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NIMH - National Institute of Mental Health

Abstract Despite antiretroviral therapy (ART), HIV-associated brain injury (HABI) persists in over half of people with HIV (PWH), manifesting as chronic cognitive impairment. While HIV-1 primarily infects microglia, driving central nervous system (CNS) neuroinflammation, current preclinical models do not recapitulate the chronic, suppressed infection characteristic of the ART era. Furthermore, they do not capture complex patient genetics and multicellular, glial and neuronal, interactions in a scalable and efficient manner. To address this need for more physiologically relevant models, we propose the development of an AI-guided triculture platform comprising major CNS cell types. This platform will use induced pluripotent stem cell (iPSC)-derived microglia, astrocytes, and neurons, using both morphological profiling and other omics-based profiling to model HABI under ART suppression. AI/machine learning (ML)-driven analysis of cellular morphology, combined with multi-omic data integration, will facilitate rapid classification and prediction of microglial functional states and their impact on neuronal health. Leveraging Modulo's established triculture system, previously successful in yielding therapeutic candidates for amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) currently in Investigational New Drug (IND)-enabling studies, we will construct a scalable HABI model under ART suppression. Our objectives are to (1) develop and validate an HIV-infected, ART-suppressed triculture platform, utilizing AI/ML-driven morphological profiling to classify HABI-specific microglial states; and (2) comprehensively characterize this model through neuroinflammatory profiling, behavioral correlates, and integration with publicly available HABI patient datasets. We hypothesize that our combined computational lab-based triculture system can effectively model HABI pathophysiology under ART conditions, enabling both rapid disease state classification and identification of therapeutic targets. Through the integration of experimental and computational approaches, this platform will provide insights into HABI mechanisms and accelerate therapeutic development. We will disseminate this model to the scientific community through publication and collaboration. Connecting in vitro modeling with patient outcomes offers a powerful tool for investigating neuroimmune dysfunction in HIV and related neurological disorders. Successful implementation will yield a platform for modeling neuroHIV under ART suppression, advancing our understanding of disease mechanisms and facilitating the discovery of novel therapeutic strategies for PWH with cognitive impairment.

NIA - National Institute on Aging

Project Summary Anti-aging antibody research, including strategies targeting interleukins and other antigens, shows promise in rejuvenating the immune system, improving metabolic functions, and extending healthy lifespans. AI-driven platforms are revolutionizing antibody development by accelerating affinity maturation and optimizing developability properties, enabling simultaneous optimization of multiple characteristics. These advancements could lead to more effective treatments for age-related diseases and a significantly improved quality of life for the growing aging population. However, zero-shot predictions for antibody affinities using pretrained models without additional target-specific data remain challenging. In this project, we propose a new strategy to address this challenge by generating diverse antibody-antigen interactions at an unprecedented scale (Aim 1) and training new AI models using these generated data in combination with data collected from literature and public databases (Aim 2). We will rigorously evaluate the performance of the new models and benchmark against the state-of-the-art methods. We will test the generality of the new models on a diverse set of antigens and experimentally validate the prediction accuracy (Aim 3). We will apply the models to identify new antibodies against new therapeutic targets associated with ageing or age-related diseases. Once complete, the proposed research will provide a powerful tool for accelerating antibody discovery and optimization as well as new antibody candidates for anti-aging treament.

NIMH - National Institute of Mental Health

Project Summary The proposed project will explore barriers and facilitators of HIV care and prevention service engagement and new intervention approaches to increase long-acting antiretroviral treatment (LAI-ART) and pre exposure prophylaxis (LAI-PrEP) uptake and persistence among 18-45-year-old Black and Latinx sexual minority men (B/LSMM) in San Diego, San Bernardino, and Riverside Counties, California, three EHE jurisdictions. This research will focus on B/LSMM with suboptimal care engagement, PrEP/ART adherence, or unknown or detectable viral load. Black and Latinx SMM bear a disproportionate burden of HIV in the US, accounting for 38% and 32% of new diagnoses among SMM, respectively. PrEP uptake is lower among B/LSMM than white SMM in California, and B/LSMM living with HIV (B/LSMM+) have lower overall ART adherence, and viral suppression. Of the 61 health jurisdictions in California, San Bernardino and San Diego Counties rank 46th and 48th in viral suppression rates and, in 2020, most Black (54%) and Latinx (52%) people with HIV (PWH) in Riverside County had received an AIDS diagnosis. Long-acting injectable forms of PrEP (LAI-PrEP) and ART (LAI-ART) have the potential to overcome some known barriers to oral PrEP and ART adherence such as missing daily PrEP and ART doses due to substance use or depression or lacking a safe and private place to store pill bottles. To date, little is known about the barriers and facilitators of LAI uptake among B/LSMM. For the proposed study we will adopt the CDC’s status neutral approach to elucidate the impact of these socio-structural inequities on LAI-PrEP and LAI-ART uptake. New strategies are needed to increase uptake of LAIs among those who can most benefit, such as B/LSMM with less than adequate care engagement and oral ART and PrEP adherence. Guided by intersectionality, syndemics theory, and the Health Equity Implementation Framework, this project has two aims. Aim1: Qualitatively explore knowledge, attitudes, and perceived barriers and facilitators of LAI-PrEP and LAI-ART uptake and identify acceptable and appropriate approaches to increase uptake among B/LSMM who report less than optimal oral PrEP/ART adherence. We will conduct 30 in-depth qualitative interviews with B/LSMM, evenly stratified by race and HIV status, and three focus groups (one in each EHE priority county) with staff and clinicians from community-based organizations serving B/LSMM. Aim2: Quantitatively assess knowledge, barriers, and facilitators of LAI-PrEP and LAI-ART uptake among B/LSMM and assess interest and acceptability of potential intervention approaches.

