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NIAID - National Institute of Allergy and Infectious Diseases

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

NIGMS - National Institute of General Medical Sciences

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

NIDA - National Institute on Drug Abuse

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

NIGMS - National Institute of General Medical Sciences

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

NIAID - National Institute of Allergy and Infectious Diseases

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

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

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

NIGMS - National Institute of General Medical Sciences

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

NIAID - National Institute of Allergy and Infectious Diseases

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

Montana Arts Council

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

Montana Arts Council

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

Morgan Community Association (MoCA)

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

Mainstreaming Menopause Advocacy Collective

The M Factor is a powerful film exploring the experiences of Black women and nonbinary people who face the challenges of perimenopause and menopause. This screening aims to provide an open, inclusive, and empowering space for Black women and nonbinary people, to find education, support, and discussion around a topic that is often overlooked but deeply impactful to our community. The screening will be held at Langston Hughes Performing Arts Institute located at 104 17th Ave S, Seattle, WA 98144 on March 16, 2025, from Noon to 4pm.

Muddy Lotus Festival

The Muddy Lotus Art planning committee will organize a free community art celebration featuring performances, demonstrations, and instruction in various artistic genres including painting, clay arts, and creative movement. It will be held on July 7, 2018 from 1 pm - 6 pm at Pritchard Island Beach located at 8400 55th Ave S.

NCI - National Cancer Institute

Project Abstract Glioblastoma outcomes have not improved substantially over the past decades, with median survival remaining at 12-15 months despite aggressive therapy. A major limitation in the current radiotherapy (RT) planning is it defines clinical target volumes (CTVs) using uniform geometric expansions around MRI-visible tumor boundaries. This conventional approach fails to capture GBM’s diffuse infiltrative spread and ignores patient-specific tumor biology. As a result, microscopic disease often extends beyond the treated field while normal brain is unnecessarily irradiated, leading to universal recurrences and treatment-induced toxicity. Although diffusion tensor imaging (DTI) can visualize white matter tracts, current tractography does not distinguish between tract pathways that facilitate tumor cell migration and those that are anatomically present but rarely involved in tumor spread. Additionally, molecular biomarkers such as MGMT methylation and TERT promoter mutations reflect distinct tumor progression patterns, yet these factors are not incorporated into RT target delineation. This project investigates DTI-based infiltrative risk mapping integrated with molecular biomarkers to improve glioblastoma progression prediction and RT CTV definition using a dataset of over 500 patients with pre-operative DTI, anatomical MRI, and molecular biomarker data. We will develop White Matter Infiltrative Risk maps by identifying population-level infiltration patterns across major white matter tracts and combining these with patient-specific fiber density maps. The infiltrative risk maps will be integrated with anatomical MRI, MGMT methylation and TERT promoter mutation status through a transformer-based deep learning framework with cross-attention mechanisms. Validation will be conducted via spatial accuracy assessment against ground truth progression, comparison with standard RT targets, and histopathological correlation using tissue samples with matched imaging coordinates from 298 patients. This fusion of advanced DTI mapping and genomics with state-of-the-art Artificial Intelligence modeling will produce voxel-level risk maps that reveal otherwise occult tumor infiltration pathways and can be directly incorporated into RT planning. This work will provide proof-of-concept for integrating infiltration pathways and biological factors into RT target definition and establish the foundation for future clinical trials testing personalized radiation therapy strategies. The goal is to transition from geometric margins to biology-guided targeting that improves GBM control while preserving healthy brain tissue.

East African Art and Culture Association

Outdated computers will be replaced and multimedia design software purchased to provide youth and families in Central and South Seattle with training in graphic design, video production, and DVD development.

East African Art and Culture Association

East African youth ages 13-22 will learn multimedia video production skills and produce their own television programs using new equipment.

