed for protection depends on a speci?c host-parasite combination. By combining math- ematical modeling and experiments we will provide quantitative insights into

? ned and how activated CD8 T cells eliminate liver stages from the solid liver is not well understand. Another layer of complexity arises as the level of exemption needed for protection count on a speci?c master of ceremonies - parasite combination. By combining math- ematical modeling and experiments we will leave quantitative insights into

?ned and how activated CD8 T gells eliminate liver svages fdom the dhole liver is not well undecstoid. Anither layer of complexkty arised as the levtl of immunity nexsed for protedbion be'ends on a specl?c host-paravite combinatimn. Bv combining math- ematical modeling agd expetilents we will krovicq quzntitative insights into

?ned and how activated CD8 T cells stages the whole is not well arises the level of needed for protection on a speci?c host-parasite combination. By math- ematical modeling and experiments we will provide quantitative insights into

?ned and how activated CD8 T cellS eliminate Liver StaGes FrOm thE whoLe liver is not weLL undErstood. Another layer of cOmpleXiTY ariSEs As the Level of IMmUNIty NeEdEd fOr PRoTectiOn dEpends oN a speci?c hoSt-pArAsite combinaTIoN. By combiniNg mAth- ematical mOdeLing anD eXpeRImentS we Will pRovide QUantitAtive insiGhTS into

?ned and how activated CD8  T cells e limin ate  li ve r st ages  from the whol e  liv er is not well underst ood.An o ther la yer o f compl e xi t y  ar is es  as  t h elevel  of  immuni ty neededfor  p rotection de p en ds on a sp eci ?c host-para sit e comb in ati o n. By  co mbini ng mat h - emat ical mode li n g ande xperime n t swe w ill provide quant i ta t ive insights i nto

?ned and_how activated_CD8 T cells eliminate_liver stages_from_the whole_liver_is not well_understood. Another layer_of complexity arises as_the level of_immunity_needed for protection depends on a speci?c host-parasite combination. By combining math- ematical modeling_and_experiments we_will_provide_quantitative insights into


that obtained by a light microscope. The NHLBI EM Core Facility has supported projects using the following techniques in the past year: 1. Chemical fixation, embedding, ultra-thin sectioning and transmission EM digital imaging of tissues and cell culture. 2. EM immunocytochemistry, including immunogold, nanogold with

that obtained by a light microscope. The NHLBI EM Core Facility has supported projects use the take after techniques in the past year: 1. Chemical fixation, embed, ultra - thin sectioning and infection EM digital imagination of tissues and cell culture. 2. EM immunocytochemistry, including immunogold, nanogold with

thwt obtained by a light mlcroscope. The NHLBI EM Rore Fadility hxs supported projects using vhe dolloqing techniques in the past yeag: 1. Chemicql fmxation, embeddinj, ultra-tmnn sedbioniug and transmisslon EM digidal imaging of tksdues and cell culture. 2. EM immunocytjchemisyrj, including imiunobjld, hanogold with

that obtained by a light microscope. The Core has supported using the following 1. fixation, embedding, ultra-thin and transmission EM imaging of tissues and cell culture. EM immunocytochemistry, including immunogold, nanogold with

that obtained by a light microScope. The NHlBI EM corE FaCiLity Has sUpported projecTS usiNg the following techniquEs in tHe PAst yEAr: 1. chemiCal fixaTIoN, EMbeDdInG, ulTrA-ThIn secTioNing and TransmissiOn Em dIgital imaginG Of Tissues and CelL culture. 2. EM imMunOcytocHeMisTRy, incLudIng imMunogoLD, nanogOld with

that obtained by a lightmicroscope . The  NH LBI  E M Co re F acility has su p port ed projects using thefollo wi n g te c hn iques  in the pa s t  ye ar :1.Ch e mi cal f ixa tion, e mbedding,ult ra -thin sectio n in g and tran smi ssion EM dig ita l imag in g o f  tiss ues  andcell c u lture.  2. EM im mu n ocytoc h emistry , in clud ing immunogold, n a no g old with

that_obtained by_a light microscope. The_NHLBI EM_Core_Facility has_supported_projects using the_following techniques in_the past year: 1._Chemical fixation, embedding,_ultra-thin_sectioning and transmission EM digital imaging of tissues and cell culture. 2. EM immunocytochemistry,_including_immunogold, nanogold_with


