Duke University

NSF Awards · FY 2024 · 2024-09

Microbial communities and microbiomes occur everywhere and impact soil health, environmental processes, human health, and many other process that impact climate resilience and the bioeconomy. To date, is has been difficult to predict how the addition of new microbial species into a community impacts microbiome function, and as such, it has been difficult to design microbiomes with desired functions. The prediction of microbiome functions from the genotypes of constituent species remains a longstanding, unsolved problem in microbiome science and engineering. The long-term goal of this project is to develop and apply an integrated experimental and computational approach to uncover the design principles at the molecular and cellular level that govern microbiome function. These models would be able to then be used in a variety of applications to solve problems related to climate resilience, human health, and the bioeconomy. In addition, the investigators will increase the inclusion and public participation in STEM by partnering with a well-established informal science education program at the Morgridge Institute for Research, serving thousands of youths per year. This project will integrate advanced machine learning techniques with high-throughput microbial community construction and metabolomics in order to elucidate design principles of molecular networks involving any cellular process (e.g. metabolism, stress, signaling) that govern microbiome functions. Notably, the proposed framework will enable the prediction of new and uncharacterized species on microbiome functions, which has not been previously demonstrated using a data-driven model. The investigators will apply this multi-scale modeling framework to study the effects of diverse bacteria on community composition and anaerobic metabolic states. While this proposal focuses on the genotype-function mapping of microbial communities, the data-driven framework will provide a foundation for the prediction of microbiome functions from omics data including transcriptional profiling data, proteomics and beyond. The novel systems biology framework could be applied more broadly to any microbiome or microbiome function. Deciphering the molecular-level design principles of microbiomes would provide a deeper insight into the organizational principles of these energetically efficient and resilient systems. 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 Awards · FY 2024 · 2024-09

This NSF project is a collaboration between researchers from Duke University and ETH-Zürich (their portion funded by the Swiss National Science Foundation) and aims to explore the thermal impacts of shrinking down the size of metal contacts to two-dimensional (2D) semiconductors. There is ongoing interest in using 2D semiconductors to enable the continuation of Moore’s law beyond the physical limits of silicon-based technology. While transistors from 2D materials show great promise, there is very little known about how thermal effects will impact their performance and the nature of electrical transport at small dimensions. Because heating will be of great importance for a fully integrated technology, it is imperative that such effects are well understood. Hence, this project will combine experimental (Duke) and theoretical (ETH-Zürich) exploration of different 2D semiconductor device structures with emphasis on the role of thermal effects. In addition to the scientific advancements, this project will also make an intentional impact on the broader community through outreach and recruitment efforts. One way will consist of bringing hands-on lab experiences to the classrooms: Duke’s portable scanning electron microscope will be brought to local high schools in the Durham area, which has a high population of students from underrepresented backgrounds. New material will also be developed and integrated into relevant graduate courses at both Duke and ETH-Zürich based on findings in this project. The thermal implications of distinct contact structures to transition metal dichalcogenides (TMDCs), including the impact of scaling, will be examined in this project. As testbed, tungsten disulfide, one of the most prominent members of the TMDC family, will be used because it can act both as n- and p-type transistor. The contact issue will be addressed from an experimental and theoretical point-of-view by combining the expertise of two researchers, Prof. Aaron D. Franklin at Duke University (USA) and Prof. Mathieu Luisier at ETH Zürich (Switzerland). Goals for the project include: 1) Developing an apparatus for performing nanoscale thermal mapping of 2D contact structures; 2) Fabricating tungsten disulfide transistors with top, edge, and mixed contact structures; 3) Ab initio electrical and thermal quantum transport modeling of contacts validated with experimental data; 4) Characterization, electrical and thermal, of tungsten disulfide transistors with different elemental metals; 5) Moment-tensor potential force-field materials combined with tungsten disulfide for modeling contacts; and 6) Experimental and theoretical demonstration of tungsten disulfide transistors with enhanced performance. Principal investigator (PI) Franklin will concentrate on the fabrication of tungsten disulfide transistors with advanced contact structures relying on different metals and geometries and on their electrical and thermal characterization. International partner Luisier, who has pioneered nanoscale device modeling techniques, will provide theoretical insights into the contact physics through ab initio simulations based on electron and phonon quantum transport and will deliver design guidelines to the experimental partner at Duke University. Targeted as part of this project are scalable contact configurations to mono-, bi-, and trilayer tungsten disulfide with relatively low electrical resistances, high thermal boundary conductance, and little device-to-device variability. Satisfying these requirements is essential to enable the deployment of the 2D technology into mainstream integrated circuit applications. This collaborative U.S.-Swiss project is supported by the U.S. National Science Foundation (NSF) and the Swiss National Science Foundation (SNSF), where NSF funds the U.S. investigator and SNSF funds the partners in Switzerland. 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.

