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National Institute of Diabetes and Digestive and Kidney Diseases

Pilot and Feasibility Program

PILOT AND FEASIBILITY PROGRAM: PROJECT SUMMARY The goal of the Cedars-Sinai Digestive Diseases Research Center (CSDDRC) Pilot and Feasibility (P&F) Program is to provide monetary support, expertise, and technical support to advance innovative basic, translational, and clinical research that matches the overall goal and themes of the Center. The central theme of the CSDDRC is mechanisms and measurements of the fibroinflammatory response in gastrointestinal (GI) tissues, which reflects Center members’ research in three subthemes: 1) Gut Microbiome, 2) Gastrointestinal (GI) and Liver Metabolism, and 3) GI and Liver Injury. The mission of CSDDRC P&F Program is to support new investigators, established investigators who are new to digestive and liver disease research, and established digestive and liver disease investigators who want to start new or collaborative research that promises to lead to a paradigm shift in the digestive diseases field. In partnership with the Enrichment Program, we will provide guidance for P&F awardees in the form of mentorship and collaboration opportunities. The CSDDRC Biomedical Research Cores will also support P&F awardees, facilitating rapid progress of their new and collaborative digestive and liver disease research. The P&F Program’s outcome measures will include the number of high-impact research publications, grant applications, and subsequent extramural funding for P&F awardees. We will accomplish our goals through the following three specific aims. Aim 1 will solicit research proposals from P&F candidates whose proposed research aligns with the central theme and the subthemes of the CSDDRC. We will advertise P&F support widely across campuses, in addition to contacting department/institute directors to solicit their recommendations for promising young and established investigators who are interested in working in digestive and liver diseases. Aim 2 will select pilot project applications that meet CSDDRC P&F Program goals using rigorous review criteria. Each year, the P&F Program will select four pilot projects to be funded by the P30 grant and matched by institutional support. Submitted applications will be peer- reviewed and preliminarily scored based on the NIH review format by three local expert reviewers. Subsequently, after oral presentations by the P&F applicants, the External Advisory Board (EAB) members will undertake a second round of review, scoring, and discussion at the P&F Program Review meeting following the CSDDRC Annual Symposium. Funding decisions will be made during the P&F Program Review meeting. Aim 3 will assist P&F project investigators with career development and obtaining extramural funding for digestive disease research. P&F awardees will benefit from the Enrichment Program’s well-organized mentoring structure, led by experienced members of the CSDDRC, which includes the Grants-in-Progress Mentoring Program, Gastrointestinal Research-in-Progress meetings, and grant application workshops. P&F awardees will also be mentored through direct interactions with P&F Program Directors, Core Directors, members of the Internal Advisory Board and EAB, and individual or collaborative mentor teams.

National Institute of Allergy and Infectious Diseases

Borrelia burgdorferi genotypic diversity, pathogenesis, and host cellular responses

PROJECT SUMMARY Lyme disease is the most common tick-borne illness in the United States, with an estimated 476,000 cases annually, and Pennsylvania (PA) consistently reports one of the highest case numbers nationwide. Borrelia burgdorferi sensu stricto (Bb) is a causative agent of Lyme disease in the US and is transmitted by Ixodes spp. ticks. Bb produces various outer surface proteins (Osp) and other mechanisms to survive in vectors, evade host immune systems, and to propagate infection within a host. Over 35 OspC genotypes have been characterized, which fluctuate in abundance in natural vector and host populations, suggesting host adaptation. While many Lyme-infected patients recover following antibiotic treatment, some may experience neurological symptoms, Lyme neuroborreliosis (LNB), which may be associated with specific genotypes. While previous studies focused on clinical manifestations, pathogenicity, genetic variations, and host immune responses using mouse models or patient samples, the genotype-specific immune responses that contribute to disease progression in humans remain poorly understood. Our central hypothesis is that certain Bb OspC genotypes, maintained in natural populations, are associated with distinct host immune responses that influence disease severity, progression, and persistence. Aim 1 will define the dynamics of OspC genotypes in tick and small mammal populations over time in Western PA to establish a 16-year longitudinal tick study and an 8-year longitudinal small mammal study. Using deep amplicon sequencing, we will quantify genotype diversity, detect low-abundance genotypes, and identify potential host-adapted genotypes. These empirical data will inform a compartmental mathematical model to evaluate OspC genotype prevalence, distribution, and public health risks, including LNB, across space and time. Aim 2 will assess how distinct Bb OspC genotypes affect the host immune landscape and cellular responses using human samples. To determine how Bb genotype contributes to disease phenotype, we will perform immune profiling studies which will include microscopy-based assessment of infected cell cultures, flow cytometric analysis of immune cell phenotypes, and measurement of genotype-specific cytokine, chemokine, and antigen production (sub-Aim2a). We will also employ multi-omics approaches that integrate single cell RNA sequencing with antibody-based protein profiling (scRNA-seq/Ab-seq) to characterize transcriptional and functional changes in immune cell populations exposed to different Bb genotypes (sub-Aim2b). This work is innovative in its integration of long-term ecological data with advanced immune profiling and single cell multi- omics to uncover genotype-specific mechanisms of Bb pathogenicity and human immune response—an approach not previously applied in Lyme disease research. These studies will clarify how specific genotypes influence immune responses and disease severity. Together, the proposed aims will identify critical genetic and immunological mechanisms that drive Bb pathogenicity and human susceptibility, informing the development of improved diagnostics, targeted therapies, and public health interventions to reduce the burden of Lyme disease.