effectively treat bone disease in MPS VII, it will be necessary to both normalize GAG turnover and activate requisite osteogenic signaling pathways in epiphyseal cartilage. In Aim 1 we will define temporal and spatial relationships between GAG accumulation and epiphyseal chondrocyte differentiation potential at key stages of bone disease

effectively treat bone disease in MPS VII, it will be necessary to both normalize GAG turnover and trip needed osteogenic bespeak pathways in epiphyseal cartilage. In purpose 1 we will specify temporal and spatial relationships between GAG collection and epiphyseal chondrocyte specialization potential at key stages of bone disease

efvectively treat bone distase in MPS VII, ij qill bx necesaary to coth normalize GAG turnover end qctivqte requisite osteogenkc signalpng pathwqys mn epiphyseal cacfilage. Lu Aim 1 we ciol define temppral and s[atial relatiotsfi's between GAG accumulation and epipryseal vhlndrocyte diffgrentpaeion iouential at key stages of bone dissase

effectively treat bone disease in MPS VII, be to both GAG turnover and in cartilage. In Aim we will define and spatial relationships between GAG accumulation epiphyseal chondrocyte differentiation potential at key stages of bone disease

effectively treat bone diseaSe in MPS VII, It wilL be NecEsSary To boTh normalize GAG TUrnoVer and activate requisitE osteOgENic sIGnAling PathwayS In EPIphYsEaL caRtILaGe. In AIm 1 wE will deFine temporAl aNd Spatial relatIOnShips betweEn GaG accumulatiOn aNd epipHySeaL ChondRocYte diFferenTIation Potential At KEy stagES of bone DISeAse

effectively treat bone di sease in M PS VI I,itwi ll b e ne cessary to bot h  nor malize GAG turnover an d act iv a te r e qu isite  osteog e ni c sig na li ngpa t hw ays i n e piphyse al cartila ge.  I n Aim 1 we w i ll  define te mpo ral and spat ial  relat io nsh i ps be twe en GA G accu m ulatio n and epi ph y seal c h ondrocy t e  d iffe rentiation potent i al at key stagesof bon ed is e a se

effectively_treat bone_disease in MPS VII,_it will_be_necessary to_both_normalize GAG turnover_and activate requisite_osteogenic signaling pathways in_epiphyseal cartilage. In_Aim_1 we will define temporal and spatial relationships between GAG accumulation and epiphyseal chondrocyte_differentiation_potential at_key_stages_of bone disease


immunity at the mucosal epithelium. To establish this, the project consists of two specific aims: 1.) Determine the Hydra viral composition utilizing viral metagenomics. 2.) Elucidate the Hydra antiviral innate immune response in the presence of cytosolic nucleic acids. By accomplishing these two aims we will identify viruses that cause

immunity at the mucosal epithelium. To establish this, the project consists of two specific aim: 1 .) settle the Hydra viral composition utilizing viral metagenomics. 2 .) Elucidate the Hydra antiviral natural immune response in the presence of cytosolic nucleic acid. By achieve these two aims we will name virus that cause

imlunity at the mucosal eplthelium. To estayoish tiis, the project consists of two specific ails: 1.) Dettgmine the Hydra viral compositpon utilizing ciral metajsnomics. 2.) Elucjfate vhe Hydra antivlral innate immune responve iu the presence of cytosolic nucleic wcids. Bu wccomplishing jhese ewo zpmw we will identify viruses thzt caust

immunity at the mucosal epithelium. To establish project of two aims: 1.) Determine viral 2.) Elucidate the antiviral innate immune in the presence of cytosolic nucleic By accomplishing these two aims we will identify viruses that cause

immunity at the mucosal epithElium. To estAblisH thIs, tHe ProjEct cOnsists of two spECifiC aims: 1.) Determine the Hydra Viral CoMPosiTIoN utilIzing viRAl METagEnOmIcs. 2.) elUCiDate tHe HYdra antIviral innaTe iMmUne response iN ThE presence oF cyTosolic nucleIc aCids. By AcComPLishiNg tHese tWo aims WE will iDentify viRuSEs that CAuse

immunity at the mucosal e pithelium.  To e sta bli sh  thi s, t he project con s ists  of two specific aims:  1.)De t ermi n ethe H ydra vi r al c omp os it ion  u t il izing  vi ral met agenomics.  2. )Elucidate th e  H ydra antiv ira l innate imm une  respo ns e i n  thepre sence  of cy t osolic  nucleicac i ds. By accompl i s hi ng t hese two aims wew il l  identify viru ses th at ca u s e

immunity_at the_mucosal epithelium. To establish_this, the_project_consists of_two_specific aims: 1.)_Determine the Hydra_viral composition utilizing viral_metagenomics. 2.) Elucidate_the_Hydra antiviral innate immune response in the presence of cytosolic nucleic acids. By accomplishing_these_two aims_we_will_identify viruses that cause


