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NIA - National Institute on Aging

ABSTRACT Numerous studies have demonstrated the "male-female health-survival paradox," where females exhibit a higher burden of age-associated disorders yet live longer than males. This paradox arises from a greater burden of chronic diseases in females, particularly those with a strong inflammatory or autoimmune component. A key factor contributing to inflammation-associated pathologies is endothelial cell (EC) dysfunction. This proposal aims to elucidate the molecular basis of sex-dependent differences in EC functions that may shape the outcomes of angiogenesis-driven diseases and aging in general. Our recent findings revealed that female ECs exhibit higher inflammation and reactive oxygen species (ROS) accumulation, with reduced angiogenic potential. These findings suggest biological sexual dimorphism in EC function, although the molecular mechanisms underlying these differences remain unclear. Toll-like receptors (TLRs), key innate proinflammatory mediators, recognize molecular patterns, including both pathogens and endogenous ligands generated by tissue damage and excessive oxidation. Analysis of multiple RNA sequencing datasets revealed that TLR2 and TLR4 pathways, specifically in ECs, are among the most significantly dysregulated in inflammation-associated pathologies and senescence. Moreover, gene expression profiling demonstrates that TLR2/4-related pathways are upregulated in female ECs compared to male ECs in vivo and in vitro. This upregulation seems to be driven by both increased TLR expression and higher levels of endogenous TLR ligands in females, collectively amplifying inflammatory responses. In vivo vascularization models showed a more substantial inflammatory component coupled with impaired angiogenesis and vascular remodeling in females. In EC-specific dual TLR2/4 knockout mice, eliminating these receptors abolished the pronounced differences between females and males in vascular models. This indicates that TLR2/4 pathways dominate sex-related differences in EC functions. While sex- specific differences in vascular diseases can arise from genetic, hormonal, or environmental factors, most research to date has focused on sex hormones. This project aims to shift the focus toward exploring the genetic components, particularly the role of endothelial TLR2 and TLR4 pathways in mediating these differences. Herein, we propose a new hypothesis: TLR2 and TLR4 on the endothelium are critical regulators of vascular responses, and augmented TLR2/4 activation contributes to increased vascular inflammation in females. We propose that endothelial TLR2/4-signaling is required for timely injury responses and tissue regeneration by regulating cytokine production and recruitment of inflammatory cells in females. We will utilize innovative transgenic mouse models, a pharmacological approach using phospholipid-based Reactive Carbonyl Scavengers (RCS) limiting the generation of TLR2 and TLR4, and state-of-the-art proteomics. Our studies will provide insights into the role of innate immune mechanisms in ECs and enhance our understanding of the genetic mechanisms responsible for sex differences in vascular pathologies, leading to more efficient therapeutics for both men and women.

NINDS - National Institute of Neurological Disorders and Stroke

Abstract The development of advanced biomaterials capable of electrical signal transmission is vital for regenerative medicine and bioelectronics, with injectable conductive nanogels showing significant promise. While naturally occurring, biocompatible extracellular conductive nanowires (ECNs) from anaerobic bacteria, such as the multi- heme cytochrome proteins, offer a compelling solution to the limitations of synthetic materials (e.g., solubility and biocompatibility), their widespread application is currently limited by challenges in their rational engineering and efficient production. Specifically, the recently discovered ECN protein family has not yet been integrated into recent novel AI protein design tools, and their complex in vivo assembly mechanisms remain poorly understood. This proposal will bridge these gaps by first identifying and engineering OmcE cytochrome nanowires that form large, ordered bundles. This involves comprehensive large-scale genomic and AlphaFold3-guided virtual screens to pinpoint novel OmcE homologs, followed by high-resolution cryo-EM characterization to elucidate their structural details and bulk conductivity measurements to confirm electrical properties. Subsequently, state- of-the-art AI tools will be employed to engineer novel OmcE variants exhibiting robust self-assembly into advanced conductive nanogels. Simultaneously, another major objective is to visualize the OmcE secretion system in situ to unravel its intricate assembly mechanism. We hypothesize that these nanowires assemble via a large outer membrane porin, analogous to the chaperone-usher pathway. Sub-tomogram averaging will be utilized to reconstruct the porin's structure at sub-nanometer resolution, providing critical molecular blueprints for the rational design of OmcE variants with enhanced self-assembly properties and enabling their efficient recombinant overexpression. Ultimately, this work will facilitate the precise engineering of "super" OmcE nanowires for conductive nanogels, offering transformative insights into their biosynthesis and establishing a foundation for a new generation of protein-based bioelectronic materials.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY Genome editing is rapidly transforming biology and medicine by enabling the precise modification of DNA sequences in vivo. The technologies used for genome editing have also provided a means to modulate the expression of a target gene by facilitating the recruitment of transcriptional effector domains to a target site. One such tool capable of recreating the native mechanisms of gene activation consists of catalytically inactive Cas9 (dCas9) fused with the histone acetyltransferase p300, which, by acetylating histones near a target site, can activate gene expression through a nearly physiological approach. Nonetheless, current dCas9-p300 systems are inefficient, unpredictable, and incompatible with adeno-associated virus (AAV) delivery, which hinders future applications of this technology. Here, we propose to integrate state-of-the-art techniques including protein engineering, machine learning, and viral-vector design to create an innovative toolkit of epigenome editors that can be used to activate gene expression in vivo. Aim 1 will leverage phylogenetic diversity and directed evolution in mammalian cells to identify p300 variants with enhance gene activation capabilities. In Aim 2, we will develop machine-learning models that integrate target-site sequence features and nucleosome architecture to predict actionable target sites for efficient acetylation and gene activation. And, in Aim 3, we will engineer split-intein and ultracompact epigenome editors that can be packaged within single or dual AAV vectors to enable in vivo gene activation. To accomplish these objectives, we have assembled a multidisciplinary team with collective expertise in epigenome editing (Dr. Perez-Pinera), computational biology (Dr. Song) and AAV gene delivery (Dr. Gaj). Our collaborative efforts will: (1) yield a toolkit of programmable, tunable, and deliverable gene-activation tools, (2) facilitate the discovery of fundamental principles for epigenome editor design, and (3) enable the development of therapeutic applications for multiple disorders including developmental and metabolic disorders. We anticipate that the innovative and interdisciplinary nature of this proposal will yield technologies that will broadly impact biotechnology and medicine.

