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NIDA - National Institute on Drug Abuse

PROJECT SUMMARY This application is submitted in response to RFA-DA-26-001: SCORCH Data Mining and Functional Validation. Human immunodeficiency virus (HIV) infects non-neuronal cells in the brain, particularly microglia, which serve as reservoirs of latent infection. HIV has deleterious effects on both non-neuronal and neuronal cell function in brain regions involved in reward, emotion, and cognition. Many of these same regions, including the nucleus accumbens (NAc), also regulate the motivational properties of opioids and other drugs of abuse. Opioid use disorder (OUD) is more prevalent in people living with HIV than in the general population, and HIV and OUD reciprocally interact, with each exacerbating the severity of the other. EcoHIV is a modified HIV strain capable of infecting microglia, macrophages, and CD4+ T cells in mice, and recapitulating key pathobiological features of chronic HIV infection in humans. As part of the SCORCH consortium, we have generated single-nucleus RNA sequencing (snRNA-seq), two-dimensional (2D) single-cell spatial transcriptomic (Spatial-seq), and 3D single- cell Spatial-seq data from the NAc of control and EcoHIV-infected mice that remained drug-naïve or had a history of intravenous (IV) opioid (oxycodone) self-administration. Sequencing data were also collected from the same groups of mice that received antiretroviral therapy (ART). Here, we will mine this unique dataset to investigate the cellular and molecular mechanisms of HIV and opioid interactions in the NAc. In AIM 1, we will analyze our sequencing data to define the genetic phenotypes and spatial organizations of the medium spiny neurons (MSNs) in the NAc that undergo the most robust transcriptional remodeling in response to HIV infection alone and in combination with opioid self-administration. This analysis will enable us to distinguish between D1- and D2-expressing MSNs, identify novel subtypes, and determine their distributions within the NAc according to established (e.g., core versus shell) or novel spatial architectures. We will also integrate our mouse sequencing data with similar datasets collected from HIV-infected and drug-experienced rats, non-human primates (NHPs), and humans, available through the SCORCH-Neuroscience Multi-omics (SCORCH-NeMO) Archive. By constructing a cross-species cell atlas of the NAc, we can prioritize HIV and opioid-responsive MSN subtypes for further analyses. In AIM 2, we will employ cutting-edge circuit mapping, electrophysiological, and molecular approaches to characterize functional adaptations in the genetically defined and spatially organized MSN subtypes that exhibit the most robust transcriptional responses to HIV infection and opioid exposure. In AIM 3, we will use the CRISPR-Cas9 system to target high-priority genes dysregulated by HIV and opioids in genetically defined and spatially organized MSN subtypes in the NAc. The effects of CRISPR-mediated gene cleavage in MSNs on IV opioid self-administration and other NAc-mediated behaviors relevant to HIV/opioid interactions will be evaluated in EcoHIV-infected mice. This highly innovative research program promises to fundamentally advance our understanding of the pathobiological interactions between HIV and opioids.

Minnesota Arts Board

The Minnesota Arts Board awards grants to artists, arts organizations, schools, and communities throughout Minnesota to support artistic creation, arts education, cultural access, and the integration of arts in community life.

Minnesota State Arts Board

Minnesota State Arts Board provides grants to support arts and cultural programming, artist fellowships, arts education, and community-based arts projects across MN.

U.S. Mission to New Zealand

The U.S. Mission to Australia s Public Diplomacy Section (PDS) announces an open competition to implement projects that advance U.S. economic, commercial, and security interests in Australia. This Annual Program Statement (APS) outlines strategic goals, expected outcomes, target audiences, eligibility criteria, and application guidelines for cooperative agreements ranging from $25,000 to $100,000, with a project duration of up to 24 months. Project proposals must address at least one of the following goals: Promote flag football in Australia; Combat antisemitism through Holocaust education; Strengthen Pacific Islands partnership by highlighting shared cultural values among the peoples of the United States, Australia, and the Pacific Islands focusing on arts, cultural heritage preservation, education, and training. In addition to aligning with one of the strategic goals, applicants should clearly explain how they advance American leadership and excellence and how the projects deliver measurable results. All programs must include a clear connection to or inclusion of American expert(s), organization(s), or institution(s) or cultural elements in a specific field that will promote increased understanding of United States policy and perspectives. Please read the entire APS package before submitting an application. Applications must be submitted by September 20, 2026, for projects beginning as early as October 1, 2026. For more information, contact PASGrantsAustralia@state.gov. Applications that do not meet the eligibility criteria and do not contain all of the required information will not be considered.

