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OD - NIH Office of the Director

ABSTRACT Protein aggregation is a shared pathology of Alzheimer’s disease and related dementias known as tauopathies. Because each disorder develops a unique combination of protein aggregate polymorphisms that may influence the course and severity of disease, elucidating the relationship between tau aggregate structure and biological activity has become a high priority in the field. Advances to date have been limited, however, by the lack of rigorously standardized aggregate preparations from tissues and cells which is the focus of many researchers at our university and beyond. Acquiring the proposed state-of-the-art high-performance liquid chromatography (HPLC) system is key component of our efforts to provide high quality protein aggregates associated with Alzheimer's Disease (AD) and Alzheimer's Disease Related Dementias (ADRD e.g. Tau to researchers at Mitchell Center for Neurodegenerative Diseases (MCND), the University of Texas and nationwide. These protein preparations will support research into the molecular basis of disease pathogenesis and catalyze efforts toward creating novel diagnostic and therapeutic strategies specifically tailored against protein aggregate polymorphs.

National Park Service

A. Project Goals 1. To advance and promote to use of research, science, and technology for conserving our nation s cultural heritage. B. Project Objectives 1. Create two videos for art conservators to expose the public to art conservation methods for recovering collections after a disaster. 2. Disseminate preservation technology information.

NIMH - National Institute of Mental Health

Project Summary The majority of Americans will experience a traumatic event during their lifetimes, but only a subset experience chronic negative psychiatric outcomes such as post-traumatic stress disorder (PTSD) and depression. Several cohort studies over the past 10 years have identified brain-based risk mechanisms early after trauma, which predict risk for chronic symptoms such as hyper-arousal, intrusive memories of the trauma, and negative affect. One of the most widely-replicated and theoretically-grounded such mechanisms involves early high amygdala responses to threat cues. Given the strength of current evidence, we propose that this is an actionable target for intervention early post-trauma, to prevent chronic impairing and distressing symptoms. Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that can induce functional brain changes as potential intervention for neuropsychiatric disorders. Emerging findings along with our preliminary data suggest that the amygdala can be reached and dampened via stimulation of a functionally connected cortical prefrontal area. Here we propose that using TMS to dampen amygdala hyperreactivity will prevent a cascade of symptoms that could develop following trauma exposure. We propose to identify Emergency Department patients who have experienced a recent traumatic event (meets DSM-5 Criterion A), and who have high initial PTSD symptoms at 1 week post-trauma. In the R61 phase we will deliver a staged single-blind TMS intervention with a lead-in sham, followed by active treatments with increasing doses, measuring amygdala reactivity at each phase. R61 milestones involve: 1: Target engagement: Determination that active TMS versus sham decreases within-subject amygdala threat reactivity (decrease in reactivity to fearful faces). 2: Dose response: Determination that 4 vs 1 session of TMS decreases these same targets. 3: Safety and feasibility: Demonstrating feasibility of recruitment and retention (75% of participants are able to complete 75% of sessions), and no Serious Adverse Events (SAE) deemed related to the TMS intervention. If these are met, the R33 phase will involve a randomized double-blind sham-controlled trial, providing a double- blind replication of the immediate effects on the amygdala target and 1-month later, as well as longitudinal assessments of TMS effects on both PTSD and depression symptoms over 3 months post-trauma. The research environment at Emory University School of Medicine will provide excellent support for the successful completion of the proposed research, particularly with state-of-the-art neuroimaging facilities, a well-developed infrastructure for identifying participants at risk for chronic trauma-related symptoms through the Grady Trauma Project and Grady Healthcare System, and a strong community of experts in trauma and neuromodulation. If the hypotheses are confirmed, this study will lay the groundwork for future early intervention trials using non- invasive dampening of amygdala reactivity to prevent chronic trauma-related symptoms.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

