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NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Significant gaps in care exist in addressing the intersection of HIV and substance use disorder (SUD) treatment. Despite pharmacists providing evidence-based services for HIV prevention and harm reduction, their potential to reach those with co-occurring HIV and SUD has not been fully realized. Dr. Tarfa, a pharmacist and PhD-trained health services researcher at Yale School of Medicine, is uniquely positioned to adapt and implement an integrated training and service provision program in community pharmacies. Dr. Tarfa’s early work showed that people with HIV are receptive to HIV/SUD care in pharmacies, and community pharmacists are willing to provide this care. The strong mentorship team of this K99/R00 will shape her into an independent investigator by supporting her in all aspects of the project. The team includes Dr. Springer, MD (HIV and addiction medicine), Dr. Rabin, PhD, MPH, PharmD (implementation science), Dr. Carpenter, PhD, MSPH (pharmacy workflow and quantitative methods), and Dr. Opara, PhD, LMSW, MPH (co-design), to leverage all stages of the project. During the K99 phase of this project, with the support of her mentorship team, Dr. Tarfa will receive training in addiction medicine, survey methodology, pharmacy service delivery workflow, co-design participatory research, and implementation science. These trainings will directly support the K99 activities to conduct: (1) a community pharmacy assessment to identify implementation determinants, current HIV/SUD service provision, and readiness for integrated care through a state-wide survey as well as focus groups with pharmacists and people with lived experience of HIV and/or SUD; and (2) utilize Community Engagement Studios for intervention adaptation/co-design including people with lived experience, pharmacists, and clinicians, to refine implementation strategies. The R00 phase will pilot the intervention and evaluate the feasibility, acceptability, and early implementation outcomes using PRISM and RE-AIM frameworks. Service uptake (HIV testing, PrEP initiation, ART provision, SUD screening, naloxone dispensing) and post- implementation interviews with pharmacy staff and service users will assess implementation outcomes and inform further refinement. This K99/R00 aligns with three of NIDA’s five strategic priorities by advancing novel prevention, treatment, and harm reduction strategies; accelerating research at the HIV-SUD intersection; and enhancing real-world implementation of community pharmacies care. The successful completion of this K99/R00 will prepare Dr. Tarfa to become an independent investigator, pioneering and evaluating pharmacy- based interventions that integrate HIV and SUD care. This will lay a strong foundation for future R01-funded research that will drive lasting change in the field.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Advancements in antiretroviral therapy (ART) have significantly increased the life expectancy of people with HIV (PWH). However, this extended longevity has brought about a heightened risk of cardiovascular disease (CVD). Notably, women with HIV (WWH) seem to face a disproportionately elevated risk of thrombotic adverse events, such as acute myocardial infarction (MI). Our group has reported significantly greater thrombogenicity in PWH using an ex vivo thrombosis model, with particularly marked findings among WWH, confirming the existence of sex-based differences in the underlying pathobiology. Although the precise mechanisms contributing to this greater increase in thrombogenic risk among WWH are not fully understood, certain key factors are emerging: (a) Generalized immune activation in HIV-1 infection strongly predicts the progression of both HIV and its comorbidities, including CVD. Women, in particular, exhibit a robust immune response and a higher risk of progressing to AIDS than men. Toll-like receptors (TLRs), crucial components of the innate immune system for their ability to recognize and respond to pathogens, including viruses, are influenced by estrogen levels and known to modulate platelet reactivity; (b) Platelets, the second most abundant blood cell type, play a crucial role in atherothrombosis and inflammation. Enhanced platelet reactivity is known to elevate the risk of CV events and has been reported in PWH. Additionally, platelets have been shown to express all 10 TLRs; (c) Age-related changes in sex-hormones affect the rates of CVD in women. Estrogens regulate vascular reactivity, blood pressure, endothelial function and also affect the immune system, and decrease in estrogen levels post menopause adversely affect traditional CV risk factors. Data suggest that WWH experience earlier menopause and more menopausal symptoms and age-related comorbidities compared to women without HIV. Drawing from these key elements, we have formulated the hypothesis that HIV primes platelets increasing their responsiveness to TLR4 and TLR7 stimulation, and changes across the menopausal transition alter TLR-driven platelet activation and thrombogenicity in WWH through estrogen. The goal of this project is to define how HIV and reproductive aging interact to increase thrombotic risk in women with HIV, using functional thrombogenic assays integrated with exploratory molecular profiling to gain mechanistic insight. These initiatives are geared towards improving strategies for preventing and managing thrombotic events in this vulnerable population, ultimately enhancing patient outcomes and quality of life.