U.S. Mission to New Zealand

The U.S. Mission to Australia’s Public Diplomacy Section (PDS) announces an open competition to implement projects that advance U.S. economic, commercial, and security interests in Australia. This Annual Program Statement (APS) outlines strategic goals, expected outcomes, target audiences, eligibility criteria, and application guidelines for cooperative agreements ranging from $25,000 to $100,000, with a project duration of up to 24 months. Project proposals must address at least one of the following goals: • Promote flag football in Australia; • Combat antisemitism through Holocaust education; • Strengthen Pacific Islands partnership by highlighting shared cultural values among the peoples of the United States, Australia, and the Pacific Islands focusing on arts, cultural heritage preservation, education, and training. In addition to aligning with one of the strategic goals, applicants should clearly explain how they advance American leadership and excellence and how the projects deliver measurable results. All programs must include a clear connection to or inclusion of American expert(s), organization(s), or institution(s) or cultural elements in a specific field that will promote increased understanding of United States policy and perspectives. Please read the entire APS package before submitting an application. Applications must be submitted by September 20, 2026, for projects beginning as early as October 1, 2026. For more information, contact PASGrantsAustralia@state.gov. Applications that do not meet the eligibility criteria and do not contain all of the required information will not be considered.

Missouri Arts Council

Missouri Arts Council provides grants to support arts and cultural programming, artist fellowships, arts education, and community-based arts projects across MO.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Streptococcus pneumoniae infection is the leading cause of community-acquired pneumonia (CAP), resulting in significant morbidity and mortality, particularly among elderly and immunocompromised individuals. Alveolar macrophages (AMs) serve as the first line of defense in the lungs, where they must efficiently clear pathogens while maintaining careful control over inflammatory responses to prevent tissue damage. The molecular mechanisms that enable this delicate balance remain poorly understood. Our research focuses on calcium (Ca2+) signaling through the mitochondrial calcium uniporter (MCU), a highly selective ion channel that controls Ca2+ entry into mitochondrial matrix. We previously discovered that deletion of MCU in bone marrow-derived macrophages severely impairs their ability to kill fungal pathogens while simultaneously triggering excessive inflammation. This dual defect stems from disrupted mitochondrial metabolism and amplified cytosolic Ca2+ signaling mediated by the plasma membrane calcium channel ORAI1. We hypothesize that MCU-mediated mitochondrial Ca2+ (mCa2+) uptake is essential for AM-mediated host defense against S. pneumoniae, and its disruption will impair bacterial clearance while promoting damaging inflammation in the lungs. To test this hypothesis, we will: 1) Define how MCU regulates AM antimicrobial functions and inflammatory responses during S. pneumoniae infection using state-of-the-art Ca2+ imaging, metabolomics, and functional assays; and 2) Determine the impact of myeloid-specific MCU deletion on host defense against pneumococcal pneumonia in vivo using a clinically relevant mouse model. We will employ mice with selective deletion of MCU in myeloid cells (including AMs) and comprehensively assess disease progression through survival studies, bacterial burden quantification, lung histopathology, and molecular analyses of inflammatory mediators. This research will provide fundamental insights into how calcium signaling governs AM function during bacterial pneumonia. Therapeutic targeting of Ca2+ signaling pathways may provide new strategies to enhance bacterial clearance while limiting inflammatory damage during pneumonia.

NIMH - National Institute of Mental Health

Mobility is a well-recognized antecedent of HIV care disengagement in South Africa, but more research is needed to understand how different types and patterns of mobility impact HIV care continuity among marginalized populations like female sex workers (FSW), who experience suboptimal antiretroviral therapy (ART) adherence and viral load suppression. Emerging evidence indicates that everyday mobility, or day-to-day movements within a contained geographic area, may be a more prominent driver of HIV care discontinuity than cross-jurisdictional mobility (typically associated with internal migration) among FSW, but these mobility dynamics and their impacts on HIV self-management and treatment-seeking remain understudied. This four-year K01 Mentored Research Scientist Development Award will facilitate the multidisciplinary training and mentorship of Dr. Joseph G. Rosen (a social and behavioral HIV prevention scientist whose scholarship has historically focused on people who use drugs), facilitating his transition to independent research that develops and tests implementation strategies to optimize HIV care continuity among mobile and displaced populations. Under the primary mentorship of Dr. Susan Ramsey, a clinical psychologist with expertise in development and evaluation of HIV care engagement interventions, the K01 training proposal includes: (i) tailored co-mentorship and experiential learning with a cohesive, multidisciplinary team of seasoned HIV researchers with complementary expertise in mobility (Dr. Mark Lurie), spatial epidemiology (Dr. Thomas Stopka), ethnography (Dr. Jaclyn Hughto), intervention development and strategy specification (Dr. Sheree Schwartz), and FSW-tailored HIV treatment delivery (Dr. Harry Hausler); (ii) didactics, coursework, and directed readings in areas of transitional scholarship for Dr. Rosen, specifically mobility and HIV treatment; and (iii) mentored primary research in South Africa, propelling Dr. Rosen's pursuits to establish an independent, thriving program of interdisciplinary, mixed-methods HIV treatment research leveraging implementation science principles and methods from social epidemiology. The goal of the proposed K01 research is to characterize patterns of everyday mobility among FSW in South Africa and identify mobility-responsive implementation strategies enhancing their HIV care continuity. Specific aims are to: (1) characterize the spatial distribution of inter-venue mobility among FSW and their prospective association with indicators of HIV care disengagement; (2) identify patterns and drivers of day-to-day mobility, as well as their perceived impact on HIV care-seeking and self-management practices, among FSW; and (3) specify a package of implementation strategies that sustain ART adherence and enhance HIV care continuity in the context of mobility among FSW. By the conclusion of this K01, Dr. Rosen will be positioned to lead independent research testing mobility-responsive implementation strategies (identified and prioritized in the proposed K01) to optimize HIV care continuity among mobile FSW through a hybrid type I effectiveness-implementation, fractional factorial trial.