NIEHS - National Institute of Environmental Health Sciences

Summary Objective: This study aims to determine whether micro- and nanoplastics (MNPs) accumulate in the human brain, evaluate their relationship with Alzheimer’s disease (AD) pathology, and explore whether environmental disadvantage, measured by the Area Deprivation Index (ADI), is related to variation in cerebral MNP burden. Rationale: MNPs are widespread environmental pollutants with emerging evidence of human tissue accumulation and potential neurotoxicity. Preliminary data show detectable MNPs in the brains of individuals with AD and progressive supranuclear palsy. Social disadvantage may increase exposure to environmental risks, potentially elevating MNP burden and susceptibility to neurodegeneration. Aims: 1. Quantify MNPs in the olfactory bulb (OB) and middle temporal gyrus (MTG) of 140 postmortem human brains (70 with AD pathology, 70 without AD pathology) using five complementary detection methods. 2. Assess associations between cerebral MNP burden and AD pathology, adjusting for age, sex, APOE genotype, postmortem interval (PMI), and other covariates. 3. (Exploratory) Examine the relationship between ADI and cerebral MNP burden, investigating whether MNP burden varies by level of socioeconomic disadvantage. Innovation: This study employs state-of-the-art environmental toxicology methods rarely applied to human brain tissue, integrated with high-resolution neuropathology and life-course social determinants data. It represents the largest and most methodologically rigorous study of cerebral MNPs to date, and the first to directly examine their links to AD and environmental disadvantage. Significance: Findings could identify a novel, modifiable environmental contributor to AD, inform targeted public health interventions, and advance our understanding of how plastic pollution and social disadvantage may shape brain disease. Impact: By bridging environmental science, neuropathology, and social epidemiology, this study could redefine how we think about environmental risks in neurodegeneration. Demonstrating a link between MNP accumulation, AD pathology, and social disadvantage would establish a new line of inquiry with major implications for public health, regulation, and disease prevention.

NIMH - National Institute of Mental Health

Abstract/Summary Advances in antiretroviral therapy (ART) have reduced the incidence of severe clinical neurocognitive complications associated with chronic HIV infection, such as HIV-associated dementia (HAD). Nevertheless, nearly half of people with HIV (PWH) still experience asymptomatic neurocognitive disorder (ANI) and mild neurocognitive disorder (MND). Opportunities for using novel, data-driven approaches, such as Artificial Intelligence (AI) in making predictions, real-time monitoring, or improving clinical decision-making to address HIV-related neurocognitive disorders (HAND) proliferate but have yet been fully realized. Recent studies have employed machine learning (ML) and/or deep learning (DL) techniques to either cluster neurocognitive phenotypes or identify key predictors of neurocognitive impairment in PWH. Data from these studies, however, are typically “siloed” and unimodal (e.g., only electronic health records [EHR] data or imaging data). Given the broad spectrum of modalities of neurocognitive disorder, multimodal approach (i.e., integration of different data modalities) provides opportunities to increase robustness and accuracy of diagnostic and prognostic models by utilizing complementary and supplementary information in modalities. However, such multimodal approach is limited often due to the lack of multimodal data and advanced methodologies such as multimodal AI. One novel and ambitious initiative funded by the NIH to advance precision medicine is the All of Us (AoU) Research Program, a centralized data repository, offering secure access to de-identified multimodal data (e.g., EHR data, genomic data, survey data, and imaging data) from almost one million program participants. In our preliminary study, we have developed a computational phenotyping that identified 6,664 confirmed PWH among 633,000+ participants as of October 2023. In response to RFA-MH- 26-105, we propose to apply multimodal AI with a series of longitudinal EHR data (laboratory and medication), genomic data, self-reported survey data (e.g., lifestyle, physical measurement, healthcare access), and imaging data in AoU to 1) identify different biotypes of neurocognitive disorders in PWH (e.g., ANI, MND, HAND) and employ ML/DL approaches to cluster neurocognitive phenotypes; 2) develop, evaluate, and validate multimodal AI models to predict neurocognitive disorders in PWH accounting for comprehensive information and enhance the model interpretability through synergistic integration of a domain-specific knowledge graph; and 3) develop a multimodal AI based decision-making prototype to assist with the identification of PWH with risk of neurocognitive disorders and pilot test its feasibility, usability, and implementation strategies in clinical settings. Personalized risk prediction through multimodal AI could improve the predictive accuracy and early detection of neurocognitive decline in PWH and inform tailored intervention and treatment for PWH. The insights gleaned from our project could also be a demonstration of the power of cutting-edge multimodal AI models to expand our capacity to accelerate HIV care and address the dynamic, complex, and evolving HIV epidemic.

