Logica Inc

COOPERATIVE SUPPORT AGREEMENT FOR MAJOR RESEARCH EQUIPMENT AND FACILITIES CONSTRUCTION (MREFC) OF THE NATIONAL ECOLOGICAL OBSERVATORY

CENTER FOR MULTIOMIC HUMAN BRAIN CELL ATLAS - ABSTRACT UNDERSTANDING CELL IDENTITIES AND THEIR SPATIAL DISTRIBUTIONS THROUGHOUT DIFFERENT REGIONS OF THE HUMAN BRAIN IS A FUNDAMENTAL STEP WHEN TRYING TO INTEGRATE PHYSIOLOGICAL, BEHAVIORAL, NEUROCHEMICAL AND MOLECULAR DATA. AT PRESENT, ALTHOUGH MAJOR CATEGORIES OF THE CELL-TYPES PRESENT IN THE HUMAN BRAIN HAVE BEEN DEFINED MOLECULARLY, THE DIFFERENT SUBTYPES WITHIN THESE CATEGORIES ALONG WITH THEIR LOCATIONS ARE FAR FROM UNDERSTOOD. GENE EXPRESSION DRIVES CELL PROGRAMS AND STATES THAT UNDERLIE DISTINCT BRAIN FUNCTIONS. OPEN CHROMATIN AND MODIFIED HISTONES MARK GENE-REGULATORY ELEMENTS THAT CONTROL CELL TYPE-SPECIFIC GENE EXPRESSION PATTERNS. CYTOSINE DNA METHYLATION (MC) IS A STABLE EPIGENOMIC SIGNATURE THAT PERSISTS IN POST-MITOTIC CELLS THROUGHOUT THEIR LIFETIME, DEFINING THEIR CELLULAR IDENTITY. SINGLE-CELL GENE EXPRESSION, OPEN CHROMATIN PROFILES AND DNA METHYLATION ASSAYS HAVE BEEN SUCCESSFULLY USED TO IDENTIFY DISTINCT CELL TYPES IN AN UNBIASED FASHION IN HETEROGENEOUS TISSUES INCLUDING THE HUMAN BRAIN. THIS UM1 PROPOSAL BUILDS ON OUR EARLIER SUCCESSES IN MOUSE BRAIN MAPPING TO PRODUCE DETAILED SINGLE-CELL MULTIMOMIC AND SPATIAL CELL MAPS AT THE SINGLE-CELL LEVEL ACROSS 100 ANATOMICALLY DEFINED REGIONS IN THE HUMAN BRAIN. PROFILING HUMAN BRAIN SAMPLES WILL PERMIT THE DISCOVERY OF UNIQUE GENE EXPRESSION PATTERNS FOR EACH MOLECULARLY-DEFINED CELL TYPE, IDENTIFY THEIR SPATIAL ORGANIZATION, AND THEIR SPECIFIC NON-CODING DNA REGULATORY REGIONS. MULTI-MODAL INTEGRATION BETWEEN EPIGENOMIC AND TRANSCRIPTOMIC SIGNATURES WILL ALLOW THE IDENTIFICATION OF NEW CELL TYPES AND UNIQUE CELL-TYPE MARKERS THAT WILL RAPIDLY BE MADE AVAILABLE TO THE ENTIRE COMMUNITY. THIS UM1 PROJECT WILL ALSO PROVIDE NEW TOOLS FOR GENETIC ACCESS OF PREVIOUSLY INACCESSIBLE BRAIN REGIONS AS WELL AS FACILITATE THE FUNCTIONAL ANALYSIS OF GENETIC VARIANTS ASSOCIATED WITH NEUROPSYCHIATRIC AND NEUROLOGICAL DISORDERS.

CANCER CENTER SUPPORT GRANT

ORGANIZATIONAL AND PROJECT MANAGEMENT SUPPORT TO COMPLETE THE NEON CONSTRUCTION READY DESIGN AND PROJECT EXECUTION PLAN.

COMPARATIVE FUNCTIONAL GENOMICS INBRE IN MAINE

AZA-FWS AMERICAN RESCUE PLAN PARTNERSHIP

MATERIALS TECHNOLOGY RESEARCH FOR ARMY MODERNIZATION AND READINESS (MT-RAMR)

TAS::89 0331::TAS RECOVERY RECOVERY ACT: STATE GEOLOGICAL SURVEY CONTRIBUTIONS TO THE NATIONAL GEOTHERMAL DATA SYSTEM.

TENNESSEE TECHNOLOGICAL UNIVERSITY CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND

CENTER FOR EPIGENOMICS OF THE MOUSE BRAIN ATLAS (CEMBA)

COMPARATIVE BIOLOGY OF TISSUE REPAIR, REGENERATION AND AGING

NEON INITIAL OPERATIONS

TENNESSEE TECHNOLOGICAL UNIVERSITY CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND

NEW COOPERATIVE AGREEMENT

COMPARATIVE FUNCTIONAL GENOMICS INBRE IN MAINE

THE INSTITUTE FOR ULTRA-STRONG COMPOSITES BY COMPUTATIONAL DESIGN (US-COMP) WILL BE FOCUSED ON THE MODELING-DRIVEN DESIGN OF A NEW CLASS OF ULTRA-HIGH-STRENGTH-LIGHTWEIGHT (UHSL) MATERIALS FOR FUTURE MANNED MARS MISSIONS. THESE MATERIALS WILL MEET THE REQUIRED MECHANICAL PERFORMANCE GOALS SET FORTH BY NASA AND EXCEED THOSE EXHIBITED BY CURRENT STATE-OF-THE-ART CARBON-FIBER COMPOSITES. US-COMP S VISION IS TO SERVE AS A FOCAL POINT FOR PARTNERSHIPS BETWEEN NASA OTHER AGENCIES INDUSTRY AND ACADEMIA TO: (1) ENABLE COMPUTATIONALLY-DRIVEN DEVELOPMENT OF CARBON NANOTUBE (CNT)-BASED UHSL STRUCTURAL MATERIALS AND (2) EXPAND THE RESOURCE OF HIGHLY SKILLED ENGINEERS SCIENTISTS AND TECHNOLOGISTS IN THIS EMERGING FIELD TO ENHANCE THE U.S. LEADERSHIP IN CRITICAL LIGHTWEIGHT STRUCTURAL MATERIALS. THIS VISION WILL BE ACHIEVED THROUGH THE FOUR PRINCIPLE OBJECTIVES: ESTABLISH A NEW COMPUTATIONALLY-DRIVEN MATERIAL DESIGN PARADIGM FOR RAPID MATERIAL DEVELOPMENT AND DEPLOYMENT DEVELOP A NOVEL UHSL STRUCTURAL MATERIAL FOR USE IN DEEP SPACE EXPLORATION. THE PANEL-LEVEL TESTS AND DEMONSTRATION OF THE NOVEL MATERIALS WILL BE CARRIED OUT TO MOVE THE DEVELOPED TECHNOLOGY TO A TECHNICAL READINESS LEVEL (TRL) OF 4. DEVELOP NOVEL MODELING PROCESSING AND TESTING TOOLS AND METHODS FOR CNT-BASED COMPOSITE MATERIALS ESTABLISH A POOL OF HIGHLY SKILLED ENGINEERS AND SCIENTISTS TO CONTRIBUTE TO THE MATERIALS DEVELOPMENT WORKFORCE. AN INTERDISCIPLINARY AND DIVERSE TEAM OF RESEARCHERS FROM ACADEMIA INDUSTRY AND NATIONAL LABS WILL PARTICIPATE IN THE PROJECT. THE COMPUTATIONAL DESIGN OF THE MATERIAL WILL BE DRIVEN BY A MODELING EFFORT TO INTEGRATE TOPOLOGICAL OPTIMIZATION ATOMISTIC MODELING MOLECULAR MODELING MESOSCALE MODELING AND CONTINUUM-BASED COMPUTATIONAL MECHANICS. INNOVATIONS IN MATERIALS SYNTHESIS AND MANUFACTURING TECHNIQUES WILL ENSURE THE PERFORMANCE AND SCALE-UP FABRICATION OF AEROSPACE-QUALITY TEST SAMPLES AND PANELS. MULTISCALE TESTING AND CHARACTERIZATION CAPABILITIES WILL BE ESTABLISHED AND INTEGRATED TO VALIDATE THE MODELING AND MANUFACTURING EFFORTS AND TO COMPLETE THE PROOF-OF-CONCEPT CYCLE. PARTICIPATION OF THE INDUSTRIAL PARTNERS WILL PROVIDE AND ENSURE THE SCALABILITY AND AEROSPACE-GRADE QUALITY OF THE DEVELOPED COMPOSITE MATERIAL. THE DEVELOPED MATERIALS AND MATERIALS DEVELOPMENT METHODS WILL HAVE A MAJOR IMPACT ON THE AEROSPACE COMMUNITY. FIRST UHSL MATERIALS WILL BE DEVELOPED WITH THE RIGOROUS STRENGTH MODULUS AND FRACTURE TOUGHNESS PROPERTIES NECESSARY FOR MANNED MARS MISSIONS. SECOND A NEW COMPUTATIONALLY-DRIVEN MATERIALS DESIGN PARADIGM WILL BE ESTABLISHED TO DEVELOP THE UHSL MATERIAL OF INTEREST AND FOR FUTURE RAPID MATERIALS DESIGN AND DEVELOPMENT EFFORTS. THIRD A FUNDAMENTAL UNDERSTANDING OF LOAD TRANSFER AND MULTISCALE FAILURE MECHANISMS OF CNT-BASED COMPOSITE MATERIALS WILL BE ESTABLISHED TO ACHIEVE THEIR THEORETICAL PERFORMANCE. FOURTH A REPRODUCIBLE ENGINEERING PERFORMANCE DATA FROM AEROSPACE-QUALITY AND SCALE-UP PANEL TEST RESULTS BUILDING UPON AEROSPACE-GRADE RESIN SYSTEMS AND HIGH-QUALITY COMMERCIALLY AVAILABLE CNT MATERIALS TO ENSURE SCALABILITY TO CONDUCT ASTM STANDARD TESTS. ANOTHER IMPORTANT EMPHASIS OF THE INSTITUTE WILL BE IN WORKFORCE DEVELOPMENT. STUDENTS WILL BE TRAINED FOR DEVELOPING AND UTILIZING ADVANCED COMPUTATIONAL AND EXPERIMENTAL APPROACHES FOR LIGHTWEIGHT MATERIALS. FUNDS WILL BE RESERVED FOR THE STUDENTS TO HAVE EXTENDED VISITS TO NASA FACILITIES DURING SUMMER MONTHS FOR DIRECT MENTORSHIP BY NASA RESEARCHERS. THESE ACTIVITIES WILL STRENGTHEN THE PARTNERSHIPS BETWEEN THE INSTITUTE MEMBERS AND NASA. WITH THE HELP OF THE HBCU PARTICIPANT (FLORIDA A&M UNIVERSITY) THE INSTITUTE WILL ESTABLISH A DIVERSE GROUP OF BOTH RESEARCHERS AND GRADUATE STUDENTS.

MATERIALS TECHNOLOGY SCIENCE AND ENGINEERING RESEARCH FOR THE ARMY (MT-SERA) [RESPONSIVE TO BAA TOPIC 1.1.2 ADVANCED MATERIALS AND MATERIALS PROCESSI

