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NIGMS - National Institute of General Medical Sciences

ABSTRACT: Antimicrobial resistance threatens our ability to treat previously curable infectious diseases and may soon become a global public health crisis. The Ray group aims to understand and characterize the molecular mechanisms of antibiotic and antiviral resistance to identify potential avenues to target resistant pathogens. This R35 MIRA pro- gram involves two distinct research projects that utilize advanced machine learning (ML) and enhanced sampling algorithms for molecular dynamics (MD) simulations to gain mechanistic insights into antimicrobial resistance and facilitate the development of future therapeutic applications. In the first project, we will study the process of ligand binding to riboswitches, a class of regulatory RNA segments that are potential targets for next-generation antibi- otics. Our goal is to identify the role of conformational dynamics and distant nucleotide mutations in modulating the binding mechanism of the small molecule inhibitors (e.g., Ribocil) to RNA targets (e.g., Flavin-mononucleotide (FMN) riboswitch). We will design neural network (NN) and explainable artificial intelligence (XAI) based collec- tive variables from system agnostic descriptor space and perform enhanced sampling simulations to compute the free energy landscape of riboswitch conformational transition and ligand binding. This work will provide key mechanistic insights into RNA-small-molecule interactions and pave the way for designing more resilient antibi- otics. In the second project, we will study how resistant mutations in the viral antigens, e.g., SARS-CoV-2 spike protein, affect the binding mechanism of neutralizing antibodies. Previous research in this area primarily focused on the antigen-antibody interface but often overlooked the long-range allosteric effect of antigen mutations on the antibody binding process. We will perform NN and XAI-guided enhanced sampling simulations to elucidate the mechanistic details of antigen-antibody recognition. In addition, we will trace the allosteric communication path- ways using mutual-information-based protein graph connectivity networks constructed for various intermediate configurations sampled from the association pathway. This work will open new avenues for the rational design of broad-spectrum monoclonal antibodies through the judicious strengthening of distant regions of the antibody structure that are less susceptible to epitope mutations.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Tuberculosis (TB) remains a leading global health problem. Though one fourth of the world’s population is infected by Mycobacterium tuberculosis (Mtb), 90% of the people infected with Mtb remain asymptomatic as latent TB infection (LTBI). The reasons why 10% of the infected people progress to active TB are still elusive. Host genetic variations play an important role in TB susceptibility and LTBI reactivation. It has been reported that one single nucleotide polymorphism G/G (SNP-G) at -2518 in the promoter region of monocyte chemoattractant protein-1 (MCP-1) is strongly associated with active pulmonary TB (PTB). The underlying mechanisms of the - 2518 SNP-G-associated PTB susceptibility, however, remain unknown. MCP-1 is one of the key chemokines that regulate migration and infiltration of monocytes and macrophages to the sites of infection. Active TB patients show high levels of MCP-1 compared to people with LTBI and healthy volunteers. Higher levels of MCP-1 have also been used as a biomarker to distinguish active TB from LTBI. Flores-Villanueva, et al. first reported that people harboring the -2518 SNP-G had higher MCP-1 and lower IL-12 in sera and were more likely to develop PTB than individuals carrying the -2518 A/A (SNP-A) haplotype. Two meta-analyses analyzing a total of 5341 active TB cases and 6075 controls in 13 case-control studies report that the -2518 G/G homozygote carriers have a 67% increased risk of TB compared with the A allele carriers and the SNP-G homozygote is a risk factor for PTB. To test whether the SNP-G affected MCP-1 transcription, we cloned the MCP-1 promoter harboring the SNP G/G and SNP A/A into a luciferase vector and checked their luciferase activity in THP1 cells after mycobacterial infection. The SNP-G promoter showed a