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NINDS - National Institute of Neurological Disorders and Stroke

SUMMARY: The 2026 Gordon Research Conference (GRC) on Sleep Regulation and Function, themed “Sleep for the Whole Organism,” will mark the seventh installment of this highly successful series. Over the course of the last decade, sleep research has experienced remarkable growth across a variety of disciplines, spanning molecular biology, systems neuroscience, and mental health. Advances in state-of-the-art technologies have enabled significant progress in our understanding of the neurocircuitry underlying non-REM and REM sleep, wakefulness, the roles of neurotransmitters and neuromodulators, genetic contributions to sleep regulation, and the impact of sleep loss on transcriptional and translational dynamics. The 2026 GRC will build on this strong foundation while expanding into new frontiers. The program will explore sleep as a whole-organism behavior, integrating both brain and body perspectives. In addition to core sessions on sleep regulatory mechanisms and emerging findings from non- mammalian species, the conference will highlight recent findings on sleep’s roles in cognition, consciousness, interoception, and waste clearance from the brain. A session will examine the interplay between sleep and post- infectious disease states, reflecting growing interest in how immune challenges—including long-term consequences of viral infections—impact sleep regulation and homeostasis. The program will further emphasize bidirectional brain-body communication, with discussions on the bi-directional interaction between sleep and peripheral physiology, metabolic state, and systemic signals. Finally, the growing interface between artificial intelligence/machine learning (AI/ML) and sleep science will be showcased, illustrating how advanced computational tools are transforming data analysis, predictive modeling, and mechanistic discovery in the field. This GRC will comprise 50 invited speakers and discussion leaders, poster sessions, in the main meeting. It will be preceded by the GRS, which will provide opportunities specifically for graduate students and post-docs. The GRC and GRS will bring together scientists of all career stages in an interactive and safe environment.

Friends of Seattle Recycled Arts Festival

Recycled art is made from materials slated for the landfill, giving these items a second life through the vision of artists to create new durable goods. This event on May 11-12,2018 will demonstrate the many ways of approaching the phrase: Reduce, Re-use, and Recycle - This will be achieved through public participation, celebration and most importantly, education. This event is free to the public and includes an Eco Fashion show, Juried Arts Gallery, Outdoor Sculpture Garden, Art-Tech-Trash interactive space, Children's Interactive Space, Art Car Round Up, donation drive for textiles and household goods, Fix-It Clinic, and the Seattle Tilth Education Booth. Participation for children and families is intentionally provided as development of future citizens that will be environmentally conscious.

National Foundation on the Arts and the Humanities

The National Endowment for the Arts (NEA), as part of its continuing effort to reduce paperwork and respondent burden, conducts a preclearance consultation program to provide the general public and Federal agencies with an opportunity to comment on proposed and/or continuing collections of information in accordance with the Paperwork Reduction Act of 1995. This program helps to ensure that requested data can be provided in the desired format; reporting burden (time and financial resources) is minimized; collection instruments are clearly understood; and the impact of collection requirements on respondents can be properly assessed. Currently, the National Endowment for the Arts is soliciting comments concerning the proposed information collection through a mixed-methods evaluation of the Creative Forces[supreg]: NEA Military Healing Arts Network Community Arts Engagement Grant Program. The evaluation uses primary and secondary data, and includes interviews, case study site visits, a Participant Survey for individuals who participate in community arts programs, and an Arts Engagement Facilitator Survey for those leading the arts activities. Copies of this ICR, with applicable supporting documentation, may be obtained by visiting www.Reginfo.gov.

Festa Italiana

The 30th Annual Italian Festival at Seattle Center is a community festival to celebrate the joy of 'All Things Italian.' With an average attendance each year of 25,000, the Italian Festival is the largest Italian-American event in the Pacific Northwest. It is free to the public and features art, music, dance, food and activities for the entire family. The dates this year are September 22 - 24, 2017, with programming from 10:00 am until 7:00 pm.

Tasveer

Tasveer will organize the 3rd South Asian International Documentary Festival February 11 - 12, 2017.  It will bring people together to engage with the cultural, artistic and activist work of the South Asian region and people. Documentaries and art will inspire conversations and actions about issues relevant to the South Asian people.

OD - NIH Office of the Director

Project Summary A group of NIH-supported investigators requests funds to purchase an NMR console to replace an outdated 500 MHz NMR spectrometer. This equipment will significantly increase access to small molecule characterization for an existing shared spectrometer that is housed in the NMR Laboratory of the UCLA Molecular Instrumentation Center Core Facility. Specifically, we request funds to purchase a broadband Bruker i-Probe and replace an outdated Bruker DRX NMR console that was installed in 1999, with an Avance Neo 500 High Performance Digital console. The new workhorse spectrometer will allow more users than now to have instant access to NMR characterization and alleviate oversaturation usage on the two most sensitive spectrometers in the facility. The new equipment will provide an extended variable temperature range, provide a wide range of nuclei, and allow complex heteronuclear coupling elucidation with a triple-resonance probe. Experienced Ph.D. staff scientists will be in charge of maintenance, repair and user training. Also, as part of this grant, UCLA will allocate funds to refurbish the magnet that supports our most sensitive equipment and prevent the complex situation of losing this critical resource, showing our institutional commitment to excellence in research supported by state-of-the-art instrumentation.

