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Community Foundation of Southeastern Connecticut

Community Foundation of Southeastern Connecticut ($100M in assets) supports nonprofits in CT through grants focused on education, community development, health, arts. Awards range from $1,000 to $30,000.

Community Foundation of Southern Wisconsin

Community Foundation of Southern Wisconsin ($200M in assets) supports nonprofits in WI through grants focused on education, community development, arts, health. Awards range from $1,000 to $50,000.

Community Foundation of St. Joseph County

Community Foundation of St. Joseph County ($200M in assets) supports nonprofits in IN through grants focused on education, community development, health, arts. Awards range from $1,000 to $50,000.

Community Foundation of Tampa Bay

Community Foundation of Tampa Bay ($500M in assets) supports nonprofits in FL through grants focused on education, health, arts, community development. Awards range from $2,500 to $150,000.

Community Foundation of the Dan River Region

Community Foundation of the Dan River Region ($50M in assets) supports nonprofits in VA through grants focused on education, community development, health, arts. Awards range from $1,000 to $25,000.

Community Foundation of the Fox River Valley

Community Foundation of the Fox River Valley ($100M in assets) supports nonprofits in IL through grants focused on education, community development, health, arts. Awards range from $1,000 to $25,000.

Community Foundation of the Lowcountry

Community Foundation of the Lowcountry ($150M in assets) supports nonprofits in SC through grants focused on education, community development, health, arts. Awards range from $1,000 to $50,000.

Community Foundation of the Ozarks

Community Foundation of the Ozarks ($500M in assets) supports nonprofits in MO through grants focused on education, community development, health, arts. Awards range from $1,000 to $75,000.

Community Foundation of the Ozarks

Community Foundation of the Ozarks ($500M in assets) supports nonprofits in AR through grants focused on education, community development, health, arts. Awards range from $2,000 to $100,000.

Community Foundation of Tompkins County

Community Foundation of Tompkins County ($50M in assets) supports nonprofits in NY through grants focused on education, environment, arts, community development. Awards range from $1,000 to $25,000.

Community Foundation of Utah

Community Foundation of Utah ($250M in assets) supports nonprofits in UT through grants focused on education, community development, health, arts. Awards range from $1,000 to $75,000.

Community Foundation of Western Massachusetts

Community Foundation of Western Massachusetts ($200M in assets) supports nonprofits in MA through grants focused on education, community development, health, arts. Awards range from $2,000 to $75,000.

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.

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.

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.

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.

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>