OD - NIH Office of the Director

Project Summary/Abstract The Center for Chemical Genomics (CCG) at the Life Sciences Institute (LSI) serves as the high throughput screening core facility, available to all faculty at the University of Michigan (U-M) and seeks funding to support the purchase of a new microplate reader, the PHERAstar FSX. The current instruments, a 17-year- old Perkin Elmer EnVision 2104 and a 21-year-old PHERAstar, have each reached the end of their operational lifespan and manufacturer support is being terminated. Given that these microplate readers are used to support approximately 90% of the screening experiments that the CCG performs, they are critical to the continuation of CCG services, and failure to obtain a replacement option for these aging machines will dramatically impact the early phase drug discovery program at U-M. The PHERAstar FSX is the ideal replacement due to its state-of-the-art capabilities, enabling the CCG to conduct a comprehensive array of experiments as requested by U-M faculty, as well as researchers external to U-M. The CCG is a critical component of both basic research and the early-phase drug discovery pipeline at U-M. It conducts approximately 20 high-throughput screening (HTS) campaigns, as well as supporting ~3-5 Structural-Activity Relationship (SAR) campaigns, annually. Despite advances in computational approaches, HTS of large chemical libraries, consisting of over 100,000 samples, remains the most commonly employed method for identifying novel compounds that modulate the activity of a target protein. This “unbiased” screening approach is used to identify active molecules that can be optimized for use as in vitro or in vivo research tools, and/or as potential drug leads. The vast majority of HTS assays are designed to utilize some form of fluorescence or luminescence as the final readout, as this approach can yield HTS assays that are both robust and cost-effective. The CCG’s microplate readers are essential for conducting these HTS assays. The CCG supports NIH projects for U-M researchers and external collaborators across an incredible breadth of research fields, including research on cancer, cardiomyopathy, nicotine and opioid addiction, and drug metabolism. The university is a national leader in academic drug discovery, demonstrated by its 15 drugs in current clinical development. The initial identification of candidate drugs is a vital part of this pipeline and aligns with the mission of the NIH and U-M’s overarching goal of improving public health. Replacing the dated microplate readers in the CCG with the PHERAstar FSX will ensure the continuation of CCG support for groundbreaking drug discovery research at the University of Michigan.

