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NIDCR - National Institute of Dental and Craniofacial Research

Project Summary The overarching goal of this R03 proposal is reduce the moisture sensitivity of dental adhesives by incorporating cellulose nanocrystals (CNCs). This work is motivated by prior research in related engineering applications (e.g., pressure sensitive adhesives, coatings) demonstrating that CNCs decrease moisture sensitivity of polymeric matrices. Despite this prior art, systematic investigation of CNC impact on dental adhesive materials has yet to be undertaken. This constitutes a major gap, as moisture sensitivity is a significant contributor to the high rate of secondary caries and therefore identifying benign materials that can address this issue is of utmost importance. Furthermore, the proposed specific aims will determine fundamental interactions between CNCs and water, determining if ‘bound’ water within a polymerized adhesive delays or eliminates water-mediated degradation mechanisms. I am qualified to lead this project, as previous and ongoing work from my research team investigates reduced water sensitivity in food packaging and adhesive materials modified with cellulose nanomaterials. Furthermore, my expertise in photopolymerized polymer networks employed as dental materials complements this expertise and makes me uniquely qualified to oversee this investigation. Building upon this foundation and expertise, the overarching hypothesis for this proposal is that long-term stability of the adhesive layer will be enhanced when CNCs are uniformly incorporated and distributed within a photopolymerized dental adhesive. This project consists of two Specific Aims. In Specific Aim 1, I will determine how the distribution of CNCs varies based on the composition of model self-etch adhesives, and how this distribution impacts moisture sensitivity, network properties, and adhesive performance when exposed to moisture. This is motivated by the high degree of heterogeneity associated with currently employed adhesive systems. In Specific Aim 2, different surface functionalizations will be explored to optimize and modify the distribution of CNCs within adhesive networks and potentially improve the impact of these additives on adhesive performance. Given the heterogeneous nature of adhesive materials, I expect surface functionalization will enable more effective distribution. This area of research constitutes a new domain at this early-stage of my career, and thus the results from this award will serve as motivation to investigate a more diverse range of bio-sourced nanomaterials (e.g., functionalization, geometries) for restoration systems where biomaterial-water interactions need to be tailored.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Cocaine use disorder (CUD) is highly comorbid in people with HIV (PWH) and can accelerate infection, alter neuropathology, and exacerbate cognitive decline despite antiretroviral therapy (ART). Many of these effects are due to the infection and dysregulation of CNS-associated myeloid cells, especially microglia, which comprise a significant reservoir in this compartment. However, the precise mechanisms by which cocaine (Coc) dysregulates microglia to enhance HIV infection are unclear, partly due to the lack of translationally relevant human microglial models suitable for mechanistic evaluation of Coc-mediated changes in viral dynamics. Classically, Coc has been thought to act by blocking dopamine transporter (DAT) activity, exposing microglia to aberrantly high dopamine concentrations. Our data show that dopamine can increase HIV infection and inflammation in microglia and other myeloid cells. However, recent data show that Coc has other mechanisms of action beyond the modulation of dopaminergic tone, involving the ER protein sigma1 (σ1), which has diverse cellular functions including the modulation of cellular stress pathways such as the unfolded protein response (UPR). Viruses, including HIV, can exploit the UPR to amplify stress-induced protein production in the host cell, enhancing viral replication. Our preliminary studies indicate that Coc’s effects on σ1 may drive a Coc-mediated increase in HIV infection in microglia, potentially through increased stress response and independent of dopamine’s effects. My preliminary data show that both Coc and σ1 agonists increase HIV replication in human inducible pluripotent stem cell (iPSC)-derived microglia (iMg). These effects are blocked by σ1 antagonism but not by inhibition of DAT or dopamine receptors. We also show increased σ1 protein expression and recruitment to the ER/nuclear envelope space in HIV-infected iMg treated with Coc, and preliminary single-cell RNAseq data suggest changes in the UPR. Therefore, we hypothesize that Coc-mediated activation of σ1 increases HIV infection of microglia via activation of the UPR. In Aim 1, we will test the involvement of σ1 in driving Coc-mediated changes in HIV infection of iMg using pharmacological and genetic modulation, and we will also confirm the absence of dopaminergic involvement. We will assess changes in viral dynamics using AlphaLISA and immunofluorescence (IF) high-content imaging. In Aim 2, we will test the hypothesis that Coc induces greater σ1 activity in the presence of HIV infection utilizing confocal and high-content IF imaging of σ1 subcellular localization in cellular compartments like the nuclear envelope, ER, and mitochondria-associated ER membrane. Movement of σ1 to these compartments is a feature of σ1 activation. In Aim 3, we will use single-cell RNAseq to test the hypothesis that Coc-induced σ1 activity drives increased HIV infection in iMg via upregulation of UPR genes. The results from these experiments will not only define novel interactions between HIV and σ1 that could reveal new antiretroviral targets but will also broadly inform on the role of σ1 in microglia and potentially identify biomarkers for prevention strategies against CUD and its associated comorbid diseases.

