University Of South Florida

NSF Awards · FY 2024 · 2024-10

Carbon-carbon (C-C) and carbon-nitrogen (C-N) cross-coupling reactions are important reactions used in the chemical and pharmaceutical industries to produce a variety of valuable products. These products include pharmaceuticals, polymers, and agrochemicals. The current methods used in the industry for cross-coupling reactions require high-temperature processes and expensive metal catalysts such as palladium (Pd). This project develops iron- and copper-based inexpensive photocatalysts for C-C and C-N cross-coupling reactions. These photocatalysts use visible light as energy input to drive cross-coupling reactions under atmospheric temperature and pressure reaction conditions. The development of iron- and copper-based photocatalysts will result in significant reductions in the overall cost, energy requirements, and greenhouse gas emissions from the cross-coupling processes. The project includes educational activities that build upon the proposed research to infuse photocatalysis and solar energy concepts into the chemical engineering curriculum at Oklahoma State University (OSU). The proposed curriculum will prepare the students for the 21st century`s challenges and directly benefit the undergraduate and graduate students at OSU. The C-C and C-N cross-coupling reactions have been conventionally carried out by homogeneous Pd complex-catalyzed batch processes. There remains a critical need to develop inexpensive heterogeneous nanocatalysts for these cross-coupling reactions since nanocatalysts are the ideal catalysts for the most desired continuous flow processes. This project will focus on the design of earth-abundant and inexpensive iron- and copper-based hybrid Mie-resonator nanoparticles as heterogeneous visible light photocatalysts for C-C and C-N cross-coupling reactions. Specifically, the project will develop the structure-property-performance relationships by examining the size/shape of hybrid Mie-resonator nanoparticles against their charge carriers generation rate, the electron-transfer efficiency, and the photocatalytic rate for the C-C and C-N cross-coupling reactions. To accomplish this research objective, the project will utilize a combination of experimental and theoretical tools, including nanoparticles geometry-controlled synthesis techniques, finite-difference time-domain optical simulations, in-situ spectroscopic techniques, and photoreactor studies. The project will also establish the conditions of photocatalytic stability for the iron- and copper-based hybrid Mie-resonator nanoparticles to operate under the cross-coupling reaction conditions. The photocatalytic stability of the hybrid Mie-resonator nanoparticles of different sizes and shapes (spheres and cubes) will be investigated as a function of light intensity. The stability and the possible phase transformation at high light intensity will be characterized using in-situ UV-Vis extinction spectroscopy. The outcomes of this specific research objective will identify the combination of optimal geometries and optimal light intensity that can maintain the photocatalytic stability of iron- and copper-based hybrid Mie-resonator nanoparticles for the C-C and C-N cross-coupling reactions. 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 · 2024-10

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). This Faculty Early Career Development Program (CAREER) grant supports research that will investigate theoretical and computational approaches to commit or defer problems with decision-making hierarchies. Problem settings in vaccine design, disaster response, and smuggling prevention, among others, involve decision-makers observing a system evolving over time who periodically decide whether to commit non-renewable resources, or defer their use, to optimize the system's overall performance. The evolution of the system is subject to randomness and its performance may depend on other decision makers, about whom there may be incomplete information, who seek to optimize their own performance. The research supported by this award seeks to determine what rules should guide commit or defer decisions in these settings, how and to what extent the decision-maker should use the information feedback observed, and how to computationally find the commit or defer decisions in specific problem settings. The educational activities include the creation of an online game to teach fundamentals of multistage decision-making to K-12 students. Standard commit or defer problems (CDPs) assume a single decision-maker and cannot model problems that involve multiple decision-makers, e.g., a Leader and a Follower, who interact in a hierarchical manner. This project will establish a mathematical and algorithmic framework to solve hierarchical CDPs. The framework will improve our understanding of real-life CDPs and their practical requirements. The project will simultaneously address a number of technical challenges. First, the Leader may face global resource constraints, such that the resources spent in one period, cannot be replenished in future periods; second, the Leader's performance depends on the optimal actions of the Follower; and third, the Leader learns about the uncertain parameters of the Follower's problem by observing their reaction to the Leader's actions. By using approaches at the interface of hierarchical and online optimization, the project will rigorously establish the manner by which commit or defer decisions should be made in hierarchical settings under uncertainty. Furthermore, the project will use tools from mathematical programming and probability to uncover how and to what extent the decision-maker should use the information that is learned, and then formulate and solve for optimal or near optimal policies in large instances of relevant applications. 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 · 2024-10

The United States (U.S.) transportation sector remains a cornerstone of the economy, contributing over 8% to the country's Gross Domestic Product (GDP). Electrification efforts are transforming this sector, aiming to enhance mobility efficiency, reduce operating and maintenance costs, and cut greenhouse gas emissions. These efforts also seek to boost energy independence and security while significantly contributing to employment, particularly in technology and innovation fields. This shift has already placed more than 2.5 million Electric Vehicles (EVs) on U.S. roads, supported by over 70 thousand charging stations nationwide. To manage this advanced and complex cyberinfrastructure (CI), EV operators and vendors rely on cloud-based EV Management Stations (EVMS), crucial for provisioning services such as charging, billing, and authentication. However, the critical nature of EVMS has made them targets for malicious attacks, often state-sponsored, exploiting rarely investigated vulnerabilities. In response, this project establishes a collaborative ecosystem among academia, industry, and the public sector to bolster the resilience of the EV CI. It aims to develop proactive methodologies to identify and analyze Internet-connected EVMS and their software, thoroughly exploring and mitigating related vulnerabilities. This initiative connects several diverse Minority Serving Institutions (MSIs) within the established ecosystem, fostering joint research and providing enriching training opportunities. Through workshops, capstones, curricula material, virtual hands-on labs, professional development, and mentorship programs, the project enhances cross-disciplinary capacities at MSIs and beyond, driving forward the future of resilient, electrified transportation. In this context, this project serves NSF's mission in promoting the progress of science and securing national defense related to this ever-evolving CI. The project pioneers advanced fingerprinting techniques employing automated web scraping, recursive unsupervised learning algorithms, and pattern matching methodologies to identify and cluster Internet-scale EVMS. The primary objective is to detect deployed configurations and their interconnections, while retrieving critical artifacts, such as firmware binaries and compiled software, for comprehensive vulnerability analysis and disclosure. Leveraging robust industry connections, the project acquires auxiliary artifacts, including EVMS source code, through advanced supply chain reconnaissance and reverse engineering methods. This initiative also devises and implements an advanced digital forensic methodology rooted in ensemble techniques and machine learning classifiers. It integrates static analysis, file system forensics, memory forensics using volatility frameworks, data carving with custom heuristics, offensive security tactics, behavioral analysis through dynamic instrumentation, and virtualization methodologies such as hypervisor introspection to meticulously analyze the security posture of EVMS firmware and web endpoints. Furthermore, the project exploits state-of-the-art innovations in Large Language Models (LLMs) to automatically identify vulnerabilities in EVMS source code and suggest tailored and sound code fixes. This is accomplished by creating an unprecedented instruction-based training dataset using supervised fine-tuning, reinforcement learning, and transfer learning techniques. Additionally, the project establishes a large-scale data and threat repository to index discovered threat models, associated vulnerabilities, and retrieved EVMS artifacts. Accessible via RESTful APIs and web-based interfaces, this repository democratizes knowledge by making the harvested EVMS assets available at large, significantly empowering EVMS-centric threat situational awareness while fostering advanced research and development. 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 · 2024-10