NIAID - National Institute of Allergy and Infectious Diseases

New HIV infections continue and cannot be eradicated by current treatments due to a life-long reservoir of infected cells. This key obstacle to cure HIV consists of a reservoir of latently infected CD4+ T cells that persist despite long-term antiretroviral therapy (ART) and cause rebound of viremia if ART is interrupted. The R37 award AI157862 “Enhanced latency reversal and reservoir clearance in macaques” was funded in July 2021 with the overarching objective to obtain a deeper and broader understanding of the latency reversal induced by a SMAC mimetic (SMACm) and its potential to reduce persistent reservoirs using an innovative “kick and kill” approach. We have learned that treatment of SIV-infected, ART-suppressed macaques with the SMACm AZD5582, that activates the ncNF-kB signaling pathway, reactivates rebound competent latent reservoirs throughout the body. We also learned that the combination of AZD5582 and the BCL-2 inhibitor venetoclax reduced the intact SIV reservoir in peripheral blood and bone marrow but did not delay viral rebound after ART interruption. These findings highlight the intricate relationship between latency reversal, reservoir size, and viral rebound. We have three priority areas for the next phase of this R37 award that build on our body of work using venetoclax as well as broadly neutralizing antibodies (bNAbs), that have both antiviral and pro-immune effects. First, focus on reservoir establishment as an optimal time to intervene (rather than the maintenance phase). Second, focus on the antiviral immunity needed to complement venetoclax as a reservoir reducing intervention. And third, a deep dive into how the spatial landscape and immunovirologic features of infection are influenced by venetoclax. Our Central Hypothesis is that bNAb therapy will synergize with promotion of infected cell apoptosis through BCL-2 inhibition to limit reservoir formation. Using our expertise in conducting rigorous in vivo studies in nonhuman primates and immunovirologic multiomic analyses, we will test our hypothesis in three Specific Aims: 1) Define how venetoclax combined with bNAb therapy during early ART impacts decay of viremia, the intact reservoir, and the spatial landscape of infection; 2) Determine how venetoclax combined with bNAb therapy during early ART influences antiviral immune responses in a tissue-specific context; 3) Evaluate the virologic and immunologic impact of venetoclax and bNAb therapy given at start of ART versus at ART interruption. The experiments proposed will provide new evidence regarding the mechanisms of HIV/SIV reservoir establishment and how this process may be perturbed. Our experiments will evaluate safety and efficacy in a preclinical model. We hope that the results we generate will contribute to a cure for people living with HIV. RELEVANCE (See instructions): New HIV infections continue and cannot be eradicated by current treatments due to a life-long reservoir of infected cells. The goal of our research program is to identify targeted immunotherapies that reduce HIV reservoir formation when given early in infection with antiretroviral treatment. Our experiments will evaluate safety and efficacy in a preclinical model to inform approaches to cure HIV.

NIA - National Institute on Aging

Alzheimer’s disease and related dementias (ADRD) are a growing public health burden and understanding modifiable ADRD causes is a national priority. Many classes of environmental chemicals, such as pesticides and per- and polyfluoroalkyl substances (PFASs) contain known neurotoxicants and are thus likely to contribute to ADRD risk, but we lack prospective data with appropriate temporality (exposures measured years before cognitive outcomes) in large and representative populations. Leveraging stored biospecimens from one of the largest, longitudinal, population-based United States cohorts, the Health and Retirement Study (HRS), we will generate a publicly available, prospective, environmental chemical resource, with exposure measures many years before the onset of ADRD or preclinical impairment. HRS participants are ages 50 and older and they have extensive existing biannual cognitive measures and ADRD fluid biomarker measures. Specifically, in Aim 1, we will perform new state-of-the-art non-targeted analysis in serum to measure chemical levels, including PFAS and pesticides, and test for association with cognitive function and decline, ADRD biomarker levels, and ADRD incidence. People are simultaneously exposed to pesticides, PFAS, and other chemicals in the neighborhoods where they live, work, play, and socialize. Social exposures, at the individual- and neighborhood-level contribute to stress and ADRD risk. Chemical and social exposure levels differ across US neighborhoods, with variation by geography and socioeconomic status. Therefore, in Aim 2, we will integrate mixtures of chemical and social exposures into the “exposome”, representing the totality of a person’s environment, when examining complex environmental contributors to ADRD. Additional evidence linking exposures and ADRD can be provided by intermediate molecular markers. These molecular intermediates may serve: 1) as biomarkers of exposure useful when direct exposure measures are not possible, 2) as mediators mechanistically linking exposure and ADRD, and 3) as connecting networks informing on overlapping pathways to deepen chemical and ADRD response understanding. In Aim 3, we will leverage existing measures of molecular intermediates, including DNA methylation, RNA expression, and immune cell profiles, with new measures of endogenous metabolomics and lipidomics, to assess molecular markers as exposure biomarkers or mediators to link exposures with incident cognitive status. Together, this project will identify individual chemicals, mixtures of chemicals, and their pathways that contribute to ADRD risk in a nationally representative sample, which will support ADRD prevention and intervention. Given widespread exposure levels to these environmental chemicals in the US, even modest associations with ADRD could represent a substantial number of preventable cases through individual- and population-level actions.

