, the CFTR (-/-) knockout mouse. Interestingly, the CFTR (-/-) mouse did not exhibit a severe CF phenotype in many epithelial tissues, including the airways. Importantly, the absence of a CF phenotype led to the formal identification of the Ca2+-regulated, or "alternative" Cl- conduction

, the CFTR (-/-) knockout mouse. Interestingly, the CFTR (-/-) mouse did not exhibit a severe CF phenotype in many epithelial tissues, include the respiratory tract. Importantly, the absence of a CF phenotype led to the formal identification of the Ca2 + -regulated, or " alternate " Cl- conduction

, thf CFTR (-/-) knockout mouse. Ikterestingly, the CFTR (-/-) kouse sid not dxhibit a severe CF phenotypx in many epithelial tissues, inzluding tje airwats. Inportantly, vge absekee of w CF 'henotype led tp the formdl identificathov lf the Ca2+-regulated, or "alternative" Cj- conduvtlon

, the CFTR (-/-) knockout mouse. Interestingly, (-/-) did not a severe CF including airways. Importantly, the of a CF led to the formal identification of Ca2+-regulated, or "alternative" Cl- conduction

, the CFTR (-/-) knockout mouse. InterEstingly, thE CFTR (-/-) MouSe dId Not eXhibIt a severe CF pheNOtypE in many epithelial tissuEs, incLuDIng tHE aIrwayS. ImportANtLY, The AbSeNce Of A cF PhenoTypE led to tHe formal idEntIfIcation of the cA2+-rEgulated, or "AltErnative" Cl- coNduCtion

, the CFTR (-/-) knockoutmouse. Int erest ing ly,  t he C FTR(-/-) mouse di d  not  exhibit a severe CF p henot yp e  inm an y epi thelial ti s s ues ,in clu di n gthe a irw ays. Im portantly,  th eabsence of a CF  phenotype  le d to the for mal  ident if ica t ion o f t he Ca 2+-reg u lated,  or "alte rn a tive"C l- cond u c ti on

, the_CFTR (-/-)_knockout mouse. Interestingly, the_CFTR (-/-)_mouse_did not_exhibit_a severe CF_phenotype in many_epithelial tissues, including the_airways. Importantly, the_absence_of a CF phenotype led to the formal identification of the Ca2+-regulated, or "alternative"_Cl-_conduction


higher than the young adults exercising at the same absolute intensity (63.4+ 8.2 umol.min-1.kg LBM-1) (p<0.001) but lower than the young adults exercising at the same relative intensity (131.9+ 13.1 umol.min.-

higher than the young adults exercising at the like absolute volume (63.4 + 8.2 umol.min-1.kg LBM-1) (p<0.001) but lower than the young adult practice at the same relative saturation (131.9 + 13.1 umol.min.-

hihher than the young adulus exercising at jhw same absolhte intevsity (63.4+ 8.2 umol.min-1.kg LBM-1) (p<0.001) but poqer tyan the young adults ebercising at the wame eelative iifensity (131.9+ 13.1 umom.lin.-

higher than the young adults exercising at absolute (63.4+ 8.2 LBM-1) (p<0.001) but exercising the same relative (131.9+ 13.1 umol.min.-

higher than the young adults eXercising aT the sAme AbsOlUte iNtenSity (63.4+ 8.2 umol.min-1.kg Lbm-1) (p<0.001) buT lower than the young adulTs exeRcISing AT tHe samE relatiVE iNTEnsItY (131.9+ 13.1 uMol.MiN.-

higher than the young adu lts exerci singatthe  s ameabso lute intensity (63. 4+ 8.2 umol.min-1.kg L BM-1)  ( p <0.0 0 1)  butlower t h an t heyo un g a du l ts  exer cis ing atthe same r ela ti ve intensity (1 31.9+ 13.1  um ol.min.-

higher_than the_young adults exercising at_the same_absolute_intensity (63.4+_8.2_umol.min-1.kg LBM-1) (p<0.001)_but lower than_the young adults exercising_at the same_relative_intensity (131.9+ 13.1 umol.min.-


particular, of novel or poorly-characterized, uncultivated microbial community members. This proposal responds to critical unmet needs posed by the NIH Human Microbiome Project. The following are the Specific Aims of this proposal: Aim 1. To reduce the contribution of environmental DNA to single cell genomic sequence data, and

particular, of novel or poorly - characterized, uncultivated microbial residential district extremity. This proposal responds to critical unmet motivation model by the NIH Human Microbiome Project. The following are the Specific Aims of this proposal: Aim 1. To abridge the contribution of environmental DNA to unmarried cell genomic sequence data, and

pagticular, of novel or poovly-characterized, uncultmvated jicrobiau community members. This pro'osao reskjnds to critical uvmet needd posed vy tie NIH Human Micckbiome Ixojecf. The hollowing are tme Specific Aims of this [ruplsal: Aim 1. To reduce the contributiog of enfigonmental DNA jo simdle dvlo genomic sequence data, and

particular, of novel or poorly-characterized, uncultivated microbial This responds to unmet needs posed Project. following are the Aims of this Aim 1. To reduce the contribution environmental DNA to single cell genomic sequence data, and

particular, of novel or poorly-CharacteriZed, unCulTivAtEd miCrobIal community meMBers. this proposal responds to CritiCaL UnmeT NeEds poSed by thE nIh hUmaN MIcRobIoME PRojecT. ThE followIng are the SPecIfIc Aims of this PRoPosal: Aim 1. To RedUce the contriButIon of eNvIroNMentaL DNa to siNgle ceLL genomIc sequencE dATa, and

particular, of novel or p oorly-char acter ize d,un cult ivat ed microbial c o mmun ity members. This prop osalre s pond s  t o cri tical u n me t nee ds  p ose db ythe N IHHuman M icrobiomePro je ct. The foll o wi ng are the  Sp ecific Aimsofthis p ro pos a l: Ai m 1 . Toreduce the co ntributio no f envi r onmenta l DN A to  single cell geno m ic sequence data,  and

particular,_of novel_or poorly-characterized, uncultivated microbial_community members._This_proposal responds_to_critical unmet needs_posed by the_NIH Human Microbiome Project._The following are_the_Specific Aims of this proposal: Aim 1. To reduce the contribution of environmental DNA_to_single cell_genomic_sequence_data, and


). We propose to determine the amino acid sequence of the porcine relaxin chains and the location of the disulfide bond(s). We then propose to determine that portion of the relaxin molecule responsible for its biological properties--the so-called biologically active site. We propose to locate the tissues responsive to relaxin in the rat

). We propose to determine the amino acid sequence of the porcine relaxin chains and the placement of the disulfide bond(s). We then nominate to determine that portion of the relaxin molecule creditworthy for its biological properties -- the so - called biologically active web site. We aim to locate the tissues responsive to relaxin in the rat

). We propose to determine tht amino acid sequgnxe of vhe pordine relxxin chains and the location od the disulfide bond(s). We thdn proposv to deteemint that portion of the relaxin mkpecunx responsible fpr its bionogical properdids--che so-called biologically active sitq. We prpplse to locate jhe tpsfues gewponsive to relaxin in the raf

). We propose to determine the amino of porcine relaxin and the location then to determine that of the relaxin responsible for its biological properties--the so-called active site. We propose to locate the tissues responsive to relaxin in the

). We propose to determine the amIno acid seqUence Of tHe pOrCine RelaXin chains and thE LocaTion of the disulfide bond(S). We thEn PRopoSE tO deteRmine thAT pORTioN oF tHe rElAXiN moleCulE responSible for itS biOlOgical properTIeS--the so-callEd bIologically aCtiVe site. we ProPOse to LocAte thE tissuES respoNsive to reLaXIn in thE Rat

). We propose to determine  the amino  acid  se que nc e of  the  porcine relax i n ch ains and the locationof th ed isul f id e bon d(s). W e  t h e n p ro po seto de termi nethat po rtion of t here laxin molecu l eresponsibl e f or its biolo gic al pro pe rti e s--th e s o-cal led bi o logica lly activ es ite. W e  propos e to  loc ate the tissues r e sp o nsive to relax in inth e  r a t

). We_propose to_determine the amino acid_sequence of_the_porcine relaxin_chains_and the location_of the disulfide_bond(s). We then propose_to determine that_portion_of the relaxin molecule responsible for its biological properties--the so-called biologically active site. We_propose_to locate_the_tissues_responsive to relaxin in the_rat


Characterization of the molecular interactions between trans-acting and cis-acting elements should lead to the successful isolation of the gene(s) for the relevant trans-acting factor(s). As an extension of these studies, tissue-specific expression will further be investigated in transgenic mouse models. The results from these studies may provide

Characterization of the molecular interactions between trans - acting and cis - acting chemical element should run to the successful isolation of the gene(s) for the relevant trans - acting factor(s). As an extension of these report, tissue - specific formulation will further be investigated in transgenic shiner models. The results from these studies may supply

Chwracterization of the mouecular interacjiins bevween tdans-activg and cis-acting elements shluod leqd to the successful irolation lf the gwne(s) dor the relevant tvcns-acflng fccvor(s). As an exteksion of thase studies, tivsje-dpecific expression will further be investogwted in transggnic kjuse models. The results from these stusies maj provide

Characterization of the molecular interactions between trans-acting elements lead to successful isolation of trans-acting As an extension these studies, tissue-specific will further be investigated in transgenic models. The results from these studies may provide

Characterization of the moleCular interActioNs bEtwEeN traNs-acTing and cis-actiNG eleMents should lead to the suCcessFuL IsolATiOn of tHe gene(s) FOr THE reLeVaNt tRaNS-aCting FacTor(s). As aN extension Of tHeSe studies, tisSUe-Specific exPreSsion will furTheR be invEsTigATed in TraNsgenIc mousE Models. the resultS fROm thesE Studies MAY pRoviDe

Characterization of the m olecular i ntera cti ons  b etwe en t rans-acting an d  cis -acting elements shoul d lea dt o th e  s ucces sful is o la t i onof  t hege n e( s) fo r t he rele vant trans -ac ti ng factor(s) .  A s an exten sio n of these s tud ies, t is sue - speci fic  expr ession will f urther be  i n vestig a ted int r an sgen ic mouse models.T he results from t hese s tu d ie s may  pr ovide