This project aims to serve the national interest by better understanding how college instructors teach the topic of reaction mechanisms in organic chemistry courses. Reaction mechanisms are recognized as one of the most difficult topics for students to learn and thus are often a barrier to students’ success in organic chemistry courses. Identifying ways help students better understand organic reaction mechanisms will enhance opportunities for students to advance in chemistry and related studies such as medicine. While prior research has investigated student learning of reaction mechanisms, less is known about how educators teach the topic and their understanding of how to best respond to students’ learning difficulties. Throughout this project, instructors’ approaches to teaching reaction mechanisms will be captured using interviews and classroom observations; thus, both instructors’ beliefs about teaching and learning, and the practices they use in teaching and in responding to student learning will be captured. Importantly, individual and collective approaches will be used to develop resources and tools for educators to reflect upon their teaching and identify opportunities to improve how they teach organic reaction mechanisms. The overall objective of the project is to explore and document instructors’ topic-specific pedagogical content knowledge (PCK) about reaction mechanisms. The project team will recruit organic chemistry educators with varying levels of experience and career trajectories (e.g., professors of teaching practice, tenure-earning faculty members, tenured faculty members), and from various institution types (e.g., small institutions, two-year institutions, predominately undergraduate institutions, research-intensive institutions) to participate in the project. Through in-depth, semi-structured interviews and multiple classroom observations of reaction mechanism-focused instruction, the project team will characterize educators’ personal (pPCK) and enacted (ePCK) pedagogical content knowledge. The PCK related to reaction mechanisms (both enacted and personal) will be used to create a description of the collective (cPCK) pedagogical content knowledge of reaction mechanisms of participating instructors. This work is expected to advance understandings of the specific strategies educators use to teach students about reaction mechanisms, how instructors address student difficulties and the strategies educators have found to be successful in teaching the topic. This project has the potential to identify the impact of different teaching strategies and enacted practices on students’ understanding, which could inform the design and implementation of professional development opportunities for organic chemistry educators. Finally, the project has the potential to impact the design of studies on instructors’ personal, enacted, and collective pedagogical content knowledge in other Science, Technology, Engineering, and Mathematics (STEM) courses. The NSF IUSE: EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through its Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT/SUMMARY Aging population is increasing, and age-related cognitive, Alzheimer’s disease (AD) and its related dementias (ADRD) prevalence sharply rising, with no prognosis, prevention or treatment. This is because we do not fully understand the mechanisms responsible for cognitive decline and ADRD progression during aging. Studies have identified many genes associated with the risk of development of familial AD, however, few have examined how the underlying mechanisms involved with aging-related risk and progression of AD. Studies of microbiota showed strong evidence that gut bacteria and metabolites significantly contribute to the development of AD and AD-related dementias (ADRD). Interestingly, we and others found that the gut microbiome signature in older adults with mild cognitive impairment (MCI), an early stage of AD, and ADRD significantly differs from cognitively healthy age-matched individuals. However, the mechanisms by which the gut microbiome impacts brain health are not well understood. Emerging evidence from literature and our preliminary data suggests that miRNAs produced from gut cells in response to microbial changes can also play important role in AD. miRNAs are known to modulate AD pathogenesis through many pathways, including targeting proteins related to Aβ clearance, neurotoxicity, synaptic loss, and cellular senescence, but the role of gut-derived miRNAs in age- related cognitive decline and ADRD is obscure. Here we propose the hypothesis that novel miRNAs of the gut appear in the blood circulation of older adults with MCI and dementia compared to healthy controls. We also posit that these gut-associated exosomal miRNAs travel through blood to brain and impact gene expression program in specific cell types of brain. To address these translationally important studies, we will use the stools and plasma samples from our ongoing study called Microbiome in aging Gut and Brain (MiaGB) consortium to determine the unique signature of gut-originating miRNAs and their mechanism of action by focusing on the two specific aims. In aim 1, we will determine the miRNA signatures that uniquely originated from gut to blood in older adults with MCI and dementia compared to cognitively healthy. In aim 2, we will determine if the exosomal miRNAs travel from gut to brain, target cell types in brain and impact their gene expression. Our studies will define the unique miRNAs of MCI and dementia compared to healthy controls, as well as establish the mechanism by which these MCI/ADRD-specific miRNAs impact specific neuronal cell functions. Our studies are built as an ancillary of the ongoing large MiaGB study for completing cost-effective, high rigor and timely manner by utilizing expertise of interdisciplinary team.

NIH Research Projects · FY 2026 · 2024-09

The COVID-19 pandemic caused by SARS-CoV-2 (CoV2) virus has left a large cohort of individuals suffering from ongoing neurological sequelae known as neuro-COVID. The condition involves CoV2 neurotropism and long-term inflammatory responses, including increases in neurodegenerative and neurotoxic proteins such as tau. Despite progress made, the molecular mechanisms underlying CoV2-induced tauopathy are unknown. Aging activates innate immune mechanisms and inflammation, and the latter has been linked to tau pathology. Together these observations have provided a strong scientific premise for this proposal, which aims to investigate CoV2-induced molecular changes in the context of aging and tauopathy to identify critical mechanisms underlying the development of neuro-COVID symptoms using mouse models. To this end, data in a mouse- adapted CoV2-MA10 virus infection in C57BL/6 mice show increased expression of genes involved in neuroinflammation and tauopathy risk that increase with age, which models neuro-COVID seen in the patient’s brains. Our preliminary studies led to the identification of two groups of proteins: one involved in protein misfolding/tauopathy (FKBP51) and the other related to innate immune activation including genes involved in IFN regulation (IFI204). Our studies also showed that CoV2-MA10 accelerates tau pathology in PS19 tau transgenic mice, establishing a model to further study tauopathy mechanisms that are accelerated by CoV2. Most notably, intranasal instillation of dendriplexes (DPX) comprising dendrimers and plasmid encoding short hairpin RNA (pshRNA) for the lead target FKBP51 in MA10-infected C57BL6 mice significantly reduced neuroinflammation, and expression of FKBP51 and Tau phosphorylation. These findings lead to the central hypothesis that age-dependent CoV2 neuro-invasion-induced tau pathology is caused by innate immune activation and elevated FKBP51 expression. We further hypothesize that CoV2 infection induces similar inflammation and protein misfolding in PS19 tauopathic mice, accelerating neuropathology and cognitive deficits. These hypotheses will be tested in the following two specific aims. SA #1 will assess age as a primary variable that exacerbates inflammation leading to tauopathy and long-term cognitive decline in C57BL/6 mice following CoV2-MA10 infection. SA #2 will examine the progression of tauopathy in PS19 transgenic mice following CoV2- MA10 Infection. Each of these aims will: i) characterize neuropathology and behavior; ii) identify target mechanisms underlying the pathology and neuro-COVID sequelae using spatial transcriptomic profiling; and iii) validate the role of FKBP51, IFI204 and other novel leads in neuropathological and cognitive consequences, using DPX formulations carrying pshRNA for these leads. This multi-PI and multi-disciplinary approach to understanding the mechanisms leading to neuro-COVID is expected to expand our basic knowledge and identify new mechanistic targets increasing our understanding of the impact of CoV2 on pre-existing age-related or genetically pre-disposed neurodegeneration.