NIH

The overall goal of the proposed CDA-2 is for Dr. Fischer to obtain advanced training in various methods of psychiatric genomics (e.g., statistical genetics, epigenetics, transcriptomics) that he can use to supplement and strengthen his existing program of research, which examines environmental risk and protective factors for various psychiatric disorders and clinical problems, including suicidal thoughts and behaviors (STBs). This training will enable Dr. Fischer to systematically and comprehensively examine the biopsychosocial etiology of STBs, which will ultimately help to inform the treatment and prevention of STBs in U.S. Veterans. To accomplish this goal, Dr. Fischer will investigate how environmental (i.e., psychosocial) risk and protective factors interact with polygenic liability for STBs, along with how epigenetic processes are associated with STB phenotypes (i.e., suicidal ideation and suicide attempts). This project is innovative in that it will be one of the first to examine whether psychosocial risk and protective factors potentiate or mitigate polygenic risk for suicide in U.S. Veterans. It will also be, by far, the largest study to date on the epigenomics of STBs and the first to derive methylation risk scores for STBs. The proposed study will leverage cutting-edge statistical methods and state-of-the-art bioinformatics to provide novel insights into the complex etiology of STBs that will ultimately help inform efforts to reduce Veteran death by suicide. This CDA-2 grant will build on Dr. Fischer’s strong scientific background in Veteran mental health, psychiatric epidemiology, and environmental risk and protective factors, along with his ongoing experiences as a clinical psychologist, to provide him with crucial new knowledge and skills, which will support the generation of novel, multidisciplinary research. Through the proposed CDA-2, Dr. Fischer will develop the ability to: 1) generate polygenic risk scores; 2) conduct gene enrichment analyses and transcriptome-wide association studies (TWAS); 3) perform drug repurposing analyses; 4) conduct epigenome-wide association studies (EWAS); 5) derive methylation risk scores; and 6) leverage advanced machine learning approaches to evaluate multi-level predictive models. Dr. Fischer’s multidisciplinary mentorship team is composed of world-leading experts working within the VA Connecticut Healthcare System and Yale University. The high-quality research and collaborative environment present at these institutions will facilitate Dr. Fischer’s transition into an independent VA researcher and equip him with the tools needed to produce impactful, innovative research that advances the U.S. Department of Veterans Affairs top research and clinical goals: suicide prevention.

NIEHS - National Institute of Environmental Health Sciences

ABSTRACT Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants known for their widespread use and adverse effects on human health (e.g., metabolic disease, cancer). Early-life exposure to PFAS is of particular concern as developmental periods are a critical window of vulnerability during which disruptions to the gut microbiota and host metabolism can have long-lasting consequences. Infants and young children are exposed to PFAS through breast milk, formula, and contaminated food or water. Despite the recognition that many environmental pollutants influence the gut microbiota, there is a lack of research assessing PFAS-induced microbiome toxicity using quantifiable and biologically meaningful endpoints. Further, given the essential connection between the host and microbiome, there is a critical need to study the impact of PFAS on the physiology and function of gut microbes and the resulting effects on host health. The proposed studies will address these gaps by elucidating the mechanisms by which PFAS influences host-microbiome interactions. The central hypothesis of this grant is that gut microbes modify PFAS toxicokinetics and mediate PFAS- associated health outcomes via the disruption of host-microbe homeostasis. Herein we present a paradigm- shifting view of bacterial-mediated mechanisms of PFAS toxicity. Two specific aims will test this hypothesis: Specific Aim 1 will evaluate the effects of PFAS on diverse gut microbes to understand microbial toxicity, bioaccumulation, and adaptation in microbial species key to health. For Specific Aim 2, mouse models will be used to determine how early-life PFAS exposure disrupts the host-gut microbiome axis leading to metabolic disorders in adulthood. Our interdisciplinary team combines expertise in perfluorinated chemical toxicology, microbiology, metabolomics, and biostatistics. To comprehensively study how PFAS exposure is linked to detrimental health outcomes, our studies use state-of-the-art technologies (e.g., metagenomics, metabolomics) to explore microbial toxicity and the broader effects of environmental chemicals on gut microbiome and its community structure and function. Results from the proposed studies will provide new and impactful data that will provide for more personalized risk assessment frameworks and support the development of microbiome- centered therapeutic strategies to mitigate the health impacts of PFAS.

Erie Community Foundation

Erie Community Foundation ($300M in assets) supports nonprofits in PA through grants focused on education, community development, health, arts. Awards range from $2,000 to $100,000.

Esmee Fairbairn Foundation

45M+ GBP/year across arts, children & young people, environment, and food. One of UK's largest independent funders.