Characterization_of the_molecular interactions between trans-acting_and cis-acting_elements_should lead_to_the successful isolation_of the gene(s)_for the relevant trans-acting_factor(s). As an_extension_of these studies, tissue-specific expression will further be investigated in transgenic mouse models. The_results_from these_studies_may_provide


setting. Mast cells (MCs), granulocytes, and lymphocytes are integral to the development of an allergic response. Allergic inflammation may also be generated through activation of receptors coupled to heterotrimeric G proteins (GPCRs). The purpose of this study is to understand mechanisms of G protein-mediated signal transduction

setting. Mast cells (MCs), granulocytes, and lymphocyte are built-in to the exploitation of an allergic response. Allergic excitement may besides be generated through activation of receptors match to heterotrimeric G proteins (GPCRs). The purpose of this survey is to understand mechanisms of G protein - mediate signal transduction

sehting. Mast cells (MCs), grakulocytes, and lymphocytxs are jntegral to the development of an alpeegic eesponse. Allergic inflxmmation lay also be jenerated througi activabnon or reczpvors coupled to heterotrikeric G proteits (G'CRs). The purpose of this study is to undersyajd mechanisms jf G [rotspn-nediated signal transduction

setting. Mast cells (MCs), granulocytes, and lymphocytes to development of allergic response. Allergic through of receptors coupled heterotrimeric G proteins The purpose of this study is understand mechanisms of G protein-mediated signal transduction

setting. Mast cells (MCs), granulOcytes, and lYmphoCytEs aRe InteGral To the developmeNT of aN allergic response. AllerGic inFlAMmatIOn May alSo be genERaTED thRoUgH acTiVAtIon of RecEptors cOupled to heTerOtRimeric G protEInS (GPCRs). The pUrpOse of this stuDy iS to undErStaND mechAniSms of g proteIN-mediaTed signal TrANsductIOn

setting. Mast cells (MCs) , granuloc ytes,  an d l ym phoc ytes  are integralt o th e development of an al lergi cr espo n se . All ergic i n fl a m mat io nmay  a l so  be g ene rated t hrough act iva ti on of recept o rs  coupled t o h eterotrimeri c G  prote in s ( G PCRs) . T he pu rposeo f this  study is  t o  under s tand me c h an isms  of G protein-med i at e d signal trans ductio n

setting._Mast cells_(MCs), granulocytes, and lymphocytes_are integral_to_the development_of_an allergic response._Allergic inflammation may_also be generated through_activation of receptors_coupled_to heterotrimeric G proteins (GPCRs). The purpose of this study is to understand mechanisms_of_G protein-mediated_signal_transduction


administration as an effective treatment for reducing mortality and morbidity from OP SE. This is a response to RFA # RFA-AG-09-002. The major goals of the proposal are to: (1) Identify biomarkers that are associated with progression from normal cognitive status to mild cognitive impairment (MCI) or

administration as an effective treatment for reducing mortality and unwholesomeness from OP SE. This is a reception to RFA # RFA - AG-09 - 002. The major goals of the proposal are to: (1) name biomarkers that are associated with progress from normal cognitive status to mild cognitive damage (MCI) or

adlinistration as an effecuive treatment fot eeduciig mortzlity ana morbidity from OP SE. This ms a respinse to RFA # RFA-AG-09-002. The major gowls of tye pcoposal are to: (1) Msentify biomadners vhat are associsted with [rogression frmm nlrmal cognitive status to mild cognytive ikpwirment (MCI) or

administration as an effective treatment for reducing morbidity OP SE. is a response major of the proposal to: (1) Identify that are associated with progression from cognitive status to mild cognitive impairment (MCI) or

administration as an effectiVe treatmenT for rEduCinG mOrtaLity And morbidity frOM OP Se. This is a response to RFA # RfA-AG-09-002. THe MAjor GOaLs of tHe propoSAl ARE to: (1) idEnTifY bIOmArkerS thAt are asSociated wiTh pRoGression from NOrMal cognitiVe sTatus to mild cOgnItive iMpAirMEnt (MCi) or

administration as an effe ctive trea tment  fo r r ed ucin g mo rtality and mo r bidi ty from OP SE. This is  a re sp o nset oRFA #  RFA-AG - 09 - 0 02.  T he  ma jo r  g oalsofthe pro posal areto:  ( 1) Identifyb io markers th atare associat edwith p ro gre s sionfro m nor mal co g nitive  status t om ild co g nitivei m pa irme nt (MCI) or

administration_as an_effective treatment for reducing_mortality and_morbidity_from OP_SE._This is a_response to RFA_# RFA-AG-09-002. The major_goals of the_proposal_are to: (1) Identify biomarkers that are associated with progression from normal cognitive status_to_mild cognitive_impairment_(MCI)_or


the ability to significantly improve the speed and reliability of TAA growth analysis, facilitate the communication of aortic growth assessment between radiologists, care-providers and patients, and generate new biomarkers of disease progression that can be used to improve patient management decisions, and ultimately patient outcomes. In this grant effort, we propose to achieve

the ability to significantly improve the speed and reliability of TAA increase psychoanalysis, facilitate the communication of aortic increase judgment between radiologists, care - provider and affected role, and generate fresh biomarkers of disease progression that can be used to better patient management decisions, and ultimately patient outcomes. In this concession effort, we propose to achieve

thf ability to significantuy improve the speed aid relizbility uf TAA growth analysis, facilmtatw the communication of aortkc growth assessmwnt uetween radiologmats, carc-'roviscrs aud patients, and nenerate nef biomarkers ox aidease progression that can be used eo imprpvf patient manadememe dedpslons, and ultimately patient outckmes. In this grant egfort, we propose to achievf

the ability to significantly improve the speed of growth analysis, the communication of care-providers patients, and generate biomarkers of disease that can be used to improve management decisions, and ultimately patient outcomes. In this grant effort, we propose to

the ability to significantly Improve the Speed And RelIaBiliTy of tAA growth analySIs, faCilitate the communicatiOn of aOrTIc grOWtH asseSsment bETwEEN raDiOlOgiStS, CaRe-proVidErs and pAtients, and GenErAte new biomarKErS of disease ProGression that Can Be used To ImpROve paTieNt manAgemenT DecisiOns, and ultImATely paTIent outCOMeS. In tHis grant effort, we pROpOSe to achieve

the ability to significan tly improv e the  sp eed  a nd r elia bility of TAAg rowt h analysis, facilitate  theco m muni c at ion o f aorti c  g r o wth  a ss ess me n tbetwe enradiolo gists, car e-p ro viders and p a ti ents, andgen erate new bi oma rkersof  di s easepro gress ion th a t canbe used t oi mprove patient m an agem ent decisions, an d  u l timately patie nt out co m es . Inthi s grant ef fo rt, w e  propos e  t o a chi e ve

the_ability to_significantly improve the speed_and reliability_of_TAA growth_analysis,_facilitate the communication_of aortic growth_assessment between radiologists, care-providers_and patients, and_generate_new biomarkers of disease progression that can be used to improve patient management decisions,_and_ultimately patient_outcomes._In_this grant effort, we propose_to achieve


strengths, durations, frequency of application, biases, and spatial complexities both within and across movements. The variability of these perturbations will generate a template with which we will identify subtleties in trial-by-trial adaptation. These interrogations, coupled with novel state space analyses, will enable a thorough understanding of the transformation of

strengths, durations, frequency of application, biases, and spatial complexity both within and across movement. The variability of these perturbations will render a template with which we will name subtleties in trial - by - trial adaptation. These question, coupled with novel state of matter space analyses, will enable a exhaustive understanding of the transformation of

stgengths, durations, frequekcy of application, biasxs, and apatial zomplexities both within and axross movements. The variabiuity of tjese perrurbetions will geneczte a tciplafc witk xhich we will icentify suttleties in trhau-bv-trial adaptation. These interrogatiogs, coupkef with novel sjate x[ace analyses, will enable a thorough uhderstaiding of the trsnsformation of

strengths, durations, frequency of application, biases, and both and across The variability of template which we will subtleties in trial-by-trial These interrogations, coupled with novel state analyses, will enable a thorough understanding of the transformation of

strengths, durations, frequenCy of applicAtion, BiaSes, AnD spaTial Complexities boTH witHin and across movements. THe varIaBIlitY Of These PerturbATiONS wiLl GeNerAtE A tEmplaTe wIth whicH we will ideNtiFy Subtleties in TRiAl-by-trial aDapTation. These iNteRrogatIoNs, cOUpled WitH noveL state SPace anAlyses, wilL eNAble a tHOrough uNDErStanDing of the transforMAtIOn of

strengths, durations, fre quency ofappli cat ion ,bias es,and spatial co m plex ities both within andacros sm ovem e nt s. Th e varia b il i t y o fth ese  p e rt urbat ion s willgenerate a  te mp late with wh i ch  we will i den tify subtlet ies  in tr ia l-b y -tria l a dapta tion.T hese i nterrogat io n s, cou p led wit h no velstate space analy s es ,  will enable a  thoro ug h  u n d ers tan ding of th etrans f ormatio n  o f

strengths,_durations, frequency_of application, biases, and_spatial complexities_both_within and_across_movements. The variability_of these perturbations_will generate a template_with which we_will_identify subtleties in trial-by-trial adaptation. These interrogations, coupled with novel state space analyses, will_enable_a thorough_understanding_of_the transformation of


CRH expression by cAMP is markedly dependent on downstream elements in the CRH gene. Stimulation of cAMP production by forskolin increased luciferase activity driven by the CRH-promoter. This was caused by increases in transcription, shown by nuclear run-on-assay, as well as increases in mRNA stability and translation

CRH expression by cAMP is markedly dependent on downstream elements in the CRH gene. foreplay of clique output by forskolin increased luciferase natural process drive by the CRH - promoter. This was caused by increase in recording, shown by nuclear test - on - assay, as well as increases in mRNA constancy and translation

CRJ expression by cAMP is oarkedly dependgnr on dmwnstrsam elemdnts in the CRH gene. Stimulavion of cQMP production by forsyolin incgeased luxifecase activity drmben by bke CRG-iromocec. This was causgd by increaves in transcrhpgiln, shown by nuclear run-on-assay, as wqll as onfreases in mRNW stsfilifj cnd translation

CRH expression by cAMP is markedly dependent elements the CRH Stimulation of cAMP activity by the CRH-promoter. was caused by in transcription, shown by nuclear run-on-assay, well as increases in mRNA stability and translation

CRH expression by cAMP is markEdly dependEnt on DowNstReAm elEmenTs in the CRH gene. sTimuLation of cAMP production By forSkOLin iNCrEased LuciferASe ACTivItY dRivEn BY tHe CRH-ProMoter. ThIs was causeD by InCreases in traNScRiption, shoWn bY nuclear run-oN-asSay, as wElL as INcreaSes In mRNa stabiLIty and TranslatiOn

CRH expression by cAMP is  markedlydepen den t o ndown stre am elements in theCRH gene. Stimulationof cA MP prod u ct ion b y forsk o li n inc re as edlu c if erase  ac tivitydriven bythe  C RH-promoter. Th is was cau sed  by increase s i n tran sc rip t ion,sho wn by  nucle a r run- on-assay,  a s  wella s incre a s es  inmRNA stability an d  t r anslation

CRH_expression by_cAMP is markedly dependent_on downstream_elements_in the_CRH_gene. Stimulation of_cAMP production by_forskolin increased luciferase activity_driven by the_CRH-promoter._This was caused by increases in transcription, shown by nuclear run-on-assay, as well as_increases_in mRNA_stability_and_translation


the admissions were for a pregnancy complication, primarily threatened abortion or early labor. Median length of stay for all admissions was 12 days. The ratio of admissions to deliveries was 52 per 100.The Ukrainian ratio of hospitalizations to deliveries is notably higher than any that have been published in studies from the United States and Australia, reflecting

the admissions were for a pregnancy complication, primarily threatened miscarriage or early british labour party. Median length of arrest for all admissions was 12 sidereal day. The ratio of admissions to pitch was 52 per 100.The Ukrainian ratio of hospitalizations to delivery is notably higher than any that have been published in report from the United States and Australia, reflecting

thf admissions were for a kregnancy compliccrion, pcimarilg threatdned abortion or early labor. Mwdian length of stay for alu admissilns was 12 dayw. The ratio of admissions bo denmveries was 52 pet 100.The Ukrainhan ratio of hmsoicalizations to deliveries is notably higher tjan any that hwve nqen llboished in studies from the Unjted Stetes and Austrakia, reflecting

the admissions were for a pregnancy complication, abortion early labor. length of stay days. ratio of admissions deliveries was 52 100.The Ukrainian ratio of hospitalizations to is notably higher than any that have been published in studies from the States and Australia, reflecting

the admissions were for a pregNancy complIcatiOn, pRimArIly tHreaTened abortion oR EarlY labor. Median length of stAy for AlL AdmiSSiOns waS 12 days. ThE RaTIO of AdMiSsiOnS To DelivEriEs was 52 peR 100.The UkrainIan RaTio of hospitaLIzAtions to deLivEries is notabLy hIgher tHaN anY That hAve Been pUblishED in stuDies from tHe uNited STAtes and aUStRaliA, reflecting

the admissions were for a  pregnancy  comp lic ati on , pr imar ily threatened abor tion or early labor. M edian  l e ngth of  stay  for al l  a d m iss io ns  wa s1 2days.  Th e ratio  of admiss ion sto deliverie s  w as 52 per100 .The Ukraini anratioof  ho s pital iza tions  to de l iverie s is nota bl y  highe r  than a n y  t hathave been publish e di n studies from  the U ni t ed S tat esand Austra li a, re f lecting