BIOLOGY OF NEUROENDOCRINE PEPTIDES

SPINAL CIRCUITS FOR THE CONTROL OF DEXTROUS MOVEMENT

HUMANITARIAN PROGRAMS

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND- INSTITUTIONAL FUNDS

RECOVERY ACT - CONSTRUCTION OF BROADBAND INFRASTRUCTURE FOR THE CENTRAL EAST REGION OF PUERTO RICO

CIRCUIT-SPECIFIC CELL TYPES IN AGING AND ALZHEIMER'S DISEASE - ABSTRACT THE LONG-TERM GOAL OF THIS PROJECT IS TO DEFINE AND IDENTIFY CIRCUIT-SPECIFIC CELL TYPES–CELLULAR SCALE CONNECTOME– THAT ARE SELECTIVELY VULNERABLE TO LOSS OF CELL BODIES OR AXONAL CONNECTIONS OR CHANGE OF TRANSCRIPTOMIC SIGNATURES OF INDIVIDUAL NEURONS DURING THE PROGRESSION OF HEALTHY AGING AND ALZHEIMER'S DISEASE (AD). EVIDENCE SUGGESTS THAT KNOWLEDGE ON THE CHANGE OF CELLULAR SCALE CONNECTOMES–CELL TYPE-SPECIFIC CIRCUITS BY COUPLING SINGLE CELL TRANSCRIPTOME WITH BRAIN CONNECTIVITY– IS NEEDED FOR HOLISTIC UNDERSTANDING OF AGING AND AD AND PROVIDES AN EXPERIMENTALLY TRACTABLE BASIS TO ADDRESS LONGITUDINAL CHANGES. THESE AGING- AND AD- ASSOCIATED CHANGES MAY INCLUDE LOSS OF CELL TYPES, CONNECTIVITY OR ALTERATIONS IN TRANSCRIPTOMIC SIGNATURES. THIS APPROACH EMPLOYED HERE IS TO TEST THE HYPOTHESIS THAT THERE ARE AGING- OR AD STATE-SPECIFIC NEURAL AND MOLECULAR CIRCUITS THAT DRIVE THE PROGRESSION OF AGING AND AD. A LARGE BODY OF EVIDENCE DEMONSTRATES THAT AD IS A HETEROGENEOUS, MULTIFACTORIAL DISEASE THAT SELECTIVELY AFFECTS CERTAIN BRAIN REGIONS, E.G. THE ENTORHINAL CORTEX (EC), WHILE OTHER AREAS, SUCH AS THE CEREBELLUM, REMAIN UNAFFECTED. RECENT STUDIES ON THE STAGING OF AD NEUROPATHOLOGY SHOWED AD-RELATED NEUROPATHOLOGY BEGINS IN THE LOCUS COERULEUS (LC) OR THE EC, FOLLOWED BY THE HIPPOCAMPUS (HC) AND THEN THE PREFRONTAL CORTEX (PFC). THE LC CONTAINS BOTH ADRENERGIC (NA) AND NON- NORADRENERGIC NEURONS AND PROVIDES THE MAJOR NA INPUTS THROUGHOUT THE ENTIRE BRAIN. NEUROPATHOLOGICAL STAGING HAS SHOWN THAT TANGLES FIST APPEAR IN THE LC AND NA ACTIVATION HAS BEEN SHOWN TO AMELIORATE AD DEFICITS. THE EC PROVIDES KEY CORTICAL INPUTS TO THE HC, WHICH IS ESSENTIAL IN LEARNING MEMORY. THE PFC PROVIDES THE TOP-DOWN REGULATION ON VARIOUS HIGHER ORDER FUNCTIONS. BUT CELL TYPES-BASED INPUT AND/OR OUTPUT NETWORKS THAT ARE SELECTIVELY VULNERABLE AT THE SINGLE NEURONS LEVEL ARE NOT WELL UNDERSTOOD. AS AGING IS A MAJOR RISK FACTOR FOR AD, IT IS IMPORTANT TO UNDERSTAND WHETHER THERE ARE DISTINCT, SIMILAR OR OVERLAPPING SELECTIVELY VULNERABLE CIRCUIT-SPECIFIC CELL TYPES BETWEEN AGING AND AD. THIS PROJECT IS TO COMBINE RETROGRADE LABELING WITH MULTIOMIC SN-RNASEQ AND SN-ATACSEQ TO LINK TRANSCRIPTOMIC AND EPIGENOMIC PROPERTIES OF CELL TYPES TO NEURONAL PROJECTIONS AND INVESTIGATE CIRCUIT-SPECIFIC CHANGES ASSOCIATED WITH PROGRESSION OF AGING AND AD IN FOUR BRAIN REGIONS, NAMELY THE LC, EC, HC AND PFC, IN BOTH MALE AND FEMALE CONTROL AND AD MICE. FOR AD MICE, THE APPNLF MOUSE LINE–THAT CARRIES KNOCKIN HUMAN MUTATIONS IN THE AMYLOID PRECURSOR PROTEIN GENE AND, IMPORTANTLY, EXPRESSES PHYSIOLOGICAL LEVELS OF ASS, MIMICKING LATE ONSET AD–WILL BE USED. THE DATA FROM THIS PROJECT WILL PROVIDE NOVEL INSIGHTS ON THE TYPES OF NEURONS VULNERABLE TO DEGENERATION AND/OR ALTERATIONS OF MOLECULAR/SIGNALING SIGNATURE NETWORKS IN A SPATIAL AND TEMPORAL FASHION AND THE CORRELATION WITH NEUROPATHOLOGY AND COGNITIVE IMPAIRMENT. THIS APPROACH IS A MAJOR STEP TOWARD ESTABLISHING MULTISCALE MODELS THAT WILL HELP TO FILL THE GAP BETWEEN THE EFFECTS OF GENETIC VARIANTS (E.G., APP, AOPE OR TREM2) ON BRAIN TOPOLOGY WITH MOLECULAR NETWORKS IN AGING AND AD.

SITE-DIRECTED RNA EDITING OF NAV1.7 AS A NOVEL ANALGESIC - CHRONIC PAIN IS A LEADING CAUSE OF DISABILITY, AFFECTING ABOUT ONE-THIRD OF ADULTS WORLDWIDE, WITH A PREVALENCE GREATER THAN HEART DISEASE, CANCER, AND DIABETES COMBINED. MISUSE AND ABUSE OF OPIATES HAVE LED TO A NATIONWIDE ADDICTION AND OVERDOSE CRISIS. THUS, THERE IS AN URGENT NEED FOR ALTERNATIVE, NON-ADDICTIVE ANALGESICS. NON-SELECTIVE VOLTAGE-GATED SODIUM CHANNEL (NAV) BLOCKERS ARE AMONG EXISTING NON-ADDICTIVE FDA-APPROVED DRUGS WHICH CAN SOMETIMES PROVIDE SYMPTOMATIC RELIEF FOR PATIENTS. HOWEVER, THEIR UTILITY IS LIMITED BY CNS AND CARDIAC SIDE EFFECTS. GENETIC AND FUNCTIONAL STUDIES OF HUMAN PAIN DISORDERS AND ANIMAL MODELS OF PAIN HAVE VALIDATED NAV1.7, A VOLTAGE-GATED SODIUM CHANNEL THAT IS PREFERENTIALLY EXPRESSED IN PERIPHERAL NEURONS, AS AN ATTRACTIVE TARGET FOR THERAPY. ISOFORM-SELECTIVE NAV BLOCKERS, HOWEVER, ARE DIFFICULT TO GENERATE AND THOSE THAT HAVE BEEN TESTED IN CLINICAL TRIALS ARE RAPIDLY CLEARED FROM THE BODY, LIMITING THEIR EFFECTIVENESS. ALTERNATIVE APPROACHES ARE NEEDED. WE PROPOSE A NOVEL, NON-ADDICTIVE APPROACH TO TREAT CHRONIC PAIN BY EDITING THE MESSAGES THAT ENCODE NAV1.7 IN ORDER TO ALTER ITS ION SELECTIVITY. BY CHANGING A SINGLE LYSINE CODON IN THE ION SELECTIVITY FILTER TO ARGININE, THE NA SELECTIVE CHANNEL WILL BECOME BOTH NA+ AND K+ SELECTIVE, EFFECTIVELY CREATING A COUNTER-CURRENT SHUNT THAT WILL DAMPEN EXCITABILITY. SITE-DIRECTED RNA EDITING (SDRE) REFERS TO NOVEL MECHANISMS TO GENERATE PROGRAMMED EDITS WITHIN RNAS. IT RELIES ON THE ADAR (ADENOSINE DEAMINASE THAT ACTS ON RNA) ENZYMES, WHICH ARE ENDOGENOUSLY EXPRESSED IN HUMAN CELLS, INCLUDING SENSORY NEURONS. DIRECTED BY A GUIDE RNA (GRNA), SDRE SYSTEMS CONVERT PRECISELY SELECTED ADENOSINES TO INOSINE, A TRANSLATIONAL MIMIC FOR GUANOSINE, WHICH CAN RECODE SPECIFIC AMINO ACIDS. FOR USE AS AN ANALGESIC, EDITING MRNA IS PREFERABLE TO DNA BECAUSE IT IS TRANSIENT, THUS LIMITING POTENTIAL OFF-TARGET EFFECTS, INCLUDING MALIGNANT TRANSFORMATIONS. IN ADDITION, ADARS ARE ENDOGENOUS WHILE ENZYMES FOR DNA MANIPULATION (E.G., CAS PROTEINS) ARE NOT, THUS SDRE WILL NOT BE AS IMMUNOGENIC. COMPARED TO SMALL MOLECULE CHANNEL BLOCKERS, SDRE CAN BE MORE SPECIFIC, BECAUSE IT RELIES ON WATSON-CRICK BASE-PAIRING OF GRNAS FOR TARGETING, AND ITS EFFECTS ARE LIKELY LONGER LASTING BECAUSE THEY WILL REMAIN AS LONG AS THE EDITED CHANNELS ARE EXPRESSED. WE PROPOSE TO USE SDRE TO EDIT NAV1.7 K1395R TO RENDER THE CHANNEL PERMEABLE TO BOTH NA+ AND K+. WE WILL GENERATE EFFICIENT AND SPECIFIC REAGENTS THROUGH AN IN VITRO SELECTION ASSAY, AND THEN TEST THEIR EFFICACY IN CELLS, HUMAN SENSORY NEURONS INDUCED FROM PLURIPOTENT STEM CELLS, AND CULTURED MOUSE AND HUMAN DRG NEURONS. FOR IN VIVO TESTING, WE WILL CONSTRUCT A TRANSGENIC MOUSE MODEL THAT IS SPECIFICALLY DESIGNED TO TEST SDRE REAGENTS TARGETING HUMAN NAV1.7 WITH THE GOAL OF AMELIORATING INFLAMMATORY, MIGRAINE AND NEUROPATHIC PAIN.

NATIONAL XENOPUS RESOURCE CENTER

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND-STUDENT AID

ASTROCYTE MODULATION OF NEURAL CIRCUIT FUNCTION AND BEHAVIOR - PROJECT SUMMARY: OVERALL “WHAT IS THE FUNCTION OF GLIAL CELLS IN NEURAL CENTERS? THE ANSWER IS STILL NOT KNOWN, AND IT MAY REMAIN UNSOLVED FOR MANY YEARS TO COME UNTIL SCIENTISTS FIND DIRECT METHODS TO ATTACK IT.” (RAMON Y CAJAL, 1901). THIS PROPHECY TURNED OUT TO BE ACCURATE. ASTROCYTES, ONE OF THE MOST ABUNDANT CELL TYPES IN THE BRAIN, HAVE LONG BEEN THOUGHT OF AS PRIMARILY PASSIVE SUPPORT CELLS. OVER THE PAST TWO DECADES, STUDIES INDICATE THAT ASTROCYTES PLAY PIVOTAL ROLES IN NERVOUS SYSTEM DEVELOPMENT, FUNCTION, AND DISEASES. HOWEVER, A MAJOR UNRESOLVED ISSUE IN NEUROSCIENCE IS HOW ASTROCYTES INTEGRATE DIVERSE NEURONAL SIGNALS UNDER HEALTHY CONDITIONS, MODULATE NEURAL CIRCUIT STRUCTURE AND FUNCTION AT MULTIPLE TEMPORAL AND SPATIAL SCALES, AND HOW ABERRANT EXCITATION AND MOLECULAR OUTPUT INFLUENCES SENSORIMOTOR BEHAVIOR AND CONTRIBUTES TO DISEASE. THE OVERALL GOAL OF THIS U19 TEAM-RESEARCH BRAIN CIRCUIT PROGRAM PROPOSAL IS TO ADDRESS THIS FUNDAMENTAL ISSUE BY DEVELOPING A DEEPER MECHANISTIC UNDERSTANDING OF ASTROCYTES’ ROLES IN NEURAL CIRCUIT OPERATION, COMPLEX BEHAVIORS, AND BRAIN COMPUTATION THEORIES. TWO OVERARCHING QUESTIONS WILL BE ADDRESSED: 1) HOW DO ASTROCYTES TEMPORALLY AND SPATIALLY INTEGRATE MOLECULAR SIGNALS FROM THE DIVERSE TYPES OF LOCAL AND PROJECTION NEURONS ACTIVATED DURING SENSORIMOTOR BEHAVIORS. 2) HOW DO ASTROCYTES CONVERT THIS INFORMATION INTO FUNCTIONAL OUTPUTS THAT MODULATE NEURAL CIRCUIT STRUCTURE AND FUNCTION AT DIFFERENT SPATIAL AND TEMPORAL SCALES. A MULTIDISCIPLINARY, COMPREHENSIVE EFFORT IS PROPOSED TO ADDRESS THESE QUESTIONS THAT CAN ONLY BE COMPLETED THROUGH CLOSE COLLABORATION BETWEEN RESEARCHERS WITH UNIQUE AND COMPLEMENTARY EXPERTISE. AN INNOVATIVE MULTI-SCALE APPROACH INTEGRATING FUNCTIONAL, ANATOMICAL, AND GENETIC ANALYSES WITH THEORETICAL MODELING WILL BE LEVERAGED. THIS APPROACH INVOLVES QUANTITATIVE BEHAVIORAL ASSAYS, LARGE-SCALE IMAGING OF CELLULAR AND MOLECULAR DYNAMICS, TARGETED CELL-TYPE-SPECIFIC MANIPULATIONS, HIGH- THROUGHPUT OMIC TECHNIQUES, GENETIC PROFILING, PROTEIN ENGINEERING, MACHINE LEARNING, AND COMPUTATIONAL MODELING. BY INTEGRATING EXPERIMENTAL AND THEORETICAL APPROACHES, MOLECULAR, CELLULAR, AND CIRCUIT MECHANISMS WILL BE DETERMINED THROUGH WHICH ASTROCYTES INFLUENCE NEURAL CIRCUITS AND CONTRIBUTE TO COMPLEX BEHAVIORS AND BRAIN COMPUTATION THEORIES. THE EXPERIMENTAL AND DATA ANALYSIS TOOLS DEVELOPED AS PART OF THIS PROJECT WILL BE INVALUABLE FOR THE BROADER NEUROSCIENCE COMMUNITY.

THE INSTITUTE FOR SOCIO-ECOLOGICAL RESEARCH WILL BE AWARDED $10.6M TO CONSTRUCT FIVE ACRES OF CORAL REEF AT THREE LOCATIONS IN PUERTO RICO: FAJARDO, MAYAGUEZ, AND LA PARGUERA. THIS WORK WILL STRENGTHEN ECOSYSTEM RESILIENCE BY ADDRESSING THE CURRENT STATE OF LOW CORAL COVER AND DIVERSITY OF REEFS IN PUERTO RICO BY ADDRESSING THE EFFECTS OF NEW CORAL DISEASES AND BY REINTRODUCING SLOW-GROWING, MASSIVE REEF-BUILDING CORAL SPECIES, INCLUDING THREATENED ORBICELLA CORAL SPECIES AND PILLAR CORAL.