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY The prevalence of diet-related diseases and health conditions such as obesity, diabetes, and cardiovascular diseases are higher among individuals in low-income neighborhoods in comparison to those in high-income communities. Reduced access to healthy and fresh produce has been linked to unhealthy dietary intakes and high rates of diet-related chronic diseases. Individuals residing in low-income neighborhoods where there is low access to healthy foods often suffer from disproportionately high levels of obesity and other diet-related health conditions. Building on our preliminary studies addressing limited food access and community resources in low-income neighborhoods, the FRESH-EATS project incorporates multiple intervention components to address multilevel factors that influence food access and dietary behaviors of families with school-aged children in low-income neighborhoods. Utilizing the NIMHD Minority Health and Health Disparities Research Framework, we propose to determine the feasibility of examining intervention implementation and outcome measures using a randomized controlled trial (RCT). In the FRESH-EATS project, there are four unique intervention components: (1) Evidence-based hands-on cooking and nutrition education (6-weekly 90-minute sessions – individual and interpersonal); (2) Family workshops addressing the lack of access to healthy foods and barriers in food environment (two 90 minute sessions – interpersonal and community); (3) Weekly food delivery throughout the intervention period and local food pantry information (community and societal); and (4) Community garden utilization providing fresh ingredients and garden education incorporated into the educational sessions (community and societal). The central hypothesis is that the FRESH-EATS is feasible to implement and improve dietary behaviors of children (ages 8-12) and their parents/caregivers that potentially reduce the risks of obesity and cardiovascular diseases, compared to individual-level education-only control. We will refine and finalize the intervention components (Aim 1) and determine the feasibility of the FRESH-EATS project using an RCT design (Aim 2). We hypothesize that this innovative community-derived, multilevel-multicomponent intervention is feasible to implement and has the potential to improve dietary behaviors of participants (children ages 8-12 and their parents/caregivers). The long-term goal is to establish sustainable food systems that support healthy eating habits and improve health outcomes among families in low-income communities, which is closely aligned with the NIMHD strategic vision and objectives.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT More than one-third of the one million older adults living in assisted living (AL) communities in the United States have a diagnosis of Alzheimer's disease or related dementia (ADRD). An estimated 40% of persons with ADRD will die there with an average length of AL stay of 2.5 years, making AL a common site for end-of-life care. The AL nursing workforce, comprising close to 300,000 full-time employees, is challenged to meet end-of-life ADRD care needs. Advance care planning (ACP) discussions are a foundational aspect of care yet can be challenging for persons with ADRD due to a lack of decision-making capacity. Staff in AL have limited education and knowledge about ACP discussions with people with ADRD and their families. Our NIH Stage 1b feasibility cluster randomized trial of the Palliative Care Education in Assisted Living for Dementia Care Providers (PCEAL-DCP) intervention pilot study in 10 Als, with AL nurses and administrators, indicated that education with a focus on the principles of ACP and approaches on how to have ACP discussions with health care surrogates of persons with ADRD could improve staff self-efficacy as well as improve documentation of ACP discussions and hospice use. The NIH NOSI (NOT-AG-21-049): Dementia Care Workforce for Those Living with Alzheimer's Disease- Related Dementias calls for research to develop training for direct care workers to identify competencies that improve organizational processes related to staffing and ADRD care outcomes. This is a five-year, NIH Stage 3 cluster randomized trial (CRT) among 30 ALs (k=30) and residents with ADRD (N=450) with a baseline, three, and six months post-intervention follow-ups using Donabedian's structure process outcome model to examine the effectiveness of the PCEAL-DCP on dementia quality-of-care outcomes including increased documentation of ACP discussions (primary outcome) and rates of hospice admission (secondary outcome at treatment sites). A secondary aim (NIH Stage 1b) will test in a sample of AL nurses, administrators, and dementia care coordinators (N=72) from the sample of 30 ALs with a baseline, one, three and six months if the PCEAL-DCP improves staff self-efficacy and perceived organizational support, which in turn will increase job satisfaction and job commitment at treatment sites. In exploratory Aim 3 (NIH Stage 1a) we will evaluate the feasibility of collecting family satisfaction with care at the end-of-life outcome data from 60% of the resident/family dyads sampled in Aim 1 (N=270) at both baseline and six-months to explore whether satisfaction levels improve more in treatment compared to control sites. Dissemination of the PCEAL-DCP could be implemented nationally and improve the quality of dementia care in ALs. Because we have manualized the training and intervention, and it has already proven to be effective in a Stage 1b feasibility clinical trial and has been approved through the Continuing Education program, the potential for widespread implementation of the PCEAL-DCP appears to be high.

NIH Research Projects · FY 2025 · 2024-09

Summary: Asthma is a common chronic airway disease that affects 21 million adults in the US with substantial morbidity and healthcare costs. Black and Latinx adults bear a disproportionate share of that burden of disease, partly due to an inequitable distribution of social determinants of health (SDOH). SDOH have 5 components: 1. economic stability, 2. education access and quality, 3. health care access and quality, 4. neighborhood and built environment and 5. social and community context. Attempts to improve asthma outcomes in these populations have mostly been unsuccessful partially because the relationship between SDOH and in Black and Latinx adults with asthma is insufficiently understood. These groups have been vastly underrepresented in research intended to mitigate health disparities, limiting the ability to disentangle the complex relationship that these racial and ethnic groups have with SDOH in the US. The few studies that did so were conducted in children, had limited, retrospective, or cross-sectional asthma outcomes data, or unidimensional SDOH data. Addressing this knowledge gap is critical to the implementation of high-yield policy and interventions that will reduce the burden of disease for these vulnerable populations. In a large pragmatic randomized controlled trial (the PREPARE study), our group collected extensive demographic, clinical, and phenotypic data in addition to prospective asthma morbidity outcome data through monthly surveys. We successfully showed that a ‘Patient-Activated, Reliever-Triggered Inhaled CorticoSteroid’ (‘PARTICS’) strategy plus usual care reduced asthma exacerbations in 1,201 Black and Latinx adults with moderate-severe asthma vs. usual care alone. We also showed that low socioeconomic status (SES) associates with worse asthma morbidity using a multidimensional SES latent variable (defined by poverty, low educational attainment, and unemployment), structural equation modeling and mediation analysis on retrospective baseline data among Black and Latinx PREPARE participants. We also found that Caribbean Latinx adults experience greater asthma morbidity vs. other Latinx subgroups, supporting our overall hypothesis that a distinct set of SDOH exposures (an SDOH exposome) within racial or ethnic groups may impact asthma outcomes. The richness of our PREPARE dataset, enhanced with our ability to analyze geocoded data on all 5 SDOH components, uniquely enables us to address these Specific Aims: Aim 1a: To determine whether Black vs. Latinx adults with moderate-severe asthma have unique SDOH exposomes that distinctly associate with worse asthma morbidity. Aim 1b: To determine whether African American vs. non-African American Black adults experience greater asthma morbidity. Aim 2: To determine baseline SDOH exposomes and clinical characteristics that predict optimal PARTICS responders. Results from this R21 award may identify unique SDOH exposomes for Black and Latinx adults that lead to high-yield interventions, plus facilitate our work implementing the PARTICS strategy, both of which may reduce morbidity in these highly impacted populations.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Parental behavior is the hallmark feature of all mammals, and is critical to the health of both parents and offspring. In the majority of mammals, since only the female can lactate, it is the mother who provides maternal care and protection of the young. Inadequate maternal care can adversely influence the development of the offspring and impair their health in adulthood. However, the neurobiological mechanisms for the regulation of maternal behavior remain to be fully understood. In women who exhibit impaired bonding with their infants, we identified several loss-of-function mutations in the TRPC5 gene, which encodes the TRPC5 ion channel, a transient receptor potential channel that conducts calcium inward currents. We used the CRISPR-Cas9 approach to generate a knock-in mouse line that mimics one such human mutation, Trpc5K34del, and found that this mutation causes severe impairments in a wide range of maternal behaviors in mouse dams, including ignoring pups, reduced nursing/crouching, inefficient retrieval, disrupting nests, and impaired prolactin release upon suckling. These findings demonstrate that intact Trpc5 function is required for normal maternal behavior, but the neurobiological mechanisms for its effect remain unclear. One objective is to test a hypothesis that Trpc5 maintains maternal behavior via activating oxytocin neurons in the paraventricular nucleus of the hypothalamus, which have been implicated in maternal behavior and mother-infant bonding. The second objective is to test whether Trpc5 acts upon dopamine neurons in the substantia nigra to provide a redundant or complementary mechanism to regulate maternal behavior. Finally, we will evaluate whether a Trpc5 activator can ameliorate impaired maternal behavior in wild-type dams induced by psychological stress. Our work, combining human genetic and mouse genetic experiments, has provided evidence to identify a novel molecular basis underlying normal maternal behavior. As a logical extension of this initial and exciting discovery, we will continue to unravel the neurobiological mechanisms by which Trpc5 maintains normal maternal behavior during the postpartum period and will provide pre-clinical evidence to identify Trpc5 as a potential target improve maternal care.