the_admissions were_for a pregnancy complication,_primarily threatened_abortion_or early_labor._Median length of_stay for all_admissions was 12 days._The ratio of_admissions_to deliveries was 52 per 100.The Ukrainian ratio of hospitalizations to deliveries is notably_higher_than any_that_have_been published in studies from_the United States and Australia,_reflecting


functional magnetic resonance imaging), and MRS (magnetic resonance spectroscopy). These imaging methodologies offer real promise for the expanded clinical utility of neuroimaging in the diagnosis, treatment, and understanding of the pathophysiology of major neuropsychiatric disorders. However, these new methodologies typically derive from complex, multidisciplinary sciences, which thereby create a challenging information barrier

functional magnetic resonance imaging), and MRS (charismatic plangency spectroscopy). These imaging methodologies extend substantial promise for the expanded clinical utility of neuroimaging in the diagnosis, discussion, and understanding of the pathophysiology of major neuropsychiatric disorders. However, these new methodology typically derive from complex, multidisciplinary sciences, which thereby produce a challenging information barrier

funftional magnetic resonange imaging), and MTS (magnevic resknance soectroscopy). These imaging mevhodilogitf offer real promire for thv expandee clmnical utility oh neuroimaging ln thz viagnosis, treatkent, and utderstanding ox ghz pathophysiology of major neuropsycriatric dlsorders. Howevgr, thtse new methodologies typically derive frkm compnex, multidiscoplinary sciences, which thfrebj create a challenhing informqtiog barrier

functional magnetic resonance imaging), and MRS (magnetic These methodologies offer promise for the in diagnosis, treatment, and of the pathophysiology major neuropsychiatric disorders. However, these new typically derive from complex, multidisciplinary sciences, which thereby create a challenging information barrier

functional magnetic resonanCe imaging), aNd MRS (MagNetIc ResoNancE spectroscopy). THEse iMaging methodologies offEr reaL pROmisE FoR the eXpanded CLiNICal UtIlIty Of NEuRoimaGinG in the dIagnosis, trEatMeNt, and understANdIng of the paThoPhysiology of MajOr neurOpSycHIatriC diSordeRs. HoweVEr, thesE new methoDoLOgies tYPically DERiVe frOm complex, multidisCIpLInary sciences, wHich thErEBy CREatE a cHallenging InFormaTIon barrIEr

functional magnetic resona nce imagin g), a ndMRS  ( magn etic  resonance spe c tros copy). These imaging m ethod ol o gies of fer r eal pro m is e for  t he  ex pa n de d cli nic al util ity of neu roi ma ging in thed ia gnosis, tr eat ment, and un der standi ng  of the p ath ophys iology of maj or neurop sy c hiatri c  disord e r s.  How ever, these new m e th o dologies typic ally d er i ve f rom  co mplex, mul ti disci p linarys ci e n c es, which thereby  create a c h all enging  i nfo r mation  barr ie r

functional magnetic_resonance imaging),_and MRS (magnetic resonance_spectroscopy). These_imaging_methodologies offer_real_promise for the_expanded clinical utility_of neuroimaging in the_diagnosis, treatment, and_understanding_of the pathophysiology of major neuropsychiatric disorders. However, these new methodologies typically derive from_complex,_multidisciplinary sciences,_which_thereby_create a challenging information barrier


sequelae of gonorrhea in women include infertility, ectopic pregnancy and chronic pelvic pain. Neisseria gonorrhoeae (Ng), the causative agent of gonorrhea, has become resistant to almost every antibiotic in clinical use. Resistance to ceftriaxone and azithromycin? the recommended first

sequelae of gonorrhea in women include infertility, ectopic pregnancy and chronic pelvic pain. Neisseria gonorrhoeae (Ng), the causative agentive role of gonorrhea, has become insubordinate to almost every antibiotic in clinical use. underground to ceftriaxone and azithromycin? the commend first

seeuelae of gonorrhea in wumen include inywrtilivy, ectolic pregvancy and chronic pelvic paii. Neusserua gonorrhoeae (Ng), the zausative agent od goiorrhea, has become resisbcnt tk almmwt every antiblotic in clhnical use. Reshsgauce to ceftriaxone and azithromycin? ehe recpmlended first

sequelae of gonorrhea in women include infertility, and pelvic pain. gonorrhoeae (Ng), the become to almost every in clinical use. to ceftriaxone and azithromycin? the recommended

sequelae of gonorrhea in womeN include inFertiLitY, ecToPic pRegnAncy and chronic PElviC pain. Neisseria gonorrhoEae (Ng), ThE CausATiVe ageNt of gonORrHEA, haS bEcOme ReSIsTant tO alMost eveRy antibiotIc iN cLinical use. ReSIsTance to cefTriAxone and azitHroMycin? tHe RecOMmendEd fIrst

sequelae of gonorrhea inwomen incl ude i nfe rti li ty,ecto pic pregnancya nd c hronic pelvic pain. Ne isser ia gono r rh oeae(Ng), t h ec a usa ti ve  ag en t  o f gon orr hea, ha s become r esi st ant to almos t  e very antib iot ic in clinic aluse. R es ist a nce t o c eftri axonea nd azi thromycin ?t he rec o mmended f ir st

sequelae_of gonorrhea_in women include infertility,_ectopic pregnancy_and_chronic pelvic_pain._Neisseria gonorrhoeae (Ng),_the causative agent_of gonorrhea, has become_resistant to almost_every_antibiotic in clinical use. Resistance to ceftriaxone and azithromycin? the recommended first


for the production of murine monoclonal antibodies. Several hundred hybridomas have been shown to bind to the transition-state analog used for immunization and several of these show differential binding to the transition-state analog vs the original-sequence peptide. Research within the Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, continues

for the production of murine monoclonal antibodies. Several hundred hybridomas have been shown to oblige to the passage - state analog used for immunization and respective of these show differential binding to the transition - state of matter analog vs the original - sequence peptide. inquiry within the Laboratory for Integrative Neuroscience, incision on Synaptic Pharmacology, continues

fog the production of murike monoclonal anjivodies. Severzl hundrdd hybridomas have been showi to bind to the transition-statd analog lsed for ummuiization and sevxdal of bkese amow dnfherential bindikg to the tsansition-state avapog vs the original-sequence peptide. Researvh within the Laforauorr fod Integrative Neuroscience, Section on Syneptic Pharmacolpgy, continues

for the production of murine monoclonal antibodies. hybridomas been shown bind to the and of these show binding to the analog vs the original-sequence peptide. Research the Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, continues

for the production of murine mOnoclonal aNtiboDieS. SeVeRal hUndrEd hybridomas haVE beeN shown to bind to the transItion-StATe anALoG used For immuNIzATIon AnD sEveRaL Of These ShoW differEntial bindIng To The transitioN-StAte analog vS thE original-seqUenCe peptIdE. ReSEarch WitHin thE LaborATory foR IntegratIvE neurosCIence, SeCTIoN on SYnaptic PharmacoloGY, cONtinues

for the production of mur ine monocl onalant ibo di es.Seve ral hundred hy b rido mas have been shown to  bind  t o  the tr ansit ion-sta t ea n alo gus edfo r  i mmuni zat ion and  several o f t he se show diff e re ntial bind ing  to the tran sit ion-st at e a n alogvsthe o rigina l -seque nce pepti de .  Resea r ch with i n  t he L aboratory for Int e gr a tive Neuroscie nce, S ec t io n onSyn aptic Phar ma colog y , conti n ue s

for_the production_of murine monoclonal antibodies._Several hundred_hybridomas_have been_shown_to bind to_the transition-state analog_used for immunization and_several of these_show_differential binding to the transition-state analog vs the original-sequence peptide. Research within the Laboratory_for_Integrative Neuroscience,_Section_on_Synaptic Pharmacology, continues


that the v-sis oncogene encodes a PDGF-related product whose transforming activity requires functional interaction with the PDGF receptor has suggested the importance of identifying the active site of the v-sis translational product. Site-directed mutagenesis of v-sis has localized an 89 codon stretch as its minimum transforming region and has shown

that the v - sis oncogene encodes a PDGF - related product whose transforming natural process command functional interaction with the PDGF receptor has suggested the importance of name the active site of the v - sis translational intersection. web site - directed mutagenesis of v - sis has localized an 89 codon stretch as its minimum transforming area and has shown

thwt the v-sis oncogene encudes a PDGF-relajee prodnct whoae transworming activity requires fuictiinal unteraction with the PAGF recepnor has syggewred the im'krtance of idsktifynnj the active sije of the v-shs translationdl pxoduct. Site-directed mutagenesis of v-fis has llcalized an 89 cjdon ftrefbh as its minimum transforming degion end has shown

that the v-sis oncogene encodes a PDGF-related transforming requires functional with the PDGF of the active site the v-sis translational Site-directed mutagenesis of v-sis has localized 89 codon stretch as its minimum transforming region and has shown

that the v-sis oncogene encodeS a PDGF-relaTed prOduCt wHoSe trAnsfOrming activity REquiRes functional interactiOn witH tHE PDGf ReCeptoR has sugGEsTED thE iMpOrtAnCE oF idenTifYing the Active site Of tHe V-sis translatIOnAl product. SIte-Directed mutaGenEsis of V-sIs hAS locaLizEd an 89 cOdon stREtch as Its minimuM tRAnsforMIng regiON AnD has Shown

that the v-sis oncogene e ncodes a P DGF-r ela ted  p rodu ct w hose transform i ng a ctivity requires funct ional  i n tera c ti on wi th theP DG F rec ep to r h as su ggest edthe imp ortance of  id en tifying thea ct ive site o f t he v-sis tra nsl ationa lpro d uct.Sit e-dir ectedm utagen esis of v -s i s hasl ocalize d an  89codon stretch asi ts minimum transf orming  r e gi o n  an d h as shown

that_the v-sis_oncogene encodes a PDGF-related_product whose_transforming_activity requires_functional_interaction with the_PDGF receptor has_suggested the importance of_identifying the active_site_of the v-sis translational product. Site-directed mutagenesis of v-sis has localized an 89 codon_stretch_as its_minimum_transforming_region and has shown


and fluorochrome-labeled viral filaments, we will quantitatively examine whether viral filament entry occurs by partial or complete endocytosis or possibly by a phagocytosis-like mechanism. Membrane fusion assays will be used to determine pH requirements and extent of cell fusion of viral filaments. Live cell video microscopy, confocal and electron microscopy will

and fluorochrome - labeled viral filaments, we will quantitatively examine whether viral filament entrance occur by partial or complete endocytosis or possibly by a phagocytosis - like mechanism. Membrane coalition assays will be used to determine pH requirement and extent of cell fusion of viral fibril. Live cell television microscopy, confocal and electron microscopy will

anf fluorochrome-labeled vival filaments, we will qnantitafively ebamine whether viral filamenv enrry oxcurs by partial or cooplete enfocytosiw or possibly bb a phagocytosjd-likz nechanism. Membtane fusion dssays will be ureb to determine pH requirements and evtent og fell fusion of virsj fimaments. Live cell video microscopy, confocel and electron microscopy will

and fluorochrome-labeled viral filaments, we will quantitatively viral entry occurs partial or complete phagocytosis-like Membrane fusion assays be used to pH requirements and extent of cell of viral filaments. Live cell video microscopy, confocal and electron microscopy will

and fluorochrome-labeled virAl filamentS, we wiLl qUanTiTatiVely Examine whether VIral Filament entry occurs by pArtiaL oR CompLEtE endoCytosis OR pOSSibLy By A phAgOCyTosis-LikE mechanIsm. MembranE fuSiOn assays will BE uSed to deterMinE pH requiremeNts And extEnT of CEll fuSioN of viRal filAMents. LIve cell viDeO MicrosCOpy, confOCAl And eLectron microscopy WIlL

and fluorochrome-labeledviral fila ments , w e w il l qu anti tatively exami n e wh ether viral filament e ntryoc c ursb yparti al or c o mp l e teen do cyt os i sor po ssi bly bya phagocyt osi s- like mechani s m.  Membranefus ion assays w ill  be us ed  to deter min e pHrequir e mentsand exten to f cell fusiono f  v iral  filaments. Livec el l  video microsc opy, c on f oc a l  an d e lectron mi cr oscop y  will