National Foundation on the Arts and the Humanities

The National Endowment for the Arts (NEA), as part of its continuing effort to reduce paperwork and respondent burden, conducts a preclearance consultation program to provide the general public and federal agencies with an opportunity to comment on proposed and/or continuing collections of information in accordance with the Paperwork Reduction Act of 1995. This program helps to ensure that requested data is provided in the desired format; reporting burden (time and financial resources) is minimized; collection instruments are clearly understood; and the impact of collection requirements on respondents is properly assessed. Currently, the NEA is soliciting comments concerning the proposed information collection of: Blanket Justification for NEA Funding Application Guidelines and Reporting Requirements. A copy of the current information collection request can be obtained by contacting the office listed below in the address section of this notice.

National Foundation on the Arts and the Humanities

The National Endowment for the Arts (NEA), as part of its continuing effort to reduce paperwork and respondent burden, conducts a preclearance consultation program to provide the general public and federal agencies with an opportunity to comment on proposed and/or continuing collections of information in accordance with the Paperwork Reduction Act of 1995. This program helps to ensure that requested data is provided in the desired format; reporting burden (time and financial resources) is minimized; collection instruments are clearly understood; and the impact of collection requirements on respondents is properly assessed. Currently, the NEA is soliciting comments concerning the proposed information collection of: Blanket Justification for NEA Funding Application Guidelines and Reporting Requirements. A copy of the current information collection request can be obtained by contacting the office listed below in the address section of this notice.

OD - NIH Office of the Director

This Shared Instrumentation Grant application requests funds to upgrade the 700 MHz NMR spectrometer at the Minnesota NMR Center (MNMR), a University of Minnesota core facility that serves as a hub for high-field NMR spectroscopy. The existing instrument is currently equipped with a 22-year-old Bruker Avance I console and TXI cryoprobe that are now obsolete, increasingly unreliable, and no longer capable of supporting many state-of-the- art experimental experiments. Hardware failures, including cryoplatform instability, auto-tuning issues, and console communication problems, have significantly reduced instrument availability and limited its utility, even as user demand continues to grow. The manufacturer no longer guarantees part availability or technical support for this aging platform, posing an ongoing risk to research continuity. The proposed upgrade includes a Bruker Avance NEO console and QCI-F CryoProbe. This combination will restore the instrument to full operational capacity and provide a significant technical leap in sensitivity, stability, and experimental flexibility. Specifically, the upgraded system will deliver improvements in 13C sensitivity, enable simultaneous 1H decoupling during 19F detection, and support 19F-detected experiments. These capabilities will open new experimental avenues for investigators studying conformational exchange, ligand screening, protein- small molecule interactions, intrinsically disordered proteins, and macromolecular dynamics on the µs–ms timescale. In addition, the system will support automation features, as well as compatibility with TopSpin 4.x software and the existing autosampler, further improving efficiency, reproducibility, and throughput. MNMR currently supports 32-36 active research groups each year, whose work results in 30-40 peer-reviewed publications annually and is supported by 16-20 NIH-funded projects. The user base spans five colleges and includes researchers from more than a dozen departments across the Twin Cities campus. Current users apply NMR to a broad spectrum of biomedical problems, including DNA repair, cancer signaling, infectious disease, metabolism, and drug discovery. The MNMR Center is also an important training resource, providing hands-on experience in high-field NMR methods for graduate students, postdoctoral fellows, and technical staff. The requested upgrade will alleviate the significant pressure currently placed on the Center’s two 600 MHz instruments, which are nearing full capacity due to users shifting away from the outdated 700 MHz instrument. By restoring this underutilized instrument to full functionality and enabling advanced biomolecular and small molecule NMR experiments, the upgrade will enhance access, expand capacity, and improve data quality for a broad and growing community of NIH-funded investigators. This investment will not only strengthen ongoing research programs but also attract new users to the MNMR Center. Thus, this proposal addresses an urgent instrumentation need and will have immediate and lasting impact on NIH-supported research across structural biology, chemical biology, and biomedical sciences at the University of Minnesota.

Rainier Arts Center

In the second edition of the 98118 Fest, we propose to center community partnership while building on our over forty years of experience in live outdoor events. 98118 Fest will take place on August 22, 2026, 12pm-6pm at Columbia Park, located at 3515 S Alaska St, Seattle WA, our community’s “living room,” and at Rainier Arts Center. The festival will showcase performances from a mix of world music and local artists. A pop-up gallery will create opportunities for local artists to sell their work. We will provide soccer- and art-themed activities for kids and families, including face painting, art making, and games. The event will be free and open to the public.