Project Summary While antiretroviral therapy (ART) has drastically reduced mother-to-child HIV transmission, increasing evidence suggests that in utero ART exposure can disrupt fetal immune development and placental function—even in the absence of vertical infection. HIV-exposed uninfected (HEU) infants experience higher rates of preterm birth, growth restriction, and immune dysregulation, yet the mechanisms remain poorly understood. Addressing these gaps is critical for reducing long-term immune-mediated morbidity in this growing population. Our central hypothesis is that ART exposure reprograms immune signaling at the maternal-fetal interface (MFI), creating a pro-inflammatory environment that impairs immune tolerance and fetal immune maturation. In response to PAR- 25-362, we propose a multi-pronged investigation into how ART influences immune cell development, antigen presentation, and extracellular vesicle (EV)-mediated communication at the MFI. Our study will use cutting-edge immunopeptidomics, transcriptomics, and functional co-culture assays to define how ART disrupts key regulatory mechanisms at the placenta. This work will generate mechanistic insights into immune dysregulation in HEU infants and inform safer therapeutic strategies during pregnancy.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Acute ischemic stroke (AIS) resulting from large vessel occlusion (LVO) is a primary cause of global morbidity and mortality. Mechanical thrombectomy (MT) is the current standard of care for LVO, and it is one of the most effective interventions in modern day medicine. This procedure involves catheter-based endovascular access to the intracranial vasculature for clot retrieval. The number of retrieval attempts required for successful recanalization is variable, influenced by clot characteristics, patient anatomy, and procedural technique. Clinical trials have established the efficacy of MT in AIS, with recent studies demonstrating a strong correlation between successful first-pass recanalization and favorable clinical outcomes. Despite the established population-level efficacy of mechanical thrombectomy (MT) in acute ischemic stroke (AIS), individual patient outcomes exhibit significant variability and prognostic uncertainty. The ability to more accurately predict MT outcomes for individual patients from clinical data would offer highly valuable guidance for clinical decision-making. Prior published works have utilized classic deterministic machine learning methods to generate singular expected outcome estimates, which do not adequately describe the broad distribution of potential outcomes. In this work, we propose to develop new probabilistic machine learning models, which directly infer outcome distributions, providing a more informative assessment of the anticipated prognosis in the setting of real-world clinical uncertainty. For this purpose, we leverage the NeuroVascular Quality Initiative – Quality Outcomes Database, which contains highly granular clinical, procedural, and outcomes data for over 10,000 MT procedures. In our first aim, we will develop multiple state-of-the-art probabilistic models to predict MT procedural success, MT first-pass success, and functional and neurological outcomes from the clinical data available in the NVQI-QOD. As part of this first aim, we will evaluate a new and extremely powerful probabilistic foundational model for Bayesian inference, and compare it to state-of-the-art tree-based probabilistic methods. In our second aim, we will utilize methods from Explainable AI (XAI) to identify the most important predictors of procedural success and clinical outcomes and then to also characterize their interactions. We anticipate that this work will provide valuable insight into the complex determinants of large vessel stroke outcomes and identify high-priority targets for future research.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary / Abstract Nociception is the process whereby a subset of somatosensory nerve fibers (called nociceptors) detects noxious stimuli and transmits this information to the central nervous system, ultimately producing a percept of discomfort or pain. Nociceptors are faced with the complex task of recognizing disparate environmental and endogenous signals of both a physical and chemical nature; these include temperature, pressure, irritants, pruritogens, and inflammatory agents. Consequently, nociceptor activation elicits acute pain as well as injury-evoked pain hypersensitivity and can contribute to so-called ‘maladaptive’ processes underlying persistent pain syndromes. Our goal is to understand how nociceptors detect, integrate, and transmit these signals under numerous environmental and physiological conditions. This proposal is aimed at identifying and characterizing molecules, cells, and mechanisms that contribute to nociception in the context of acute (protective) or pathological (chronic) pain states. Our approach is multifaceted and ranges from structural biology to integrative physiology. At the most reductionist level, we will use biophysical, biochemical, and pharmacological tools to elucidate structural mechanisms underlying ion channel function, with an emphasis on identifying proteins and other cellular elements that physically and functionally engage with members of the TRP ion channel family that play key roles in nociception. We will also leverage cutting edge approaches in electron cryo-microscopy and tomography to visualize these channels and signaling complexes in cellular membranes and, ultimately, in their native environment of the primary afferent nociceptor. At a more integrative level, we shall probe mechanisms of intero-nociception by asking how primary afferent nociceptors interact with tissues to detect noxious signals and transmit this information to the spinal cord. We will focus on the intestine and joints, using mice as genetically tractable models for understanding mechanisms underlying chronic visceral or osteoarthritic (OA) pain. We will employ state-of-the-art techniques, such as genetically encoded neurotransmitter sensors and single cell sequencing, to characterize interactions between nociceptors and sensory epithelial cells in the gut or subchondral bone in joints. Because visceral and OA pain are more prevalent in women, we will ask if these interactions or other properties of resident nociceptors differ with sex or with age, which is also a significant factor contributing to OA. Models of OA or visceral hypersensitivity will be used to ask if genetic, functional, or anatomical characteristics of nociceptors change under maladaptive states. Visceral and OA pain remain poorly managed, reflecting our current lack of mechanistic insight into these common debilitating disorders. Together, these studies will help bridge this knowledge gap and facilitate the development of novel analgesic therapies.