significant increase in luciferase activity compared to the SNP-A promoter. The MCP-1 transcripts in human macrophages carrying the homozygous SNP-G/G were also the highest than the cells harboring the SNP-A/A and the SNP-A/G after Mtb infection. We also found that BCG induced a strong nuclear binding specifically to the SNP-G and a small group of nuclear proteins called E- box binding protein bound to SNP-G. By reexamining the flanking sequence over the SNP, we found that the SNP-G but SNP-A constitutes the E-box motif (5’-CAGCTG-3’) in the MCP-1 promoter. The E-box-binding proteins are composed of a large superfamily basic helix-loop-helix (bHLH) proteins that transcriptionally regulate many functions in cancer, sex determination and development of the nervous system and muscles. How bHLH proteins regulate MCP-1 expression and affect mycobacterial growth are unknown and will be explored with the following two aims. Aim 1: Identify the E-box-binding proteins that bind to the SNP-G and regulate MCP-1 gene expression in Mtb-infected human macrophages. Aim 2: Explore the molecular mechanisms by which the SNP- G in MCP-1 promoter affects Mtb growth in human macrophages. The results will help us understand the molecular mechanisms of how -2518 G/G homozygote in the MCP-1 promoter contributes to TB susceptibility and reveal a novel role for the E-box binding proteins in control of host defense against Mtb infection.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY / ABSTRACT The cost of treating pain in the United States exceeds $500 billion annually, yet pain remains a large problem with nearly one-third of the population reporting chronic pain. Opioids are very potent analgesics (i.e. relieve pain), but also have many negative effects such as addiction, sedation, and deadly respiratory depression. These adverse effects have led to the opioid overdose crisis, which now claims over 80,000 American lives per year. As these dangerous adverse effects are mediated by the central nervous system, a promising approach for the safe and non-addictive treatment for pain is to target the peripheral nervous system. Inhibiting these neurons can alleviate pain by preventing synaptic transmission of painful signals to the brain. The long-term goal of this project is to understand the mechanisms underlying the long-term inhibition of opioid receptor signaling that are known to occur in peripheral neurons. Our previous work has identified that 14-3-3γ, a highly conserved scaffolding protein, is a critical mediator of the long-term inhibition of the kappa opioid receptor (KOR) by norbinaltorphimine. We demonstrated that induced expression of 14-3-3γ blocks KOR-mediated antinociception and antinociceptive signaling. This inhibition appeared to be selective to KOR and did not reduce KOR-mediated signaling that has been linked to peripheral sensitization. In effect, expression of 14-3-3γ in peripheral neurons biased KOR-mediated signaling away from analgesic pathways and towards pronociceptive pathways. This proposed work will use multidisciplinary methods to investigate the apparent specific interaction between 14-3-3γ and KOR, and will pharmacologically define the impact on cellular signaling. Specifically, 1) the impact of 14-3-3γ expression on the transducer profile or localization of KOR will be determined in primary cultures of peripheral sensory neurons using biosensors and microscopy, 2) molecular models, mutagenesis, live-cell microscopy, and biochemical assays will elucidate the molecular specificity between KOR and 14-3-3γ, and 3) structural determination and super-resolution microscopy methods will determine the molecular mechanism of inhibition. Additionally, these studies will serve as an outstanding training vehicle. My long-term goal is to become an independent scientist that studies structure, function, and impact of opioid receptor regulation and signaling. The innovative research approach described within this application will ensure that I have comprehensive training in the fields of pharmacology, biochemistry, and structural biology to form the basis of my future research career. Ultimately, this grant will lay the foundation for a successful career as an independent investigator studying mechanisms of opioid receptor signaling and regulation, and how these insights can be leveraged to help human health.