NIAID - National Institute of Allergy and Infectious Diseases

Infants are especially susceptible to intracellular pathogens because their immune system is not fully equipped to fight against these microorganisms. As a result, infant infections are a leading cause of mortality, with >1.5 million children dying of infections before 5 years of age in 2022 alone. The current consensus is that before birth, conventional T cells are skewed in favor of T regulatory or T helper (Th) 2 responses, leaving neonates and infants more vulnerable to pathogens cleared by Th1 immunity. Therefore, Vγ9Vδ2 (or simply Vδ 2) T cells, are particularly important in early life, because they are poised to secrete Th1 cytokines even before birth and acquire potent cytotoxic function shortly after birth. Despite their protective role against pathogens, human Vδ2 cells, which are absent in mice, are not well studied in neonates and infants. Our long-term goal is to elucidate their functional heterogeneity because understanding their features in the first few months of life will allow us to harness their properties to protect infants from infections. This task is challenging for many reasons, including the difficulty in obtaining samples from the infants at highest risk of early infections, such as premature babies. Our recent observations, obtained using spectral flow cytometry (SFC) and single cell RNA-seq, converge to show phenotypic and functional heterogeneity of cord blood (CB) Vδ2 cells, with heightened stemness compared to their adult counterpart and a cluster of PD1-hi cells (absent in adults) that may follow a distinct functional program specific for the early life stage. We posit that differences in Vδ2 cell cluster composition at birth have functional consequences and result in improved or decreased antimicrobial activity depending on the composition. The resulting overarching hypothesis is that human neonatal V δ2 lymphocytes exist in heterogenous functional/differentiation states impacting host immune competence in the critical early life window. As a multidisciplinary team of immunologists and computational biologists, we propose to characterize cord blood Vδ2 cells in existing specimens, including samples of premature babies, using state of the art techniques –Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE- seq) and SFC- with the following aims. Aim 1. Evaluate the phenotypic and functional heterogeneity of Vδ2 T cells at birth and in early life in relation to age, with a focus on a unique subset of PD1-hi cells present in cord blood. Aim 2: Assess how the composition of Vδ2 T cells at birth impacts function of these cells at the population level, combining CITE-seq analysis with depletion and transduction experiments. The goal of this proposal is to develop a robust molecular and functional map of a critical subset of innate-like T cells, which will provide a valuable reference for the cellular heterogeneity in the neonatal human immune system and a foundation for future proposals aimed at understanding Vδ2 cell biology in early life.

NIA - National Institute on Aging

ABSTRACT IdenƟfying Alzheimer’s disease (AD) in its presymptomaƟc stage can allow early intervenƟon and improve paƟent care. Crucially, the AD-induced amyloid/tau pathology is not limited to hippocampal insult or memory loss, but also impairs /disrupts funcƟonal connecƟons that integrate sensory inputs in the cortex. As these sensory deficits often precede the decline of cogniƟve funcƟon in AD paƟents, understanding their characterisƟc altered funcƟonal connecƟvity and neural hyperacƟvity patterns early in the AD cascade has the potenƟal to yield new diagnosƟc biomarkers or therapies. Similarly, blood flow decline and endothelial dysfuncƟon posited by the vascular hypothesis of AD remains underexplored. While the availability of transgenic AD mouse models has created a unique platiorm for invesƟgaƟng how AD pathogenesis can disturb the neurovascular unit (NVU), design limitaƟons of imaging hardware, e.g. bulky PET, MR or SPECT, that are not developed/opƟmized to probe AD onset, make it unfeasible to image AD pathogenesis at the spaƟal scale of the NVU. Specifically, AD insults the NVU on mulƟple fronts including neural, vascular/blood flow change that span from neurons to cortex-wide brain acƟvity changes, which are modulated with uneven sleep cycle fragmentaƟon/disrupted circadian rhythms. In contrast, preclinical imaging methods are restricted to short duraƟons (< 2 h) due to anesthesia use when imaging a small animal AD model with a device >1000× in size (e.g. PET), and even the state-of-the-art AD studies assess AD-inflicted NVU change only once in every 1-2 months, which substanƟally under-samples the Ɵme course of AD onset. Moreover, since no two brains age the same, subject-specificity can also mask AD-related NVU changes when imaged intermittently. Therefore, new imaging technologies that can generate large neuroimaging datasets and covering mulƟple temporal (days-months), spaƟal (neurons-whole cortex), and modal (neural-vascular) scales are needed to characterize the “funcƟonal fingerprints” of cortex-wide NVU disrupƟon during AD onset. Therefore, we are proposing the development of NeuroCube, which is a miniaturized microscope that will enable mulƟmodal, cortex-wide in vivo imaging >30 days during AD onset in mice. Unlike extant microscopes that lack capacity for long-term operaƟon (<3 h), we will use 3D-prinƟng and fabricate NeuroCube as a robust unit for longitudinal imaging amidst the harsh, jolty condiƟons in an animal enclosure (Aim 1A). To avoid photobleaching, we will use low-light levels, obtain images at low-signal-to-noise raƟos (SNR)/resoluƟon (50 µm), and recover high-SNR/resoluƟon (10 µm) images via a deep learning (DL) backed generaƟve adversarial network (GAN) (Aim 1B). To limit oversized data volumes, we will image in 1-min bursts (0.75 GB) per hour, and curate an imaging dataset that characterize cortex-wide changes of AD, together with gender/age-matched controls (Aim 2). We believe that The NeuroCube and publicly shared in vivo AD datasets will become a vital new tool for the broad AD research community. Moreover, NeuroCubes could be widely useful for interrogaƟng cortex-bound dysfuncƟon in aging and other brain disease.

OD - NIH Office of the Director

Project Summary/Abstract The Athinoula A. Martinos Center for Biomedical Imaging, a core facility of the Massachusetts General Hospital (MGH), conducts cutting-edge research across all domains of biomedical image acquisition and analysis. It provides advanced technologies and computational resources to researchers from institutions throughout the Boston area and the northeastern United States, including the Massachusetts Institute of Technology (MIT), Harvard University, Boston University, Tufts University, and many Harvard- and MIT-affiliated research hospitals. Research at the Martinos Center pursues two primary goals: (1) advancing imaging technologies and analytical methods, along with their integration with complementary fields such as human genetics, and (2) applying these tools to drive basic science and translational research that ultimately improves clinical care. The Center’s combined expertise makes it an international leader in structural and functional magnetic resonance imaging (MRI) and spectroscopy (MRS), magnetoencephalography (MEG) and electroencephalography (EEG), near-infrared spectroscopy (NIRS), diffuse optical tomography (DOT), and positron emission tomography (PET). These imaging modalities generate a vast volume of data daily, fueled by numerous NIH-funded projects. To analyze these data, investigators at the Martinos Center develop and deploy advanced computational tools for image processing, machine learning, and visualization. As these activities create an extraordinary computational demand, this application requests funding for a new, state-of- the-art high-performance computing (HPC) system to support the Center’s needs for years to come, offering substantial improvements in performance and reliability over the aging computational resources, which is becoming a bottleneck for innovation. The new system will enhance research at the Martinos Center by enabling the development and maintenance of optimization-based and deep-learning methods for biomedical image analysis, the design and evaluation of novel image acquisition protocols, as well as large-scale morphometric, multimodal, and population-level analyses. This HPC infrastructure will be a critical asset for the Center's expanding research community and its continued leadership in advancing biomedical imaging science.