NIAID - National Institute of Allergy and Infectious Diseases

Mobility is a well-recognized antecedent of HIV care disengagement in South Africa, but more research is needed to understand how different types and patterns of mobility impact HIV care continuity among marginalized populations like female sex workers (FSW), who experience suboptimal antiretroviral therapy (ART) adherence and viral load suppression. Emerging evidence indicates that everyday mobility, or day-to-day movements within a contained geographic area, may be a more prominent driver of HIV care discontinuity than cross-jurisdictional mobility (typically associated with internal migration) among FSW, but these mobility dynamics and their impacts on HIV self-management and treatment-seeking remain understudied. This four-year K01 Mentored Research Scientist Development Award will facilitate the multidisciplinary training and mentorship of Dr. Joseph G. Rosen (a social and behavioral HIV prevention scientist whose scholarship has historically focused on people who use drugs), facilitating his transition to independent research that develops and tests implementation strategies to optimize HIV care continuity among mobile and displaced populations. Under the primary mentorship of Dr. Susan Ramsey, a clinical psychologist with expertise in development and evaluation of HIV care engagement interventions, the K01 training proposal includes: (i) tailored co-mentorship and experiential learning with a cohesive, multidisciplinary team of seasoned HIV researchers with complementary expertise in mobility (Dr. Mark Lurie), spatial epidemiology (Dr. Thomas Stopka), ethnography (Dr. Jaclyn Hughto), intervention development and strategy specification (Dr. Sheree Schwartz), and FSW-tailored HIV treatment delivery (Dr. Harry Hausler); (ii) didactics, coursework, and directed readings in areas of transitional scholarship for Dr. Rosen, specifically mobility and HIV treatment; and (iii) mentored primary research in South Africa, propelling Dr. Rosen's pursuits to establish an independent, thriving program of interdisciplinary, mixed-methods HIV treatment research leveraging implementation science principles and methods from social epidemiology. The goal of the proposed K01 research is to characterize patterns of everyday mobility among FSW in South Africa and identify mobility-responsive implementation strategies enhancing their HIV care continuity. Specific aims are to: (1) characterize the spatial distribution of inter-venue mobility among FSW and their prospective association with indicators of HIV care disengagement; (2) identify patterns and drivers of day-to-day mobility, as well as their perceived impact on HIV care-seeking and self-management practices, among FSW; and (3) specify a package of implementation strategies that sustain ART adherence and enhance HIV care continuity in the context of mobility among FSW. By the conclusion of this K01, Dr. Rosen will be positioned to lead independent research testing mobility-responsive implementation strategies (identified and prioritized in the proposed K01) to optimize HIV care continuity among mobile FSW through a hybrid type I effectiveness-implementation, fractional factorial trial.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY: People Living with HIV (PLWH) are at increased risk of both acute and chronic lung diseases. Although the use of effective anti-retroviral therapy (ART) has diminished the burden of infectious lung disease, morbidity and mortality from chronic lung diseases in PLWH has been steadily increasing. HIV infection is associated with increased risks of pneumonia from bacteria, viruses, fungi and parasites. More importantly, bacterial pneumonia (caused by Streptococcus pneumoniae) is one of the most frequent respiratory infections that cause severe or very severe symptoms in both ART-naive and ART-exposed children infected with HIV. While the clinical consequences of HIV-associated lung infections in PLWH are well documented, knowledge on cellular and molecular mechanisms leading to HIV-associated lung disease is very limited. Hence, a deeper understanding on immune mechanisms that lead to increased susceptibilities to lung infections may define potentially new therapeutic targets for treating PLWH. To this end, the research proposed here aims to unravel the physiologic impact of HIV infection on dendritic cell (DC) differentiation and determine DC functions during respiratory infections. The major hypothesis of our proposed research is that chronic HIV-1 infection results in increased susceptibilities to microbial co-infections in the lungs, due exaggerated inflammatory signals- and HIV auxiliary proteins- induced DC defects. The rationale is that ongoing chronic inflammation induced in response to HIV and consistent circulation of HIV accessory proteins suppress the differentiation program of DCs in the periphery, which eventually leads to reduced DC numbers and functions in the lungs during life-threatening respiratory infections. To test our hypothesis, we will use a combination of xenotransplantation, in-vitro culture, molecular cell biology, biochemical & immunology studies. In the first specific aim, we would test if HIV-1 infection suppressed DC differentiation pathways and identify the cytokine(s) responsible for HIV-1-induced DC differentiation defects. In the second specific aim, we would identify if the presence of HIV accessory proteins impairs DC differentiation and molecular program. In the third specific aim, we would evaluate if chronic HIV infection results in impaired immune differentiation and determine if human DC functions are compromised during respiratory infections. Studies proposed in Aims 1, 2 & 3 are complimentary and informed by the data of each other, but not dependent on the outcome of the other Aims. A thorough knowledge on mechanisms through which HIV-infection induces DC defects and increased susceptibilities to respiratory infections would be essential in treating HIV- associated immunodeficiencies. In addition, our studies are designed to evaluate novel treatment strategies to restore immune differentiation and functions during chronic HIV infection.