NIGMS - National Institute of General Medical Sciences

Abstract This proposal seeks to understand emerging non-canonical roles of phosphagen kinases in cellular and organismal stress responses. Phosphagen kinases are a class of enzymes that include creatine kinases. They are well-known to support energy balance, but other functions are less well-understood. Recent research suggests that augmenting the activity of these enzymes may be sufficient to increase cellular stress responses, which are important in preserving tissue health during aging and disease. This makes phosphagen kinases potentially exciting targets for aging and disease intervention, but we still don’t fully understand how they work. Furthermore, their functions may depend on which tissues different versions of the enzymes are present in and what they are doing in each tissue. Understanding tissue-specific roles of enzymes is challenging in humans and laboratory models such as rodents and cell culture. In contrast, the roundworm, C. elegans, is a well-established and efficient model system that is perfectly suited for addressing these questions, and it shares many genes and biological processes in common with humans. In this study, we propose to use this model to: 1) Identify which of three different versions of phosphagen kinases support tolerance to diverse stresses 2) Test the hypothesis that phosphagen kinases protect cells by acting similarly to antioxidants and preserving the function of energy machinery. Simultaneously, identify which tissues are most affected by phosphagen kinase function and sensitive to its loss through tissue-specific genetic manipulations. 3) Determine whether phosphagen kinase function changes the way other enzymes and genes act to support stress response using new genetic sequencing technologies. Altogether, this work will illuminate mechanisms of phosphagen kinase function under stress. paving the way for novel aging and disease interventions. Furthermore, through this funding, at least 9 undergraduate students and 2 graduate students will be trained in state-of-the-art biomedical science, fostering the next generation of scientists and America’s continued superiority in biomedical research.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract The forkhead box (FOX) family of transcription factors (TFs) regulate key biological processes across eukaryotes. One member, FOXG1, functions as a transcriptional repressor which regulates neurodevelopment within embryonic brains, and has been implicated in a range of neurodevelopmental disorders. The FOX family of TFs is defined by the presence of a conserved DNA-binding domain (DBD). The molecular mechanisms of this DBD on its own, and how mutations to this region impair its function and lead to disease, have been well studied. However, how the intrinsically disordered regions (IDRs) outside of the folded DBD influence FOX TF function remains understudied. There is a critical need to understand the role of these IDRs given that dozens of disease-associated mutations have been identified within the IDRs of FOXG1. In the proposed work, we aim to investigate the role of IDRs on FOXG1 chromatin binding, nuclear organization, and function in gene regulation. My preliminary data have revealed that FOXG1 forms nanoscale clusters in nuclei of live cells which drives its tight binding to chromatin. However, a disease-associated variant of FOXG1, which has truncations within its central IDR, no longer forms DNA-associated clusters. Additionally, I found that FOXG1 forms biomolecular condensates via phase separation which contributes to its association with DNA. Biomolecular condensates are dynamic structures often formed through IDR-mediated phase separation and have been recently implicated as an underlying mechanism for TF clustering in vivo to regulate gene expression at specific genomic loci. Intriguingly, we found that mutations within the same central IDR of FOXG1 which show a loss in nuclear clustering also show a loss of phase separation. We have identified a conserved enrichment of aromatic amino acids within the central IDR of FOXG1 using a state-of-the-art sequence analysis approach in collaboration with Dr. Rohit Pappu’s group at WashU. I have determined that these conserved aromatic residues are critical for FOXG1 phase separation, nuclear clustering, and chromatin association. From this preliminary data, I hypothesize that FOXG1 utilizes IDR-driven phase separation to form nuclear condensates which directly regulate its chromatin binding and function as a transcriptional repressor. We propose to test this hypothesis with a series of computational, biophysical, and cellular approaches designed to 1) identify critical sequence features within FOXG1 IDRs and predict their function on phase separation and chromatin binding, 2) quantify the effects that individual IDRs and critical amino acid residues have on FOXG1 phase separation, 3) determine how FOXG1 IDRs influence its DNA binding strength at a single-molecule level both in vitro and in cellulo, and 4) identify the role of FOXG1 IDRs in transcriptional repression. Collectively, the results from this study will provide critical insights from single-molecule to mesoscale levels into how IDRs regulate FOX TF activity and how mutations in these regions can lead to disease.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY mRNA & lipid nanoparticle (RNA-LNP) therapeutics are a versatile new drug modality used for vaccines, gene editing, cell reprogramming, & protein replacement. While vaccines aim to stimulate immunity, other applications must avoid immune activation. Achieving the right immune outcome is critical, as unintended responses can lead to harm or therapeutic failure. Much of the focus of RNA-LNP immunity has been on professional antigen presenting cells (pAPC), such dendritic cells (DC). However, RNA-LNP transfect diverse cell types, including hepatocytes & skeletal myocytes, yet little is known about the role, if any, these cells play in RNA-LNP immunity. To understand better the role of non-pAPCs in the immune response to RNA-encoded protein – with the goal of establishing rules for the design of RNA-LNP that can more precisely & safely control the direction of the immune responses – we generated RNAs that are selectively silenced in different cell populations. Our preliminary data indicate that RNA expression within hepatocytes greatly reduces the quantity of Ag-specific T cells, whereas RNA expression in muscle fibers boosts Ag-specific T cells; establishing that these cells are not bystanders, but active participants, in how RNA-LNP immunity unfolds. We also find that