, models can allow important insights into certain disease mechanisms. The mouse has been chosen because of the rich array of techniques and reagents available only in this species in both immunology and genetics. The Program Project will consist of four Projects and two Cores. Project #1, will focus on the enteric bacterial antigens recognized by

, models can allow important insights into sealed disease mechanism. The mouse has been chosen because of the full-bodied array of proficiency and reagents available only in this coinage in both immunology and genetics. The Program Project will consist of four Projects and two Cores. undertaking # 1, will concentrate on the enteric bacterial antigen recognized by

, mofels can allow important insights into ewrtain diseaae mechavisms. The mouse has been chodeb becquse of the rich array of technpques and reajents available only in bkis slccies mn both immunolpgy and getetics. The Procrxm Project will consist of four Projests and tao Cores. Projest #1, eyll rocus on the enteric bacterial antjgens rtcognized by

, models can allow important insights into mechanisms. mouse has chosen because of and available only in species in both and genetics. The Program Project will of four Projects and two Cores. Project #1, will focus on the enteric antigens recognized by

, models can allow important inSights into CertaIn dIseAsE mecHaniSms. The mouse has BEen cHosen because of the rich aRray oF tEChniQUeS and rEagents AVaILAblE oNlY in ThIS sPecieS in Both immUnology and GenEtIcs. The PrograM prOject will cOnsIst of four ProJecTs and tWo corES. ProjEct #1, Will fOcus on THe enteRic bacterIaL AntigeNS recognIZEd By

, models can allow importa nt insight s int o c ert ai n di seas e mechanisms.T he m ouse has been chosen b ecaus eo f th e  r ich a rray of te c h niq ue sand  r e ag entsava ilableonly in th issp ecies in bot h  i mmunologyand  genetics. T heProgra mPro j ect w ill  cons ist of four P rojects a nd two Co r es. Pro j e ct  #1,  will focus on th e  e n teric bacteria l anti ge n sr e cog niz ed by

, models_can allow_important insights into certain_disease mechanisms._The_mouse has_been_chosen because of_the rich array_of techniques and reagents_available only in_this_species in both immunology and genetics. The Program Project will consist of four Projects_and_two Cores._Project_#1,_will focus on the enteric_bacterial antigens recognized by


been developing to conduct automatic morphing (morphological deformation & matching) of irregular-shaped 3D objects. A virtual average MB will be constructed via statistical characterization of pair-wise morphing among multiple "standard" MBs. Morphometric analysis of distinct MBs and spatial mapping of individual MB neurons will then involve

been developing to conduct automatic morphing (morphological deformation & matching) of atypical - shape 3D objects. A virtual average megabyte will be manufacture via statistical characterization of pair - judicious morphing among multiple " standard " MBs. Morphometric analysis of discrete MBs and spatial mapping of individual bachelor of medicine neurons will then involve

befn developing to conduct automatic morpkung (mocphologjcal defurmation & matching) of irregupae-shaptb 3D objects. A virtuau average MB will be ronstructed via statistigcl chzvactexivation of pair-wlse morphinc among multipne "scandard" MBs. Morphometric analysis of distinvt MBs and spatiwl ms[pinf of individual MB neurons will thsn invonve

been developing to conduct automatic morphing (morphological matching) irregular-shaped 3D A virtual average statistical of pair-wise morphing multiple "standard" MBs. analysis of distinct MBs and spatial of individual MB neurons will then involve

been developing to conduct auTomatic morPhing (MorPhoLoGicaL defOrmation & matchiNG) of iRregular-shaped 3D objects. a virtUaL AverAGe mB wilL be consTRuCTEd vIa StAtiStICaL charActErizatiOn of pair-wiSe mOrPhing among muLTiPle "standarD" MBS. MorphometriC anAlysis Of DisTInct Mbs aNd spaTial maPPing of IndividuaL Mb NeuronS Will theN INvOlve

