University Of Southern California

NIH Research Projects · FY 2024 · 2024-09

Project Summary Lipid accumulation, inflammation and metabolic dysregulation are hallmarks of liver disease. Nonalcoholic fatty liver disease(NAFLD) has recently emerged as one of the leading global etiologies of liver disease as it affects approximately 25% of the global population. Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of NAFLD, and approximately 40% of patients will progress to this stage; with another subset proceeding towards carcinogenesis. Unfortunately, many of these patients will go undetected as they progress to hepatocellular carcinoma which has a median survival of just 11 months. It is thus crucial to better characterize the interface between NAFLD and NASH to best improve patient outcomes. To better understand the molecular signals driving this transition we have targeted the insulin signaling pathway where we have established a liver specific deletion model of PTEN, the negative regulator of the insulin signaling pathway, that recapitulates human disease progression. Our preliminary data has shown that dysregulation in eicosanoid metabolism correlates with PTEN loss such that prostaglandin synthesis is significantly enhanced while proresolving cyp450 associated eicosanoid synthesis is downregulated. These correlations between PTEN, prostaglandin, and cyp450 associated protein expression levels are preserved agnostic of PTEN deletion when examining publicly available data. The PI3K/AKT signaling pathway is unequivocally induced upon PTEN deletion and as such we aim to further investigate the role of AKT in driving this bioactive lipid metabolism dysregulation. Utilizing genetic knockout hepatocytes, our data has shown that AKT regulates eicosanoid synthesis in an isoform specific manner. Further, eicosanoid have long been implicated in playing a role in modulating macrophage chemotaxis and polarization. Our data has also shown significant enrichment of macrophages, and previous work demonstrated that depletion of this macrophage accumulation via AKT2 deletion attenuated disease progression. As such, we aim to investigate the role of AKT specific isoforms in regulating hepatic eicosanoid biosynthesis, and the effect this has on macrophage chemotaxis and polarization in liver disease. Completion of this project will show the potential therapeutic benefit that targeting eicosanoid signaling may have in NAFLD and NASH. This work will also elucidate the mechanistic roles of each AKT isoform in regulating hepatic eicosanoid metabolism and chronic inflammation to provide more insights for the scientific community at large.

NSF Awards · FY 2024 · 2024-09

Quantum information processing brings fundamental new paradigms for sensing, computing and communication. It will enable foundational innovations in many fields from physics to chemistry, to energy and finance, to secure digital infrastructure, and more. However, the ability to communicate quantum information effectively and efficiently across distance is a crucial pre-requisite for reaping the benefits of many quantum applications, including large-scale quantum computing, distributed quantum sensing and quantum-enhanced (secure) communications. Building on top of recent advances in developing a quantum network along two separate lines, this project will develop a new hybrid architecture that will reap the benefits of both continuous-variable and discrete-variable quantum networking, and design algorithms and protocols to enable high-rate and high-fidelity distribution of quantum entanglement resources across long distances and for various future quantum applications. The research will result in concepts and tools to empower the future quantum infrastructure and ecosystem. The project will help develop the future quantum workforce by actively involving and broadening participation from high school and undergraduate students in quantum-related research. The key innovation of this project is a new hybrid continuous-discrete variable quantum network architecture, and a suite of models, algorithms and protocols, for understanding and enabling high-rate high-fidelity entanglement distribution for quantum computing, sensing and communication applications. To achieve this goal, the proposed research encompasses both theoretical and practical considerations around: how to model and optimize physical processes and protocols for generating and manipulating continuous- and discrete-variable entangled states, how to measure and optimize performance metrics of a hybrid continuous-discrete variable quantum network system with scalability, and what application-level utilities might such a hybrid network enable compared to an infrastructure using either continuous- or discrete-variable components alone. To answer these questions, the expected contributions of this project are: (1) developing new models and protocols for hybrid continuous- and discrete-variable entanglement generation, manipulation and conversion; (2) designing a generic hypergraph-based framework for optimizing the design of a hybrid network for end-to-end entanglement distribution; (3) developing models and algorithms to support future quantum applications in computing, communication and sensing with the hybrid architecture. The outcomes of this research will inform and empower the development of future quantum network technologies, by significantly expanding the flexibility in combining and utilizing heterogeneous devices and technologies in an end-to-end manner. 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 National Science Foundation Research Traineeship (NRT) award to the University of Southern California (USC) will be used to educate graduate students at the interface of Artificial Intelligence (AI) and Operations Research (OR). Both disciplines study how to make smart decisions, and their technologies have complementary strengths. Cross-fertilizing AI and OR technologies, as done in the research part of this project, has the potential to result in technology breakthroughs. However, integrating technologies from different disciplines is difficult, and different disciplines have different ideas about what constitutes a good solution (often due to disciplinary training). Therefore, this project provides graduate students with interdisciplinary training to prepare them for their research at the interface of AI/OR. Overall, it anticipates training a diverse cohort of 38 Ph.D. students, including 19 funded trainees, from computer science and operations research. Another 10 Ph.D. students and 15 Master’s students are expected to enroll in the AI/OR program courses each year. These students will be trained to work in interdisciplinary settings and have more tools available than their non-interdisciplinarily educated peers to create technology and systems for decision-making/support. The project will also make the created course material broadly available as a stepping stone toward introducing joint AI/OR Ph.D. degrees at USC and other universities. The project creates a graduate specialization (in the form of a certificate program) for Ph.D. students enrolled in the computer science (CS) and industrial and systems engineering (ISE) departments of USC. The students will perform research at the interface of AI and OR while taking four graduate courses that teach a blend of AI and OR technologies (plus their applications to the design of decision-making/support tools) in an integrated and uniform way. Each course will integrate technical and ethics material (to prevent the many issues that have plagued the fielding of decision-making support systems in the past) and involve projects with use cases provided by several USC centers. The program will be supported by workshops (that teach the students important non-technical skills such as communication, teamwork, equity and inclusion, team leadership, mentoring, project management, and entrepreneurship), a weekly seminar with research talks by the students and invited speakers, and an annual research showcase. Several components of the program will be designed to encourage interdisciplinary interactions among students and between students and faculty members to bridge the gap in research culture between AI and OR. 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.

