Trustees Of Dartmouth College

CANCER CENTER SUPPORT GRANT

NEW HAMPSHIRE IDEA NETWORK OF BIOLOGICAL RESEARCH EXCELLENCE (NH-INBRE)

CAUSES AND CONSEQUENCES OF HEALTH CARE EFFICIENCY

NORTHEAST NODE OF THE NATIONAL DRUG ABUSE CLINICAL TRIALS NETWORK

A PROSPECTIVE STUDY OF CRITICAL ENVIRONMENTAL EXPOSURES IN FORMATIVE EARLY LIFE THAT IMPACT LIFELONG HEALTH IN RURAL US CHILDREN: THE NEW HAMPSHIRE BIRTH COHORT STUDY

TOXIC METALS IN THE NORTHEAST: FROM BIOLOGICAL TO ENVIRONMENTAL IMPLICATIONS

ITARGET: INSTITUTE FOR BIOMOLECULAR TARGETING

HEALTHCARE INNOVATION CHALLENGETHE HIGH VALUE HEALTHCARE COLLABORATIVE: ENGAGING PATIENTS TO MEET THE TRIPLE AIM

CENTER FOR MOLECULAR EPIDEMIOLOGY

CENTER FOR QUANTITATIVE BIOLOGY: A FOCUS ON "OMICS", FROM ORGANISMS TO SINGLE CELLS

ICE DRILLING PROGRAM OFFICE

ACCELERATING THE USE OF EVIDENCE-BASED INNOVATION IN HEALTHCARE SYSTEMS

TECHNOLOGY-BASED TREATMENTS FOR SUBSTANCE USE DISORDERS

SYNERGY: THE DARTMOUTH CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE

A PROSPECTIVE STUDY OF CRITICAL ENVIRONMENTAL EXPOSURES IN FORMATIVE EARLY LIFE THAT IMPACT LIFELONG HEALTH IN RURAL US CHILDREN: THE NEW HAMPSHIRE B

PHYSICALLY-BASED BIODOSIMETRY FOR TRIAGE AFTER A LARGE RADIATION INCIDENT

ICE DRILLING PROGRAM OFFICE

FUNCTIONAL ANALYSIS OF A MODEL FILAMENTOUS FUNGUS

DARTMOUTH CENTER FOR CANCER NANOTECHNOLOGY EXCELLENCE

DARTCF: THE DARTMOUTH CYSTIC FIBROSIS RESEARCH CENTER

TRANSDISCIPLINARY RESEARCH IN CANCER OF THE LUNG (TRICL)

CELLULAR AND MOLECULAR MECHANISMS OF LUNG DISEASE

ADVANCED SURGICAL CENTER FOR TRANSLATIONAL RESEARCH AT DARTMOUTH

VISUAL MEDIA INFLUENCES ON ADOLESCENT SMOKING BEHAVIOR (Y10-14 RENEWAL)

QUANTITATIVE BIOLOGY RESEARCH INSTITUTE

PROTEIN COMPARTMENTATION

THE NEURAL BASES OF PLACEBO EFFECTS AND THEIR RELATION TO REGULATORY PROCESSES

MECHANISMS OF MEMBRANE FUSION

DARTMOUTH COLLEGE INSTITUTIONAL EMERGENCY GRANT UNDER CARES ACT

CENTER FOR MOLECULAR, CELLULAR, AND TRANSLATIONAL IMMUNOLOGICAL RESEARCH

ICE DRILLING PROGRAM -THIS AWARD PROVIDES SUPPORT TO THE ICE DRILLING PROGRAM (IDP) TO PROVIDE COMMUNITY LEADERSHIP AND TO OPERATE AND MAINTAIN A FACILITY TO SUPPORT ICE DRILLING ENGINEERING, FIELD SUPPORT, AND EDUCATION AND OUTREACH. THE INTELLECTUAL MERIT OF THIS PROJECT IS EMBODIED IN THE FOUR CLOSELY LINKED LEADERSHIP GOALS OF THIS PROJECT WHICH INCLUDE: 1) PRODUCING AND MAINTAINING LONG-TERM AND SHORT-TERM INTEGRATED SCIENCE AND DRILLING TECHNOLOGY PLANS IN COLLABORATION WITH THE U.S. AND INTERNATIONAL ICE CORING AND DRILLING RESEARCH COMMUNITIES, 2) PROVIDING FIELD SUPPORT WITH DRILLING EQUIPMENT AND EXPERTISE TO SUPPORT NSF-FUNDED SCIENCE, 3) IDENTIFYING NEW TECHNOLOGY NEEDS AND SEEKING FUNDING FOR TECHNOLOGY DEVELOPMENT AND ACQUISITION, AND 4) ENHANCING COMMUNICATION AND INFORMATION EXCHANGE RELATED TO ICE CORING AND DRILLING SCIENCE AND TECHNOLOGY WITHIN THE US AND INTERNATIONAL ICE SCIENCE COMMUNITY. THESE GOALS RELATE TO THE IMPORTANCE OF EVIDENCE FROM THE POLAR ICE SHEETS FROM ICE CORES, SUBGLACIAL BEDROCK CORES, AND BOREHOLES TO ACCESS THE SUBGLACIAL AQUEOUS ENVIRONMENT, WHICH HAS LED TO MANY IMPORTANT DISCOVERIES THAT HAVE REVOLUTIONIZED CLIMATE SCIENCE. THESE DISCOVERIES HAVE ALSO HAD IMPORTANT IMPACTS ON POLICY AND THUS ALSO HAVE SOCIETAL RELEVANCE. CONTINUED U.S. SCIENTIFIC LEADERSHIP IN THIS AREA DEPENDS CRITICALLY NOT ONLY ON THE SUPPORT OF SCIENTISTS DOING THIS RESEARCH BUT ALSO ON THE CONTINUED SUPPORT OF A DEDICATED FACILITY TO PROVIDE THE FIELD DRILLING SUPPORT AND ACCOMPLISH ENGINEERING AND TECHNOLOGY DEVELOPMENT ACTIVITIES. THIS PROGRAM AND ITS EDUCATION AND PUBLIC OUTREACH ACTIVITIES WILL NURTURE THE INCLUSION OF STUDENTS OF MANY AGES, RACES, AND GENDERS, WILL HELP TO LAUNCH GRADUATE STUDENTS INTO PROMISING CAREERS, AND THE RESULTING SCIENTIFIC DISCOVERIES WILL BENEFIT ALL CITIZENS. ACHIEVING THE GOALS OF THIS PROJECT WILL ENABLE THE U.S. ICE SCIENCE RESEARCH COMMUNITY TO REALIZE IMPLEMENTATION OF THEIR NATIONAL AND INTERNATIONALLY-COORDINATED SCIENTIFIC GOALS, LEAD THE WORLD IN ICE SCIENCE DISCOVERIES, NURTURE THE EDUCATION AND DEVELOPMENT OF THE NEXT GENERATION OF SCIENTISTS AND ENGINEERS, AND HELP TO COMMUNICATE THE IMPORTANCE OF THE DISCOVERIES TO ALL. 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 PLANNED FOR THIS AWARD.

BALLOON ARRAY FOR RSBP RELATIVISTIC ELECTRON LOSSES (BARREL)THE BARREL PROPOSAL PRESENTED A PERSUA

NH MCH LEADERSHIP TRAINING PROGRAM

VIRAL & HOST FACTORS IN HERPETIC REACTIVATION

GENETIC AND MOLECULAR DISSECTION OF THE NEUROSPORA CLOCK

INTEGRATED FOUNDATIONS OF SENSING, MODELING, AND DATA ASSIMILATION FOR SEA ICE PREDICTION

DIRECT AND REPEATED CLINICAL MEASUREMENT OF PO2 FOR ENHANCING CANCER THERAPY

DARTMOUTH COLLEGE EMERGENCY FINANCIAL AID GRANTS UNDER CARES ACT

FINANCIAL ASSISTANCE, AS MANDATED BY CONGRESS, TO THAYER SCHOOL OF ENGINEERING OF DARTMOUTH COLLEGE

LINKING ACTIN CYTOSKELETON TO MEMBRANE DYNAMICS IN MITOCHONDRIAL FISSION

ORGANIZATION OF THE MAMMALIAN MITOTIC SPINDLE

NEW HAMPSHIRE IDEA NETWORK OF BIOLOGICAL RESEARCH EXCELLENCE (NH-INBRE)

HEARING IMPAIRMENT IN HIV-INFECTED AND HIV/TB-COINFECTED INDIVIDUALS IN TANZANIA

DARTMOUTH LUNG BIOLOGY CENTER FOR MOLECULAR, CELLULAR AND TRANSLATIONAL RESEARCH

NIAMS MULTIDISCIPLINARY CLINICAL RESEARCH CENTER

ADVANCING SYSTEMS APPROACHES TO PERSONAL AND POPULATION BREAST CANCER SCREENING

IMMUNOBIOLOGY OF MYELOID AND LYMPHOID CELLS

RII TRACK-2 FEC: NEURAL BASIS OF ATTENTION

RII TRACK-2 FEC: COMPUTATIONAL METHODS AND AUTONOMOUS ROBOTICS SYSTEMS FOR MODELING AND PREDICTING HARMFUL CYANOBACTERIAL BLOOMS

REGULATION OF HOST INNATE AND ADAPTIVE IMMUNITY BY BACTERIAL TYPE III EFFECTORS

HUMAN AND MOUSE TRANSCRIPTOME PROFILING IDENTIFIES CROSS-SPECIES HOMOLOGY OF MONONUCLEAR PHAGOCYTES - PROJECT SUMMARY/ABSTRACT THE MONONUCLEAR PHAGOCYTE (MP) SYSTEM PLAYS A FUNDAMENTAL ROLE IN BOTH INNATE AND ADAPTIVE IMMUNITY. IT INCLUDES THREE BROAD CLASSES OF MPS EXTENSIVELY CHARACTERIZED IN THE MOUSE: (1) MACROPHAGES, INCLUDING ALVEOLAR MACROPHAGES, LANGERHANS CELLS, AND THREE DISTINCT SUBTYPES OF INTERSTITIAL MACROPHAGES; (2) TISSUE-TRAFFICKING MONOCYTES; AND (3) DENDRITIC CELLS (DCS), WHICH FALL INTO TWO MAIN TYPES (DC1 AND DC2), THOUGH DC2 CAN BE FURTHER SUBDIVIDED. ALL THESE MPS, EXCEPT AMS AND LCS, WHICH ARE UNIQUE TO LUNG AND SKIN, RESIDE IN MULTIPLE ORGANS, INCLUDING THE HEART, SKIN, LIVER, AND GUT. MP SUBTYPES DEMONSTRATE A CLEAR DIVISION OF LABOR DURING INNATE AND ADAPTIVE IMMUNITY WITH LITTLE TO VIRTUALLY NO FUNCTIONAL REDUNDANCY, WHICH MEANS THAT SPECIFIC INTERACTIONS AMONG THEM ARE CRUCIAL FOR OPTIMAL IMMUNE RESPONSES AGAINST VIRAL, BACTERIAL, AND FUNGAL INFECTIONS. CURRENTLY, HOWEVER, MULTIPLE FUNDAMENTAL GAPS FOR THE IDENTIFICATION AND UNDERSTANDING OF HOW THESE MPS FUNCTION IN HUMAN ORGANS LIMIT OUR ABILITY TO DEVELOP PREVENTION AND TREATMENT STRATEGIES ACROSS DISEASES. THIS PROJECT WILL INVESTIGATE CROSS-SPECIES AND CROSS-TISSUE HOMOLOGIES AT THE CELLULAR, GENE EXPRESSION AND FUNCTIONAL LEVELS. WE WILL OBTAIN FRESH HUMAN AND MOUSE TISSUE FROM MULTIPLE ORGANS (LUNG, SKIN, AND THEIR DRAINING LYMPH NODES), AND EMPLOY THREE BROAD APPROACHES. FIRST, WE WILL USE BOTH BULK RNA SEQUENCING (RNA-SEQ) AND SINGLE-CELL RNA SEQUENCING (SCRNA-SEQ) TO IDENTIFY CROSS-SPECIES AND CROSS-TISSUE HOMOLOGY. RNA-SEQ PROVIDES SEQUENCING DEPTH (I.E., WHOLE-TRANSCRIPTOME COVERAGE), AND SCRNA-SEQ PROVIDES THE ABILITY TO CONFIRM BULK HOMOLOGOUS MP SUBTYPES AND EXAMINE THE HETEROGENEITY WITHIN PREVIOUSLY DEFINED MP SUBTYPES. THUS, BIOINFORMATICS ANALYSES WILL IDENTIFY CLUSTERS OF HOMOLOGOUS MP CELL TYPES AND ALIGN THEM ACROSS SPECIES. SECOND, FOR EACH CLUSTER IDENTIFIED, WE WILL IDENTIFY GENES CONSERVED ACROSS SPECIES AND TISSUES, AND THOSE THAT ARE UNIQUE TO A GIVEN HOMOLOGOUS MP SUBTYPE, TERMED MARKER GENES. THE RESULTS OF THESE ANALYSES WILL PROVIDE SPECIFIC GENETIC MARKERS FOR HUMAN MP SUBTYPES AND GENETIC TREATMENT TARGETS. BROADLY SPEAKING, THERE ARE TWO CATEGORIES OF KEY MARKER GENES WE WILL FUNCTIONALLY INVESTIGATE: THOSE CONSERVED IN HUMAN-MOUSE MP COUNTERPARTS THAT (1) HAVE BEEN WELL-DEFINED IN MICE, BUT NOT PREVIOUSLY INVESTIGATED IN THEIR HUMAN COUNTERPARTS; AND (2) NOT WELL-DEFINED OR EXTENSIVELY STUDIED IN EITHER SPECIES. THIRD, WE WILL UNDERTAKE A RIGOROUS FUNCTIONAL VALIDATION OF THE KEY GENES IDENTIFIED IN HUMAN-MOUSE MP COUNTERPARTS. THIS INCLUDES (A) IN-VIVO MURINE MODELS WITH SELECTIVE DEPLETION OF SPECIFIC GENES USING TRANSGENIC AND CONDITIONAL KNOCKOUT (KO) MICE; (B) IN VITRO MODEL SYSTEMS FOR HUMAN MPS, INCLUDING ASSAYS FOR ANTIGEN ACQUISITION AND PROCESSING, CELLULAR INTERACTIONS, AND INDUCTION OF ADAPTIVE IMMUNE RESPONSES; AND (C) CREATE TIME-LAPSE VIDEOS WITH CELLULAR-LEVEL MICROSCOPY FOR FUNCTIONAL AND MORPHOLOGICAL CHARACTERIZATION.