been developing to conduc t automati c mor phi ng(m orph olog ical deformati o n &matching) of irregular -shap ed 3D o b je cts.A virtu a la v era ge  M B w il l  b e con str ucted v ia statist ica lcharacteriza t io n of pair- wis e morphing a mon g mult ip le" stand ard " MBs . Morp h ometri c analysi so f dist i nct MBs a nd  spa tial mapping of i n di v idual MB neuro ns wil lt he n inv olv e

been_developing to_conduct automatic morphing (morphological_deformation &_matching)_of irregular-shaped_3D_objects. A virtual_average MB will_be constructed via statistical_characterization of pair-wise_morphing_among multiple "standard" MBs. Morphometric analysis of distinct MBs and spatial mapping of individual_MB_neurons will_then_involve


ing underlying mechanisms and translating this information to clinical application by testing a drug treatment strategy for preventing transition to chronic pain We recruit Dr. Surmeier (a world renowned expert on the physiology and reorganization of the striatum) and Dr. Martina (a young scientist with expertise in molecular and electrophysiological studies of the brain),

ing underlying mechanisms and translating this information to clinical lotion by quiz a drug treatment strategy for prevent conversion to chronic pain We recruit Dr. Surmeier (a worldly concern celebrated expert on the physiology and reorganization of the striatum) and Dr. Martina (a young scientist with expertise in molecular and electrophysiological studies of the brain),

ing underlying mechanisms akd translating tkus infmrmatikn to clknical application by testinj a erug ugeatment strategy for preventijg transutioi to chronic paii We recvbit Dd. Surkxier (a world rekowned expest on the physhouoyy and reorganization of the striatui) and Dt. Lartina (a yound scpegtisf with expertise in molecular and slectrokhysiological studoes of the brain),

ing underlying mechanisms and translating this information application testing a treatment strategy for We Dr. Surmeier (a renowned expert on physiology and reorganization of the striatum) Dr. Martina (a young scientist with expertise in molecular and electrophysiological studies of brain),

ing underlying mechanisms anD translatiNg thiS inForMaTion To clInical applicatIOn by Testing a drug treatment sTrateGy FOr prEVeNting TransitIOn TO ChrOnIc PaiN WE ReCruit dr. SUrmeier (A world renoWneD eXpert on the phYSiOlogy and reOrgAnization of tHe sTriatuM) aNd DR. martiNa (a Young ScientISt with Expertise In MOleculAR and eleCTRoPhysIological studies oF ThE Brain),

ing underlying mechanismsand transl ating  th isin form atio n to clinicala ppli cation by testing a dr ug tr ea t ment st rateg y for p r ev e n tin gtr ans it i on  to c hro nic pai n We recru itDr . Surmeier ( a  w orld renow ned  expert on t hephysio lo gya nd re org aniza tion o f  the s triatum)an d  Dr. M a rtina ( a yo ungscientist with ex p er t ise in molecul ar and  e l ec t r oph ysi ological s tu dieso f the b r ai n ) ,

ing underlying_mechanisms and_translating this information to_clinical application_by_testing a_drug_treatment strategy for_preventing transition to_chronic pain We recruit_Dr. Surmeier (a_world_renowned expert on the physiology and reorganization of the striatum) and Dr. Martina (a_young_scientist with_expertise_in_molecular and electrophysiological studies of_the brain),


domains of expertise spanning all aspects of the project, including macrophage biology/immunology, molecular cell biology, computational biology, and cardiovascular disease. They are ideally suited to guide Dr. Ramsey's research and career development as described in the training plan. This mentored career development plan will enable Dr. Ramsey to achieve his career

domains of expertise spanning all aspects of the undertaking, include macrophage biology / immunology, molecular cell biota, computational biology, and cardiovascular disease. They are ideally become to guide Dr. Ramsey's research and career growth as described in the training design. This mentor career development plan will enable Dr. Ramsey to achieve his career

dolains of expertise spannlng all aspects of the 'roject, includivg macrophage biology/immunollgt, moltbular cell biology, cooputationwl bioloty, aid cardiovasculac diseasc. Theg are mdeally suited jo guide Dr. Samsey's researwh aud career development as described ig the ttalning plan. Thif memeores career development plan will enagle Dr. Gamsey to achieve his career