NIH Research Projects · FY 2026 · 2024-09

Sub-Saharan Africa (SSA) has the world’s fastest-growing population and movement from SSA to the United States (US) is contributing to increasing demographic heterogeneity and US population health and aging. Our knowledge of the health of SSA foreign-born individuals relies largely on comparisons by nativity status using US-based cross-sectional surveys. These comparisons tend to aggregate individuals born in SSA with Blacks born in Latin America and the Caribbean (LAC), limiting precision in comparisons with US-born Blacks. Available evidence suggests that SSA-born individuals tend to have better physical health than US-born Blacks, positing selection processes, health behaviors, family and support networks, and social and cultural contexts of origin. However, mental health, particularly depression, tends to be worse among the foreign-born, with indications that greater exposure to US environments may undermine health over time. Existing US data are insufficient to disentangle the forces shaping these patterns. In particular, they cannot distinguish whether observed differences reflect pre-arrival exposures, selection into US residence, or experiences following arrival. Collecting comparable data in both the US and country of origin is essential to establish the baseline needed to interpret US health patterns by nativity status and to assess changes in health behaviors and outcomes over time. The Ghanaian Migrant Health Study (GMHeS) addresses this gap by collecting and analyzing linked, binational data for Ghana, where the research team has established partnerships and prior and ongoing formative work. The project will: (1) recruit linked binational samples of Ghanaians in Ghana and Ghanaian foreign-born individuals in the US using multiple sample recruitment strategies (including probability and link-tracing sampling designs) and diverse data sources (census, survey and administrative); (2) follow the sample in Ghana and the foreign-born sample in the US longitudinally; (3) use these multi-sited data to examine physical and mental health among Ghanaian foreign-born individuals in the US in comparison with US-born Black populations and Ghanaians in Ghana, and (4) advance understanding of how life course exposures before and after US residence, social networks, and selection processes shape health outcomes. This innovative project enables rigorous cross-national comparisons of population health in Ghana and the United States, providing critical insights into the contribution of foreign-born populations to the health and aging profile of the US. Although we examine population from a single origin, the study develops scalable approaches for broader application, supporting future comparisons by nativity status and advancing understanding of US population health.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY A fundamental feature of perception is the ability to recognize objects or object features despite changes in presentation, such as size, position, or context. Elucidating the mechanisms by which cortical populations and circuits build representations that are invariant to these manipulations will significantly advance our understanding of the biological underpinnings of perception. Based on limited biological work examining invariant tuning properties of neurons in visual cortex, studies in the field of object recognition hypothesize that invariance, or tolerance to identity-preserving transformations, increases gradually as signals ascend the visual processing hierarchy. In contrast, studies investigating how invariance is computed for perception of motion across different object types have hypothesized that different types of invariances are computed in discrete, subsequent steps. For example, humans and nonhuman animals alike perceive the pattern direction of motion of drifting plaids despite the fact that plaids are composed of two overlaid gratings that drift in divergent directions. This perception requires direction invariance (tolerance to the component grating directions of motion) and spatial invariance (tolerance to differences in spatial features across different types of plaids). Previously published work proposes that direction and spatial invariance are computed in series. First, spatial invariance is achieved by complex, direction selective cells in V1 and next, direction invariance is computed upon integration of the signals encoding component directions of motion in higher order areas of cortex. However, data from other studies and my own preliminary data do not agree with this two-stage model. We find direction invariance in V1 prior to the representations achieving spatial invariance. These data suggest that the computation for spatial invariance for pattern motion encoding may occur gradually, as is proposed in object recognition pathways. Therefore, my central hypothesis is that motion encoding circuits compute spatial invariance gradually over multiple transformations to build an invariant percept of pattern motion. Using multiphoton imaging and optogenetic manipulations in mouse visual cortex, I will test this hypothesis with two specific aims. In Aim 1, I will test if spatial invariance increases gradually throughout the processing hierarchy and, if so, whether the increase is inherited by receiving biased inputs that come from the most invariant neurons in the preceding population, or if spatial invariance is computed de novo upon integration of heterogenous inputs. In Aim 2, I will investigate how single cell and population level pattern motion representations inform pattern motion perception by training mice in a direction discrimination task. Overall, the significance of this work will be to advance our understanding of how invariance is built for pattern motion perception, resolving current controversies in the field and revealing fundamental principles of cortical computations that increase invariance for perception.

NIH Research Projects · FY 2025 · 2024-09

Our objective is to use novel mobile health (mHealth) behavioral intervention approaches to enable patients who have undergone hematopoietic stem cell transplant (HCT) to effectively cope with their symptoms to improve their ability to engage in physical activity that can improve physical disability. In a NCI R21 study, we developed a hybrid in-person and mHealth Coping Skills Training for Symptom Management and Daily Steps (Step Up) intervention protocol, including mobile app. Step Up provides HCT patients with cognitive behavioral coping skills training and occupational therapy (OT)-led activity coaching sessions to enhance their ability to cope with symptoms – fatigue, pain, distress – that interfere with physical activity. Step Up has been developed by experts in symptom management, members of the HCT medical team, and with extensive input from HCT patients. Our R21 results show Step Up is feasible, acceptable to patients, and demonstrates a strong signal for intervention benefits, including improvements in physical disability, symptoms, and activity (daily steps). The next step in this research program is to use a randomized controlled trial (RCT) to test the efficacy of Step Up compared to Usual Care Plus (UC+). Step Up includes one in-person symptoms coping skills session and two activity coaching sessions during intensive outpatient care. Then, following discharge home, an additional four integrated symptom coping and activity coaching sessions are delivered via videoconferencing. Step Up includes a mobile app and activity trackers (Fitbits) to capture daily symptom, activity, and biometric data allowing the study team to provide real-time personalized feedback. Our central hypothesis is Step Up will lead to improvements in physical disability (primary outcome), as well as secondary outcomes of symptom severity, physical activity, and digital biomarkers reflective of symptom burden following HCT. A RCT (N=177) will be used to pursue three specific aims: 1) Test the efficacy of Step Up for improving physical disability, as well as symptom severity, physical activity, and self-efficacy for symptom management compared to UC+; 2) Examine the relationship between symptoms and activity; and 3) Test the efficacy of Step Up for improving digital biomarkers reflective of symptom burden (heart rate, activity, sleep time) measured via Fitbits. The proposed work is innovative and impactful for HCT patients as it addresses interfering symptoms, integrates evidence- based coping skills training with OT sessions to increase activity while decreasing symptoms that interfere with activity, and uses mHealth technology for personalized real-time feedback to patients. Positive results would provide the first demonstration of efficacy of a hybrid-delivered cognitive behavioral coping skills training and activity coaching intervention that reduces physical disability by concurrently and synergistically decreasing symptom burden and increasing activity. The proposed research has the potential to produce significant public health benefit by redesigning existing modes of behavioral intervention delivery, improving continuity and coordination of care, and ultimately enhancing patient outcomes.