NCI - National Cancer Institute

A High-Performance Instrument for Dedicated Brain Imaging and in Combination with Whole Body PET for Oncology: The goal of this project is to develop a high-performance brain PET scanner in an academic- industry partnership with Siemens to operate in tandem with a total-body PET that will open up new oncologic applications that leverage simultaneous high-resolution brain and body imaging, and also be capable to operate as a stand-alone device for brain-only imaging to widen its clinical use. Dynamic brain-body imaging is currently only provided by total-body PET systems, though the spatial resolution of these devices is limited for brain imaging. The new instrument will provide < 2-mm spatial resolution (isotropic) and system TOF resolution near 160 ps for an unprecedented combination of spatial resolution and effective sensitivity. We will achieve our goal through 3 specific aims: (1) Develop and test performance of the brain scanner, and integrated with TB PET; (2) Adapt and evaluate image generation methods for quantitative brain imaging; and (3) Test clinical performance and evaluate brain-body imaging protocols in humans with emerging tracers, including 18F-FES and 18F-Fluciclovine (FACBC), as well as 18F-FDG. In Aim 1 we will develop and optimize a high-resolution detector design based on Siemens state-of-the-art technology, using experimental measurements as input to Monte Carlo simulations to model the system and test the data correction and image generation methods developed in Aim 2. The scanner development will be driven by requirements for high performance, using robust manufacturing practices. The scanner will be built and integrated with the PennPET Explorer scanner and performance will be characterized using physical measures and phantom studies. In Aim 2 we will develop and apply methodology to produce accurate quantitative images focusing on data driven methodologies for calibrations and for brain motion correction, energy-based methods for scatter correction, deep learning-based methods for attenuation correction (for use without CT), and image- based resolution modeling to achieve uniform spatial resolution within the imaging FOV. In Aim 3, we will design human protocols and evaluate the clinical performance in two small cohorts of patients with melanoma, breast and lung cancer undergoing Amino Acid (FACBC) and FDG PET or with breast cancer starting estrogen receptor (ER)-targeted therapy and undergoing 18F-FES and FDG PET. These studies will demonstrate the benefits of the high-resolution brain scanner and its capability to provide simultaneous brain-body imaging for oncologic applications. The human studies with the Brain-TB PET scanner will provide feedback on the technology, as well as the patient and end-user experience that will guide translation of the prototype to a commercial product integrated with the Siemens Vision Quadra.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT Pathogen transmission via indirect routes such as fomite, waterborne, and airborne transmission are hallmarks of both endemic and pandemic spread. Viruses such as Influenza, SARS-CoV-2, and measles are notable examples, in addition to deadly microbes such as Bordetella pertussis, Mycobacterium tuberculosis, and Coccidioides species. However, the rapid detection and analysis of airstreams as part of biosurveillance, public health monitoring, or epidemiological research remains challenging. Current state-of-the-art methods rely on bulky apparatuses for both the collection and detection of airborne agents; most of these methods are ill suited to rapid response point-of-testing within medical facilities, workplace locals, or public spaces. Further, these technologies are based on bulk Polymerase Chain Reaction (PCR) and Loop-mediated isothermal amplification (LAMP) methods that have limited quantitative accuracy. Thus, more portable and accurate platforms are needed to address the types of rapid response and ubiquitous monitoring that is required to minimize outbreaks in the 21st century. Towards this objective, this grant will address the need for an improved method of airborne pathogen detection through the development of the digital droplet Aerosol Capture & Quantification (ddACQ) system. The ddACQ system consists of two novel technologies, a filter particle array and a droplet buoyancy counter. The filter particle array allows for the capture of airborne pathogens or biological agents and generation of microfluidic droplets when mixed with an oil and water reagent solution. A phone-powered heat block then drives a one-step isothermal digital droplet reaction. Digital techniques have several key advantages over classical quantitative PCR and LAMP techniques, namely single molecule detection and direct quantification without a standard curve. Finally, the droplet buoyancy counter allows for smartphone based read out of the reaction immediately at the testing site in under an hour. Together, the innovations within and implementation of the ddACQ system represents a novel application of microfluidic principles and an enabling technology for both pathogen transmission research and public health monitoring applications.