National Heart Lung and Blood Institute

Cardiorespiratory and autonomic impacts of coolants in e-cigarette aerosols

PROJECT SUMMARY / ABSTRACT Coolants such as menthol, WS-3, and WS-23 are widely used in electronic cigarettes (e-cigs) to reduce irritation and enhance appeal—especially among youth. Despite their prevalence, the cardiopulmonary toxicity of these agents remains poorly characterized. Recent work shows that e-cig aerosols can disrupt autonomic nervous system regulation and cardiac electrophysiology, increasing catecholamine release, enhancing sympathetic regulation of cardiac rhythm, and provoking arrhythmias. Proof is also mounting that nicotine’s sympathomimetic traits mediate these pathogenic effects. Preliminary data from our laboratory show that coolants increase systemic nicotine levels, blunt respiratory reflexes, and potentiate arrhythmias upon exposures to e-cigarette aerosols, suggesting a paradoxical role for coolants in suppressing ventilatory responses while intensifying cardiovascular risk. These findings take on added significance in light of recent case reports of sudden cardiac arrest in young e-cigarette users, including some in otherwise healthy individuals. This project will elucidate how e-cigarette coolants alter exposure to harmful and potentially harmful constituents (HPHCs)—particularly nicotine and aldehydes—concurrent with their effects on cardiovascular and respiratory physiology. Using robust murine models with continuous ECG, blood pressure, and pleural pressure telemetry, we will assess how coolants alter the acute and chronic effects of e-cigarette aerosols on cardiac electrophysiology, autonomic tone, ventilatory function, hemodynamics, and toxicant exposure. We will also evaluate how coolant concentration and device power modulate these effects. In parallel, we will determine whether adolescent mice exhibit heightened susceptibility to these effects compared to adults, with attention to sex differences and the persistence of cardiotoxicity after exposure cessation. This comprehensive, multi-modal approach incorporates novel protocols for arrhythmia inducibility, high-resolution physiologic monitoring, and complementary analyses of biomarkers of exposure and effect. By clarifying how coolants interact with HPHCs—especially nicotine and aldehydes—to drive cardiopulmonary injury across age and sex, this work addresses high-priority research areas identified in RFA-OD-25-001, including the toxicological evaluation of e-cigarette constituents and their cardiopulmonary effects. The results will inform regulatory policy and public health strategies aimed at mitigating cardiovascular risk associated with e-cigarette use, particularly among vulnerable youth.

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Baby Toolbox Training and Certification Program

PROJECT SUMMARY Our objective is to improve early childhood outcomes and support the expansion of the NIH Infant and Toddler Toolbox (Baby Toolbox) by providing comprehensive training support to those interested in using it. The Baby Toolbox is a brand new, nationally-normed assessment for infants 1-42 months, commissioned by NICHD and released for public use in 2025. The Baby Toolbox is administered entirely on an iPad and includes 35 measures across six domains using novel technology (e.g., gaze tracking, automatic scoring, computerized adaptive testing). It has the potential to bring harmonization to the developmental fields, but in order for it to become a common currency for developmental research as envisioned, researchers need to know how to administer it and how to train others to administer it. We propose an education program that will include a week-long training workshop, certification activities, and post-workshop support to create expert cohorts of Baby Toolbox test administrators. Individuals who attend the workshops can become certified test trainers, capable of training others at their home institutions to administer the assessment thus creating a self-sufficient training model. Through the proposed educational program, we will provide funding to cover lodging, meals, and incidentals during the workshop, in addition to subsidizing transportation to/from the workshop and provide a one-year subscription to the Baby Toolbox. A portion of slots will also be set aside for those without current grant funding. Our team is highly qualified to complete these tasks because we have led the effort to develop the Baby Toolbox assessment and have already completed multiple training workshops for contract deliverables. This grant would continue the efforts started by the NICHD in funding the Baby Toolbox by helping support its rollout, implementation, and growth. To meet these goals, we have the following aims: Aim 1: Create cohorts of trained Baby Toolbox examiners who can catapult the Baby Toolbox into widespread use by hosting a comprehensive week-long education program (training workshop) yearly for individuals to learn how to administer and train others to administer the Baby Toolbox, Aim 2: Expand the use of the Baby Toolbox by recruiting and financially supporting individuals who will bring the Baby Toolbox into a variety of research and clinical settings. Aim 3: Build a virtual training resource of videos and materials to support ongoing fidelity checks with certified trainers, and future training efforts.

National Institute of Allergy and Infectious Diseases

Antibody-guided design of a human astrovirus vaccine

PROJECT SUMMARY Viral diarrheal diseases cause substantial global morbidity and mortality. Diarrheal disease is the second leading cause of childhood mortality in the world, accounting for over 10% of all deaths of children under 5 years old. Gobally, over 1 billion cases of diarrheal diseases occur every year, making prevention of these diseases a public health concern of the highest priority. Human astrovirus (HAstV) infection is a leading cause of viral diarrhea in children and has been shown to cause chronic gastrointestinal disease and fatal neurological disease in immunocompromised patients. There are nearly 4 million cases of HAstV infection each year in the United States alone, and there are no clinically approved HAstV-specific vaccines or therapeutics. Antibody-guided vaccine development leverages a deep understanding of productive antiviral antibody responses in order to design vaccine immunogens that deliberately focus the induced response toward highly conserved epitopes with the goal of reliably inducing broad, durable immunity. Using a cutting-edge monoclonal antibody (mAb) discovery approach based on next-generation antigen barcoding, single cell multi-omics, and sophisticated bioinformatics, we will exhaustively screen the HAstV- specific antibody repertoires of geographically distinct donor cohorts to uncover the structural and immunogenetic features that differentiate broad and potently neutralizing HAstV mAbs. A more complete understanding of these exceptional – and potentially very rare – mAbs will accelerate the development of HAstV vaccines and therapeutics. We have assembled a collaborative, multidisciplinary group of investigators with a long history of productive collaboration and with highly complementary areas of expertise. We expect our work will result in the discovery of thousands of novel anti-HAstV mAbs from cohorts of healthy adult and pediatric participants. Detailed genetic, functional, and structural characterization of these mAbs will reveal conserved sites of viral vulnerability, uncover the precise molecular mechanisms of viral neutralization, and inform our development of a broadly protective HAstV vaccine.