NIH Research Projects · FY 2024 · 2024-09

Late language emergence (late talking), affects one in five children in the United States today. Therefore, a question pediatricians often face at the 24-month well child visit is which late talking children will require specific assessment and early intervention services to improve their language abilities and long-term outcomes. To connect the right child with the right early intervention there is an urgent need to identify specific developmental trajectories associated with late talking. To date, late talking research has mostly relied on data from relatively small cohort and intervention studies, and included participants who may not be representative of broader pediatric populations growing up in America today. The use of real world data from electronic health records (EHR) offer a unique opportunity to address these gaps by studying large, representative cohorts of children, over longer periods of time to better understand distinct late talking developmental trajectories. While EHR data has been used to study neurodevelopmental and neurological conditions associated with late language emergence, only two EHR studies have specifically focused on late talking. These studies have relied on ICD diagnostic codes to identify the late talking phenotype in EHR records, an approach with inherent weaknesses. Disparities related to child sex, race, ethnicity, primary home language, and insurance status may result in delayed capture of ICD diagnostic codes in the medical record. Furthermore, delays may occur between when parents’ first share concerns with a professional about their child’s development and documentation via an ICD diagnosis of developmental conditions, including late talking. This study aims to improve how EHR data are used to study late talking by employing novel machine learning approaches (natural language processing) to identify late talkers within EHR databases, create open and shared data resources to identify late talking children within EHR, and leverage inherent advantages of EHR data to delineate late talking developmental trajectories. Our experienced research team of psychiatrists, language experts, pediatricians, informaticists, and data scientists are well positioned to achieve our study aims. Our long-term goal is to delineate distant trajectories associated with late talking, thus enabling a personalized intervention approach to improve child outcomes. In follow-up work, we will seek to develop a multi-site consortia to study and intervene with late talkers in real world environments. This will ultimately improve clinical decision-making and referral practices for late talking children.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY This proposal presents a three-year research career development program focused on elucidating the molecular mechanisms and clinical significance of a pathologic macrophage population (Spp1+ macrophages) in peripheral arterial disease (PAD). The candidate is a currently an Assistant Professor of Surgery in the Division of Vascular & Endovascular Surgery at Duke University. He has clinical expertise in PAD and research experience in skeletal muscle biology (CTSA KL2). He has now chosen to focus on the role immune system, particularly macrophages, play in orchestrating skeletal muscle repair in PAD. Hence, he has sought additional training. The proposed experiments and didactic work will provide the candidate with a unique skillset that will enable him to transition to independence as a surgeon-scientist. Novel therapies for limb loss remain an unmet need. The long-term goal of my research program is to elucidate the molecular mechanisms of skeletal muscle regeneration in PAD and develop cellular therapies for limb preservation. Preliminary work in my lab has identified Spp1+ macrophages (Spp1+MΦ) as a pro-inflammatory macrophage population that is associated with failed muscle regeneration in PAD patients. The overall objectives of this proposal are to determine the mechanisms and clinical significance of Spp1+MΦ in PAD. The central hypothesis is that Spp1+MΦ inhibit muscle regeneration by inhibiting muscle stem cell (MuSC) and macrophage reparative programs. The rationale for this project is that determining the processes that regulate macrophage- mediated tissue repair and establishing a link between macrophage phenotype and clinical outcomes will provide a strong foundation for the development of immune-based therapies for PAD. The hypothesis will be tested by pursuing three specific aims: 1) Determine if Spp1+MΦ inhibit MuSC regeneration in the ischemic limb; 2) Determine if Spp1+MΦ inhibit macrophage polarization to a regenerative phenotype in the ischemic limb; and 3) Determine if Spp1+MΦ are positively correlated with myopathy, limb loss and mortality in human PAD patients. In Aims 1 and 2, we will perform hind limb ischemia on mice with conditional overexpression or ablation of Spp1 in myeloid cells. We will assess muscle regeneration and macrophage polarization via histologic, immunofluorescence (IF), and transcriptional analysis. In Aim 3, we will leverage our large institutional PAD tissue repository and use spatial transcriptomics and IF analysis to link Spp1+MΦ with dystrophic muscle and adverse clinical outcomes, such as major amputation and mortality. The research proposed in this application is innovative because it represents a dramatic paradigm shift in the scientific approach to PAD. This proposal places the investigative spotlight on the interplay between the immune system and skeletal muscle repair in PAD. The proposed research is significant because it is expected to provide a strong scientific justification for the continued investigation of muscle specific approaches, particularly immune-based strategies, for limb preservation in PAD patients.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract The olfactory epithelium is the peripheral organ for smell, housing millions of primary olfactory sensory neurons. Insults such as inflammation, infection, toxins or trauma can damage the olfactory epithelium and perturb olfactory function, causing lasting anosmia, hyposmia or parosmia. We lack both a basic understanding of what goes wrong when people lose their sense of smell, and effective therapies for sensorineural olfactory disorders, as highlighted by our current inability to treat post-COVID olfactory dysfunction impacting millions of people. Thus, there is an urgent unmet need to define mechanisms driving olfactory neuronal homeostasis and dysfunction in humans. In rodents, each olfactory neuron harbors a unique transcriptome based upon the singular olfactory receptor it expresses, organized into coherent gene expression programs. Fixed gene expression programs specify each neuron’s identity, and flexible programs are dynamically adjusted based upon odor exposure. These findings have enabled genome-wide characterization of odor responses in vivo in mice, across the entire olfactory neuron population. However, humans express far fewer olfactory receptors than mice, and neither their specific receptive odor repertoire nor their dynamic in vivo transcriptional variation have been well-defined. Unlike in rodents, we know little about how gene expression is organized in human olfactory neurons, how populations of human olfactory neurons respond to defined odors, or how odor-evoked olfactory neuron activity is altered in the setting of disease. The experiments proposed here will identify organized patterns of gene expression in olfactory neurons isolated from human biopsies, in both controls and in subjects with objective smell loss, via two specific aims: Specific Aim 1 will establish the axes of transcriptional variation in human OSNs; Specific Aim 2 will assess responses to odor at the single cell level in the human olfactory epithelium. Olfactory mucosal biopsies from normosmic or hyposmic subjects will be analyzed using single cell RNA-sequencing. Presenting a specific odorant to subjects prior to biopsy and sequencing, an approach termed Act-seq will be employed to query the responses of the entire olfactory neuron array to a given odor in vivo. Act-seq will be compared from normosmic or post-Covid hyposmic olfactory samples. Completion of the proposed work will (1) directly define human odor-induced alterations in olfactory cells in normal or diseased conditions, (2) provide the first in vivo human olfactory receptor de- orphanization, and (3) produce novel datasets that will be broadly useful to the neurobiology and chemosensory research communities. These results, defining mechanisms driving olfactory neuronal homeostasis and dysfunction in humans, will form a basis for future clinical research trials aimed at promoting recovery of olfaction.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Half of adolescents with pediatric systemic lupus erythematosus (pSLE) do not take medications regularly as prescribed. Non-adherence increases the risk of uncontrolled disease and poor health outcomes. Non- adherence to hydroxychloroquine (HCQ), a highly effective medication recommended for nearly all patients with pSLE, is especially difficult to identify due to the poor predictive performance of available measures. To identify and ultimately reduce HCQ non-adherence in pSLE, I propose to: 1) use pharmacokinetic model simulations to define an HCQ concentration cutoff as an objective measure of non-adherence; 2) develop a novel, patient-facing digital intervention that delivers personalized feedback on HCQ concentrations to promote taking HCQ as prescribed; and 3) test feasibility and preliminary efficacy of the intervention in 25 adolescents with pSLE. Results will provide a non-adherence cutoff that will be immediately useful to identify non- adherence in clinical care. Results will also generate preliminary data to plan a larger efficacy trial designed to reduce non-adherence. The Mentored Career Development Award will provide the dedicated time, structured training, and mentorship required to advance my existing clinical pharmacology, analytic, and trial skills and develop new skills in digital interventions. My overarching career goal is to optimize therapeutics to improve health outcomes in pSLE and other pediatric rheumatic diseases using patient-centric methods. By completing the proposed research and training plans within the world-class research environment at Duke, I will acquire the skills and experience necessary to apply for independent funding and launch an academic research career dedicated to optimizing treatment and improving health outcomes in pediatric rheumatic diseases.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY Cells rely on precise sensing and prompt responses to mechanical and osmotic changes to maintain functionality and survival. Recent breakthroughs, including the identification of mechanosensitive and osmo-sensitive ion channels, have revolutionized our understanding of cellular responses to these stimuli. Despite this, the pathophysiological mechanisms of these processes in disease remain elusive. In this application, we aim to address this knowledge gap by creating a mouse model with a human gain-of-function V44M mutation of TMEM63B, a newly discovered mechano- and osmo-sensing ion channel. The V44M TMEM63B channelopathy is associated with a diverse range of human symptoms, including epilepsy, intellectual disabilities, and distinctive blood cell disorders. Our preliminary studies revealed an unexpected trait of the V44M mutation. This channelopathy mutation not only alter the ion channel activity of TMEM63B but also bestows a novel function that has been lost in TMEM63 proteins during evolution. Specifically, the V44M mutation enables lipid scrambling - the bidirectional translocation of lipids across cell membranes. This function is reminiscent of the capabilities seen in TMEM63B's evolutionary cousins, the TMEM16 lipid scramblases. To explore the in vivo implications of this mutation in human diseases, we propose creating a TMEM63B-V44M knockin mouse with controlled cell-type specific expression. This model will allow specifically dissect the mutated ion channel's role and its newfound lipid transport property across various cell types and disease contexts. Post-validation with our robust functional assays in this application, this mouse line will be made available to researchers across diverse disciplines including hematology, neurobiology, and more. This pioneering TMEM63B channelopathy mouse model will be invaluable to uncover the unknown pathophysiology of this mysterious mechano- and osmo-sensing ion channels in health and disease and shine light on therapeutics to treat TMEM63B related diseases.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The overall goal of this research is to determine how lipid metabolism supports oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) stem cells. Leukemia stem cells (LSC) are responsible for relapse in AML, and a major goal in the field is identifying novel ways to eradicate AML-LSC. Recently, lipids have been identified as essential metabolic substrates for AML-LSC; however, the mechanisms linking lipids and OXPHOS are not known. To address this, I have determined relapse-specific candidate genes using RNA-Sequencing data from a cohort of pediatric AML patients characterized through the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) study. The results suggest that fatty acid oxidation (FAO) is repurposed to drive heme biosynthesis and fuel OXPHOS in AML relapse. In this K38 StAARTS application, I will test this hypothesis by studying lipid metabolism and OXPHOS in vitro with AML cell lines and in vivo using pediatric patient-derived xenografts. Aim 1 will use stable isotope metabolite tracing experiments to determine if palmitate is a key carbon source for heme in AML cells with LSC properties. Then, Aim 2 will test the effects of a high-fat diet on the growth and aggressiveness of pediatric AML-LSC xenografts obtained through St. Jude’s Public Resource Of Patient- derived and Expanded Leukemias (PROPEL) program. AML-LSC from Aim 2 will also be tested for the effects of a high-fat diet on OXPHOS activity and heme-containing protein content using comprehensive proteomic profiling through the Duke Molecular Physiology Institute’s Metabolomics and Proteomics Core. The results from these studies will provide a mechanistic link between lipid metabolism and OXPHOS in AML-LSC and have the potential to identify new therapeutic targets. My Mentor team, Institutional Environment and Career Development Plan, together with my clinical Hematology-Oncology fellowship, will provide a superb training experience that will ensure the success of this research and prepare me for a future transition to independence as a Pediatric Hematology-Oncology physician scientist.

