In addition, our Senior Electronics/Computer Technician Mr. Jeff Struthers will provide 10% effort within the Core to support maintenance of computers and peripheral equipment used in research in all projects and cores. The remainder of his time is distributed among the projects to support each project's unique research equipment electronics and hardware needs.

In addition, our Senior Electronics / Computer Technician Mr. Jeff Struthers will provide 10% effort within the Core to support sustenance of computer and peripheral equipment used in research in all projects and core. The remainder of his time is circulate among the projects to support each undertaking's alone research equipment electronics and hardware indigence.

In addition, our Senior Elegtronics/Computer Technirian Mr. Jeff Stfuthers will provide 10% effort wuthin the Core to support mxintenancv of compyterw and peripisral eqmnpmenf useb mn research in sll projecds and cores. Tve rzmainder of his time is distributed wmong tne projects to sopporu ewch lgomect's unique research equipment slectroiics and hardwate needs.

In addition, our Senior Electronics/Computer Technician Mr. will 10% effort the Core to peripheral used in research all projects and The remainder of his time is among the projects to support each project's unique research equipment electronics and hardware

In addition, our Senior ElectrOnics/CompuTer TeChnIciAn mr. JeFf StRuthers will proVIde 10% eFfort within the Core to suPport MaINtenANcE of coMputers ANd PERipHeRaL eqUiPMeNt useD in ResearcH in all projEctS aNd cores. The reMAiNder of his tIme Is distributeD amOng the PrOjeCTs to sUppOrt eaCh projECt's uniQue researCh EQuipmeNT electrONIcS and Hardware needs.

In addition, our Senior E lectronics /Comp ute r T ec hnic ianMr. Jeff Strut h erswill provide 10% effor t wit hi n  the Co re to  suppor t  m a i nte na nc e o fc om puter s a nd peri pheral equ ipm en t used in re s ea rch in all  pr ojects and c ore s. The  r ema i nderofhis t ime is distri buted amo ng the pr o jects t o su ppor t each project'su ni q ue research eq uipmen te le c t ron ics  and hardw ar e nee d s.

In_addition, our_Senior Electronics/Computer Technician Mr._Jeff Struthers_will_provide 10%_effort_within the Core_to support maintenance_of computers and peripheral_equipment used in_research_in all projects and cores. The remainder of his time is distributed among the_projects_to support_each_project's_unique research equipment electronics and_hardware needs.


more genetically diverse mouse population of mice, namely an outbred population derived from the Collaborative Cross. The primary mapping population is a HS formed from the C57BL/6, DBA.2j, BALB/c and LP strains. Mapping in these HS4 will provide QTL resolution of approximately 1-

more genetically diverse mouse population of mice, namely an outbred population derived from the Collaborative Cross. The basal function population is a HS formed from the C57BL/6, DBA.2j, BALB / c and LP strains. function in these HS4 will provide QTL solution of approximately 1-

moge genetically diverse muuse population of micx, namelg an outcred population derived from tye Coolaborative Cross. The orimary mwpping pipuletion is a HS focjed from the D57NL/6, DBC.2j, BALB/c and LP xtrains. Ma[ping in these HR4 cill provide QTL resolution of approvimatelu 1-

more genetically diverse mouse population of mice, outbred derived from Collaborative Cross. The HS from the C57BL/6, BALB/c and LP Mapping in these HS4 will provide resolution of approximately 1-

more genetically diverse mouSe populatiOn of mIce, NamElY an oUtbrEd population deRIved From the Collaborative CrOss. ThE pRImarY MaPping PopulatIOn IS A HS FoRmEd fRoM ThE C57BL/6, DbA.2j, bALB/c anD LP strains. mapPiNg in these HS4 wILl Provide QTL ResOlution of appRoxImatelY 1-

more genetically diversemouse popu latio n o f m ic e, n amel y an outbred p o pula tion derived from theColla bo r ativ e  C ross.  The pr i ma r y  ma pp in g p op u la tionisa HS fo rmed fromthe  C 57BL/6, DBA. 2 j,  BALB/c an d L P strains. M app ing in  t hes e  HS4wil l pro vide Q T L reso lution of  a p proxim a tely 1-

more_genetically diverse_mouse population of mice,_namely an_outbred_population derived_from_the Collaborative Cross._The primary mapping_population is a HS_formed from the_C57BL/6,_DBA.2j, BALB/c and LP strains. Mapping in these HS4 will provide QTL resolution of_approximately_1-


the skills needed for educational and career success. The long term aim of the proposed research is to define the molecular structure and function of the midkine signal transduction pathway which regulates cellular proliferation and differentiation Special emphasis in this effort is placed on the molecular cloning of the cell surface Midkine signal transduction receptor which we have recently

the skills needed for educational and career success. The long condition purpose of the proposed research is to define the molecular social organization and function of the midkine signal transduction pathway which regulates cellular proliferation and specialization particular emphasis in this attempt is placed on the molecular cloning of the cell airfoil Midkine signal transduction receptor which we have recently

thf skills needed for educxtional and cargee succxss. The long tefm aim of the proposed reseacch us to define the molecular rtructure and funxtioi of the midkine signal bxansdhgtion 'athway which rggulates celnular proliferdtkou and differentiation Special emphasys in tnid effort is plwced jn tgv nolecular cloning of the cell surfact Midkine signal ttansduction receptor which we jave recently

the skills needed for educational and career long aim of proposed research is and of the midkine transduction pathway which cellular proliferation and differentiation Special emphasis this effort is placed on the molecular cloning of the cell surface Midkine transduction receptor which we have recently

the skills needed for educatiOnal and carEer suCceSs. THe Long Term Aim of the proposED resEarch is to define the moleCular StRUctuRE aNd funCtion of THe MIDkiNe SiGnaL tRAnSductIon Pathway Which regulAteS cEllular proliFErAtion and diFfeRentiation SpEciAl emphAsIs iN This eFfoRt is pLaced oN The molEcular cloNiNG of the CEll surfACE MIdkiNe signal transductIOn REceptor which we Have reCeNTlY

the skills needed for edu cational a nd ca ree r s uc cess . Th e long term ai m  ofthe proposed researchis to  d e fine th e mol eculars tr u c tur ean d f un c ti on of  th e midki ne signaltra ns duction path w ay  which reg ula tes cellular  pr olifer at ion and d iff erent iation Specia l emphasi si n this efforti s  p lace d on the molecula r  c l oning of the c ell su rf a ce M idk ine  signal tr an sduct i on rece p to r w hic h  we have rece ntly

the_skills needed_for educational and career_success. The_long_term aim_of_the proposed research_is to define_the molecular structure and_function of the_midkine_signal transduction pathway which regulates cellular proliferation and differentiation Special emphasis in this effort_is_placed on_the_molecular_cloning of the cell surface_Midkine signal transduction receptor which_we have_recently


of HCV, including some of those discovered in this laboratory, are being biologically amplified in chimpanzees, packaged and distributed for use as challenge inocula in studies of passive and active immunoprophylaxis, etc. Full-length cDNA clones of HCV (genotypes 1a, 1b and 2a)

of HCV, including some of those discovered in this laboratory, are being biologically amplified in chimpanzee, box and distribute for use as challenge inoculant in studies of passive and active immunoprophylaxis, etc. broad - length complementary dna clone of HCV (genotypes 1a, 1b and 2a )

of HCV, including some of tmose discovered nb this laborztory, ard being biologically amplifixd ib chinpanzees, packaged and aistributvd for usw as xhallenge mhocula lu stusles oy 'assive and actlve immunopsophylaxis, etc. Fjlp-length cDNA clones of HCV (genotypef 1a, 1b amd 2a)

of HCV, including some of those discovered laboratory, being biologically in chimpanzees, packaged challenge in studies of and active immunoprophylaxis, Full-length cDNA clones of HCV (genotypes 1b and 2a)

of HCV, including some of those Discovered In thiS laBorAtOry, aRe beIng biologicallY AmplIfied in chimpanzees, packAged aNd DIstrIBuTed foR use as cHAlLENge InOcUla In STuDies oF paSsive anD active immUnoPrOphylaxis, etc. fUlL-length cDNa clOnes of HCV (genOtyPes 1a, 1b aNd 2A)

of HCV, including some of  those dis cover edinth is l abor atory, are bei n g bi ologically amplified i n chi mp a nzee s ,packa ged and di s t rib ut ed  fo ru se  as c hal lenge i nocula instu di es of passiv e  a nd activeimm unoprophylax is,  etc.Fu ll- l ength  cD NA cl ones o f  HCV ( genotypes  1 a , 1b a n d 2a)

of_HCV, including_some of those discovered_in this_laboratory,_are being_biologically_amplified in chimpanzees,_packaged and distributed_for use as challenge_inocula in studies_of_passive and active immunoprophylaxis, etc. Full-length cDNA clones of HCV (genotypes 1a, 1b and_2a)


processes involving RNA; specifically the nuclear DEAD-box RNA helicases p68 and p72 have been shown to be required for the processing of microRNA primary transcripts. MicroRNAs are critical for normal developmental processes are disregulated under pathological conditions. We demonstrate that Csm physically interacts with argonaute-2, a

processes involving RNA; specifically the nuclear DEAD - box RNA helicases p68 and p72 have been testify to be command for the processing of microRNA primary transcripts. MicroRNAs are critical for normal developmental processes are disregulated under diseased conditions. We demonstrate that Csm physically interacts with argonaute-2, a

prlcesses involving RNA; sptcifically the nueoear DXAD-box DNA helizases p68 and p72 have been showi to be rtzuired for the prozessing ov microRBA pcimary transcripva. MicroVUAs adc criciral for normal cevelopmendal processes drd bisregulated under pathological condytions. Ee demonstrate trat Bsi phgsically interacts with argonaute-2, z

processes involving RNA; specifically the nuclear DEAD-box p68 p72 have shown to be microRNA transcripts. MicroRNAs are for normal developmental are disregulated under pathological conditions. We that Csm physically interacts with argonaute-2, a

processes involving RNA; specIfically thE nuclEar dEAd-bOx RNa helIcases p68 and p72 havE Been Shown to be required for thE procEsSIng oF MiCroRNa primarY TrANScrIpTs. micRornAS are cRitIcal for Normal deveLopMeNtal processeS ArE disregulaTed Under patholoGicAl condItIonS. we demOnsTrate That CsM PhysicAlly interAcTS with aRGonaute-2, A

processes involving RNA;specifical ly th e n ucl ea r DE AD-b ox RNA helicas e s p6 8 and p72 have been sh own t ob e re q ui red f or thep ro c e ssi ng  o f m ic r oR NA pr ima ry tran scripts. M icr oR NAs are crit i ca l for norm aldevelopmenta l p rocess es  ar e  disr egu lated  under pathol ogical co nd i tions. We demo n s tr atethat Csm physical l yi nteracts withargona ut e -2 , a

processes_involving RNA;_specifically the nuclear DEAD-box_RNA helicases_p68_and p72_have_been shown to_be required for_the processing of microRNA_primary transcripts. MicroRNAs_are_critical for normal developmental processes are disregulated under pathological conditions. We demonstrate that Csm_physically_interacts with_argonaute-2,_a


efficient transgene delivery to classified neurons. First, we will synthesize massive libraries of mutated AAV vectors and synthetic promoters, in which each variant is paired with a unique DNA barcode. We will then scRNA-Seq to capture the transcriptome for each cell and quantify the AAV and promoter- specific barcodes in every cell

efficient transgene delivery to classified neurons. First, we will synthesize massive library of mutate AAV vectors and synthetic promoter, in which each form is paired with a unique deoxyribonucleic acid barcode. We will then scRNA - Seq to capture the transcriptome for each cell and quantify the AAV and promoter- specific barcodes in every cell

efvicient transgene delivevy to classified neuronv. Firsf, we wilu synthesize massive librarixs od mutqted AAV vectors and shnthetic iromoters, in xhich each variaif is palxed wjbh a bnmque DNA barcodg. We will than scRNA-Seq to cxpcure the transcriptome for each cell and qusnhify the AAV agd pgoioted- specific barcodes in every cell

efficient transgene delivery to classified neurons. First, synthesize libraries of AAV vectors and variant paired with a DNA barcode. We then scRNA-Seq to capture the transcriptome each cell and quantify the AAV and promoter- specific barcodes in every cell

efficient transgene deliverY to classifIed neUroNs. FIrSt, we Will Synthesize massIVe liBraries of mutated AAV vecTors aNd SYnthETiC promOters, in WHiCH EacH vArIanT iS PaIred wIth A unique dNA barcode. we wIlL then scRNA-SeQ To Capture the TraNscriptome foR eaCh cell AnD quANtify The aAV anD promoTEr- specIfic barcoDeS In everY Cell

efficient transgene deliv ery to cla ssifi edneu ro ns.Firs t, we will syn t hesi ze massive libraries o f mut at e d AA V  v ector s and s y nt h e tic  p ro mot er s ,in wh ich  each v ariant ispai re d with a uni q ue  DNA barco de.  We will the n s cRNA-S eq  to captu rethe t ranscr i ptomefor eachce l l andq uantify t he  AAV  and promoter- sp e ci f ic barcodes in  every  c e ll

efficient_transgene delivery_to classified neurons. First,_we will_synthesize_massive libraries_of_mutated AAV vectors_and synthetic promoters,_in which each variant_is paired with_a_unique DNA barcode. We will then scRNA-Seq to capture the transcriptome for each cell_and_quantify the_AAV_and_promoter- specific barcodes in every_cell


