California Institute Of Technology

THE OPERATION AND MAINTENANCE OF THE LASER INTERFEROMETER GRAVITATIONAL WAVE OBSERVATORY (LIGO)

LIGO LABORATORY OPERATIONS AND MAINTENANCE 2019-2023

THE CONSTRUCTION OF THE ADVANCED LASER INTERFEROMETER GRAVITATIONAL WAVE OBSERVATORY (ADVLIGO)

TAS::89 0321::TAS; NEW- JOINT CENTER FOR ARTIFICIAL PHOTOSYNTHESIS (JCAP), PI NATHAN LEWIS

RESEARCH INFRASTRUCTURE: LIGO LABORATORY OPERATIONS AND MAINTENANCE 2024-2028 -- EXPLORING THE GRAVITATIONAL-WAVE COSMOS -RESEARCHERS AT NSF'S LASER INTERFEROMETER GRAVITATIONAL WAVE OBSERVATORY (LIGO) SEEK TO OBSERVE AND UNDERSTAND GRAVITATIONAL WAVES. GRAVITATIONAL WAVES (GWS) ARE OSCILLATIONS IN SPACE AND TIME THAT ARE GENERATED WHENEVER MASS MOVES SUDDENLY. THEY CAN CARRY INFORMATION ABOUT COSMIC CATASTROPHES, SUCH AS THE COLLISIONS OF BLACK HOLES AND NEUTRON STARS. SINCE 2015, LIGO HAS OBSERVED MORE THAN ONE HUNDRED GW EVENTS, REVEALING ENTIRELY NEW INFORMATION ABOUT THESE EXOTIC OBJECTS, WHICH ARE LOCATED TENS OR HUNDREDS OF MILLIONS OF LIGHT YEARS AWAY. THIS AWARD WILL ENABLE LIGO TO SEARCH FOR ADDITIONAL GW SIGNALS AND TO IMPROVE LIGO?S SENSITIVITY SO THAT IT CAN OBSERVE EVEN MORE DISTANT CATACLYSMS. LIGO IS THE WORLD?S PREMIER GRAVITATIONAL WAVE OBSERVATORY. IT IS A KEY PART OF AN EMERGING GLOBAL NETWORK OF SIMILAR DETECTORS. THESE ARE NOW IN OPERATION OR UNDER DEVELOPMENT IN ITALY (VIRGO), JAPAN (KAGRA), AND INDIA (LIGO INDIA). CONCURRENT MEASUREMENTS BY LIGO, VIRGO, AND OPTICAL, RADIO, AND X-RAY OBSERVATORIES HAVE INAUGURATED THE ERA OF MULTI-MESSENGER ASTRONOMY, WHERE SYNERGISTIC DETECTIONS OF GRAVITATIONAL WAVES AND ELECTROMAGNETIC WAVES REVEAL ENTIRELY NEW AND EXCITING INFORMATION ABOUT THE COSMOS. LIGO?S HISTORIC GW OBSERVATIONS WERE RECOGNIZED BY THE AWARD OF THE 2017 NOBEL PRIZE IN PHYSICS TO LIGO PIONEERS BARRY BARISH, KIP THORNE, AND RAINER WEISS. THIS AWARD WILL STIMULATE THE DEVELOPMENT OF A SCIENTIFIC AND TECHNICALLY EDUCATED WORKFORCE, ADVANCE THE MULTIDISCIPLINARY APPLICATION OF LIGO-RELATED TECHNOLOGY, AND IT WILL DISSEMINATE INFORMATION ABOUT LIGO-RELATED SCIENCE AND TECHNOLOGY TO THE GENERAL PUBLIC. THIS AWARD WILL FUND THE OPERATION OF THE EXISTING LIGO APPARATUS, AS WELL AS INSTALLATION, COMMISSIONING, AND OPERATION OF ENHANCEMENTS TO THE APPARATUS THAT WILL IMPROVE LIGO?S SENSITIVITY. THIS, AND RELATED RESEARCH ACTIVITIES, WILL CREATE CONTINUED OPPORTUNITIES FOR INTERDISCIPLINARY COLLABORATION BETWEEN LIGO STAFF MEMBERS, POST-DOCS, AND STUDENTS, AND THE APPROXIMATELY 1400 RESEARCHERS AND STUDENTS AT 127 UNIVERSITIES WORLD-WIDE THAT COLLABORATE WITH LIGO. FUNDING IS PROVIDED FOR THE CONTINUED OPERATION OF THE LIGO OBSERVATORIES AT HANFORD, WASHINGTON, AND LIVINGSTON, LOUISIANA, THE ASSOCIATED SCIENCE AND ENGINEERING SUPPORT PROGRAMS AT CALTECH AND MIT, AND FOR CARRYING OUT EDUCATION AND PUBLIC OUTREACH PROGRAMS THAT DISSEMINATE INFORMATION ABOUT LIGO. FUNDING WILL BE AWARDED THROUGH A NEW COOPERATIVE AGREEMENT FOR THE PERIOD FROM JANUARY 1, 2024, THROUGH DECEMBER 31, 2028. THE EFFORT INCLUDES: ? MAINTENANCE AND OPERATION OF THE LIGO SITES AND INTERFEROMETERS, ? COMMISSIONING THE INTERFEROMETERS TO ENHANCE THEIR SENSITIVITY TO GWS, ? CONDUCTING ASTROPHYSICAL DATA ANALYSIS AND DETECTOR CHARACTERIZATION TO DISCRIMINATE GW SIGNALS FROM NOISE SOURCES, ? CARRYING OUT RESEARCH AND DEVELOPMENT TO ENHANCE DETECTOR SENSITIVITY BEYOND THE CURRENT DESIGN PERFORMANCE, ? CURATION OF LIGO DATA AND ITS DISSEMINATION TO THE BROADER RESEARCH COMMUNITY, ? PROVISION OF SOFTWARE AND COMPUTING RESOURCES TO LIGO, AND THE DEVELOPMENT OF NEW COMPUTING TOOLS AND METHODS THAT EXTEND LIGOS DATA ANALYSIS CAPABILITIES, AND ? CONTINUATION OF THE VIBRANT OBSERVATORY-BASED LIGO EDUCATION AND PUBLIC OUTREACH PROGRAM. 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.

SUPPORT FOR OPERATIONS AND MANAGEMENT OF LIGO

DEVELOPMENT STRUCTURE AND FUNCTION OF BROADLY NEUTRALIZING ANTI-HIV ANTIBODIES

ALLIANCE ALZHEIMERS DISEASE MODEL PORTAL

IRSA ENABLES CUTTING-EDGE RESEARCH BY PROVIDING CRITICAL LONG-TERM ACCESS TO DATA SETS DOCUMENTATION AND ANALYSIS TOOLS FROM 18 PAST AND ONGOING ASTRONOMICAL MISSIONS. THESE INCLUDE IMAGES AND PHOTOMETRY FROM AN UNPARALLELED ARRAY OF INFRARED ALL

RESEARCH ACCOMPLISHMENTS AND GOALS OF THE EXPERIMENTAL HIGH ENERGY PHYSICS GROUP

THE WORK TO BE PERFORMED INCLUDES STUDIES IN QCD THEORY, LATTICE GAUGE THEORY, & HIGH ENERGY PARTICLE PHENOMENOLOGY; EXP

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

LIQUID SUNLIGHT ALLIANCE (LISA)

NEW; LIGHT-MATERIAL INTERACTIONS IN ENERGY CONVERSION -- EFRC; PI - HARRY ATWATER

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

WE PROPOSE TO ESTABLISH A COOPERATIVE AGREEMENT BETWEEN NASA AND CALTECH TO ENABLE CALTECH/IPAC TO CONTINUE OPERATING AND ADVANCING THE NASA/IPAC EXTRAGALACTIC DATABASE (NED) AND THE NASA/IPAC INFRARED SCIENCE ARCHIVE (IRSA). IPAC HAS BEEN CARRYING OUT THIS IMPLEMENTATION FOR ABOUT 28 YEARS FOR NED AND 25 YEARS FOR IRSA AND IS THEREFORE WELL PLACED TO CONTINUE THIS EFFORT UNDER THE COOPERATIVE AGREEMENT VEHICLE. MOREOVER THIS VEHICLE RESULTS IN EFFICIENCY GAINS THAT WILL ALLOW IPAC TO DEVELOP A TECHNOLOGY INITIATIVE TO ENABLE NED AND IRSA TO KEEP UP WITH THE FAST-MOVING INNOVATIONS IN THE AREAS OF DATA CURATION DATA MINING AND DATA ACCESS AND DISTRIBUTION.

THE A+ UPGRADE TO ADVANCED LIGO

WORMBASE: A CORE DATA RESOURCE FOR C. ELEGANS AND OTHER NEMATODES

POWERING THE PLANET: A CHEMICAL BONDING CENTER IN THE DIRECT CONVERSION OF SUNLIGHT INTO CHEMICAL FUEL

CCI SOLAR FUELS

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

AUTONOMOUS DIAGNOSTICS TO ENABLE PREVENTION AND THERAPEUTICS (ADEPT: DXOD - LRS)

THE NEUROBIOLOGY OF SOCIAL DECISION-MAKING

EGG TO EMBRYO: GENE REGULATORY CIRCUITRY IN DEVELOPMENT

WORMBASE: A CORE DATA RESOURCE FOR C. ELEGANS AND OTHER NEMATODES

HIGHER PRECISION HUMAN AND MOUSE TRANSCRIPTOMES

PREDOCTORAL TRAINING IN BIOLOGY AND CHEMISTRY

WORMBASE: A CORE DATA RESOURCE FOR C ELEGANS AND OTHER NEMATODES

A BRAIN CIRCUIT PROGRAM FOR UNDERSTANDING THE SENSORIMOTOR BASIS OF BEHAVIOR

STEM CELL-ENGINEERED TUMOR IMMUNITY IN MAN

INSTITUTE FOR QUANTUM INFORMATION AND MATTER (IQIM)

HIGH ENERGY PHYSICS

TRANSPORTPDB: CENTER FOR THE X-RAY STRUCTURE DETERMINATION OF HUMAN TRANSPORTERS

THE INSTITUTE FOR QUANTUM INFORMATION AND MATTER: ADVANCING THE ENTANGLEMENT FRONTIER

NANOSYSTEMS BIOLOGY CANCER CENTER 2

A GLOBAL MAP OF INTERACTIONS AMONG HUMAN CELL SURFACE PROTEINS AND SECRETED LIGANDS - PROJECT SUMMARY/ABSTRACT THE CHALLENGE ADDRESSED BY THIS PROPOSAL IS TO GENERATE A MAP, THE GLOBAL HUMAN CELL-SURFACE INTERACTOME, THAT DEFINES IN VITRO INTERACTIONS AMONG THE EXTRACELLULAR DOMAINS OF HUMAN CELLSURFACE PROTEINS (CSPS) AND SECRETED PROTEINS. THIS MAP WILL HAVE A MAJOR IMPACT ON BIOMEDICAL RESEARCH, BECAUSE CELL-CELL INTERACTIONS MEDIATED BY CSPS ARE CENTRAL TO HUMAN PHYSIOLOGY, CONTROLLING ALMOST EVERY BIOLOGICAL PROCESS THAT IS AFFECTED BY DISEASE. CSPS AND SECRETED LIGANDS COMPRISE THE MAJORITY OF THE THERAPEUTIC TARGETS THAT HAVE BEEN SUCCESSFULLY DEVELOPED IN RECENT YEARS. KNOWLEDGE OF INTERACTION PARTNERS IS ESSENTIAL FOR ASSESSING THE THERAPEUTIC POTENTIAL OF A CSP, SINCE THIS KNOWLEDGE DEFINES THE BIOLOGICAL PROCESSES THAT IT CONTROLS. FOR EXAMPLE, PD-1 WAS IDENTIFIED AS A NEGATIVE REGULATOR OF T CELL FUNCTION IN 1992, BUT ITS VALUE AS A TARGET FOR CANCER IMMUNOTHERAPY ONLY BECAME CLEAR MUCH LATER, WHEN ITS LIGAND PD-L1 WAS IDENTIFIED AND FOUND TO BE EXPRESSED ON TUMOR CELLS. WE WILL NOT ONLY GENERATE A COMPLETE MAP OF IN VITRO INTERACTIONS AMONG HUMAN CSPS AND SECRETED PROTEINS, BUT ALSO ASSESS THE FUNCTIONS OF THESE INTERACTIONS IN CELLS OF THE HUMAN IMMUNE AND NERVOUS SYSTEMS. THIS IS A HUGE PROJECT, BECAUSE THERE ARE ABOUT 2000 HUMAN SINGLE-TRANSMEMBRANE DOMAIN CSPS AND 200 “ORPHAN” SECRETED FACTORS. CREATION OF A MAP OF PAIRWISE INTERACTIONS AMONG ALL OF THESE PROTEINS REQUIRES TESTING 4.8 MILLION INTERACTIONS. THIS IS BEYOND THE CAPACITY OF CURRENT SCREENING METHODS, SO EXECUTION OF THIS SCREEN AT AN ACADEMIC INSTITUTION WILL REQUIRE THE DEVELOPMENT OF NEW TECHNOLOGIES. THIS PROJECT IS TOO LARGE TO BE SUPPORTED BY A TRADITIONAL RO1, BUT IS PERFECTLY SUITED TO THE TRANSFORMATIVE RESEARCH AWARD MECHANISM. HERE WE PROPOSE NEW WAYS TO MULTIPLEX BOTH IN VITRO BIOCHEMICAL SCREENS AND IN VIVO FUNCTIONAL SCREENS, SO AS TO MAKE IT POSSIBLE TO DEFINE ALL IN VITRO INTERACTIONS AMONG CSPS AND SECRETED LIGANDS AND TO ASSESS THE FUNCTIONS OF MANY OF THESE WITHIN A 5-YEAR FUNDING PERIOD. TO DO THIS, WE WILL FIRST MULTIPLEX AND SENSITIZE IN VITRO INTERACTOME SCREENS USING COLOR-CODED BEADS AND HIGH-AVIDITY NANOPARTICLES. WE WILL THEN DEVELOP METHODS TO CONVERT IN VITRO PROTEIN INTERACTION SCREENS INTO HIGH-THROUGHPUT DNA SEQUENCING SCREENS, WHICH HAVE A HUGE MULTIPLEXING CAPACITY. FOR THE FUNCTIONAL SCREENS, MULTIPLEXING SINGLE- CELL ANALYSIS OF CELL FATE PERTURBATIONS CAN ALLOW US TO ASSESS THE EFFECTS OF MANY DIFFERENT LIGANDS ON SINGLE IMMUNE SYSTEM AND NEURAL CELLS IN A SINGLE EXPERIMENT. THE RATIONALE FOR THE OVERALL APPROACH DESCRIBED HERE IS THAT IT DEFINES A STEPWISE PROCESS IN WHICH WE SYSTEMATICALLY DEVELOP AND OPTIMIZE SCREEN TECHNOLOGIES, THEN USE THE TECHNOLOGY THAT PERFORMS BEST FOR EXECUTION OF THE ACTUAL SCREENS.