NIH Research Projects · FY 2025 · 2024-09

Abstract Hypertension (HTN) is a prevalent cardiovascular condition and a leading risk factor for other cardiovascular diseases. If it remains untreated, HTN can lead to numerous comorbidities such as stroke, dementia, diabetes, kidney disease, obstructive sleep apnea, and neurological disorders. Despite advances in prevention and multi- drug therapy, a significant proportion of patients remain resistant or refractory to current treatments. In most cases, treatment-resistant HTN is strongly neurogenic, characterized by a dysfunctional autonomic nervous system (ANS) most recently linked to gut dysbiosis. However, mechanisms of host-microbiota interaction in HTN are not well defined. Our new preliminary data suggests that a breakdown in the neural gut-brain communication resulting from gut dysbiosis may be mediated by reduced serotonergic receptor signaling on the vagal afferent projections from the gut to the nucleus of the solitary tract. In this application, we propose to use state of the art in vivo imaging, electrophysiology and neural stimulation approaches in transgenic and humanized rats in order to interrogate specific molecular and neural mechanisms of host-microbiota interaction in health and HTN, while evaluating the potential of sub-diaphragmatic vagal stimulation for bio-electronic medicine to alleviate the symptoms of gut dysbiosis in HTN.

NIH Research Projects · FY 2024 · 2024-09

Newborns in the neonatal intensive care unit (NICU) often undergo invasive procedures or surgeries that cause prolonged pain. Cumulative pain exposures during early brain development alter brain growth, decrease brain volume, and lead to neurodevelopmental sequelae. Therefore, monitoring and treating neonatal pain is a central goal of NICU care, and opioid-based pain regimens are regularly used to treat pain after surgery. However, prolonged opioid exposures can also lead to delayed feeding, prolonged mechanical ventilation, impaired brain growth, and neurodevelopmental sequelae. Optimally, neonatal pain should be managed to minimize pain, stress, and opioid exposures. If bedside nurses can detect the infant’s pain while it is still mild, then non-opioid drugs and non-pharmacologic therapies can be used to prevent it from becoming severe. Thus, optimized post-surgical analgesia will protect neonates from the trauma of either prolonged acute pain vs. prolonged opioid exposures, and the long-term effects of both these on the newborn brain. However, measuring neonatal pain accurately and consistently is difficult, as the current approaches are subjective and unreliable when practiced by different NICU nurses. Nursing workload in the NICU also does not allow for continuous pain assessment and monitoring. The objective of the proposed research is to develop an automated pain monitoring system that objectively measures pain continuously based on several biomarkers. The proposed Neonatal Pain Monitoring System (NPMS) will prompt the nurse with pain alarms, coupled with a pain management protocol that minimizes pain, stress, and opioid dosing during post-operative neonatal care. This project in the UG3 phase aims to: 1) develop and validate AI-driven neonatal pain biomarker signatures and an automated NPMS that can constantly assess neonatal pain to identify the onset and offset of postoperative pain, 2) create a pain management protocol that utilizes the information provided by NPMS to minimize postoperative pain and opioid use. The UH3 phase aims to complete a randomized controlled trial using postoperative pain scores, clinical outcomes, pain-related stress, acute pain events, pain trajectories, and provider surveys to compare the two randomized groups with and without AI-driven pain biomarker monitoring. Expected outcomes include neonatal pain biomarker signature models, an automated NPMS that uses these models, and a pain management protocol that utilizes NPMS to minimize postoperative pain and opioid use. These novel tools will equip the bedside nurses to manage surgical newborn pain pre-emptively and more effectively, which will reduce central sensitization, thus reducing pain scores (primary outcome), the need for opioids or other analgesics/sedatives, and improving their post-surgical clinical outcomes (secondary outcomes). This collaborative, multi-disciplinary team has the track-records, advanced skills, and access to sufficient patient populations to successfully execute the proposed aims and significantly advance the field of post-surgical care.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Cancer has been characterized as a chronic, poorly healing wound where inflammatory and proliferative processes continue unchecked without normal healing and resolution of inflammation. In one sense, cancer represents an imbalance of pro-inflammatory over pro-resolving processes. In colorectal cancer (CRC), we propose this pro-inflammatory imbalance may be driven by arachidonic acid (AA)-rich Western diets and associated downstream lipid metabolism. The role of AA in cancer development and progression, however, is still controversial when in vitro, in vivo, and human data are considered. Our preliminary LC-MS/MS data suggest a disordered lipoxygenase pathway CRC lipid metabolism, where AA, its derivatives (e.g, LTB4, 5- HETE), and principal genes (e.g., ALOX5, ALOX5AP) are largely over-expressed in tumor vs. normal samples. Recent in vivo murine data suggest dead cancer cell membranes (apoptotic debris), commonly generated from rapidly growing or treated tumors, may be the main source of AA that promotes tumor growth. Surprisingly, single cell RNASEQ data suggest the majority of AA lipid modulating genes are expressed in the immune cells of the tumor microenvironment (TME) rather than in the tumor cells themselves, suggesting a role for AA in regulating the immune TME. Moreover, our preliminary analysis of > 2000 CRCs suggest the immune activity of the TME is a strong predictor of long-term CRC survival. The recent proliferation of checkpoint inhibitors has fully demonstrated the potential to modulate the TME to enable cancer cures. Understanding precisely how disordered AA lipid metabolism impacts the immunity of the CRC TME is thus a critical unmet need that could lead to novel therapeutic approaches for CRC based on lipid metabolism and signaling. Here we propose to: 1) add a novel feature of quantified AA pathway lipid mediators to a large “reference” set of human highly clinically- and molecularly curated CRCs. We will determine their ability to distinguish, and possibly refine, subclasses defined by: a) consensus molecular subtyping (CMS) with enriched vs. diminished immune TMEs; b) TME immune activation scores; c) CRC genotypes; 2) assess the effect of AA-based pro-inflammatory vs. pro-resolution mediators on paired, isogeneic patient derived organoids (PDOs), with and without intact immune TMEs, to clarify mechanisms of action; 3) define the role of AA and ALOX5 in tumor growth and metastatic progression in a murine, syngeneic CRC orthotopic model. We will anchor the experimental plan on AA supplementation resembling the Western diet in order to demonstrate its inflammatory effects on CRC. These aims will decipher the potential of regulating AA and its lipid derivatives as a novel therapeutic approach to enhance the immune activity of the TME.