NCI - National Cancer Institute

Project Summary The postnatal development of the mammary gland is dependent on a multitude of cellular programs that are orchestrated by steroid and peptide hormones as well as locally produced cytokines. Two Janus kinases, JAK1 and JAK2, are obligatory intracellular signaling mediators of many peptide hormones and cytokines that have essential functions for the growth, differentiation, and survival of the mammary epithelium. Previous work from several laboratories including our own has established that JAK1 and JAK2 have non-redundant functions for the activation of specific Signal Transducers and Activators of Transcription (STATs) in normal and neoplastic epithelial cells. Important roles of these canonical JAK/STAT signaling cascades during mammogenesis are generally thought to be limited to the differentiation and remodeling of alveolar cells during the gestation cycle. In contrast to this notion, our team has discovered that JAK1 and JAK2 synergistically control the postnatal development of the mammary epithelial ductal tree. We uncovered that STAT proteins are activated in a compensatory manner in ductal epithelial cells, but the collective results from several genetically engineered mouse models revealed that the cooperative functions of JAK1 and JAK2 are not facilitated by their downstream STATs. Unlike in JAK1/2 mammary-specific double knockout mice, the growth and survival of mammary epithelial cells do not require the expression and/or activation of the seven known mammalian STAT proteins. We, therefore, propose that the biologically relevant functions of JAKs during postnatal mammary gland development are facilitated by noncanonical molecular signaling mechanisms of JAK1 and JAK2. Additional preliminary findings also raise the issue of whether the significant biological roles of JAKs are solely dependent on the functionality of their tyrosine kinase domains. To interrogate the noncanonical functions of JAK signaling, we will first establish whether the JAK1/2-dependent signaling mechanisms that govern the development of a mammary gland are dependent on the kinase and/or scaffold functions of JAKs (aim 1). Next, we will investigate the activation of JAK substrates that are currently known and use state-of-the-art genomic and proteomic approaches to identify novel targets and pathways that rely on JAK1 and JAK2 without the expression and activation of STATs (aim 2). Since JAK1/2 kinase inhibitors were clinically ineffective in treating advanced breast cancers, we will investigate the significance of noncanonical JAK signaling in mammary tumor cells and the effects of pharmacologically targeting JAK1/2 for degradation in human-relevant breast cancer models (aim 3). The collective outcomes of this project are expected to provide substantial new insights into the central roles of peptide hormone and cytokine signaling in mammary gland development. The anticipated results from the three aims will elucidate novel molecular mechanisms by which Janus kinases signal within normal and neoplastic epithelial cells beyond the activation of STAT proteins and establish whether pharmacologically targeting JAK1/2 for degradation is a suitable strategy for the treatment of breast cancer.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY A functional cure for HIV that maintains lifelong suppression of viremia without antiretroviral therapy (ART) remains an urgent unmet need. Broadly neutralizing antibodies (bnAbs) can control HIV, but vaccines have failed to induce them because they require unusual structural features that are not readily generated by natural B cell maturation. Genome engineering now allows mature bnAb genes to be inserted into the immunoglobulin heavy chain (IgH) locus of primary B cells, where they function as antigen receptors capable of undergoing germinal center maturation and forming memory responses. In mice, IgH-reprogrammed B cells generate durable bnAb titers near therapeutic levels after vaccination. However, the in vivo behavior of genome-engineered human B cells has not been tested due to the lack of an appropriate model. The recently developed Truly Human Xenograft (THX) mouse supports robust antigen-dependent human B cell responses and thus provides a unique opportunity to establish a preclinical platform for engineered B cell therapies. In Specific Aim 1, we will determine whether IgH-reprogrammed human B cells can participate in germinal center reactions and generate memory and long-lived plasma cells following vaccination in THX mice. In Specific Aim 2, we will establish an HIV infection and treatment model in THX mice, adapting mucosal challenge, ART suppression, and analytical treatment interruption protocols to evaluate viral rebound and reservoir establishment. Completion of these aims will demonstrate feasibility of eliciting vaccine-responsive bnAb memory responses from genome-engineered human B cells in vivo, while also establishing the THX mouse as a physiologically relevant platform for HIV infection and treatment studies. Together, this work will provide a critical foundation for advancing engineered B cell vaccines as a potential functional cure for HIV.