THE USE OF RECOMBINING GENETIC MARKERS FOR DEMOGRAPHIC INFERENCE

GRADUATE RESEARCH FELLOWSHIP PROGRAM

ZWICKY TRANSIENT FACILITY

IMR-MIP DANSE - DISTRIBUTED DATA ANALYSIS FOR NEUTRON SCATTERING EXPERIMENTS - CNST

THE FUNCTIONS, MECHANISMS, AND REGULATION OF N-TERMINAL ARGINYLATION

UBIQUITIN LIGASES MECHANISMS AND FUNCTIONS OF THE N-END RULE PATHWAY

RESEARCH ACCOMPLISHMENTS AND GOALS OF THE THEORETICAL HIGH ENERGY PHYSICS GROUP

COLLABORATIVE RESEARCH: ASTRONOMY WITH CARMA

CENTER FOR THE PREDICTIVE MODELING AND SIMULATION OF HIGH ENERGY DENSITY DYNAMIC RESPONSE OF MATERIALS

US LHCNET: TRANSATLANTIC NETWORKING FOR THE LHC AND THE US HEP COMMUNITY: EVO A GLOABAL SCALE NETWORKED INFRASTURE FOR COLLABORATION BY THE LHC AND T

ASTRONOMICAL STUDIES WITH THE CALTECH SUBMILLIMETER OBSERVATORY

MRSEC: CENTER FOR THE SCIENCE AND ENGINEERING OF MATERIALS

COLLABORATIVE RESEARCH: THE MOLECULAR PROGRAMMING PROJECT

EQUIPMENT: COSMIC EXPLORER BEAMTUBE EXPERIMENT -THE 2015 DISCOVERY AND ONGOING OBSERVATIONS OF GRAVITATIONAL WAVES BY NSF'S LASER INTERFEROMETER GRAVITATIONAL-WAVE OBSERVATORY (LIGO) HAVE TRANSFORMED MANKIND'S PERCEPTION OF THE UNIVERSE, REVOLUTIONIZING MODERN ASTROPHYSICS, COSMOLOGY, AND GENERAL RELATIVITY. UPGRADES TO THE 4-KILOMETER LIGO DETECTORS CONTINUE TO EXPAND THEIR HORIZONS, BUT LIGO CAN ULTIMATELY ONLY ACCESS THE LOCAL GRAVITATIONAL NEIGHBORHOOD. TO ACHIEVE A COSMOLOGICAL REACH, COMPLEMENT TRADITIONAL MODES OF OBSERVATION, AND GRAVITATIONALLY PROBE THE UNIVERSE BACK TO ITS INFANCY WILL REQUIRE LARGER-SCALE ?NEXT-GENERATION? INTERFEROMETERS. THE PLANNED COSMIC EXPLORER (CE) OBSERVATORY, TEN TIMES LARGER THAN LIGO, WILL MAINTAIN AND ADVANCE US LEADERSHIP IN THIS REVOLUTIONARY NEW FIELD. HOWEVER, CONSTRUCTING THE 40-KM ULTRAHIGH-VACUUM (UHV) LASER BEAMTUBES NEEDED TO REALIZE CE REPRESENTS A KEY TECHNICAL CHALLENGE. THIS AWARD WILL SUPPORT THE DEVELOPMENT AND TESTING OF SCALABLE TECHNOLOGY TO IMPLEMENT HIGH-PERFORMANCE, RELIABLE, AND ECONOMICAL VACUUM BEAMTUBES AT THE LARGEST PHYSICAL SCALE EVER ATTEMPTED, ON A TIMESCALE COMPATIBLE WITH CE CONSTRUCTION AND OBSERVATIONS. BY HELPING TO ENABLE CE, THE COSMIC EXPLORER BEAMTUBE EXPERIMENT (CEBEX) ADVANCES GRAVITATIONAL WAVE OBSERVATIONAL SCIENCE, WHILE PROJECTING NOVEL STUDIES OF ULTRAHIGH VACUUM ENVIRONMENTS FOR PHYSICAL SCIENCE RESEARCH, MANUFACTURING TECHNOLOGY, AND SURFACE SCIENCE INTO NEW REALMS. UNDER THIS AWARD, THE CEBEX TEAM, BASED AT LIGO HANFORD OBSERVATORY, WILL DESIGN, CONSTRUCT, AND TEST A 1.2M DIAMETER BY 120M LONG PROTOTYPE UHV BEAMTUBE SECTION AS A TECHNOLOGY PATHFINDER FOR THE CE OBSERVATORY. THE SCALE OF THIS ACTIVITY REQUIRES THE CONSTRUCTION OF A PURPOSE-BUILT LAB STRUCTURE ON AVAILABLE LAND AT THE CURRENT LIGO SITE. BEAMTUBE MATERIALS, CONSTRUCTION METHODS, AND INDUSTRIAL PROCESSES WILL BE IMPLEMENTED AND TESTED TO CONFIRM FEASIBILITY, SCALABILITY, AND COMPLIANCE WITH CE REQUIREMENTS. IN THE FINAL YEAR OF THE PLANNED 4.25-YEAR AWARD, THE TEAM WILL APPLY THE RESULTS OF THIS RESEARCH TO DELIVER TO NSF AN EFFICIENT CONCEPTUAL REFERENCE DESIGN, PARAMETRIC COST ESTIMATE, AND SCHEDULE FRAMEWORK FOR CE BEAMTUBE CONSTRUCTION. THESE WILL FORM KEY UNDERPINNINGS OF PENDING FUTURE CE DESIGN AND CONSTRUCTION INITIATIVES. 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.

PARTIAL SUPPORT OF JOINT USGS-CALTECH SOUTHERN CALIFORNIA SEISMIC NETWORK

TAS::57 3600::TAS (MURI) REVOLUTIONARY ADVANCES IN CORRELATED ELECTRON MATERIALS: FROM STRONGLY COORDINATED ELECTRONS TO LARGE SCALE DFT

TAS::57 3600::TAS "(MURI-2016) UNIVERSAL ELECTROMAGNETIC SURFACE: EXPLOITING ACTIVE ELECTRONICS AND ACTIVE ORIGAMI TO GENERATE A PROGRAMMABLE

TAS::57 3600::TAS (MURI) 'SCALABLE CERTIFICATION OF QUANTUM COMPUTING DEVICES AND NETWORKS'

REGION-SPECIFIC, INDUCIBLE AXONAL TRACT-TRACING IN BRAIN

THE PURPOSE OF THIS COOPERATIVE AGREEMENT IS TO FUND RESEARCH IN SUPPORT OF THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY, MICROSYSTEMS TECHNOLOGY OFFICE, FOR THE GENERATING RF WITH PHOTONIC OSCILLATORS FOR LOW NOISE PROGRAM.

SMART MEMS RECORDING SYSTEMS FOR VISUAL CORTICAL STUDIES

PARTIAL SUPPORT OF JOINT USGS-CALTECH SOUTHERN CALIFORNIA SEISMIC NETWORK

DURING FY25-30 THE VOLUME OF IRSA'S HOLDINGS WILL GROW BY AN ORDER OF MAGNITUDE (SEC.2) AS WE INGEST DATA FROM EUCLID SPHEREX NEORVEYOR ULTRASAT AND ARIEL. THESE NEW MISSIONS WILL BE TRANSFORMATIONAL IN ALL SCIENCE AREAS HIGHLIGHTED IN THE 2020 DECADAL SURVEY REPORT. IRSA WILL ALSO CONTINUE TO RELEASE DATA FROM NEOWISE IRTF AND THE COMMUNITY RESOURCES WHICH HAVE A STRONG TRACK RECORD OF ENABLING NOVEL RESEARCH. WE WILL ALSO CONTINUE OUR SUCCESSFUL INITIATIVE TO PROVIDE PUBLIC ACCESS TO SIMULATED DATA NECESSARY FOR THE SUCCESS OF THE NEXT GENERATION OF COSMOLOGY SURVEYS.

NANOSYSTEMS BIOLOGY CANCER CENTER

PHYSICAL GENOMICS: FROM SINGLE-CELL TO EVOLUTIONARY DYNAMICS

MO & DA OF THE ADVANCE COMPOSITION EXPLORER MISSION PHASE 2DATA AN ALYSIS ACTIVITIES BY CALTECH'S

THE PURPOSE OF THIS COOPERATIVE AGREEMENT IS TO FUND RESEARCH TO THE AWARDEE TO CARRY OUT SUPPORT TO BTO IN THE AMOUNT OF 722,098 ON CONTRACT HR0011-

22ROMAN220020 RAPID ROMAN ALERTS PROMPTLY FROM IMAGE DIFFERENCING

CENTER: INSTITUTE FOR QUANTUM INFORMATION AND MATTER: IQIM -EXPLORING THE SURPRISING PHENOMENA THAT ARISE IN COMPLEX QUANTUM SYSTEMS IS ONE OF THE MOST EXCITING FRONTIERS OF 21ST-CENTURY SCIENCE. UNDERSTANDING AND HARNESSING HIGHLY ENTANGLED QUANTUM SYSTEMS WILL YIELD NEW MATERIALS, NEW COMMUNICATION AND COMPUTATION METHODS, AND NEW INSIGHTS INTO THE STRUCTURE OF THE UNIVERSE. THE INSTITUTE FOR QUANTUM INFORMATION AND MATTER (IQIM) WILL ADVANCE THIS FRONTIER THROUGH THE COLLABORATIVE EFFORTS OF THEORISTS AND EXPERIMENTALISTS INVESTIGATING EXOTIC COLLECTIVE PHENOMENA WHICH AMPLIFY THE WEIRDNESS OF THE QUANTUM WORLD TO MACROSCOPIC SCALES. IQIM WILL ESTABLISH NEW PARADIGMS FOR UNDERSTANDING NATURE AND LAY THE FOUNDATIONS FOR POTENTIALLY REVOLUTIONARY TECHNOLOGIES, WHILE TRAINING A NEW GENERATION OF LEADERS WHO WILL DEFINE THE FUTURE OF QUANTUM SCIENCE AND ENGINEERING. IN ADDITION, IQIM WILL STOKE THE PUBLIC'S FASCINATION WITH THE MYSTERIES OF THE QUANTUM REALM, ENHANCING PUBLIC ENGAGEMENT THROUGH THE DEVELOPMENT OF GAMES AND VIDEOS AND STRATEGIC USE OF SOCIAL MEDIA. IQIM RESEARCH IS ORGANIZED INTO THREE MAJOR ACTIVITIES. MA-1 (QUANTUM INFORMATION PHYSICS) CONNECTS IDEAS DRAWN FROM COMPUTER SCIENCE, INFORMATION THEORY, ENGINEERING, AND MATHEMATICS TO EXPERIMENTAL QUANTUM INFORMATION PLATFORMS SUCH AS SUPERCONDUCTING CIRCUITS AND TRAPPED ULTRACOLD ATOMS. MA-2 (NEXT-GENERATION QUANTUM METROLOGY) EMPHASIZES OPPORTUNITIES TO ENHANCE QUANTUM SENSING USING HIGHLY CONTROLLABLE QUANTUM SYSTEMS INCLUDING ATOMS AND SPINS COUPLED TO OPTICAL CAVITIES, AND STRONGLY CORRELATED MATERIALS. MA-3 (BUILDING AND DRIVING QUANTUM MATTER) BUILDS ON RECENT ADVANCES IN QUANTUM MATERIALS AND QUANTUM SIMULATION PLATFORMS TO REALIZE PREVIOUSLY INACCESSIBLE PHASES OF MATTER, WITH EMPHASIS ON FRACTIONALIZED PHASES, TOPOLOGICAL SUPERCONDUCTIVITY, DEFECT-BOUND QUANTUM WIRES, AND DYNAMICAL FLOQUET PHASES. BY COMBINING QUANTUM COMPUTING, SIMULATION, MATERIALS, AND METROLOGY INTO A UNIFIED CENTER LOCATED ON A SINGLE CAMPUS, IQIM IS BUILDING AN INTERCONNECTED COMMUNITY WELL SUITED TO TAKE ADVANTAGE OF THE SYNERGY AMONG THESE RESEARCH THRUSTS. BY FOCUSING ON THE POTENTIAL FOR QUANTUM TECHNOLOGY TO FACILITATE SCIENTIFIC DISCOVERIES, THIS RESEARCH CAN LAY THE FOUNDATIONS FOR FUTURE TECHNOLOGIES NOT YET IMAGINED. 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.

THE SUPPORT AND IMPROVEMENT OF SHAKEALERT 2021-2023: COLLABORATIVE RESEARCH WITH UNIV. OF CALIFORNIA AT BERKELEY, CALIFORNIA INSTITUTE OF TECHNOLOGY, UNIV. OF WASHINGTON, AND UNIV. OF OREGON

MEMOIR: RECORDING, AND IN SITU READOUT OF CELL LINEAGE AND TRANSCRIPTIONAL HISTORY

PARTIAL SUPPORT OF JOINT USGS-CALTECH SOUTHERN CALIFORNIA SEISMOGRAPHIC NETWORK

MO&DA OF THE ADVANCED COMPOSITION EXPLORER MISSION (ACE)

CENTER FOR OPTO FLUIDIC INTEGRATION.