, dormant and proliferative tumor cell phenotypes. 5. Extend key observations to human breast and head and neck squamous tumors. Support is requested for 9 predoctoral and 6 postdoctoral positions to establish a training program in the interdisciplinary area of Pharmacoinformatics. This program is proposed because current approaches to the discovery of

, dormant and proliferative tumor cell phenotypes. 5. Extend cardinal observation to human breast and head and neck squamous tumors. documentation is request for 9 predoctoral and 6 postdoctoral positions to establish a education program in the interdisciplinary area of Pharmacoinformatics. This program is propose because current approaches to the discovery of

, dogmant and proliferative uumor cell phenotipws. 5. Exvend keg observxtions to human breast and hxad qnd ntbk squamous tumors. Suoport is gequested for 9 predoctorem and 6 ijstdkgtoran positions to gstablish a draining progrdm iu the interdisciplinary area of Phariacoinfprlatics. This prjgrak is lgokosed because current approaches fo the viscovery of

, dormant and proliferative tumor cell phenotypes. key to human and head and requested 9 predoctoral and postdoctoral positions to a training program in the interdisciplinary of Pharmacoinformatics. This program is proposed because current approaches to the discovery of

, dormant and proliferative tuMor cell pheNotypEs. 5. EXteNd Key oBserVations to human BReasT and head and neck squamouS tumoRs. sUppoRT iS requEsted foR 9 PrEDOctOrAl And 6 PoSTdOctorAl pOsitionS to establiSh a TrAining prograM In The interdiSciPlinary area oF PhArmacoInForMAtics. thiS progRam is pROposed Because cuRrENt apprOAches to THE dIscoVery of

, dormant and proliferativ e tumor ce ll ph eno typ es . 5.  Ext end key observ a tion s to human breast andheadan d  nec k  s quamo us tumo r s. S upp or tisre q ue stedfor  9 pred octoral an d 6  p ostdoctoralp os itions toest ablish a tra ini ng pro gr ami n the  in terdi scipli n ary ar ea of Pha rm a coinfo r matics. T hi s pr ogram is proposed be c ause current a pproac he s  t o the  di scovery of

, dormant_and proliferative_tumor cell phenotypes. 5._Extend key_observations_to human_breast_and head and_neck squamous tumors._Support is requested for_9 predoctoral and_6_postdoctoral positions to establish a training program in the interdisciplinary area of Pharmacoinformatics. This_program_is proposed_because_current_approaches to the discovery of


be generated in which ADAR2 levels have been altered by over expression or by selective ablation of ADAR2 auto editing. Multiple, independent mouse lines will be assessed for gross alterations in animal phenotype, changes in the level of ADAR2 expression/activity, alterations in editing patterns for previously identified ADAR2 substrates and

be generated in which ADAR2 levels have been altered by over expression or by selective ablation of ADAR2 car editing. Multiple, autonomous shiner lines will be assessed for gross alteration in animal phenotype, changes in the level of ADAR2 construction / activeness, alterations in edit patterns for previously identified ADAR2 substrate and

be generated in which ADAR2 levels have begn alterxd by ober exprdssion or by selective ablatmon if ADQR2 auto editing. Multipue, indepejdent moyse ounes will us assessed fod grovw alterations ln animal pvenotype, changas iu the level of ADAR2 expression/activiey, altetahions in editigg pseterhs for previously identified ADAR2 aubstraues and

be generated in which ADAR2 levels have by expression or selective ablation of mouse will be assessed gross alterations in phenotype, changes in the level of expression/activity, alterations in editing patterns for previously identified ADAR2 substrates and

be generated in which ADAR2 levEls have beeN alteRed By oVeR expRessIon or by selectiVE ablAtion of ADAR2 auto editing. multiPlE, IndePEnDent mOuse linES wILL be AsSeSseD fOR gRoss aLteRations In animal phEnoTyPe, changes in tHE lEvel of ADAR2 ExpRession/activIty, AlteraTiOns IN editIng PatteRns for PReviouSly identiFiED ADAR2 sUBstrateS ANd

be generated in which ADA R2 levelshavebee n a lt ered  byover expressio n  orby selective ablationof AD AR 2  aut o  e ditin g. Mult i pl e ,  in de pe nde nt mo use l ine s willbe assesse d f or  gross alter a ti ons in ani mal  phenotype,cha nges i nthe level  of  ADAR 2 expr e ssion/ activity,  a l terati o ns in e d i ti ng p atterns for previ o us l y identified A DAR2 s ub s tr a t esand

be_generated in_which ADAR2 levels have_been altered_by_over expression_or_by selective ablation_of ADAR2 auto_editing. Multiple, independent mouse_lines will be_assessed_for gross alterations in animal phenotype, changes in the level of ADAR2 expression/activity, alterations_in_editing patterns_for_previously_identified ADAR2 substrates and


more than 90% of the times. Peto's formula overestimated the true variance when the survival rates were less than or equal to 0.5. The accuracy of the three different variance estimators is investigated using the relative bias, mean square error and confidence coefficient criteria. the absolute value of the relative bias for the modified

more than 90% of the times. Peto's formula overestimated the true discrepancy when the survival pace were less than or equal to 0.5. The accuracy of the three different variance calculator is investigated using the relative diagonal, intend square error and confidence coefficient criteria. the absolute value of the proportional bias for the modified

moge than 90% of the times. Peuo's formula overestimatev the tdue varixnce when the survival rates wwre ltfs than or equal tu 0.5. The acburacy of the rhree diffxdent vavnance cstimctirs is investinated using the relative tixs, mean square error and confidence cjefficirnh criteria. the abspjute naoue of the relative bias for fhe modpfied

more than 90% of the times. Peto's the variance when survival rates were 0.5. accuracy of the different variance estimators investigated using the relative bias, mean error and confidence coefficient criteria. the absolute value of the relative bias for modified

more than 90% of the times. Peto's foRmula overeStimaTed The TrUe vaRianCe when the surviVAl raTes were less than or equal To 0.5. The AcCUracY Of The thRee diffEReNT VarIaNcE esTiMAtOrs is InvEstigatEd using the RelAtIve bias, mean sQUaRe error and ConFidence coeffIciEnt criTeRia. THe absOluTe valUe of thE RelatiVe bias for ThE ModifiED

more than 90% of the time s. Peto'sformu laove re stim ated  the true vari a ncewhen the survival rate s wer el esst ha n orequal t o  0 . 5 . T he  a ccu ra c yof th e t hree di fferent va ria nc e estimators is  investiga ted  using the r ela tive b ia s,m ean s qua re er ror an d  confi dence coe ff i cientc riteria . th e ab solute value of t h er elative bias f or the  m o di f i ed

more_than 90%_of the times. Peto's_formula overestimated_the_true variance_when_the survival rates_were less than_or equal to 0.5._The accuracy of_the_three different variance estimators is investigated using the relative bias, mean square error and_confidence_coefficient criteria._the_absolute_value of the relative bias_for the modified


the localized energy depositions from I-125 disintegrations will be used to ask about the basis of aberration formation. Mammalian cells (human and hamster) will be irradiated at different stages of the cell cycle and the frequencies and types of chromosomal changes, cell survival and cytokinetic changes monitored. Low

the localized energy depositions from I-125 disintegrations will be use to necessitate about the basis of aberration constitution. Mammalian cell (human and hamster) will be irradiated at different stage of the cellular telephone cycle and the frequencies and types of chromosomal changes, cell survival and cytokinetic change monitored. Low

thf localized energy deposltions from I-125 disintegretions sill be jsed to ask about the basis lf abereation formation. Mammauian celld (human qnd iamster) will be mdradiatcb at slfferznv stages of the cell cycla and the freqgevcnes and types of chromosomal changes, cell sirgival and cytohineuic chahges monitored. Low

the localized energy depositions from I-125 disintegrations used ask about basis of aberration hamster) be irradiated at stages of the cycle and the frequencies and types chromosomal changes, cell survival and cytokinetic changes monitored. Low

the localized energy depositIons from I-125 dIsintEgrAtiOnS wilL be uSed to ask about tHE basIs of aberration formatioN. MammAlIAn ceLLs (Human And hamsTEr) WILl bE iRrAdiAtED aT diffEreNt stageS of the cell CycLe And the frequeNCiEs and types Of cHromosomal chAngEs, cell SuRviVAl and CytOkineTic chaNGes monItored. Low

the localized energy depo sitions fr om I- 125  di si nteg rati ons will be us e d to  ask about the basis o f abe rr a tion fo rmati on. Mam m al i a n c el ls  (h um a nand h ams ter) wi ll be irra dia te d at differe n tstages ofthe  cell cycleand  the f re que n ciesand  type s of c h romoso mal chang es ,  cells urvival a nd  cyt okinetic changesm on i tored. Low

the_localized energy_depositions from I-125 disintegrations_will be_used_to ask_about_the basis of_aberration formation. Mammalian_cells (human and hamster)_will be irradiated_at_different stages of the cell cycle and the frequencies and types of chromosomal changes,_cell_survival and_cytokinetic_changes_monitored. Low


in applying these novel technologies. Therefore, the Special Scientific Procedures Core: Genomics plays a critical supportive role in the proposed CIDAR. The Genomics Core has three primary aims, necessary to the completion of CIDAR goals: (1) to provide basic laboratory services to CIDAR investigators such as blood draws

in applying these novel technologies. Therefore, the Special Scientific Procedures Core: Genomics toy a critical supportive function in the proposed CIDAR. The Genomics Core has three primary aims, necessary to the completion of CIDAR finish: (1) to provide basic laboratory serve to CIDAR investigator such as blood draws

in applying these novel teghnologies. Thereyire, thx Specizl Sciengific Procedures Core: Genomirs poays q critical supportive fole in tje propowed RIDAR. The Genomira Core mcs thdce prnmery aims, necesssry to the completion of CKDCR goals: (1) to provide basic laboratorr servived to CIDAR invgstigseors such as blood draws

in applying these novel technologies. Therefore, the Procedures Genomics plays critical supportive role Genomics has three primary necessary to the of CIDAR goals: (1) to provide laboratory services to CIDAR investigators such as blood draws

in applying these novel technOlogies. TheReforE, thE SpEcIal SCienTific ProcedureS core: genomics plays a critical SuppoRtIVe roLE iN the pRoposed ciDar. the geNoMicS CORe Has thRee Primary Aims, necessAry To The completioN Of cIDAR goals: (1) To pRovide basic lAboRatory SeRviCEs to CiDAr inveStigatORs such As blood drAwS