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Despite gains in men’s engagement in HIV testing, prevention, and treatment in sub-Saharan Africa (SSA), men are still less likely than women to test for HIV, less likely to start antiretroviral treatment (ART) and pre-exposure prophylaxis (PrEP), and more likely to default from care and have virological failure. Highly mobile Lake Victoria fishermen in Kenya are at high risk of HIV acquisition due to their mobility and a transactional sex economy embedded within the fish trade. Fishermen have difficulty accessing services during typical clinic hours, and HIV-related stigma and gender norms that run counter to men’s healthcare- seeking also limit their uptake of HIV testing, prevention and treatment. Our recently completed social network-based, HIV status-neutral intervention (“Owete”) significantly increased HIV testing and linkage for ART or PrEP among Kenyan fishermen. HIV self-testing was higher in intervention network clusters (60% vs. 10%, p<0.001), as was linkage to health facilities among those who tested (67% vs. 16%, p<0.001). In Owete we identified close social networks of men and trained socially connected men in networks to act as “Promoters” of HIV testing, prevention and treatment. Promoters distributed HIV self-test kits and a small (KSh500, $4) transport voucher redeemable at linkage to health facilities to men in their networks. Promoters were trained to encourage peers to test and link to either PrEP or ART. We have engaged the Kenya Ministry of Health to now address how the Owete intervention can best be deployed at scale to proceed with wide-scale implementation of the intervention. Challenges to wider-scale implementation of Owete in Kenya are: costs and complexity of full social network surveys and promoter selection, and a limited evidence base for the amount and use of vouchers as an incentive to link to care. We will use the Multiphase Optimization Strategy (MOST) to identify an effective, scalable, and cost- effective version of Owete. In the MOST Preparation Phase, we will Identify scalable options for selection of network central Promoters and incentive levels (Aim 1). We will: use existing data from Owete and modeling to identify candidate components, set optimization criterion, and pilot-test candidate components in one beach. In the MOST Optimization Phase, we will comparatively test Promoter selection strategies, voucher effects, examine mechanisms of intervention action (Aim 2). In a 2x3 factorial trial, we will assess HIV self-testing and linkage outcomes at 3 and 6 months in 6 beaches, and use mixed methods to identify pathways of intervention action. We will estimate the incremental cost-effectiveness of candidate intervention combinations (Aim 3), employing time-driven activity-based costing and Markov modeling to assess cost-effectiveness; and use optimization criteria to identify the most effective, feasible, and cost- effective combination of Promoter selection strategy and incentive level for scale-up. Impact: This research will result in a scalable approach to engaging mobile men in HIV testing and care to reduce HIV in Africa.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT This proposal will evaluate the comparative effectiveness of advanced therapies (biologics and small molecules) used to treat pediatric Crohn’s Disease using innovative pharmacoepidemiologic methods. Crohn’s Disease, a type of inflammatory bowel disease (IBD), affects over 50,000 children in the U.S. and, when poorly controlled, can lead to pain, fatigue, growth failure, and irreversible surgery. While more than 10 advanced therapies are FDA-approved for adults with Crohn’s Disease, only two—both anti-tumor necrosis factor (Anti- TNF) biologics—are approved for children. This approval gap influences treatment choice, as children with Crohn’s Disease are typically treated initially with FDA-approved anti-TNFs, prior to mechanistically-diverse off- label therapies, despite growing adult data suggesting comparable or even superior safety and effectiveness of alternative agents. These treatment decisions are often influenced by insurers requiring failure of FDA- approved anti-TNFs prior to prescription of second-line off-label therapies, confounding direct comparisons. Innovative risk adjustment methods are needed to overcome these barriers to inform treatment selection and match the right medication to each patient’s unique type of Crohn’s Disease. In Aim 1, Dr. Constant will compare the clinical effectiveness of anti-TNFs and anti-interleukin biologics, an emerging medication class with comparable effectiveness to anti-TNFs in adult studies. Analyses will leverage a validated multicenter retrospective cohort of pediatric patients with Crohn’s Disease to power state-of-the-art causal inference methods which account for demographic and disease-related confounders influencing treatment choice. In Aim 2, he will validate and expand upon these findings through a prospective observational cohort study incorporating patient-reported outcomes to capture a comprehensive view of comparative effectiveness. In Aim 3, he will pilot a pragmatic randomized clinical trial comparing two off-label advanced therapies (risankizumab and upadacitinib) among children with anti-TNF-refractory Crohn’s Disease. This aim will assess the feasibility of comparing off-label therapies within a pragmatic trial structure, allowing for evolving real-world treatment strategies including dose escalation, across a broadly inclusive pediatric Crohn’s Disease population. This research and training plan is supported by a complementary multidisciplinary mentorship team, led by co- primary mentors and nationally recognized pharmacoepidemiologists Dr. James Feinstein and Dr. Frank Scott. Content mentors with aim-specific expertise include Dr. Debashis Ghosh (Aim 1: causal inference), Dr. Lindsey Albenberg (Aim 2: prospective observational research and patient-reported outcomes), and Dr. Calies Menard- Katcher (Aim 3: innovative clinical trial design). This work will advance real-world evidence to inform therapy selection for children with Crohn’s Disease and lay the foundation for future R01-level multicenter pragmatic randomized trials to definitively compare therapies under real-world conditions, launching Dr. Constant’s career as an independent investigator and leader in pediatric IBD comparative effectiveness research.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY The Duke University Program in Computational Biology and Bioinformatics (CBB) is a predoctoral training program with a 20-year track-record of training graduate students at the interdisciplinary intersection of the quantitative and biomedical sciences. CBB is a degree-granting program typically composed of 30–40 students and drawing on approximately 750 faculty from departments across the Schools of Medicine, Engineering, and Arts & Sciences. CBB provides rigorous training in quantitative approaches from computer science, statistics, mathematics, physics, and engineering to enable its students to successfully address challenges in applications to biomedical science. CBB students engage in cutting edge research, developing and applying novel quantitative methods to a broad range of questions in genomics, structural biology, molecular and evolutionary genetics, medical data science, systems biology, microbiome studies, cancer biology and immunology. As a means of fostering excellence in research, CBB students 1) work independently and collaboratively as part of a team, 2) conduct research responsibly, with a commitment to data sharing and reproducible analysis, 3) effectively communicate science to a broad range of audiences, 4) teach in formal and informal settings, and 5) develop professional and leadership skills in preparation for individualized career paths. The training program incorporates foundational courses in statistics, computer science and molecular biology, with enough time built into the program to allow students with diverse research and academic experience to achieve early proficiency in these areas through additional training. The breadth of research areas and potential dissertation research projects are explored through at least 3 rotations performed in CBB faculty labs, along with seminars, journal clubs and an annual off-site research retreat. The training program also includes required courses in Responsible Conduct of Research and Reproducible Research, with participation by both students and faculty. Career development activities are designed to address success as a beginning graduate student and then develop skills and tools to be a successful professional. With this powerful combination of skills, CBB alumni are in high demand, choosing career paths spanning academic research and teaching; industrial research from startups to big pharma and tech; and government institutes. The statistics summarizing our program over the past 5 years provide evidence for a successful training program, timely graduation (average 5.7 years to PhD), successful placement (100% of graduates working in academics, government or industry) and excellent training outcomes (avg. 2.7 publications per student). This training grant will provide funding for the first two years for three students with deficiencies in one of the cores, CBB disciplines, and will allow them extra training time to deepen skills relevant to their dissertation research. This T32 program will allow the Duke’s CBB program to amplify the individualized intellectual and professional development of independent and creative young quantitative scientists.

NIGMS - National Institute of General Medical Sciences

Project Summary Structural variants (SVs) are complex genetic rearrangements of medium to large size (>50 bp) that overall impact more base-pairs of the genome than any other type of genetic variants. These variants are implicated in many diseases, such as neurodevelopmental disorders (NDDs) and cancers. However, our understanding of their contribution to complex diseases remains incomplete. The large-scale studies have mostly focused on non-repetitive regions of genome and coding segments, overlooking potentially relevant areas outside these regions. These limitations are the result of lack of ability to accurately predict and genotype SVs in complex and repetitive regions of the genome, and the complexity of interpreting the functional impact of non-coding SVs. One of the primary objectives of my research is to study the hidden contribution of SVs to complex disorders by addressing these and other shortcomings in our current analysis. Despite the recent advances in computational methods using whole-genome sequencing (WGS) data, accurately predicting and genotyping SVs in repetitive regions of the genome, such as segmental duplications, remains challenging. Even with long-read WGS data, state-of-the-art SV callers are still unable to detect a significant fraction of the SVs in these hard-to-call regions, as demonstrated by the analysis of T2T-CHM13 data. Approximately 15% of the genome comprises regions that are difficult to accurately call variants, and our analysis of the T2T-CHM13 and HG002 assemblies suggests that these regions contain a significant high proportion of SVs. In addition, studying SVs in diseases also requires specialized novel methods, for accurate detection of de novo or somatic SVs. Development of these methods will open the door for comprehensive study of the contribution of SVs in hard-to-call genomic regions to complex disorders. Another major limitation of current studies of SVs in complex disorders is due to challenges in our ability to interpret non-coding SVs. It is hypothesized that non-coding SVs can contribute to complex disorders through a variety of mechanisms. One major such mechanism is the ability of non-coding SVs to disrupt transcriptional regulation. For example, this can occur through changes in the 3D genome architecture, which subsequently modify enhancer-gene interactions and result in ectopic gene expression. Thus, there is a need for development of accurate methods for predicting the impact of non-coding SVs on transcriptional regulation and cell-type specific gene-enhancer interactions. Finally, development of these tools will result in much needed comprehensive investigation of non-coding SVs observed in large-scale complex disorder studies for their impact on transcriptional regulation landscape, 3D genome structure and enhancer-gene interaction. The overall objectives of this proposal are as follows: 1. Dissecting contribution of SVs in hard-to-call genomic regions to complex disorders: Our first objective focuses on deciphering the role of SVs in previously inaccessible and hard-to-call regions of the genome. We will develop innovative methods to enhance the detection and genotyping of SVs, including both de novo and somatic variants, in these regions. We will also leverage these tools to construct a comprehensive catalog of SVs in these regions, utilizing an expanding collection of long-read WGS data from both normal and disease samples. Finally, we will quantify and explore the contribution of SVs in these regions to complex disorders, including autism and cancer. 2. Studying the role of non-coding SVs in complex disorders: Our second objective is to study impact of non-coding SVs to complex disorders. It is hypothesized that certain non-coding SVs can contribute to complex disorders by reshaping the gene regulation landscape. This can involve disrupting 3D genome architecture, altering gene-enhancer interactions, and driving ectopic gene expression. As part of this project we will develop methods to predict the impact of non-coding SVs on the gene-enhancer interactions landscape. We will utilize these methods to study the contribution of non-coding SVs through such a mechanism on complex disorders. In the next five years, my lab's overarching goal is to enhance our understanding of the role of SVs in human diseases and health. The results of this research will expand our understanding of the contribution of SVs to complex disorders, help discovery of novel disease biomarkers, reduce the missing heritability gap in complex disorders, and even discover potential novel drug targets that have been ignored till now.

