Princeton University

U.S. CMS OPERATIONS AT THE LHC

U.S. CMS OPERATIONS AT THE LHC

COOPERATIVE INSTITUTE FOR MODELING THE EARTH SYSTEM (CIMES)

FRAGILE FAMILIES AND CHILD WELLBEING IN MIDDLE CHILDHOOD

ENGINEERING RESEARCH CENTER (ERC) ON MID-INFRARED TECHNOLOGIES FOR HEALTH AND THE ENVIRONMENT (MIRTHE)

RENEW THE COOPERATIVE INSTITUTE FOR MODELING THE EARTH SYSTEM (CIMES) TO CONDUCT RESEARCH IN SUPPORT OF NOAA'S MISSION AND STRATEGIC GOALS IN AREAS RELATED TO EARTH SYSTEM SCIENCE FOR BETTER UNDERSTANDING AND PREDICTION ACROSS TIME SCALES FROM DAYS TO DECADES, AND FROM LOCAL TO GLOBAL SCALES, AND INTEGRATING PHYSICAL, CHEMICAL, AND BIOLOGICAL COMPONENTS. CIMES RESEARCH WILL ADDRESS THE FOLLOWING THREE THEMES: 1. EARTH SYSTEM MODELING: DEVELOPING AND IMPROVING EARTH SYSTEM MODELS (ESMS), NUMERICAL MODELS WHICH SIMULATE THE CLIMATE AND EARTH SYSTEM, AND ALLOW PREDICTION OF THE FUTURE EVOLUTION OF THIS SYSTEM. THESE MODELS INCLUDE THE DYNAMICAL, PHYSICAL, CHEMICAL AND BIOLOGICAL COMPONENTS OF THE ATMOSPHERE-OCEAN-LAND SYSTEM AND THE COUPLING BETWEEN THEM. 2. SEAMLESS PREDICTION ACROSS TIME AND SPACE SCALES: APPLYING THE ESMS TO PREDICTIONS ON TIME-SCALES FROM DAYS TO CENTURIES AND OVER SPATIAL SCALES FROM THOSE OF EXTREME EVENTS TO GLOBAL SCALES, MAKING USE OF THE SAME FLEXIBLE CODE-BAS

NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION (NOAA) COOPERATIVE INSTITUTES 2013 - CICS-PRINCETON RENEWAL

ENERGY FRONTIER RESEARCH CENTER FOR COMBUSTION SCIENCE -- EFRC

S2I2: INSTITUTE FOR RESEARCH AND INNOVATION IN SOFTWARE FOR HIGH ENERGY PHYSICS (IRIS-HEP)

HIGH ENERGY PHYSICS

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

INSTITUTE FOR RESEARCH AND INNOVATION IN SOFTWARE FOR HIGH ENERGY PHYSICS (IRIS-HEP) -THE QUEST TO UNDERSTAND THE FUNDAMENTAL BUILDING BLOCKS OF MATTER IN THE UNIVERSE AND THEIR INTERACTIONS IS ONE OF THE OLDEST AND MOST AMBITIOUS OF HUMAN SCIENTIFIC ENDEAVORS. IN ELEMENTARY PARTICLES PHYSICS, THE MOST SUCCESSFUL THEORY TO DATE IS KNOWN AS THE STANDARD MODEL OF PARTICLE PHYSICS. EXPERIMENTAL FACILITIES SUCH AS CERN'S LARGE HADRON COLLIDER (LHC) REPRESENT A HUGE STEP FORWARD IN THIS QUEST AS EVIDENCED BY THE DISCOVERY OF THE HIGGS BOSON. THE NEXT PHASE OF THIS GLOBAL SCIENTIFIC PROJECT WILL BE THE HIGH-LUMINOSITY LHC (HL-LHC), WHICH WILL COLLECT DATA STARTING CIRCA 2029 AND CONTINUE INTO THE 2030'S. THE PRIMARY SCIENCE GOAL AT THE HL-LHC IS TO SEARCH FOR PHYSICS BEYOND THE STANDARD MODEL. WHILE THE STANDARD MODEL HAS BEEN SUCCESSFUL IN EXPLAINING EXPERIMENTAL EVIDENCE TO DATE, SCIENTISTS KNOW THAT IT IS NOT BE COMPLETE, BECAUSE IT DOES NOT ACCOUNT FOR DARK MATTER OR NEUTRINO MASSES, FOR EXAMPLE. IN THE HL-LHC ERA, THE ATLAS AND CMS EXPERIMENTS WILL RECORD 10 TIMES AS MUCH DATA FROM 100 TIMES AS MANY COLLISIONS AS WERE USED TO DISCOVER THE HIGGS BOSON. AS SUCH, SIGNIFICANT R&D ADVANCES MUST BE ACHIEVED IN THE SOFTWARE FOR ACQUIRING, MANAGING, PROCESSING AND ANALYZING HL-LHC DATA TO REALIZE THE SCIENTIFIC POTENTIAL OF THE UPGRADED ACCELERATOR AND DETECTORS AND THE PLANNED LHC SCIENCE PROGRAM. IN THIS CONTEXT, THE INSTITUTE FOR RESEARCH AND INNOVATION IN SOFTWARE FOR HIGH ENERGY PHYSICS (IRIS-HEP) WILL PLAY A LEADING ROLE TO DELIVER THE SOFTWARE AND COMPUTING SYSTEMS REQUIRED TO MEET THE CHALLENGES POSED BY THE LHC IN THE HIGH LUMINOSITY ERA. THIS PROJECT ADDRESSES KEY ELEMENTS OF THE INTERNATIONAL ROADMAP FOR HEP SOFTWARE AND COMPUTING R&D FOR THE 2020S AND IMPLEMENTS THE UPDATED IRIS-HEP STRATEGIC PLAN FOR THE NEXT PHASE OF SOFTWARE UPGRADES FOR HL-LHC PHYSICS PUBLISHED IN DECEMBER 2022. IRIS-HEP WILL ADVANCE R&D IN THREE HIGH-IMPACT AREAS: (1) DEVELOPMENT OF INNOVATIVE ALGORITHMS FOR DATA RECONSTRUCTION AND TRIGGERING; (2) DEVELOPMENT OF HIGHLY PERFORMANT ANALYSIS SYSTEMS THAT REDUCE `TIME-TO-INSIGHT' AND MAXIMIZE THE HL-LHC SCIENTIFIC POTENTIAL; AND (3) DEVELOPMENT OF DATA ORGANIZATION, MANAGEMENT AND ACCESS (DOMA) SYSTEMS FOR THE COMMUNITY'S UPCOMING EXABYTE ERA. IRIS-HEP WILL SUSTAIN INVESTMENTS IN TODAY'S DISTRIBUTED HIGH-THROUGHPUT COMPUTING (DHTC) AND BUILD AN INTEGRATION PATH TO DELIVER ITS FACILITIES R&D ACTIVITIES INTO THE DISTRIBUTED PRODUCTION INFRASTRUCTURE. AS AN INTELLECTUAL HUB, IRIS-HEP WILL LEAD EFFORTS TO (1) BUILD CONVERGENCE RESEARCH BETWEEN HEP AND THE CYBERINFRASTRUCTURE, DATA SCIENCE AND COMPUTER SCIENCE COMMUNITIES FOR NOVEL APPROACHES TO ADDRESS THE COMPELLING SOFTWARE AND COMPUTING CHALLENGES OF HL-LHC ERA HEP EXPERIMENTS, (2) ENGAGE BROADLY WITH RESEARCHERS AND STUDENTS FROM U.S. UNIVERSITIES AND LABS EMPHASIZING PROFESSIONAL DEVELOPMENT AND TRAINING, AND (3) SUSTAIN HEP SOFTWARE AND UNDERLYING KNOWLEDGE RELATED TO THE ALGORITHMS AND THEIR IMPLEMENTATIONS OVER THE TWO DECADES REQUIRED. IN ADDITION TO ENABLING THE BEST POSSIBLE HL-LHC SCIENCE, IRIS-HEP WILL BRING TOGETHER THE LARGER CYBERINFRASTRUCTURE AND HEP COMMUNITIES TO ADDRESS THE COMPLEX ISSUES AT THE INTERSECTION OF EXASCALE HIGH-THROUGHPUT COMPUTING AND EXABYTE-SCALE DATASETS IN WAYS BROADLY RELEVANT TO MANY RESEARCH DOMAINS WITH EMERGING DATA-INTENSIVE NEEDS. THE EDUCATION AND TRAINING PROVIDED BY THE INSTITUTE IN THE FORM OF SUMMER SCHOOLS AND A FELLOWS PROGRAM WILL CONTRIBUTE TO A HIGHLY QUALIFIED STEM WORKFORCE. 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.

A SILICON-DRIFT-CHAMBER, A PARALLEL COMPUTER FORM, & READOUT DEVELOPMENT FOR AN ELECTROMAGNETIC CALORIMETER FOR THE SSC.

SOUTHERN OCEAN CARBON AND CLIMATE OBSERVATIONS AND MODELING (SOCCOM)

PRINCETON CENTER FOR COMPLEX MATERIALS

PRINCETON CENTER FOR COMPLEX MATERIALS

UNIV RESEARCH ENGINEERING AND TECHNOLOGY INSTITUTE (URETI) BIOINSPIRED MULTIFUNCTIONAL NANOCOMPOSITE

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

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.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

CENTER FOR QUANTITATIVE BIOLOGY

MECHANISMS OF NEURAL CIRCUIT DYNAMICS IN WORKING MEMORY ANDDECISION-MAKING

BIOINSPIRED LIGHT-ESCALATED CHEMISTRY (BIOLEC)

PRINCETON CENTER FOR COMPLEX MATERIALS

PREDOCTORAL TRAINING IN GENETICS AND MOLECULAR BIOLOGY

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

PFC: CENTER FOR THE PHYSICS OF BIOLOGICAL FUNCTION

NSF I-CORPS HUB: NORTHEAST REGION

THE FRAGILE FAMILIES CARDIOVASCULAR HEALTH FOLLOW UP STUDY

EXPLOSIVE EVOLUTION UNDER STRESS: THE DRIVING FORCES OF CANCER DYNAMICS (MAIN)

SOUTHERN OCEAN CARBON AND CLIMATE OBSERVATIONS AND MODELING (SOCCOM2)

COOPERATIVE INSTITUTE FOR CLIMATE SCIENCE - LINKING LAND MODELS WITH TOP DOWN ESTIMATES OF THE CARBON BUDGET

MECHANISMS OF NEURAL CIRCUIT DYNAMICS IN WORKING MEMORY AND DECISION-MAKING - PROJECT SUMMARY/ABSTRACT: OVERALL THE OVERARCHING GOAL OF THIS U19 PROGRAM IS TO DETERMINE HOW NEURAL COMPUTATIONS ACROSS BRAIN REGIONS PRODUCE TWO CORE COGNITIVE PROCESSES, WORKING MEMORY AND DECISION-MAKING, AND THUS TO DERIVE FUNDAMENTAL PRINCIPLES OF BRAIN FUNCTION. THIS RENEWAL APPLICATION PROPOSES TO PURSUE POWERFUL NEW THEMES THAT EMERGED FROM OUR PREVIOUS WORK AND TO BROADEN OUR SCOPE SUBSTANTIALLY. TO DO SO, THE EIGHT PIS PLAN A TIGHTLY INTEGRATED SET OF EXPERIMENTAL AND COMPUTATIONAL STUDIES OF MICE DOING THE ACCUMULATING TOWERS TASK—IN WHICH THEY MUST REMEMBER HOW MANY TOWERS FLASH ON EACH SIDE AS THEY RUN DOWN A MAZE IN VIRTUAL REALITY—AND RELATED TASKS. THE FIRST THEME ARISES FROM THE FINDING THAT NEURONS ACROSS THE BRAIN ENCODE TASK VARIABLES AND ARE NECESSARY FOR TASK PERFORMANCE. ALMOST ALL OF THESE AREAS EXHIBIT SEQUENTIAL ACTIVITY, IN WHICH NEURONS ARE ACTIVE AT DIFFERENT TIMES IN THE TASK AND, TOGETHER, TILE THE TRIAL DURATION. PROJECT 1 WILL IDENTIFY THE TASK FEATURES THAT DRIVE SEQUENTIAL ACTIVITY, USE COOLING TO IDENTIFY NEURAL CIRCUITS THAT GENERATE SEQUENTIAL ACTIVITY, AND ELUCIDATE ITS ANATOMICAL BASIS BY COMBINING TRANSMISSION ELECTRON MICROSCOPY AND COMPUTATIONAL MODELING. A SECOND THEME IS THAT MANIFOLD INFERENCE METHODS, APPLIED TO LARGE-SCALE HIPPOCAMPAL RECORDINGS IN OUR TASK, REVEAL THE GEOMETRY OF A JOINT NEURAL REPRESENTATION FOR AN EXTERNAL VARIABLE (POSITION) AND AN INTERNAL, COGNITIVE VARIABLE (ACCUMULATED EVIDENCE). PROJECT 2 WILL EXTEND OUR WORK ON THE GEOMETRY OF NEURAL REPRESENTATIONS TO OTHER BRAIN REGIONS. WE WILL EXAMINE HOW GEOMETRIES AND REPRESENTATIONS IN THESE REGIONS INTERACT WITH EACH OTHER, AND WE WILL DEVELOP MODELS TO EXPLAIN HOW THE OBSERVED NEURAL MANIFOLDS ARISE. A THIRD THEME, FUELED BY OUR DEVELOPMENT OF STATISTICAL METHODS TO INFER INTERNAL BRAIN STATES, IS THAT ANIMALS’ BRAINS OCCUPY QUALITATIVELY DIFFERENT STATES FROM TRIAL TO TRIAL DURING THE SAME TASK BLOCK. OUR DATA SUGGESTS THAT BEHAVIOR IN EACH STATE REQUIRES DIFFERENT NEURAL STRUCTURES AND CIRCUITS—IN THE SAME ANIMAL AND THE SAME TRIAL BLOCK. PROJECT 3 WILL USE MULTI-REGION RECORDINGS AND PERTURBATIONS TO INVESTIGATE WHETHER STATES ARE LOCAL TO SUBCIRCUITS VERSUS GLOBAL ACROSS THE BRAIN, EXTEND OUR BEHAVIORAL INFERENCE METHODS TO NEURAL DATA, AND EXAMINE TO WHAT EXTENT OUR INFERRED STATES ARE LINKED TO INTERNAL STATES OF AROUSAL, THIRST, AND HUNGER. ELUCIDATING HOW MULTIPLE CIRCUITS PERFORMING LOCAL COMPUTATIONS COMBINE INTO A BRAIN IN ACTION IS THE GOAL OF PROJECTS 4 AND 5. PROJECT 4 WILL PROBE FUNCTIONAL INTERACTIONS IN MULTI-REGION RECORDINGS, INCLUDING VERY LARGE-SCALE SIMULTANEOUS ELECTROPHYSIOLOGICAL RECORDINGS WITH NEXT-GENERATION SILICON PROBES; AND THROUGH TARGETED EXPERIMENTS WILL TEST TWO HYPOTHESES OF HOW SUBCORTICAL REGIONS INTERACT WITH NEOCORTEX. PROJECT 5 WILL GENERATE A SET OF MECHANISTIC MODELS THAT INSTANTIATE SPECIFIC HYPOTHESIZED ROLES OF DIFFERENT BRAIN REGIONS. THESE LOCAL MODELS WILL BE COMBINED INTO A SINGLE MULTI-REGIONAL MODEL, INFORMED BY DATA FROM ALL PROJECTS, THAT WILL ENABLE US TO DISSECT THE ROLES OF INDIVIDUAL REGIONS AND THEIR INTERACTIONS IN PERFORMANCE OF THE MANY VARIANTS OF OUR DECISION-MAKING TASK.

