Governing Council Of The University Of Toronto

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH SUPPORTING THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY (DARPA) ACCELERATED MOLECULAR DISCOVERY (AMD) PROGRAM.

MAPPING THE REFERENCE GENETIC NETWORK OF A EUKARYOTIC CELL

DEVELOPMENT AND TESTING OF ANTHRAX TOXIN INHIBITORS

SYSTEMATIC ANALYSIS OF MORPHOGENESIS, COMMENSALISM, AND VIRULENCE IN A LEADING HUMAN FUNGAL PATHOGEN

NATURAL EVOLUTION OF QUANTUM-COHERENT LIGHT HARVESTING BY CRYPTOPHYTE ALGAE & ITS APPLICATION IN QUANTUM SENSORS

TARGETING HSP90 IN CRYPTOCOCCAL FUNGAL PATHOGENESIS

FERROCHELATASE AS A MEDIATOR OF OCULAR ANGIOGENESIS

TARGETING THE CASEIN KINASE 1 (CK1)-LIKE KINASE YCK2 IN FUNGAL PATHOGENESIS - SUMMARY/ABSTRACT FUNGAL PATHOGENS HAVE AN ENORMOUS IMPACT ON HUMAN HEALTH WORLDWIDE. IN THE U.S. ALONE, BLOODSTREAM INFECTIONS HAVE INCREASED BY OVER 200% IN RECENT DECADES, ASSOCIATED WITH AN INCREASING NUMBER OF PEOPLE WITH COMPROMISED IMMUNE FUNCTION DUE TO TREATMENT FOR CANCER, ORGAN TRANSPLANTATION, AND HIV. POOR CLINICAL OUTCOME FOR MOST INVASIVE FUNGAL INFECTIONS IS ATTRIBUTABLE TO THE VERY LIMITED NUMBER OF EFFECTIVE ANTIFUNGALS AVAILABLE AND THE EMERGENCE OF CLINICAL RESISTANCE TO EACH OF THE THREE MAIN MODES OF ACTION THEY TARGET. PROTEIN KINASES HAVE EMERGED AS RICHLY REWARDING TARGETS IN THE DEVELOPMENT OF DRUGS FOR DIVERSE DISEASES, RANGING FROM CANCER TO METABOLIC DISORDERS, BUT KINASES AS A CLASS HAVE REMAINED COMPLETELY UNTAPPED IN THE QUEST FOR NEW ANTIFUNGALS. TO BEGIN TO FILL THIS VOID, WE TESTED A PANEL OF WELL-CHARACTERIZED, STRUCTURALLY DIVERSE KINASE INHIBITORS FOR ACTIVITY AGAINST A DRUG-RESISTANT ISOLATE OF CANDIDA ALBICANS, THE MOST COMMON HUMAN FUNGAL PATHOGEN. THIS SCREEN IDENTIFIED SEVERAL COMPOUNDS WHICH WERE ACTIVE AGAINST C. ALBICANS AND THE EMERGING PATHOGEN, CANDIDA AURIS. USING CHEMICAL GENOMIC APPROACHES, WE ESTABLISHED THE PRIMARY TARGET OF OUR MOST ACTIVE COMPOUNDS AS YCK2, A FUNGAL MEMBER OF THE WIDELY EXPRESSED CASEIN KINASE 1 (CK1) FAMILY. USING GENETIC TECHNIQUES, WE CONFIRMED THAT YCK2 IS REQUIRED FOR GROWTH IN CULTURE UNDER HOST-RELEVANT CONDITIONS, IS REQUIRED TO MAINTAIN ECHINOCANDIN-RESISTANCE IN CULTURE, AND ENABLES THE VIRULENCE OF ECHINOCANDIN-RESISTANT C. ALBICANS IN BOTH IMMUNE-COMPETENT AND IMMUNE-COMPROMISED MICE. NOW, WE WILL EXPLOIT SELECTIVITY HANDLES REVEALED BY CO-CRYSTAL STRUCTURES OF THE YCK2 KINASE DOMAIN IN COMPLEX WITH OUR LEAD AND SEVERAL OTHER INHIBITORS TO OPTIMIZE POTENCY, FUNGAL SELECTIVITY, AND PHARMACOLOGICAL PROPERTIES. PURSUING TWO SCAFFOLDS IN PARALLEL AS A DE-RISKING STRATEGY, OUR GOAL IS TO DELIVER ONE OR MORE ADVANCED LEADS FOR FUTURE DEVELOPMENT OF A CLINICAL DRUG CANDIDATE. TO ACHIEVE THIS GOAL, OUR MULTIDISCIPLINARY TEAM WILL USE ITS EXPERTISE IN CHEMISTRY, STRUCTURAL BIOLOGY, PHARMACOLOGY, AND FUNGAL BIOLOGY TO PURSUE THE FOLLOWING AIMS: AIM 1: STRUCTURE-ENABLED SYNTHESIS OF YCK2 INHIBITORS WITH IMPROVED ANTIFUNGAL ACTIVITY AIM 2: OPTIMIZE CELLULAR AND WHOLE ANIMAL PHARMACOLOGY OF FUNGAL YCK2 INHIBITORS AIM 3: EVALUATE TOLERABILITY AND EFFICACY IN MOUSE MODELS OF SYSTEMIC FUNGAL INFECTION BY DRUG-RESISTANT CLINICAL ISOLATES WITH AND WITHOUT CONCURRENT SUB-THERAPEUTIC ECHINOCANDIN TREATMENT THE YCK2 INHIBITORS WE DEVELOP IN ACHIEVING THESE AIMS ARE EXPECTED TO POSSESS SINGLE AGENT ACTIVITY IN VIVO AS WELL AS REVERSE/PREVENT RESISTANCE TO ECHINOCANDINS. THE DEVELOPMENT OF THESE COMPOUNDS WILL BE INVALUABLE NOT ONLY FROM THE PERSPECTIVE OF ESTABLISHING A NEW TARGET SPACE FOR DISCOVERY AND DEVELOPMENT OF MECHANISTICALLY DISTINCT SINGLE-AGENT ANTIFUNGALS BUT ALSO IN PIONEERING A RESISTANCE-AVERSIVE COMBINATION APPROACH TO ANTIFUNGAL THERAPY THAT HAS PROVEN ESSENTIAL IN CONTROLLING OTHER INFECTIOUS DISEASES.

