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

PROJECT SUMMARY Differentiation of human primordial germ cells (hPGCs) from human pluripotent stem cells is the first step toward in vitro gametogenesis, which would enable mechanistic studies and treatment of infertility due to loss of gametes. The mechanisms of hPGC differentiation are poorly understood. As a result, current protocols produce heterogeneous mixtures of hPGC-like cells (hPGCLCs) and other cell types. Our long-term goal is to obtain a systems-level understanding of the signaling and gene regulatory network that control primordial germ cell differentiation in vitro and use this to improve directed differentiation of hPGCLCs for potential therapeutic purposes. The objective of this proposal is to quantitatively determine cell signaling requirements of hPGCLC differentiation with unprecedented spatial and temporal resolution. The central hypothesis is that heterogeneous differentiation and maturation of hPGCLCs is due to heterogeneous cell signaling activity. The rationale is that if we identify what distinguishes more mature hPGCLCs from less mature ones and other cell types that arise at the same time, we can understand defects in their differentiation in vivo and in vitro and create better hPGCLCs. Our hypothesis will be tested through two specific aims: 1) Determine the combinatorial signaling dynamics responsible for hPGCLC induction by single cell tracking of signaling and fate markers in live cells combined with highly multiplexed immunofluorescence. 2) Determine if there are distinct phases of induction and maintenance and elucidate the signaling logic and gene regulatory network that controls hPGCLC maintenance and maturation. Our approach is conceptually innovative by testing if a unique history of signaling determines hPGCLC fate, by accounting for the interplay between exogenous and endogenous signaling in vitro, and by delineating clearly distinct phases of differentiation that start with induction. More generally we are breaking new ground by taking a systems-level approach to human germ line biology that tests hypotheses rigorously and quantitatively by representing them as mathematical models. The proposed work is also experimentally innovative as we use substrate micropatterning to achieve reproducible hPGCLC differentiation and are the first lab to establish long-term high throughput tracking of differentiating pluripotent stem cells as well as the first to adapt multiplexed immunofluorescence to stem cell models of early development. The expected outcome of our work is better fundamental understanding of human germ line differentiation and improved methods to produce hPGCLCs for research of in vitro gametogenesis.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus of significant public health concern. To date there are no effective licensed antiviral treatments or a vaccine. Therefore, elucidating the molecular biology of these viruses and the interactions with the host cell are foundational to identifying and developing effective treatment options. The single-stranded positive-sense RNA genome of ZIKV mimics a cellular mRNA. Specifically, the viral RNA encodes a single open reading frame, has structured untranslated regions (UTRs) adjacent to the open reading frame, and contains a N5’-methyl guanosine cap. Unlike mRNAs however, flaviviruses lack a poly(A) tail. From a multiple sequence alignment of all mosquito-borne flaviviruses we identified conserved regions containing 3-6 tandem adenosines in the 3’ UTR. These A-rich regions are localized in single-stranded regions within and between the XRN-1 resistant pseudoknots (xrRNA), dumbbell and 3’ stem loop (3’SL) RNA structures. In preliminary experiments we investigated the role of the A-rich region between xrRNA2 and the pseudo- dumbbell RNA structure (pre-pseudo/Y-dumbbell). Specifically, we generated three different mutations in a ZIKV Renilla luciferase reporter replicon and infectious clone. These mutants revealed that the pre-YDB A-rich region had a role in translation in both mammalian and mosquito cell lines. Different mass spectrometry studies have shown that the cellular poly(A) binding protein (PABP) interacts with the ZIKV 3’ UTR. Additionally, PABP was previously shown to interact with a region in the dengue virus 3’ UTR that harbors an A-rich motif. In preliminary studies we find that depletion of PABP1 decreased ZIKV, but not cellular, protein levels and viral titers without affecting cell viability. We therefore hypothesize that A-rich regions in the ZIKV 3’ UTR function to recruit cellular RNA binding proteins such as PABP1 to promote distinct steps in the virus infectious cycle. In Aim 1 we will mutate the A-rich regions in the infectious clone and a subgenomic luciferase reporter replicon to investigate the function of select A-rich regions on translation, replication, and viral fitness in mammalian and mosquito cells. In Aim 2, we will investigate the role of PABP1 on ZIKV gene expression and determine if PABP1 and other cellular RNA binding proteins bind A-rich regions in the ZIKV 3’ UTR. Overall, this study will advance our understanding of how flavivirus 3’ UTRs interact with the host to promote distinct steps in the infectious cycle in two vastly different hosts. Understanding how specific sequences in RNA genome function could lead to the therapeutic advancement namely the development of an attenuated vaccine ZIKV strain. Moreover, defining similar and unique RNA-protein interactions between mammalian and mosquito hosts could inform future vector control strategies.