NIH Research Projects · FY 2025 · 2024-09

Summary NAD+ is biosynthesized mainly through the salvage pathway and is central for cellular homeostasis and energy production. Deficiency of NAD+ results in disruption of cellular functions, leading to decreased ability to regenerate and repair. In heart failure (HF), the heart undergoes metabolic disruption leading to redox imbalance with increased NADH/NAD+ ratio. Therefore, we hypothesized that “Activating NAD+ plays a central role in attenuating Heart failure.” Current therapeutics manage the disease symptoms, however, do not address the core issues of HF. Based on our innovation with US patents and new preliminary data, Nampt activator P7C3 is a prototype for generation of new pharmacological class of small molecules for cardioprotection. Using medicinal chemistry, 3D-SAR, cell permeability and drug design approaches we will activate NAD+ by P7C3-based novel small molecules for attenuating HF. A combination and tiered approach will be utilized for evaluating and narrowing down the new compound pipeline using in vitro models, followed with efficacy studies. Initial screening through in vitro assay will identify the molecules that are of high affinity and activity. Subsequently, 8-9 new small molecules will be tested using ex vivo Langendorff system for evaluating the cardiac changes, and NAD+ generation capacity. Finally, 1-2 lead small molecule(s) will be tested using in vivo system with preclinical model of HF using isoproterenol infusion, alternate HF models include db/db and MI to evaluate the pharmacological specificity by using a combination of cardiac-specific Nampt KO and wildtype (C57Bl/6J) mice for demonstrating the increased function with NAD+ activation in HF. The milestone-based approach for R61 phase will be utilized for medicinal chemistry, including design and synthesis of new small molecules, in vitro Nampt activity, cell permeability and toxicity, and assessment of therapeutic candidate's ex vivo. Whereas, in the R33 phase, we will perform pre-clinical assessment and pharmacological evaluation of 1-2 lead small molecule(s) in vivo. The proposal provides a systematic plan for continuous assessment and refinement of project management to develop P7C3-based small molecules for testing and refinement to achieve the milestones in a timely manner. The University of South Florida is a top producer of patents and is highly supportive with cost matching during R33 phase. In addition, the USF hosts incubator companies which along with pharmaceutical research companies in Tampa Bay area have shown interest and support for this project. The PI is an expert and well known in the region with pharmaceutical incubator companies and has received Florida High Tech Corridor matching awards and therefore anticipate developing the lead compounds for commercialization through the next stage of development. Overall, the successful completion of the project will allow new product development with rigorous and robust evaluation along with project management of novel small molecules for therapeutic development and discovery of innovative new class of “NAD+ activators” for translational development.

NIH Research Projects · FY 2025 · 2024-09

Recent studies have reported widespread transcription of mammalian enhancers into noncoding RNAs in a stimulus-dependent manner. Growing evidence shows that these RNAs, known as enhancer RNAs (eRNAs), have essential roles in orchestrating higher-order chromatin interactions to facilitate gene expression and phenotypic outcomes during development and disease. As a result, eRNAs are emerging as an important component of the gene regulatory machinery. Due to their recent discovery, the expression, and roles of eRNAs in vascular dementia are virtually unknown. Recently, we applied a combination of genome-wide RNA- seq and genome-wide enhancer mapping using H3K27ac ChIP-seq to identify several ischemia-induced eRNAs at multiple time-points of reperfusion in the mouse cerebral cortex. This was the first study on eRNAs in brain vascular injury. We found an important role for one such eRNA in modulating post-stroke brain damage and gene expression. In the current project, we will apply our expertise in eRNA discovery and function to identify eRNAs that are expressed in the adult hippocampus specifically during the development of vascular dementia. Using a standardized bilateral carotid artery stenosis (BCAS) model of vascular dementia, we will induce hippocampal hypoperfusion in the mouse brain across a 30-day time-window. In Aim 1, we will use an unbiased, genome-wide approach incorporating H3K27ac ChIP-seq and RNA-seq to map active enhancer elements and their respective eRNAs from the earliest stages of cerebral hypoperfusion (day-3 post-BCAS) to the manifestation of vascular dementia (day-30 post-BCAS). In Aim 2, along the same timeline we will apply the cutting-edge method of Hi-C to capture genome-wide higher order chromatin interactions to pinpoint enhancer-to-gene promoter contacts and map their dynamics along the BCAS trajectory. Together, this work will identify novel enhancers and eRNAs that are activated specifically in response to BCAS-induced hypoperfusion in the hippocampus and generate a catalog of putative enhancer-gene relationships that may encompass regulatory networks. These data will lay the foundation for future mechanistic and functional studies investigating these regulatory networks and their impact on the development of the hippocampal pathophysiology and vascular dementia.

NSF Awards · FY 2024 · 2024-09

Teamwork is an integral part of engineering and computer science curricula. However, underrepresented students, particularly Black and Latinx students, especially those of lower socioeconomic status, tend to encounter adverse team experiences beyond those generally encountered by all students. A team-based learning environment that values each individual student’s assets can potentially decrease occurrences of negative team experiences rooted in racial bias, increase belongingness, and provide students with teamwork skills to succeed in the increasingly global job market. The goal of this collaborative project is to identify and understand pedagogical strategies that promote equity in team experiences for Black and Latinx students in engineering and computer science classrooms. The research team will use an asset-based approach drawing upon students’ cultural, behavioral, and cognitive assets to inform team compositions that will foster cooperation, collaboration, and inclusion leading to equitable outcomes in team-based assignments. Additionally, the research team will couple this novel approach to team formation with training that educates faculty and students about conscious and unconscious bias, intercultural conflict, and culturally responsive communication to improve team dynamics. Enhancing the persistence of Black and Latinx students to degree completion and subsequent entrance into the STEM workforce can increase the diversity and global competitiveness of the STEM workforce in the U.S. which, in turn, promotes national economic prosperity. The research team will perform a quasi-experimental, quantitatively driven, sequential, mixed methods design in three phases guided by a socioecological framework. The unit of analysis will focus on undergraduate teams formed in engineering and computer science courses that assign team-based assignments at the University of South Florida, Virginia Tech, and West Point. Undergraduate Black and Latinx students will partner with the PIs and co-PIs to make decisions about the research design, data collection and analysis, and dissemination of research results. The intellectual merits of this study will provide insights regarding the use of cultural, behavioral, and cognitive assets in the formation of equitable engineering and computer science student teams. By leveraging the new insights, the research impact will be to create more inclusive and equitable classroom environments to help alleviate challenges encountered in team-based undergraduate assignments. This project is a step toward transforming the STEM higher education system by illuminating the cultural assets that Black and Latinx students bring to the classroom and by providing inclusive team training to establish better team working environments and pedagogical strategies to improve overall learning experiences. This collaborative project is funded by the EDU Racial Equity in STEM Education activity, which is supported by the Directorate for STEM Education (EDU). This activity supports research and practice projects that investigate how considerations of racial equity factor into the improvement of science, technology, engineering, and mathematics (STEM) education and workforce. Awarded projects seek to center the voices, knowledge, and experiences of the individuals, communities, and institutions most impacted by systemic inequities within the STEM enterprise. Programs across EDU contribute funds to the Racial Equity activity in recognition of the alignment of its projects with the collective research and development thrusts of the four divisions of the directorate. 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