in applying these novel t echnologie s. Th ere for e,  the  Spe cial Scientifi c  Pro cedures Core: Genomics  play sa  cri t ic al su pportiv e  r o l e i nth e p ro p os ed CI DAR . The G enomics Co reha s three prim a ry  aims, nec ess ary to the c omp letion  o f C I DAR g oal s: (1 ) to p r ovidebasic lab or a tory s e rvicest o  C IDAR  investigators su c ha s blood draws

in_applying these_novel technologies. Therefore, the_Special Scientific_Procedures_Core: Genomics_plays_a critical supportive_role in the_proposed CIDAR. The Genomics_Core has three_primary_aims, necessary to the completion of CIDAR goals: (1) to provide basic laboratory services_to_CIDAR investigators_such_as_blood draws


fiscal responsibility and regulatory compliance; and Aim 3. Manage lead prioritization and documentation, the refinement of the Product Development Plan and a path to Commercialization. [unreadable] While much progress has been made to control preventable infectious diseases, infections remain a major cause of morbidity and mortality. Many of the traditional treatments for

fiscal responsibility and regulatory compliance; and Aim 3. Manage spark advance prioritization and software documentation, the refinement of the Product Development Plan and a path to Commercialization. [ indecipherable ] While much progress has been make to control preventable infectious diseases, contagion remain a major cause of unwholesomeness and deathrate. Many of the traditional treatments for

fidcal responsibility and vegulatory complnqnce; aid Aim 3. Manage uead prioritization and doculebtatiin, the refinement of tfe Producn Developnent Plan and a path to Commedgialivavion. [unreadable] While mucv progress has bdeu made to control preventable infectyous dixewses, infectionf rekwin z major cause of morbidity and morfality. Kany of the ttaditional treatments for

fiscal responsibility and regulatory compliance; and Aim lead and documentation, refinement of the path Commercialization. [unreadable] While progress has been to control preventable infectious diseases, infections a major cause of morbidity and mortality. Many of the traditional treatments for

fiscal responsibility and reGulatory coMpliaNce; And aiM 3. ManAge lEad prioritizatIOn anD documentation, the refinEment Of THe PrODuCt DevElopmenT plAN And A pAtH to coMMeRcialIzaTion. [unrEadable] WhiLe mUcH progress has BEeN made to conTroL preventable InfEctiouS dIseASes, inFecTions Remain A Major cAuse of morBiDIty and MOrtalitY. mAnY of tHe traditional treaTMeNTs for

fiscal responsibility and  regulator y com pli anc e;  and  Aim  3. Manage lea d  pri oritization and docume ntati on ,  the re finem ent oft he P rod uc tDev el o pm ent P lan  and apath to Co mme rc ialization.[ un readable]Whi le much prog res s hasbe enm ade t o c ontro l prev e ntable  infectio us diseas e s, infe c t io ns r emain a major cau s eo f morbidity an d mort al i ty . Man y o f the trad it ional treatme n ts f o r

fiscal_responsibility and_regulatory compliance; and Aim_3. Manage_lead_prioritization and_documentation,_the refinement of_the Product Development_Plan and a path_to Commercialization. [unreadable]_While_much progress has been made to control preventable infectious diseases, infections remain a major_cause_of morbidity_and_mortality._Many of the traditional treatments_for


miRNA therapies in combination with currently used chemotherapies and targeted-therapeutics in cell culture, xenografts and in the Kras;p53 double mutant. This work is novel, timely and has clear and significant implications for human health and survival. The identification of miRNAs and targeted-therapies to perturb miRNA imbalance

miRNA therapies in combination with currently used chemotherapies and target - remedy in cellular telephone culture, xenografts and in the Kras;p53 double mutant. This study is novel, timely and has absolved and meaning implications for human health and survival. The identification of miRNAs and targeted - therapies to perturb miRNA imbalance

miGNA therapies in combinauion with currently used chemofherapier and targeted-therapeutics ii ceol cuoture, xenografts and iv the Krad;p53 doublw muuant. This work is novel, tliely wnd kaw clear and sinnificant ikplications fos fulan health and survival. The identifycation ov miRNAs and twrgeued-eherziits to perturb miRNA imbalance

miRNA therapies in combination with currently used targeted-therapeutics cell culture, and in the is timely and has and significant implications human health and survival. The identification miRNAs and targeted-therapies to perturb miRNA imbalance

miRNA therapies in combinatiOn with currEntly UseD chEmOtheRapiEs and targeted-tHErapEutics in cell culture, xenOgrafTs ANd in THe kras;p53 Double mUTaNT. thiS wOrK is NoVEl, TimelY anD has cleAr and signiFicAnT implicationS FoR human healTh aNd survival. ThE idEntifiCaTioN Of miRnAs And taRgeted-THerapiEs to pertuRb MIRNA imBAlance

miRNA therapies in combin ation with  curr ent lyus ed c hemo therapies andt arge ted-therapeutics in ce ll cu lt u re,x en ograf ts andi nt h e K ra s; p53  d o ub le mu tan t. This  work is n ove l,  timely andh as  clear and  si gnificant im pli cation sfor human  he althand su r vival.  The iden ti f icatio n  of miR N A sandtargeted-therapie s  t o  perturb miRNA  imbal an c e

miRNA_therapies in_combination with currently used_chemotherapies and_targeted-therapeutics_in cell_culture,_xenografts and in_the Kras;p53 double_mutant. This work is_novel, timely and_has_clear and significant implications for human health and survival. The identification of miRNAs and_targeted-therapies_to perturb_miRNA_imbalance


be analyzed for differences in intracellular localization;and 3) a search will be conducted for Akt2-specific substrates. It is anticipated that these studies will significantly extend the knowledge of physiological insulin-independent signaling and ultimately lead to the identification of potential targets for therapeutic intervention in diabetes mellitus. The spatial distribution of energy from ionizing

be analyzed for differences in intracellular localization;and 3) a search will be conducted for Akt2 - specific substrates. It is anticipate that these cogitation will significantly cover the cognition of physiological insulin - independent signaling and ultimately conduct to the identification of potential target for therapeutic intervention in diabetes mellitus. The spatial distribution of department of energy from ionizing

be analyzed for differencer in intracellular locelizatikn;and 3) a search will be conducted foc Akr2-specufic substrates. It is xnticipatvd that tyese wtudies will signinncantmn extznv the knowledge of physionogical insulit-ivdzpendent signaling and ultimately lewd to tne identificatiog of [otehnicl targets for therapeutic intedventioi in diabetes mrllitus. The spatial distrihutiln of energy from lonizing

be analyzed for differences in intracellular localization;and search be conducted Akt2-specific substrates. It will extend the knowledge physiological insulin-independent signaling ultimately lead to the identification of targets for therapeutic intervention in diabetes mellitus. The spatial distribution of energy from

be analyzed for differences iN intracellUlar lOcaLizAtIon;aNd 3) a sEarch will be conDUcteD for Akt2-specific substraTes. It Is ANticIPaTed thAt these STuDIEs wIlL sIgnIfICaNtly eXteNd the knOwledge of pHysIoLogical insulIN-iNdependent SigNaling and ultImaTely leAd To tHE idenTifIcatiOn of poTEntial Targets foR tHErapeuTIc interVENtIon iN diabetes mellitus. tHe SPatial distribuTion of EnERgY FRom IonIzing

be analyzed for differenc es in intr acell ula r l oc aliz atio n;and 3) a sea r ch w ill be conducted for A kt2-s pe c ific su bstra tes. It is a nti ci pa ted  t h at  thes e s tudieswill signi fic an tly extend t h eknowledgeofphysiologica l i nsulin -i nde p enden t s ignal ing an d  ultim ately lea dt o thei dentifi c a ti on o f potential targe t sf or therapeutic  inter ve n ti o n  in  di abetes mel li tus.T he spat i al d i str i bution of ene rgy from io n izi ng

be_analyzed for_differences in intracellular localization;and_3) a_search_will be_conducted_for Akt2-specific substrates._It is anticipated_that these studies will_significantly extend the_knowledge_of physiological insulin-independent signaling and ultimately lead to the identification of potential targets for_therapeutic_intervention in_diabetes_mellitus._The spatial distribution of energy_from ionizing


cell apoptosis, proliferation, invasion, and metastasis. Specifically, the FAT domain interacts with the alpha helical LD2 and LD4 motifs of Paxillin to promote its biological effects. The structure of the FAT-Paxillin complex has been solved by x-ray crystallography however has been challenging to target with small molecules

cell apoptosis, proliferation, invasion, and metastasis. Specifically, the FAT domain interacts with the alpha helical LD2 and LD4 theme of Paxillin to advertise its biological effects. The structure of the FAT - Paxillin building complex has been solved by adam - ray crystallography however has been challenging to target with little molecules

cepl apoptosis, proliferatiun, invasion, and metastesis. Spscificaluy, the FAT domain interacts xith the qlpha helical LD2 and LA4 motifs lf Paxiloin uo promote its biological effecfd. Thz wtructure of tme FAT-Paxilnin complex hav cezn solved by x-ray crystallography horever hss been challengyng uo eargsn cith small molecules

cell apoptosis, proliferation, invasion, and metastasis. Specifically, domain with the helical LD2 and promote biological effects. The of the FAT-Paxillin has been solved by x-ray crystallography has been challenging to target with small molecules

cell apoptosis, proliferatioN, invasion, aNd metAstAsiS. SPeciFicaLly, the FAT domaiN InteRacts with the alpha helicAl LD2 aNd ld4 motIFs Of PaxIllin to PRoMOTe iTs BiOloGiCAl EffecTs. THe strucTure of the FaT-PAxIllin complex HAs Been solved By x-Ray crystalloGraPhy howEvEr hAS been ChaLlengIng to tARget wiTh small moLeCUles

cell apoptosis, prolifera tion, inva sion,  an d m et asta sis.  Specifically, theFAT domain interacts w ith t he alph a  h elica l LD2 a n dL D 4 m ot if s o fP ax illin  to  promot e its biol ogi ca l effects. T h estructureofthe FAT-Paxi lli n comp le x h a s bee n s olved  by x- r ay cry stallogra ph y  howev e r has b e e nchal lenging to target wi t h small molecu les

cell_apoptosis, proliferation,_invasion, and metastasis. Specifically,_the FAT_domain_interacts with_the_alpha helical LD2_and LD4 motifs_of Paxillin to promote_its biological effects._The_structure of the FAT-Paxillin complex has been solved by x-ray crystallography however has been_challenging_to target_with_small_molecules


photon counting to systems with fluorescence quenching. Second, we introduced a new and simpler to use method of analyzing single-molecule data (2). Third, we applied (3) this new method to interpret fluorescence resonance energy tranfer in polyproline (in collaboration with the W.A. Eaton's group,

photon counting to systems with fluorescence quenching. Second, we introduced a newfangled and bare to use method of analyzing unmarried - molecule data (2). Third, we lend oneself (3) this new method to rede fluorescence resonance energy tranfer in polyproline (in collaboration with the W.A. Eaton's group,

phlton counting to systems with fluoresceuxe queiching. Aecond, wd introduced a new and simplxr ti use method of analyzing skngle-molebule data (2). Thmrd, we applied (3) vgis new methos to nnverpret fluoresgence resondnce energy trdnwex in polyproline (in collaboration wieh the E.A. Eaton's group,

photon counting to systems with fluorescence quenching. introduced new and to use method Third, applied (3) this method to interpret resonance energy tranfer in polyproline (in with the W.A. Eaton's group,

photon counting to systems wiTh fluorescEnce qUenChiNg. secoNd, we Introduced a new ANd siMpler to use method of analYzing SiNGle-mOLeCule dAta (2). ThirD, We APPliEd (3) ThIs nEw MEtHod to IntErpret fLuorescencE reSoNance energy tRAnFer in polypRolIne (in collaboRatIon witH tHe W.a. eaton'S grOup,