NCI - National Cancer Institute

ABSTRACT Cancer therapies such as allogeneic hematopoietic stem cell transplant (HCT) are associated with significant toxicities, which can significantly impair function and quality of life. This may be ameliorated by actions such as engaging in physical activity during treatment; however, many patients find it difficult to maintain these behaviors. This challenge is magnified by the stress of a life-threatening situation: many patients have limited coping skills, which may contribute to depressive affect and withdrawal that further diminishes functional capacity. Acceptance and Commitment Therapy (ACT) is an evidence-based cognitive behavioral therapy (CBT) intervention that has been effective in reducing symptom interference in a variety of clinical populations, including individuals with late-stage cancer. ACT may be particularly well-suited to conditions of cancer in which patients experience unavoidable treatment-related discomforts (e.g., fatigue, pain, nausea), and thoughts/feelings that are distressing but not illogical or irrational (e.g., possibility of death). Unlike traditional CBT that focuses on changing unwanted thoughts/feelings, ACT focuses on psychological flexibility: having an open and receptive posture with respect to moment-to-moment experiences; and acting effectively in their presence, guided by personal values (i.e., what is most important to the individual and how they want to live the moments of their lives). In the context of HCT, ACT may help HCT patients focus on actions that may help maintain adequate physical activity, despite physical and emotional discomfort, thereby optimizing transplant outcomes. Caregivers are also central for HCT success, particularly during the most acute stages of pre- and post-transplant. Including caregivers in skills training may help them encourage their loved one to eat or move when it is most challenging, despite their own distressing thoughts/feelings about their loved one’s illness. We piloted an ACT skills protocol we named “ACTivate” that consists of 7 ACT skills sessions delivered to HCT patient and caregiver dyads by Zoom between transplant Day -30 and Day +90. Patients and caregivers rated the sessions as highly acceptable, with 95% recommending ACT to others in similar situations. Moreover, while we hypothesized that ACT would attenuate the decreases in physical function that are typically seen post-HCT, patients who received ACTivate increased their 6-minute walk distance after HCT; they also reported better functional well-being at Day 90 compared with controls. We now propose to conduct a more rigorous test of the intervention in a multicenter randomized controlled trial to evaluate the impact of ACTivate on physical function, psychological flexibility, and clinical outcomes. We will also examine multimodal processes of change and the impact of caregiver psychological flexibility and self-efficacy and association with patient outcomes. This is the first study that targets psychological barriers to maintaining physical activity during HCT using ACT. If successful, it could establish an evidence- based protocol to increase treatment tolerance in HCT. Future studies may evaluate the applicability of the protocol to other cancer treatments and conditions.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY/ABSTRACT Clemson University’s rapid growth in externally funded research has propelled it to R1 status, reflecting its expanding impact in advanced scientific inquiry. Five of Clemson’s nine academic colleges are STEM-fo- cused, encompassing over 30 academic units. In the last decade, Clemson’s NIH-funded portfolio has grown from $5.5 million in 2014 to $26 million in 2024, currently spanning 85 awards across 57 investigators. This growth is fueled by the university’s strategic investments in research infrastructure, equipment, and facilities. These actions foster a resource-rich environment capable of attracting and retaining top research talent. Three major NIH Centers of Biomedical Research Excellence (COBRE) underscore Clemson’s priorities: the Eukaryotic Pathogens Innovation Center (EPIC), the South Carolina COBRE for Translational Research Improving Muscu- loskeletal Health (SC-TRIMH), and the Clemson University Center for Human Genetics. To further strengthen Clemson’s research capabilities, we seek to acquire a Refeyn mass photometer, a transformative technology that enables single-particle mass measurements. Unlike bulk methods such as dynamic light scattering (DLS), mass photometry quantifies molecular mass, providing an unparalleled view of heterogeneity, oligomerization states, and binding interactions at the single-molecule level. This technology is valuable across disciplines and research foci on campus, from probing protein-ligand and protein-protein inter- actions that occur in eukaryotic pathogens (EPIC) to evaluating biomolecular assembly and integrity in mus- culoskeletal research (SC-TRIMH). Investigators in human genetics can rapidly assess protein-DNA/RNA interactions and more complex heterogenous multi protein-protein-DNA/RNA complexes. The Refeyn mass photometer offers remarkable advantages: (1) Minimal sample requirement—only a few microliters of material are needed; (2) Low per-sample cost, approximately $2, making it accessible to both established laboratories and student trainees; (3) Ease of operation, a simple pipetting step onto a glass slide significantly reduces technical barriers; and (4) Broad applicability, it excels in characterizing oligomeric states, monitoring antibody binding, and confirming molecular compositions in diverse sample types. By installing this mass photometer at Clemson, we will foster interdisciplinary collaboration, enrich hands- on learning opportunities, and expand the capabilities of ongoing NIH-funded projects. Moreover, this cutting- edge instrument will position Clemson researchers at the forefront of next-generation single-particle analytics, supporting a range of studies—from early discovery to late-stage translational research. Although it also inte- grates seamlessly into cryo-EM workflows, the mass photometer’s utility extends well beyond structural biology. Ultimately, this S10 instrumentation request will allow Clemson to elevate its research enterprise, amplify productivity, accelerate innovation, and strengthen the university as a leader in biomedical and research.

NIGMS - National Institute of General Medical Sciences

Modified Project Summary/Abstract Section An award is requested for Loyola University New Orleans to acquire a Laser Scanning Confocal Microscope to enrich faculty research, student training, and local outreach activities. This microscope will enable a variety of research pursuits by undergraduate students across 3 major departments, Biological Sciences, Chemistry and Biochemistry, and Psychology and Neuroscience. Research projects that will be advanced by this equipment include the understanding of a micropeptide in neuronal biology of the aging brain that is a novel target for dementia and Alzheimer’s disease study. Further, we study transcription factors in connective tissue development and aging that are important for chronic diseases such as Rheumatoid Arthritis. We also have research efforts studying cell polarity in cancer, the molecular mechanisms of tissue regeneration, and characterization of the micro-organisms of local wetland ecosystems that impact the health and economies of Louisiana inhabitants. Participation in research at Loyola University New Orleans is a central component of undergraduate education, and a confocal microscope would advance our research efforts, and prepare our students for graduate study or careers in STEM. Loyola University New Orleans is a primarily undergraduate institution. All labs are focused on the training of undergraduate students to offer them the best possible preparation for graduate and professional schools. This confocal microscope will be the central piece of equipment used in a new mid-curriculum course in the Biological Sciences entitled ‘Microscopy for the life sciences.’ In this course, students will receive training on the microscope and then will independently perform a number of imaging projects with samples ranging from whole organisms (environmental aquatic samples) to organ systems (intact C. elegans nervous system) to tissue sections to live and fixed cellular samples. After exposure to different uses for the confocal, students will design and perform independent research in the laboratories of their individual PIs using their new-found expertise. Further, the microscope will be used in outreach efforts to southeast Louisiana high school teachers and students to inspire the next generation of educators and researchers in this region of the US. This is critical to sustaining the biomedical research workforce in this area.

NIGMS - National Institute of General Medical Sciences

Modified Project Summary/Abstract Section This proposal requests funding for a Wyatt DAWN 8 Multi-Angle Light Scattering (MALS) system coupled with Size Exclusion Chromatography (SEC), referred to as SEC-MALS. The SEC-MALS system enables the measurements of molar mass, hydrodynamic radius, aggregation state, and sample heterogeneity of biomolecules and nanoparticles. The SEC-MALS system will support research with a biomedical focus in multiple departments, including Chemistry, Biology, Pharmacy, and the School of Medicine. In addition to supporting research, the instrument will enhance undergraduate training in biochemistry, organic, and polymer chemistry labs, aiding student training for careers in medicine and human related health fields. The long-term goal of this proposal is to build research and educational capacity at UT Tyler by enabling in-house access to advanced characterization tools. The SEC-MALS will eliminate reliance on external facilities, accelerate research, and improve hands-on student learning in STEM and biomedical fields. Plans are in place to extend access to researchers at nearby institutions, maximizing the instrument’s regional impact across East Texas.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract The overarching goal of this proposal is to explore novel aspects of the actin cytoskeleton organization and function in health and disease. The remarkable functional versatility of the actin cytoskeleton stems from its ability to assemble into a variety of diverse structures – branched networks/meshes and aligned bundles. This architectural complexity is orchestrated by actin-binding proteins, whose activity is delicately regulated in response to internal and external signals. Human plastins are versatile actin-binding proteins that organize actin filaments into higher-order assemblies: bundles and networks. Plastins are involved in cytokinesis, migration, and stabilization of membrane protrusions, but also in the pathogenesis of the following diseases: carcinogenesis, neurodegeneration, and hereditary and infectious diseases. Despite the importance and long- lasting interest of the research community in these proteins, understanding of their interaction with actin and their regulation is superficial. Our first research direction is to contribute to human health and well-being by advancing the understanding of the actin cytoskeleton organization by actin-bundling proteins plastins and their contribution to pathologies (e.g., congenital diseases and metastatic cancers) at the molecular and cellular levels. Playing numerous vital roles in human defense mechanisms, the actin cytoskeleton is a common target for numerous bacterial pathogens, which developed various elegant and sophisticated ways to disrupt and usurp it by producing actin-targeting effectors. By hijacking the actin cytoskeleton, pathogenic toxins disturb cell morphology, cell motility, phagocytosis, epithelial permeability, and antigen presentation. Being constantly adjusted to the host cytoskeleton by co-evolution, they recognize weaknesses in the host defense and represent powerful tools that foster the understanding of the cytoskeleton on molecular and cellular levels. The urge for a thorough understanding of bacterial pathogenicity is further necessitated by the dissemination of multidrug- resistant pathogens that undermine the efficiency of antibiotics. The second research direction of this proposal is to decipher the in-depth molecular and cellular mechanisms of bacterial effectors targeting the actin cytoskeleton to i) enable alternative ways of targeting pathogens and ii) get a deeper understanding of the actin cytoskeleton per se. The current proposal is directly relevant to the NIH mission as it focuses on three families of bacterial effectors, all produced by human pathogens: Vibrio cholerae and Vibrio parahaemolyticus VopF/VopL (1) and VopM/VopV (2), and Legionella pneumophila MavH, RavH, and VipA (3). Furthermore, the proposal is of interest for a general understanding of human physiology as each of the above toxins reveals novel properties of the actin cytoskeleton. Finally, the understanding of the molecular and cellular mechanisms governing the function of actin-bundling proteins plastins contributes to explaining the pathology of plastin-related human diseases.