QUANTUM MATERIALS BY DESIGN WITH ELECTROMAGNETIC EXCITATION

ACCURATE MOLECULAR DECISION MAKING DURING PROTEIN BIOGENESIS

MASSIVELY PARALLEL HIGH-SPEED 3D FUNCTIONAL PHOTOACOUSTIC COMPUTED TOMOGRAPHY OF THE ADULT HUMAN BRAIN

CHEMICAL SYNTHESIS OF CHIRAL BIOACTIVE MOLECULES

MSIP: THE KECK PLANET FINDER

COLLABORATIVE RESEARCH: ASTRONOMY WITH CARMA

HIGH-SPEED PANORAMIC 3D PHOTOACOUSTIC COMPUTED TOMOGRAPHY OF THE BREAST

CENTER FOR THE PREDICTIVE MODELING AND SIMULATION OF HIGH ENERGY DENSITY DYNAMIC RESPONSE OF MATERIALS

TARGETING DIET MICROBIOME INTERACTIONS IN THE PATHOGENESIS OF PARKINSONS DISEASE

THE DSA: A FAST RADIO BURST LOCALIZATION MACHINE

PREDICTING AND CONTROLLING THE RESPONSE OF PARTICULATE SYSTEMS THROUGH GRAIN-SCALE ENGINEERING

MATERIALS ON THE BRINK: UNPRECEDENTED TRANSFORMING MATERIALS.

CONTINUED SUPPORT AND DEVELOPMENT OF SBML AND ESSENTIAL SBML INFRASTRUCTURE

ENGINEERED AAV IDENTIFICATION, VALIDATION, AND DISSEMINATION PIPELINE FOR BRAIN CELL TYPE-SPECIFIC MANIPULATION ACROSS SPECIES - PROJECT SUMMARY: THIS TEAM INITIATIVE WILL PROVIDE THE BROAD NEUROSCIENCE COMMUNITY WITH A CELL TYPE-SPECIFIC ADENO- ASSOCIATED VIRUS (AAV) ARMAMENTARIUM FOR EASY AND NON-INVASIVE IMPLEMENTATION OF NOVEL AND EMERGING MOLECULAR TOOLS FOR ANATOMICAL AND FUNCTIONAL ANALYSIS OF THE NERVOUS SYSTEM IN RODENTS, NON-HUMAN PRIMATES, AND HUMAN ORGANOIDS. WE WILL CHARACTERIZE ENGINEERED AAV CAPSIDS FOR CELL TYPE- AND BRAIN REGION-SPECIFIC GENE DELIVERY (AIM 1). WE WILL PAIR THESE CAPSIDS WITH CARGOS OF RECENTLY OPTIMIZED AND NEWLY DEVELOPED SENSORS AND EFFECTORS, LARGELY ENABLED BY THE BRAIN INITIATIVE, AND VALIDATE THEIR FUNCTIONAL UTILITY FOR LARGE- SCALE MONITORING AND MANIPULATION OF BRAIN FUNCTION ACROSS SPECIES (AIM 2). FINALLY, WE WILL ESTABLISH AN ELECTRONIC AAV RESOURCE PORTAL TO CATALOGUE AND DISSEMINATE ALL OF THESE TOOLS TO THE BROADER RESEARCH COMMUNITY (AIM 3). THIS PROPOSAL PROMISES TO VALIDATE A BROAD ARRAY OF ENGINEERED SYSTEMIC AAVS WITH ACCESS TO MOLECULARLY DEFINED NEURONAL CELL TYPES FOR DELIVERY OF BRAIN-RELEVANT CARGO AND FUNCTIONAL INTERROGATION OF BRAIN CELLS ACROSS SPECIES. TO MAXIMIZE THE UTILITY OF THESE TOOLS TO THE NEUROSCIENTIFIC COMMUNITY, WE WILL ENGAGE IN BROAD COLLABORATION AND DISSEMINATION. BUILDING ON THE CLOVER CENTER’S ESTABLISHED NETWORK OF AAV PRODUCTION FACILITIES, WE WILL FACILITATE THE BROAD ADOPTION OF SYSTEMIC AAVS THROUGH CONSULTATION AND COLLABORATION, INCLUDING PROVISION OF COST- FREE SAMPLE AAV PREPS. WE WILL EXPLORE METHODOLOGICAL INNOVATIONS IN AAV PRODUCTION AND ADMINISTRATION WHILE CATALYZING THE EARLY-STAGE ADOPTION AND VALIDATION OF ENGINEERED CAPSIDS IDENTIFIED IN THIS PROPOSAL BY CREATING AN ELECTRONIC AAV RESOURCE FOR DISSEMINATION OF REAGENTS AND BEST PRACTICES, CONTAINING CATALOGUED AAV BRAIN ATLASES AND A DATA RE-CAPTURE PORTAL FOR CONTINUOUS, CROWD-SOURCED VALIDATION. THE EXPERTISE AND INFRASTRUCTURE BUILT OVER THE LIFE OF THIS PROPOSAL WILL FORM THE FOUNDATION OF A LONG-TERM COMPREHENSIVE CENTER FOR AAV BRAIN SENSUS (SAFE AND EFFECTIVE NEUROMODULATOR AND SENSOR UTILIZATION ACROSS SPECIES) THAT WILL OPEN NEW DOORS FOR NEUROSCIENCE TOOL VALIDATION AND DISSEMINATION.

THE GOAL OF THIS OPPORTUNITY IS TO FUND ARCHIVES THAT MAKE SCIENTIFIC DATA FROM NASA ASTROPHYSICS FLIGHT MISSIONS AND NASA-FUNDED RESEARCHERS AVAILABLE TO THE US COMMUNITY OR THAT HOLD BIBLIOGRAPHIC AND CATALOG INFORMATION RELATED TO THOSE DATA.

COLLABORATIVE RESEARCH: ASTRONOMY WITH CARMA - RAISING OUR SITES

CENTER FOR THE PREDICTIVE MODELING AND SIMULATION OF HIGH ENERGY DENSITY DYNAMIC RESPONSE OF MATERIALS

THIS PROPOSAL IS FOR A 5-YEAR EXTENSION OF NASA GRANT NNX08AI11G. THIS GRANT IS FOR MISSION OPERATIONS AND SCIENTIFIC DATA ANALYSIS (MO&DA) OF DATA F

PROJECT INFRASTRUCTURE FOR THE ROMAN GALAXY REDSHIFT SURVEY

TAS::57 3600::TAS "INTEGRATED MICRO-AND NANO-OPTOMECHANICAL DEVICES FOR SENSORS OSCILLATORS AND PHOTONICS"

THE 2015 HELIOPHYSICS SENIOR REVIEW PANEL UNDERTOOK A REVIEW OF 15 MISSIONS CURRENTLY IN OPERATION IN APRIL 2015. THE PANEL FOUND THAT ALL THE MISSIONS CONTINUE TO PRODUCE SCIENCE THAT IS HIGHLY VALUABLE TO THE SCIENTIFIC COMMUNITY AND THAT THEY ARE AN EXCELLENT INVESTMENT BY THE PUBLIC THAT FUNDS THEM. AT THE TOP LEVEL THE PANEL FINDS: NASA S HELIOPHYSICS DIVISION HAS AN EXCELLENT FLEET OF SPACECRAFT TO STUDY THE SUN HELIOSPHERE GEOSPACE AND THE INTERACTION BETWEEN THE SOLAR SYSTEM AND INTERSTELLAR SPACE AS A CONNECTED SYSTEM. THE EXTENDED MISSIONS COLLECTIVELY CONTRIBUTE TO ALL THREE OF THE OVERARCHING OBJECTIVES OF THE HELIOPHYSICS DIVISION. O UNDERSTAND THE CHANGING FLOW OF ENERGY AND MATTER THROUGHOUT THE SUN HELIOSPHERE AND PLANETARY ENVIRONMENTS. O EXPLORE THE FUNDAMENTAL PHYSICAL PROCESSES OF SPACE PLASMA SYSTEMS. O DEFINE THE ORIGINS AND SOCIETAL IMPACTS OF VARIABILITY IN THE EARTH/SUN SYSTEM. ALL THE MISSIONS REVIEWED HERE ARE NEEDED IN ORDER TO STUDY THIS CONNECTED SYSTEM. PROGRESS IN THE COLLECTION OF HIGH QUALITY DATA AND IN THE APPLICATION OF THESE DATA TO COMPUTER MODELS TO BETTER UNDERSTAND THE PHYSICS HAS BEEN EXCEPTIONAL. THE FUNDS INVESTED IN THE MISSION OPERATION&DATA ANALYSIS (MO&DA) BUDGET ARE PROVIDING AN EXCELLENT RETURN IN TERMS OF OUR BETTER UNDERSTANDING THE GEOSPACE ENVIRONMENT IN WHICH OUR TECHNOLOGICAL SOCIETY FUNCTIONS. THE REVIEW NOTED A FEW SERIOUS PROBLEMS WITHIN THE PORTFOLIO. FOR VARIOUS REASONS SOME OF THE MISSIONS ARE NOT BEING FUNDED AT AN ADEQUATE LEVEL (THE TOTAL MO&DA BUDGET IS UNFORTUNATELY LOW SUCH THAT THERE IS NOT ENOUGH MONEY TO DO THE SCIENCE PROPOSED). FOR THE VOYAGER MISSION THERE ARE MULTIPLE PROBLEMS REGARDING DATA ACCESS AND ARCHIVAL STORAGE THAT NEED TO BE ADDRESSED. IN ADDITION THE PERFORMANCE OF THE MAGNETOMETER TEAM IS SERIOUSLY DEFICIENT. THE SDO MISSION HAS FINANCIAL AND MANAGEMENT PROBLEMS THAT NEED TO BE ADDRESSED AT THE NASA HQ LEVEL.

HOMEOSTATIC MECHANISMS REGULATING MITOCHONDRIAL HEALTH

MULTIMODAL MPET & MMRI IMAGING INSTRUMENTATION

(MURI-06) SPECIFICATION, DESIGN AND VERIFICATION OF DISTRIBUTED EMBEDDED SYSTEMS

EXPLORING & EXPLOITING THE DYNAMIC OPTICAL SKY

BIOGENIC GAS NANOSTRUCTURES AS MOLECULAR IMAGING REPORTERS FOR ULTRASOUND

NEXT-GENERATION SPATIAL -OMICS: HIGH-THROUGHPUT, SINGLE-MOLECULE PROTEOMIC IMAGING WITH SUBCELLULAR RESOLUTION - PROJECT SUMMARY DEEP PROTEOMIC AND METABOLOMIC PROFILING OF BIOLOGICAL TISSUES IS AN OVERARCHING GOAL OF MODERN BIOLOGICAL AND BIOMEDICAL RESEARCH. IT REMAINS A KEY – AND CONSPICUOUS – MISSING COMPONENT FROM THE FULL SPECTRUM OF -OMICS THAT MAINLY CAPITALIZE ON NEXT-GENERATION SEQUENCING OF DNA AND RNA. TODAY'S EXISTING METHODOLOGIES FOR PROTEOMIC AND METABOLOMIC ANALYSIS CURRENTLY LAG FAR BEHIND THE CAPABILITIES OF TOOLS FOR GENOMICS AND TRANSCRIPTOMICS, BOTH IN TERMS OF DEPTH-OF-COVERAGE AND THROUGHPUT. THE PROPOSED EFFORT WILL MEET THIS CHALLENGE BY ADVANCING REVOLUTIONARY NEW METHODS FOR LABEL-FREE SINGLE-MOLECULE PROTEOMIC AND METABOLOMIC PROFILING AND COMBINING THEM WITH NOVEL METHODS FOR SUB-CELLULAR SPATIAL ANALYSIS. PROTEIN CONCENTRATIONS WITHIN A MAMMALIAN CELL SPAN ~8 ORDERS OF MAGNITUDE; IN HUMAN BLOOD SERUM THIS INCREASES TO ~11 ORDERS. YET, WITHIN THESE IMMENSELY COMPLEX MILIEUS, EVEN THE MOST SPARSELY EXPRESSED PROTEINS ARE IMPORTANT. CELLULAR SIGNALING, GENE REGULATION, EARLY RESPONSES TO EXOGENOUS BIOLOGICAL STIMULI, AND DISEASE ONSET ALL GENERALLY RESULT IN THE EXPRESSION OF SMALL COPY NUMBERS OF PROTEINS. IT IS THUS ESSENTIAL BOTH TO DISCOVER RARE CELLULAR PROTEINS AND TO ATTAIN HOLISTIC PROTEOMIC MAPS – BUT THESE GOALS REMAIN FAR BEYOND PRESENT TECHNOLOGICAL CAPABILITIES. FURTHER, DECIPHERING THE INSTANTANEOUS STATE OF AN ORGANISM'S PROTEOME – AND, ESPECIALLY, OBSERVING ITS POST-TRANSLATIONAL MODIFICATIONS (PTMS) AS THEY DYNAMICALLY EVOLVE IN RESPONSE TO CELLULAR FUNCTION, STRESS, AND DISEASE – WILL PROVIDE TRANSFORMATIONAL KNOWLEDGE FOR MANY FIELDS. DEEP PROTEOME DISCOVERY WILL TACKLE THE CELLULAR PROTEOME'S COMPLEXITY, ALLOWING IDENTIFICATION OF PROTEINS OVER ITS ENTIRE DYNAMIC RANGE OF CONCENTRATION – FROM THE MOST PROLIFICALLY EXPRESSED CELLULAR PROTEINS TO THOSE ONLY SPARSELY EXPRESSED WITH A FEW COPIES PER CELL. THIS PROJECT'S SUCCESS WILL ENABLE DEEP SPATIAL PROFILING OF THE CELLULAR PROTEOME AND METABOLOME WITH HIGH THROUGHPUT AND, THEREBY, DISCOVERY OF RARE CELLULAR PROTEINS AND METABOLITES. IT WILL FUNDAMENTALLY CHANGE THE RESOLUTION OF PROTEIN ANALYSIS DOWN TO THE LEVEL OF INDIVIDUAL MOLECULES IN SUBCELLULAR COMPARTMENTS. ITS ACHIEVEMENT WILL COMPLETE THE CONSTELLATION OF SINGLE-CELL -OMICS, THEREBY BROADLY ADVANCING RESEARCH WORLDWIDE IN FIELDS THAT SPAN FROM FUNDAMENTAL BIOLOGY TO THE FRONTIERS OF CLINICAL MEDICINE. IN THE PROPOSED EFFORT, EXISTING AND WELL-VALIDATED TECHNIQUES FOR SPATIALLY-RESOLVED TISSUE SAMPLING WILL BE PUSHED DOWNWARD INTO THE SUB-CELLULAR REALM. SCALING THESE METHODS DOWNWARD IS FEASIBLE NOW SOLELY BECAUSE OF THE SINGLE-MOLECULE RESOLUTION OF THE PROPOSED APPROACH. THIS PROJECT BUILDS UPON A SIGNIFICANT BODY OF RECENT EFFORTS FOCUSED UPON CREATING INSTRUMENTATION FOR DEEP PROFILING OF THE SINGLE-CELL PROTEOME. THE EFFORT PROPOSED HERE WILL FURTHER ADVANCE THESE ACHIEVEMENTS – AND WILL INCORPORATE HIGH-RESOLUTION TISSUE-SAMPLING METHODS TO DELIVER, WITH MINIMAL LOSS, BIOLOGICAL ANALYTES TO INSTRUMENTATION ENABLING SINGLE-MOLECULE ANALYSIS. PURSUED TOGETHER, THESE EFFORTS WILL ENABLE THE FIRST REALIZATION OF SPATIAL PROTEOMICS WITH SUB-CELLULAR RESOLUTION.