TARGETING HSP90 IN CRYPTOCOCCAL FUNGAL PATHOGENESIS - SUMMARY/ABSTRACT INTRINSIC AND ACQUIRED DRUG RESISTANCE OF PATHOGENIC MICROORGANISMS POSES A GRAVE THREAT TO HUMAN HEALTH AND HAS ENORMOUS ECONOMIC CONSEQUENCES WORLDWIDE. FUNGAL PATHOGENS PRESENT A PARTICULAR CHALLENGE BECAUSE THEY ARE EUKARYOTES AND SHARE MANY OF THE SAME BIOLOGICAL PROCESSES AS THE HUMAN HOSTS THEY INFECT. AMONG THE MOST PROBLEMATIC FUNGAL PATHOGENS ARE SPECIES OF CRYPTOCOCCUS, WHICH CAUSE OVER 180,000 DEATHS PER YEAR ACROSS THE GLOBE. CRYPTOCOCCAL MENINGITIS, THE MAJOR CLINICAL MANIFESTATION OF THE DISEASE, HAS A 100% MORTALITY RATE IF LEFT UNTREATED. EVEN WITH BEST AVAILABLE THERAPIES, MORTALITY RATES REMAIN HIGH BECAUSE THE NUMBER OF DRUG CLASSES THAT HAVE DISTINCT TARGETS IN FUNGI IS VERY LIMITED AND THE USEFULNESS OF CURRENT ANTIFUNGAL DRUGS IS COMPROMISED BY EITHER DOSE-LIMITING HOST TOXICITY OR THE FREQUENT EMERGENCE OF HIGH-GRADE RESISTANCE. NEW, NON- CROSS-REACTIVE TARGETS FOR THERAPEUTIC INTERVENTION ARE URGENTLY NEEDED. IN WORK PERFORMED WITH PRIOR SUPPORT FROM NIAID, WE HAVE SHOWN THAT TARGETING THE MOLECULAR CHAPERONE HSP90 IN CRYPTOCOCCUS AND OTHER FUNGI PROVIDES A POWERFUL STRATEGY TO ENHANCE THE EFFICACY OF ANTIFUNGAL DRUGS AND ABROGATE DRUG RESISTANCE. THE “DRUGGABILITY” OF HSP90 HAS BEEN WELL ESTABLISHED BY MANY SMALL MOLECULES TARGETING THIS PROTEIN FOR THE TREATMENT OF HUMAN CANCERS. THE POOR ANTIFUNGAL ACTIVITY AND TOXICITY OF CURRENTLY AVAILABLE DRUGS, HOWEVER, DEMAND DEVELOPMENT OF FUNGAL-SELECTIVE INHIBITORS AS PROPOSED IN THIS REVISED RESUBMISSION. TO PURSUE THE GOAL OF FUNGAL SELECTIVITY, OUR INTERDISCIPLINARY TEAM HAS NOW SOLVED THE STRUCTURE OF THE DRUG- BINDING DOMAIN OF CANDIDA ALBICANS AND CRYPTOCOCCUS NEOFORMANS HSP90, BOTH IN UNBOUND AND INHIBITOR-BOUND STATES. THESE CHEMO-STRUCTURAL STUDIES IDENTIFIED FUNGAL-SPECIFIC DIFFERENCES IN CONFORMATIONAL FLEXIBILITY THAT ALLOWED US TO DESIGN, SYNTHESIZE AND CHARACTERIZE FUNGAL-SELECTIVE INHIBITORS OF A NEW CHEMICAL CLASS. NOW, LEVERAGING THE NEW CHEMISTRY AND STRUCTURE-BASED DESIGN APPROACHES WE DEVELOPED WITH PREVIOUS FUNDING, WE WILL USE OUR COMPLEMENTARY EXPERTISE IN FUNGAL CHEMICAL AND MOLECULAR BIOLOGY (COWEN) AND MEDICINAL CHEMISTRY (BROWN) TO CONTINUE PURSUING STRUCTURE ACTIVITY RELATIONSHIP (SAR) STUDIES, BUT NOW AUGMENTED BY NEWLY DEVELOPED COMPUTATIONAL ALGORITHMS TO GENERATE INHIBITORS WITH BROAD-SPECTRUM ANTIFUNGAL ACTIVITY. THE EFFICACY OF COMPOUNDS ALONE AND IN COMBINATION WITH A STANDARD ANTIFUNGAL WILL BE TESTED IN CULTURE AND IN MICE AGAINST DRUG-RESISTANT C. ALBICANS AND C. NEOFORMANS. IN ADDITION TO GENERATING IMPORTANT BASIC INSIGHTS, OUR RESULTS ARE LIKELY TO IMPACT THE TREATMENT OF INVASIVE FUNGAL INFECTIONS IN THE NEAR FUTURE BY PROVIDING PROMISING LEADS FOR DEVELOPMENT OF ACTUAL ANTIFUNGAL DRUG CANDIDATES THAT OPERATE IN A NEW WAY.

NEUROIMAGING REVEALS TREATMENT-RELATED CHANGES IN DLD: A RANDOMIZED CONTROLLED TRIAL - PROJECT SUMMARY/ABSTRACT ALTHOUGH THE IMPACT OF DEVELOPMENTAL LANGUAGE DISORDER (DLD), A PREVALENT PRESCHOOL DISORDER, CAN BE MITIGATED THROUGH EVIDENCE-BASED AND EARLY INTERVENTIONS, LITTLE IS KNOWN ABOUT THE NEURAL BASIS OF DLD, ESPECIALLY IN YOUNG CHILDREN, YET IS USEFUL IN THE DESIGN OF EFFICACIOUS TREATMENTS. WHILE MUCH OF THE EVIDENCE HAS BEEN FURNISHED BY STUDIES EXAMINING DOMAIN-SPECIFIC PROCESSES (LANGUAGE NETWORK), DOMAIN-GENERAL PROCESSES RELATING MEMORY AND LANGUAGE ALSO OFFER VALUABLE TESTING GROUND AND PRESENT THE OPPORTUNITY TO ADVANCE THE CURRENT KNOWLEDGE BASE. THE PROCEDURAL CIRCUIT DEFICIT HYPOTHESIS (PDH) POSITS THAT GRAMMAR DEFICITS ARE EXPLAINED BY AN IMPAIRMENT OF PROCEDURAL MEMORY (RULE LEARNING, “KNOWING HOW”). THIS IMPAIRMENT IS ASSOCIATED WITH STRUCTURAL ABNORMALITIES IN CONNECTIONS BETWEEN FRONTAL BRAIN REGIONS AND BASAL GANGLIA, WITH CORRESPONDING UNDERACTIVATION AND REDUCED FUNCTIONAL CONNECTIVITY. HOWEVER, THE DECLARATIVE MEMORY SYSTEM (SEMANTIC, “KNOWING WHAT”), SUPPORTED BY CORTICAL AND SUBCORTICAL REGIONS IN THE TEMPORAL LOBES, INCLUDING HIPPOCAMPUS, IS SPARED, ACTING AS A COMPENSATORY MECHANISM TO OFFSET GRAMMAR DEFICITS. THIS PROPOSED RESEARCH WILL USE NEUROIMAGING (FUNCTIONAL MRI AND DIFFUSION IMAGING) TO DESCRIBE THE NEURAL BASIS (FUNCTIONAL AND STRUCTURAL CONNECTIVITY) OF GRAMMAR LEARNING AND TREATMENT-RELATED CHANGE BY WAY OF THE PDH. WE WILL GATHER CRITICAL DATA REGARDING GRAMMAR LEARNING IN PRESCHOOLERS WITH DLD BEFORE, AFTER, AND FOLLOWING A BREAK IN INTERVENTION (COMPUTER-ASSISTED TREATMENT: DLD TREATMENT; “BUSINESS AS USUAL”: DLD NO TREATMENT) AS PART OF A RANDOMIZED CONTROLLED TRIAL. WE WILL ALSO INCLUDE TYPICALLY DEVELOPING (TD) PEERS TO INFORM DEVELOPMENT VS DISORDER. OUR CENTRAL HYPOTHESIS IS THAT TREATMENT DESIGNED TO IMPROVE GRAMMAR LEARNING WILL NORMALIZE THE PROCEDURAL LEARNING NETWORK IN ASSOCIATION WITH INCREASES IN LANGUAGE FUNCTION AND THAT THE DEGREE OF IMPROVEMENT MAY BE ASSOCIATED WITH THE UNDERLYING NEUROBIOLOGY OF BASELINE GRAMMAR DEFICITS. BUILDING ON A ROBUST HISTORY OF RECRUITMENT AND TREATMENT OF PRESCHOOLERS WITH DLD, WE WILL ENROLL 184 PRESCHOOLERS, 100 WITH DLD (N=50 TREATMENT; N=50 NO TREATMENT CONTROLS) AND 84 TD. AIM 1 WILL ESTABLISH THE RELATIONSHIP BETWEEN FUNCTIONAL AND STRUCTURAL CONNECTIVITY FOR PRESCHOOLERS WITH DLD AND THEIR TD PEERS BETWEEN REGIONS IN THE PROCEDURAL LEARNING AND DECLARATIVE NETWORKS. IN AIM 2, WE WILL ESTABLISH THE NEUROBIOLOGICAL BASIS OF TREATMENT-RELATED CHANGES IN DLD ONLY. WE EXAMINE POTENTIAL CHANGES IN FUNCTIONAL AND STRUCTURAL CONNECTIVITY BETWEEN REGIONS OF THE PROCEDURAL LEARNING AND DECLARATIVE MEMORY NETWORKS, AND INVESTIGATE WHETHER TREATMENT-RELATED CHANGES OCCUR INTO THE TYPICAL RANGE (DLD AND TD). TO MEET OUR SCIENTIFIC GOALS, WE PAIR BEHAVIORAL TOOLS (TRADITIONAL GRAMMAR TOOLS) WITH NEUROIMAGING TO DESCRIBE CO-OCCURRING BEHAVIORAL PERFORMANCE UNDERLYING LEARNING AND OUTCOME. THIS RESEARCH WILL CONTRIBUTE NOVEL INSIGHTS INTO MECHANISMS UNDERLYING LEARNING AND IMPAIRMENT TO HELP ADVANCE THE EVIDENCE-BASED MANAGEMENT OF DLD.