OD - NIH Office of the Director

Acute radiation syndrome (ARS) is a multi-organ failure (MOF) syndrome, resulting from accidental exposure to irradiation and/or nuclear terrorism. Acute and delayed effects of acute radiation exposure (DEARE) can also be seen in the clinic after radiotherapy. While there are FDA-approved drugs for mitigating hematopoietic ARS (H-ARS), there are no treatment for repairing irradiated intestines, primary cause of death and a critical component of gastrointestinal ARS (GI-ARS). A common feature of radiation injury is damage to the microvascular capillary endothelial cells (ECs) that are not only organotypically programmed to modulate metabolism but also provide tissue-specific angiocrine growth factors that orchestrate intestinal repair and regeneration post-radiation. Indeed, intestinal-specific microvascular ECs (InSECs), defined by the expression of transcription factor NKX2-3, establish instructive vascular niches that are essential for maintenance, repair and regeneration of intestinal stem cells (ISC) of irradiated intestines. We show that InSECs choreograph the polarization of the monocytes into reparative IL1beta macrophages that could play a key role in resolving radiation injury. The objective of this proposal is to leverage reproducible in vitro extra-corporeal perfusable vascularized intestinal organoids models to test approaches to restore normal homeostatic functions of InSEC. Thus, we hypothesize that radiation impairs NKX2-3+ InSEC-derived instructive signals and retards recruitment and programming of intestinotropic macrophages that convey reparative signals for intestinal repair. Restoration of NKX2-3 transcriptional signatures in InSECs would reconstitute angiocrine and intestinotropic macrophage functions, essential for resolution and recovery after radiation injury. Delivery of pro-reparative factors such as amphiregulins and epiregulins supplied by macrophages and InSECs could mitigate radiation-inflicted intestinal injury. These hypotheses will be tested through executing the following specific aims: Aim 1: Develop and characterize GI-ARS injury models in human Gut-On-VascularNet organoid extracorporeal platform. Aim 2: To characterize the “instructive” angiocrine signaling pathways of InSEC on pro-regenerative monocytic polarization that mitigate radiation injury to HIOs. Aim 3: To screen for intestinotrophic radiation MCMs to mitigate GI-ARS by using the Gut-On-VascularNet platform. To this end, Rafii and Guha groups plan to capitalize on an engineered scalable near-physiological and reproducible extra- corporeal human Gut-on-VascularNet platform to study radiation injury in GI-ARS. Leveraging this platform, also allows for examining the role of radiation in perfusable microfluidic devices harboring NKX2-3+ InSECs vascularized intestinal organoids to screen for angiocrine factors and reparative macrophages to mitigate GI- ARS. The human Gut-On-VascularNet platform would bridge the gap between animal models and humans for the approval of radiation countermeasures for mitigation of GI-ARS under the FDA “animal rule” guidance.

NINDS - National Institute of Neurological Disorders and Stroke

Spinal cord injury (SCI) affects over 300,000 patients in the US, often leading to severe complications. For example, more than 80% of these patients experience urinary dysfunctions, significantly diminishing their quality of life and sense of dignity. No effective treatment exists for these patients, as SCI frequently results in significant and permanent loss of neurons essential for normal functions. Progenitor cell transplantation is currently the most prevalent approach for replacing lost neurons following SCI. While progenitor cell transplantation has advanced to clinical trials, it presents several risks, including immunoreactions, uncertainty regarding the timeframe for transplantation following injury, and ethical considerations. Tumorigenesis is also a major concern with transplantation of cells derived from induced pluripotent stem cells. As an alternative, this project focuses on adult neurogenesis from resident glial cells in the adult spinal cord. This strategy not only generates neurons immune-compatible with the host but also ameliorates the pathological lesion microenvironment. Excitingly, our preliminary results demonstrate that adult neurogenesis promotes bladder function recovery following contusive SCI. Given that clinically relevant contusion SCI often leads to significant neuronal loss, generating a large number of new neurons may be particularly beneficial. Through recent in vivo screens, we identified a combination of transcription factors capable of rapidly inducing substantial neurogenesis from resident glial cells in the adult spinal cord. In this collaborative project, we will first systematically investigate the molecular and cellular mechanisms underlying induced adult neurogenesis after contusive SCI. Next, we will examine the maturation and synaptic integration of these newly generated neurons. Finally, we will assess their role in restoring bladder function post-SCI. Utilizing state-of-the-art technologies, this study has the potential to introduce a paradigm-shifting therapeutic strategy for treating autonomic dysfunction in SCI patients.