photon counting to system s with flu oresc enc e q ue nchi ng.Second, we int r oduc ed a new and simpler t o use  m e thod of  anal yzing s i ng l e -mo le cu leda t a(2).Thi rd, weapplied (3 ) t hi s new method to  interpret  fl uorescence r eso nanceen erg y  tran fer  in p olypro l ine (i n collabo ra t ion wi t h the W . A .Eato n's group,

photon_counting to_systems with fluorescence quenching._Second, we_introduced_a new_and_simpler to use_method of analyzing_single-molecule data (2). Third,_we applied (3)_this_new method to interpret fluorescence resonance energy tranfer in polyproline (in collaboration with the_W.A._Eaton's group,


of high quality animal resources. To meet these objectives we propose three major projects within the animal resources program: 1. Renovate animal surgery facilities to provide a suitable environment for recovery surgery and meet DHHS guidelines. 2. Improve satellite animal housing facilities to meet DHHS guidelines. (No funds are requested for this project

of high quality animal resources. To meet these aim we nominate three major projects within the animal resources program: 1. animate animal surgery facilities to supply a suitable environment for recovery operating room and meet DHHS guidelines. 2. better satellite animal housing facilities to suffer DHHS guidepost. (No funds are requested for this project

of high quality animal resuurces. To meet jhwse oboectivea we prooose three major projects wivhin the qnimal resources progrxm: 1. Renovwte animql snrgery facilities to proynde a duitcboe environment for recovary surgery ang oezt DHHS guidelines. 2. Improve satellitq animak jousing facilijies uo ieet DHHS guidelines. (No funds are requssted fmr this projevt

of high quality animal resources. To meet we three major within the animal surgery to provide a environment for recovery and meet DHHS guidelines. 2. Improve animal housing facilities to meet DHHS guidelines. (No funds are requested for this

of high quality animal resourCes. To meet tHese oBjeCtiVeS we pRopoSe three major prOJectS within the animal resourCes prOgRAm: 1. ReNOvAte anImal surGErY FAciLiTiEs tO pROvIde a sUitAble envIronment foR reCoVery surgery aND mEet DHHS guiDelInes. 2. Improve sAteLlite aNiMal HOusinG faCilitIes to mEEt DHHS GuidelineS. (NO Funds aRE requesTED fOr thIs project

of high quality animal re sources. T o mee t t hes eobje ctiv es we proposet hree  major projects within  thean i malr es ource s progr a m: 1 . R en ov ate  a n im al su rge ry faci lities topro vi de a suitabl e  e nvironment  fo r recovery s urg ery an dmee t  DHHS  gu ideli nes. 2 .  Impro ve satell it e  anima l  housin g fa cili ties to meet DHHS gu i delines. (No f unds a re re q u est edfor this p ro ject

of_high quality_animal resources. To meet_these objectives_we_propose three_major_projects within the_animal resources program:_1. Renovate animal surgery_facilities to provide_a_suitable environment for recovery surgery and meet DHHS guidelines. 2. Improve satellite animal housing_facilities_to meet_DHHS_guidelines._(No funds are requested for_this project


, we propose to investigate in greater detail the effects of guanine nucleotide depletion on DNA synthesis and cell cycle progression. The relative expression of IMPDH I and II during the cell cycle and as a function of cellular proliferation will be examined in normal and neoplastic cell lines. Genomic clones containing the regulatory regions for the two genes

, we propose to investigate in greater detail the effects of guanine nucleotide depletion on deoxyribonucleic acid deduction and cellular telephone cycle progression. The relative formulation of IMPDH I and II during the cell cycle and as a routine of cellular proliferation will be examine in normal and neoplastic cell credit line. Genomic clones containing the regulative regions for the two genes

, we propose to investigate ln greater detail the ehfects kf guanive nucleotide depletion on DIA stnthewis and cell cycle proeression. Nhe relatuve txpression of IMPVG I and II dudlng tke cell cycle anc as a funwtion of cellunaf 'roliferation will be examined in nowmal anc jeoplastic celj limqs. Gsnomic clones containing the regulztory rtgions for the two genes

, we propose to investigate in greater effects guanine nucleotide on DNA synthesis relative of IMPDH I II during the cycle and as a function of proliferation will be examined in normal and neoplastic cell lines. Genomic clones containing regulatory regions for the two genes

, we propose to investigate in gReater detaIl the EffEctS oF guaNine Nucleotide deplETion On DNA synthesis and cell cYcle pRoGRessIOn. the reLative eXPrESSioN oF ImPDh I ANd iI durIng The cell Cycle and as A fuNcTion of cellulAR pRoliferatiOn wIll be examineD in Normal AnD neOPlastIc cEll liNes. GenOMic cloNes contaiNiNG the reGUlatory REGiOns fOr the two genes

, we propose to investigat e in great er de tai l t he  eff ects  of guanine nu c leot ide depletion on DNA s ynthe si s  and ce ll cy cle pro g re s s ion .Th e r el a ti ve ex pre ssion o f IMPDH Iand  I I during the ce ll cycle a ndas a functio n o f cell ul arp rolif era tionwill b e  exami ned in no rm a l andn eoplast i c  c elllines. Genomic cl o ne s  containing th e regu la t or y reg ion s for thetw o gen e s

, we_propose to_investigate in greater detail_the effects_of_guanine nucleotide_depletion_on DNA synthesis_and cell cycle_progression. The relative expression_of IMPDH I_and_II during the cell cycle and as a function of cellular proliferation will be_examined_in normal_and_neoplastic_cell lines. Genomic clones containing_the regulatory regions for the_two genes


treatment with cisplatin and IR is well-tolerated and leads to durable responses in mouse xenograft and genetic models of lung cancer. Quite unexpectedly, we show that in addition to potentiating DNA damage, two clinical ATR kinase inhibitors (ATRi?s), with unrelated structures, block expression of the immune checkpoint protein PD

treatment with cisplatin and IR is well - tolerated and leads to durable responses in shiner heterograft and genic models of lung cancer. Quite by chance, we show that in summation to potentiating DNA price, two clinical ATR kinase inhibitors (ATRi?s), with unrelated structures, forget expression of the immune checkpoint protein PD

trfatment with cisplatin akd IR is well-tolgrqted aid leada to durxble responses in mouse xenojrafr and genetic models of lune cancer. Euite unwxpertedly, we show tizt in additioh to 'oventiating DNA camage, two clinical ATR nivade inhibitors (ATRi?s), with unrelated ftructuted, block expresfion jf tgv lmmune checkpoint protein PD

treatment with cisplatin and IR is well-tolerated to responses in xenograft and genetic unexpectedly, show that in to potentiating DNA two clinical ATR kinase inhibitors (ATRi?s), unrelated structures, block expression of the immune checkpoint protein PD

treatment with cisplatin and iR is well-toLeratEd aNd lEaDs to DuraBle responses in MOuse Xenograft and genetic modEls of LuNG canCEr. quite UnexpecTEdLY, We sHoW tHat In ADdItion To pOtentiaTing DNA damAge, TwO clinical ATR KInAse inhibitOrs (aTRi?s), with unrElaTed strUcTurES, blocK exPressIon of tHE immunE checkpoiNt PRotein pd

treatment with cisplatinand IR iswell- tol era te d an d le ads to durable resp onses in mouse xenogra ft an dg enet i cmodel s of lu n gc a nce r.  Q uit eu ne xpect edl y, we s how that i n a dd ition to pot e nt iating DNA  da mage, two cl ini cal AT Rkin a se in hib itors  (ATRi ? s), wi th unrela te d  struc t ures, b l o ck  exp ression of the im m un e  checkpoint pr oteinPD

treatment_with cisplatin_and IR is well-tolerated_and leads_to_durable responses_in_mouse xenograft and_genetic models of_lung cancer. Quite unexpectedly,_we show that_in_addition to potentiating DNA damage, two clinical ATR kinase inhibitors (ATRi?s), with unrelated structures,_block_expression of_the_immune_checkpoint protein PD


21, 22). Burnham's Center-driven component will apply our multidisciplinary expertise in cell biology, cellular imaging, and high throughput microscopy (HTM) algorithm and instrumentation development to address this fundamental unmet need in chemical genomics and drug discovery. The broad objectives are to: (1) develop validated 3D model

21, 22). Burnham's Center - driven component will apply our multidisciplinary expertness in cellular telephone biota, cellular imaging, and high throughput microscopy (HTM) algorithm and instrumentation exploitation to address this fundamental unmet indigence in chemical genomics and drug discovery. The across-the-board objectives are to: (1) evolve validated 3D model

21, 22). Bkrnham's Center-driven comkonent will apply our muntidisdiplinarh expertise in cell biology, rellylar umaging, and high throuehput micgoscopy (HRM) aotorithm anv instrumentatjln dzvxlopment to addtess this futdamental unmed vezd in chemical genomics and drug dissovery. Yhf broad objectyves wre fo: (1) develop validated 3D model

21, 22). Burnham's Center-driven component will apply expertise cell biology, imaging, and high instrumentation to address this unmet need in genomics and drug discovery. The broad are to: (1) develop validated 3D model

21, 22). Burnham's Center-driven compoNent will apPly ouR muLtiDiScipLinaRy expertise in cELl biOlogy, cellular imaging, anD high ThROughPUt MicroScopy (HTm) AlGORitHm AnD inStRUmEntatIon DevelopMent to addrEss ThIs fundamentaL UnMet need in cHemIcal genomics And Drug diScOveRY. The bRoaD objeCtives ARe to: (1) deVelop valiDaTEd 3D modEL

21, 22). Burnham's Center- driven com ponen t w ill  a pply  our  multidiscipli n aryexpertise in cell biol ogy,ce l lula r  i magin g, andh ig h thr ou gh put  m i cr oscop y ( HTM) al gorithm an d i ns trumentation de velopmenttoaddress this  fu ndamen ta l u n met n eed  in c hemica l  genom ics and d ru g  disco v ery. Th e br oadobjectives are to :  ( 1 ) develop vali dated3D mo d e l

21, 22)._Burnham's Center-driven_component will apply our_multidisciplinary expertise_in_cell biology,_cellular_imaging, and high_throughput microscopy (HTM)_algorithm and instrumentation development_to address this_fundamental_unmet need in chemical genomics and drug discovery. The broad objectives are to: (1)_develop_validated 3D_model


expansion in non-coding sequence of the myotonin protein kinase (MtPK) gene, the disease mechanism remains unclear even in its general outline. There is little experimental support for the initial hypothesis that a change in the amount or function of MtPK peptide explains the phenotype. Alternative hypotheses that the disease involves an effect

expansion in non - coding sequence of the myotonin protein kinase (MtPK) gene, the disease mechanism remains unclear even in its general outline. There be short experimental support for the initial hypothesis that a change in the measure or function of MtPK peptide explains the phenotype. alternate hypotheses that the disease involves an effect

exoansion in non-coding seqmence of the myojobin prmtein iinase (MgPK) gene, the disease mechanidm remauns unclear even in itr general outline. Thece is little expxdimental suppkvt fox vhe initial hyppthesis thdt a change in tfe amount or function of MtPK peptide explaims the phenotype. Alttrnwtivs hypotheses that the disease invomves an effect

expansion in non-coding sequence of the myotonin (MtPK) the disease remains unclear even is experimental support for initial hypothesis that change in the amount or function MtPK peptide explains the phenotype. Alternative hypotheses that the disease involves an effect

expansion in non-coding sequeNce of the myOtoniN prOteIn KinaSe (MtpK) gene, the diseaSE mecHanism remains unclear evEn in iTs GEnerAL oUtlinE. There iS LiTTLe eXpErImeNtAL sUpporT foR the iniTial hypothEsiS tHat a change in THe Amount or fuNctIon of MtPK pepTidE explaInS thE PhenoTypE. AlteRnativE HypothEses that tHe DIsease INvolves AN EfFect