NIH Research Projects · FY 2025 · 2024-09

Project Summary To this date, we are still uncovering the exact morphological and functional changes that retina cells undergo throughout retinal degenerative disease timecourse. Furthermore, as common to many neurodegenerative diseases, our knowledge is incomplete when it comes to understanding how these morphological changes to cells affects their role in neural networks, as well as the factors that impact these changes in connectivity. With this proposal, we will take what we have learned from multiscale computational modeling of extracted early data from patho-connectomes, or connectomics volumes constructed from early degeneration stages pathological or neurally degenerating tissues, and pursue large scale network creation and modeling for all four stages of retinal degeneration. For model creation, we will combine the construction of patho-connectomes of photoreceptor to ganglion cell pathways in each stage of degeneration based on TEM images of diseased retina with a genetically-modified, monosynaptic G-deleted rabies viral tracing approach to visualize distinct retinal ganglion cells (RGCs) projection classes and characterize their unique dendritic morphologies. While the first (TEM-based reconstruction) provides unprecedented detail of morphological features of the individual pathways to ganglion cells limited to small areas of tissue and is not viable for mapping long range connections, the second (viral tracing) allows for the reconstruction of the entire retina ganglion cell layer, for all stages of degeneration. Combined, these two strategies will allow us to create a complete mesoscale connectivity atlas of retina and generate its global neural network. This will be the “first of its kind,” large-scale, morphological atlas of the four known phases of retinal degeneration, which will result in unprecedented knowledge of the neuronal changes associated with eye diseases and the development of biomimetic therapeutics. These models will be integrated in our parallel multiscale Admittance Method (AM)-NEURON computational platform, which integrates modeling of exogenous electric field application with neural activity of complex networks to provide insights into the physiological consequences of morphological changes on retinal signaling.

NSF Awards · FY 2024 · 2024-09

Reliable concentration measurements of chemical elements require careful quality control. Part of this quality control depends on the use of reference materials of known concentration to assess the accuracy of measurements and intercalibrate between laboratories. For trace element concentration analyses of seawater, the supply of reference materials has become exhausted in recent years. This project aims to collect large samples of water from the Pacific Ocean and Gulf of Mexico to be used as a new set of reference materials. Trace metal concentrations will be measured by several experts using different methods and conditions. The concentration values will be compared against one another, and a consensus value will be developed by these experts using state-of-the-art statistics. The remainder of these large-volume water sample will be stored for distribution to the scientific community in the future. These consensus materials are expected to improve the quality and accuracy of seawater trace metal concentration data over the next decade. Several students will participate in the three research cruises and receive training on trace metal sampling and intercalibration studies. The project also provides support for an early career scientist. The primary objective of this project is to improve the quality of trace metal data in the ocean over the next decade through optimized methodologies and well-studied consensus samples that can be used to assess accuracy. Samples will be collected from the surface and 1000 m at Station ALOHA, which brackets common ranges of open ocean dissolved metal concentrations. In addition, two surface stations in the Gulf of Mexico that have lower salinities and higher organic content due to the influence of the Mississippi River outflow will be used to test the boundaries of sample storage and analytical intercalibration. Samples will be collected and homogenized within large volume tanks and dispensed into 500mL bottles for archiving and distribution to the community. These samples will be analyzed initially by fifteen laboratories worldwide for a suite of trace metal concentrations, to address two goals. First, the data will be compared statistically, via a collaboration with an expert statistician from the National Institutes of Standards and Technology, to calculate consensus concentration values for each element. This consensus concentrations will be reported on the GEOTRACES website, and the statistical best practices will be published. Second, this network of collaborators will explore common intercalibration issues that have arisen over the last decade by utilizing a range of analytical methodologies and conditions. The primary scientific impact of this project will be a set of well-studied consensus samples that can be used to monitor the accuracy of trace metal analyses of seawater over the next decade. This project will support one early-career scientist, one PhD student from the University of Southern California, and 5-15 graduate and/or undergraduate students from Texas A&M University who will participate in the staging and collection of samples from these expeditions. 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 EArly-concept Grant for Exploratory Research (EAGER) project will investigate a physics-based environment called Dronevision that will enable its users to see illuminated objects with their naked eyes and to have haptic interactions with them using their bare hands. It will use microdrones to materialize objects and synthetic actors for sensorimotor interaction with one or more human subjects. If successful, this work will fundamentally transform how researchers and the general public think about human-computer interaction. Applications of a Dronevision are diverse, ranging from education to manufacturing, healthcare, and entertainment. An immersive version of a Dronevision has the potential to revolutionize how people work, learn and educate, play and entertain, communicate, and socialize, potentially ushering in a whole new branch of science. The project includes the participation of PhD students, training them on a "high risk-high payoff" research topic with the opportunity to identify interdisciplinary dissertation topics. A conscious effort will be made to recruit students from underrepresented groups. Dronevision will use miniature sized drones called Flying Light Specks, configured with light sources, computation, and networking capability, to implement embodied reasoning about objects and their properties. A swarm of drones will illuminate objects and provide physics-based sensorimotor interactions. This project will attempt to address several unsolved research challenges. First, a drone should be configured with lights bright enough that render the drone invisible while flying and accommodating human interaction (e.g., poking). Second, drones should be able to localize in the Dronevision space with millimeter accuracy. This accuracy is required to provide realistic illuminations and to quantify the force exerted by a human subject accurately. Third, in response to the human exerted force, a swarm of drones should exert force back against the user consistent with Newtonian physics using the laws of motion, mass, and gravity. This project will work to design and develop transformative techniques for these challenges to implement translation, rotation, collision, and friction between objects illuminated in a Dronevision. It will evaluate these techniques quantitatively through studies with human participants to evaluate qualitative tradeoffs from the human perspective. 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