NIMH - National Institute of Mental Health

ABSTRACT The long term goals of these studies are to identify motor imitation as a biomarker of autism spectrum disorder (ASD) to both deepen understanding of brain and behavioral mechanisms for comorbid conditions and improve diagnosis with a cost-effective, objective, and reliable assessment method we developed. Although ASD is defined by core deficits in social-communicative functioning and restricted interests and repetitive behaviors, an ASD diagnosis is often accompanied by clear impairments in motor control and learning that present early and persist through childhood and into adulthood. Prominent among these ASD-associated motor impairments is difficulty imitating others’ actions (i.e., motor imitation). Imitation is crucial to social-communicative development, and impaired imitation has long been recognized as a likely contributor to the core difficulties in ASD. Crucially, while movement difficulties are associated with several developmental conditions that commonly co-occur with ASD, including attention deficit hyperactivity disorder (ADHD) and intellectual disability (ID), current literature suggests that deficits in motor imitation may distinguish these overlapping conditions and capture variation relevant to underlying biology of ASD. Efforts to establish imitation as a biomarker of ASD have been hampered by a lack of objective, reliable assessment, with studies thus far applying labor intensive methods that require subjective assessment by highly trained researchers/clinicians. Our team has pioneered the development of an automated Computerized Assessment of Motor Imitation (CAMI) to quantify ASD-associated imitation deficits with better diagnostic discrimination ability than traditional methods. A remaining challenge in developing motor imitation as a phenotypic biomarker is to establish the specific neural mechanisms contributing to imitation deficits. Previous fMRI studies on motor imitation in ASD have shown mixed results, possibly due to the significant limitations in assessing naturalistic motor imitation in the fMRI scanning environment, where there are substantial constraints on motion. To address this challenge, our team develops high-density diffuse optical tomography (HD-DOT) that enables fMRI-comparable image quality in an open setting. Herein, we propose to establish the specificity of motor imitation impairments (Aim 1) as well as the brain mechanisms underlying such impairments (Aim 2) of ASD relative to ADHD and ID. Our proposed study, by integrating state-of-the-art methods for quantitative, objective motor imitation assessment and concurrent identification of ASD-specific underlying neural correlates, has substantial potential to profoundly improve predictive diagnostic utility over current subjective clinical assessments and thereby aid public health efforts to identify and support affected children. ASD-specific neurobehavioral biomarkers identified through our proposed CAMI and HD-DOT methods may advance clinical subtyping of ASD and opportunities for individualized treatment, refine monitoring response to intervention, and inform underlying neurobiological mechanisms.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Tuberculosis (TB) in humans results from infection with members of the Mycobacterium tuberculosis complex (MTBC). The disease is endemic in many parts of the world. So is bovine tuberculosis (bTB) - a well-recognized zoonotic disease of bovine species (cattle and buffalo) also caused by infection with members of the MTBC. India has the world’s highest TB burden in humans, with more than 2M new cases and 400,000 TB-related deaths each year. India also hosts the largest bovine herd on the planet (~300M animals), and our recent studies suggest that more than 22M of those animals may suffer from bTB. Yet the risk of zoonotic TB (zTB) resulting from transmission of MTBC from bovines to humans in India and other high-TB burden settings is unknown. This is a major knowledge gap, and elimination of TB will be considerably more difficult if there is spillover from a domestic livestock reservoir to humans. This is of particular concern in countries such as India where the frequent consumption of unpasteurized milk and close contact with infected animals likely present additional elevated risks for zoonotic transmission. Because of this, the World Health Organization (WHO) and other supranational organizations have developed a "Roadmap for zoonotic TB" that calls for the establishment of a stronger evidence base to improve understanding of the burden and risk pathways of zTB to guide an effective response. To fill these knowledge gaps, we propose studies with the overall objective of estimating the risk associated with zTB in a high-TB-burden setting. We will accomplish this by applying rigorous quantitative risk assessment augmented by state-of-the-art whole-genome sequence (WGS)-based molecular epidemiology and multi-host transmission modeling. Performed at well-established study sites in Vellore and Tiruvallur districts in Tamil Nadu, India, our Specific Aims are to: 1) Estimate the risk of human TB associated with exposure to cattle, buffalo, or the consumption of raw milk in ~1,750 human cases and ~3,500 controls; 2) Apply WGS-based approaches to define the genetic diversity and molecular epidemiology and perform phylodynamic and phylogeographic analysis of MTBC lineages circulating in human TB cases, sympatric cattle and buffalo, and locally sourced raw milk; and 3) Perform multi-host transmission modeling to quantitatively assess zTB risk to humans and the potential benefits of control. These studies involve the application of innovative and powerful nested case-control epidemiological surveys with WGS-based genotyping and mathematical modeling. The results of our studies will inform and refine estimates of zTB risk, enable identification of transmission chains at a local scale, and transform our understanding of spillover and circulation of MTBC strains between human and bovine hosts. In the long-term, our findings will provide sustained positive impact through the development of evidence-based approaches to quantify and reduce risk of zTB in support of the global efforts to end TB.