NSF Awards · FY 2024 · 2024-09

The 6th Geoscience Alliance (GA-6) conference builds on a successful series of national conferences aiming to broaden the participation of Native Americans in geoscience and environmental sciences. The first five Geoscience Alliance conferences brought together a total of more than 500 graduate, undergraduate, and K-12 students, educators, Elders, community members, and professionals representing 40 Tribes, Bands, and Native Villages. The GA-6 conference will take place in North Carolina and is expected to increase participation from the Southeast and Mid-Atlantic, regions that have been underrepresented at prior Geoscience Alliance conferences. The conference theme, Geoscience and Environmental Justice in Indigenous Communities, considers the distributions of environmental benefits and burdens along with the environmental policies, practices, and power dynamics that influence these distributions. Noting that Indigenous communities regularly shoulder disproportionately large environmental burdens from pollution, resource extraction, and climate change, conference participants will learn about, share, and discuss some of the ways that Indigenous and western knowledges can be used to address these problems and promote environmental justice. By increasing the involvement of Native American communities underrepresented in geoscience and environmental science, the conference will help enhance human capacity in these fields at a national level. Despite growing recognition that Indigenous knowledge systems have much to offer the geoscience and environmental sciences, Indigenous peoples themselves are among the most underrepresented groups in careers and degree programs in these fields. This underrepresentation has implications for scientific research, science education, management, and other areas. The 6th Geoscience Alliance (GA-6) conference will help address this issue by building on a successful series of national conferences aimed at broadening the participation of Native Americans in geoscience and environmental sciences. The conference theme engages with Indigenous environmental justice, an area of academic research and a social movement that is both relevant to public policy and linked to scientific issues related to air and water quality, natural resource management, and climate change. In particular, the GA-6 conference will elevate Indigenous perspectives in environmental justice research, education, and engagement to spur ideas, dialog, and collaboration among participants and their networks. The three-day conference will include activities proven successful in previous Geoscience Alliance conferences: discussion circles, workshops, poster sessions, and field trips. The main objectives of the GA-6 conference are learning; networking and career progress; understanding; making it memorable; and growing the community. The conference will fulfill each of these objectives under the established and effective Geoscience Alliance principle that everyone teaches and everyone learns. The GA-6 conference will also serve to disseminate information to participants about opportunities such as Research Experience for Undergraduate programs, internships, and academic degree programs. A focus on networking at the conference will support all participants in developing a strong network of peers and collaborators. 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.