unrestricted RNA expression can lead to hepatic & muscle cell killing when there are pre-existing Ag-specific T cells, and this toxicity can be ameliorated using synthetic target sites for hepatocyte- or muscle-specific miRNA to silence the RNA in these cells. The objective of this project is to elucidate the mechanisms by which RNA-LNP transfection & expression in pAPCs and non-pAPCs, specifically myocytes & hepatocytes, modulate the T cell response to RNA-encoded protein, and to harness these insights to improve the safety and efficacy of cancer and CAR T cell vaccines. In Aim 1, we will determine how RNA expression within hepatocytes dampens T cell response, and test whether silencing RNA cancer vaccines in hepatocytes can enhance tumor immunity & reduce toxicity. In Aim 2, we will test the hypothesis that the T cell response to RNA-LNP is boosted by RNA expression in muscle fibers that serve as a prolonged Ag reservoir that maintains T cell stimulation. In Aim 3, we will test the hypothesis that RNA-LNP transfection of hepatocytes & myocytes turns on stress & infection response pathways that results in RNA-derived antigen being transferred from non-pAPCs to pAPCs for T cell education. These studies will utilize a variety of state-of-the-art models, methods, & technologies, including novel RNA formulations for tailored cell expression, genetic mouse models for immune analysis, spatial transcriptomics for identifying the pathways activated by RNA-LNP in tissues, & normathermic machine perfusion to study RNA-LNP in whole human livers. This project will: (1) help define our understanding of how myocytes & hepatocytes contribute to RNA-LNP immunity, (2) provide novel approaches for modulating the direction of RNA-LNP immunity, and (3) enable more tailored design of RNA cancer vaccines that maximize immune activation & minimize healthy cell killing, which can be used to improve immunotherapies.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Abstract Although ART can reduce morbidity and prolong life, it does not cure HIV or fully restore health. Despite ART, people living with HIV (PWH) continue to have higher average levels of inflammation and immune activation, which are thought to be a major cause for the higher incidence of diseases in many organ systems (non-AIDS morbidity) and reduced life expectancy that persist even after years of suppressive ART. While the causes of immune activation may be multifactorial, it is thought that a major cause is the continued expression of HIV RNA, protein, and/or virions by subsets of HIV-infected cells. Within the gut, where most infected cells reside, expression of these viral products likely contributes to dysfunction of the gut mucosal barrier and leakage of gut microbial products into the circulation, leading to further increases in inflammation and immune activation. However, it is not clear which viral products contribute to immune activation and the sequelae of treated HIV. To investigate this question, aim 1 will utilize stored and prospective samples from a cohort of ART-suppressed PWH to determine the degree to which low-level plasma HIV RNA, levels of different cell-associated HIV transcripts of varying maturity, and p24 protein expression in blood and gut correlate with the inflammatory proteome in plasma. It is also unclear what subsets of cells express these viral products, and what factors determine whether a given infected cell will express HIV. To answer these questions, aim 2 will utilize novel single cell approaches to characterize the cell phenotypes, chromatin accessibility, transcriptomes, clonotypes, and surface protein expression of single HIV-infected (HIV DNA+) and HIV-transcribing (HIV RNA+) cells from the blood and gut of ART-suppressed PWH (aim 2A), and will then test how genes identified through single cell RNA-seq (scRNA-seq) affect HIV expression (aim 2B). While HIV researchers have identified some drugs that can inhibit HIV transcription, there is a critical need for new therapies aimed at reducing HIV expression and/or blocking reactivation from latency. We have identified new drugs that appear to block activation-induced increases in HIV transcription and virion release. In aim 3, we will compare both published and new drugs for their ability to enhance baseline blocks to HIV transcription or prevent activation-induced reversal of the blocks to HIV transcription and splicing in cells from the blood and gut of HIV-infected individuals. The results from aims 1-3 could lead directly to the identification of new drug targets and new agents aimed at a functional cure and/or reducing HIV-associated immune activation.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract CD8+ T cells are unique in effective sensing and killing of intracellular pathogen-infected cells and tumor cells. Because current vaccines are designed to induce high titer pathogen-specific antibodies for host protection, new vaccines focused on promoting effective memory CD8+ T cells are needed. Since a single naive CD8+ T cell has the potential to give rise to multiple types of progenies, it is essential to understand how naive T cells are primed to form distinct effector and memory cells. It is generally accepted that the strength of cognate antigen (Ag) stimulation determines the size of the primary response and of the memory cell pool, and that strong cognate Ag signals coupled with robust co-stimulation and cytokines altogether drive naive CD8+ T cells towards an effector rather than a memory cell fate. The current dogma also states that cognate Ag stimulation does not lead to functionally distinct subsets of memory CD8+ T cells. In contrast, however, we recently discovered that the strength and the stability of cognate Ag/MHC interactions with the T cell receptor (TCR) determine the development of memory cell functional characteristics, in particular stem-cell associated characteristics, through epigenetic imprinting. Stem cell memory CD8+ T (TSCM) cells have been shown to exhibit superior functional features, progeny potential, self-renewal capacity and longevity. Using state of the art conditional mouse models, high dimensional spectral flow cytometry, lentiviral-based inducible gain or loss of function experiments, and computational modeling approaches, we will define the features of T cell epitopes, key TCR structural modes of recognition, TCR signaling pathways, genetic and epigenetic regulators that enhance the differentiation of TSCM cells in vivo. We will validate our findings in models of chronic infections and tumors. This research directly impacts the rational design of more effective vaccines and adoptive T cell transfer therapies.