U.S. National Science Foundation

The NSF ADVANCE program contributes to the National Science Foundation's goal of a more diverse and capable science and engineering workforce.1 In this solicitation, the NSF ADVANCE program seeks to build on prior NSF ADVANCE work and other research and literature concerning gender, racial, and ethnic equity. The NSF ADVANCE program goal is to broaden the implementation of evidence-based systemic change strategies that promote equity for STEM2 faculty in academic workplaces and the academic profession. The NSF ADVANCE program provides grants to enhance the systemic factors that support equity and inclusion and to mitigate the systemic factors that create inequities in the academic profession and workplaces. Systemic (or organizational) inequities may exist in areas such as policy and practice as well as in organizational culture and climate. For example, practices in academic departments that result in the inequitable allocation of service or teaching assignments may impede research productivity, delay advancement, and create a culture of differential treatment and rewards. Similarly, policies and procedures that do not mitigate implicit bias in hiring, tenure, and promotion decisions could lead to women and racial and ethnic minorities being evaluated less favorably, perpetuating historical under-participation in STEM academic careers and contributing to an academic climate that is not inclusive. All NSF ADVANCE proposals are expected to use intersectional approaches in the design of systemic change strategies in recognition that gender, race and ethnicity do not exist in isolation from each other and from other categories of social identity. The solicitation includes four funding tracks: Institutional Transformation (IT), Adaptation, Partnership, and Catalyst, in support of the NSF ADVANCE program goal to broaden the implementation of systemic strategies that promote equity for STEM faculty in academic workplaces and the academic profession. The Institutional Transformation (IT) track is designed to support the development, implementation, and evaluation of innovative systemic change strategies that promote gender equity for STEM faculty within an institution of higher education. The Adaptation track is designed to support the work to adapt, implement, and evaluate evidence-based systemic change strategies that have been shown to promote gender equity for STEM faculty in academic workplaces and the academic profession. Adaptation projects can either: 1) support the adaptation of evidence-based systemic change strategies to promote equity for STEM faculty within an institution of higher education; or 2) facilitate national or regional STEM disciplinary transformation by adapting evidence-based systemic change strategies to non-profit, non-academic organizations. The Partnership track is designed to support the work to facilitate the broader adaptation of gender equity and systemic change strategies. Partnership projects are expected to result in national or regional transformation in STEM academic workplaces and the academic profession and demonstrate significant reach. Partnership projects can focus on the transformation of institutions and organizations and/or the transformation within one or more STEM disciplines. The Catalyst track is designed to broaden the types of IHEs that are able to undertake data collection and institutional self-assessment work to identify systemic gender inequities impacting their STEM faculty so that these can be addressed by the institution. Please note that NSF ADVANCE does not provide fellowships, research, or travel grants to individual students, postdoctoral researchers, or faculty to pursue STEM degrees or research. Undergraduate STEM opportunities can be found at stemundergrads.science.gov and graduate STEM opportunities at stemgradstudents.science.gov. [1]Building the Future Investing in Innovation and Discovery: NSF Strategic Plan 2018-2022. https://www.nsf.gov/pubs/2018/nsf18045/nsf18045.pdf. [2] All the STEM fields supported by NSF are supported by the ADVANCE program including the learning, social, behavioral, and economic sciences. ADVANCE does not support the clinical science fields.

U.S. National Science Foundation

With a focus on two-year Institutions of Higher Education (IHEs), the Advanced Technological Education (ATE) program supports the education of technicians for the high-technology fields that drive our nation's economy. The program involves partnerships between academic institutions (grades 7-12, IHEs), industry, and economic development agencies to promote improvement in the education of science and engineering technicians. It is strongly recommended that projects be faculty-led and required that courses and programs are credit-bearing, although materials developed may also be used for incumbent worker education. Materials may also be adapted and implemented as credit-bearing courses. The ATE program supports curriculum development; professional development of college faculty and secondary school teachers; career pathway development for both students and incumbent workers; and other activities including applied research projects that advance the knowledge base related to technician education. The ATE program encourages partnerships with other entities that may impact technician education. For example, with the National Institute of Standards and Technology (NIST) Manufacturing Extension Partnerships (MEPs) (http://www.nist.gov/mep/index.cfm) as applicable to support technician education programs and the industries they serve; and Manufacturing USA Institutes(https://manufacturing.gov/) addressing workforce development issues. The ATE program encourages proposals from Minority Serving Institutionsas well as other institutions that support the recruitment, retention, and completion (certificate, degree, program)of the full spectrum of diverse talent that society has to offer, which includes underrepresented and underserved communities, in STEM technician education programs that award associate degrees.

NIAID - National Institute of Allergy and Infectious Diseases

7. PROJECT SUMMARY/ABSTRACT The biomedical landscape is undergoing a rapid transformation driven by advances in cell and gene therapy (CGT), a field revolutionizing treatment and clinical research for conditions once deemed untreatable. Within this evolving context, HIV cure research has reached a pivotal phase where CGT approaches have moved beyond theory and into clinical trials. These novel interventions hold the potential to achieve durable, antiretroviral therapy (ART)-free viral suppression. Such a breakthrough would have profound implications for public health in the United States (U.S.) and globally. With over 1.2 million Americans living with HIV (PWH) and the healthcare system bearing the substantial costs of lifelong ART, a scalable and durable ART-free regimen could reduce clinical burden, improve quality of life, and transform HIV care. CGT strategies, designed to make cells HIV- resistant or enhance immune responses, are among the most promising candidates for a globally scalable HIV cure. Current approaches under investigation include chimeric antigen receptor (CAR) T cells, CRISPR-Cas9 gene editing, and genetically modified hematopoietic stem cells. Despite scientific and regulatory progress, several critical barriers remain to their ethical and effective implementation. First, there is limited understanding of how PWH perceive the risks, benefits, and overall acceptability of CGT-based interventions. Although early- phase HIV CGT trials are underway, real-world data on community perspectives are scarce, complicating efforts to design person-centered trials. Second, little is known about how PWH and research staff navigate the complexities of CGT trial implementation. These trials are time- and resource-intensive; yet the experiences and support needs of staff, who play a critical role in trial success, are seldom studied. Third, innovative models such as end-of-life (EOL) translational research offer unprecedented opportunities to study HIV cure-related strategies. The University of California San Diego's Last Gift program engages terminally ill PWH who voluntarily donate tissues at the EOL to study HIV persistence; some interventional experiments are already underway ex vivo. The next frontier will involve in vivo testing of experimental CGT strategies in this translational research model. While promising, this raises novel ethical, regulatory, and logistical challenges requiring careful evaluation. Our Specific Aims are: Aim 1 will determine the anticipated acceptability of HIV CGT approaches among PWH in the U.S. Aim 2 will characterize the experiences of PWH participating in, and research staff implementing, CGT-based HIV cure trials. Aim 3 will establish the ethical, regulatory, and procedural feasibility of introducing in vivo CGT interventions into the EOL translational research model at UCSD. This R21 will generate critical insights into the social, operational, and ethical dimensions of HIV CGT implementation in the U.S. Findings will inform trial design, stakeholder engagement, and policy development to ensure ethical, feasible, and acceptable CGT strategies. Ultimately, this research will support innovation in HIV cure science, reduce the long-term burden of HIV care, and promote innovation that is relevant to the health of all Americans.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Project Summary The Digital Health Research and AI Training Program at the University of North Texas (UNT) provides a hands-on summer research experience for high school science teachers in the Dallas-Fort Worth (DFW) region. This initiative immerses educators in digital health, AI-driven healthcare solutions, and wearable health technologies, equipping them with the skills to integrate real-world digital health applications into STEM curricula. Under the guidance of faculty mentors from engineering, health sciences, and education, participating teachers conduct research in active digital health and AI labs, gaining direct exposure to cutting-edge work in embedded systems, biosensors, medical imaging, and AI-powered diagnostics. The program places ten high school teachers in research laboratories, where they engage in structured study design, bio-signal data collection, and machine learning analysis of physiological signals such as ECG, PPG, and motion data. Educators also participate in targeted workshops designed to provide foundational knowledge in AI, digital health research, and embedded systems, ensuring they have the necessary prerequisites to apply these concepts in their teaching. Through hands-on training, teachers develop wearable health devices, implement real-time bio-signal processing, and explore AI-driven digital health applications, culminating in collaborative research studies with university faculty. Using a Community of Practice model, teachers work alongside faculty and peers to develop STEM lesson plans, curriculum maps, and instructional materials aligned with Next Generation Science Standards (NGSS) and Texas Essential Knowledge and Skills (TEKS). This program directly addresses the lack of hands-on AI and digital health research training opportunities for high school educators in the DFW region, bridging the gap between academic research and STEM education. By integrating biosensors, real-time signal processing, and embedded AI concepts into classroom instruction, educators empower students to engage with real-world biomedical challenges and explore careers in digital health, healthcare AI, and digital health technologies. The program includes a comprehensive evaluation plan assessing curriculum improvement, classroom implementation, and student engagement in biomedical AI topics. Teachers participate in pre- and post-program assessments, classroom observation studies, and long-term tracking of student learning outcomes. The initiative also incorporates structured dissemination opportunities, enabling educators to present their research experiences and curriculum materials at regional STEM education conferences, school district professional development workshops, and AI in healthcare summits. This initiative enhances teacher expertise in digital health and AI, expands the STEM workforce pipeline, and fosters student interest in healthcare innovation by providing a sustainable professional development model. Through collaborations with local research institutions, industry partners, and K-12 networks, the program ensures a lasting impact on high school STEM education in the DFW region.