NIMH - National Institute of Mental Health

Globally, people with HIV (PWH) with comorbid common mental disorders (CMDs) experience worse HIV-related outcomes than those without, including decreased antiretroviral therapy (ART) adherence, reduced viral suppression, and increased mortality. These same mechanisms drive poor HIV outcomes in the United States, underscoring the need for scalable mental health interventions to improve domestic HIV care. Despite their high prevalence and impact, CMDs remain under-diagnosed and undertreated among PWH, particularly in low- and middle-income countries (LMICs), due to weak mental health infrastructure and severe workforce shortages. Similar access barriers persist in resource-constrined United States settings, including rural and safety-net clinics, making task-shifting directly relevant to US populations. Testing task-shifted interventions in LMICs provides a rigorous scientific advantage. Conducting this study in Vietnam—rather than the US—is a deliberate strategy to evaluate the intervention under conditions where its core mechanisms are most observable. Vietnam’s limited mental health workforce and high burden of untreated CMDs create a high-contrast environment that amplifies intervention effects and clarifies causal pathways linking mental health improvements to HIV outcomes. This constraint-based setting enables identification of the minimally effective components, efficient delivery strategies, and essential supervision structures required for scalability. In contrast, more resource-rich and heterogeneous US systems can obscure these mechanisms, limiting the ability to optimize implementation. Establishing effectiveness and efficiency under constraint strengthens internal validity and enhances generalizability to resource-constrained U.S. settings facing similar barriers. Problem-solving therapy (PST) is an evidence-based, non-specialist-delivered intervention shown to improve mental health outcomes in sub-Saharan Africa. Yet, its impact on HIV outcomes among PWH has not been established, particularly among those initiating or re-initiating ART, who may derive the greatest benefit. We recently culturally adapted PST for PWH with CMDs in Vietnam and demonstrated feasibility, acceptability, and high-fidelity delivery in a pilot randomized trial, with promising signals of effectiveness. We propose a randomized, controlled, hybrid type I effectiveness-implementation trial to evaluate adapted PST versus enhanced usual care among PWH initiating or re-initiating ART with CMDs in Vietnam. We will assess CMD and HIV outcomes, cost-effectiveness, and implementation factors to support translation. We hypothesize that PST will improve CMD outcomes at 3 months and viral suppression at 6 months. By rigorously testing PST in a resource-constrained setting, we will generate actionable evidence and an implementation blueprint to support scalable, cost-effective integration of mental health care into HIV services, accelerating translation to improve outcomes in resource-constrained US populations.

