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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.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Abstract Multispectral fluorescence imaging enables simultaneous measurement of many molecular targets in situ, but quantitative interpretation is limited by spectral unmixing under photon-count noise. Most current pipelines, adapted from spectral remote sensing, assume Gaussian noise and continuous intensities; fluorescence mi- croscopy instead yields discrete, often overdispersed photon counts. This model–data mismatch reduces accu- racy, sensitivity to weak markers, and reproducibility. This R03 project will establish statistically principled, reproducible models for quantitative biological imaging by developing and validating a count-aware unxming framework that aligns with photon-count physics. The first aim of the project is to develop a unified, likelihood-based framework for spectral unmixing using count data dis- tribution models with structured regularization. The second aim is to validate and benchmark the framework on simulated and experimental datasets against state-of-the-art approaches, demonstrating improved signal accu- racy, localization, and biological interpretability. The expected outcome is a computationally efficient, statistically rigorous approach to count-based modeling that improves unmixing accuracy, robustness in low-photon regimes, and cross-session reproducibility. This new technology lays a robust foundation and pushes the boundaries of quantitative and reproducible spatial biology. By improving the precision and reproducibility of multispectral fluorescence imaging, this project directly supports the NIH mission to advance fundamental knowledge and develop tools that enhance biomedical research, disease diagnosis, and translational discovery.

NCI - National Cancer Institute

PROJECT ABSTRACT / SUMMARY The ribosome is a fine-tuned regulator of gene expression through multiple layers of regulation, including post- transcriptional RNA modifications. Cancer cells have “hijacked” the translation machinery to exert rapid and selective translational control of the cancer proteome in a matter that is distinct from normal cells. Changing the landscape of the hundreds of modifications in the catalytic core of the ribosome may be one of the strategies cancer cells use to reprogram their translatome. Work from our labs has been the first to demonstrate a functional link between rRNA modifications and cancer etiology. We have discovered that one of the most deregulated oncogenic signals, RAS, directly controls the expression of multiple snoRNAs, which are small non-coding RNAs that guide rRNA modifications. As a paradigm example, we have shown that one of the snoRNAs, SNORA24, plays a pivotal role in bypassing oncogene-induced senescence (OIS), a critical tumor-suppressive mechanism. We attribute this profound effect of a snoRNA on cancer progression due to its role in controlling lipid metabolism, a key feature of cancer development. This is reinforced by our findings that SNORA24 controls the translation of lipid metabolism transcripts, which is recognized as one of the hallmarks of liver cancer. We further show that additional snoRNAs driven by RAS expression are critical for cell fitness of colon cancer cells and have opposing roles on control of global protein synthesis. In cancer, the dysregulation of these modifications has been increasingly recognized as a contributor to tumor development, progression, and drug resistance. However, a systematic analysis of snoRNA function in cancer biology, the mechanistic and biochemical basis for their function as well as the breadth of these modifications for distinct human cancers is lacking. Here we will combine the expertise of our two labs as well as collaborators to (1) mechanistically dissect the biochemical and structural basis for rRNA modifications on control of cancer metabolism, (2) use state-of-the-art CRISPR screen to directly assess snoRNA function in different steps of tumorigenesis in-vivo and whether this is guided directly by rRNA modifications, as well as (3) create an atlas of all RNA modification changes in primary human prostate cancer and their impact on the cancer translatome. In addition, here we will build off of a novel technology known as Pan-Mod-Seq that can simultaneously measure all known rRNA modifications in dozens of cancer samples at the same time. We will be in a strong position to further analyze the prospective and retrospective associations of these modifications on cancer progression, metastasis and therapeutic response. Understanding the role of rRNA modifications in cancer will provide insights into disease mechanisms and open new avenues for diagnostic biomarkers and therapeutic interventions.

National Park Service

Complete the work of historians who began documenting the history of Tuskegee Institute,train Tuskegee University students and members of the community on the art and science of collecting oral history.

European Commission - HORIZON

Creative alliances: Fostering global partnerships in cultural policies and CCI innovation. Call: Culture, Creativity and Inclusive Society 2026. Programme: HORIZON. Keywords: Digitalisation/ICT and cultural heritage, International relations, Policy development, Policy making and economics, Social innovation, Social sciences, interdisciplinary, Visual arts, performing arts, design. Open call from the EU Funding & Tenders Portal.

Creative Growth, Inc

Support for a program of studio arts instruction, gallery exhibition and promotion for 152 adult artists with developmental, physical, and emotional disabilities.