Food and Drug Administration

For generic drug development, population pharmacokinetics (popPK) analysis is a critical part of the emerging technology of model-based bioequivalence (BE) analysis. PopPK models provide support for generalizing the conclusion of BE to groups that were not included in a BE study. The popPK model selection is essentially a multiple-objectives/variables optimization problem. Recent years have witnessed the overwhelming success of the reinforcement learning (RL) approaches in addressing optimization problem. Thus, the objective of this project is to develop a model selection method for the popPK analysis using the deep-learning based RL algorithm. Specific Aim 1: Develop a model selection method using a deep-learning based RL algorithm. A thorough survey should be conducted to gain a good understanding of the current state of the art for deep-learning based RL algorithms and their applications. The most appropriate algorithm/pipeline should be adopted to develop the model selection method. Specific Aim 2: Design simulations reflecting different scenarios of PK data, such as independent/correlated covariates, simple/complex (e.g., multiple peaks) time-concentration profiles and sparse-sampling design. The simulated datasets should be used to conduct systematic performance checks. Specific Aim 3: Identify proper metrics for performance evaluation. The selected metrics should be unbiased and mathematically/statistically meaningful. Specific Aim 4: Conduct performance evaluation. The developed model selection method and at least a stepwise regression and a genetic algorithm-based approach should be applied to the simulated datasets to perform popPK model building. The selected performance evaluation metrics should be used to compare the performance of the different methods. Specific Aim 5: Use real PK dataset(s) to demonstrate the applicability and advantage of using the developed method in popPK model building.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract This proposal seeks to develop a new class of HIV-1 inhibitors that disrupt critical intracellular host–virus protein– protein and viral protein–RNA interactions. Anti-HIV therapeutics targeting essential host–virus interactions are expected to reduce drug resistance relative to drugs targeting viral proteins alone, as host factors mutate less readily and resistant viral mutants may lose host binding capacity, thus becoming non-infectious. The long-term goal of this project is to develop novel antiretrovirals that target interactions between HIV-1 integrase (IN) and the host factor Integrase Interactor-1 (INI1), which may also dually disrupt IN interactions with viral RNA due to structural mimicry between the IN-binding domain of INI1 (Rpt1) and TAR RNA. IN is essential for viral cDNA integration and also regulates late stages of replication through interactions with TAR RNA and host proteins including INI1. Cells lacking INI1 fail to produce HIV-1 particles, and viruses encoding IN mutants defective for INI1 or RNA binding produce morphologically defective, noninfectious virions. Structural studies reveal that the IN-binding domain of INI1 mimics TAR RNA, explaining shared binding interfaces and phenotypes. We hypothesize that inhibitors disrupting IN/INI1 interactions will also disrupt IN/RNA binding, leading to defective particle formation and inhibition of HIV-1 replication. As a proof-of-concept, we developed a hydrocarbon-stapled helical peptide derived from the INI1 helix-1 that blocks both IN/INI1 and IN/RNA interactions in vitro, potently inhibits HIV-1 replication, and induces the production of morphologically defective, noninfectious particles. Building on this premise, we aim to identify small-molecule inhibitors of IN/INI1 and IN/RNA interactions. High-throughput virtual screening of the NCI therapeutic library for compounds that dock onto IN/INI1 interface and identified glycyrrhizic acid (GL) as a top candidate. GL is a natural compound with reported anti-HIV-1 activity in vitro and in patients, previously implicated in inhibiting viral entry via membrane modulation. We hypothesize that GL inhibits HIV-1 replication through dual mechanisms: disruption of IN/INI1 and IN/RNA interactions during late events and inhibition of viral entry during early events. In Aim 1, we will characterize GL-mediated inhibition of IN/INI1 and IN/RNA interactions in vitro and in vivo. In Aim 2, we will define GL’s mechanism of action during early and late replication stages of HIV-1 by analyzing particle production, Gag processing, virion morphology, viral entry, reverse transcription, nuclear import, and integration. We will also isolate and characterize GL- resistant viruses and assess GL’s activity against ART-resistant strains. Completion of this project will establish GL as a lead compound for a novel class of dual-targeting HIV-1 inhibitors with the potential to reduce resistance while providing comprehensive training in virology, molecular biology, mechanistic analysis, and antiviral drug discovery.