NIMH - National Institute of Mental Health

Globally, people with HIV (PWH) with comorbid common mental disorders (CMDs) experience worse HIV-related outcomes than those without, including decreased antiretroviral therapy (ART) adherence, reduced viral suppression, and increased mortality. These same mechanisms drive poor HIV outcomes in the United States, underscoring the need for scalable mental health interventions to improve domestic HIV care. Despite their high prevalence and impact, CMDs remain under-diagnosed and undertreated among PWH, particularly in low- and middle-income countries (LMICs), due to weak mental health infrastructure and severe workforce shortages. Similar access barriers persist in resource-constrined United States settings, including rural and safety-net clinics, making task-shifting directly relevant to US populations. Testing task-shifted interventions in LMICs provides a rigorous scientific advantage. Conducting this study in Vietnam—rather than the US—is a deliberate strategy to evaluate the intervention under conditions where its core mechanisms are most observable. Vietnam’s limited mental health workforce and high burden of untreated CMDs create a high-contrast environment that amplifies intervention effects and clarifies causal pathways linking mental health improvements to HIV outcomes. This constraint-based setting enables identification of the minimally effective components, efficient delivery strategies, and essential supervision structures required for scalability. In contrast, more resource-rich and heterogeneous US systems can obscure these mechanisms, limiting the ability to optimize implementation. Establishing effectiveness and efficiency under constraint strengthens internal validity and enhances generalizability to resource-constrained U.S. settings facing similar barriers. Problem-solving therapy (PST) is an evidence-based, non-specialist-delivered intervention shown to improve mental health outcomes in sub-Saharan Africa. Yet, its impact on HIV outcomes among PWH has not been established, particularly among those initiating or re-initiating ART, who may derive the greatest benefit. We recently culturally adapted PST for PWH with CMDs in Vietnam and demonstrated feasibility, acceptability, and high-fidelity delivery in a pilot randomized trial, with promising signals of effectiveness. We propose a randomized, controlled, hybrid type I effectiveness-implementation trial to evaluate adapted PST versus enhanced usual care among PWH initiating or re-initiating ART with CMDs in Vietnam. We will assess CMD and HIV outcomes, cost-effectiveness, and implementation factors to support translation. We hypothesize that PST will improve CMD outcomes at 3 months and viral suppression at 6 months. By rigorously testing PST in a resource-constrained setting, we will generate actionable evidence and an implementation blueprint to support scalable, cost-effective integration of mental health care into HIV services, accelerating translation to improve outcomes in resource-constrained US populations.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY We propose to establish an interdisciplinary training grant called the Program for Advancing Training in Cell Biology Research (PACeR) at the University of Utah. With unique resources including a cryo-electron microscopy core, state-of-the-art cell imaging facilities, and a vibrant cell biology research community with 37 faculty members across 11 departments, the University of Utah offers an exceptional training environment in cell biology research. This training grant will provide infrastructure and support to an already strong cell biology research community, uniting cell biology researchers across campus and accelerating training of future scientists in this area. The goals of PACeR are to provide intentional and individualized mentorship and training for talented students to create the next leaders in cell biology and to create an environment/culture where trainees feel accepted and recognized as valuable members of the scientific community. These goals are achieved through coursework in cell biology, biostatistics, ethics, and responsible conduct of research, as well as trainee-specific activities, including: bimonthly PACeR group discussions, where trainees will work on presentations skills and receive individualized feedback on their project and presentation; a grant writing and reviewing program, in which trainees will review NIH grant applications in mock study section format as they prepare their own fellowship applications; mentorship training and opportunities to mentor undergraduate students; industry internships; and annual individualized development plan meetings designed to align research objectives with career goals. Most of PACeR’s programming will be intentionally limited to small groups to foster community and cohesiveness among trainees; however, we propose joint annual symposia with other training groups on campus for synergy, collaboration, and networking. Trainees will also interact and engage with scientists of all backgrounds as part of the Rising Stars Symposia and the award-winning University of Utah SACNAS Chapter. Trainees will enter PACeR from four distinct PhD programs, which matriculate an average of 52 training grant eligible students each year. The mentor pool comprises faculty with proven track records of research excellence and mentorship. Mentors have trained 262 PhD students over the past 10 years, and 96% of those trainees are currently pursuing research-related careers. The program will be overseen by a 6-member advisory committee (that includes the co-directors), and program evaluation will be conducted in a collaborative fashion between the advisory board and a centralized office that oversees all T32 training programs at our institution, using an evidence-based evaluation system. We are requesting support for eight predoctoral trainee positions (four in the first year). With its interdisciplinary approach, outstanding mentorship, and focus on cutting-edge research, the PACeR program is poised to produce world-class leaders in cell biology research, driving innovation and advancing scientific discovery at the University of Utah and beyond.