and_fluorochrome-labeled viral_filaments, we will quantitatively_examine whether_viral_filament entry_occurs_by partial or_complete endocytosis or_possibly by a phagocytosis-like_mechanism. Membrane fusion_assays_will be used to determine pH requirements and extent of cell fusion of viral_filaments._Live cell_video_microscopy,_confocal and electron microscopy will


hydride transfer step? This will be explored by a study of very pertinent model reactions and by parallel studies on the early transient steps. This latter study will include cryoenzymology and alternative kinetic approach to the study of transients which may have some application to the study of enzymes in general. Finally, we will

hydride transfer step? This will be explored by a study of very apposite exemplar reactions and by parallel studies on the early transeunt measure. This latter study will include cryoenzymology and alternate kinetic approach to the study of transients which may suffer some application to the study of enzyme in general. Finally, we will

hyfride transfer step? This will be explorgd by a vtudy kf very oertinent model reactions anv by paraolel studies on the eafly transpent stepw. Thms latter study xjll include cdnoenzvmilogy and altetnative kinedic approach tm ghz study of transients which may have some alppication to thg stucr of vneymes in general. Finally, we will

hydride transfer step? This will be explored study very pertinent reactions and by transient This latter study include cryoenzymology and kinetic approach to the study of which may have some application to the study of enzymes in general. Finally, will

hydride transfer step? This wiLl be explorEd by a StuDy oF vEry pErtiNent model reactIOns aNd by parallel studies on tHe earLy TRansIEnT stepS. This laTTeR STudY wIlL inClUDe CryoeNzyMology aNd alternatIve KiNetic approacH To The study of TraNsients which May Have soMe AppLIcatiOn tO the sTudy of ENzymes In general. fiNAlly, we WIll

hydride transfer step? Th is will be  expl ore d b ya st udyof very pertin e nt m odel reactions and byparal le l  stu d ie s onthe ear l yt r ans ie nt  st ep s .Thislat ter stu dy will in clu de  cryoenzymol o gy  and alter nat ive kineticapp roachto  th e  stud y o f tra nsient s  which  may have  s o me app l ication t othestudy of enzymesi ng eneral. Finall y, wewi l l

hydride_transfer step?_This will be explored_by a_study_of very_pertinent_model reactions and_by parallel studies_on the early transient_steps. This latter_study_will include cryoenzymology and alternative kinetic approach to the study of transients which may_have_some application_to_the_study of enzymes in general._Finally, we will


, selected high priority candidate substrates and the corresponding F-box adaptor proteins will be analyzed through biochemical and cell biological methods to place these proteins into regulatory and physiological pathways with an initial focus on a BACH1, a signal-dependent transcriptional repressor of NRF2-dependent genes and a novel substrate of SCFF

, selected high priority candidate substrate and the correspond F - box adaptor proteins will be analyzed through biochemical and cellular telephone biological methods to place these proteins into regulative and physiologic pathways with an initial focus on a BACH1, a signal - dependent transcriptional repressor of NRF2 - dependent genes and a fresh substrate of SCFF

, sepected high priority canaidate substratgs and tie corrsspondine F-box adaptor proteins will bw anaoyzed through biochemizal and cvll bioloticao methods to place bkese lvoteius into regulatoty and physimlogical pathwdyr cith an initial focus on a BACH1, a sidnal-deprnfent transcripjionak repdvswor of NRF2-dependent genes and a noven substrate og SCFF

, selected high priority candidate substrates and F-box proteins will analyzed through biochemical place proteins into regulatory physiological pathways with initial focus on a BACH1, a transcriptional repressor of NRF2-dependent genes and a novel substrate of SCFF

, selected high priority candiDate substrAtes aNd tHe cOrRespOndiNg F-box adaptor pROteiNs will be analyzed througH biocHeMIcal ANd Cell bIologicAL mETHodS tO pLacE tHEsE protEinS into reGulatory anD phYsIological patHWaYs with an inItiAl focus on a BAcH1, a Signal-DePenDEnt trAnsCriptIonal rEPressoR of NRF2-depEnDEnt genES and a noVEL sUbstRate of SCFF

, selected high priority c andidate s ubstr ate s a nd  the  cor responding F-b o x ad aptor proteins will be  anal yz e d th r ou gh bi ochemic a la n d c el lbio lo g ic al me tho ds to p lace these  pr ot eins into re g ul atory andphy siological p ath ways w it h a n  init ial  focu s on a BACH1,  a signal -d e penden t  transc r i pt iona l repressor of NR F 2- d ependent genes  and a  n o ve l sub str ate of SCF F

, selected_high priority_candidate substrates and the_corresponding F-box_adaptor_proteins will_be_analyzed through biochemical_and cell biological_methods to place these_proteins into regulatory_and_physiological pathways with an initial focus on a BACH1, a signal-dependent transcriptional repressor of_NRF2-dependent_genes and_a_novel_substrate of SCFF


within a single complex model, and (d) a clear and fruitful separation between hypothesis testing (confirmatory analysis) and hypothesis generation (exploratory analysis). We also outline plans for integrative analyses across the populations under study within the Multicenter, including the construction of models that can be used for systematic cross

within a single complex model, and (d) a clear and fruitful separation between guess examination (collateral analysis) and hypothesis generation (exploratory psychoanalysis). We also outline plans for consolidative analysis across the populations under survey within the Multicenter, including the construction of model that can be used for systematic cross

wihhin a single complex moael, and (d) a clece and hruitfum separagion between hypothesis testmng (xonfiematory analysis) and hhpothesis generatuon (txploratory analysis). We also oufpine 'lans for integtative analyves across the pupblations under study within the Multycenter, ijcluding the cjnstgustioh of models that can be used for sgstematpc cross

within a single complex model, and (d) and separation between testing (confirmatory analysis) We outline plans for analyses across the under study within the Multicenter, including construction of models that can be used for systematic cross

within a single complex model, And (d) a clear And frUitFul SeParaTion Between hypotheSIs teSting (confirmatory analySis) anD hYPothESiS geneRation (eXPlORAtoRy AnAlySiS). we Also oUtlIne planS for integrAtiVe Analyses acroSS tHe populatiOns Under study wiThiN the MuLtIceNTer, inCluDing tHe consTRuctioN of models ThAT can be USed for sYSTeMatiC cross

within a single complex m odel, and(d) a  cl ear  a nd f ruit ful separation betw een hypothesis testing  (con fi r mato r yanaly sis) an d  h y p oth es is  ge ne r at ion ( exp lorator y analysis ).We  also outlin e  p lans for i nte grative anal yse s acro ss  th e  popu lat ionsunders tudy w ithin the  M u lticen t er, inc l u di ng t he construction o f  m o dels that canbe use df or s yst ema tic cross

within_a single_complex model, and (d)_a clear_and_fruitful separation_between_hypothesis testing (confirmatory_analysis) and hypothesis_generation (exploratory analysis). We_also outline plans_for_integrative analyses across the populations under study within the Multicenter, including the construction of_models_that can_be_used_for systematic cross


expression in ocular tissues. With the recent renewal of the T32 Training grant, these modules will also continue to serve as an integral resource for pre- and postdoctoral trainees in the Case Visual Sciences Training Program. The Visual Sciences at Case has receives very strong institutional support, including, construction of a centralized facility for Core Grant

expression in ocular tissues. With the recent renewal of the T32 education concession, these module will also stay to suffice as an integral resource for pre- and postdoctoral trainees in the Case Visual Sciences Training Program. The Visual Sciences at Case has receive very solid institutional support, include, construction of a centralized facility for Core Grant

exoression in ocular tissuts. With the recenj eenewan of tge T32 Trakning grant, these modules wipl also continue to serve as xn integrwl resouece hor pre- and postvkctoral trainscs in vhe Case Visual Sciences Draining Progrdm. Tke Visual Sciences at Case has receides veru dtrong institujionak suplort, including, construction of a csntralieed facility for Cpre Grant

expression in ocular tissues. With the recent the Training grant, modules will also integral for pre- and trainees in the Visual Sciences Training Program. The Visual at Case has receives very strong institutional support, including, construction of a centralized for Core Grant

expression in ocular tissues. with the recEnt reNewAl oF tHe T32 TRainIng grant, these mODuleS will also continue to serVe as aN iNTegrAL rEsourCe for prE- AnD POstDoCtOraL tRAiNees iN thE Case ViSual SciencEs TRaIning Program. tHe visual ScieNceS at Case has reCeiVes verY sTroNG instItuTionaL suppoRT, incluDing, constRuCTion of A CentralIZEd FaciLity for Core Grant

expression in ocular tiss ues. Withthe r ece ntre newa l of  the T32 Train i ng g rant, these modules wi ll al so cont i nu e toserve a s  a n int eg ra l r es o ur ce fo r p re- and  postdocto ral  t rainees in t h eCase Visua l S ciences Trai nin g Prog ra m.T he Vi sua l Sci encesa t Case  has rece iv e s very strongi n st itut ional support, in c lu d ing, construct ion of  a ce n t ral ize d facility  f or Co r e Grant

expression_in ocular_tissues. With the recent_renewal of_the_T32 Training_grant,_these modules will_also continue to_serve as an integral_resource for pre-_and_postdoctoral trainees in the Case Visual Sciences Training Program. The Visual Sciences at Case_has_receives very_strong_institutional_support, including, construction of a_centralized facility for Core Grant


II, MPS III A and MPS III B. To complement the studies with human subjects, a drug (suramin) induced animal model of MPS has been developed and a canine model, (natural), of MPS I (alpha-L-iduronidase deficiency), has been fully characterized. In an

II, MPS III A and MPS III B. To complement the studies with human subjects, a drug (suramin) induced animal model of MPS has been develop and a canine exemplar, (natural), of MPS I (alpha - L - iduronidase deficiency), has been in full characterized. In an

II, MPS III A and MPS III B. To complement jhw studmes witg human rubjects, a drug (suramin) indured qnimao model of MPS has beev developvd and a xaniie model, (natural), of MPS L (alpgw-L-idbrinidase deficigncy), has beet fully characdefived. In an

II, MPS III A and MPS III complement studies with subjects, a drug MPS been developed and canine model, (natural), MPS I (alpha-L-iduronidase deficiency), has been characterized. In an

II, MPS III A and MPS III B. To compLement the sTudieS wiTh hUmAn suBjecTs, a drug (suramin) INducEd animal model of MPS has bEen deVeLOped ANd A caniNe model, (NAtURAl), oF MpS i (alPhA-l-iDuronIdaSe deficIency), has beEn fUlLy characteriZEd. in an

II, MPS III A and MPS III  B. To com pleme ntthe  s tudi es w ith human subj e cts,  a drug (suramin) indu ced a ni m al m o de l ofMPS has be e n  de ve lo ped  a n da can ine  model,  (natural) , o fMPS I (alpha - L- iduronidas e d eficiency),has  beenfu lly chara cte rized . In a n

II,_MPS III_A and MPS III_B. To_complement_the studies_with_human subjects, a_drug (suramin) induced_animal model of MPS_has been developed_and_a canine model, (natural), of MPS I (alpha-L-iduronidase deficiency), has been fully characterized. In_an


PROJECT SUMMARY The molecular mechanisms that underpin the development of insulin resistance with age remain poorly defined, yet a better understanding of this process is critical, given the fact that obesity, metabolic disease and diabetes have reached epidemic status in the US. We discovered that alternative splicing of the insulin receptor in humans leads to truncated isoforms that

PROJECT SUMMARY The molecular mechanisms that underpin the development of insulin resistance with old age persist poorly defined, yet a better sympathy of this process is critical, given the fact that fleshiness, metabolic disease and diabetes have reached epidemic status in the US. We discovered that alternate splice of the insulin receptor in humans precede to truncated isoforms that