NIGMS - National Institute of General Medical Sciences

Optical microscopy is a cornerstone of biomedical research, enabling detailed visualization of biological structures and processes. However, traditional refractive microscopes are inherently limited by chromatic aberrations, group delay dispersion, and narrow spectral ranges, while existing reflective designs suffer from central obscuration, reducing contrast and efficiency. These limitations restrict the ability to perform high-resolution, broadband, and multimodal imaging, hindering advancements in biomedical research. To address these challenges, we propose the development of an ultra-broadband microscope based on an innovative obscuration-free, off-axis freeform reflective optical architecture. This system is designed to achieve diffraction-limited performance across an ultra-broadband spectral range — from the ultraviolet (UV) to the infrared (IR) — while eliminating chromatic aberrations and minimizing optical dispersion. By leveraging freeform optics and an unobscured reflective design, this technology will provide superior contrast, higher optical efficiency, and enhanced imaging capabilities beyond the limitations of conventional refractive or reflective microscopes. A key innovation of this project lies in the development of off-axis freeform reflective configurations and novel optomechanical integration strategies to create a compact, ultra-broadband-compatible microscope. This project will focus on three key objectives: (1) Design and optimization of a compact, high- performance off-axis reflective microscope with diffraction-limited imaging across a wide spectral range. (2) Prototype fabrication and assembly, advancing high-precision diamond-turning techniques to ensure superior optical quality and robust system integration. (3) Performance validation through rigorous experimental testing across UV, visible, and infrared spectra, benchmarking the prototype against state-of-the- art commercial refractive and reflective microscopes. The anticipated outcome is a transformative microscope platform that enables high-contrast, ultra- broadband imaging with an unprecedented working spectrum. This technology will establish a new paradigm for high-performance optical microscopy, unlocking new opportunities in biomedical research and expanding imaging capabilities across multiple disciplines. This proposal directly aligns with the objectives of NIGMS NOFO (PAR-25-203) by advancing a demonstrated proof-of-concept ultra-broadband microscope into a fully functional prototype with broad applicability in biomedical and biological sciences research. By overcoming fundamental optical constraints, this microscope has the potential to transform biomedical imaging and biological research, facilitating new discoveries and expanding the frontiers of optical microscopy.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY With the most people ever in history currently living with HIV, finding a cure remains a global priority. Non-human primates (NHPs) are a clinically relevant model for developing strategies for HIV cure. The safety and efficacy of therapeutic curative approaches in ART-suppressed SIV-infected NHP have provided the basis for several strategies currently in human clinical trials. While the current daily ART regimen has advanced preclinical SIV cure research, it has its drawbacks. In addition to the high costs for staffing and drug administration, daily ART injections require daily manipulation of the NHP and unintended immune activation and perturbation from the carrier molecule Kleptose. Long-acting ART offers a novel and promising therapeutic approach as an alternative to both treat and prevent HIV. However, the impact of LA-ART on the latent viral reservoir is unknown and may alter approaches to cure HIV. Here, we are proposing to use LA-ART therapeutically in SIV-infected rhesus macaques to achieve full viral suppression. In specific aim 1, we will determine the ability of a long-acting antiretroviral regimen to achieve durable viral suppression in SIVmac239-infected rhesus macaques and assess the impact on the latent viral reservoir. In aim 2, we will characterize the safety, tolerability, and pharmacokinetics of repeated dosing of long-acting ART regimen and evaluate its effects on anti-SIV immunity. The results generated here will be directly compared to previously published historical controls that received conventional daily ART. This work will provide a safe and viable alternative to current daily antiretroviral therapies and lay the foundation for the next generation of ART in non-human primates.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary: Development of Nav channel targeting antisense oligonucleotides as chronic pain therapeutics using an integrated platform based on machine learning and optical electrophysiology Effective treatment of chronic pain, including severe neuropathic pain conditions, such as erythromelalgia (EM) and small fiber neuropathy (SFN), remains a significant unmet medical need. Current therapies often lack full efficacy or come with serious risk, such as addiction associated with opioids. Antisense oligonucleotides (ASOs) offer a promising solution by knocking down specific mRNA transcripts with a long duration of action (~3 months) for sustained relief. ASOs have been successfully applied to patients to treat severe neurological disease. Here, we propose to develop an ASO therapeutic targeting the voltage-gated sodium channel, Nav1.7, which is highly expressed in dorsal root ganglion (DRG) neurons. Nav1.7 is a target with strong human genetics validation in pain transmission, including neuropathic pain. Reduction of channel expression via a therapeutic ASO may overcome the challenges of small molecules by mimicking the mechanism for congenital insensitivity to pain (CIP) resulting from hNav1.7 loss-of-function mutations. Administering the ASO via intrathecal (IT) injection will enable precise knockdown of Nav1.7 expression in DRG tissues in a state-independent manner with minimal risks for autonomic side effects, paving the way for an effective and targeted chronic pain therapy. To enable the selection of a Nav1.7 specific ASO with the desired profiles, Quiver has developed breakthrough technologies: (i) high throughput readout of neuronal excitability based on all-optical electrophysiology, (ii) combination of patient genetics and state-of-the-art human iPSC sensory neuron differentiation protocol for pain therapeutics validation in patient-based models, and (iii) a machine learning-guided ASO design and discovery platform for identifying the best ASO candidates with maximum therapeutic index. As an entry point, Quiver has identified a potent and selective hNav1.7 lead ASO (QV-2421) with confirmed activity in primary DRG neurons from relevant species and a clean in vivo CNS tolerability profile through in sillico prediction and empirical validation. In the UG3 phase, we will apply our breakthrough technology in combination with well-established preclinical assays to optimize the ASO lead. Quiver will collaborate with Boston Children's Hospital (BCH) to validate the functional impact of the lead ASO in sensory neurons derived from EM/SFN patients with neuropathic pain conditions. We will also evaluate long term in vivo tolerability and investigate translational biomarker approaches. Based on these studies, we aim to select one optimized ASO lead candidate with an acceptable tolerability profile and in vivo NHP PK/PD data profile by the end of the UG3 phase. In the UH3 phase, we will conduct dose-range finding toxicology studies, establish clinical biomarkers, perform large-scale manufacturing of the ASO candidate for IND-enabling studies, and initiate a Phase I clinical trial in young adult EM patients. The UH3 phase will conclude with the identification of an ASO candidate with an acceptable toxicology and preclinical profile that is advanced through IND-submission to enable the initiation of Phase I clinical trial. Our ultimate goal is to deliver a much-needed, non-opioid therapy to patients suffering from severe, chronic pain.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT HIV-1 infection remains a global health crisis. While highly active antiretroviral therapy (ART) allows most people to live with HIV, ART is not curative. HIV-1 exists within a reservoir of latently-infected cells as an integrated provirus DNA that is rekindled for virus gene expression and viral recrudescence upon ART cessation. The field of HIV Cure is accordingly constantly developing new ways, on the one hand, to permanently silence HIV-1 gene expression (block and lock), or, on the other hand, to enhance gene expression and then to eliminate HIV+ cells from the body (shock and kill). HIV-1 structural proteins and replication enzymes are expressed from proviral DNA as Gag and Gag-Pol polyprotein precursors, respectively, which are cleaved into constitutive components by the viral protease (PR) enzyme during virus assembly and maturation. Retroviral PRs are quasi site specific enzymes, and retroviruses have accordingly evolved to regulate PR activity to limit the extent of cellular proteolysis, which otherwise could be leveraged to detect the virus as a foreign invader. Indeed, the field has in recent years described effective small molecule kill modulators, called RT-TACKs, because they work by engaging the reverse transcriptase (RT) domain within Gag-Pol to effect premature Gag-Pol dimerization, which in turn prematurely activates the viral PR to cleave cellular inflammasome modulators and elicit pyroptotic cell death. In addition to protease and RT, the integrase domain encompasses part (the C-terminal portion) of Gag- Pol. Integrase has previously been implicated in regulating PR activity during HIV-1 maturation, but the underlying molecular mechanisms have remained unclear. In this study, we have assessed if integrase-targeting compounds might also elicit pyroptotic cell death. The work described in this application will determine the developmental potential of integrase-targeted activator of cell kill (IN-TACK) compounds for elimination of HIV+ cells.