DEVELOPMENT OF SPIN PROBES FOR CELL-TAGGING AND OXIMETRY

SATC: FRONTIERS: COLLABORATIVE: SECURITY AND PRIVACY IN THE LIFECYCLE OF IOT FOR CONSUMER ENVIRONMENTS (SPLICE)

IDENTIFICATION AND ANALYSIS OF CIRCADIAN CLOCK-CONTROLLED GENES

GENETIC AND MOLECULAR DISSECTION OF THE NEUROSPORA CLOCK

MOLECULAR FLUORESCENCE-GUIDED SURGERY PLATFORM

NON-MELANOMA SKIN CANCER IN NEW HAMPSHIRE

BEHAVIORAL TREATMENT OF ADOLESCENT MARIJUANA USE

PREOPERATIVE IMAGE UPDATING FOR GUIDANCE DURING BRAIN TUMOR RESECTION

GENETIC ANALYSIS OF NATURAL VARIATION IN THE CONTROL OF WATER USE EFFICIENCY AND RESPONSE TO DROUGHT STRESS IN BRASSICA RAPA

FUNCTIONAL ANATOMIC STUDIES OF INTERPERSONAL DISTRESS

NOVEL PEDIATRIC NEUROCOGNITIVE SCREENING USING CENTRAL AUDITORY TESTS

CENTER FOR MOLECULAR EPIDEMIOLOGY - ABSTRACT THE FIELD OF EPIDEMIOLOGY HAS GAINED INCREASING PROMINENCE IN THE RESEARCH COMMUNITY AND BECAME A HOUSEHOLD WORD IN 2020. EPIDEMIOLOGY PROVIDES THE TOOLS TO UNCOVER THE UNDERLYING CAUSES OF HUMAN ILLNESS AND TO, IN TURN, INFORM CLINICAL PRACTICE AND PREVENTIVE STRATEGIES, ADVISE POLICY AND REGULATORY ACTIONS, AND MOVE SCIENTIFIC ADVANCEMENTS FORWARD. IN PHASES I AND II, OUR CENTERS OF BIOMEDICAL RESEARCH EXCELLENCE (COBRE) CENTER FOR MOLECULAR EPIDEMIOLOGY AT DARTMOUTH HAS EFFECTIVELY ADVANCED RESEARCH IN THE FIELD. AS THE ONLY CENTER FOR MOLECULAR EPIDEMIOLOGY IN NORTHERN NEW ENGLAND AND ONE OF THE ONLY COBRE PROGRAMS WITH THIS FOCUS NATIONALLY, WE HAVE SUCCESSFULLY RECRUITED AND MENTORED THE NEXT GENERATION OF INDEPENDENT EARLY CAREER INVESTIGATORS. WE FURTHER SUPPORTED ESTABLISHED INVESTIGATORS TO ENLARGE THEIR RESEARCH PROGRAMS, FORM NEW COLLABORATIONS AND INTEGRATE THE LATEST BIOMEDICAL DISCOVERIES, INNOVATIONS, AND METHODS. IN DOING SO, WE DRAMATICALLY GREW OUR RESEARCH PRODUCTIVITY AND GRANT PORTFOLIO, AS EVIDENCED BY THE STEEP RISE IN THE NUMBER OF PUBLICATIONS, PRESENTATIONS, AND GRANTS AWARDED SINCE THE INCEPTION OF OUR COBRE CENTER. AS PART OF ACHIEVING SUSTAINABILITY, WE FORMED A NEW DEPARTMENT OF EPIDEMIOLOGY AND DEVELOPED INNOVATIVE CROSS- DISCIPLINARY TRAINING GRANTS. OUR COHESIVE CENTER BRINGS TOGETHER TALENTED INVESTIGATORS FOCUSING ON 1) APPLYING NEW SCIENTIFIC DISCOVERIES AND TECHNOLOGIES TO ADDRESS MAJOR HUMAN HEALTH CONCERNS, 2) IDENTIFYING EARLY INDICATORS OF DISEASE PATHOGENESIS, AND 3) EXPLORING COMMON PATHWAYS OF DISEASE ETIOLOGY AND PROGRESSION IN HUMAN POPULATIONS, INCLUDING THOSE RELATED TO HEALTH INEQUITIES. IN THIS PHASE III APPLICATION, WE WILL PROGRESS OUR MOLECULAR EPIDEMIOLOGY RESEARCH INFRASTRUCTURE FORWARD TO FULL INDEPENDENCE AND SUSTAINABILITY. SPECIFICALLY, WE WILL 1) EVOLVE A STATE-OF-THE-ART BIOREPOSITORY AND BIOSPECIMEN RESOURCE FACILITY CORE THAT SUPPLIES THE CRITICAL SERVICES RESPONSIVE TO THE ONGOING AND FUTURE NEEDS OF BIOMEDICAL SCIENTISTS, 2) EXPAND THE PIPELINE OF TALENTED, DIVERSE MOLECULAR EPIDEMIOLOGISTS, AND PROVIDE THE REQUISITE MENTORSHIP, CAREER DEVELOPMENT, AND RESEARCH RESOURCES TO CULTIVATE CUTTING-EDGE RESEARCH AND MAKE INVESTIGATORS COMPETITIVE FOR NIH FUNDING, AND 3) ENHANCE THE GOVERNANCE STRUCTURE, IMPLEMENTATION APPROACHES, STAKEHOLDER ENGAGEMENT, AND EVALUATION THAT WILL STRENGTHEN OUR CENTER’S IMPACT, PROMOTE ITS STRATEGIC VISION, AND FORGE TIES WITH REGIONAL AND NATIONAL PARTNERS. OUR SUCCESS IN PHASES I AND II, COMBINED WITH STRONG INSTITUTIONAL SUPPORT, POSITIONS US TO SERVE AS A VITAL RESOURCE IN MOLECULAR EPIDEMIOLOGY FOR NORTHERN NEW ENGLAND, FOR COBRE AND IDEA NETWORKS OF BIOMEDICAL RESEARCH EXCELLENCE (INBRE) PROGRAMS, AND MORE BROADLY.

THE INTENSITY OF ENERGETIC PARTICLES TRAPPED IN EARTH'S RADIATION BELTS VARIES BY ORDERS OF MAGNITUDE ON TIMESCALES FROM MINUTES TO DAYS. THIS DYNAMIC VARIABILITY IS CONTROLLED BY A SHIFTING BALANCE BETWEEN DIFFERENT ACCELERATION AND LOSS MECHANISMS. PRECIPITATION INTO THE ATMOSPHERE HAS BEEN RECOGNIZED FOR DECADES AS A MAJOR LOSS MECHANISM YET CRITICAL QUESTIONS ABOUT THE PHYSICAL PROCESSES REMAIN. SIGNIFICANT PROGRESS HAS BEEN MADE IN IDENTIFYING THE PLASMA WAVES THAT DRIVE ATMOSPHERIC PRECIPITATION [E.G. THORNE 2010 FOR REVIEW]. HOWEVER THE PHYSICAL "MODES" IN WHICH THESE ACT IS NOT WELL SPECIFIED: ELECTRONS MAY BE SCATTERED SLOWLY THROUGH A DIFFUSIVE PROCESS [E.G. SHPRITS ET AL. 2008 REVIEW] OR RAPIDLY THROUGH NONLINEAR PROCESSES [E.G. ALBERT 2000; BORTNIK ET AL. 2008 OMURA ET AL. 2015]. THE PHYSICAL MODE DETERMINES THE SCATTERING RATE AND THUS THE IMPACT ON THE RADIATION BELTS. THEREFORE IT IS IMPORTANT TO ESTABLISH WHERE AND HOW FREQUENTLY LOSS MECHANISMS ACT IN DIFFERENT MODES FOR PARTICLES OF DIFFERENT ENERGIES. THE RELATIVISTIC ELECTRON ATMOSPHERIC LOSS (REAL) CUBESAT MISSION WILL CHARACTERIZE DIFFERENT MODES OF ATMOSPHERIC LOSS BY MAKING HIGH TIME RESOLUTION MEASUREMENTS OF THE ELECTRON PITCH ANGLE AND ENERGY DISTRIBUTIONS IN LOW EARTH ORBIT (LEO) OVER A WIDE ENERGY RANGE FROM KEV TO MEV. LEO IS IDEAL FOR MEASURING PRECIPITATION SINCE THE ATMOSPHERIC LOSS CONE IS LARGER (~60 DEG) THAN AT THE EQUATOR (FEW DEGREES). THE OVERARCHING GOAL OF REAL IS TO IMPROVE OUR UNDERSTANDING OF THE PHYSICAL MECHANISMS RESPONSIBLE FOR SCATTERING RADIATION BELT ELECTRONS INTO THE ATMOSPHERE. REAL WILL INVESTIGATE SPECIFIC ASPECTS OF THESE MECHANISMS BY ANSWERING THE FOLLOWING SCIENCE QUESTIONS: 1.) WHEN AND WHERE DO DIFFERENT PRECIPITATION LOSS MODES (DIFFUSION STRONG DIFFUSION AND NONLINEAR SCATTERING) OCCUR 2.) HOW DO ELECTRON PRECIPITATION LOSS MODES DEPEND ON ENERGY 3.) WHAT IS THE RELATIVE IMPACT OF DIFFERENT PRECIPITATION LOSS MODES ON THE RADIATION BELTS REAL CONTRIBUTES TO THE HELIOPHYSICS OBJECTIVE TO "UNDERSTAND THE SUN AND ITS INTERACTIONS WITH EARTH AND THE SOLAR SYSTEM INCLUDING SPACE WEATHER" BY INVESTIGATING ELECTRON LOSS MECHANISMS IN THE MAGNETOSPHERE. REAL ADDRESSES TWO HELIOPHYSICS SCIENCE GOALS "EXPLORE THE PHYSICAL PROCESSES IN THE SPACE ENVIRONMENT FROM THE SUN TO THE EARTH AND THROUGHOUT THE SOLAR SYSTEM" AND "DEVELOP THE KNOWLEDGE AND CAPABILITY TO DETECT AND PREDICT EXTREME CONDITIONS IN SPACE TO PROTECT LIFE AND SOCIETY AND TO SAFEGUARD HUMAN AND ROBOTIC EXPLORERS BEYOND EARTH" BY IMPROVING OUR UNDERSTANDING OF WAVE-PARTICLE INTERACTIONS IN SPACE PLASMAS LEADING TO IMPROVED PREDICTIVE MODELS OF THE RADIATION BELTS.

MODULAR SOCIAL INTELLIGENCE FOR TEAMING AND COALITION ADAPTATION OF HETEROGENOUS AUTONOMOUS COOPERATIVE AGENTS (ACAS) TOPIC#6