The ADVANCE Population Cancer Research (PCR) Training Program at the University of Southern California (USC) is based on a strong foundation of biomedical research, population science training, and professional education at USC and the Department of Population and Public Health Sciences (DPPHS). The ADVANCE PCR will use a comprehensive approach to increase the knowledge, skill, and capacity of predoctoral students in population-based research to enhance cancer control and prevention for all populations with precision using novel approaches and with experience in community engagement. We will do this through two key and highly integrated pillars: (1) academic training in population sciences and the science of cancer prevention and control research, and (2) professional training in population sciences and cancer prevention and control research. The proposed activities within the academic training pillar are designed to increase knowledge and understanding about key concepts in population health and cancer research in heterogenous populations through various academic offerings that include a new Population Health Certificate training, elective courses offered at DPPHS that will complete the core training in epidemiology, biostatistics, or health behavior research of our trainees, scientific seminar offerings with unique focus on population science, cancer prevention and control and cancer research, and hands-on training in applying this knowledge through mentored population cancer research, which will culminate in the PhD dissertation. These academic learning activities will be complemented with activities that will sustain the professional education pillar and will include training navigation to provide precision mentoring and professional and career development through workshops and participation in scientific activities. To enhance the professional education pillar, the ADVANCE PCR program will provide community engagement training through participation in community outreach and engagement events, community education opportunities, and partnership with a community mentor to work on community-based projects. These two training pillars will work synergistically to promote population-based research and provide training in three key areas: population research that considers the variability that exist across populations, multi-level preventive interventions, and methodology to prepare the next generation for careers in population cancer research.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Temporomandibular jaw joint osteoarthritis (TMJ OA) and other disorders of the TMJ affect up to 12% of the US population. OA in general is the leading cause of disability in the US and is characterized by the deterioration of the superficial cartilage lining the joints. A contributor to the high incidence of TMJ OA is the fact that humans are unable to regenerate the specialized superficial cartilage of joints. Current treatments are limited to minimizing pain instead of restoring natural joint structure and function. The Crump lab has recently shown that adult zebrafish can regenerate the superficial cartilage of the synovial jaw joint after injury. This model relies on transecting a major ligament supporting the jaw, which results in joint degeneration in the short term and full regeneration of the superficial cartilage lining the jaw joint after the ligament heals. The limitations of this surgical model are that it is labor-intensive, low-throughput, and highly variable. Using an f13a1b enhancer which we discovered drives highly specific activity in superficial cartilage of the jaw and other neural crest-derived joints, I have generated transgenic lines to specifically ablate joint cartilage. Using this ablation model, I have found that jaw joint superficial cartilage regeneration is highly reproducible, and this will allow me to investigate the source of new cartilage cells. For this proposal, I plan to optimize the transgenic model for joint cartilage ablation, and then investigate the sources of the regenerating cartilage. To do so, I have identified through single-nuclei chromatin accessibility studies several cell type-specific enhancers that will allow me to mark and lineage trace putative progenitors during joint regeneration. Three potential sources of regenerated joint chondrocytes will be investigated: 1) The perichondrium surrounding the jaw joint could house progenitor cells that move into the joint upon ablation and form new superficial chondrocytes. 2) Deeper chondrocytes at the joint, which share properties with growth plate chondrocytes, could transdifferentiate into superficial chondrocytes following ablation. 3) Rare superficial chondrocytes that escape ablation could proliferate and repopulate the joint surface. Using newly identified cell type-specific enhancers, I will create CreERT transgenic lines to trace the contributions of each population during jaw joint cartilage regeneration. In parallel, I will carry out a single-cell multiomic analysis of the regenerating jaw joint to discover in an unbiased way potential progenitor cells activated by injury that may mediate repair. By identifying the source of jaw joint cartilage regeneration in zebrafish, I will be poised to further explore the molecular basis by which zebrafish can regenerate their joint tissues. In the future, we hope to uncover whether similar populations exist in the human TMJ that can be activated to counteract OA.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT. Despite advances in long-term antiretroviral therapy, people living with HIV (PLWH) exhibit residual viral replication and chronic inflammation that can drive a range of clinical co-morbidities. At the same time, efforts to develop a vaccine that could prevent, control, or eliminate HIV have not yet been successful. To bypass this problem, recent advances in CRISPR gene editing offer the possibility of engineering B cells directly, to secrete custom antibodies such as broadly neutralizing antibodies (bnAbs) that control HIV. As a living drug, engineered B cells could act as sensors, responding to HIV replication or vaccination, and secreting bnAbs that could reach therapeutic levels. In addition, B cells play critical roles integrating the innate and adaptive immune systems through antibody effector functions, presentation of antigens on both HLA class I and II, and by providing costimulatory signals to T cells. However, despite the potential of engineered B cells to form a novel HIV cell therapy, a potential barrier to their development is the suboptimal function of B cells in PLWH, which includes defects in T cell help. A major goal of this project is to develop an approach to provide the necessary T cell help and produce bnAb-engineered B cells that would be functional in PLWH. In Aim 1, we will design a series of synthetic protein signaling molecules that engage B cell circuits induced by T helper cells, and screen their function in reporter cell lines. In Aim 2, we will examine the ability of these molecules to drive B cell functions in primary human B cells and tonsil organoid models of vaccination. Finally, in Aim 3, we will examine the ability of engineered B cells to respond to and control HIV in a series of in vitro and in vivo models. This project encompasses cutting edge concepts and tools of cell and gene therapy. The lab and environment I have selected for this fellowship has both the facilities and expertise to fully support me in this endeavor. In addition, USC’s clinical cell therapy program is supported by both a cGMP facility and a CIRM-funded Alpha clinic, with training programs in cell therapy and expertise to help. The project also needs access to materials from PLWH, waste tonsil samples and mouse facilities suitable for HIV humanized mice work, which are all available in this environment. I will also be afforded opportunities for training in a world-class clinical environment with mentors who understand the challenges and immense opportunities afforded by a career as a physician-scientist. My training plan integrates both clinical and research experiences throughout the different phases of the MD/PhD program, to ensure that I gain the skills necessary to become a physician scientist with expertise in gene and cell therapy, poised to use these new types of medicine in my own clinical practice and future research.