NIEHS - National Institute of Environmental Health Sciences

Preterm birth (PTB) affects 10% of pregnancies globally, with rates rising 12% between 2014-2022, incurring healthcare costs exceeding $25 billion annually in the US alone. While inflammation is a known trigger of PTB, the environmental factors driving this inflammatory response remain poorly understood. A critical knowledge gap exists in understanding how emerging environmental contaminants, particularly micro- and nanoplastic (MNP) particles, associate with PTB and alter placental immune function. Our preliminary data provide compelling evidence that MNPs bioaccumulate in human placentae at concentrations 23.9 times higher than in blood. Using pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS), we found significantly elevated MNP levels in preterm versus term placentae (224.7 vs 175.5 µg/g tissue; p=0.0032), with specific polymers showing 17-157% higher concentrations in preterm cases. The long-term objective of this research is to establish how environmental MNP exposure correlates with adverse pregnancy outcomes and identify modifiable risk factors for PTB prevention. Leveraging our completed longitudinal pregnancy cohort study (the Bacteria and Birth Study; BaBs Trial, n=585; PTB=103, term=367) with comprehensive maternal-infant biospecimens collected from first trimester through 6 weeks postpartum (>93,000 samples), we will: Aim 1) Define temporal patterns of MNP accumulation by quantifying 12 environmentally relevant polymers in maternal blood, urine, placental tissue, and cord blood (n=3,500 specimens) using Py- GC/MS, while integrating data on other environmental toxicants to establish exposure signatures that predict PTB risk; and Aim 2) Characterize the pathophysiology of MNP-associated placental dysfunction through systematic analysis of inflammatory markers (n=1,200 samples), histopathological changes (n=351 placentae), and immune cell distributions mapped by spatial transcriptomics (n=30 placentae). This comprehensive molecular and cellular characterization will establish the foundation for future mechanistic studies using animal models and in vitro systems. This research is innovative in challenging current paradigms of PTB etiology while introducing state-of-the- art methods to track environmental exposures during pregnancy. Our unique approach combines advanced analytical capabilities (Py-GC/MS- submicron plastics detection) with high-resolution spatial profiling to reveal how MNP exposure correlates with altered maternal-fetal immune balance. Success will establish: 1) The first longitudinal assessment of MNP accumulation patterns during pregnancy; 2) Novel biomarkers for identifying at- risk pregnancies; and 3) Key molecular and cellular changes associated with MNP accumulation in human placentae. These findings will directly inform the design of future mechanistic studies while directly providing evidence-based guidance for reducing harmful exposures during pregnancy, particularly benefiting vulnerable populations disproportionately affected by PTB.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY A substantial fraction of the HIV reservoir that persists in the face of antiretroviral therapy (ART) actively expresses a multitude of HIV proteins, yet the mechanisms by which they avoid detection and/or elimination by the immune system is unclear. The features of these “translationally-active” HIV reservoir cells have remained elusive due to lack of tools to identify and characterize them at the single-cell level. In this proposal, we leverage three new technologies we have pioneered and/or adapted to both better understand these cells, as well as to target them therapeutically. The first technology, HIV-prex, is a single-cell sequencing technology we developed to simultaneously characterize the transcriptomes of translationally-active HIV reservoir cells from ART- suppressed people with HIV (PWH). The second technology is MIBI-TOF, a high-parameter imaging method enabling in-depth analysis of translationally-active reservoir cells in their local tissue microenvironments. The last technology is TRACeR, a bioengineered platform we developed to identify and target translationally-active HIV reservoir cells on the basis of their cell-surface presentation of HIV peptides bound to MHC class I (MHC-I). These approaches will be applied across three aims, using both banked and prospectively-collected blood and tissue specimens from the UCSF SCOPE cohort of PWH. In Aim 1, we will establish the transcriptional and proteomic features of translationally-active reservoir cells – including the HIV peptides presented by MHC-I on their cell surfaces – from ART-suppressed PWH, and compare their features to reactivated latent reservoir cells. The features of the active reservoir cells will be tracked longitudinally over the course of 2-20 years of suppressive ART, and be compared between men vs. women. In Aim 2, we will compare the features of translationally-active reservoir cells from blood and multiple tissue compartments (gut, lymph node), as well as establish the spatial context of these cells in the gut, the main site of HIV persistence. In Aim 3, we will develop a novel method to eliminate translationally-active reservoir cells, through re-engineering of the top HIV TRACeRs into BiTE therapeutics, the test their efficacy using in vitro models as well as ex vivo using specimens from PWH. Elimination of translationally-active reservoir cells has important translational value as it can diminish the chronic inflammation linked to co-morbidities in ART-treated PWH. Furthermore, it can help achieve HIV remission given the potential of these cells to cause immune dysfunction and lead to viral rebound upon ART interruption. Collectively, our aims will improve our understanding of translationally-active HIV reservoir cells – an important but poorly understood component of the HIV reservoir – and develop targeted strategies to directly eliminate them.

NIGMS - National Institute of General Medical Sciences

Project Summary The University of Mississippi Medical Center (UMMC) is home to the State’s only academic health science center and has a rich history of high-level biomedical research. As the States only level 1 trauma facility, level IV NICU, Children’s Hospital and Cancer Care Program, Sickle Cell Anemia Program, Transplant Program, and Bone Marrow Transplant Unit, our Hospitals and Clinics treat the most critically ill in Mississippi. In addition, the population of patients consists of the most at risk socioeconomic backgrounds. There is a great need to increase the number of physician scientists trained on the front lines where social and economic determinants greatly impact the health care of our residents. Therefore, the goal of this proposal is to establish and grow the University of Mississippi Medical Center MSTP in order to have a long-term impact to increase clinician scientists uniquely trained to tackle the most challenging problems that our health care system faces. Recognizing the exceptional resources, faculty, and environment at UMMC, leadership heavily invested in the MD/PhD program, setting the groundwork for support of the next generation of MD/PhD students. Over the last 5 years, 10 MD/PhD students have graduated from a variety of graduate programs supported by the School of Graduate Studies that include Cellular and Molecular Biology, Microbiology and Immunology, Experimental Therapeutics and Pharmacology, Neuroscience, Physiology, Biomedical Materials Science, and Population Health. Nearly 80 program faculty provide perspectives from all backgrounds and range from junior to established investigators that have trained over 300 PhD students. State of the art equipment, infrastructure, and research cores established largely by NIGMS funded Centers for Biomedical Research Excellence and the Mississippi Center for Clinical and Translational Research provide an optimal training environment where students can learn whole animal physiology, -omics approaches to understanding disease mechanisms, cell and molecular biology techniques, population health and more. Finally, recruitment strategies and geographical location make UMMC the ideal home to meet NIH goals to train physician scientists that represent a wide range of socio-economic backgrounds.