FOREST-ATMOSPHERE CARBON TRANSFER & STORAGET (FACT II) OMTERACTOMG EFFECTS OF ELEVATED C02 AND 03 ON ASPEN FOREST ECOSYSTEMS

DECODING AND TARGETING THE LKB1-AMPK SIGNALING PATHWAY IN CANCER

HISTORICALLY BLACK COLLEGES AND UNIVERSITIES PROGRAM

HORMONAL REGULATION OF MAMMALIAN GENE EXPRESSION

BUSINESS TECHNICAL ASSISTANCE

HUMANITARIAN ACTIVITIES

AIRBORNE IMAGING SPECTROMETER, SPECTROMETER ALGORITHM DEVELOPMENT, AND SPECTROMETER COMPONENTS

ARCHAEOLOGICAL SITE MAINTENANCE PROGRAM AT REDSTONE

SPINAL CIRCUITS FOR MECHANICAL ITCH AND LIGHT TOUCH

INTERDISCIPLINARY MINORITY FELLOWSHIP PROGRAM

BASE DESCRIPTION: MULTIPLE YEAR AWARD - YEAR ONE IS INCREMENTALLY FUNDED (IF). THIS IS A FIVE YEAR AWARD. THE AWARD IS IN RESPONSE TO COOPERATIVE A

MINORITY FELLOWSHIP PROGRAM IN MENTAL HEALTH AND SUBSTANCE ABUSE SERVICES AND SERVICES FOR TRANSITION AGE YOUTH

OVERCOMING MECHANISMS OF THERAPEUTIC RESISTANCE IN PANCREATIC DUCTAL ADENOCARCINOMA - PROJECT SUMMARY – OVERALL WHILE MORTALITY RATES FOR MANY CANCERS ARE DECLINING, PANCREATIC DUCTAL ADENOCARCINOMA (PDA) REMAINS A HIGHLY LETHAL MALIGNANCY WITH THE WORST 5-YEAR SURVIVAL RATE OF THE COMMON MALIGNANCIES. UNFORTUNATELY, CURRENT THERAPIES ARE LARGELY INEFFECTIVE IN PDA, AN OUTCOME ATTRIBUTED IN LARGE PART TO THERAPEUTIC RESISTANCE. THE HIGHLY FIBROTIC AND POORLY VASCULARIZED TUMOR MICROENVIRONMENT (TME) RESTRICTS BOTH NUTRIENT AVAILABILITY AND DRUG DELIVERY, AND PROVIDES PRO-SURVIVAL AND IMMUNOSUPPRESSIVE CUES. THESE LIMITATIONS CREATE ENERGY STRESSES THAT DRIVE METABOLIC ADAPTATIONS TO SUPPORT TUMOR GROWTH AND THERAPEUTIC RESISTANCE. MOREOVER, THE HYPERACTIVATION OF PRO-SURVIVAL AND RESISTANCE PATHWAYS IN TUMOR AND STROMAL CELL TYPES RESULTS IN AN INTEGRATED RESISTANCE NETWORK. THE INDUCTION OF THESE PATHWAYS IS ORCHESTRATED BY CELL-TO-CELL COMMUNICATIONS WITHIN THE TME, INCLUDING ABERRANT GLYCOSYLATION (CA-19-9) AND THE SECRETION OF IMMUNOSUPPRESSIVE AND PRO-SURVIVAL PARACRINE FACTORS, SUCH AS LEUKEMIA INHIBITORY FACTOR (LIF) FROM CANCER-ASSOCIATED FIBROBLASTS (CAFS). IN ADDITION, CELLS ADAPT TO THE HYPOXIC, NUTRIENT-DEPLETED TME BY UPREGULATING CELL TYPE-SPECIFIC SURVIVAL PROGRAMS, INCLUDING AUTOPHAGY. ULTIMATELY, TO SUPPORT AND RESPOND TO THESE SIGNALING AND METABOLIC PROGRAMS, BOTH THE TUMOR AND STROMAL CELL EPIGENOMES ARE REPROGRAMMED, LEADING TO CELLULAR HETEROGENEITY AND PLASTICITY THAT RESTRICTS DURABLE THERAPY RESPONSES. EACH OF THESE PROGRAMS PROMOTE RESISTANCE TO A BROAD RANGE OF THERAPEUTICS, INCLUDING CHEMOTHERAPIES, TARGETED THERAPIES, AND IMMUNE CHECKPOINT INHIBITORS. THE CENTRAL HYPOTHESIS OF THIS PROGRAM IS THAT PANCREATIC CANCER HAS CO-OPTED AN INTEGRATED NETWORK OF EPIGENETIC PROGRAMS, PARACRINE SIGNALING PATHWAYS, AND METABOLIC ADAPTATIONS TO PROMOTE TUMOR SURVIVAL AND THERAPEUTIC RESISTANCE. BUILDING UPON THE INVESTIGATORS’ COMPLEMENTARY EXPERTISE IN EPIGENETICS, CELL SIGNALING, AND METABOLIC ADAPTATIONS, AS WELL AS COMMON INTERESTS IN PANCREATIC CANCER, THIS PROGRAM SEEKS TO UNDERSTAND THE INTERACTIONS THAT HINDER PDA THERAPEUTIC RESPONSES, WITH THE ULTIMATE GOAL OF IDENTIFYING VULNERABILITIES THAT CAN BE EXPLOITED AND TARGETED TO OVERCOME DRUG RESISTANCE. IMPORTANTLY, THE PROGRAM WILL UTILIZE ADVANCED MONO- AND CO-CULTURE ORGANOID SYSTEMS, CUTTING-EDGE MOUSE MODELS, NOVEL THERAPEUTICS, SINGLE-CELL APPROACHES, AND HUMAN CLINICAL SPECIMENS TO DELINEATE THE CONTRIBUTIONS OF BOTH TUMOR CELLS AND THEIR STROMAL SUPPORT NETWORK TO THERAPEUTIC RESISTANCE. MOREOVER, PROPOSED COOPERATIVE AND INNOVATIVE APPROACH WILL REVEAL HOW THESE RESISTANCE NODES ARE INTEGRATED AND CAN BE TARGETED TO IMPROVE THERAPEUTIC OUTCOMES IN PDA.

MIDWESTERN REGIONAL CENTER OF THE NATIONAL INSTITUTE FOR CLIMATIC CHANGE RESEARCH

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH SUPPORTING THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY DARPA BIOLOGICAL TECHNOLOGIES BTO RESOURCE PROGRAM.

UNKNOWN TITLE

STRETHENING TECHNOLOGY

ATLAS FOR NEURONAL AND GLIAL CELL TYPES SELECTIVELY VULNERABLE TO PROTEINOPATHIES DURING PROGRESSION OF ALZHEIMER'S DISEASE - ABSTRACT THE LONG-TERM GOAL OF THIS PROJECT IS TO ELUCIDATE MULTIMODAL MECHANISMS UNDERLYING SELECTIVE VULNERABILITY OF NEURONAL AND NON-NEURONAL CELLS TO PROTEINOPATHIES DURING THE PROGRESSION OF ALZHEIMER'S DISEASE (AD). THE MOST NOTABLE FEATURE OF AD IS ITS STRIKINGLY AGE- AND SEX-DEPENDENT REGIONAL ONSET AND PROGRESSION–SELECTIVE VULNERABILITY–WHICH IS MANIFEST IN DISTINCT CLINICAL PRESENTATIONS, E.G., MEMORY IMPAIRMENT IN AD AND PATTERNS OF BRAIN DEGENERATION. RECENT STUDIES ON THE STAGING OF AD NEUROPATHOLOGY SHOWED AD-RELATED TAUOPATHY BEGINS IN THE LOCUS COERULEUS (LC), FOLLOWED BY NEUROFIBRILLARY TANGLES IN THE ENTORHINAL CORTEX (EC), FOLLOWED BY HIPPOCAMPAL (HC), AND THEN NEOCORTEX, E.G., PREFRONTAL CORTEX (PFC). ONE HYPOTHESIS FOR SELECTIVE VULNERABILITY IS THAT MAJOR AD RISK GENES ARE REGIONALLY RESTRICTED, BUT THE RESULTS SHOW THEY ARE RATHER BROADLY EXPRESSED. A BODY OF EVIDENCE SUPPORT THAT GLIA PLAY MULTIPLE ESSENTIAL ROLES AT DIFFERENT BRAIN REGION IN AD PATHOGENESIS. THESE DATA SUGGEST THAT SELECTIVE VULNERABILITY IS LIKELY A RESULT OF INTERPLAY OF INTRINSIC PROPERTIES OF NEURONS AND GLIAL CELLS IN THEIR RESPONSE TO PROTEINOPATHIES IN A DYNAMIC AND SPATIOTEMPORAL MANNER AT VULNERABLE BRAIN REGIONS. FOR EXAMPLE, EC NEURONS PROJECT MULTIPLE BRAIN REGIONS INCLUDING THE EC, PFC AND CEREBELLUM. YET, DEGENERATION OF EC AND PFC OCCURS AT DIFFERENT STAGES. IN CONTRAST, THE CEREBELLUM IS LARGELY NOT AFFECTED. THERE IS EMERGING EVIDENCE THAT SUBPOPULATIONS OF MICROGLIA TREAT EXCITATORY AND INHIBITORY NEURONS DIFFERENTLY. COULD DIFFERENT GLIAL CELL TYPES OR DIFFERENTIAL RESPONSE TO PROTEINOPATHIES IN DIFFERENT PROJECTING SOURCES AND/OR TARGETS CONTRIBUTE TO SELECTIVE VULNERABILITY? THESE RESULTS UNDERSCORE THE CENTRAL IMPORTANCE OF UNDERSTANDING THE DIVERSITY OF CELL TYPES AND MOLECULAR SIGNATURE DIFFERENCES IN BOTH SEXES AT SPATIOTEMPORAL, SINGLE-CELL RESOLUTION AND MULTIMODAL SCALES BETWEEN VULNERABLE AND LESS VULNERABLE NEURONAL AND GLIAL POPULATIONS SUSCEPTIBLE TO PROTEINOPATHIES IN AD. MAPTS305N;INT10+3 AND APPNL-F KNOCK-IN (KI) AD MICE DISPLAYING TAU AND ASS PROTEINOPATHIES, RESPECTIVELY, WILL BE USED TO ACHIEVE THIS GOAL. PRELIMINARY RESULTS WERE OBTAINED TO SUPPORT THE PROJECT. FIRST, BARCODED SINGLE-NEURONS BRAIN-WIDE PROJECTION MAPPING IN CONTROLS DEMONSTRATES SEX- AND AGE- DEPENDENT DIFFERENCES IN PROJECTIONS OF LC NEURONS TO SELECTIVE TARGETS. THE RESULTS SHOWED RECIPROCAL INNERVATIONS AMONG THESE FOUR BRAIN REGIONS. SECOND, THE ANALYSIS OF 16-MONTH-OLD CONTROL AND APPNL-F MICE SHOWED ABERRANT INNERVATION PATTERNS BY NOREPINEPHRINE (NE) NEURONS. THIRD, IMPAIRED PREPULSE INHIBITION (PPI) HAS BEEN SUGGESTED TO BE A BIOMARKER FOR PRODROMAL AD. IMPORTANTLY, PPI IMPAIRMENT WAS OBSERVED IN THE 5-MONTH-OLD APPNL-F MICE. FINALLY, SINGLE NUCLEI (SN)-RNASEQ OF THE EC FROM 16-MONTH-OLD CONTROL AND APPNL-F MICE SHOWED SELECTIVE LOSS OF NEURONAL AND NON-NEURONAL CELL TYPES AND DIFFERENTIAL EXPRESSION OF A LIST OF GENES, INCLUDING THOSE ASSOCIATED WITH NEURONAL AND GLIAL FUNCTION AND IMPAIRED PPI. SN-TRANSCRIPTOMICS AND-EPIGENOMICS WILL BE EMPLOYED TO IDENTIFY VULNERABLE CELL TYPES FOLLOWED BY SPATIAL TRANSCRIPTOMICS TO INVESTIGATE SPATIOTEMPORAL CORRELATION BETWEEN PROTEINOPATHIES AND VULNERABLE CELL TYPES AND GENE NETWORKS.

BIPARTISAN INFRASTRUCTURE LAW (BIL) SUPPLYING REFINED BATTERY MATERIALS INTO THE UNITED STATES ELECTRIC VEHICLE BATTERY SUPPLY CHAIN BY SYNERGIZING LITHIUM-ION BATTERY RECYCLING WITH MINE WASTE RECLAMATION. THE OBJECTIVE OF THIS PROJECT IS TO FURTHER DEVELOP, DEMONSTRATE, AND VALIDATE THE PROPOSED SYNERGIZED BATTERY RECYCLING AND METAL REFINING TECHNOLOGY THAT ENABLE AN EFFICIENT EXTRACTION AND RECOVERY OF BATTERY METALS FROM FLEXIBLE FEEDSTOCKS INCLUDING END-OF-LIFE LI-ION BATTERIES, SCRAPS FROM MANUFACTURING, AND ORE DERIVED FEEDSTOCK.

COMBINING SINGLE CELL APPROACHES AND A DEVELOPMENTAL PERSPECTIVE TO DISCOVER STEM CELL CONTROL CIRCUITS AND THE CELLULAR AND MOLECULAR BASES OF CANCE

SOMATIC CELL CYCLE REGULATION BY PHOSPHORYLATION

CORE GRANT FOR VISION RESEARCH

THIS PROJECT PLATFORM WILL MITIGATE CURRENT DRUG-BASED TREATMENTS' LIMITATIONS BY AVOIDING OFF-TARGET AND SYSTEMIC SIDE EFFECTS WHILE PROVIDING A NOVEL, SCALABLE APPROACH TO CLINICAL APPLICATIONS WITH UNPARALLELED PRECISION AND SAFETY. A SONOGENETIC METHOD WILL BE USED TO ALLEVIATE SYMPTOMS OF A CLINICALLY RELEVANT INDICATION IN MICE AND LARGE ANIMAL MODELS.