expansion in non-coding s equence of  themyo ton in  pro tein  kinase (MtPK) gene , the disease mechanis m rem ai n s un c le ar ev en in i t sg e ner al  o utl in e .There  is  little  experimen tal  s upport for t h einitial hy pot hesis that a  ch ange i nthe amoun t o r fun ctiono f MtPK  peptideex p lainst he phen o t yp e. A lternative hypoth e se s  that the dise ase in vo l ve s aneff ect

expansion_in non-coding_sequence of the myotonin_protein kinase_(MtPK)_gene, the_disease_mechanism remains unclear_even in its_general outline. There is_little experimental support_for_the initial hypothesis that a change in the amount or function of MtPK peptide_explains_the phenotype._Alternative_hypotheses_that the disease involves an_effect


will provide valuable information on the pathogenesis of Batten disease. [unreadable] [unreadable] [unreadable] Regulation of the number of insulin receptors on the cell surface plays a critical role in determining insulin sensitivity. In order to study the mechanism of transcriptional regulation of the insulin receptor gene, we have cloned the 5'-end of

will provide valuable information on the pathogenesis of Batten disease. [ unreadable ] [ unreadable ] [ indecipherable ] rule of the issue of insulin receptors on the cellular telephone surface play a critical role in determining insulin sensitivity. In holy order to study the mechanism of transcriptional regulation of the insulin sense organ gene, we have clone the 5'-end of

wipl provide valuable infovmation on the pcrhogenxsis of Batten aisease. [unreadable] [unreadablx] [uneeadavle] Regulation of the vumber of insulin rectptors on the cell surfacc plagd a ermtical role in cetermininc insulin senshtkvnty. In order to study the mechanism jf tranxcgiptional regujatipg of nht insulin receptor gene, we have cmoned tie 5'-end of

will provide valuable information on the pathogenesis disease. [unreadable] [unreadable] of the number cell plays a critical in determining insulin In order to study the mechanism transcriptional regulation of the insulin receptor gene, we have cloned the 5'-end of

will provide valuable informAtion on the PathoGenEsiS oF BatTen dIsease. [unreadabLE] [unrEadable] [unreadable] RegulAtion Of THe nuMBeR of inSulin reCEpTORs oN tHe CelL sURfAce plAys A criticAl role in deTerMiNing insulin sENsItivity. In oRdeR to study the mEchAnism oF tRanSCriptIonAl regUlatioN Of the iNsulin recEpTOr gene, WE have clONEd The 5'-eNd of

will provide valuable inf ormation o n the  pa tho ge nesi s of  Batten diseas e . [u nreadable] [unreadable ] [un re a dabl e ]Regul ation o f  t h e  nu mb er  of  i n su lin r ece ptors o n the cell  su rf ace plays ac ri tical role  in  determining  in sulinse nsi t ivity . I n ord er tos tudy t he mechan is m  of tr a nscript i o na l re gulation of the i n su l in receptor ge ne, we  h a ve c lon edthe 5'-end  o f

will_provide valuable_information on the pathogenesis_of Batten_disease._[unreadable] [unreadable]_[unreadable]_Regulation of the_number of insulin_receptors on the cell_surface plays a_critical_role in determining insulin sensitivity. In order to study the mechanism of transcriptional regulation_of_the insulin_receptor_gene,_we have cloned the 5'-end_of


will result in much higher drug levels in the infected lymph node tissue than conventional preparations of the same antibiotics. Thus, the primary site of germination and development of weaponized biological agents will be sufficiently saturated with drugs to prevent or stop disease development at the very early stage (before the onset of symptoms). The objective of this project

will result in much higher drug levels in the septic lymph lymph node tissue than ceremonious preparations of the same antibiotics. therefore, the primary site of germination and development of weaponize biological agent will be sufficiently saturated with drug to prevent or check disease development at the very early stagecoach (before the onset of symptoms). The aim of this project

wipl result in much higher drug levels in the inhected mymph noae tissue than conventional 'repqratiins of the same antibiutics. Thud, the prumarb site of germinefion and devemlpmeut of weaponized biologican agents will te sbfficiently saturated with drugs to [revent og stop disease devtlo[menf at the very early stage (before tge onseu of symptoms). The pbjective of this project

will result in much higher drug levels infected node tissue conventional preparations of primary of germination and of weaponized biological will be sufficiently saturated with drugs prevent or stop disease development at the very early stage (before the onset symptoms). The objective of this project

will result in much higher druG levels in tHe infEctEd lYmPh noDe tiSsue than convenTIonaL preparations of the same AntibIoTIcs. THUs, The prImary siTE oF GErmInAtIon AnD DeVelopMenT of weapOnized biolOgiCaL agents will bE SuFficiently SatUrated with drUgs To prevEnT or STop diSeaSe devElopmeNT at the Very early StAGe (befoRE the onsET Of SympToms). The objective oF ThIS project

will result in much highe r drug lev els i n t hein fect ed l ymph node tiss u e th an conventional prepar ation so f th e  s ame a ntibiot i cs . Thu s,  t hepr i ma ry si teof germ ination an d d ev elopment ofw ea ponized bi olo gical agents  wi ll besu ffi c ientl y s atura ted wi t h drug s to prev en t  or st o p disea s e  d evel opment at the ver y  e a rly stage (bef ore th eo ns e t  of  sy mptoms). T he  obje c tive of th i s pro j ect

will_result in_much higher drug levels_in the_infected_lymph node_tissue_than conventional preparations_of the same_antibiotics. Thus, the primary_site of germination_and_development of weaponized biological agents will be sufficiently saturated with drugs to prevent or_stop_disease development_at_the_very early stage (before the_onset of symptoms). The objective_of this_project


disrupting these pathways could be useful for cancer prophylaxis in chronic inflammatory states. We found that TNFalpha and NFkappaB play a key role in hepatitis-associated tumorigenesis in a specific mouse model and propose that paracrine TNFalpha stimulation functions as a tumor promoter in inflammation-associated cancer via NFkappaB activation. Short

disrupting these pathways could be useful for cancer prophylaxis in chronic inflammatory state. We discover that TNFalpha and NFkappaB play a key role in hepatitis - consort tumorigenesis in a specific mouse model and project that paracrine TNFalpha stimulation functions as a tumor showman in excitement - associated cancer via NFkappaB energizing. Short

didrupting these pathways gould be useful yir canrer prolhylaxis in chronic inflammatory staves. Qe foynd that TNFalpha and VFkappaB ilay a ket roow in hepatmfis-assognated bumorngxnesis in a spegific mouse model and pro[ore that paracrine TNFalpha stimulatiog functoojs as a tumor kromouer in jnflammation-associated cancer via HFkappaU activation. Shprt

disrupting these pathways could be useful for in inflammatory states. found that TNFalpha role hepatitis-associated tumorigenesis in specific mouse model propose that paracrine TNFalpha stimulation functions a tumor promoter in inflammation-associated cancer via NFkappaB activation. Short

disrupting these pathways coUld be usefuL for cAncEr pRoPhylAxis In chronic inflaMMatoRy states. We found that TNFAlpha AnD nFkaPPab play A key rolE In HEPatItIs-AssOcIAtEd tumOriGenesis In a specifiC moUsE model and proPOsE that paracRinE TNFalpha stiMulAtion fUnCtiONs as a TumOr proMoter iN InflamMation-assOcIAted caNCer via NfKApPaB aCtivation. Short

disrupting these pathways  could beusefu l f orca ncer  pro phylaxis in ch r onic  inflammatory states.We fo un d  tha t  T NFalp ha andN Fk a p paB  p la y a  k e yroleinhepatit is-associa ted  t umorigenesis in  a specifi c m ouse model a ndpropos etha t  para cri ne TN Falpha stimul ation fun ct i ons as a tumor p ro mote r in inflammation - as s ociated cancer  via N Fk a pp a B  ac tiv ation. Sho rt

disrupting_these pathways_could be useful for_cancer prophylaxis_in_chronic inflammatory_states._We found that_TNFalpha and NFkappaB_play a key role_in hepatitis-associated tumorigenesis_in_a specific mouse model and propose that paracrine TNFalpha stimulation functions as a tumor_promoter_in inflammation-associated_cancer_via_NFkappaB activation. Short


hybridization, laser confocal, 2 photon and live cell technologies. Furthermore, our considerable experience in computerized image processing and morphometry will allow quantitative analysis of observed phenomena to corroborate earlier, possibly quite subtle qualitative changes. This core will be used extensively by all projects, though the imaging tools used will vary from project to project.

hybridization, laser confocal, 2 photon and live cell technologies. Furthermore, our considerable experience in computerized image processing and morphometry will leave quantitative psychoanalysis of observed phenomena to confirm in the first place, possibly quite subtle qualitative changes. This kernel will be used extensively by all projects, though the imagination creature used will deviate from project to project.

hyhridization, laser confocxl, 2 photon and live cenl tecgnologier. Furthermore, our considerabpe expeeience in computerized image prlcessing and norphometrb will allow qhwnticavive analysis on observed [henomena to cmrfoyorate earlier, possibly quite subtle qualitstlve changes. Thys cpwe wjll be used extensively by all pronects, tiough the imagimg tools used will vary frlm pgoject to project.

hybridization, laser confocal, 2 photon and live Furthermore, considerable experience computerized image processing analysis observed phenomena to earlier, possibly quite qualitative changes. This core will be extensively by all projects, though the imaging tools used will vary from project project.

hybridization, laser confocaL, 2 photon and Live cEll TecHnOlogIes. FUrthermore, our cONsidErable experience in compUteriZeD ImagE PrOcessIng and mORpHOMetRy WiLl aLlOW qUantiTatIve analYsis of obseRveD pHenomena to coRRoBorate earlIer, Possibly quitE suBtle quAlItaTIve chAngEs. ThiS core wILl be usEd extensiVeLY by all PRojects, THOuGh thE imaging tools used WIlL Vary from projecT to proJeCT.

hybridization, laser conf ocal, 2 ph otonand  li ve  cel l te chnologies. Fu r ther more, our considerable  expe ri e ncei ncompu terized im a g e p ro ce ssi ng an d mor pho metry w ill allowqua nt itative anal y si s of obser ved  phenomena t o c orrobo ra tee arlie r,possi bly qu i te sub tle quali ta t ive ch a nges. T h i score  will be used ext e ns i vely by all pr ojects ,t ho u g h t heimaging to ol s use d  will v a ry f r omp roject to pro ject.

hybridization,_laser confocal,_2 photon and live_cell technologies._Furthermore,_our considerable_experience_in computerized image_processing and morphometry_will allow quantitative analysis_of observed phenomena_to_corroborate earlier, possibly quite subtle qualitative changes. This core will be used extensively by_all_projects, though_the_imaging_tools used will vary from_project to project.


the DG where c-fos-ir was consistent: a subset of GCs in dorsal DG. In contrast, the majority of MCs with c-fos-ir were ventral. Because the main projection of ventral MCs is to dorsal GCs, these data suggest that ventral MCs excite dorsal G

the DG where c - fos - ir was consistent: a subset of GCs in dorsal DG. In contrast, the majority of megahertz with coulomb - fos - ir were adaxial. Because the main protrusion of ventral megahertz is to dorsal gigahertz, these data suggest that ventral MCs excite dorsal G

thf DG where c-fos-ir was coksistent: a subsej if GCs in dodsal DG. Kn contrast, the majority of LCw wity c-fos-ir were ventral. Cecause tje main projtction of ventral MCs is bj doddal YCw, these data soggest that eentral MCs exwige dorsal G

the DG where c-fos-ir was consistent: a GCs dorsal DG. contrast, the majority ventral. the main projection ventral MCs is dorsal GCs, these data suggest that MCs excite dorsal G

the DG where c-fos-ir was consisTent: a subseT of GCS in DorSaL DG. IN conTrast, the majoriTY of Mcs with c-fos-ir were ventraL. BecaUsE The mAIn ProjeCtion of VEnTRAl Mcs Is To dOrSAl gCs, thEse Data sugGest that veNtrAl mCs excite dorSAl g

the DG where c-fos-ir was  consisten t: asub set  o f GC s in  dorsal DG. In cont rast, the majority ofMCs w it h  c-f o s- ir we re vent r al . Bec au se  th em ai n pro jec tion of  ventral M Csis  to dorsal G C s,  these dat a s uggest thatven tral M Cs  ex c ite d ors al G

the_DG where_c-fos-ir was consistent: a_subset of_GCs_in dorsal_DG._In contrast, the_majority of MCs_with c-fos-ir were ventral._Because the main_projection_of ventral MCs is to dorsal GCs, these data suggest that ventral MCs excite_dorsal_G


ionizing radiation with cost efficiency have potentials for significant improvement of public healthcare. In this three year study we plan to (i) develop 2D MWT system; (ii) develop an appropriate image algorithm and (iii) assess feasibility of the technology for extremities soft tissue imaging, including sensitivity and resolution of the technology.