COGNITIVE THALAMUS - PROJECT SUMMARY THE PULVINAR (PUL) AND MEDIODORSAL (MD) NUCLEI ARE HIGHER ORDER THALAMIC STRUCTURES THAT ARE KNOWN TO PLAY CRITICAL ROLES IN VARIOUS COGNITIVE DOMAINS. HOWEVER, THE PRECISE MECHANISMS ARE UNKNOWN, WITH THEORIES SUGGESTING THEIR ROLE IN EITHER GATING OR FACILITATING FUNCTIONAL CONNECTIVITY ACROSS THEIR CORTICAL TARGETS. IMOPRTANTLY, RECENT EVIDENCE FROM SCHIZOPHRENIA PATIENTS SUGGESTS THAT THESE HIGHER ORDER THALAMIC-CORTICAL INTERACTIONS ARE PERTURBED AND MAY EVEN BE CAUSATIVE TO DISEASE ETIOLOGY. IN THIS CENTER, WE HAVE ASSEMBLED A GROUP OF INVESTIGATORS WHO WILL UTILIZE BEHAVIOR, ELECTROPHYSIOLOGY, IMAGING IN HUMAN AND NON-HUMAN ANIMALS TO 1. IDENTIFY COGNITIVE FUNCTIONAL ORGANIZATION PRINCIPLES OF HIGHER-ORDER THALAMIC NUCLEI IN INTERACTING WITH CORTEX; 2. TRANSLATE THALAMIC FUNCTIONALITY FROM ANIMAL MODELS TO THE HEALTHY AND DISEASED HUMAN BRAIN; AND 3. DEVELOP A BIOLOGICALLY PLAUSIBLE MODEL FOR THE HUMAN HIGHER-ORDER THALAMUS. THE CENTER WILL BE DIVIDED INTO 5 SCIENTIFIC PROJECTS AND 3 CORES. PROJECT 1 (PI USREY) WILL COMBINE ELECTROPHYSIOLOGY AND OPTICAL PERTURBATIONS TO STUDY INTERACTIONS BETWEEN PUL AND EARLY VISUAL CORTICAL AREAS DURING ATTENTIONAL PROCESSING. PROJECT 2 (PI KASTNER) WILL TAKE A LARGE-SCALE NETWORK APPROACH IN THE MACAQUE TO STUDY INTERACTIONS BETWEEN THE PRIMATE-SPECIFIC MDPUL SUBDIVISION AND FRONTO-PARIETAL NETWORKS IN ATTENTION, AND ALSO STUDY INTERACTIONS BETWEEN THE MD AND FRONTAL CORTICAL AREAS IN HIERARCHICAL REASONING AND TASK SWITCHING. PROJECT 3 (PI HALASSA) WILL COMBINE OPTICAL PERTURBATIONS, ELECTROPHYSIOLOGY AND DISEASE MODELING IN TUPAIA TO STUDY INTERACTIONS BETWEEN PUL REGULATION OF DORSAL VS. VENTRAL STREAM SELECTION IN ATTENTION, AND MD REGULATION OF FRONTAL CORTICAL INTERACTIONS IN HIERARCHICAL REASONING. PROJECT 4 (PI COLLINS/ARCARO) WILL COMBINE FUNCTIONAL NEUROIMAGING AND BEHAVIOR IN HUMANS TO INTERROGATE PUL AND MD ENGAGEMENT WITH THEIR CORTICAL PARTNERS IN ATTENTION AND HIERARCHICAL REASONING, RESPECTIVELY. THIS WILL BEGIN AN EXCITING ENDEAVOR OF DETERMINING WHAT TYPES OF HIGHER ORDER THALAMIC CONTRIBUTIONS TO COGNITION HAVE EXPANDED IN THE HUMAN BRAIN. PROJECT 5 (PI WOODWARD) WILL EXAMINE BEHAVIOR-BRAIN RELATIONSHIPS (ATTENTION-PUL AND DECISION MAKING-MD) IN SCHIZOPHRENIA PATIENTS, WHERE THE STRUCTURAL INTEGRITY OF HIGHER ORDER THALAMIC CONNECTIVITY TO CORTICAL PARTNERS IS KNOWN TO BE IMPAIRED. CORE A (PIS KASTNER, HALASSA AND USREY) WILL ADMINISTRATIVELY MANAGE THIS CENTER AND INVOLVE IMPORTANT OUTREACH AND TRAINING ACTIVITIES. CORE B (PI CHEN) WILL PROVIDE ANALYTICAL SUPPORT FOR ALL PROJECTS AND STREAMLINE DATA COLLECTION, CURATION AND SHARING ACROSS PIS WITH COMMON FORMAT, AS WELL AS ALLOW FOR DATA SHARING WITH THE BROADER COMMUNITY. CORE C (PI KOPELL) WILL GENERATE COMPUTATIONAL MODELS THAT WILL BE ITERATIVELY REFINED BY THE COLLECTED DATA AND PROVIDE TESTABLE PREDICTION ON AN ONGOING BASIS. ALTOGETHER, SUCCESSFUL LAUNCHING OF THIS CENTER PROMISES TO PROVIDE NEW FRAMEWORKS FOR THE NEURAL CIRCUITRY UNDERLYING COGNITIVE PROCESSING AND HOW THE THALAMUS MAY BE A TARGET FOR ENHANCING COGNITION IN SCHIZOPHRENIA.

GRADUATE RESEARCH FELLOWSHIP PROGRAM

ADVANCED ACTPOL

SSQIP - SCALABLE SILICON-BASED QUANTUM INFORMATION PROCESSING

DARKSIDE -ASTRONOMICAL OBSERVATIONS HAVE PROVIDED STRONG EVIDENCE THAT THE KNOWN MATTER ACCOUNTS FOR ONLY A SMALL FRACTION OF THE OBSERVED TOTAL MASS-ENERGY OF THE UNIVERSE. A LEADING DARK MATTER CANDIDATE IS THE SO-CALLED WEAKLY INTERACTING MASSIVE PARTICLE, OR WIMP, A PREDICTED RELIC PARTICLE OF THE BIG BANG. DIRECT (NON-GRAVITATIONAL) DETECTION OF DARK MATTER WOULD BE A TRANSFORMATIONAL DISCOVERY OF FUNDAMENTAL IMPORTANCE BROADLY TO THE SCIENCES, OPENING NEW INVESTIGATIONS OF THE DARK UNIVERSE. SUCH FIRST MEASUREMENTS OF DARK MATTER MAY BE POSSIBLE VIA WIMP-NUCLEUS COLLISIONS DETECTABLE AT LOW-BACKGROUND, LOW-ENERGY THRESHOLD DETECTORS CAPABLE OF DISTINGUISHING A SMALL NUMBER OF NUCLEAR RECOILS FROM WIMP COLLISIONS OVER A LONG EXPOSURE PERIOD. LIQUID ARGON HAS BEEN IDENTIFIED TO HAVE UNIQUE LIGHT EMISSION PROPERTIES THAT PROVIDE EXCELLENT SENSITIVITY FOR SUCH WIMP COLLISIONS WHILE PROVIDING STRONG BACKGROUND SUPPRESSION. THIS AWARD PROVIDES SUPPORT FOR THE FABRICATION OF A NEXT-GENERATION WIMP DARK MATTER EXPERIMENT, DARKSIDE-20K. THE DARKSIDE INTERNATIONAL COLLABORATION HAS PIONEERED THE USE OF LIQUID ARGON WITH HIGH RADIOPURITY TO SEARCH FOR RARE WIMP INTERACTIONS. THE DARKSIDE-20K DETECTOR, WITH A DESIGNED FIDUCIAL EXPOSURE VOLUME OF APPROXIMATELY 20KT OF LOW-BACKGROUND LIQUID ARGON, WILL OPERATE IN THE INFN LABORATORI NAZIONALI DEL GRAN SASSO DEEP UNDERGROUND LAB. THE US NSF DARKSIDE TEAM IS SUPPORTED VIA THIS AWARD TO BUILD THE CENTRAL DARK MATTER DETECTOR LIQUID ARGON TIME-PROJECTION CHAMBER, INCLUDING THE ASSOCIATED HIGH-VOLTAGE DELIVERY, CRYOGENIC, PURIFICATION AND CALIBRATION SYSTEMS. THE AWARDED ACTIVITIES INVOLVE TRANSFERABLE TECHNOLOGIES THAT INCLUDE: THE PRODUCTION OF LOW-RADIOACTIVITY UNDERGROUND ARGON FOR THE EXPERIMENT AS WELL AS FOR NUCLEAR TEST BAN VERIFICATION AND RADIOMETRIC DATING; STUDIES OF UNDERGROUND GAS SOURCES; DEVELOPMENT OF LOW-BACKGROUND, LARGE-AREA, SINGLE-PHOTON CRYOGENIC SILICON PHOTOMULTIPLIER PHOTOSENSORS; LIQUID ARGON-BASED TIME-OF-FLIGHT POSITRON EMISSION TOMOGRAPHY SYSTEM FOR ENHANCED CANCER SCREENING, AND; THE WORLD?S TALLEST CRYOGENIC DISTILLATION TOWER TO IMPROVE AVAILABILITY OF STABLE RARE ISOTOPES FOR MEDICAL AND ENERGY APPLICATIONS. ALSO INCLUDED ARE TRAINING AND EDUCATION OPPORTUNITIES, INCLUDING A SUMMER SCHOOL EXPERIENCE IN THE CORTEZ-DURANGO REGION THAT WILL OFFER INCREASED ACCESS TO UNDERREPRESENTED GROUPS IN STEM. THE US DARKSIDE PROGRAM LED THE DARKSIDE-50 EXPERIMENTAL PROGRAM THAT DEMONSTRATED THE VIABILITY OF BACKGROUND-FREE SEARCHES IN LIQUID ARGON. THE DARKSIDE-20K EXPERIMENT WILL EXTEND THE SENSITIVITY OF WIMP DARK MATTER SEARCHES IN THE CROSS-SECTION VS. MASS RANGE TO 4.6E-48 CM-SQUARED FOR THE 90% CONFIDENCE LIMIT EXCLUSION, AND TO 1.5E-47 CM-SQUARED 5 SIGMA DISCOVERY SIGNIFICANCE FOR A 1 TEV/C-SQUARED WIMP MASS AFTER A 500T-YR EXPOSURE. UNIQUE US EXPERTISE IN THE CONSTRUCTION OF NOBLE LIQUID DETECTORS IS LEVERAGED TO ENSURE THE SUCCESS OF THIS NEXT GENERATION DETECTOR. THE SCALE OF PROJECT, AND ITS RESULTANT SENSITIVITY, EXCEEDS THAT OF DETECTORS CURRENTLY OPERATING, LEADING TO DISCOVERY, CONFIRMATION, OR EXCLUSION OF THE WIMP DARK MATTER HYPOTHESIS TO THE LEVEL WHERE COHERENT SCATTERS FROM ATMOSPHERIC NEUTRINOS BECOME AN IRREDUCIBLE BACKGROUND. 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.

COMPUTATIONAL CHEMICAL SCIENCE CENTER: CHEMISTRY IN SOLUTION AND AT INTERFACES

"TERRORISM GOVERNANCE AND DEVELOPMENT"