EPSCOR CREST PHASE I: CENTER FOR ENERGY TECHNOLOGIES -WITH SUPPORT FROM THE CENTERS OF RESEARCH EXCELLENCE IN SCIENCE AND TECHNOLOGY (CREST), THIS PROJECT AIMS TO BEGIN A CENTER AT MONTANA TECHNOLOGICAL UNIVERSITY. THE CENTER?S MISSION IS TO REPURPOSE THE THOUSANDS OF ACRES OF DEAD FOREST DEBRIS CONSUMED ANNUALLY IN WILDFIRES BY DEVELOPING TECHNOLOGIES THAT USE THIS RESOURCE FOR ELECTRICITY GENERATION AND STORAGE APPLICATIONS. WHILE THE NEED IS ACUTE, PROGRESS IS CURRENTLY LIMITED BY 1) LACK OF ACCESSIBLE AND RELIABLE ENERGY CONVERSION APPROACHES, AND 2) CHALLENGES WITH COLD WEATHER ELECTRICITY STORAGE. THE CENTER?S GOALS INCLUDE PRODUCING INEXPENSIVE, EFFICIENT FUELS FROM BIOMASS, GENERATING ELECTRICITY FROM THESE FUELS, AND MAKING COLD-WEATHER BATTERIES FROM NEW MATERIALS PRODUCED FROM BIOMASS ALONG WITH STUDENT COHORTS STUDYING THESE SPECIFIC ISSUES AND MAKING THEIR OWN NEW SOLUTIONS. THIS PROJECT AIMS TO 1) DEVELOP A MOBILE REACTOR TO TRANSFORM FOREST BIOMASS INTO ECONOMIC PRODUCTS AND THROUGH MACHINE LEARNING PROCESS OPTIMIZATION, 2) DEVELOP SOLID OXIDE FUEL CELLS TO GENERATE ELECTRICITY FROM WOOD-DEBRIS SYNGAS, 3) CREATE NANOSTRUCTURED CARBON WEB ELECTRODES FOR BIO-OIL UPGRADING AND SUPERCAPACITORS, AND 4) DEVELOP RADICAL ORGANIC BATTERIES OPTIMIZED FOR COLD WEATHER. METHODS INCLUDE ELECTROSPINNING FOR WEB FABRICATION, IN-SITU ELECTROCHEMICAL/OPTICAL ANALYSIS, AND MACHINE LEARNING. EXPECTED RESULTS INCLUDE SCALABLE METHODS FOR BIOMASS CONVERSION TO VALUE-ADDED PRODUCTS, MATERIALS DEVELOPMENT FOR ELECTRICITY CONVERSION AND STORAGE FROM THESE PRODUCTS, AND IMPROVED PROCESS CONTROL TECHNOLOGIES. A NEW WORKFORCE WILL BE DEVELOPED THROUGH THE STUDENT COHORTS CAPABLE OF PRODUCING SOLUTIONS TO LOCAL ENERGY NEEDS. THE CENTERS OF RESEARCH EXCELLENCE IN SCIENCE AND TECHNOLOGY (CREST) PROGRAM PROVIDES SUPPORT TO ENHANCE THE RESEARCH CAPABILITIES OF INSTITUTIONS THROUGH THE ESTABLISHMENT OF CENTERS THAT EFFECTIVELY INTEGRATE EDUCATION AND RESEARCH. 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.

HISTIDINE PHOSPHORYLATION AS A NEW TARGET FOR CANCER THERAPY

ORGANIZATION AND FUNCTION OF MOUSE VISUAL CORTICAL AREAS

MICHIGAN TECHNOLOGICAL UNIVERSITY: NEW AWARD. CONTROL NUMBER: 1564-1523 TITLE: ''NEXTCAR: CONNECTED AND AUTOMATED CONTROL FOR VEHICLE DYNAMICS AND POWERTRAIN OPERATION ON A LIGHT-DUTY MULTI-MODE HYBRID ELECTRIC VECHICLE''

MARINE BIOLOGICAL LABORATORY: NEW MARINER AWARD. CONTROL NUMBER: 1726-1506 TITLE: ''THE DEVELOPMENT OF TECHNIQUES FOR TROPICAL SEAWEED CULTIVATION AND HARVESTING'' THE MARINE BIOLOGICAL LABORATORY WILL DESIGN AND DEVELOP A FARM SYSTEM OF A TROPICAL SEAWEED, EUCHEUMA ISIFORME, FOR THE PRODUCTION OF BIOMASS FOR CONVERSION TO BIOFUELS THAT WILL NOT ONLY MECHANIZE THE SEEDING AND HARVESTING PROCESS TO DRASTICALLY REDUCE LABOR COSTS, BUT WILL ALSO ALLOW FARMS TO BE DEPLOYED IN OFFSHORE AREAS FOR GREATLY EXPANDED LARGE-SCALE PRODUCTION. ----------

SIGNAL TRANSDUCTION BY TYROSINE PHOSPHORYLATION

FECAL MICROBIOME TRANSPLANT NATIONAL REGISTRY

LTER-PLUM ISLAND ECOSYSTEMS: DYNAMICS OF COASTAL ECOSYSTEMS IN A REGION OF RAPID CLIMATE CHANGE, SEA-LEVEL RISE, AND HUMAN IMPACTS

HOST-MICROBE INTERACTIONS: HARNESSING CO-EVOLUTION TO TREAT DISEASE

DEFENSE PRODUCTION ACT (DPA) TITLE III - MICRO-CREDENTIALS IN EXTRACTIVE TECHNOLOGIES AT MONTANA TECHNOLOGICAL UNIVERSITY

SINGLE-CELL APPROACHES TO REVEAL HOW JUMPING GENES INDIVIDUALIZE NEURAL CIRCUITS

LTER: PLUM ISLAND ECOSYSTEMS, THE IMPACT OF CHANGING LANDSCAPES AND CLIMATE ON INTERCONNECTED COASTAL ECOSYSTEMS -THE PLUM ISLAND ECOSYSTEMS LONG TERM ECOLOGICAL RESEARCH (PIE LTER) SITE CONSISTS OF A LINKED WATERSHED-MARSH-ESTUARINE SYSTEM CONNECTED TO THE GULF OF MAINE. THE GOAL OF THE PIE LTER IS TO ADVANCE OUR PREDICTIVE UNDERSTANDING OF THE LONG-TERM RESPONSE OF COUPLED LAND-MARSH-ESTUARY-OCEAN ECOSYSTEMS TO CHANGES IN THREE KEY DRIVERS: CLIMATE, SEA LEVEL AND HUMAN ACTIVITIES. THIS RESEARCH SHEDS LIGHT ON HOW MARSHES ARE RESPONDING TO SEA-LEVEL RISE AND CONTROLS ON CARBON STORAGE, OR BLUE CARBON, IN MARSH AND ESTUARINE ECOSYSTEMS. TO UNDERSTAND HOW NUTRIENTS AND CARBON FROM LAND INFLUENCE THE ESTUARY AND HOW MARSHES AND ESTUARIES CONTRIBUTE TO OCEANIC CARBON AND NUTRIENT BUDGETS, THE INVESTIGATORS ARE MEASURING THE FLOWS OF CARBON AND NUTRIENTS ACROSS THE WATERSHED-TO-OCEAN CONTINUUM. TO UNDERSTAND HOW ESTUARINE AND MARSH ECOSYSTEM FOOD WEBS ARE CHANGING WITH SEA LEVEL RISE AND WARMING TEMPERATURES, THE INVESTIGATORS ARE MEASURING CHANGES IN ABUNDANCE OF KEY SPECIES AND ANALYZING THE ENTIRE FOOD WEB USING TRACER TECHNIQUES. THIS INFORMATION IS BEING SHARED WITH MANAGERS FROM LOCAL, REGIONAL AND FEDERAL AGENCIES, AS WELL AS NON-PROFIT ORGAINZATIONS. IN COLLABORATION WITH MASS AUDUBON THE INVESTIGATORS ARE RUNNING A K-12 SCHOOLYARD PROGRAM, ?SALT MARSH SCIENCE?, WHICH PROVIDES TEN SCHOOLS WITH EXPERIENTIAL LEARNING OPPORTUNITIES FOR STUDENTS AND TEACHERS. THEY ALSO WORK WITH THE GULF OF MAINE INSTITUTE (GOMI), A NON-PROFIT THAT PROVIDES INTENSIVE TRAINING AND ON-GOING SUPPORT TO TEACHERS TO HELP THEM DEVELOP ENVIRONMENTAL COMMUNITY-BASED STEWARDSHIP PROJECTS. THE PIE LTER IS ORGANIZED AROUND THREE QUESTIONS THAT BUILD ON PREVIOUS FINDINGS AND INTEGRATE LONG-TERM STUDIES WITH NEW OBSERVATIONS, EXPERIMENTS, AND MODEL DEVELOPMENT. ACTIVITIES WITHIN THE THREE QUESTIONS INTEGRATE ACROSS THE ENTIRE WATERSHED-MARSH-ESTUARY DOMAIN TO FACILITATE A BROADER SYNTHESIS OF LONG-TERM DATA AND NEW OBSERVATIONS. THE FIRST QUESTION IS: ?HOW ARE THE SOURCES AND FATES OF ORGANIC MATTER AND NUTRIENTS IN THE LINKED WATERSHED/ESTUARY SYSTEM BEING ALTERED BY CHANGING LAND USE, SEA-LEVEL RISE (SLR), CLIMATE, AND GEOMORPHOLOGY?? TO ANSWER THIS, THE INVESTIGATORS ARE EXAMINING HOW THE LINKED COASTAL SYSTEM INFLUENCES ESTUARINE PRODUCTION AND WATER QUALITY, AS WELL AS THE ROLE OF COASTAL ECOSYSTEMS IN MODULATING CARBON AND NUTRIENT FLUXES TO THE NEARSHORE OCEAN THROUGH A COMBINATION OF EXPANDED OBSERVATIONS AND NUMERICAL MODELING. THE SECOND QUESTION, ?HOW DO FOOD WEBS AND ENERGY FLOW RESPOND TO NEW GEOMORPHIC CONFIGURATIONS, SLR, CHANGING CLIMATE, AND ASSOCIATED ESTUARINE RESPONSES?? IS BEING ANSWERED THROUGH A NEW INTEGRATIVE EFFORT TO DETERMINE HOW THE LANDSCAPES? ABILITY TO TRANSFER ENERGY TO FOOD WEBS CHANGES WITH HABITAT. THIS EFFORT IS COMBINING LONG-TERM ABUNDANCE DATA, STABLE ISOTOPE DATA ON NICHE SIZE, AND MAPPING OF LANDSCAPE FEATURES TO MODEL HOW FUTURE CHANGES IN THE MARSH-ESTUARY CONFIGURATION WILL MODIFY ENERGY FLOW. GIVEN THE IMPORTANCE OF COASTAL ECOSYSTEMS IN SUPPORTING NEARSHORE FOOD WEBS, UNDERSTANDING HOW THIS LINK WILL CHANGE WITH CLIMATE, LAND USE CHANGE, AND SLR IS CRITICAL. FINALLY, THE INVESTIGATORS ARE ASKING: ?WHAT INTERNAL FEEDBACKS MIGHT ACCELERATE, SLOW DOWN, OR EVEN REVERSE THE PREDICTED CHANGES IN EMERGENT MARSH CONFIGURATION AND THE FATE OF CARBON, NUTRIENTS AND ENERGY?? SOCIETY NEEDS TO UNDERSTAND MORE ABOUT INTERNAL FEEDBACKS THAT MIGHT INCREASE MARSH RESILIENCE OR COMPROMISE MARSH SURVIVAL AS SEA LEVELS RISE, SYSTEMS WARM, AND WATERSHED INPUTS CONTINUE TO CHANGE. WITH NEW COLLABORATIONS, THE TEAM IS ALSO LEVERAGING LARGE-SCALE MARSH RESTORATION TO TEST HYPOTHESES ON FEEDBACK MECHANISMS WITHIN THE SYSTEM. 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.