Creative Saskatchewan

Creative Saskatchewan supports the province's creative industries including film, music, publishing, and visual arts through grants and market development funding.

Creative Time

Grants for public art projects that challenge social conventions and push the boundaries of art in public spaces.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Antiretroviral therapy (ART) results in suppression of Human Immunodeficiency Virus (HIV) replication, increase in CD4+ T cell count, and partial restoration of immune responses. Yet despite suppressive ART, both transcriptionally silent and transcriptionally active [i.e. cell-associated RNA (CA-RNA)] HIV viruses remain in various CD4+ T cell subsets in persons living with HIV (PLWH) and are proposed to contribute to residual immune activation, lower immune reconstitution and development of comorbidities. Much attention has been given in our field to the clinical significance of continued HIV expression after ART, but we still lack plasma host biomarkers that could illustrate the impact of CA-RNA or could link CA-RNA to future risk for comorbidities. Part of the limitation to address this gap has been that studies attempting to find a correlation between HIV reservoir levels and plasma markers of immune activation have included only a limited number host cellular or plasma variables, have not started with a pre-defined cohort with known reservoir levels, have not linked variables to predefined prognostic biomarkers, and/or have yielded inconsistent results (see background). This R21 now addresses these limitations by studying a cohort with known HIV reservoir levels and by introducing recent advances in Somalogic-based technology inclusive of (a) measuring a large set (at least 7000) of plasma proteins and (b) determining links of predefined host biomarker "signatures" to risk scores for comorbidity outcomes as shown by our preliminary data and other studies. This R21 proposal is possible as a result of the collection through the BEAT-HIV Martin Collaboratory program of plasma and peripheral blood mononuclear cells (PBMC) from 94 ART suppressed PLWH with known distribution of HIV proviral DNA measured by the Intact Provirus Assay (IPDA) which in turn is associated with CA-RNA. Specifically, we hypothesize that in PLWH on suppressive ART the levels of cell-associated HIV RNA will be associated with a) plasma host proteomic biomarkers, and b) pre-defined clinical comorbidity risk scores for cardiovascular, liver/kidney, and metabolic disease following age adjustment. We will test this hypothesis by the following specific aims: (1) identify host plasma biomarkers among 7000 protein measures that will best predict PLWH on ART with higher CA-RNA independently of age, and (2) determine if plasma clinical prognostic scores for comorbidity risks of cardiovascular, liver/kidney, and metabolic disease are higher in PLWH on ART with high CA-RNA when adjusted for age. Completion of this R21 proposal will provide foundational data to further evaluate the usage of biomarker changes in future RO1s describing strategies targeting transcriptionally active reservoirs on ART. The long-term impact of this proposal is its potential to advance cure-directed strategies targeting HIV expressing cells (i.e., immune-based, gag- pol/CARD8 activating, etc.) and to make possible early determinations in biomarker changes of significance to prognosis risk profiles upon a reduction of persistent HIV reservoirs.

OD - NIH Office of the Director

Summary The California NanoSystems Institute (CNSI) at the University of California, Los Angeles (UCLA), is committed to pioneering nanobiology and biomedical research. Central to this mission, the Electron Imaging Center for Nanosystems (EICN), established in 2007, provides cutting-edge cryogenic electron microscopy (cryoEM) instruments and specialized expertise to elucidate the mechanisms of molecular machinery at the nanometer scale. A previous NIH S10 award was pivotal in installing the world’s first operational Titan Krios in 2008, a landmark achievement that fueled the cryoEM revolution of the past decade. This instrument produced data for one of the earliest near-atomic-resolution single-particle cryoEM structures and played a critical role in Moderna’s groundbreaking mRNA vaccine development. Building on this success, a second NIH S10 award enabled the acquisition of a Titan Krios G4 in 2024, equipped with advanced technologies for both cryoEM imaging and cryogenic electron tomography (cryoET) tilt series acquisition. These state-of-the-art instruments support hundreds of registered UCLA users, facilitating atomic-level structural analysis of isolated or enriched biological complexes for a wide range of research applications. While EICN’s cryoEM and cryoET capabilities meet current user needs, the lack of a cryogenic focused ion beam (cryoFIB) instrument significantly restricts our large user base from conducting in situ structural studies within cells and tissues using cryoET. Most cells, exceeding 1 µm in thickness, are too dense for electron penetration and require precise milling into lamellae of 200 nm or less to enable high-resolution cryoEM or cryoET imaging. This application seeks funding to acquire an Aquilos 2 cryoFIB instrument, which will empower NIH-supported biomedical research across 38 user laboratories (including 26 major users) within EICN’s extensive user community. The proposed cryoFIB will substantially enhance EICN’s cellular cryoET capabilities, advancing federally funded research in critical areas such as viral and microbial infections, neurodegenerative disorders, tumorigenesis, therapeutic development, drug design, and vaccine delivery systems, as well as the PI continuous cryoEM/cryoET method development. The Aquilos 2 cryoFIB will benefit from robust institutional support, including dedicated staff, ongoing instrument maintenance, and operational resources, ensuring long-term impact and accessibility. The instrument will be managed by EICN’s highly experienced core facility team, which has successfully operated the facility for 18 years since its inception. The principal investigator, managing director, facility technician, and user coordinator possess the technical expertise and operational experience necessary to ensure the cryoFIB’s seamless integration and productive use. This high-end S10 instrument will immediately bolster NIH- funded biomedical research across UCLA’s colleges of natural sciences, engineering, and the David Geffen School of Medicine, driving transformative discoveries in structural biology and beyond.