NIA - National Institute on Aging

Project Summary Cognitive decline and neurodegenerative disorders, such as Alzheimer’s disease (AD), disproportionately affect women, who face a 48% lifetime risk of developing dementia—a nearly 40% higher risk compared to men. Heightened vulnerability in women is attributed not only to genetic and lifestyle factors but also to neurobiological shifts during midlife transitions, including menopause. Each year, 25 million women enter the menopause transition, a critical period marked by declining estrogen and neurobiological changes underlying hot flashes, sleep disruption, mood disturbances, and cognitive shifts. Despite this, sex-specific risk factors remain poorly understood, and current prediction models of AD remain predominantly sex-neutral, failing to account for reproductive history, hormonal changes, and endocrine interventions. Addressing these gaps is essential for early detection, precise risk stratification, and tailored prevention strategies for cognitive decline in women. This project seeks to uncover the neurobiological mechanisms of menopause, quantify the impact of menopausal hormone therapy (MHT) on brain health, and identify sex-specific molecular mediators of adverse brain outcomes. Using longitudinal neuroimaging, plasma proteomics, and clinical assessments, we will elucidate individual risk profiles and define actionable biomarkers for preventing late-life brain aging. We propose to (a) map neurobiological changes during menopause transition among a cohort of 120 pre- and perimenopausal women aged 40–48, an underrepresented age group in existing studies, using state-of-the-art neuroimaging, hormone, and symptom profiling. We hypothesize that perimenopausal estrogen loss leads to dysconnectivity and myelin degradation in estrogen-sensitive brain networks, correlating with symptoms (aim 1); (b) Evaluate sex-specific risk and resilience factors for adverse brain outcomes using four decades of data from the Atherosclerosis Risk in Communities (ARIC) study (N=2,649). Brain aging outcomes will be examined based on timing and formulation of MHT, testing the “critical window” hypothesis of early initiation being neuroprotective (aim 2); and (c) Identify plasma proteomic profiles mediating sex-specific risks by integrating longitudinal imaging and proteomics. We hypothesize that proteins in inflammatory and metabolic pathways link hormonal changes to adverse brain aging (aim 3). This research will yield neurobiological maps of menopause, characterize MHT's long-term impact on brain health, and identify molecular markers for precision prevention. Findings will transform clinical care by informing personalized guidelines for maintaining cognitive health in women across their lifespan.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Broadly neutralizing antibodies (bnAbs) and the antibody-like biologic eCD4-Ig (eCD4) can suppress established HIV-1 and SHIV infections when they are present at sufficient concentrations. BnAbs and eCD4 can be delivered passively or expressed from a recombinant adeno-associated virus (rAAV) vector. rAAV expression bypasses cost and compliance concerns associated with periodic antibody infusions, as well as side-effects associated with a life-time of use of conventional or long-acting antiretroviral therapy (ART). Moreover, unlike ART, long- term antibody-mediated control engages multiple effector arms of the immune system, potentially accelerating the rate of decay of the proviral reservoir. eCD4, a potency and half-life enhanced CD4-Ig fused to a coreceptor-mimetic sulfopeptide, has several advantages over bnAbs. It is exceptionally broad, neutralizing all 200-plus HIV-1 and SIV isolates assayed. rAAV-expressed eCD4 (rAAV-eCD4) can protect from multiple high-dose challenges of both SHIV and SIV. eCD4 can combine with non-neutralizing CD4-inducible antibodies common in the sera of infected persons to mediate very potent antibody-dependent cell-mediated cytotoxicity (ADCC). More recently, we have shown that more potent and bioavailable forms of eCD4, combined with the bnAb 10-1074, can fully suppress established SHIV infections in both infant and adult macaques. We are therefore close to robust functional cures in rhesus macaques. The current application seeks to bring us across the finish line and identify antibodies and eCD4-Ig variants that would best function in a human clinical trial. To do so, we will therefore in Aim 1 compare new eCD4 sulfopeptide variants, determine the Fc-domain that best limits anti-drug antibodies and enhances expression, and ensure in vivo that eCD4 poses no risk of immune interference. Aim 2 presumes that a bnAb partner of eCD4 will be useful in maintaining long term viral suppression and asks what class of antibodies works with eCD4 most effectively. Several properties are considered: their inherent bioavailablity, potency, and breadth, and how they complement eCD4 to limit potential viral escape. Aim 3 then seeks to improve the former properties by employing a novel system whereby human antibodies affinity mature in wild-type mice, starting with bnAbs modified with largely germline framework regions, and selecting in vivo those with greater potencies and longer half-lives. Aim 4 applies knowledge that we have accumulated from the previous decades and insights from the previous aims to establish and compare functional cures mediated by eCD4 paired with optimized forms of CD4-binding site bnAbs and V3-glycan antibodies. Collectively, these aims will directly inform human clinical trials designed to suppress established HIV-1 infections without ART.