NIH Research Projects · FY 2025 · 2024-09

Project Summary - Clostridioides difficile is a leading cause of infectious diarrhea and the most common cause of healthcare-associated infection (HAIs) in the US, resulting in >450,000 infections and 29,000 deaths annually. In fact, C. difficile was recently labeled as one of five “urgent threat” organisms by the CDC. Despite its prevalence, C. difficile acquisition and transmission remain poorly understood. Recent changes in testing strategies led to the surprising discovery that patients with C. difficile are more often colonized than infected. Hospitals routinely place patients infected with C. difficile on “contact precautions” to prevent transmission. However, this shifting epidemiology has led to an infection prevention dilemma: should patients with C. difficile colonization be placed on contact precautions? The answer to this question is unknown. Recently published infection prevention guidelines labeled this issue as “unresolved”. As a result, non-standardized practices are being used. In our cohort of hospitals, 50% of hospitals place these patients on contact precautions and 50% do not, suggesting that a substantial number of admitted patients are at potential risk of harm through either a) unnecessary use of contact precautions OR b) through preventable exposure to C. difficile. The overall objective of this proposal is to determine if contact precautions should be used in patients with C. difficile colonization. First, we will determine the frequency, location, and amount of environmental C. difficile contamination among 300 patients with C. difficile colonization (150 with diarrhea and 150 without diarrhea) compared to 150 patients with C. difficile infection (Specific Aim 1). Using these same rooms, we will then determine the frequency, location, and amount of C. difficile contamination of 900 healthcare providers' (HCP) hands, HCP clothes, and 450 pieces of mobile, shared equipment following routine inpatient care of patients with C. difficile colonization (Specific Aim 2). Finally, we will use ~1,500 C. difficile isolates from our unique C. difficile biorepository and study activities in SA 1 and 2 to evaluate potential sources for C. difficile in-hospital transmission using molecular epidemiology and whole genome sequencing (Specific Aim 3). This proposal will capitalize on the strengths of the Duke Center for Antimicrobial Stewardship and Infection Prevention, including our collective expertise in infection prevention and environmental contamination, our proven infrastructure for studies involving environmental sampling, and our validated microbiological, statistical, and molecular epidemiological methods. Our central hypothesis is that patients with C. difficile colonization contaminate their environment (surfaces, HCP, and equipment) as frequently as patients with C. difficile infection and, as a result, are a source of in hospital transmission. The proposed research is innovative because it represents a substantive departure from the status quo of infection prevention and will use innovative methods to evaluate a critical infection prevention dilemma. This proposal will be significant because it will provide critical information about the role of colonization in C. difficile transmission and whether contact precautions should be used for this patient group.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY This Exploratory/Developmental Research Grant proposal seeks to advance the state of the art in diagnostic ophthalmic imaging with a novel, robotically-aligned optical coherence tomography (OCT) system capable of automatically measuring a retinal biomarker that cannot currently be identified with standard of care OCT devices. Prevention of irreversible vision loss in leading retinal diseases such as diabetic retinopathy (DR) depends on identification of disease changes. While DR has historically been researched and treated as a microvascular complication of diabetes, much less is understood regarding the changes in neurons and photoreceptors in DR. Prior studies in animal models with induced diabetes have demonstrated atrophy in the outer nuclear layer (ONL), which primarily consists of photoreceptor cell bodies. However, the lack of sufficient data in humans means there is still not a widely accepted understanding of the role of photoreceptor loss in DR. OCT is a low coherence interferometric technique that has found widespread adoption in ophthalmology for providing high-resolution, volumetric imaging of the retina. Quantifying changes in the ONL with OCT offers a non-invasive method to follow and understand the course of the photoreceptor degeneration in DR described above. However, conventional OCT systems are not able to discriminate the ONL from Henle’s Fiber Layer (HFL). In order to visualize HFL and therefore isolate the ONL, the pupil entry position of the OCT sample beam must be offset for each individual cross-sectional B-scan. To perform this process volumetrically would require manual adjustment and a great deal of operator time and input. Our research group has pioneered the invention of a robotically-aligned OCT (RAOCT) system capable of imaging both the anterior and posterior eye with active tracking to compensate for subject motion. Our RAOCT system exhibits precise lateral, axial, and angular control of the sample beam and can perform autonomous imaging of freestanding individuals. In the proposed project, we will leverage the micrometer-scale control of the pupil entry position with RAOCT to develop a method for automatically acquiring retinal volumes that provide complete visualization of HFL and the ONL, without the need for operator input. The expected outcome of this proposal is a set of technologies that will provide automated measurements of a retinal biomarker that is otherwise unable to be measured with conventional methods. We expect that our proposed RAOCT system will consistently provide reproducible ONL thickness measurements when accounting for the obscured presence of HFL. We will also demonstrate our device in the clinic in patients with and without diabetic retinopathy. We believe that our results will contribute to our understanding of photoreceptor changes in DR and pave the way for future studies that investigate using ONL thickness measurements to monitor the progression of leading retinal diseases.

NIH Research Projects · FY 2025 · 2024-09

This K22 proposal aims to enhance the applicant’s prior quantitative training through a combination of formal coursework and informal mentorship, supporting their transition to independence as a molecular cancer epidemiologist investigating biological mechanisms underlying disparities in female cancers. Ovarian cancer (OC), the deadliest gynecological malignancy, exhibits marked differences in outcomes that are not fully explained by clinical or socioeconomic factors. Chronic stress—an embodiment of adverse social conditions—has emerged as a potential contributor to these disparities through its influence on biological systems, including the vaginal microbiome. The vaginal microbiome can shape the tumor microenvironment via production of pro-carcinogenic metabolites and reduction of antineoplastic metabolites. Its composition and function are influenced by host factors and social determinants, including chronic stress exposure. Despite growing evidence linking microbiome-related inflammation to cancer progression, no studies have evaluated how chronic stress may alter vaginal fluid metabolite profiles and metabolic signatures in OC patients, nor how these changes may relate to disease aggressiveness and recurrence. Guided by ecosocial theory, which posits that adverse living and working conditions are literally biologically incorporated leaving bodily marks, this study will apply an untargeted metabolomics approach to analyze cervicovaginal fluid from 120 OC patients, with detailed assessment of chronic stress exposure at both individual and neighborhood levels. The specific aims are to: i). Characterize vaginal fluid metabolite profiles and metabolic signatures among OC patients, ii). Assess differences by chronic stress in vaginal fluid metabolite profiles and metabolic signatures among OC patients, and iii). Evaluate the relative importance of vaginal fluid metabolites and chronic stress on OC aggressiveness and recurrence. Completion of the proposed K22 will advance scientific understanding of how chronic stress and vaginal microbiome-derived metabolites contribute to OC progression. This knowledge may inform the development of prognostic biomarkers and therapeutic strategies targeting microbiome-mediated pathways. Clinically, the study may support the integration of vaginal metabolite profiling into personalized care approaches for OC patients. The proposed training and research will equip the applicant with the skills and resources necessary to establish an independent research program in molecular cancer epidemiology.