U.S. National Science Foundation

The Advancing Informal STEM Learning (AISL) Program is committed to funding research and practice, with continued focus on investigating a range of informal STEM learning (ISL) experiences and environments that make lifelong learning a reality. This program seeks proposals that center engagement, broadening participation, and belonging, and further the well-being of individuals and communities who have been and continue to be excluded, underserved, or underrepresented in STEM along several dimensions. The current solicitation encourages proposals from institutions and organizations that serve public audiences, and specifically focus on public engagement with and understanding of STEM, including community STEM; public participation in scientific research (PPSR); science communication; intergenerational STEM engagement; and STEM media. Projects funded by AISL should contribute to research and practice that further illuminates informal STEM learning s role in engagement, broadening participation, and belonging in STEM; personal and educational success in STEM; advancing public engagement in scientific discovery; fostering interest in STEM careers; creating and enhancing the theoretical and empirical foundations for effective informal STEM learning; improving community vibrancy; and/or enhancing science communication and the public s engagement in and understanding of STEM and STEM processes. The AISL Program funds five types of projects: (1) Synthesis; (2) Conference; (3) Partnership Development and Planning; (4) Integrating Research and Practice; and (5) Research in Support of Wide-reaching Public Engagement with STEM. NOTES: Activities primarily focused on formal educational systems or outcomes are outside the scope of work supported by this program. AISL does not fund formal elementary, middle, or high school, or undergraduate or graduate education, whether in-person or online. Similarly, AISL does not fund formal workforce training (e.g., professional certifications and degree-earning programs) that is not aimed directly at informal STEM learning professionals. While the language in the Broadening Participation in STEM section draws attention to the diversity of institutions of higher education (IHEs), the AISL program encourages submissions from the full spectrum of diverse talent that society has to offer to include those from Non-profit, Non-academic Organizations, and Tribal Nations as core to the program s Broadening Participation and overall efforts to engage the diverse talent from communities and advance informal STEM education. Non-profit, Non-academic Organizations are directly associated with educational or research activities but do not grant degrees. They include but are not limited to independent museums, observatories, research laboratories, professional societies, and similar organizations located in the U.S. The term Tribal Nation means an American Indian or Alaska Native tribe, band, nation, pueblo, village, or community that the Secretary of the Interior acknowledges as a federally recognized tribe pursuant to the Federally Recognized Indian Tribe List Act of 1994, 25 U.S.C. 5130-5131.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT | NARRATIVE The thymus instructs T cell immunity and central tolerance, yet its therapeutic potential remains clinically untapped as the signals that drive thymic epithelial cell (TEC) differentiation remain incompletely understood. The thymic epithelium comprises a highly specialized set of cells that attract lymphoid progenitors, promote their proliferation and maturation into thymocytes, and facilitate the selection of a diverse, self-tolerant T cell receptor (TCR) repertoire. The role of the thymus in building immune identity begins before birth. The organ peaks in size in infancy and then structurally and functionally involutes over time. This process causes the decline in immune competence with age (immune senescence). The impact of this phenomenon was exposed during the COVID-19 pandemic when waning immunity left the elderly more vulnerable to adverse outcomes. Thymus insult also occurs in many patients through medications, radiation, infections and graft-versus-host disease. The most severe form of thymic compromise is congenital athymia, the inborn absence of the thymus due to genetic mutations. Genetic or acquired thymic injury leads to immunodeficiency, autoimmunity, inflammation and increased cancer risk. Regenerating thymic function, e.g., through human induced pluripotent stem cell (iPSC)-derived regenerative thymic tissues holds greatest therapeutic promise for these patients. We have used single-cell transcriptomics of human fetal anterior foregut-derived organs to uncover the signals that drive TEC differentiation. We have translated these insights into a novel differentiation platform for the derivation of TECs from iPSCs in vitro. When iPSC-derived TEC organoids are transplanted into athymic NSG nude (NSG-Foxn1-/-) mice engrafted with human hematopoietic stem cells, they function like the human thymus, giving rise to human ab-T cells with a diverse TCR repertoire, gd-T cells and regulatory T cells. In this application, we now seek to advance the translation of iPSC-derived TECs (iTECs) by testing their safety and efficacy as cell therapy for vulnerable patient populations in need of improved T cell immunity. In Aim 1, we will determine the capacity of iTECs to promote T cell reconstitution, functional antigen-specific T cell responses and the development of a broad TCR repertoire in vivo. In Aim 2, we will assess if T cells educated on iTEC are tolerant to “self” but respond to “non-self”. In addition, we will directly analyze the HLA-associated peptide repertoire presented on iTECs using immunopeptidomics. In Exploratory Aim 3, we will test if HLA-editing of iPSCs for iTECs derivation affects antigen-specific immune responses, TCR repertoire, and immunopeptidome in vivo. Advancing the translation of iPSC-derived TECs into a cell therapy is an entirely new strategy to leverage the therapeutic potential of T cells from inside the body and could begin a new chapter of immunotherapeutics.