Non-technical description Marine invertebrates often have mutually beneficial partnerships with microorganisms that biosynthesize compounds with nutritive or defensive functions and are integral for survival. Additionally, these “natural products” often have bioactive properties with human health applications fighting infection or different types of cancer. This project focuses on the ascidian (“sea squirt”) Synoicum adareanum, found in the Anvers Island region of the Antarctic Peninsula, and was recently discovered to contain high levels of a natural product, palmerolide A (palA) in its tissues. The microorganism that produces palA is a new bacterial species, Candidatus Synoicihabitans palmerolidicus, found in a persistent partnership with the sea squirt. There is still much to be learned about the fundamental properties of this sea squirt-microbe-palA system including the geographical range of the animal-microbe partnership, its chemical and microbiome complexity and diversity, and the biological effect of palA in the sea squirt. To address these questions, this multidisciplinary research team will investigate the sea squirt-microbiome partnership in the Antarctic Peninsula and McMurdo Sound regions of the Ross Sea using a state-of-the-art strategy that will advance our understanding of the structural and functional features of the sea squirt and microbiome in detail, and reveal the roles that the palA natural product plays in the host ecology in its native Antarctic seafloor habitat. The project will broaden diversity and provide new opportunities for early career students and postdoctoral researchers to participate in field and laboratory-based research that builds an integrative understanding of Antarctic marine biology, ecology, physiology and chemistry. In addition, advancing the understanding of palA and its biological properties may be of future benefit to biomedicine and human health. Technical description Marine invertebrates and their associated microbiomes can produce bioactive natural products; in fact, >600 such compounds have been identified in species from polar waters. Although such compounds are typically hypothesized to serve ecological roles in host survival through deterring predation, fouling, and microbial infection, in most cases neither the producing organism nor the genome-encoded biosynthetic enzymes are known. This project will study an emerging biosynthetic system from a polar ascidian-microbe association that produces palA, a natural product with bioactivity against the proton-pumping enzyme V-type H+-ATPase (VHA). The objectives include: (i) Determining the microbiome composition, metabolome complexity, palA levels, and mitochondrial DNA sequence of S. adareanum morphotypes at sites in the Antarctic Peninsula and in McMurdo Sound, (ii) Characterizing the Synoicum microbiome using a multi-omics strategy, and (iii) Assessing the potential for co-occurrence of Ca. S. palmerolidicus-palA-VHA in host tissues, and (iv) exploring the role of palA in modulating VHA activity in vivo and its effects on ascidian-microbe ecophysiology. Through a coupled study of palA-producing and non-producing S. adareanum specimens, structural and functional features of the ascidian microbiome metagenome will be characterized to better understand the relationship between predicted secondary metabolite pathways and whether they are expressed in situ using a paired metatranscriptome sequencing and secondary metabolite detection strategy. Combined with tissue co-localization results, functional ecophysiological assays aim to determine the roles that the natural product plays in the host ecology in its native Antarctic seafloor habitat. The contributions of the project will inform this intimate host-microbial association in which the ascidian host bioaccumulates VHA-inhibiting palA, yet its geo-spatial distribution, cellular localization, ecological and physiological role(s) are not known. In addition to elucidating the ecophysiological roles of palA in their native ascidian-microbe association, the results will contribute to the success of translational science, which aligns with NSF’s interests in promoting basic research that leads to advances in Biotechnology and Bioeconomy. The project will also broaden diversity and provide new opportunities for early career students and postdoctoral researchers to participate in field and laboratory-based research that builds an integrative understanding of Antarctic marine biology, ecology, physiology and chemistry. 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 project aligns with the National Science Foundation’s mission for “the Professional Formation of Engineers, to create and support an innovative and inclusive engineering profession for the 21st Century”. The research project aims to address the recommendation of the National Academy of Sciences, Engineering, and Medicine (NASEM) to study the effects of mentorship on persistence and success in STEMM. This study will examine the correlation and impact between mentorship outcomes and persistence in engineering for First-Time In College (FTIC) undergraduate women. A non-dyad mentoring network involving the pairing of mentees with an assembled number of mentors will be established based on deep-level similarities in sociocultural identities. Mentees will be paired with near-peer mentors in the upper-level division, an academic advisor/coach, faculty, and an industry mentor. Training modules for mentors will be developed to enhance effective and inclusive mentorship. Resource guides on mentoring best practices, mentoring tools, and training will be provided to all mentors to prepare and support their mentoring activities. Both mentors and mentees will be prompted with discussion topics. For example, prompt questions could include, “Tell me about a time when you struggled in a course and what you did to pass?” Mentees are expected to engage in formalized group activities that facilitate academic awareness, provide college survival tips, and support talent development and student success skills. Also, they are expected to participate in journal entries, focus group studies, and regular one-on-one meetings with their four mentors at different stages of their academic pursuits. A set of instruments, including reflection prompts, interviews, an inclusive demographics questionnaire, a Sense of Belonging, and Academic Self-Efficacy Scales, will be administered to respective participants in this mentorship structure. This research project will be used to understand the impact of sociocultural contexts on mentoring structures, their processes, and their outcomes in the persistence of FTIC women in engineering. Specifically, to (1) determine the impact of traditional mentorship on FTIC women and their attrition rate in engineering at the University of South Florida; (2) investigate the effect of a structured mentorship model on FTIC women and their decision-making to continue pursuing engineering; (3) determine the effects of similar social and cultural perspectives of mentor and mentee relationships on the sense of belonging from their first year and beyond; (4) determine the impact of different social and cultural identities between mentors and mentees from their first year and beyond; and (5) examine and identify competency for sociocultural awareness relevancy to mentorship. Badura’s self-efficacy theory and Tinto’s theoretical framework will be employed to educate, motivate, prepare, and engage mentees. Statistical analysis and a coding software designed for qualitative and mixed-method assessment will be used to evaluate data, media, and text to decipher the outcomes between traditional and non-traditional mentoring structures and to examine the impact of similar sociocultural identities. The research will be conducted through a collaboration between engineering faculty at the University of South Florida and an engineering education faculty mentor at the University of Cincinnati. Results from this study will help expand the current knowledge base for creating and integrating a mentoring support system that intentionally targets engineering identity, persistence, and retention rates for students from populations underrecognized and underserved in STEM. The research outcome can potentially reveal, validate, and address the academic disparities in STEM education in the select population. 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