NIGMS - National Institute of General Medical Sciences

Summary Biological size control is of broad importance to all processes of life. Among cytoskeletal assemblies, proper chromosome segregation depends on regulated, stable length of the metaphase spindle and elongation in anaphase B. While the interplay of force and biochemical regulation is central to understanding the spindle, our understanding of this interplay is limited. As a result, we still lack a predictive theory of spindle regulation. One notable knowledge gap is the role of the nuclear envelope in closed mitosis, wherein the spindle segregates chromosomes within the intact nucleus. Nuclear envelope remodeling is essential for proper chro- mosome segregation, and increasing evidence suggests that the envelope can exert significant force on the spindle. However, we currently do not know what sets the magnitude of this force, nor nuclear envelope con- tributions to spindle regulation. Our recent model implementation has opened up simulation of spindle-nuclear envelope coupling, enabling the proposed project. The central objective of this study is to determine the inter- play between force and biochemistry responsible for regulated spindle length, stability, and elongation in closed mitosis. Aim 1: Identify the mechanisms by which force and biochemistry regulate the metaphase spindle. Aim 2: Determine the mechanisms by which force and biochemistry regulate spindle elongation. This project is significant because it will identify new principles of spindle regulation, using a minimal, geneti- cally tractable system to uncover conserved physical principles of cytoskeleton-nucleus coupling. The results will advance understanding of how physical and molecular constraints shape cytoskeletal assemblies. Insights from this project will inform related research on organelle remodeling, shape sensing, and compartmentaliza- tion. It will also develop cutting-edge modeling tools for the cytoskeleton and nuclear envelope. This project is innovative because while spindle regulation has been studied previously, we will test novel idea that the nuclear envelope and spindle mechanical interactions are important for spindle regulation in closed mitosis. In addition, we will elucidate the mechanisms of spindle stability, healing, and response to envelope force, which have seen little previous study. The project will develop state-of-the-art computational models of spindle regulation, create new fission-yeast spindle and NE mutants and protocols for spindle perturbation, and integrate multiple advanced assays to perturb and quantify spindle dynamics. This project will elucidate the sensing of and feedback between biochemistry and spindle-generated and nuclear envelope forces. Mitotic spindle defects can lead to chromosome missegregation and genome instability, con- tributing to cancer, developmental disorders, and degenerative disease. Mutations that alter nuclear envelope morphology are associated with disease states such as muscular dystrophy, and disruption of nuclear integrity can cause DNA damage and is also associated with cancer. This project will add to our understanding of the underlying cellular mechanisms contributing to these health conditions.

NIGMS - National Institute of General Medical Sciences

Project Summary Cells adapt to their surrounding environments by forming dynamic contact with each other. These contacts are maintained by molecular interactions between receptors and ligands on cell surfaces. The immunoglobulin (Ig) fold, as the largest and most typical class of domains for cell surface recognition, is widely distributed in almost all types of cell surface receptors and their corresponding ligands. Some Ig domains can interact with multiple targets with various binding affinities. The difference in binding specificity of these proteins is a crucial determinant of their biological functions. Moreover, a majority of cell surface proteins contain multiple Ig domains in their extracellular regions. Not all of these domains are directly involved in binding partner recognition. To understand the function of cell surface proteins, it is necessary to determine which specific domains are responsible for binding, how Ig domain binding selectivity is determined, and why multiple extracellular domains need to be evolved. However, it is currently highly challenging to measure the extracellular interactions between cell surface proteins on a systematic level. These interactions are difficult to detect by standard biochemical assays due to the transient nature of their binding kinetics. Computational modeling can reach dimensions that are currently unapproachable in the laboratory. Unfortunately, even the state-of-the-art deep-learning-based methods, such as AlphaFold 3, are not sensitive enough to model the transient interactions among cell surface proteins. Thus, the objective of this proposal is to develop new methods that can be used to predict and simulate the specific interactions between cell surface proteins with Ig domains. We have constructed a non-redundant structural database for Ig domain interactions. Using this database, we will first develop a computational platform that combine protein language model and attention-based deep-learning model to identify potential new interactions between cell surface proteins. Moreover, we will generate a short list of domain pairs between two multi-domain cell surface proteins that are highly likely to mediate their interaction, therefore greatly reducing the complexity of experimental tests. We will further design a two-stage machine-learning strategy to predict the binding constants between specific Ig domains. We will use this method to understand why specific Ig domains can bind to multiple ligands with various affinities. Finally, we will propose a multiscale framework by incorporating protein conformational fluctuations estimated from molecular dynamics simulations into a new mesoscale model. We will use the multiscale framework to explore how multiple Ig domains regulate the intercellular interactions between cell surface proteins. All of our computational predictions will be experimentally validated by our long-term collaborators through an iterative process. Our long-term goal is to elucidate how interactions between cell surface proteins influence and regulate immune signaling and neural plasticity. Ultimately, the computational methods developed in this project are designed to be broadly applicable, enabling the study of protein interactions across diverse domain families beyond our primary systems of interest.

NCI - National Cancer Institute

PROJECT SUMMARY Drugs can be modified by human gut bacteria, leading to variability in efficacy and side-effects across people. Yet most of the ~19,000 FDA-approved drugs have not been tested for bacterial metabolism, and for those that have been screened, the responsible microbial enzymes are rarely known. Anti-cancer drugs epitomize this knowledge gap, with huge patient-to-patient variability and multiple documented links to specific bacterial strains and genes that alter drugs post-administration. This hinders our ability to design, prescribe, and dose cancer chemotherapies accurately and safely. A major roadblock is the immense diversity of microorganisms within a person’s gastrointestinal tract (the gut microbiota), including dynamic variability in enzyme presence/absence across strains of the same species, making it necessary to track causal genes not just taxa. Furthermore, state- of-the-art experimental screening approaches have insufficient scale to accommodate the rapidly growing list of drugs subject to gut bacterial metabolism. To remove these obstacles, we propose to develop a computational technology platform based on chemical and protein similarity that matches microbial enzymes with the drugs they are likely to modify. Supporting feasibility, our multi-PI team developed a prototype of this platform, called Similarity algorithms that Identify MicrobioMe Enzymatic Reactions (SIMMER). In the proposed project, we now aim to overcome three key limitations preventing the SIMMER prototype from being broadly applicable: the paucity of validated reactions for training and evaluation (Aim 1), variable performance across enzyme classes (Aim 2), and inability to query starting from a protein sequence rather than a chemical reaction (Aim 3). We will tackle these challenges by using large language models to incorporate protein structural similarity alongside sequence homology, linking traditionally siloed reaction-centric and sequence-based databases, and generating large-scale functional data to iteratively evaluate and improve SIMMER’s algorithms. The resulting tool will enable users to predict drugs that a given protein could modify and to prioritize gut microbial enzymes capable of performing known drug transformations. We have opted to focus on anti-cancer drugs as an initial proof-of-concept, given the rigorous prior literature implicating the microbiome in cancer therapy and the broad potential for translational impact. SIMMER 2.0 will speed up the discovery of chemotherapy-metabolizing enzymes, enabling focused work on specific drug classes and types of cancer. In addition, SIMMER predictions themselves will be useful for drug design and as inputs to personalized dosing algorithms. This cancer-focused project will be a key milestone towards a comprehensive map of all FDA-approved drugs and their microbial interactions. More broadly, the proposed methods will be easily extendable to other chemicals besides drugs, including diet- and host-derived small molecules.