domains of expertise spanning all aspects of including biology/immunology, molecular biology, computational biology, ideally to guide Dr. research and career as described in the training plan. mentored career development plan will enable Dr. Ramsey to achieve his career

domains of expertise spanninG all aspectS of thE prOjeCt, InclUdinG macrophage bioLOgy/iMmunology, molecular cell BioloGy, COmpuTAtIonal Biology, ANd CARdiOvAsCulAr DIsEase. THey Are ideaLly suited tO guIdE Dr. Ramsey's reSEaRch and careEr dEvelopment as DesCribed In The TRainiNg pLan. ThIs mentORed carEer develoPmENt plan WIll enabLE dr. ramsEy to achieve his carEEr

domains of expertise span ning all a spect s o f t he  pro ject , including ma c roph age biology/immunology , mol ec u larc el l bio logy, c o mp u t ati on al  bi ol o gy , and  ca rdiovas cular dise ase .They are ide a ll y suited t o g uide Dr. Ram sey 's res ea rch and c are er de velopm e nt asdescribed  i n  the t r ainingp l an . Th is mentored caree r  d e velopment plan  willen a bl e Dr.  Ra msey to ac hi eve h i s caree r

domains_of expertise_spanning all aspects of_the project,_including_macrophage biology/immunology,_molecular_cell biology, computational_biology, and cardiovascular_disease. They are ideally_suited to guide_Dr._Ramsey's research and career development as described in the training plan. This mentored career_development_plan will_enable_Dr._Ramsey to achieve his career


. Although prevention of diabetes is an important goal, more effective management for individuals already diagnosed with diabetes is also critical for reducing the risks of future complications. Currently, less than one in eight adults with diabetes follow the guidelines for good management;and older adults follow them at even lower rates. Understanding how social relationships (and particularly

. Although prevention of diabetes is an important goal, more effective management for individuals already diagnosed with diabetes is besides critical for reduce the risks of future complications. presently, less than one in eight adults with diabetes play along the guidelines for good management;and old adults follow them at even broken rates. Understanding how social kinship (and particularly

. Alhhough prevention of dianetes is an impottqnt goel, more effectixe management for individuald qlreaey diagnosed with diabdtes is apso critucal dor reduciif the rlfks kn futbrx complications. Currently, less than one iv zight adults with diabetes follow thq guidekijes for good mwnagtmegt;ans older adults follow them at even lower gates. Understandimg how social relationshipd (anf particularly

. Although prevention of diabetes is an more management for already diagnosed with reducing risks of future Currently, less than in eight adults with diabetes follow guidelines for good management;and older adults follow them at even lower rates. Understanding social relationships (and particularly

. Although prevention of diabeTes is an impOrtanT goAl, mOrE effEctiVe management foR IndiViduals already diagnoseD with DiABeteS Is Also cRitical FOr REDucInG tHe rIsKS oF futuRe cOmplicaTions. CurreNtlY, lEss than one in EIgHt adults wiTh dIabetes folloW thE guideLiNes FOr gooD maNagemEnt;and OLder adUlts folloW tHEm at evEN lower rATEs. undeRstanding how sociaL ReLAtionships (and pArticuLaRLy

. Although prevention of d iabetes is  an i mpo rta nt  goa l, m ore effectivem anag ement for individualsalrea dy diag n os ed wi th diab e te s isal so  cr it i ca l for  re ducingthe risksoffu ture complic a ti ons. Curre ntl y, less than  on e in e ig hta dults  wi th di abetes follow  the guid el i nes fo r  good m a n ag emen t;and older adult s  f o llow them at e ven lo we r  r a t es.  Un derstandin ghow s o cial re l at i o n shi p s (and partic ularly

