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Tasveer

Tasveer will organize a free nine-day literary and storytelling festival focusing on South Asian culture in January 2019. It will feature presentations and workshops on writing fiction, comedy, screenplays, graphic novels, and other ways of telling a story. The events will take place at Seattle Art Museum Located at 1300 1st Ave and Northwest Film Forum located at 1515 12th Ave.

NHGRI - National Human Genome Research Institute

ABSTRACT Noncoding genetic variation that alters gene regulation is of paramount importance for health, disease, and evolution. Diseases ranging in incidence from the most common to the most rare all have substantial risk associated with regulatory variation; and most of the genetic differences between closely related species are noncoding. Whole genome sequencing can directly identify that variation but to realize its potential to elucidate the genetic determinants of health and disease, will require accurate annotation of this noncoding variation for functionality. In coding sequence, the genetic code allows variants to be annotated to a rough hierarchy of likely functional effects and pathogenicity. In noncoding sequence such annotation is less clear. Perturbation assays, i.e., assays that modify genetic or epigenetic states and measure the effect of those perturbations on regulatory endpoints, offer a possible path to annotating noncoding variation. However, to fully leverage this data, novel and sophisticated statistical and machine learning approaches are required to extract useful information from those assays, to integrate that information across regulatory endpoints, and to extrapolate findings so that annotation of previously unobserved (unperturbed) variation in diverse cell types is possible. The goal of the Duke Prediction Center is to develop the analytic approaches and tools that will allow for the routine annotation of noncoding variation for functionality and ultimately pathogenicity. Aim 1 is to establish best practices in perturbation assay design and analysis. This will allow IGVF characterization centers design their experiments so that, when coupled with optimized analyses, the data produced will be maximally informative for subsequent predictive modeling. Aim 2 is to develop novel mechanistic machine learning approaches for predicting the functional effect of noncoding variation on function in diverse cell-types. Aim 3 is to identify noncoding genomic regions that are subject to functional constraint which will be leveraged in prioritizing variants for pathogenicity. The expected outcomes of this project will be (i) robust estimates of optimal experimental design parameters and recommendations for analysis tools and best practices for the various assays used within the IGVF consortium, (ii) predicted functional effects of observed variation to be shared through the IGVF variant/phenotype catalog as well as a state-of-the-art machine learning method (and associated tools) that can identify previously-unknown interactions among genomic variants, both observed and novel, and predict their functional impact in diverse cell types, and (iii) a list of regulatory elements subject to functional constraint shared through the IGVF variant/phenotype catalog and a principled prioritization framework (and associated tools) for interpreting variation within patient genomes for pathogenicity. Due to the considerable success of genetics, there are thousands of unknown regulatory causes of disease. Each of those causes is an opportunity to improve treatment, diagnostics, or prevention. This project will be a major advance towards unlocking that potential.

Destiny Arts Center

Support for the organization’s programs and activities: martial arts, dance, theater, youth leadership, and violence prevention at their main site, and outreach classes in schools and community centers.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT This K23 award will facilitate Dr. Grau’s transition into an independent investigator who develops and tests scalable interventions with attention to health disparities to meet the variation in needs among individuals with post-traumatic stress disorder (PTSD) and hazardous alcohol use (HAU). Targeted research and training activities will extend his knowledge and build his expertise in developing and testing scalable interventions that integrate therapist-delivered and digital components to effectively engage and treat patients with PTSD+HAU in under resourced community settings like Federally Qualified Health Centers (FQHCs). Training: Dr. Grau proposes a comprehensive training plan with the following training aims: (1) Develop expertise in mobile health interven-tions, (2) Gain skills in qualitative data collection and analysis and (3) Acquire key skills in and knowledge of optimization trial design and conduct. Context: PTSD is an extremely damaging psychiatric condition when left untreated, especially for individuals with low-income who are served in FQHCs. Brief, modified evidence-based PTSD treatments are effective and feasible in FQHCs; however, co-occurring problems, most notably HAU, negatively impact treatment engagement and effectiveness. As such, there is a critical need to develop scala-ble interventions that treat PTSD+HAU while maximizing engagement in under resourced community settings such as FQHCs. Responsive to the NIMH Strategic Plan, Goal 3 (Strive for Prevention and Cures), Objectives 3.2 (Develop strategies for tailoring existing interventions to optimize outcomes), and 3.3 (Test interventions for effectiveness in community practice settings), the overall research objective is to develop and test a multimodal intervention that integrates therapist-delivered and digital interventions to treat PTSD+HAU in FQHCs. Re-search Plan: Aim 1 will assess the feasibility and acceptability of three stepped care, therapist-delivered inter-vention components for PTSD+HAU in our partner FQHC. Aim 2 will refine the therapist-delivered components and develop digital components (e.g., personalized text messages) in preparation for a PTSD+HAU hybrid ex-perimental design (HED). Aim 3 will assess the feasibility, acceptability, and preliminary effectiveness of a PTSD+HAU HED in FQHCs combining therapistdelivered and digital interventions to maximize engagement in treatment. Aim 3 results will inform a fully powered HED (future R01 submission) to create a multimodal adap-tive intervention for PTSD+HAU with patients in community health settings. Key innovations include state-of-the-art training, PTSD+HAU scalable intervention development with real world patients in community settings, and use of the HED design. Optimization of adaptive interventions for community patients with PTSD+HAU is a critical next step and will have significant impact on PTSD treatment in FQHCs.