NIH Research Projects · FY 2025 · 2024-09

Abstract: Intratelencephalic (IT) excitatory cortical neurons project only within telencephalic structures – the cortex and striatum – and make only callosal, corticostriatal, and intrahemispheric connections. They exhibited massive amplification and diversification during mammalian cortical evolution and are therefore thought to underlie the unique capabilities of human cognition. Despite their importance, little is currently known about distinct IT subtypes and their contributions to cortical organization, function, and dysfunction in disease. Upper layer and deep layer IT neurons diverge in their axonal trajectories: upper layer IT neurons make predominantly callosal cortico-cortical, intrahemispheric, and ipsilateral corticostriatal connections, whereas deep IT neurons project fewer callosal axons and instead project more heavily to bilateral striatum. Upper layer IT neurons demonstrate high differential gene expression in autism, a syndrome with predominant cognitive symptoms, while IT neurons with corticostriatal connections are hypothesized to contribute to motor disorders. Thus, dissecting IT subtypes is essential to understanding their unique contributions to neurological disease. One such disease that presents with varying cognitive and motor impairment is perinatal hypoxic ischemic encephalopathy (HIE), the most common brain injury in term neonates. HIE often injures the cortex and striatum, prime targets of IT neurons. Sequelae include cognitive or motor symptoms, suggesting that HIE may differentially disrupt cortico-cortical and corticostriatal circuits mediated by distinct IT subtypes. My preliminary transcriptomic data suggest that deep IT neurons demonstrate a greater burden of differential gene expression after HIE than upper IT neurons, particularly in gene pathways that regulate axon development. In this proposal, I utilize two novel knock-in mouse lines, Wfs1-Flp and Deptor-CreER, that label superficial and deep IT subsets, respectively. In Aim 1, I will perform anterograde and retrograde axonal tracing to fully characterize the cortico-cortical and corticostriatal axonal projections from primary motor cortex in each mouse line. In Aim 2, I will perform the Vannucci model of HIE in Wfs1-Flp and Deptor-CreER mice to assess changes in cortico-cortical and corticostriatal axonal projections from upper and deep layer IT neurons after HIE. Finally, in Aim 3, to assess cell-specific changes in gene expression after HIE with high spatial precision, I will utilize the cutting-edge spatial transcriptomics platform MERFISH in mouse cortex after HIE compared to control cortex. I will amplify the power of this approach by integrating MERFISH data with my existing single nucleus RNA sequencing data from mouse cortex after HIE, providing an innovative informatics pipeline that combines the high detection power of single nucleus transcriptomics with the laminar precision of spatial transcriptomics. Through this work, I will disentangle the cell-specific responses of IT subtypes to HIE, laying the groundwork to understand how disruptions in IT microcircuitry differentially contribute to cognitive versus motor symptoms and uncovering candidate targets for future pursuit as cell-targeted therapies to ameliorate IT dysfunction after HIE.

NSF Awards · FY 2024 · 2024-09

Lightning on its own is spectacular, dangerous, and costly. Despite its importance, basic questions about how it initiates in clouds, how it expands, how it makes contact with objects, and what conditions are most likely to lead to dangerous lightning remain at best only partly answered. This project will develop a comprehensive observing system using radio and optical wavelengths to measure and image lightning flash development in fundamentally new ways with high resolution in both time and space. The uniquely comprehensive capabilities of the instrument will enable it to answer open questions about lightning itself, to address key questions about the links between lightning and atmospheric science more broadly, and to improve the ability to predict and mitigate its impact. The instrument is also designed to be available to a broad user base and for the data to be shared as widely as possible to help train the next generation of scientists in the field. This project will design and deliver a uniquely capable multi-modality radio and optical lightning imager to be used by the broader atmospheric physics and electricity community to probe many facets of the structure and physics of lightning that are inaccessible to existing instrumentation. The guiding principle behind the concept that the measurement capabilities needed to address the most important questions in lightning and lightning-atmosphere coupling are not yet available because existing instruments generally lack the ability to combine high quality radio imaging with quantitative measurements of the internal physics of different lightning processes. The instrument is composed of 4 subsystems that operate together: a reconfigurable multiband VHF-UHF lightning imaging radio interferometer; a 6-band optical photometer; an ultra- broadband (150 MHz–5 GHz) single channel antenna; and a multi-field low frequency (100 Hz–20 MHz) electric and magnetic field sensor. The individual subsystems are highly capable on their own, but when integrated they create an instrument capable of fundamentally new measurements that will impact areas that span from the internal physics of lightning to the impact of lightning on large scale atmospheric chemistry and climate change. 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 Awards · FY 2024 · 2024-09

This award funds research in macroeconomics and bounded rationality. The team starts with the observation that in the formalization of representativeness (Kahneman and Tversky, 1972) developed by Gennaioli and Shleifer (2010), overreaction and confidence are affected by uncertainty, as a news effect interacts with an uncertainty effect. In the time series domain, this interaction emerges in a smooth version of Diagnostic Expectations (DE). Under Smooth Diagnostic Expectations (Smooth DE), agents overreact to new information. Since new information typically changes not just the conditional mean, but also the conditional uncertainty, changes in uncertainty surrounding current and past beliefs affect the severity of the DE distortion and confidence. As a result, Smooth DE ends up connecting two vastly popular branches of Economics that have largely proceeded in parallel: the Diagnostic Expectations literature and the Uncertainty literature (Bloom, 2014). The research consists of three projects. In the first project, the team highlights the inherent link between representativeness and uncertainty and introduces Smooth DE as the natural time series formalization of such a link. Under Smooth DE, agents over-react to new information as captured by the change in the current distribution of future events with respect to a reference distribution. Changes in uncertainty surrounding current and past beliefs affect the extent of the DE distortion. Smooth DE implies a joint and parsimonious micro-foundation for key properties of survey data: (1) overreaction of conditional mean to news, (2) stronger overreaction for weaker signals and longer forecast horizons, and (3) overconfidence in subjective uncertainty. In the second project, the team studies quantitative business cycle models that leverage insights from the Smooth DE framework, as well as from the team’s previous work on DE, imperfect information, and non-linear solution methods. The goal is to provide a rigorous and parsimonious account of business cycle properties that emerges from a smooth DE model with signal extraction. An analytical RBC model featuring Smooth DE accounts for overreaction and overconfidence in surveys, as well as three salient properties of the business cycle: (1) asymmetry, (2) countercyclical micro volatility, and (3) countercyclical macro volatility. A negative shock that raises perceived uncertainty increases the over-reaction to both idiosyncratic and aggregate shocks, and deepens the contraction. This rich and novel propagation arises because the intensity of the DE distortion is state-dependent. In the third project, the team focuses on actionable implications. Under smooth DE, the severity of the DE distortion varies in response to the level of uncertainty faced by agents. The team uncovers a novel role for decision makers: by reducing uncertainty, decision makers can now reduce the severity of the DE distortion and thus stabilize agents’ psychological biases. Thus, a redistributive rules that reduce cross-sectional uncertainty could also be beneficial for macroeconomic stabilization. The team studies the novel welfare implications of this belief stabilization 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.