PRENATAL AND CHILDHOOD EXPOSURE TO FLUORIDE AND NEURODEVELOPMENT

DEVELOPMENT OF FACE PROCESSING EXPERTISE IN CHILDREN

THE COMPETENCE REGULON IN STREPTOCOCCUS MUTANS BIOFILMS

REDUCING RESIDUAL DEPRESSIVE SYMPTOMS WITH WEB-BASED MINDFUL MOOD BALANCE

VARIABLE BRAIN OXYCODONE METABOLISM ALTERS DRUG EFFECT

TAS::57 3600::TAS "PHOTOINDUCED ELECTRONIC ENERGY TRANSFER: THEORETICAL AND EXPERIMENTAL ISSUES FOR LIGHT HARVESTING APPLICATIONS"

HARNESSING THE PIWI PIRNA PATHWAY TO SILENCE HIV

RECEPTORS MEDIATING DRUG DEPENDENCE

UNIV. OF TORONTO MHSC IN BIOETHICS INTERNATIONAL STREAM

GENETICS AND PHENOMICS OF WIDESPREAD NEUROPATHIC TRIGEMINAL PAIN IN THE MOUSE

DENTAL AND CRANIOFACIAL PAIN: AFFERENT AND BRAINSTEM MECHANISMS

SYSTEMATIC CHARACTERIZATION OF UNCONVENTIONAL RNA BINDING PROTEINS

EXAMINING THE LINK BETWEEN HIPPOCAMPAL PATHOLOGY AND MENINGEAL INFLAMMATION IN PROGRESSIVE MS

ALCOHOL AND ZEBRA FISH: BEHAVIORAL SCREENS FOR MUTANTS

A HIGH THROUGHPUT PLATFORM FOR NUCLEAR RECEPTOR LIGAND AND DRUG DISCOVERY

INJECTABLE AND BIODEGRADABLE VITREOUS SUBSTITUTE TO RESTORE VISION FUNCTION FOLLOWING RETINAL DETACHMENT

DETERMINING THE SEQUENCE AND STRUCTURE SPECIFICITIES OF RNA-BINDING PROTEINS

TRANSPORT DYNAMICS OF ULTRACOLD ATOMS

CLOSING THE LOOP FOR THE DISCOVERY OF NOVEL CATALYSTS AND MECHANISMS FOR DEPOLYMERIZATION OF FUNCTIONAL MATERIALS

NEW COMPOSITE MATERIAL DESIGN BASED ON STUDIES OF TOOTH-COMPOSITE AND MICROBIAL I

DEVELOPMENT AND VALIDATION OF NANOPARTICLE-MEDIATED MICROFLUIDIC PROFILING APPROACH FOR RARE CELL ANALYSIS

COMBINATORIAL DESIGN OF NONVIRAL BASE EDITING SYSTEMS FOR TREATING CYSTIC FIBROSIS WITH NONSENSE MUTATIONS - PROJECT SUMMARY CYSTIC FIBROSIS (CF) IS A DEBILITATING GENETIC DISORDER THAT PREDOMINANTLY IMPACTS THE LUNGS AND PANCREAS DUE TO MUTATIONS IN THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR) GENE. SPECIFICALLY, NONSENSE MUTATIONS, WHICH PRODUCE TRUNCATED, NON-FUNCTIONAL PROTEINS, ACCOUNT FOR APPROXIMATELY 11% OF ALL CF CASES. CURRENTLY, THESE MUTATIONS LACK TARGETED, EFFECTIVE THERAPEUTIC SOLUTIONS. OUR RESEARCH ENDEAVORS TO ADDRESS THIS UNMET CLINICAL NEED BY HARNESSING THE CAPABILITIES OF ADENINE BASE EDITORS (ABES) TO CORRECT PREMATURE TERMINATION CODONS (PTCS) THROUGH TRANSLATIONAL READTHROUGH, THEREBY RESTORING FUNCTIONAL PROTEIN EXPRESSION. TO FACILITATE EFFICIENT DELIVERY, WE AIM TO FORMULATE LIPID NANOPARTICLES (LNPS) SPECIFICALLY ENGINEERED FOR PULMONARY ABE DELIVERY. THE PROJECT IS SEGMENTED INTO THREE PIVOTAL OBJECTIVES: 1) THE CHEMICAL REFINEMENT OF RNA-ENCODED ABES TO ACHIEVE OPTIMAL ON-TARGET GENE-EDITING; 2) THE DEVELOPMENT AND FINE-TUNING OF LNP FORMULATIONS TO OVERCOME CHALLENGES INTRINSIC TO PULMONARY DELIVERY; AND 3) COMPREHENSIVE IN VIVO VALIDATION USING A CFTR NONSENSE MUTATION MOUSE MODEL TO ASSESS BOTH THERAPEUTIC EFFICACY AND SAFETY PROFILES. BY FOCUSING ON NANOPARTICLE-MEDIATED LUNG CELL ENGINEERING, OUR APPROACH LAYS THE FOUNDATION FOR A GROUNDBREAKING, NON-VIRAL BASE EDITING PLATFORM THAT COULD REVOLUTIONIZE TREATMENT PROTOCOLS FOR CF AND OTHER DISEASES STEMMING FROM PTCS. EMPLOYING CUTTING-EDGE METHODOLOGIES, INCLUDING THE OPTIMIZATION OF MRNA SEQUENCES ENCODING ABES, GRNA DESIGN, AND NOVEL FOUR-COMPONENT COMBINATORIAL LIPID CHEMISTRY, OUR PROJECT HAS THE POTENTIAL TO SUBSTANTIALLY ADVANCE GENOMIC EDITOR DELIVERY TO THE PULMONARY SYSTEM. THESE INNOVATIONS COULD RECONFIGURE THERAPEUTIC STRATEGIES FOR CF AND OTHER GENETIC DISEASES CAUSED BY NONSENSE MUTATIONS. THE FEASIBILITY OF THIS HIGH-IMPACT WORK IS REINFORCED BY OUR LAB'S ESTABLISHED EXPERTISE IN THESE TECHNOLOGIES, MAKING IT A VIABLE CANDIDATE FOR SIGNIFICANTLY ADVANCING THE NONVIRAL DELIVERY OF GENOMIC MEDICINES AND THEREBY ENHANCING THE THERAPEUTIC OPTIONS FOR A WIDE ARRAY OF LUNG DISEASES.