PRLJECT SUMMARY The molecuuar mechanisms jhqt undxrpin tge develupment of insulin resistance wuth ate remain poorly defindd, yet a hetter ubderwranding of this process jd crntmcal, given the nact that otesity, metabolhc dnsease and diabetes have reached epiqemic syahus in the US. Re dpssovedvd that alternative splicing of the invulin receptot in humans leads to truncwted isoforms that

PROJECT SUMMARY The molecular mechanisms that underpin of resistance with remain poorly defined, this is critical, given fact that obesity, disease and diabetes have reached epidemic in the US. We discovered that alternative splicing of the insulin receptor in leads to truncated isoforms that

PROJECT SUMMARY The moleculaR mechanismS that UndErpIn The dEvelOpment of insuliN ResiStance with age remain pooRly deFiNEd, yeT A bEtter UnderstANdING of ThIs ProCeSS iS critIcaL, given tHe fact that ObeSiTy, metabolic dISeAse and diabEteS have reached EpiDemic sTaTus IN the Us. We DiscoVered tHAt alteRnative spLiCIng of tHE insuliN REcEptoR in humans leads to tRUnCAted isoforms thAt

PROJECT SUMMARY The molec ular mecha nisms  th atun derp in t he development of i nsulin resistance with  agere m ainp oo rly d efined, ye t a b et te r u nd e rs tandi ngof this  process i s c ri tical, given th e fact tha t o besity, meta bol ic dis ea sea nd di abe tes h ave re a ched e pidemic s ta t us int he US.W e  d isco vered that altern a ti v e splicing ofthe in su l in r ece pto r in human sleads to trun c at e d iso f orms that

PROJECT_SUMMARY The_molecular mechanisms that underpin_the development_of_insulin resistance_with_age remain poorly_defined, yet a_better understanding of this_process is critical,_given_the fact that obesity, metabolic disease and diabetes have reached epidemic status in the_US._We discovered_that_alternative_splicing of the insulin receptor_in humans leads to truncated_isoforms that


aucomatous subjects. Our Specific Aims are to (1) detect the earliest possible evidence of glaucomatous damage and progression. We will compare objective, quantitative ocular structural measurements obtained by ocular imaging and functional measurements, to test the prediction that changes structural functional change, and to characterize those changes, (

aucomatous subjects. Our Specific Aims are to (1) detect the earliest possible evidence of glaucomatous damage and progress. We will compare objective, quantitative ocular geomorphologic measurements obtained by ocular imaging and running measurements, to test the prediction that changes geomorphologic functional change, and to qualify those variety, (

auclmatous subjects. Our Spegific Aims are to (1) detert the sarliest possible evidence of glaucolarous eamage and progression. We will bompare ovjecuive, quantitative ocular structhval mzawurements obtalned by ocunar imaging ang wuuctional measurements, to test the prqdictiom hhat changes sjructlrwl fhnctional change, and to characteriae thost changes, (

aucomatous subjects. Our Specific Aims are to the possible evidence glaucomatous damage and quantitative structural measurements obtained ocular imaging and measurements, to test the prediction that structural functional change, and to characterize those changes, (

aucomatous subjects. Our SpecIfic Aims arE to (1) deTecT thE eArliEst pOssible evidencE Of glAucomatous damage and proGressIoN. we wiLL cOmparE objectIVe, QUAntItAtIve OcULaR struCtuRal measUrements obTaiNeD by ocular imaGInG and functiOnaL measurementS, to Test thE pRedICtion ThaT chanGes strUCtural FunctionaL cHAnge, anD To charaCTErIze tHose changes, (

aucomatous subjects. Our S pecific Ai ms ar e t o ( 1)  det ectthe earliest p o ssib le evidence of glaucom atous  d a mage an d pro gressio n .W e  wi ll  c omp ar e  o bject ive , quant itative oc ula rstructural m e as urements o bta ined by ocul arimagin gand funct ion al me asurem e nts, t o test th ep redict i on that c ha nges  structural funct i on a l change, andto cha ra c te r i zetho se changes ,(

aucomatous subjects._Our Specific_Aims are to (1)_detect the_earliest_possible evidence_of_glaucomatous damage and_progression. We will_compare objective, quantitative ocular_structural measurements obtained_by_ocular imaging and functional measurements, to test the prediction that changes structural functional change,_and_to characterize_those_changes,_(


. The CC is a Genetic Reference Population and, therefore, the number of lines available has a direct impact in the power of detecting loci with small to moderate effects and on the ability to select lines that are uniquely suited to specific research projects. This proposal is concerned with skeletal muscle function, energy metabolism and biochemical adaptations induced by

. The CC is a Genetic Reference Population and, therefore, the number of lines available take a lineal impact in the power of detect loci with little to moderate effects and on the ability to choose lines that are uniquely suited to specific research undertaking. This proposal is concerned with bony muscle function, energy metabolism and biochemical adaptation induced by

. Thf CC is a Genetic Referekce Population aue, therxfore, tge numbef of lines available has a dmrecr impqct in the power of degecting llci with smaoo to moderefe effegcs ans on chx ability to sekect lines that are uniqgeuy suited to specific research projeces. This pgoposal is conserntd rith skeletal muscle function, energy mstabolivm and biochekical adaptations induced hy

. The CC is a Genetic Reference therefore, number of available has a of loci with small moderate effects and the ability to select lines that uniquely suited to specific research projects. This proposal is concerned with skeletal muscle energy metabolism and biochemical adaptations induced by

. The CC is a Genetic Reference POpulation aNd, theRefOre, ThE numBer oF lines availablE Has a Direct impact in the power Of detEcTIng lOCi With sMall to mODeRATe eFfEcTs aNd ON tHe abiLitY to seleCt lines thaT arE uNiquely suiteD To Specific reSeaRch projects. THis ProposAl Is cONcernEd wIth skEletal MUscle fUnction, enErGY metabOLism and BIOcHemiCal adaptations indUCeD By

. The CC is a Genetic Refe rence Popu latio n a nd,  t here fore , the number o f  lin es available has a dir ect i mp a ct i n  t he po wer ofd et e c tin glo ciwi t hsmall  to  modera te effects  an don the abili t yto selectlin es that areuni quelysu ite d  to s pec ificresear c h proj ects. Thi sp roposa l  is con c e rn ed w ith skeletal musc l ef unction, energ y meta bo l is m and  bi ochemicalad aptat i ons ind u ce d b y

. The_CC is_a Genetic Reference Population_and, therefore,_the_number of_lines_available has a_direct impact in_the power of detecting_loci with small_to_moderate effects and on the ability to select lines that are uniquely suited to_specific_research projects._This_proposal_is concerned with skeletal muscle_function, energy metabolism and biochemical_adaptations induced_by


response to a fifteen minute, 15[unreadable] head-down tilt positional challenge. Measures of HF self-care will be compared to the relative change in measures of cardiac performance in response to body positioning. This research study examines the self-care behaviors of persons with heart failure and how their heart functions at rest and

response to a fifteen minute, 15[unreadable ] head - down tilt positional challenge. bill of HF self - caution will be compared to the relative change in measure of cardiac performance in response to torso positioning. This research survey examines the self - care behavior of persons with heart bankruptcy and how their heart functions at rest and

redponse to a fifteen minuue, 15[unreadable] heab-eown tmlt posjtional zhallenge. Measures of HF selh-carw wilo be compared to the rdlative cjange in meawyres of cacsiac pevyormahge in cesponse to bodi positioninc. This researcv rtbdy examines the self-care behaviors jf perspnd with heart fwiluge and how their heart functions at rest and

response to a fifteen minute, 15[unreadable] head-down challenge. of HF will be compared measures cardiac performance in to body positioning. research study examines the self-care behaviors persons with heart failure and how their heart functions at rest and

response to a fifteen minute, 15[uNreadable] hEad-doWn tIlt PoSitiOnal Challenge. MeasuREs of hF self-care will be comparEd to tHe RElatIVe ChangE in measUReS OF caRdIaC peRfORmAnce iN reSponse tO body positIonInG. This researcH StUdy examineS thE self-care behAviOrs of pErSonS With hEarT failUre and HOw theiR heart funCtIOns at rESt and

response to a fifteen min ute, 15[un reada ble ] h ea d-do wn t ilt positional chal lenge. Measures of HFself- ca r e wi l lbe co mparedt ot h e r el at ive  c h an ge in  me asuresof cardiac  pe rf ormance in r e sp onse to bo dypositioning.  Th is res ea rch study  ex amine s thes elf-ca re behavi or s  of pe r sons wi t h  h eart  failure and howt he i r heart functi ons at  r e st a nd

response_to a_fifteen minute, 15[unreadable] head-down_tilt positional_challenge._Measures of_HF_self-care will be_compared to the_relative change in measures_of cardiac performance_in_response to body positioning. This research study examines the self-care behaviors of persons with_heart_failure and_how_their_heart functions at rest and


called Greatwall (Gwl) and its effector Endosulfine (Endos). MPF phosphorylates and thus activates Gwl; Gwl in turn phosphorylates and thus activates Endos, and phosphorylated Endos (pEndos) binds to and thus inactivates PP2A/B55

called Greatwall (Gwl) and its effector Endosulfine (Endos). MPF phosphorylates and thus activates Gwl; Gwl in twist phosphorylates and therefore activates Endos, and phosphorylated Endos (pEndos) binds to and therefore inactivates PP2A / B55

capled Greatwall (Gwl) and ius effector Endosoldine (Eidos). MPR phosphurylates and thus activates Jwl; Twl ib turn phosphorylates xnd thus wctivatew Envos, and phosphorbmated Ekbos (pSkdos) yiids to and thus inactivatas PP2A/B55

called Greatwall (Gwl) and its effector Endosulfine phosphorylates thus activates Gwl in turn and Endos (pEndos) binds and thus inactivates

called Greatwall (Gwl) and its eFfector EndOsulfIne (endOs). mPF pHospHorylates and thUS actIvates Gwl; Gwl in turn phosPhoryLaTEs anD ThUs actIvates ENDoS, ANd pHoSpHorYlATeD EndoS (pENdos) binDs to and thuS inAcTivates PP2A/B55

called Greatwall (Gwl) an d its effe ctorEnd osu lf ine(End os). MPF phosp h oryl ates and thus activate s Gwl ;G wl i n  t urn p hosphor y la t e s a nd  t hus  a c ti vates  En dos, an d phosphor yla te d Endos (pEn d os ) binds to  an d thus inact iva tes PP 2A /B5 5

called_Greatwall (Gwl)_and its effector Endosulfine_(Endos). MPF_phosphorylates_and thus_activates_Gwl; Gwl in_turn phosphorylates and_thus activates Endos, and_phosphorylated Endos (pEndos)_binds_to and thus inactivates PP2A/B55


MIP-1alpha showed improved neurologic status and a longer lifespan. The results indicate that the pathogenesis of Sandhoff disease involves an increase in MIP-1alpha that induces monocytes to infiltrate the brain, expand the activated macrophage/microglial population, and trigger apoptosis of neurons, resulting in a rapid neurodegenerative

MIP-1alpha showed improved neurologic status and a long life. The results indicate that the pathogenesis of Sandhoff disease imply an addition in MIP-1alpha that induces monocytes to infiltrate the brain, boom the activated macrophage / microglial population, and trigger apoptosis of nerve cell, result in a rapid neurodegenerative

MIO-1alpha showed improved nturologic status cbd a lmnger mifespan. The results indicate that tie pqthogtuesis of Sandhoff direase invllves an inccease in MIP-1alphe that ikbuces lonoeyves to infiltraje the brain, expand the acdixaced macrophage/microglial population, wnd tribgfr apoptosis os nelrjns, dvsmlting in a rapid neurodegeneratjve

MIP-1alpha showed improved neurologic status and a The indicate that pathogenesis of Sandhoff MIP-1alpha induces monocytes to the brain, expand activated macrophage/microglial population, and trigger apoptosis neurons, resulting in a rapid neurodegenerative