SINGLE CELL ANALYSIS OF THE KINOME - PROJECT SUMMARY PROFILING KINASES AND THEIR ACTIVITIES IN SINGLE CELLS WILL ENABLE EXPLORATION OF CELL TYPE SPECIFIC FUNCTIONAL AND BIOCHEMICAL PATHWAYS. WHILE WE HAVE LEARNED A GREAT DEAL ABOUT TRANSCRIPTIONAL STATES OF DIFFERENT CELL TYPES IN THE PAST DECADE THROUGH SINGLE CELL GENOMICS, WE STILL UNDERSTAND LITTLE ABOUT PROTEINS AND IN PARTICULAR KINASES NETWORKS IN DIVERSE CELL POPULATIONS. THIS IS LARGELY BECAUSE SINGLE-CELL KINOME ANALYSIS FACES MAJOR TECHNICAL CHALLENGES. UNLIKE NUCLEIC ACIDS, PROTEINS CANNOT BE AMPLIFIED, MAKING DETECTION OF MINUTE QUANTITIES FROM SINGLE CELLS DIFFICULT. WE RECENTLY DEMONSTRATED A PROOF-OF-PRINCIPLE EXPERIMENT TO ACCURATELY DETECT PROTEIN PTM ISOFORMS IN SINGLE CELLS. HERE WE PROPOSE TO SCALE THIS METHOD UP TO PROFILE KINASES AT THE GLOBAL LEVEL IN SINGLE CELLS IN BOTH CELL CULTURE AND IN TISSUES. WE WILL INTEGRATE THE SINGLE CELL KINOME ANALYSIS WITH RNA MEASUREMENTS TO IDENTIFY CELL TYPE SPECIFIC KINASE PROFILES. ULTIMATELY, WE WILL MAP THE KINOME WITH SPATIAL CONTEXT IN THE MOUSE AND HUMAN BRAIN TO EXAMINE THE KINASE PATHWAYS INVOLVED IN AGING AND NEURODEGENERATION WHICH COULD IDENTIFY DRUGGABLE TARGETS. THIS PROJECT IS A MAJOR DEPARTURE FROM OUR CURRENT RESEARCH. ITS GOALS ARE AMBITIOUS BUT ACHIEVABLE. THE PROJECT WILL LEVERAGE OUR EXPERTISE IN SINGLE CELL TECHNOLOGY DEVELOPMENT AND IN APPLICATION OF NEW TECHNOLOGY TO DIVERSE BIOLOGICAL SYSTEMS.

SONOGENETIC REMOTE CONTROL OF CELLULAR FUNCTION - SUMMARY THE DISCOVERY AND DEVELOPMENT OF FLUORESCENT PROTEINS AND OPTOGENETICS REVOLUTIONIZED BIOLOGY BY MAKING IT POSSIBLE TO IMAGE AND CONTROL SPECIFIC CELLULAR PROCESSES WITH VISIBLE LIGHT. WHILE THESE TOOLS HAVE ENABLED COUNTLESS BIOLOGICAL DISCOVERIES, THE POOR PENETRATION OF LIGHT INTO LIVING TISSUE MAKES IT DIFFICULT TO USE OPTICAL TECHNIQUES IN INTACT ANIMALS. AS A RESULT, BIOLOGICAL PHENOMENA RANGING FROM THE SIGNALING OF NEURONS IN DEEP- BRAIN REGIONS, TO THE INFILTRATION OF IMMUNE CELLS INTO TUMORS, TO THE MICROBIAL COLONIZATION OF THE GI TRACT, ARE CHALLENGING TO STUDY WITHIN THEIR NATURAL IN VIVO CONTEXT. IF INSTEAD OF LIGHT IT WERE POSSIBLE TO VISUALIZE AND MANIPULATE CELLULAR FUNCTION USING A MORE PENETRANT FORM OF ENERGY SUCH AS ULTRASOUND, THIS WOULD OPEN PREVIOUSLY INACCESSIBLE DOMAINS OF IN VIVO BIOLOGY TO DIRECT INVESTIGATION. IN ADDITION, IT WOULD ENHANCE THE DEVELOPMENT OF CELL-BASED THERAPIES BY ALLOWING CELLULAR AGENTS TO BE SEEN AND CONTROLLED AFTER ADMINISTRATION INTO THE HUMAN BODY. THE PHYSICS OF ULTRASOUND MAKE IT AN IDEAL MODALITY FOR DEEP-TISSUE CELLULAR COMMUNICATION. SOUND WAVES IN THE MHZ RANGE ARE WEAKLY SCATTERED BY TISSUE AND CAN THEREFORE PENETRATE SEVERAL CM INTO THE BODY. WITH WAVELENGTHS ON THE ORDER OF 100 ΜM AND TRAVEL TIMES < 1 MS, ULTRASOUND CAN ACCESS MANY KEY STRUCTURES AND PROCESSES. WHEN FOCUSED, SOUND WAVES CAN DELIVER MECHANICAL AND THERMAL ENERGY TO PRECISE ANATOMICAL LOCATIONS. THESE PROPERTIES HAVE ALREADY MADE ULTRASOUND ONE OF THE WORLD’S MOST WIDELY USED TECHNOLOGIES FOR MEDICAL IMAGING AND NON-INVASIVE SURGERY. HOWEVER, THE POTENTIAL OF ULTRASOUND TO SERVE AS A TOOL FOR CELLULAR IMAGING AND CONTROL HAS BEEN RELATIVELY UNTAPPED DUE TO A LACK OF METHODS TO CONNECT IT TO THE FUNCTION OF SPECIFIC CELLS AND BIOMOLECULES. IN PREVIOUS WORK, THE SHAPIRO LAB HAS PIONEERED THE USE OF ULTRASOUND IN CELLULAR AND MOLECULAR IMAGING BY DEVELOPING THE FIRST ACOUSTIC REPORTER GENES AND BIOSENSORS FOR ULTRASOUND, AIMING TO “DO FOR ULTRASOUND WHAT FLUORESCENT PROTEINS HAVE DONE FOR FLUORESCENCE MICROSCOPY”. THE MAJOR GOAL OF OUR PROPOSED NEW RESEARCH DIRECTION IS TO “DO FOR ULTRASOUND WHAT OPTOGENETICS HAS DONE FOR LIGHT” BY GIVING SOUND WAVES THE ABILITY TO CONTROL SPECIFIC CELLULAR FUNCTIONS SUCH AS NEURONAL EXCITATION, GENE EXPRESSION AND INTRACELLULAR SIGNALING IN VIVO. THE BASIC PRINCIPLE OF OUR APPROACH IS TO (1) USE FOCUSED ULTRASOUND TO DEPOSIT ACOUSTIC ENERGY AT A SPECIFIC LOCATION IN TISSUE, (2) USE GENETICALLY ENCODED “ACOUSTIC ANTENNAE” TO CONVERT THIS ENERGY INTO LOCAL MECHANICAL FORCE, AND (3) USE THIS FORCE TO ACTUATE MECHANOSENSITIVE RECEPTORS TO PRODUCE SPECIFIC CELLULAR SIGNALS. WE WILL IMPLEMENT THIS APPROACH IN NEURONS AND IMMUNE CELLS TO ENABLE UNIQUE NEUROSCIENCE AND CELL THERAPY APPLICATIONS. IF SUCCESSFUL, THIS WORK WILL HELP ESTABLISH THE NEW FIELD OF SONOGENETICS BY PROVIDING RESEARCHERS AND CLINICIANS WITH THE UNPRECEDENTED ABILITY TO “POINT AND CLICK” ON CELLS DEEP WITHIN THE BODY AND TELL THEM WHAT TO DO.

CIRCUIT-SPECIFIC DELIVERY OF LARGE CARGO ACROSS THE NERVOUS SYSTEMS OF ADULT MAMMALS AND EMBRYOS VIA NOVEL ENGINEERED SYSTEMIC VECTORS

DEVELOPMENTAL PROGRESSION DRIVING GASTRULATION OF THE DROSOPHILA EARLY EMBRYO

PLACENTAL MODELS TO SUPPORT EMBRYOGENESIS IN VITRO

THE PURPOSE OF THIS COOPERATIVE AGREEMENT IS TO FUND RESEARCH IN SUPPORT OF BTO IN THE AMOUNT OF 1,904,794 ON CONTRACT HR0011-17-2-0037.

MULTIPLEX FLUORESCENCE OPTOFLUIDIC MICROSCOPY FOR DIAGNOSIS OF ENTERIC PARASITES

DYNAMICS OF CHROMOSOME ORGANIZATION AND CHROMATIN STATES IN SINGLE CELLS

SPIDER: A LARGE ANGULAR SCALE MILLIMETER-WAVE POLARIMETERWE PROPOSE SPIDER: A NEW LONG-DURATION BALLOON EXPERIMENT TO MAP THE POLARIZATION OFTHE CM

NICOTINIC LIGANDS FOR SMOKING CESSATION

NEW START MURI TITLE: DISORDER ENGINEERING: A GEOMETRY-ENHANCED NETWORK THEORY FOR IRREGULAR METAMATERIALS (GENT-MET)

ELECTRON TRANSFER PROCESSES IN IRON AND COPPER PROTEINS

METAL-CATALYZED COUPLING REACTIONS

ASTRONOMICAL STUDIES WITH THE CALTECH SUBMILLIMETER OBSERVATORY

THE PURPOSE OF THIS COOPERATIVE AGREEMENT IS TO FUND RESEARCH IN SUPPORT OF THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY DARPA MICROSYSTEMS TECHNOLOGY OFFICE MTO FOR THE LASERS FOR UNIVERSAL MICROSCALE OPTICAL SYSTEMS LUMOS PROGRAM.

THE SELF-TUNING BRAIN: CELLULAR AND CIRCUIT MECHANISMS OF BEHAVIORAL RESILIENCE

HOW PHASE-SEPARATION IN THE NUCLEUS ORGANIZES 3D SPATIAL ASSEMBLY AND GENE REGULATION

UNDERSTANDING THE ROLE OF TUMOR MICROENVIRONMENT IN LOW GRADE GLIOMA PROGRESSION TO MALIGNANCY - ABSTRACT OUR PCA RESEARCH CENTER BRINGS TOGETHER THE UCLA NEUROSURGERY TEAM WITH THE CALTECH SPATIAL SINGLE CELL TEAM TO CONSTRUCT A COMPARATIVE SPATIAL ATLAS OF LOW-GRADE GLIOMAS. THE COLLABORATION BETWEEN THE THREE COMPONENTS OF THE PCA RESEARCH CENTER HAS ALREADY GENERATED PRELIMINARY DATA IN SEVERAL GLIOMA SAMPLES. WE WILL EXPAND THIS EFFORT TO GENERATE A COMPARATIVE ATLAS OF GLIOMAS WITH DISTINCT PROGRESSION OUTCOMES USING INTEGRATED SPATIAL TRANSCRIPTOMICS, PROTEOMICS, AND CHROMOSOME PROFILING. BY COMPARING THE LOW-GRADE GLIOMAS THAT EVENTUALLY TRANSFORM WITH ONES THAT STAY INDOLENT OR DO NOT RECUR, AND WITH IDH-MUTANT HIGH-GRADE GLIOMAS, WE AIM TO UNDERSTAND THE MOLECULAR AND CELLULAR MECHANISMS AT THE LOW-GRADE STAGE THAT ARE PREDICTIVE OF MALIGNANT TRANSFORMATION (MT) AND TO SUGGEST INTERVENTION STRATEGIES TO PREVENT MT. THE COMPARATIVE ANALYSIS WILL EXAMINE THREE TYPES OF CHANGES IN LOW-GRADE GLIOMAS WITH DIFFERENT OUTCOMES: CELL TYPE COMPOSITION, TUMOR MICROENVIRONMENT, AND PATHWAY SPECIFIC GENE EXPRESSION. FROM UCLA’S BRAIN TUMOR TRANSLATION RESOURCE (BTTR) CENTER, WE HAVE ALREADY COLLECTED 99 FRESH-FROZEN LOW-GRADE GLIOMA SAMPLES AND WILL COLLECT APPROXIMATELY AN ADDITIONAL 100 SAMPLES OF LOW-GRADE GLIOMA WITH DIFFERENT OUTCOMES (MT, INDOLENT, AND NO- RECURRENCE). 38% OF THE CURRENT COHORT OF PATIENTS ARE FROM UNDER-REPRESENTED MINORITY GROUPS; WE WILL CONTINUE TO RECRUIT FROM A DIVERSE PATIENT POOL IN ORDER TO BETTER UNDERSTAND WHICH PATIENTS MAY BE AT HIGHER RISK FOR MALIGNANT TRANSFORMATION AND THEREFORE NEED MORE FREQUENT SURVEILLANCE OR EARLIER INTERVENTION. WE WILL THEN GENERATE AN INTEGRATED MULTI-MODAL SPATIAL ATLAS TARGETING 2500 MRNAS, 10 PROTEINS AND 10 DNA CNVS AND TRANSLOCATIONS. FROM THE HIGH SENSITIVITY AND MULTIPLEXED RNA SEQFISH ASSAYS, WE WILL BE ABLE TO CAPTURE NOT ONLY CELL TYPE AND MICROENVIRONMENT INFORMATION, BUT ALSO GENES AND PATHWAYS THAT COULD BE CAUSAL FOR PROGRESSION TO MALIGNANCY. LASTLY, WE WILL USE THE DATA TO 1) PREDICT TUMOR PROGRESSION BASED ON THE CELL TYPE COMPOSITIONS AND MICROENVIRONMENTS; 2) DESIGN INTERVENTION STRATEGIES BASED ON THE SPATIAL DATA, USING COUNTERFACTUAL INFERENCE MODELS TO AFFECT IMMUNE INFILTRATING AND OTHER PREDICTORS OF PROGRESSION; AND 3) BUILD A MODEL OF TUMOR PROGRESSION DYNAMICS BASED ON GENE EXPRESSION AND MECHANICS OF THE TISSUE. OUR COMPREHENSIVE LOW-GRADE GLIOMA TISSUE COLLECTION, THE INTEGRATED SPATIAL DATASET WITH TRANSCRIPTOMICS, PROTEOMICS AND CHROMOSOMAL ABNORMALITIES, AND THE MODELS BUILT USING ADVANCED MACHINE-LEARNING TOOLS WILL EXTEND THE EXISTING CAPABILITIES OF THE HTAN CONSORTIUM AND BE INTEROPERABLE. THE ATLAS AND THE COMPUTATIONAL TOOLS WILL BE USED BY US AND THE WIDER SCIENTIFIC COMMUNITY TO FURTHER UNDERSTAND THE MECHANISMS LEADING TO MALIGNANT TRANSFORMATION.