LOCAL CONNECTIONS OF INHIBITORY CORTICAL NEURONS

NEURAL CIRCUIT MECHANISMS OF SOCIAL HOMEOSTASIS IN INDIVIDUALS AND SUPRAORGANISMAL SOCIAL GROUPS

REGULATION OF HEPATIC GLUCONEOGENESIS BY THE CREB:TORC2 PATHWAY

CELL REGULATION, DIFFERENTIATION AND CANCER

ARCTIC LTER: CLIMATE CHANGE AND CHANGING DISTURBANCE REGIMES IN ARCTIC LANDSCAPES

MOLECULAR DETERMINANTS OF NEURAL DEVELOPMENT

PUBLIC HEALTH ENTOMOLOGY FOR ALL - LARGE PARTS OF THE NATION?S MOST VULNERABLE POPULATIONS, INCLUDING MANY HIGH-RISK URBAN DISTRICTS, FINANCIALLY-DISTRESSED RURAL COMMUNITIES, AND NATIVE AMERICAN RESERVATIONS, ARE AT A HIGHER RISK OF EXPOSURE TO VECTORS OF DISEASE. LOW-INCOME COMMUNITIES IN URBAN SETTINGS ARE OFTEN AT A HIGHER RISK FOR EXCESSIVE EXPOSURE TO A VARIETY OF CHEMICALS, INCLUDING THOSE FOR PEST MANAGEMENT, WHICH EXACERBATE HEALTH DISPARITIES. THE CURRENT NATIONAL APPROACH TO COMPETENTLY TRAINING VECTOR PROFESSIONALS CURRENTLY IS HIGHLY COMPARTMENTALIZED AND DISJOINTED. WHEN IT COMES TO PUBLIC HEALTH, CERTIFICATION OF BEST PRACTICES CAN HELP REDUCE UNNECESSARY EXPOSURE TO PESTICIDES WHILE ALSO MORE EFFECTIVELY MANAGING VECTORS OF DISEASE, THUS HELPING REDUCE POTENTIAL HEALTH DISPARITIES AND IMPROVE COMMUNITY WELLNESS. THE NATION HAS LEARNED FROM PREVIOUS VECTOR-BORNE DISEASE CRISES THAT THERE IS A DANGEROUS SHORTFALL OF TRAINED VECTOR CONTROL PROFESSIONALS AT ALL LEVELS OF EXPERIENCE AND EMPLOYMENT, INCLUDING APPLICATORS, TRAINERS, AND MANAGEMENT. AS PART OF THE OBJECTIVES TO ?TARGET AND TRAIN?, THE ENTOMOLOGICAL SOCIETY OF AMERICA (ESA) IS IN A POSITION TO HELP FILL THE EDUCATION GAP THROUGH THE EXPANDED PARTICIPATION IN THE DOMESTIC CREDENTIALING PROGRAM FOR APPLIED VECTOR MANAGEMENT PROFESSIONALS, THE PUBLIC HEALTH ENTOMOLOGIST (PHE) CERTIFICATE. IN PARTNERSHIP WITH THE CDC, WE SEEK TO EXPAND QUALIFIED AND COMPETENT PUBLIC HEALTH WORKFORCE, LEVERAGING AND EXPANDING THE EXISTING PHE CERTIFICATION PROGRAM BY ENROLLING MORE INDIVIDUALS FROM HIGH RISK COMMUNITIES TO HELP ESTABLISH A NATIONAL NETWORK OF CERTIFIED PROFESSIONALS WHO CAN HELP RESPOND TO A VECTOR-BORNE DISEASE OUTBREAK. THE PURPOSE OF APPLYING FOR THIS OPPORTUNITY IS TO HELP CDC AS WELL AS ESA GROW OUR COLLECTIVE CAPACITY TO REACH FRONTLINE PERSONNEL. ANOTHER PART OF THIS IS PROPOSAL IS LEVERAGING AND EXPANDING THE VECTOR-BORNE DISEASE NETWORK (VBDN), A COALITION OF MORE THAN TWO DOZEN ORGANIZATIONS INC LUDING MEMBERSHIP AND TRADE ASSOCIATIONS, VECTOR CONTROL GROUPS, AND EDUCATIONAL INSTITUTIONS SUCH AS THE CDC REGIONAL CENTERS OF EXCELLENCE ON VECTOR-BORNE DISEASES. THIS GROUP, IN CONJUNCTION WITH OTHER SUBJECT MATTER EXPERTS, CAN PROACTIVELY ?INTEGRATE AND EXTEND? TO PREPARE FOR THE NEXT EMERGING OR RE-EMERGING VBD OUTBREAK BY CONVENING SUBJECT MATTER EXPERTS TO SHARE INFORMATION, PROBLEM-SOLVE, AND DISSEMINATE BEST PRACTICES WITH A FOCUS ON CULTURALLY-COMPETENT ENGAGEMENT. THE FRAMEWORK PROPOSED COULD BE APPLIED PROACTIVELY AS WELL AS REACTIVELY IN THE FACE OF AN EMERGING OR RE-EMERGING OUTBREAK.WITH SUPPORT FROM THE CDC, ESA CAN HELP REDUCE BARRIERS TO TRAINING MORE PROFESSIONALS AND LEVERAGE THESE EFFORTS TO HELP REACH VULNERABLE POPULATIONS. WE AIM TO HELP PREPARE CDC?S NETWORK OF FRONTLINE RESPONDERS BY CERTIFYING PROFESSIONALS, EXPANDING THE EXISTING NETWORK IN HIGH-RISK COMMUNITIES, AND DISSEMINATING INFORMATION AND GUIDANCE IN RESPONSE TO THE NEXT VECTOR-BORNE CRISIS.

SAN DIEGO NATHAN SHOCK CENTER

TRAVELING WAVES IN NEOCORTICAL CIRCUITS: MECHANISMS, COMPUTATIONAL ROLES IN SENSORY PROCESSING, AND IMPACT ON SENSORY PERCEPTION - PROJECT SUMMARY/ABSTRACT AN IMPORTANT LONGSTANDING GOAL IN NEUROSCIENCE RESEARCH IS TO UNDERSTAND HOW LARGE-SCALE SPATIOTEMPORAL PATTERNS OF NEURAL ACTIVITY EMERGE IN THE BRAIN AND WHETHER THEY HAVE A DIRECT ROLE IN SHAPING THE BRAIN’S COMPUTATIONAL PROCESSES AND THEREBY MAMMALIAN BEHAVIOR. NOTABLY, TRAVELING WAVES OF NEURAL ACTIVITY HAVE BEEN IMPLICATED IN SENSORY, COGNITIVE, AND MOTOR BEHAVIORS, AND THIS TEAM RECENTLY FOUND THAT INTRINSIC TRAVELING WAVES (ITWS) IN VISUAL CORTICAL AREAS PREDICT THE MAGNITUDE OF EVOKED SPIKING ACTIVITY AND VISUAL PERCEPTUAL SENSITIVITY IN AWAKE, BEHAVING NON-HUMAN PRIMATES. HOWEVER, IT REMAINS UNCLEAR WHETHER ITWS REFLECT AN UNDERLYING FUNDAMENTAL MECHANISM OF CORTICAL FUNCTION OR WHETHER THEY MIGHT SIMPLY BE EPIPHENOMENAL. THIS PROJECT WILL EXAMINE THE ROLE OF NEOCORTICAL ITWS IN VISUAL PERCEPTION AND IS GUIDED BY A THEORETICAL MODEL OF ITW ACTIVITY THAT MAKES SPECIFIC TESTABLE AND FALSIFIABLE PREDICTIONS ABOUT THE MECHANISMS THAT GIVE RISE TO THE SPATIOTEMPORAL FEATURES OF ITWS AND THEIR ROLES IN SENSORY BEHAVIOR. THE MODEL IS BASED ON A NETWORK OF SPIKING NEURONS AND PREDICTS THAT ITWS EMERGE FROM THE ANATOMICAL ORGANIZATION OF HORIZONTAL CORTICAL FIBERS AND RESULT IN SHIFTS IN THE BALANCE OF EXCITATORY (E) AND INHIBITORY (I) POPULATION ACTIVITY THAT TRAVEL AS WAVES, THE MODEL FURTHER PREDICTS THAT ITWS ARE RETINOTOPICALLY COORDINATED ACROSS VISUAL CORTICAL AREAS, AND THAT THIS COORDINATION IS THE MECHANISM BY WHICH ITWS IMPROVE PERCEPTION. HOWEVER, THESE PREDICTIONS COULD BE WRONG. EMPIRICAL TESTS OF THE MODEL’S PREDICTIONS WILL REQUIRE ACTIVITY MEASUREMENTS FROM SPECIFIC NEURON-TYPES, ACROSS WIDE FIELDS- OF-VIEW, AND WITH EXCELLENT SPATIAL AND TEMPORAL RESOLUTION IN AWAKE BEHAVING ANIMALS. TO PERFORM SUCH MEASUREMENTS, THE TEAM RECENTLY INVENTED SEVERAL NEW TECHNOLOGIES: (1) GENETICALLY ENCODED FLUORESCENT VOLTAGE INDICATORS (GEVIS) THAT THEY WILL TARGET TO SPECIFIC E OR I NEURAL POPULATIONS; (2) A CUSTOM-BUILT DUAL-COLOR FLUORESCENCE MESOSCOPE TO TRACK THE SUBTHRESHOLD POPULATION VOLTAGE DYNAMICS OF 2 NEURON-TYPES AT ONCE, ACROSS A 8-MM FIELD-OF-VIEW SPANNING MULTIPLE CORTICAL AREAS IN MARMOSET AND MOUSE CORTEX; (3) TRANSPARENT ELECTRODE ARRAYS THAT ALLOW MEASUREMENTS OF LFPS TO BE PERFORMED ACROSS THE CORTEX CONCURRENTLY WITH VOLTAGE IMAGING STUDIES OF E AND I POPULATION ACTIVITY; (4) TRANSPARENT LAMINAR ELECTRODE ARRAYS TO MEASURE THE SPIKING ACTIVITY OF CELLS ACROSS THE DIFFERENT CORTICAL LAYERS. BY COMBINING THE USE OF THESE FOUR INNOVATIONS IN MARMOSETS AND MICE PERFORMING A VISUAL DETECTION TASK, THE TEAM WILL TEST THE PREDICTIONS OF THE THEORETICAL MODEL AND LEARN HOW DIFFERENT CORTICAL NEURON-TYPES IMPACT ITW DYNAMICS AND PERCEPTUAL SENSITIVITY. AIM 1 TESTS THE HYPOTHESIS THAT E/I POPULATION ACTIVITY TRAVELS AS ITWS IN MICE AND MARMOSETS. AIM 2 TESTS THE PREDICTION THAT ITWS ARE COORDINATED RETINOTOPICALLY ACROSS CORTICAL AREAS, AND THAT THIS COORDINATION ENHANCES PERCEPTUAL SENSITIVITY. AIM 3 WILL ACCOUNT MECHANISTICALLY FOR THE RESULTS OF AIMS 1 AND 2 IN A THEORETICALLY GROUNDED SPIKING NETWORK MODEL. OVERALL, BY USING INNOVATIVE NEW TECHNOLOGIES THIS INTERDISCIPLINARY TEAM WILL PROVIDE KEY INSIGHTS INTO LONGSTANDING CONCEPTUAL ISSUES OF PROFOUND IMPORTANCE TO BRAIN RESEARCH.

21-ULI STEP-B-0075 CARBONLESS ELECTRIC AVIATION (CLEAN)

CIRCADIAN PHOTOENTRAINMENT IN MAMMALS

DEVELOPMENT AND OPERATION OF THE NEON PROJECT MANAGEMENT OFFICE

TAM RECEPTORS AND FLAVIVIRUS INFECTION

SEE NOTICE OF AWARD, ATTACHMENT 1 - TERMS AND CONDITIONS, ATTACHMENT D STATEMENT OF WORK, ABSTRACT.

GENETIC MODELS OF SPORADIC ALZHEIMERS DISEASE IN THE MARMOSET - ABSTRACT THE LONG-TERM GOAL OF THIS PROJECT IS TO DEVELOP, CHARACTERIZE, AND VALIDATE GENETICALLY MODIFIED MARMOSET MODELS OF SPORADIC ALZHEIMER'S DISEASE (AD) THAT WILL SERVE AS TOOLS FOR INVESTIGATING MOLECULAR AND CELLULAR DISEASE MECHANISMS, AND FOR IDENTIFYING THERAPEUTIC TARGETS. AD IS THE MOST COMMON CAUSE OF DEMENTIA, WITH THE MAJORITY OF CASES (~95%) APPEARING TO BE SPORADIC, WHICH IS CAUSED BY COMPLEX INTERACTIONS BETWEEN MULTIPLE GENE VARIANTS AND ENVIRONMENTAL FACTORS. NUMEROUS MODELS OF AD HAVE BEEN DEVELOPED (E.G., MICE); THESE MODELS ARE PRIMARILY FOCUSED ON FAMILIAL FORMS OF AD AND HAVE ENABLED SIGNIFICANT PROGRESS TOWARD UNDERSTANDING AD, BUT THEY FAIL TO RECAPITULATE THE FULL SPECTRUM OF MOLECULAR, CELLULAR, BEHAVIORAL, AND COGNITIVE PATHOLOGIES OBSERVED IN AD AND PROVIDE POOR PREDICTIVE VALUE WHEN TRYING TO TRANSLATE FINDINGS TO HUMAN CLINICAL TRIALS. SEVERAL LINES OF EVIDENCE SUGGEST THAT MARMOSETS MAY EFFECTIVELY BRIDGE THE GAP BETWEEN MICE AND HUMANS FOR BOTH BASIC AND TRANSLATIONAL NEUROSCIENCE RESEARCH. FIRST, MARMOSETS AND HUMANS HAVE VERY SIMILAR BRAIN STRUCTURES, COGNITIVE/SOCIAL BEHAVIORAL REPERTOIRES, METABOLISM, AND IMMUNE FUNCTIONS. SECOND, COMPARED TO OTHER PRIMATES, MARMOSETS HAVE SHORT LIFESPAN, SMALL BODY SIZE, AND HIGH REPRODUCTIVE POWER. FINALLY, GENE EDITING TOOLS ARE NOW AVAILABLE TO GENERATE VARIOUS TYPES OF GENETICALLY MODIFIED MARMOSETS. APOLIPOPROTEIN E (APOE) IS THE STRONGEST RISK FACTOR FOR LATE-ONSET, SPORADIC AD AND ALSO INCREASES THE AGE- DEPENDENT RISK OF MONOGENIC FAMILIAL AD AND INCIDENCE OF AD IN WOMEN. THERE ARE THREE APOE ALLELES IN HUMANS WITH THE APOE*E4 ALLELE CONFERRING INCREASED RISK AND THE APOE*E2 ALLELE CONFERRING DECREASED RISK RELATIVE TO THE COMMON APOE*E3 ALLELE. APOE ISOFORMS DIFFERENTIALLY MODULATE BOTH AMYLOID-SS (ASS)-DEPENDENT AND ASS-INDEPENDENT PATHWAYS TO AFFECT BRAIN HOMEOSTASIS, INCLUDING TAU-MEDIATED NEURODEGENERATION, MICROGLIAL INFLAMMATION, LIPID TRANSPORT, SYNAPTIC INTEGRITY, GLUCOSE METABOLISM AND CEREBROVASCULAR FUNCTION. THESE THREE APOE ALLELES DIFFER WITH REGARD TO CYSTEINE (C) AND ARGININE (R) AMINO ACIDS AT POSITIONS 112 AND 158 (C112/C158 IN APOE2; C112/R158 IN APOE3; AND R112/R158 IN APOE4). SEVERAL LINES OF EVIDENCE DEMONSTRATE THAT R61 IS CRITICAL FOR APOE4-MEDIATED AD RISK. MARMOSET APOE (MAPOE) IS ENCODED BY A SINGLE ALLELE AND CONTAINS THE EQUIVALENT OF R112 AND R158, BUT LACKS THE CRITICAL R61 EQUIVALENT (IT CONTAINS T INSTEAD), SUGGESTING THAT IT BEHAVES LIKE HUMAN APOE3. TO TEST THIS HYPOTHESIS, MAPOE T61R MUTANT PROTEIN WAS GENERATED TO TEST THE EFFECT ON INFLAMMATORY RESPONSES INDUCED BY LIPOPOLYSACCHARIDES IN MICROGLIAL CELLS. THE MAPOE T61R VARIANT RESULTED IN A MORE ROBUST RESPONSE COMPARED TO WILD TYPE MAPOE. SIMILAR RESULTS WERE FOUND WHEN HUMAN APOE4 WAS USED (APOE4>APOE3). TAKEN TOGETHER, THESE PRELIMINARY RESULTS INDICATE THAT MAPOE T61R IS FUNCTIONALLY EQUIVALENT TO HUMAN APOE4. FURTHER, SEVERAL PAIRS OF CRISPR GRNAS FOR GENERATING AN APOE NULL MUTATION HAVE BEEN IDENTIFIED. TO INVESTIGATE THE ROLE OF APOE IN SPORADIC AD IN THE MARMOSET, APOE NULL AND T61R MUTANT MARMOSETS WILL BE GENERATED AND CHARACTERIZED.