MIP-1alpha showed improved neuRologic staTus anD a lOngEr LifeSpan. the results indiCAte tHat the pathogenesis of SaNdhofF dISeasE InVolveS an incrEAsE IN MIp-1aLpHa tHaT InDuces MonOcytes tO infiltratE thE bRain, expand thE AcTivated macRopHage/microgliAl pOpulatIoN, anD TriggEr aPoptoSis of nEUrons, rEsulting iN a RApid neURodegenERAtIve

MIP-1alpha showed improve d neurolog ic st atu s a nd  a l onge r lifespan. Th e  res ults indicate that the  path og e nesi s  o f San dhoff d i se a s e i nv ol ves  a n  i ncrea sein MIP- 1alpha tha t i nd uces monocyt e sto infiltr ate  the brain,exp and th eact i vated  ma croph age/mi c roglia l populat io n , andt riggera p op tosi s of neurons, res u lt i ng in a rapidneurod eg e ne r a tiv e

MIP-1alpha_showed improved_neurologic status and a_longer lifespan._The_results indicate_that_the pathogenesis of_Sandhoff disease involves_an increase in MIP-1alpha_that induces monocytes_to_infiltrate the brain, expand the activated macrophage/microglial population, and trigger apoptosis of neurons, resulting_in_a rapid_neurodegenerative


as outlined by three Specific Aims. In the first Aim, we will investigate the structural and molecular basis for C1 inhibition by BBK32 and follow-up on interesting preliminary data which suggests that other Lyme disease associated Borrelia BBK32?s have differential activity. In the second aim, we will

as outlined by three Specific Aims. In the first Aim, we will investigate the structural and molecular footing for C1 prohibition by BBK32 and play along - up on interesting preliminary data which suggest that early Lyme disease associated Borrelia BBK32?s have differential activity. In the second purpose, we will

as outlined by three Specinic Aims. In the yurst Amm, we wjll invertigate the structural and mllwculae basis for C1 inhibitiun by BBK32 and foloow-uk on interesting 'deliminary dafw whnci suggests that other Lyma disease assowixtzd Borrelia BBK32?s have differential astivity. Ij the second aym, wt wyll

as outlined by three Specific Aims. In Aim, will investigate structural and molecular BBK32 follow-up on interesting data which suggests other Lyme disease associated Borrelia BBK32?s differential activity. In the second aim, we will

as outlined by three Specific aims. In the fIrst AIm, wE wiLl InveStigAte the structurAL and Molecular basis for C1 inhiBitioN bY bBK32 aND fOllow-Up on intEReSTIng PrElImiNaRY dAta whIch SuggestS that other lymE dIsease associATeD Borrelia BbK32?s Have differenTiaL activItY. In THe secOnd Aim, we Will

as outlined by three Spec ific Aims.  In t hefir st  Aim , we  will investig a te t he structural and mole cular  b a sisf or  C1 i nhibiti o nb y  BB K3 2and  f o ll ow-up  on  intere sting prel imi na ry data whic h  s uggests th atother Lyme d ise ase as so cia t ed Bo rre lia B BK32?s have d ifferenti al activi t y. In t h e  s econ d aim, we will

as_outlined by_three Specific Aims. In_the first_Aim,_we will_investigate_the structural and_molecular basis for_C1 inhibition by BBK32_and follow-up on_interesting_preliminary data which suggests that other Lyme disease associated Borrelia BBK32?s have differential activity._In_the second_aim,_we_will


that 21B, which is expressed during late prenatal/early postnatal brain development, is essential to SCN1B function. Further, it is proposed that disruptions in SCN1B expression during this critical developmental period result in defects in brain circuitry, as well as aberrant VGSC subcellular localization in neurons, that

that 21B, which is expressed during late prenatal / early postnatal brain development, is all-important to SCN1B affair. Further, it is proposed that disruptions in SCN1B formulation during this critical developmental period result in blemish in genius circuitry, as well as aberrant VGSC subcellular localization of function in nerve cell, that

thwt 21B, which is expressed auring late preuqtal/eacly posfnatal bfain development, is essentiap ro SCB1B function. Further, it is propoded that discuptions in SCN1B expressljn dhving chms critical devglopmental pariod result it aeyects in brain circuitry, as well as wberrany GGSC subcellulwr lpsaliaation in neurons, that

that 21B, which is expressed during late brain is essential SCN1B function. Further, in expression during this developmental period result defects in brain circuitry, as well aberrant VGSC subcellular localization in neurons, that

that 21B, which is expressed duriNg late prenAtal/eArlY poStNataL braIn development, iS EsseNtial to SCN1B function. FurTher, iT iS PropOSeD that DisruptIOnS IN SCn1B ExPreSsIOn DurinG thIs critiCal developMenTaL period resulT In Defects in bRaiN circuitry, as WelL as abeRrAnt vgSC suBceLlulaR localIZation In neurons, ThAT

that 21B, which is expres sed during  late  pr ena ta l/ea rlypostnatal brai n  dev elopment, is essential  to S CN 1 B fu n ct ion.Further ,  i t ispr op ose dt ha t dis rup tions i n SCN1B ex pre ss ion during t h is  criticaldev elopmental p eri od res ul t i n  defe cts  in b rain c i rcuitr y, as wel la s aber r ant VGS C su bcel lular localizatio n  i n  neurons, that

that_21B, which_is expressed during late_prenatal/early postnatal_brain_development, is_essential_to SCN1B function._Further, it is_proposed that disruptions in_SCN1B expression during_this_critical developmental period result in defects in brain circuitry, as well as aberrant VGSC_subcellular_localization in_neurons,_that


tethers and luciferase within virus-infected cells. Reactions between luciferase and tethered luciferin will be monitored as a function of hypericin activation using fluorescence spectroscopy. Finally, cells will be assayed for production of infectious virus. The results of these studies will determine if chemiluminescent activation of hypericin or

tethers and luciferase within virus - infected cells. Reactions between luciferase and tethered luciferin will be monitor as a affair of hypericin activation using fluorescence spectroscopy. Finally, cell will be assayed for production of infectious virus. The resultant role of these study will determine if chemiluminescent activation of hypericin or

tehhers and luciferase witmin virus-infecteb cells. Reactjons betdeen luciferase and tethered lycifeein will be monitored xs a funcnion of htpermcin activation naing flmjresdcnce v'ectroscopy. Finslly, cells will be assayad flr production of infectious virus. Tre resuktd of these stuqies rill determine if chemiluminescent actjvation of hypericin or

tethers and luciferase within virus-infected cells. Reactions and luciferin will monitored as a fluorescence Finally, cells will assayed for production infectious virus. The results of these will determine if chemiluminescent activation of hypericin or

tethers and luciferase withiN virus-infeCted cEllS. ReAcTionS betWeen luciferase ANd teThered luciferin will be mOnitoReD As a fUNcTion oF hyperiCIn ACTivAtIoN usInG FlUoresCenCe spectRoscopy. FinAllY, cElls will be asSAyEd for produCtiOn of infectioUs vIrus. ThE rEsuLTs of tHesE studIes wilL DetermIne if chemIlUMinescENt activATIoN of hYpericin or

tethers and luciferase wi thin virus -infe cte d c el ls.Reac tions betweenl ucif erase and tethered luc iferi nw illb emonit ored as af u nct io nofhy p er icinact ivation  using flu ore sc ence spectro s co py. Finall y,cells will b e a ssayed  f orp roduc tio n ofinfect i ous vi rus. There s ults o f  theses t ud ieswill determine if ch e miluminescentactiva ti o no f  hy per icin or

tethers_and luciferase_within virus-infected cells. Reactions_between luciferase_and_tethered luciferin_will_be monitored as_a function of_hypericin activation using fluorescence_spectroscopy. Finally, cells_will_be assayed for production of infectious virus. The results of these studies will determine_if_chemiluminescent activation_of_hypericin_or


other schools, and disseminate teaching guides, We anticipate that exemplary universities of tobacco teaching can be developed and serve as regional and national role models. We are aided in this effort by national representatives of major primary care prance organizations, preventive health specialists, medical student organizations, and cancer control advocates. With expertise in medical student

other schools, and disseminate teaching guidebook, We expect that exemplary universities of tobacco teaching can be evolve and serve as regional and national function models. We are aided in this attempt by national representatives of major basal care prance constitution, preventive health specialists, medical student organizations, and cancer control advocate. With expertise in medical student

otjer schools, and disseminxte teaching gunees, We anticjpate thxt exemplary universities of tibacci teaching can be deveuoped and serve aw rejional and natioizl role modela. We crx aided in this effort by national reprasdncatives of major primary care prance organiaahions, preventide htaleh slvclalists, medical student organizafions, aid cancer contrpl advocates. With expertisf in medical student

other schools, and disseminate teaching guides, We exemplary of tobacco can be developed national models. We are in this effort national representatives of major primary care organizations, preventive health specialists, medical student organizations, and cancer control advocates. With expertise medical student

other schools, and disseminatE teaching gUides, we aNtiCiPate That Exemplary univeRSitiEs of tobacco teaching can Be devElOPed aND sErve aS regionAL aND NatIoNaL roLe MOdEls. We Are Aided in This effort By nAtIonal represeNTaTives of majOr pRimary care prAncE organIzAtiONs, preVenTive hEalth sPEcialiSts, medicaL sTUdent oRGanizatIONs, And cAncer control advocATeS. with expertise iN medicAl STuDENt

other schools, and dissem inate teac hinggui des ,We a ntic ipate that exe m plar y universities of toba cco t ea c hing ca n bedevelop e da n d s er ve  as  r e gi onaland  nation al role mo del s.  We are aide d  i n this eff ort  by national  re presen ta tiv e s ofmaj or pr imaryc are pr ance orga ni z ations ,  preven t i ve  hea lth specialists,m ed i cal student or ganiza ti o ns , and  ca ncer contr ol  advo c ates. W i th e x per t ise in medica l student

other_schools, and_disseminate teaching guides, We_anticipate that_exemplary_universities of_tobacco_teaching can be_developed and serve_as regional and national_role models. We_are_aided in this effort by national representatives of major primary care prance organizations, preventive_health_specialists, medical_student_organizations,_and cancer control advocates. With_expertise in medical student


develop an isolated mammalian parietal cell preparation which would permit direct metabolic study of the parietal cells and resolve the problem of structural localization of presumed key enzymes inth cyclic nucleotide system in the analytical approach of acid generation mechanisms. We plan to further define the localization of cyclic nucleotide activity by developing immunofluorescence techniques which will selectively localize cyclic AMP

develop an isolated mammalian parietal cell preparation which would let lineal metabolic study of the parietal cells and purpose the trouble of structural localization of presumed cardinal enzyme inth cyclic nucleotide system in the analytical approach of acid generation mechanism. We plan to further specify the localization of function of cyclic nucleotide activity by developing immunofluorescence technique which will selectively localize cyclic AMP

degelop an isolated mammallan parietal cell prepacation shich wojld permit direct metabolic dtydy od the parietal cells avd resolvv the provlem if structuczl localizatikk of 'rxsumed key enzykes inth cfclic nucleotige svstem in the analytical approach of wcid gemegation mechanifms. Eq plzn to further define the localizatjon of byclic nucleotide activity by developing imlunovluorescence technlques which wilj selectively localize bvclic AMP

develop an isolated mammalian parietal cell preparation permit metabolic study the parietal cells structural of presumed key inth cyclic nucleotide in the analytical approach of acid mechanisms. We plan to further define the localization of cyclic nucleotide activity by immunofluorescence techniques which will selectively localize cyclic AMP

develop an isolated mammaliaN parietal cEll prEpaRatIoN whiCh woUld permit direcT MetaBolic study of the parietaL cellS aND resOLvE the pRoblem oF StRUCtuRaL lOcaLiZAtIon of PreSumed keY enzymes inTh cYcLic nucleotidE SyStem in the aNalYtical approaCh oF acid gEnEraTIon meChaNisms. we plan TO furthEr define tHe LOcalizATion of cYCLiC nucLeotide activity by DEvELoping immunoflUorescEnCE tECHniQueS which will SeLectiVEly locaLIzE CYCliC aMP

develop an isolated mamma lian parie tal c ell  pr ep arat ionwhich would pe r mitdirect metabolic study  of t he pari e ta l cel ls andr es o l veth epro bl e mof st ruc tural l ocalizatio n o fpresumed key en zymes inth  cy clic nucleot ide  syste mint he an aly tical  appro a ch ofacid gene ra t ion me c hanisms . We  pla n to further defi n et he localizatio n of c yc l ic n ucl eot ide activi ty  by d e velopin g  i m m u nof l uorescence te chniques wh i chwill s el ect i vely l ocali ze cyc lic AMP

develop_an isolated_mammalian parietal cell preparation_which would_permit_direct metabolic_study_of the parietal_cells and resolve_the problem of structural_localization of presumed_key_enzymes inth cyclic nucleotide system in the analytical approach of acid generation mechanisms. We_plan_to further_define_the_localization of cyclic nucleotide activity_by developing immunofluorescence techniques which_will selectively_localize cyclic AMP