MECHANICS AND MECHANISMS OF IMPULSE LOADING, DAMAGE AND FAILURE OF MARINE STRUCTURES AND MATERIALS

COLLABORATIVE RESEARCH: MOLECULAR PROGRAMMING ARCHITECTURES, ABSTRACTIONS, ALGORITHMS, AND APPLICATIONS

PROTECTION FROM MUCOSAL PATHOLOGY BY GUT MICROFLORA DURING EXPERIMENTAL COLITIS

PROJECT TITLEOPERATION MAINTENANCE SUPPORT AND IMPROVEMENT OF THE SHAKEALERT EARTHQUAKE EARLY WARNINGSYSTEM FOR THE WEST COAST 20242027COLLABORATIVE RESEARCH WITH UNIV. OF CALIFORNIA BERKELEY CALIFORNIA INSTITUTE OF TECHNOLOGY UNIV. OF WASHINGTON AND UNIV. OF OREGONPROJECT PERIOD8 15 2024 THROUGH 8 14 2027AWARD PURPOSEOPERATION MAINTENANCE SUPPORT AND IMPROVEMENT OF THE SHAKEALERT EARTHQUAKE EARLY WARNING SYSTEM FOR THE WEST COAST. THE REGIONAL GEOPHYSICAL NETWORKS ON THE U.S. WEST COAST IN CALIFORNIA CA OREGON OR AND WASHINGTON WA WILL CONTINUE TO COLLABORATE WITH EACH OTHER AND THE U.S. GEOLOGICAL SURVEY USGS AND PROVIDE DATA EXPERTISE AND INFRASTRUCTURE FOR THE USGS SHAKEALERT EARTHQUAKE EARLY WARNING SYSTEM.ACTIVITIES TO BE PERFORMED COMPLETE THE NETWORK OF SENSOR STATIONS REMEDIATE UNDERPERFORMING STATIONS AND OPERATE AND MAINTAIN STATIONS. ENSURE CONTINUOUS AND SECURE DATA FLOW TO THE REGIONAL CENTRAL PROCESSING CENTERS BY MAINTAINING AND CONFIGURING VARIOUS KINDS OF TELEMETRY DEVICES OPTIMIZING DATA ROUTES AND DESIGNING AND IMPLEMENTING REDUNDANT DATA PATHS. CONTINUOUS MONITORING OF STATION HEALTH DATA QUALITY AND DATA FLOW. MAINTENANCE OF THE SOFTWARE AND IT INFRASTRUCTURE AT EACH OF THE REGIONAL PROCESSING CENTERS WHERE SHAKEALERT ALERT PRODUCTS ARE GENERATED. INCREMENTALLY REPLACE THE INTERNAL MESSAGE BROKERS AND MAKE OTHER SYSTEM CHANGES INTENDED TO INCREASE ROBUSTNESS AND FLEXIBILITY. CONTINUOUS EVALUATION AND IMPROVEMENT OF THE CORE ALGORITHMS WITH A SPECIAL FOCUS ON VERY LARGE EARTHQUAKES EARTHQUAKE SEQUENCES AND OFFSHORE EARTHQUAKES. EVALUATE WHETHER ADDITIONAL MEASUREMENTS SUCH AS BACKAZIMUTH AND POLARIZATION ESTIMATES AND SPHASE ARRIVAL TIMES MAY FURTHER IMPROVE THE SYSTEM S RELIABILITY AND ACCURACY. INVESTIGATE WHETHER THE SYSTEMS RELIABILITY AND ACCURACY MIGHT BE IMPROVED BY COMBINING THE RESULTS FROM THE THREE CORE ALGORITHMS IN DIFFERENT WAYS. FOR EXAMPLE INVESTIGATE WHETHER GFAST PGD WHICH IS IMPORTANT FOR VERY LARGE EARTHQUAKES AND WHICH IS BASED ON PEAK GROUND DISPLACEMENTS SHOULD ESTIMATE ITS DISTANCE TO THE FINITE SOURCE ESTIMATE RATHER THAN THE POINT SOURCE ESTIMATE. TAKE INITIAL STEPS TOWARD INCORPORATING NEW TYPES OF DATA SUCH AS DATA FROM SMALL APERTURE ARRAYS AND DATA ACQUIRED USING DISTRIBUTED ACOUSTIC SENSING.DELIVERABLES AND EXPECTED OUTCOMESTIMELY AND ACCURATE EARTHQUAKE EARLY WARNINGS FOR A LARGE PROPORTION OF THE POPULATION OR INFRASTRUCTURE EXPERIENCING STRONG SHAKING DUE TO AN EARTHQUAKE IN OR NEAR CA OR OR WA. IMPROVED UNDERSTANDING AND TUNING OF THE SYSTEM WITH EACH SIGNIFICANT EARTHQUAKE AND PROACTIVE TESTING USING SCENARIOS AND PREVIOUSLY RECORDED DATA. WELLARTICULATED EXPLANATIONS OF THE SYSTEM S STRENGTHS AND LIMITATIONS THAT ALLOW USERS INCLUDING THIRDPARTY ALERT DISTRIBUTORS TO MAKE INFORMED DECISIONS. INCREASED AWARENESS AND USE OF THE SHAKEALERT EARTHQUAKE EARLY WARNING SYSTEM.INTENDED BENEFICIARYIESTHE U.S. GEOLOGICAL SURVEY INHABITANTS OF CA OR AND WA EMERGENCY MANAGEMENT STATE AGENCIES PRIVATE AND PUBLIC ENTITIES WISHING TO TAKE PROTECTIVE MEASURES UPON NOTIFICATION OF IMMINENT GROUND SHAKING DUE TO AN EARTHQUAKE.SUBRECIPIENT ACTIVITIESN A

PHOTONIC AND PHONONIC TECHNOLOGIES FOR SUPERCONDUCTING QUANTUM INFORMATION SYSTEMS

PROGRESSIVE ACQUISITION OF NOVEL NEURAL CREST DERIVATIVES ALONG THE NEURAL AXIS DURING VERTEBRATE EVOLUTION

LEARNING TO RECOGNIZE FOR VISUAL SURVEILLANCE

STABILITY AND ROBUSTNESS OF HIPPOCAMPAL REPRESENTATIONS OF SPACE - PROJECT SUMMARY HOW DOES THE BRAIN BALANCE THE NEED TO PRESERVE PRIOR KNOWLEDGE WITH THE NECESSITY TO CONTINUOUSLY LEARN NEW INFORMATION? THE TRADEO BETWEEN STABILITY AND PLASTICITY IS INHERENT IN BOTH BIOLOGICAL AND ARTICIAL LEARNING SYSTEMS CONSTRAINED BY NITE RESOURCES AND CAPACITY. THE HIPPOCAMPUS IS A BRAIN REGION CRITICAL FOR MEMORY FORMATION AND SPATIAL LEARNING, WHICH CAN PROVIDE A POWERFUL EXPERIMENTAL SYSTEM FOR CHARACTERIZING THIS TRADEO. THE ROLE OF THE HIPPOCAMPUS IN SPATIAL COGNITION IS SUPPORTED BY THE NDING THAT PYRAMIDAL NEURONS IN THIS AREA (PLACE CELLS) RE IN SPECIC LOCATIONS IN AN ENVIRONMENT (PLACE ELDS). THE POPULATION OF PLACE CELLS ACTIVE IN AN ENVIRONMENT IS BELIEVED TO FORM A NEURAL REPRESENTATION OR COGNITIVE MAP OF THAT ENVIRONMENT. SPATIAL LEARNING IS CRITICAL FOR SURVIVAL AND INVOLVES TWO COMPETING CONSTRAINTS: REPRESENTATIONS OF SPACE MUST BE PLASTIC TO ENABLE FAST LEARNING OF NEW ENVIRONMENTS AND CHANGES IN BEHAVIORAL CONTINGENCIES, AND STABLE OVER TIME TO ENABLE RECOGNITION OF FAMILIAR ENVIRONMENTS, RELIABLE NAVIGATION, AND LEVERAGING OF PREVIOUS LEARNING. HOW DO THESE COMPETING CONSTRAINTS AECT THE STABILITY OF PLACE ELDS ACROSS TIME? THE EXPERIMENTAL CHARACTERIZATION OF THE LONG-TERM STABILITY OF SPATIAL REPRESENTATIONS IN THE HIPPOCAMPUS HAS BEEN CHALLENGING AS IT REQUIRES TRACKING THE ACTIVITY OF MULTIPLE PLACE CELLS ACROSS EXTENDED PERIODS OF TIME (DAYS TO WEEKS). WE PROPOSE TO USE NOVEL APPROACHES IN LARGE-SCALE ELECTROPHYSIOLOGY AND IMAGING IN BEHAVING RODENTS TO CHARACTERIZE WHICH NEURONS CHANGE THEIR SPATIAL TUNING AND HOW THESE CHANGES DEPEND ON BEHAVIOR. FURTHERMORE, WE WILL USE RECORDINGS AND CIRCUIT PERTURBATIONS TO CHARACTERIZE THE ACTIVITY PATTERNS THAT PREDICT CHANGES IN TUNING STABILITY. OUR ANALYSIS WILL BE CARRIED OUT IN THE CONTEXT OF A THEORETICAL FRAMEWORK FOR UNDERSTANDING THE INTERPLAY BETWEEN PLASTICITY AND STABILITY OF HIPPOCAMPAL REPRESENTATIONS. CHARACTERIZING THE EVOLUTION OF NEURAL REPRESENTATIONS IS OF FUNDAMENTAL IMPORTANCE IN UNDERSTANDING HOW INFORMATION IS MAINTAINED ACROSS BRAIN CIRCUITS AND HOW SUCH MAINTENANCE IS PERTURBED IN BRAIN DISORDERS.

QUANTUM METROLOGY WITH ATOMIC SYSTEM: PRINCIPLES AND IMPLEMENTATIONS

BIOLOGICAL CONSEQUENCES OF ENZYMATIC INACTIVATION OF PSEUDOMONAS PYOCYANIN

VISUOMOTOR PROSTHETIC FOR PARALYSIS - THE OBJECTIVE OF THE PROPOSED RESEARCH IS TO OBTAIN SCIENTIFIC KNOWLEDGE OF VISUOMOTOR TRANSFORMATIONS IN POSTERIOR PARIETAL CORTEX (PPC) AND PRIMARY MOTOR CORTEX (M1) FROM TETRAPLEGIC SUBJECTS IN A CLINICAL TRIAL TO ADVANCE THE DEVELOPMENT OF NEURAL PROSTHETICS. WE HAVE SHOWN IN CLINICAL TRIALS CONDUCTED OVER THE PAST 6 YEARS THAT PPC CAN CONTROL NEURAL PROSTHETICS FOR ASSISTING TETRAPLEGIC SUBJECTS. OTHER GROUPS HAVE CONCENTRATED ON M1 AND LIKEWISE FIND CONTROL FOR NEURAL PROSTHETICS. IN OUR STUDIES OF PPC WE HAVE FOUND THAT BESIDES TRAJECTORY SIGNALS TO MOVE ROBOTIC LIMBS OR CONTROL COMPUTER CURSORS, THERE ARE A PLETHORA OF VISUOMOTOR SIGNALS THAT REPRESENT INTENDED MOVEMENTS OF MOST OF THE BODY, MOVEMENT GOALS, COGNITIVE STRATEGIES, AND EVEN MEMORY SIGNALS. OUR CENTRAL HYPOTHESIS IS THAT PPC AND M1 WILL ENCODE VISUOMOTOR PARAMETERS IN BOTH SIMILAR AND DIFFERENT WAYS, AND THAT ALGORITHMS CAN BE DEVELOPED TO LEVERAGE THOSE SIGNALS FROM THE TWO AREAS THAT ARE COMPLIMENTARY TO IMPROVE PROSTHETIC RANGE AND PERFORMANCE. IMPLANTS WILL BE MADE IN BOTH M1 AND PPC, ENABLING SIMULTANEOUS RECORDING IN THE SAME SUBJECTS, ELEVATING CONCERNS OF COMPARING DATA FROM DIFFERENT LABS COLLECTED IN DIFFERENT INDIVIDUALS WITH DIFFERENT IMPLANTS AND DIFFERENT TASKS. THIS CENTRAL HYPOTHESIS WILL BE TESTED IN TWO BROAD AIMS, FOR WHICH WE HAVE SUBSTANTIAL PRELIMINARY DATA. AIM 1 WILL EXAMINE THE CONTROL OF THE BODY BY THE TWO AREAS. IT IS HYPOTHESIZED THAT M1 WILL DEMONSTRATE STRONG SPECIFICITY FOR THE CONTRALATERAL LIMB (IMPLANTS WILL BE MADE IN THE HAND KNOB) WHEREAS PPC WILL CODE MOVEMENTS FOR MOST OF THE BODY AND ON BOTH CONTRA AND IPSILATERAL SIDES BY LEVERAGING ITS PARTIALLY MIXED ENCODING OF PARAMETERS (SUBAIM 1A). WHEREAS M1 IS HYPOTHESIZED TO CODE SPATIAL VARIABLES EXCLUSIVELY DURING ATTEMPTED OR IMAGINED ACTIONS, IT IS HYPOTHESIZED THAT PPC ALSO ENCODES COGNITIVE SPATIAL VARIABLES IN TASK APPROPRIATE REFERENCE FRAMES (SUBAIM 1B). IN SUBAIM 1C WE WILL EXAMINE HOW MULTIPLE BODY PARTS ARE COMBINED IN MOVEMENT REPRESENTATIONS, HYPOTHESIZING THAT M1 AND PPC WILL EMPLOY A DIVERSE SET OF MECHANISMS INCLUDING LINEAR SUMMATION, NON-LINEAR COMBINATIONS, AND MOVEMENT SUPPRESSION EXPRESSED IN DIFFERENT WAYS AS A FUNCTION OF BRAIN AREA AND THE SPECIFIC MOVEMENT SET. AIM 2 WILL EXAMINE THE TEMPORAL ASPECTS OF ENCODING IN THE TWO AREAS. IN SUBAIM 2A WE WILL TEST THE HYPOTHESIS THAT THE NEURAL DYNAMICS DURING SUSTAINED PERIODS OF MOVEMENT ARE LARGELY UNCHANGING IN BOTH AREAS. IN SUBAIM 2B WE HYPOTHESIZE THAT, DURING SEQUENTIAL MOVEMENTS, M1 CODES ONLY THE ONGOING MOVEMENT WHEREAS PPC CODES BOTH THE CURRENT AND SUBSEQUENT MOVEMENTS. FINALLY, IN SUBAIM 2C WE WILL EXAMINE THE CODING OF MOVEMENT SPEED, WITH THE HYPOTHESIS THAT THERE ARE SEPARATE SUBSPACES IN BOTH M1 AND PPC FOR DIRECTION AND SPEED OF MOVEMENT.