HEALTH PROMOTION AND DISEASE PREVENTION RESEARCH CENTER

ESSENTIAL EFFECTORS OF MYC FUNCTION

CONGRESSIONALLY MANDATED FUNDING FOR DARTMOUTH COLLEGE

DYNAMIC BRAIN REPRESENTATIONS UNDERLYING EMOTIONAL EXPERIENCE

CONNECTIVITY AND FUNCTION OF THE ASYMMETRIC HABENULO-INTERPEDUNCULAR PATHWAY

CHILDREN'S ENVIRONMENTAL HEALTH & DISEASE PREVENTION RESEARCH CENTER AT DARTMOUTH

CDIGMP REGULATION OF BIOFILM FORMATION

CENTER FOR MOLECULAR, CELLULAR, AND TRANSLATIONAL IMMUNOLOGY

MECHANISMS OF COPII-DEPENDENT TRANSPORT

REGULATION OF SISTER-CHROMATID COHESION IN DROSOPHILA

MECHANISMS IN COPII-DEPENDENT TRANSPORT

CLASS II DIRECTED CARBOMETALATION PROCESSES FOR HETEROCYCLE SYNTHESIS

VARIATIONS IN COLONOSCOPY SCREENING: A POPULATION BASED STUDY

LOW BACK: A MULTI-CENTER CLINICAL TRIAL

TECHNOLOGY DIFFUSION, HEALTH OUTCOMES, AND HEALTHCARE EXPENDITURES

MECHANISMS OF PHOSPHORYLATION SIGNALING BY PHOSPHOPROTEIN PHOSPHATASES

A GENOMEWIDE STUDY OF LUNG CANCER IN NEVER SMOKERS

ALTERNATIVE BREAST CANCER IMAGING MODALITIES

THE ROLE OF FAMILY FUNCTIONING AND RACE/ETHNICITY ON THE EFFICACY OF AN OPIOID MISUSE PREVENTION VIDEOGAME INTERVENTION FOR ADOLESCENTS - OPIOID MISUSE FREQUENTLY STARTS IN ADOLESCENCE. IN 2018, AN ESTIMATED 699,000 ADOLESCENTS AGED 12-17 AND 1.9 MILLION YOUNG ADULTS AGED 18-25 MISUSED OPIOIDS IN THE PAST YEAR. AS SUCH, ADOLESCENCE IS THE TIME TO INTERVENE WITH PREVENTION INTERVENTIONS. HOWEVER, FEW INTERVENTIONS EXIST THAT PREVENT INITIATION OF OPIOID MISUSE. DIGITAL INTERVENTIONS SUCH AS SERIOUS VIDEOGAMES CAN IMPROVE HEALTH BEHAVIORS AND ARE ACCESSIBLE BY ADOLESCENTS. ALTHOUGH DIGITAL INTERVENTIONS ARE FEASIBLE AND EFFECTIVE, THIS FINDING IS NOT UNIVERSAL ACROSS ADOLESCENT GROUPS AND THE FACTORS THAT FACILITATE OR HINDER THEIR EFFICACY ARE UNCLEAR. THIS PROPOSAL WILL STUDY FACTORS THAT MAY ACT AS FACILITATORS OR BARRIERS TO THE EFFICACY OF DIGITAL INTERVENTIONS BY STUDYING THE EFFECTS OF FAMILY FUNCTIONING AND RACE/ETHNICITY ON HOW ADOLESCENTS RESPOND TO PLAYSMART, A NOVEL DIGITAL VIDEOGAME INTERVENTION DEVELOPED TO PREVENT THE INITIATION OF OPIOID MISUSE. FAMILY FUNCTIONING, WHICH DESCRIBES ASPECTS OF THE RELATIONSHIP BETWEEN PARENT AND ADOLESCENT, AND RACE/ETHNICITY HAVE BEEN LINKED TO OPIOID MISUSE AND MAY INFLUENCE THE RESPONSE TO PREVENTION INTERVENTIONS. SPECIFIC FAMILY FUNCTIONING FACTORS INCLUDE: PARENT- ADOLESCENT CONFLICT, FAMILY COHESION, PARENT-ADOLESCENT CONNECTION, PARENT-ADOLESCENT COMMUNICATION, PARENTAL MONITORING AND FAMILY SUPPORT OF ADOLESCENTS. ADOLESCENTS FROM DIFFERENT RACIAL/ETHNIC GROUPS HAVE DIFFERENT RISK AND PROTECTIVE FACTORS FOR THE DEVELOPMENT OF OPIOID MISUSE AND THE WAY ADOLESCENTS RESPOND TO PROGRAMS TO PREVENT SUBSTANCE USE MAY BE DIFFERENT BASED ON THEIR RACE/ETHNICITY. HOWEVER, STUDIES EXAMINING THE EFFECT OF FAMILY FUNCTIONING AND RACE/ETHNICITY ON THE RESPONSE TO DIGITAL INTERVENTIONS TO PREVENT OPIOID MISUSE ARE LACKING. THE SPECIFIC AIMS OF THIS DIVERSITY SUPPLEMENT PROPOSAL ARE: 1) TO ASSESS IF ADOLESCENT REPORT OF FAMILY FUNCTIONING (A) MODIFIES THE EFFECT OF PLAYSMART IN REDUCING RISK FACTORS FOR OPIOID MISUSE (PERCEPTION OF GREAT RISK OF HARM FROM OPIOID MISUSE, INTENTIONS TO MISUSE OPIOIDS, SELF-EFFICACY FOR REFUSING OPIOIDS) AND (B) INFLUENCES THE LEVEL OF GAME ENGAGEMENT; 2) TO ASSESS IF THE EFFECT OF PLAYSMART IN REDUCING RISK FACTORS FOR OPIOID MISUSE DIFFERS BY ADOLESCENT RACE/ETHNICITY; AND 3) TO EXPLORE IF DIFFERENCES IN HOW ADOLESCENTS AND THEIR PARENTS PERCEIVE FAMILY FUNCTIONING AFFECTS PLAYSMART OUTCOMES. WE HYPOTHESIZE THAT: 1) PARTICIPANTS WITH HIGH BASELINE SCORES OF FAMILY FUNCTIONING IN THE PLAYSMART GROUP WILL HAVE BETTER OUTCOMES AT THREE MONTHS POST- RANDOMIZATION COMPARED TO PARTICIPANTS WITH LOW SCORES OF FAMILY FUNCTIONING IN THE PLAYSMART GROUP AND COMPARED WITH PARTICIPANTS IN THE CONTROL GROUP; AND 2) NON-HISPANIC WHITE ADOLESCENTS WILL HAVE BETTER OUTCOMES AT THREE MONTHS POST-RANDOMIZATION COMPARED TO BLACK AND HISPANIC ADOLESCENTS. FINDINGS FROM THIS PROPOSAL WILL ADVANCE OUR UNDERSTANDING OF FACTORS THAT IMPACT DIGITAL PREVENTION PROGRAMS TARGETING OPIOID MISUSE AND INFORM NOVEL STRATEGIES TO IMPROVE THE EFFICACY OF DIGITAL INTERVENTIONS TO PREVENT NEGATIVE HEALTH OUTCOMES AND PROMOTE ADAPTIVE BEHAVIORS ACROSS A DIVERSE POPULATION OF ADOLESCENTS.

TISSUE RESIDENT MEMORY T CELL RESPONSES TO CANCER

MOLECULAR AND CELLULAR BIOLOGY AT DARTMOUTH

TRAINING IN THE SCIENCE OF CO-OCCURRING DISORDERS

TOPIC(009) WEARABLE HEALTH AND HAZARD BIOSENSOR TECHNOLOGY FOR THE WARFIGHTER

PIP3-INDEPENDENT REGULATION OF AKT1 ACTIVITY IN T CELLS

MAPPING THE GENOME OF COHERENT QUANTUM DEFECTS FOR QUANTUM INFORMATION SCIENCE

TWC: FRONTIER: COLLABORATIVE: ENABLING TRUSTWORTHY CYBERSYSTEMS FOR HEALTH AND WELLNESS

HOST-MICROBE INTERACTIONS

THE MAIN GOAL OF THIS CENTER IS TO FILL CRITICAL KNOWLEDGE GAPS IN THE ROLE OF ARSENIC (AS) IN DRINKING WATER AND FOOD TO CHILD GROWTH, DEVELOPMENT A

TIMING AND REGULATION OF MEIOTIC COMMITMENT IN S CEREVISIAE

VISTA IS A NEGATIVE CHECKPOINT REGULATOR OF INNATE IMMUNITY

THE BASIC TRIAL: IMPROVING IMPLEMENTATION OF EVIDENCE-BASED APPROACHES AND SURVEILLANCE TO PREVENT BACTERIAL TRANSMISSION AND INFECTION - WE PROPOSE TO ESTABLISH A BEST PRACTICE FOR IMPLEMENTATION OF A MULTIFACETED APPROACH DESIGNED TO ATTENUATE PERIOPERATIVE ESKAPE (ENTEROCOCCUS, S. AUREUS, KLEBSIELLA, ACINETOBACTER, PSEUDOMONAS, ENTEROBACTER SPP.) TRANSMISSION AND ASSOCIATED SURGICAL SITE INFECTION (SSI) DEVELOPMENT. PERIOPERATIVE ESKAPE TRANSMISSION (INOCULUM) CONTRIBUTES TO THE DEVELOPMENT OF SURGICAL SITE INFECTIONS (SSIS) WHICH AFFECT 3-5% OF PATIENTS UNDERGOING SURGERY. SSIS INCREASE PATIENT MORBIDITY, PROLONG HOSPITALIZATION, INCREASE THE RISK OF INTENSIVE CARE UNIT ADMISSION, AND INCREASE THE RISK OF DEATH 2-FOLD. ESKAPE PATHOGENS ARE PARTICULARLY PROBLEMATIC. SUSTAINED REDUCTIONS IN EPIDEMIOLOGICALLY-RELATED, PERIOPERATIVE S. AUREUS TRANSMISSION EVENTS ACHIEVED VIA A MULTI-FACETED APPROACH INCLUDING SURVEILLANCE FEEDBACK OPTIMIZATION RESULTED IN SUBSTANTIAL SSI REDUCTIONS (88% DECREASE). AN EVIDENCE-BASED APPROACH FOR ATTENUATION OF THE PERIOPERATIVE BACTERIAL INOCULUM2 MUST INTEGRATE IMPROVEMENTS IN PROVIDER HAND HYGIENE, INTRAVASCULAR CATHETER DESIGN/HANDLING, ENVIRONMENTAL CLEANING/ORGANIZATION, AND PATIENT DECOLONIZATION. IN THIS APPLICATION, WE PROPOSE A TYPE 1 HYBRID EFFECTIVENESS-IMPLEMENTATION USING A 2X2 FACTORIAL CLUSTER-RANDOMIZED DESIGN GUIDED BY RE-AIM. WE AIM TO IDENTIFY A BEST PRACTICE FOR ADDRESSING THE PERIOPERATIVE ESKAPE INOCULUM. WE WILL EXAMINE THE RELATIVE EFFECTIVENESS OF INCREASED SITE AWARENESS AND COMMITMENT TO GENERATING IMPROVEMENTS VIA TECHNICAL ASSISTANCE (TA), TEAM COACHING IMPLEMENTATION OF AN EVIDENCE-BASED SET OF INTERVENTIONS (EBIP), AND TA OR EBIP WITH ESKAPE TRANSMISSION SURVEILLANCE FEEDBACK. OUR STRONG PRELIMINARY DATA FROM A RANDOMIZED TRIAL IMPLEMENTING A MULTIFACETED PROGRAM WITH SURVEILLANCE HAS DEMONSTRATED SUBSTANTIAL AND STATISTICALLY SIGNIFICANT REDUCTIONS IN TRANSMISSION OF S. AUREUS AND 90-DAY SSIS AND RECENTLY REPRODUCED OUR RANDOMIZED TRIAL FINDINGS IN AN ADDITIONAL EXTERNAL SITE. THEREFORE, OUR PRIOR RESEARCH STRONGLY SUGGESTS THAT THE PROPOSED RESEARCH SHOULD BE DONE AND JUSTIFIES SCALING UP TO DISSEMINATION AND IMPLEMENTATION. OUR EXCEPTIONAL MULTIDISCIPLINARY TEAM IS WELL EQUIPPED TO SUCCESSFULLY COMPLETE THE PROPOSED TRIAL AND AIMS. IN THE PROPOSED TRIAL GUIDED BY RE-AIM, WE WILL ADVANCE SCIENTIFIC KNOWLEDGE AND INFORM FUTURE DISSEMINATION AND IMPLEMENTATION BY INVESTIGATING HOW BEST TO SCALE-UP AN ALREADY SUCCESSFUL MULTIFACETED APPROACH TO NATIONAL DISSEMINATION THROUGH EITHER TA OR EBIP WITH OR WITHOUT SURVEILLANCE. WE WILL CONDUCT A RIGOROUS COST- EFFECTIVENESS ANALYSIS INCLUDING EVALUATION OF NET COST SAVINGS. THE PROPOSED TRIAL GUIDED BY RE-AIM (AIM 1), THE ADDITION OF 1-YEAR FOLLOW-UP FOR SUSTAINABILITY (AIM 2), AND COST-EFFECTIVENESS ANALYSIS (AIM 3) WILL PROVIDE THE ESSENTIAL SCIENTIFIC KNOWLEDGE TO ADOPTERS AND ORGANIZERS TO BE ABLE TO REPRODUCE THE MOST EFFECTIVE DELIVERY METHOD OF OUR INTERVENTIONS TO THEIR LOCAL SETTING IN ADDITION TO INFORMING OUR INVESTIGATIVE TEAM WHICH APPROACH TO SCALE-UP TO REACH NATIONAL DISSEMINATION.

EVOLUTION OF ASPERGILLUS FUMIGATUS VIRULENCE

THE ROLE OF VISIT AUDIO RECORDINGS IN TRIADIC DEMENTIA CARE - PROJECT SUMMARY ONE IN NINE PEOPLE AGED 65 OR OLDER IN THE US LIVES WITH ALZHEIMER'S DISEASE (AD) OR ALZHEIMER'S DISEASE-RELATED DEMENTIA (ADRD). PATIENTS LIVING WITH DEMENTIA (PLWD) AND THEIR CARE PARTNERS RELY ON PRIMARY CARE CLINIC VISITS FOR DEMENTIA INFORMATION, MANAGEMENT, AND COMMUNITY REFERRALS. QUALITY INTERPERSONAL COMMUNICATION IS ASSOCIATED WITH IMPROVED HEALTH-RELATED OUTCOMES. MODELS OF TRIADIC INTERACTIONS PURPORT THAT INFORMATION EXCHANGE, RAPPORT, AND PATIENT AND CARE PARTNER ENGAGEMENT IN GOAL SETTING AND DECISION-MAKING ARE KEY TO EFFECTIVE INTERPERSONAL COMMUNICATION. HOWEVER, THE DEGREE TO WHICH EFFECTIVE INTERPERSONAL COMMUNICATION IS ACHIEVED DURING TRIADIC VISITS IS UNKNOWN, AND FEW INTERVENTIONS TO SUPPORT IT EXIST. USING AUDIO RECORDINGS OF CLINIC VISITS IS A NOVEL, EVIDENCE-BASED STRATEGY WITH THE POTENTIAL TO SUPPORT TRIADIC INTERACTIONS, YET ITS APPLICATION IS UNEXPLORED IN DEMENTIA. THE OBJECTIVE OF THIS PROPOSAL IS TO DESIGN AN INTERVENTION THAT ENHANCES INTERPERSONAL COMMUNICATION IN TRIADIC VISITS USING VISIT RECORDINGS. APPLICANTS WILL FOLLOW THE NIH STAGE MODEL TO REDESIGN THEIR VISIT RECORDING PLATFORM, HEALTHPAL, WHICH LEVERAGES NATURAL LANGUAGE PROCESSING TO STRUCTURE VISIT INFORMATION. THE SPECIFIC AIMS ARE: AIM 1 (STAGE 0): CONDUCT A PROSPECTIVE OBSERVATIONAL STUDY, WITH OUTPATIENT CLINIC VISITS OF 200 TRIADS (PLWD/CARE PARTNER/CLINICIAN) AUDIO RECORDED FOR 12 MONTHS; 1.A. EXAMINE THE ASSOCIATION BETWEEN INTERPERSONAL COMMUNICATION IN TRIADIC AD/ADRD VISITS AND HEALTH-RELATED OUTCOMES; 1.B. IDENTIFY BARRIERS AND ENABLERS TO INTERPERSONAL COMMUNICATION IN TRIADIC AD/ADRD VISITS; AIM 2 (STAGE 1A): ADAPT HEALTHPAL TO ENHANCE INTERPERSONAL COMMUNICATION IN TRIADIC AD/ADRD VISITS; AND AIM 3 (STAGE 1B): DEMONSTRATE THE USABILITY, FEASIBILITY, ACCEPTABILITY, AND POTENTIAL EFFECTIVENESS OF HEALTHPAL IN AD/ADRD. APPLICANTS HYPOTHESIZE: 1) CONSTRUCTS FROM MODELS OF INTERPERSONAL COMMUNICATION WILL BE ASSOCIATED WITH HEALTH-RELATED OUTCOMES; 2) HEALTHPAL WILL SURPASS USABILITY, FEASIBILITY AND ACCEPTABILITY METRICS FOR DYADS AND CLINICIANS. IN AIM 1 APPLICANTS WILL USE AN EXPLANATORY SEQUENTIAL MIXED METHODS DESIGN. INFORMED BY THE BEHAVIOR CHANGE WHEEL, TARGETS FOR BEHAVIOR CHANGE WILL BE IDENTIFIED USING QUANTITATIVE ASSESSMENT OF INTERPERSONAL COMMUNICATION DURING TRIADIC VISITS (200 DYADS, 3 VISITS ANNUALLY; ~600 VISITS), SUPPLEMENTED BY SEMI-STRUCTURED INTERVIEWS WITH A PURPOSIVE SAMPLE OF 1A TRIADS (N=42); IN AIM 2, WE WILL USE PARTICIPATORY DESIGN METHODS (N=60) TO REDESIGN HEALTHPAL USING FINDINGS FROM AIM 1; AND IN AIM 3 WE WILL USE AN OPEN LABEL, SINGLE-ARM, MULTI-SITE PILOT TRIAL (N=30) TO DETERMINE USABILITY, FEASIBILITY AND ACCEPTABILITY OF HEALTHPAL AND GATHER PRELIMINARY DATA ON ITS IMPACT ON INTERPERSONAL COMMUNICATION IN TRIADIC AD/ADRD VISITS. THIS WORK IS A NECESSARY FIRST STEP TO IMPROVING PLWD TRIADIC CARE BY IDENTIFYING BEHAVIORS THAT IMPACT INTERPERSONAL COMMUNICATION AND THEIR ASSOCIATIONS WITH HEALTH- RELATED OUTCOMES. THE INTERVENTION DEVELOPED, AND THE EXTENSIVE DATA COLLECTED, WILL SERVE AS A POWERFUL RESOURCE THAT CAN BE LEVERAGED TO ADDRESS OTHER GAPS IN CLINICAL KNOWLEDGE RELATED TO THE CARE OF PLWD.

