Grants

NEI - National Eye Institute

Project Abstract This proposal aims to transform the accessibility of digital thematic maps for the 285 million blind and low vision (BLI) individuals worldwide. Thematic maps are essential for understanding complex data in various domains, including climate analysis, electoral processes, and emergency management. However, these maps are currently inaccessible to BLI individuals, as screen readers often fail to recognize them, and they lack customization options for low vision users. If an alternative is provided, it is a simple table lacking any geographic information. This project seeks to commercialize Audiom, an innovative, multimodal, and Large Language Model (LLM) chat-based digital map viewer. Unlike existing alternatives, Audiom is designed to be fully compliant with Web Content Accessibility Guidelines (WCAG), enabling BLI individuals to engage fully in scientific and civic domains. The project will develop Audiom from a prototype into a fully commercial platform that integrates with mainstream map tools, laying the groundwork for further research into non-visual and multimodal cartography. Audiom offers a unique visual experience for low vision users, allowing customization through speech, textures, and high contrast borders. For non-visual users, Audiom provides an auditory and tactile experience, enabling navigation through a map with arrow keys or touchscreen swipes, with pitch and speech indicating the value of features. The specific aims of this project are threefold: 1) Optimize user performance with the Audiom interface through user-centered design iterations; 2) Execute community-based comparative usability studies to evaluate Audiom's effectiveness for BLI and sighted users; and 3) Create, commercialize, and distribute a productionready Software Development Kit (SDK) for accessible digital thematic maps, facilitating easy integration with existing digital map tools. By achieving these aims, Audiom will not only make thematic maps accessible to BLI individuals, ensure compliance with the Americans with Disabilities Act (ADA) and the Rehabilitation Act for government entities, but also make mainstream the field of non-visual cartography. The commercialization of Audiom will empower BLI scientists, enhance civic participation, and improve the quality of life for BLI individuals by allowing them to use digital maps for the first time.

NSF

Out-of-school STEM (Science, Technology, Engineering, and Mathematics) learning settings can foster a prepared future workforce through offering a wide range of novel, real-world applications of STEM concepts and skills. Care facilities, such as hospitals, are one setting in which many people spend a substantial amount of time. They afford numerous opportunities for people to learn and apply a range of STEM concepts and skills, yet research and development activities have not fully explored how these settings can maximize STEM learning in support of a more innovative and prepared workforce. This project will address this gap by developing and researching making activities for youth (ages 12-18) who spend time in care facilities. Youth, who have previously spent a substantial duration of time in hospitals, will partner with the project team and other expert care providers to co-develop making activities that are grounded in the experiences of youth in care facilities. For example, the youth and project team may co-develop making activities designed to improve various technologies, such as stethoscopes, used to provide care. Research will explore whether and how these making activities supported the STEM agency, interest, and understanding of youth participants. The resulting educational materials, such as specific maker activities and guidelines on how to implement them responsibly among youth receiving care, will be disseminated nationally to all, resulting in the advancement of youths' STEM learning and the application of their STEM skills in a previously understudied learning context. The project team will partner with previously hospitalized youth and child life specialists, trained professionals who provide expert guidance and support to families whose children are receiving care, to iteratively develop, test, and refine making activities that can be used by professionals in similar positions across the United States. Research will identify which maker activity formats and topics are feasible for child life specialists to implement among youth with a range of different conditions and durations of stay in care facilities. After determining feasibility in partnership with expert providers, the project team and partners will implement making activities with youth in care facilities. Mixed methods research will explore whether and how the youth co-designers experienced an increase in STEM agency, and whether and how the use of maker activities and accompanying learning materials impacted the STEM understandings and interest of youth who stay in care facilities. Resulting learning materials will include making activities, and companion videos, which can be used to increase the STEM interest and skills of youth who receive care in hospitals and similar settings. These materials will be widely disseminated nationally to care providers, informal STEM educators, and other audiences in order to advance the application of STEM skills across a broad range of settings and to result in a more proficient STEM workforce that is prepared to evaluate and innovate upon existing technologies. This Integrating Research and Practice project is funded by the Advancing Informal STEM Learning (AISL) program, which seeks to advance new approaches to, and evidence-based understanding of, the design and development of STEM learning in informal environments. This includes providing everyone multiple pathways for accessing and engaging in STEM learning experiences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF

This project aims to serve the national interest by improving undergraduate education to better prepare future engineering and computing professionals to use and develop artificial intelligence (AI). The increasing integration of AI-enabled technologies across domains creates workforce opportunities for students as well as providing mechanisms for improving human well-being. The project's significance lies in its innovative use of situated case studies to help students understand AI complexity, differing stakeholder requirements, and to develop critical reasoning about AI applications. Through early exposure in first-year courses, the project aims to develop transferable mindsets and skills that students can apply throughout their careers, advancing their understanding of how to prepare a workforce capable of AI innovation and supporting the nation’s economic well-being. The project goals include developing and implementing six case studies that focus on familiar AI applications such as career preparedness, campus sustainability, autonomous vehicles, and mental health systems using a Situated AI Literacy framework. The scope encompasses implementation across first-year engineering and computing courses at Youngstown State University and George Mason University, serving over 500 students during the project period, with additional dissemination through faculty development workshops reaching ten external institutions. The methodology employs role-play case study discussions integrating three key competencies- complex systems cognition, perspectival understanding, and critical thinking. The project plans to use mixed-methods evaluation, including pre- and post-surveys, concept maps, discussion transcripts, and focus groups to assess student learning gains across these elements. The research investigates how the case studies support the development of multi-level AI understanding, stakeholder perspective-taking, and critical assessment of AI benefits and limitations. The NSF IUSE: EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through the Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF

This project aims to serve the national interest by improving undergraduate education to better prepare future engineering and computing professionals to use and develop artificial intelligence (AI). The increasing integration of AI-enabled technologies across domains creates workforce opportunities for students as well as providing mechanisms for improving human well-being. The project's significance lies in its innovative use of situated case studies to help students understand AI complexity, differing stakeholder requirements, and to develop critical reasoning about AI applications. Through early exposure in first-year courses, the project aims to develop transferable mindsets and skills that students can apply throughout their careers, advancing their understanding of how to prepare a workforce capable of AI innovation and supporting the nation’s economic well-being. The project goals include developing and implementing six case studies that focus on familiar AI applications such as career preparedness, campus sustainability, autonomous vehicles, and mental health systems using a Situated AI Literacy framework. The scope encompasses implementation across first-year engineering and computing courses at Youngstown State University and George Mason University, serving over 500 students during the project period, with additional dissemination through faculty development workshops reaching ten external institutions. The methodology employs role-play case study discussions integrating three key competencies- complex systems cognition, perspectival understanding, and critical thinking. The project plans to use mixed-methods evaluation, including pre- and post-surveys, concept maps, discussion transcripts, and focus groups to assess student learning gains across these elements. The research investigates how the case studies support the development of multi-level AI understanding, stakeholder perspective-taking, and critical assessment of AI benefits and limitations. The NSF IUSE: EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through the Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NYC Department of Cultural Affairs

Developing Artists Theater Company

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary - Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive neurologic disorder due to failed catabolism of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). Patients with SSADHD exhibit intellectual disability with autistic features and epilepsy (with a high rate of sudden unexpected death in epilepsy, SUDEP). SSADHD symptoms are largely a result of the namesake enzyme deficit that leads to the pathologic accumulation of GABA and its metabolic by-product γ-hydroxybutyrate (GHB). The present standard of care for SSADHD includes behavioral therapy and anti-seizure drug medications – but these treatment options are ineffective and do not address the underlying genetic root cause. Notably, recent targeted drug trials have failed to improve core SSADHD symptoms, highlighting a major unmet medical need for disease- modifying treatment such as gene replacement therapy. Our proof-of-concept studies demonstrated phenotype reversal in SSADHD mice from a symptomatic stage when treated with a blood-brain barrier (BBB) penetrable adeno-associated virus capsid (AAV-PHP.eB) containing a novel viral payload encompassing a human full length native promoter (FLnP) coupled with a functional copy of the human SSADH-encoding gene ALDH5A1 (AAV-FLnP-hALDH5A1, US patent filed). Importantly, post-mortem analyses of treated mice revealed a direct relationship between survival and transgene expressions in the cerebral cortex and myocardium, highlighting a need for dose finding upon clinically relevant AAV delivery. Galibra Neuroscience, Inc. has obtained a license to develop AAV-FLnP-hALDH5A1, now named GAL005, to further determine the optimal dose in an AAV-BI-hTFR1 capsid, an engineered serotype that utilizes human transferrin receptors on the BBB to penetrate into the CNS. We will use a “humanized” mouse strain in which exons 4 – 19 of the mouse Tfrc gene encoding the extracellular domain are replaced by a knock-in of the corresponding region of human TFRC gene (i.e., TFRC KI mice) to measure biodistribution of GAL005 upon intravenous delivery (via retro-orbital injection) for clinical translation relevance. In this R41 STTR-Phase I proposal, we focus on two Specific Aims to advance the clinical readiness of GAL005 for the investigational new drug (IND)-enabling studies. This project will subcontract to the Rotenberg lab at BCH for biodistribution of GAL005 transfection in humanized mice (Aim 1). In parallel, an SSADHD model mouse developed by the Rotenberg lab will be crossed with TFRC KI mice, providing a preclinical model for final efficacy testing (Aim 2). In summary, we will measure payload biodistribution and preclinical toxicology of GAL005 and create a new humanized SSADHD mouse strain compatible with GAL005. If successful, this work will form the basis for completing IND-enabling studies and proceeding to the clinic, bringing the first CNS- and peripheral-targeting gene replacement therapy for a devastating ultra-rare orphan disease to market.

NHLBI - National Heart Lung and Blood Institute

ABSTRACT Sinus node dysfunction (SND) is a significant heart rhythm disorder that affects both young patients with congenital heart conditions and adults due to aging or secondary complications from other heart diseases. For symptomatic patients, pacemaker implantation is often required, particularly in children, where it frequently indicates worsening heart function and poor clinical outcomes. Despite its high prevalence, the underlying causes and progression of SND remain poorly understood. A major challenge in advancing treatments is the lack of a reliable human model that effectively replicates the sinoatrial node and its dysfunction. This project aims to address this gap by utilizing human cardiac pacemaker organoids derived from iPSCs to model SND. We hypothesize that integrating nonmyocytes into these organoids plays a crucial role in accurately mimicking the sinoatrial node and the progression of SND. By applying constant or cyclic mechanical strain, we will simulate the disease environment to better understand its mechanisms. These organoids will mirror the cellular diversity of the native sinoatrial node, offering a rigorous platform to explore the etiology of SND. The ultimate goal is to identify key molecular targets that could lead to novel therapies, reducing the need for permanent pacemaker implants and improving patient outcomes.