NIDA - National Institute on Drug Abuse

Despite the success of antiretroviral therapy (ART), HIV remains incurable due to the persistence of viral reservoirs, particularly in the central nervous system (CNS). Myeloid cells—macrophages and microglia— serve as long-lived HIV reservoirs in the CNS and are implicated in neuroinflammation and HIV-associated neurocognitive disorders (HAND). Unlike CD4+ T cells, infected myeloid cells exhibit a state we define as semi‗quiescence, in which transcription from the HIV-1 promoter persists, but viral protein production is minimal. This persistent yet attenuated activity complicates efforts to eradicate the virus from the CNS. Our preliminary data show that ART-treated human monocyte-derived macrophages (hMDMs) maintain stable proviral levels over time, with reduced p24 Gag protein expression but active transcription. Chromatin immunoprecipitation (ChIP-qPCR) analysis of these cells revealed euchromatin markers at the viral LTR, consistent with transcriptionally active but translationally restricted infection. Strikingly, treatment with benzodiazepines (BDZs)—commonly prescribed to people living with HIV—reactivates viral protein production in these cells, suggesting they may act as latency reversal agents (LRAs) in the CNS. BDZs appear to target RUNX1, a transcription factor that interacts with the HIV-1 LTR, and may disrupt epigenetic control of viral persistence. We hypothesize that HIV-infected myeloid cells adopt a unique global epigenetic signature early in infection, orchestrated in part by RUNX1 and HIV Tat, which modulates effector function and maintains semi-quiescence. BDZs may override this regulation, reactivating latent virus and worsening neuroinflammatory outcomes. We aim to: 1) define the global epigenetic landscape of HIV-infected hMDMs under ART and characterize how RUNX1 and Tat occupancy correlates with gene expression and viral activity and 2) determine how BDZ exposure alters the global epigenetic state of infected and uninfected hMDMs, testing the hypothesis that BDZs promote viral reactivation via a euchromatic shift. This research will uncover new mechanisms of HIV persistence in myeloid reservoirs and inform safer therapeutic strategies for PLWH, especially those at risk for HAND.

NIGMS - National Institute of General Medical Sciences

ABSTRACT / SUMMARY Reactive oxygen species (ROS) and regulation of redox pathways are critical to human health and disease, as they influence cellular metabolism, signaling, and stress responses. Disruptions in redox homeostasis contribute to the pathophysiology of numerous disorders, including neurodegenerative diseases, muscular degeneration, and drug-induced cardiotoxicity. However, the tools for monitoring redox dynamics in living human cells remain limited in dimensionality, sensitivity, and applicability to disease-relevant models. To overcome these challenges, my research program aims to develop a next-generation, multiplexed optical platform for quantitative redox phenotyping and apply it to disease modeling and drug screening in human induced pluripotent stem cell (iPSC)- derived systems. Over the past five years, my lab has engineered two advanced genetically encoded hydrogen peroxide (H₂O₂) sensors, oROS-G and oROS-HT, exhibiting improved dynamic range, kinetics, and spectral flexibility. We established a high-throughput optical screening platform and integrated machine learning approaches to accelerate protein sensor engineering. These sensors have been applied in diverse host systems, including iPSC-derived neurons and cardiomyocytes, and have revealed new aspects of redox signaling in cell health. Building on this foundation, our future research will continue along three complementary directions. First, we will complete the development of a fully multiplexed, intensity-based TreDox sensor suite to simultaneously monitor oxidative pressure and antioxidant capacity with single-cell resolution in real time. Second, we will engineer lifetime-resolved redox biosensors and use fluorescence lifetime imaging microscopy (FLIM) to enable robust, expression-independent quantification of intracellular redox states. Third, using single-cell optical phenotyping, we will apply these tools to profile redox imbalances and early cytotoxicity signals in human iPSC- derived cardiomyocytes, neurons, and skeletal muscle cells. We aim to detect subtle cellular imbalances in redox pathways that precede cellular dysfunction and are often missed by traditional high throughput assays. This research program will fill critical gaps in our ability to study redox biology in human-derived host systems by integrating state-of-the-art protein engineering, advanced imaging, and human stem cell models. The tools and knowledge generated will improve our understanding of redox-linked disease mechanisms, enhance the predictive power of preclinical drug testing, and establish a flexible, generalizable platform for functional phenotyping at single-cell resolution.