ionizing radiation with cost efficiency have potential for meaning improvement of public healthcare. In this three year study we design to (i) break 2D MWT system; (ii) develop an appropriate double algorithm and (iii) assess feasibility of the technology for extremity soft tissue imaging, admit sensitivity and resolution of the technology.

ionlzing radiation with cosu efficiency have potentmals fod signifkcant improvement of public iealrhcart. In this three yeaf study wv plan to (i) dtvelop 2D MWT systxj; (ii) deyzlop zk appxo'riate image alnorithm and (iii) assess fedskbnlity of the technology for extremityes sofy hissue imaging, incktdinf sensitivity and resolution of ths technmlogy.

ionizing radiation with cost efficiency have potentials improvement public healthcare. this three year develop MWT system; (ii) an appropriate image and (iii) assess feasibility of the for extremities soft tissue imaging, including sensitivity and resolution of the technology.

ionizing radiation with cost Efficiency Have pOteNtiAlS for SignIficant improveMEnt oF public healthcare. In thiS threE yEAr stUDy We plaN to (i) devELoP 2d mWT SyStEm; (iI) dEVeLop an AppRopriatE image algoRitHm And (iii) assess FEaSibility of The Technology foR exTremitIeS soFT tissUe iMaginG, incluDIng senSitivity aNd REsolutIOn of the TEChNoloGy.

ionizing radiation with co st efficie ncy h ave  po te ntia ls f or significant impr ovement of public heal thcar e. In t h is  thre e years tu d y  we  p la n t o( i)  deve lop  2D MWT  system; ( ii)  d evelop an ap p ro priate ima gealgorithm an d ( iii) a ss ess feasi bil ity o f thet echnol ogy for e xt r emitie s  soft t i s su e im aging, includings en s itivity and re soluti on of t hetec hnology.

ionizing radiation_with cost_efficiency have potentials for_significant improvement_of_public healthcare._In_this three year_study we plan_to (i) develop 2D_MWT system; (ii)_develop_an appropriate image algorithm and (iii) assess feasibility of the technology for extremities soft_tissue_imaging, including_sensitivity_and_resolution of the technology.


Fu lab, Dr. Kasinski performed two very distinct projects that were interrelated based on the ultimate goal of developing targeted therapeutics: in one project Dr. Kasinski utilized biochemical assays to identified IKK- as a direct target of EF24, an analogue of curcumin that ultimately made its way into clinical trials. For

Fu lab, Dr. Kasinski performed two very distinct projects that were interrelated free-base on the ultimate finish of developing targeted remedy: in one project Dr. Kasinski utilize biochemical assays to identified IKK- as a lineal aim of EF24, an analogue of curcumin that ultimately made its manner into clinical trials. For

Fu lab, Dr. Kasinski performtd two very distiuxt prooects tgat were interrelated based on the uptumate goal of developing tafgeted thvrapeuticw: in ine projecv Dr. Kasluski hbilizzd biochemical axsays to igentified IKK- ds a direct target of EF24, an analogue of curcumon that ultimatejy msqe ifs way into clinical trials. For

Fu lab, Dr. Kasinski performed two very that interrelated based the ultimate goal one Dr. Kasinski utilized assays to identified as a direct target of EF24, analogue of curcumin that ultimately made its way into clinical trials. For

Fu lab, Dr. Kasinski performed tWo very distInct pRojEctS tHat wEre iNterrelated basED on tHe ultimate goal of develoPing tArGEted THeRapeuTics: in oNE pROJecT DR. KAsiNsKI uTilizEd bIochemiCal assays tO idEnTified IKK- as a DIrEct target oF EF24, An analogue of CurCumin tHaT ulTImateLy mAde itS way inTO cliniCal trials. foR

Fu lab, Dr. Kasinski perf ormed twoverydis tin ct  pro ject s that were in t erre lated based on the ult imate  g o al o f  d evelo ping ta r ge t e d t he ra peu ti c s:  in o neproject  Dr. Kasin ski  u tilized bioc h em ical assay s t o identified  IK K- asadir e ct ta rge t ofEF24,a n anal ogue of c ur c umin t h at ulti m a te ly m ade its way intoc li n ical trials. F or

Fu_lab, Dr._Kasinski performed two very_distinct projects_that_were interrelated_based_on the ultimate_goal of developing_targeted therapeutics: in one_project Dr. Kasinski_utilized_biochemical assays to identified IKK- as a direct target of EF24, an analogue of_curcumin_that ultimately_made_its_way into clinical trials. For


function at 1/2 sites. We extended our analysis of p53 mutants in yeast-based systems to a clinical study of breast cancer patients undergoing neoadjuvant treatment. Several transcriptionally active p53 mutants identified in breast had subtle defects in transcription at REs that can only be revealed at low expression levels achievable in the

function at 1/2 sites. We extended our analysis of p53 mutant in yeast - free-base systems to a clinical study of breast cancer patients undergo neoadjuvant treatment. Several transcriptionally active p53 mutants identify in breast had subtle defect in transcription at REs that can entirely be revealed at low formulation level achievable in the

fujction at 1/2 sites. We extekded our analysis of p53 kutanta in yeart-based systems to a clinicap wtudy of breast cancer patidnts undeggoing neiadjnvant treatment. Several bxanscdlptiouaoly active p53 motants identhfied in breasd fab subtle defects in transcription at REs thst can only be rgvealtd wt lkw expression levels achievable in the

function at 1/2 sites. We extended our p53 in yeast-based to a clinical undergoing treatment. Several transcriptionally p53 mutants identified breast had subtle defects in transcription REs that can only be revealed at low expression levels achievable in the

function at 1/2 sites. We extended Our analysiS of p53 mUtaNts In YeasT-basEd systems to a clINicaL study of breast cancer paTientS uNDergOInG neoaDjuvant TReATMenT. SEvEraL tRAnScripTioNally acTive p53 mutanTs iDeNtified in breASt Had subtle dEfeCts in transcrIptIon at Res ThaT Can onLy bE reveAled at LOw exprEssion levElS AchievABle in thE

function at 1/2 sites. We  extendedour a nal ysi sof p 53 m utants in yeas t -bas ed systems to a clinic al st ud y  ofb re ast c ancer p a ti e n tsun de rgo in g  n eoadj uva nt trea tment. Sev era ltranscriptio n al ly activep53  mutants ide nti fied i nbre a st ha d s ubtle  defec t s in t ranscript io n  at RE s  that c a n  o nlybe revealed at lo w  e x pression level s achi ev a bl e inthe

function_at 1/2_sites. We extended our_analysis of_p53_mutants in_yeast-based_systems to a_clinical study of_breast cancer patients undergoing_neoadjuvant treatment. Several_transcriptionally_active p53 mutants identified in breast had subtle defects in transcription at REs that_can_only be_revealed_at_low expression levels achievable in_the


) as well as how the cells naturally destroy disordered proteins that fail to traffic out of the ER. Searching databases we have found that many secreted, acidic proteins encode similar peptide motifs that we propose are used to interact with a conserved ER cargo receptor. This proposed cargo receptor then traffics negatively charged proteins (as well as

) as well as how the cells naturally destroy disordered protein that fail to traffic out of the ER. research databases we have found that many secrete, acidic protein encode similar peptide motifs that we propose are practice to interact with a conserved ER cargo receptor. This proposed cargo sense organ then traffic negatively charged protein (as well as

) as well as how the cells nxturally destroi eisordxred prkteins tfat fail to traffic out of tie EE. Seaeching databases we haxe found nhat many secceted, acidic provsins engjde almilax 'eptide motifs jhat we propmse are used tm knceract with a conserved ER cargo recqptor. Tnid proposed cardo rtce[tor nhtn traffics negatively charged prkteins (es well as

) as well as how the cells disordered that fail traffic out of have that many secreted, proteins encode similar motifs that we propose are used interact with a conserved ER cargo receptor. This proposed cargo receptor then traffics charged proteins (as well as

) as well as how the cells naturaLly destroy DisorDerEd pRoTeinS thaT fail to traffic OUt of The ER. Searching databaseS we haVe FOund THaT many SecreteD, AcIDIc pRoTeIns EnCOdE simiLar Peptide Motifs that We pRoPose are used tO InTeract with A coNserved ER carGo rEceptoR. THis PRoposEd cArgo rEceptoR Then trAffics negAtIVely chARged proTEInS (as wEll as

) as well as how the cells  naturally  dest roy  di so rder ed p roteins that f a il t o traffic out of the E R. Se ar c hing da tabas es we h a ve f oun dth atma n ysecre ted , acidi c proteins  en co de similar p e pt ide motifs  th at we propos e a re use dtoi ntera ctwitha cons e rved E R cargo r ec e ptor.T his pro p o se d ca rgo receptor then tr a ffics negative ly cha rg e dp r ote ins  (as wellas

) as_well as_how the cells naturally_destroy disordered_proteins_that fail_to_traffic out of_the ER. Searching_databases we have found_that many secreted,_acidic_proteins encode similar peptide motifs that we propose are used to interact with a_conserved_ER cargo_receptor._This_proposed cargo receptor then traffics_negatively charged proteins (as well_as


how their biosynthesis and degradation are regulated, their physiologic functions, how they act in vivo, and the structure of the various biosynthetic enzymes. For this purpose we have constructed null mutants in each of the biosynthetic steps in both Escherichia coli and Saccharomyces cerevisiae, and have prepared overexpression systems for the biosynthetic enzymes

how their biosynthesis and degradation are regulated, their physiologic functions, how they act in vivo, and the social organization of the diverse biosynthetic enzymes. For this purpose we have construct null mutant in each of the biosynthetic steps in both Escherichia coli and Saccharomyces cerevisiae, and have prepared overexpression arrangement for the biosynthetic enzymes

hoa their biosynthesis and degradation arg eegulaved, thejr physiulogic functions, how they acv in vivo, and the structure of ghe variols biosynrhetmc enzymes. For tijs purpose we mave eoistructed null kutants in each of the bhoryuthetic steps in both Escherichia coji and Xafcharomyces cetevispaq, ans have prepared overexpression sysfems fog the biosynthetiv enzymes

how their biosynthesis and degradation are regulated, functions, they act vivo, and the enzymes. this purpose we constructed null mutants each of the biosynthetic steps in Escherichia coli and Saccharomyces cerevisiae, and have prepared overexpression systems for the biosynthetic

how their biosynthesis and deGradation aRe regUlaTed, ThEir pHysiOlogic functionS, How tHey act in vivo, and the struCture Of THe vaRIoUs bioSynthetIC eNZYmeS. FOr ThiS pURpOse we HavE constrUcted null mUtaNtS in each of the BIoSynthetic sTepS in both EscheRicHia colI aNd SACcharOmyCes ceRevisiAE, and haVe prepareD oVErexprESsion sySTEmS for The biosynthetic enZYmES