East African Arts & Cultural Association

The East African Arts & Cultural Association will celebrate Seattle Ethiopians' Week with a 5 day public celebration to be held July 2-6, 2017. It will take place at King's Hall located at 2929 27th Ave S. The celebration will convene the Ethiopian community to express their heritage, engage Ethiopian youth in relevant community issues, showcase Ethiopian performing and visual arts, and strengthen mutual understanding and respect between a wide variety of cultures.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY In the era of modern antiretroviral therapy (ART), cardiometabolic diseases have become a leading cause of morbidity and mortality among people with HIV (PWH). Type 2 diabetes, a major contributor to cardiovascular and kidney disease, now affects approximately one in five PWH. PWH face unique metabolic challenges due to HIV infection and ART, including chronic inflammation and disrupted glucose and lipid metabolism. Despite these distinct metabolic derangements, population-specific evidence guiding the pharmacologic management of diabetes in PWH remains limited. This project seeks to generate real-world evidence addressing critical knowledge gaps on the comparative effectiveness of commonly used glucose-lowering agents—metformin, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, and sulfonylureas. The candidate is an internal medicine physician with a background in pharmacoepidemiology at Johns Hopkins University. During the award period, he will be mentored by a multidisciplinary team whose expertise spans diabetes and cardiometabolic comorbidities in PWH, machine learning, and causal inference methods. His long-term career goal is to become an independent clinician-investigator applying innovative machine learning and epidemiologic methods to improve clinical care for PWH with diabetes and other chronic conditions. The overarching objective of this project is to generate robust evidence to inform the pharmacologic management of type 2 diabetes among PWH. The proposed study will focus on three aims: (1) characterize the utilization of glucose-lowering therapies; (2) evaluate the comparative effectiveness of glucose-lowering therapies on glycemic control; and (3) estimate the effect of different glucose-lowering therapies on cardiovascular and renal outcomes and mortality among PWH with diabetes. This work will leverage the North American AIDS Cohort Collaboration on Research and Design (NA- ACCORD), a large, representative, multi-site cohort of over 190,000 people with HIV in the United States and Canada. Comparing glucose-lowering therapies on key clinical outcomes will generate population-specific evidence to inform clinical care for the growing population with HIV and diabetes. In parallel, the project will support the candidate’s development of the expertise needed to become an independent investigator capable of applying advanced quantitative methods to generate robust clinical evidence and improve the treatment of diabetes and other chronic conditions among PWH.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Broadly neutralizing antibodies (bNAbs) are a promising immunotherapy for the treatment and cure of HIV-1. Clinical trials passively infusing bNAbs have proven their ability to significantly reduce viral loads but pre- existing and de novo resistance remains the limiting factor to their success. Rationally designing improved bNAb combinations that impose stronger constraints on viral resistance is required to achieve bNAb control of HIV. As with antiretroviral therapy (ART), successful bNAb strategies will likely require combinations where resistance can only emerge through multiple mutations that incur a high fitness cost. Targeting Env epitopes less tolerant of mutations is central to achieving this goal. Broadly neutralizing antibodies against the CD4bs function by directly blocking viral binding to cellular CD4 receptors on its primary target, CD4 T cells. Since these bNAbs mimic CD4 interactions, CD4bs bNAbs are advantageous in that escape mutations can carry a fitness cost by impairing viral CD4 receptor binding. Additionally, these bNAbs take longer to escape from than antibodies targeting other Env epitopes. Focusing bNAb strategies on the CD4bs therefore shows promise for increasing the difficulty of viral escape. Importantly, recent data has shown that CD4bs bNAbs can have different, non-overlapping resistance mutations, which indicates that a CD4bs bNAb combination could put distinct selection pressures on the CD4 binding site. Thus, we hypothesize that two CD4bs bNAbs together will exert strong selection pressure on the receptor binding site inducing multiple resistance mutations that either delay escape or severely reduce replication. We will test this hypothesis with 2 specific aims: AIM 1. Quantify the ease of virus escape from multiple CD4bs bNAbs and AIM 2. Identify selection pressures imposed by CD4bs bNAb combinations. First, to identify the bNAb pairing with the least overlap in resistance, we will assess neutralization patterns of 3 clinically relevant bNAbs VRC07-523, 1-18, and N49-P9.6 against CD4bs bNAb resistant viruses. We will quantify the resistance overlap between every bNAb pairing and define an optimal combination. To understand if CD4bs bNAbs with distinct resistance phenotypes can indeed delay or prevent the emergence of viral escape, time to escape from this combination will be quantitated in an in vitro CD4 T cell assay. Finally, to get a mechanistic understanding of viral escape from multiple CD4bs bNAbs, we will map mutational escape pathways from the CD4bs bNAb combinations and quantify the impact of each mutation on viral fitness. These findings will reveal if independent resistance mutations arose in response to each bNAb, as well as if gaining resistance exerts a fitness cost. Successful completion of these aims will reveal if including multiple CD4bs bNAbs in combination regimes is advantageous and greatly expand our understanding of CD4bs bNAb neutralization mechanisms. These findings will directly inform new bNAb combination strategies for the treatment and cure of HIV.

NINDS - National Institute of Neurological Disorders and Stroke

Summary Genetic ataxias are slowly progressing neurodegenerative diseases causing severe disability for which no disease-modifying therapy exists. Though individually they are rare diseases, together they affect nearly 15,000 people worldwide. Current clinical scales for assessment of ataxia severity and progression are ineffective for evaluation of treatment effects during the timeframe of typical clinical trials, necessitating inclusion of high numbers of patients, which often is not feasible, to achieve statistically meaningful outcomes. These challenges could be addressed if reliable, sensitive, and preferably minimally invasive biomarkers for ataxia severity and progression were available for use in clinical trials. Unfortunately, such biomarkers do not presently exist. Therefore, we propose an initial study combining both biomarker discovery using proteomic and transcriptomic approaches, and testing of several promising candidate biomarkers in blood samples from patients with the most common dominant and recessive types of genetically inherited ataxia. We will utilize state-of-the-art techniques including Olink®’s proximity extension proteomics, NextGen RNA sequencing, and electrochemiluminescence immunoassays. The analyses will be done in patient plasma and neuronal extracellular vesicles isolated from the plasma, increasing the likelihood of discovering biomarkers reporting on specific biochemical changes in the central nervous system. The study will generate an initial set of potential biomarkers, providing the basis for subsequent, larger testing and validation in the context of R01 or U01 applications, addressing a current urgent gap in developing effective therapies for patients with genetic ataxias. Additionally, the proteomic and transcriptomic data will allow pathway analysis that may shed new light on the mechanisms underlying the pathogenesis of specific types of genetic ataxia, including both common and distinct features among them.