NIA - National Institute on Aging

Cognition is intricately linked to the metabolic processes of the brain, yet existing computational models often overlook the metabolic costs associated with cognitive function. This oversight is critical, especially in neurodegenerative diseases like Alzheimer's, where metabolic dysfunctions play a significant role in cognitive decline. Despite advancements, research biases towards familial AD models have hindered a comprehensive understanding of metabolic changes in aging and late- onset AD, calling for focused investigations into sporadic late-life AD models. Our proposal aims to bridge this gap by comprehensively studying neuro-metabolic coupling using state-of-the-art imaging techniques and computational models. We propose a multifaceted approach involving in vivo microscopy, wide-field imaging, and MRI to elucidate the intricate relationship between neuronal activity and metabolic processes such as oxidative phosphorylation, glucose, lactate, and creatine dynamics. Our specific Aims include (1) Modeling SingleCell Neurometabolic Coupling: Utilizing in vivo two- photon microscopy, we will investigate the astrocyte-neuronal lactate shuttle and quantify the relationship between red blood cell velocity, lactate levels, and neural activity in late-onset AD mouse models. (2) Establishing Cortical Network Models of Neuro-Metabolic Coupling: We will employ multispectral wide-field imaging to examine the role of oxidative phosphorylation in neuronal connectivity, validate computational models with experimental capillary obstructions, and assess sex-specific differences in mitochondrial function. (3) Building a WholeBrain Theory of Neuro-Metabolic Coupling: Through non-invasive brain imaging techniques, we will explore the impact of glucose and creatine metabolism on whole-brain functional connectivity. We will integrate data from animal models and human cohorts to predict Excitation- Inhibition Balance patterns and identify metabolic biomarkers of cognitive decline. This project addresses critical gaps in our understanding of neuro-metabolic coupling in aging and late-onset AD, offering insights into metabolic vulnerabilities and potential targets for personalized therapeutic interventions. Our proposal combines modern neuroscience with multiscale imaging to construct comprehensive models of neuro-metabolic coupling, providing a novel framework for understanding brain function and dysfunction in aging and AD. By integrating data from animal models and human cohorts, we will uncover new insights into the metabolic underpinnings of cognitive decline, advance early diagnosis, and develop more accurate metabolic biomarkers for AD.

Seattle Chinatown International District Preservation and Development Authority

Community murals at 13th & Fir Family Housing is a collaborative effort between 206 Zulu and The Seattle Chinatown International District Preservation and Development Authority (SCIDpda). We aim to design, develop and execute public art for the forthcoming 13th & Fir Family Housing, a 6 story building providing space for 156 low-income family-sized apartment units, community-based commercial and retail services, and a childcare center. This project will create large scale art that is impactful and reflective of the immediate neighborhoods' collective values and diverse community. The art implementation will happen in phases as more funding is secured. This grant supports Phase I of the project. Phase I is anticipated to be completed by December 31, 2023.