NIGMS - National Institute of General Medical Sciences

Project Summary: Horseradish peroxidase (HRP) is a critical reporter enzyme widely used in diagnostics, and research tools due to its ability to amplify signal in assays like ELISAs, Western blots, and immunohistochemistry. However, current HRP reagents are largely derived from horseradish root, which results in heterogeneous mixtures of isoenzymes with varying glycosylation patterns, activity, and stability. This variability compromises reproducibility, complicates regulatory compliance, and presents significant manufacturing challenges. Moreover, recombinant HRP production has been historically hindered by its complex structural requirements, including the incorporation of a heme cofactor, multiple disulfide bonds, calcium ions, and glycosylation, which are difficult to replicate in microbial hosts. As a result, efforts to create a consistent, recombinant HRP alternative have proven unsuccessful, with current solutions like poly-HRP showing significant limitations in batch-to-batch consistency which is critical in high sensitivity assays. This SBIR Phase I project aims to overcome these challenges by using state-of-the-art computational protein design to develop a novel recombinant HRP mimetic that exhibits high stability, catalytically active properties, and scalability. Our approach involves two primary innovations: the design of a stable, de novo HRP enzyme that can be expressed efficiently in microbial systems, and the development of a self-assembling HRP nanoparticle that enables precise control of enzyme stoichiometry and enhances performance consistency. The proposed HRP mimetic will not only ensure high-quality production of HRP reagents but also enable genetic fusions with other functional domains, opening the door to more consistent and reliable diagnostic development. Our team has developed promising preliminary data indicating a highly de-risked application that will have a big impact. Our preliminary data demonstrate the feasibility of using computational protein design to create a de novo HRP that is easy to manufacture, and with this grant, we intend to transform it into a high-impact product with broad applications.

NEI - National Eye Institute

This proposal seeks support for students and junior investigators (travel awardees) to attend the 2025 International Society for Eye Research (ISER)/BrightFocus Foundation (BFF) glaucoma meeting titled "Concepts and Breakthroughs in Glaucoma" to be held October 8th-11th, 2025 at the Emory Conference Center and Hotel in in Atlanta, Georgia. As in past meetings, our goal is to bring together basic scientists, clinician-scientists, students and fellows for presentations and in-depth discussions on recent exciting research advances and developments in the molecular mechanisms underlying glaucomatous pathology, both in the conventional outflow tract and the optic nerve head. We have already recruited three thought leaders in glaucoma to deliver keynote lectures. As in past meetings, platform sessions will be selected exclusively from submitted abstracts, with one session reserved for travel awardees. We are also organizing again a one-day "crash course" in glaucoma for people newcomers to the field and students/junior investigators, consistent with our goal of increasing young scientist participation. The Specific Aims of the conference are to: 1. Enhance the emerging careers of at least 30 young investigators working in glaucoma research by providing travel awards. 2. Provide a forum for the dissemination of the most recent advances in glaucoma research. 3. Create an environment that facilitates the exchange of novel ideas among basic and clinician-scientists, fostering opportunities for collaboration among vision scientists with multiple scientific expertise. 4. Bring together scientists working in disparate areas of glaucoma research. We anticipate that this meeting will provide state-of-the-art information on recent advances in glaucoma and serve as an important resource for those involved in the translation of these findings into novel therapeutics. The conference will also provide new opportunities, avenues for new discovery, and a forum to develop potential collaborations among the attendees. The requested funds will support the travel, accommodation and registration of at least 30 trainees to attend this focused meeting.

OD - NIH Office of the Director

Summary: The Lundquist Institute (TLI) is requesting funds to purchase a Leica STELLARIS confocal microscope to be housed in its established, centrally managed core facility. This new system is intended to replace an aging 12- year-old Leica SP8 microscope that no longer meets the evolving needs of our research community. A broad user group of 12 investigators (10 of whom are NIH-funded), who are all making significant and pioneering contributions to cross- disciplinary research at the interface between developmental biology, cell biology, molecular biology, cancer, endocrinology, neurobiology, immunology, and host-pathogen interactions, will immediately benefit from the transformative imaging capabilities of the instrument. The STELLARIS system offers major advancements in confocal imaging technology, including a tunable white light pulsed laser for fluorescence lifetime imaging microscopy (FLIM), integrated with the high-speed FALCON FLIM platform and capable of multiplexing up to 11 spectral channels. These features provide users with quantitative imaging modalities to monitor complex dynamic processes in live and fixed samples. The instrument also includes LIGHTNING super-resolution capabilities based on adaptive deconvolution, expanded spatial coverage, and Leica's proprietary HyD detectors with tunable spectral sensitivity (1-nm precision, 400–850 nm), enabling high- resolution, low-phototoxicity imaging across a wide range of fluorophores. Acquisition of this system will ensure continued access to state-of-the-art imaging technology, enabling investigators to generate high-quality, multidimensional datasets and address increasingly complex biological questions. This instrument will directly enhance the rigor, reproducibility, and competitiveness of NIH-supported research at TLI by facilitating transformative insights into molecular and cellular mechanisms of health and disease.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract Germinal matrix-intraventricular hemorrhage (GM-IVH) is a significant neurological complication associated with high mortality rates and substantial neurodevelopmental disabilities. While the majority of GM-IVH cases are clinically asymptomatic, it is the most common cause of hydrocephalus in premature infants. Progressive cerebral ventricular dilation is an important diagnostic component of hydrocephalus and is typically identified through trans-fontanelle, cranial Ultrasound (CUS) in neonates. It is safe, cost-effective and can be conducted at the bedside with minimal disruption to the infant. However, current CUS clinical application is limited by numerous constraints, including: i) results are contingent upon the skills and experience of the ultrasonographer and radiologist Iii) limited access to the appropriate equipment and trained personnel in certain institutions due to prohibitive costs iii) due to the medical complexity of this vulnerable patient population, there is often a need to minimize stress, which can delay acquisition of important imaging when a patient is too unstable to undergo standard, often time consuming diagnostic US assessment. Within the last six years, conformable ultrasound electronics have been intensively investigated for imaging of many internal organs, however, to our knowledge, there are currently no studies on the feasibility of trans- fontanelle continuous ventricular ultrasound. Our goal is to investigate the monitoring of ventricular volume in neonates with GM-IVH using a wearable, adhesive ultrasound patch, and test the feasibility of simultaneous measurement of ventricular and sub-arachnoid size as well as cerebral blood flow. We hope this research will standardize interpretation, increase availability and reduce costs. Our work will introduce a novel patch design along with advanced piezoelectric transducers design, and a new image reconstruction method along with machine learning analysis of standard measurements such as ventricular index (VI), and anterior horn width (AHW), but also introduce AI based volumetric analysis. This work will be based on (1) novel patch design and advanced microfabrication of electronics (electronic science and engineering), (2) signal decoding for beamforming and image reconstruction (biomedical engineering and signal processing) and (3) clinical study on neonates and machine learning analysis (biomedical engineering and artificial intelligence). This study will provide the first in vivo validation of a conformable cranial ultrasound patch for neonatal brain monitoring with a significant advancement in neonatal monitoring, combining state-of-the-art piezoelectric sensor technology with advanced deep learning algorithms. We aim to demonstrate generalizability, robustness, and the potential to standardize CUS in this at-risk patient populations. This could ultimately reduce the incidence of severe neurodevelopmental impairment by providing uniform neurodiagnostic accuracy in a condition that is a major cause of mortality and neurodevelopmental impairment in this fragile population.

Conseil des arts et des lettres du Québec

CALQ supports artistic and literary creation in Quebec through grants to artists and organizations in all disciplines including theatre, dance, music, visual arts, literature, and film.