NCI - National Cancer Institute

Summary The Epstein Barr virus is a DNA tumor virus that is associated with human pathologies including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, stomach cancer, nasopharyngeal carcinoma and autoimmune diseases. EBV is particularly problematic in the HIV/AIDS population where EBV associated lymphomas are especially prevalent. While more than 90% of the world’s population carries EBV, the virus typically exists in a “latent” state with little impact on the host. In response to certain stimuli or local microenvironmental cues, however, EBV enters the viral lytic replication program, leading to viral spread both within and between hosts. Despite the known role of viral latency proteins in EBV associated cancers, there are well-established links between elevated lytic replication and the onset of EBV associated cancers. Further, general elevation of EBV lytic replication is observed in the context of HIV co-infection (+ or – ART), likely contributing to the increased susceptibility of HIV infected individuals to EBV associated lymphomas and autoimmune diseases. With minimal genetic content, viruses are highly dependent on host cell resources for their replication and they elicit extensive alterations of host cell metabolic processes to facilitate efficient virus replication. One of the most conserved and well studied virus-host interactions in herpesvirus replication is “host shut off” where virus encoded factors degrade host cell RNAs destined for translation, freeing up translation resources for dedicated production of high amounts of viral structural proteins. Recently, the Glaunsinger lab showed that despite inducing global Pol III activation of host B2 SINE elements, the murine γ-herpesvirus, MHV68, inhibits host Pol II transcription as a second arm of host shut off, further promoting preferential viral protein synthesis. Using EBV reactivation models that facilitate interrogation of transcriptome changes in pure reactivating cell populations, we have gained insights into remarkable and unexpected interactions between EBV and the host cell transcriptome. Unlike MHV68, we found that EBV sustains cell Pol II gene expression at canonical promoters during lytic replication and strikingly, causes transcription at >10,000 new Pol II initiation sites across the cell genome. While the reason for the broad induction of predominantly non-coding Pol II (EBV) or Pol III (MHV68) transcription across host genomes is unclear, it could relate to some role in remodeling nuclear structure or redistribution of nuclear resources. Our studies also revealed that EBV reactivation induces widespread, noncanonical exon skipping, the extent of which surpasses the degree of exon skipping observed upon severe depletion of most spliceosome components. Preliminary analysis of KSHV reactivation similarly revealed widespread induction of exon skipping indicating that splicing disruption is not unique to EBV. Previous studies have shown that exon skipping can cause either nuclear retention or cytoplasmic nucleolytic degradation by the cellular nonsense mediated RNA decay (NMD) pathway; and we show that nearly 50% of exon skipping events observed during reactivation are NMD candidates. We hypothesize that EBV (and KSHV) lytic replication induces extensive non-canonical exon skipping of cell transcripts resulting in either nuclear retention or degradation through the cytoplasmic NMD pathway as a second, new arm of host shut off. While classic host shut off has been studied for many years, how specificity for cell transcripts is achieved has been largely enigmatic. Notably, herpesviral lytic genes exhibit a remarkably consistent feature of being primarily mono-exonic (i.e. unspliced). We hypothesize that splicing derangement is a new arm of host shut off that facilitates selective targeting of spliced cell transcripts to free up resources for high-level production of viral proteins. In this proposal, we will test this hypothesis, we will begin to address the mechanisms through which EBV induces splicing derangement and we will begin to address the consequences of splicing derangement on host and viral gene expression.

NHLBI - National Heart Lung and Blood Institute

Project Summary / Abstract People with HIV (PWH) experience a high risk of cardiovascular disease (CVD). The risk appears more pronounced for women with HIV (WWH), particularly for heart failure, yet this group remains understudied. Our prior work in the Women’s Interagency HIV Study (WIHS), now the MACS-WIHS Combined Cohort Study (MWCCS), found that WWH exhibit higher MRI-measured myocardial fibro- inflammation than sociodemographically similar women without HIV (WWOH). This risk was more marked in women with unsuppressed viremia or low nadir CD4+ count in the past 5 years. WWH showed frequent viremia in this preceding period, during which adherence with antiretroviral therapy (ART) was suboptimal. Yet viremia was common even among ART-adherent women. Use of integrase inhibitors, which afford greater tolerability but produce weight gain, was recent at the time. Most WWH were post-menopausal, a condition where low estradiol could foster viremia. While post- menopausal estradiol level has been associated with CVD in general populations, its role in HIV- associated heart disease in postmenopausal women is uncertain. Central to the findings is the potential role of dysregulated immune cell subsets – including T-cell differentiation, exhaustion, senescence, cytotoxicity and loss of regenerative capacity – which have been variously implicated in HIV progression and cardiovascular comorbidities, as well as acute myocarditis in non-HIV settings. Here we propose to repeat MRI in returning participants ~8 years after their initial scans to address these questions in a prospective manner. Specifically, we will evaluate the contributions of HIV, subsequent unsuppressed viremia and lymphopenia, and longer duration of integrase inhibitor use to longitudinal progression of cardiac fibro-inflammation; relate circulating post-menopausal estradiol level to progression of cardiac fibro-inflammation and examine its association with unsuppressed viremia; and perform high-density phenotyping of circulating immune cell subsets and features in post-menopausal WWH to determine their associations with progression of cardiac fibro-inflammation progression. The longitudinal study design will permit assessment of the course of myocardial disease and the prospective associations of HIV-specific factors, blood estradiol, and immune cell subsets and functionally relevant features in WWH, strengthening inferences. This proposal will yield valuable new knowledge regarding the HIV, sex hormone and immune determinants of myocardial disease progression in aging women, which will offer insights into pathophysiology and new potential directions for treatment of heart disease in this high-risk group.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