NIAID - National Institute of Allergy and Infectious Diseases

SUMMARY Nearly 40 million people globally and 1.2 million people in the United States are living with HIV. Although antiretroviral therapy (ART) has transformed HIV from a fatal disease to a manageable chronic condition, lifelong treatment poses substantial challenges, and ART does not cure the infection. Based on data in humans and non- human primate models linking high quality CD8+ T cell responses with low viral loads, there is strong rationale for targeting HIV-specific CD8+ T cells to promote control of HIV. However, due in part to limitations of existing CD8+ T cell assays, the field currently lacks a mechanistic understanding of which features of the CD8+ T cell response might drive effective control of HIV rebound. The overarching goal of this project is to comprehensively define the mechanistic features of CD8+ T cell responses that most strongly relate to control of HIV after stopping ART. To do this, we will study peripheral blood samples collected before analytic treatment interruption (ATI) and longitudinally after rebound in participants from ATI sub-studies within the San Franscisco SCOPE cohort, including several who maintained low viral loads (<2,000 copies/mL) for several months after stopping ART. We recently developed a novel nanoparticle class I peptide:Human Leukocyte Antigen (pHLA) pool assay that enables simultaneous measurement of pHLA specificity, T cell receptor (TCR) avidity and breadth of peptide recognition, and transcriptional signature at a clonotype level from up to 1000 HIV-specific CD8+ T cell responses per sample. In Aim 1, we will use this tool to identify features of HIV-specific CD8+ T cell clonotypes that respond as HIV reactivates during viral rebound. In Aim 2, we will apply newly-developed single-copy sequencing methods to plasma HIV sequences in order to characterize the development of HIV escape to autologous CD8+ T cell responses during and after rebound. Finally, to connect these distinct but inter-related data types, in Aim 3, we will utilize mathematical models that describe viral dynamics and evolution simultaneously to model dynamic CD8+ T cell-virus interactions that promote control of HIV after ART is stopped. This highly collaborative project with clinical, immunology, virology, and mathematical investigators will identify the mechanistic properties of CD8+ T cell responses required for successful control rebound HIV across a large group of post-treatment controllers. Our work will provide a target for the next generation of immunotherapies for HIV cure and inform T cell-based therapeutics for other chronic infections and cancers.

NIGMS - National Institute of General Medical Sciences

Modeling Multimetallic Transition Metal Catalysts to Enhance Organic Synthesis Transition metal catalyzed reactions have emerged as an extremely important aspect of modern organic synthesis and drug discovery. Typically, this involves the use of a single transition metal and an organic ligand. In contrast, an emerging frontier in organic synthesis is the use of two active transition metals that have interdependent catalytic cycles. This type of multimetallic catalysis has significant potential to achieve new transformations as well as greater reactivity and higher selectivity. However, while a few general patterns and classifications have emerged for multimetallic reactions there remains a general lack of understanding that can be applied across many types of reactions. Also, multimetallic reactions often have especially complex reaction mechanisms and reaction conditions that require the development and application of new atomistic modeling approaches. Therefore, this work will develop and use state-of-the-art quantum-chemical and data science approaches to model and predict multimetallic transition metal catalyzed organic reactions. The modeling will focus on two types of multimetallic reactions. The first is multimetallic catalyzed reactions that involve metal hydrogen atom transfer (MHAT) reaction steps. These reactions are important because they result in alkene functionalization to build complex organic compounds. The second is multimetallic catalyzed cross-coupling reactions. These reactions are important because cross-couplings provide key compounds for drug discovery. In addition to providing new insights into existing chemical reactions this work will demonstrate new tools and approaches to computational design and identification of new multimetallic catalysts, which remains a challenging frontier in organic chemistry.