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.

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.

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.

Richard and Helen DeVos Foundation

Supports Christian organizations, education, community development, and arts in West Michigan and nationally.

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.

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.

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 HIV and Mycobacterium tuberculosis (Mtb) are among the world’s deadliest infections, and co-infection is particularly devastating because each pathogen accelerates the progression and severity of the other. Notably, for reasons that are not well understood, people living with HIV (PLWH) remain at elevated TB risk despite effective antiretroviral therapy (ART) and viral suppression. Our goal is to define how HIV-TB co-infection, even with virologic control, impairs Mtb immunity. Macrophages and CD4+ T cells are central to the pathogenesis of both diseases; Mtb infects lung macrophages and depends to CD4+ T cells to prevent disease progression, while HIV infects both macrophages and CD4+ T cells. Macrophages can harbor latent HIV proviruses, which persist despite treatment. Both pathogens reprogram macrophage metabolism, which is intimately linked to antimicrobial functions. However, the impact of co-infection on macrophage immunometabolism and Mtb control remains unclear. In addition, although antiretroviral treatment (ART) can restore CD4+ T cell counts to normal ranges, the T cells often remain dysfunctional and exhibit signs of exhaustion. We unite leading HIV and TB investigators and leverage unique cellular and animal models of HIV latency. We hypothesize that, despite ART and virologic suppression, PLWH experience macrophage immunometabolic reprogramming that enhances TB susceptibility and that ART-restored CD4+ T cells are dysfunctional and fail to enhance microbicidal properties of macrophages. Using dual-reporter human macrophage models and ex vivo studies of PLWH and controls, we will profile antimicrobial and immunometabolic responses of Mtb-infected macrophages, and we will test the contribution of exhausted CD4+ T cells to macrophage dysfunction. A long-standing obstacle to studying HIV- TB coinfection has been the absence of a small animal model. We will use a novel humanized mouse model that recapitulates human lung immune cell populations and HIV infection dynamics, including active viral replication, latency establishment, and viral suppression with ART. We will assess how untreated and treated HIV infection affects Mtb pathogenesis, assessing pathogen burden, immunometabolic responses, and cellular infection patterns, using spectral flow cytometry, scRNAseq and metabolic profiling. These studies will clarify the molecular basis of immune dysfunction during HIV-TB co-infection and inform on host-directed therapies to restore immune function and improve outcomes.

National Park Service

A. Research: develop and implement new technologies for the preservation and conservation of cultural heritage. B. Training: adapt new and existing technologies to the field of art conservation. Offer training courses and convene experts on technical and scientific aspects of hands-on conservation. C. Information Management: serve as knowledge centers and clearinghouses for conservation and preservation information. D. Grants: serve the preservation and conservation community by offering professional development opportunities through internships, scholarships, and grants. E. Conference participation: to include holding sessions, participation in exhibits and sharing meeting facilities. RECIPIENT AGREES