TAS::57 3600::TAS "SINGLE-SITE IMAGING OF FERMIONS IN TWO-DIMENSIONAL OPTICAL LATTICES"

EPIGENETIC MEDIATION OF ENDOCRINE AND IMMUNE RESPONSE IN AN ANIMAL MODEL OF GULF WAR ILLNESS

CHARACTERIZATION OF ANTHRAX LETHAL TOXIN

PROGRAMS AT THE FIELDS INSTITUTE FOR RESEARCH IN MATHEMATICAL SCIENCES

FUNCTIONAL GENETIC SCREENING TO ELUCIDATE NOVEL MITOCHONDRIAL DNA REPAIR FACTORS USING ORGANELLE-TARGETED CHEMICAL PROBES

TAS::57 3600::TAS "PHOTOINDUCED ELECTRONIC ENERGY TRANSFER: THEORETICAL AND EXPERIMENTAL ISSUES FOR LIGHT HARVESTING APPLICATIONS"

PROGRAMS AT THE FIELDS INSTITUTE FOR RESEARCH IN MATHEMATICAL SCIENCES

PHOTO-CHEMICAL TOOLS FOR MANIPULATING NEURAL PLASTICITY

DISCOVERY OF NOVEL SURFACE BIOMARKERS OF LATENTLY HIV-INFECTED CELLS USING LAMPREY ANTIBODY TECHNOLOGY

COHERENT CONTROL OF COLD AND ULTRACOLD BIMOLECULAR REACTIONS

QUANTUM COHERENCE AND DYNAMICS IN BIOLOGICAL PROCESSES: MOLECULAR ISOMERIZATION IN VISON

PREGNANCY IN WOMEN WITH DISABILITIES: USING NOVEL METHODS TO CHARACTERIZE RISK

CONFERENCE: SUPPORT FOR US-BASED PARTICIPANTS IN PROGRAMS AT THE FIELDS INSTITUTE FOR RESEARCH IN MATHEMATICAL SCIENCES -THIS FUNDING WILL SUPPORT PARTICIPATION OF US-BASED MATHEMATICIANS AND STATISTICIANS IN THE FIELDS INSTITUTE'S COLLABORATIVE PROGRAMS, STRENGTHENING THEIR CONTRIBUTIONS TO KNOWLEDGE FRONTIERS, INNOVATION AND CUTTING-EDGE MATHEMATICS RESEARCH. THIS PROGRAM EMBODIES NSF'S OBJECTIVE OF FOSTERING INTEGRATION OF RESEARCH AND EDUCATION THROUGH PROGRAMS THAT RECRUIT, TRAIN, AND PREPARE A DIVERSE SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS WORKFORCE TO ADVANCE THE FRONTIERS OF SCIENCE AND PARTICIPATE IN THE KNOWLEDGE ECONOMY. FIELDS INSTITUTE PROGRAMS INCLUDE CONFERENCES AND WORKSHOPS SPAN FUNDAMENTAL AND APPLIED MATHEMATICS RESEARCH, INDUSTRIAL PARTNERSHIPS, MATHEMATICS EDUCATION, AND OUTREACH TO THE BROADER PUBLIC. THEMATIC AND FOCUS PROGRAMS, ALONG WITH OTHER ACTIVITIES, BRING TOGETHER LEADING EXPERTS, RESEARCHERS FROM DIFFERENT CAREER STAGES, POSTDOCS, AND STUDENTS FOR SUSTAINED PERIODS OF COMMUNICATION AND COLLABORATION ON IMPORTANT MATHEMATICAL PROBLEMS OF CURRENT SIGNIFICANCE. PROGRAM PARTICIPANTS GAIN ADVANCED TRAINING AND DEVELOPMENT OPPORTUNITIES THROUGH THEIR INTERACTIONS WITH THE INSTITUTE'S VISITORS AND PARTICIPANTS. FIELDS INSTITUTE PROGRAMS CONNECT MATHEMATICIANS WITH EXPERTS AND INDUSTRY PRACTITIONERS IN RELATED DISCIPLINES, EXPOSING TRAINEES TO REAL-WORLD CHALLENGES. NSF FUNDING WILL ENABLE US-BASED PARTICIPANTS WHO HAVE NO OTHER FEDERAL SUPPORT AND PARTICIPANTS WHO ARE STUDENTS, POST-DOCTORAL SCHOLARS, OR MEMBERS OF GROUPS THAT ARE UNDER-REPRESENTED IN THE MATHEMATICAL SCIENCES TO PARTICIPATE IN FIELDS INSTITUTE PROGRAMS. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

R&D, SCIENCE AND ENGINEERING, IN THE AREA OF PHYSICS

R&D, SCIENCE AND ENGINEERING, IN THE AREA OF PHYSICS

PERSONALIZING EXPLANATIONS IN ONLINE PROBLEMS USING MULTI-ARMED CONTEXTUAL BANDITS

TAS:57 3600::TAS 'QUANTUM COHERENCE AND DYNAMICS IN BIOLOGICAL PROCESSES: MOLECULAR ISOMERIZATION IN VISION'

TAS::57 3600::TAS 'TURBULENCE EVOLUTION THROUGH PREMIXED FLAMES AND ITS RELATIONSHIP WITH FLAME STRUCTURE' DATED 13 OCT 2016