Dia de Los Muertos PNW

Día de Los Muertos PNW will host Ballard’s first Día de Los Muertos Parade & Festival. Located at 2200 block of Ballard Avenue NW - from NW 17th Avenue to NW Market Street . A family friendly event that celebrates tradition, memory, and community. The evening parade starting at 5:30pm will feature Catrinas, Mariachis, Charros, Native American groups, youth, floats, and other community groups, followed with live Latino music, cultural installations. The project highlights Latino culture, fosters inclusivity, and strengthens neighborhood connection through art, music, food, and remembrance. The event is free and open to the public.

Dia de Muertos Committee

The Dia the Muertos committee will be hosting the The Dia de Muertos celebration at Seattle Center on October 30-31, 2021 located at 305 Harrison St. This celebration is part of Festal Cultural Festivals and brings to life the vibrant Mexican tradition remembering and honoring our departed ones through colorful art, history, musical performances, and cultural activities that transport spectators and participants to different regions of Mexico. The is to connect Mexican and Latinx communities to their heritage and share these rich traditions with the broader community. The theme this year is the fall of the Aztec Empire at the hands of the Spanish forces in August of 1521. The event is free and open to public.

Dietrich Foundation

Funds arts, culture, health, and education in the Pittsburgh, PA region.

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

PROJECT SUMMARY For a pregnancy to succeed, the immune environment at the maternal-fetal interface must be precisely regulated to support fetal development. Uterine natural killer (uNK) cells–the most abundant lymphocyte at the maternal- fetal interface–are thought to contribute to various physiological aspects of gestation crucial for fetal development. Their critical role in pregnancy is evidenced by studies linking abnormalities in uNK cells to adverse pregnancy outcomes, particularly in uterine transplant recipients. Our preliminary findings provide the first direct evidence showing that the loss of uNK cells in the pregnant murine uterus significantly reduces litter sizes and increases resorption rates, further underscoring their indispensable role in pregnancy. Despite mounting evidence linking uNK cell dysfunction with adverse pregnancy outcomes, critical knowledge gaps in uNK cell biology persist, particularly regarding the origins and functional specialization of these cells within the uterine microenvironment. Our lab has previously shown that the uNK cell population is heterogeneous, consisting of both tissue-resident NK (trNK) cells and conventional NK (cNK) cells. While the developmental trajectory of cNK cells has been well-established, the developmental origins of uterine trNK cells remain unresolved. Here, we will investigate the origins and differentiation of uterine trNK cells in the virgin and pregnant murine uterus. Our preliminary findings show that both trNK cells and cNK cells in the murine uterus are Eomesodermin-dependent both at steady-state and during pregnancy, suggesting uterine trNK cells derive from the cNK cell lineage. Additionally, our initial studies demonstrate that progenitors in the bone marrow can give rise to uterine trNK cells. Together, our data support the central hypothesis that uterine trNK cells originate from the cNK cell lineage and are derived from either 1) early NK cell precursors in the bone marrow or 2) mature cNK cells in the periphery. Recognizing that these possibilities are not mutually exclusive, we will clarify the origins and developmental kinetics of uterine trNK cells using cutting-edge techniques and novel mouse models, including adoptive transfer studies in a newly engineered reporter mouse as well as advanced whole-mount confocal imaging. We also hypothesize that peripheral cNK cells can differentiate into uterine trNK cells during murine pregnancy and are driven to do so by molecular factors in the pregnant uterus. To explore the potential plasticity of peripheral cNK cells in the pregnant uterus, we will leverage innovative mouse models and state-of-the-art spatial transcriptomics to identify key regulatory signals and cell populations governing this transition. Collectively, this proposal will address key gaps in uNK cell biology by providing critical insights into the origins and differentiation of uNK cells that have the potential to uncover novel therapeutic targets for patients with uNK cell abnormalities, particularly uterine transplant recipients, ultimately improving reproductive health outcomes.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY The ongoing purpose of the Medical University of South Carolina (MUSC) Digestive Disease Training Program is to educate and mentor a cadre of researchers who will drive the future of liver and gastrointestinal (GI)-related biomedical research within three fundamental thematic areas: 1) Inflammation and Fibrosis; 2) Metabolic Disease; and 3) Organ and Tissue Failure. These themes are highly-relevant to major disease states affecting the health of the GI tract and liver and build upon the strengths of our established researchers. The emphasis of the program is to train graduate students in the art of basic biomedical research in a manner that will advance the study of the fundamental mechanisms underlying digestive and liver disease. Success will expand the pool of qualified digestive disease researchers and facilitate the development of novel treatments. Trainees will be selected from a pool of applicants that enter the MUSC College of Graduate Studies. After completing a basic biomedical sciences curriculum during their first year in as graduate students, trainees appointed to the Digestive Disease Training Program will take newly-developed courses that focus on digestive disease research and that complement their dissertation research projects. In addition, they will have access to courses offering instruction in professional development, experimental design and analyses, and rigorous, responsible conduct of research. Students’ coursework will be complemented with a number of enrichment activities including a Digestive Disease Seminar Series, a Journal Club, an Annual Digestive Disease Retreat, and numerous career development opportunities, such as a digital badge in science communication. The program will be supported by a growth in digestive disease research at MUSC that is driven by strategic institutional investments, programmatic support, and the recruitment of key faculty. MUSC’s robust clinical environment, collaborative research environment, and investments in numerous research cores will continue to advance digestive disease research on campus and provide trainees with a robust and scholarly training environment.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