Montana Department of Commerce

The Coal Endowment Program provides grants to local governments for infrastructure improvements including water and wastewater systems, bridges, and public buildings in Montana communities, with funds derived from coal severance tax revenues.

Manhattan School of Music

Upgrade of their sound, lighting, rigging and HVAC systems; repairs of the backstage area; renovation of the stage and public spaces

Manhattan Theatre Club, Inc.

The Friedman’s upgrade to its sound system includes the purchase of a Clear-Com intercom system and amps. These upgrades will provide outstanding levels of audio performance with regard to clarity, reliability and functionality.

ABC No Rio

Demolition of existing building to double the size of gallery and performance space, install insulation and soundproofing, install an elevator and make building ADA compliant, install new energy-and-water-efficient building-wide systems.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY This proposal responds to the Notice of Special Interest “Understanding Sudden Death in the Young” (SDY) (NOT-HL-22-040) by building on our previous body of research in Robert’s Program on SUDP (Sudden Unexpected Death in Pediatrics) at Boston Children’s Hospital with additional phenotypic and genetic data collected in the NIH/CDC SDY Registry, to better define the molecular underpinnings of sudden and unexpected death in individuals 0-20 years of age (definition of SUDP and SDY). Sudden infant death syndrome (SIDS) and sudden unexplained death in childhood (SUDC) (included in the definition of SUDP and SDY) are responsible for nearly one in ten deaths in US children. While public health efforts aim to minimize risk in the sleep environment for SIDS, the persistent mortality indicates that affected children may possess intrinsic vulnerabilities that increase their susceptibility to death. Robert’s Program on SUDP uses deep phenotyping, genetic analysis, and engagement of families to study SUDP as a constellation of undiagnosed diseases. Our premise is that intrinsic biological contributions to SUDP include neurodevelopmental, epilepsy- related, cardiac, metabolic, and respiratory factors that have a genetic basis. Our multidisciplinary approach mirrors undiagnosed disease programs, using deep phenotyping and comprehensive genomic analysis to identify unrecognized conditions. Our previous “proof of concept” study, funded in part as an R21, utilized exome sequencing and found evidence of genetically based susceptibilities in 11% of SUDP cases in genes related to neurological, cardiac, and systemic disease. For this proposal we hypothesize that we will identify contributions to SUDP through a multiomics approach, using GS and metabolomic data to identify potential underlying Mendelian disorders and to investigate genetic risk using polygenic scores (PGS) for phenotypes of interest in SUDP. In Aim 1 we will identify monogenic contributions to SUDP by phenotyping and performing genome sequencing (GS) in prospective cases from Robert’s Program trios (estimated 270 over the grant period) and analyzing these data together with GS and phenotype data from the SDY Registry (estimated 250 prospective cases over the grant period). When added to the existing cohort of nearly 1000 cases from the SDY Registry and Robert’s Program, total data will include over 1400 cases. We will also conduct long-read sequencing in Robert’s Program cases to identify monogenic contributions missed by GS alone. In Aim 2 we will explore risk for SUDP using validated PGS with phenotypic overlap to SUDP mechanisms (e.g., epilepsy and Brugada syndrome) in Robert’s Program and SDY Registry cases. In Aim 3 we will utilize metabolomics in Robert’s Program cases to uncover biochemical signatures of underlying metabolic disease. The impact of this research is the elucidation of genetic mechanisms in SUDP, advancing the forensic molecular autopsy in establishing a cause of mortality and assessing novel methods of identifying genetic and metabolomic underpinnings of SUDP.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Bile acids (BAs) are core gastrointestinal (GI) metabolites with dual functions in lipid absorption and cell signaling. The past decade has seen a resurgence in BA research thanks to seminal studies – including from our lab – that established BAs as direct regulators of intestinal immune cells. Nuclear receptors (NRs) – a large family of ligand- regulated transcription factors – are a primary source of host BA receptors in the GI tract, including in immune cells. Still, only a fraction of the putative BA-NR ‘interactome’ has been explored, in part because gold-standard reporter assays needed to identify NR ligands are tedious and singleplex. Our goal is to build and use multiplex NR reporter systems capable of mapping global interactions between physiologically defined BA pools and all 48 NRs. To this end, we have developed a novel ‘multi-GI-omics’ platform that features parallel sampling of nearly 100 endogenous BA species and metabolites from across three GI sites of individual mice, and that yields high-resolution insights into dynamics of small intestinal BA reabsorption – a key and rate-limiting step in enterohepatic circulation that determines which BAs in the small intestinal lumen ultimately gain access to mucosal immune and epithelial cells in vivo. Using this approach, we described that the pool of endogenous BAs which circulates through the distal small intestine (i.e., ileum) of fasting C57BL/6 mice totals at least 0.3 moles/g and contains at least 42 discrete species. 80% of this pool is comprised of a small handful of ‘primary’ BA species synthesized in the liver [e.g., taurine-conjugated cholic acid (tCA)], and is maintained by an active transport mechanism (Asbt/Slc10a2) unique to ileal enterocytes. The remaining 20% includes mostly ‘secondary’ BAs – produced via microbial metabolism of primary BAs in the large intestine [e.g., deoxycholic acid (DCA), lithocholic acid (LCA)] – and enter the ileum via passive diffusion. Most recently, we have discovered that spontaneous ileal inflammation (i.e., ileitis) – a hallmark of human Crohn’s disease modelled experimentally in TNFARE mice – alters ileal BA absorption in ways that produce a smaller and more pro-inflammatory BA pool. In seeking to screen for putative NR-dependent mechanisms through which healthy or ileitis-associated mouse BA pools may elicit tolerogenic or inflammatory immune responses, respectively, we have performed pilot studies using a multiplex NR reporter system, called trans-FACTORIALTM available at Attagene, Inc. Appreciating both the transformative potential of multiplex NR reporter systems generally, as well as the limitations of the trans- FACTORIALTM system specifically, we have begun building a more universal NR reporter format that features DNA-barcoded fluorescent reporter genes readable by flow cytometry or RNA-seq. Our hypothesis is that using and refining multiplex NR reporter systems will lay the foundation for more broadly deciphering the BA:NR ‘interactome’, while also enhancing NR ligand and drug discovery research by us and others.