WIDE-BANDGAP PEROVSKITES FOR EFFICIENT, STABLE TANDEMS

ULTRASTABLE REDUCED-DIMENSIONAL LEAD PEROVSKITES

FIELD EVALUATION OF PASSIVE AERATION SYSTEM FOR AQUACULTURE IN BANGLADESH

CHARACTERIZING BILINGUAL SPEECH SOUND PRODUCTION IN JAMAICAN CREOLE AND ENGLISH-SPEAKING PRESCHOOLERS

CHARACTERIZING ACCURACY AND VARIABILITY IN SPEECH SOUND PRODUCTIONS ACROSS BIDIALECTAL AND BILINGUAL PRESCHOOLERS - PROJECT SUMMARY/ABSTRACT SPEECH SOUND DISORDER (SSD) IS A HIGH-INCIDENCE DEVELOPMENTAL DISABILITY THAT CAN RESULT IN LONG-TERM NEGATIVE IMPACTS ON ACADEMIC AND CAREER ACHIEVEMENT. ALTHOUGH THE IMPACTS OF SSD CAN BE MITIGATED THROUGH EVIDENCE-BASED INTERVENTIONS, THE CHALLENGE OF DIAGNOSING AND MANAGING SSD IS GREATLY EXACERBATED WHEN WORKING WITH CLIENTS FROM LINGUISTICALLY DIVERSE BACKGROUNDS. A CLINICIAN EVALUATING A CHILD WHO USES MORE THAN ONE LANGUAGE DAILY MUST AVOID OVER-DIAGNOSING DISORDER IN CASES MORE ACCURATELY CHARACTERIZED AS DIFFERENCES WHILE ALSO GUARDING AGAINST UNDER-DIAGNOSIS OF SSD IN THIS POPULATION. THIS NEED TO REDUCE MISDIAGNOSIS OF SSD IS PARTICULARLY PRESSING IN UNDERSTUDIED CONTEXTS, NAMELY CHILDREN WHO ARE BIDIALECTAL OR BILINGUAL IN TWO CLOSELY RELATED LANGUAGES. IN THESE CASES, PRODUCTION VARIATION IS UBIQUITOUS YET MIGHT BE FLAGGED AS BEING ATYPICAL IN THE DIAGNOSTIC PROCESS. LANGUAGES INTERACT DIFFERENTLY DEPENDING ON THEIR TYPOLOGICAL PROPERTIES, AND THE BODY OF EXISTING LITERATURE FOCUSED ON A SMALL SET OF RELATIVELY WELL-DOCUMENTED CASES (E.G., SPANISH- ENGLISH) RUNS THE RISK OF ARRIVING AT AN OVERLY HOMOGENOUS MODEL OF SPEECH DEVELOPMENT AND DISORDERS. BY STUDYING TWO GROUPS OF CHILDREN – THOSE ACQUIRING AFRICAN AMERICAN ENGLISH AND STANDARDIZED AMERICAN ENGLISH (AAE/SAE) AND THOSE ACQUIRING JAMAICAN CREOLE AND JAMAICAN ENGLISH (JC/JE) – THIS PROPOSAL NOT ONLY BENEFITS UNDERSERVED POPULATIONS BUT WILL ALSO BROADEN THE THEORETICAL BASE FOR UNDERSTANDING SPEECH DEVELOPMENT AND DISORDERS IN LINGUISTICALLY DIVERSE CONTEXTS. ALTHOUGH OUR TEAM HAS MADE RECENT STRIDES TOWARD UNDERSTANDING TRADE-OFFS BETWEEN ACCURACY AND VARIABILITY IN A BILINGUAL CONTEXT, ADDITIONAL ELABORATION OF THE THEORETICAL FRAMING IS NEEDED TO INFORM THE DIAGNOSTIC SIGNIFICANCE OF PRODUCTION VARIATION WHEN LANGUAGES ARE LINGUISTICALLY RELATED. WE PROPOSE TO MODEL THE RELATIONSHIP BETWEEN ACCURACY AND VARIABILITY IN PRODUCTION USING THE ARTICULATORY MAP ([A-MAP]; MCALLISTER BYUN ET AL., 2016) AND GRADUAL LEARNING ALGORITHM ([GLA] BOERSMA AND HAYES, 2001). APPLICATION OF THE A-MAP AND GLA ARE NEEDED TO ACCOUNT FOR TYPOLOGICAL PATTERNS OF PHONETIC AND PHONOLOGICAL LEARNING ACROSS LANGUAGE CONTEXTS BOTH THEORETICALLY (A-MAP) AND COMPUTATIONALLY (GLA). THE LONG-TERM GOAL OF THIS RESEARCH IS TO ARRIVE AT A COHERENT UNDERSTANDING OF PRODUCTION VARIATION TO REDUCE MISDIAGNOSIS OF SSD IN UNDERREPRESENTED POPULATIONS. USING TRANSCRIPTION- BASED MEASURES OF ACCURACY AND ACOUSTIC (SPECTRAL)-BASED MEASURES OF VARIABILITY, WE WILL TEST THE PREDICTIONS OF THE A-MAP AND GLA IN PRESCHOOL-AGED BIDIALECTAL AAE/SAE AND BILINGUAL JC/JE SPEAKERS. STATISTICAL MODELING OF THE RELATIVE CONTRIBUTIONS OF ACOUSTIC-BASED MEASURES OF VARIABILITY AND TRANSCRIPTION-BASED MEASURES OF ACCURACY TO A GOLD STANDARD DIAGNOSIS WILL BE USED TO IDENTIFY THE OPTIMAL DIAGNOSTIC CRITERIA FOR DISORDER STATUS. THE DATA WE GENERATE WILL SUPPORT A METHODOLOGICAL TEMPLATE FOR PROTOCOLS THAT REDUCE MISDIAGNOSIS OF SSD IN BIDIALECTAL AND BILINGUAL CHILDREN TO MEET THE NIDCD 2023-2027 STRATEGIC OBJECTIVE THEME 4: GOAL 3 TO ADVANCE UNDERSTANDINGS ABOUT COMMUNICATION DISORDERS IN UNDERREPRESENTED POPULATIONS.

DEVELOPMENT OF (PROTOTYPE) BEAD ARRAY FLOW CYTOMETER WITH MASS SPECTROMETER DETEC

INVESTIGATING THE ANALYSIS OF DATA FROM ADAPTIVE EXPERIMENTS

UNDERSTANDING THE CAUSES, CONSEQUENCES, AND SEVERITY OF ELDER MISTREATMENT: A LONGITUDINAL, POPULATION-BASED STUDY

DYNAMICS AND SPIN TRANSPORT OF ULTRACOLD FERMIONS

TOOLS FOR MANIPULATING LOCAL PROTEIN SYNTHESIS IN THE BRAIN

INTELLIGENT CHEMISTRY FOR AUTONOMOUS CHEMISTRY

METAL TAGGING OF BIOACTIVE MOLECULES FOR PROGNOSTIC ASSAYS COUPLED WITH ICP-MS

MACHINE LEARNING TO INFORM HEALTH SERVICES AND POLICY FOR TRAUMATIC BRAIN INJURY

ADVANCING ASSESSMENT OF EPISODIC DISABILITY TO ENHANCE HEALTHY AGING AMONG ADULTS WITH HIV: DEVELOPING A SHORT-FORM HIV DISABILITY QUESTIONNAIRE (HDQ) FOR USE IN CLINICAL PRACTICE