ACTPOL: THE ATACAMA COSMOLOGY TELESCOPE WITH POLARIZATION

SMALL RNAS AS NOVEL MODULATORS OF MICROBE-HOST INTERACTIONS - THE RISE IN ANTIBIOTIC RESISTANCE HAS SEVERELY DEPLETED OUR ARSENAL FOR COMBATTING DEADLY BACTERIAL PATHOGENS. MEANWHILE, DESPITE INCREASED APPRECIATION OF THE MYRIAD WAYS THAT MICROBIOME BACTERIA IMPACT HUMAN HEALTH, MOST OF THE SIGNALS THAT BACTERIA USE TO INFLUENCE HOSTS REMAIN UNKNOWN. THIS PROPOSAL SEEKS TO ADDRESS BOTH OF THESE CHALLENGES BY LEVERAGING OUR TEAM’S UNIQUE EXPERTISE AND RECENT DISCOVERY THAT ANIMALS CAN DIRECTLY SENSE AND RESPOND TO BACTERIAL SMALL RNAS (SRNAS). SINCE THE DISCOVERY OF ANTIBIOTICS IN THE 1920S, THE PATHOGENESIS FIELD HAS PRIMARILY FOCUSED ON SMALL MOLECULES: NEARLY ALL KNOWN ANTIBIOTICS AND BACTERIAL SIGNALING MOLECULES ARE SMALL MOLECULES. BUT WE SORELY NEED NEW, ORTHOGONAL APPROACHES. NUCLEIC ACID-BASED THERAPIES HAVE EMERGED AS AN EXCITING NEW PLATFORM FOR RAPID DRUG DEVELOPMENT. DUE TO THEIR CHEMICAL SIMILARITY, THE PHARMACOLOGY OF NUCLEIC ACIDS IS ESTABLISHED, SUCH THAT ONCE WE KNOW WHAT SEQUENCE TO TARGET, THE DRUG DEVELOPMENT PIPELINE IS RELATIVELY STREAMLINED (AT LEAST IN COMPARISON TO SMALL MOLECULE DRUGS). FOR EXAMPLE, A BATTEN DISEASE PATIENT WAS RECENTLY SUCCESSFULLY TREATED WITH A PERSONALIZED SYNTHETIC ANTISENSE RNA, LESS THAN A YEAR AFTER HER GENOME WAS SEQUENCED. RNA-BASED INTERVENTIONS HAVE TYPICALLY NOT BEEN CONSIDERED FOR BACTERIA BECAUSE BACTERIAL RNAS WERE THOUGHT TO FUNCTION EXCLUSIVELY WITHIN THE BACTERIA. HOWEVER, WE RECENTLY OVERTURNED THIS PARADIGM BY PROVING THAT MODEL ANIMAL HOSTS CAN DIRECTLY “READ” THE SRNAS PRODUCED BY THE HUMAN PATHOGEN, PSEUDOMONAS AERUGINOSA, USING THE RNA-INTERFERENCE (RNAI) MACHINERY TO RESPOND TO THE BACTERIAL SRNAS. THIS RESULT IS PARTICULARLY EXCITING BECAUSE IT SUGGESTS A PREVIOUSLY UNAPPRECIATED ROLE FOR THE RNAI MACHINERY IN SENSING AND RESPONDING TO BACTERIA. IT ALSO SUGGESTS THAT UNDERSTANDING SRNA-BASED MICROBE-HOST SIGNALING COULD HELP DEVELOP NEW THERAPIES TO HELP HOSTS WARD OFF PATHOGENS OR PROMOTE COMMENSAL COLONIZATION. HOWEVER, ADVANCING SUCH NEW ANTIMICROBIAL STRATEGIES IS CURRENTLY HINDERED BY OUR LACK OF KNOWLEDGE REGARDING THE SPACE OF SRNA-MEDIATED BACTERIA-HOST INTERACTIONS AND THE MOLECULAR MECHANISMS BY WHICH THEY FUNCTION. HERE, WE PROPOSE TO BUILD OFF OUR DISCOVERY OF SRNA-HOST SIGNALING TO SIGNIFICANTLY CLOSE THIS KNOWLEDGE GAP. THIS WILL BE ACCOMPLISHED IN THREE COMPLEMENTARY PARTS THAT SPAN MULTIPLE HOSTS AND MICROBES: GLOBALLY MAPPING HUMAN GUT MICROBIOME COMMUNITY SRNA-HOST INTERACTIONS AND FUNCTIONS, DETERMINING HOW MAMMALIAN CELLS RESPOND TO PATHOGEN SRNAS, AND USING C. ELEGANS TO CHARACTERIZE THE MOLECULAR MECHANISMS OF SRNA-HOST INTERACTIONS. TO ACHIEVE THESE GOALS WE WILL COMBINE THE EXPERTISE OF OUR TEAM, COMPRISED OF LEADERS IN THE FIELDS OF HUMAN MICROBIOME AND COMPUTATIONAL BIOLOGY (DONIA), MICROBIAL PATHOGENESIS AND ANTIBIOTIC DEVELOPMENT (GITAI), AND C. ELEGANS BEHAVIOR AND GENOMICS (MURPHY). OUR COMBINED EFFORTS THUS HAVE THE POTENTIAL TO ESTABLISH NEW PARADIGMS FOR MICROBE-HOST INTERACTIONS AND PAVE THE WAY TO DESPERATELY-NEEDED NEW THERAPIES.

ORGANOTROPIC METASTATIC SECRETOMES AND EXOSOMES IN BREAST CANCER

BIOGENESIS AND MAINTENANCE OF THE OUTER MEMBRANE OF GRAM-NEGATIVE BACTERIA

QUANTITATIVE AND COMPUTATIONAL BIOLOGY GRADUATE PROGRAM

ENGINEERING EXOTIC STATES OF LIGHT WITH SUPERCONDUCTING CIRCUITS

SYNCHOTRON X-RAY BASED ELECTRONIC STRUCTURE STUDY OF CORRELATED QUANTUM MATERIALS

IBEX - INTERSTELLAR BOUNDARY EXPLORER

(MURI-20) UNCOVERING AND APPLYING THE INTERFACIAL DESIGN PRINCIPLES OF MULTIPHASIC NATURAL AND SYNTHETIC ORGANELLES

NRSA TRAINING GRANT IN QUANTITATIVE NEUROSCIENCE

RECIPROCAL GENETIC-ENVIRONMENTAL INTERACTIONS DURING CHILDHOOD AND ADOLESCENCE

WHILE THERE ARE VIABLE ALTERNATIVE THEORIES OF COSMOGENESIS, INCLUDING STRING COSMOLOGIES AND CYCLIC UNIVERSE MODELS, INFLATION IS NOW WIDELY ACCEP

VISUALIZATION OF GENE ACTIVITY IN THE DROSOPHILA EMBRYO

HIGH ENERGY PHYSICS RESEARCH

TAS:: 57 3600::TAS (MURI-09) "INFORMATION DYNAMICS AS FOUNDATION FOR NETWORK MANAGEMENT"

FLUORESCENT PROBES FOR STUDYING COPPER OXIDATION BIOLOGY

NEW: TMS: DESIGN PRINCIPLES FOR QUANTUM HALL STATES; PI-RAVINDRA BHATT

PHOTOREDOX CATALYSIS APPLICATIONS IN ORGANOMETALLICS AND CHEMICAL BIOLOGY

MICROSTATES TO MACRODYNAMICS:A NEW MATHEMATICS OF BIOLOGY.

COLLABORATIVE RESEARCH: UNDERSTANDING, COPING WITH, AND BENEFITING FROM INTRACTIBILITY.

SPEAKER-LISTENER COUPLING: A NOVEL NEURAL APPROACH FOR ASSESSING COMMUNICATION

CRACKING THE CODE OF TRANSGENERATIONAL INHERITANCE OF BEHAVIOR - PROJECT SUMMARY TRANSGENERATIONAL EPIGENETIC INHERITANCE (TEI) HAS BEEN OBSERVED IN WORMS, FLIES, AND MICE, AND PROPOSED IN HUMANS (E.G., DUTCH HUNGER WINTER), BUT THE UNDERLYING AND REGULATORY MOLECULAR MECHANISMS ARE LARGELY UNKNOWN. SIMILARLY, WE DO NOT YET UNDERSTAND HOW UBIQUITOUS TRANS-KINGDOM SIGNALING BETWEEN PATHOGENS AND HOSTS IS. THEREFORE, IT IS CRITICAL TO STUDY THESE MECHANISMS IN MODEL SYSTEMS. WE RECENTLY DISCOVERED THAT THE NEMATODE C. ELEGANS, WHICH BOTH EATS AND IS INFECTED BY BACTERIA, CAN SURVEY ITS ENVIRONMENT, DETECT AND LEARN TO AVOID PATHOGENS, AND THEN PASS THIS INFORMATION ON TO FOUR GENERATIONS OF ITS PROGENY (MOORE, ET AL., CELL 2019); WE PROPOSE THAT THIS IS A NASCENT FORM OF ADAPTIVE IMMUNITY. WELL-CONSERVED MOLECULAR PROCESSES (RNA INTERFERENCE, COMPASS HISTONE MODIFICATION, PIRNAS) ACROSS SEVERAL TISSUES (INTESTINE, GERMLINE, AND NEURONS) ARE REQUIRED TO ALTER BEHAVIOR IN RESPONSE TO PSEUDOMONAS AERUGINOSA (PA14). WORMS "READ" SMALL RNA BACTERIAL SIGNALS, INTERPRET THIS INFORMATION AS A PREDICTOR OF FUTURE INFECTION, AND TRANSMIT THE INFORMATION TO ALTER BEHAVIOR BY DOWNREGULATING A NEURONAL GENE WITH COMPLEMENTARY SEQUENCE (KALETSKY, ET AL. BIORXIV 2020; KALETSKY ET AL. NATURE, IN PRESS). HOW IS THE SRNA SIGNAL CONVEYED FROM THE GERMLINE TO NEURONS? WE FOUND THAT THE TY3/GYPSY RETROTRANSPOSON CER1 IS REQUIRED FOR LEARNED PATHOGENIC AVOIDANCE, TEI, AND SURVIVAL ON PA14. THIS IS PARADIGM SHIFTING: CONVENTIONAL WISDOM HOLDS THAT RETROTRANSPOSONS ARE DELETERIOUS, AND THAT PIRNAS ARE CRITICAL TO REPRESS THESE GENOMIC PARASITES. OUR RESULTS INSTEAD SUGGEST THAT CER1 MAY HAVE BEEN SELECTED TO FIGHT AGAINST THE MOST ABUNDANT PATHOGENS IN C. ELEGANS' ENVIRONMENT. WE HYPOTHESIZE THAT CER1 FORMS VESICLE- LIKE PARTICLES THAT CARRY SRNAS TO NEURONS. PROPOSED EXPERIMENTS WILL CHARACTERIZE THE NATURE OF THE GERMLINE-TO- NEURON SIGNAL, DETERMINE THE EVOLUTIONARY CONSERVATION OF THE MECHANISM, AND DETERMINE HOW THE TRANSGENERATIONAL “CLOCK” IS SETT. BECAUSE THE MOLECULAR COMPONENTS WE HAVE ALREADY OBSERVED ARE CONSERVED, OUR RESULTS WILL IDENTIFY CANDIDATE MOLECULAR REQUIREMENTS FOR TEI IN OTHER ANIMALS.

MECHANISMS OF MRNA LOCALIZATION AND TRANSLATIONAL CONTROL IN DROSOPHILA DEVELOPMENT

"(MURI 05) RENEWABLE BIO-SOLAR HYDROGEN PRODUCTION FROM ROBUST OXYGENIC PHOTOTROPHS DATED 17 NOV 04 AND REVISED 31 MAR 05" (THE RECIPIENT'S TECHNICAL

THE PHYSICS OF SURFACE STATES WITH INTERACTIONS MEDIATED BY BULK PROPERTIES, DEFECTS AND SURFACE CHEMISTRY

GENETIC VIRAL AND HOST ADAPTATIONS TO BREACH SPECIES BARRIERS OF HCV

(MURI 07) GENERATION OF COMPREHENSIVE SURROGATE KINETIC MODELS AND VALIDATION DATABASES FOR SIMULATING LARGE MOLECULAR WEIGHT HYDROCARBON FUELS

CONTE CENTER: UNDERSTANDING LATENT CAUSE INFERENCE IN HEALTH AND ILLNESS - CONTE CENTER – UNDERSTANDING LATENT CAUSE INFERENCE IN HEALTH AND ILLNESS LATENT CAUSE INFERENCE IS THE FUNDAMENTAL COGNITIVE PROCESS BY WHICH WE DRAW BOUNDARIES BETWEEN SITUATIONS THAT HAVE DIFFERENT UNDERLYING RULES, AND THEREFORE REQUIRE SEPARATE LEARNING AND DECISION MAKING. EVERY PIECE OF INFORMATION THAT ENTERS OUR BRAIN IS FIRST CATEGORIZED AS PERTAINING TO SOMETHING WE ALREADY KNOW ABOUT (AN OLD LATENT CAUSE) OR SOMETHING COMPLETELY NEW (A NEW LATENT CAUSE). BECAUSE LATENT CAUSE INFERENCE IS AT THE HEART OF PERCEPTION, LEARNING, EVALUATION, AND ACTION SELECTION, ALTERATIONS IN THIS PROCESS MAY BE AT THE CORE OF A WIDE VARIETY OF MENTAL HEALTH CONDITIONS. FOLLOWING A COMPUTATIONAL PSYCHIATRY APPROACH THAT BRIDGES ABSTRACT SYMPTOMS TO BASIC NEUROCOGNITIVE MECHANISMS USING COMPUTATIONAL MODELS, WE PROPOSE A COMPREHENSIVE INVESTIGATION OF LATENT CAUSE INFERENCE AS A PROPOSED NEW TRANSDIAGNOSTIC NIMH RESEARCH DOMAIN CRITERIA (RDOC) DOMAIN. WE PROPOSE A RESEARCH PROGRAM CENTERED AROUND THREE THEMES: QUANTIFYING INDIVIDUAL DIFFERENCES IN LATENT CAUSE INFERENCE AND RELATING THEM TO MENTAL HEALTH SYMPTOMS, TESTING FOR ALTERATIONS OF THIS PROCESS IN CLINICAL SAMPLES, AND DELINEATING THE NEURAL CIRCUITRY UNDERLYING LATENT CAUSE INFERENCE. THESE THEMES CUT ACROSS FOUR PROPOSED PROJECTS (P1-P4): P1 – LATENT CAUSE INFERENCE AS A FUNDAMENTAL COGNITIVE PROCESS WILL RELATE INDIVIDUAL DIFFERENCES IN LATENT CAUSE INFERENCE TO DIMENSIONAL MENTAL HEALTH SYMPTOM FACTORS, AND IDENTIFY THE NEURAL CIRCUITRY INVOLVED IN CREATING AND REUSING LATENT CAUSES. P2 – LATENT CAUSE INFERENCE IN COMPULSION WILL TEST A NOVEL INTERPRETATION OF COMPULSIVE DISORDERS (E.G., OBSESSIVE COMPULSIVE DISORDER, DRUG MISUSE) AS ARISING FROM OVER-SPLITTING OF LATENT CAUSES. P3 – LATENT CAUSE INFERENCE IN ANXIETY WILL INVESTIGATE THE INTERACTION OF LATENT CAUSE INFERENCE WITH MEMORY RETRIEVAL AND UPDATING, AND THEIR FAILURE MODES IN ANXIETY DISORDERS. P4 – NEURAL MECHANISMS UNDERLYING LATENT CAUSE INFERENCE WILL PROBE NEURAL MECHANISMS OF LATENT CAUSE INFERENCE USING HIGH-DENSITY NEURONAL RECORDINGS AND CHEMOGENETIC MANIPULATION OF OREXIN IN RAT AMYGDALA. THE PROPOSED PROJECTS ARE TIGHTLY INTERCONNECTED, ALL EMPLOYING A SHARED THEORETICAL FRAMEWORK AND COMPUTATIONAL MODELING APPROACH AND RELYING ON INTEGRATION OF METHODS AND RESULTS TO OBTAIN A COMPREHENSIVE UNDERSTANDING OF LATENT CAUSE INFERENCE IN MENTAL ILLNESS AND IN HEALTH. THEY WILL BUILD ON THREE RESEARCH CORES (BEHAVIORAL TESTING AND CLINICAL ASSESSMENT, COMPUTATIONAL MODELING, AND NEUROIMAGING). THE INVESTIGATORS HAVE A LONG AND PRODUCTIVE HISTORY OF COLLABORATION, AND EACH IS ORGANICALLY INVOLVED IN MULTIPLE PROJECTS AND/OR CORES, ENSURING OPTIMAL INTEGRATION OF KNOWLEDGE AND METHODS. THE CONTE CENTER WILL ALLOW US TO CONDUCT A MULTIDIMENSIONAL AND TRANSLATIONAL CHARACTERIZATION OF A NEW CANDIDATE COGNITIVE PROCESS FOR THE RDOC MATRIX, TYING IT TO MENTAL ILLNESSES AND UNCOVERING ITS NEURAL MECHANISMS.