COMPARATIVE EFFECTIVENESS OF ADVANCED IMAGING IN CANCER

EVOLVED HETEROGENEITY CONTRIBUTES TO CHRONIC FUNGAL LUNG INFECTIONS

MECHANISMS THAT COORDINATE CELL SIZE WITH MITOTIC ENTRY

GENETIC AND MOLECULAR DISSECTION OF WNT PATHWAY ACTIVATION SUPPLEMENT

MEMBRANE-ACTIVE QUINOLINE AND QUINAZOLINE ANTIBACTERIALS THAT TARGET GRAM POSITIVE PATHOGENS

LEVERAGING SOCIAL MEDIA TO DEVELOP THE CANNABIS EXPOSURE INDEX (CEI), A STANDARDIZED MEASURE OF CANNABIS USE

STRUCTURAL ANALYSIS OF VIBRIO CHOLERAE VIRULENCE GENE REGULATORY PROTEINS

GENETIC DETERMINANTS OF VIRULENCE IN VIBRIO CHOLERAE

TRANS-GENERATIONAL EFFECTS OF SOCIAL LEARNING

IMPROVING CSIRT SKILLS, DYNAMICS, AND EFFECTIVENESS

MECHANISM OF PRION NEUROTROPISM

IDENTIFICATION AND ANALYSIS OF CIRCADIAN CLOCK-CONTROLLED GENES

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP) -THE NATIONAL SCIENCE FOUNDATION (NSF) GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP) IS A HIGHLY COMPETITIVE, FEDERAL FELLOWSHIP PROGRAM. GRFP HELPS ENSURE THE VITALITY AND DIVERSITY OF THE SCIENTIFIC AND ENGINEERING WORKFORCE OF THE UNITED STATES. THE PROGRAM RECOGNIZES AND SUPPORTS OUTSTANDING GRADUATE STUDENTS WHO ARE PURSUING RESEARCH-BASED MASTER'S AND DOCTORAL DEGREES IN SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS (STEM) AND IN STEM EDUCATION. THE GRFP PROVIDES THREE YEARS OF FINANCIAL SUPPORT FOR THE GRADUATE EDUCATION OF INDIVIDUALS WHO HAVE DEMONSTRATED THEIR POTENTIAL FOR SIGNIFICANT RESEARCH ACHIEVEMENTS IN STEM AND STEM EDUCATION. THIS AWARD SUPPORTS THE NSF GRADUATE FELLOWS PURSUING GRADUATE EDUCATION AT THIS GRFP INSTITUTION. 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.

FUNGAL SPORE SENSING BY MDA5 IS NECESSARY FOR ANTIFUNGAL IMMUNITY AGAINST ASPERGILLUS FUMIGATUS

PSEUDOMONAS-HOST INTERACTIONS IN CYSTIC FIBROSIS

MICROWAVE IMAGING FOR NEOADJUVANT CHEMOTHERAPY MONITORING

IMPROVE AKI: A CLUSTER-RANDOMIZED TRIAL OF TEAM-BASED COACHING INTERVENTIONS TO IMPROVE ACUTE KIDNEY INJURY

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

SCALING UP SCIENCE-BASED MENTAL HEALTH INTERVENTIONS IN LATIN AMERICA

HEALTH PROMOTION AND FITNESS FOR YOUNGER AND OLDER ADULTS WITH SMI

GERIATRICS WORKFORCE ENHANCEMENT PROGRAM

FUNCTIONAL DEIMMUNIZATION OF THERAPEUTIC PROTEINS

QUANTUM THEORY FOR SPECTRAL ANALYSIS, PREDICTION, AND CONTROL OF CLASSICAL SYSTEMS

CHOLESTEROL AND SPHINGOLIPID METABOLISM IN ALZHEIMER'S DISEASE

NATIONAL CENTER FOR DISASTER MENTAL HEALTH RESEARCH

INDUCTION OF CYTOTOXIC T CELLS BY PULMONARY DENDRITIC CELLS

SYNERGY: THE DARTMOUTH CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE

UNDERSTANDING AND DESIGNING PHOSPHIDE SOLAR ABSORBERS WITH HIGH CARRIER LIFETIME

INHIBITION OF THE WNT RECEPTOR COMPLEX BY THE TUMOR SUPPRESSOR ADENOMATOUS POLYPOSIS COLI

EFFECTS OF SOCIAL CONTEXT ON THE NEURAL CORRELATES OF CUE REACTIVITY

MODELING AND MANIPULATING SOCIAL PERCEPTS IN INDIVIDUALS - PROJECT SUMMARY BIASES IN WHETHER AND HOW SOCIAL INTERACTIONS ARE PERCEIVED ARE A HALLMARK SYMPTOM OF MOST MAJOR MENTAL ILLNESSES (E.G., PEOPLE WITH AUTISM TEND TO UNDER-PERCEIVE SOCIAL INTERACTIONS, PEOPLE WITH PARANOID SCHIZOPHRENIA TEND TO OVER-PERCEIVE SOCIAL INTERACTIONS, AND PEOPLE WITH DEPRESSION TEND TO PERCEIVE SOCIAL INTERACTIONS IN A NEGATIVE LIGHT). THESE BIASES LIKELY REFLECT THE EXTREME END OF A CONTINUUM THAT EXISTS IN THE NORMATIVE POPULATION, SUGGESTING THAT CHARACTERIZING INDIVIDUAL DIFFERENCES IN SOCIAL-PERCEPTUAL STYLES IS CRITICAL TO FURTHERING OUR UNDERSTANDING OF DISEASE. THAT HUMANS ARE PRIMED TO PERCEIVE SOCIAL INTERACTIONS EVEN IN STRIPPED-DOWN, UNLIFELIKE STIMULI (E.G., ANIMATIONS OF GEOMETRIC SHAPES) IS A PHENOMENON THAT HAS LONG BEEN RECOGNIZED AND EXPLOITED TO STUDY SOCIAL COGNITION IN BOTH NORMATIVE AND PATIENT POPULATIONS. HOWEVER, WHEN IT COMES TO THESE BASIC STIMULI, WHILE WE MAY HAVE THE INTUITION THAT WE “KNOW IT WHEN WE SEE IT”, WE DO NOT UNDERSTAND WHAT IT IS ABOUT STIMULI DEEMED SOCIAL THAT MAKES THEM SOCIAL—IN OTHER WORDS, WHICH SPECIFIC VISUAL FEATURES ARE REQUIRED, AND IN WHAT DOSES. FURTHERMORE, BECAUSE TASK PARADIGMS ARE OFTEN A SIMPLE BINARY CHOICE (I.E., ‘SOCIAL’ OR ‘RANDOM’), WE DO NOT UNDERSTAND HETEROGENEITY ACROSS INDIVIDUALS IN TERMS OF THEIR THRESHOLDS FOR DECIDING IF A GIVEN STIMULUS REPRESENTS A SOCIAL INTERACTION, AND IF SO, WHAT KIND OF SOCIAL INTERACTION (I.E., POSITIVE OR NEGATIVE). A CRITICAL STEP TOWARD UNDERSTANDING AND CORRECTING BIASED SOCIAL COGNITION IN MENTAL ILLNESS IS TO DEFINE THE FUNDAMENTAL SENSORY FEATURES OF BASIC SOCIAL INTERACTIONS, AND DETERMINE HOW AND WHY DIFFERENT PEOPLE COMPUTE DIFFERENTLY ON THESE FEATURES TO GIVE RISE TO DIFFERENT SOCIAL PERCEPTS. THIS WILL OPEN THE DOOR TO INTERVENTIONS THAT CAN PREVENT AN INDIVIDUAL FROM GOING DOWN A BIASED PATH. IN THIS PROJECT, WE WILL ESTABLISH A SOCIAL STIMULUS CLASS FOR WHICH WE HAVE PRECISE, PARAMETRIC CONTROL OVER LOW-LEVEL VISUAL FEATURES. THIS WILL ALLOW US TO CONSTRUCT INDIVIDUAL “SOCIAL TUNING CURVES” FOR VARIOUS TYPES OF SOCIAL INTERACTIONS AND DETERMINE HOW VARIABILITY IN THESE TUNING CURVES RELATES TO TRAIT PHENOTYPES. COMBINING THESE STIMULI WITH SIMULTANEOUS NEUROIMAGING (FMRI) AND EYE-TRACKING WILL SHED LIGHT ON WHERE IN THE PROCESSING HIERARCHY PERCEPTS DIVERGE WITHIN AND ACROSS INDIVIDUALS, AND ALLOW US TO TEST THE HYPOTHESIS THAT SOCIAL PERCEPTS EMERGE EARLIER IN THE CORTICAL HIERARCHY THAN PREVIOUSLY THOUGHT. THIS WOULD INDICATE THAT IDIOSYNCRATIC SOCIAL COGNITION IS MORE CLOSELY LINKED TO AUTOMATIC, SENSORY-DRIVEN PROCESSES THAN CONTROLLED REFLECTION, A DISTINCTION THAT IS IMPORTANT FOR INFORMING DIAGNOSTIC AND INTERVENTIONAL TOOLS. FINALLY, WITHIN A SET OF DENSELY SAMPLED INDIVIDUALS, WE WILL DIRECTLY TEST CAUSALITY BETWEEN STIMULUS FEATURES, BRAIN ACTIVITY, AND PERCEPTS USING REAL-TIME FMRI TO IMPLICITLY STEER INDIVIDUALS TOWARD A GIVEN PERCEPT BASED ON ONGOING PATTERNS OF BRAIN ACTIVITY. THE OUTCOME OF THE PROPOSED RESEARCH WILL BE A CAUSAL MODEL OF HOW STIMULUS FEATURES AND BRAIN DYNAMICS INTERACT TO GIVE RISE TO A GIVEN SOCIAL PERCEPT WITHIN A GIVEN INDIVIDUAL. THIS MODEL WILL PROVIDE TESTABLE HYPOTHESES REGARDING TARGETED THERAPIES TO NORMALIZE BIASED COGNITION IN MENTAL ILLNESSES.

ALTERED AUDITORY NETWORKS IN HIV-INDUCED CENTRAL NERVOUS SYSTEM DYSFUNCTION

CLOZAPINE FOR CANNABIS USE DISORDER IN SCHIZOPHRENIA

NOVEL BIOMARKERS TO PREDICT READMISSION IN PEDIATRIC AND ADULT HEART SURGERY

COMPARATIVE MOLECULAR PHYSIOLOGY OF MAMMALIAN FORMINS

PREFRONTAL-AMYGDALA INTERACTIONS IN SOCIAL LEARNING

CSF AND THE CENTRAL CHEMICAL CONTROL OF BREATHING.