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

SUMMARY Reading comprehension (RC) is one of the most complex skills that we utilize daily and is crucial for functioning in modern society, but despite its significance for academic achievement, employment prospects, and mental health, many children and adults do not exhibit proficient RC abilities. New theoretical models aiming to explain variability in RC suggest a dynamic interplay and co-development among ‘precursor’ foundational and cognitive- linguistic skills, interacting with environmental and socio-ecological factors across the developmental timeline of learning to read. Behavioral and neuroimaging studies in school-age children have demonstrated critical mechanistic support for these multifactorial RC models by identifying the developmental trajectories of precursor skills and further showing that brain areas, tracts, and networks typically underlying language and cognitive skills are also involved in RC. Nevertheless, the precursor skills that support RC start developing in infancy and the brain correlates underlying these precursors begin to develop in utero, which suggests that typical and atypical RC developmental trajectories could diverge long before school age. As such, examining RC development using a multifactorial, longitudinal approach that includes brain and behavior starting in infancy is critical for developing theoretical frameworks that can inform early preventative and intervention strategies. Here, we propose a comprehensive longitudinal study of RC development in which we examine direct and indirect effects on RC from brain, behavioral, familial risk, and environmental data from infancy to adolescence. To achieve this goal, we will combine two existing longitudinal cohorts, one ranging from infancy to late childhood (n = 174) and the other from preschool to early adolescence (n = 137). By applying state-of-the-art pediatric neuroimaging analyses, multiple indicator growth model structural equation models, and an innovative behavior- brain co-development measurement index to this unique, combined dataset, we will be able to identify brain and behavioral measures in infancy that directly and indirectly support subsequent RC development (Aim1). We will further characterize how longitudinal trajectories of behavioral measures as well as brain structure, function, and white matter organization contribute to RC development and how familial risk and environmental factors shape these trajectories (Aim 2). Finally, we will examine how the co-development of brain and behavior, as measured with an innovative co-development index, relates to subsequent RC (Aim 3). If successful, we will contribute the first multifactorial longitudinal model of RC development comprising direct and indirect effects from brain, behavior, brain-behavior co-development, familial risk, and environmental measures beginning in infancy. Understanding RC development using a multifactorial longitudinal lens will be crucial for building theoretical models and developing experimental designs focused on early preventative and intervention approaches long before the start of formal schooling.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract Mechanistic understanding of living things requires our understanding of how proteins and DNA interact together to generate functional chromosomes. The structure and dynamics of chromosomes ultimately controls all functions of cells, and in turn, multicellular organisms, including humans. Understanding chromosome structure and dynamics and the underlying biochemical interactions defining them are central to preserving human health, dealing with genetic disorders, and fighting pathogenic organisms. Dramatic reorganizations of chromosomes occur throughout the cell cycle: in humans, hundred-million-base-pair long DNAs are genetically deactivated and refolded into the metaphase form to facilitate mitosis, following which are reorganized into cell nuclei harboring once again active gene expression. My laboratory studies chromosome structure and dynamics using a novel combination of cell- and molecule-scale mechanics with state-of-the-art genetic, biochemical, single-molecule and mathematical modeling tools. Chromosome mechanics at the nanonewton scale are central to cell division due to large mitotic spindle forces, and the well-defined elasticity of chromosomes also provides a quantitative readout of internal structural changes. Those micron-scale dynamic reorganizations of chromosomes are controlled by piconewton forces and nanometer steps generated by individual protein machines. Direct mechanistic analysis of chromosome organizational principles and their relation to underlying molecular interactions will transform our understanding of how cells interpret, fold and change their genomes. In turn this will advance understanding of pathologies where those functions are impaired including genetic disorders and cancers and will improve our understanding of how to target those functions in pathogenic organisms. Over the next five years my laboratory will analyze roles Structure of Maintenance of Chromosomes protein complexes (SMCs: condensin, cohesin and SMC5/6 in eukaryotes) and other key genome-acting proteins in organizing chromosomes across the three kingdoms of life, using single- molecule mechanics approaches to directly observe their function. In parallel we will use chromosome and nuclear mechanics studies to study their roles in organizing chromatin at the larger scales of metaphase chromosomes and cell nuclei. The remarkable stability of DNA-protein complexes will be studied using single- molecule and cell-level experiments on “facilitated dissociation” (FD), preliminary studies for which indicate that pathways for spontaneous dissociation – the backbone of our understanding of biochemical interactions – may be kinetically irrelevant compared to competitive binding pathways. This promises a complete revision of how we think about binding affinity in the crowded, competing in vivo environment, replacing the concept of a ligand-receptor affinity with a large competition kinetic matrix, with transformative implications for how we think about regulation of biochemical interaction networks in vivo. Experimental results will be linked to mathematical models and coarse-grained computer simulations of molecular function and genome/chromosome folding.