STRUCTURAL ANALYSIS OF GOLGI TRAFFICKING PROTEINS

FUNCTIONS OF THE THALAMUS IN PERCEPTION AND COGNITION

STRUCTURE AND FUNCTION OF A CUBIC MILLIMETER OF CORTEX: CROWDSOURCING FOR PROOFREADING AND DISCOVERY

INTEGRATION AND VISUALIZATION OF DIVERSE BIOLOGICAL DATA

ESTABLISHMENT OF LONG-RANGE TISSUE POLARITY IN THE MAMMALIAN EPIDERMIS

NAME OF EFFORT: CARS: A PLATFORM FOR SCALING FORMAL VERIFICATION TO COMPONENT-BASED VEHICULAR SOFTWARE STACKS. TYPE OF AWARD: COOPERATIVE AGREEMEN

MODELING THE NEURAL BASIS OF EPISODIC MEMORY

PEPTIDE AUTOINDUCERS OF STAPHYLOCOCCAL PATHOGENICITY

STRUCTURE, FUNCTION AND APPLICATIONS OF INTEINS

THIS COOPERATIVE AGREEMENT SHALL BE PERFORMED IN ACCORDANCE WITH STATEMENT OF WORK, ENTITLED 'DECADES: DEEPLY-CUSTOMIZED ACCELERATOR-ORIENTED DATA S

METABOLISM IN ACTION: QUANTITATIVE FLUXES IN MAMMALS

MECHANICAL CLOCKS DURING FETAL DEVELOPMENT - PROJECT SUMMARY DEVELOPMENT IS ALL ABOUT TIMING. FROM FERTILIZED EGG TO NEWBORN INFANT, EMBRYONIC DEVELOPMENT PROCEEDS AS A HIGHLY COORDINATED SEQUENCE OF STEREOTYPED EVENTS. THE ORDER AND TIMING OF EACH STAGE OF THE PROCESS, INCLUDING THE TIMING OF TISSUE MORPHOGENESIS AND DIFFERENTIATION OF PROGENITOR CELLS, ARE ESSENTIAL FOR BUILDING MATURE ORGANS IN TIME FOR BIRTH. DEFECTS IN TIMING ARE ASSOCIATED WITH BOTH CONGENITAL BIRTH DEFECTS AS WELL AS CHRONIC DISEASES IN THE ADULT, INCLUDING ASTHMA, EMPHYSEMA, RENAL FAILURE, AND TYPE II DIABETES. WHAT CONTROLS THE TEMPO OF DEVELOPMENT – THE CENTRAL METRONOME OF THE EMBRYO – IS ONE OF THE GREAT MYSTERIES OF BIOLOGY. ONLY A HANDFUL OF MOLECULAR TIMERS HAVE BEEN DISCOVERED TO-DATE, INCLUDING THE CIRCADIAN AND SEGMENTATION CLOCKS, BOTH OF WHICH OPERATE AS TRANSCRIPTIONAL OSCILLATORS THAT ARE ENTRAINED BY PERIODIC ACTIVATION OF EXTRACELLULAR BIOCHEMICAL STIMULI. HOWEVER, IT IS UNCLEAR HOW BIOCHEMICAL SIGNALS THAT ARE TRANSMITTED BY DIFFUSION CAN COUPLE THE RATES OF DEVELOPMENT OF ORGANS THAT ARE SEPARATED BY LARGE DISTANCES WITHIN THE EMBRYO. WE RECENTLY DISCOVERED UNEXPECTEDLY THAT THE RATE OF MORPHOGENESIS OF THE EMBRYONIC MAMMALIAN LUNG IS ENTRAINED BY MECHANICAL FORCES FROM LUMINAL FLUID PRESSURE, WHICH CONTROLS THE FREQUENCY OF SYNCHRONIZED EPITHELIAL BRANCHING AND SMOOTH MUSCLE CONTRACTION ACROSS THE ORGAN. THESE FINDINGS SUGGEST THE PRESENCE OF A “MECHANICAL CLOCK” IN THE FETUS. BECAUSE FLUID PRESSURE IS TRANSMITTED INSTANTANEOUSLY BETWEEN DISTANT TISSUES, A MECHANICAL CLOCK COULD SYNCHRONIZE THE RATES OF DEVELOPMENT ACROSS ORGANS, PERMITTING COORDINATED MATURATION BEFORE BIRTH. HERE, WE PROPOSE TO INVESTIGATE THE COUPLING OF LUNG, KIDNEY, AND PANCREATIC DEVELOPMENT, ORGANS THAT ARE ALL CONNECTED BY FLUID WITHIN AND AROUND THE EMBRYO AND THAT FORM VIA BRANCHING MORPHOGENESIS. WE WILL DEFINE HOW THE MAGNITUDE OF PRESSURE CONTROLS THE RATES OF PROLIFERATION, DIFFERENTIATION, AND MORPHOGENESIS USING MICROFLUIDICS APPROACHES. WE WILL ALSO IDENTIFY THE OSCILLATORY SIGNALING PATHWAYS THAT ARE INDUCED BY PRESSURE AND INVESTIGATE HOW FLUID FORCES ARE TRANSMITTED BETWEEN DISTANT ORGANS TO ENSURE THAT THEIR RATES OF DEVELOPMENT ARE COUPLED. WE WILL COMBINE ORGAN-ON-A-CHIP MODELS, TISSUE-SPECIFIC REPORTER ANIMALS, TRANSGENIC KNOCKOUT MICE, SINGLE-CELL TRANSCRIPTOMICS AND PROTEOMICS, AND QUANTITATIVE TIME-LAPSE IMAGING ANALYSIS, AND COMPLEMENT THESE WITH STUDIES OF HUMAN PATIENT SAMPLES AND MOUSE MODELS OF ENTRAINMENT DEFECTS. THIS WORK WILL UNCOVER HOW THE SHARED MECHANICAL ENVIRONMENT OF FETAL ORGANS PERMITS THEM TO GROW AND MATURE COORDINATELY IN TIME FOR BIRTH, WHICH IS ESSENTIAL FOR DESIGNING NEW APPROACHES TO TREAT DISORDERS ASSOCIATED WITH CONGENITAL DEFECTS AND DEVELOPMENTAL PREMATURITY, AS WELL AS CHRONIC DISEASES IN THE ADULT.

DENDRITIC INTEGRATION AND CEREBELLAR SYNAPTIC PLASTICITY

CEREBELLAR DETERMINANTS OF FLEXIBLE AND SOCIAL BEHAVIOR ON RAPID TIME SCALES IN AUTISM MODEL MICE.

EXPLORING THE DARK UNIVERSE: PANORAMIC IMAGING AND SPECTROSCOPY WITH THE SUBARU 8 METER TELESCOPE

NEW COOPERATIVE AGREEMENT "TRANSPORT IN DISORDERED HYPERUNIFORM SYSTEMS AND NETWORKS"

THERMALLY ROBUST CHEMOTAXIS AND THERMOTAXIS IN ESCHERICHIA COLI

PUBLIC USE DATA ON MEXICAN IMMIGRATION

THE BIOPHYSICAL AND MOLECULAR MECHANISMS OF RELIABILITY IN DEVELOPMENT

PROBING CORRELATED SUPERCONDUCTORS AND THEIR PHASE TRANSITIONS ON THE NANOMETER SCALE

MULTISENSORY INTEGRATION OF FACES AND VOICES IN THE PRIMATE TEMPORAL LOBE

INFRASTRUCTURE FOR POPULATION RESEARCH AT PRINCETON

UNCOVERING THE NEURAL MECHANISMS THAT FLEXIBLY LINK SENSORY PROCESSING TO BEHAVIOR

NEW START GRANT

ASSESSING PUBLIC ENGAGEMENT IN THE ARAB WORLD: THE FIFTH WAVE OF THE ARAB BAROMETER

COLLABORATIVE RESEARCH: A DEPLETED ARGON DETECTOR FOR A DARK MATTER SEARCH

GENETIC ANALYSIS OF PROTEIN EXPORT

COMPREHENSIVE AND ROBUST TOOLS FOR ANALYSIS OF TUMOR HETEROGENEITY AND EVOLUTION

DISSEMINATION OF FLYWIRE, A WHOLE-BRAIN CONNECTOMICS RESOURCE - THIS PROPOSAL WILL DISSEMINATE FLYWIRE, A DROSOPHILA WHOLE BRAIN CONNECTOMICS RESOURCE. WE USED ADVANCES IN AI TO SEGMENT ALL NEURONS FROM A WHOLE BRAIN EM VOLUME CALLED FAFB. THE AUTOMATED SEGMENTATION IS OF HIGH ENOUGH QUALITY THAT, IN COMBINATION WITH INNOVATIVE PROOFREADING TOOLS, SCIENTISTS CAN RELATIVELY QUICKLY PROOFREAD CIRCUITS OF INTEREST. THE COMMUNITY OF CURRENT COLLABORATORS INCLUDES ABOUT 160 SCIENTISTS FROM 40 LABS, WHO HAVE SO FAR SUCCEEDED AT PROOFREADING MORE THAN 15% OF THE NEURONS IN THE FLY BRAIN. SEVERAL PUBLICATIONS HAVE RESULTED, AND MORE ARE ON THE WAY. PROOFREADING IS REQUIRED BECAUSE AUTOMATED SEGMENTATION, WHILE GOOD, CONTAINS ERRORS THAT MUST BE FIXED WITH MANUAL CORRECTION. JANELIA/HHMI SPENT 50 PERSON-YEARS PROOFREADING AN EM VOLUME THAT CONTAINS ROUGHLY ONE-THIRD OF THE NEURONS IN ANOTHER FEMALE BRAIN, A RESOURCE CALLED THE HEMIBRAIN. A WHOLE BRAIN CONNECTOME, IN CONTRAST, WILL MAKE IT POSSIBLE TO ADDRESS QUESTIONS ABOUT BRAIN-WIDE CIRCUIT ORGANIZATION AND ABOUT ANY BRAIN REGION. WE CREATED THIS UNIQUE RESOURCE WITH A THREE-YEAR GRANT FROM THE BRAIN INITIATIVE, AND ARE NOW SEEKING ADDITIONAL FUNDING TO DISSEMINATE THE RESOURCE MORE WIDELY. OUR FRAMEWORK FOR DISSEMINATION WILL SET THE STANDARD FOR EMERGING, LARGER CONNECTOMICS DATASETS, SUCH AS THOSE OF MAMMALS. WE PROPOSE THREE AIMS FOR DISSEMINATION THAT INCLUDE OUTREACH EFFORTS, DEPLOYING A CENTRALLY-MANAGED PROOFREADING TEAM, AND ENHANCING THE USER INTERFACE AND TOOLS AVAILABLE TO ACCESS FLYWIRE DATA. IN PARTICULAR, A COMMUNITY MANAGER WILL ORGANIZE THE COMMUNITY OF SCIENTISTS WORKING IN FLYWIRE, WILL RECRUIT AND TRAIN NEW USERS, WILL RUN WORKSHOPS, AND WILL COORDINATE ACCESS TO THE TRAINED PROOFREADERS. SCIENTISTS CAN APPLY TO HAVE AN EXPERT PROOFREADER ASSIST WITH THEIR CIRCUIT RECONSTRUCTION PROJECTS, AND WE WILL GIVE PRIORITY TO NEW USERS. FINALLY, IN THE FIRST YEAR OF THE PROJECT WE WILL IMPLEMENT GUI TOOLS IN FLYWIRE THAT FACILITATE DISCOVERY WITHOUT NECESSITATING PROGRAMMING SKILLS.

COGNITIVE AND NEURAL MECHANISMS OF DECISION AND CONTROL

TO EQUIP STAKEHOLDERS IN MENA WITH INFORMATION TO LEAD LOCAL PROBLEM SOLVING EFFORTS FOR INCLUSIVE ECONOMIC GROWTH AND PARTICIPATORY GOVERNANCE

GENETICS OF FUNCTIONAL INTERACTIONS IN YEAST

STRUCTURE AND BEHAVIOUR OF YEAST TELOMERES

COLLABORATIVE RESEARCH WITH THE ATACAMA COSMOLOGY TELESCOPE (ACT): PROBING FUNDAMENTAL PHYSICS THROUGH OBSERVATIONS OF COSMIC STRUCTURE

DEVELOPMENT OF NEW PROTEOMICS TECHNOLOGY AND ITS APPLICATION TO STUDY CELLULAR ORGANIZATION

STRUCTURE, FUNCTION AND APPLICATIONS OF INTEINS

PRINCETON CENTER FOR COMPLEX MATERIALS

NEW SYNTHETIC METHODS ENABLED BY EXCITED-STATE REDOX CHEMISTRY

OPTIMAL ASSET DISTRIBUTION FOR ENVIRONMENTAL ASSESSMENT AND FORECASTING BASED ON OBSERVATIONS, ADAPTIVE SAMPLING, AND NUMERICAL PREDICTION

IMPROVED METHODS FOR INFERENCE OF GENOTYPE-SPECIFIC RESPONSE TO ENVIRONMENTAL TOXINS

THIS GRANT SHALL BE PERFORMED IN ACCORDANCE WITH THE STATEMENT OF WORK (SOW) ENTITLED "ULTRA-SENSITIVE FIBER-OPTIC MAGNETOMETER ARRAY" DTD 07 JULY 09

DNA REPLICATION AND CHROMOSOME STRUCTURE IN YEAST

FITT: DEVELOPMENT OF LOW VOLTAGE LOW POWER TRANSISITOR BASED ON TOPOLOGICAL SURFACE STATES

CHEMICAL PROBES FOR STUDYING FORMALDEHYDE BIOLOGY

SEMIPARAMETRIC MODELS FOR LARGE SCALE-BIOMEDICAL DATA

COLLABORATIVE RESEARCH: DARKSIDE-20K: A GLOBAL PROGRAM FOR THE DIRECT DETECTION OF DARK MATTER USING LOW-RADIOACTIVITY ARGON