NIGMS - National Institute of General Medical Sciences

Conversion of somatic cells into pluripotent stem cells using the transcription factors Oct4, Sox2, Klf4 and cMyc (OSKM) has revolutionized biology and medicine. While the OSKM approach has provided a paradigm for reprogramming, a deeper understanding of cell fate plasticity could bring efficient regeneration and rejuvenation therapies within reach. Somatic cells give rise to induced pluripotent stem cells (iPSCs) infrequently and slowly, indicating that the plasticity of somatic cells is generally limited. We found that the bioactive compound KL871 promotes a cell state of remarkable potential for reprogramming: in the presence of KL871, OSKM reprogram all myeloid progenitors into iPSCs within 3 days, a process known to be slow (>10 days) and inefficient (<0.1%). To pursue the mechanistic basis underlying KL871-instigated cell fate plasticity, we synthesized a photoaffinity derivative of KL871 and found it to be a Yeats4 binder. Yeats4 is a member of the YEATS domain-containing epigenetic reader: it binds to acetylated lysines on histones (H3K27ac and H3K14ac) to recruit chromatin remodeling complexes Tip60/p400 and SRCAP that are not only histone acetyl transferases (HAT) but also deposit H2A.Z, leading to transcriptional activation. We found that KL871 promotes Yeats4-associated chromatin activities, including rapidly increasing histone acetylation as well as chromatin-associated Yeats4 and H2A.Z. Further, knocking down Yeats4 abolished the KL871-instigated reprogramming effects. We therefore hypothesize that KL871 promotes cell fate plasticity via augmenting Yeats4 function. While wide-ranging efforts have been devoted to developing inhibitors or degraders of epigenetic factors, chemical strategies to augment the function of epigenetic regulators are rare and challenging. To date, no small molecule compound is known to increase Yeats4’s reader function. We propose to capitalize on the KL871:Yeats4 relationship to understand how it promotes Yeats4 activity and determine how KL871-bound Yeats4 regulates chromatin and cell fate plasticity. With the strengths of our cross disciplinary teams in cell fate reprogramming (Dr. Shangqin Guo) and chemical biology (Dr. Craig Crews), we are at a unique position to pursue the following aims. 1) Define how KL871 binds to Yeats4; 2) Determine the chromatin consequences following KL871:Yeats4 interaction; 3) Assess cell plasticity following KL871:Yeats4 manipulation, and 4) Perform structure-activity relationship study to develop improved Yeats4-modulatory compounds. Supported by compelling preliminary data and novel tools, we propose to learn how to engineer somatic cell fate plasticity by understanding the underlying biochemical and molecular basis.

NIMH - National Institute of Mental Health

PROJECT SUMMARY ABSTRACT Effective interventions to reduce the functional impact of core features of autism spectrum disorder (ASD) in school-aged children are critically needed. This R61/R33 application proposes to test whether in-person computer training delivered individually by a coach engages an electroencephalographic (EEG) biomarker of cognitive control (N2 event-related potential [ERP] amplitude) and whether changes in the target neural response mediate the reduction of restricted and repetitive behaviors and interests. An extensive clinical and cognitive neuroscience literature documents reduced cognitive control among autistic children compared to neurotypical children and a relation between cognitive control and repetitive features of autism––providing a solid rationale for our training program. Based on this work, we predict that developing more effective cognitive control, metacognition, and working memory will enhance neural responses to conflicting information (i.e., a neural marker of effective cognitive control) and changes will correspond with decreases in restricted and repetitive behaviors and interests. The R61 study will randomly assign 95 autistic children (ages 8-11yrs) to a novel computer-based Cognitive Control Training combined with Metacognition Coaching or to a waitlist control group. Before and after intervention, EEG will be used to examine engagement of the target neural responses. We expect the group assigned to Cognitive Control Training + Metacognition Coaching to exhibit significantly larger changes in N2 ERP amplitude in incongruent relative to congruent trials than the waitlist group. If this hypothesis is supported, the R33 will be implemented and 140 autistic children (8-11yrs) will be randomly assigned to either: 1) Cognitive Control Training + Metacognition Coaching; or 2) MentalUP Educational Games, an active control condition that provides computer-based cognitive training. Both Cognitive Control Training + Metacognition Coaching and MentalUP will be delivered individually during 15 in-person sessions. Before and after intervention, we will collect neural responses and behavioral measures of cognitive control and working memory. We expect target engagement (greater differentiation of N2 amplitude) to be associated with reduced restricted and repetitive behaviors and interests. This study is innovative in several ways and has the potential for large clinical and scientific impact. It is the first study to examine a cost-effective computer-based cognitive control intervention for ASD that provides in-person metacognition coaching. This could increase functioning for autistic children at a time when intensive intervention delivery is waning. The study will use biomarkers and validated behavioral measures of cognitive control and metacognition in the context of an ASD clinical trial. Finally, the study will provide critical information about the relation between cognitive control and clinically relevant ASD outcomes, thereby providing insight into the mechanisms underlying behavioral challenges for autistic children. Promising results from this study would provide the basis for a larger clinical trial to investigate the efficacy of cognitive control training and mediators and moderators of its effects.