National Institute of Allergy and Infectious Diseases

Research on End-user Acceptability.and Long-term Impacts of HIV Cure Strategies (REALISE)

ABSTRACT Despite remarkable advances in HIV cure science, emerging cure candidates will likely involve trade-offs (e.g., incomplete eradication, monitoring burdens) and must compete with increasingly convenient long-acting ART; without early implementation guidance, even efficacious products may see limited uptake, particularly among the ~30–40% of people with HIV (PWH) in the U.S. who are not durably suppressed. We propose REALISE, a multidisciplinary program to define plausible cure profiles, quantify end-user preferences, and project population-level impact to inform product design and policy before market entry. Aim 1 conducts qualitative interviews with ~30 researchers and developers to delineate credible 10–20-year cure and long-acting treatment scenarios (eradication vs functional control, safety, monitoring, durability), yielding bounded “target product profiles.” Aim 2 elicits patient-centered preferences through a two-stage study: formative interviews (n=60; ≥50% not virally suppressed) to identify salient attributes; best-worst scaling (n=360 across Missouri, Georgia, and San Francisco) to prioritize attributes; and a discrete choice experiment (n=360) to quantify trade-offs versus alternative therapies, with latent class analysis to identify preference segments and estimate potential reach. Aim 3 integrates preference-based uptake from Aim 2 with Aim 1 efficacy and cost inputs in a mathematical model to estimate health impact, QALYs, net QALYs, and incremental cost-effectiveness across heterogeneous populations and Ending the HIV Epidemic jurisdictions. Innovation lies in linking cure R&D horizons to end-user preferences and transmission-dynamic outcomes, an approach that anticipates real-world use rather than retrofitting after approval. Deliverables include ranked cure attributes for product optimization, uptake projections including among unsuppressed PWH, and jurisdiction-specific value assessments to guide public health investment. By aligning cure design with what patients will accept and systems can sustain, REALISE will accelerate effective deployment of future cure strategies and maximize their contribution to Ending the HIV Epidemic. In doing so, this study advances NIH's priorities by connecting implementation science with prevention, treatment, and cure research. Using a multidisciplinary strategy to refine and extend `target product profiles,' REALISE will ensure cure development reflects patient needs and accelerate translation into real-world benefit.

National Institute of Allergy and Infectious Diseases

Linear diribonucleotides regulation of bacterial physiology and infections

RNA degradation was thought to proceed through endonucleolytic fragmentation, followed by exo- ribonuclease trimming which generate short RNA fragments that are turned over into mononucleotides by oligoribonuclease (Orn). In the last funding period, we published data supporting that only specific enzymes (Orn, NrnA, NrnB, and NrnC) cleave diribonucleotides into monoribonucleotides, and that prokaryotic organisms need to encode at least one diribonuclease to fulfill this specific function. These results support a new perspective on RNA degradation in which the short oligoribonucleotides are processed through a sequence of discrete steps involving distinct enzymes. In addition, linear diribonucleotides appear to be biologically active molecules since we reported that mutants lacking these enzymes accumulate diribonucleotides and have altered cell growth, biofilm formation, motility, and sporulation. Here we present additional preliminary data supporting diribonucleotides as active signaling molecules in the cell including: 1. Specific enzymes act trinucleases to generate diribonucleotides, 2. RNase AM of Pseudomonas aeruginosa ∆orn is a cryptic diribonuclease, 3. Two enzymes in central metabolism are diribonucleotide- binding proteins, and 4. P. aeruginosa ∆orn has virulence defects in an animal model of catheter-associated urinary tract infection. Our past publications and preliminary data provide the scientific premise for our hypothesis that cells generate linear dinucleotides from RNA degradation and linearization of cyclic dinucleotides, which can bind target proteins to alter cell physiology and pathogenesis. To test these aims, we will perform the following specific aims: In Aim 1, we will characterize the generation and degradation of diribonucleotides by characterizing how diribonucleases and triribonucleases bind their respective substrates through molecular biology, biochemistry, and computational docking. In Aim 2, we will identify effects of dinucleotides on bacterial metabolism and physiology by characterizing the binding proteins that specifically interact with linear diribonucleotides. Building on our success of identifying cellular diribonucleotide receptors, we will screen for additional proteins from open reading libraries of P. aeruginosa and Bacillus anthracis. We will exploit the strains available to us that lack all diguanylate cyclases to reveal whether the effect of linear diribonucleotides is independent of c-di-GMP signaling. In Aim 3, we will characterize the effect of expression levels of dinucleases and the effect of dinucleotide accumulation on bacterial physiology and pathogenesis. We will develop mass spectrometry methods to detect di- and triribonucleotides. We will employ existing mutants lacking diribonucleases, including P. aeruginosa ∆orn to study the defects in chronic infection in a murine model of catheter-associated urinary tract infection. Results from these studies will advance our understanding of RNA degradation and open a new area of signaling by linear diribonucleotides with the potential to be applied to novel antibacterial strategies.

National Institute of Allergy and Infectious Diseases

Mentoring investigators in patient-oriented research on HIV and public health

PROJECT SUMMARY/ABSTRACT Despite marked progress in treatment and prevention, HIV remains a significant public health threat in the US and globally. Innovative strategies are needed to effectively deploy interventions and reduce HIV incidence, which requires a sustained and committed workforce. Dr. Dennis is an infectious disease physician and researcher at the University of North Carolina (UNC) at Chapel Hill, Division of Infectious Diseases. She seeks the protected time of the K24 award to ensure adequate time and effort to provide mentorship in patient- oriented HIV research focused on applied public health strategies. Dr. Dennis has a track record of performing high-quality patient-oriented research supported by independent funding. Her research bridges basic, clinical, and epidemiologic science by using HIV-1 molecular epidemiology and phylogenetics to understand HIV transmission at the population level and to use this information to direct prevention. She has expanded this work to optimize strategies to detect and respond to HIV networks using mixed-methods approaches. The overall goal of this work is to uncover the links between these sub-epidemics - which are overlapping sub- epidemics defined by risk groups, geography, social interaction - to facilitate the design of timely, effective interventions. The research specific aims are 1) Investigate HIV transmission networks using molecular epidemiology and phylodynamics (R01AI135970), 2) Evaluate uptake of HIV treatment and prevention services in public health with social network approaches (supported by R01AI169602), and 3) Pilot a network-based characterization of early syphilis infections to inform strategies to increase the uptake of injectable antiretrovirals for HIV treatment and prevention (supported by K24). With the support of the K24, she will leverage resources at UNC to support mentorship and professional development to strengthen new directions (implementation science, community-engaged research). Dr. Dennis is deeply committed to expanding her mentorship and dedicated to fostering diverse mentees with lived experiences that are critical for sustaining the HIV workforce. Dr. Dennis is Co-Director of the UNC Center for AIDS Research (CFAR) Scientific Working Group which focuses on Ending the HIV Epidemic efforts in North and South Carolina. She has strong institutional support and a multidisciplinary team of advisors, including the UNC CFAR, and is an advisor on the UNC T32 HIV/STI institutional training program. She has collaborated for the past 10 years with NC Division of Public Health and with multiple investigators and trainees at the UNC Gillings School of Public Health. She is active in the UNC Infectious Diseases Fellowship program, providing clinical and research mentorship to numerous ID fellows. Her clinical activity provides practical grounding and relevance in patient-oriented research. The K24 will provide 50% of Dr. Dennis’ salary and additional funds to support mentees’ research. The proposed research is timely and aligned with the National HIV/AIDS Strategy and will support the protected time needed to mentor the next-generation of investigators in HIV patient-oriented research.