People living with HIV/AIDS (PLWH) are at increased risk for type 2 diabetes due to age-related metabolic changes and risk factors such as poor dietary quality, HIV infection and ART use. Diabetes is commonly reported among PLWH as people live longer, with estimates varying from 12-30%. Novel cost-effective non pharmaceutical approaches to prevent diabetes for aging PLWH are needed but require multilevel interventions that address the structural factors affecting dietary change and medical adherence. Food insecurity is 2-3 times higher in PLWH than the general population. Food insecurity is associated with poorer dietary quality due to consumption of cheaper, less nutritious foods, stress, and poor health outcomes, such as diabetes, lower ART adherence, lower CD4+ counts, and unsuppressed viral load. Few dietary interventions, however, have targeted prevention or management of diabetes in PLWH, and those that have, are small, provide pre-packaged meals, and/or lack a control group. While pre-made meals designed for specific diseases can improve health outcomes, they do not address nutrition knowledge and cooking efficacy, which are important for developing long term dietary behavior change. Studies using meal kits (high quality ingredients and simple recipes) have been shown to improve dietary quality, food insecurity, and psychosocial health, but studies have been limited by a lack of nutrition education needed for long-term use of meal kits. Dietary recommendations for prevention of diabetes in PLWH, who are food insecure, have been hindered by a glaring gap in a lack of well-designed interventions and rigorously collected data. To address this gap, Project GLOW (Glucose Levels for Optimizing Wellness for People Living with HIV) aims to improve diet, glycemic and HIV outcomes for aging PLWH with prediabetes through implementation of a food security intervention at a clinic in the Boston/Suffolk County EMA, a priority jurisdiction for ending the HIV Epidemic. Guided by the Exploration, Preparation, Implementation and Sustainment (EPIS) framework, we will engage patients and health care providers to identify barriers and facilitators to study processes and change in health outcomes to implement and refine the intervention. Our hypothesis is that tailored education with complementary food provision will reduce food insecurity and improve dietary behaviors and glycemic and HIV outcomes. This pilot and feasibility trial will randomize 100 PLWH aged >40 years to intervention (n=50) or usual care (n=50) with measures at baseline and 16-weeks and post 12 months for sustainment. This study contributes to NIDDK’s scientific goal of advancing research to disseminate and implement evidence based prevention strategies and treatments in clinics and community settings, to improve the health of all people, more rapidly and more effectively.

Renaissance 21

Project L.I.T. by Star Tech Global Academy will engage youth in multimedia art projects that uplift community spaces and connect with community leaders. This free project will be in hybrid format with both virtual and in-person participation in 3 Teen Centers across Seattle: Garfield, Rainier Beach, and Southwest Teen Life Center. Community members will be recruited as project staff to guide teens through workshops that teach leadership, community building, and multimedia design skills. Hands-on workshops will connect youth with role models and spotlight their work to improve community spaces and motivate to Lead, Inspire, and Transform (L.I.T.).

National Park Service

Through this agreement, the NPS and NCTA will work together on a variety of programs and activities, including: organizing crafts and museum exhibits; developing traditional music presentations and programs; training park personnel in cultural presentation techniques; assisting local non-profit groups with organizing cultural events in national parks; and strategically linking artist and art organizations with parks to create a sense of place, broaden the scope of experience for American artists (especially youth), while improving quality of life.