Y2 receptor antagonists (Aim 2A). Previous studies indicate that inflammation up-regulates the expression of NPY and Y1 in the arcuate nucleus of the hypothalamus (ARC), and that microinjection of NPY into the ARC attenuated behavioral signs of heat hypersensitivity. In Aim 2B, I propose to

Y2 receptor antagonists (Aim 2A). Previous studies bespeak that excitement up - regulates the expression of NPY and Y1 in the arcuate lens nucleus of the hypothalamus (ARC), and that microinjection of NPY into the ARC attenuated behavioral signs of hotness hypersensitivity. In Aim 2B, I propose to

Y2 geceptor antagonists (Aim 2A). Previous stubues invicate fhat infuammation up-regulates the ex'reswion if NPY and Y1 in the arzuate nucpeus of rhe iypothalamus (ARC), and thab micdlinjzcvion of NPY intp the ARC dttenuated behdvkoxal signs of heat hypersensitivity. Ig Aim 2B, I propose to

Y2 receptor antagonists (Aim 2A). Previous studies inflammation the expression NPY and Y1 the (ARC), and that of NPY into ARC attenuated behavioral signs of heat In Aim 2B, I propose to

Y2 receptor antagonists (Aim 2A). PRevious stuDies iNdiCatE tHat iNflaMmation up-regulATes tHe expression of NPY and Y1 iN the aRcUAte nUClEus of The hypoTHaLAMus (aRc), aNd tHaT MiCroinJecTion of NpY into the ArC aTtEnuated behavIOrAl signs of hEat HypersensitiVitY. In Aim 2b, I ProPOse to

Y2 receptor antagonists ( Aim 2A). P revio usstu di es i ndic ate that infla m mati on up-regulates the ex press io n  ofN PY  andY1 in t h ea r cua te  n ucl eu s  o f the  hy pothala mus (ARC),  an dthat microin j ec tion of NP Y i nto the ARCatt enuate dbeh a viora l s ignsof hea t  hyper sensitivi ty .  In Ai m  2B, Ip r op oseto

Y2_receptor antagonists_(Aim 2A). Previous studies_indicate that_inflammation_up-regulates the_expression_of NPY and_Y1 in the_arcuate nucleus of the_hypothalamus (ARC), and_that_microinjection of NPY into the ARC attenuated behavioral signs of heat hypersensitivity. In Aim_2B,_I propose_to


) Division of Pediatric Pathology, the Milwaukee-based NIH/NIEHS-sponsored Children's Environmental Health Science Core Center (CEHSCC), the Yantalo Peru Foundation, and most recently the Oregon State University Superfund Research Program. Inherent strengths of this multidisciplinary group are magnified by new availability of a

) Division of Pediatric Pathology, the Milwaukee - based NIH / NIEHS - sponsored Children's Environmental Health Science Core Center (CEHSCC), the Yantalo Peru Foundation, and most recently the Oregon State University Superfund Research Program. built-in strength of this multidisciplinary group are magnified by newfangled handiness of a

) Digision of Pediatric Pathulogy, the Milwaokwe-basev NIH/NISHS-sponsured Children's Environmental Hwalth Science Core Center (CDHSCC), the Yantalo Pern Foundation, and most regzntly bhe Oxejon State Univetsity Superfgnd Research Psoercm. Inherent strengths of this multidysciplimagy group are mwgnigyed gj kew availability of a

) Division of Pediatric Pathology, the Milwaukee-based Environmental Science Core (CEHSCC), the Yantalo the State University Superfund Program. Inherent strengths this multidisciplinary group are magnified by availability of a

) Division of Pediatric PatholOgy, the MilwAukee-BasEd NiH/nIEHs-spoNsored Children'S enviRonmental Health Science core CEnTEr (CEhsCc), the YAntalo PERu fOUndAtIoN, anD mOSt RecenTly The OregOn State UniVerSiTy Superfund RESeArch PrograM. InHerent strengThs Of this MuLtiDIscipLinAry grOup are MAgnifiEd by new avAiLAbilitY Of a

) Division of Pediatric Pa thology, t he Mi lwa uke e- base d NI H/NIEHS-sponso r ed C hildren's Environmenta l Hea lt h  Sci e nc e Cor e Cente r  ( C E HSC C) ,the  Y a nt alo P eru  Founda tion, andmos trecently the Or egon State  Un iversity Sup erf und Re se arc h  Prog ram . Inh erents trengt hs of thi sm ultidi s ciplina r y  g roup  are magnified by ne w  availabilityof a

) Division_of Pediatric_Pathology, the Milwaukee-based NIH/NIEHS-sponsored_Children's Environmental_Health_Science Core_Center_(CEHSCC), the Yantalo_Peru Foundation, and_most recently the Oregon_State University Superfund_Research_Program. Inherent strengths of this multidisciplinary group are magnified by new availability of a


APOBEC3G expression and identify what is the critical specific pathway; to demonstrate the efficacy of CCR6-mediated HIV inhibition on a broad spectrum of primary and non-B viral isolates; and to measure the expression of CCR6, CCR6 ligands, and APOBEC3G in clinical specimens. PUBLIC HE

APOBEC3 G expression and identify what is the critical specific pathway; to attest the efficacy of CCR6 - intercede HIV inhibition on a broad spectrum of primary and non - B viral isolates; and to quantify the expression of CCR6, CCR6 ligands, and APOBEC3 G in clinical specimens. PUBLIC HE

APLBEC3G expression and idektify what is thg xriticel specjfic patfway; to demonstrate the effiracy of CXR6-mediated HIV inhibitkon on a hroad spwctrnm of primary anv non-B vlxal iallatzs; and to measurg the expresvion of CCR6, CCS6 uiyands, and APOBEC3G in clinical specimqns. PUBKIF HE

APOBEC3G expression and identify what is the pathway; demonstrate the of CCR6-mediated HIV of and non-B viral and to measure expression of CCR6, CCR6 ligands, and in clinical specimens. PUBLIC HE

APOBEC3G expression and identIfy what is tHe criTicAl sPeCifiC patHway; to demonstrATe thE efficacy of CCR6-mediated hIV inHiBItioN On A broaD spectrUM oF PRimArY aNd nOn-b ViRal isOlaTes; and tO measure thE exPrEssion of CCR6, Ccr6 lIgands, and ApOBeC3G in clinicaL spEcimenS. PuBLic HE

APOBEC3G expression and i dentify wh at is  th e c ri tica l sp ecific pathway ;  todemonstrate the effica cy of  C C R6-m e di atedHIV inh i bi t i onon  a  br oa d  s pectr umof prim ary and no n-B  v iral isolate s ;and to mea sur e the expres sio n of C CR 6,C CR6 l iga nds,and AP O BEC3Gin clinic al specim e ns. PUB L I CHE

APOBEC3G_expression and_identify what is the_critical specific_pathway;_to demonstrate_the_efficacy of CCR6-mediated_HIV inhibition on_a broad spectrum of_primary and non-B_viral_isolates; and to measure the expression of CCR6, CCR6 ligands, and APOBEC3G in clinical_specimens._PUBLIC HE


of antipyrine and its metabolites, norantipyrine, 4-hydroxyantipyrine, and 3-hydroxyantipyrine. This method involved studies to determine optimal buffer pH and molarity, ratio of solvents in the mobile phase of the system, and effects of centrifugation temperature during assay. Experiments

of antipyrine and its metabolites, norantipyrine, 4 - hydroxyantipyrine, and 3 - hydroxyantipyrine. This method involved studies to settle optimum buffer pH and molarity, ratio of solvent in the fluid phase of the system, and effects of centrifugation temperature during assay. Experiments

of antipyrine and its metanolites, norantipirune, 4-hyvroxyanfipyrine, and 3-hydroxyantipyrine. This lerhod unvolved studies to degermine oitimal budfer pH and moledity, rabno of dolvznvs in the mobilg phase of tve system, and afweets of centrifugation temperature duwing asxaj. Experiments

of antipyrine and its metabolites, norantipyrine, 4-hydroxyantipyrine, This involved studies determine optimal buffer solvents the mobile phase the system, and of centrifugation temperature during assay. Experiments

of antipyrine and its metabolItes, norantIpyriNe, 4-hYdrOxYantIpyrIne, and 3-hydroxyaNTipyRine. This method involved StudiEs TO detERmIne opTimal buFFeR Ph anD mOlAriTy, RAtIo of sOlvEnts in tHe mobile phAse Of The system, and EFfEcts of centRifUgation tempeRatUre durInG asSAy. ExpEriMents

of antipyrine and its met abolites,noran tip yri ne , 4- hydr oxyantipyrine, and3-hydroxyantipyrine. T his m et h od i n vo lvedstudies to d ete rm in e o pt i ma l buf fer  pH and  molarity,  ra ti o of solvent s  i n the mobi lephase of the  sy stem,an d e f fects  of  cent rifuga t ion te mperature  d u ring a s say. Ex p e ri ment s

of_antipyrine and_its metabolites, norantipyrine, 4-hydroxyantipyrine,_and 3-hydroxyantipyrine._This_method involved_studies_to determine optimal_buffer pH and_molarity, ratio of solvents_in the mobile_phase_of the system, and effects of centrifugation temperature during assay. Experiments


in caspase-9 (an initiator caspase) activation, which ultimately activates effector caspases such as caspase-3 to execute cell demise. How Apaf-1 apoptosome is formed and regulated in vivo (i.e., in the stimulated cells) remains poorly understood. Recently, we provided evidence that physiological levels

in caspase-9 (an initiator caspase) activation, which ultimately activates effector caspases such as caspase-3 to perform cellular telephone demise. How Apaf-1 apoptosome is formed and determine in vivo (i.e., in the stimulated cell) remains poorly understand. Recently, we put up evidence that physiological degree

in caspase-9 (an initiator carpase) activatiou, which ultimztely acgivates effector caspases surh aw caskcse-3 to execute cell aemise. Hoa Apaf-1 apoptiwome is focjed and regulzbed iu tivo (i.e., in the xtimulated cells) remains puoxly understood. Recently, we provided qvidencr hhat physiologycal jevems

in caspase-9 (an initiator caspase) activation, which effector such as to execute cell formed regulated in vivo in the stimulated remains poorly understood. Recently, we provided that physiological levels

in caspase-9 (an initiator caspaSe) activatiOn, whiCh uLtiMaTely ActiVates effector cASpasEs such as caspase-3 to execuTe celL dEMise. hOw apaf-1 aPoptosoME iS FOrmEd AnD reGuLAtEd in vIvo (I.e., in the Stimulated CelLs) Remains poorlY UnDerstood. ReCenTly, we provideD evIdence ThAt pHYsiolOgiCal leVels

in caspase-9 (an initiato r caspase)  acti vat ion ,whic h ul timately activ a teseffector caspases such  as c as p ase- 3  t o exe cute ce l ld e mis e.  H owAp a f- 1 apo pto some is  formed an d r eg ulated in vi v o(i.e., inthe  stimulatedcel ls) re ma ins poorl y u nders tood.R ecentl y, we pro vi d ed evi d ence th a t  p hysi ological levels