NEI - National Eye Institute

Abstract: This project aims to establish distributed federated learning (FL) approaches for multi-task training of foundational machine learning (ML) models for diabetic retinopathy (DR), using multi-modal, real-world optical coherence tomography (OCT) data (OCT cross-section, OCT angiography (OCTA), and OCT enface). DR is one of the leading causes of severe vision loss. Early detection, prompt intervention, and reliable assessment of treatment outcomes are essential to prevent irreversible vision loss from DR. However, there are major challenges towards developing clinically relevant holistic algorithms that can perform multi-tasks, i.e., multi-class classification of disease stages (diagnosis), prediction of onset and progression of disease stages (prognosis), and assessment of treatment outcomes. They require large amounts of well curated and labelled datasets from a diverse sub-population for robust performance. Moreover, efforts towards large, centralized datasets for ML research are hindered by significant barriers to data sharing and privacy concerns. In this project, we propose to develop foundational ML models that allow efficient learning of feature representations from a large corpus of ophthalmic imaging data for various downstream tasks – breaking the task-specific paradigm of current ML models. We also establish novel federated ML approaches, where the model training is distributed across institutions instead of sharing patient data. Our first aim is to establish and validate a domain adaptive FL framework for DR diagnosis across four independent institutions. We propose a novel ophthalmic adaptive personalized FL (optho-APFL) technique to tackle domain shift caused by heterogeneous data distribution at different institutions (due to different sub-population density and OCT devices/imaging protocols). We will conduct experiments on the FL deployment in a clinical setting and integrate a granular differential privacy (DP) algorithm into our FL framework to provide ‘patient-level’ data privacy. Key success criterion is to deploy the FL framework and validate FL-trained ML models against state-of-the-art models for DR diagnosis. The second aim is to develop foundational ML models with self-supervised learning (SSL) to learn multiple tasks within the same framework from label invariant OCT/OCTA data, where different institutions don’t need to have labeled data for each of the tasks. We will train these foundational models in a centralized and FL framework for comparative analysis. Key success criterion is to i) validate foundational model performance for multi-task learning (MTL) (DR staging, prediction of NPDR to PDR progression, and prediction of DME treatment evaluation) on new clinical data (centralized and FL approach, and ii) identify task-specific quantitative OCT/OCTA (mean and artery-vein specific) features. As an alternative approach, we propose diffusion probabilistic modeling (DPM) for SSL to learn holistic representations from multi-modal OCT data for MTL, and to explore dynamic federated averaging approaches. Success of this project will establish OCT/OCTA based distributed foundational models for objective MTL in DR using label-invariant data across multi-institutions and standardize OCT/OCTA features for MTL.

NINDS - National Institute of Neurological Disorders and Stroke

ABSTRACT Alternative splicing vastly expands the functional repertoire of genes, and is especially important during human synapse development. Human synapses have unique structures and compositions, but the mechanisms involved in their development remains elusive. Investigations into human-specific aspects of synaptic machinery have revealed a critical role for Rho guanine nucleotide exchange factor (GEF) signaling. TRIO is a large multi-domain RhoGEF with essential roles in neuronal and synaptic development. TRIO is also a genome-wide significant risk factor for neurodevelopmental disorders and glutamatergic synapses have been implicated by genomic, neuropathological, and functional studies as key sites of pathogenesis. Individuals with pathogenic TRIO variants are characterized by intellectual disability, developmental delay, and seizures. The TRIO gene produces multiple distinct isoforms that differentially incorporate TRIO’s functional domains including two GEF domains that having opposing functions on the actin cytoskeleton. Thus, precise control of TRIO’s GEF domains through expression and localization of isoforms is paramount for its function. However, the diversity and expression patterns of TRIO isoforms are poorly understood, and their impact on human synapse development is unknown. A complete catalogue of isoform diversity is necessary for a holistic view of gene function, and is critical for gene therapy designs, interpreting clinical variants, and revealing novel biological mechanisms. Here, we will leverage state- of-the-art long-read sequencing, iPSC-models and fluorescence imaging to characterize human TRIO isoforms. Our central hypothesis is that TRIO produces an array of isoforms with distinct expression patterns and domain architectures that assist with the precise timing and spatial control of synaptic development. In Aim 1, we will combine exon capture and long-read sequencing technologies to systematically profile full-length TRIO transcripts in the human brain. We will create comprehensive isoform maps at three postnatal time points, and analyze novel isoforms for differential expression, presence of clinical variants, and protein motifs. In Aim 2, human iPSC-derived neuron models will be utilized to assess the localization and functional roles of individual isoforms in synaptic compartments. Together, this work will reveal a high-resolution map of the structure, expression and function of TRIO isoforms in the human brain, providing mechanistic insight into human synapse development and TRIO-related neurodevelopmental disorders.