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Factors Driving Wear and Implant Failure in Total Shoulder Arthroplasty

Apr 30, 2031

Polyethylene (PE) wear and implant-related failure remain leading causes of revision in total shoulder arthroplasty (TSA), a procedure which now surpasses the growth rate of hip and knee arthroplasty. Both anatomic (aTSA) and reverse (rTSA) TSA outcomes are heavily influenced by complex interactions between rotator cuff function, scapular motion, implant design, and patient-specific loading—factors not adequately captured in current preclinical implant testing standards. Emerging evidence suggests that PE wear progression in TSA is highly dependent on shoulder kinematics, joint loading, implant positioning, and individual patient factors. Nonetheless, data on in vivo motion and load profiles remain sparse, and few tools exist to link these profiles to clinically relevant wear patterns or associated periprosthetic inflammatory tissue responses. Accordingly, the primary objective of this project is to develop validated, patient-specific models that predict PE wear in TSA and identify modifiable surgical, design, and rehabilitation targets to improve implant longevity and restore patient mobility. Additionally, we will establish histopathological hallmarks that indicate TSA failure caused by PE wear debris. Our central hypothesis is that specific shoulder kinematics and joint loading drive distinct PE wear patterns in TSA associated with mechanical failure or inflammatory-mediated osteolysis, depending on implant design and positioning. To achieve the overall objective of this work, shoulder motions and muscle excitations across 25 activities of daily living will be collected at pre-op and post-op (>6 months) in both aTSA and rTSA patients, with long-term follow-up of patient-reported outcomes via validated surveys (5 years). Unsupervised machine learning will categorize patients into movement-based phenotypes, which will then inform a multi-scale modeling framework to estimate in vivo shoulder joint loads and implant wear across the varying movement strategies. Predicted wear patterns will be validated using state-of-the-art preclinical wear simulators. Simultaneously, we will quantify how patient, surgical, and implant factors contribute to wear in retrieved TSA components (>400 samples), correlating imaging-based wear patterns with clinical outcomes, patient-reported function, inflammatory tissue responses, and radiographic indications of loosening. For that purpose, we will establish benchmarks of TSA wear rates and introduce a new histopathological approach augmented by infrared spectroscopic imaging. This work is innovative because we are linking patient-specific movement patterns following TSA with multi-scale computational models to predict PE wear, breaking the current approaches of using generic motions and loads in existing testing standards. This work will produce the first integrated, publicly available database of TSA kinematics, joint loading, and PE wear patterns and rates, along with validated computational tools to inform implant design, surgical planning, rehabilitation strategies, and personalized risk assessment. Ultimately, these advances will improve functional outcomes and long-term success for TSA patients and enable better preclinical testing methods and standards.

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Maternal Depression and Antidepressant Effects on Fetal Brain Structure and Function (FABMOMS)

Feb 28, 2031

PROJECT ABSTRACT Major depressive disorder (MDD) is one of the most common diseases in childbearing women, with a prevalence of 12.7% in pregnancy and 21.9% the year after birth. Exposure to maternal stress and depressive symptoms alters fetal/infant neurodevelopment, functional brain connectivity, and networks implicated in stress processing. About 5% of pregnant women are prescribed a serotonin selective or serotonin norepinephrine reuptake inhibitor (collectively, SRI). Remission of maternal MDD is crucial to the health and functioning of the mother and family. In observational studies typical of this field, differentiating the effects of drug exposure on offspring from the sequelae of the underlying psychiatric disease, both physiological and psychosocial, is challenging. Substantial progress has been made using sophisticated study designs and analytic approaches with large pregnancy cohorts that reduce the risk of spurious associations. Increased rates of overall and cardiac defects, stillbirth, preterm birth, and fetal growth have been largely explained by confounding by factors associated with both MDD and these outcomes rather than SRI exposure. Assessing the neurobehavioral development of children exposed in utero to SRI is the current research priority in this field. Our team pioneered the development of novel and safe fetal and neonatal quantitative magnetic resonance imaging (qMRI) tools, which will be combined with an evaluation of maternal heart rate variability to explore associations between exposures to stress, psychiatric symptoms and SRI on fetal and neonatal brain structure and function. The overarching goal of this project is to evaluate the separate and interactive effects of exposure to antidepressants in utero and maternal MDD on fetal and infant brain structure and function, with a specific focus on the hippocampus. We will accomplish this by evaluating four groups of pregnant women who have: 1) MDD treated with SRI to remission), 2) MDD treated with SRI (non-remitted, with both depressive symptom and SRI exposure), 3) MDD untreated with antidepressants, and 4) no current MDD or SRI treatment. Maternal assessments will occur at intake and in the early third trimesters and in then newborn period (at the time of fetal/newborn MRI) after birth. Maternal and infant evaluations will continue at 6 and 12 months postpartum. Maternal psychosocial and psychiatric status will provide extensive data on the context in which mothers experience pregnancy and infant care and allow adjustment for factors that will inevitably differ across groups. Lastly, we will explore the effects of maternal choline on MDD and offspring brain development. As these exposures and neurodevelopmental studies are conducted, exploring primary preventive strategies is a public health imperative. We will explore a potential mediator, poor maternal choline intake, a modifiable risk factor for both maternal MDD and altered fetal hippocampal growth and infant neurobehavior.