THE PARTNERS FOR CHANGE PROJECT:IMPROVING WELL-BEING FOR YOUTH IN THE NH CHILD WELFARE SYSTEM

INFORMATION EXTRACTION FROM EMRS TO PREDICT READMISSION FOLLOWING ACUTE MYOCARDIAL INFARCTION

IMPACT OF FOOD MARKETING AND CROSS-PROMOTIONS ON PRESCHOOLERS' DIETARY INTAKE

THINKING OUTSIDE THE CLINIC: A DIGITAL HEALTH APPROACH FOR YOUNG ADULTS WITH TYPE 1 DIABETES

DISSECTING THE MOLECULAR MECHANISMS OF SELECTIVE AUTOPHAGY

NRT: TRANSFORMATIVE RESEARCH AND GRADUATE EDUCATION IN SENSOR SCIENCE, TECHNOLOGY AND INNOVATION

TC: LARGE: TRUSTWORTHY INFORMATION SYSTEMS FOR HEALTHCARE (TISH)

MATHEMATICS AND DATA SCIENCE FOR IMPROVED PHYSICAL MODELING AND PREDICTION OF SEA ICE

RURAL GATEWAYS: FOSTERING THE DEVELOPMENT OF RURAL LIBRARIANS AS INFORMAL SCIENCE FACILITATORS

RETINOIC ACID IN GUT IMMUNE HOMESTATIS AND INFECTION

A NEURAL SYSTEMS APPROACH TO UNDERSTANDING THE DYNAMIC COMPUTATIONS UNDERLYING OUR SENSE OF DIRECTION

SIMULTANEOUS MICROWAVE AND MR IMAGING FOR IMPROVED DIAGNOSIS OF BREAST ABNORMALITIES

TUBERCULOSIS RESEARCH INSTITUTE AT MUHAS

DARTMOUTH/BOSTON UNIVERSITY AITRP

TRAINING PROGRAM FOR QUANTITATIVE POPULATION SCIENCES IN CANCER

EPR SCANNER FOR TUMOR OXIMETRY IN THE CLINIC - PROJECT SUMMARY THIS ACADEMIC-INDUSTRIAL PARTNERSHIP (AIP) PROPOSAL SEEKS TO DEVELOP A ROBUST AND EASY-TO-USE CLINICAL SCANNER FOR TUMOR OXYGEN MEASUREMENT (OXIMETRY) IN CANCER PATIENTS. BY KNOWING QUANTITATIVE TUMOR OXYGEN LEVELS IN REAL TIME, RADIOTHERAPY COULD BE BETTER PLANNED AND DELIVERED AT TIMES WHEN THERE WILL BE AN OPTIMAL THERAPEUTIC RATIO, THUS SIGNIFICANTLY IMPROVING CANCER CARE. THE PROPOSED APPROACH SEEKS TO LEVERAGE THE UNIQUE CAPABILITIES OF THE IN VIVO ELECTRON PARAMAGNETIC RESONANCE (EPR) OXIMETRY TECHNOLOGY THAT WE HAVE DEVELOPED FOR MEASUREMENT IN HUMAN SUBJECTS INTO A MEDICAL DEVICE THAT IS READY FOR ROUTINE CLINICAL USE. THE SCANNER CAN MAKE DIRECT AND REPEATED MEASUREMENTS OF TUMOR OXYGEN BY TYPICAL END-USERS IN A CLINICAL SETTING. THE EPR RESEARCH TEAM AT THE GEISEL SCHOOL OF MEDICINE (DARTMOUTH COLLEGE) HAS SUCCESSFULLY DEMONSTRATED THE CLINICAL FEASIBILITY AND SAFETY OF EPR OXIMETRY FOR MEASURING TUMOR OXYGEN IN THE CLINIC, AND NOW SEEKS TO EXPAND UPON THAT SUCCESS THROUGH A COLLABORATIVE PARTNERSHIP WITH VIEWRAY®, A MEDICAL-DEVICE COMPANY THAT IS ENGAGED IN MRI IMAGE-GUIDED RADIATION THERAPY. THE CLINICAL SCANNER WILL BE DESIGNED TO MAKE IT EASIER TO OPERATE BY CLINICAL STAFF AND SUFFICIENTLY ROBUST AND RELIABLE FOR ITS INTENDED USE IN A VARIETY OF CLINICAL SETTINGS. THE FOLLOWING SPECIFIC AIMS ARE PROPOSED TO ACHIEVE THE OVERALL OBJECTIVE OF DEVELOPING AN ADVANCED EPR SCANNER FOR OXIMETRY THAT IS READY TO BE MANUFACTURED AND USED IN ROUTINE CLINICAL CARE TO ENHANCE CANCER THERAPY: (AIM 1) DESIGN AND CONSTRUCT A 600-MHZ PULSE EPR SYSTEM FOR CLINICAL OXIMETRY; (AIM 2) FABRICATE A NEW CLASS OF COMPACT, LIGHTWEIGHT, AND ADVANCED RESONATOR DESIGNS SPECIFICALLY OPTIMIZED FOR PO2 MEASUREMENTS IN HUMAN TUMORS; (AIM 3) DEVELOP HARDWARE AND SOFTWARE INTERFACE WITH ADVANCED MEASUREMENT CAPABILITIES AND USER-FRIENDLY OPERATION SUITABLE FOR USE IN THE CLINIC; (AIM 4) ASSEMBLE, TEST, AND EVALUATE THE SCANNER FOR REPEATED MEASUREMENTS OF OXYGEN CONCENTRATION USING TISSUE PHANTOMS AND ANIMAL MODELS OF TUMOR; AND (AIM 5) EVALUATE THE EFFICACY, USABILITY, AND SAFETY OF THE OXYGEN SCANNER AS A MEDICAL DEVICE AND VALIDATE ITS USE TO MAKE OXYGEN MEASUREMENTS IN CANCER PATIENTS AND HUMAN FACTORS ENGINEERING. THE EPR SCANNER, FULLY INTEGRATED WITH THE HARDWARE AND SOFTWARE MODULES, WILL BE EVALUATED IN RELATION TO ITS ABILITY TO MEET OR EXCEED REGULATORY STANDARDS AND FOR ITS PRACTICALITY AS A CLINICAL DEVICE. THE NEW FIRST-IN-CLINICAL SCANNER WILL BE A VERY VALUABLE TOOL IN THE CLINIC FOR ACCURATE PROGNOSIS AND DEVELOPMENT OF EFFECTIVE TREATMENT STRATEGIES FOR CANCER THERAPY. IT CAN ALSO BE A VALUABLE CLINICAL TOOL FOR OTHER CLINICAL CONDITIONS WHERE TISSUE OXYGEN IS A CRITICAL VARIABLE FOR DECISION MAKING, E.G., PATIENTS WITH DIABETIC PERIPHERAL VASCULAR DISEASE.

MULTIPLEX PRECISION MEDICINE SYSTEM FOR EARLY-WARNING OF PROGRESSION TOWARD SHOCK AFTER TRAUMA

MOLECULAR MULTI-SPECIES APPROACH FOR TRANS-SYNAPTIC LABELING OF NEURAL CIRCUITS - DIVERSITY SUPPLEMENT

DEEPCOPD: DEVELOPMENT AND IMPLEMENTATION OF DEEP LEARNING TO PREDICT AND PREVENT COPD HEALTH CARE ENCOUNTERS - IN THE US, ~24 MILLION PERSONS LIVE WITH COPD, HALF UNDIAGNOSED, AND ~150,000 DIE OF COPD ANNUALLY. COPD CAUSES OVER 700,000 US HOSPITALIZATIONS AND COSTS NEARLY $50 BILLION PER YEAR. THE HUMAN AND FINANCIAL BURDENS OF COPD COULD LIKELY BE REDUCED IF DISEASE PROGRESSION AND OTHER ADVERSE EVENTS COULD BE ANTICIPATED, ENABLING CAREGIVERS TO FOCUS FINITE RESOURCES ON AT-RISK PATIENTS. WE PROPOSE TO CREATE A DECISION-SUPPORT TOOL THAT INTEGRATES BIOMEDICAL INFORMATICS WITH ADVANCED MACHINE LEARNING (ML) AND DEEP LEARNING (DL) ALGORITHMS TO PREDICT ACUTE AND CHRONIC HEALTHCARE ENCOUNTERS (HOSPITAL ADMISSIONS, READMISSIONS, AND ED ENCOUNTERS) AND MAJOR DISEASE PROGRESSION EVENTS (HOME OXYGEN THERAPY) FOR OUTPATIENTS WITH COPD. SUCH A TOOL WOULD CONFER IMMEDIATE CLINICAL BENEFITS AND ACCELERATE RESEARCH ON COPD DISEASE PROGRESSION AND TREATMENT. PREDICTIVE MODELING IS WIDELY USED TO IDENTIFY HIGH-RISK PATIENTS FOR CARE MANAGEMENT IN COPD AND OTHER DISORDERS, WITH A STRONG EMPHASIS ON READMISSION RISK. HOWEVER, EXTANT TECHNIQUES ARE NOT SUFFICIENTLY ACCURATE AND DO NOT IDENTIFY THE SPECIFIC NATURE OF LIKELY FUTURE MEDICAL EVENTS, ESTIMATE TIME-TO-EVENT, AND SPECIFICALLY FORECAST MEDICAL ENCOUNTERS AND DISEASE PROGRESSION EVENTS FOR INDIVIDUALS WITH COPD. RECENT RESEARCH IN DISEASE PROGRESSION MODELING SUPPORT THE APPLICATION OF DL AND OTHER ML METHODS TO ELECTRONIC HEALTH RECORDS (EHRS) TO PREDICT ASPECTS OF HEALTH HISTORY. EHRS CONTAIN BOTH READILY ACCESSIBLE STRUCTURED DATA (E.G., LAB RESULTS IN WELL-DEFINED FIELDS) AND UNSTRUCTURED TEXTS SUCH AS PHYSICIAN’S NOTES. UNSTRUCTURED TEXTS CONTAIN A GREAT DEAL OF CLINICAL INFORMATION, BUT THIS INFORMATION IS LABORIOUS TO ACCESS; IMPEDING ITS ROUTINE USE IN RESEARCH AND THE CLINIC. THIS HAS MOTIVATED ATTEMPTS TO USE NATURAL LANGUAGE PROCESSING (NLP) METHODS TO AUTOMATE ANNOTATION. WE WILL APPLY NLP TO IDENTIFY SYMPTOMS, TREATMENTS, PROCEDURES, DIAGNOSES, SOCIAL RISK FACTORS, AND FUNCTIONAL STATUS FROM CLINICAL NOTES, EXPANDING THE DATA AVAILABLE FROM EHRS FAR BEYOND THE USUAL CODED VARIABLES. ALSO, AND DISTINCTIVELY, WE WILL CARRY OUT A STEPPED-WEDGE CLINICAL IMPLEMENTATION OF THE PROPOSED PREDICTIVE TOOL AND EVALUATE ITS PERFORMANCE, A FIRST FOR ML AND DL PREDICTION OF COPD HEALTH EVENTS. THEREFORE, WE PROPOSE FOUR SPECIFIC AIMS: AIM 1: TRANSFORM EHR DATA STREAMS TO PROVISION PATIENT-LEVEL FEATURE SETS FOR ML AND DL CONSUMPTION. AIM 2: DEVELOP A SET OF ML AND DL MODELS TO PREDICT THE TIME-TO-EVENT FOR HOME OXYGEN THERAPY INITIATION AND HEALTHCARE ENCOUNTERS AMONG PATIENTS WITH COPD. AIM 3: TO DEVELOP AND IMPLEMENT A PROSPECTIVE PERFORMANCE SURVEILLANCE AND CALIBRATION MAINTENANCE SYSTEM TO MAINTAIN THE FINAL AIM 2 MODEL FOR EACH OUTCOME. AIM 4: EVALUATE ADOPTION AND USABILITY OF THE DEEPCOPD TOOLKIT IN NEAR-REALTIME CLINICAL USE IN TWO HEALTHCARE SYSTEMS. THE APPLICATION IS RESPONSIVE TO THE NHLBI IDEA2HEALTH (NOT-HL-19-712).

IGERT: POLAR ENVIRONMENTAL CHANGE

(PQ3) IMMUNE EPIGENETIC BIOMARKERS OF BLADDER CANCER OUTCOMES

DISSECTING IMMUNE SURVEILLANCE TO GAMMAHERPESVIRUSES

T CELL FUNCTION IN MURINE GAMMAHERPESVIRUS INFECTION

HYPOXIA ADAPATATION AND FUNGAL VIRULENCE OF ASPERGILLUS FUMIGATUS

MULTI-PROBE FLUORESCENCE IMAGING FOR RAPID INTRA-OPERATIVE TUMOR MARGIN ASSESSMENT

OPTICAL IMAGING FUSED WITH TOMOSYNTHESIS FOR IMPROVED BREAST CANCER

ADVANCING AND APPLYING PERIPHERAL AND CENTRAL AUDITORY FINDINGS IN HIV/AIDS. - WITH NIH SUPPORT, THE UBONGO SIKIVU COHORT OF BOTH PEOPLE LIVING WITH HIV (PLWH) AND UNINFECTED CONTROLS WAS ESTABLISHED IN TANZANIA AND HAS HAD REGULAR ASSESSMENTS OF THEIR PERIPHERAL HEARING ABILITY OVER 10+ YEARS WITH DETAILED CENTRAL AUDITORY AND NEUROCOGNITIVE ASSESSMENTS ADDED OVER THE LAST 5 YEARS. THIS COHORT IS UNIQUELY POSITIONED TO ADDRESS THE ISSUES POSED BY PAR-20-127 “ADVANCING HIV/AIDS RESEARCH WITHIN THE MISSION OF THE NIDCD.” DATA FROM THE COHORT HAS ALREADY ANSWERED IMPORTANT QUESTIONS ABOUT THE OTOTOXICITY OF ANTI-RETROVIRALS, THE EFFECTS OF HIV INFECTION AND TREATMENT ON BOTH PERIPHERAL AND CENTRAL HEARING PARAMETERS, AND THE RELATIONSHIP OF CENTRAL AUDITORY TEST (CAT) RESULTS TO NEUROCOGNITIVE PERFORMANCE. BY FOLLOWING THIS COHORT LONGITUDINALLY QUESTIONS ABOUT HOW CATS COULD BE USED TO PREDICT OR TRACK NEUROCOGNITIVE PERFORMANCE AND HOW AGE AND LONG-TERM ANTI-RETROVIRAL TREATMENT AFFECT THE AUDITORY SYSTEM CAN BE ANSWERED. TO DATE, THE MOST SIGNIFICANT RESULT HAS BEEN DEMONSTRATING THAT CAT RESULTS CORRELATE WITH COGNITIVE PERFORMANCE. THIS SUGGESTS CAT RESULTS MIGHT BE USEFUL FOR FORECASTING OR TRACKING COGNITIVE DECLINE OVER TIME. THE NEXT IMPORTANT STEPS ARE DETERMINING WHETHER WORSENING CAT PERFORMANCE PRECEDES THE LATER DEVELOPMENT OF COGNITIVE DEFICITS IN PLWH AND WHICH CENTRAL AUDITORY TESTS AND OTHER VARIABLES CAN PREDICT NEUROCOGNITIVE DEFICITS ACCURATELY. NEUROCOGNITIVE SCREENING TESTS ARE OFTEN SENSITIVE TO EDUCATION, LITERACY, AND CULTURE. FULL NEUROCOGNITIVE TEST BATTERIES CAN BE DIFFICULT TO EMPLOY, PARTICULARLY IN THE DEVELOPING WORLD WHERE CLINICIAN TIME IS LIMITED, FEW TRAINED PERSONNEL ARE AVAILABLE, AND NORMATIVE DATA OFTEN DO NOT EXIST. USING CATS WOULD BE A MAJOR ADVANCE FOR FOLLOWING HIV+ PATIENTS BECAUSE THE CATS CAN BE SHORT (A GAP DETECTION TEST TAKES 5 MINUTES), EASY TO EXPLAIN (THE HEARING-IN-NOISE TEST AND TRIPLE DIGIT TASK INVOLVE IDENTIFYING WORDS OR NUMBERS IN BACKGROUND NOISE), OR EFFORTLESS FOR THE SUBJECT (THE FFR TEST REQUIRES NO SUBJECT INPUT AT ALL). THIS PROJECT’S GOAL IS TRACKING THE TRAJECTORY OF PERIPHERAL AUDITORY, CENTRAL AUDITORY, AND NEUROCOGNITIVE PERFORMANCE OVER TIME BY CONTINUING TO FOLLOW THIS COHORT. WITH THESE LONGITUDINAL DATA MACHINE LEARNING AND OTHER STATISTICAL TECHNIQUES WILL BE APPLIED TO ASSESS WHICH FACTORS FORECAST THE SUBSEQUENT DEVELOPMENT OF COGNITIVE DEFICITS AND WHICH FACTORS OR COMBINATION OF FACTORS IDENTIFY THOSE WITH EXISTING NEUROCOGNITIVE DEFICITS. AN INTERNATIONAL TEAM WITH EXPERIENCE IN CENTRAL AUDITORY TESTING AND NEUROCOGNITIVE TESTING IN PLWH HAS BEEN ASSEMBLED. DR. NINA KRAUS AND HER NORTHWESTERN TEAM ARE INTERNATIONALLY RECOGNIZED EXPERTS IN THE AUDITORY FFR. THE DAR ES SALAAM TEAM HAS EXTENSIVE EXPERIENCE IN OTOLARYNGOLOGY AND PERFORMING PERIPHERAL AUDITORY, CENTRAL AUDITORY, AND NEUROCOGNITIVE TESTS. DRS. ROTH AND BOIVIN ARE EXPERTS IN ASSESSING NEUROCOGNITIVE FUNCTION. DR. GUI HAS DIVERSE BIOSTATISTICAL EXPERIENCE. DR. NIEMCZAK IS AN EXPERT IN PERIPHERAL AND CENTRAL AUDITORY PROCESSING. THIS TEAM AND LONGITUDINAL COHORT OFFER THE UNIQUE ABILITY TO ASSESS THE USE OF CATS IN EVALUATING COGNITION AS WELL AS THE EFFECTS OF AGING AND MEDICATIONS ON BOTH CENTRAL AND PERIPHERAL AUDITORY FUNCTION IN PLWH.