US LHCNET: TRANSATLANTIC NETWORKING FOR THE LHC AND THE US HEP COMMUNITY; EVO: A GLOBAL-SCALE NEWTOR

MOLECULAR GENETICS OF CNS DEVELOPMENT

THE SYNTHESIS OF BIOACTIVE POLYCYCLIC NATURAL PRODUCTS

GENETIC AND NEURONAL MECHANISMS THAT REGULATE ZEBRAFISH SLEEP - ABSTRACT SLEEP DISORDERS ARE PERVASIVE, CONTRIBUTE TO MORBIDITY IN SEVERAL PSYCHIATRIC DISORDERS, AND CAUSE AN ANNUAL ECONOMIC BURDEN OF $100 BILLION. HOWEVER, DESPITE ITS IMPORTANCE FOR HEALTH, THE MECHANISMS THAT REGULATE SLEEP ARE POORLY UNDERSTOOD. WE ARE TAKING A NEW APPROACH TO THIS PROBLEM BY EXPLOITING USEFUL FEATURES OF ZEBRAFISH TO ANSWER AN IMPORTANT AND BASIC QUESTION: WHAT GENETIC AND NEURONAL MECHANISMS REGULATE SLEEP? SLEEP IS REGULATED BY A HOMEOSTATIC PROCESS THAT REFLECTS INTERNAL CUES OF SLEEP NEED AND A CIRCADIAN PROCESS THAT IS ENTRAINED BY ENVIRONMENTAL CUES AND RESTRICTS SLEEP TO THE APPROPRIATE TIME. SLEEP IS ALSO DIRECTLY AND RAPIDLY REGULATED BY A PHENOMENON KNOWN AS MASKING, IN WHICH LIGHT INDUCES WAKE AND DARK INDUCES SLEEP IN DIURNAL ANIMALS. FACTORS THAT REGULATE THE HOMEOSTATIC PROCESS HAVE BEEN IDENTIFIED, INCLUDING OUR RECENT FINDING THAT THE SEROTONERGIC RAPHE PROMOTE SLEEP HOMEOSTASIS IN ZEBRAFISH AND MICE. WE ALSO SHOWED THAT MELATONIN IS ESSENTIAL FOR CIRCADIAN REGULATION OF SLEEP IN ZEBRAFISH, AND IDENTIFIED A PATHWAY IN THE BRAIN THAT REGULATES MASKING. HERE WE BUILD UPON THESE DISCOVERIES TO ELUCIDATE MECHANISMS THAT UNDERLIE HOMEOSTATIC, CIRCADIAN, AND LIGHT-DEPENDENT REGULATION OF SLEEP. WE WILL INVESTIGATE THESE MECHANISMS USING ZEBRAFISH, A DIURNAL VERTEBRATE WITH SEVERAL ADVANTAGES THAT COMPLEMENT RODENT MODELS, USING A COMBINATION OF GENETIC, OPTOGENETIC, AND CHEMOGENETIC PERTURBATIONS COUPLED WITH HIGH-THROUGHPUT BEHAVIORAL ASSAYS AND WHOLE-BRAIN NEURONAL ACTIVITY MONITORING WITH SINGLE CELL RESOLUTION. IN PROJECT 1, WE WILL IDENTIFY RAPHE SUBSYSTEMS THAT PROMOTE SLEEP HOMEOSTASIS, AND IDENTIFY GENETIC AND NEURONAL CIRCUITS THAT ACT UPSTREAM AND DOWNSTREAM OF THESE SUBSYSTEMS IN SLEEP CONTROL. IN PROJECT 2, WE WILL IDENTIFY MELATONIN RECEPTORS THAT MEDIATE THE SLEEP-PROMOTING FUNCTION OF MELATONIN, AND ALSO PERFORM A SCREEN TO IDENTIFY NEURONS THROUGH WHICH MELATONIN IMPLEMENTS CIRCADIAN REGULATION OF SLEEP. PROJECT 3 BUILDS ON OUR RECENT DISCOVERY THAT THE HYPOTHALAMIC NEUROPEPTIDE PROKINETICIN 2 SUPPRESSES BOTH LIGHT- AND DARK-INDUCED MASKING BEHAVIOR. SIMILAR TO PROJECT 1, WE WILL IDENTIFY GENETIC AND NEURONAL CIRCUITS THAT ACT UPSTREAM AND DOWNSTREAM OF PROKINETICIN 2 TO REGULATE MASKING. IN PROJECT 4, WE WILL VALIDATE A LARGE NUMBER OF HUMAN SLEEP DISORDER CANDIDATE GENES THAT WERE IDENTIFIED BY GENOME-WIDE ASSOCIATION STUDIES. WE WILL DO SO BY LEVERAGING ZEBRAFISH TO EFFICIENTLY AND INEXPENSIVELY GENERATE AND TEST MANY MUTANT LINES FOR SLEEP PHENOTYPES. WE WILL DETERMINE THE MECHANISMS THROUGH WHICH VALIDATED CANDIDATE GENES REGULATE SLEEP, AND INTEGRATE THESE GENES INTO THE PATHWAYS IDENTIFIED IN PROJECTS 1-3. THE HOMEOSTATIC (PROJECT 1), CIRCADIAN (PROJECT 2) AND LIGHT-DEPENDENT (PROJECT 3) MECHANISMS THAT REGULATE SLEEP, AS WELL AS THE SLEEP DISORDER GENES IDENTIFIED IN HUMANS AND VALIDATED IN ZEBRAFISH (PROJECT 4), ARE LIKELY TO BE INTEGRATED AT MULTIPLE LEVELS TO PRODUCE EITHER SLEEP OR WAKEFULNESS. THIS RESEARCH PROGRAM PROVIDES A UNIFIED PLATFORM TO EXPLORE INTERACTIONS BETWEEN GENES AND NEURONS IDENTIFIED IN EACH PROJECT. THIS WILL ALLOW US TO DERIVE A COMPREHENSIVE UNDERSTANDING OF MECHANISMS THAT REGULATE SLEEP, AND WILL SET THE STAGE FOR NOVEL THERAPIES FOR SLEEP DISORDERS.

FUNCTIONAL LNFE-NX MODELS OF BIOLOGICAL N2 FIXATION

A SPATIALLY RESOLVED MOLECULAR ATLAS OF HUMAN ENDOTHELIUM

SENSORY MOTOR TRANSFORMATIONS IN HUMAN CORTEX - ABSTRACT: THE LONG-TERM OBJECTIVE OF THIS APPLICATION IS TO UNDERSTAND CORTICAL PROCESSING OF SENSORY TO MOTOR TRANSFORMATIONS WITHIN THE HUMAN CEREBRAL CORTEX. A VAST NUMBER OF COMPUTATIONS MUST BE PERFORMED TO ACHIEVE SENSORY-GUIDED MOTOR CONTROL. STANDING OUT AMONG THESE COMPUTATIONS, VISUAL INFORMATION OF THE GOALS OF ACTION MUST BE TRANSFORMED FROM THE COORDINATES OF THE RETINA TO THE COORDINATES OF EFFECTORS USED FOR MOVEMENT, FOR INSTANCE LIMB COORDINATES FOR REACHING UNDER VISUAL GUIDANCE AND TO WORLD COORDINATES FOR INTERACTIONS IN THE ENVIRONMENT. ONCE AN OBJECT IS GRASPED, SOMATOSENSORY SIGNALS FROM THE HAND ARE REQUIRED FOR DEXTEROUS MANIPULATION OF GRASPED OBJECTS. INTERNAL MODELS WITHIN THE SENSORY MOTOR PATHWAY ARE ESSENTIAL FOR ESTIMATING THE CURRENT STATE OF THE BODY AND THE EXTERNAL ENVIRONMENT, ACCOUNTING FOR LAGS IN SENSORY FEEDBACK, AND CALIBRATING THE BODY TO THE ENVIRONMENT. WE WILL USE THE RARE OPPORTUNITY OF BEING ABLE TO RECORD FROM POPULATIONS OF SINGLE NEURONS IN A CLINICAL STUDY DESIGNED TO DEVELOP NEURAL PROSTHETICS FOR TETRAPLEGIC PARTICIPANTS PARALYZED BY SPINAL CORD INJURIES. CORTICAL IMPLANTS OF MICROELECTRODE ARRAYS WILL BE MADE WITHIN THREE KEY LOCATIONS IN THE SENSORIMOTOR SYSTEM: PRIMARY MOTOR CORTEX, PRIMARY SOMATOSENSORY CORTEX, AND POSTERIOR PARIETAL CORTEX. THESE MICROELECTRODE ARRAYS ENABLE BOTH RECORDING AND INTRACORTICAL MICROSTIMULATION. WE WILL TEST THE HYPOTHESIS THAT SOMATOSENSORY AND MOTOR CORTEX REPRESENT IMAGINED REACHES IN HAND COORDINATES, BUT POSTERIOR PARIETAL CORTEX IS TASK DEPENDENT, AND ITS POPULATION NEURAL ACTIVITY CAN FLEXIBLY CHANGE COORDINATE FRAMES TO ENABLE ENCODING OF THE SPATIAL RELATIONS WITHIN THE BODY (ARM AND EYES), BETWEEN THE BODY AND WORLD (ARM AND REACH TARGETS; OBJECTS RELATIVE TO SELF), AND WITHIN THE WORLD (RELATIVE POSITION OF OBJECTS IN THE WORLD) AS REQUIRED BY TASK DEMANDS. PERCEPTS EVOKED BY INTRACORTICAL MICROSTIMULATION AND IMAGINED SENSATIONS WILL BE USED TO UNDERSTAND THE REPRESENTATION OF CUTANEOUS AND PROPRIOCEPTIVE INFORMATION WITHIN PRIMARY SOMATOSENSORY CORTEX AND POSTERIOR PARIETAL CORTEX. THE HYPOTHESIS TO BE TESTED IS THAT IMAGINED SENSATION AND ELECTRICALLY EVOKED SENSATIONS ARE HIGHLY OVERLAPPING—NOT JUST IN PRIMARY SOMATOSENSORY CORTEX BUT ALSO IN POSTERIOR PARIETAL CORTEX. LASTLY, WE HYPOTHESIZE THAT THE POSTERIOR PARIETAL CORTEX CONTAINS IN HUMANS AN INTERNAL MODEL OF STATE ESTIMATION THAT SHOWS PLASTICITY FOR BOTH NATURAL AND BRAIN-CONTROL BEHAVIORS AND TRANSFERS THIS LEARNING TO MOTOR CORTEX. THESE STUDIES WILL NOT ONLY GREATLY ADVANCE OUR UNDERSTANDING OF THE HUMAN SENSORIMOTOR CORTICAL CIRCUIT, BUT ALSO WILL PROVIDE BASIC KNOWLEDGE FOR THE DESIGN OF FUTURE NEURAL PROSTHETICS.