PROJECT SUMMARY Alcohol-associated hepatitis (AH) is a severe form of liver disease and a leading cause of liver-related mortality in the U.S., yet the therapeutic landscape remains critically underserved. Clinical trials for new AH therapies are profoundly impaired by low patient enrollment and poor retention, creating a major bottleneck that has stalled therapeutic advancement for decades. To address these challenges, this proposal leverages an innovative approach using state-of-the-art artificial intelligence (AI) to create "digital twins" – virtual patient representations that can simulate disease trajectories and treatment response. Our central hypothesis is that digital twins, generated via advanced diffusion models, can effectively emulate randomized clinical trial results and simulate control group responses, enabling in-silico trial designs that reduce enrollment requirements while maintaining statistical rigor and privacy. Our strong preliminary data support this hypothesis, demonstrating the successful generation of high-fidelity synthetic hepatology datasets that preserve critical clinical relationships, survival outcomes, and patient privacy. Furthermore, we have successfully executed a full in-silico trial using digital twins, providing a robust proof-of-concept for our proposed methods. Building on this foundation, this project will pursue two specific aims: • Aim 1: Develop digital twins from a comprehensive, multi-institutional AH dataset and perform a target trial emulation of the landmark STOPAH study to validate the framework's ability to reproduce the findings of a large-scale randomized controlled trial. • Aim 2: Validate the digital twins for accurately simulating control group responses in both a completed (retrospective) and an ongoing (prospective) AH clinical trial conducted by the NIH-funded AlcHepNet consortium. This research is innovative as it represents the first systematic application of digital twins to overcome long- standing clinical trial barriers in AH. Successful completion will provide a validated platform to accelerate therapeutic development, reduce trial costs, and inform regulatory science for AI-driven clinical research. The institutional environment at Mayo Clinic provides unparalleled mentorship, access to extensive clinical datasets, and computational resources. This K08 mentored career development award is essential for my transition into an independent physician-scientist pioneering AI-driven precision medicine to improve outcomes for patients with alcohol-associated liver disease.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Project Summary Quantitation of intracellular metabolite pools is essential for a complete understanding of cell properties, phenotype, and responses in research, biomarker discovery, and screening potential disease therapeutics. Chromatographic separation followed by mass spectrometric detection is the state of the art for high multiplex, selective, and sensitive metabolite quantitation. However, this approach involves attempting to rapidly quench cell metabolism and extract metabolites without impacting metabolite levels. Furthermore, this approach requires multiple types of chromatography for different types of metabolites, and cannot easily provide spatiotemporal information. Spatiotemporal measurements of intracellular metabolites have been achieved by developing genetically encoded metabolite sensors, but these sensors are typically limited to one metabolite, are often not quantitative, and cannot be quickly incorporated into cell samples. We will develop high multiplex metabolite sensors that overcome these limitations to enable new types of observations, experiments, and spatiotemporal metabolomics studies. The sensors will employ Pdots—semiconducting polymers collapsed into nanoparticles—which exhibit high brightness, photostability, and a large color panel for spectral multiplexing. For Pdot sensing, we initially developed ratiometric Pdot sensors sensitive to general physiological conditions (pH, temperature, O2, NADH), then leveraged the O2- and NADH-sensitive Pdots to create two generalizable Pdot metabolite sensor platforms for quantitatively imaging any metabolite that can be oxidized or reduced. These platforms involve attaching a metabolite-specific O2- or NADH-dependent enzyme to an O2- or NADH-sensitive Pdot. However, these enzyme-coated Pdot metabolite sensors require a separate Pdot without an enzyme coating to correct for endogenous O2 or NADH levels. Since O2 and NADH levels can vary spatially within a cell, it is critical that the two Pdots be close together. To achieve this requirement, here we will explore using Pdot dimers consisting of one enzyme-coated Pdot and one uncoated Pdot. We will assess the feasibility of using the Pdot dimer sensors for high-multiplex intracellular metabolite measurements via the following two Aims: (1) Demonstrate accurate multiplex intracellular metabolite measurements in live human cells. (2) Explore two approaches to rapid, scalable cytoplasmic delivery of Pdot sensors.