NIAID - National Institute of Allergy and Infectious Diseases

The University of North Carolina (UNC) Global HIV Prevention and Treatment Clinical Trials Unit (CTU) has a well-established record of high quality, innovative clinical research, strong network and scientific leadership. The CTU engages with critically important populations infected with and at high risk of HIV in southeastern US, southern Africa and southeast Asia. Our CTU is led by three experienced principal investigators (Joseph Eron MD, Mina Hosseinipour MD and David Wohl MD) and will support all four NIH Clinical Trials Networks (CTN); Adult Therapeutic Strategies, HIV Prevention, Vaccine Prevention and Pediatric, Adolescent and Maternal Therapeutic Strategies. Our four experienced Clinical Research Sites (CRS) include Chapel Hill CRS (Adult Strategies, Prevention and Vaccine CTN) led by Dr. Wohl, Greensboro CRS (Adult Strategies, Prevention and Vaccine CTN) led by Cornelius Van Dam MD, Malawi CRS (all four CTN) led by Lameck Chinula MD and Vietnam CRS (Adult Strategies, Prevention and Vaccine CTN) led by Vivian Go PhD. Participants with HIV include those newly diagnosed (including with acute infection), PWH stably suppressed on therapy, PWH with adherence challenges to care or medication, and PWH with drugresistant HIV. We will enroll PWH at risk for comorbidities and PWH or without HIV including those with co-epidemic pathogens such as tuberculosis (TB) and Hepatitis B virus (HBV) which affect USA populations but the higher disease prevalence in Malawi and Vietnam allows research efficiency. We have skilled, experienced clinical and translational investigators working hand-in-hand with junior investigators in US and international settings, who will engage and execute the network scientific agenda. A globally representative set of senior scientists and public health leaders on our Scientific and Strategic Advisory Group advise the CTU leadership team. The CTU administration has a highly organized structure that is responsive to our research teams and CRSs. Each CRS engages the communities representing the affected populations in an interactive, openminded way. State-of-art communication and experienced, outstanding and well-organized laboratory, pharmacy, regulatory, quality and data management support the CTU, CRSs. Using this robust framework the UNC Global CTU is positioned optimally to continue our scientific, and network leadership and clinical trials support to all four NIH HIV networks, contributing to the elimination of HIV and significant co-infections in the USA and globally.

U.S. National Science Foundation

The URO program provides support for operations, technical enhancements, scientific investigations, and student training at university-based radio facilities. A primary function of funded University Radio Observatories is to provide focused research environments that foster hands-on student involvement in state-of-the-art radio astronomy instrumentation. UROs also serve the general astronomical community by providing open access to a substantial fraction of available telescope time.

Friends of Uptown Art Walk

The friends of Uptown Art walk will be launching from May 2nd to May 30th, 2025, a transformative gallery show and community activation revitalizing the Uptown arts scene while championing fat liberation, mutual aid, and inclusion—particularly for QTBIPOC individuals. Through strategic outreach, partnerships with local businesses/arts organizations, and promotion, this project will strengthen participation in Third Thursday Art Walks, fostering a thriving arts ecosystem. FAT, a fat liberation gallery show hosted at The Fishbowl Gallery, located at 323 2nd Ave W will feature artwork, discussions, and interactive programming that challenge societal norms and celebrate fatness. Programming includes an opening reception, vendor market, movement session, speaker event, clothing swap, healing arts workshop, community discussion, and closing reception—empowering attendees to embrace body autonomy and liberation. The event is free and open to the public.

Uptown Arts & Culture Coalition

Uptown Arts & Culture Coalition (UACC) seeks funding for a community movie night at Counterbalance Park on September 19, 2024. This event will engage the neighborhood with a free, family-friendly screening of short films during Uptown Artwalk. Specific event goals: attract 150+ attendees; engage 5+ local businesses for partner promotion; increase Uptown Artwalk attendance; highlight Uptown arts & culture organizations; demonstrate Counterbalance Park's potential as a public, outdoor event venue. Seattle Parks & Recreation will provide A/V; SIFF will provide film curation; Uptown Alliance, Tidy Uptown, Uptown Artwalk, & UACC will share planning and promotion. We hope to purchase ADA-accessible planking to ensure wheelchair access to the gravel-covered park. We seek support for event insurance, film licensing fees, and complimentary refreshments. We respectfully request $3,000 to support this community-led event to benefit residents, artists, and businesses in Uptown.

Shunpike

Shunpike will carry out a three-phase public art project that starts with artist residencies on the former site of Teatro Zinzanni, continues with the Artists of Color Expo & Symposium (ACES) in the Armory at Seattle Center on November 17-18th, and concludes with community-generated and youth-created murals surrounding the Seattle International Film Festival's Uptown Cinema. Resident artists will show their work and speak of their experience at ACES. This will inform the public art intended for the Uptown Cinema murals, ensuring community and youth engagement through a racial equity lens.