NIH Research Projects · FY 2025 · 2024-09

Sensory receptor ion channels in somatosensory neurons are responsible for the sensory detection of stimuli such as temperature changes and irritants. This information is then transmitted to the spinal cord and brain, eliciting somatosensory perception, including nociception. Integration of sensory information occurs at higher levels (e.g., spinal cord and/or brain), as well as at the sensory receptor level where certain polymodal sensory receptors can sense diverse sensory signals and integrate them into common signaling pathways. Our current research seeks a molecular-level understanding of the design principles governing somatosensation and nociception by membrane sensory receptor channels, as well as their broader contextualization. We also aim to study disease mutations and develop small molecules targeting these sensory receptors/channels through a combination of structural, functional, pharmacological, computational biology, chemical biology, and cellular studies. These studies strive to answer important questions in neurobiology: What is the molecular basis of somatosensation by sensory receptor channels and can we develop a general model of their activity? How do mutations in these sensory receptors give rise to neuronal disorders? And, can we develop non-opioid drugs that target these receptors to treat conditions ranging from chronic itch to migraine?

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Central Nervous System (CNS) polypharmacy is a cumulative exposure to 3 or more medications with CNS-acting properties. CNS medications include anticholinergics, antidepressants, antipsychotics, benzodiazepines, gabapentinoids, hypnotics, opioids, and muscle relaxants. A growing number of older Americans are prescribed multiple CNS-acting medications and are affected by CNS polypharmacy, which is rapidly becoming a wide-spread geriatric syndrome. CNS polypharmacy leads to adverse outcomes such as physical and cognitive impairment and medication-related falls, serious injuries, hospitalization, diminished quality of life, and even death. Deprescribing, the systematic process of tapering or stopping medications, offers potential to reduce the burden of CNS medications. However, deprescribing may also result in the exacerbation of underlying symptoms for which CNS medications were originally prescribed. Existing guidelines, such as Beers or STOPP, do not take into consideration the complex interplay of multiple medications and individual patient’s unique clinical characteristics, which are necessary for individualized, patient-centered care. Essential are individualized deprescribing solutions that account for these complexities. This project will identify varying benefits and harms of deprescribing across individuals and medications classes. We will then subsequently develop individualized treatment rules (ITRs) for personalized medication discontinuation recommendations based on patients’ unique clinical characteristics to support clinical practice. First, using causal inference methods, we will analyze PCORNet multi-site electronic health record (EHR) data with linked Medicare claims data to quantify the probability of medication discontinuation based on patients’ observed clinical characteristics. Then we will employ supervised and unsupervised machine learning (ML) methods, such as decision trees and clustering techniques, to accurately predict patient outcomes after medication class discontinuation based on that patient’s unique clinical characteristics. Our team will leverage prior experience in causal inference and machine learning applied to EHR data to estimate deprescribing's clinical benefits and harms. We'll ultimately integrate these results into a user-friendly clinical interface, ensuring trustworthy ML and transparent model decision-making processes. As an initial step, we'll engage clinicians, patients, and community partners early in the design phase to assess understanding and trust in ML-based deprescribing guidance. This will prepare us for a future large-scale clinical trial to test the efficacy in achieving deprescribing goals.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT The notochord is a conserved axial structure in all chordates that provides crucial structural support for the embryonic axis and, in vertebrates, the vertebral column or spine. Despite its significant role during development, the mechanical properties of the vertebrate notochord remain poorly understood. Unlike basal chordates, in which the notochord is a continuous pressurized tube, in vertebrates, the notochord's interior is made of large vacuolated cells. Each vacuolated cell contains one fluid-filled vacuole that occupies most of the cell volume. Vacuolated cells have been proposed to facilitate symmetrical vertebrae formation by absorbing the force of constricting vertebral bone growth on the notochord. Previous work showed that localized vacuolated cell defects lead to spine deformities at the location of the compromised cells, suggesting that the notochord can respond locally. Using acute mechanical stresses and genetic manipulations, I will investigate the structure's response to perturbations and the specific role of the vacuoles in this response. This research is complemented with a training plan that indlcudes didactic biology training and rigorous professional development within an interdisciplinary environment to enhance the breadth of knowledge and expertise of the trainee.

NIH Research Projects · FY 2025 · 2024-09

The adverse effects of poor treatment in healthcare settings on cardiovascular health are poorly understood, particularly among aging adults. Traditionally, poor treatment has been investigated as an exposure variable that is not attributed to a single or actionable location. Within a healthcare system, healthcare researchers have the opportunity to directly implement evidence-based interventions to mitigate harmful practices. Studies have shown that patient-provider interactions can lead to patient’s foregoing preventative care early in the life course, a consequential choice that can lead to adverse health outcomes. Identifying the adverse impacts of patient-provider interactions is important for improving patient-physician interactions. The predoctoral phase (F99/Aim 1) will employ longitudinal data from the Health and Retirement Study (HRS) to investigate the impact of poor treatment in a healthcare setting on the incidence of stroke and myocardial infarction in adults aged 50 and older. My hypothesis is that middle-aged individuals who experience poor treatment in healthcare are more likely to have negative cardiovascular outcomes at older ages. To evaluate this hypothesis, this phase will use rigorous epidemiological methods to measure the relationship between patient-provider interactions and increased cardiovascular risk. We aim to understand how such patientprovider interactions can worsen cardiovascular health and potentially lead to related cognitive health dilemmas. My research then transitions into a postdoctoral phase further focusing on the complex relationships among patient-provider interactions, aging, and cognitive health. My postdoctoral research (K00/Aim 2) will estimate the longitudinal effects of poor treatment in a healthcare setting on the cognitive health of adults aged 50 and older and identify factors contributing worse health outcomes. The project builds on my ongoing research supported by a National Institute on Aging (NIA) Supplement award, establishing a foundational research trajectory for understanding the health impacts of patient-provider interactions in aging populations. Throughout both phases, my structured training and research will be interdisciplinary, employing rigorous epidemiological methods for causal inference and leveraging qualitative insights to contextualize the findings. I will gain valuable skills in longitudinal data analysis and multilevel modeling, equipping me to comprehensively address these complex health issues. My work aims to instigate improvements in healthcare by enhancing our understanding of patient-provider interactions and health outcomes. This research and training trajectory aligns with NIA's priorities and is crucial for my development as an independent researcher focusing on the intersection of aging and health improvement.