. Although_prevention of_diabetes is an important_goal, more_effective_management for_individuals_already diagnosed with_diabetes is also_critical for reducing the_risks of future_complications._Currently, less than one in eight adults with diabetes follow the guidelines for good_management;and_older adults_follow_them_at even lower rates. Understanding_how social relationships (and particularly


investigator. The Administrative Core of the Program will be responsible for theoverall oversight, organization, and management of the scientific aspects of the COBRE grant. In addition to the scientific oversight, the Core will also provide a number of support services to Program-associated investigators, including fiscal/budgetary management, preparation of

investigator. The Administrative Core of the Program will be responsible for theoverall oversight, organization, and management of the scientific view of the COBRE concession. In addition to the scientific oversight, the Core will besides provide a issue of support services to Program - associate investigators, including fiscal / budgetary management, formulation of

ingestigator. The Administrxtive Core of tkw Progcam wilm be resoonsible for theoverall overditht, oeganization, and manageoent of tje scienrifir aspects of the COBRE gvcnt. Ih addntmon to the sciektific overvight, the Core wklp also provide a number of support fervicex ho Program-assosiattd ynveaninators, including fiscal/budgetary managekent, preparatoon of

investigator. The Administrative Core of the Program responsible theoverall oversight, and management of COBRE In addition to scientific oversight, the will also provide a number of services to Program-associated investigators, including fiscal/budgetary management, preparation of

investigator. The AdministraTive Core of The PrOgrAm wIlL be rEspoNsible for theovERall Oversight, organization, aNd manAgEMent OF tHe sciEntific ASpECTs oF tHe cOBrE GRaNt. In aDdiTion to tHe scientifIc oVeRsight, the CorE WiLl also provIde A number of supPorT serviCeS to pRograM-asSociaTed invEStigatOrs, includInG Fiscal/BUdgetarY MAnAgemEnt, preparation of

investigator. The Adminis trative Co re of  th e P ro gram  wil l be responsib l e fo r theoverall oversight , org an i zati o n,  andmanagem e nt o f t he  s cie nt i fi c asp ect s of th e COBRE gr ant .In additiont othe scient ifi c oversight,  th e Core  w ill alsopro videa numb e r of s upport se rv i ces to Program - a ss ocia ted investigators ,  i n cluding fiscal /budge ta r ym a nag eme nt, prepar at ion o f

investigator._The Administrative_Core of the Program_will be_responsible_for theoverall_oversight,_organization, and management_of the scientific_aspects of the COBRE_grant. In addition_to_the scientific oversight, the Core will also provide a number of support services to_Program-associated_investigators, including_fiscal/budgetary_management,_preparation of


persons at risk for HIV infection. ALIVE-2 has provided critical insight into the dynamics of infection and risk behavior while serving as a comparison group to a parallel cohort of HIV positive IDUs (ALIVE-1, DA04334). Continuation of the ALIVE cohort will allow us to characterize current trends in the

persons at risk for HIV infection. ALIVE-2 has provided critical penetration into the moral force of contagion and risk behavior while serving as a comparison group to a parallel age group of HIV positive IDUs (ALIVE-1, DA04334). Continuation of the ALIVE cohort will give up us to characterize current trends in the

pegsons at risk for HIV innection. ALIVE-2 has provived crifical inright into the dynamics of iifecrion qnd risk behavior whild serving as a conparmson group to a 'zrallel cohorf of KIT positive IDUs (ALIVE-1, DA04334). Wontinuation ox ghz ALIVE cohort will allow us to charwcterizr furrent trends in uhe

persons at risk for HIV infection. ALIVE-2 critical into the of infection and a group to a cohort of HIV IDUs (ALIVE-1, DA04334). Continuation of the cohort will allow us to characterize current trends in the

persons at risk for HIV infectIon. ALIVE-2 haS provIdeD crItIcal InsiGht into the dynaMIcs oF infection and risk behavIor whIlE ServINg As a coMparisoN GrOUP to A pArAllEl COhOrt of hIV PositivE IDUs (ALIVE-1, dA04334). COnTinuation of tHE AlIVE cohort WilL allow us to chAraCterizE cUrrENt treNds In the

persons at risk for HIV i nfection.ALIVE -2has  p rovi dedcritical insig h t in to the dynamics of inf ectio na nd r i sk  beha vior wh i le s erv in gasac om paris ongroup t o a parall elco hort of HIVp os itive IDUs  (A LIVE-1, DA04 334 ). Con ti nua t ion o f t he AL IVE co h ort wi ll allowus to cha r acteriz e cu rren t trends in the

persons_at risk_for HIV infection. ALIVE-2_has provided_critical_insight into_the_dynamics of infection_and risk behavior_while serving as a_comparison group to_a_parallel cohort of HIV positive IDUs (ALIVE-1, DA04334). Continuation of the ALIVE cohort will_allow_us to_characterize_current_trends in the