NIA - National Institute on Aging

Project Summary/Abstract The world's population is aging rapidly, and by 2050, the population over 60 years will exceed 2 billion people or 25% of the total global population. Tissue repair is critical for the survival of all organisms. Aging causes a gradual decline in tissue integrity, partly due to a decline in stem cell function, a major hallmark of aging. Due to its accessibility and temporal predictability, cutaneous wound healing provides a valuable model framework to characterize the effects of aging on tissue injury1. Aging disrupts the precisely coordinated immune cell response that orchestrates the three phases of cutaneous wound healing. However, it is unknown whether this disruption is initiated by the aging of the tissue itself or the aging of the immune system. Recently, a breakthrough study showed that the aging immune system or “immunosenescence” precedes and drives organ aging2. Thus, an inference from this concept is that the mechanism by which aging impairs wound healing is largely dependent on how aging impairs the immune system. Our long-term goal is to identify how aging impairs immune cell function and show that we can restore youthful wound healing by reversing immune aging. Hematopoietic stem cells (HSCs) are remarkable cells in our bone marrow that make at least one trillion new blood cells daily. We have shown that HSCs produce all of our circulating immune cells and regulate their gene expression by “epigenetic reprogramming”. We will use sophisticated “single-cell epigenomics,” some of which were developed in our laboratories, to characterize how aging affects the gene expression of individual immune cells and how that expression is regulated by epigenetic modifications. We have three Aims: Aim 1: Determine if aging impairs wound healing by an HSC-Autonomous mechanism. Aim 2: Identify the aging-specific- HSC oxidant stress that drives immune aging and impairs wound healing. Aim 3: Identify the master epigenetic enzyme(s) in aged HSCs that epigenetically reprogram the gene expression of wound macrophages and their cross-talk with fibroblasts and keratinocytes. Once we identify the “master epigenetic enzyme” affected by aging in HSCs that reprograms the gene expression of immune cells, we will reverse the effects of aging on the master epigenetic enzyme to restore youthful wound healing. The fact that the effects are “epigenetic” implies that the effects of aging, at least on the immune system, are reversible and, by proof of principle, would open the door to new molecular therapies to reverse the effects of aging.

NIMH - National Institute of Mental Health

AI-based decision support system for Addressing Emergency Department return Among Mental Health Patients Project Summary In 2022, more than 1 in 5 U.S. adults (59.3 million, 23.1% of the adult population) live with mental health (MH) illness. About 1 in 8 Emergency Department (ED) visits involve MH and/or substance use diagnoses. A study indicated MH patients are 4.7 times more likely to be frequent ED users, defined as those with three or more in the previous 3 months, compared to non-MH patients. Each preventable ED return visit contributes to the $32 billion preventable ED costs to the healthcare system annually. While prediction models exist for ED returns among general patient populations or specific groups such as elderly patients, there is a lack of validated models developed to predict ED returns among MH patients. The challenge stems from the complex and unique factors affecting the ED return of MH patients, including clinical, operational, and social determinants of health (SDoH) factors. This complexity makes it challenging for clinicians to anticipate ED return for MH patients using their clinical judgment. Therefore, there is a need for advanced analytical approaches that can process complex patient data and integrate it through real-time clinical decision support (CDS). This project will: 1) Develop a Large Language Model (LLM)-based system for to automatically extract MH ED return risk factors (MERRF) from clinical notes. We will develop a system using state-of-the-art LLM techniques, including Retrieval-Augmented Generation, to accurately extract key risk factors (e.g., SDoH, medication adherence, and poor outpatient follow-up) from unstructured clinical notes. The system’s accuracy will be validated through manual chart reviews by clinical experts and multisite validation. 2) Develop explainable Machine Learning (ML) models to predict ED returns for MH patients. We will develop and validate multisite explainable ML models that integrate structured clinical data with extracted MERRF to identify high risk of ED return among MH patients. We will create an explainability framework that translates ED return risk factors into natural language, making it easy for social workers and providers to understand both the ML-generated ED return risk scores and their contributing factors for each MH patient. 3) Develop and Integrate Artificial Intelligence (AI)- MH ED Return Risk Assessment (MERRA) CDS Tool in the EHR. Using human-centered design (HCD) design principles, we will engage ED stakeholders (e.g., social workers) to develop the proposed AI-MERRA CDS and investigate its integration into ED workflow. Through iterative design and testing, we will optimize the CDS usability and clinical relevance. 4) Evaluate the AI-MERRA CDS Implementation and Feasibility. We will implement a quasi-experimental pilot study at UABHS to evaluate AI-MERRA CDS. We will assess implementation outcomes (e.g., adoption) through quantitative metrics and semi-structured interviews with ED clinicians. Findings will inform a future large scale, multisite implementation of AI-MERRA through a randomized clinical trial. This project is highly feasible and will advance mental health ED care through innovative AI solutions.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT The mucus layer of the digestive system plays a key role in innate immunity, protecting intestinal epithelium from commensal bacteria, pathogens, and toxins. Goblet cells (GCs), secretory cells residing in the intestinal epithelium, are essential for mucin secretion to form this protective mucus layer and maintain its integrity. Ulcerative colitis (UC) is strongly correlated with a compromised colonic mucus layer and a decrease in the number and function of GCs, eventually resulting in inflammatory flare-ups. Unfortunately, current UC treatments display only limited eƯicacy and high recurrence rates, and mostly target the inflammatory process, without inducing mucosal regeneration. In this proposal, we aim to leverage the powerful regenerative potential of the patient’s own cells by activating colon-resident intestinal stem cells (ISCs) to diƯerentiate into GCs. We hypothesize this will augment mucus secretion and rebuild the broken mucosal barrier, eventually preventing pathogen invasion and the consequent inflammatory cascade. Accordingly, the first aim of our study will include artificial intelligence (AI)-guided identification of small molecules that boost GC diƯerentiation. We plan to build on our expertise in ISC diƯerentiation, combined with leveraging existing large biological datasets, including multi-omics datasets and chemical libraries to identify compounds that stimulate GC diƯerentiation. Our second aim is evaluation of AI-identified compounds in UC murine colon organoids (colonoids), and in colonoids derived from UC patients’ biopsies for identification of the most potent GC inducers in this clinically relevant in-vitro model. Our third aim will be dedicated to assessing the therapeutic impact of the top GC boosting molecules in an acute UC murine model. Our proposed strategy to harness the innate stemness of colonic ISCs is envisioned to result in renewal of the colonic GC pool, enhancement of GC-induced mucus secretion and restoration of the mucus barrier function and its key role in innate immunity. We believe the potent stem-cell boosting molecules identified in this study may eventually be developed into a novel treatment modality to replenish the mucus layer and significantly ameliorate inflammatory flares and related symptoms in UC patients.

Akamai Foundation

Supports STEM education and environmental sustainability through technology partnerships.