Harwinton

Municipal Security System

Minikahda Water District

MWD Distribution System Replacement Project

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS). Susceptibility to MS is significantly associated with Class II alleles, in particular DRB1*15:01:01(DR15). Autoimmune response of the self-reactive CD4 T cells to myelin antigens is a major component of MS immunopathogenesis. Several CNS antigens are thought to be the targets for CD4 T cells and there are numerous viral and bacterial peptides that activate myelin basic protein (MBP)-specific T cells. This suggests that cross-reactivity of CD4 T cells might represent one mechanism whereby infections trigger disease. Myelin antigens are widely used to induce Experimental autoimmune encephalomyelitis (EAE). The actual myelin-reactive CD4 T cells potential cross- reactivity is very poorly characterized. To better define the T cell receptor (TCR) repertoire and its specificity in MS, we applied single cell paired TCR sequencing method, an algorithm to determine convergence of TCRs across individuals, and a robust platform for antigen discovery. Without enriching the T cells for any particular antigen specificity, we performed unbiased TCR sequencing of activated T cells from the blood and cerebrospinal fluid (CSF) of MS patients and healthy controls. In MS patients, we found higher clonal expansion and overlap of CD4 T cells in the blood and CSF, convergence of CD4 TCRs among multiple DR15 MS patients with common sequences/motifs, and cross-reactivity to human adenovirus (HAdV) peptide and with MBP. We generated DR15 tetramer with HAdV-peptide and in a small new cohort of DR15 patients and controls show the existence of HAdV and MBP cross-reactive CD4 T cells in the blood. Moreover, we generated a new HAdV-TCR transgenic mice to test hypothesis of cross-reactivity. Altogether, we show that a convergent CD4 TCR from multiple MS patients react with MBP and a peptide from viral origin and these cells can be detected in the blood of patients. Altogether, our results showed that CD4 T cells in MS cross-react to MBP and a peptide from viral origin. Therefore, our central hypothesis is that cross-reactive myelin specific CD4 TCR repertoire in a subpopulation of MS patients is triggered by adenovirus antigen. We will test this hypothesis with the following aims: Aim 1. To assess the cross-reactive CD4 TCR repertoire between MBP- and HAdV in MS patients and healthy individuals. Aim 2. To mechanistically determine the impact of a HAdV- and MBP-cross-reactive CD4-TCR in mouse model.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract Support is requested for a Keystone Symposia conference entitled “Myeloid Cells: Functional Heterogeneity with Therapeutic Promise,” organized by Drs. Charlotte L. Scott, Shalin H. Naik and Thomas Fabre, with scientific programming input from Keystone Symposia. The meeting will take place February 23–26, 2026 at the Keystone Resort in Keystone, Colorado, USA. Myeloid cells play crucial roles in the innate immune system, responding to infections and maintaining tissue homeostasis. Despite their significant therapeutic promise, the potential of myeloid cells is yet to be fully realized. This Keystone Symposia meeting aims to bring together key leaders in academia and industry to discuss recent insights regarding myeloid cell functional heterogeneity and how to target these cells for therapeutic interventions. This conference will highlight recent advances in our understanding of the role of myeloid cells in different disease settings, including cancer, infection and other immune-mediated disorders, which will enable new translational perspectives for understanding, treating, and preventing infectious and immunologic diseases. The meeting program will provide opportunities for attendees to gain a deeper understanding of unique and conserved myeloid cell