Human Impacts Institute

A new round of health and art fellows will work to explore the concept of a �just transition� to make environmental health data and sustainable advancements more accessible to the public.

Human Impacts Institute

A new round of health and art fellows will work to explore the concept of a �just transition� to make environmental health data and sustainable advancements more accessible to the public.

ACC APG - Natick

The Soldier Center is seeking solutions in the following scientific and technical areas: Combat Feeding & Equipment Ration development, field feeding systems Soldier Protection & Survivability Headborne protection, modular armor, chemical/biological protection, nanotechnology Modeling & Simulation Soldier effectiveness, operational survivability Human Performance & Biomechanics Body-worn systems, hand-held devices, soldier-centric sensors Expeditionary Maneuver Support Energy efficiency, EMI/EMP protection, battlefield mobility Aerial Delivery Advanced airdrop systems for personnel and cargo Simulation & Training Technology Medical training, AI-based battlefield visualization, cyberspace warfare training This Broad Agency Announcement (BAA) is intended to fulfill requirements for scientific study and experimentation directed toward advancing state-of-the-art technologies and/or increasing knowledge and understanding as a means of eliminating current technology barriers. This BAA DOES NOT focus on specific systems or hardware solutions. This BAA identifies DEVCOM SOLDIER CENTER research/exploratory development areas of interest and provides prospective offerors information on the preparation of proposals along with proposal evaluation factors. The Government may award purchase orders, contracts, grants, cooperative agreements, or other transactions against this BAA. Read the Full BAA & Submission Guidelines: On SAM.gov https://sam.gov/opp/e8c7609f0f154df4afda846595bca888/view

National Endowment for the Humanities

USA-250: CELEBRATING JOHN PHILIP SOUSA IN SOUTH DAKOTA [IN CELEBRATION OF AMERICA?S 250TH ANNIVERSARY, THE SOUTH DAKOTA STATE UNIVERSITY (SDSU) SCHOOL OF PERFORMING ARTS AND THE OSCAR LARSON PERFORMING ARTS CENTER IN BROOKINGS, SOUTH DAKOTA PROPOSE A DYNAMIC AND HISTORICALLY GROUNDED TWO-DAY PUBLIC SYMPOSIUM AND CONCERT PROGRAM TITLED "USA-250: CELEBRATING JOHN PHILIP SOUSA IN SOUTH DAKOTA." THIS INITIATIVE WILL ILLUMINATE THE ENDURING LEGACY OF JOHN PHILIP SOUSA, WHOSE MUSIC PLAYED A PIVOTAL ROLE IN SHAPING AMERICAN PATRIOTIC IDENTITY.]

NIH

Background: How can we apply the community health worker (CHW) model to help both care partners and Veterans with serious illness in rural areas? Little is known about this approach. We will test a VA-supported intervention successfully piloted in the Durham VA and surrounding rural communities in 2021. VA’s Office of Rural Health, Caregiver Support Program and National Social Work Office are aware and support this work. Significance: Clinically, this work will help improve care for rural Veterans with serious illness by supporting care partners in their caregiving role in the community thus bolstering the care of Veterans receiving primary support from care partners in rural areas. A strength of our intervention is that it adapts and extends a successful model of individualized support commonly used outside of the VA. This approach maximizes the potential for sustainability, broad dissemination, and care delivery impact across the VA. This work will be generalizable. Strategically, this SDR proposal responds to the National Academies report recommending all health systems, including VA, develop processes to routinely identify, assess, and support needs of care partners. Our project meets rural health access, long-term care/aging, engagement science, and caregiving HSR priorities for investigator-initiated research focused on rural populations. Additionally, our proposed efforts fit squarely with the VA’s Rural Health State of the Art conclusion that we must expand VA partnerships in the community and help Veterans and their families understand their options for care and support in the community and at the VA. Innovation & Impact: This project is innovative because of its focus on social and practical needs of care partners, advances the science of community engagement in VA care and support, and situates a care partner- focused community health worker model squarely in the VA system for the first time. The entire project is guided by a Community Advisory Board (CAB) composed of social service, serious illness care, and rural care experts plus Veterans and care partners with lived experience. Specific Aims: Aim 1. Determine CHW effectiveness in reducing care partner burden, increasing Veterans' well-being, and increasing care partner-Veteran satisfaction with VA care in the intervention group compared with the usual care (CSP) group: We will apply our feasible CHW intervention to a larger sample, randomized control trial. (Hl) Care partners randomized to the intervention group will have lower mean Zarit-12 scores at 6 months compared to the control group. (H2) Care partners and Veterans randomized to the intervention group will have higher mean 1-item CAHPS Global Satisfaction scores at 6 months compared to the control group. (H3) Veterans randomized to the intervention group will have higher mean Warwick Edinburgh Mental Well- Being scores at 6 months compared to the control group. Aim 2: Following intervention, explore Veterans' and care partners' experience of care and support using subgroup semi-structured interviews in the intervention group. We then facilitate CAB Delphi Method sessions (including study Veterans, CHWs, and care partners) exploring Aims 1/2 data using equity-focused intervention mapping for wider implementation. Aim 3: Conduct budget impact analysis from the VA perspective to evaluate cost-drivers and assess feasibility to inform adaptation and implementation of the intervention within Durham VA Health Care System. Methodology: Two-arm randomized control trial using validated measures. We follow this using qualitative exploration with participants plus a Delphi method exploring implementation with the community advisory board and participants. We end with a unique business impact analysis of the intervention. Next Steps/Implementation: We are supported/advised by VA’s Office of Rural Health and Caregiver Support Program in Durham, NC with additional advisement from National Social Work Office, Chaplaincy, Palliative Care, county Veteran Services and Area Agencies on Aging (see LOS). If successful, this intervention can be added to the options available from CSP to support rural care partners and their seriously ill Veterans.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