NINDS - National Institute of Neurological Disorders and Stroke

Drosophila Neurobiology: Genes, Circuits & Behavior (2026‐2030) ABSTRACT The primary objective of the proposed three‐week course is to provide training in state‐ of‐the‐art and emerging experimental approaches to study the nervous system in one of the most successful invertebrate model organisms, Drosophila melanogaster. The course, titled “Drosophila Neurobiology: Genes, Circuits & Behavior”, is designed to introduce students at all career levels to a wide variety of research topics and techniques, including the latest approaches to study nervous system development, connectivity, and behavior. Daily research seminars present comprehensive overviews of specific subfields of nervous system anatomy and function and/or focus on specific techniques and approaches to study diverse aspects of neurobiology. The course fully leverages the conserved genetics and orthologous morphology of Drosophila to analyze neural development, neuronal physiology, and behavior, thereby emphasizing the relevance of this powerful model system to yield conceptual insights and inspire approaches to advance our understanding of human brain function and dysfunction. There will be a significant emphasis on the disruption and reorganization of neural circuits during the onset of neurological diseases or addiction. Instructors are selected based on their contributions and expertise in the field, with each instructor providing in‐depth knowledge in specific areas that complement each other. Additionally, instructors invite lecturers who have made significant contributions in their fields to provide current updates on the latest developments in research and future directions in their areas of interest. Participants are chosen by the course lead instructors from large pools of applicants and range from advanced graduate students to principal investigators. Because of the short duration of the course, participants can attend and receive intense training in an environment free from other demands on their time and attention. This neurobiology laboratory course thus offers a unique opportunity for scientists to gain expertise in an advanced invertebrate model within neuroscience and to apply the concepts and techniques to their own research interests. Importantly, participants are encouraged to disseminate what they learn in the course at their home labs and institutes. Participant feedback on course modules and instructors is collected each year and the long‐term impact of the course is assessed through tracking of alumni career trajectories. The overall effectiveness of the course is demonstrated by the fact that 64% of course alumni have gone on to lead their own research groups as professors.

NCATS - National Center for Advancing Translational Sciences

Summary The objective of this T32 proposal is to provide rigorous training in all aspects of translational research related to regenerative medicine. There is a bourgeoning need for creative, critical, and responsible transdisciplinary scientists as thought leaders and administrators who will spearhead national efforts to bring regenerative medicine into widespread clinical practice. This national need was demonstrated by Congress’s 21st Century Cures Act that established regenerative medicine as one of four national research areas in desperate need of clinical translation. This proposal integrates Boston University’s marquee programs in tissue regeneration, stem cell biology, biomedical engineering, human organoid in vitro disease modeling, gene editing, tissue repair after infectious injuries, and computational biomedicine to produce an extraordinarily rigorous and comprehensive training program in the emerging, futuristic discipline known broadly as “regenerative medicine.” This proposed funding of our already successful Regenerative Medicine Training Program (RMTP), now in its 8th year, is geared to transitioning our UM1-associated program into a formal T32 program with a clinically-focused training experience over 2 years for 6 pre-doctoral trainees at a time. Our proposed T32 RMTP incorporates mentored cross-disciplinary research, exciting courses taught by the leaders of these marquee programs, career development coaching, and additional training in critical thinking, scientific writing, oral presenting, and familiarity with the complex ethics that will face tomorrow’s national thought leaders as regenerative medicine research moves from bench to bedside. An additional goal of this T32 is training in 10 regenerative medicine-specific core competencies that also can be utilized for distribution nationally across the CTSA. These competencies will maintain rigor of training in translational science and prepare our trainees to become leaders in translational regenerative medicine research. With 27 graduates of our RMTP already trained, 19% of whom are MD/PhD dual degree trainees, our program represents a proven state-of-the-art training ground for translational scientists with 89% retention in scientific or health-related research to date. The many deliverables of this T32 RMTP will include shareable patient-specific stem cell repositories procured from at risk patient populations, sophisticated protocols that will allow any CTSA institution to prepare patient-derived organoids in vitro, and hands-on training courses or on line modules that will disseminate this expertise freely across the entire CTSA. This “open-source” approach to science is central to the mission of BU’s Center for Regenerative Medicine, the physical home of many of our T32 faculty, labs and resources.