populations across tissues and diseases and explore how these might be leveraged therapeutically. Through rigorous discussions, this meeting aims to outline key questions for future research that will harness the power of myeloid cells and showcase current and emerging technologies. A key feature of this meeting is that it will be co-located with another Keystone Symposia conference, “Hematopoiesis.” This partnership will provide valuable insights into the interconnected roles of hematopoietic stem cells and myeloid lineages in both health and disease. Inclusive poster sessions, panel discussions, shared meals and social activities will promote networking, encourage the sharing of cross-disciplinary insights and provide broader scientific perspectives important for future research collaborations towards the development of successful therapeutic strategies.

DEPT OF DEFENSE.DEPT OF THE NAVY.NAVSUP.NAVSUP WEAPON SYSTEMS SUPPORT.NAVSUP WSS PHILADELPHIA.NAVSUP WEAPON SYSTEMS SUPPORT

N0038326PR0R076_ FMS REPAIR ACO

OD - NIH Office of the Director

Specific Aims: NAMs Technology Development Center for Women’s Health, “NAMs TDC-WH” The “NAMs TDC-WH” brings together an international multidisciplinary team, from basic scientists to clinical practitioners, lower the barriers for developing new drugs to treat a spectrum of gynecology disorders ranging from endometriosis to heavy menstrual bleeding and polycystic ovary syndrome (PCOS). This overarching goal will be facilitated by an existing well-funded core infrastructure at MIT in Center for Gynepathology Research that links clinicians, engineers, and scientists in academia and industry to build living patient avatars for endometriosis, adenomyosis and other gynecology diseases (Figure 1. The living patient avatars that will be rigorously tested and translated in the NAMS TDC-WH have been developed since their inception as “combinatorial NAMs”. Computational systems biology and bioinformatics analysis of clinical data (deep phenotyping and -omics) guided the design and operation of microphysiological systems (MPS) to capture key biological phenomena involved in disease and response to drugs, with performance of the MPS benchmarked against in vivo data. For this proposed project, we expand the computational and the clinical teams to capture a more comprehensive picture of the patient population, including genetic diversity and evolving aspects of the pain phenotype. We focus primarily here on combinatorial NAMs for female reproductive tissues, but include liver and other organ systems, recognizing the systemic nature of these diseases and the requirement that any drugs developed with gynecology tissues as a target require metabolic and safety assessments in a systemic manner. We test the hypothesis that pain phenotypes in humans relevant for endometriosis can be captured adequately via the combinatorial NAMs approach. The aims of the TDC-WH are to (i) elevate these technologies to the rigorous criteria needed for regulatory activities related to planning and interpreting human clinical trials for these drugs (ii) further strengthen the ties to the clinical phenotyping, genetics and bioinformatics communities whose input are needed to design physiologically relevant NAMs and benchmark them against in vivo for specific therapeutic targets (iii) translate the NAMs into use via example pre-clinical use cases in collaboration with Pharma. Finally, in addition to the technologies that have already been commercialized or in the process of being commercialized, we aim to translate the new platform technologies under development into wide availability through commercial partners. This will be accomplished through a comprehensive spectrum of education and outreach activities, including videos, hands-on tutorials, and translation of alpha versions of technologies for early feedback on user experience.