IMMIGRANT INTEGRATION AND HEALTH: MULTIDIMENSIONAL AND CROSS-NATIONAL ANALYSES OVER THE LIFE COURSE - PROJECT SUMMARY TITLE: IMMIGRANT INTEGRATION AND HEALTH: MULTIDIMENSIONAL AND CROSS-NATIONAL ANALYSES OVER THE LIFE COURSE. OLDER IMMIGRANTS OF COLOR HAVE HIGH LEVELS OF COGNITIVE IMPAIRMENT AND PHYSICAL DISABILITY, WHICH STANDS IN SHARP CONTRAST TO THE “HEALTHY IMMIGRANT EFFECT” WHERE RECENT IMMIGRANT ARRIVALS TEND TO BE HEALTHIER THAN THE NATIVE-BORN. WITH THE ELDERLY IMMIGRANT POPULATION IN THE U.S. PROJECTED TO QUADRUPLE BY 2050, THE DECLINE OF THE HEALTHY IMMIGRANT EFFECT OVER THE LIFE COURSE REPRESENTS A GROWING PUBLIC HEALTH CONCERN. THE EXISTING LITERATURE HAS MADE MUCH PROGRESS IN IDENTIFYING ASSOCIATIONS BETWEEN TIME SINCE IMMIGRATION AND ACCELERATED HEALTH DECLINES. HOWEVER, IT REMAINS UNCLEAR 1) WHICH MECHANISMS WITHIN THE BROAD PROCESS OF ACCULTURATION AND INTEGRATION DRIVE THIS DECLINE, 2) HOW THE TIMING OF INTEGRATION OVER THE LIFE COURSE AFFECTS HEALTH, AND 3) THE ROLE OF U.S. INSTITUTIONAL DESIGNS IN SHAPING IMMIGRANT HEALTH DECLINES, PARTICULARLY AMONG POPULATIONS OF COLOR. THIS PROJECT WILL LEVERAGE LINKED SURVEY AND ADMINISTRATIVE DATA TO DEVELOP MULTIDIMENSIONAL AND LONGITUDINAL MEASURES OF IMMIGRANT INTEGRATION AND EVALUATE THEIR IMPACT ON OLDER ADULTS’ HEALTH. WE WILL ALSO INVESTIGATE THE ROLE OF INSTITUTIONAL DESIGNS ON IMMIGRANTS’ HEALTH USING A CROSS-NATIONAL COMPARISON BETWEEN THE U.S. AND CANADA. SPECIFIC AIM 1 INVESTIGATES HOW SOCIAL, ECONOMIC, AND RESIDENTIAL DIMENSIONS OF INTEGRATION AFFECT TRAJECTORIES OF PHYSICAL FUNCTIONING AND COGNITIVE IMPAIRMENT AMONG BLACK, HISPANIC, WHITE, AND OTHER IMMIGRANTS AFTER AGE 60. WE HYPOTHESIZE THAT DIFFERENT DIMENSIONS OF INTEGRATION WILL AFFECT DIFFERENT DIMENSIONS OF HEALTH IN LATER LIFE. FURTHERMORE, WE EXPECT THAT BLACK AND HISPANIC IMMIGRANTS WILL RECEIVE ESPECIALLY SMALL OR NEGATIVE RETURNS TO INTEGRATION DUE TO HIGHER EXPOSURE TO RACISM. SPECIFIC AIM 2 ADOPTS A CROSS-NATIONAL DESIGN TO COMPARE THE EFFECT OF ECONOMIC INTEGRATION TRAJECTORIES ON U.S. AND CANADIAN IMMIGRANTS’ PHYSICAL HEALTH, INCLUDING THE RACIAL DIFFERENCES IN THESE EFFECTS. WE HYPOTHESIZE THAT THE TIMING OF ECONOMIC INTEGRATION WILL BE CONSEQUENTIAL FOR IMMIGRANTS’ LATER-LIFE HEALTH OUTCOMES BECAUSE HEALTH (DIS)ADVANTAGES ARE CUMULATIVE OVER THE LIFE COURSE. WE FURTHER EXPECT THAT THESE CONSEQUENCES ARE MORE PRONOUNCED IN THE U.S. THAN IN CANADA BECAUSE THE LATTER HAS UNIVERSAL HEALTHCARE, AND IMMIGRANTS HAVE ACCESS TO PROGRAMS AND RESOURCES REGARDLESS OF THEIR INDIVIDUAL ECONOMIC CONDITIONS. THE RESEARCH TEAM CONTAINS AN INTERDISCIPLINARY GROUP OF SOCIOLOGISTS, DEMOGRAPHERS, AND HEALTH POLICY SCHOLARS WHO HAVE THE NECESSARY EXPERTISE AND FAMILIARITY WITH THE DATA AND METHODOLOGY TO PRODUCE NEW EVIDENCE ON IMMIGRANT INTEGRATION AND OLDER IMMIGRANTS’ HEALTH. THE OUTCOMES OF THIS PROJECT CAN ADVANCE OUR UNDERSTANDING OF HOW RACIAL AND IMMIGRANT HEALTH DISPARITIES EMERGE AND WHAT INTERVENTIONS CAN MOST EFFECTIVELY REDUCE THEM.

DEEP STRUCTURED LEARNING FOR SCENE UNDERSTANDING

TAS::57 3600::TAS "A POSTERIORI QUANTIFICATION OF RATE-CONTROLLING EFFECTS FROM HIGH-INTENSITY TURBULENCE-FLAME INTERACTIONS USING 4D MEASUREMENT"