NCATS - National Center for Advancing Translational Sciences

SUMMARY This National Research Service Award (NRSA) Institutional Research Training Grant Proposal (T32) aims to support a research year for pre-doctoral medical students with a focus on Healthcare Artificial Intelligence (AI) and Technological Innovations. The program's primary objective is to identify and train potential physician scientist leaders in the fields of AI-assisted diagnostics, clinical decision support tools, personalized medicine prognostics, and biomedical instrumentation. Our program will provide support for a dedicated research year embedded within our newly launched 3-year medical school curriculum, providing comprehensive research exposure, advanced technical skill development and career training within 4 years of training. This initiative is the first institutional training program aimed at supporting dedicated research time for medical students and the first focused on this rapidly evolving discipline. This T32 program capitalizes on NYU Langone Health's strengths in foundational AI research, clinical decision support implementation, healthcare innovation, and implementation science. These strengths are complemented by indispensable support from our Clinical and Translational Science Institute (CTSI), educational partners within NYU Grossman School of Medicine and Vilcek Institute of Graduate Biomedical Sciences, and our faculty’s world renowned clinical and research expertise. Our program will provide trainees with the skills needed to lead and execute research projects using state-of-the-art approaches; training in relevant technical skills in computation, statistics and biotechnology; and career support to ensure their future success. The training program will also equip trainees with data literacy, multidisciplinary communication skills, a systems-based approach to research and clinical practice, and a deep understanding of the considerations required when developing novel healthcare technologies. We see the greater impact of this as being two-fold. First, this training grant will foster a new category of physicians who are not only experts in their clinical specialty but also pioneers in translational AI research and innovations. In the wake of the ongoing AI revolution, it is imperative for physicians to comprehend and contribute to the ever-growing role of predictive and large language models in the context of disease prevention and improved patient outcomes. Secondly, our T32 will help to address the continuing shortage of physicians participating in biomedical research, particularly in this burgeoning field. By providing dedicated research time for medical students without requiring a PhD-level commitment, the program aims to lower the barriers of entry and increase research competence across a larger cohort of trainees. In conclusion, this T32 program is poised to create a new generation of AI and technologically literate physician researchers and by integrating this program with existing CTSI training programs and research initiatives, we will create a unique educational platform that will ensure our scholars are future leaders in translational medicine and healthcare.