National Institute of Neurological Disorders and Stroke

Improving Disease-Modifying Therapy Uptake among Patients with Multiple Sclerosis

May 31, 2030

Project Summary/Abstract Recent advances in the epidemiology of multiple sclerosis (MS) indicate that its prevalence is similar among White (238 per 100,000) and Black (226 per 100,000) populations. These data challenge historic assumptions about individuals with northern European heritage having higher risk and prevalence of MS. Evidence also suggests that MS incidence may be higher than previously recognized in the United States and increasing over time with more individuals identified and diagnosed year over year. MS continues to impose significant and growing burden on patients, healthcare systems and society. These health differences in the diagnosis, treatment and symptom management of MS in light of the increasing prevalence of MS in the US are an important public health issue that requires broader urgent research and policy attention to reduce the overall disease burden. In this study, we will use real-world data derived from the electronic health records (EHR) from four large academic medical centers (University of Kentucky, University of Virginia, Virginia Commonwealth University, and University of Southern California). Extracted EHR data from these four medical centers will be deidentified, combined, and harmonized. We will use this combined data set to examine (1) whether there are any differences in the timely treatment of disease modifying therapy (DMT) among different MS populations, (2) any disparities in the management of symptoms and comorbidities, (3) how non-medical factors of health such as income, education, and health insurance status (patientlevel), linguistically appropriate care provision (provider-level), and neighborhood factors (system-level) affect these outcomes and influence disparities across populations, and (4) assess whether disparities exist in the risks of cardiovascular disease CVD and mortality in MS subgroups and examine if these disparities can be reduced with improved treatment of MS and vascular comorbidities. In pursuing these objectives, we will identify clinical solutions (e.g., optimal DMT sequences) and non-medical factors such as neighborhood factors such as poverty, educational achievement, crime rates, civic participation, and housing quality, access to care factors, and cultural and linguistic match between providers and patients that substantially contribute to health disparities. For actionable solutions, we will rank-order these factors by their relative importance in addressing disparities, which will guide decision-making at the policy, system, and provider level. Our long-term objective is to develop public health strategies and scalable solutions to reduce overall burden in the management of MS. This project is expected to help policy makers and health system administrators in prioritizing interventions and to have implications for clinical practice in improving care of all patients with MS in neurology clinics, at the healthcare system level, and for national health policy.

National Institute of Diabetes and Digestive and Kidney Diseases

Effects of Apolipoprotein A4 on Lipid Metabolism via Sympathetic Regulation

May 31, 2029

Obesity increases the risks and progression of hypertriglyceridemia, metabolic dysfunction- associated steatotic liver disease (MASLD), and cardiovascular diseases. Previous studies demonstrate that a single injection of apolipoprotein A4 (APOA4) elevates sympathetic neural activity and fatty acid β-oxidation in adipose tissues; and consistent infusion of APOA4 in obese mice fed a high-fat diet lowers fat mass, reduces hypertriglyceridemia, elevates brown adipose tissue thermogenesis, and attenuates steatosis and enhances sympathetic neural activity in the liver. This project hypothesizes that APOA4 reduces hypertriglyceridemia by regulating lipid metabolism through sympathetic stimulation in adipose tissues (Specific Aim 1) and sympathetic action in the liver (Specific Aim 2). The role of sympathetic action via the neurotransmitter norepinephrine and adrenergic receptor-mediated pathways will be investigated, and their necessity in APOA4-mediated lipid metabolism will be tested. A strength of this project is the interdisciplinary collaboration between investigators with established successful collaboration and publications. The project will provide physiological, molecular, and neurochemical mechanisms underlying how APOA4 differentially regulates metabolism through sympathetic activation in various types of adipose tissues and the liver in male and female obese mice. Findings would provide impetus to develop unique, novel, targeted therapeutic applications against hypertriglyceridemia and MASLD. Importantly, this project will expose undergraduates and graduate students to meritorious research, provide students with hands-on biomedical research experience, and strengthen research environment at R15 eligible institutions.

NIH Office of the Director

SUPPORT SERVICES FOR THE PREVENTION AND TREATMENT THROUGH A COMPREHENSIVE CARE CONTINUUM FOR HIV-AFFECTED ADOLESCENTS IN RESOURCE CONSTRAINED SETTINGS IMPLEMENTATION SCIENCE NETWORK

Aug 24, 2028

Support Services for the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings Implementation Science Network (PATC3H-IN) (UG1/UM2) Program The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) requires support for logistical and operational coordination, website and communication management, analytic and data management, infrastructure for emerging research, regulatory, and monitoring of research activities for the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings Implementation Science Network (PATC3H-IN) (UG1/UM2) Program. The NICHD and partner NIH Institutes anticipate funding 8 PATC3H-IN UG1 awards in Asia and throughout sub-Saharan Africa in 2023 through a cooperative agreement mechanism for interventions of high public health significance: The prevention of new HIV infections among adolescents at risk, and the identification of, linkage to and retention in care of, and long-term viral suppression among youth living with HIV in low-to-middle income countries with high HIV burden. The PATC3H-IN network will expand and/or improve on successes achieved by its predecessor, PATC3H, to new geographic settings and/or risk populations and stimulate much needed implementation science (IS) research in the prevention of new HIV infections among adolescents at risk and the identification of, and linkage and retention to care of and long-term viral suppression among youth living with HIV in low-to-middle income countries (LMICs). PATC3H-IN will establish a network of investigators with multidisciplinary expertise on the youth-specific PHCC and in IS research, whose mission will be to evaluate promising prevention innovations contextually and developmentally tailored for HIV uninfected at-risk youth, and treatment and care interventions for youth living with HIV which have demonstrated efficacy and/or effectiveness in adolescent or adult populations and to translate them into public health practices. The structure of PATC3H-IN will consist of multiple interdependent functional components: (1) Five Clinical Research Centers (CRC) awarded through the UG1 grant mechanism; (2) one Implementation Science Coordinating Center (ISCC) to be awarded through a UM2 grant mechanism in 2024; and (3) a Scientific Leadership Committee (SLC). The CRCs will conduct clinical research and clinical trials, including implementation, effectiveness, and hybrid implementation-effectiveness studies at their 8-or more participating Clinical Research Performance Sites (CRPS). The ISCC will establish infrastructure to support research education and capacity building across PATC3H-IN, as well as infrastructure for stakeholder engagement in and dissemination of findings from PATC3H-IN and advanced statistical modeling support across PATC3H-IN. The ISCC will also provide infrastructure for conducting foundational research to support the work of clinical sites, including possible modeling studies and translation projects, as well as national surveys, and/or systematic collection and analysis of relevant policies and laws. Lastly, the SLC will be responsible for PATC3H-IN governance, oversight, and coordination, and will develop and implement the network research agenda, convening working groups as needed, prioritizing emerging research projects, efficiently managing the development of clinical protocols, implementing and completing clinical trials, and ensuring timely publication and communication of results.