MECHANISM OF RNA LOCALIZATION IN DROSOPHILA DEVELOPMENT

TOWARD THE TISSUE-OME: A MAP OF THE C. ELEGANS CELL-SPECIFIC TRANSCRIPTOME

MECHANO-MICROBIOLOGY: HOW PHYSICAL FORCES CONTROL BACTERIAL-HOST INTERACTIONS

PROTEOMIC TOOLS TO UNCOVER THE ROLE OF CHROMATIN REMODELING IN HIV-1 INFECTION

HIFISTELL: HIGH-FIDELITY SIMULATIONS FOR STELLARATORS

COLLABORATIVE RESEARCH: A COMMUNITY RESOURCE FOR GENOME-SCALE IDENTIFICATION OF GENOTYPE-PHENOTYPE RELATIONSHIPS IN A MODEL PHOTOSYNTHETIC EUKARYOTE

CONTROL OF THE 4D CHROMATIN LANDSCAPE UNDERLYING GENE ACTIVITY DURING DEVELOPMENT

INVESTIGATING PERINEURONAL NETS AND HIPPOCAMPAL PLASTICITY IN EARLY LIFE ADVERSITY-INDUCED ANXIETY

NEURAL BASIS OF VISUAL ATTENTION

CHEMICALLY RECYCLABLE POLYOLEFINS

THE STANDARD DARK-MATTER AND DARK-ENERGY DOMINATED COSMOLOGICAL MODEL (LCDM) HAS PROVEN TO BE REMARKABLY SUCCESSFUL IN DESCRIBING THE CURRENT STATE AND PAST EVOLUTION OF THE UNIVERSE. HOWEVER THERE REMAIN SIGNIFICANT UNCERTAINTIES REGARDING THE PHYSICAL MECHANISMS THAT ESTABLISHED THE INITIAL CONDITIONS UPON WHICH THE LCDM PREDICTIONS RELY. THEORIES OF COSMIC GENESIS - THE EXTREMELY HIGH ENERGY MECHANISMS THAT ESTABLISHED THESE CONDITIONS - SHOULD BE EXPECTED TO PROVIDE A NATURAL DESCRIPTION OF THE NEARLY FLAT GEOMETRY OF THE UNIVERSE THE EXISTENCE OF SUPER-HORIZON DENSITY CORRELATIONS AND THE ADIABATIC GAUSSIAN AND NEARLY SCALE-INVARIANT NATURE OF THE OBSERVED PRIMORDIAL DENSITY PERTURBATIONS. THE PRIMARY OBJECTIVE OF SPIDER IS TO SUBJECT MODELS OF THE EARLY UNIVERSE TO OBSERVATIONAL TEST PROBING FUNDAMENTAL PHYSICS AT ENERGY SCALES FAR BEYOND THE REACH OF TERRESTRIAL PARTICLE ACCELERATORS. THE MAIN SCIENTIFIC RESULT WILL BE TO CHARACTERIZE OR PLACE STRINGENT UPPER LIMITS ON THE LEVEL OF THE ODD-PARITY POLARIZATION OF THE CMB. IN THE CONTEXT OF THE INFLATIONARY PARADIGM SPIDER WILL CONFIRM OR EXCLUDE THE PREDICTIONS OF THE SIMPLEST SINGLE-FIELD INFLATIONARY MODELS NEAR THE LYTH BOUND CHARACTERIZED BY TENSOR TO SCALAR RATIOS R ~ 0.03. WHILE VIABLE ALTERNATIVES TO THE INFLATIONARY PARADIGM ARE AN ACTIVE AND IMPORTANT AREA OF INVESTIGATION INCLUDING STRING COSMOLOGIES AND CYCLIC MODELS EARLY UNIVERSE MODELS DESCRIBED BY INFLATIONARY PERIODS ARE NOW WIDELY ACCEPTED AS THE UNDERLYING CAUSE BEHIND MUCH OF WHAT WE OBSERVE IN COSMOLOGY TODAY. NEVERTHELESS WE KNOW VERY LITTLE ABOUT THE MECHANISM THAT WOULD DRIVE INFLATION OR THE ENERGY SCALE AT WHICH IT OCCURRED AND THE PARADIGM FACES SIGNIFICANT QUESTIONS ABOUT THE VIABILITY OF THE FRAMEWORK AS A SCIENTIFIC THEORY. FORTUNATELY INFLATIONARY PARADIGMS AND ALTERNATIVE THEORIES OFFER DISTINCT PREDICTIONS REGARDING THE STATISTICAL PROPERTIES OF THE COSMIC MICROWAVE BACKGROUND RADIATION. SPIDER WILL USE MEASUREMENTS OF THE POLARIZATION OF THE CMB TO SEARCH FOR THE SIGNATURE OF PRIMORDIAL GRAVITATIONAL WAVES THAT ARE PREDICTED WITHIN THE CURRENTLY FAVORED THEORIES OF INFLATION. A DEFINITIVE DETECTION OF THIS SIGNAL WOULD PROVIDE THE FIRST DIRECT INSIGHT INTO THE UNDERLYING PHYSICS OF INFLATION AS WELL AS A MEASUREMENT OF ITS ENERGY SCALE. A STRINGENT LIMIT ON THE AMPLITUDE OF THIS SIGNAL WOULD EXCLUDE THE CURRENTLY FAVORED CLASS OF INFLATIONARY MODELS BOLSTERING THE CASE FOR ALTERNATIVE THEORIES. SPIDER IS A SUBORBITAL LONG-DURATION BALLOON PAYLOAD HOUSING SIX CRYOGENIC SMALL-APERTURE (HALF-DEGREE RESOLUTION) MILLIMETER-WAVE POLARIMETERS. THE FREQUENCY BANDS OF THE INDIVIDUAL POLARIMETERS ARE CHOSEN TO OPTIMIZE OVERALL SENSITIVITY TO THE INFLATIONARY CMB POLARIZATION SIGNAL IN THE PRESENCE OF GALACTIC FOREGROUNDS. BY MAKING EXTREMELY DEEP HIGH FIDELITY MEASUREMENTS OF THE ENTIRE PORTION OF THE SOUTHERN SKY THAT IS RELATIVELY FREE OF GALACTIC EMISSION THE SPIDER DATA COMPLEMENT THOSE OF PLANCK (IN SENSITIVITY AND CONTROL OF SYSTEMATICS) PIPER (IN FREQUENCY COVERAGE) AND EBEX (IN SKY COVERAGE AND ANGULAR SCALE). THE DATA FROM SPIDER'S INAUGURAL FLIGHT IN 2015 HAS RESULTED IN HIGH SIGNAL-TO-NOISE MAPS OF THE SOUTHERN GALACTIC HEMISPHERE COVERING 10% OF THE FULL SKY AT EACH OF 94 AND 150 GHZ. THE PAYLOAD IS NOW BEING FABRICATED AND FITTED WITH A SUITE OF 285 GHZ CAMERAS TO EXTEND OUR FREQUENCY COVERAGE IMPROVING OUR ABILITY TO DISENTANGLE THE GALACTIC AND COSMOLOGICAL SIGNALS. IF ITS SIGNATURE IS PRESENT IN THE CMB SPIDER'S FREQUENCY COVERAGE AND FIDELITY TO A BROAD RANGE OF ANGULAR SCALES ENABLE THE EXPERIMENT TO TAKE A STEP BEYOND DETECTION TOWARD THE CHARACTERIZATION OF THE GRAVITATIONAL WAVE INDUCED SIGNATURE IN THE CMB. ADDITIONALLY SPIDER SERVES AS A TRAINING GROUND FOR YOUNG SCIENTISTS INCLUDING 16 GRADUATE STUDENTS (9 FEMALE 7 MALE).

EPIGENETIC PRIMING OF RESPONSE TO FUTURE STRESSORS - PROJECT SUMMARY EARLY LIFE ADVERSITY (ELA) IS ONE OF THE STRONGEST LIFETIME RISK FACTORS FOR DEPRESSION, ANXIETY, SUICIDE, AND OTHER PSYCHIATRIC DISORDERS, PARTICULARLY AFTER FACING ADDITIONAL STRESSFUL EVENTS LATER IN LIFE. ELA SENSITIZES INDIVIDUALS TO FUTURE STRESSORS AND DOUBLES THE LIKELIHOOD THAT A STRESSOR IN ADULTHOOD WILL RESULT IN AN EPISODE OF DEPRESSION OR ANXIETY. HOWEVER, THE NEUROBIOLOGICAL BASIS OF THIS STRESS SENSITIVITY, OR PRIMING, REMAINS ALMOST ENTIRELY UNEXPLORED. CLINICAL AND PRECLINICAL STUDIES DEMONSTRATE A ROLE FOR THE VENTRAL TEGMENTAL AREA (VTA) IN ELA- ATTRIBUTABLE MOOD AND ANXIETY DISORDERS, AND THAT ELA ALTERS THE COURSE OF VTA DEVELOPMENT AND ITS FUNCTION IN RESPONSE TO BOTH STRESSORS AND REWARDS. USING A MOUSE MODEL TO INVESTIGATE THE NEUROBIOLOGICAL IMPACT OF ELA, I PREVIOUSLY FOUND THAT ELA LEADS TO LIFELONG TRANSCRIPTOMIC CHANGES IN VTA INCLUDING UNIQUE TRANSCRIPTIONAL RESPONSE TO ADULT STRESSORS, WHICH PARALLELS LATENT BEHAVIORAL CHANGES WE HAVE OBSERVED. GENE EXPRESSION IS REGULATED BY EPIGENETIC MECHANISMS, AND IT WAS RECENTLY SHOWN THAT THE CHROMATIN LANDSCAPE CONTINUES TO MATURE POSTNATALLY DURING A TIME WHEN ELA HAS THE GREATEST IMPACT ON STRESS SENSITIVITY. CHROMATIN DYNAMICALLY RESPONDS TO DEVELOPMENTAL AND ENVIRONMENTAL CUES, ACTS AS A SUBSTRATE OF MOLECULAR MEMORY IN CELLS, AND FACILITATES ADAPTIVE GENE EXPRESSION RESPONSE TO RECURRING STIMULI, A PHENOMENON TERMED EPIGENETIC PRIMING. IN THIS BIOBEHAVIORAL RESEARCH AWARDS FOR INNOVATIVE NEW SCIENTISTS (BRAINS) PROPOSAL, I WILL TEST THE CONCEPTUALLY INNOVATIVE HYPOTHESIS THAT ELA ALTERS MATURATION OF THE CHROMATIN LANDSCAPE, PRIMING CHROMATIN IN A CELL-TYPE- SPECIFIC MANNER AS A BIOLOGICAL MECHANISM OF HEIGHTENED REACTIVITY TO FUTURE STIMULI. IN AIM 1 WE WILL APPLY CUTTING- EDGE SEQUENCING APPROACHES AND COMPUTATIONAL ANALYSES TO UNDERSTAND HOW THE CHROMATIN LANDSCAPE MATURES ACROSS NORMAL POSTNATAL DEVELOPMENT WITH CELLULAR SPECIFICITY, HOW ELA ALTERS THESE TRAJECTORIES, AND WHETHER SUCH CHANGES ARE ENGAGED IN ENHANCED RESPONSE TO FUTURE STRESSORS. IN AIM 2 WE WILL DEVELOP NOVEL EPIGENOME EDITING TOOLS TO PRIME TARGETED GENOMIC LOCATIONS, WHICH WE WILL TEST IN VITRO AND APPLY IN VIVO TO UNDERSTAND MECHANISMS OF SENSITIVITY TO FUTURE STIMULI. WHILE OUR CRISPR/DCAS9-BASED EPIGENOME PRIMING APPROACH ENTAILS A DEGREE OF RISKY INNOVATION, IT IS BALANCED BY PROMISING PRELIMINARY DATA AND WE PROVIDE ALTERNATIVE APPROACHES THAT WOULD MITIGATE FAILURE OF THIS HIGH-RISK HIGH-REWARD EXPERIMENT. THE PROPOSED RESEARCH WILL IDENTIFY THE NEUROEPIGENETIC MECHANISMS THROUGH WHICH DEVELOPMENTAL BRAIN PLASTICITY ENCODES ADVERSITY AND CONFERS SENSITIVITY TO FUTURE STRESSORS. THIS PROPOSAL IS DIRECTLY RELEVANT TO THE NIMH STRATEGIC GOAL TO EXAMINE MENTAL ILLNESS TRAJECTORIES ACROSS THE LIFESPAN. UNDERSTANDING HOW ELA ALTERS THE COURSE OF BRAIN DEVELOPMENT AT THE LEVEL OF THE EPIGENOME HAS THE POTENTIAL TO TRANSFORM OUR UNDERSTANDING OF THE NEURODEVELOPMENTAL ORIGINS OF ELA-ATTRIBUTABLE MENTAL ILLNESS AND POTENTIAL CRITICAL WINDOWS FOR INTERVENTION. THE ADVISORY COUNCIL FORMED THROUGH THIS BRAINS AWARD WILL OPTIMALLY SUPPORT THE ULTIMATE GOAL OF TRANSLATING OUR FINDINGS INTO DEVELOPMENT OF NOVEL TREATMENTS TO MITIGATE THE IMPACT OF CHILDHOOD ADVERSITY ON ADVERSE MENTAL HEALTH OUTCOMES.

MODELS AND METHODS FOR POPULATION GENOMICS

PREDICTING AND ANALYZING PROTEIN INTERACTION NETWORKS

SRN: INTEGRATED URBAN INFRASTRUCTURE SOLUTIONS FOR ENVIRONMENTALLY SUSTAINABLE, HEALTHY AND LIVABLE CITIES.