METAL-CATALYZED NUCLEOPHILIC SUBSTITUTION REACTIONS OF ALKYL ELECTROPHILES - PROJECT SUMMARY / ABSTRACT THE DISCOVERY OF POWERFUL NEW METHODS FOR THE SYNTHESIS OF ORGANIC COMPOUNDS CAN BE ENABLING FOR BIOMEDICAL RESEARCH, E.G., BY PROVIDING MORE READY ACCESS TO KNOWN FAMILIES OF TARGET MOLECULES OR ACCESS FOR THE FIRST TIME TO NEW CLASSES OF MOLECULES. CATALYTIC AND ENANTIOSELECTIVE METHODS FOR CARBON–CARBON, CARBON– NITROGEN, AND CARBON–OXYGEN FORMATION ARE OF PARTICULAR INTEREST, DUE TO ISSUES INCLUDING SUSTAINABILITY, THE POTENTIALLY DIVERGENT BIOACTIVITY OF THE TWO ENANTIOMERS OF A COMPOUND, AND THE PREDOMINANCE OF SUCH BONDS IN THE BACKBONE OF ORGANIC MOLECULES, RESPECTIVELY. THE SUBSTITUTION REACTION OF AN ALKYL ELECTROPHILE BY A NUCLEOPHILE IS A PARTICULARLY STRAIGHTFORWARD APPROACH TO THE ASSEMBLY OF ORGANIC MOLECULES. CLASSICAL PATHWAYS FOR SUBSTITUTION, SUCH AS THE SN1 AND THE SN2 REACTIONS, ARE LIMITED IN SCOPE WITH RESPECT TO BOTH THE ELECTROPHILE AND THE NUCLEOPHILE. FURTHERMORE, THESE PATHWAYS ALMOST NEVER PROVIDE ACCESS TO HIGHLY ENANTIOENRICHED PRODUCTS FROM READILY AVAILABLE RACEMIC STARTING MATERIALS. THROUGH THE USE OF TRANSITION-METAL CATALYSIS, WHEREIN THE ELECTROPHILE IS CONVERTED INTO AN ORGANIC RADICAL, IT IS POSSIBLE TO BEGIN TO ADDRESS BOTH OF THE KEY CHALLENGES IN NUCLEOPHILIC SUBSTITUTION REACTIONS OF ALKYL ELECTROPHILES–BROADER SCOPE AND CONTROL OF ENANTIOSELECTIVITY. FOR EXAMPLE, CHIRAL NICKEL AND COPPER COMPLEXES CAN CATALYZE THE ENANTIOCONVERGENT COUPLING OF A NUMBER OF RACEMIC SECONDARY AND TERTIARY ALKYL ELECTROPHILES WITH A VARIETY OF NUCLEOPHILES. TO DATE, ONLY A SMALL FRACTION OF THE CONCEIVABLE PERMUTATIONS OF ELECTROPHILIC AND NUCLEOPHILIC PARTNERS FOR METAL-CATALYZED SUBSTITUTION REACTIONS OF ALKYL ELECTROPHILES HAVE BEEN EXPLORED, AND STILL FEWER SUCH PROCESSES HAVE BEEN RENDERED ENANTIOSELECTIVE. THE GOAL OF THIS RESEARCH PROGRAM IS TO ADDRESS THE MANY UNSOLVED CHALLENGES IN THIS AREA. EFFORTS WILL FOCUS ON THE DEVELOPMENT OF MILD AND VERSATILE METHODS TO COUPLE FAMILIES OF ELECTROPHILES AND NUCLEOPHILES THAT HAVE NOT PREVIOUSLY BEEN SHOWN TO BE SUITABLE REACTION PARTNERS IN ALIPHATIC SUBSTITUTION REACTIONS, INCLUDING HIGHLY HINDERED SUBSTRATES, WHILE CONTROLLING STEREOSELECTIVITY AT THE SAME TIME (AT UP TO TWO STEREOCENTERS), INCLUDING WITH RACEMIC ELECTROPHILES AND NUCLEOPHILES THAT LACK DIRECTING GROUPS. SUCCESS IN THIS ENDEAVOR WILL SUBSTANTIALLY FACILITATE THE SYNTHESIS OF ENANTIOENRICHED MOLECULES. MECHANISTIC STUDIES WILL BE PURSUED IN ORDER TO PROVIDE INSIGHT INTO THE PATHWAYS BY WHICH THE NEW METAL- CATALYZED SUBSTITUTION REACTIONS PROCEED. THE MECHANISTIC INVESTIGATIONS WILL FACILITATE REACTION DEVELOPMENT, AS WELL AS ENHANCE THE COMMUNITY’S UNDERSTANDING OF FUNDAMENTAL CHEMICAL REACTIVITY.

PIRE: GROWTH: GLOBAL RELAY OF OBSERVATORIES WATCHING TRANSIENTS HAPPEN

HYBRIDIZATION CHAIN REACTION: IN SITU AMPLIFICATION FOR BIOLOGICAL IMAGING

SUPPORT AND IMPROVEMENT OF SHAKEALERT 2019-021: COLLABORATIVE RESEARCH WITH UNIVERSITY OF CALIFORNIA, BERKELEY; CALTECH; UNIVERSITY OF WASHINGTON; AND UNIVERSITY OF OREGON

TRAVERSING THE “DEATH VALLEY” SEPARATING SHORT AND LONG TIMES IN NON-EQUILIBRIUM QUANTUM DYNAMICAL SIMULATIONS OF REAL MATERIALS

CELL LINEAGE AND TRANSCRIPTIONAL ANALYSIS OF THE VERTEBRATE NEURAL PLATE BORDER

ROLE OF ATR IN CELL CYCLE CHECKPOINTS

SPATIAL GENOMICS SINGLE CELL ANALYSIS OF AGING BRAINS

MODULAR NANOPHOTONIC PROBES FOR DENSE NEURAL RECORDING AT SINGLE-CELL RESOLUTION

DATA-DRIVEN CLOSURE MODELS AND CONSTITUTIVE RELATIONS: THE DEVELOPMENT OF PRINCIPLED METHODOLOGIES FOR COMPLEX MULTI-PHYSICS APPLICATIONS (WHITE PAPER TRACKING #22-000002556)

"(MURI FY04) NOVEL DEVICES FOR PLASNONIC AND NANOPHOTONIC NETWORKS: EXPLOITING X-RAY WAVELENGTHS AT OPTICAL FREQUENCIES"

MOLECULAR MECHANISM OF PROTEIN TARGETING BY THE SIGNAL RECOGNITION PARTICLE

TEMPLATION OF LONG-CHAIN SEQUENCE-CONTROLLED HETEROPOLYMER

DECIPHERING THE FUNCTION AND MECHANISMS OF LNCRNA-MEDIATED ORGANIZATION OF NUCLEAR COMPARTMENTS

UNDERSTANDING THE CIRCUIT FOR TOPOLOGICAL OBJECT TRACKING

MULTIPLEX RNA IMAGING IN SINGLE CELLS BY SUPERRESOLUTION MICROSCOPY& BARCODE FISH

MOLECULAR GENETIC DISSECTION OF CENTRAL AMYGDALA MICROCIRCUITRY UNDERLYING FEAR A

SYSTEM DYNAMICS AND GENE NETWORK ARCHITECTURE OF EARLY T-CELL DEVELOPMENT

MICRORNA FUNCTION IN THE IMMUNE SYSTEM

MOLECULAR MECHANISM OF THE PIRNA BIOGENESIS

COLLABORATIVE RESEARCH: A SEARCH FOR THE ELECTRIC DIPOLE MOMENT OF THE NEUTRON

HIGH-THROUGHPUT MODELING OF AUTISM RISK GENES USING ZEBRAFISH

GENE REGULATORY NETWORK CONTROLLING PREMIGRATORY CRANIAL VS TRUNK NEURAL CREST

IMAGING NEUROMODULATION IN THE BRAIN

NOVEL TOOLS TO COMPREHENSIVELY MAP DYNAMIC ORGANIZATION OF RNA AND DNA IN HIGHER-ORDER NUCLEAR STRUCTURES WITHIN SINGLE CELLS

TAS::97 0400::TAS 'QUANTUM NETWORKS WITH SINGLE ATOMS, PHOTONS AND PHONONS'

NEXT-GENERATION SPATIAL -OMICS: HIGH-THROUGHPUT, SINGLE-MOLECULE PROTEOMIC IMAGING WITH SUBCELLULAR RESOLUTION - PROJECT SUMMARY DEEP PROTEOMIC AND METABOLOMIC PROFILING OF BIOLOGICAL TISSUES IS AN OVERARCHING GOAL OF MODERN BIOLOGICAL AND BIOMEDICAL RESEARCH. IT REMAINS A KEY – AND CONSPICUOUS – MISSING COMPONENT FROM THE FULL SPECTRUM OF -OMICS THAT MAINLY CAPITALIZE ON NEXT-GENERATION SEQUENCING OF DNA AND RNA. TODAY'S EXISTING METHODOLOGIES FOR PROTEOMIC AND METABOLOMIC ANALYSIS CURRENTLY LAG FAR BEHIND THE CAPABILITIES OF TOOLS FOR GENOMICS AND TRANSCRIPTOMICS, BOTH IN TERMS OF DEPTH-OF-COVERAGE AND THROUGHPUT. THE PROPOSED EFFORT WILL MEET THIS CHALLENGE BY ADVANCING REVOLUTIONARY NEW METHODS FOR LABEL-FREE SINGLE-MOLECULE PROTEOMIC AND METABOLOMIC PROFILING AND COMBINING THEM WITH NOVEL METHODS FOR SUB-CELLULAR SPATIAL ANALYSIS. PROTEIN CONCENTRATIONS WITHIN A MAMMALIAN CELL SPAN ~8 ORDERS OF MAGNITUDE; IN HUMAN BLOOD SERUM THIS INCREASES TO ~11 ORDERS. YET, WITHIN THESE IMMENSELY COMPLEX MILIEUS, EVEN THE MOST SPARSELY EXPRESSED PROTEINS ARE IMPORTANT. CELLULAR SIGNALING, GENE REGULATION, EARLY RESPONSES TO EXOGENOUS BIOLOGICAL STIMULI, AND DISEASE ONSET ALL GENERALLY RESULT IN THE EXPRESSION OF SMALL COPY NUMBERS OF PROTEINS. IT IS THUS ESSENTIAL BOTH TO DISCOVER RARE CELLULAR PROTEINS AND TO ATTAIN HOLISTIC PROTEOMIC MAPS – BUT THESE GOALS REMAIN FAR BEYOND PRESENT TECHNOLOGICAL CAPABILITIES. FURTHER, DECIPHERING THE INSTANTANEOUS STATE OF AN ORGANISM'S PROTEOME – AND, ESPECIALLY, OBSERVING ITS POST-TRANSLATIONAL MODIFICATIONS (PTMS) AS THEY DYNAMICALLY EVOLVE IN RESPONSE TO CELLULAR FUNCTION, STRESS, AND DISEASE – WILL PROVIDE TRANSFORMATIONAL KNOWLEDGE FOR MANY FIELDS. DEEP PROTEOME DISCOVERY WILL TACKLE THE CELLULAR PROTEOME'S COMPLEXITY, ALLOWING IDENTIFICATION OF PROTEINS OVER ITS ENTIRE DYNAMIC RANGE OF CONCENTRATION – FROM THE MOST PROLIFICALLY EXPRESSED CELLULAR PROTEINS TO THOSE ONLY SPARSELY EXPRESSED WITH A FEW COPIES PER CELL. THIS PROJECT'S SUCCESS WILL ENABLE DEEP SPATIAL PROFILING OF THE CELLULAR PROTEOME AND METABOLOME WITH HIGH THROUGHPUT AND, THEREBY, DISCOVERY OF RARE CELLULAR PROTEINS AND METABOLITES. IT WILL FUNDAMENTALLY CHANGE THE RESOLUTION OF PROTEIN ANALYSIS DOWN TO THE LEVEL OF INDIVIDUAL MOLECULES IN SUBCELLULAR COMPARTMENTS. ITS ACHIEVEMENT WILL COMPLETE THE CONSTELLATION OF SINGLE-CELL -OMICS, THEREBY BROADLY ADVANCING RESEARCH WORLDWIDE IN FIELDS THAT SPAN FROM FUNDAMENTAL BIOLOGY TO THE FRONTIERS OF CLINICAL MEDICINE. IN THE PROPOSED EFFORT, EXISTING AND WELL-VALIDATED TECHNIQUES FOR SPATIALLY-RESOLVED TISSUE SAMPLING WILL BE PUSHED DOWNWARD INTO THE SUB-CELLULAR REALM. SCALING THESE METHODS DOWNWARD IS FEASIBLE NOW SOLELY BECAUSE OF THE SINGLE-MOLECULE RESOLUTION OF THE PROPOSED APPROACH. THIS PROJECT BUILDS UPON A SIGNIFICANT BODY OF RECENT EFFORTS FOCUSED UPON CREATING INSTRUMENTATION FOR DEEP PROFILING OF THE SINGLE-CELL PROTEOME. THE EFFORT PROPOSED HERE WILL FURTHER ADVANCE THESE ACHIEVEMENTS – AND WILL INCORPORATE HIGH-RESOLUTION TISSUE-SAMPLING METHODS TO DELIVER, WITH MINIMAL LOSS, BIOLOGICAL ANALYTES TO INSTRUMENTATION ENABLING SINGLE-MOLECULE ANALYSIS. PURSUED TOGETHER, THESE EFFORTS WILL ENABLE THE FIRST REALIZATION OF SPATIAL PROTEOMICS WITH SUB-CELLULAR RESOLUTION.

ACOUSTICALLY TARGETED MOLECULAR CONTROL OF CELL TYPE SPECIFIC NEURAL CIRCUITS IN NON-HUMAN PRIMATES

ULTRASONIC NEUROMODULATION: ESTABLISHING MECHANISMS AND PARAMETERS TO OPTIMIZE TARGETED NEUROMODULATION AND CONTROL SENSORY SIDE-EFFECTS

PHOTON TUNNELING: SHEDDING NEW LIGHT ON BIOMEDICINE

FLUORESCENT BIOSENSORS FOR SUBCELLULAR PHARMACOKINETICS

INSTITUTE FOR QUANTUM INFORMATION

PROGRAMMABLE DNA BINDING OLIGOMERS FOR CONTROL OF TRANSCRIPTION

CONTROL OF CELL CYCLE TRANSITIONS

A SYNTHETIC ELECTRONICS ROUTE TO SCALABLE AND COMPETITIVE MOLECULAR QUBIT SYSTEMS

PHOTOINDUCED, COPPER-CATALYZED C-N COUPLING REACTIONS

QUANTITATIVE SINGLE-CELL ANALYSIS OF MAMMALIAN NOTCH SIGNALING STATES

MECHANISTIC DETAILS OF KEY INTEGRAL-MEMBRANE ENZYMES FOR ANTIMICROBIAL DISCOVERY

ORGANIC SYNTHESIS REAGENTS ON TRANSITION METALS

BIOPHYSICAL, STRUCTURAL AND FUNCTIONAL ANALYSIS OF MECHANOSENSITIVE CHANNELS

DEVELOPMENT OF INEXPENSIVE, ABUNDANT SEMICONDUCTORS FOR SOLAR ENERGY CONVERSION: PHOTOELECTROCHEMISTRY OF ZN3P2, FES2, AND WS2 FOR THE PRODUCTION...