NIDCD - National Institute on Deafness and Other Communication Disorders

The goal of the proposed randomized controlled trial is to evaluate the impacts of the Promoting Early Engagement, Relationships, and Socialization (PEERS) intervention on the language and social experiences and skill development of young children with developmental language disorder (DLD). PEERS is a peer-mediated intervention designed to help children with DLD form social connections with their classmates and engage in more positive, reciprocal peer interactions. The sample includes 100 preschool classrooms randomly assigned to the treatment (n = 50) or a business-as-usual control condition (n = 50). In each classroom, one target child (3- to 5-years old; n = 100) with DLD who experiences peer exclusion and has pragmatic language difficulties is identified. Also in each classroom, two peers (n = 200) referred to as buddies with relatively strong language skills and peer connections are identified. In treatment classrooms, teachers implement the peer-mediated intervention for a six-month period in the spring of the school year. Buddies are trained to use age-appropriate strategies to socially engage with the target child during center time with incidental teacher support. Target children’s and buddies’ language and social experiences with peers are observed throughout the preschool year, and assessments of language and social skills are collected at three timepoints to understand target children’s and buddies’ development in these areas. Target children are also followed beyond the preschool year, with 3 additional assessment timepoints through two years post-intervention to understand long-term impacts of intervention participation. To evaluate the effectiveness of PEERS, the present study has three aims. First, the trajectories of target children’s language and social experiences will be examined across the preschool year using a combination of in-person observations and state-of-the-art sensing technologies. Second, target children’s short-term (through the spring of preschool) and long-term (two years post-intervention) gains in language and social skills will be examined using a combination of direct and indirect assessments. Third, the extent to which target children’s language and social experiences with their preschool peers mediates the effects of PEERS on the trajectories of the target children’s language and social skills development of will be tested. Overall, we expect participation in PEERS to have meaningful, positive impacts on the language and social experiences and skills of the target children.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Type 2 diabetes (T2D) affects over 30 million US adults and remains a pressing public health challenge. While the gut microbiome is increasingly recognized as a contributor to T2D pathogenesis, the role of the human virome, including eukaryotic viruses and bacteriophages, has been largely overlooked, despite compelling mechanistic evidence and recent advances in sequencing and serological technologies, and computational tools that now enable comprehensive virome profiling. Moreover, most human microbiome studies have focused on species- or genus-level taxa, failing to capture strain-level functional differences that can have distinct metabolic and immunological consequences. This project will comprehensively characterize the “serological microbial-viral interactome”—the host’s systemic antibody response to microbial and viral exposures—and investigate its relationship with T2D development. Using Phage ImmunoPrecipitation Sequencing (PhIP-Seq), we will profile antibody responses to a large antigen library spanning bacteria, viruses, bacteriophages, and fungi. These data will be integrated with shotgun metagenomic and metatranscriptomic sequencing of fecal samples to assess microbial composition, strain-level diversity, gene functions, and active microbial transcription. State-of-the-art bioinformatic tools will be used to analyze both the gut microbiome and virome, including functional and strain-resolved profiling. We will apply this multi-omics framework in a prospectively designed, nested case-control study of 1,200 participants from two large US cohorts, the Hispanic Community Health Study/Study of Latinos (SOL) and the Nurses’ Health Study II (NHSII), comprising 600 healthy individuals who later developed incident T2D and 600 matched controls. We will test three key hypotheses: (1) antibody responses to microbial and viral antigens are associated with T2D risk; (2) strain-specific microbial features and their functions contribute to T2D pathogenesis; and (3) gut microbiome and virome features modify host immune responses and their links to T2D. Findings will be validated in an independent cohort, LifeLines DEEP, a population-based prospective study of 1,272 individuals who were free from T2D at baseline. By integrating serological and multi-omics data in a rigorously designed, prospective, multi-cohort study, this project will provide the first comprehensive systems-level assessment of how microbial and viral exposures shape host immunity and influence T2D risk. Results will advance the identification of novel microbial pathways and immune biomarkers, paving the way for microbiome-informed prediction, prevention, and therapeutic strategies for T2D.