NIDCR - National Institute of Dental and Craniofacial Research

ABSTRACT Bacteriophages are integral components of the human microbiome, shaping microbial diversity and influencing host health, yet our understanding of phage-host dynamics remains limited, particularly for integrated phages. Recent discoveries reveal that lysogenic phages dominate the human gut microbiome over lytic phages, but current methods using short-read sequencing fail to capture phage integration sites and host attribution. This project will elucidate integrated phage-host dynamics in the human microbiome using innovative long-read sequencing approaches. The central hypothesis of this proposal is that integrated phages play critical roles in microbial community dynamics that can be detected, experimentally tested, and modeled to advance our understanding of microbiome function. Our preliminary data demonstrates that long-read sequencing dramatically improves phage genome assembly, host attribution, and integration site identification. Specifically, we have shown that geNomad most accurately detects phage boundaries when compared to ‘gold standard’ structural variation evidence of phage boundaries from Sniffles (DNA structural variant detector). We have also successfully propagated non-plaque-forming phages using stool-based cultures and discovered that p- crAssphage (Carjivirus communis) adopts a phage-plasmid lifestyle, challenging traditional models. Additionally, we have developed a quantitative modeling framework that revealed surprisingly low rates of phage induction in the microbiome. Building upon these findings, we will: (Aim 1) develop a computational framework to identify integrated prophages, their hosts, and integration sites from long-read metagenomic data, including a nextflow pipeline for assembly and annotation; (Aim 2) establish a stool-based culturomics platform to isolate non-plaque- forming phages and identify their bacterial hosts using meta-Hi-C sequencing and qPCR-based growth dynamics analysis; and (Aim 3) create computational models for viral-host population dynamics to test longstanding hypotheses about virus-host interactions in the human gut, extending our modeling to account for within-host spatial structure. Our multidisciplinary team brings together expertise in microbiome science, genomics and clinical applications (Bhatt), quantitative modeling and microbial biophysics (Huang), and evolutionary dynamics and microbial ecology (Good). We have collaborated successfully for several years and are supported by robust computational resources and experimental facilities. This project offers technological innovations through novel long-read sequencing pipelines and conceptual advances in understanding lysogenic phage ecology and lifestyle diversity. Successful completion will yield a suite of computational and experimental methods to identify integrated phages, their hosts, and viral-host interactions within the human microbiome, significantly enhancing our understanding of how phages impact human health and potentially informing future phage-based therapeutic strategies for microbiome modulation.

NSF

The massive expansion in the production of data has led to natural computational challenges in uncertainty quantification. In particular, Bayesian methodology can account for sources of uncertainty, but requires techniques known to be computationally demanding. These difficulties are exacerbated when data are spatially and/or temporally correlated. The current solutions predominantly use either approximations or inefficient iterative methods such as Markov chain Monte Carlo (MCMC). This project resolves the computational challenges in uncertainty quantification with novel statistical methodology that does not require approximations and MCMC. Big data has impacted nearly every area of science, and as a result, methodological development and software for scalable, exact, MCMC free Bayesian methodology will have a substantial effect. Not only will the proposed methodology and software be an advancement in statistics, but it will be useful across a broad range of disciplines that deal with complex spatio-temporal processes such as neuroscience, climatology, demography, econometrics, ecology, meteorology, oceanography, and official statistics. The investigator will educate and train graduate students, and disseminate project findings through journal publications, public-use software, and conference presentations. The objective of this project is to develop conjugate distribution theory for scalable Bayesian hierarchical models that create a larger framework for statisticians and subject matter scientist to perform MCMC free Bayesian inference without approximating the posterior distribution. In particular, this project will develop and extend the generalized conjugate multivariate (GCM) distribution, which allows one to simulate directly from the exact posterior distribution for a particular large class mixed effects models. This exact sample is referred to as Exact Posterior Regression (EPR). In Aim 1, the investigator will develop extensions of GCM and EPR to new settings including ordinal and nominal data, exact MCMC free inference for certain hyperparameters, and theoretical connections to existing statistical models. Aim 2 involves extensions of EPR to multivariate spatio-temporal and multiscale spatial data, allowing one to leverage several sources of dependence to improve predictions and perform spatial change of support (COS) without the use of MCMC or approximate Bayesian methods. To achieve scalability, in Aim 3, the investigator will develop an exact Bayesian hierarchical model that repeatedly subsets the data in an informative manner that does not impose additional assumptions on the data. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF

Plants and pathogens interact in complex ways, with the outcome of this interaction being determined by various factors including their genetics, resident microbiome, and, most crucially, the environment. Variability in plant growing environments, including changes in temperature, have been linked to severe local outbreaks for various pathogens. The most effective way to control plant diseases is the use of disease-resistant cultivars. While current breeding programs evaluate disease resistant cultivars for their durability against concurrent pathogen populations, the sensitivity of plant resistance genes to growing temperatures is rarely considered while assessing their durability. The goal of this project is to develop crops with stable immunity that can tackle the simultaneous challenge of evolving pathogen pressure and suboptimal plant growth temperatures. This project led by a team of scientists from the United States, the United Kingdom, and Germany has the potential to develop crop varieties that are tolerant to changing growing temperatures and outcomes from this work has the potential to ensure future food security. This project will also support continued efforts by the team to provide STEM-based research experiences for high school students, and outreach events for the public in Alabama and Virginia. Graduate students and research associates that are a part of this project will be actively involved in these outreach events aimed to raise awareness of how plant growth temperatures impact plant health and disease pressure. Predicting plant disease outcomes in the face of projected suboptimal growing conditions is challenging for multiple reasons. Host responses to multiple simultaneous stresses are simply not additive. Multivariate selection pressures brought about by temperature fluctuations alter ecological, epidemiological, physiological and evolutionary processes in the host as well as pathogen populations and alter their responses due to trade-offs among traits under selection, thereby altering host-pathogen dynamics. The proposed work will utilize field and growth chamber experiments in parallel to understand how pathogen and plant carrying different resistance genes respond to temperature alteration. This project will investigate multi-generation host-pathoadaptation and assess fitness trade-offs that constrain the evolution in both plant and pathogen. The project will make explicit links between physiological and genetic processes in host and pathogen that inform potential candidates for breeding programs to make heat resilient and disease resistant crops. The project will evaluate temperature sensitivity of resistance genes in pepper and tomato in terms of their stability, function and alteration of immune pathways. This study has direct translational relevance for durable management of resistance genes in the context of variable environmental conditions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