OPTICAL ANALOGS TO MRI CONTRAST AGENTS FOR SURGICAL GUIDANCE OF BRAIN TUMOR RESECTION - ABSTRACT SURGICAL RESECTION IS A FIXTURE IN THE TREATMENT OF INTRACRANIAL TUMORS, AND THERE IS MOUNTING DATA INDICATING THAT OVERALL AND PROGRESSION-FREE SURVIVAL IMPROVE FOR GROSS TOTAL RESECTION COMPARED TO SUBTOTAL RESECTION. THE CURRENT STANDARD OF CARE FOR MANAGING INTRACRANIAL TUMORS RELIES HEAVILY ON MRI OF GADOLINIUM-BASED CONTRAST AGENTS (GD-MRI), WHICH PLAYS A CENTRAL ROLE IN DIAGNOSIS, SURGICAL PLANNING, INTRA-SURGICAL GUIDANCE, AND FOLLOW-UP MONITORING. DURING SURGERY, PATIENTS ARE SPATIALLY REGISTERED TO THE PRE-OPERATIVE MRI AND MRI-DERIVED TUMOR CONTOURS PROJECTED OVER THE VISUAL FIELD WITHIN THE SURGICAL MICROSCOPE TO GUIDE RESECTION. DESPITE THE WIDESPREAD DEPLOYMENT OF THESE SOPHISTICATED TOOLS IN SURGERY, SUBTOTAL RESECTION RATES REMAIN STUBBORNLY HIGH. THE PRIMARY CULPRITS INCLUDE DIFFICULTY IN IDENTIFYING TUMOR VISUALLY AND THE DIMINISHING ACCURACY OF THE PRE-OP REGISTRATION DUE TO BRAIN DEFORMATION AS THE SURGERY PROGRESSES. IN THIS CONTEXT, EXPANSIVE EFFORTS HAVE SOUGHT TO ALLEVIATE THESE SHORTCOMINGS, INCLUDING THE USE OF INTRA-OPERATIVE STEREOVISION AND/OR ULTRASOUND WITH BRAIN DEFORMATION MODELS TO UPDATE THE PRE-OP MRI AND THE USE OF FLUORESCENT AGENTS TO LABEL TUMOR IN THE VISUAL FIELD. ALTHOUGH PROMISING, BOTH OF THESE APPROACHES HAVE KNOWN SHORTCOMINGS. SPECIFICALLY, THE DATA SOURCES USED FOR UPDATING PRE-OP MRI ARE ONLY SURROGATE CORRELATES WITH MRI, AND MOST CURRENT FLUORESCENCE GUIDED SURGERY (FGS) EFFORTS FOCUS ON TARGETED AGENTS DESIGNED TO MARK MOLECULAR FEATURES OF TUMOR CELLS, WHICH HAVE SHOWN HIGH INTRA-PATIENT/TUMORAL HETEROGENEITY. THIS PROJECT AIMS TO SOLVE BOTH OF THESE SHORTCOMINGS DIRECTLY BY LEVERAGING THE EXISTING CLINICAL UNDERSTANDING OF GD-MRI IN MANAGING INTRACRANIAL TUMORS. SPECIFICALLY, WE WILL IDENTIFY AND EVALUATE FLUORESCENT AGENTS THAT MIMIC THE KINETIC BEHAVIOR OF CONVENTIONAL MRI-BASED CONTRAST AGENTS TO GUIDE INTRACRANIAL TUMOR SURGERY. THIS APPROACH WILL TRANSFER THE WELL-UNDERSTOOD BEHAVIOR OF GD-MRI DIRECTLY INTO THE VISUAL FIELD, ENABLE RAPID, INTRA-SURGICAL ADMINISTRATION OF THE AGENT, AND PROVIDE AN IDEAL DATA INPUT FOR UPDATING OF PRE-OP MRI DURING SURGERY. OUR APPROACH IS PREMISED ON COMPELLING PRELIMINARY DATA IN SMALL ANIMAL GLIOMA MODELS SHOWING HIGHLY CORRELATIVE UPTAKE BETWEEN GD-MRI AND SEVERAL UNTARGETED OPTICAL AGENTS. TO ADVANCE THIS STRATEGY WE WILL, (1) RIGOROUSLY VALIDATE THESE RESULTS AND EXAMINE ADDITIONAL OPTICAL AGENT CANDIDATES USING MRI AND OUR CUSTOM HYPERSPECTRAL WHOLE-BODY IMAGING CRYOMACROTOME, (2) ESTABLISH CONCORDANCE BETWEEN CANDIDATE OPTICAL AGENTS AND GD-MRI IN A NEW PORCINE GLIOMA MODEL USING OUR INTRA-OPERATIVE MRI FACILITY AND FGS INSTRUMENTS, AND (3) ASSESS THE CAPACITY TO USE THE OPTICAL AGENT DATA TO UPDATE THE PRE-OP MRI. WE WILL ALSO QUANTITATIVELY COMPARE UPTAKE OF THE CANDIDATE AGENTS, GD-MRI AND ALA-PPIX, THE CURRENT STANDARD FOR FGS OF GLIOMA. COMPLETING THE AIMS OF THIS PROJECT WILL ESTABLISH THE OPTICAL ANALOG STRATEGY AS A COMPELLING APPROACH FOR SURGICAL GUIDANCE AND LAY THE GROUNDWORK FOR CLINICAL TRANSLATION.

ALCOHOL MARKETING AND UNDERAGE DRINKING

FUNCTIONAL ANALYSIS OF ACAT

CONFORMATIONAL PROPERTIES OF CYTOCHROME C IN APOPTOSIS

TARGETING VISTA ERADICATES LARGE, ESTABLISHED PD-1/CTLA-4 RESISTANT TUMORS

MECHANISM OF DYNEIN-MEDIATED SPINDLE POSITIONING

IMPACT OF AGING ON MUCOSAL IMMUNE PROTECTION IN THE FEMALE REPRODUCTIVE

VISTA, A NOVEL REGULATOR OF IMMUNITY AND AUTOIMMUNITY

EFFECTIVENESS OF PRE-OPERATIVE MRI IN BREAST CANCER SURGERY AND OUTCOMES

INFUSING DATA SCIENCE INTO UNDERGRADUATE STEM EDUCATION

SEROTONIN MODULATION OF THE DEVELOPMENT OF NEURAL CIRCUITS UNDERLYING REWARD PROCESSING AND IMPULSIVITY IN ADOLESCENTS - PROJECT SUMMARY THE GOAL OF THIS PROPOSAL FOR THE BIOBEHAVIORAL RESEARCH AWARDS FOR INNOVATIVE NEW SCIENTISTS (BRAINS) PROGRAM IS TO UNDERSTAND TYPICAL AND ATYPICAL ADOLESCENT DEVELOPMENT OF REWARD PROCESSING AND IMPULSIVE BEHAVIOR. THESE COMPLEX PHENOTYPES ARE FOUND IN MANY PSYCHIATRIC DISORDERS INCLUDING ATTENTION DEFICIT HYPERACTIVITY DISORDER, BORDERLINE PERSONALITY DISORDER, AND SCHIZOPHRENIA. ADOLESCENCE IS A SENSITIVE PERIOD FOR THE EMERGENCE OF DYSREGULATED REWARD PROCESSING AND DISORDERED IMPULSIVITY, AND FOR THE DEVELOPMENT OF UNDERLYING NEURAL CIRCUITS THOUGHT TO BE RESPONSIBLE. HOWEVER, IT IS UNCLEAR WHAT FACTORS PUSH DEVELOPMENT TOWARDS PATHOLOGICAL TRAJECTORIES AND IT IS UNKNOWN HOW PATHOLOGY IS ENCODED BY CHANGES IN NEURAL CIRCUITS. THE ADOLESCENT BRAIN COGNITIVE DEVELOPMENT (ABCD) LONGITUDINAL STUDY OF HUMAN BRAIN AND BEHAVIOR IS UNDERWAY TO IDENTIFY FACTORS IN ADOLESCENCE THAT PREDICT IMPULSIVITY AND OTHER REWARD-RELATED PHENOTYPES. SIMILAR LONGITUDINAL DATA FROM MICE ARE NECESSARY TO ALLOW MOLECULAR, CELLULAR, AND CIRCUIT-LEVEL INTERROGATION OF ADOLESCENT DEVELOPMENT. THIS KNOWLEDGE IS CRITICAL FOR TARGETED INTERVENTIONS TO ALTER AND PREVENT DEVELOPMENTAL PATHOLOGY. THIS PROPOSAL DEVELOPS A FRAMEWORK FOR MOUSE ABCD STUDIES. WE USE AN INNOVATIVE APPROACH TO MEASURE COMPLEX BEHAVIORAL PHENOTYPES IN THE HOMECAGE THAT ALLOWS FOR TESTING ON A TIMESCALE COMPATIBLE WITH ASSESSING THE DYNAMIC CHANGES DURING ADOLESCENCE. THIS PROPOSAL FOCUSES ON THE ROLE OF SEROTONIN MODULATION OF CORTICOSTRIATAL PROJECTIONS IN DRIVING ADOLESCENT MATURATION OF REWARD PROCESSING AND IMPULSIVITY. USING TRANSGENIC MOUSE LINES FOR CELL-TYPE AND TIME PERIOD-SPECIFIC MANIPULATIONS, WE WILL INVESTIGATE CIRCUIT-LEVEL MECHANISMS OF SEROTONIN MODULATION OF ADOLESCENT DEVELOPMENTAL TRAJECTORIES. THE HIGH-RISK, HIGH-REWARD USE OF IN VIVO CALCIUM IMAGING IN ADOLESCENTS WILL UNCOVER THE SINGLE CELL AND ENSEMBLE- LEVEL CHANGES OCCURRING IN THE ADOLESCENT BRAIN THAT SUPPORTS ADOLESCENT BEHAVIORAL MATURATION. USING MICROENDOSCOPE TECHNOLOGY WE WILL IDENTIFY NEURAL CHANGES AT THE CELLULAR LEVEL THROUGHOUT ADOLESCENCE, AND DEFINE A TRAJECTORY OF PATHOLOGICAL DEVELOPMENT. THESE STUDIES WILL POINT TO A TIMEFRAME AND MECHANISM FOR TARGETED PREVENTION AND TREATMENT OF DEVELOPMENTAL PATHOLOGY RELATED TO REWARD PROCESSING AND IMPULSIVITY. OUR RESULTS WILL INFORM REFINEMENT OF PHARMACOTHERAPIES AIMED AT MODULATING SEROTONIN SIGNALING IN ADOLESCENTS FOR THE TREATMENT OF DEPRESSION, ANXIETY, AND OBSESSIVE COMPULSIVE DISORDER. THIS RESEARCH PROJECT IS HIGHLY APPROPRIATE FOR BRAINS FUNDING BECAUSE IT DIRECTLY ADDRESSES TWO KEY OBJECTIVES IN THE NIMH STRATEGIC PLAN AND APPLIES NOVEL METHODS AND TECHNIQUES TO ADVANCE OUR UNDERSTANDING OF THE MAJOR CONCEPTUAL QUESTION OF WHAT DRIVES ADOLESCENT MATURATION. AS AN EARLY CAREER INVESTIGATOR, FUNDING FOR THIS AMBITIOUS PROPOSAL, WHICH I’M UNIQUELY EQUIPPED TO CARRY OUT, WOULD ALLOW ME TO LAUNCH AN INNOVATIVE BASIC RESEARCH PROGRAM AIMED AT UNDERSTANDING THE ATYPICAL DEVELOPMENT OF REWARD PROCESSING AND IMPULSIVITY.