This study aims to develop new methods for detecting pre-cancerous dysplasia on colonoscopy and histology in patients with inflammatory bowel disease (IBD). IBD is associated with a higher incidence of colorectal cancer compared to the general population. However, IBD dysplasia is more difficult to detect on colonoscopy because lesions are flat, irregular in shape, and coincide with inflammation. In efforts to combat visualization problems, most gastroenterologists continue to perform random mucosal biopsy for increased sensitivity of dysplasia detection on colonoscopy. Accessory measures to help enhance dysplasia detection including high- definition endoscopy, dye chromoendoscopy, and narrow band imaging require extensive expertise, increase procedure duration, and have not been definitively shown to improve dysplasia detection rates. In addition to difficulty detecting dysplasia on colonoscopy, pathologists face similar ambiguity when evaluating dozens of biopsies provided from every colonoscopy. Beyond reviewer fatigue, pathologists are challenged to separate inflammation from dysplasia and the grade of severity, typically requiring referral to experts at high volume centers for second opinion review. Machine learning and computer vision methods are well suited to address clinician limitations in detecting visual features of IBD-related colonic dysplasia. Our multi-disciplinary team’s prior work developing methods to improve endoscopic disease activity assessments and quantify histologic imaging using machine learning will be adapted and applied to dysplasia detection in this proposed project. We will pursue three aims to achieve our goal of determining whether computer vision models can match or exceed the diagnostic ability of experts for detecting dysplasia on colonoscopy and histology. Aim 1 will build computer vision models trained to infer histologic ground truth using endoscopic imaging for detecting the presence of dysplasia on standard colonoscopy video from multiple centers. Methods will incorporate both still image classifier pipelines and new generative diffusion-based model architectures for full video analysis. Aim 2 will evaluate the performance of both experts and new FDA-approved AI assistant tools in colonoscopy for detecting dysplasia on colonoscopy, comparing results to best performing video-based dysplasia models. Finally, Aim 3 will apply computer vision quantitative histology to predict the presence of dysplasia on routine colonic biopsy, leveraging state-of-the-art histologic image segmentation methods for both enhanced pathologist annotation and modeling. Optimized dysplasia model performance will be tested and piloted in a real-world digital pathology workflow to evaluate the feasibility and performance of automated dysplasia detection in clinical practice. We expect these advancements will transform IBD dysplasia assessment by eliminating the need for cumbersome mucosal interrogation methods, improving accuracy of dysplasia detection, personalizing dysplasia surveillance and management, and providing a deployable technologic solution to elevate the quality of IBD care rendered by less-experienced clinicians.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

PROJECT SUMMARY/ABSTRACT Traditional clinical measures to assess motor impairments typically focus on the overall outcome of the movement, rather than examining the specific kinematics underlying how the movement was performed. Kinematic based analyses are likely to be a significant improvement over traditional measures, as they can be more sensitive to mild impairments or small amounts of change, and can detect specific impairments including compensatory strategies to guide targeted interventions. However, there are many challenges in applying kinematic analysis to the upper limbs, including the need for specialized equipment and the lack of metrics that can reflect the rich spatiotemporal movement patterns seen in arm motion. Even within an unimpaired population, there is significant heterogeneity in the movement strategies individuals employ, and these strategies may change across the lifespan. Our long-term goal is to infer a patient’s “movement phenotype” from a recording of their movement that can be done in the clinic with limited equipment and time. As a first step, the objective of this 3-year project is to develop the methodology to identify motor phenotypes in a normative population using multimodal sensing and deep learning-based clustering strategies. We will first collect a large normative dataset on 400 individuals (ages 5-85+) using multiple camera views and inertial measurement units (IMUs) while participants perform prescribed unilateral and bilateral reaching movements and a functional bilateral pouring and drinking task. We will then use deep representation networks to encode the motion in latent space and apply optimization-based clustering over these latent encodings to determine movement phenotypes. After identifying motor phenotypes from all tasks on the full multimodal dataset (aim 1), we will then determine a clinically optimal subset of sensors and tasks required for reliable phenotyping (aim 2) via algorithmic means including phenotype-aware knowledge distillation. These reduced, clinic-friendly configurations will be evaluated against the full system for cluster fidelity, robustness to noise, and practical feasibility. This work advances the state-of-the-art by fusing markerless vision and wearable IMUs with self- supervised contrastive representation learning and phenotype-aware knowledge distillation to capture normative motor phenotypes in a clinically viable manner. At the conclusion of this three-year project, we will have both a multimodal normative dataset and methodology that we can then apply to clinical populations across the lifespan. We expect that the ability to phenotype movements in clinical populations will represent a large step towards precision rehabilitation.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Inflammatory bowel diseases (IBD) represent a major quality of life burden due to persistent symptoms, including abdominal pain, diarrhea, malnutrition, weight loss, and depression. Multiple factors cause IBD including lifestyle choices (e.g., poor diet), genetics, and the gut microbiota. To improve the detection and treatment of IBD there exists a critical need to increase understanding of the reciprocal relationship between diet, gut microbiota function, and inflammation. The candidate, J. Alfredo Blakeley-Ruiz, is a PhD scientist with extensive expertise in the use of the multi-omics approaches metagenomics and metaproteomics. Using integrated metagenomics-metaproteomics it is possible to observe overall shifts in microbial metabolism, while also measuring the responses of the immune system through the quantification of host proteins. Thus, integrated metagenomics-metaproteomics represents a powerful tool for untangling the relationship between diet, gut microbiota function, and inflammation. The candidate's long-term goal is to develop metaproteomics tools to identify the dietary components and microbiome functions that contribute to inflammation in IBD patients, so that dietary recommendations can be made to ameliorate inflammation in patients suffering from IBD and other intestinal diseases. This proposal builds on the candidate's expertise by providing training in the skills needed to connect his metaproteomic data to the host's intestinal immune response. The protected time provided by this proposal will allow the candidate to focus on training in (1) techniques for profiling GI physiology, (2) translatable models of IBD and the evaluation of their pathology, and (3) the husbandry of in vivo models. This training will allow the candidate to investigate the mechanisms behind how diet induced changes in microbiome function negatively impact the immune system leading to increased IBD pathology. The central hypothesis is that the digestibility and glycan conjugates of dietary proteins synergize with complex carbohydrates (e.g., starch and fermentable fiber) to change gut microbiome metabolism. This affects susceptibility to IBD via microbial metabolism mediated changes in the local immune cell landscape and colonic barrier integrity. This hypothesis will be investigated by feeding wild type and IL-10-/- mice with conventional or humanized microbiomes different combinations of fiber and protein diets, evaluating their colonic immune cell landscape, intestinal barrier integrity, and IBD pathology. These readouts will be linked to microbial and host protein quantities of metaproteomes to tease apart the mechanisms behind how diet-induced changes in microbiome function lead to IBD. NCSU is the perfect institutional environment for this research and training plan. The College of Veterinary Medicine gives access to the clinician scientists, core facilities, animal research facilities (NCSU gnotobiotic core), and didactics needed to fulfill the training plan of this proposal. NCSU has state of the art mass spectrometry (METRIC) and sequencing facilities (Genomics Sciences Laboratory) needed to conduct metagenomic and metaproteomic measurements.