PROGRAMMABLE ELECTROCHEMICAL GENE CIRCUIT SENSORS?FOR INFECTIOUS DISEASE DETECTION

DEVELOPMENT AND DEPLOYMENT OF AN ELECTROCHEMICAL ANTIGEN TESTING SYSTEM FOR SARS-COV-2 - PROJECT SUMMARY: THE COVID-19 PANDEMIC HAS HIGHLIGHTED THE SHORTCOMINGS OF EXISTING TESTING APPROACHES FOR VIRAL INFECTION. DIAGNOSING ACTIVE INFECTIONS USING PCR OR OTHER AMPLIFICATION STRATEGIES IS CONSTRAINED TO CENTRALIZED TESTING FACILITIES THAT HAVE LIMITED CAPACITY. NEW POINT-OF-CARE MOLECULAR TESTING APPROACHES, WHILE PROVIDING A MEANS TO TEST OUTSIDE OF LABORATORIES, HAVE LOW THROUGHPUT AND TURNAROUND TIMES THAT ARE NOT COMPATIBLE WITH WIDESPREAD, RAPID SCREENING. MOREOVER, THE USE OF NASOPHARYNGEAL SWABS IS HIGHLY PROBLEMATIC GIVEN THE DIFFICULTLY OF ACQUIRING AND PROCESSING THIS SAMPLE TYPE. ANTIBODY TESTS INTEGRATED INTO LATERAL FLOW DEVICES UTILIZE A MORE TRACTABLE SAMPLE TYPE AND ARE EFFECTIVE FOR ESTIMATING INFECTION RATES, BUT ARE NOT USEFUL FOR DETECTING ACTIVE INFECTIONS. IN THIS PROPOSAL WE DESCRIBE A NEW VIRAL DETECTION APPROACH THAT IS RAPID, AMENABLE TO MASSIVELY DECENTRALIZED TESTING, AND PROVIDES A NEW MEANS TO PERFORM VIRAL INFECTION ASSESSMENT AS A TOOL TO COMBAT THE CURRENT COVID-19 PANDEMIC AND CONTROL FUTURE VIRAL OUTBREAKS. THE NEW TECHNOLOGY POWERING THIS APPROACH IS A BREAKTHROUGH IN REAGENTLESS SENSING ACCOMPLISHED USING ELECTROCHEMICAL READOUT THAT WILL ENABLE RAPID SCREENING FOR SARS-COV-2 INFECTION. THE SENSORS WILL DIRECTLY DETECT VIRAL PARTICLES AND VIRAL PROTEINS BASED ON A UNIQUE SIGNAL TRANSDUCTION MECHANISM AND CAN BE USED FOR IN SITU MEASUREMENTS INSIDE OF THE MOUTH OR IN SALIVA SAMPLES. THE FACT THAT NO EXTERNAL REAGENTS ARE REQUIRED MAKES THIS APPROACH PARTICULARLY AMENABLE TO DECENTRALIZED ON-DEMAND TESTING. PROJECT DELIVERABLES WILL INCLUDE A SCREENING SYSTEM THAT WILL ALLOW FOR DIRECT SARS-COV-2 DETECTION FROM A SALIVA SAMPLE (WITHOUT THE GENERATION OF AEROSOLS) IN A TIME FRAME RELEVANT AT-HOME COMMUNITY SCREENING. THIS WILL ACCELERATE THE AVAILABILITY OF HIGH-QUALITY AND REAL-TIME DATA TO SUPPORT A RAPID RESPONSE TO BETTER DETECT AND MANAGE COVID-19. IN ADDITION, THE LOW COST AND PORTABLE NATURE OF THE DIAGNOSTIC DEVICE WILL ALLOW FOR DEPLOYMENT TO LOW- AND MIDDLE-INCOME COUNTRIES TO HELP PREVENT THE RAPID SPREAD OF COVID-19 WITHIN THOSE POPULATIONS. THE RAPID VIRAL DETECTION SYSTEM WILL: 1) PROVIDE AN ALTERNATIVE TO PCR-BASED TESTING AND ACCELERATE THE AVAILABILITY OF HIGH-QUALITY DIAGNOSTIC INFORMATION TO ALLOW AMERICANS TO BETTER MANAGE THE PANDEMIC; 2) DEVELOP AN EFFECTIVE INTERVENTION THAT WILL PROVIDE RAPID, ACTIONABLE DIAGNOSTIC INFORMATION ON COVID-19 STATUS; 3) ENABLE CLINICAL STUDIES THAT ASSESS VIRAL LOAD AS A FUNCTION OF MEDICAL COUNTERMEASURES BY FACILITATING SERIAL AND CONTINUOUS MONITORING OF PATIENTS FOR SARS-COV-2.

TECHNOLOGY FOR TEN-MINUTE RESOLUTION PROTEIN INTERACTION MAPPING AT PROTEOME SCALE - PROJECT SUMMARY GENES MEDIATE THEIR EFFECTS THROUGH NETWORKS OF MACROMOLECULAR INTERACTIONS. LARGE-SCALE STUDIES HAVE MAPPED PROTEIN INTERACTIONS FOR HUMANS AND SEVERAL MODEL ORGANISMS. HOWEVER, EVEN FOR S. CEREVISIAE, THE MOST INTENSIVELY-STUDIED EUKARYOTIC MODEL, KNOWLEDGE OF THE PROTEIN INTERACTION NETWORK REMAINS BOTH INCOMPLETE AND ‘STATIC’, IN THE SENSE THAT EACH GLOBAL INTERACTION MAPPING STUDY HAS USED ESSENTIALLY THE SAME GROWTH ENVIRONMENT AND GENETIC BACKGROUND. MOREOVER, DESPITE THE MANY KNOWN EXAMPLES OF SIGNALLING INTERACTIONS THAT APPEAR AND FADE RAPIDLY AFTER AN ENVIRONMENTAL STRESS, LARGE-SCALE INTERACTION MAPS REPRESENT THE TIME- AVERAGE OF INTERACTION OVER MANY GENERATIONS OF A CELL. WE PREVIOUSLY EXTENDED THE YEAST TWO-HYBRID (Y2H) INTERACTION ASSAY WITH A ‘BARCODE FUSION GENETICS’ (BFG) STRATEGY, WHICH USES INTRACELLULAR RECOMBINATION TO FORM CHIMERIC BARCODES THAT IDENTIFY BAIT/PREY PROTEIN COMBINATIONS. THIS ‘BFG-Y2H’ METHOD ENABLED MULTIPLEXING OF MILLIONS OF INTERACTION ASSAYS, WITH INTERNAL BIOLOGICAL REPLICATION, ALL WITHIN A SINGLE EN MASSE EXPERIMENT, AND HAS ALREADY BEEN USED FOR PROTEOME-SCALE MAPPING OF YEAST INTERACTIONS UNDER FOUR GROWTH ENVIRONMENTS. HERE WE PROPOSE A FURTHER EXTENSION, IN WHICH THE PROMOTER THAT TRADITIONALLY REPORTS ON INTERACTION STATUS IS USED TO TRANSCRIBE THE CHIMERIC BAIT/PREY BARCODE LOCUS. SEQUENCING THESE ‘INTERACTION TAGS’ CAN THUS PROVIDE A QUANTITATIVE MEASURE OF PROMOTER OUTPUT. IMPORTANTLY, THE RAPID DYNAMICS OF TRANSCRIPT PRODUCTION AND DEGRADATION HAVE THE POTENTIAL TO ENABLE MEASUREMENT OF INTERACTION DYNAMICS WITH ~10-MINUTE TIME RESOLUTION, AT PROTEOME SCALE, IN LIVING CELLS.