U.S. Mission to Oman

The Public Diplomacy Section of U.S. Embassy Muscat announces an open competition to support projects that advance U.S. foreign policy priorities in Oman while strengthening the long-standing partnership between the United States and the Sultanate of Oman. This Annual Program Statement outlines strategic funding priorities, eligibility criteria, and application guidelines for grants ranging from $1,000 to $50,000, with project durations of up to 12 months. Successful proposals should clearly demonstrate how their projects support U.S. public diplomacy goals; showcase American excellence, expertise, innovation, and values, and strengthen the bilateral relationship. The goals of U.S. policy in the region are to: 1) secure opportunities that advance U.S. commercial and strategic interests; 2) promote trusted cooperation in emerging technologies, innovation, and space; and 3) deepen people-to-people ties that showcase American excellence. Applicants should clearly explain how their projects support U.S. public diplomacy goals, strengthen the U.S.-Oman partnership, and highlight American expertise, leadership, and innovation. Programs should include a clear U.S. element, such as engagement with U.S. experts, institutions, companies, universities, artists, athletes, alumni, or professional networks; the use of American models, standards, technologies, or best practices; or activities that increase understanding of the United States and its partnership with Oman. Program Description1. Project Background, Goals, and Objectives The Public Diplomacy Section of U.S. Embassy Muscat is pleased to invite applications for federal assistance funding opportunities, pending availability of funds, through its Public Diplomacy Small Grants Program. This Annual Program Statement outlines the Embassy s funding priorities, strategic themes, and procedures for submitting proposals. Applicants should carefully follow all instructions below. The Public Diplomacy Section seeks proposals for programs that advance U.S. foreign policy priorities in Oman while strengthening the long-standing partnership between the United States and Oman. Competitive proposals should clearly demonstrate how the proposed project makes the United States safer, stronger, or more prosperous; and showcases American excellence, expertise, innovation. Programs should include a clear U.S. element, such as engagement with U.S. experts, institutions, companies, universities, artists, athletes, alumni, or professional networks; the use of American models, standards, technologies, or best practices; or activities that increase understanding of the United States and its role as a trusted partner for Oman. 2. Program Objectives Applicants may submit proposals that address one of the program goals below. Proposals should focus on one or more of the priority outcomes, but applicants may also recommend their own objectives if they clearly align with U.S. Embassy Muscat priorities. Goal 1. Advancing U.S.-Oman Commercial Ties, and Shared Prosperity: This goal supports programs that make the United States more prosperous by expanding U.S.-Oman economic cooperation, strengthening commercial ties, and highlighting the value of trusted U.S. expertise, technology, standards, and business practices. Projects may support Omani entrepreneurs, students, business leaders, and institutions in sectors that advance shared economic priorities, including innovation, trade and investment, tourism, logistics, clean energy, creative industries, and other areas linked to Oman s economic diversification goals. Programs should demonstrate how engagement with U.S. experts, companies, universities, or professional networks can help Omani audiences develop practical skills, build market-oriented solutions, and identify opportunities for long-term U.S.-Oman commercial cooperation. Project Audience(s): Entrepreneurs, students, business professionals, chambers of commerce, academic institutions, economic organizations, youth, and relevant civil society partners. Priority Outcome(s): Applicants may focus on one or more of the outcomes listed below. Applicants are encouraged to propose additional objectives and innovative activities that address this priority program area. Increased awareness among Omani audiences of opportunities for U.S.-Oman trade, investment, entrepreneurship, and private-sector collaboration. Stronger connections between Omani entrepreneurs, students, or business leaders and U.S. experts, companies, universities, or professional networks. Greater understanding of American business practices, innovation models, market-based solutions, and trusted U.S. standards in sectors important to Oman s economic growth. New partnerships or project ideas that position the United States as a preferred partner for economic cooperation, entrepreneurship, and commercial innovation in Oman. Goal 2. Strengthening Sports Diplomacy, Youth Leadership, and Major-Event Expertise: This goal supports programs that use sports to advance U.S. public diplomacy goals, strengthen people-to-people ties, and share American excellence in sports management, coaching, athletic development, sports entrepreneurship, and major-event planning. As the United States prepares to host major global sporting events, including the Olympics, proposals may draw on U.S. experience in organizing, managing, and leveraging sports events to support youth development, community engagement, tourism, and economic opportunity. Projects should demonstrate how U.S. sports expertise can benefit Omani athletes, coaches, sports institutions, youth organizations, and communities while strengthening positive perceptions of the United States and expanding long-term U.S.