National Endowment for the Humanities

DEVELOPING EDUCATIONAL AND COMMUNITY PROGRAMS AT THE SPEAKER?S HOUSE [HISTORIC TRAPPE WILL LAUNCH A NEW SLATE OF PUBLIC HUMANITIES PROGRAMMING AT THE SPEAKER?S HOUSE, THE RESTORED HOME OF FREDERICK MUHLENBERG, FIRST SPEAKER OF THE U.S. HOUSE OF REPRESENTATIVES. TIMED TO COINCIDE WITH THE 250TH ANNIVERSARY OF AMERICAN INDEPENDENCE AND THE GRAND OPENING OF THE HOUSE IN APRIL 2026, THIS PROJECT WILL ENGAGE PUBLIC AUDIENCES WITH THE POLITICAL, RELIGIOUS, AND DOMESTIC LIFE OF THE EARLY AMERICAN REPUBLIC. EDUCATIONAL PROGRAMS INCLUDE ARCHAEOLOGY WORKSHOPS FOR CHILDREN AND FAMILIES; IMMERSIVE FOODWAYS DEMONSTRATIONS IN THE RESTORED KITCHEN; A LECTURE SERIES LED BY NATIONALLY RECOGNIZED SCHOLARS; AND CURRICULUM-ALIGNED FIELD TRIPS THAT TEACH CIVIC HISTORY THROUGH SITE-BASED INTERPRETATION.]

NEI - National Eye Institute

PROJECT SUMMARY Glaucoma, the most common worldwide cause of irreversible blindness, is characterized by progressive dysfunction and death of retinal ganglion cells (RGCs) and degeneration of optic nerve (ON). There is a significant unmet clinical need for neuroprotectants. Our previous studies of ON traumatic injury and glaucoma demonstrated that axon injury induce neuronal endoplasmic reticulum (ER) stress in RGCs. We were able to protect the injured RGC somata and axons if we blocked the detrimental effects of ER stress by manipulating two key downstream molecules in opposite ways: a) deletion of CCAAT/enhancer binding protein homologous protein (CHOP), and/or b) activation of X-box binding protein 1 (XBP-1). Using complimentary cell-based high throughput screening (HTS) of small molecule libraries, we identified multiple series of chemical modulators of ER stress (CHOP inhibitors and XBP-1 activators), which are promising neuroprotectant candidates. We will further optimize these chemical ER stress modulators, determine their in vivo efficacies in clinically relevant mouse glaucoma models, and illustrate their mechanism of action. We expect the results through these studies will identify preclinical drug candidates and provide essential information for clinical application of ER stress modulation, and establish translational strategies for safe and effective clinical management of glaucoma patients.

NSF

This BCSER Individual Investigator Development (IID) project will investigate course, department and institutional variables that influence teaching assistants (TA) instructional behavior in undergraduate chemistry laboratory courses. The PI will conduct think-aloud interviews with chemistry laboratory TAs that would be used to design a survey to unpack systems that affect TA instructional behavior. The survey will be implemented nationally across various institutional types. The findings from the surveys can provide insights into TA interactions in chemistry laboratory courses, thereby supporting TA training reform and positively impact undergraduate students enrolled in these courses. The findings will be shared through the facilitation of workshops, presentations at chemistry specific conferences that will impact practitioners and researchers, and journal publications. This project will build the Principal Investigator's capacity to carry out high-quality STEM education research, with the goal of improving the experiences of students in general chemistry laboratory courses. By exploring how TAs’ noticing opportunities for meaningful learning, specifically moments that invite all students to engage with chemistry in terms of the cognitive, affective, and psychomotor dimensions, the project will allow the PI to develop foundational skills and gain practical experience in designing and implementing cutting edge STEM education research using innovative methods and tools. The PI will develop new expertise in survey development and analysis, factor analysis and Hierarchical Linear Modeling. The PI will work with a mentor in quantitative methods and survey design and an advisory board. The PI will apply these quantitative research methods to design a survey instrument to assess the interactions of TAs in the chemistry laboratory. The success of this project will be assessed through the PI's interaction with an external advisory board. The project is supported by NSF's EDU Core Research Building Capacity in STEM Education Research (ECR: BCSER) program, which is designed to build investigators' capacity to carry out high-quality STEM education research. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Project Summary Lymphedema occurs when a part of the lymphatic system fails to remove lymph fluid resulting in edema and impaired immune function. Lymphedema impacts more than 10 million individuals in the United States (US) and is frequently reported as a complication in cancer-related surgery, affecting up to 30% of breast cancer survivors, as well as patients treated for prostate, ovarian, head and neck cancers, and melanoma. Nevertheless, lymphedema remains incurable. Despite conservative treatments like compression therapy and physiotherapy, disease progression occurs, which reduces patient quality of life and increases healthcare costs. The current standard imaging for lymphedema diagnosis is lymphoscintigraphy (LSG). LSG (2D planar imaging) shows the distribution of counts detected by gamma cameras at two fixed angles (anterior/posterior positions). LSG is widely available, easy to perform, and has long been considered the gold standard owing to its high sensitivity for lymphedema diagnosis. Since advanced surgical treatments such as lymphatic venous anastomosis are emerging, enhancing LSG is essential to guide lymphedema care and innovation. The primary limitation of 2D LSG is noise due to low photon counts. Lymphatic vessels are relatively small, lymph flow is generally much slower than blood flow, and gamma cameras capture only about 0.01% of emitted photons fromlymph fluid due to their low sensitivity. Consequently, LSG may require extended scan durations to collect sufficient photons, often resulting in noisy, low-quality images. In addition, attenuation correction (AC) is not available in 2D planar imaging, leaving LSG non- quantitative without calculating absolute activity concentrations (Bq/mL) at each voxel. Currently, visual assessment by physicians (qualitative analysis) remains the clinical standard for evaluating lymphedema. Therefore, to address the unmet needs of classical 2D LSG, we will develop a denoising solution (Aim 1) and quantitative imaging and analysis tools (Aim 2). In Aim 1, we will develop a deep learning (DL)-based denoising solution for LSG. A clinical dataset will be created by prospectively acquiring 150 studies as well as recruiting 10 subjects undergoing lymphatic venous anastomosis (Task 1.1). To address clinical data diversity, an anthropomorphic digital phantom dataset (1,000 subjects) will be created using the XCAT phantom that includes organs, muscles, bones, soft tissues, and a scalable lymphatic system (Task 1.2). Using these datasets, two state-of-the-art networks for PET denoising will be adapted for LSG denoising (Task 1.3). In Aim 2, we will develop DL-based attenuation correction (DL-AC) methods for quantitative LSG (qLSG) and establish quantitative analysis metrics for objective evaluation. For qLSG, a convolutional neural network (CNN) will be trained to translate CT scout images (2D topograms) to 2D μ-maps for AC in LSG (scout-2-μ-map translation). In addition, a direct DL-AC model will be developed to translate 2D anterior/posterior planar images (input) to 2D true activity maps (output) (NC-2-AC translation) (Task 2.1). We will develop quantitative imaging biomarkers using qLSG and evaluate their correlation with visual assessment by physicians (Task 2.2). The proposed project will enhance LSG by developing quantitative imaging and analysis tools readily translatable to clinical practice, which will improve care for patients with lymphedema in various clinics across the Plastic Surgery Department, the Lymphedema Center, and Children’s Medical Center.