NIH

Significance to VA: This CDA-2 application requests support for a 5-year mentored research project to identify multi-omics risk and resilience factors for opioid use disorder (OUD) and chronic pain, conditions that disproportionately burden Veterans. Veterans face elevated OUD risk due to higher rates of chronic pain and opioid exposure than the general population, yet key genetic and environmental contributors to risk and resilience are poorly understood. This project will address these gaps by leveraging genomic and bioinformatic methods to improve prevention and treatment strategies. The proposed research aligns with the mission of the Veterans Healthcare Administration by focusing on the intersection of chronic pain and OUD—high-priority issues with substantial disease burden—and advancing precision medicine approaches to improve treatment outcomes for Veterans. It will provide me with training to support my development as an early-career investigator committed to improving the care of Veterans with chronic pain who are risk for OUD. Innovation and Impact: The proposed research is innovative in its focus on resilience to OUD, representing the first multi-omics analysis of this phenomenon in Veterans with chronic pain. The integration of genetic, epigenetic, transcriptomic, and proteomic data using network-based machine learning models will enable a holistic understanding of biological pathways that drive OUD and chronic pain. These novel, transformative methods align with state-of-the-art data science approaches to translate genomic findings into actionable insights. The project establishes a framework for integrating multi-omics findings with clinical data, paving the way for precision medicine approaches tailored to Veterans’ unique needs. These innovations will advance scientific knowledge and clinical care to help alleviate the burdens of OUD and chronic pain among Veterans. Specific Aims: (1) Identify genetic variants associated with OUD risk and resilience in Veterans with chronic pain and examine how clinical factors moderate these associations. (2) Characterize epigenetic changes linked to risk and resilience factors in Veterans. (3) Integrate multi-omics (genetic, epigenetic, and in silico predicted transcriptomic and proteomic) data using network-based machine learning models to identify key biological pathways and gene networks that underlie risk and resilience to OUD and chronic pain. Methodology: The proposed study employs an integrative multi-omics approach to investigate OUD and chronic pain in Veterans, leveraging data from the Million Veteran Program (MVP). Genome-wide association studies will identify genetic variants associated with risk and resilience, epigenome-wide association studies will assess methylation changes, and multi-omics data will be integrated using network-based machine learning models. Key outcomes include the identification of genetic and epigenetic contributors to OUD resilience and the elucidation of underlying biological pathways. The population of interest is Veterans with chronic pain. Comparison groups include Veterans with and without OUD to delineate factors that distinguish resilience from risk. Data sources are MVP genomic, epigenomic, and phenotypic datasets, and predicted transcriptomic and proteomic data using publicly available reference sources. Path to Translation/Implementation: A core element of this research is its clear translational pathway to improving Veterans’ healthcare. Immediate steps will leverage identified biological pathways and gene networks to develop biomarkers for OUD risk and resilience in chronic pain patients. These biomarkers could inform clinical decision-making, such as identifying high-risk Veterans and tailoring pain management strategies to their individual genetic and epigenetic profiles. Longer-term goals include using foundational insights to inform therapy development, including precision medicine approaches that target pathways identified in the study. Through collaborations with the VA’s clinical and research infrastructure, we aim to ultimately translate findings into interventions that reduce OUD risk and alleviate chronic pain among Veterans.

NIH

Significance to VA: Treatment-resistant depression (TRD) is a serious mental health problem in Veterans, frequently comorbid with post-traumatic stress disorder (PTSD), and in need of novel and effective treatments. Also, TRD in Veterans is associated with a high risk of suicide, addiction, unemployment and medical morbidity. Innovation and Impact: Clinical studies have revealed antidepressant effects of psilocybin for depression and TRD in civilians, but less is known about its efficacy and safety in Veterans. Very limited data is available on the effects of psilocybin in the treatment of comorbid PTSD and when used in combination with serotonin reuptake inhibitor antidepressants. This state-of-art clinical trial will evaluate the safety and efficacy of psilocybin in the treatment of TRD with and without PTSD to advance knowledge in psychedelic therapy in Veterans. Methodology: This multi-site, double-blind, randomized controlled trial will evaluate the efficacy and risks of psilocybin for the treatment of TRD in U.S. military Veterans with and without (±) concurrent PTSD. Eligible and consenting Veterans will be randomized (N=240) and undergo two psilocybin dosing sessions along with preparation, administration, and integration psychological support. For the 1st psilocybin administration, participants will receive either a 1mg dose (control condition) or a 25mg dose (active) under blinded conditions. At their 2nd psilocybin dosing visit 4 weeks later, all participants will receive a 25mg dose. Outcomes will be measured by a centralized independent evaluator masked from all treatments at 2 and 4 weeks after each dosing session and over 6 months follow-up. Both expected and unanticipated adverse events will be collected by type, severity and relatedness to the study drug after each dosing session and at follow-up. Assessments of subjective experiences of psilocybin, expectancy and blinding are included in the protocol. Specific Aim 1 (Efficacy): Evaluate the short-term antidepressant effects of 25mg psilocybin compared to 1mg psilocybin for TRD under blinded conditions by centralized evaluator. Primary Hypothesis: Participants treated with the 25mg psilocybin dose (n=120) will show a significantly greater decrease on the Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to week-4 post-dose compared to the 1mg psilocybin dose control group (n=120). The Hamilton Depression scale is also collected as a common data element. Specific Aim 2 (Safety): Evaluate risks in participants who took ≥ one psilocybin dose with the Swiss Psychedelic Side Effects Inventory and other reported adverse events. Exploratory Aims (E): E1 PTSD: For the subgroup with TRD+PTSD (~50% of the sample), estimate the change from baseline to week 4 on Clinician-Administered PTSD Scale-Revised (CAPS- 5-R) by group. E2 2nd Dose: Examine the antidepressant effects of one vs two 25mg dosing sessions by comparing change in MADRS from baseline to week 8 (i.e., ~4 weeks after the 2nd dose) between the group receiving the 1mg dose followed by the 25mg dose versus the group treated with two 25mg doses. E3 Response & Remission: Explore rates of response (ΔMADRS ≥50% reduction) and remission (MADRS score ≤10) at week 4, week 8 and month 6, within group and between groups. E4 Other Relevant Outcomes: Explore potential effects of treatment on patient-reported and other outcomes over time, including expectancy, depression, PTSD, suicidality, psychological flexibility, and functional outcomes. Measure altered experience during psilocybin dosing sessions and explore impact on outcomes and functional unblinding. Qualitative Aim: Participants (~10 per site; n=50) will be interviewed on topics of acceptance, satisfaction, and facilitators/barriers of treatment with psilocybin to gain a better understanding of Veteran preferences on the treatment itself, the composition/structure of the psychological support model and future implementation of clinical psychedelic treatment programs in VA. Path to Translation/Implementation: Industry-sponsored studies seeking FDA approval are already underway. The timing of FDA-approval of psilocybin should align with the conclusion of this study. VA can use these results to make decisions on offering psilocybin treatment and to guide implementation within VA mental health systems.