NIDA - National Institute on Drug Abuse

Project Summary/Abstract Substance use disorders (SUD) pose a major public health crisis that exacts heavy tolls on communities and healthcare systems, yet current survey data remain underutilized due to limitations in conventional analytic methods. This project proposes to develop a novel behavioral foundation model that transforms qualitative epidemiological survey responses into robust, quantitative latent representations of substance use behaviors. By harmonizing data from NESARC-III, NSDUH, and UK Biobank, we will “textualize” both structured and free- text responses into unified narratives that capture the nuanced details of individual experiences. Our approach leverages advanced natural language processing to convert diverse survey data into coherent, machine- interpretable inputs, and fine-tunes state-of-the-art, open-source large language models (LLMs) with integrated demographic tokens to enhance subgroup-specific predictions. We will rigorously validate the model’s performance against established machine learning techniques using metrics such as area under the ROC curve, calibration, and cross-dataset generalizability. Downstream applications include precise risk stratification for SUD outcomes, latent clustering to identify distinct risk and resilience profiles, and data-driven survey instrument optimization. Open-access dissemination of our tools will empower precision public health initiatives, enhance early identification of high-risk groups, and support targeted interventions to reduce the societal burden of substance use disorders.

NIGMS - National Institute of General Medical Sciences

1 PROJECT SUMMARY 2 Successful development of new active pharmaceutical ingredients (APIs) requires synthesizing many 3 structurally related compounds to optimize pharmacokinetic properties related to absorption, distribution, 4 metabolism, excretion, and toxicology. However, the expense of time and resources needed to synthesize each 5 candidate makes API optimization a bottleneck. As a result, researchers have developed a relatively short list of 6 expedient synthetic methods on which they rely to develop APIs. These methods tend to involve fragment 7 couplings that forge new C-C, C-N, or C-O bonds by joining two building blocks, which allows those seeking new 8 APIs to purchase libraries of suitable building blocks and explore their pairwise couplings in modular fashion. 9 The modularity of this approach means that each new fragment increases the quantity of structures that can be 10 explored in a nonlinear fashion. However, some of the most frequent substructures in APIs—saturated medium- 11 sized nitrogen-containing heterocycles—are not well represented in commercial catalogues of building blocks, 12 due to limitations in state-of-the-art synthetic methods used to produce them. The ability to create custom building 13 blocks in a modular fashion, which would enable both more thorough and more efficient structure optimizations 14 of APIs, would represent a significant advance in modern synthetic chemistry. However, current synthetic 15 limitations make exploration of 3D structural variants of these heterocycles difficult. 16 This proposal outlines a strategy to develop new catalytic methods that will convert readily accessible starting 17 materials into structurally complex heterocyclic building blocks in modular fashion. The modularity of the 18 proposed methods, the accessibility of starting materials, and the proposed catalyst control of stereochemistry 19 in these chiral products will make exploration of new, chiral variants of these important building blocks more 20 practical. The proposed research includes a tandem fragment coupling-cyclization approach to assemble 21 multiple building blocks to construct structurally complex, medium-sized, saturated heterocycles. Mechanistic 22 experiments and computational exploration of key mechanistic steps is proposed so that both activity and 23 selectivity of the catalysts can be understood and iteratively improved with the assistance of new data 24 representations and machine learning. Accomplishing these goals would provide practitioners access to diverse 25 structural variants of important building blocks for API development, as well as demonstrate the future role of 26 machine learning as a tool that can accelerate the development of methods with a large scope.

NIAID - National Institute of Allergy and Infectious Diseases

Export of RNA from the nucleus is essential for all eukaryotic cells and has emerged as a major step in the control of gene expression. mRNA molecules are required to complete a complex series of processing events most of which are highly conserved across eukaryotes, reflecting their ancient origin, The mRNA export factor Mex67/NXF1 (yeast/vertebrates) transports its RNA cargo from the nucleus through the nuclear pore complex (NPC) to the cytoplasm on a distinct ATP dependent pathway. In most eukaryotes, Mex67/NXF1 exists as a single protein; however, additional tissue-specific isoforms of NXF1 exist in multicellular organisms (i.e. humans). However, significant deviation from the canonical pathway as described from animals and fungi has emerged in the trypanosomatids, a group of divergent unicellular parasitic protozoa. We recently discovered that Trypanosomes have three very distinct paralogs of Mex67 which we termed TbMex67, TbMex67b and TbMex67L (for Like), with differing roles in mRNA export and ribosome biogenesis. Our focus is on TbMex67 and TbMex67b, which function as general mRNA export factors, albeit also associate with paralog-specific subsets mRNA cargo and differing protein interactomes in the mammalian bloodstream form (BSF) versus the insect procyclic form (PCF) of the organism, reminiscent of the tissue-specific NXF1 variants observed in metazoa. Trypanosomatids lack individual gene promoter control, instead relying heavily on post- transcriptional gene regulation and potentially, making RNA export a crucial component in the control of gene expression. It is our hypothesis that TbMex67 and TbMex67b function to help differentially regulate the expression of genes in different life cycle stages, possibly on alternate mRNA export pathways. To determine this, we will continue to characterize the paralog-specific protein interactomes and RNA cargos of the two Mex67 proteins quantitatively and comprehensively in cells in the different life stages by utilizing and adapting methods we have pioneered, as well as standard biochemical techniques. Our preliminary work has identified putative analogs of the transcription-export complex THO/TREX which has long been considered as absent in these parasites. In addition, we have previously shown that trypanosomes depend on the Ran GTPase system, a major departure from the canonical textbook model of an ATP-dependent mRNA export machinery. We hypothesize that this system will provide a new perspective on how Ran can be utilized to mediate directional transport across the NPC. Our strategy will include classical biochemical techniques involving exogenously expressed components that have been successfully employed to delimit nucleocytoplasmic transport in yeast and humans, as well as state of the art proteomic and structural methods to compute topological maps of the TbMex67-Ran machinery. With significant implications for the mechanisms that control gene expression and hence differentiation, responses to altered environments and fitness as a parasite, these deviations may reveal additional, unsuspected, mRNA export pathways.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