NCI - National Cancer Institute

PROJECT SUMMARY Osimertinib (osi), a third-generation EGFR tyrosine kinase inhibitor (TKI), has significantly improved outcomes for patients with EGFR-mutant lung cancer, but resistance is inevitable, and it is not curative. Understanding the mechanisms driving resistance is critical to developing more effective treatments. Emerging evidence suggests that osi induces replication stress. I am investigating ATR, a kinase activated by replication stress, for its role in promoting cell cycle progression after osi treatment. Additionally, osi-induced replication stress may sensitize tumors to DNA-damaging chemotherapy by overwhelming DNA repair machinery. Consistently, recent clinical trials have shown that combining osi with chemotherapy improves progression-free survival, and trastuzumab deruxtecan (TDXd), the only antibody-drug conjugate approved in lung cancer, is effective against EGFR-TKI- resistant tumors. The central hypothesis of this study is that osi-induced replication stress activates ATR to attenuate this stress and promote cell cycle progression, leading to resistance. Furthermore, ATR inhibition and TDXd is expected to delay tumor relapse following osi treatment. Using patient-derived models, this project will: Aim 1) determine if ATR is necessary to promote cell cycle progression during the acquisition of osi resistance and identify ATR-dependent pathways mediating this process. Aim 2) will evaluate if residual tumors persisting after osi treatment exhibit elevated replication stress and ATR activity, and whether ATR inhibition and TDXd can delay relapse. Human tumors treated with EGFR-TKIs, +/- chemotherapy, will also be profiled using imaging mass spectrometry (IMC) to detect if DNA damage repair (DDR) activity correlates with treatment response and predict sensitivity to ATR inhibition and TDXd. This research will address the critical need to understand the role of ATR activity in osi resistance and provide novel insights into the presence of DDR in human tumors. Together these insights will explore the clinical potential of ATR inhibitors and TDXd for treating EGFR-mutant tumors. The project will utilize Yale School of Medicine’s (YSM) state-of-the-art facilities, confocal microscopes from the Yale Center for Cellular and Molecular Imaging (CCMI) and a Cytometry Time-Of-Flight (CyTOF) Helios Imaging Mass Cytometer for the IMC study. Access to patient-derived cell lines (PDCs) and xenograft tissues (PDXs) from the Yale Advanced-Stage Lung Cancer Tissue Collection Study, managed by the Sponsor, will further facilitate this research. This F31 Fellowship will provide the Principal Investigator (PI) with essential training in advanced techniques such as mass spectrometry and IMC while supporting the PI's development in translational research skills and scientific communication. Additionally, acquiring this training is crucial for the PI who intends to pursue a future career studying therapeutic biomarkers, that target synthetic lethal interactions, to bridge gaps in cancer patient care with translational research. Leveraging the F31 Fellowship to maximize resources and training will ensure the project's success and support the PI’s growth into an independent researcher.

Eyebeam

Residency grants for artists working at the intersection of art, technology, and social justice.

NIGMS - National Institute of General Medical Sciences

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.

U.S. National Science Foundation

To facilitate fundamental research in the atmospheric sciences, the Division of Atmospheric and Geospace Sciences (AGS) supports state-of-the-art instruments and facilities through the Facilities for Atmospheric Research and Education (FARE) Program. The FARE Program includes the Lower Atmosphere Observing Facilities (LAOF) and the Community Instruments and Facilities (CIF). Lower Atmospheric Observing Facilities The National Science Foundation (NSF) Division of Atmospheric and Geospace Sciences (AGS)Lower Atmospheric Observing Facilities (LAOF) Program oversees a portfolio of multi-user national facilities that are sponsored by NSF for use by the geosciences research community. Program management resides within AGS in the NCAR and Facilities Section (NFS) which provides a single point for coordination of planning and resources.The LAOF program enables geoscience research through the provision of specialized facilities, instrumentation, and field support services necessary to carry out the scientific field work associated with investigations of a wide range of geophysical phenomena. The program is actively involved in oversight of LAOF facilities and decisions about the acquisition, operation, maintenance, upgrading and replacement of these facilities based on input from the scientific community. LAOF funding supports both the planning for scientific field programs (e.g., experimental design, operational plans, logistical support) and the deployment of NSF-sponsored facilities. Proposals to the LAOF program are acceptedby invitation only. Please contact the FARE program director if you intend to submit a proposal to this program. Community Instrumentation and Facilities (CIF) The CIF program provides the NSF-sponsored atmospheric sciences research community with access to specialized instrumentation for field and laboratory-based studies.The program requests proposals from instrument and facility providers who will make their equipment available for community use through an NSF-defined request process.Support will be provided for limited technician time, minor upgrades, and travel for outreach.

U.S. National Science Foundation

To facilitate fundamental research in the atmospheric sciences, the Division of Atmospheric and Geospace Sciences (AGS) supports state-of-the-art instruments and facilities through the Facilities for Atmospheric Research and Education (FARE) Program. The FARE Program includes the Lower Atmosphere Observing Facilities (LAOF) and the Community Instruments and Facilities (CIF). Lower Atmospheric Observing Facilities The National Science Foundation (NSF) Division of Atmospheric and Geospace Sciences (AGS)Lower Atmospheric Observing Facilities (LAOF) Program oversees a portfolio of multi-user national facilities that are sponsored by NSF for use by the geosciences research community. Program management resides within AGS in the NCAR and Facilities Section (NFS) which provides a single point for coordination of planning and resources.<br /><br />The LAOF program enables geoscience research through the provision of specialized facilities, instrumentation, and field support services necessary to carry out the scientific field work associated with investigations of a wide range of geophysical phenomena. The program is actively involved in oversight of LAOF facilities and decisions about the acquisition, operation, maintenance, upgrading and replacement of these facilities based on input from the scientific community. LAOF funding supports both the planning for scientific field programs (e.g., experimental design, operational plans, logistical support) and the deployment of NSF-sponsored facilities. Proposals to the LAOF program are acceptedby invitation only. Please contact the FARE program director if you intend to submit a proposal to this program. Community Instrumentation and Facilities (CIF) The CIF program provides the NSF-sponsored atmospheric sciences research community with access to specialized instrumentation for field and laboratory-based studies.The program requests proposals from instrument and facility providers who will make their equipment available for community use through an NSF-defined request process.Support will be provided for limited technician time, minor upgrades, and travel for outreach.