OD - NIH Office of the Director

Project summary/abstract Academic drug discovery centers (ADDCs) have emerged as a key resource and core facility for two distinct and interrelated pursuits: (1) the practice of chemical biology, with the discovery of chemical tools and probes to dissect biological mechanisms, and (2) the identification of small molecule ‘hits’ against molecular targets or cellular phenotypes as starting points for drug discovery. The Small Molecule Discovery Center at UCSF is one of the pioneering ADDCs and has deep expertise in diverse state-of-the-art hit-identification strategies, from biophysical fragment-based drug discovery (FBDD) to complex microscopy-based screens. Among the major advances in the industrialization of the drug discovery process over the past few decades is miniaturization of assay volume, from 96-well to 384-well to 1536-well plate formats. 1536-well plates incorporate assay volumes on the order of 2-microliters, offering much faster screening – leading to increased chemical diversity screened – as well as reduced consumption of precious or expensive assay components. One of the greatest challenges in running multi-step assays in 1536-well plates is the addition of liquids and their removal—usually by aspiration. The quality of liquid exchanges dramatically affects the performance of multi- component and multi-step screening assays. The development and commercialization of a centrifugation-based approach to liquid removal from 1536-well plates allows the running of high throughput cell-based and molecular- based drug screening assays. The Small Molecule Discovery Center at UCSF currently lacks the ability to evacuate the contents of 1536-well plates-which limits us to 384-well formats for assays requiring the evacuation and exchange of liquids. We are requesting a BlueWasher for our integrated robotic automation screening platform, which incorporates roboticized plate handling, liquid handing, automated incubation, and imaging systems for both biochemical- and cell-based assay formats. We are also requesting funds for an integrated robotic arm and plate hotels (BlueBench) to run multi-plate high throughput screens in batch mode. The increase in scale and efficiency that the incorporation of this equipment will provide to the Small Molecule Discovery Center core facility in moving from 384-well to 1536-well format will significantly increase the impact of Center’s work for UCSF PIs and project teams. Both the quantitative and qualitative aspects of increased the chemical diversity explored and the robustness and reproducibility of the assays will contribute to increased productivity for the Center in achieving its research services and shared-use goals.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT ABSTRACT After a few weeks of antiretroviral therapy (ART), HIV-1 RNA often decays to undetectable levels in blood. The initial decay is typically rapid due to the loss of short-lived, HIV-infected CD4+ T cells, but despite being adherent to ART, some people experience a subsequent period of slower decay and may require months to years to reach virologic suppression. The clinical significance of ‘slow decay’ of HIV-1 RNA after starting ART is currently unknown. Assessing the clinical significance of ‘slow decay virus’ requires identify the mechanisms generating it and exploring whether there is ongoing inflammation and neuronal damage in these people. There are three potential mechanisms that may generate ‘slow decay virus’ and they may have very different clinical implications. (1) Continued HIV-1 replication due to ineffective ART, poor ART adherence or drug- resistance. (2) Alternatively, ART could stop HIV-1 replication, but HIV-1 virions may continue to be produced by HIV-infected CD4+ T cells or (3) macrophage. Virus production without replication that emerges at the time of ART initiation is called primary nonsuppresible viremia (NSV) and is mechanistically distinct from secondary NSV observed in people who were previously suppressed. We recently examined four people who required approximately a year to become suppressed and found that ART stopped HIV-1 replication, but HIV-infected macrophage continued to produce substantial amounts of virus. These preliminary results are consistent with the long-held belief that after starting ART there is a period of rapid viral decay due to loss of HIV-infected CD4+ T cells, but some people have a subsequent period of slower decay due to continued virus production from long- lived, HIV-infected macrophage. The proposed work will expand on these observations and examine the mechanisms generating ‘slow decay virus’ in a much larger cohort of people on ART and explore the clinical implications of having ‘slow decay virus’ after starting ART (i.e. primary NSV). We will use existing, archived, longitudinal blood samples from 99 people in the MACS/WIHS Combined Cohort Study (MWCCS) who did not suppress HIV-1 RNA to undetectable levels by 6 months on ART (i.e. people with ‘slow decay virus’) and samples from 30 people who suppressed virus with typical, rapid kinetics. The proposed experiments will identify the mechanisms generating ‘slow decay virus’ during ART and the clinical implications of ‘slow decay virus’ (Aim 1). In our previous study, we also observed that ‘slow decay virus’ produced by macrophage often had nonsense/frameshift mutations in the HIV-1 vpr gene that may have promoted continued HIV-1 production from macrophage during ART. Specifically, we will explore whether ‘slow decay virus’ populations produced by macrophage have mutations in vpr or other genes that impact macrophage survival and/or HIV-1 production from infected macrophage (Aim 2). We will accomplish these aims using cutting-edge, but highly rigorous approaches. Accomplishing these aims will address clinical concerns about ‘slow decay virus’, the source of ‘slow decay virus’ as well as the role that Vpr plays in HIV-1 persistence and expression in macrophage during ART.

Centers for Disease Control - NCEZID

<p>The CDC announces the availability of FY 2027 funds for a cooperative agreement to continue enhanced national surveillance for human prion diseases, also known as transmissible spongiform encephalopathies (TSEs), in the United States. The purpose is to continue an active surveillance program to help confirm suspected and clinically diagnosed cases of human prion disease and to monitor the occurrence of potentially emerging human prion diseases in the United States. Outcomes are enhanced national surveillance for always fatal human prion diseases through improved diagnoses and continued monitoring for emerging or new prion diseases in the United States. These outcomes are accomplished through the funding of a specialized center to conduct state-of-the-art diagnostic techniques. Prion diseases can only be confirmed through brain tissue analyses, and many facilities lack the expertise and/or the willingness, due to infection control concerns, to handle and accurately diagnose specimens from suspected cases. Since 1997, the Centers for Disease Control and Prevention (CDC) has funded a center to provide prion disease diagnostic services, which has allowed for disease confirmation, evaluation of disease trends over time, and identification of disease subtypes. Data have been shared with CDC experts who partner with center staff, providing guidance and epidemiological knowledge. This collaboration has contributed to accurate national surveillance findings and helped to provide confidence that novel prion diseases, such as a human form of the animal prion disease, chronic wasting disease, have not been occurring in the country.</p>

Centers for Disease Control - NCEZID

The CDC announces the availability of FY 2027 funds for a cooperative agreement to continue enhanced national surveillance for human prion diseases, also known as transmissible spongiform encephalopathies (TSEs), in the United States. The purpose is to continue an active surveillance program to help confirm suspected and clinically diagnosed cases of human prion disease and to monitor the occurrence of potentially emerging human prion diseases in the United States. Outcomes are enhanced national surveillance for always fatal human prion diseases through improved diagnoses and continued monitoring for emerging or new prion diseases in the United States. These outcomes are accomplished through the funding of a specialized center to conduct state-of-the-art diagnostic techniques. Prion diseases can only be confirmed through brain tissue analyses, and many facilities lack the expertise and/or the willingness, due to infection control concerns, to handle and accurately diagnose specimens from suspected cases. Since 1997, the Centers for Disease Control and Prevention (CDC) has funded a center to provide prion disease diagnostic services, which has allowed for disease confirmation, evaluation of disease trends over time, and identification of disease subtypes. Data have been shared with CDC experts who partner with center staff, providing guidance and epidemiological knowledge. This collaboration has contributed to accurate national surveillance findings and helped to provide confidence that novel prion diseases, such as a human form of the animal prion disease, chronic wasting disease, have not been occurring in the country.