MINORITY FELLOWSHIP PROGRAM IN MENTAL HEALTH & SUBSTANCE ABUSE SERVICES

THE DISCOVERY OF HUMAN PEPTIDE ENCODING GENES

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

EPIGENOMIC CELL-TYPE CLASSIFICATION AND REGULATORY ELEMENT IDENTIFICATION IN THE HUMAN BRAIN

MAHOPE O KE KULA KE A'O MAU ANA: KE KA'A 'ENEHANA (STEAMOBILE)

REGULATION OF MEMORY CD8 T CELL DEVELOPMENT

3/3-SCHIZOPHRENIA GENETICS AND BRAIN SOMATIC MOSAICISM

XENOPUS MUTANT RESOURCE

MONTANA TECHNOLOGICAL UNIVERSITY - HIGHER EDUCATION EMERGENCY RELIEF FUND-IHE/INSTITUTION

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

GENERATION OF FUNCTIONAL HUMAN ORGANS AND TISSUES USING INTERSPECIFIC BLASTOCYST COMPLEMENTATION

IN-SITU REAL TIME MONITORING AND CONTROL OF MOLD MAKING AND FILLING PROCESSES

GENETIC FACTORS CONTROLLING THE INTENSITY OF SOCIAL BEHAVIOR

TENNESSEE CYBERCORPS: A HYBRID PROGRAM IN CYBERSECURITY

REGULATORY T CELL LINEAGE STABILITY CONTROLLED BY FOXP3 CNS2

(PQ5) MITOCHONDRIAL HETEROGENEITY IN MELANOMA TUMOR AND IMMUNE RESPONSES

TOLERANCE DEFENSES IN HOST-MICROBIOTA INTERACTIONS

OISE-PIRE SUSTAINABILITY, ECOSYSTEM SERVICES, AND BIOENERGY DEVELOPMENT ACROSS THE AMERICAS

DISSECTING NEURAL MECHANISMS INTEGRATING MULTIPLE INPUTS IN C. ELEGANS

SINGLE CELL ANALYSIS FOR FORENSIC EPIGENETICS (SAFE)

BIOLOGICAL UNDERSEA ENERGY (BLUE) BIOLOGICAL TECHNOLOGIES OFFICE BROAD AGENCY ANNOUNCEMENT

AMERICAN RECOVERY AND REINVESTMENT ACT - SBDD - WEST VIRGINIA GEOLOGICAL AND ECONOMIC SURVEY

PALMER, ANTARCTICA LONG TERM ECOLOGICAL RESEARCH PROJECT

HIGH-THROUGHPUT MAPPING OF SELECTIVELY VULNERABLE CELL TYPES AND PROJECTIONS IN AGING AND ALZHEIMER'S DISEASE

MECHANISMS OF SYNAPTIC DYSFUNCTION IN PARKINSON'S AND OTHER SYNUCLEIN-LINKED DISE

SOLVING THE VALENCE ASSIGNMENT PROBLEM - PROJECT SUMMARY THE ABILITY TO DISCRIMINATE BETWEEN WHAT IS “GOOD” AND “BAD” IS TERMED VALENCE PROCESSING, AND PATHOLOGICAL PERTURBATIONS IN VALENCE PROCESSING CAN EXPLAIN MENTAL HEALTH DISORDERS RANGING FROM ANXIETY AND DEPRESSION TO COMPULSIVITY AND BIPOLAR DISORDER. THE KEY TO DEVELOPING MORE EFFECTIVE TREATMENTS FOR MENTAL HEALTH DISORDERS WITH FEWER SIDE-EFFECTS WILL BE IN THE SYNAPTIC, CELLULAR, AND CIRCUIT MECHANISMS. THIS PROPOSAL NOT ONLY LAYS OUT A VERY SPECIFIC RESEARCH PLAN TO PROBE THE FUNCTIONAL ROLE OF A NEUROPEPTIDE, NEUROTENSIN (NT), BUT IT ALSO LAYS OUT A COMPREHENSIVE, SYSTEMATIC APPROACH TO INVESTIGATING NEUROMODULATORY SYSTEMS. THE GENERAL APPROACH INCLUDES: 1) IDENTIFY A CIRCUIT THAT PLAYS A CAUSAL AND CRITICAL ROLE IN VALENCE PROCESSING, 2) PROFILE THE TRANSCRIPTOME OF THIS CIRCUIT COMPONENT, 3) SELECT FOR SURFACE RECEPTORS OR OTHER DRUGGABLE TARGETS, 4) DETERMINE THE CONTRIBUTION OF THIS NEUROMODULATORY SIGNAL ON PLASTICITY, 5) ESTABLISH THE INPUT-OUTPUT ARCHITECTURE OF THE NEUROMODULATORY INNERVATION AND POSTSYNAPTIC, DOWNSTREAM TARGETS, AND 6) ESTABLISH A CAUSAL ROLE FOR THIS PARTICULAR NEUROMODULATORY SIGNAL IN NEURAL ACTIVITY AND BEHAVIOR ASSOCIATED WITH VALENCE PROCESSING. THE SPECIFIC HYPOTHESES INCLUDED IN THIS PROPOSAL ARE: THAT NT SERVES TO GUIDE PLASTICITY TO THE APPROPRIATE TARGET, THAT THERE ARE PARALLEL CIRCUITS THAT HAVE SOME LOCAL INTERACTION IN THE BLA, AND THAT NT ALTERS THE CODING DYNAMICS BY INCREASING SIGNAL-TO-NOISE RATIO BY AMPLIFYING SIGNAL BY MODULATION OF GLUTAMATERGIC TRANSMISSION. A SUCCESSFUL OUTCOME OF THIS PROJECT WILL PROVIDE A SPECIFIC MODEL FOR HOW A NEUROMODULATORY SIGNAL SUCH AS NT CAN SOLVE THE “VALENCE ASSIGNMENT PROBLEM.”

UNBIASED EPIGENOMIC AND TRANSCRIPTOMIC PROFILING OF NON-NEURONAL CELLS IN THE MOUSE BRAIN

LTER: THE ROLE OF BIOGEOCHEMICAL AND COMMUNITY OPENNESS IN GOVERNING ECOLOGICAL CHANGE IN ARCTIC ECOSYSTEMS

REGULATION OF MEMORY CD8 T CELL DEVELOPMENT

EPIGENOME-BASED CELL CENSUS AND REGULATORY ELEMENT DISCOVERY IN THE AGING MOUSE BRAIN

COMPLETION OF THE NEON CYBER INFRASTRUCTURE CONSTRUCTION-READY DESIGN

BIPARTISAN INFRASTRUCTURE LAW (BIL): SECOND-LIFE BATTERY IN MOBILE EV CHARGING APPLICATION FOR RURAL TRANSPORTATION (SMART) THE OBJECTIVE OF THE PROJECT IS TO RESEARCH, DEVELOP AND DEMONSTRATE FOUR SECOND-LIFE BATTERY (SLB)-INTEGRATED MOBILE CHARGING STATIONS (MCS) SUPPORTING EV CHARGING IN DISADVANTAGED RURAL AREAS ACHIEVING =35% REDUCTION OF UPFRONT INVESTMENT COST FOR MCSS WHEN COMPARED TO EXISTING PRODUCTS BASED ON NEW BATTERIES, WHILE PROVIDING COMPARABLE ELECTRIC VEHICLE (EV) CHARGING CAPACITIES.

MECHANISMS GOVERNING DEVELOPMENT OF VISUAL CONNECTIONS

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

EXTRAMURAL RESEARCH FACILITIES IMPROVEMENT PROGRAM DATA*

TO COVER ANY COSTS ASSOCIATED WITH SIGNIFICANT CHANGESTO THE DELIVERY OF INSTRUCTION DUE TO THE CORONAVIRUS.

HISTORICALLY BLACK COLLEGES AND UNIVERSITIES PROGRAM

A COMMUNITY LABORATORY FACILITY FOR EXPLORING AND SENSING OF AEROSOL-CLOUD-DRIZZLE PROCESSES: THE AEROSOL-CLOUD-DRIZZLE CONVECTION CHAMBER

DEVELOPMENT OF AN IMPROVED, LOW-COST POLIO VACCINE (IR-IPV)

THE PURPOSE OF THE PROPOSED PROJECT IS TO BUILD THE CAPACITY OF FUNDED LOCAL EDUCATION AGENCIES (LEA) TO ESTABLISH AND MAINTAIN SAFE AND SUPPORTIVE ENVIRONMENTS FOR STUDENTS AND STAFF AS AN APPROACH T

CAPTIVE PROPAGATION AND INTRODUCTION OF HAWAIIAN AND MARIANAS ISLANDS FOREST BIRDS

DEVELOPMENT OF METHODS FOR MULTI-OMIC ANALYSIS OF DNA METHYLATION AND CHROMATIN ARCHITECTURE IN SINGLE CELLS

ASTROCYTE REGULATION OF NEURONAL AMPA GLUTAMATE RECEPTORS

HORIZONTAL GENE TRANSFER AS A SOURCE OF EVOLUTIONARY INNOVATION IN METAZOANS

SALK INSTITUTE FOR BIOLOGICAL STUDIES NINDS CENTER CORE GRANT

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

CYBERCORPS SCHOLARSHIP FOR SERVICE (RENEWAL): AN ENHANCED AND INTEGRATED SCHOLAR EXPERIENCE IN CYBERSECURITY

LTER-PIE: INTERACTIONS BETWEEN EXTERNAL DRIVERS, HUMANS AND ECOSYSTEMS IN SHAPING ECOLOGICAL PROCESS IN A MOSAIC OF COASTAL LANDSCAPES AND ESTUARINE

MONTANA TECHNOLOGICAL UNIVERSITY - HIGHER EDUCATION EMERGENCY RELIEF FUND

BIOCURRENTS RESEARCH CENTER

PEPTIDERGIC NEUROMODULATION OF MICROCIRCUITS THAT CONTROL CHEMOSENSATION-INDUCED BEHAVIORS

SAN CLEMENTE LOGGERHEAD SHRIKE CAPTIVE BREEDING PROJECT NAVAL BASE CORONADO AND COMMANDER, US PACIFIC FLEET, ENVIRONMENTAL PROGRAM

ARABIDOPSIS 2010: TOOLS AND TECHNOLOGIES TO ENABLE GENOME-WIDE SCREENS IN ARABIDOPSIS

DEFINING CRITICAL P53 THERAPEUTIC TARGETS AND MECHANISMS

MECHANISM OF BETA-CATENIN AND APC-REGULATED TRANSCRIPTION OF WNT TARGET GENES

DE-EE0009862 WITH TENNESSEE TECHNOLOGICAL UNIVERSITY TITLED RURAL REIMAGINED: BUILDING AN ELECTRIC VEHICLE (EV) ECOSYSTEM AND GREEN ECONOMY FOR TRANSFORMING LIVES IN ECONOMICALLY DISTRESSED APPALACHIA. 0000 - NEW AWARD