National Park Service

Researching, planning, documenting and producing interpretive programming for the public in the traditional cultural arts as mandated in park legislation and Comprehensive Interpretive Plans.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Sjögren’s disease (SjD) is a systemic autoimmune disease in which destructive lymphocytic infiltration of the salivary (SG) and lacrimal glands leads to chronic dry eyes and mouth. It is one of the most common autoimmune diseases and causes significant disease morbidity but lacks approved disease modifying therapy. A hallmark histologic feature of SjD is dense immune infiltrate of the SG called focal lymphocytic sialadenitis (FLS). The CXCR3 chemokine signaling is an essential system for recruiting T cells to tissues and regulating their behavior. We and others show increased expression of the CXCR3 ligands, CXCL9 and CXLC10, in the SG in SjD, primarily in fibroblasts, endothelial cells, and antigen presenting cells. In this proposal, we will examine the mechanisms by which CXCR3 signaling controls the recruitment, maintenance, and activation of T cells in the SG. We hypothesize that CXCL9 and CXCL10 production by different cell types within the SG plays distinct roles in the formation and maintenance of FLS. The proposal will focus on understanding 1) which cells express CXCL9 an CXCL10 through the course of disease and 2) how different cellular sources of CXCL9 and CXCL10 influence T cell behavior and phenotype in the SG. We will perform complementary studies of human SG biopsies and mouse models of SjD to make mechanistic insights into disease-relevant immunopathogenesis. Dr. Yockey will perform the work in this K08 proposal in the Center for Immunology and Inflammatory diseases (CIID) at the Massachusetts General Hospital (MGH) under the mentorship of Dr. Andrew Luster, an expert in chemokine signaling, and Dr. Cory Perugino, an expert in human immunology. The CIID is a state-of-the-art multidisciplinary research center focused on investigating the mechanisms of immune-mediated inflammatory diseases. Dr. Yockey has developed a career development plan with four objectives to acquire: 1) Skills in tissue imaging and spatial transcriptomics, 2) Expertise in human T cell biology, 3) Knowledge of chemokine signaling and stroma-immune interactions, 4) Proficiency in histologic assessment of the salivary gland. Dr. Yockey has assembled a Training Advisory Committee and team of collaborators with unmatched and complementary expertise in key areas including SjD biology and computational biology. By completing these research and training plans, Dr Yockey will establish the intellectual and technical skills necessary to become an independent investigator. Importantly, she will develop expertise to conduct parallel studies using mouse models and patient samples to be able to ask human- relevant, fundamental questions about autoimmunity pathogenesis. She plans to use these important skills to spend the rest of her career advancing the care of patients with SjD and other autoimmune diseases by deciphering mechanisms of immune-mediated tissue damage.

U.S. National Science Foundation

The Nation s advanced research cyberinfrastructure (CI) ecosystem catalyzes discovery and innovation across all areas of science and engineering (S&amp;E) research and education. The increasingly complex and rapidly evolving S&amp;E landscape requires an agile, integrated, robust, trustworthy, and sustainable CI ecosystem that will drive new thinking and transformative discoveries in all areas of research and education. The success of this vision depends on the ability of the research community to be able to easily and effectively access and use state-of-the-art research CI resources and services in a timely way. This, in turn, drives a set of requirements on the development, operation, and evolution of the CI ecosystem. First, research CI resources and services must be designed to leverage and drive innovations, and they must be user-centric and interoperable to enable the efficient, flexible end-to-end discovery pathways that are increasingly essential for the conduct of research. Second, the information, expertise, and services needed to maximally utilize the CI ecosystem must be disseminated broadly and concertedly to the research community. The NSF Cyberinfrastructure Centers of Excellence (CI CoE) Program aims to realize the above vision by supporting hubs of expertise and innovation targeting specific areas, aspects, or stakeholder communities of the research CI ecosystem. Supported CI CoEs provide expertise and services related to CI technologies and solutions; gather, develop, and communicate community best practices; and serve as readily-available resources for both the research community and the CI community. A key objective of this program is to support CI CoEs that drive advancements in and positively impact the CI ecosystem through structured but strongly community-engaging and community-serving approaches.Overall, CI CoEs are a means of concentrating resources on a specific area of identified need in support of the broader goal of advancing capabilities and performance of the national CI ecosystem [1]. Activities. Successful CI CoE projects will perform a range of functions such as: Exploring emerging technologies, disruptions, opportunities, and community needs, and developing proactive design and adoption strategies, practices, and other approaches in response; Nurturing communities of stakeholders and experts in their area(s) of focus (foci) with the overall goal of achieving self-sustaining communities of practice; and Providing services, training, and outreach to target communities. Topics and Pathways. NSF anticipates creating such CI CoEs in response to specific needs and gaps. NSF anticipates issuing Dear Colleague Letters to indicate interest in pilot CI CoE proposals on particular focus areas. NSF may initially invest in two-year pilot CI CoE projects which aim to develop concepts and plans and demonstrate feasibility through pilot activities as preparatory precursors to eventual proposals for establishing full-scale CI CoEs. The level of support for pilot CI CoE projects is expected to vary, based on the topic and range of activities proposed. Lifecycle and expected endpoint. CI CoEs are typically expected to operate for five years and may be renewed, subject to the outcome of performance reviews, NSF prioritization, continuing demonstrated need for the CI CoE, and availability of funds, consistent with NSF merit review principles. Guidance to proposers. Individuals interested in submitting a proposal for a CI CoE project are strongly encouraged to discuss their project idea with the cognizant CI CoE Program Director(s) in the relevant areas prior to submission. Additional guidance may be provided in Dear Colleague Letters issued to announce interest in pilot CI CoE proposals on particular focus areas. [1] An example is the NSF Cybersecurity Center of Excellence, Trusted CI, https://trustedci.org.