NIGMS - National Institute of General Medical Sciences

Antibiotic resistant infections are one of the highest causes of morbidity and mortality around the world. The evolutionary rate of bacteria makes finding effective antibiotics to treat infections difficult. A promising alternative to traditional antibiotics is endolysins. These proteins lyse specific bacteria without inducing resistance. While effective, these enzymes suffer from low stability, limiting their use in clinical and agriculture settings. Additionally, there are a lack of tools available to assess their activity in a high throughput manner. Thus, new tools to improve endolysins are needed. The proposed project develops an engineered endolysin for improved activity. The model endolysin that will be used in the focus of this study is CHAPK. CHAPK demonstrates high lytic activity against Staphylococcus species but exhibits suboptimal activity at physiological conditions. In Aim 1, a panel of internally quenched substrates will be synthesized to assess CHAPK activity. These substrates will be characterized with recombinant enzyme and bacterial lysate to demonstrate its ability to report on hydrolysis events. Aim 2 will establish how these substrates can be used to evolve CHAPK for improved thermostability. A computation-guided approach will be used to select sites to mutate for improved thermostability. After generating the library, the synthetic substrate will be used to screen the mutants in a high-throughput manner. The top hits will be purified and further characterized. This proposal will expand the methods available to assess endolysin activity as well as provide a more guided approach to improving these potential therapeutics. The work proposed will be driven by undergraduate researchers and a postbaccalaureate student through summer and senior thesis research projects. Undergraduate students will also engage in this work through a course-based research experience. Funding from this project will increase participation from the next generation of scientists in the fields of chemistry and chemical biology. Additionally, the research environment at Scripps and Pitzer Colleges will be enhanced by increasing the number of research opportunities available for students, fostering new collaborations, and increasing the number of state-of-the-art instrumentations in the Department of Natural Sciences.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Management of anticoagulant medication, including for the management of low-risk pulmonary embolism, is challenging and frequently does not follow evidence-based guideline recommendations. On the one hand, up to 40% of all patients with an acute pulmonary embolism are at sufficiently low risk for complication that guidelines recommend outpatient management rather than hospitalization. However, this evidence-based practice is rarely utilized in the United States. On the other hand, when oral anticoagulants are prescribed for pulmonary embolism and other common thrombotic conditions, up to 25% of prescriptions do not follow evidence-based guidance and patients are exposed to unnecessary life-threatening risks of thromboembolism or bleeding. The research activities supported by this K24 award will complement Dr. Barnes’ ongoing NIH- funded R01 project that aims to improve the use of outpatient management of low-risk pulmonary embolism across 12 health systems in Michigan. This award also leverages Dr. Barnes’ current AHRQ R18-funded project that uses both electronic health record alerts and clinical pharmacists to improve safe- and evidence- based anticoagulant prescribing. While Dr. Barnes’ career goal is to develop, implement, and evaluate anticoagulation stewardship efforts, such as the ones being tests in his current R01 and R18 projects, he also is passionate about mentoring the next generation of patient-oriented researchers who focus on implementation science methodology. Dr. Barnes will leverage ongoing NIH R01 funded projects to expose his mentees to practical aspects of implementation science, including implementation mapping and qualitative assessments of implementation adaptation. Dr. Barnes will also focus on his own career development by gaining critical training in optimization trial design and advanced mentoring skills. Dr. Barnes has assembled a senior, diverse, and highly committed set of advisors to oversee his personal career development. He has also identified several channels for increasing his mentorship opportunities with clinician-scientists eager to develop as independent patient-oriented researchers who focus on implementation of evidence-based clinical medicine.