ARABIDOPSIS 2010: REGULATORY NETWORKS CONTROLLING HORMONE-MEDIATED GROWTH

MICHIGAN TEACHER EXCELLENCE PROGRAM (MITEP): A MODEL FOR IMPROVING EARTH SCIENCE EDUCATION NATIONWIDE

THE ARCTIC LTER PROJECT: REGIONAL VARIATION IN ECOSYSTEM PROCESSES AND LANDSCAPE LINKAGES

SPATIAL REGULATION OF DEVELOPMENTAL GENE EXPRESSION

UNKNOWN TITLE

THE ROLE OF BAF RELATED COMPLEXES IN REGULATORY T CELL DEVELOPMENT AND FUNCTION

USING GEROSCIENCE TO UNDERSTAND AND TREAT ALZHEIMER'S DISEASE

EXTRAMURAL RESEARCH FACILITIES CONSTRUCTION CONSTRUCTIO*

MINORITY FELLOWSHIP PROGRAM MENTAL HEALTH AND SUBSTANCE ABUSE SERVICES AND SERVICES FOR TRANSITION AGE YOUTH

IMPACT OF TIME-RESTRICTED FEEDING IN REDUCING CANCER RISK THROUGH OPTIMIZING MITOCHONDRIA FUNCTION - PROJECT SUMMARY THIS APPLICATION, IN RESPONSE TO RFA-CA-004 “RESEARCH ANSWERS TO NATIONAL CANCER INSTITUTE'S (NCI) PROVOCATIVE QUESTIONS (R01 CLINICAL TRIAL OPTIONAL),” WILL ADDRESS “PQ2: HOW DOES INTERMITTENT FASTING AFFECT CANCER INCIDENCE, TREATMENT RESPONSE, OR OUTCOME?” OBESITY AND AGE ARE TWO MAJOR RISK FACTORS FOR CANCER DEVELOPMENT. THUS, THERAPEUTIC INTERVENTIONS THAT PREVENT OR DELAY THE DEVELOPMENT OF EXCESSIVE WEIGHT GAIN AND/OR AGE-ASSOCIATED PHYSIOLOGICAL DYSFUNCTION HOLD GREAT PROMISE FOR REDUCING CANCER RISK IN THE INCREASINGLY OBESE AND ELDERLY GLOBAL POPULATION. ONE SUCH INTERVENTION IS TIME-RESTRICTED EATING (TRE), A PRAGMATIC FORM OF INTERMITTENT FASTING IN WHICH DAILY CALORIC INTAKE IS CONSTRAINED TO A CONSISTENT WINDOW OF 8–12 HOURS WITHOUT EXPLICITLY REDUCING TOTAL CALORIC INTAKE. IN YOUNG MALE MICE, TIME-RESTRICTED FEEDING (TRF) REDUCES CANCER RISK BY PREVENTING OBESITY AND METABOLIC DISEASES. TRF HAS ALSO BEEN SHOWN TO REDUCE BREAST CANCER XENOGRAFT PROGRESSION IN OBESE MICE. IN HUMANS, SHORT-TERM CLINICAL STUDIES OF TRE HAVE REVEALED METABOLIC IMPROVEMENTS THAT PREDICT REDUCED CANCER RISK, AND EPIDEMIOLOGICAL EVIDENCE SUGGESTS THAT PROLONGED NIGHTLY FASTING CAN REDUCE THE RISK OF CANCER, INDEPENDENT OF CHANGES IN BODY WEIGHT. THIS PROMISING PRELIMINARY EVIDENCE SUGGESTS THAT TRE MAY BE AN EFFECTIVE INTERVENTION FOR REDUCING CANCER RISK. HOWEVER, THE EFFECTS OF TRF IN AGED ANIMALS AND IN THE CONTEXT OF AN OBESOGENIC WESTERN DIET HAVE NOT YET BEEN ESTABLISHED, AND THE MECHANISMS BY WHICH TRF REDUCES CANCER RISK REMAIN UNKNOWN. THIS APPLICATION BUILDS UPON PROMISING PRELIMINARY DATA AND LEVERAGES THE COMPLEMENTARY SKILLS OF THE RESEARCH TEAM TO ADDRESS THESE CRITICAL GAPS IN KNOWLEDGE. BOTH OBESITY AND AGING ARE ASSOCIATED WITH MITOCHONDRIAL DYSFUNCTION AND THE PRODUCTION OF PRO-TUMORIGENIC MITOCHONDRIAL METABOLITES. PROPOSED EXPERIMENTS TEST THE HYPOTHESIS THAT TRF OPTIMIZES MITOCHONDRIA FUNCTION THROUGH BOTH CELL-AUTONOMOUS AND SYSTEMIC MECHANISMS, THEREBY REDUCING CANCER RISK. IN AIM 1, THE IMPACT OF TRF ON MITOCHONDRIA FUNCTION AND RELATED PHYSIOLOGIES WILL BE ESTABLISHED IN AGED MICE. NUTRIENT METABOLISM, ENERGY CONSUMPTION, AND MITOCHONDRIA FUNCTION WILL BE ASSESSED IN THESE MICE. IN AIM 2, AN INNOVATIVE COMBINATION OF METABOLOMICS AND MITOCHONDRIA RESPIRATION ASSAYS WILL BE USED TO TEST THE IMPACT OF TRF ON MITOCHONDRIA FUNCTION IN NORMAL AND CANCER CELLS (ASSESSING BOTH CELL-AUTONOMOUS AND NON-CELL-AUTONOMOUS MECHANISMS). THE EFFECTS OF TRF ON TUMOR INCIDENCE WILL BE ASSESSED BY SUBJECTING TUMOR-PRONE MICE TO TRF. IN AIM 3, PLASMA COLLECTED FROM A RECENTLY CONCLUDED HUMAN TRE INTERVENTION STUDY WILL BE USED TO TEST THE EFFECT OF TRE ON MITOCHONDRIA FUNCTION AND CANCER RISK IN HUMANS. THE PROPOSED COMPARATIVE ANALYSIS OF TRE IN HUMANS AND MICE WILL PROVIDE CRITICAL MECHANISTIC INSIGHT INTO HOW ONE FORM OF INTERMITTENT FASTING CAN HELP PREVENT CANCER ONSET AND IMPROVE TREATMENT OUTCOMES.

NEW COMPUTATIONAL METHODS FOR DATA-DRIVEN PROTEIN STRUCTURE PREDICTION

DEVELOPMENTAL PHYSIOLOGY OF CILIATED EPITHELIA

DYNAMICS OF ACTIVITY-INDUCED TRANSCRIPTION IN SINGLE DENTATE GRANULE CELLS

PHYSIOLOGY AND FUNCTION OF BASAL GANGLIA SUBCIRCUITS IN SEQUENCE LEARNING

ORIENTATION INDEPENDENT DIC AND POLARIZATION MICROSCOPY

REGULATION OF HEPATIC GLUCONEOGENESIS BY THE CREB:TORC2 PATHWAY

LASER BEAM CONTROL

NEURAL SYSTEMS AND BEHAVIOR

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

CONTINUATION OF THE SPACE ALLIANCE TECHNOLOGY OUTREACH PROGRAM (SATOP), INCLUDING BUSINESS INCUBATOR

THE CONTRIBUTION OF OLD AGE-ASSOCIATED PROTEOTOXICITY TO INFLAMMATION AND DEMENTIA

CYBERCORPS SCHOLARSHIP FOR SERVICE: CYBERSECURITY WORKFORCE PREPARATION

THE ROLE OF LONG-LIVED PROTEINS IN THE SURVIVAL OF NERVE CELLS

NEURAL CONTROL OF SKILLED MOVEMENTS: AN ETHOLOGICAL DISSECTION OF GENETICALLY TRACTABLE MAMMALIAN MOTOR CIRCUITS

EPIGENETIC ALTERATIONS OF THE DEVELOPING BRAIN IN ANIMAL MODELS OF SCHIZOPHRENIA

REGULATION OF NF-KAPPA B

TOOLS AND TECHNOLOGIES TO ENABLE GENOME-WIDE SCREENS IN ARABIDOPSIS

THIS FUNDING IS TO SUPPORT UNIVERSITY'S STUDENTS WHOSE LIVES HAVE BEEN DISRUPTED, MANY OF WHOM ARE FACING FINANCIAL CHALLENGES AND STRUGGLING TO MAKE ENDS MEET DUE TO COVID-19 PANDEMIC

PROJECT TITLE ENABLING THE FUTURE OF GREAT LAKES BIOLOGICAL RESOURCE ASSESSMENTPROJECT PERIOD 9 1 2022 8 31 2023THE OVERARCHING GOAL OF THE PROPOSED USGS MTU MTRI COLLABORATION IS TO RESEARCH NEW AND EXPERIMENTAL BIOLOGICAL ASSESSMENT TOOLS THAT IMPROVE THE SPATIAL COVERAGE, ACCURACY, PRECISION, AND USEFULNESS OF USGS S GREAT LAKES SCIENCE PROGRAM THREE SPECIFIC TECHNOLOGICAL INNOVATIONS WILL BE INVESTIGATED TO ACHIEVE THIS GOAL UNDERWATER AND SURFACE AUTONOMY, UNDERWATER IMAGING, AND MACHINE LEARNING THESE INNOVATIONS COMBINED WILL GENERATE NEW KNOWLEDGE THAT IS USEFUL TO GREAT LAKES NATIONAL RESOURCE MANAGERS THESE INNOVATIONS WILL ENABLE USGS TO COLLECT AND PROCESS LAKE WIDE SURVEYS OF PREY FISH ABUNDANCES, ANSWERING DISCRETE RESEARCH QUESTIONS ABOUT THE FISH, LIMNOLOGY, AND ECOSYSTEMS MAP HABITATS AND DEVELOP MORE EFFICIENT TECHNOLOGICAL SOLUTIONS TO PERSISTENT SAMPLING PROBLEMS TO AID IN THE ACCOMPLISHMENT OF THIS GOAL, MICHIGAN TECH WILL WORK COLLABORATIVELY WITH USGS SCIENTISTS ON THE FOLLOWING ACTIVITIES ENGINEER, COORDINATE, AND DEPLOY ROBOTIC TECHNOLOGIES TO AUTONOMOUSLY COLLECT DATA ABOUT FISHERIES AND LAKE ECOSYSTEMS ASSIST WITH THE DELIVERY OF ANNUAL SURVEY RESULTS FOR BENTHIC FISHES FROM USGS S AUV IMAGERY DEVELOP AUTOMATED SOLUTIONS FOR INTERPRETATION AND PROCESSING OF BIOLOGICAL AND PHYSICAL FEATURES IN UNDERWATER IMAGERY, VIDEO, AND ACOUSTIC DATA ADVANCE TECHNIQUES FOR LARGE SCALE UNDERWATER MAPPING OF PHYSICAL HABITAT AND GEOMORPHOLOGY USING ACOUSTIC TECHNOLOGIES AUTOMATE THE INTERPRETATION OF SATELLITE AND AERIAL REMOTE SENSING DATA FOR PHYSICAL AND BIOLOGICAL FEATURES OF THE LAKE ENVIRONMENT DEVELOP COMPUTATIONAL TECHNOLOGIES, WORKFLOWS, AND SOFTWARE TO ACCELERATE DATA PROCESSING, ANALYSIS, AND DELIVERY TO PARTNERS ASSIST WITH PRODUCTION OF OPEN SOURCE TOOLS AND DATA THAT CAN BE EASILY ASSIMILATED BY THE PUBLIC AND USGS S PARTNERS THE DELIVERABLES AND OUTCOMES OF THIS PROJECT INCLUDE CUSTOM SOFTWARE FOR ROUND GOBY OBJECT IDENTIFICATION CUSTOM SOFTWARE FOR SUBMERGED AQUATIC VEGETATION PERCENT COVER ESTIMATION CUSTOM SOFTWARE FOR DREISSENID MUSSEL COVER AND COUNT PEER REVIEWED PUBLICATIONS ON RESEARCH RESULTS MULTIBEAM BATHYMETRY, BACKSCATTER, AND DERIVED PRODUCTS FOR GEOGRAPHIES OF INTEREST ANNOTATED IMAGE DATA SETS LABELLED FOR FISH, ALGAE, AND MUSSELS PUBLICLY RELEASED DATA SETS USED IN ANALYSES AND REPORTS ON RESEARCH OUTCOMES THE INTENDED BENEFICIARIES OF THIS WORK INCLUDE USGS STAKEHOLDERS, INCLUDING NATURAL RESOURCE AND LAND MANAGERS IN THE GREAT LAKES MICHIGAN TECHNOLOGICAL UNIVERSITY MTU AND MICHIGAN TECH RESEARCH INSTITUTE MTRI HAVE BEEN ASSISTING THE USGS IN THE PRIMARY RESPONSIBILITY OF ASSISTING NATURAL RESOURCE AND LAND MANAGERS BY PROVIDING THEM WITH SOUND BIOLOGICAL INFORMATION AND ASSISTANCE IN APPLYING THE INFORMATION TO THEIR NEEDS

NEUROBIOLOGY SUMMER COURSE

ESTABLISHMENT AND MODULATION OF DNA METHYLATION PATTERNS IN ARABIDOPSIS

THIS INVESTMENT SUPPORTS THE ESTABLISHMENT OF THE BUSINESS DISASTER RESPONSE CENTER TO BE LOCATED IN CAGUAS, PUERTO RICO TO SUPPORT BUSINESS IMPACTED BY HURRICANE MARIA (DR 4339) AND HURRICANE IRMA (4336). THIS CENTER WILL SUPPORT BUSINESSES LOCATED IN 12 MUNICIPALITIES WITH DISASTER RECOVERY, NEEDED INCUBATION SPACE, SUPPORTIVE BUSINESS EDUCATION, AND ACCESS TO CAPITAL THROUGH THE REGIONAL CDFI. IT IS EXPECTED TO CREATE 324 JOBS, RETAIN 360 JOBS, WITH A PRIVATE INVESTMENT OF $660,000 IN THE FIRST THREE YEARS. IN ADDITION, IT PROJECTS $2 MILLION IN EXPORTS IN THE FIRST THREE YEARS.

THIS INVESTMENT SUPPORTS THE ESTABLISHMENT OF THE BUSINESS DISASTER RESPONSE CETNER TO BE LOCATED IN CAGUAS, PUERTO RICO TO SUPPORT BUSINESSES IMPACTED BY HURRICANE MARIA (DR4339) AND HURRICANE IRMA (DR4336). THIS CETNER WILL SUPPORT BUSINESSES LOCATED IN 12 MUNICIPALITIES WITH DISASTER RECOVERY, NEEDED INCUBATION SPACE, SUPPORTIVE BUSIENSS EDUCATION, AND ACCESS TO CAPITAL THROUGH THE REGIONAL CDFI. IT IS EXPECTED TO CREATE 324 JOBS, RETAIN 360 JOBS, WITH A PRIVATE INVESTMENT OF $660,000 IN THE FIRST THREE YEARS. IN ADDITION, IT PROJECTS $2M IN EXPORTS DURING THE FIRST YEARS.