National Institute of Environmental Health Sciences

Impact of environmental toxicants on frontal cortical circuits

Jun 10, 2028

Abstract: Human mercury (Hg) exposure has been known for many decades to produce cognitive impairment and mood disorder symptoms. Hg is a global pollutant that poses widespread potential for neurotoxic exposure, earning it a position on the WHO’s list of the top 10 chemicals of major public health concern. However, little is known about the neural mechanisms that lead to neuropsychiatric symptoms from Hg exposure. The objective of this application is to identify specific mechanisms, within the neocortical circuits that control emotion and cognition, that are disrupted by the neurotoxicant, methylmercury (MeHg). The neocortex exhibits especially strong bioaccumulation of Hg, magnifying the risk to these circuits. Therefore, we hypothesize that chronic MeHg exposure leads to persistent circuit dysfunction in prefrontal and insular cortices (mPFC and aIC) – two brain regions critical in control of emotion and cognition. Our recent work showed that mPFC neurons in brain slices are negatively affected by acute MeHg exposure, resulting in hyperexcitability and altered synaptic transmission. Currently, it unknown how these acute effects on synaptic transmission translate to altered neuronal function in vivo. This proposal applies an integrative approach to determine the in vivo effects of MeHg on mPFC and aIC circuits, at the systems neurophysiology, synaptic and molecular levels. We will compare the effects of MeHg exposure on in vivo spiking activity patterns in brain regions of the mPFC-aIC circuit, using multiunit electrophysiological recordings in awake animals. Action potentials will be recorded simultaneously from multiple neurons, distributed across cortical layers, to evaluate effects on spike frequency, temporal patterning and correlation. Using acute brain slices derived from animals chronically treated with MeHg in vivo, electrophysiologically recorded synaptic estimates will be made to compare the effects of MeHg exposure on synaptic transmission and EI-balance within brain regions of the mPFC-aIC circuit. Based on previous evidence, we hypothesize that TDP-43 hyper-phosphorylation and aggregation link MeHg exposure to mPFC and aIC dysfunction. Therefore, immunohistochemistry will be used to measure TDP-43 hyper-phosphorylation and nuclear redistribution from animals treated in vivo +/- MeHg. In addition, tissue will be co-labeled with antibodies for nPAS4, a well-stablished molecular marker of activity, to determine whether TDP-43 hallmarks correlate with MeHg-induced hyper-excitability. The results of our study will substantively improve our mechanistic understanding of how Hg disrupts frontal cortical function and contribute to our understanding of the biological basis of emotional and cognitive sympoms. Identifying specific actions of MeHg at the functional microcircuitry level and cellular/molecular level will help significantly in finding novel targets for therapeutic interventions. If our hypothesis is correct, this will also raise the question of the extent to which chronic low-level environmental mercury exposure contributes to the etiology of fronto-cortical disorders with symptoms that overlap mercury exposure but do not have definitive genetic origins. This is particularly important because fronto-cortical disorders are predominantly sporadic in nature.

National Institute of Allergy and Infectious Diseases

Uncovering genetic determinants of carbapenem resistance in Klebsiella pneumoniae

May 31, 2028

Carbapenem-resistant Klebsiella pneumoniae represents an urgent global health threat due to its increasing prevalence and high mortality rates, necessitating a comprehensive understanding of its resistance mechanisms. While key resistance mechanisms and their genetic determinants are known, such as beta- lactamases and porin mutations, the cause of resistance in many strains remains elusive. Moreover, other strains that carry known genetic carbapenem-resistance factors have been found to still be susceptible to carbapenems for unclear reasons. Further, strains can carry genetic elements which, while not conferring resistance directly, can promote resistance indirectly by accelerating its acquisition, such as through mutations in DNA repair systems or mobile genetic elements. To address these knowledge gaps, we propose a genome-wide association study (GWAS), with the aim of maximizing the discovery of gene variants associated with meropenem resistance, with experimental validation of candidates to identify true causal variants. We will overcome limitations of prior studies in the following ways: 1) We have compiled an expanded data set of publicly available K. pneumoniae genomes from strains isolated across a wide distribution of countries, with in hand access to >100 isolates upon which experimental validation studies will be performed. 2) We will perform comprehensive capture of genetic variants by employing a reference-free GWAS, utilizing unitigs, stretches of DNA sequence that represent the entire spectrum of genetic variation. 3) We will enhance statistical power to detect genetic variants with even subtle effects on resistance by using a quantitative, continuous minimum inhibitory concentration (MIC) phenotype to meropenem rather than a binary designation of resistant or susceptible. 4) We will reduce the number of false positives arising from correlation, or linkage disequilibrium (LD), with known carbapenemase and other known resistance factors by performing a conditional GWAS, where known factors are included as covariates. 5) We will further mitigate confounding effects due to population structure and LD, which cause non-random relationships between variants, by utilizing a pangenome-wide regression with an elastic net penalty. 6) Crucially, we will functionally validate our findings, which will include genetic variants associated with increased resistance, whether through direct or indirect mechanisms, as well as those that may restore susceptibility in strains already possessing known resistance factors. We will bridge the gap between GWAS findings and functional validation by leveraging our high-throughput experimental capabilities. This integrated approach promises to uncover novel mechanisms of carbapenem resistance, its acquisition, and susceptibility in K. pneumoniae, with the potential to inform the development of future diagnostics or therapeutic strategies.