NSF Awards · FY 2024 · 2024-09

This project will develop new AI-based techniques to detect anomalous behavior of individuals and groups based on their GPS locations. Most everyone with a cell phone generates data on their location multiple times per day, and this data is gathered by commercial companies for sale to advertisers. Besides advertising, this data can be used to discover behavior that is different from normal. This abnormal behavior can indicate that a person is starting to suffer from a mental disability like Alzheimer’s disease, and early detection can lead to early treatment when it is most effective. Anomalous behavior can also indicate that a person or group is planning or carrying out an illegal or terrorist act. The investigators will develop new AI algorithms for detecting anomalous location behavior of both individuals and groups, which will be the main innovation of this research. The investigators are aware of the sensitivity of location data, and they have been frequent innovators of techniques for protecting location privacy. In the course of this research, the investigators will not attempt to identify any individuals nor groups from their location data. The goal of this project is to detect anomalous behavior of individuals and groups based on their GPS location trajectories. The investigators will develop a temporal graph neural network (GNN) to discover behavior that differs from normal. Given that a GNN requires constant-length vector inputs, the first step will be to encode GPS trajectories and their context. This is a challenge, because raw trajectories are represented with varying numbers of time-stamped latitude/longitude points. The trajectory encoding will also include the context of the trajectory in terms of which roads were used, which locations were visited, and which points of interest were nearby the visits. Using an LSTM recurrent neural network, the context-rich trajectories will be represented dynamically as the input trajectories change over time. This novel, multifaceted representation of trajectories will provide the rich context that is necessary to classify normal and abnormal location behavior. After embedding the trajectories, the investigators will train a dynamic GNN to characterize location behavior of normal individuals as well as the location behavior of groups of individuals. The graph will change over time as the embedded trajectories change with time. The trained GNN will be the main component of the investigators’ dynamic graph anomaly detection (DGAD) approach. DGAD will take the time-evolving graphs from the GNNs and predict the next graph in the temporal sequence. If the predicted graph deviates significantly from the actual computed graph, this indicates a possible anomaly. Significantly, the anomaly can appear as a deviation from an individual’s embedded trajectory (i.e. a node attribute on the graph) or as a structural deviation of the graph (e.g. the edges connecting groups of individuals). In this way, the DGAD will find anomalous behavior of both individuals and groups, which is the project’s main innovation. 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

ABSTRACT The development of biomarkers for Alzheimer’s disease resulted in the use of positron emission tomography (PET) and biofluid assays to detect AD pathology before clinical symptoms. However, these studies were conducted in predominantly non-Hispanic white populations to establish cut-off values for clinical trial recruitment, which have not translated well to Hispanic and African Americans (AA). The proposed project aims to comprehensively measure phosphorylated tau species p-tau217 in plasma from the Health and Aging Brain Study-Health Disparities (HABS-HD) study. We have previously demonstrated that combining p-tau217 with Aβ42/40 ratio and other AD covariates into predictive models resulted in detecting amyloid positivity at ≥ 20 Centiloids with 88% sensitivity and 90% specificity. We propose to leverage the HABS-HD cohort plasma samples to quantify plasma Aβ42/40 and p-tau217 levels in amyloid PET positive and negative in Hispanic and AA populations to determine cutoffs relevant to ethnicity and race. The overarching hypothesis of this project is that plasma biomarkers related to AD pathology present differently among diverse populations and as a result have different relations to established clinical outcomes such as PET amyloid levels and cognitive outcomes. To test this hypothesis, we propose to characterize plasma p-tau217 and Aβ42/40 in Mexican Americans, AA and non-Hispanic white populations of the HABS-HD study. Additionally, we propose to investigate how other AD hallmarks are associated with p-tau217 and Aβ42/40 in these individual populations. Resultant data will not only document the biomarker protein levels for the HABS-HD cohort for sharing in the longitudinal study but may also inform on whether amyloid PET scans can be reduced in the screening process.