MAHOPE - KU 'A'ALI'I

CONSERVATION AND MANAGEMENT IN PROTECTED AREAS: PARTICIPATORY BIODIVERSITY MONITORING IN AMAZONIAN PROTECTED AREAS

INTERSECTIONAL GENETIC DISSECTION OF SPINAL CIRCUITS PROCESSING PAIN AND ITCH

INVESTIGATING THE EFFECTS OF STRUCTURAL VARIANTS ON 3D GENOME ORGANIZATION AND GENE REGULATION IN CANCER GENOMES

ENGINEERING HUMAN ISLET-LIKE ORGANOIDS FOR TRANSPLANTATION

STRUCTURAL BASIS FOR ACTIVITY OF AND RESISTANCE TO HIV INTEGRASE INHIBITORS

STRUCTURAL BASIS FOR ACTIVITY OF AND RESISTANCE TO HIV INTEGRASE INHIBITORS - ABSTRACT THE HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1, HEREAFTER REFERRED TO AS HIV) CURRENTLY INFECTS ~40 MILLION PEOPLE WORLDWIDE, AND THE NUMBER OF INFECTED INDIVIDUALS CONTINUES TO RISE. IN THE ABSENCE OF A CURE, ANTIRETROVIRAL THERAPY REPRESENTS THE PRIMARY TREATMENT OPTION, BECAUSE IT SLOWS DISEASE PROGRESSION AND REDUCES NEW INFECTIONS. INTEGRASE (IN) STRAND TRANSFER INHIBITORS (INSTIS) ARE A CLASS OF ANTIRETROVIRAL THERAPEUTICS THAT BLOCK INTEGRATION OF VIRAL DNA INTO HOST CHROMOSOMES, A PROCESS THAT IS MEDIATED BY THE VIRAL IN ENZYME, WHICH ASSEMBLES INTO OLIGOMERIC NUCLEOPROTEIN COMPLEXES ON THE ENDS OF VIRAL DNA, TERMED “INTASOMES”. INSTIS SELECTIVELY TARGET INTASOMES AND REPRESENT FIRST-LINE THERAPIES IN THE CLINIC. HOWEVER, THE EMERGENCE OF IN VARIANTS RESISTANT TO INSTIS IS BECOMING A GREATER CLINICAL PROBLEM. STRUCTURAL BIOLOGY APPROACHES CAN SHED LIGHT ON THE MECHANISMS UNDERLYING DRUG ACTION AND RESISTANCE, PROVIDING USEFUL INFORMATION FOR RATIONALLY IMPROVING THE CURRENT INSTIS. WHEN COMPLEMENTED WITH ANCILLARY TECHNIQUES, SUCH AS BIOCHEMICAL ACTIVITY ASSAYS, BIOPHYSICAL THERMODYNAMIC AND KINETIC MEASUREMENTS, CELLULAR VIROLOGY, AND DIVERSE COMPUTATIONAL APPROACHES INCLUDING FREE ENERGY CALCULATIONS, THE STRUCTURES PRECISELY DETAIL MECHANISMS OF RESISTANCE AGAINST SPECIFIC INSTIS AND PROVIDE GUIDANCE FOR DESIGNING AND DEVELOPING NOVEL 3RD GENERATION INSTIS TO FIGHT INFECTIONS. IN THIS PROPOSAL, APPROACHES CENTERED AROUND USING REVOLUTIONARY ADVANCES IN CRYO-ELECTRON MICROSCOPY FOR STRUCTURAL STUDIES WILL SHOW HOW INSTIS INTERACT WITH THEIR NATURAL DRUG TARGET, THE HIV INTASOME (BOTH WT AND MUTANT), AND ELUCIDATE THE MECHANISMS BY WHICH RESISTANCE TO THESE DRUGS EMERGES. THERE ARE THREE SPECIFIC AIMS THAT WILL: (1) EXTEND AND BUILD UPON CURRENT EFFORTS TO PROVIDE A MECHANISTIC UNDERSTANDING OF BOTH WHY AND HOW SELECT VIRAL RESISTANT VARIANTS (VRVS) ARISE IN RESPONSE TO THE CLINICALLY USED DRUG DOLUTEGRAVIR (DTG) OR THE MOST POTENT DEVELOPMENTAL IN-HOUSE COMPOUND THAT 4D, WHICH IS CURRENTLY UNDER PRE-CLINICAL EVALUATION; (2) BROADLY IDENTIFY AND ANALYZE NOVEL MECHANISMS AND PATHWAYS OF DRUG RESISTANCE THAT ARISE IN RESPONSE TO TREATMENT WITH 2ND GENERATION DRUGS, HIGHLIGHTING BOTH PRIMARY AND COMPENSATORY MUTATIONS, AND PROVIDING STRATEGIES TO PREDICT FUTURE VARIANTS; (3) SELECT FOR RESIDUAL RESISTANT VARIANTS ARISING IN RESPONSE TO TREATMENT WITH NOVEL 3RD GENERATION INSTIS THAT WERE SYNTHESIZED BASED ON THE CONCEPT OF SUBSTRATE MIMICRY, MANY OF WHICH EFFECTIVELY INHIBIT VIRAL RESISTANT VARIANTS THAT ARISE IN RESPONSE TO TREATMENT WITH 2ND GENERATION CLINICALLY USED INSTI DRUGS, AND EXPLAIN MECHANISMS UNDERLYING THE SUPERIOR POTENCY OF NOVEL COMPOUNDS. THIS WORK WILL IMPROVE OUR UNDERSTANDING OF AN IMPORTANT CLASS OF DRUGS USED TO TREAT PEOPLE LIVING WITH HIV, IDENTIFY MECHANISMS, PATHWAYS, AND PATTERNS OF CLINICALLY RELEVANT RESISTANCE TO INSTIS, AND PROVIDE SPECIFIC GUIDELINES FOR THEIR RATIONAL IMPROVEMENT.

PREVENTING THE TRANSMISSION OF MITOCHONDRIAL DISEASES THROUGH HETEROPLASMIC SHIFT

THE ROLE OF DNA METHYLATION DYNAMICS AND PATTERNING IN POSTMITOTIC NEURONAL-MATURATION

EPIGENOMIC MAPPING APPROACHES FOR CELL-TYPE CLASSIFICATION IN THE BRAIN

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

SPATIOTEMPORAL PATTERNS OF NEURAL ACTIVITY AND THEIR ROLE IN PERCEPTION

LENTIVIRAL VECTORS FOR GENE TRANSFER

CROSS-TALK BETWEEN THE CIRCADIAN CLOCK AND THE CAMP SIGNALING PATHWAY

MOLECULAR SIGNAL INTEGRATION FOR ROOT GROWTH CONTROL

ROLE OF LKB1 AND AMPK IN METFORMIN AND TZD CONTROL OF GLUCOSE METABOLISM IN LIVER

THE CONTRIBUTION OF KIDNEY DISEASE TO AGE-ASSOCIATED COGNITIVE DECLINE

C. ELEGANS AS A MODEL FOR TELOMERE MAINTENANCE IN CANCER

INITIAL EVENTS IN PHOTORECEPTOR SIGNALING

GENETIC CONTROL OF MOTOR NEURON DEVELOPMENT AND FUNCTION

TRAINING IN METHODS OF COMPUTATIONAL NEUROSCIENCE

THE FUNCTION OF GERM GRANULES IN MAINTAINING PLURIPOTENCY IN THE C. ELEGANS GERMLINE

UNDERSTANDING THE ROLE OF AUTOPHAGY-REGULATED CELL DEATH IN THE ESCAPE FROM REPLICATIVE CRISIS

DEVELOPMENT OF MARMOSET MODELS OF NEURODEGENERATIVE DISEASE USING EMBRYONIC STEM CELL-BASED GENE-EDITING APPROACHES

HUMANIZED MONOCLONAL ANTIBODY TO TREAT ACINETOBACTER INFECTIONS

CALIFORNIA CONDOR BI-NATIONAL RECOVERY AND REINTRODUCTION PROGRAM, UNITED STATESAND MEXICO

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH SUPPORTING THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY DARPA GUARANTEEING AI ROBUSTNESS AGAINST DECEPTION GARD PROGRAM. THE TERM OF THE BASE PERIOD FOR THIS AGREEMENT COMMENCES ON THE EFFECTIVE DATE OF THE AWARD AND CONTINUES THROUGH TWELVE 12 MONTHS THEREAFTER.

MULTISCALE MODELING AND LARGE-SCALE RECORDINGS OF TRAUMA-INDUCED EPILEPTOGENESIS

ENVIRONMENTAL CONTRIBUTION TO NEURONAL-METHYLOME DYNAMICS IN ANIMAL MODELS OF AUTISM SPECTRUM DISORDERS

DEVELOPING A NONINVASIVE METHOD TO MANIPULATE SPECIFIC CELL TYPES WITHIN THE MAMMALIAN BRAIN

INFEWS/T3: REDUCING HOUSEHOLD FOOD, ENERGY AND WATER CONSUMPTION: A QUANTITATIVE ANALYSIS OF INTERVENTIONS AND IMPACTS OF CONSERVATION

OPTIMIZED CIRCADIAN RHYTHMS FOR THE PREVENTION OF ALZHEIMER'S DISEASE

CHARACTERIZATION OF SPINAL CIRCUITS UNDERLYING MOTOR SYNERGY FUNCTION - ABSTRACT: THE CNS PERFORMS EXTREMELY COMPLEX COMPUTATIONS WITH REMARKABLE EFFICIENCY. THIS IS EXEMPLIFIED BY THE ABILITY TO SEAMLESSLY EXECUTE MOTOR BEHAVIORS THAT NECESSITATE THE COORDINATION OF MULTIPLE MUSCLE GROUPS CONTROLLING JOINTS WITH MANY DEGREES OF FREEDOM. IT IS THOUGHT THAT ONE STRATEGY TO SIMPLIFY MOTOR COMPUTATIONS IS TO ADOPT A CIRCUIT ORGANIZATION THAT LINKS COMBINATIONS OF MOTOR POOLS INTO FUNCTIONAL UNITS CALLED “SYNERGIES” OR “PRIMITIVES”. THUS, THE CIRCUIT ELEMENTS THAT UNDERLIE MOTOR SYNERGIES ARE THOUGHT TO REPRESENT THE BASIC BUILDING BLOCKS FOR ORCHESTRATING THE NEURAL CONTROL OF ROUTINE MOTOR BEHAVIORS. ELEGANT STIMULATION AND RECORDING EXPERIMENTS FROM LABS WORKING WITH AMPHIBIANS, RODENTS, AND PRIMATES HAVE FOUND EVIDENCE FOR MOTOR SYNERGY CIRCUITS WITHIN THE SPINAL CORD. THE MAJOR QUESTIONS ADDRESSED IN THIS GRANT ARE: (A) WHAT IS THE UNDERLYING CELLULAR AND CONNECTIVITY ORGANIZATION OF LUMBAR SPINAL MOTOR SYNERGY CIRCUITS, (B) WHAT NEURONAL SUBTYPES COMPRISE THESE CIRCUITS, AND (C) WHAT INTRINSIC AND EXTRINSIC FACTORS SHAPE THE FORMATION OF THESE CIRCUITS? THE LABORATORY HAS USED TRANS-SYNAPTIC NEURONAL TRACING, OPTOGENETICS, AND MOLECULAR SCREENS TO IDENTIFY A HETEROGENOUS (SATB1+, SATB2+, TCFAP2B+, TCF4+) POPULATION OF INTERCONNECTED EXCITATORY AND INHIBITORY PRE- MOTOR INTERNEURONS WITHIN LAMINA V OF THE LUMBAR SPINAL CORD. BASED ON THEIR PROPERTIES THESE LAMINA V CELLS ARE GENERICALLY REFERRED TO AS MOTOR SYNERGY ENCODERS (MSE). THE HYPOTHESIZE IS THAT THE MSE CELL NETWORK COMPRISES A MAJOR COMPUTATIONAL NODE FOR MOTOR CONTROL WITHIN THE SPINAL CORD. THESE CELLS RECEIVE INPUTS FROM THE CORTEX AND SENSORY NEURONS SUCH AS THOSE THAT RELAY PROPRIOCEPTIVE INFORMATION. THUS, MSE NEURONS ARE WELL POSITIONED TO MEDIATE COORDINATED MUSCLE ACTIVATION PATTERNS ARISING FROM COMMAND CENTERS FOR VOLITIONAL MOVEMENT AS WELL AS REFLEX PATHWAYS ACTIVATED BY SENSORY FEEDBACK LOCALLY WITHIN THE SPINAL CORD. THE AIMS OF THIS GRANT ARE DESIGNED TO UNRAVEL THE WIRING AND CELLULAR CONSTITUENTS WITHIN MOTOR SYNERGY CIRCUITS, AND TO EXAMINE HOW THESE CIRCUITS FORM DURING EMBRYONIC DEVELOPMENT AND EARLY POSTNATAL LIFE. AIM 1 WILL CREATE A CELLULAR ATLAS AND CONNECTIVITY MAP OF MSE NEURONS. THIS WILL DEFINE WHETHER THE MOLECULAR HETEROGENEITY OF MSE NEURONS CORRESPONDS TO SEPARATE MOTOR POOL CIRCUIT-MODULES OR PHYSIOLOGICALLY-DIFFERENT CLASSES OF NEURONS USED FOR CONTROLLING ALL MOTOR POOLS. AIM 2 WILL DEFINE THE PATTERN OF PROPRIOSPINAL FEEDBACK FROM MUSCLES ONTO MSE NEURONS. HERE THE GOAL IS TO ESTABLISH WHETHER THE MSE CIRCUIT IS BASED ON SIMPLE LABELED LINE PATHWAYS OR HAS A MORE COMPLEX INPUT-OUTPUT RELATIONSHIP. AIM 3 WILL USE TRANSCRIPTION FACTOR KNOCKOUTS TO DETERMINE WHETHER HARDWIRED INTRINSIC GENETIC PROGRAMS ESTABLISH THE MSE CIRCUITRY. AIM 4 WILL TEST WHETHER THE FUNCTIONAL MSE NETWORK ARISES FROM ACTIVITY DEPENDENT FEEDBACK FROM PROPRIOCEPTIVE SENSORY NEURONS. TAKEN TOGETHER, THESE AIMS WILL PROVIDE A DETAILED MOLECULAR-CELLULAR UNDERSTANDING OF A CRITICAL NODE WITHIN THE LOCAL SPINAL SYSTEM FOR COMPUTING AND COORDINATING MOTOR ACTIVATION PATTERNS. THESE FINDINGS MAY HELP TARGET MOTOR CIRCUITS USING GENETICS AND/OR NEURAL ACTIVITY TO FACILITATE RECOVERY FROM SPINAL CORD INJURY.