Project Summary/Abstract Increasing the number of infants in the neonatal intensive care unit (NICU) who can be fed using mothers’ own milk (MOM) is crucial for reducing expensive co-morbidities experienced by premature and ill infants. Mothers on NICU infants have delayed secretory activation (SA) and challenges to maintain SA, and coming to volume (≥500 mL/d by d 14 postpartum, CTV). However, the biological mechanisms that are involved in inhibiting the initiation and establishment of lactation in this at-risk population are generally poorly understood. SA involves the closing of tight junctions in the mammary gland and the transition to copious milk production. Following this transition, the mammary gland transitions from endocrine to paracrine/autocrine regulation of lactation, leading to an increase in milk volume. Both SA and CTV are critical for initiation and maintenance of lactation, and prior data suggest that both may be impacted by maternal health factors. In our prior work, we found that both transcriptomic gene expression and lipid metabolism are associated with milk production in mothers of term infants later in lactation. However, similar work has not been done during early lactation or in the NICU population. In this project, we will use samples from a highly-controlled parent trial to investigate the molecular and metabolic pathways that are associated with the achievement of SA and CTV in the first 2 weeks postpartum (pp). We will use transcriptomics, as well as biochemical analysis of inflammatory and lipid metabolism pathways to elucidate the biological mechanisms associated with 1) the achievement of SA by week 1 pp and 2) pumped milk volume at 2 weeks in a population of mothers with infants in the NICU. As participants in the parent clinical trial, all mothers will receive consistent, state-of-the art lactation support and care, reducing the possibility of variability in access and quality of care. The results of this study will provide evidence to support the development of future interventions that are targeted to promote sufficient milk production and prevent lactation problems in vulnerable populations.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT ABSTRACT New Delhi metallo-β-lactamase-producing Enterobacterales (NDM-E) are the fastest growing carbapenemase threat in the United States, with mortality exceeding 40% and treatment options remaining limited. Clinicians often approach NDM-E as if resistance mechanisms are uniform, yet accumulating evidence shows that allelic variation (e.g., NDM-1, NDM-5) and co-resistance mechanisms profoundly alter antibiotic efficacy. The absence of allele-level therapeutic guidance undermines precision treatment strategies and compromises outcomes. This proposal addresses this gap by integrating genotype, phenotype, and patient-level outcomes to inform care. Aim 1 defines the genetic epidemiology of NDM-E and links allele-specific diversity to susceptibility of cefiderocol (FDC), aztreonam-avibactam (A-A), and late-stage investigational agents cefepime-taniborbactam (C-T), cefepime-zidebactam (C-Z), and cefepime-nacubactam (C-N), generating an “NDM-allele antibiogram” to guide therapy. Aim 2 identifies mechanisms of resistance to NDM-directed antibiotics by evaluating resistant organisms with susceptible reference isolates and performing comparative genomics to elucidate resistance emergence. Aim 3 compares outcomes of FDC- versus A-A-treated patients with NDM-E infections, evaluating 30-day mortality and 90-day resistance emergence, with propensity score methodology mitigating confounding. A collection of approximately 800 isolates from Northwestern University, Johns Hopkins University, and the University of Pennsylvania will undergo broth microdilution, short- and long- read sequencing, and bioinformatic analysis, with patient data linked to allele-specific resistance correlates. Career development is central to this award: Dr. Hareza will receive structured training in whole-genome sequencing, bioinformatics, and high-dimensional statistical methods, reinforced by formal coursework in advanced biostatistics and causal inference and by immersive laboratory rotations with expert microbiologists. Mentorship from Drs. Pranita Tamma and Alan Hauser, supported by a multidisciplinary advisory team, will ensure both methodological rigor and clinical relevance. Northwestern University provides an ideal training environment with state-of-the-art genomics facilities, nationally recognized infectious diseases expertise, and robust bioinformatics and biostatistical cores, while protected effort ensures dedicated time for mentored research and training. The long-term goal is to position Dr. Hareza as an independent investigator leading an R01-funded program in precision-guided management of antimicrobial resistance. Ultimately, this project will advance patient care by translating allele-level resistance mechanisms into actionable therapeutic guidance while launching his independent research career in antimicrobial resistance.