THE RELATION OF GENETIC FACTORS, FOOD CUES, AND SELF-REGULATION WITH EXCESS CONSUMPTION AND ADIPOSITY IN CHILDREN

STRUCTURAL MECHANISM OF MAMMALIAN PRION INFECTIVITY

CENTER FOR IMPLEMENTATION SCIENCE - SUMMARY THE OVERARCHING GOAL OF THIS COBRE IS TO ESTABLISH A MULTIDISCIPLINARY RESEARCH PROGRAM IN IMPLEMENTATION SCIENCE AT DARTMOUTH COLLEGE AND TO PROVIDE TRAINING, EXPERT MENTORSHIP AND NEW SCIENTIFIC INFRASTRUCTURE TO TRAIN AND SUPPORT A CRITICAL MASS OF EARLY-STAGE INVESTIGATORS AS THEY TRANSITION INTO INDEPENDENT INVESTIGATORS DEDICATED TO ADVANCING THE FIELD OF IMPLEMENTATION SCIENCE. IMPLEMENTATION SCIENCE IS THE STUDY OF METHODS TO PROMOTE THE INTEGRATION OF RESEARCH FINDINGS AND EVIDENCE INTO HEALTHCARE POLICY AND PRACTICE AS A CRITICAL EMERGING DISCIPLINE IN BIOMEDICAL RESEARCH. THIS MULTIDISCIPLINARY FIELD COMBINES METHODS FROM MEDICAL ANTHROPOLOGY, HEALTHCARE AND BEHAVIORAL ECONOMICS, INTERVENTION EFFECTIVENESS AND PROCESS RESEARCH, IMPROVEMENT SCIENCE, EDUCATION AND LEARNING, SOCIAL PSYCHOLOGY, ORGANIZATION AND MANAGEMENT, AND MARKETING. CURRENTLY, THERE IS $3 BILLION ANNUALLY IN FEDERAL FUNDING FOR IMPLEMENTATION RESEARCH. YET, THERE IS A CRITICAL GAP IN ACADEMIC DEVELOPMENT OPPORTUNITIES FOR JUNIOR FACULTY TO BE TRAINED AND MENTORED IN THE IMPLEMENTATION SCIENCES OR RESOURCES TO INCREASE THEIR ACADEMIC TRAJECTORY TOWARDS INDEPENDENCE. DESPITE THE ESCALATION IN FUNDING AND THE UNIQUE NEEDS OF IDEA STATES FOR EFFECTIVE BIOMEDICAL HEALTH INTERVENTIONS, IDEA STATES CONTINUE TO LAG IN IMPLEMENTATION RESEARCH FUNDING. THEREFORE, WE PROPOSE TO BUILD STATE-OF-THE-ART INFRASTRUCTURE IN IMPLEMENTATION SCIENCE TO ACCELERATE BIOMEDICAL RESEARCH FUNDING FOR IMPLEMENTATION IN THE IDEA STATE OF NEW HAMPSHIRE, AND CREATE SYSTEMS AND TRAINING OPPORTUNITIES FOR USE BY OTHER IDEA STATES REGIONALLY AND NATIONWIDE. OUR PROPOSED CENTER FOR IMPLEMENTATION SCIENCE, SUPPORTED BY CENTERS OF BIOMEDICAL RESEARCH EXCELLENCE (COBRE) MECHANISM, WILL SUPPORT AND ADVANCE RESEARCH BY JUNIOR FACULTY, BUILDING ON DARTMOUTH’S RECOGNIZED ACADEMIC AND RESEARCH EXCELLENCE. THE PROPOSED CENTER WILL SUPPORT FIVE RESEARCH PROJECT LEADERS AND WILL ADDRESS THE FOLLOWING SPECIFIC AIMS: AIM 1: TO ESTABLISH A MULTIDISCIPLINARY COBRE CENTER FOR IMPLEMENTATION SCIENCE; AIM 2: TO IMPLEMENT AND SUSTAIN A VIBRANT ORGANIZATION AND MANAGEMENT PLAN FOR THE CENTER; AND AIM 3: TO ACCELERATE THE TRANSITION OF JUNIOR FACULTY INTO NIH GRANT- COMPETITIVE, STRONG? INDEPENDENT INVESTIGATORS. IMPACT: THE PROPOSED CENTER FOR IMPLEMENTATION SCIENCE WILL PROVIDE NEEDED FUNDING, NEW SCIENTIFIC RESOURCES, AND MENTORSHIP TO ADVANCE JUNIOR FACULTY INTO INDEPENDENT RESEARCH CAREERS FOCUSED ON THE STUDY AND APPLICATION OF IMPLEMENTATION SCIENCE. THE INITIAL RESEARCH PROJECTS WILL SUPPORT THE DEVELOPMENT OF A SELF-SUSTAINING, MULTIDISCIPLINARY, RESEARCH PROGRAM IN IMPLEMENTATION SCIENCE AND PROVIDE A NEEDED RESOURCE FOR IDEA CENTERS FOR BIOMEDICAL RESEARCH EXCELLENCE NATIONALLY TO FOSTER NATIONAL COLLABORATION AND ACCELERATE NIH FUNDING INDEPENDENCE.

MICRORNA RELATED GENETIC VARIATION AND HEAD AND NECK CANCER

TARGETING TUMORS WITH NF1 LOSS

APPLYING NOVEL TECHNOLOGIES AND METHODS TO INFORM THE ONTOLOGY OF SELF-REGULATION

CO-OPTING ENDOGENOUS PATHOGEN AUTOLYSINS AS NEXT GENERATION ANTIBIOTICS

MAPPING MOLECULAR PATHWAYS THAT CONTROL PRION METABOLISM - PROJECT SUMMARY MAMMALIAN PRION DISEASES, SUCH AS CREUTZFELDT-JAKOB DISEASE (CJD), CHRONIC WASTING DISEASE (CWD), BOVINE SPONGIFORM ENCEPHALOPATHY (BSE), AND SCRAPIE, ARE A GROUP OF INFECTIOUS NEURODEGENERATIVE DISORDERS CAUSED BY THE AUTOCATALYTIC CONVERSION OF THE HOST-ENCODED PRION PROTEIN, PRPC, INTO A GROUP OF MISFOLDED, INFECTIOUS CONFORMERS COLLECTIVELY TERMED PRPSC. MULTIPLE LINES OF EVIDENCE FROM BIOCHEMICAL, GENETIC, AND CELL BIOLOGICAL STUDIES SUGGEST THAT PRPC AND PRPSC EMPLOY SPECIFIC PATHWAYS FOR BIOSYNTHESIS, TRAFFICKING, AND DEGRADATION IN LIVING CELLS. HOWEVER, FULL ELUCIDATION OF THESE PATHWAYS HAS BEEN HINDERED THE LACK OF TRACTABLE MODEL ORGANISMS FOR GENETIC SCREENING. TO OVERCOME THIS OBSTACLE, WE RECENTLY DEVELOPED METHODS TO DETECT BOTH PRPC AND PRPSC IN BRAIN-DERIVED CAD5 CELLS USING FLUORESCENCE-ACTIVATED CELL SORTING (FACS). WE WILL USE THESE SENSITIVE SORTING METHODS TO PERFORM CRISPR (CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS)/CAS9 WHOLE GENOME LIBRARY SCREENS IN CAD5 CELLS INFECTED WITH DIFFERENT PRION STRAINS. THESE STUDIES WILL BE THE FIRST TO FULLY MAP THE MOLECULAR PATHWAYS THAT CONTROL THE BIOSYNTHESIS, TRAFFICKING, AND DEGRADATION OF BOTH PRPC AND PRPSC MOLECULES, AND THEREBY GREATLY ADVANCE OUR FUNDAMENTAL KNOWLEDGE OF PRION CELL BIOLOGY. OUR UNBIASED SCREENS WILL ALSO REVEAL THE RATE LIMITING STEPS OF PRION FORMATION AND CLEARANCE, THEREBY IDENTIFYING THE MOST SUSCEPTIBLE TARGETS FOR DRUG THERAPY.

CONCURRENT OPTICAL SPECTROSCOPY AND BREAST MRI TO IMPROVE DIAGNOSIS WITHOUT CONTRAST INJECTION

GNEISS ROCKET GEOPHYSICAL NON EQUILIBRIUM IONOSPHERIC SYSTEM SCIENCE ROCKET

MECHANISMS OF RESISTANCE TO CELL CYCLE CHECKPOINT KINASE INHIBITORS

THE EFFECT OF CLINIC VISIT AUDIO RECORDINGS FOR SELF-MANAGEMENT IN OLDER ADULTS - PROJECT SUMMARY UP TO EIGHTY PERCENT OF CLINIC VISIT INFORMATION IS FORGOTTEN BY PATIENTS IMMEDIATELY POST VISIT. THIS IS A SIGNIFICANT BARRIER TO SELF-MANAGEMENT, ESPECIALLY IN OLDER ADULTS WITH MULTIMORBIDITY LEADING TO POOR HEALTH OUTCOMES. AFTER VISIT SUMMARIES (AVS) CAN IMPROVE RECALL, YET CONCERNS EXIST ABOUT THEIR LAYOUT, ACCURACY AND LOW PATIENT UPTAKE. A NEW STRATEGY TO AUGMENT THE AVS IS TO SHARE VISIT RECORDINGS WITH PATIENTS. WHEN PATIENTS RECEIVE AN AUDIO RECORDING OF THE VISIT, 71% LISTEN AND 68% SHARE IT WITH A CAREGIVER, RESULTING IN GREATER RECALL. DESPITE GROWING INTEREST, THERE IS LIMITED RESEARCH ON THE IMPACT OF RECORDING AND SHARING CLINIC VISITS OF PATIENT SELF- MANAGEMENT ABILITY, HEALTH OUTCOMES OR HEALTHCARE UTILIZATION OF OLDER ADULTS. THE OBJECTIVE OF THIS PROPOSAL IS TO CONDUCT A MULTISITE TRIAL EVALUATING THE IMPACT OF ADDING AN AUDIO RECORDING OF CLINIC VISITS (AUDIO) TO USUAL CARE IN OLDER ADULTS WITH MULTIMORBIDITY, INCLUDING DIABETES, COMPARED TO AVS ALONE (USUAL CARE; UC). THE SPECIFIC AIMS ARE: AIM 1 CONDUCT A THREE-SITE TRIAL IN PRIMARY CARE WHERE OLDER PATIENTS WITH MULTIMORBIDITY INCLUDING DIABETES (N=336) WILL BE RANDOMIZED TO RECEIVE AN AUDIO RECORDING AS WELL AS AVS (AUDIO) VERSUS AVS ALONE (UC) FOR ALL SCHEDULED CLINIC VISITS OVER 12 MONTHS; PATIENTS WILL BE ASSESSED AT BASELINE, 1 WEEK, 6 MONTHS AND 12 MONTHS; AIM 2 IDENTIFY FACTORS THAT IMPACT THE IMPLEMENTATION AND SUSTAINABLE USE OF VISIT AUDIO RECORDINGS. APPLICANTS HYPOTHESIZE (MAIN EFFECT) THAT: COMPARED TO THOSE RECEIVING UC, PATIENTS RANDOMIZED TO ALSO RECEIVE AUDIO RECORDINGS (AUDIO) OF CLINIC VISITS WILL REPORT A GREATER SELF-MANAGEMENT ABILITY (PRIMARY OUTCOME), WITH IMPROVED QUALITY OF LIFE, MEDICATION ADHERENCE, AND SATISFACTION (SECONDARY OUTCOMES) AT 12 MONTHS. APPLICANTS WILL EXPLORE THE IMPACT OF AUDIO ON GENERAL MEDICAL REGIMEN ADHERENCE, DIABETES QUALITY OF CARE INDICATORS, HEALTHCARE UTILIZATION AND CLINICIAN PRACTICE BEHAVIOR. THEY WILL ALSO EXPLORE POTENTIAL MODERATORS OF AUDIO, ASKING WHETHER ITS IMPACT ON SELF-MANAGEMENT IS GREATER FOR INDIVIDUALS AT HIGHEST RISK OF POOR SELF-MANAGEMENT INCLUDING THOSE WITH LESS CAREGIVER SUPPORT, MODERATE TO SEVERE DEPRESSION, LOWER HEALTH LITERACY, AND HIGH DISEASE BURDEN. IN AIM 2, APPLICANTS WILL INTERVIEW PATIENTS, CAREGIVERS, CLINICIANS, AND CLINIC STAFF TO IDENTIFY BARRIERS AND FACILITATORS TO THE IMPLEMENTATION AND SUSTAINABLE USE OF RECORDINGS USING THE CONSOLIDATED FRAMEWORK FOR IMPLEMENTATION RESEARCH (CFIR). THE RESEARCH IS INNOVATIVE: I) IT SEEKS TO SHIFT CURRENT CLINICAL PRACTICE WHERE VISIT INFORMATION IS PROVIDED VIA AVS, BY ADDING RECORDINGS; II) THE ROUTINE PROVISION OF VISIT RECORDINGS OVER TIME MOVES BEYOND PRIOR STUDIES FOCUSED ON ONE-OFF RECORDINGS OF SPECIALTY CARE VISITS; AND III) A TRIAL IN REAL-WORLD SETTINGS OF PATIENTS WITH MULTIMORBIDITY, WHO ARE OFTEN EXCLUDED FROM TRIALS, IS NOVEL AND HAS GREATER EXTERNAL VALIDITY. RESULTS ARE EXPECTED TO HAVE A MAJOR POSITIVE IMPACT AS THEY WILL INCREASE CLINICAL UNDERSTANDING OF THE IMPACT AND IMPLEMENTATION OF AUDIO RECORDING ON THE SIGNIFICANT CHALLENGE OF IMPROVING PATIENT SELF-MANAGEMENT IN THE FACE OF THE PUBLIC HEALTH BURDEN OF MULTIMORBIDITY.