NHLBI - National Heart Lung and Blood Institute

ABSTRACT/SUMMARY: Fanconi Anemia (FA) is the leading cause of inherited bone marrow failure (BMF) affecting thousands of patients worldwide. While allogenic (allo)-hematopoietic stem cell transplantation (HSCT) outcomes have been improving for FA patients, these treatments currently cause significant morbidity and mortality in part due to the non-specific and genotoxic chemotherapy and/or irradiation conditioning traditionally used pre-transplant. This is especially problematic in FA patients due to their exquisite sensitivity to DNA damage which results in DNA interstrand crosslinks (ICLs) and heightened risk of malignancies in all patients. Our long-term goal is to develop alternative non-toxic FA therapies using cell and gene therapy. Towards this goal, we have generated HSC-targeted conditioning approaches using monoclonal antibodies (mAbs) and mAb-drug-conjugates against the CD117 HSC cell-surface protein that clear host HSCs without non-specific tissue damage. However, from this research we have found that host HSC depletion is not critical in the FA setting. This has been further observed in the setting of autologous FANCA lentiviral gene therapy and somatic mosaicism, which have both shown that a small number of initial functional hematopoietic stem and progenitor cells (HSPCs) can stabilize hematopoiesis in FA patients. The overall objective of this work is to leverage distinctive strategies that elude the immune system to safely establish functional HSPCs in the bone marrow that can maintain hematopoiesis in the FA setting. The preliminary data supports a central hypothesis that stable hematopoiesis with ability to repair DNA ICLs can be established in FA without the use of genotoxic chemotherapy or irradiation due to the competitive advantage of functional HSPCs over failing FA HSPCs. This hypothesis will be tested through three specific aims in FA mice: 1) Achieving and optimizing haploidentical in utero HSCT without use of any conditioning, 2) Evaluating post-natal HSCT with immune conditioning alone, and 3) Developing HSC and systemic CRISPR-based base editing correction methods using engineered virus-like-particles (eVLPs) to stabilize host FA cells. The proposed research is both innovative and significant because it will identify multiple strategies that safely enable stabilization of hematopoiesis in the FA setting that will subsequently be translated into non-genotoxic therapies for FA patients. These novel approaches that enable functional HSC correction using both cell and gene therapy strategies are aimed at treatment of FA at different stages of hematopoietic disease, with the additional capacity to uniquely correct FA mutations in non-hematopoietic tissues. This work will have a major impact on improving treatment for FA patients and findings from this research will subsequently be utilized to improve the treatment of millions of people worldwide that suffer from diverse hematopoietic and genetic diseases.

NSF

This project aims to serve the national interest by improving curricula in mining technician education to align training with innovations in the mining industry. The College of Western Idaho will establish a mining technician Associate of Science (MINE A.S.) degree program to prepare graduates to fill technical career openings in the high-demand mining and geosciences industries. With the re-emergence of domestic critical mineral mining to support the nation’s shifting industrial landscape, there is a growing need to train students to use state-of-the art mining and surveying tools and equipment, such as ground penetrating radar (GPR), lidar, UAVs (uncrewed aerial vehicles), and various surveying, drilling, and water testing tools. The project will serve the NSF mission and public interest by advancing understanding about how to effectively prepare community college students for the technical demands of the mining industry through coursework, fieldwork, and faculty development. The project will support regional economic development by re-introducing mining technician training in partnership with local and regional employers, nurturing relationships between academia and industry to equip A.S. graduates with the scientific, technical, and professional skills mining employers seek. The industry-aligned project will offer direct pathways into mining industry technician-level jobs leading to industry certifications that prepare all students to enter well-paying jobs. The project's goal is to establish a MINE.A.S. program. Objectives are to (1) enroll three cohorts of students (50 to 60 over the project period); (2) train faculty in the uses and course integration of industry-standard mining and surveying equipment; and (3) build partnerships with Idaho mining employers to provide all MINE.A.S. students with significant hands-on training experiences. Key activities will include purchasing and integrating industry-aligned mining and surveying equipment into several geological sciences, environmental sciences, and engineering courses; developing two new MINE.A.S. courses (Mining Capstone and Survey Engineering); implementing a MINE.A.S. outreach and recruitment strategy; providing a yearly faculty development series led by industry experts; establishing a new MINE.A.S. Industry Advisory Technical Advisory Committee; and adding employer-paid summer internships. All graduates will complete the requirements to obtain Mine Safety and Health Administration (MSHA) certification and enter mining careers. Project evaluation will assess, inform, and disseminate learning about the essential components of course curricula and fieldwork to prepare the technician-level mining and geological sciences workforce. This project is funded by the Advanced Technological Education program that focuses on the education of technicians for the advanced-technology fields that drive the nation's economy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF

Understanding animal movement is imperative for the conservation and management of highly threatened species. However, frameworks that leverage existing data sets are currently lacking and needed to improve our knowledge of how animals move across the landscape, and to understand what factors most impact these movements. For example, there is an increasing need to better understand the effect of weather patterns and habitat conditions on annual movements of migratory species. This knowledge is often limited because it requires an understanding of patterns of movement and linkages of populations across large spatial scales for a large number of individuals. Currently, there is ever-increasing data available for wildlife populations, such as long-term, fine-scale GPS-tracking data of individual animals, as well as large-scale observation networks that capture the distribution of wildlife populations. Fine-scale information is usually obtained by fitting individual animals with GPS-units that allow for near continuous location-tracking throughout the year. Citizen science networks include observations collected by members of the public on species that they detect when engaging in various activities (e.g., hiking, birding), which can be used to map the distribution of the species through time. This work is focused on the development of statistical models that will allow, for the first time, the integration of individual movement and species distribution data to learn about large-scale species-level movement behavior. The methods and tools developed will advance society's ability to learn about difficult to observe processes that shape the distribution of migratory populations in space and time. Despite extensive work on methods for integrating multiple data sources, previous attempts to integrate tracking data with citizen-science data fail to leverage the statistical advances made in each individual field and fail to formally integrate the two data-sources in a robust and comprehensive framework. Tracking data provides information about individual movements but represents a small subset of the population. Distribution data provides comprehensive information about species distribution, but represents aggregate behavior of individuals that differ in their migratory routes and behavioral response to the landscape. The integrated framework proposed in this research will formally integrate these two data sources using flexible, interpretable parametric statistical models, which will allow researchers to obtain previously unavailable insights into the link between individual variation, subpopulations, and drivers of movement, while accounting for uncertainty and the spatio-temporal dynamics of species distributions. In addition, this research will develop models for the full-annual cycle of an individual, as opposed to just the migratory route, allowing for additional inference regarding migratory connectivity and seasonal behavior. Further, this work will apply the novel statistical models to understand the migratory behavior of species of both conservation and hunting concern, which will help managers understand the spatio-temporal risks to which different proportions of the population are exposed. This information can help prioritize when and where to take management actions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death among adults in the United States; nonetheless, we lack disease-modifying therapies. Herein, we hypothesize that lithium may be a novel disease-modifying agent for emphysema in smokers. Lithium is an abundant naturally occurring element that is ubiquitous in soil and groundwater from where it enters our food chain and drinking water supply. Once ingested, lithium is distributed across total body water as it diffuses freely across cell membranes. Lithium can be quite toxic when used in the high doses needed to treat mood disorders. In contrast, natural low-level lithium intake from food and water is associated with multiple beneficial effects, including a lower risk of suicide, depression, Parkinson’s and Alzheimer’s diseases, and improved longevity in independent studies. Therefore, low-dose lithium supplements are available over the counter in the US. Lithium exerts biological effects by activating WNT/β-catenin signaling, which is essential for lung development and to repair damaged alveoli, such as those observed in smokers with emphysema. Our preliminary work suggests that lithium may be a novel protective agent against emphysema. These preliminary findings are based on data from animal models, human patient-derived precision-cut lung slices, users of lithium medication in independent cohorts, assessment of circulating lithium levels in nonusers of lithium medication, and analysis of environmental lithium exposure using independent environmental datasets. During this award, we will assess circulating lithium levels in smokers enrolled in two COPD research cohorts and determine if they are associated with emphysema progression, use extensive proteomic and genomic data from both cohorts to identify the subset of smokers most likely to experience less emphysema progression by augmenting circulating lithium levels, and assess the dose-response relationship between lithium and WNT/β-catenin activity in explanted COPD lung tissues. Our overall objective is to advance lithium from ex vivo and observational human studies to clinical trials as a novel disease-modifying agent for emphysema by substantiating efficacy, implementing precision medicine, and defining a dosing strategy.

Geological Survey

See attached Notice of Intent

NCI - National Cancer Institute

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second-most common cause of cancer- related death in the United States. Detecting PDAC early has been challenging due to its rapid progression and late presentation. Recent collaborative efforts among NCI, PanCAN, and NIDDK have resulted in multiple studies utilizing electronic medical records (EMRs). They provide opportunities to advance the early detection of PDAC, since the approach taken in the research setting is identical to what would be used in clinical practice. Future implementation in EMRs could lead to earlier diagnostic testing or interventions, enable the rapid identification of cancer trends or risk factors, and allow for quicker action. These studies, including our own, have demonstrated that individuals with glycemically-defined New Onset Hyperglycemia and Diabetes (NOD) have a significantly higher risk of being diagnosed with PDAC within 3 years of meeting diabetes mellitus criteria. The Enriching New-Onset Diabetes for Pancreatic Cancer (ENDPAC) score further stratifies individuals with NOD based on their PDAC risk, considering factors such as weight changes, blood glucose levels, and age at diabetes onset. However, several challenges need to be addressed to ensure the success of PDAC early detection. Firstly, it is important to better define the at-risk population for PDAC, as NOD alone may not be sufficient. Individuals with new-onset prediabetes and those with worsening long-standing diabetes mellitus may also be viable targets for early detection of PDAC. Secondly, more effective enrichment strategies leveraging biomarkers are critical, as directly applying existing biomarkers may not yield optimal results. For example, the ENDPAC score, which was developed primarily in a predominantly white NOD population, should be adapted for other high-risk groups, such as individuals with NOPD, LSDM, and diverse demographic populations to ensure broader applicability. We will develop a comprehensive set of methods to address these challenges, aimed at identifying high-risk populations, exploring promising biomarkers using EMR data, and integrating them with advanced biomarkers in an efficient manner. Given the expertise of our team and the strength of our collaborative partnerships, the advancements in methodologies, and the potential clinical applications, we anticipate that our efforts will yield tangible clinical benefits in the near term.