U.S. National Science Foundation

The Alliances for Graduate Education and the Professoriate (AGEP) program aims to develop the human capital and administrative and academic infrastructure that will enable the placement of underrepresented minorities (URMs; African-Americans, Alaska Natives, Native Americans, Hispanic Americans, and Native Pacific Islanders) in faculty positions at American universities, colleges and community colleges. Please note that AGEP welcomes participation by URM students with disabilities. From its inception in 1998 as the Minority Graduate Education (MGE) program, it has grown from 8 participating universities to 108 institutions, including about 80% of the top producers of African American and Hispanic PhDs. AGEP institutions have been successful at increasing the numbers of URMs enrolled in and graduated from their STEM graduate programs. The educational research portfolio contributes to the body of literature of successful practices in student recruitment, retention, persistence, and attainment of STEM undergraduate and graduate degrees, especially for populations underrepresented in STEM disciplines: African-Americans, Alaskan Natives, Native Americans, Hispanic Americans, and Native Pacific Islanders. AGEP welcomes the participation of URM persons with disabilities.AGEP alliances further the graduate education of underrepresented STEM students through the doctorate level, preparing them for fulfilling opportunities and productive careers as STEM faculty and research professionals. AGEP also supports the transformation of institutional culture to attract and retain STEM doctoral students into the professorate.

U.S. Mission to Myanmar

1. Project Background, Goals and Objectives American Center Yangon Small Grants projects must clearly advance America First foreign policy principles by demonstrating how the proposed activities make the United States safer, stronger, and more prosperous, while celebrating Freedom250 and American excellence. Priority will be given to projects that deliver tangible, measurable benefits to U.S. interests; elevate U.S. leadership and credibility; promote reciprocal and mutually beneficial engagement with Burma and focus on one of the priority areas outlined below. AMERICA FIRST: MAKING AMERICA SAFER Programs that directly advance the security and resilience of the United States by promoting American democratic governance and interests in Burma. This includes initiatives that reinforce the rule of law, counter trafficking, digital freedom, anti-scam awareness and corruption that threaten U.S. interests, uphold American-defined human rights, and empower civil society to create an environment that aligns with U.S. peace and security priorities in the region. AMERICA FIRST: MAKING AMERICA STRONGER Programs that advance America First priorities by equipping Burma s students and young adults with skill based and vocational training that strengthens U.S. relevant economic competitiveness. Proposals should promote accurate understanding of U.S. education, institutions, and culture; prepare potential qualified candidates for lawful study and exchange opportunities related to the United States; and build durable linkages with American academic, vocational, and cultural institutions. These may also include activities that strengthen the United States global leadership by promoting American values, and civic engagement rooted in U.S. principles. These programs should deepen U.S. influence in Burma, reinforce American cultural and educational standards, and build enduring partnerships that serve American diplomatic and strategic interests. AMERICA FIRST: MAKING AMERICA MORE PROSPEROUS Projects that advance U.S. Burma economic ties and U.S. prosperity by strengthening entrepreneurs and businesses that align with U.S. commercial and strategic interests. Activities that expand economic opportunities for the United States by fostering innovation, entrepreneurship, and workforce development that benefit American businesses and industries. Priority will be given to programs that promote U.S.-led STEM education, vocational training aligned with American economic priorities, or trade capacity building that directly supports U.S. economic growth and reduces reliance on adversarial actors. AMERICA FIRST: AMERICAN EXCELLENCE Projects that showcase the superiority of American leadership, innovation, arts, and community service. These initiatives should highlight U.S. achievements and role models, inspire admiration for American values, and promote collaboration that advances U.S. interests in technology, entrepreneurship, education, and the arts, ensuring America s continued prominence on the global stage. Activities may include programs that feature U.S. experts or content on Indo Pacific strategy, maritime and economic security, or resilient supply chains, and that clearly communicate U.S. strengths, values, and strategic objectives to Burma based audiences. ENGLISH LANGUAGE LEARNING Programs that advance America First priorities by providing Business English and English for Entrepreneurship essential to U.S. linked trade, investment, and regional stability. Proposals should build high level English skills needed to work with American companies, navigate U.S. standards and contracts, participate in regional supply chains, and engage in lawful, rules based economic activity. Activities may include targeted English training for professionals, entrepreneurs, and future business leaders that uses U.S. materials, terminology, and case studies and clearly supports U.S. economic and strategic interests in the Indo Pacific. Project Audiences: Youth and Young Adults: Including students, recent graduates, and emerging professionals in both urban centers and rural regions of Burma, with a focus on those from underserved or marginalized communities in Yangon. Civil Society Organizations: Local NGOs, advocacy groups, and community-based organizations in Yangon, engaged in promoting democratic governance, human rights, anti-corruption, and rule of law reforms. Commercial Advancement: Individuals and entities involved in innovation, trade, and workforce development that align with U.S.-Burma economic ties and regional supply chains. Educational and Cultural Institutions: Schools, vocational training centers, universities, and cultural organizations that facilitate bilateral exchanges and promote American cultural and educational standards. Project Goals: Advance democratic governance and the rule of law in Burma by empowering civil society organizations to promote human rights, anti-corruption, and digital freedoms aligned with U.S. peace and security priorities. Enhance the skills and employability of Burmese youth and young adults through vocational training and English language programs that prepare them for lawful educational exchanges and economic participation linked to the United States. Strengthen U.S.-Burma economic ties by supporting entrepreneurship, innovation, and workforce development programs that foster trade capacity building and reduce reliance on adversarial actors. Promote American cultural excellence and leadership by facilitating educational, artistic, and community service initiatives that highlight U.S. values and strategic objectives in the Indo-Pacific region. Support sustainable, measurable outcomes by encouraging projects that incorporate robust monitoring, evaluation, and reporting mechanisms to demonstrate progress toward U.S. foreign policy goals. Project Objectives: Objective 1: Promote American Democratic Governance Enhance the institutional and operational capacity of at least 10 civil society organizations over a 12-month period to effectively advocate for rule of law, anti-trafficking measures, digital freedoms, and anti-corruption reforms. Success will be measured by the adoption and implementation of key organizational policies (e.g., financial management, transparency protocols), increased advocacy activities, and demonstrable influence on public policy aligned with U.S. peace and security priorities. Objective 2: Empower Youth through Vocational and English Language Training Provide vocational skills development and high-level English language instruction to a minimum of 1,500 youth and young adults, improving their readiness for lawful educational exchanges, workforce participation, and engagement with U.S.-linked economic opportunities. Progress will be assessed via standardized skill assessments, participant retention rates, and post-training employment or education placement data. Objective 3: Commercial Advancement and Economic Competitiveness Support at least 200 entrepreneurs and small businesses through training, mentorship, and capacity-building activities that promote innovation, STEM education, and trade capacity building. Programs should align with American economic priorities by enhancing workforce skills, facilitating access to U.S. markets, and reducing reliance on adversarial actors. Indicators of success include business growth metrics, increased participation in regional supply chains, and measurable expansion of U.S.-Burma commercial ties. Objective 4: Showcase American Excellence and Values Develop and implement cultural, educational, and leadership programs that highlight American innovation, arts, community service, and strategic expertise in areas such as Indo-Pacific security, maritime resilience, and economic policy. These initiatives should engage local audiences, promote admiration for American values, and strengthen bilateral cultural ties. Success will be measured by audience reach, participant feedback, and enhanced understanding of U.S. strategic objectives. Note: Please see detail information by clicking Related Document tab.