ULTRASMALL MICROFABRICATED LASER CAVITIES

ENGINEERING PROTEINS FOR ANTI-VIRAL APPLICATIONS

FUNDAMENTAL STUDIES IN NUCLEAR PHYSICS

NEURONAL SUBSTRATES OF HEMODYNAMIC SIGNALS IN THE PREFRONTAL CORTEX

ATOMIC STRUCTURE OF THE NUCLEAR PORE COMPLEX

IN VIVO IMAGING OF SINGLE CIRCULATING CELLS

A CHEMICAL APPROACH TO ELUCIDATING THE STRUCTURE-FUNCTION RELATIONSHIPS OF CHONDR

USGS - CALTECH COOPERATIVE JOINT RESEARCH AGREEMENT WITH SPACE

VIBRATIONAL THERMODYNAMICS OF MATERIALS

DETERMINING THE EXPLANATORY UTILITY OF COMPUTATIONAL REINFORCEMENT-LEARNING THEORIES OF GOAL-DIRECTED AND HABITUAL CONTROL AT BEHAVIORAL AND NEURAL LEVELS

MECHANISMS THAT REGULATE ZEBRAFISH HYPOCRETIN NEURON DEVELOPMENT AND FUNCTION

PROGRAMMING STEM CELL FATE USING A NOVEL SYNTHETIC PLATFORM

FIREBALL-2: THE NEXT GENERATION OF UV SCIENCE TECHNOLOGY AND LEADERSHIP

INTEGRATIVE FUNCTIONAL MAPPING OF SENSORY-MOTOR PATHWAYS

REGULATION OF CULLIN-RING LIGASES BY NEDD8

WHOLE-BRAIN FUNCTIONAL IMAGING AND ANALYSIS OF ZEBRAFISH SLEEP - ABSTRACT SLEEP OCCUPIES A THIRD OF OUR LIVES AND SLEEP-RELATED AILMENTS COST AN ESTIMATED $100 BILLION PER YEAR, YET THE MECHANISMS GOVERNING ITS REGULATION REMAIN POORLY UNDERSTOOD. DESPITE THE SUBSTANTIAL PROGRESS THAT HAS BEEN MADE IN THE DISCOVERY AND UNDERSTANDING OF SPECIFIC SLEEP-PROMOTING AND WAKE-PROMOTING NEURONAL AND MOLECULAR PATHWAYS, WHAT IS MISSING IS AN INTEGRATED UNDERSTANDING OF HOW THESE MECHANISMS WORK TOGETHER IN THE BRAIN TO REGULATE SLEEP AND WAKE AS WHOLE-BRAIN BEHAVIORAL STATES. TOWARD THIS GOAL, WE PROPOSE A CONCEPTUALLY SIMPLE YET POWERFUL APPROACH: RECORD THE ACTIVITY OF EVERY NEURON IN THE BRAIN DURING NORMAL SLEEP AND WAKE STATES, AND IN RESPONSE TO PERTURBATIONS THAT INDUCE THESE STATES, THEN APPLY MATHEMATICAL ANALYSIS AND MODELING TO UNCOVER FUNDAMENTAL PRINCIPLES THAT UNDERLIE SLEEP. THE MAIN GOALS OF THIS EXPLORATORY PROJECT ARE TO DEVELOP AND VALIDATE IMAGING, ANALYSIS, AND MODELING TOOLS THAT WILL SERVE AS A FOUNDATION FOR A SUBSEQUENT LARGER-SCALE APPLICATION THAT WILL COMPREHENSIVELY IDENTIFY AND CHARACTERIZE SLEEP-REGULATING CIRCUITS, AND GENERATE MODELS TO EXPLAIN THE NEURONAL CIRCUIT PRINCIPLES THAT UNDERLIE SLEEP. WE WILL USE THE SMALL AND TRANSPARENT LARVAL ZEBRAFISH, A VERTEBRATE MODEL WITH WELL-CHARACTERIZED SLEEP BEHAVIOR WHOSE REGULATION IS CONSERVED WITH THAT OF MAMMALS. USING THIS MODEL AND OUR CUSTOM-DEVELOPED TWO-PHOTON SELECTIVE PLANE ILLUMINATION MICROSCOPY (2P-SPIM) PLATFORM, WE WILL PERFORM WHOLE-BRAIN RECORDINGS OF NEURONAL ACTIVITY WITH CELLULAR-RESOLUTION DURING BOTH NATURAL AND INDUCED SLEEP AND WAKE STATES. WE WILL THEN APPLY MATHEMATICAL TOOLS TO EXTRACT INSIGHTS FROM THESE WHOLE-BRAIN RECORDINGS TO IDENTIFY THE NEURAL SUBSTRATES THAT UNDERLIE SLEEP. OUR ANALYSIS WILL ALLOW US TO BOTH TEST EXISTING MODELS OF SLEEP REGULATION AND TO PROPOSE NEW MODELS BASED ON OUR DATA. THIS PROJECT WILL BE THE FIRST TO ACHIEVE COMPREHENSIVE OBSERVATION AND ANALYSIS OF VERTEBRATE SLEEP AT SUCH SCALE AND RESOLUTION. THE UNIQUE INSIGHTS GAINED FROM THESE STUDIES WILL PAVE THE WAY TOWARD A MORE COMPLETE UNDERSTANDING OF THE NEURONAL MECHANISMS THAT UNDERLIE SLEEP, WHOSE DYSFUNCTION IMPOSES A SIGNIFICANT BURDEN ON SOCIETY.

TEMPORAL PROGRAM FOR CELL FATE SPECIFICATION IN THE MOUSE EMBRYO

NEURAL REPRESENTATION OF MATING PARTNERS BY MALE C. ELEGANS

NEMS ARRAY MGAS

MOLECULAR GENETICS OF CNS DEVELOPMENT

MINIMALLY INVASIVE ULTRASONIC BRAIN-MACHINE INTERFACE - ABSTRACT BRAIN-MACHINE INTERFACES (BMIS) ARE ONE OF THE KEY MOTIVATING APPLICATIONS FOR THE BRAIN INITIATIVE’S DRIVE TO DEVELOP INNOVATIVE TECHNOLOGIES FOR LARGE-SCALE RECORDING OF NEURAL ACTIVITY, BENEFITING NOT ONLY BMI, BUT MANY OTHER NEUROSCIENCE STUDIES. THE MOST ADVANCED TECHNIQUES FOR NEURAL RECORDING AND BMIS ARE CURRENTLY INVASIVE, CAUSING LOCAL DAMAGE TO LIVING BRAIN TISSUE, LIMITING THEIR APPLICATIONS IN HUMAN NEUROSCIENCE RESEARCH AND BMI. ON THE OTHER HAND, NONINVASIVE TECHNIQUES TYPICALLY OFFER RELATIVELY LOW SPATIAL RESOLUTION AND SENSITIVITY. A MINIMALLY INVASIVE BMI WOULD BRIDGE THE GAP BETWEEN THESE EXTREMES, OPENING A NEW AVENUE FOR NEUROSCIENCE RESEARCH AND NEUROPROSTHETICS. RECENTLY, FUNCTIONAL ULTRASOUND (FUS) IMAGING WAS INTRODUCED AS A BREAKTHROUGH TECHNOLOGY FOR LARGE-SCALE RECORDING OF NEURAL ACTIVITY – PROVIDING HIGHLY SENSITIVE IMAGING OF ACTIVITY-DEPENDENT CHANGES IN BLOOD FLOW WITH A SPATIOTEMPORAL RESOLUTION OF ~100 ΜM AND 100 MS AT SEVERAL-CM DEPTH. IMPORTANTLY, FUS CAN RECORD FROM OUTSIDE THE BRAIN AND PROTECTIVE DURA MATER TISSUE, VASTLY EXPANDING ITS POTENTIAL USE IN NEUROSCIENCE APPLICATIONS AND BMIS ALIKE. WHILE FUS IS A HEMODYNAMIC TECHNIQUE, ITS EXCELLENT SPATIOTEMPORAL PERFORMANCE AND SINGLE-TRIAL SENSITIVITY OFFER A SUBSTANTIALLY CLOSER CONNECTION TO THE UNDERLYING NEURONAL SIGNALS THAN ACHIEVABLE WITH OTHER HEMODYNAMIC METHODS SUCH AS FMRI. IN THIS PROJECT, WE WILL PUSH THE BOUNDARIES OF FUS AS A TECHNOLOGY FOR LARGE-SCALE RECORDING OF NEURAL ACTIVITY BY DEVELOPING A FUS-BASED MINIMALLY INVASIVE BMI. THIS PROPOSAL IS BASED ON PRELIMINARY DATA ACQUIRED BY THE COLLABORATING INVESTIGATORS SHOWING THAT ULTRAFAST FUS IMAGING OF THE POSTERIOR PARIETAL CORTEX IN NON-HUMAN PRIMATES (NHP) PROVIDES SUFFICIENT INFORMATION TO PREDICT PLANNED MOVEMENTS FROM SINGLE TRIAL FUS RECORDINGS. THESE REMARKABLE FINDINGS SUGGEST THAT IT MAY BE POSSIBLE TO USE FUS AS THE BASIS FOR A MINIMALLY INVASIVE BMI THAT IS IMPLANTED IN THE SKULL AND DOES NOT PENETRATE THE DURA OR BRAIN TISSUE. TURNING THIS POTENTIAL INTO REALITY REQUIRES SEVERAL FUNDAMENTAL ADVANCES IN FUS NEURAL IMAGING TECHNOLOGY, WHICH WILL GREATLY ENHANCE THE UTILITY OF THIS LARGE-SCALE NEURAL IMAGING TECHNIQUE ACROSS NEUROSCIENCE APPLICATIONS. THESE ADVANCES INCLUDE (1) MAXIMIZING THE SPEED, DATA PROCESSING AND INFORMATION CONTENT EXTRACTED FROM FUS TO ENABLE A HIGH- PERFORMANCE, REAL-TIME ACUTE BMI; (2) DEVELOPING A SURGICALLY IMPLANTABLE FUS TECHNOLOGY FOR CHRONIC, LONGITUDINAL MINIMALLY INVASIVE RECORDING OF NEURAL ACTIVITY FROM A SPECIFIC BRAIN REGION; AND (3) EXTENDING THE FUS TECHNOLOGY FROM 2D TO 3D TO FACILITATE APPLICATIONS REQUIRING REAL-TIME IMAGING OF LARGE BRAIN VOLUMES. THIS PROPOSAL IS ENABLED BY TWO KEY INNOVATIONS MADE BY THE CO-PIS: THE INVENTION OF FUS BY TANTER, AND THE DISCOVERY BY THE COLLABORATIVE TEAM OF ANDERSEN, SHAPIRO AND TANTER THAT FUS SIGNALS CONTAIN INFORMATION THAT CAN BE USED FOR BMI. IN ADDITION, SEVERAL NEW INNOVATIONS ARE INTRODUCED THROUGH THE PROPOSED WORK INCLUDING TECHNIQUES TO ACQUIRE AND PROCESS FUS DATA IN REAL TIME, ADVANCES IN FUS HARDWARE AND SURGICAL TECHNIQUES FOR CHRONIC IMPLANTATION, AND ADVANCES TO ENABLE WIDE-FIELD AND SPARSE REAL-TIME 3D IMAGING. IF SUCCESSFUL, THIS PROJECT WILL SIGNIFICANTLY ADVANCE THE CAPABILITIES OF FUS AS A WIDELY USEFUL TECHNOLOGY FOR RAPID, SENSITIVE, LARGE-SCALE NEURAL IMAGING AND ENABLE MINIMALLY INVASIVE BMI.

SUGAR-SEQ: A NEW TECHNOLOGY FOR SINGLE-CELL GLYCAN AND GENE EXPRESSION PROFILING IN AD

FUNDAMENTAL STUDIES IN NUCLEAR PHYSICS AND ASTROPHYSICS

NANOPROBE ARRAYS FOR MASSIVELY PARALLEL 3-D RECORDINGS OF BRAIN ACTIVITY

NIH PIONEER AWARD

PROJECT TITLE: PARTIAL SUPPORT OF JOINT USGS-CALTECH SOUTHERN CALIFORNIA SEISMIC NETWORKPROJECT PERIOD: 2 1 2025 THROUGH 1 32 2030AWARD PURPOSE: THIS AWARD PARTIALLY SUPPORTS THE OPERATION AND MAINTENANCE OF THE SOUTHERN CALIFORNIA SEISMIC NETWORK AND THE SOUTHERN CALIFORNIA EARTHQUAKE DATA CENTER.ACTIVITIES TO BE PERFORMED: (1) OPERATE SCSN (CI) SEISMIC STATIONS, TELEMETRY, AND CENTRAL DATA PROCESSING SITES (2) ACQUIRE REAL-TIME SCSN PARTNER DATA (3) GENERATE AND REPORT REAL-TIME PRODUCTS, LOCATION, MAGNITUDE, SHAKEMAP, AND OTHERS (4) RESPOND TO FEMA, CALOES, MEDIA, AND PUBLIC INQUIRIES ABOUT EARTHQUAKES (5) CONTINUE THE POST-PROCESSING OF THE SCSN EARTHQUAKE CATALOG AND SUBMIT TO COMCAT (6) MAINTAIN SOFTWARE USED FOR ACQUISITION, PROCESSING, ARCHIVING, AND NOTIFICATION (7) OPERATE SCEDC TO ARCHIVE AND DISTRIBUTE WAVEFORMS, PHASE PICKS, AND THE SCSN CATALOG (8) CONTRIBUTE TO DATA SHARING, INTEGRATION, AND DEVELOPMENT OF CISN AND ANSS AND (9) CONTINUE AQMS AWS SOFTWARE DEVELOPMENT WITHIN THE SCOPE OF ANSS MONITORING OBJECTIVES AND PERFORMANCE STANDARDS TO ADD NEW FEATURES AND IMPROVE ROBUSTNESSDELIVERABLES AND EXPECTED OUTCOMES: (1) TIMELY DELIVERY OF REAL-TIME EARTHQUAKE SOURCE PARAMETERS AND SHAKEMAPS THAT LEAD TO OTHER DOWNSTREAM PRODUCTS (2) ARCHIVAL AND PUBLIC ACCESS OF SCSN CATALOG, TIME-SERIES AND ASSOCIATED PRODUCTS AND (3) OPERATION AND MAINTENANCE OF THE ANSS STATION INFORMATION SYSTEM (SIS).INTENDED BENEFICIARIES: THE CITIZENS OF THE UNITED STATES OF AMERICA.SUBRECIPIENT ACTIVITIES: N A