National Endowment for the Humanities

DIPLOMACY AT HOME: THE DOMESTIC LIVES OF THE FOUNDING FAMILIES [THE KATONAH MUSEUM OF ART (KMA) WILL PRESENT DIPLOMACY AT HOME: THE DOMESTIC LIVES OF THE FOUNDING FAMILIES, SCHEDULED TO BE ON VIEW FROM JUNE 28-OCTOBER 4, 2026. THE KMA IS ORGANIZING THIS EXHIBITION IN PARTNERSHIP WITH THE FRIENDS OF JOHN JAY HOMESTEAD, WHICH SUPPORTS THE PRESERVATION AND ACTIVITIES OF THE JOHN JAY HOMESTEAD STATE HISTORIC PARK, AND THE RICHARD HAMPTON JENRETTE FOUNDATION. DIPLOMACY AT HOME: THE DOMESTIC LIVES OF THE FOUNDING FAMILIES WILL EXAMINE THE LIVES OF THE FOUNDERS THROUGH OBJECTS FROM THEIR HOMES?INCLUDING FURNITURE, FINE ART, DECORATIVE OBJECTS, AND PERSONAL POSSESSIONS?TO HIGHLIGHT THEIR SYMBOLIC VALUE IN DEFINING THE FOUNDING FAMILIES? CENTRAL ROLE AS THE ARCHITECTS WHO FRAMED THE FOUNDATION FOR OUR COLLECTIVE NATIONAL HISTORY. THE EXHIBITION ALIGNS WITH THE HOMESTEAD?S 250TH ANNIVERSARY AND WILL BE A CORNERSTONE OF THE EVENTS PLANNED BY THE TOWN OF BEDFORD AND WESTCHESTER COUNTY AS PART OF THE NATION-WIDE CELEBRATION OF THE COUNTRY?S 250TH.]

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY Antimicrobial resistance represents a critical global health threat, demanding new antibiotics with novel scaffolds and mechanisms of action. Anaerobic bacteria – particularly the Clostridia, which comprise up to 40% of the human gut microbiome – represent an underexplored reservoir of bioactive natural products. These organisms have evolved unusual biosynthetic machinery and remarkable oxygen-sensitive radical enzymes to synthesize structurally unique molecules with critical physiological functions. Yet, their biosynthetic potential remains largely untapped due to significant technical challenges in their genetic manipulation. This proposal outlines our comprehensive strategy to unlock Clostridial biosynthesis, combining complementary genomics-driven and activity-guided approaches. Topic 1 focuses on characterizing a unique family of cobalamin-dependent radical S-adenosylmethionine (B12-rSAM) enzymes fused with non-ribosomal peptide synthetase (NRPS) adenylation domains that we discovered through mining of Clostridial genomes. We hypothesize these enzymes catalyze the stereoselective methylation of the carbon backbone of the incoming amino acid as it is loaded onto the assembly line – a reaction with no precedent in NRPS biochemistry, that could ultimately be harnessed to improve the stability and activity of peptide-derived antibiotics. We will characterize these enzymes both biochemically through in vitro assays of purified proteins, and through in vivo gene cluster activation and product characterization in the native producers. Topic 2 targets discovery of novel antimicrobials from cellulolytic Clostridia, which appear from bioinformatic analysis to be particularly gifted antibiotic producers. We will express promising biosynthetic gene clusters in our newly developed Clostridial chassis strain, and activate cryptic pathways in native producers through hypothesis-driven elicitor screening. My group’s unique combination of expertise in Clostridial metabolic engineering, oxygen-sensitive enzyme biochemistry, and development of state- of-the-art genetic tools positions us to overcome longstanding barriers in anaerobic natural products research. Success will yield new antimicrobial compounds and reveal novel biosynthetic chemistry, ultimately contributing new therapeutic strategies against drug-resistant pathogens and for the microbiome.

Discover Music in the Park

Friends of Discover Music in the Park will organize a free outdoor classical music and dance concert in Discovery Park. The event will be held on Sunday, August 20, from 1:00 to 3:00pm, at the upper field next to Daybreak Star Cultural Center, and is planned for around 500 attendees. Outreach will be done to the general public with focus on the Magnolia and Queen Anne neighborhoods, families, students, Tent City 5, Discovery Park visitors, community groups, and arts organizations that are interested in expanding music and arts performances in Seattle's parks.

NCI - National Cancer Institute

PROJECT SUMMARY Acute myeloid leukemia (AML) is the most common form of adult acute leukemia yet has a 5-year overall survival of only 32.9%. Thus, identifying new strategies to target AML would address a critical unmet need for patients. Protein homeostasis (proteostasis) refers to a network of mechanisms used to maintain the quality of the proteome. The role of proteostasis regulation in AML has not yet been thoroughly examined. Proteasome inhibitors are approved to treat multiple myeloma, but they exhibit little clinical efficacy in AML. They work well in myeloma because they readily disrupt proteostasis in myeloma cells which already exhibit increased basal levels of proteotoxic stress from paraprotein production, resulting in activation of an integrated stress response (ISR). The ISR is a stress pathway activated by eIF2a and can ultimately induce apoptosis. In contrast to myeloma, AML cells require additional perturbations to the proteostasis network to activate the ISR when treated with proteasome inhibitors. I recently found that proteasome inhibition induces compensatory activation of the autophagy and the heat shock response pathways to preserve proteostasis. However, disruption of either autophagy or the heat shock response in combination with proteasome inhibition potently kills AML cells by activating a terminal ISR. This raises the possibility that the integrated nature of the proteostasis network confers resistance to proteasome inhibition, and that concurrent targeting of multiple mechanisms is required to disrupt proteostasis. The central goal of this proposal is to test the hypothesis that disrupting the proteostasis network can impair AML. In Aim 1, I will disrupt proteostasis within AML cells by inhibiting protein degradation with both proteasome and autophagy inhibitors, and determine if PKR, an eIF2a kinase, mediates ISR activation during this process. I will also determine if proteostasis disruption increases IL24, an immunomodulatory cytokine, and perform proteomics studies to determine whether it can be used as a biomarker for proteostasis disruption. In Aim 2, I will examine if proteostasis disruption through deletion of HSF1, a master transcription factor of the heat shock response, coupled with proteasome inhibition activates PERK, another eIF2a kinase, to turn on the ISR. This project will utilize vertebrate animals for establishing humanized cancer models to evaluate the in vivo effects of modulating proteostasis which would be a necessary step toward translational studies. Overall, I will begin to uncover how the proteostasis network is configured within AML in vitro and in vivo, and establish how it can be therapeutically targeted. My career goal is to become a physician-scientist who will make discoveries leading to new therapies for patients with hematologic malignancies. For this K08 award, I have assembled an exceptional team of experts at UC San Diego, a world-renowned research institution, that will provide training on the proteostasis network, state-of-the-art proteomics, and translational research in AML. With outstanding institutional support and an accomplished mentoring team, I aim to gain additional skills necessary for leading a successful laboratory in translational research and develop proteostasis-targeting therapies in blood cancers.