NIDA - National Institute on Drug Abuse

Project Summary/Abstract African Americans living with HIV experience accelerated neurocognitive aging despite effective antiretroviral therapy (ART). This project, "Contribution of Neuronal Mitochondrial Dysfunction and Microglial HIV Reservoirs to Neurocognitive Aging in African Americans with Nicotine Addiction and Viral Suppression," investigates how persistent microglial HIV reservoirs, exacerbated by nicotine exposure, disrupt neuronal mitochondria and accelerate cognitive decline. Smoking increases oxidative stress and inflammation, compounding mitochondrial dysfunction and neuroinflammation, leading to greater neuronal injury. Microglia sustain these pathological processes despite systemic viral suppression, contributing to HIV-associated neurocognitive disorders (HAND). Our long-term goal is to mitigate HAND by targeting the core drivers of neurocognitive decline—neuronal mitochondrial dysfunction and persistent microglial HIV reservoirs—particularly in African Americans with nicotine addiction. We hypothesize that chronic microglial HIV reservoir activity accelerates neuronal mitochondrial dysfunction and that nicotine amplifies these effects, leading to earlier and more severe neurocognitive deficits. To test this hypothesis, we propose the following specific aims: Aim 1: Quantify mitochondrial DNA (mtDNA) in neuron-derived extracellular vesicles (NEVs) from blood plasma to assess neuronal mitochondrial dysfunction and its link to neurocognitive impairment in African Americans with nicotine addiction and viral suppression. Aim 2: Measure HIV RNA in microglia-derived extracellular vesicles (MEVs) from blood plasma to assess microglial reservoir activity and its contribution to neurocognitive aging in African Americans with nicotine addiction and viral suppression. We will recruit African American participants stratified by HIV status, smoking behavior, age, and sex. NEVs and MEVs will be isolated from blood plasma using neuron- and microglia-specific antibodies. Biomarkers— mtDNA (neuronal mitochondrial dysfunction) and HIV RNA (microglial reservoirs)—will be quantified using droplet digital PCR (ddPCR) for mtDNA and reverse transcription-ddPCR (RT-ddPCR) for HIV RNA. Neurocognitive function will be assessed with standardized tests, and statistical analyses will correlate biomarker levels with demographic variables and cognitive outcomes. Our preliminary findings indicate increased mtDNA in NEVs and detectable HIV RNA in MEVs among African American men with HIV who smoke, supporting the study’s hypothesis. By integrating biomarker assays with neurocognitive testing, this project will elucidate how microglial HIV reservoirs and nicotine disrupt neuronal mitochondrial integrity and contribute to cognitive decline. Findings will inform precision-medicine strategies to reduce HAND-related health disparities in African Americans living with HIV and nicotine addiction.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT The latent HIV-1 reservoir that persists despite the effect antiretroviral therapy (ART) comprises infected cells with intact integrated proviruses that are transcriptionally near silent. The existence and maintenance of this reservoir in essentially all ART-treated individuals is a major barrier to curative interventions in HIV-1 infection, and necessitates the lifelong administration of ART. In the preliminary studies that underpin this proposal we developed a xenograft based model system in NSG mice that reliably generates populations of human primary memory CD4+ T-cells that contain latent proviruses carrying reporter genes. Our methods overcome some of the key limitations of existing approaches to study HIV-1 latency. We determined hundreds of HIV-1 integration sites in active and latent cell populations and uncover relationships between provirus genomic location, infected cell clonal expansion, and the establishment of HIV-1 latency after engraftment. Uniquely, we have recovered and cultivated in large numbers primary memory CD4+ T cell single-cell clones each harbouring a unique HIV-1 integration site in which latency was (or was not) established in vivo. Comparison of these clones with the small number of CD4+ T cell clones that harbor intact HIV-1 proviruses that have been cultivated from ART-treated individuals reveals features in common that suggest that the model system we have developed more accurately recapitulates features of HIV- 1 latency than those deployed heretofore. In Aim 1, we will build on our preliminary studies by deriving a diverse collection of primary CD4+ T-cell single cell clones that harbor latent or active HIV-1 proviruses. Therein, we will investigate the stability, dynamics an mechanisms of transitions between active and latent states at defined integration sites and, whether the new DNA synthesis that accompanies cell proliferation enables these transitions. We will determine relationships between the epigenetic profile of loci containing proviruses and whether proviruses are transcriptionally active or latent. We will further assess how the physiologic status of T-cell clones conspires with epigenetic profile of loci containing proviruses to impact the establishment of latency and transitions between active and latent states. In Aim 2 we will manipulate epigenetic modifications at or surrounding the site of provirus integration in the genome of primary memory CD4+ T-cell clones and determine their effects on HIV-1 latency. We will build a custom, targeted sgRNA library, focused on epigenetic modifiers and gene expression regulators and identify genes that affect HIV-1 latency in various genomic contexts. We will further conduct genome wide CRISPR screens in primary memory CD4+ T-cell clones to identify genes that regulate latency therein. Ultimately, we will aim to provide mechanistic insights into HIV-1 latency and evidence about how manipulation of latency might be accomplished, such that HIV-1 infection might be cured.

NIAID - National Institute of Allergy and Infectious Diseases

Controlled Delivery of Adjuvanted Multivalent Fusion Peptide Focused HIV Vaccines Project Summary The development of a safe and effective vaccine against HIV-1 continues to be a global health priority and has posed a formidable scientific challenge. Recent advances in vaccinology and immunology highlight great promise in enhancing potency of vaccine-induced immunity using prolonged delivery of vaccine immunogens and adjuvants. Striking increases in the induction and persistence of germinal centers produced by such regimens in rodents and non-human primates highlight the enormous benefit in affinity maturation of vaccine-specific B cells, which is critical for HIV-1 targeted vaccines. Notably, we have recently found that the SOSIP+3M-052 combination induced antigen-specific long-lived plasma cells that successfully trafficked to the bone marrow in non-human primates (NHPs) and were found to be stable for 2-3.5 years in independent studies. We seek to capitalize on these insights with five mutually reinforcing components: (i) safe and injectable hydrogels, based on unique chemistry of tunable bond formation and disconnection, that provide uniquely tunable extended release properties; (ii) safe and highly immunogenic virus-like particle platforms for multivalent antigen display; (iii) platform-switching heterologous immunization to focus the immune response on the HIV-1 fusion peptide; (iv) state-of-the-art SOSIP-based envelope glycoprotein (Env) immunogens; and (v) a nanoparticle-based form of the TLR7/8 targeted adjuvant 3M-052. These tools will be used to generate vaccine-induced durable and protective HIV-1 specific immunity, and to study responses at the cellular, molecular, and antibody-epitope levels in NHPs to maximize the changes of clinical success. Our three specific aims blend innovative chemistry, immunogen display, and delivery (Finn lab) with optimization of vaccination strategies coupled with deep immunological and vaccinological analyses in rodents and NHPs (Kasturi Lab). Upon successful completion of the program, we will have validated a modular class of vaccine formulations and identified key determinants of vaccine-induced durable and protective humoral immunity. This work will enable rapid future optimization of candidate vaccines against HIV-1, and potentially other pathogens, to elicit broad and long-lasting protection.