To advance the science on social factors associated with the well-being – defined broadly to include social, economic, physical, psychological, and relational dimensions – of new populations, in this project social scientists are convened to present their research on new populations in the United States and influences on their well-being. With sustained levels of new populations to the country, it is crucial to promote scientific knowledge on their well-being as their population is critical for the sustenance, prosperity, and health of the nation. Representing advances in this area across a variety of disciplines – including anthropology, education, criminal justice, sociology, and economics – the scholarship presented at this convening will be published in peer-reviewed journals to enhance public knowledge on the barriers and promoters to the well-being of new populations, thereby benefiting US society. Specific efforts will be undertaken to recruit scholars from under-represented backgrounds and institutions of varying research capacities, to add a diversity of perspectives to the field. Making sound decisions rooted in empirical evidence concerning new populations requires that we create spaces that amplify academic work on the subject, while also creating opportunities for the public to engage with this scholarship in consumable forms. In this conference, a collaborative effort between the George Washington University and the University of South Florida, participants present high-impact research on the well-being of new populations and take part in applied workshops on best practices for communicating that research to decision makers and the public-at-large. The intellectual merit of the conference includes its interdisciplinary and translational orientation to the application of empirical research. The translational workshops prepare a cohort of scholars with the knowledge and skills to bring empirical insights on publicly engaged scholarship on the well-being of new populations beyond the academy into decision making spaces. 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/ Abstract The greatest unmet need in family caregivers of persons living with dementia (PLWD) is support for these caregivers’ mental health. Family caregivers of PLWD express a desire for mental health support and a need to learn strategies to cope better with the emotions and thoughts that arise from caregiving situations and to balance care demands with other important aspects of life. Acceptance and commitment therapy (ACT) is an evidence-based transdiagnostic approach that can promote mental health through acceptance and mindfulness processes and behavior change processes that support living in alignment with values. Previous studies focused on in-person ACT programs, but internet- delivered self-help ACT programs have the potential to increase caregivers’ access to mental health support at low cost. The current study's objectives are to adapt and finalize our artificial intelligence (AI)- enabled ACT app for family caregivers of PLWD and to test its feasibility, acceptability, and usability. The proposed study will have two phases. The first phase aims to adapt our AI-enabled ACT web app (WeACT) through collaboration with a community advisory board (Aim 1). The second phase aims to evaluate the feasibility, acceptability, and usability of the WeACT app program for family caregivers of PLWD as a small feasibility (Aim 2). This feasibility study will involve a convergent mixed-methods study design (i.e., a one-group pretest–posttest design with a phenomenological approach). Twenty family caregivers of PLWD will be recruited and asked to use the WeACT app in the manner determined in Aim 1. Feasibility and usage of the app will be assessed with the number of days and total minutes of engagement with the app during the study period. Adherence to the app-based program will be determined through the completion rates of ACT modules, evaluations, and ACT practice on the app in the manner determined in Aim 1. Caregivers’ acceptability, perceived usability, and experiences in the program will be explored using an individual interview and a usability scale. Preliminary data on caregivers’ mental health outcomes and ACT processes will be collected using self-reported questionnaires. We will refine and finalize the app based on the feedback from caregivers (Exploratory Aim). This study will provide important guidance for further development of the WeACT app for future larger-scale clinical trials to promote mental health in family caregivers of PLWD. Given the evidence that the greatest unmet need among family caregivers of PLWD is support for mental health, the findings will contribute to the timely development of an evidence-based, easily accessible mental health app.

NSF Awards · FY 2024 · 2024-09

Semiconductor chips are essential components to everyday living, and unpredictability in the global supply chain has implications across a wide range of industries and applications. The future of semiconductor manufacturing requires a convergence approach to design and deploy diverse new technologies in materials, chemical and materials processes, devices, and architectures through the development of application-driven systems. Semiconductor microfabrication technology cuts across traditional science and engineering disciplines and represents an opportunity to bring students together from diverse disciplines to learn in a stimulating and interdisciplinary environment. A skilled and diverse pipeline of workers is critical to building a sustainable domestic semiconductor industry and to achieving national economic and security goals. This National Science Foundation Research Traineeship (NRT) award to the University of South Florida will develop and implement a comprehensive and experiential learning based education, research, training, and skills development program in semiconductor design, manufacturing, and packaging. The project anticipates training 75 Ph.D. and 133 M.S. students, including 15 Ph.D. and 8 M.S. funded trainees from: Chemical, Biological, and Materials Engineering; Computer Science Engineering; Electrical Engineering; Industrial and Management Systems Engineering; Mechanical Engineering; and Medical Engineering disciplines. The NRT project will develop and implement a new interdisciplinary curriculum and will feature novel courses in fundamentals of materials, processing, metrology, and device fabrication with specific applications to semi-conductor technology development. This project includes the combination of convergent research and educational experiences to support trainees in achieving several learning outcomes: a) foster systemic change in graduate curricula with the potential to fundamentally enrich knowledge and research in semiconductor manufacturing, and b) infuse science and engineering principles as well as cutting-edge technology into the graduate curriculum. The technical focus has three major research efforts: (a) Processing/Metrology/Applications of Semiconductors, (b) Circuit System/Hardware, Artificial Intelligence of Semiconductors, and (c) Heterogeneous Packaging Semiconductors. The program will enable trainees to: i) work with faculty and semiconductor partner mentors to define research problems using a convergence approach to design and develop application-driven semiconductor systems and devices, ii) carry out semiconductor-based research projects, and iii) develop interdisciplinary expertise and global competency skills in areas such as communication, teamwork, project management, ethics, and leadership. Trainees with entrepreneurial interest will have the opportunity to complete the University of South Florida’s NSF Innovation Corps (I-CorpsTM) site training. The NSF Research Traineeship (NRT) Program is designed to encourage the development and implementation of bold, new potentially transformative models for STEM graduate education training. The program is dedicated to effective training of STEM graduate students in high priority interdisciplinary or convergent research areas through comprehensive traineeship models that are innovative, evidence-based, and aligned with changing workforce and research needs. 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