INNOVATIVE DESIGN AND PROCESSING OF MULTI-FUNCTIONAL ADAPTIVE STRUCTURAL MATERIALS

TAURUS: A BALLOON-BORNE POLARIMETER FOR COSMIC REIONIZATION AND GALACTIC DUST

DEVELOPMENTAL PATTERNING OF THE ANTERIOR NEURAL PLATE IN A SIMPLE CHORDATE

A PATH TO PERSONALIZED PHENOTYPIC PREDICTION: UNLOCKING THE CONTEXT-DEPENDENCY OF ALLELIC EFFECTS

INTRA- AND INTER- SPECIES COMMUNICATION IN BACTERIA

TELOMERE MAINTENANCE AND REPLICATION FORK PROGRESSION IN YEAST AND HUMAN CELLS

CELL-CYCLE CONTROL OF CELL POLARITY IN EPIDERMAL PATTERNING AND DIFFERENTIATION

VERTICALLY INTEGRATED APPROACH TO VISUAL NEUROSCIENCE: MICROCIRCUITS TO BEHAVIOR

IMAGING AND STIMULATION OF NEURAL ACTIVITY AT CELLULAR RESOLUTION IN AWAKE MICE

METHODS AND LOGIC IN MOLECULAR BIOLOGY TRAINING PROGRAM - THE METHODS AND LOGIC IN MOLECULAR BIOLOGY TRAINING PROGRAM (MLMB) AT PRINCETON UNIVERSITY EDUCATES CAREFULLY SELECTED INDIVIDUALS FOR THE RESEARCH, TEACHING, AND ADVOCACY NEEDS OF THE NATION. THE MLMB BRINGS TOGETHER THE MULTI-DISCIPLINARY LIFE SCIENCE COMMUNITY AT PRINCETON WITH 54 TRAINING FACULTY. OUR PROGRAM IS HIGHLY COLLABORATIVE AND TRAINS STUDENTS TO ACQUIRE THE SKILLS TO BECOME LEADERS IN ANY FIELD THEY CHOOSE. THE MLMB TRAINING FACULTY REPRESENT 7 ACADEMIC DEPARTMENTS AND 3 RESEARCH INSTITUTES, INCLUDING 33 FROM MOLECULAR BIOLOGY, 4 FROM CHEMISTRY, 5 FROM CHEMICAL & BIOLOGICAL ENGINEERING, 2 FROM ECOLOGY & EVOLUTIONARY BIOLOGY, 3 FROM COMPUTER SCIENCE, 2 FROM PHYSICS, 2 FROM MECHANICAL & AEROSPACE ENGINEERING, 1 FROM THE LEWIS SIGLER GENOMICS INSTITUTE, AND 2 FROM THE NEUROSCIENCE INSTITUTE. THE FACULTY PROVIDES EXPERTISE IN DIVERSE BIOLOGICAL MODEL SYSTEMS, OFFERING TRAINING IN GENETICS, GENOMICS, PROTEOMICS, METABOLOMICS, BIOCHEMISTRY, BIOPHYSICS, CANCER, CELL BIOLOGY, DEVELOPMENT, MICROBIOLOGY, IMMUNOLOGY, AND NEUROSCIENCE. ALL FACULTY ARE THEMSELVES RIGOROUSLY MENTORED, UNDERGOING ANNUAL MANDATORY MENTORING TRAINING, AND ASSESSED BY THE MLMB COMMITTEE. THE MLMB IS ADMINISTRATIVELY SUPPORTED BY THE DEPARTMENT OF MOLECULAR BIOLOGY (MOL) AND SELECTS ITS STUDENTS FROM THE POOL OF MOL GRADUATE STUDENTS. THE MLMB IS THE ONLY TRAINING GRANT THAT SUPPORTS MOL STUDENTS. THE MOL GRADUATE PROGRAM RECEIVES OVER 400 APPLICATIONS PER YEAR, ATTRACTING SOME OF THE BEST STUDENTS IN THE COUNTRY. RESEARCH IS PERFORMED IN WELL-EQUIPPED LABORATORIES WITH SUPPORT FROM STATE-OF-THE-ART CORE FACILITIES. THE TRAINING PROGRAM CONSISTS OF INTER-DISCIPLINARY, SKILL-BUILDING ORIENTED COURSE WORK, LABORATORY ROTATIONS, A GENERAL EXAM, THESIS RESEARCH, THESIS COMMITTEE MEETINGS, INDIVIDUAL DEVELOPMENTAL PLANS, AND AN ARRAY OF MLMB SPECIALIZED COURSES AND ACTIVITIES THAT PROVIDE STUDENTS WITH SCIENCE COMMUNICATION, LEADERSHIP, AND MANAGEMENTS SKILLS, IN CONJUNCTION WITH DIVERSE CAREER DEVELOPMENT OPPORTUNITIES. TRAINEES GAIN TEACHING EXPERIENCE AND RECEIVE INTENSIVE TRAINING IN SCIENTIFIC RIGOR/REPRODUCIBILITY AND RESPONSIBLE CONDUCT OF RESEARCH. OUR MENTORSHIP PROGRAM FURTHER HELPS ALL STUDENTS WITH ISSUES SUCH AS WORK/LIFE BALANCE AND CAREER DEVELOPMENT. WE HAVE A SUCCESSFUL DIVERSITY AND INCLUSION PROGRAM TO HELP RECRUIT AND RETAIN STUDENTS FROM GROUPS THAT ARE UNDER-REPRESENTED IN THE LIFE SCIENCES. OUR GENDER AND RACIAL DEMOGRAPHICS HAVE MATCHED THOSE OF THE NATION FOR OVER A DECADE. ROUTINE INTERNAL AND EXTERNAL ASSESSMENT OF THE MLMB TRAINING PROGRAM EVALUATES BOTH FACULTY AND STUDENTS AND ENABLES US TO IDENTIFY NEEDS FOR NEW COURSES, POLICIES, AND ACTIVITIES THAT KEEP THE PROGRAM FRESH. OUR SUCCESS IS BEST JUDGED BY THE PRODUCTIVITY AND SUCCESS OF OUR GRADUATES. STUDENTS WHO GRADUATED IN THE PAST 10 YEARS HAD AN AVERAGE OF 4.1 PUBLICATIONS PER TRAINEE AND 95% ARE STILL ENGAGED IN SCIENCE-RELATED CAREERS. OUR MLMB PROGRAM THUS NUCLEATES THE VIBRANT MULTI-DISCIPLINARY RESEARCH COMMUNITY AT PRINCETON AND DELIVERS SCIENTISTS BROADLY TRAINED WITH THE INTERDISCIPLINARY SKILLS THEY NEED TO SOLVE TOMORROW’S CHALLENGES. SUPPORT FOR 12 TRAINEES FOR THEIR 2ND AND 3RD YEARS (24 SLOTS) IS REQUESTED.

GENETIC REGULATORY MECHANISM IN DEVELOPMENT AND DIFFERENTIATION

NEW RULES AND TOOLS TO UNDERSTAND AND CONTROL TISSUE-TISSUE COLLISIONS.

GRANT

CENTER FOR RESEARCH ON EXPERIENCE AND WELL BEING

EGF RECEPTOR MEDIATED SIGNALING IN DROSPHILIA

QUANTUM ENTANGLEMENT SCIENCE AND TECHNOLOGY (QUEST) PROGRAM

NEURONAL SPREAD OF HERPESVIRUS INFECTION

PERINEURONAL NETS, HIPPOCAMPAL PLASTICITY AND AUTISM SPECTRUM DISORDER

MAX - MULTI-TON ARGON AND XENON TPCS

NEW COOPERATIVE AGREEMENT TO PRINCETON UNIVERSITY IN ACCORDANCE WITH ARPA-E FOA NUMBER DE-FOA-0002171 (PERFORM)AND APPLICATION CONTROL NUMBER 2171-1603. PROJECT TITLE: ''STOCHASTIC MODELS, INDICES & OPTIMIZATION ALGORITHMS FOR PRICING & HEDGING RELIABILITY RISKS IN MODERN POWER GRIDS'' THE APPLICANT PROPOSES TO ADAPT THE SCIENCE OF RISK MEASURES,CREDIT RATINGS AND ACTUARIAL PRODUCTS TO QUANTIFY THE IMPACT OF UNCERTAINTIES OF RENEWABLES PRODUCTION, LOAD AND DERS ON ELECTRICITY MARKET OPERATIONS.

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH IN SUPPORT OF A SENSOR PROGRAM IN THE AMOUNT OF 1,370,869 ON CONTRACT HR0011-19-2-0006.

THEORETICAL PHYSICS

COLLABORATIVE RESEARCH: EXPEDITIONS IN COMPUTING: THE SCIENCE OF DEEP SPECIFICATION

INDIVIDUAL DIFFERENCES THROUGH SELF-REINFORCEMENT OF SUBOPTIMAL STRATEGIES - PROJECT SUMMARY/ABSTRACT WHAT PRODUCES INDIVIDUAL DIFFERENCES IN BEHAVIOR? THIS FUNDAMENTAL QUESTION HAS CLASSICALLY BEEN GIVEN TWO ANSWERS: NATURE AND NURTURE. HERE, WE SUGGEST THAT THOSE TWO ANSWERS, WHILE BOTH CRITICAL AND CORRECT, ARE INSUFFICIENT TO FULLY EXPLAIN INDIVIDUAL VARIABILITY. INSTEAD, WE PROPOSE THAT THE VAST DIFFERENCES IN BEHAVIOR BETWEEN INDIVIDUALS ARISE IN PART FROM DIFFERENT INDIVIDUALS FORMING DIFFERENT REWARD ASSOCIATIONS WITHIN THE SAME ENVIRONMENT. THIS RESULTS FROM THE FACT THAT THE WORLD IS COMPLEX AND HIGH-DIMENSIONAL, IN THAT THERE ARE ALMOST ALWAYS MULTIPLE POSSIBLE ACTIONS OR EVENTS THAT COULD BE ATTRIBUTED TO REWARD. GIVEN THE KEY ROLE OF DOPAMINE NEURONS AS THE BRAIN’S POSITIVE FEEDBACK SYSTEM FOR BEHAVIORAL CONTROL, THE SPECIFIC HYPOTHESIS IS THAT SMALL DIFFERENCES ACROSS INDIVIDUALS IN INITIAL CONDITIONS ULTIMATELY PRODUCE LARGE DIFFERENCES IN WHICH FEATURES OF THE ENVIRONMENT THAT THE INDIVIDUAL ATTRIBUTES TO REWARD. THIS HYPOTHESIS IS INSPIRED IN PART BY COMPLEX SYSTEMS THEORY, WHICH EMPHASIZES THE ROLE OF POSITIVE FEEDBACK IN GENERATING AND AMPLIFYING SMALL DIFFERENCES, CREATING OUTCOMES THAT SEEM STOCHASTIC. TO ADDRESS THIS HYPOTHESIS, WE WILL LEVERAGE OUR RECENT FINDING THAT DIFFERENT DOPAMINE NEURONS CALCULATE REWARD PREDICTION ERROR ACROSS DIFFERENT DIMENSIONS OF THE ENVIRONMENT. SPECIFICALLY, WE WILL USE DOPAMINE NEURON RECORDINGS TO INFER THE TIME-VARYING FEATURES OF THE ENVIRONMENT THAT EACH ANIMAL USES TO PREDICT REWARD, AND THEN BUILD REINFORCEMENT LEARNING MODELS OF EACH INDIVIDUAL BASED ON THESE FEATURES. ULTIMATELY, THIS TESTABLE FRAMEWORK AIMS TO EXPLAIN BOTH NORMAL VARIATION ACROSS INDIVIDUALS, AS WELL AS THE UBIQUITOUS CONTRIBUTION OF DOPAMINE IN MEDIATING A DISPARATE RANGE OF NEUROPSYCHIATRIC DISEASES.

"DEVELOPING CONSISTENT EARTH SYSTEM DATA RECORDS FOR THE GLOBAL TERRESTRIAL WATER CYCLE."WE PROPOSE TO DEVELOP CONSISTENT LONG-TERM EARTH SYSTEM DA