Fish and Wildlife Service

Task 1. Redesigning Website for Easier Search and Navigation Functions Starting in the late 1990s, American Trails (AT) began a collection of online trail resources documents, web pages, and links for the trails community to utilize. This collection has grown to over 6,000 pages, all stored in static, HTML code that requires manual updating. While this method worked for us for many years, the mass amount of resources has led to a website that is loaded with information, but that can be difficult to navigate. A user may have to click through multiple pages to find a given resource. Our current search method, using Google indexing, can be helpful, but as a keyword-only search method, it often returns dozens of pages of articles for the user to sort through. AT proposes building a single, powerful Content Management System (CMS) to organize and store these resources a system that will be powerful, fast, clear, and simple to use and that will provide an unparalleled resource library for the trails community including FWS users who have requested better access to information on the American Trails website. The Trail Resource CMS we propose will provide detailed search options title, State, Agency, category, keywords, and full article text search of thousands of American Trails resources. Updating the website will make it easier for the American people as well as FWS employees to better help navigate the most current up to date information on wildlife trails, refuges, and considering habitat in trail planning, construction and maintenance. By updating to the CMS American Trails will be able to better organize data, make it more accessible and easier for FWS to look up information and find trail resources. Task 2. National Recreation Trails National Recreation Trails may be designated by the Secretary of Interior to recognize exemplary trails of local and regional significance in response to an application from the trail's managing agency, such as a management unit of FWS. Through designation, these trails are 5 recognized as part of America's national system of trails as authorized by the National Trail System Act of 1968 (Public Law 90-543). The FWS vision document Conserving the Future: Wildlife Refuges and the Next Generation recommends creative thinking about enabling visitors to learn about FWS resources: "We must actively encourage and provide new opportunities for people of all ages and backgrounds to connect with nature by visiting their national wildlife refuges, personally or virtually." Trails in particular can provide the low-impact managed use that can help meet FWS goals for the future. Designation of trails on FWS lands as NRTs has been identified by FWS staff as a way to encourage visitation of trails that would benefit from increased attention. Trails are a critical way that visitors discover the beauty, history, and natural heritage of the National Wildlife Refuge System, and NRT designation is a cost-effective way to provide visibility to Refuge resources. The NRT website and database are essential tools for reaching the public with up to date information on FWS trails and other recreation opportunities. In 2015, analysis of website visitation documented that 40,446 trails were searched and located using the database on average, per month, by the public. In addition, visitors printed out 5,636 trail records from the database. The cost for updating these online resources is minimal compared to traditional public information techniques such as staffing visitors' centers, printing brochures, and attending public events. Most of the FWS NRTs designated in 2008-2015 have included good information in their applications that can be used for website creation and to populate the NRT designation. However, older designations are typically sketchy with details. Information that is of most use to visitors includes trail description, directions to trailheads, points of interest, and related activities. Helping visitors know the trail location relative to cities and highways is also important, and this can be done both descriptively and via downloadable maps (provided by the Refuges). The database records also should link to Refuge websites where news, events, and current conditions are available. Finally, a photo gives a good identity to the trail and makes it more appealing as visitors search the database. Most Refuge websites do not provide much information on trails. The Featured NRT website pages are an opportunity to provide useful visitor information in an attractive article format that includes trail features, seasonal interest, route descriptions, photos, and digital maps. FWS identifies "special attention to opportunities offered for youth and people with disabilities" as a priority for visitor information. Finally, these pages are also a great way to recognize volunteers and Friends groups who help with construction, maintenance, and interpretation. All FWS-managed National Recreation Trails are good candidates for new Featured NRT pages. We will continue to identify which of the NRTs do not have an existing Internet presence. All of these pages will link to agency and nonprofit websites supporting the trails. Task 3. National Trails Training Partnership (NTTP) Refuge Managers need to build sustainable, cost-effective trails that provide the public with memorable experiences of wildlife and natural areas. Expertise in trail development and management, especially in important habitat areas, needs to reach staff as well as volunteers and cooperating organizations. The US Fish &amp; Wildlife Service is a party to the 2011 memorandum of understanding for the National Trails Training Partnership (NTTP), which is an extension of the 2003-04 agreements that began this initiative to promote trail-related training. The current MOU among seven Federal agencies and 24 national organizations states: "The purpose of this MOU is to develop and expand a framework of cooperation among the Parties at the national, regional, State, and local levels for planning and implementing mutually beneficial projects, activities, and programs for workforce development, training, and education associated with trails and related outdoor recreation and transportation activities." With efforts to promote public health and engage youth in natural resources by building and promoting trails and greenways, the environmental issues are increasingly important to planners 7 and managers. An important way to reduce visitor impacts is to improve planning of trails in habitat areas and use best practices for building and managing trails. Quality trails also facilitate environmental education as well as resource protection. The NTTP website, developed and maintained by American Trails, is a key element in making available resources to help in developing and managing trail systems. This website is available to trail building and management agencies and organizations, as well as to members of the general public who are interested in trails training. Another task is providing resources to help improve accessibility to public lands. Our goal is to provide effective technical information on building better, more sustainable trails, which also increases the level of accessibility. NTTP has also been effective in promoting best practices as well as identifying training providers. Federal agencies, organizations, and States have worked together through NTTP to improve coordination on training nationwide. Specific training available from a variety of providers includes skills for conservation and youth corps organizations, curricula for college-level students, and training to address local needs of agencies and organizations. Task 4. Technical Assistance Technical assistance and information sharing for FWS staff and cooperating organizations is essential to providing attractive as well as cost-effective recreation facilities. The key issues are effective delivery of technical information, improving accessibility, and managing visitor facilities in habitat areas. The FWS vision document Conserving the Future encourages new technology for sharing information and connecting with the public. Recommendation 15 states: "Develop integrated mechanisms for using web-based and other emerging technologies to store and share data, communicate within the System, and inspire and educate visitors and the public." Technical assistance also involves documenting the experience of staff who are retiring. Conserving the Future states: "As we transition from an older to a younger workforce, we must look for ways to transfer knowledge from senior staff." The key challenge for Refuge Managers is how trails can best be built while recognizing the needs and sensitivities of wildlife and the environment. We need to look at good examples on the Refuges, identify best practices in place in other jurisdictions, and document how new or improved trails contribute to both conservation and environmental education. As trails become even more popular, and are the subject of efforts to promote public health and outdoor activity, environmental issues are increasingly important. The desired result is to enable Refuge managers to build the best, most cost-effective trails. While trails may seem like simple projects, managers may not be experienced with state-of-the-art practices. Managers need the technical knowledge to make decisions on surfacing, maintenance, and facilities, as well as management issues of habitat impacts, seasonal closures, and wildlife watching. Providing the best information, as well as contacts with other trail managers on similar projects will lead to the most effective problem solving for trail development. It is also important to manage trails and visitors in ways that reduce impacts while increasing positive experiences and learning opportunities. Refuge managers and others in the field of parks and outdoor recreation need effective technical information on building better, more sustainable trails, which are also increasing the level of accessibility. With years of confusion and uncertainty over actual requirements for accessibility, many agencies have either ignored the need for more accessible trails, or have avoided tackling new trail projects. With the recent publication of final regulations for trails and facilities on federal land there is a critical need to interpret, publicize, and share information on accessible trails. To provide better assistance with trails in habitat areas, we need to continue development of the website area for "Planning Trails with Wildlife in Mind: A Handbook for Trail Planners. Material from the original print publication by Colorado State Parks has been adapted by American Trails to an online presentation at: www.americantrails.org/wild/default.htm. The goal of the Handbook and the new website area is to help planners and managers create trails that make a positive contribution to stewardship of open space and habitat. It is still the only 9 comprehensive resource that details both the impacts and benefits of trails as visitor management tools. Planning Trails with Wildlife in Mind was intended to encourage new contributions and add to the body of knowledge to improve our planning efforts. When it was compiled in 1998, the subject was just beginning to be studied. We need to involve FWS staff in expanding this information source with examples from the Refuges. We also need to make this information available to the public, volunteers, and environmental education providers. Task 5. International Trails Symposium The American Trails International Trails Symposium is the best opportunity for a comprehensive learning experience on all aspects of trail planning, development, and management. The 2017 Symposium will be held in Dayton, Ohio May 7-10, 2017. Over many years of attending the Symposium, FWS representatives have been able to share success stories with trail and greenway advocates, managers, planners, and users, as well as tourism and business interests. American Trails sponsors the International Trails Symposium every two years, The Symposium offers ways to publicize the FWS mission and resources, as suggested in Conserving the Future: "We must also look for ways to build relationships with people who have not had traditional links to wild lands and wildlife, and encourage them to visit refuges." The Symposium is also an important opportunity for FWS representatives to learn from, share success stories, and network with staff of other agencies, communities, and trail organizations. The goal is to create a culture of stewardship for our public lands as well as connections from our communities to nature. This Symposium will continue to build on previous conferences that have offered a variety of presentations on the topic of trails and wildlife. With an increasing need for solving problems and creating more cost-effective and sustainable trails, the theme for the 2017 Symposium is Trails Take Flight: Connecting People, Places, and Possibilities. Symposium programs will explore the many pathways to success for all types of trails, from cities to the backcountry, including trail design, sustainability, safety, advocacy, and health, as well as possibilities for the future. This Symposium will address the need for more technical training through a new partnership with the Professional TrailBuilders Association. We will offer a series of Sustainable Trails Workshops and programs during the Concurrent Educational Sessions, featuring solutions-based topics. In addition, Mobile Workshops will bring attendees to featured Dayton, Ohio area sites to share lessons learned from trail planning, partnerships, maintenance, and visitor management. Task 6. International Trails Symposium Hulet Hornbeck Emerging Leaders Scholarship Program Given the spectrum of challenges surrounding human health, underserved communities, and disengaged youth, there is an important need to enable more young people to have the valuable educational experiences such as attending the International Trails Symposium. The Hulet Hornbeck Emerging Leaders Scholarship Program was launched in 2013 as part of the American Trails International Trails Symposium. The program was named in memory of lifelong trail activist Hulet Hornbeck. At the 2013 International Trails Symposium, American Trails provided scholarships to 18 talented young leaders and recently brought 16 talented young adults to the 2015 International Trails Symposium on scholarship. Recipients were immersed in learning best practices and trends in the field to help pave the path to careers in trails, conservation, and outdoor recreation. Many attendees met and mentored these aspiring young trail professionals at the Symposium to encourage them on their way to becoming tomorrow s trail leaders. Diversity and inclusivity are important aspects of the Hulet Hornbeck Emerging Leaders Scholarship Program. This initiative was developed to provide unique training and mentoring opportunities to inspire young adults to choose a career path so they can leave a lasting legacy in the field of natural resources. Scholarship candidates are young adults who have an interest in trails, conservation, and outdoor recreation, and are interested in learning about these as potential career paths. See more on the accomplishments of this program in Youth Scholars Assessment of 2013 International Trails Symposium. Involvement in the Symposium also exposes young professionals to multi-generational dialogue about conservation and recreation. Diversity and inclusivity are important to us so that we can meet everyone s deepest needs, values, and long-term interests. We welcome individuals of all backgrounds to apply regardless of past trails experience. We are more interested in potential. During past Emerging Leaders programs, established resource professionals benefitted just as much from the exchange as the field looks to foster new leadership. onserving the Future clearly states the concern facing Federal land management agencies as well as organizations such as American Trails: "We are an overwhelmingly white and aging organization that struggles with being relevant in this rapidly changing society." The FWS vision document expands on the agency's commitment to student and youth programs in Recommendation 22: "Recruit and retain a workforce that reflects the ethnic, age, socioeconomic, and cultural backgrounds, and language diversity of contemporary America." A mentor pairing for every scholarship recipient (whom share a common interest/career goal) ensures that he or she will reap lasting benefits from the experience. These future leaders will learn best practices and trends in outdoor recreation and resource conservation to help pave the path to careers in these fields. An unexpected outcome of the successful 2015 program was that established resource professionals benefitted as well from sharing their expertise and in looking to foster new leadership in their own agencies. Authorizing statues for this program include Fish and Wildlife Conservation Act of 1934 (16 U.S.C. 2901-2911); Fish and Wildlife Act of 1956 (16 U.S.C. 742(a)-754); Refuge Recreation Act of 1962 (16 U.S.C. 460k-460k(4)); National Wildlife Refuge System Administration Act of 1966 (16 U.S.C. 668dd); Youth Conservation Corps Act of 1972 (16 U.S.C. 1701-1706); Archaeological Resources Protection Act of 1979 (16 U.S.C. 470aa-47011); The National Wildlife Refuge System Act of 1997 (Public Law 105-57); National Wildlife Refuge System Volunteer and