NIMH - National Institute of Mental Health

Abstract Despite the high prevalence of major depressive disorder (MDD) and its projected rise as the leading cause of global disease burden by 2030, treatment efficacy remains suboptimal. First-line antidepressants have modest efficacy (~50%), and high placebo response rates (~40%) contribute to the failure of antidepressant trials and hinder new drug development. While research underscores the role of antidepressant expectancies in modulating mood across various brain regions, there is a critical need to elucidate how expectancy-driven neural dynamics interact with downstream mood regulation processes to induce sustained mood improvement. Our recent work provides the first computational account of antidepressant placebo effects, where reinforcement learning (RL) model-predicted expectancies—encoded in the salience network (SN)—trigger mood changes perceived as reward signals, which reinforce antidepressant expectancies through an expectancy-mood loop. Furthermore, we and others have demonstrated that enhanced functional connectivity (FC) between the SN and default mode network (DMN) during expectancy processing and at rest predicts long-term antidepressant placebo effects. This evidence suggests that antidepressant expectancies, originating from contextual treatment cues, are represented in the SN and influence mood regulation through top-down connections with the DMN. To test this hypothesis, this study will investigate the causal roles of the SN, DMN, and SN-DMN FC in antidepressant placebo effects using Theta Burst Stimulation (TBS). In a 2x3 factorial design, 200 patients with MDD will be randomized to three counter-balanced TBS conditions (intermittent, continuous, and sham, within-subject) targeting either the SN or DMN (between-subject). These acute experimental manipulations will modulate trial-by-trial expectancy and mood ratings and the neural encoding of model-based expectancies and mood reward signals during the “antidepressant placebo fMRI task”, which manipulates placebo-associated expectancies using visually cued fast-acting antidepressant infusions and sham visual neurofeedback. Led by experts in placebo effects, reinforcement learning, depression, and neuromodulation, this study combines a robust theoretical framework, state-of-the-art neuroimaging, precision functional mapping for personalized TBS targeting, and accelerated TBS, ensuring scientific rigor. The insights gained from this study will deepen our understanding of the neural mechanisms behind placebo effects, enhancing clinical trial design, advancing neuroimaging predictors of treatment response, and accelerating the development of expectancy-based interventions for MDD.

NIDA - National Institute on Drug Abuse

Project Summary/Abstract Opioid use disorder (OUD) is a devastating public health crisis, characterized by a lack of inhibitory control over drug seeking. Opioid use causes persistent adaptations in the excitatory circuitry governing motivated behavior, enabling drug-paired cues to trigger seeking despite negative consequences. Therefore, understanding how opioids engage and adapt unique glutamatergic circuit elements to promote maladaptive, reward-driven behavior would provide significant insight into habitual heroin use and identify treatment strategies to prevent relapse. This K99/R00 proposal seeks to determine the projection-specific glutamatergic neurons that functionally guide motivated behavior and reveal the pathway-specific circuit adaptations that emerge during heroin use to drive reward seeking. As I begin my independent career, I aim to develop a research program that investigates the spatiotemporal dynamics of drug-naive and drug-experienced glutamatergic networks and causally implicate pathway-specific ensembles in guiding reward-driven behavior and relapse. The Otis laboratory identified that the glutamatergic pathway from the paraventricular thalamus to the nucleus accumbens shell (PVT→NAc) pervasively governs naturalistic reward-seeking behavior, and stimulation of this pathway is sufficient to profoundly inhibit motivated action. Recently, I established that heroin use dampens PVT→NAc projection activity and weakens downstream synaptic efficacy, functionally disinhibiting reward seeking. Using two-photon (2P) calcium imaging in head-fixed, self-administering mice, we found three unique ensembles emerge in the PVT→NAc pathway during taking, with inhibitory neuronal dynamics reliably predicting goal-directed behavior in sucrose- and heroin-seeking tasks. However, it is currently unknown whether this inhibitory ensemble functionally encodes motivated behavior and actively guides reward seeking. During the K99, I will receive world-class training in 2P single-cell optogenetics to selectively photostimulate the inhibitory PVT→NAc ensemble that encodes goal-directed behavior in sucrose-seeking mice, both before and after heroin exposure. I will learn advanced computational analysis to determine the outcome of ensemble photostimulation on the within- projection dynamics guiding inhibitory control and heroin-induced disinhibition of seeking (Aim 1). I will expand my investigations into other key glutamatergic inputs to the NAc and determine the heroin-induced adaptations in hippocampal circuit- and cell-type-specific connectivity that facilitates relapse (Aim 2) and hippocampus-to- NAc-specific projection neurons that guide heroin-motivated behavior (Aim 3). Collectively, this proposal tests the hypothesis that heroin induces functional adaptations in pathway-specific glutamatergic circuit elements to drive maladaptive reward seeking. Results will reveal the network computations that guide motivated behavior in naïve and drug-exposed systems. This K99/R00 will grant me the unparalleled opportunity to receive training in state-of-the-art approaches as I develop my own independent research program in OUD.