MOLECULAR PROBES OF THE MECHANISMS OF CYTOCRHOME P450

MECHANISMS OF HEPATITIS B VIRUS CCCDNA FORMATION

FMRG: ARTIFICIAL INTELLIGENCE DRIVEN CYBERMANUFACTURING OF QUANTUM MATERIAL ARCHITECTURES -QUANTUM MATERIAL ARCHITECTURES CONSIST OF GRAPHENE AND OTHER TWO-DIMENSIONAL MATERIALS, WHICH, WHEN STACKED IN PRECISE THREE-DIMENSIONAL ARCHITECTURES, EXHIBIT UNIQUE AND TUNABLE MECHANICAL, ELECTRICAL, OPTICAL, AND MAGNETIC PROPERTIES. THESE THREE-DIMENSIONAL ARCHITECTURES HAVE BROAD POTENTIAL APPLICATIONS AND ARE HIGHLY PROMISING COMPONENTS FOR MICROCHIPS, BATTERIES, ANTENNAS, CHEMICAL AND BIOLOGICAL SENSORS, SOLAR-CELLS AND NEURAL INTERFACES. HOWEVER, CURRENTLY, DUE TO THE LACK OF FUNDAMENTAL UNDERSTANDING OF THE PHYSICAL AND CHEMICAL PROCESSES, IT HAS BEEN DIFFICULT TO CONTROL OR SCALE THE MANUFACTURING OF THESE THREE-DIMENSIONAL STRUCTURES. THIS FUTURE MANUFACTURING (FM) GRANT IS TO DEVELOP A TRANSFORMATIVE FUTURE MANUFACTURING PLATFORM FOR QUANTUM MATERIAL ARCHITECTURES USING A CYBERMANUFACTURING APPROACH, WHICH COMBINES ARTIFICIAL INTELLIGENCE, ROBOTICS, MULTISCALE MODELING, AND PREDICTIVE SIMULATION FOR THE AUTOMATED AND PARALLEL ASSEMBLY OF MULTIPLE TWO-DIMENSIONAL MATERIALS INTO COMPLEX THREE-DIMENSIONAL STRUCTURES. THIS PLATFORM ENABLES FUTURE PRODUCTION OF HIGH-QUALITY, CUSTOM QUANTUM MATERIAL ARCHITECTURES FOR BROAD AND CRITICAL APPLICATIONS, SUPPORTING CONTINUED U.S. LEADERSHIP IN TECHNOLOGY DEVELOPMENT. THE RESEARCH IN CYBERMANUFACTURING IS INTEGRATED WITH INNOVATIVE EDUCATIONAL PROGRAMS FOR CROSS-DISCIPLINARY TRAINING OF SCIENTISTS AND ENGINEERS, ESPECIALLY, WOMEN AND UNDERREPRESENTED MINORITIES, IN ADVANCED MANUFACTURING, ARTIFICIAL INTELLIGENCE AND QUANTUM STRUCTURES, AS WELL AS ENGAGING THE PUBLIC IN FUTURE MANUFACTURING CONCEPTS. THIS GRANT RESEARCH FOCUSES ON A FUNDAMENTALLY NEW METHOD FOR SCALABLE MANUFACTURING OF 3D QUANTUM MATERIAL ARCHITECTURES OR VAN DER WAALS HETEROSTRUCTURES (VDWHS) USING MICROFLUIDIC ASSEMBLY. VDWHS ARE COMPOSED OF UNLIMITED COMBINATIONS OF ATOMICALLY THIN LAYERS AND EXHIBIT INTERESTING EMERGING FUNCTIONALITIES. THE KEY PROCESS INNOVATION IS PRECISION MICROFLUIDIC FOLDING OF 2D MATERIALS, WHICH HAS BEEN DEMONSTRATED AT A SMALL-SCALE. THIS METHOD HAS PROMISING POTENTIAL TO SCALE UP TO WAFER SCALE, WITH NO FUNDAMENTAL LIMIT ON SCALING. A SECOND KEY INNOVATION IS EMBEDDING ARTIFICIAL INTELLIGENCE (AI) ACROSS ALL ASPECTS OF THE MANUFACTURING PROCESS FLOW, FROM LOW-LEVEL PRECISION CONTROL, TO AUTOMATED CHARACTERIZATION, TO HIGH-LEVEL STRUCTURE PREDICTIONS. PREDICTIVE SIMULATION AND VISUALIZATION TOOLS COMBINED WITH IN SITU SPECTROSCOPY ALLOW REAL-TIME ANALYSIS OF ATOMIC-SCALE PHYSICAL AND CHEMICAL PROCESSES AND THEIR CONTROL. MOREOVER, PARALLEL SELF-ASSEMBLY IN MICROFLUIDIC ENVIRONMENTS IS INVESTIGATED AS A PATHWAY TOWARD TRULY SCALABLE MANUFACTURING. THE EXPECTED OUTCOME OF THE AWARD IS TO PRODUCE SUPERLATTICES CONSISTING OF TENS OF ATOMIC LAYERS WITH PRECISELY ENGINEERED STACKING ORDER AND ALIGNMENT, LEADING TO FUNDAMENTALLY NEW CUSTOM QUANTUM MATERIAL ARCHITECTURES WITH ELECTRONIC AND PHOTONIC PROPERTIES IMPOSSIBLE TO OBTAIN FROM CONVENTIONAL MATERIAL ARCHITECTURES. THIS RESEARCH ADVANCES FUNDAMENTAL KNOWLEDGE IN MATERIAL PHYSICS, NANOSCALE ELECTRONICS AND PHOTONIC SCIENCE LEADING THE WAY TO MANUFACTURING OF FUTURE DEVICES, SUCH AS TWISTRONICS. A KEY OUTCOME IS AN AI-DRIVEN, ROBOTICS-CONTROLLED CYBERMANUFACTURING MICROFLUIDIC PLATFORM THAT IS CAPABLE OF MANUFACTURING COMPLEX STRUCTURES FOR EMERGING QUANTUM AND OTHER DEVICE APPLICATIONS. THIS FUTURE MANUFACTURING RESEARCH GRANT IS SUPPORTED BY THE FOLLOWING DIVISIONS IN THE ENGINEERING DIRECTORATE: CIVIL, MECHANICAL AND MANUFACTURING INNOVATION; ELECTRICAL, COMMUNICATIONS AND CYBER SYSTEMS; AND ENGINEERING EDUCATION AND CENTERS; AND THE FOLLOWING DIVISIONS IN THE MATHEMATICAL AND PHYSICAL SCIENCES: MATERIALS RESEARCH; CHEMISTRY; AND MATHEMATICAL SCIENCES. 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.

VIEWS OF GENDER IN EARLY CHILDHOOD

ENANTIOSELECTIVE ENAMINE CATALYSIS WITH ALDEHYDES

CROWDSOURCING THE FLY CONNECTOME

SYSTEMATIC CHARACTERIZATION OF BIOACTIVE MOLECULES FROM THE HUMAN MICROBIOME - ABSTRACT A COMPLEX INTERPLAY EXISTS BETWEEN THE HUMAN MICROBIOME AND THE HOST, RESULTING IN CLEAR EFFECTS ON HUMAN PHYSIOLOGY AND MICROBIOME ECOLOGY. A PROMISING AVENUE TO DISSECT THIS INTERPLAY AT A MECHANISTIC LEVEL IS THROUGH THE STUDY OF MICROBIOME-DERIVED MOLECULES THAT MEDIATE IMPORTANT MICROBE-MICROBE AND MICROBE-HOST INTERACTIONS. IN THIS APPLICATION, WE PROPOSE A HYBRID COMPUTATIONAL- SYNTHETIC BIOLOGY APPROACH TO DISCOVER, RATIONALLY PRIORITIZE AND SYSTEMATICALLY CHARACTERIZE MICROBIOME- DERIVED MOLECULES. WE PROPOSE TO APPLY THIS APPROACH TO THREE STRUCTURALLY DIVERSE CLASSES OF BIOACTIVE MOLECULES THAT ARE WIDELY ENCODED BY THE HUMAN MICROBIOME BUT REMAIN SEVERELY UNDERSTUDIED IN TERMS OF BOTH STRUCTURE AND FUNCTION. FIRST, GUIDED BY THE COMPUTATIONAL ANALYSIS OF BIOSYNTHETIC GENE CLUSTERS IN METAGENOMIC SEQUENCING DATA FROM THE HUMAN MICROBIOME OF THOUSANDS OF SUBJECTS, WE WILL SELECT SPECIFIC MEMBERS OF THE THREE MOLECULAR CLASSES FOR EXPERIMENTAL CHARACTERIZATION. SECOND, WE WILL USE GENOME EDITING OF NATIVE MEMBERS OF THE MICROBIOME AND SYNTHETIC BIOLOGY IN A MULTI-HOST HETEROLOGOUS EXPRESSION PLATFORM TO CHARACTERIZE THE SELECTED PATHWAYS AND THEIR PRODUCTS. FINALLY, WE WILL EMPLOY AN ARRAY OF IN VITRO, CELL-BASED AND MOUSE COLONIZATION ASSAYS TO INTERROGATE THE ROLE OF THE DISCOVERED MOLECULES IN MEDIATING RELEVANT HOST AND MICROBIOME FUNCTIONS. TAKEN TOGETHER, OUR APPROACH WILL UNVEIL AN UNDERMINED SECTION OF THE INTERPLAY BETWEEN THE HUMAN MICROBIOME AND THE HOST AND PROVIDE DIVERSE MICROBIOME-DERIVED BIOACTIVE MOLECULES AS TOOLS FOR FUTURE MECHANISTIC STUDIES AND THERAPEUTIC INTERVENTIONS.

BOREXINO SOLAR NEUTRINO EXPERIMENT

NEW SUPERCONDUCTING MATERIALS

A WEB-BASED FRAMEWORK FOR MULTI-MODAL VISUALIZATION AND ANNOTATION OF NEUROANATOMICAL DATA - PROJECT SUMMARY/ABSTRACT MODERN EXPERIMENTAL APPROACHES ALLOW RESEARCHERS TO COLLECT A VARIETY OF WHOLE-BRAIN DATA FROM THE SAME ANIMAL VIA DIFFERENT ANATOMICAL LABELS, INCLUDING TRACERS, GENETIC MARKERS, AND FIDUCIAL MARKS FROM RECORDING ELECTRODES. UNFORTUNATELY, VIEWING AND ANALYSIS METHODS HAVE NOT KEPT PACE WITH THE COMPLEXITY OF THESE DATASETS, WHICH CAN BE AS LARGE AS SEVERAL TERABYTES. THIS LIMITATION MAKES IT TIME- AND RESOURCE-INTENSIVE TO VIEW AND MANIPULATE LIGHT-MICROSCOPY DATA OR TO SHARE THESE DATASETS WITH DISTANT LABORATORIES. CURRENTLY AVAILABLE SOFTWARE SOLVES SOME ASPECTS OF THIS PROBLEM, BUT NO EXISTING PROGRAM PROVIDES A USER-FRIENDLY WAY TO VISUALIZE, ANNOTATE, AND COMPARE LARGE NEUROANATOMICAL DATASETS ACROSS RESEARCH SITES, WITH MINIMAL INVESTMENT OF COMPUTATIONAL RESOURCES. WE PROPOSE TO DEVELOP A WEB-BASED TOOL, NAMED BRAINSHARER, TO ALLOW RESEARCHERS TO ACCESS, VISUALIZE, ALIGN, SHARE, AND SEMI-AUTOMATICALLY ANNOTATE BRAIN-WIDE DATA WITHIN A COMMON FRAMEWORK. THE FOUNDATION FOR THIS TOOL WILL BE PROVIDED BY NEUROGLANCER, A GENERIC WEB-BASED VOLUMETRIC VIEWER FIRST DEVELOPED AT GOOGLE AND THEN ADAPTED FOR USE IN ELECTRON MICROSCOPY LABORATORIES. WHILE SOME OF ITS CURRENT FEATURES ARE USEFUL ACROSS APPLICATIONS, EXISTING VERSIONS OF NEUROGLANCER ARE NOT OPTIMIZED FOR LIGHT-MICROSCOPY DATA. IN PARTICULAR, THEY DO NOT REALIZE THE POTENTIAL FOR SHARING, VIEWING, AND EDITING DATA ACROSS MULTI-LABORATORY COLLABORATIONS, SUCH AS U19 PROJECTS. TO ENABLE BRAINSHARER TO SERVE DATA RAPIDLY AND TO SAVE AND RESTORE SESSIONS, WE WILL ADD A MODULAR DISTRIBUTED DATABASE TO SYNCHRONIZE METADATA ACROSS LABORATORIES. IN ADDITION, WE WILL TAILOR BRAINSHARER FOR LIGHT MICROSCOPY BY DISPLAYING DATA IN FORMATS INDEPENDENT OF THE IMAGING MODALITY, ADDING SEMIAUTOMATIC MEANS TO SEGMENT CELL BODIES AND PROCESSES, ADDING TOOLS FOR ANNOTATION (WITH SPECIAL ATTENTION TO DEFINING CYTOLOGICAL BOUNDARIES IN THREE DIMENSIONS AND TRACING PROJECTION PATHWAYS), AND ADDING WAYS TO INCORPORATE AUXILIARY DATA SUCH AS ELECTRODE TRACKS. IN ADDITION, WE WILL INTEGRATE ALIGNMENT TOOLS INTO BRAINSHARER, SO THAT SEPARATE DATASETS CAN BE CO-REGISTERED, VISUALIZED, AND ANNOTATED IN THE SAME FRAMEWORK, ALONG WITH ESTABLISHED AND EMERGING ATLASES. AS TEST BEDS FOR DEVELOPMENT OF BRAINSHARER, WE WILL USE THREE TYPES OF DATASETS FROM OUR U19 PROJECTS: WHOLE-BRAIN DISYNAPTIC AND POLYSYNAPTIC TRACING, ACTIVITY-BASED STAINING WITH C-FOS, AND NEUROVASCULAR DATA. ALL SOFTWARE, TRAINING DATASETS, AND VIDEO TUTORIALS FOR BRAINSHARER WILL BE MADE FREELY AVAILABLE TO THE COMMUNITY, HOSTED ON OUR WEBSITE, ALONG WITH A SLICE HISTOLOGY DATASET AND AN ELECTROPHYSIOLOGY DATASET WITH PROBES IMPLANTED THROUGHOUT THE BRAIN. TO ORIENT NEW USERS, WE WILL ALSO PROVIDE A JUPYTER NOTEBOOK FOR CONVERTING RAW, INTERMEDIATE, AND REGISTERED LIGHT-SHEET DATA, ALONG WITH DETECTED CELLS AND BRAIN ATLASES, TO PRECOMPUTED FORMAT, SO THEY CAN BE LOADED INTO BRAINSHARER. WHEN COMPLETE, BRAINSHARER WILL MAKE IT STRAIGHTFORWARD FOR RESEARCHERS TO USE THEIR LAPTOPS TO COMBINE AND COMPARE LARGE DATASETS FROM DIFFERENT ANATOMICAL LABELS FOR VIEWING AND ANALYSIS RELATIVE TO REFERENCE ATLASES, AND TO SHARE THIS INFORMATION ACROSS PERFORMANCE SITES, THUS INCREASING THE EASE OF USE AND INTEROPERABILITY OF BIG DATA IN NEUROSCIENCE.

TAS::89 0222::TAS; NEW; TITLE: THE IMPACT OF GLOBAL WARMING ON THE CARBON CYCLE OF ARCTIC PERMAFROST: AN EXPERIMENTAL AND FIELD BASED STUDY; PI: TULL

MOLECULAR AND GENETIC ANALYSIS OF CHROMATIN STRUCTURE

LASSO PEPTIDE DISCOVERY

COLLABORATIVE RESEARCH: DIRECT SEARCH FOR DARK MATTER WITH UNDERGROUND ARGON AT LNGS

INTERACTION-BASED COMPUTATIONAL METHODS FOR ANALYZING CANCER GENOMES

"NEW; EQUATION-FREE AND VARIABLE-FREE MODELING FOR COMPLEX/MULTISCALE SYSTEMS: COARSE-GRAINED COMPUTATION IN SCIENCE AND ENGINEERING USING FINE-GRAIN