NINR - National Institute of Nursing Research

Project Summary Emergency Department (ED) decision-making is inherently complex, influenced by uncertainty, time pressure, and high-stakes consequences. ED crowding exacerbates these challenges by increasing distractions and cognitive load, often leading to suboptimal decisions and adverse outcomes. Triage nurses are typically the first point of contact for medical needs assessment. For example, their role in prioritizing patients is one of the most consequential decisions, yet current triage accuracy is only about 60% compared to expert benchmarks. This performance gap stems from the complexity of ED scenarios, which often exceed human cognitive limits. Artificial Intelligence (AI), including Large Language Models (LLMs), offer the potential to support triage nurses and all members of the ED team by improving decision-making on many ED tasks, especially during crowding. Advantages of such tools include rapid processing of large volumes of data, operating without fatigue, and being deployable on demand – all while rivaling human decision-making on a wide variety of tasks. With recent advances in AI, there is a timely opportunity to investigate its utility in supporting ED decision-making. While AI/LLMs could be vital support for ED decision-making, there is no gold standard (expert annotated labeled data) by which to evaluate the quality or accuracy ED decisions, and no standardized tasks or metrics. We propose to develop a set of gold-standard ED decisions derived by expert annotation on patient cases for a set of decision-making tasks, and establish a set of metrics for assessing decision-making performance. In addition, we will fine-tune and validate fine-tuned LLMs, with the best-performing model termed “AI-Triage+”. We will then test the performance of AI-Triage+ on ED decision-making-tasks vs. status quo (human decisions) and existing pre-trained (generalist) AI models. AIM 1: Compare the performance of AI models to a gold standard on five ED decision-making tasks: ESI (Emergency Severity Index) level recommendation, Patient-facing diagnostic question generation, Acceptable safe wait time values for each patient, Recommend diagnostic tests and ED procedures for the patient, and Recommend ED resource level based on the patient's needs (aka patient disposition). We will assess overall model performance and performance on specific subsets of cases, e.g., by diagnoses, age group, ED workload (overcrowding score). AIM 2: Estimate the impact of AI models' decisions on clinical outcomes. Using existing risk equations, we will estimate how different ED decisions by AI models will impact ICU admissions or death in ED, hospital admissions, and length of hospital stay. We will also explore the potential of AI-Triage+ to improve ED efficiency at a system level. This work directly supports the NINR focus on systems and models of care, offering foundational tools and insights to guide AI integration into ED practice.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract Over 300 million people undergo surgery annually, each made possible by modern anesthesia, a complex series of medical interventions that induce a controlled, unresponsive state. In the perioperative period, anesthesia providers are faced with increasingly complex medical decisions as patient care and surgical procedures continue to evolve. Medication errors and adverse events comprise a large proportion of anesthetic adverse events, ranging from 5-28%, in part stemming from significant individual physiological variability and poorly understood drug interactions. Traditional methods for improving care, such as randomized control trials, are impractical due to the number of combinations of interventions during one anesthetic. To address this gap, the development of computational tools that harness the wealth of generated perioperative data presents a significant opportunity to support anesthesia practice. However, current approaches have been limited by low outcome generalizability, small patient datasets, manual simplification of complex time-dependent features, and poor clinical actionability. To address these challenges, this study hypothesizes that global, time-aware artificial intelligence modeling approaches can fundamentally capture the physiologic and pharmacologic principles in anesthetic care. The study will be accomplished via three specific aims: 1) the construction of a global foundation model with reusable representations of patients and their procedures for multiple, simultaneous output prediction, 2) real-time network-based modeling of patient physiology in response to combinatorial drug interventions, and 3) development of a causal inference framework to support identifying optimal, dynamic treatment regimens. The proposed research is innovative because it leverages large-scale perioperative datasets with the development and application of sophisticated artificial intelligence and statistical methods to model the intricacies of perioperative practice. The research project is significant because successful development of these methods to teach machines these fundamental principles has the potential to serve as a versatile foundation for a wide range of downstream tasks in perioperative medicine. The proposed integrated research and training will be accomplished at Stanford University with the support of an exceptional mentorship team. The candidate will build on a solid background in anesthesiology, biomedical informatics, machine learning, and statistics research to gain relevant expertise in clinical informatics, advanced artificial intelligence methodologies, time-series analysis, causal inference, and scientific communication. Together, the research and training will advance the candidate’s long-term goal to develop an independent research program as a physician-scientist aimed at the development and application of translational artificial intelligence tools that impact perioperative care. Ultimately, the continuum of research will have a positive impact by providing a strong methodological base for targeted applications for improving precision anesthesiology practice.

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

ABSTRACT The multinucleated syncytiotrophoblast (STB) is a tissue-sized single cell that separates the maternal and fetal vasculature during pregnancy. The STB wraps around the villous trees of the placenta lobules, encasing them in a cell with billions of nuclei in a common cytoplasm. This giant single cell facilitates the exchange of nutrients, is essential for fetal immunoprotection, is the primary producer of pregnancy hormones, and performs critical metabolic roles. Further, the STB must simultaneously respond to gradients in oxygen, nutrients, maternal hormones, and pathogens that fluctuate in space and time. How does a single cell support these diverse homeostatic tasks and simultaneously respond to local stresses? We hypothesize that the multinucleate organization is fundamental to supporting the many demands of production, metabolism, and stress response required of a single STB cell. Recent work and our preliminary data show that individual nuclei within the STB indeed have distinct transcriptional programs despite all sharing the same cell cytoplasm. This indicates that STB nuclei are heterogeneous in activity and function. Notably, GO terms for each of the STB nuclear clusters show mutually exclusive expression of homeostatic STB functions or stress response genes. Therefore, nuclear individuality could both facilitate the myriad of STB functions and the insulation of the stress response by spatially clustering in different regions depending on local functions or conditions. Major gaps in knowledge include how different nuclear identities are spatially patterned in the tissue, how nuclear identities arise mechanistically, and the functional consequences of nuclear heterogeneity within the STB cell. Spatial organization of the STB is disrupted in multiple forms of preeclampsia, a pregnancy disease that stems from improper placentation in the first trimester or maternal inflammation. We predict that the systemic stress seen in preeclampsia perturbs the functional balance and spatial organization of homeostatic and stress response pathways in STB nuclei. The proposed experiments will analyze heterogeneous gene expression in healthy and preeclamptic placentas with the following aims: Aim 1: Dissect the spatial patterns of RNA expression and localization in the STB cell and Aim 2: Identify the function and mechanism of heterogeneous nuclear gene expression in the STB. We will apply state-of-the-art spatial transcriptomics on placentas from healthy and preeclamptic pregnancies to analyze gene expression patterning in different locations of the STB. Using super-resolution, live-cell imaging, and genetic manipulations of placenta organoids, we will determine the mechanisms generating specialized nuclear transcription and the functional consequences of heterogeneous nuclear gene expression. This work will establish a functional atlas of STB nuclear identity patterning in health and preeclampsia and act as a guide to discover molecular drivers of pregnancy disease.