NIH Research Projects · FY 2025 · 2024-08

Summary Phosgene gas has been used as a terrorist weapon, in warfare and has injured many Americans in transportation or industrial accidents. Phosgene targets the lungs, causing severe edema and lung injury after inhalation, with high lethality in exposure victims. Despite these devastating effects, no mechanism-based treatment for phosgene injury has been developed. The renin-angiotensin-aldosterone system (RAAS) plays a key role in cardiopulmonary homeostasis. However, RAAS is dysregulated during acute respiratory distress syndrome (ARDS) contributing to underlying pathophysiology. Pro-resolving mediators that are generated during the inflammation cascade are short-lived due to degradation by an enzyme called soluble epoxide hydrolase (sEH). Several pulmonary studies showed that inhibition of sEH ameliorated the study outcomes. In our preliminary studies, we noted both dysregulation of RAAS and pro-resolving epoxides after phosgene inhalation. We found that administration of angiotensin- converting enzyme (ACE) inhibitors such as Captopril, Enalapril, or Lisinopril improved survival rate, decreased pulmonary protein leak, and diminished bronchoalveolar inflammatory cell counts. Similarly, when soluble epoxide hydrolase inhibitors (sEHIs) were administered to mice after phosgene inhalation, the survival rate significantly improved. Therefore, targeting RAAS and sEH seems to be highly promising. In this application, based on our strong preliminary data, we hypothesize that targeting the RAAS, including angiotensin- converting enzyme (ACE) and aldosterone, and stimulating resolution pathways by administration of soluble epoxide hydrolase inhibitors (sEHIs) post phosgene exposure ameliorates lung injury, leading to decreased morbidity and improved recovery. The following aims are proposed: Aim 1: Screen the efficacy of RAAS modulators and sEHIs in mouse models of phosgene gas-induced lung injury. Aim 2: Determine the pharmacokinetics of the lead drug candidate and test the efficacy in a 48-hour observation model of swine phosgene gas-induced lung injury. Aim 3: Determine therapeutic efficacy of the lead candidate in an extended 28-day observation swine model of phosgene-induced lung injury. Successful completion of the proposed work will provide pivotal information on the development of targeted treatment to protect against phosgene gas-induced lung injuries – a critical unmet need, and will prepare us for Biomedical Research Development Authority (BARDA)-enabling studies and eventual FDA approval under the animal rule.

NIH Research Projects · FY 2025 · 2024-08

Abstract Desmosomes are cell adhesion structures that provide mechanical stability to the epidermis and other tissues. Their canonical function is to link cells to the underlying intermediate filament network, and disruption of these linkages can lead to diverse pathologies including skin blistering and cardiomyopathies/dysplasias. For example, in autoimmune diseases collectively known as pemphigus, pathogenic antibodies targeting the desmosomes result in life-threatening blistering and loss of barrier function. We have identified a novel role for desmosomes in organizing the localization of mRNAs in the cell, as well as the localization of translational machinery and regulators. Further, perturbing desmosomes through wounding or through treatment with pathogenic pemphigus antibody disrupts the desmosome-dependent localization of translational regulators to the cell cortex. Based on these data, we propose that desmosomes are major regulators of mRNA and translational pathways. Additionally, we hypothesize that desmosomes are sensors of tissue integrity that alter translation in response to defective adhesion. Here we will determine the molecular mechanisms underlying cortical recruitment of mRNAs and translational regulators. Further, to define the functional relevance of translational control by desmosomes, we will determine the acute translational response upon desmosome disruption during both wounding and pemphigus. In addition, we will use single molecule live-imaging approaches to determine the sites of protein translation under both homeostatic conditions and when desmosomes are disrupted. This work will define novel mechanisms for cell adhesions in regulating post- transcriptional gene expression, which may have essential functions in sensing and responding to defects in epithelial integrity.

NSF Awards · FY 2024 · 2024-08

This project builds on observations in the Neuse Estuary (North Carolina) that have been collected previously and expands upon them through 3-d modeling with a widely used model called ROMS (short for Regional Ocean Modeling System). Unique features of the Neuse Estuary include a close to 90 degree bend and a micro-tidal environment, with wind forcing thus thought to be dominant over tides. Wind effects on estuaries are understudied because usually tides are more prevalent and cause most of the mixing. In this case, the proposed model experiments will investigate how wind forcing at different angles relative to the two connecting estuary legs as well as the duration and intervals of the wind events affect circulation and salinity distributions in a model set-up that resembles the Neuse Estuary. The results from this work will inform communities around the Neuse Estuary how to better interpret water quality time series, knowing more about the circulation features that affect residence and flushing times of the estuary. The results will also help enhance prediction and management of water quality in the Neuse Estuary. More specifically, the project will investigate how the circulation and salinity distribution in estuaries with curved sections respond to wind events using simulations on idealized and real estuary domains. Of primary interest is how interaction between estuary legs parallel and perpendicular to the wind, and lateral circulation and mixing in the connecting curved region, impact the strengths of horizontal and vertical salinity gradients and the distance that high salinity water extends upstream. Also of interest is how wind event duration and interval between wind events relative to timescales associated with wind mixing, wind-driven currents, and the baroclinic response, control the circulation and salinity distribution. To address these questions, simulations on idealized estuary domains using ROMS will be conducted. Three sets of simulations will be performed in which parameters are varied systematically: 1) constant wind at varying angles to a straight estuarine channel; 2) constant wind on an estuary with perpendicular legs connected by a curved region, varying wind speed, direction, freshwater inflow, and radius of curvature; and 3) finite length wind events, varying event duration and separation. Finally, simulations on a realistic Neuse Estuary domain will be conducted to examine how theory developed from idealized simulations can be applied to a real wind-dominated estuary. This work will advance understanding of wind effects on estuary dynamics by extending it to more general estuarine geometries that have bends and more realistic situations in which wind varies with time. 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.