The Earth's core is the source of the magnetic field and is composed mainly of iron with a smaller amount of light elements. Despite the core’s significance, the extreme pressure and temperature conditions in the region make it challenging to study the constituent materials under relevant conditions. This research project, a collaboration among scientists from Arizona State University, Carnegie Institution, and University of South Florida, will investigate the properties of iron-sulfur (Fe-S) alloys under the pressure-temperature conditions of the core for their crystal structures, melting, and crystallization processes. The team will perform dynamic compression experiments to the necessary pressures and temperatures, paired with molecular dynamics simulations to aid in the interpretation of the results. One of the fundamental questions this project seeks to answer is how sulfur, an important light element in the Earth's iron core, influences the melting behavior and crystal structures of iron alloys at extreme conditions. This information is vital for understanding the complex structures observed in the Earth's core and could reveal the origins of its heterogeneities. Beyond its scientific goals, this project has significant educational and societal impacts. It provides interdisciplinary training for early career researchers and offers hands-on research opportunities for undergraduate students, particularly those underrepresented in the geosciences. The project's findings will be integrated into educational materials, enhancing science education through accessible, high-quality resources. In this two-year collaborative research project, the team will perform dynamic-compression experiments and molecular dynamics simulations to study the crystal structure, melting, and crystallization of iron-sulfur (Fe-S) alloys at the pressure-temperature (P-T) conditions of the Earth’s core. This work aims to provide essential data for understanding the temperature and structure of the Earth’s core. The Earth's metallic core, generating a magnetic field, presents complex structures revealed by recent seismic studies. However, the extreme P-T conditions pose significant challenges for experimental investigations of core constituents. These dynamic compression experiments will be enabled by sample synthesis in ASU’s FORCE facility. Using large laser facilities, the project will access a range of compression pathways, enabling in-situ X-ray diffraction for monitoring the phase changes in the iron-sulfur alloy system. More specifically, shock-ramp experiments enable an initial shock melts the sample, followed by isentropic compression to re-solidify the sample at high P-T, directly observing the crystallization of Fe-S liquid into stable alloy phases. Complementary machine learning molecular dynamics simulations will model Fe-S behavior under dynamic compression, providing insights into phase transitions and crystal structures. This research addresses key questions: What crystal structures are stabilized in the Fe-S system at core conditions? How does sulfur influence Fe melting? Can Fe-S crystallization explain inner core heterogeneities? The project supports three PIs’ collaborative mentoring of three early career researchers (two postdocs and one Ph.D. student), offering interdisciplinary training in dynamic compression, static compression, and molecular dynamics. Data analysis and simulation codes developed will be included in Jupyter notebook teaching modules, shared for educational and research purposes. Outreach will involve public presentations at ASU and Carnegie Institution, highlighting the Earth's core's significance. This project is co-funded by the Geophysics and Petrology and Geochemistry Programs in the Division of Earth Sciences. 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 The oligomeric forms of two amyloid β (Aβ) peptides, Aβ40 and Aβ42, are considered as the primary toxic agents in the etiology of Alzheimer’s disease (AD). However, the exact conditions leading to the onset and progression of Aβ oligomerization in the brain remain largely unknown. Both in vivo and in vitro experiments show that Aβ aggregation is promoted by increased Aβ concentrations, low pH, and elevated ionic strengths. These conditions are transiently met in the extracellular space (ECS) in the brain during metabolic stress and spreading depolarization (SD) associated with numerous pathologies, including ischemic stroke, aneurysmal subarachnoid hemorrhage, traumatic brain injury, and migraine. All these conditions are risk factors for developing sporadic AD. The low-pH conditions are also met in endo/lysosomes. Accordingly, we will test the hypothesis that recurrent metabolic stress and SD events promote Aβ aggregation in the ECS and/or in endo/lysosomes. The proposal further posits that short-term episodes of brain acidification and/or ion increases might result in different populations of Aβ40 and/or Aβ42 aggregates than chronic, repetitive episodes. However, the wide range of spatiotemporal scales involved and the dynamic nature of the complex interactions between different Aβ species and physiochemical variables in the brain preclude testing these hypotheses through experiments alone. We propose to use novel approaches in multiscale modeling, high resolution microscopy, antibody staining, and measurement of paralysis phenotype to determine the role of the drastic physiochemical changes due to metabolic stress and SD in the onset and progression of Aβ40 and Aβ42 aggregation in the brain. We will achieve this by using a range of innovative techniques: 1) high resolution imaging, optical spectroscopy, and conformational-specific antibodies to determine how KCl, NaCl, pH, and Aβ concentration affect different aggregate species of Aβ40 and Aβ42; 2) Markov chain models and Kinetic Monte Carlo algorithms to investigate Aβ aggregation at a wide range of spatiotemporal scales from nanoseconds to months and nanometers to tens of micrometers; 3) biophysical model for metabolic stress and SD, taking into account dynamic changes in ion concentrations and pH in the ECS, neuron, and astrocyte; cell swelling and shrinkage of ECS; O2 homeostasis; and neurovascular coupling; 4) detailed model for the function of endo/lysosomes under physiological conditions and metabolic stress; 5) a comprehensive model to investigate the aggregation of Aβ40 and Aβ42 in the ECS and endo/lysosomes in the neuron and astrocyte simultaneously in brain region-specific manner; and 6) paralysis, phenotype, antibody staining, and microscopy to test model predictions in the C. elegans strain JKM7 expressing the human Aβ42 peptide. In addition to understanding the conditions leading to the aggregation of Aβ40 and Aβ42 at spatiotemporal scales that are not possible to explore through experiments alone, the resulting brain- region specific models for the function of neurons, astrocytes, neurovascular coupling, and endo/lysosomes will find broader applications in computational neuroscience.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY / ABSTRACT Many survivors of respiratory infections (i.e., pneumonia, and SARS-CoV-2) have subsequent incident dementia causing decreased quality of life and are at a higher risk of developing Alzheimer’s disease and related dementias. The cause of this association between pneumonia and dementia is unknown. It is also unknown how bacterial pneumonia causes neurovascular unit dysfunction. Pseudomonas aeruginosa is a pathogen capable of causing bacterial pneumonia and can elicit cytotoxic tau from the mouse lung and induce neuronal tau seeding, reduce dendritic spine density, and impair synaptic plasticity and cognition in mice. Additionally, I have shown that P. aeruginosa causes microglia and astrocyte activation, blood-brain barrier breakdown, and tau pathology in wild-type mice 24 hours post-infection. At lower doses of P. aeruginosa, I have seen microglia activation but no blood-brain barrier dysfunction. Microglia can influence blood-brain barrier breakdown and tau pathology as well as regulate neuroimmune pathways. Taken together, this has led to the hypothesis that pneumonia first causes microglia activation, leading to blood-brain barrier breakdown, and tau phosphorylation in the brain. Using a quadruple labeled mouse model (PrismPlus), I will image longitudinally from just 3 hours post-infection to elucidate the temporal resolution and mechanisms of neurovascular unit dysfunction in the brain. I will also assess neurovascular unit dysfunction in matched pneumonia vs. non-pneumonia post-mortem brain and lung tissue. This project will be the first step towards developing novel and effective therapies to protect neurovascular function in patients with severe lung infections, while allowing me to master the amazing technique of multiphoton imaging of mouse brain through a cranial window. Migraine disorders have a global prevalence of approximately 15% and are the third highest cause of disability-adjusted life years. However, much is still unknown about the pathology of migraines, particularly at the capillary level, and more effective treatments are needed. For the K00 phase, I will utilize my mastery of intravital imaging of the neurovascular unit at the capillary level, to investigate neurovascular and neuroimmune mechanisms in migraine mouse models.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY The lymphatic system is a unidirectional vasculature that absorbs interstitial fluid in the lymphatic capillaries to transfer the lymph fluid through the collecting lymphatic vessels, the lymph nodes, and then back into the blood circulation. To prevent reflux, the collecting vessels form intraluminal bicuspid valves with an extracellular matrix (ECM) core in response to oscillatory shear stress generated by lymph flow. Lymphatic malformations (LMs) are lesions due to inherited or somatic mutations that lead to a defective lymphatic vasculature with the overall incidence as high as 1:2000 live births. Multiple somatic activating mutations in KRAS have been recently identified in LM patients who commonly present with lymphedema, chylous ascites, or life-threatening chylothorax. KRAS mutations are associated with a loss of lymphatic valves in a mouse model of LMs and valve regression has been proposed to cause chylothorax via retrograde lymph flow into the chest. To further investigate, we combined the tamoxifen-inducible, lymphatic-specific Flt4CreERT2 with Kras-LSL-G12D mice to induce restricted expression of KRAS-G12D in postnatal pups. Our preliminary data show that lymphatic vessels expressing KRAS-G12D are almost devoid of valves compared to controls in multiple tissues. RNA-sequencing of human dermal lymphatic endothelial cells (hdLECs) overexpressing KRAS-G12D or mCherry as a vector control reveal the upregulation of several components of the plasminogen activator (PA) pathway and matrix metalloproteinases (MMPs) that was confirmed by qRT-PCR. Plasmin, the product of the PA pathway, can activate the same MMPs, which can then cleave the ECM proteins found in the valve leaflet core (e.g. laminin- a5, collagen, and fibronectin-EIIIA). We hypothesize that hyperactive KRAS signaling increases the expression of key PA enzymes that then activate several upregulated MMPs that degrade the ECM core of lymphatic valves. In Aim 1, we will investigate the PA pathway by assessing the expression of key PA enzymes, and by utilizing in vitro zymography approaches to assess MMP activation. In Aim 2, we will attempt to rescue lymphatic valve defects by genetically targeting the PA pathway or by pharmacological inhibition of MMPs.