NASA

NASA SBIR Phase I funds innovative aerospace and technology R&D including data analytics, autonomous systems, and advanced computing. Post-reauthorization solicitations expected Spring 2026.

U.S. Fish and Wildlife Service

The National Coastal Wetlands Conservation Grant Program annually provides grants of up to $1 million to coastal and Grant Lakes states, as well as U.S. Territories to protect, restore and enhance coastal wetland ecosystems and associated uplands. The grants are funded through the Sport Fish Restoration and Boating Trust Fund, which is supported by excise taxes on fishing equipment an motorboat fuel.

National Aeronautics and Space Administration

National Space Grant College and Fellowship Program - Opportunities in NASA STEM FY 2020 – 2024

NC Department of Agriculture and Consumer Services

The NC Department of Agriculture provides grants to farmers, agribusinesses, food banks, and rural organizations for agricultural development, food system infrastructure, farmland preservation, and rural community support.

Washington Headquarters Services

NDEP STEM Open NFO

Nebraska Department of Economic Development

The Business Innovation Act provides grants to Nebraska small businesses and startups for prototype development, innovation, and commercialization of new technologies, supporting the state's entrepreneurial ecosystem.

Neighborhood House

Work with middle and high school age youth around the High Point low-income housing community in Southwest Seattle to develop and implement a community needs survey and then create app, website, or podcast projects to address identified needs and build awareness of Science, Technology, Engineering and Math (STEM) careers.

NEST+m New Explorations into Science, Technology + Math

Build a science lab equipped with hydroponic farmingtechnology with nutrient film technique, vertical growing systems, integrated pest management, a fish farm and a rain water cachment system.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary The NeuroNauts Scholars program seeks to cultivate the next generation of neuroscience researchers by providing eight high school students with immersive, hands-on research experiences in areas central to neurological health. The long-term goal is to expand the biomedical workforce by sparking early interest in neuroscience and equipping students with the skills to advance our understanding of brain and nervous system function. Under the expert guidance of UWF faculty, students will participate in an intensive eight-week summer program that integrates authentic laboratory research and interactive seminars. The program’s goals are to: 1. Provide hands-on training in experimental design, data collection, and analysis using cutting-edge neuroscience methodologies. 2. Enhance students’ understanding of neural mechanisms including neuroplasticity and neural network dynamics that underlie brain function and the pathogenesis of neurological disease. 3. Develop complementary skills in scientific writing, presentation, and critical analysis to prepare students for advanced studies and careers in neuroscience. 4. Foster a supportive research environment through personalized mentoring, continuous monitoring of student progress, and regular evaluation of program effectiveness. Program outcomes will be rigorously assessed through quantitative metrics and qualitative feedback using an online assessment system (EvaluateUR),, ensuring that the curriculum remains responsive to student needs. By bridging theoretical knowledge with practical research, the NeuroNauts Scholars program directly supports NINDS’s mission to advance our understanding of the brain and reduce the burden of neurological disease, while building a robust future biomedical research workforce.