NSF Awards · FY 2024 · 2024-09

NON-TECHNICAL SUMMARY: Most technological devices today rely on thin films at various stages of their production. Despite being a small fraction of the overall material used, these films—measuring just a few microns or less in thickness—play a crucial role in energy production, transmission, and storage. Traditional methods of fabricating thin films for energy applications involve vacuum deposition; while this produces high-quality films, it also demands significant energy input and expensive equipment. These requirements pose major obstacles to reducing the overall cost of thin film technologies. To address these challenges, this project, supported by the Solid State and Materials Chemistry program in the Division of Materials Research and the Macromolecular, Supramolecular and Nanochemistry Program in the Division of Chemistry at NSF, explores solution-based methods for depositing thin films that are more energy-efficient and cost-effective. Central to this approach are liquid inks that, once applied to a surface, decompose during curing and heating to form the desired thin film. A primary goal of this project is developing liquid inks to create sulfosalt thin films (drawing inspiration from naturally occurring minerals) for solar energy applications. Additionally, the project aims to dissolve elemental allotropes of phosphorus to create a new class of inks for producing phosphide-containing thin films. An integral part of this project is providing research opportunities to students from Cerritos College, a minority-serving community college in Los Angeles County. Through a summer internship program in materials chemistry, community college students will data mine natural mineral targets at the Natural History Museum of Los Angeles. They will then attempt to convert these promising minerals into thin films and study their properties. This program aims to give students valuable STEM research experience, which is often unavailable at the community college level, thereby improving their chances of transferring to four-year institutions. TECHNICAL SUMMARY: There is significant interest in developing new inks for low-cost thin film deposition with an emphasis on expanding the flexibility of bulk materials that can be dissolved to generate these inks, impacting both composition and raw material costs. Thiol-amine-based inks meet these criteria. This project leverages the characteristics of thiol-amine inks to explore two novel directions in materials chemistry. First, the inherent flexibility of thiol-amine solvent-based ink formulation will be utilized for the compositionally controlled deposition of perovskite-inspired solar absorber thin films. These films will be based on environmentally stable, lead-free sulfosalt minerals containing cations with high-Z ns2 lone pairs. The research will investigate self-healing properties in these thin films, examine the extent of stereochemically active lone pair structural distortions using synchrotron techniques, and evaluate the most promising candidates as solar absorbers. Second, this project will extend thiol-amine solvents beyond the solution deposition of metal chalcogenide thin films. The solution-phase reaction of white and red allotropes of phosphorus with various zero-valent metals and/or the co-dissolution of Zintl anions with metal cations will be explored for the deposition of metal phosphide thin films using this entirely new class of inks. 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 Background: Multiple organ failure is associated with a persistent systemic inflammatory response. Neutrophils, the most abundant leukocytes in blood, are important effectors of this response. Our preliminary data identified gene expression changes in human neutrophils common to patients with 1) septic shock due to an intraparenchymal infectious source (such as pneumonia and abdominal abscess); and 2) sterile vasoplegic shock after major surgery requiring cardiopulmonary bypass. This included increased levels of genes important for leukocyte extravasation and migration through tissues. Importantly, these changes were not seen in neutrophils from patients with sepsis from primary bloodstream and urinary tract infections, that is, from patients without parenchymal injury. Similar changes have been reported in patients after traumatic injury. Hypothesis: We hypothesize that neutrophils responding to diverse inflammatory insults causing parenchymal damage display a common, pro-invasive gene expression program. Methods: In Aim 1, we will use existing whole-transcriptome RNA-seq human neutrophil data from our laboratory to define the gene expression signature common to septic shock with intraparenchymal source; multiple organ failure after major surgery; and traumatic injury. Upstream regulators of key gene modules will be investigated as well as relevant biological pathways. In Aim 2, we will validate the gene expression signature in secondary analysis of 11 published human neutrophil and leukocyte transcriptome datasets. These datasets include microarray, bulk RNAseq, and single cell RNAseq data from septic patients with intraparenchymal versus non-intraparenchymal source, surgical patients, and patients with traumatic injury. In both Aim 1 and Aim 2, we will compare differences in dynamic expression between patients who developed multiple organ failure, versus those who recovered without complications. Expected Results: We expect to identify and validate a targeted neutrophil gene expression program specific to parenchymal damage; to define the dynamic expression of this program in the development of multiple organ failure versus good recovery; and to identify candidate upstream regulators for future investigation. Impact and Long-Term Goals: This study will address current gaps in understanding of the specificity of the systemic inflammatory response and its relationship to multiple organ failure.

NSF Awards · FY 2024 · 2024-09

Mathematics plays a critical role in students’ career choices as well as their success in STEM fields. Unfortunately, math performance often declines as students’ progress through the grade levels and the aftermath of the COVID19 pandemic has worsened the situation. Research has shown that when teachers have strong content and pedagogical content knowledge that they can provide better quality mathematics instruction to their students and improve student outcomes. The goal of this project is to enhance elementary school teachers’ capacity to improve students’ mathematics learning through a scaled professional development program that uses artificial intelligence (AI) to create a personalized, active learning environment for teachers. The professional development program focuses on key elements of content-specific expertise needed for teaching, such as enhancing teachers’ understanding of the foundational ideas behind numbers and operations concepts that are developed across grade levels, as well as teachers’ understanding of how students learn these concepts and how various instructional tools and practices can improve students’ learning. By creating a professional development that is adaptive to the individualized needs of teachers and is accessible to teachers anywhere and at any time, this work has the potential to change student outcomes at scale. The professional development program utilizes advances in AI to create an inquiry-based learning environment for teachers to enhance their understanding through solving problems of practice. Equipping teachers with the knowledge and skills crucial for quality teaching has the potential to improve mathematics teaching and learning at scale, which has the potential to reduce the opportunity gaps to quality teaching faced by underserved students. The specific focus of this project is to enhance elementary school teachers’ content and pedagogical content knowledge of numbers and operations using a multiple-AI-agent to guide teachers’ development of a conceptual understanding of the content as well as ways to make the content more accessible to their students. Rather than AI delivering the information, the AI tool will serve as a facilitator to create a learning environment in which teachers meaningfully engage with purposefully developed activities and learn through the process. The research questions the work addresses are: (1) In what ways can advances in AI be incorporated into the AI-based interactive professional development program? (2) How well does the AI-based professional development program enhance teachers’ content and pedagogical content knowledge of numbers and operations? and (3) How well does the AI-based professional development program enhance the quality of mathematics teaching and students learning of numbers and operation? The professional development program and AI tool will be developed through multiple iterations and inputs from several key stakeholders, such as teachers, teacher educators, and content experts. The study will use a mixed methods approach. The effectiveness of the fully developed program on instruction and student learning will be explored through a randomized controlled trial with 200 elementary school teachers. The final version of the program will be made available online. The Discovery Research preK-12 program (DRK-12) seeks to significantly enhance the learning and teaching of science, technology, engineering, and mathematics (STEM) by preK-12 students and teachers, through research and development of innovative resources, models, and tools. Projects in the DRK-12 program build on fundamental research in STEM education and prior research and development efforts that provide theoretical and empirical justification for proposed projects. 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 · 2024-08