National Institute of Allergy and Infectious Diseases

Avian influenza virus prevention in the domestic host by a deactivated vaccine

May 31, 2028

Abstract Influenza viruses, which affect both birds and mammals, pose a substantial public health concern. An estimated 10% of the global population annually becomes infected, resulting in 300,000 to 600,000 deaths worldwide. Our research objectives are to develop a Hemagglutinin (HA) and Neuraminidase (NA) based rabies-vectored vaccine against highly pathogenic Avian Influenza (HPAI) A virus H5N1. We have already demonstrated the vaccine’s immunogenicity and protective efficacy against HPAI H5N1 Vietnam 1203. To advance this research, we propose to utilize a novel RAVB-based deactivated vaccine that harbors the H5 antigens of the current homologous circulation (clade 2.3.4.4b) and a construct expressing N1. Our first aim will involve comparing the H5 or H5/N1 RABV-based vaccines against challenges by PR8 recombinants carrying H5N1 proteins in mice. We will employ a single immunization and a prime/boost approach, either with or without an adjuvant approved for use in animals and humans (SEPIVAC SWE™). We will assess the role of T cells in the vaccine-induced protection by performing CD4/CD8 depletion before challenge Our second aim will utilize the vaccine approach identified to protect our mouse system in dairy cows. Subsequently, we will assess the vaccine’s efficacy against challenges administered intranasally and intramammary. We will verify the role of the vaccine-induced antibodies in protection against H5N1 by performing passive transfer studies of purified IgG from vaccinated cows before challenge. In summary, this study will evaluate the efficacy and delineate the mechanism of protection of a safe and well- established vaccine platform to protect against HPAI H5 and explore its potential as an animal and human vaccine.

National Institute of Environmental Health Sciences

2026 Thiol-Based Redox Regulation and Signaling Gordon Research Conference and Gordon Research Seminar

May 31, 2027

PROJECT SUMMARY This proposal requests support for the 10th meeting of the biennial Gordon Research Conference (GRC) and associated Gordon Research Seminar (GRS) on Thiol-Based Redox Regulation and Signaling to be held at the Rey Don Jaime Grand Hotel, Castelldefels, Spain on July 11-12 (GRS) and July 12-17 (GRC), 2026. Regulation of protein function through the post-translational modification of specific cysteine residues (thiol oxidation) plays an important role in cellular adaptation to local and global changes to endogenous and environmental oxidants. A key challenge for the redox-signaling field is to understand how thiol-based signaling mechanisms are integrated into cellular redox homeostasis and how these events facilitate communication between molecules, organelles, cells, and tissues to initiate and coordinate a specialized biological outcome. Significant emphasis for the 2026 meeting will be placed on an exploration of a wider range of cysteine thiol chemistry placed within a cellular context of other, often competing, oxidative or acyl modifications, some of which derive from environmental exposures, and contribute to cancer, aging and the progression of disease. In addition, we will discuss new insights into how cellular redox status impacts metabolic disease and new mathematical and analytical approaches to understand how redox gradients or “waves” impact the spatial and temporal aspects of signaling. A long-term objective is to use this new information to develop diagnostics and therapeutics for a wide range of redox-associated diseases that impact public health. This meeting provides a unique forum for extensive and immersive interaction among chemists, biologists, structural biologists and redox tool-builders, interested in a range of animal and cellular model systems, with clinical researchers and physicians focused on disease processes. While the thematic area of the conference is intentionally broad, its relevance to specialized NIH institutes is highly significant. Not only is redox toxicity proposed as a primary driver of chemically-induced pathology in humans, notably in aging and age-associated diseases, protection from these pathologies by “supersulfides” holds considerable promise. In keeping with the GRC tradition, the 2026 meeting will highlight presentations that emphasize unpublished work, creating a distinctive intellectual experience that enhances the excitement of the meeting. Investigators new to the meeting, junior investigators and graduate and post-graduate trainees will be welcomed. The associated GRS will provide a more intimate forum where graduate and postdoctoral trainees present their research to their peers, while receiving constructive comments from a few senior investigators who serve as mentors. We intend that the GRS/GRC meetings will attract and increase retention of junior scientists in the field of redox biology. We anticipate that the GRC will enhance the education of researchers at all career levels, generate new ideas and collaborations aimed at understanding thiol-based redox regulation and dysfunction, and enable future progress in the prevention, detection, and treatment of a wide-range of human diseases associated with perturbations in redox homeostasis.

National Institute of General Medical Sciences

Facilitating the Advancement of Research and Education for Undergraduate Students by Incorporating Laser Scanning Confocal Microscopy (FAREUS-LSCM)