NHLBI - National Heart Lung and Blood Institute

PROJECT ABSTRACT There is a fundamental gap in predicting adverse outcomes and guiding precision-based treatment for the most severe and lethal form of peripheral artery disease (PAD), chronic limb threatening ischemia (CLTI). Patients face a dual threat: profound morbidity and mortality from major adverse limb and cardiovascular (CV) events (MALE and MACE). Yet clinical management remains reactive because we lack tools to predict these distinct outcomes. Circulating proteins are central integrators of these vascular pathologies, directly interacting with the arterial wall. Multiplex proteomics (Olink Explore) quantifies thousands of proteins linked to vascular pathology, yet its potential in CLTI remains largely untapped, leaving a critical gap in predicting outcomes and guiding treatment—especially for antithrombotic agents like rivaroxaban, which reduce events but carry bleeding risk. We will overcome this gap by leveraging harmonized clinical testing and adjudicated outcomes from two NHLBI cohorts (TIDE and PACE) plus VOYAGER-PAD—the largest trial of low-dose rivaroxaban in PAD, including 1,533 CLTI patients—to discover and validate signatures predictive of MALE, MACE, and therapeutic response to rivaroxaban—informing strategies that optimize benefit and minimize harm. To address gaps in high-molecular weight protein coverage with the Olink panel, we will integrate lipid and lipoprotein measurements from clinical assays (outside the panel). Early analyses suggest thrombosis drives limb events, whereas atherosclerosis-related inflammation underlies cardiac events. Guided by these signals, we will prioritize putatively causal proteins via Mendelian Randomization and validate top candidates with ELISA. Central hypothesis: multiplex proteomics will (1) identify proteomic signatures predicting MALE/MACE, (2) improve risk stratification beyond clinical factors, and (3) define patients most likely to benefit from low-dose rivaroxaban while minimizing bleeding risk. We will test this via three aims: derive a CLTI-specific proteomic signature of MALE (Aim 1) and MACE (Aim 2) beyond clinical measures among TIDE/PACE participants. Validation for Aims 1 and 2 will occur in the placebo arm of VOYAGER-PAD CLTI trial. Aim 3: determine whether proteomic signatures identify CLTI patients with a favorable therapeutic response to low-dose rivaroxaban (benefit >> risk) by applying causal machine learning to model heterogeneity of treatment effect and deliver a net-benefit classifier. This project applies state-of-the-art proteomic assays and machine learning to an understudied, undertreated population, will develop and validate tools for risk prediction and treatment optimization in CLTI, shifting care from reactive salvage to precision biological management, reducing preventable amputations, CV events, and deaths. Ultimately, it will establish a precision-guided, scalable pathway to lessen the national burden of CLTI.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY / ABSTRACT Proteins are often used for drug targets. Understanding the structure, function, and reaction mechanisms of proteins is crucial. Over the last three decades, inductively detected Electron Paramagnetic Resonance (EPR) has been utilized to elucidate the structure, function, and reaction mechanisms of enzymes and membrane proteins, as well as to quantify reactive oxygen and nitrogen species. The EPR is useful because it is a highly sensitive, powerful, and versatile technique. Proteins such as metalloproteins, membrane proteins, and G-proteins are challenging to purify in sufficient quantities to obtain measurable signals using standard EPR methods. These proteins, Metalloproteins, membrane proteins, and G-proteins constitute almost 30% of all drug targets. However, due to the scarcity of sufficient samples, understanding the structure-function relation using EPR is challenging and thus poorly understood. This proposal focuses on developing a novel micro-resonator to increase the sensitivity of the current state-of-the-art X-band EPR spectrometer by an order of magnitude. If successful, the unprecedented sensitivity for EPR spectroscopy would broaden its applicability to low- yield biomacromolecular samples whose structures are currently poorly understood due to a lack of sensitivity. The resonator is at the heart of any EPR spectrometer, which interfaces with the samples and enhances the signal-to-noise ratio. The ultimate goal of the proposed project is to design, simulate, build, and demonstrate the proposed novel micro-resonator. The proposed project also focuses on a resonator design that is easy to manufacture using a standard commercial PCB substrate and integrates seamlessly with the existing X-band EPR spectrometer. The preliminary simulated result indicates that the proposed resonator would exhibit ultra-high sensitivity due to its high quality factor (Q ~ 9000), nanoliter fill factor, and highly efficient magnetic field concentration for Electron Paramagnetic Resonance.

NIMH - National Institute of Mental Health

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIMH - National Institute of Mental Health

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIMH - National Institute of Mental Health

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIMH - National Institute of Mental Health

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIDA - National Institute on Drug Abuse

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIMH - National Institute of Mental Health

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.