Project Summary Before leaving high school, approximately 1 in 4 sexual minority adolescents will attempt to end their own life; a rate that is nearly four times higher than their heterosexual peers. Social determinants in the family context through parental acceptance or rejection is a major, consistent risk factor. Despite progress in social acceptance of sexual minorities, in 2015 the Pew Research Council noted that 40% of parents reported they would be upset or somewhat upset if their child came out as sexual minority. Parental acceptance is a crucial upstream determinant for sexual minority adolescents’ wellness, but remarkably scant research has focused on how parents get to acceptance; a vital unanswered question impeding intervention development. The stall in research is partially due to the hard-to-reach nature of the hidden population of parents of sexual minorities. The goal of this sequential explanatory mixed methods project is to explore parents’ mental health and help-seeking behaviors after their child comes out as sexual minority. With substantial work in social determinants of sexual minority suicide prevention, our team is uniquely positioned to complete the proposed exploratory study, which aligns with the developmental purposes of the R21 mechanism and responds directly to the Notice of Special Interest in Research on Family Support and Rejection in the Health and Well- Being of SGM Populations (NOT-OD-23-166). We aim to (1) compare four strategies to recruit parents of sexual minorities to a brief, online survey about their mental health and help-seeking when their child came out; (2) describe parents’ mental health after their child’s coming out and the help- seeking resources parents sought for their mental health to navigate their child’s coming out; and (3) explore pathways, facilitators, and barriers to parents’ help-seeking for individual-level and family- level health needs after their child came out, including resources they wished they had and suggestions to improve help-seeking resources. For Aim 1, we will examine the effectiveness of 4 strategies to recruit parents of sexual minority adolescents to complete an online survey to explore mental health (e.g., depressive symptoms, ambiguous loss) and help-seeking behaviors when their child came out. For Aim 2, we will use the survey data from Aim 1 to examine correlates of mental health symptomology, overall help-seeking behaviors, and among specific forms of formal (e.g., medical professional) vs. informal (e.g., pastoral professional) help-seeking behaviors. For Aim 3, we will use semi-structured interviews to deeply explore parents’ experiences around their mental health and help-seeking behaviors when their child came out to them. Using a family systems perspective to explore the help-seeking needs of parents of sexual minorities opens new avenues for upstream prevention and implementation studies to address health disparities for sexual minorities.

NIH Research Projects · FY 2025 · 2024-08

SUMMARY Hepatic stellate cells participate in liver wound healing but also in progression of liver fibrosis and promotion of liver cancer. Heterogeneous subsets of activated HSC (aHSC) are generated and assumed to have different functionalities in liver disease. Severe alcohol-associated hepatitis (AH) is manifested as acute on chronic liver failure with high mortality on the background of cirrhosis harboring heightened aHSC activity. Yet, the roles of aHSC in AH are understudied. This gap is remarkable considering known functions of aHSC in both liver inflammation and fibrosis, the two key pathologic features of AH. Our scRNA-seq analysis revealed the emergence of a novel subset of aHSC co-expressing the HSC marker Lrat and the portal fibroblast marker Fbln2 in a murine AH model. The Lrat+Fbln2+ aHSC arise from Lrat+ quiescent HSC per genetic lineage tracing and constitute the most profibrotic, myofibroblastic and inflammatory aHSC subset. Ade-convolution analysis of AH patient liver vs. healthy liver RNA-seq, supports an expansion of such subset in AH patients and IHC and FISH confirm the presence of FBLN2+ aHSC expressing inflammatory and immunoregulatory genes in AH patient livers. In a list of differentially overexpressed genes in Lrat+Fbln2+ cells via scRNA-seq, we identified Prrx1 known for myofibroblast (MFB) differentiation, the orphan nuclear receptor Nr4a2, and Cyp1b1. Supervised re-clustering by Prrx1 and Nr4a2 expression and subsequent RNA velocity and copy number variant (CNV) estimate analyses, suggest the roles of these two nuclear proteins in the clonal development of Fbln2+ aHSCs. Further, in vitro loss of function studies on FBLN2+ LX2 cells, reveal CYP181 being a driver of NR4A2 and PRRX1 expression and unique positive cross-regulations among them in the genesis and maintenance of the proinflammatory MFB phenotype of LX2 cells. Based on these results, we propose to test the hypothesis that CYP181 positively controls PRRX1 and NR4A2 which in turn positively feedback-regulate CYP181 to support a clonal development of the FBLN2+ aHSC and contribute to the AH phenotype characterized by heightened fibrosis, inflammation, and immunoregulation. To test this hypothesis, we aim to determine: 1) if and how CYP181, PRRX1 and NR4A2 cross-regulate to generate FBLN2+ aHSC; 2) the phylogenic makeup of the Lrat+Nr4a2+Prrx1+ subpopulation via simultaneous CNV and SNV analysis at single cell level; 3) if CYP181 is required for the genesis of Lrat+Fbln2+ aHSCs in vivo and contributes to the AH pathologic phenotype by using Cyp1b1'1f,-Fbln2-iCre-ERT2 mice; and 4) the translational relevance and spatial characteristics of CYP181+, PRRX1+, NR4A2+ aHSCs in non-AH AALD vs. AH patient livers and insights into their implications in a transition from the former to the latter. Through these efforts, we plan to pursue our ultimate goal of identifying a disease-causing aHSC clone in AH, defining its underlying genetic and molecular mechanisms, and designing innovative AH therapeutic approaches targeting such clone.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT The challenge of repairing extensive bone injuries remains an unmet clinical challenge. Our research is dedicated to exploring a novel mouse model of large-scale bone regeneration to unravel the intricate cellular and molecular events necessary for the large-scale regeneration. While the outer periosteum and the inner endosteum are recognized as sources of new osteoblasts during normal bone homeostasis, the precise mechanisms governing the initiation and coordination of repair are not well-understood. We hypothesize a two- phase repair process following large-scale injury. Initially, a sentinel-type cell population marked by the expression of Sox9 transitions from quiescent to activated state. In the second phase, we propose that this subpopulation orchestrates the recruitment of other cells, including bone marrow-derived subpopulations, and culminating in a callus spanning the injury site. Building on our previous work, which has shown the requirement for Sox9-lineage cells in large-scale repair, in Aim 1 we investigate the mechanisms that trigger activation of these cells in response to injury. Specifically we test that the gene Fos is required for their activation and for the transcription of genes important for coordinating repair. In Aim 2 we determine if these Sox9-lineage cells recruit bone marrow stromal cells expressing Cxcl12, with this interaction being vital for robust bone callus generation. Finally, In Aim 3, we determine if Sox9-lineage cells originating from the rib possess distinctive features that enable them to facilitate the healing of critical-sized femur injuries, possibly through recruiting Cxcl12-lineage cells from the femur bone-marrow niche. The successful completion of these experiments will provide invaluable insights into the critical cell types and mechanisms driving large-scale repair in a mammalian model. These insights could lay the groundwork for future pre-clinical studies targeting challenging skeletal injuries in patients.