May 31, 2027

PROJECT SUMMARY/ABSTRACT The University of Puerto Rico at Aguadilla (UPR-Aguadilla) requests funding to acquire a Nikon AX Galvo Confocal Laser Scanning Microscope (LSCM) with a TI2-E inverted platform and a four- laser configuration (405/488/561/640 nm) to establish transformative imaging capabilities at our resource-limited institution serving 96% Pell Grant recipients. This state-of-the-art instrument addresses a critical infrastructure gap, enabling high-resolution fluorescence imaging, live-cell microscopy, and quantitative analysis essential for competitive biomedical research and undergraduate education. The LSCM will directly support four active research projects spanning parasitology (monogenean host-specificity studies), plant pathology (coffee biocontrol development), environmental chemistry (metalloprotein biomarkers), and neuroscience (astrocyte dysfunction in diabetic epilepsy) while integrating into core laboratory courses including Immunology (BIOL 4009) and Undergraduate research courses (BIOL 3108 and QUIM 4999). Our multidisciplinary faculty, in partnership with the Neuroimaging and Electrophysiology Facility (NIEF) Excellence Imaging Center, offers expertise in confocal microscopy, encompassing advanced imaging and specialized sample preparation techniques. This collaboration ensures effective implementation of the technology, sustained technical support, and high-quality training programs that will enhance research productivity and broaden educational impact. The broad, long-term objective is to transform UPR-Aguadilla from a primarily teaching institution into a research-active campus capable of producing graduate-school-ready students equipped with cutting-edge technical skills. Access to advanced confocal microscopy will stimulate new research collaborations, enhance faculty productivity, and provide 30-40 students annually with hands-on experience in modern imaging technologies currently absent from our curriculum. The instrument will strengthen our partnership with the emerging Natural History Museum of Puerto Rico for specimen digitization and support comprehensive outreach programs targeting 25-50 high school students annually through "Seeing Science Up Close" workshops. Expected outcomes include 1- 2 peer-reviewed publications within three years, establishment of 1-2 new institutional collaborations, and measurable enhancement of biomedical research capacity. This investment will significantly advance STEM education and research opportunities at UPR-Aguadilla while expanding access to cutting-edge scientific instrumentation for students pursuing biomedical careers and contributing to the development of skilled researchers in the biomedical sciences.

Recent views on pre-registration

Andy Jahn

University of Michigan

May 2, 2025

A discussion on some recent perspectives on pre-registration, which has become a growing trend in the past few years. This is not just limited to neuroimaging, and it applies to most scientific fields. We will start with this overview editorial by Simmons et al. (2021): https://faculty.wharton.upenn.edu/wp-content/uploads/2016/11/34-Simmons-Nelson-Simonsohn-2021a.pdf, and also talk about a more critical perspective by Pham & Oh (2021): https://www.researchgate.net/profile/Michel-Pham/publication/349545600_Preregistration_Is_Neither_Sufficient_nor_Necessary_for_Good_Science/links/60fb311e2bf3553b29096aa7/Preregistration-Is-Neither-Sufficient-nor-Necessary-for-Good-Science.pdf. I would like us to discuss the pros and cons of pre-registration, and if we have time, I may do a demonstration of how to perform a pre-registration through the Open Science Framework.

University of Texas at Arlington

Structural & Functional Neuroplasticity in Children with Hemiplegia

Christos Papadelis

Feb 21, 2025

About 30% of children with cerebral palsy have congenital hemiplegia, resulting from periventricular white matter injury, which impairs the use of one hand and disrupts bimanual co-ordination. Congenital hemiplegia has a profound effect on each child's life and, thus, is of great importance to the public health. Changes in brain organization (neuroplasticity) often occur following periventricular white matter injury. These changes vary widely depending on the timing, location, and extent of the injury, as well as the functional system involved. Currently, we have limited knowledge of neuroplasticity in children with congenital hemiplegia. As a result, we provide rehabilitation treatment to these children almost blindly based exclusively on behavioral data. In this talk, I will present recent research evidence of my team on understanding neuroplasticity in children with congenital hemiplegia by using a multimodal neuroimaging approach that combines data from structural and functional neuroimaging methods. I will further present preliminary data regarding functional improvements of upper extremities motor and sensory functions as a result of rehabilitation with a robotic system that involves active participation of the child in a video-game setup. Our research is essential for the development of novel or improved neurological rehabilitation strategies for children with congenital hemiplegia.

University of Cambridge UK

Screen Savers : Protecting adolescent mental health in a digital world

Amy Orben

Dec 3, 2024

In our rapidly evolving digital world, there is increasing concern about the impact of digital technologies and social media on the mental health of young people. Policymakers and the public are nervous. Psychologists are facing mounting pressures to deliver evidence that can inform policies and practices to safeguard both young people and society at large. However, research progress is slow while technological change is accelerating.My talk will reflect on this, both as a question of psychological science and metascience. Digital companies have designed highly popular environments that differ in important ways from traditional offline spaces. By revisiting the foundations of psychology (e.g. development and cognition) and considering digital changes' impact on theories and findings, we gain deeper insights into questions such as the following. (1) How do digital environments exacerbate developmental vulnerabilities that predispose young people to mental health conditions? (2) How do digital designs interact with cognitive and learning processes, formalised through computational approaches such as reinforcement learning or Bayesian modelling?However, we also need to face deeper questions about what it means to do science about new technologies and the challenge of keeping pace with technological advancements. Therefore, I discuss the concept of ‘fast science’, where, during crises, scientists might lower their standards of evidence to come to conclusions quicker. Might psychologists want to take this approach in the face of technological change and looming concerns? The talk concludes with a discussion of such strategies for 21st-century psychology research in the era of digitalization.

The quest for brain identification

Enrico Amico

Aston University

Mar 21, 2024

In the 17th century, physician Marcello Malpighi observed the existence of distinctive patterns of ridges and sweat glands on fingertips. This was a major breakthrough, and originated a long and continuing quest for ways to uniquely identify individuals based on fingerprints, a technique massively used until today. It is only in the past few years that technologies and methodologies have achieved high-quality measures of an individual’s brain to the extent that personality traits and behavior can be characterized. The concept of “fingerprints of the brain” is very novel and has been boosted thanks to a seminal publication by Finn et al. in 2015. They were among the firsts to show that an individual’s functional brain connectivity profile is both unique and reliable, similarly to a fingerprint, and that it is possible to identify an individual among a large group of subjects solely on the basis of her or his connectivity profile. Yet, the discovery of brain fingerprints opened up a plethora of new questions. In particular, what exactly is the information encoded in brain connectivity patterns that ultimately leads to correctly differentiating someone’s connectome from anybody else’s? In other words, what makes our brains unique? In this talk I am going to partially address these open questions while keeping a personal viewpoint on the subject. I will outline the main findings, discuss potential issues, and propose future directions in the quest for identifiability of human brain networks.

1.8 billion regressions to predict fMRI (journal club)

Mihir Tripathy

Jul 28, 2023

Public journal club where this week Mihir will present on the 1.8 billion regressions paper (https://www.biorxiv.org/content/10.1101/2022.03.28.485868v2), where the authors use hundreds of pretrained model embeddings to best predict fMRI activity.