NIMH - National Institute of Mental Health

Project Summary/Abstract The overarching aim of the proposed project is to develop and validate novel, multimodal, scalable, time- and cost-efficient assessment protocol for comprehensive characterization of key subdomains of restricted and repetitive behaviors (RRB) that can assist in the diagnostic process, facilitating etiologically oriented research, the treatment selection, and monitoring symptomatology over time. Although RRB are a core, clinically impactful feature of autism spectrum disorder (ASD), existing measures are limited by poor ability to comprehensively capture all relevant RRB subdomains and currently, there are no dedicated clinician interviews nor protocols to capture and quantify daily variations of distinct RRBs in ASD or in neurogenetic disorders. In the proposed project, we will build on the Dimensional Assessment of Restricted and Repetitive Behaviors (DARB), an informant-report questionnaire developed and validated by our group following the NIH Patient-Reported Outcome Measurement Information System framework. DARB has a comprehensive item bank developed to assess eight distinct RRB subdomains and has been shown to have a stable and replicable 8-factor structure, strong model and conditional reliability, invariance across age, sex and diagnostic status, and excellent test-retest replicability. In the current proposal, we will aim to: develop and validate the computerized adaptive test (CAT) version of the DARB (DARB-CAT) to maximize precision and reduce patient burden by individually tailored item selection and administration (Specific Aim 1), refine and validate a clinician interview version of the DARB (DARB-I) (Specific Aim 2) and develop an ecological momentary assessment (EMA) RRB protocol (DARB-EMA) to capture daily and weekly changes in specific RRB and contexts in which they occur (Specific Aim 3). We will also develop and pilot a platform that will integrate the administration, scoring and reporting of the DARB-CAT, DARB-I and DARB-EMA components (Exploratory Aim 4). Finally, we will explore mechanisms underlying RRB subdomains (Exploratory Aim 5). This project will generate the world’s first comprehensive, multimodal RRB assessment ecosystem incorporating state-of-the-art psychometric principles that will have a significant potential to enhance the pathway from screening to clinical and neurobiological characterization to treatment tailoring and tracking.

NIGMS - National Institute of General Medical Sciences

Project Summary Free fatty acids (FFAs) and lipids are important biological compounds that are involved in almost every biological process. Studying the lipidome can provide information on the roles of lipids, ranging from nutrient absorption and cell signaling to cancer metastasis. However, identifying the complete chemical structures of many lipids is a long-standing analytical challenge. Lipids possess an enormous number of isoforms (compounds with the same chemical formula but different arrangements of atoms), but current analytical technology struggles to distinguish many of them. This means many lipid signatures remain uncharacterized and their biomedical activities remain unknown. This project will address this significant gap in lipidomics research by developing a novel multimodal system that will be used to unambiguously identify FFAs and lipids in complex biomedically- relevant samples. This will be accomplished by using a novel high-resolution ion mobility-mass spectrometry (IM-MS) platform employing two different types of fragmentation. A novel high-resolution IM module based on 'traveling cups' (termed cupped IMS) will provide new state-of-the-art IM separations of FFA and lipid isomers, many of which are notoriously difficult to separate due to their high structural similarity. Collision cross section (CCS) measurements gained from such HR-IMS separations will provide a key physical metric by which to differentiate these structurally similar FFAs and lipids. A new ultraviolet photodissociation capability will be installed into an Orbitrap mass spectrometer to provide information on the locations of lipid double bonds along alkyl chains, which is often missing in gold-standard MS-based workflows. The Orbitrap-MS will also provide high-resolution mass measurements, which can be used to derive the chemical formulae of FFAs and lipids. Having chemical formula information is an essential first step when beginning to determine the structure of an unknown lipid. The Orbitrap will also provide collision induced dissociation capabilities, which are useful for identifying to which class of lipids an unknown compound belongs. New data-dependent acquisition (DDA) and data-independent acquisition (DIA) methods will be developed to enable automated acquisition of MS/MS spectra from the new multimodal system, and informatics workflows will be developed to leverage data processing software already capable of reading Thermo-Fisher .RAW files. A novel UVPD informatics capability will be developed to interpret the multimodal data from this new system. The data will be benchmarked against gold-standard LC-MS/MS lipidomics workflows to show significantly improved lipid identifications from lipid extracts of HeLA cells, which has tremendous implications in diseases like breast cancer. The discoveries made by the multimodal system proposed here will significantly advance the field of lipidomics research. Furthermore, this research will show that multimodal systems are critical tools that will one day be used in general structural identification workflows where reference data from authentic compounds are not available.