NIDA - National Institute on Drug Abuse

Project Summary/Abstract Human immunodeficiency virus (HIV) and substance use are ongoing public health dilemmas throughout the United States and worldwide. Drugs such as cocaine and opioids can potentiate the pathophysiology of HIV within the central nervous system (CNS), exacerbating HIV-induced neurocognitive impairment among people living with HIV (PLWH) on antiretroviral therapy (ART). The recent sharp rise in cocaine overdose deaths is largely driven by co-use of synthetic opioids such as fentanyl. Polysubstance use (PSU) is very common among PLWH who use drugs, particularly PSU of cocaine and opioids. Nevertheless, very little is known regarding how cocaine and opioids interact to dysregulate reward learning and motivation, especially in the context of HIV. Taken together, identifying the unique cellular mechanisms underlying drug seeking and relapse-like behavior in the context of HIV and PSU is imperative for developing targeted and effective treatment strategies for substance use among PLWH. This proposal aims to elucidate the contribution of central and peripheral immune mechanisms to HIV-induced dysregulation of reward seeking, with the goal of identifying novel treatment targets for PLWH who use drugs. Our work thus far has revealed that mice infected with the chimeric HIV construct, EcoHIV, display potentiated cocaine-seeking behavior, impaired extinction learning, as well as dysregulated peripheral immune function. Moreover, our work has revealed a potential role of microglia and astrocytes in facilitating these deficits as well as independent and interactive effects of ART and EcoHIV on striatal neuroimmune function. Corticostriatal neural circuitry crucially mediates extinction learning and facilitates adaptive changes in behavior in response to changes in environmental contingencies. Moreover, corticostriatal dysfunction is heavily implicated in HIV at both the clinical and preclinical levels. Both cocaine and opioids disrupt peripheral immune function and homeostasis of corticolimbic glial cells, but no studies to date have interrogated how co-use of these drugs interact with HIV and ART to impair central and peripheral immune function. During the K99 phase of this proposal (Aims 1 & 2), I will leverage quantitative imaging and morphometric analysis of microglia and astrocytes to characterize the impact of opioid-cocaine PSU on the structural plasticity and reactivity of corticostriatal glial cells in the context of EcoHIV infection and ART. In parallel, I will also examine proinflammatory activation of peripheral lymphocytes and macrophages via flow cytometry and multiplex cytokine arrays. Transitioning to independence in the R00 phase, I will combine my training in flow cytometry and quantitative cellular imaging with my expertise in systems neuroscience to study the functional contributions of corticostriatal microglia to neurocircuit function in the context of HIV and PSU (Aim 3). This research has the potential to reveal novel, clinically-translational insights into the unique neuroimmune consequences of PSU in the context of HIV and ART treatment, which will help identify new treatment targets for comorbid HIV and PSU.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Abstract Obesity and overweight impose significant clinical and economic burdens, impacting over 64% of U.S. adults, leading to healthcare costs exceeding $170 billion annually. This project focuses on glucagon-like peptide-1 receptor agonists (GLP-1s), first approved for weight loss in 2021, a promising treatment for obesity that not only induces substantial weight loss but also improves metabolic conditions such as cardiovascular disease and diabetes. Despite their effectiveness, the high cost of GLP-1s, over $7,000 per year, has resulted in limited insurance coverage, thereby restricting patients' ability to access these potentially transformational medicines. The central objective of this research is to determine if GLP-1 therapy can offset their high costs by reducing overall healthcare spending for patients who initiate treatment. Clinical trials show the clinical benefits of GLP- 1s but have limitations, including no established link between weight loss with GLP-1s and healthcare spending and short follow-up periods that make it difficult to assess long-term outcomes. By leveraging a large national dataset, Truveta, which contains Electronic Health Records for over 100 million patients, linked with insurance claims, the study aims to provide much-needed long-term evidence on spending. We will leverage state-of-the-art matching, and real-world evidence methods to achieve three key aims: (1) evaluating long-term cost offsets and medication costs after GLP-1 initiation, (2) assessing how these costs vary across patient subgroups defined by characteristics like BMI, age, and comorbidities, and (3) estimating the GLP-1 breakeven price and the time required to achieve budget neutrality. These findings will inform insurers and policymakers, contributing to future coverage and reimbursement decisions, with significant implications for Medicare, Medicaid, and private insurers. The project directly responds to calls from the Congressional Budget Office and other key stakeholders for more research on the economic impact of GLP-1 therapies.