NIAID - National Institute of Allergy and Infectious Diseases

SUMMARY Enterohemorrhagic Escherichia coli (EHEC) is a foodborne pathogen that breaches the intestinal epithelium and causes outbreaks of bloody diarrhea and hemolytic uremic syndrome. Despite the threat EHEC poses to public health, several gaps remain in our understanding of its unique infectious mechanism. EHEC’s native target is the intestinal epithelium, which primarily consists of polarized enterocytes that display actin-based protrusions known as microvilli on their apical/luminal surface. During infection, EHEC destroys microvilli and attaches firmly to the apical host cell surface. Subsequently, EHEC reorganizes the host cytoskeleton to form dynamic actin- rich structures known as “pedestals,” which are suggested to aid in cell-to-cell spread, enhancing its colonization of the intestine. Notably, EHEC remains extracellular during infection and exploits host cytoplasmic proteins by secreting bacterial effector proteins into the host. The current model for EHEC pathogenesis requires two bacterial secreted effectors, Translocated intimin receptor (Tir) and E. coli secreted protein F in prophage U (EspFU), for pedestal formation. Once translocated into the host cytoplasm, Tir inserts into the plasma membrane through an undefined mechanism and binds to intimin, an EHEC surface protein, via its extracellular domain to initiate bacterial attachment. EspFU then drives actin pedestal assembly by activating Arp2/3, an actin nucleating complex. Actin assembly in turn promotes pedestal motility for efficient bacterial cell-to-cell spread. Despite EspFU being the major driver of actin pedestal assembly and motility, an EHEC strain lacking EspFU (EHECDEspFU) still forms pedestals and colonizes the intestine, suggesting that other pathways, independent of EspFu, remain to be discovered. Interestingly, Tir and EspFU do not bind directly to each other, rather they sequester the host protein Insulin Receptor Tyrosine Kinase Substrate (IRTKS) to form a Tir-IRTKS-EspFU complex. In addition to its scaffolding function, IRTKS has been implicated in outward membrane curvature via its Inverse BAR (I-BAR) domain and more recently in the actin assembly of microvilli via its actin binding Wiskott- Aldrich homology 2 (WH2) domain. How the I-BAR and/or WH2 domains contribute to EHEC infection remains unexplored. My preliminary data shows that overexpression of IRTKS leads to increased bacterial attachment and that the loss of IRTKS results in decreased levels of Tir beneath adherent bacteria. These results suggests that IRTKS contributes to bacterial attachment and to the enrichment of Tir in the apical plasma membrane. Based on published and preliminary data, I hypothesize the I-BAR and WH2 domains of IRTKS promote Tir- mediated EHEC attachment and subsequent actin pedestal assembly, respectively. This project will take advantage of state-of-the-art microscopy and biochemical methods to test this hypothesis by: (Aim 1) defining how IRTKS promotes bacterial attachment, and (Aim 2) determining if IRTKS contributes to actin pedestal assembly and motility independent of EspFU. This work will allow us to build a comprehensive mechanistic model of EHEC pathogenesis and develop our understanding of EHEC’s infectious life cycle.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

The kidney transports ions, solutes, and water through energy-intensive processes that depend on the efficient synthesis of ATP via oxidative phosphorylation (OxPhos). Central to OxPhos is the mitochondrial (mt) electron transport chain (ETC), which generates ATP through chemiosmosis by driving ATP synthase activity. However, ATP production is not the only ETC-associated function essential for kidney health. The ETC also regulates intermediary metabolism and maintains cellular redox balance by oxidizing NADH and FADH2 to regenerate NAD+ and FAD. Furthermore, through its regulation of intermediary metabolism, the ETC intersects with hypoxia-inducible factor (HIF)- dependent oxygen sensing, underscoring its pivotal role in linking cellular metabolism to cellular adaptation to hypoxia. Despite its central importance in kidney physiology and disease, in vivo studies dissecting these diverse ETC functions have been limited by the lack of suitable genetic models. The interconnections between mt electron transport, redox balance, and intermediary metabolism in kidney homeostasis and pathogenesis therefore remain incompletely understood. To address these knowledge gaps, we take advantage of novel mouse models with targeted disruption of mt complexes I and III using pan-epithelial and nephron segment-specific gene targeting. Aim 1 examines the metabolic and biochemical consequences of complex I and complex III deficiency in the kidney through comprehensive in vivo and in vitro analyses. Using state-of-the-art approaches, including metabolic flux analysis, mass spectrometry-based metabolite imaging, and 3D super- resolution structured illumination microscopy, we delineate nephron segment-specific effects of ETC disruption on epithelial homeostasis and function. Aim 2 tests the hypothesis that aberrant intermediary metabolism, rather than ATP deficiency per se, drives epithelial dysfunction and tubulointerstitial injury in kidneys with ETC dysfunction. Through genetic restoration of redox balance and metabolite flux without reestablishing OxPhos, we will distinguish the molecular and pathological consequences of dysregulated intermediary metabolism from those of impaired ATP synthesis. Aim 3 investigates how aberrant intermediary metabolism and altered redox potential regulate HIF oxygen sensing and contribute to epithelial injury.