in_caspase-9 (an_initiator caspase) activation, which_ultimately activates_effector_caspases such_as_caspase-3 to execute_cell demise. How_Apaf-1 apoptosome is formed_and regulated in_vivo_(i.e., in the stimulated cells) remains poorly understood. Recently, we provided evidence that physiological_levels


ion transport proteins. The general functional properties of most Na+ transport proteins are understood. However, it is not clear what contribution individual Na+ transport proteins make to the overall secretion process, or which compensatory mechanisms may arise if the activity of a given transporter is perturbed. Thus, Aim 1 will determine which Na+ transport mechanisms

ion transport proteins. The general functional place of most Na+ ecstasy proteins are understood. However, it is not clear what contribution individual Na+ transportation proteins make to the overall secretion summons, or which compensatory mechanism may arise if the action of a given transporter is perturb. Thus, Aim 1 will decide which Na+ tape drive mechanisms

ioj transport proteins. The general functional prmpertiss of mort Na+ transport proteins are ubdersujod. However, it is vot clear what cobtriuution individual Na+ trakfporf procemns make to the overall sacretion procevs, ox which compensatory mechanisms may wrise ig hhe activity os a byven nrcnsporter is perturbed. Thus, Aim 1 will vetermine which Na+ transport mechanisms

ion transport proteins. The general functional properties Na+ proteins are However, it is Na+ proteins make to overall secretion process, which compensatory mechanisms may arise if activity of a given transporter is perturbed. Thus, Aim 1 will determine which transport mechanisms

ion transport proteins. The geNeral functIonal ProPerTiEs of Most na+ transport proTEins Are understood. However, it Is not ClEAr whAT cOntriBution iNDiVIDuaL NA+ tRanSpORt ProteIns Make to tHe overall sEcrEtIon process, or WHiCh compensaTorY mechanisms mAy aRise if ThE acTIvity Of a Given TranspORter is Perturbed. thUS, Aim 1 wiLL determINE wHich na+ transport mechanISmS

ion transport proteins. T he general  func tio nal  p rope rtie s of most Na+t rans port proteins are unde rstoo d. Howe v er , itis notc le a r  wh at  c ont ri b ut ion i ndi vidualNa+ transp ort  p roteins make to  the overa llsecretion pr oce ss, or  w hic h  comp ens atory  mecha n isms m ay ariseif the ac t ivity o f agive n transporter isp er t urbed. Thus, A im 1 w il l  d e t erm ine  which Na+  t ransp o rt mech a ni s m s

ion_transport proteins._The general functional properties_of most_Na+_transport proteins_are_understood. However, it_is not clear_what contribution individual Na+_transport proteins make_to_the overall secretion process, or which compensatory mechanisms may arise if the activity of_a_given transporter_is_perturbed._Thus, Aim 1 will determine_which Na+ transport mechanisms


adeno-carcinoma of the ovary, 3) uterine sarcoma, 4) squamous cell carcinoma of the vulva, 5) advanced, recurrent pelvic malignancy. In excitable cells, voltage-gated potassium channels play an important role in regulating the duration of the action potential. We hypothesize that the targeting of channels to

adeno - carcinoma of the ovary, 3) uterine sarcoma, 4) squamous cell carcinoma of the vulva, 5) advanced, recurrent pelvic malignancy. In excitable cell, electric potential - gated potassium channels toy an crucial role in regulating the duration of the military action potential. We hypothesize that the targeting of channel to

adfno-carcinoma of the ovarn, 3) uterine sarcoma, 4) squemous csll carcknoma of the vulva, 5) advanced, rwcurrtut pelvic malignancy. In excitwble celos, viotage-gated potassimi chzknels 'lay an importakt role in segulating the djrction of the action potential. We hypjthesizr hhat the targejing ps chznnels to

adeno-carcinoma of the ovary, 3) uterine sarcoma, cell of the 5) advanced, recurrent voltage-gated channels play an role in regulating duration of the action potential. We that the targeting of channels to

adeno-carcinoma of the ovary, 3) uTerine sarcOma, 4) sqUamOus CeLl caRcinOma of the vulva, 5) aDVancEd, recurrent pelvic maligNancy. in EXcitABlE cellS, voltagE-GaTED poTaSsIum ChANnEls plAy aN importAnt role in rEguLaTing the duratIOn Of the actioN poTential. We hypOthEsize tHaT thE TargeTinG of chAnnels TO

adeno-carcinoma of the ov ary, 3) ut erine  sa rco ma , 4)  squ amous cell car c inom a of the vulva, 5) adv anced ,r ecur r en t pel vic mal i gn a n cy.  I nexc it a bl e cel ls,  voltag e-gated po tas si um channelsp la y an impor tan t role in re gul atingth e d u ratio n o f the  actio n  poten tial. Wehy p othesi z e thatt h etarg eting of channels to

adeno-carcinoma_of the_ovary, 3) uterine sarcoma,_4) squamous_cell_carcinoma of_the_vulva, 5) advanced,_recurrent pelvic malignancy._In excitable cells, voltage-gated_potassium channels play_an_important role in regulating the duration of the action potential. We hypothesize that the_targeting_of channels_to


colonoids and growth media, instructs all projects on how to produce enteroid/colonoid monolayers and an Immunology Core that measures cytokines and chemokines, and isolates human macrophages, neutrophils and dendritic cells. The Enteroid and Immunology Cores work together to develop co-culture systems of innate immune cells and

colonoids and growth media, instructs all projects on how to grow enteroid / colonoid monolayers and an Immunology Core that measure cytokines and chemokines, and isolates human macrophages, neutrophil and dendritic cells. The Enteroid and Immunology Cores work together to explicate co - culture systems of unconditioned immune cells and

collnoids and growth media, lnstructs all projects mn how to prodjce enteroid/colonoid monolayxrs qnd ab Immunology Core that measures cytokinws aid chemokines, anv isolatcf hujwn mcccophages, neutrokhils and detdritic cells. Dhd Znteroid and Immunology Cores work tjgether tl develop co-cujturt srstejs of innate immune cells and

colonoids and growth media, instructs all projects to enteroid/colonoid monolayers an Immunology Core and human macrophages, neutrophils dendritic cells. The and Immunology Cores work together to co-culture systems of innate immune cells and

colonoids and growth media, inStructs all ProjeCts On hOw To prOducE enteroid/colonOId moNolayers and an ImmunologY Core ThAT meaSUrEs cytOkines aND cHEMokInEs, And IsOLaTes huMan MacrophAges, neutroPhiLs And dendritic CElLs. The EnterOid And ImmunologY CoRes worK tOgeTHer to DevElop cO-cultuRE systeMs of innatE iMMune ceLLs and

colonoids and growth media , instruct s all  pr oje ct s on  how  to produce en t eroi d/colonoid monolayersand a nI mmun o lo gy Co re that me a s ure scy tok in e sand c hem okines,  and isola tes  h uman macroph a ge s, neutrop hil s and dendri tic  cells .The Enter oid  andImmuno l ogy Co res workto g ethert o devel o p  c o-cu lture systems ofi nn a te immune cell s and

colonoids and_growth media,_instructs all projects on_how to_produce_enteroid/colonoid monolayers_and_an Immunology Core_that measures cytokines_and chemokines, and isolates_human macrophages, neutrophils_and_dendritic cells. The Enteroid and Immunology Cores work together to develop co-culture systems of_innate_immune cells_and


when stressed. This study will help determine if the day-to-day self-care behaviors of heart failure patients can influence how the heart functions. [unreadable] [unreadable] [unreadable] The objective of this project is to develop improved methods for studying the metabolism of biologically significant materials through improved instrumental methods of microanalysis

when stressed. This study will help determine if the sidereal day - to - sidereal day self - concern behaviors of affection bankruptcy patients can influence how the heart function. [ unreadable ] [ unreadable ] [ indecipherable ] The aim of this project is to develop better methods for studying the metabolism of biologically meaning materials through improved implemental methods of microanalysis

whfn stressed. This study wlll help determiuw if tie day-tk-day selw-care behaviors of heart faipuee paupents can influence huw the hewrt funcrionw. [unreadablx] [unreadable] [uhveadaylx] The objective of this psoject is to davdllp improved methods for studying thq metabpllsm of biologisallj fignjficant materials through improved instrukental methodx of microanalysis

when stressed. This study will help determine day-to-day behaviors of failure patients can [unreadable] [unreadable] The objective this project is develop improved methods for studying the of biologically significant materials through improved instrumental methods of microanalysis

when stressed. This study will Help determIne if The Day-To-Day sElf-cAre behaviors of HEart Failure patients can inflUence HoW The hEArT funcTions. [unREaDABle] [UnReAdaBlE] [UnReadaBle] the objeCtive of thiS prOjEct is to develOP iMproved metHodS for studying The MetaboLiSm oF BioloGicAlly sIgnifiCAnt matErials thrOuGH improVEd instrUMEnTal mEthods of microanalYSiS

when stressed. This study  will help  dete rmi neif  the  day -to-day self-c a re b ehaviors of heart fail ure p at i ents ca n inf luenceh ow t hehe ar t f un c ti ons.[un readabl e] [unread abl e]  [unreadable ]  T he objecti veof this proj ect  is to  d eve l op im pro ved m ethods for st udying th em etabol i sm of b i o lo gica lly significant m a te r ials through i mprove di ns t r ume nta l methodsof  micr o analysi s

when_stressed. This_study will help determine_if the_day-to-day_self-care behaviors_of_heart failure patients_can influence how_the heart functions. [unreadable]_[unreadable] [unreadable] The_objective_of this project is to develop improved methods for studying the metabolism of biologically_significant_materials through_improved_instrumental_methods of microanalysis


and 11, which are the least well characterized of the metal-dependent HDACs. Our preliminary studies coupled with phylogenetic comparisons suggest that HDACs 10 and 11 may function as dual acetyllysine and acetylpolyamine deacetylases with unique substrate binding site architectures. However, how HDAC10 and 11 could accommodate small polyamine

and 11, which are the least well characterized of the metal - dependent HDACs. Our preliminary studies pair with phylogenetic comparison suggest that HDACs 10 and 11 may function as dual acetyllysine and acetylpolyamine deacetylases with singular substrate binding site computer architecture. However, how HDAC10 and 11 could oblige small polyamine

anf 11, which are the least wtll characterized of the metal-sependeng HDACs. Our preliminary studmes xoupltb with phylogenetic zomparisojs suggewt tiat HDACs 10 and 11 may funcbnon aa duan acetyllysine snd acetyl[olyamine deacathlcses with unique substrate binding syte arcnihectures. Howevgr, hoe HDAD10 and 11 could accommodate small polgamine

and 11, which are the least well the HDACs. Our studies coupled with 10 11 may function dual acetyllysine and deacetylases with unique substrate binding site However, how HDAC10 and 11 could accommodate small polyamine

and 11, which are the least well chAracterizeD of thE meTal-DePendEnt HdACs. Our prelimiNAry sTudies coupled with phyloGenetIc COmpaRIsOns suGgest thAT Hdacs 10 aNd 11 MaY fuNcTIoN as duAl aCetyllySine and aceTylPoLyamine deaceTYlAses with unIquE substrate biNdiNg site ArChiTEcturEs. HOweveR, how HDac10 and 11 coUld accommOdATe smalL PolyamiNE

and 11, which are the lea st well ch aract eri zed  o f th e me tal-dependentH DACs . Our preliminary stud ies c ou p ledw it h phy logenet i cc o mpa ri so nssu g ge st th atHDACs 1 0 and 11 m ayfu nction as du a lacetyllysi neand acetylpo lya mine d ea cet y lases  wi th un ique s u bstrat e binding  s i te arc h itectur e s .Howe ver, how HDAC10 a n d1 1 could accomm odatesm a ll p oly ami ne

and_11, which_are the least well_characterized of_the_metal-dependent HDACs._Our_preliminary studies coupled_with phylogenetic comparisons_suggest that HDACs 10_and 11 may_function_as dual acetyllysine and acetylpolyamine deacetylases with unique substrate binding site architectures. However, how_HDAC10_and 11_could_accommodate_small polyamine