NIDCR - National Institute of Dental and Craniofacial Research

The Temporomandibular Joint (TMJ) is the most-used joint in the body. The TMJ cartilage carries out the essential function of enabling free joint movement during speech and mastication. TMJ Osteoarthritis (TMJ-OA) consist of osteochondral tissue degeneration and is a growing epidemic that afflicts men and women not only in United States but across the globe. It is well established that altered expression and activation of catabolic enzymes underlies joint cartilage destruction observed in TMJ-OA, however the precise mandibular chondrocyte behavior during TMJ cartilage degeneration and regeneration is not well understood. Notch signaling has been identified as a potential catabolic and anabolic mediator of TMJ-OA. Understanding Notch cellular signaling that regulate osteochondral tissue degeneration can lead us to development of new therapeutic targets. To sufficiently advance our understanding of Notch signaling in TMJ degeneration-regeneration and translate our findings, will require robust experimentation, including preclinical studies in TMJ degeneration model. Our long-term goal is to develop a clinically relevant approach to modulate Notch signaling to prevent TMJ degeneration and facilitate its regeneration. Our central hypothesis is that Notch ligand (Jagged 1 / 2) is a potential target for TMJ- OA, and they work via upregulation of bone morphogenetic protein 2 (BMP2) and Indian hedgehog (Ihh) signaling pathway. This work will be completed in three specific aims, using novel mouse model and state of art genomic technology. Our preliminary work has demonstrated that Jagged 1 is significantly over expressed (both mRNA & protein) in TMJ degeneration both in mice and humans. In specific aim 1, we will disrupt Jagged1/2 in lineage specific manner in chondrocytes and osteoblasts of subchondral bone. In specific aim 2, we will define the pathophysiological mechanism by which Notch ligand (Jagged 1 / 2) leads to TMJ degeneration and regeneration at single cell level and in specific aim 3, our experiments will translate our mechanistic observation and study the role Jagged1/2 plays in traumatic TMJ injury and repair, specifically using anti-Jagged 1 antibodies to reduce TMJ degeneration. The proposed project has immense potential to reveal new regulatory pathways that modulates TMJ degeneration and regeneration and to open new insights on understanding the disease mechanism and developing therapeutic interventions.

NIGMS - National Institute of General Medical Sciences

Project Summary Chromatin structure and function are dynamically regulated by ATP-dependent chromatin remodelers and Sirtuin histone deacetylases, two critical enzyme families that play pivotal roles in DNA transcription, replication, repair, and genome stability. Chromatin remodelers use ATP hydrolysis to reposition and modify nucleosomes, while Sirtuins, NAD⁺-dependent histone deacetylases, modulate chromatin states through site-specific histone deacetylation. These enzymes often work in concert to fine-tune chromatin accessibility and gene expression. Although their roles have been studied to some extent, their precise mechanisms and the nature of their interplay remain poorly defined, underscoring the need for further investigation into their complex interactions with chromatin. Building on my laboratory’s strong track record in chromatin biology, structural studies, and functional assays, as well as compelling preliminary data, my research program aims to uncover the individual molecular mechanisms of chromatin remodelers and Sirtuins, as well as focus on their coordination in regulating nucleosome dynamics and chromatin structure. Supported by a highly collaborative network and innovative methodologies, this work aims to tackle fundamental unanswered questions in chromatin biology, with the potential to drive significant advancements in the field Two major themes drive this research. The first explores ATP-dependent chromatin remodelers, specifically CHD and ISWI ATPases, examining their catalytic mechanisms, substrate specificity, and the influence that histone post-translational modifications (PTMs) have on their remodeling activity. State-of-the-art approaches, including high-resolution cryo-electron microscopy (cryo-EM), molecular dynamics simulations, and advanced biochemical assays, will reveal the dynamics of remodeling cycles and interactions with chromatin. The second theme focuses on the Sirtuin family of deacetylases and their interplay with chromatin remodelers. Structural and functional studies, coupled with tools like synthetic nucleosomes with defined PTMs, real-time FRET-based translocation assays, and cross-linking mass spectrometry, will provide unprecedented insights into their coordination and regulatory roles. By leveraging our expertise, robust preliminary data, and a world-class support network, this research will not only advance our understanding of chromatin modulation but will also drive the entire field forward, offering critical insights into gene regulation, genome integrity, and the development of therapeutic strategies targeting chromatin dysfunction in diseases such as cancer and neurodegeneration.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT There are ~40 million people world-wide infected by the Human Immunodeficiency Virus (HIV). In the absence of a functional cure, antiretroviral therapy (ART) represents the primary treatment option against HIV. ART regimens containing the integrase strand transfer inhibitors (INSTIs) form first-line treatments for people living with HIV/AIDS (PLWH). INSTIs work by blocking the function of the viral intasome, which is the nucleoprotein complex that forms on the linear ends of the viral long-terminal repeats and mediates the insertion of viral DNA into host target DNA. Despite significant advances afforded by the inclusion of INSTIs to ART regimens, resistance to even the latest drugs is becoming a greater clinical problem. In the clinical literature, there are specific sets of drug-resistant mutations (DRMs) within the IN protein that arise most frequently to INSTI therapy, including individual mutations E138K, G140A/S, and Q148H/K/R. Eventually, the virus evolves more complex combinations of mutations, including the clinically relevant triple mutants E138K/G140A/Q148K (KAK) and E138K/G140S/Q148H (KSH). In preliminary data, models of HIV fitness landscapes built from viral sequences derived from PLWH suggest that the pathways through which combinations of complex triple mutant KAK and KSH combinations emerge can vary dramatically. However, the underlying basis for how and why distinct DRM combinations preferentially emerge remains unclear. This work will test the fundamental hypothesis that the pathways toward drug resistance evolution can be rationalized using atomic resolution structures, supported by multiple experimental measures of viral fitness. In three specific aims, this work will (i) derive drug- specific pathway orderings for KAK and KSH combinations using tools that measure prevalence-based fitness based on extensive viral sequencing data available from PLWH, (ii) determine atomic structures of HIV intasomes along KAK and KSH pathways using the latest technological advances in cryogenic electron microscopy, and (iii) gain dynamic and mechanistic insights into select DRMs along KAK and KSH pathways. Collectively, the structural snapshots will be ordered along the predicted pathway trajectories and, together with existing fitness measurements and complementary molecular dynamics-based analyses, will begin to rationalize the pathways of drug resistance evolution, as well as the associated mechanisms of drug resistance to INSTI therapy. Although the mechanistic analyses of drug resistance have been interrogated in the past, considerably less attention has been given to understanding pathways of drug resistance evolution. Dissecting both pathways and mechanisms of patient-derived clinically relevant complex DRM combinations that arise in response to treatment will build a foundation for prospectively forecasting the evolutionary trajectories leading to drug resistance. The principles can be extended to other infectious diseases, beyond HIV.