how their biosynthesis an d degradat ion a rereg ul ated , th eir physiologi c  fun ctions, how they act i n viv o, andt he  stru cture o f  t h e  va ri ou s b io s yn theti c e nzymes.  For thispur po se we have c o ns tructed nu llmutants in e ach  of th ebio s ynthe tic  step s in b o th Esc herichiaco l i andS accharo m y ce s ce revisiae, and hav e  p r epared overexp ressio ns ys t e msfor  the biosy nt hetic enzymes

how_their biosynthesis_and degradation are regulated,_their physiologic_functions,_how they_act_in vivo, and_the structure of_the various biosynthetic enzymes._For this purpose_we_have constructed null mutants in each of the biosynthetic steps in both Escherichia coli_and_Saccharomyces cerevisiae,_and_have_prepared overexpression systems for the_biosynthetic enzymes


iles as well as estrogen metabolism, to determine the mechanism by which estrogen sensitivity is lost. Finally a study of epithelial growth will be examined by in vitro cultivation of epithelial cells on estrogen-stimulated extracellular matrix proteins secreted by gingival fibroblasts, to determine if gingival epithelial cell proliferation, attachment, and keratin proteins are dependent on

iles as well as estrogen metabolism, to determine the mechanism by which estrogen sensitivity is lost. ultimately a discipline of epithelial growth will be examined by in vitro cultivation of epithelial cell on estrogen - stimulated extracellular matrix proteins secrete by gingival fibroblast, to determine if gingival epithelial cell proliferation, attachment, and keratin proteins are dependent on

iled as well as estrogen meuabolism, to determine thx mechahism by dhich estrogen sensitivity id oost. Dinally a study of epighelial ggowth wilo be wxamined bb in vitvj cumbivatnoi of epithelial cells on astrogen-stimuldtdd extracellular matrix proteins secrqted by glngival fibrobjastx, to svttrmine if gingival epithelial celm proliheration, attachkent, and keratin proteins wre fependent on

iles as well as estrogen metabolism, to mechanism which estrogen is lost. Finally will examined by in cultivation of epithelial on estrogen-stimulated extracellular matrix proteins secreted gingival fibroblasts, to determine if gingival epithelial cell proliferation, attachment, and keratin proteins dependent on

iles as well as estrogen metabOlism, to detErminE thE meChAnisM by wHich estrogen seNSitiVity is lost. Finally a studY of epItHEliaL GrOwth wIll be exAMiNED by In ViTro CuLTiVatioN of EpithelIal cells on EstRoGen-stimulateD ExTracellulaR maTrix proteins SecReted bY gIngIVal fiBroBlastS, to detERmine iF gingival EpITheliaL Cell proLIFeRatiOn, attachment, and keRAtIN proteins are dePendenT oN

iles as well as estrogen m etabolism,  to d ete rmi ne  the  mec hanism by whic h  est rogen sensitivity is l ost.Fi n ally astudy  of epi t he l i algr ow thwi l lbe ex ami ned byin vitro c ult iv ation of epi t he lial cells  on  estrogen-st imu latedex tra c ellul armatri x prot e ins se creted by  g i ngival fibrobl a s ts , to  determine if gin g iv a l epithelial c ell pr ol i fe r a tio n,attachment ,and k e ratin p r ot e i n s a r e dependent o n

iles as_well as_estrogen metabolism, to determine_the mechanism_by_which estrogen_sensitivity_is lost. Finally_a study of_epithelial growth will be_examined by in_vitro_cultivation of epithelial cells on estrogen-stimulated extracellular matrix proteins secreted by gingival fibroblasts, to_determine_if gingival_epithelial_cell_proliferation, attachment, and keratin proteins_are dependent on


iris aperture delivery system will be compared to an ExciMed UV200 with a fixed beam diameter used in conjunction with an ablatable contact mask. A comparison will be made of the two methods in rabbits and monkeys. In Phase I, initial development of the contract mask will be performed and a range of operating parameters

iris aperture delivery system will be compared to an ExciMed UV200 with a fixed radio beam diameter use in conjunction with an ablatable contact mask. A comparison will be make of the two methods in rabbits and imp. In Phase I, initial exploitation of the contract mask will be perform and a range of operating parameter

irls aperture delivery sysuem will be compatee to ai ExciMsd UV200 wigh a fixed beam diameter usev in conjynction with an ablatacle contabt mask. A comkarison will be mese of tmz two lethmvs in rabbits akd monkeys. Hn Phase I, inidixl development of the contract mask wyll be legformed and a tange jf olvrcting parameters

iris aperture delivery system will be compared ExciMed with a beam diameter used contact A comparison will made of the methods in rabbits and monkeys. In I, initial development of the contract mask will be performed and a range operating parameters

iris aperture delivery systeM will be comPared To aN ExCimed Uv200 witH a fixed beam diaMEter Used in conjunction with aN ablaTaBLe coNTaCt masK. A compaRIsON WilL bE mAde Of THe Two meThoDs in rabBits and monKeyS. IN Phase I, initiAL dEvelopment Of tHe contract maSk wIll be pErForMEd and A raNge of OperatINg paraMeters

iris aperture delivery sy stem willbe co mpa red  t o an  Exc iMed UV200 wit h  a f ixed beam diameter use d inco n junc t io n wit h an ab l at a b leco nt act  m a sk . A c omp arisonwill be ma deof  the two met h od s in rabbi tsand monkeys.  In  Phase  I , i n itial  de velop ment o f  the c ontract m as k  willb e perfo r m ed  and  a range of opera t in g  parameters

iris_aperture delivery_system will be compared_to an_ExciMed_UV200 with_a_fixed beam diameter_used in conjunction_with an ablatable contact_mask. A comparison_will_be made of the two methods in rabbits and monkeys. In Phase I, initial_development_of the_contract_mask_will be performed and a_range of operating parameters


The objectives of the proposed research are to elucidate developmental processes of respiratory neuron network maturation and to identify brainstem respiratory centers/circuits necessary for perinatal breathing. The central hypothesis is that hindbrain respiratory neuron networks undergo critical developmental maturation during the late embryonic, perinatal, and post-natal periods in mammals, and that

The objectives of the proposed research are to elucidate developmental summons of respiratory neuron net maturation and to identify brainstem respiratory center / tour necessary for perinatal breathing. The central hypothesis is that hindbrain respiratory neuron network undergo critical developmental festering during the late embryonic, perinatal, and post - natal time period in mammals, and that

Thf objectives of the propused research ate to elncidate developoental processes of respiratlrt neueon network maturation and to ifentify vraiistem respiratorb centers/circujbs neeewsary for perikatal breatving. The centrdl hvpothesis is that hindbrain respiratjry neutoj networks undgrgo bryticzl developmental maturation during the laue embryonic, perinstal, and post-natal periods in lammals, and that

The objectives of the proposed research are developmental of respiratory network maturation and necessary perinatal breathing. The hypothesis is that respiratory neuron networks undergo critical developmental during the late embryonic, perinatal, and post-natal periods in mammals, and that

The objectives of the proposeD research aRe to eLucIdaTe DeveLopmEntal processes OF resPiratory neuron network mAturaTiON and TO iDentiFy brainSTeM REspIrAtOry CeNTeRs/cirCuiTs necesSary for perInaTaL breathing. ThE CeNtral hypotHesIs is that hindBraIn respIrAtoRY neurOn nEtworKs undeRGo critIcal develOpMEntal mATuratioN DUrIng tHe late embryonic, peRInATal, and post-nataL perioDs IN mAMMalS, anD that

The objectives of the pro posed rese archare  to  e luci date  developmental proc esses of respiratory n euron  n e twor k  m atura tion an d  t o ide nt if y b ra i ns tem r esp iratory  centers/c irc ui ts necessary fo r perinata l b reathing. Th e c entral  h ypo t hesis  is  that  hindb r ain re spiratory  n e uron n e tworksu n de rgocritical developm e nt a l maturation d uringth e  l a t e e mbr yonic, per in atal, and pos t -n a t a l p e riods in mamm als, and th a t

The_objectives of_the proposed research are_to elucidate_developmental_processes of_respiratory_neuron network maturation_and to identify_brainstem respiratory centers/circuits necessary_for perinatal breathing._The_central hypothesis is that hindbrain respiratory neuron networks undergo critical developmental maturation during the_late_embryonic, perinatal,_and_post-natal_periods in mammals, and that


trichomoniasis and giardiasis. The comprehensive data sets to be generated will also be instrumental in selecting the most promising candidates as novel leads for the improved treatment of these infections, and potentially infections with other important pathogens, including Entamoeba histolytica, Trypanosoma cruzi, Helicobacter

trichomoniasis and giardiasis. The comprehensive data sets to be generated will also be implemental in choose the about promising candidates as novel leads for the improved discussion of these infections, and potentially infections with other significant pathogens, including Entamoeba histolytica, Trypanosoma cruzi, Helicobacter

trlchomoniasis and giardiaris. The comprehgnwive deta seta to be eenerated will also be instrnmenral ib selecting the most pfomising bandidatew as bovel leads for thc impdlved vreatment of thgse infectiots, and potentidluy infections with other important paehogens, ijcluding Entamjeba ristklytica, Trypanosoma cruzi, Helicobadter

trichomoniasis and giardiasis. The comprehensive data sets generated also be in selecting the leads the improved treatment these infections, and infections with other important pathogens, including histolytica, Trypanosoma cruzi, Helicobacter

trichomoniasis and giardiasIs. The comprEhensIve DatA sEts tO be gEnerated will alSO be iNstrumental in selecting The moSt PRomiSInG candIdates aS NoVEL leAdS fOr tHe IMpRoved TreAtment oF these infeCtiOnS, and potentiaLLy Infections WitH other importAnt PathogEnS, inCLudinG EnTamoeBa histOLytica, trypanosoMa CRuzi, HeLIcobactER

trichomoniasis and giardi asis. Thecompr ehe nsi ve  dat a se ts to be gener a tedwill also be instrumen tal i ns elec t in g the  most p r om i s ing  c an did at e sas no vel  leadsfor the im pro ve d treatmento fthese infe cti ons, and pot ent iallyin fec t ionswit h oth er imp o rtantpathogens ,i ncludi n g Entam o e ba  his tolytica, Trypano s om a  cruzi, Helico bacter

trichomoniasis_and giardiasis._The comprehensive data sets_to be_generated_will also_be_instrumental in selecting_the most promising_candidates as novel leads_for the improved_treatment_of these infections, and potentially infections with other important pathogens, including Entamoeba histolytica, Trypanosoma_cruzi,_Helicobacter


of each domain and ensure that we have identified all components needed to assess personality disorder comprehensively; (2) testing the identified components on another large sample of patients and high-risk individuals, including information provided by family and/or friends, and Axis I symptomatology, and (3) testing the clinical utility

of each domain and ensure that we have identified all components need to measure personality disorder comprehensively; (2) testing the identified part on another large sample of affected role and gamey - risk person, including information put up by family and/or friends, and Axis I symptomatology, and (3) test the clinical utility program

of each domain and ensure uhat we have idenjidied anl comlonents veeded to assess personality dusordtg comprehensively; (2) terting the identifued romponents on another lavye sajile oy 'atients and hinh-risk indieiduals, includhne nnformation provided by family and/or friendx, wnd Axis I symktomauoljgy, znd (3) testing the clinical utility

of each domain and ensure that we all needed to personality disorder comprehensively; on large sample of and high-risk individuals, information provided by family and/or friends, Axis I symptomatology, and (3) testing the clinical utility

of each domain and ensure that We have idenTifieD alL coMpOnenTs neEded to assess peRSonaLity disorder comprehensIvely; (2) TeSTing THe IdentIfied coMPoNENts On AnOthEr LArGe samPle Of patieNts and high-RisK iNdividuals, inCLuDing informAtiOn provided by FamIly and/Or FriENds, anD AxIs I syMptomaTOlogy, aNd (3) testing ThE ClinicAL utilitY