GENETIC ANALYSIS OF HERPESVIRUS TROPISM AND VIRULENCE

PARTICLE ASTROPHYSICS AT PRINCETON: SOLAR NEUTRINO AND DARK MATTER STUDIES WITH BOREXINO AND DARKSIDE

SYSTEMS BIOLOGY OF MAPK SIGNALING IN EARLY DROSOPHILA EMBRYO

ANALYSIS OF ZEBRAFISH NPT AND SWT MUTANTS IN LEFT-RIGHT PATTERNING

MAPPING EXPERIENCE-DEPENDENT CHANGE IN A CIRCUIT FOR AGGRESSION - ABSTRACT HOW DOES THE BRAIN GENERATE AND MAINTAIN A PERSISTENT HIGH-AGGRESSION STATE? WHILE PATHOLOGICAL, PERSISTENT AGGRESSION IS A COMMON SYMPTOM IN MANY DIVERSE MENTAL HEALTH DISORDERS INCLUDING SCHIZOPHRENIA, BIPOLAR DISORDER, POST-TRAUMATIC STRESS DISORDER, AUTISM, RETT SYNDROME, AND TRAUMATIC BRAIN INJURY, WE LACK A FUNDAMENTAL UNDERSTANDING OF THE NEURAL MECHANISMS UNDERLYING PERSISTENT SOCIAL STATES. MANY MODELS OF AGGRESSION POSIT THAT THIS DYSREGULATION OCCURS THROUGH THE FAILURE OF “TOP-DOWN” INHIBITORY CONTROL OF SUBCORTICAL CIRCUITS FOR AGGRESSION, THROUGH THE CIRCUIT AND SYNAPTIC BASIS FOR THESE MODELS REMAIN UNCLEAR. HERE, WE PROPOSE THAT PATHOLOGICAL AGGRESSION MAY HIJACK CIRCUIT MECHANISMS USED TO GENERATE PERSISTENT AGGRESSIVE STATES IN ADAPTIVE CONTEXTS. IN PARTICULAR, THE EXPERIENCE OF AGGRESSION HAS LONG BEEN KNOWN TO FACILITATE THE EMERGENCE OF A PERSISTENT HIGH-AGGRESSION STATE, ENABLING ANIMALS TO DEFEND TERRITORY AND STATUS ACROSS LONG PERIODS OF TIME. EXAMINING HOW EXPERIENCE “UPDATES” NEURAL CIRCUITS IN THE HEALTHY BRAIN TO FACILITATE FUTURE AGGRESSION PROVIDES A UNIQUE WINDOW ON HOW THESE CIRCUITS BECOME DYSREGULATED UNDER PATHOLOGICAL CONDITIONS. WHAT ARE THE NEURAL MECHANISMS UNDERLYING EXPERIENCE-DEPENDENT UPDATING? TO EXPLORE THIS, WE WILL LOOK LONGITUDINALLY AT THE CHANGING RELATIONSHIP BETWEEN NEURAL ACTIVITY IN THE VENTROMEDIAL HYPOTHALAMUS, VENTROLATERAL AREA (VMHVL), AN AGGRESSION OUTPUT AREA WITH A WELL-DESCRIBED ROLE IN AGGRESSION IN BOTH SEXES, AND ITS “UPSTREAM” INHIBITORY INPUTS. IN THIS PROPOSAL, WE WILL TEST THE NOVEL HYPOTHESIS THAT AGGRESSION EXPERIENCE STABILIZES A PERSISTENT AGGRESSIVE STATE THROUGH A CIRCUIT “REROUTING” MECHANISM RATHER THAN CHANGES IN THE ACTIVITY OF INHIBITORY CONTROL LOCI. USING A VARIETY OF METHODS FOR SUPERVISED AND UNSUPERVISED BEHAVIORAL ANALYSIS, VIRALLY MEDIATED ANATOMICAL TRACING, SYNAPTIC PHYSIOLOGY, OPTOGENETICS AND CELLULAR RESOLUTION HIGH-DENSITY RECORDINGS, WE WILL LOOK LONGITUDINALLY AT HOW EXPERIENCE ALTERS THE FUNDAMENTAL PROPERTIES OF THIS CIRCUIT TO IMPLEMENT BEHAVIORAL CHANGE. FIRST, WE WILL MAP THE PUTATIVE IDENTITY OF CIRCUIT NODES WITH THE ARCHITECTURAL CAPACITY TO REROUTE INHIBITION AND CHARACTERIZE THE CHANGES IN SYNAPTIC STRENGTH OF THIS CIRCUIT ACROSS EXPERIENCE. NEXT, WE WILL SPECIFICALLY EXAMINE THE RELATIONSHIP BETWEEN THE ACTIVITY OF THE REGULATORY INPUT AND THE CIRCUIT-LEVEL OUTPUT ACROSS EXPERIENCE. LASTLY, WE WILL PERFORM HIGH-DENSITY POPULATION RECORDINGS TO ELUCIDATE THE CHANGES IN THE UNDERLYING COMPUTATIONS BEING PERFORMED BY THE CIRCUIT TO STABILIZE A HIGH AGGRESSION STATE. TOGETHER, THESE DATA WILL PROVIDE A COMPREHENSIVE INTEGRATED FRAMEWORK FOR UNDERSTANDING HOW EXPERIENCE GENERATES A PERSISTENT BEHAVIORAL STATE, AND WILL PAVE THE WAY FOR NOVEL ACTIVITY-DEPENDENT TOOLS THAT MAY BE ABLE TO DETECT NEURAL SIGNATURES OF EXPERIENCE AND BEHAVIORAL PERSISTENCE IN PATIENT POPULATIONS AT RISK FOR AGGRESSION DYSREGULATION.

TRANSLATIONAL REGULATION OF PATTERNING IN DROSOPHILA

PRINCETON CENTER FOR THE DEMOGRAPHY OF AGING

MRI CONSORTIUM: DEVELOPMENT OF A LARGE PLASMA DEVICE FOR STUDIES OF MAGNETIC RECONNECTION AND RELATED PHENOMENA

MOLECULAR MECHANISMS REGULATING AGE-RELATED COGNITIVE DECLINE IN C. ELEGANS

MECHANISMS OF NEURAL CIRCUIT DYNAMICS IN WORKING MEMORY

INTER-GRINDING OF WASTE ACTIVATORS AND LOW-GRADE CALCINED KAOLIN CLAY FOR ONE-PART ALKALI-ACTIVATED CONCRETE TECHNOLOGY (INTERAACT)

PHOTOREDOX CATALYSIS FOR CHEMICAL SYNTHESIS

NEW AWARD: ONLINE, IN-SITU MONITORING COMBUSTION TURBINES USING WIRELESS PASSIVE CERAMIC SENSORS

THE PLANNED PERIOD OF PERFORMANCE IS NOVEMBER 1 2017 THROUGH OCTOBER 31 2019. THE FOLLOWING ACTIVITIES WILL BE PERFORMED DURING THE EXTENDED MISSION BY PRINCETON. A. PROVIDE PI LEADERSHIP OF THE IBEX SCIENCE EFFORT THROUGHOUT THE EXTENDED MISSION B. MANAGE THE PRINCETON SCIENCE EFFORT THROUGHOUT THE EXTENDED MISSION C. PREPARE AND SUBMIT QUARTERLY TECHNICAL PROGRESS REPORTS D. SUPPORT TEAM TELECONS 1 TO 2 TIMES PER MONTH E. ATTEND SCIENCE TEAM MEETINGS AND SCIENTIFIC CONFERENCES AS CALLED BY THE PI F. DEVELOP ALGORITHMS AND SOFTWARE AS REQUEST BY THE PI IN SUPPORT OF IBEX DATA ANALYSIS OR THEORY EFFORTS G. ANALYZE AND PUBLISH IBEX INVESTIGATION SCIENCE DATA H. RECEIVE AND ANALYZE PAYLOAD SCIENCE DATA; WORK WITH THE IBEX TEAM TO DEVELOP MODELS ALGORITHMS ETC. TO ANALYZE THE SCIENCE DATA; PUBLISH IBEX SCIENCE RESULTS; SUPPORT THE ARCHIVAL OF SCIENCE DATA

INDIVIDUAL DIFFERENCES AND BIO-INSPIRED DESIGN OF VEHICLE GROUP DYNAMICS

DARKSIDE-20K - URANIA PROJECT

---------- TRUSTEES OF PRINCETON UNIVERSITY: NEW CONDITIONAL SMARTFARM AWARD. CONTROL NUMBER: 2250-1538 TITLE: “NITRONET: SMART SYSTEM TO QUANTIFY NITROUS OXIDE EMISSIONS” ----------

NEURAL DYNAMICS SUPPORTING INTEGRATION AND RECALL OVER LONG TIMESCALES DURING NATURAL CONTINUOUS INPUT

TARGETING HEPATITIS B VIRUS CCCDNA DURING HBV/HIV CO-INFECTION - PROJECT SUMMARY COINFECTION WITH HBV AND HIV-1 IS COMMON, AND HIV COINFECTION CAN EXACERBATE PROGRESSION OF VIRAL HEPATITIS AND ACCELERATE LIVER DISEASE PROGRESSION. IN FACT, ENDSTAGE LIVER DISEASES, INCLUDING FIBORIS/CIRRHOSIS AND HEPATOCELLULAR CARCINOMA, HAVE BECOME THE MOST COMMON CAUSES OF DEATH IN PEOPLE LIVING WITH HIV (PWH) WORLDWIDE. HIV INFECTION CANNOT BE CURED CURRENTLY BUT CAN BE EFFICIENTLY SUPPRESSED WITH HIGHLY ACTIVE OR COMBINATION ANTI-RETROVIRAL THERAPY (HAART OR CART). CURRENTLY AVAILABLE HBV DRUGS CAN SUPPRESS VIRAL REPLICATION, BUT ONLY A SMALL SUBSET OF PATIENTS ARE CURED BY THESE TREATMENTS. ALTHOUGH A PROPHYLACTIC VACCINE IS AVAILABLE FOR HBV, IT HAS NO THERAPEUTIC BENEFIT. CONSEQUENTLY, NEW THERAPEUTIC APPROACHES ARE URGENTLY NEEDED TO COMBAT CHRONIC HBV INFECTION, PARTICULARLY IN THE CONTEXT OF HIV COINFECTION. HERE, WE WILL CAPITALIZE ON SEVERAL TECHNICAL AND CONCEPTUAL BREAKTHROUGHS FROM OUR LAB TO ESTABLISH PROOF-OF-CONCEPT FOR INTERFERING WITH PERSISTENT HBV INFECTION VIROLOGICALLY. WE HAVE RECENTLY MADE IMPORTANT DISCOVERIES THAT PROVIDE A STRONG FOUNDATION FOR THE MAJOR DIRECTION OF THIS PROPOSAL. THE PLOSS LAB IDENTIFIED KEY COMPONENTS OF THE DNA LAGGING STRAND SYNTHESIS MACHINERY THAT ARE NECESSARY AND SUFFICIENT FOR FORMATION OF HBV CCCDNA, THE REPLICATION INTERMEDIATE CRUCIAL FOR VIRAL PERSISTENCE. CLINICAL DATA FROM HBV PATIENTS INDICATE THAT CCCDNA TURNOVER OCCURS RELATIVELY RAPIDLY (SEVERAL MONTHS), OFFERING A POSSIBILITY OF CURING HBV WITH FINITE THERAPY BY COMPLETELY BLOCKING CCCDNA REPLENISHMENT. THUS, WE AIM TO DETERMINE WHETHER LIVER-SPECIFIC TRANSIENT GENETIC DISRUPTION OF POLYMERASES AND OTHER CO-FACTORS IN VIVO CAN ABROGATE HBV INFECTION (AIM 1). SINCE WE RECENTLY DEMONSTRATED THAT HBV CCCDNA FORMATION IS SUPPORTED IN MOUSE HEPATOCYTES, WE CAN TAKE ADVANTAGE OF THE POWER OF MOUSE GENETICS TO RIGOROUSLY TEST OUR HYPOTHESIS THAT GENETIC DISTRUPTION OF HOST FACTORS INVOLVED IN CCCDNA FORMATION CAN ABROGATE HBV INFECTION. FURTHERMORE, WE WILL EXTEND OUR ANALYSIS TO BLOCKING HBV CHRONICITY IN THE CONTEXT OF AN UNDERLYING HIV COINFECTION (AIM 2). TO ACHIEVE THIS GOAL, WE WILL TAKE ADVANTAGE OF A NOVEL HUMANIZED MOUSE MODEL CO-ENGRAFTED WITH HLA-MATCHED HUMAN HEPATOCYTES AND COMPONENTS OF A HUMAN HEMATOLYMPHOID SYSTEM. OUR PRELIMINARY DATA DEMONSTRATE THAT SUCH DUALLY ENGRAFTED MICE SUPPORT CHRONIC INFECTIONS WITH BOTH HBV AND HIV AND CAN MOUNT ANTIGEN-SPECIFIC T CELL RESPONSES. THIS HUMANIZED MOUSE MODEL PROVIDES UNPRECEDENTED OPPORTUNITIES FOR STUDYING THE COMPLEX INTERPLAY OF HBV/HIV CO-INFECTIONS AND WILL BE DEPLOYED HERE TO TEST RIGOROUSLY WHETHER BLOCKING HBV CCCDNA FORMATION CAN ABROGATE HBV PERSISTENCE. WE WILL CAPITALIZE ON OUR EXTENSIVE COMPLEMENTARY EXPERTISES IN VIROLOGY AND IMMUNOLOGY OF HIV-1/HBV (SU), HEPATITIS VIRUSES (PLOSS) AND HUMANIZED MOUSE TECHNOLOGY TO ACHIEVE THESE EXCITING AIMS. OUR WORK WILL ADVANCE THE FIELD OF HBV AND HIV-1 RESEARCH BY SHOWING THAT A NOVEL SMALL ANIMAL MODEL CAN BE SUCCESSFULLY USED TO UNDERSTAND HIV/HBV COINFECTION AND IMMUNE RESPONSES AND TO MODEL TREATMENTS FOR THE ASSOCIATED LIVER DISEASE.

TOWARD A BRAIN-INSPIRED MODEL OF THE FLEXIBILITY AND AUTONOMY OF HUMAN BEHAVIOR

BRAIN-TO-BRAIN DYNAMICAL COUPLING: A NEW FRAMEWORK FOR THE COMMUNICATION OF SOCIAL KNOWLEDGE

USING NATURALLY EVOLVED PHENOTYPIC VARIATION TO DECIPHER THE POSITIONAL REGULATORY CODE OF MAMMALIAN SKIN

MRI: DEVELOPMENT OF A VIRTUAL CLOUD COMPUTING INFRASTRUCTURE

REALIZING HIGH FIDELITY GATES IN PROTECTED QUBITS AND MULTIMODE QUANTUM PROCESSORS

TAS::57 3605::TAS (RECOVERY) MULTIFUNCTIONAL COLLOIDAL NANOCATALYSTS FOR LIQUID FUEL COMBUSTION

FOSSIL FREE SEQUENCING OF ARCHAIC GENOMES

CHEMICAL PROBES TO STUDY METHIONINE REDOX BIOLOGY

MECHANISMS MEDIATING IMMUNE RESPONSE UPON SENSING OF NUCLEAR VIRAL DNA

DISSECTING SENSORIMOTOR PATHWAYS UNDERLYING SOCIAL INTERACTIONS: MODELS, CIRCUITS, AND BEHAVIOR

MAPPING THE DNA DAMAGE RESPONSE IN HUMAN CELLS WITH HIGH-RESOLUTION FUNCTIONAL GENOMICS

COLLABORATIVE RESEARCH: R & D TOWARD DARKSIDE-G2, A SECOND-GENERATION DIRECT SEARCH FOR DARK MATTER