NIH Research Projects · FY 2024 · 2024-08

Project Summary Psychiatric emergencies comprise a large and increasing proportion of emergency department (ED) visits, with many psychiatric patients receiving suboptimal care while boarding in EDs. The Emergency Medical Treatment and Labor Act (EMTALA) established a duty for hospitals to screen and stabilize patients presenting to EDs regardless of ability to pay. EMTALA requires that any patient with a medical or psychiatric complaint presenting to a dedicated ED have a timely screening exam, stabilization of emergent conditions, and transfer to another facility for a higher level of care if services required for stabilization are unavailable at the original facility. Hospitals violating EMTALA are at risk for termination of Medicare provider agreements, which typically results in hospital closure or downgrading of emergency services. Despite potentially grave consequences, hospitals continue to violate EMTALA. Overall, 17% of EMTALA citations are labeled by the enforcing agency as involving psychiatric conditions. However, a review of recently available data suggests that these labels underestimate citations involving psychiatric conditions. Specific conditions and circumstances (e.g., suicidal ideation, threats to staff) resulting in care denial or outcomes of involved patients (e.g., hospitalization, death, incarceration) have not been explored. A more rigorous exploration and categorization of individual citations associated with the care of patients with psychiatric emergencies is warranted to inform care, encourage compliance, and maintain uninterrupted provision of emergency services. Higher odds of EMTALA citations are found among hospitals that are large, urban, for-profit, and disproportionately serve Medicaid patients. However, hospital-level factors associated with EMTALA citations involving psychiatric emergencies have not been explored. Hospitals with less capacity to care for patients with psychiatric conditions on-site are more likely to discharge patients compared with hospitals that have greater capacity. Whether the capacity of a hospital (or lack thereof) to stabilize patients with psychiatric emergencies is associated with risk of EMTALA citation remains uninvestigated. A multidisciplinary team, including an AHRQ-supported sponsor, co-sponsor, and key advisors, will provide support and guidance as the applicant develops and completes projects to 1) identify and characterize EMTALA citation events involving psychiatric emergencies, 2) explore novel measures of hospital capacity to care for patients with psychiatric emergencies, and 3) evaluate the association between hospital capacity to care for patients with psychiatric emergencies and receipt of EMTALA citations. Through didactics and completion of these projects, the applicant will gain experience with 1) health policy/analysis, 2) qualitative methods, 3) quantitative methods, 4) impactful dissemination of findings, and 5) writing compelling funding proposals, as he trains to become an independent health services researcher.

NIH Research Projects · FY 2026 · 2024-08

Dental, Oral and Craniofacial health (DOC) plays a significant factor in the overall well-being of the population. About half of all birth defects are associated with craniofacial malformations. Many other genetic conditions manifest themselves via phenotypes in the face and skull and are associated with communication disorders, neurological development and other factors. Furthermore, oral health plays a significant role in overall human health. Driven by the importance of DOC research to overall human health, the National Institute of Dental and Craniofacial Research (NIDCR) established the FaceBase Consortium in 2009 to advance research relevant to the NIDCR mission by creating comprehensive datasets of craniofacial development and dysmorphologies in order to disseminate these datasets to the wider craniofacial research community and support reuse of data for new research projects and collaborations. Since its creation, FaceBase has become a central data repository resource funded for dental and craniofacial researchers. We propose to build on the success of FaceBase to date to 1) expand our community outreach, training, and education resources by fostering an active community of users across the translational spectrum of Dental, Oral and Craniofacial (DOC) research and related disciplines trained in use of FaceBase, 2) enhance FaceBase services to efficiently serve a growing community ranging from single investigators to multi-consortia, and empower scientists across the translational spectrum of DOC research and other relevant health studies to advice their research using FAIR, TRUSTworthy, scientifically robust, data-driven, and AI/ML/DL-ready resources, and 3) build on our robust and agile project management structure to meet the new requirements of the extended use cases and community envisioned by this proposal.