NHLBI - National Heart Lung and Blood Institute

Our primary goal is to acquire new insights into chronic GVHD (cGVHD) pathobiology to create new therapies to limit fibrosis. We’ve shown that T:B cell engagement can initiate cGVHD by causing pathogenic αhost immunoglobulin (Ig) deposition that exacerbates tissue injury, recruits monocytes (monos) and TGFβ-secreting macrophage (Macs), and stimulates fibroblast/myofibroblast/endothelial cell pro-fibrinogenic cytokines. Our central hypothesis is that developing effective αfibrotic therapies requires greater elucidation of tissue cellular mechanisms and dynamic evolution processes that culminate in cGVHD. We will use state-of-the-art techniques in valid mouse models to expose cGVHD vulnerabilities. Tissues will be obtained at an early and late timepoint from cGVHD mice with bronchiolitis obliterans (BO) or scleroderma (Scl) to assess cGVHD progression in lymphoid and cGVHD organs. In an innovative, scientifically and technologically unprecedented, approach we will interrogate cGVHD mechanisms in BO and Scl models by spatially and temporally resolving and integrating proteomics with whole genome transcriptomics at a single cell resolution within histopathological regions of interest. This will result in a spatiotemporal atlas mapping how specific cells drive cGVHD disease progression in both lymphoid and target tissues; an invaluable tool for future studies. Our specific aims will test the hypotheses that: Aim 1. Interrogating T cell:B cell crosstalk at cGVHD tissue sites will lead to novel therapeutics and individualized applications. During the mechanistic discovery phase, we will infuse bifunctional (suppressive and cytolytic) αCD19 scFv chimeric antigen receptor (CAR19) Tregs to preclude B cell support of pathogenic IgG secretion, leveraging our murine cGVHD/BO cell atlas to assess the means by which these cells disrupt cGVHD progression. Aim 2. cGVHD tissue injury recruits monos that evolve into αinflammatory, pro-fibrinogenic Macs and engagement with fibroblasts/myofibroblasts to initiate fibrosis. Coupling mono and Mac reporter and deleter donor mice with spatiotemporal multi-omics, we will define the mechanisms by which monos and Macs enter cGVHD tissues and pro-fibrotic cytokines are produced, leading to new and key therapeutic targets. To halt fibrosis, mannosylated lipid nanoparticles with TGFβ1 siRNA will be given to selectively bind CD206+ Macs linked to murine cGVHD/BO and Scl. Aim 3. Mac communication with fibroblasts/myofibroblasts causes fibrosis that can be halted by fibroblast activation protein (FAP) CAR Tregs. Utilizing our first of its kind cell atlas of disease progression, we will elucidate the nature of crosstalk between profibrogenic TGFβ-producing Macs, fibroblasts, myofibroblasts and endothelial cells culminating in tissue fibrosis. We show FAP upregulation in cGVHD lung (BO), skin (Scl) and cGVHD/Scl patients and will infuse FAP CAR Tregs to eliminate damaged cells. We will fill cGVHD pathophysiology knowledge gaps for mechanistic insights focused on T:B and Mac: fibroblast/myofibroblast/endothelial cell (fibrosis) crosstalk, test novel therapies in clinically relevant models and, with mature data, assist Dr. Pavletic to lead cGVHD CAR trials at the NIH Clinical Center using intramural funds