Montana Arts Council

Project grants from the Montana Arts Council support specific arts and cultural projects including performances, exhibitions, arts education, and community arts initiatives that expand public access to the arts in Montana communities.

Montana Arts Council

The Montana Arts Council provides operating support grants to established arts organizations that demonstrate excellence in programming, community engagement, and organizational management, strengthening Montana's cultural infrastructure.

Morgan Community Association (MoCA)

The Morgan Community Association will host the Morgan Junction Festival on June 22, 2019 from 10am - 4pm at Morgan Junction Park located at 6413 California Ave SW. The free event will feature interactive arts and crafts activities for youth.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract The endoplasmic reticulum (ER) is an interconnected membrane compartment that is comprised of distinct functional morphologies, including tubules and sheets. How the cell reprograms the ER morphology to support different functionalities in normal and disease states is not fully resolved. Recently, we have uncovered that transmembrane mucin biopolymers can generate membrane curvature and that some prominent mucins, such as Muc1, have prolonged ER residency. In this project, we will test the central hypothesis that transmembrane mucins act as membrane curvature generators on the luminal face of the ER to regulate the ER morphology, function, and interactions with other organelles. Implicit in this hypothesis is the new notion that changes in cellular mucin expression could dynamically reprogram the functional morphology of the ER. Our aims are to (1) determine how transmembrane mucins generate forces in the ER to regulate the ER structure and function, (2) identify the molecular determinants that govern the accumulation of transmembrane mucins in the ER, and (3) investigate the downstream consequences of the mucin-reprogrammed ER on mitochondria and other cellular organelles that interact with the ER. To complete our aims, we will leverage our unique expertise in engineering the molecular structure of mucins and controlling their genetic expression. We will combine this expertise with state-of-the-art imaging approaches that include expansion microscopy (ExM) for resolution of the ER morphology, spectral imaging for dissection of organelle interactions, and optical reporters for quantitative analysis of protein trafficking through the secretory system. New optical biosensors will directly measure the entropic forces that are hypothesized to underlie membrane curvature generation by mucins. These tools will be used in parallel with traditional approaches within the field of cell biology for assessment of organelle structure/function. Theoretical models on mucin force generation will be used to support the analysis and interpretation of our results. The expression of Muc1 and other transmembrane mucins can change dramatically with changes in cell fate, oncogenic transformation, inflammation, and conditions of stress. For instance, professional secretory cells and most carcinoma cells express high levels of Muc1. Our project aims to mechanistically dissect a heretofore unrecognized role for mucins in physically shaping the ER structure and its interactions with other cellular organelles. Given the ubiquity of transmembrane mucin expression in normal secretory cells and cancer, the fundamental understanding that we seek is of broad significance to human health.