MODULAR TISSUE ENGINEERING COMPONENTS FOR VASCULARIZED 3-D CONSTRUCTS

TARGETED NANOTECHNOLOGY FOR PRECISE DELIVERY OF SYNERGISTIC COMBINATION CHEMOTHERAPY EXPLOITING DEFICIENCIES IN DNA REPAIR IN HIGH-GRADE SEROUS OVARI

EVALUATION OF CANADA'S MENTHOL BAN

MEASURING AND DESCRIBING NUCLEOSOME REMODELER SEQUENCE PREFERENCES - PROJECT SUMMARY/ABSTRACT HUGHES - “MEASURING AND DESCRIBING NUCLEOSOME REMODELER SEQUENCE PREFERENCES” DETERMINING HOW CELLS INTERPRET REGULATORY SEQUENCE IS A DIFFICULT BUT IMPORTANT PROBLEM THAT BROADLY IMPACTS DISCIPLINES INCLUDING HUMAN GENETICS, DEVELOPMENT, AND EVOLUTION. COMPUTATIONAL APPROACHES IN THIS AREA ARE USUALLY FOCUSED ON TRANSCRIPTION FACTOR (TF) BINDING SITES. THERE IS SUBSTANTIAL EVIDENCE, HOWEVER, THAT NUCLEOSOME REMODELERS, WHICH WORK TOGETHER WITH TFS TO GENERATE OPEN CHROMATIN AT REGULATORY SITES, ALSO POSSESS SOME LEVEL OF SEQUENCE SPECIFICITY. THIS SPECIFICITY COULD INVOLVE DIRECT SEQUENCE RECOGNITION, ABILITY TO MOVE OR EVICT NUCLEOSOMES OVER SOME SEQUENCES BUT NOT OTHERS, AND/OR LONGER-RANGE MECHANISMS SUCH AS SEQUENCE DEPENDENCE OF PACKING NUCLEOSOME ARRAYS AGAINST A BARRIER. HERE, WE PROPOSE TO DEVELOP METHODS TO IDENTIFY AND DESCRIBE THE SEQUENCE DEPENDENCE OF EACH OF THESE MECHANISMS, WHICH CAN BE APPLIED TO ANY REMODELING ENZYME. TO AVOID THE COMPLEX AND CONFOUNDING EFFECTS OF OTHER FACTORS, THE METHODS WILL EMPLOY BIOCHEMICAL ASSAYS WITH PURIFIED COMPONENTS. THE RESULTING DATA WILL THEN BE INTERROGATED TO IDENTIFY SEQUENCE FEATURES THAT CORRELATE WITH AND PREDICT NUCLEOSOME OCCUPANCY AND MOVEMENT IN RESPONSE TO EACH TYPE OF REMODELER, AND MODELS CONSTRUCTED THAT CAN DETECT AND SCORE THESE FEATURES WITHIN ANY GIVEN SEQUENCE. THESE MODELS CAN BE USED ANALOGOUSLY TO AND IN CONJUNCTION WITH WIDELY USED TRANSCRIPTION FACTOR MOTIF MODELS. IF SUCCESSFUL, THESE METHODS COULD BE APPLIED TO THE MANY VARIANTS OF REMODELING COMPLEXES. THE RESULTING MODELS SHOULD BE WIDELY APPLICABLE IN THE STUDY OF GENE REGULATION, ANALOGOUS TO TRANSCRIPTION FACTOR DNA BINDING MOTIFS. DEVELOPMENT AND VALIDATION OF THIS METHOD COULD THEREFORE HAVE WIDESPREAD IMPACT IN HUMAN GENETIC ANALYSIS AND BROAD APPLICABILITY IN MOLECULAR GENETIC RESEARCH.

TOOLS FOR MANIPULATING LOCAL PROTEIN SYNTHESIS IN THE BRAIN

POLYSIALIC ACID AS A MEDIATOR OF BREAST CANCER PROGRESSION AND A POTENTIAL BIOMARKER FOR RISK STRATIFICATION

TAS::57 3600::TAS "STUDIES OF QUANTUM MAGNETISM WITH ULTRA-COLD LATTICE FERMIONS"

DATA ASSIMILATION TO LEVERAGE DIVERSE DATASETS FOR IMPROVED CO2 & CH4 FLUX ESTIMATION AND FUTURE OBSERVING SYSTEM DESIGN

DICTIONARY OF OLD ENGLISH [DOE]

NANOSTRUCTURED BLOCK COPOLYMER COATINGS FOR BIOFOULING INHIBITION

THIS IS A CONTINUATION OF N00014-14-1-0232 DEEP STRUCTURED LEARNING FOR SCENE UNDERSTANDING

FREQUENCY- POLARIZATION HYPER-ENTANGLED PHOTONS IN LONG-DISTANCE FIBER TRANSMISSION

SITE-RESOLVED QUANTUM SIMULATION OF FERMION LATTICE PROBLEMS

LOCAL CELL DELIVERY STRATEGIES

PREVENTING CIVIL WAR RECURRENCE: LOCAL PARTNERSHIPS FOR EFFECTIVE REINTEGRATION

SPATIALLY RESOLVED STUDIES OF POLYMER FILM DYNAMICS UNDER WATER STUDIED BY NOVEL SCANNING PROBE MICROSCOPIES

DEVELOPMENT OF DNA-TEMPLATED IR QUANTUM DOTS

DICTIONARY OF OLD ENGLISH [DOE]

DICTIONARY OF OLD ENGLISH

INSTITUTIONALIZING MINORITY REPRESENTATION IN POST-TRANSITION MYANMAR

QUANTIFYING STRESS IN MARINE MAMMALS: MEASURING BIOLOGICALLY ACTIVE CORTISOL IN CETACEANS AND PINNIPEDS

GLOBAL ANALYSIS OF HSP90 CLIENT PROTEINS IN CANDIDA ALBICANS

DEVELOPMENTAL REGULATION OF MEMORY SPECIFICITY BY THE BRAIN EXTRACELLULAR MATRIX

REACTIVE NITROGEN BIOGEOCHEMICAL CYCLING IN THE GFDL EARTH SYSTEM MODELS: ADVANCING UNDERSTANDING OF THE ATMOSPHERE-LAND INTERACTIONS UNDER CHANGING

STIR PROPOSAL: RADIATIONLESS TRANSITIONS INDUCED BY NATURAL INCOHERENT LIGHT

A LOCAL PROBE FOR UNIVERSAL NON-EQUILIBRIUM DYNAMICS

MATHEMATICAL MODELLING FOR THE EVALUATION OF AUTOMATED SPEECH RECOGNITION SYSTEMS -- RESEARCH AREA 3.3.1(C)

RAPID NEUROPSYCHOLOGICAL ASSESSMENT IN SPECIAL POPULATIONS: DEVELOPING APPROPRIATE PSYCHOMETRICS

EVALUATING COMMUNITY INVOLVEMENT IN THE PREVENTION OF ASTHMA IN PUERTO RICO

ICAP-27: THE 27TH INTERNATIONAL CONFERENCE ON ATOMIC PHYSICS

"THE 27TH INTERNATIONAL CONFERENCE ON ATOMIC PHYSICS DATED 16 SEP 19"(THE GRANTEE'S TECHNICAL PROPOSAL) IS HEREBY INCORPORATED BY REFERENCE. THIS INS

TO FUND TRAVEL FOR UP TO 3 SPEAKERS TO PARTICIPATE IN TWO ONE-DAY EVENTS ON THE US AND CANADIAN ELECTIONS AND BILATERAL RELATIONSHIP.

EVOLUTION OF SENSORY INTEGRATION IN JUMPING SPIDERS

LOAD REDISTRIBUTION FOR STEEL-CONCRETE COMPOSITE STRUCTURES

MOLECULARLY TARGETED NANOTECHNOLOGY FOR ENHANCED RADIATION TREATMENT O LOCALLY ADVANCED BREAST CANCER