of each domain and ensure  that we h ave i den tif ie d al l co mponents neede d  toassess personality dis order  c o mpre h en sivel y; (2)t es t i ngth eide nt i fi ed co mpo nents o n anotherlar ge  sample of p a ti ents and h igh -risk indivi dua ls, in cl udi n g inf orm ation  provi d ed byfamily an d/ o r frie n ds, and A xi s Isymptomatology, a n d( 3) testing the  clini ca l  u t i lit y

of_each domain_and ensure that we_have identified_all_components needed_to_assess personality disorder_comprehensively; (2) testing_the identified components on_another large sample_of_patients and high-risk individuals, including information provided by family and/or friends, and Axis I_symptomatology,_and (3)_testing_the_clinical utility


that control the centriole duplication and centrosome maturation cycles. Through our own genome-wide RNAi screen and from other published screens, we now have a large number of candidate genes that play critical roles in these two cycles. What is lacking in the field is a true understanding of these proteins functions. Our lab uses

that control the centriole duplication and centrosome maturation cycles. Through our own genome - broad RNAi sieve and from other published screens, we immediately have a large issue of campaigner genes that play critical roles in these two cycles. What is lacking in the playing field is a true understanding of these protein functions. Our lab uses

thwt control the centriole duplication anb centrmsome jaturatiun cycles. Through our own geiome-qide ENAi screen and from ogher publpshed scrwens, qe now havx a largc numgcr of randidate genes that play critical rolev kn these two cycles. What is lacking ig the foepd is a true ugderxeandjng of these proteins functions. Oud lab uves

that control the centriole duplication and centrosome Through own genome-wide screen and from have large number of genes that play roles in these two cycles. What lacking in the field is a true understanding of these proteins functions. Our uses

that control the centriole duPlication aNd cenTroSomE mAturAtioN cycles. Through OUr owN genome-wide RNAi screen aNd froM oTHer pUBlIshed Screens, WE nOW HavE a LaRge NuMBeR of caNdiDate genEs that play CriTiCal roles in thESe Two cycles. WHat Is lacking in tHe fIeld is A tRue UNdersTanDing oF these PRoteinS functionS. OUR lab usES

that control the centriol e duplicat ion a ndcen tr osom e ma turation cycle s . Th rough our own genome-w ide R NA i  scr e en  andfrom ot h er p ubl is he d s cr e en s, we  no w havea large nu mbe rof candidate ge nes that p lay  critical ro les  in th es e t w o cyc les . Wha t is l a ckingin the fi el d  is at rue und e r st andi ng of these prote i ns functions. Our  lab u se s

that_control the_centriole duplication and centrosome_maturation cycles._Through_our own_genome-wide_RNAi screen and_from other published_screens, we now have_a large number_of_candidate genes that play critical roles in these two cycles. What is lacking in_the_field is_a_true_understanding of these proteins functions._Our lab uses


EM and nectin-1 are the most efficient at mediating entry and most important in HSV pathogenesis. Reactivation of HSV-1 can lead to recurrent disease in the form of oral ulcers or more serious disease including encephalitis and herpes stromal keratitis (HSK). The precise mechanism of HSK pathogenesis is not fully understood

EM and nectin-1 are the most efficient at mediating entry and about authoritative in HSV pathogenesis. Reactivation of HSV-1 can lead to recurrent disease in the human body of oral ulcer or more serious disease including encephalitis and herpes stromal keratitis (HSK). The precise mechanism of HSK pathogenesis is not amply understood

EM wnd nectin-1 are the most tfficient at medicring eitry ans most ioportant in HSV pathogenesis. Rwactication of HSV-1 can lead to recurgent diseqse mn the form of oczl ulcevf or lore werious diseasg including ancephalitis atd hzrpes stromal keratitis (HSK). The precyse mecnajism of HSK pajhogemqsis ps not fully understood

EM and nectin-1 are the most efficient entry most important HSV pathogenesis. Reactivation recurrent in the form oral ulcers or serious disease including encephalitis and herpes keratitis (HSK). The precise mechanism of HSK pathogenesis is not fully understood

EM and nectin-1 are the most effiCient at medIatinG enTry AnD mosT impOrtant in HSV patHOgenEsis. Reactivation of HSV-1 cAn leaD tO RecuRReNt disEase in tHE fORM of OrAl UlcErS Or More sEriOus diseAse includiNg eNcEphalitis and HErPes stromal KerAtitis (HSK). The PreCise meChAniSM of HSk paThogeNesis iS Not fulLy understOoD

EM and nectin-1 are the mo st efficie nt at  me dia ti ng e ntry  and most impo r tant  in HSV pathogenesis.React iv a tion of  HSV- 1 can l e ad t o r ec ur ren td is easeinthe for m of oralulc er s or more se r io us disease  in cluding ence pha litisan d h e rpesstr omalkerati t is (HS K). The p re c ise me c hanismo f  H SK p athogenesis is no t  f u lly understood

EM and_nectin-1 are_the most efficient at_mediating entry_and_most important_in_HSV pathogenesis. Reactivation_of HSV-1 can_lead to recurrent disease_in the form_of_oral ulcers or more serious disease including encephalitis and herpes stromal keratitis (HSK). The_precise_mechanism of_HSK_pathogenesis_is not fully understood


irabilis, the two most common ureolytic uropathogens, express urcase only in the presence of urea. This urea-dependent expression is mediated by UreR, a transcriptional activator belonging to the AraCfamily of regulators. Evidence suggests that urea interacts directly with UreR, and thus is the

irabilis, the two most common ureolytic uropathogens, express urcase only in the bearing of urea. This urea - pendent expression is mediated by UreR, a transcriptional activator belong to the AraCfamily of regulator. Evidence suggests that urea interacts directly with UreR, and therefore is the

irahilis, the two most commok ureolytic uropcrhogenv, exprsss urcare only in the presence of ucea. Rhis yrea-dependent expressiun is medpated by YreR, q transcri'fional activaflr bzlinging to the SraCfamily of regulators. Exibence suggests that urea interacts dyrectly wlth UreR, and trus ps the

irabilis, the two most common ureolytic uropathogens, only the presence urea. This urea-dependent a activator belonging to AraCfamily of regulators. suggests that urea interacts directly with and thus is the

irabilis, the two most common uReolytic urOpathOgeNs, eXpRess UrcaSe only in the preSEnce Of urea. This urea-dependenT exprEsSIon iS MeDiateD by UreR, A TrANScrIpTiOnaL aCTiVator BelOnging tO the AraCfaMilY oF regulators. EVIdEnce suggesTs tHat urea interActS direcTlY wiTH UreR, And Thus iS the

irabilis, the two most com mon ureoly tic u rop ath og ens,  exp ress urcase on l y in  the presence of urea.  This  u r ea-d e pe ndent  expres s io n isme di ate db yUreR,  atranscr iptional a cti va tor belongin g  t o the AraC fam ily of regul ato rs. Ev id enc e  sugg est s tha t urea intera cts direc tl y  withU reR, an d th us i s the

irabilis, the_two most_common ureolytic uropathogens, express_urcase only_in_the presence_of_urea. This urea-dependent_expression is mediated_by UreR, a transcriptional_activator belonging to_the_AraCfamily of regulators. Evidence suggests that urea interacts directly with UreR, and thus is_the


mice deficient in the production of Ebi3 have accelerated development of atrophy and spasmolytic polypeptide expressing metaplasia (SPEM), important preneoplastic epithelial cell lesions. We have also observed that Tregs, which are critical suppressors of gastritis and resulting lesions, exhibit a defective phenotype in Ebi3-/-

mice deficient in the production of Ebi3 have accelerated growth of atrophy and spasmolytic polypeptide carry metaplasia (SPEM), important preneoplastic epithelial cell lesions. We have besides observed that Tregs, which are critical suppressors of gastritis and resulting lesion, exhibit a defective phenotype in Ebi3-/-

mife deficient in the prodmction of Ebi3 harw accenerates develooment of atrophy and spasmolbtic polykvptide expressing metxplasia (SIEM), imporrant preneoplasvjc epitmzlial gell nxsions. We have slso obsereed that Tregs, wfieh are critical suppressors of gastrytis anc gesulting lesijns, txhybit a defective phenotype in Ebi3-/-

mice deficient in the production of Ebi3 development atrophy and polypeptide expressing metaplasia lesions. have also observed Tregs, which are suppressors of gastritis and resulting lesions, a defective phenotype in Ebi3-/-

mice deficient in the productIon of Ebi3 haVe accEleRatEd DeveLopmEnt of atrophy anD SpasMolytic polypeptide exprEssinG mETaplASiA (SPEM), ImportaNT pRENeoPlAsTic EpIThElial CelL lesionS. We have alsO obSeRved that TregS, WhIch are critIcaL suppressors Of gAstritIs And REsultIng LesioNs, exhiBIt a defEctive pheNoTYpe in EBI3-/-

mice deficient in the pro duction of  Ebi3  ha veac cele rate d developmento f at rophy and spasmolyticpolyp ep t idee xp ressi ng meta p la s i a ( SP EM ),im p or tantpre neoplas tic epithe lia lcell lesions .  W e have als o o bserved that  Tr egs, w hi cha re cr iti cal s uppres s ors of  gastriti sa nd res u lting l e s io ns,exhibit a defecti v ep henotype in Eb i3-/-

mice_deficient in_the production of Ebi3_have accelerated_development_of atrophy_and_spasmolytic polypeptide expressing_metaplasia (SPEM), important_preneoplastic epithelial cell lesions._We have also_observed_that Tregs, which are critical suppressors of gastritis and resulting lesions, exhibit a defective_phenotype_in Ebi3-/-


in pulmonary fibrosis and emphysema, both of which are of extensive clinical significance. Recent reports of the effects of ECM on cellular proliferation and differentiation make it clear that ECM constituents cannot be regarded as an inert scaffold, but that they exert significant effects at the metabolic level. The overall goal of the proposed research is thus

in pulmonary fibrosis and emphysema, both of which are of extensive clinical significance. Recent report of the effect of ECM on cellular proliferation and differentiation make it clear that ECM constituent cannot be regarded as an inert scaffold, but that they exert meaning effects at the metabolic level. The overall goal of the propose research is thus

in pulmonary fibrosis and tmphysema, both of which ere of sxtensivd clinical significance. Receit rwportw of the effects of ECO on cellllar proluferetion and differxhtiatiok maks it elxar that ECM cokstituents wannot be regasddd as an inert scaffold, but that they exert xihnificant effests se ths metabolic level. The overall goal of the proposed resrarch is thus

in pulmonary fibrosis and emphysema, both of of clinical significance. reports of the proliferation differentiation make it that ECM constituents be regarded as an inert scaffold, that they exert significant effects at the metabolic level. The overall goal of proposed research is thus

in pulmonary fibrosis and empHysema, both Of whiCh aRe oF eXtenSive Clinical signifICancE. Recent reports of the effEcts oF Ecm on cELlUlar pRoliferATiON And DiFfEreNtIAtIon maKe iT clear tHat ECM consTitUeNts cannot be rEGaRded as an inErt Scaffold, but tHat They exErT siGNificAnt EffecTs at thE MetaboLic level. THe OVerall GOal of thE PRoPoseD research is thus

in pulmonary fibrosis and  emphysema , bot h o f w hi ch a re o f extensive cl i nica l significance. Recent  repo rt s  oft he  effe cts ofE CM o n c el lu lar  p r ol ifera tio n and d ifferentia tio nmake it clea r  t hat ECM co nst ituents cann otbe reg ar ded as an  in ert s caffol d , butthat they  e x ert si g nifican t ef fect s at the metaboli c  l e vel. The overa ll goa lo ft h e p rop osed resea rc h ist hus

in_pulmonary fibrosis_and emphysema, both of_which are_of_extensive clinical_significance._Recent reports of_the effects of_ECM on cellular proliferation_and differentiation make_it_clear that ECM constituents cannot be regarded as an inert scaffold, but that they_exert_significant effects_at_the_metabolic level. The overall goal_of the proposed research is_thus