NIDA - National Institute on Drug Abuse

Project Summary: HIV infection and cocaine use are comorbid conditions that can exacerbate each other's harmful effects, as ART is not sufficient to fully suppress HIV transcription or prevent latency reactivation. HIV gene products (RNA and proteins) greatly contribute to perpetual immune activation and inflammation throughout the system, primarily in the central nervous system (CNS) of people with HIV (PWH). Additionally, viral latency, the main cause of HIV persistence, is also largely regulated at the transcriptional level. Therefore, defining all the mechanisms that control HIV transcription is essential before utilizing them therapeutically to limit HIV persistence and associated comorbidities, such as neuroinflammation, which is prevalent even in well-controlled PWH. DNA breaks are a common occurrence during the transcription of genes, which are required to be repaired via transcription-coupled repair (TCR). Without TCR, during transcription of a gene, breaks in the template DNA cause frequent RNAPII pausing or degradation, which halts transcription. Interestingly, upon cocaine exposure to microglia, we noted both the increased DNA-dependent protein kinase (DNA-PK) activity and corresponding enhanced HIV transcription and replication. Additionally, we found that DNA-PK knockdown results in the dissociation of TCR machinery from LTR, showing a direct role of DNA-PK. However, in microglia, the major HIV reservoir in the CNS, the impact of DNA-PK-mediated TCR during HIV transcription in the context of ART and cocaine, and the potential therapeutic reversal using clinically tested DNA-PK inhibitors (DNA-PKi), remains largely unexplored. This study aims to address this critical knowledge gap, using brain organoids harboring microglia. Together, these facts offer a strong premise for the hypothesis that DNA-PK plays a crucial role during TCR and neutralization of negative factors in relieving RNAPII pausing during HIV transcription, and cocaine further supports these effects by stimulating both the level and activity of DNA-PK; however, clinically tested DNA-PKi can reverse this process, limiting viral load and rebound after ART interruption. Aim 1 will investigate the role of cocaine-induced DNA-PK in relieving RNAPII pausing via TCR in brain organoids and iPSC-derived microglia +/- ART. Aim 2 will define the impact of DNA-PK mediated regulation of negative transcription factors (NFs) during RNAPII pause-release. Aim 3 will test the efficacy of clinically tested DNA-PKi in blocking HIV transcription and viral rebound upon ART interruption in the context of cocaine +/- ART in brain organoids. The proposed high-risk/high-payoff exploratory study with great translational potential is closely aligned with the main objective of this FOA: 1) we propose to develop new tools and techniques in our lab - DNA curtain methodology/assay and human brain organoids harboring microglia; 2) define a novel mechanism, DNA-PK- mediated TCR, in regulating HIV transcription, latency, and rebound in the context of cocaine+/- ART.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Description/Summary Reticulocyte maturation, the final stage of erythropoiesis, is critical for blood formation. Despite its importance in disease pathology, including inherited and acquired disorders of the erythrocyte, it is an understudied area. A major aspect of reticulocyte maturation is gradual loss of salt and water over time. Maintenance of water and solute homeostasis is critical to survival of both the reticulocyte and the mature erythrocyte. We have identified a novel regulator of erythrocyte hydration in erythropoiesis. In conjunction with the kinase WNK1, this TGF beta- stimulated clone (TSC) 22 family member controls potassium-chloride cotransport in reticulocytes and mature erythrocytes, shrinking reticulocytes to their normal volume in mature red blood cells. The goal of specific aim one is the identification of interacting proteins and characterization of regulator-WNK1 interactions and their influence on cellular hydration. The goal of specific aim two is elucidation of the influence of genetic variants on erythrocyte phenotype in humans and murine in vivo models of perturbed erythrocyte hydration. The overall goal of this proposal, which combines state of the art cellular, molecular, and genetic technologies in an innovative, multidisciplinary manner, is to characterize the structure and function of regulatory complexes in erythroid cells to better understand the mechanisms regulating erythrocyte volume homeostasis. These studies will extend our knowledge of normal erythropoiesis, particularly reticulocyte maturation. They will also provide a better understanding of the contribution of regulatory proteins to erythroid cell traits and its contribution to erythroid cell phenotype in inherited and acquired disorders of the erythrocyte.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY/ABSTRACT Ischemic stroke represents the second leading cause of death worldwide, and the direct costs of stroke are approximately $71.6 billion. These costs are disproportionately driven by patients with large vessel occlusions (LVO). Recent advances in urgent thrombectomy (clot removal) have led to improved outcomes, yet more than 50% of patients fail to achieve good functional outcomes even in the most recent trials. Developing neuroprotectants in order to mitigate neuronal injury immediately following the ischemic event is now a primary focus for researchers in this area. Among numerous proposed neuroprotectant strategies, hypothermia, or brain cooling, remains the most promising. Numerous previous investigators have proposed selective brain cooling of the brain only rather than full-body cooling, especially in conjunction with thrombectomy procedures since the access catheters to the carotid arteries are already in place and could be utilized to selectively cool the brain immediately after clot removal. These selective cooling approaches use the indwelling procedural catheters either for infusion of cold saline directly into the intracranial blood flow or cold saline to cool flowing blood as it passes along an indwelling catheter wall. Both of these approaches are limited by the cold saline's inherent warming as it travels to the target location. Also, saline will cause both fluid overload as well as dilution of oxygen- rich blood. Further, the devices being developed are not similar to the modern, high- performance catheters currently in use in thrombectomy procedures, which likely will limit their use. The long-term goal of this research and development proposal is to enable an advanced cooling system that targets the practitioners---neurointerventionalists, neurointensive care physicians, and perfusionists--- to provide them with a state-of-the-art cooling catheter system that focuses on ease of use rather than engineering principles, yet enables speed, depth, and duration of cooling superior to any other device. The first Specific Aim of this R21 proposal involves the design, construction, and bench-testing of a coaxial infusion catheter. Milestones for this Aim will include both heat transfer and mechanical design metrics as well as in vitro tests assessing the efficacy and safety of our catheter on the bench. Aim 2 will assess efficacy and safety in leading preclinical in vivo models. The research plan will include placement of the device in the carotid arteries in swine and measuring the speed, depth, and duration of parenchymal cooling. If successful, this research program will improve the neurological function of patients suffering from large vessel occlusion acute ischemic stroke by protecting brain tissue that would otherwise not be salvaged.