-Oman cooperation in the sports sector. Project Audience(s): Youth, athletes, coaches, sports federations and clubs, schools, universities, sports entrepreneurs, community organizations, and relevant public or private-sector partners. Priority Outcome(s): Applicants may focus on one or more of the outcomes listed below. Applicants are encouraged to propose additional objectives and innovative activities that address this priority program area. Increased exchange of U.S. and Omani expertise in sports management, coaching, leadership, athletic development, and major-event planning. Expanded professional connections between Omani sports institutions, coaches, athletes, or youth organizations and U.S. sports experts or institutions. Greater understanding of how sports diplomacy can support entrepreneurship, education, health, tourism, and community development. Increased recognition of the United States as a global leader in sports innovation, major-event management, and sports diplomacy. Goal 3. Showcasing American Excellence in Culture, Heritage, and Creative Industries: This goal supports programs that showcase American excellence, creativity, innovation, and cultural leadership while strengthening cultural understanding between the United States and Oman. Projects may connect American and Omani artists, cultural institutions, heritage professionals, designers, filmmakers, musicians, writers, museum professionals, and creative entrepreneurs. Programs may highlight the role of culture and heritage in strengthening national identity, mutual understanding, tourism, and economic opportunity. Projects may also showcase U.S. excellence in creative industries, including film, music, design, museums, digital storytelling, gaming, publishing, architecture, cultural entrepreneurship, and other creative sectors where the United States has global influence. Projects under this goal should support marking the 250th anniversary of the founding of the United States. Freedom 250 programs should highlight American history, constitutional traditions, innovation, entrepreneurship, creativity, civic ideals, and the people-to-people ties that connect the United States and Oman. Project Audience(s): Artists, cultural institutions, museums, heritage professionals, students, youth, creative entrepreneurs, educators, writers, filmmakers, designers, alumni, and the public. Priority Outcome(s): Applicants may focus on one or more of the outcomes listed below. Applicants are encouraged to propose additional objectives and innovative activities that address this priority program area. Increased collaboration between U.S. and Omani cultural, creative, or heritage professionals and institutions. Greater public understanding of the United States through American arts, culture, history, innovation, and creative industries. Strengthened skills among Omani artists, cultural professionals, or creative entrepreneurs through engagement with U.S. experts, institutions, or models. Programs that connect Omani heritage and American creative expertise through exhibitions, workshops, public programs, digital storytelling, or joint cultural initiatives. Freedom 250 programs that increase awareness of American history, constitutional freedoms, innovation, entrepreneurship, and the long-standing U.S.-Oman partnership. Goal 4. Advancing Emerging Technologies, Space Cooperation, and Innovation: This goal supports programs that make the United States safer, stronger, and more prosperous by expanding U.S.-Oman cooperation in emerging technologies, space science, and innovation. Projects should showcase U.S. leadership in science, technology, and space while supporting Omani talent, institutional capacity, and innovation ecosystems in areas of shared strategic interest. Projects may focus on artificial intelligence, cybersecurity, data science, digital transformation, advanced manufacturing, biotechnology, clean technology, trusted digital infrastructure, satellite technology, Earth observation, STEM education, commercial space, or space entrepreneurship. Competitive proposals should include a clear U.S. connection, such as collaboration with U.S. universities, research institutions, technology companies, NASA-related educational resources, private-sector innovators, U.S. exchange alumni, or American experts. Programs should demonstrate how U.S. expertise, standards, and innovation models can help Omani students, researchers, entrepreneurs, educators, and professionals develop practical skills, build trusted partnerships, and contribute to long-term U.S.-Oman cooperation in technology and space. Project Audience(s): Students, youth, universities, researchers, entrepreneurs, technology professionals, STEM organizations, science communicators, educators, civil society organizations, and relevant public or private-sector partners. Priority Outcome(s): Applicants may focus on one or more of the outcomes listed below. Applicants are encouraged to propose additional objectives and innovative activities that address this priority program area. 1. Increased understanding among Omani audiences of U.S. leadership, standards, and best practices in emerging technologies, advanced technologies, space science, and innovation. 2. Stronger connections between Omani students, researchers, entrepreneurs, or professionals and U.S. technology, STEM, or space-related experts, institutions, and innovation networks. 3. Practical skills development in areas such as artificial intelligence, cybersecurity, data analysis, digital entrepreneurship, technology governance, STEM education, satellite technology, or space entrepreneurship, utilizing American platforms and providers. 4. Greater awareness of trusted, responsible, and secure U.S. technology solutions that support innovation, economic growth, institutional resilience, and shared security. 5. Programs that encourage U.S.-Oman collaboration in space education, Earth observation, climate and environmental monitoring, commercial space, science communication, or related fields.