STATEWIDE INTERVENTION TO REDUCE EARLY MORTALITY IN PERSONS WITH MENTAL ILLNESS

PAIRED-AGENT IMAGING FOR RESECTION DURING SURGERY (PAIRS) FOR HEAD & NECK CANCERS

OPTICAL SCATTER IMAGING SYSTEM FOR SURGICAL SPECIMEN MARGIN ASSESSMENT DURING BREAST CONSERVING SURGERY

SUSTAINING TISSUE RESIDENT MEMORY T CELLS - ABSTRACT DURABLE IMMUNITY TO CANCER IS SUSTAINED BY MEMORY T CELLS. IN CONTRAST TO CIRCULATING MEMORY SUBSETS, WHICH TRAFFIC IN AND OUT OF THE BLOOD, TISSUE-RESIDENT MEMORY (TRM) CELLS ARE TRANSCRIPTIONALLY PROGRAMED FOR PROLONGED RESIDENCE AND RECALL FUNCTION WITHIN TISSUE. COLLABORATIVE STUDIES BETWEEN OUR LABORATORIES WERE AMONG THE FIRST TO IDENTIFY A REQUIREMENT FOR TRM CELLS IN IMMUNITY TO CANCER. USING A MELANOMA-ASSOCIATED VITILIGO (MAV) MOUSE MODEL THAT CLOSELY MIMICS THE VITILIGO THAT DEVELOPS IN IMMUNE CHECKPOINT INHIBITOR-TREATED MELANOMA PATIENTS WHO BENEFIT FROM PROLONGED DISEASE-FREE SURVIVAL, WE SHOWED THAT SKIN TRM CELLS ARE NECESSARY AND SUFFICIENT FOR LONG TERM PROTECTIVE IMMUNITY AGAINST MELANOMA IN THE DERMIS. HOWEVER, MECHANISMS FOR CONTROLLING TRM CELL PERSISTENCE AND IDENTITY AS WELL AS THE CONTRIBUTION OF TRM CELLS TO TUMOR IMMUNITY AT SITES OF FREQUENT METASTASIS REMAIN UNCLEAR. IN THIS APPLICATION, WE EXAMINE AN UNEXPECTED MECHANISM FOR TRM CELL MAINTENANCE IN THE SKIN AND REVEAL A NEW SUBSET OF VITALLY IMPORTANT TRM CELLS THAT PERSIST IN TUMOR-DRAINING LYMPH NODES. IN THE SKIN OF MICE WITH MAV, AS WELL AS MELANOMA PATIENTS WITH VITILIGO, IMMUNOFLUORESCENT IMAGING REVEALED THAT TRM CELLS FORM LYMPHOID AGGREGATES CONTAINING LARGE POPULATIONS OF CD11C-EXPRESSING MYELOID CELLS. WHILE PRIOR WORK INDICATES THAT CD11C+ DENDRITIC CELLS (DCS) ARE CRITICAL FOR INITIATING IMMUNE RESPONSES BUT DISPENSABLE FOR REACTIVATING TRM WE FIND THAT DEPLETION OF CD11C-EXPRESSING CELLS RESULTS IN RAPID DISAGGREGATION AND LOSS OF CD8 TRM CELLS IN THE SKIN. WE FURTHER SHOW THAT THE CXCR6/CXCL16 AXIS IS REQUIRED FOR TRM CELL PERSISTENCE AND TUMOR PROTECTION IN THE SKIN. THESE FINDINGS IDENTIFY A CRITICAL REQUIREMENT FOR CXCL16-EXPRESSING MYELOID CELLS IN COORDINATING THE ORGANIZATION AND RETENTION OF CXCR6-EXPRESSING TRM IN THE TISSUE, WHICH WILL BE EXAMINED IN SPECIFIC AIM 1. THE IMPORTANCE OF THE CXCR6/CXCL16 AXIS AND PERSISTING SELF ANTIGEN IN CONTROLLING TRM CELL FUNCTION AND PLASTICITY WILL BE TESTED IN SPECIFIC AIM 2. FINALLY, PARALLEL MECHANISMS WILL BE EXPLORED IN LYMPH NODES (LNS) WHERE OUR PRELIMINARY STUDIES LED US TO DISCOVER A NOVEL POPULATION OF TUMOR-SPECIFIC T CELLS THAT IS CRUCIAL FOR PROTECTION AGAINST MELANOMA GROWTH IN LYMPH NODES. THE PRESENCE OF LN TRM CELLS HAS NOT PREVIOUSLY BEEN SHOWN IN THE SETTING OF CANCER. A ROLE FOR APCS AND CHEMOKINES IN MAINTAINING SUCH RESPONSES IS ESSENTIALLY UNKNOWN, AND WILL BE THE FOCUS OF SPECIFIC AIM 3. THIS PROPOSAL WILL THUS TEST THE OVERARCHING HYPOTHESIS THAT TUMOR-SPECIFIC TRM CELLS— BOTH IN SKIN AND DRAINING LYMPH NODES—RELY ON KEY INTERACTIONS WITH APCS AND CHEMOKINES FOR THEIR PROPER POSITIONING, MAINTENANCE, AND ANTI-TUMOR FUNCTION.

ENVIRONMENTAL OXYGEN TRANSITIONS AND ASPERGILLOSIS DISEASE PROGRESSION

METALLACYCLE-MEDIATED COUPLING IN STEREOSELECTIVE SYNTHESIS

A CEREBLON SIGNALING NETWORK IN WNT-DRIVEN CANCERS - A CEREBLON SIGNALING NETWORK IN WNT-DRIVEN CANCERS ABSTRACT THE LONG-TERM OBJECTIVE OF THIS STUDY IS TO INVESTIGATE HOW CEREBLON (CRBN) REGULATES THE WNT SIGNAL TRANSDUCTION PATHWAY AND TO DEMONSTRATE HOW THIS CAN BE EXPLOITED TO TARGET WNT-DRIVEN COLORECTAL CANCERS (CRCS). WNT SIGNALING IS ESSENTIAL FOR INTESTINAL STEM CELL MAINTENANCE AND ABERRANT ACTIVATION OF THIS PATHWAY DRIVES THE INITIATION AND PROGRESSION OF NEARLY ALL CRCS. TO DATE, NO DRUGS THAT INHIBIT THE WNT PATHWAY HAVE BEEN FDA- APPROVED, PARTLY DUE TO THE LACK OF DRUGGABLE TARGETS THAT CAN BYPASS COMMON WNT PATHWAY MUTATIONS IN CRC. IN A CONCEPTUAL BREAKTHROUGH, OUR RECENTLY PUBLISHED FINDINGS REVEAL THAT CEREBLON (CRBN), THE SUBSTRATE RECEPTOR OF THE CRL4CRBN E3 UBIQUITIN LIGASE THAT IS A DRUG TARGET IN HEMATOLOGICAL MALIGNANCIES, PLAYS A CRITICAL ROLE IN WNT SIGNAL TRANSDUCTION. WE FOUND THAT CRBN PROMOTES THE DEGRADATION OF A SUBSET OF SUBSTRATES, INCLUDING CASEIN KINASE 1A (CK1A), A NEGATIVE REGULATOR OF WNT SIGNALING AND A KEY COMPONENT OF THE SS-CATENIN DESTRUCTION COMPLEX. MOREOVER, WNT STIMULATION INDUCES THE INTERACTION OF CRBN WITH CK1A TO PROMOTE ITS UBIQUITINATION AND DEGRADATION. FURTHERMORE, WE SHOWED THAT THE ROLE OF CRBN IN WNT SIGNALING IS CONSERVED IN HUMAN CELLS, MOUSE INTESTINAL ORGANOIDS, ZEBRAFISH, AND DROSOPHILA. THESE STUDIES DEMONSTRATE THE FIRST ENDOGENOUS MECHANISM OF CRBN REGULATION AND PROVIDE A NOVEL MEANS OF CONTROLLING WNT PATHWAY ACTIVITY, WITH RELEVANCE FOR ANIMAL DEVELOPMENT AND DISEASE. THE GOAL OF THIS PROJECT IS TO USE IN VITRO, EX VIVO, AND IN VIVO APPROACHES TO GAIN A BETTER UNDERSTANDING OF HOW THE CLINICALLY RELEVANT ANTI-CANCER TARGET, CRBN, PROMOTES WNT SIGNAL TRANSDUCTION. THE THREE SPECIFIC AIMS ARE TO: 1) IDENTIFY THE MECHANISMS BY WHICH WNT STIMULATION ACTIVATES CRBN; 2) IDENTIFY WNT-STIMULATED CRBN INTERACTORS THAT REGULATE TUMORIGENESIS; AND 3) ELUCIDATE THE ROLE OF CRBN IN WNT-DEPENDENT CANCER PROGRESSION. BECAUSE CRBN IS A WELL-STUDIED TARGET FOR THE DEVELOPMENT OF DRUGS TO TREAT HEMATOLOGICAL MALIGNANCIES, THE KNOWLEDGE GAINED FROM THIS STUDY WILL AID IN THE DEVELOPMENT OF MORE SELECTIVE SMALL MOLECULES AS WELL AS SUGGEST INNOVATIVE TREATMENT STRATEGIES FOR CRC AND OTHER WNT-DRIVEN CANCERS.

MRI FLUORESCENCE TOMOGRAPHY FOR QUANTIFYING TUMOR RECEPTOR CONCENTRATION IN VIVO

NNA TRACK 1: INNOVATIONS IN ENERGY TECHNOLOGIES AND EMPOWERMENT IN ARCTIC FISHING COMMUNITIES

THE ROLE OF BRAIN RESIDENT T CELLS IN ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT T CELLS WERE FIRST OBSERVED IN POSTMORTEM BRAINS OF ALZHEIMER’S DISEASE (AD) PATIENTS DECADES AGO, YET VERY LITTLE IS KNOWN ABOUT THEIR ROLE IN DISEASE PROGRESSION. AD IS MARKED BY OLIGOMERIZATION OF SPECIFIC PROTEINS THAT CAN ACCUMULATE INTO EXTRACELLULAR PLAQUES, DRIVING RESEARCH TO UNDERSTAND INNATE IMMUNE CELLS IN AD DUE TO THEIR POTENTIAL FOR REACTING TO AND CLEARING THESE PLAQUES. MORE RECENT EVIDENCE SUGGESTS THAT ADAPTIVE IMMUNE CELLS PLAY A SIGNIFICANT ROLE IN AD; NUMBERS OF CD8+ T CELLS ARE SIGNIFICANTLY INCREASED IN AD BRAINS, AND EXPANSION OF A SUBSET OF MEMORY CD8+ T CELLS IN THE CEREBROSPINAL FLUID OF AD PATIENTS IS NEGATIVELY ASSOCIATED WITH COGNITION. TO DATE, T CELL DEPLETION AND KNOCK-OUT STUDIES IN MICE HAVE YIELDED CONFLICTING DATA ON THE INFLUENCE OF T CELLS IN AD. HOWEVER, A POPULATION OF T CELLS THAT HAS LONG BEEN OVERLOOKED DUE TO THEIR ONLY RECENT DISCOVERY AND THE HISTORIC VIEW OF THE BRAIN AS IMMUNE PRIVILEGE ARE TISSUE RESIDENT MEMORY T CELLS (TRM), WHICH RESIDE IN THE BRAIN AND ARE OPTIMALLY POSITIONED TO EXERT LOCAL IMMUNE ACTIVATION. AS THERE IS CURRENTLY NO DEFINED T CELL ANTIGEN IN ALZHEIMER’S DISEASE, WE WILL TAKE AN INNOVATIVE APPROACH TO MODEL TRM ACTIVATION IN THE BRAIN USING A MODEL ANTIGEN. THIS WILL BE THE FIRST STUDY TO EXAMINE TRM IN CONTEXT OF ALZHEIMER’S DISEASE AND TO EXAMINE THE IMPACT OF T CELL ACTIVATION IN A DEFINED MANNER ON AD PROGRESSION. THE OBJECTIVES OF THIS PROPOSAL ARE TO I) TEST THE ABILITY OF BRAIN CD8+ TRM TO TRIGGER INNATE IMMUNE CELL ACTIVATION, INCLUDING NK CELLS, MICROGLIA AND MACROPHAGES, IN A MOUSE MODEL OF AD, II) DETERMINE THE IMPACT OF BRAIN CD8+ TRM ACTIVATION ON ALZHEIMER’S DISEASE PROGRESSION IN MICE, INCLUDING COGNITION AND PATHOLOGY, AND III) DETERMINE THE MIGRATION DYNAMICS, ABUNDANCE AND CLONALITY OF CD8+ TRM IN MOUSE AND HUMAN AD BRAIN. THESE GOALS WILL BE ATTAINED BY COMPLEMENTING CLASSICAL IMMUNOLOGIC TECHNIQUES FOR STUDYING TRM IN MOUSE MODELS WITH A CONTINUING COLLABORATION WITH ONSITE NEUROPATHOLOGISTS TO STUDY T CELLS FROM HUMAN POSTMORTEM TISSUE FROM AD AND NON-NEUROLOGICALLY INVOLVED BRAIN TISSUE AT A SINGLE CELL LEVEL. COLLECTIVELY, THESE EXPERIMENTS WILL ENHANCE OUR UNDERSTANDING OF THE ROLE OF CD8+ TRM IN ALZHEIMER’S DISEASE AND HAS POTENTIAL TO PROVIDE INSIGHT INTO T CELL FUNCTIONS IN OTHER NEUROLOGICAL DISEASES, REVEAL NOVEL THERAPEUTIC TARGETS, AND OVERALL BUILD A FOUNDATIONAL UNDERSTANDING OF TRM FUNCTIONS IN THE BRAIN.

ANTIOXIDANT STATUS, DIET, AND EARLY PREGNANCY

PERSONALIZED DEEP LEARNING MODELS OF RAPID CHANGES IN MAJOR DEPRESSIVE DISORDER SYMPTOMS USING PASSIVE SENSOR DATA FROM SMARTPHONES AND WEARABLE DEVICES

INCENTIVES, COGNITIVE TRAINING, AND INTERNET THERAPY FOR TEENS WITH POORLY CONTRO

MENTAL HEALTH CARE UNDER NEW PAYMENT STRATEGIES

STEMMING THE TIDE: THE ROLE OF PAYMENT AND DELIVERY SYSTEM REFORM IN COMBATING THE OPIOID EPIDEMIC