NSF Awards · FY 2024 · 2024-08

This doctoral dissertation research project investigates how key evolutionary changes in locomotion influenced the relationship between cognition and movement performance in humans. Two significant shifts in locomotion occurred during the course of human evolution: (1) a transition to bipedal walking, and (2) the incorporation of long-distance aerobic activity associated with a hunting and gathering lifestyle. Each of these shifts altered movement and influenced how the brain and the rest of the body interact during locomotion. It is possible that both transitions required enhanced cognitive resources given that bipedalism challenges balance and stability, while long distance hunting and gathering combines endurance activities with cognitive tasks such as navigation, communication, and searching. To examine this question, this project uses dual-task laboratory experiments that demand the simultaneous performance of cognitive and locomotor (balance and endurance) skills. Results from this study inform fall risk prevention specially for high performance professionals who are required to perform dual-task activities. Undergraduate students are trained in research techniques and scientific communication, and K-5 students are provided with online educational programs and hands on after-school workshops. This study applies a novel experimental approach to assess the cognitive and locomotive costs of the brain-body interaction during bipedal walking. The methods applied are well established, but their integration in the analysis of cognition and locomotion is innovative. The project’s primary objectives are to determine (1) how bipedalism impacts the cognitive demands of locomotion and (2) how the shift to longer-duration hunting and gathering affects the relationship between cognitive demands and endurance. To address these aims, participants recruited into the study will be asked to complete single (motor) and dual cognitive-motor tasks in even and uneven terrains, with or without walking poles, and under non-endurance and endurance (30-minute walks) conditions. Cognitive tasks will include serial subtracting, n-back (identify whether the letter shown is the same one as two letters ago) and Stroop world color interference (where worlds for color are shown in different color fonts, and then the participants are asked whether the word and the color are congruent). The study’s relevance is high as both bipedal locomotion and higher cognitive functions are two of the most notable trends in human evolution. 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 · 2024-08

PROJECT SUMMARY Our multidisciplinary team endeavors to address critical knowledge gaps regarding the impact of type 1 diabetes (T1D) on neurocognitive outcomes among a diverse population of children. Throughout the study, our team will observe factors that contribute to neurocognitive outcomes, such as nutritional and lifestyle behaviors, environmental exposures, and social determinants of health (SDOH). We will also explore the potential protective effects of diabetes management technologies, such as continuous glucose monitoring (CGM) and automated insulin delivery systems, to promote better neurocognitive outcomes for these children. The cooperative agreement’s overarching goals are to establish a clinical consortium comprised of a pre-pubertal diverse cohort of children with newly diagnosed T1D to evaluate the impact of T1D on neurocognitive function and to identify potential clinical and environmental risk and protective factors associated with neurocognitive function in T1D. The project’s board led by Drs. Page, Raymond, and Xiang, demonstrate their commitment to scientific development and the execution of a nationwide consortium by proposing to serve as one of the 10 Clinical Centers operating within the proposed NIDDK consortium to recruit and track a nationally diverse cohort (estimate = 1000 children) representing the pediatric population of patients with T1D. Therefore, our project’s board and multidisciplinary team will leverage our recruitment sites at both Children’s Hospital Los Angeles and Kaiser Permanente Southern California to enroll 100 participants (5-11y); 50 with newly diagnosed T1D and 50 age, gender, and race/ethnicity matched controls for this longitudinal study. The team will monitor: glycemic control (CGM metrics and hemoglobin A1c); lifestyle (diet, sleep, and physical activity); environmental exposures and SDOH; brain development; and neurocognitive and neuropsychological outcomes. Our team will partner with the Steering Committee to establish our long-term objectives to harmonize methods and develop an optimal protocol for collecting and storing plasma, urine, and stool samples to create a biobank for future biomarker investigations that predict neurocognitive outcomes in children with T1D. The team’s three specific aims are to first identify the effects of glycemic control on neurocognitive outcomes in children ages 5-11 with a new T1D diagnosis, second to determine the impact and neurocognitive outcomes in children with T1D concerning children’s diet, sleep, physical activity, obesity, environmental exposures, and SDOH, and third to perform an integrated analysis to identify subgroups of children with T1D at an increased risk for adverse neurocognitive outcomes, including the influence of sex, race/ethnicity, lifestyle, and SDOH.

NIH Research Projects · FY 2025 · 2024-08

The 4 allele of apolipoprotein E (APOE4) is associated with accelerated aging and mortality as well as increased vulnerability to Alzheimer’s disease (AD). Although the causal links between APOE4, aging, and AD risk remain to be fully defined, candidate mechanisms include regulation of systemic immunometabolic outcomes. Our recent findings demonstrate that treatment with the novel mitochondrial-derived peptide MOTS-c increases healthy lifespan. Indeed, pathways identified to be beneficially regulated by MOTS-c overlap with pathways thought to underlie relationships among APOE4, aging, and AD. In this proposal, we investigate the central hypothesis that MOTS-c is a geroprotective peptide that targets systemic APOE4 phenotypes implicated in driving age-related cognitive impairment and AD pathogenesis. We will investigate this hypothesis by studying systemic and neural effects of MOTS-c across age in mice with human APOE genotypes both in the absence and presence of AD transgenes and in tau mice. Our studies will interrogate potential mechanisms hypothesized to underlie the protective actions of MOTS-c with an emphasis on lipid homeostasis and macrophage reprogramming. We propose three aims that are highly interactive across the labs of the two mPI labs who have strong expertise in AD and APOE (Dr. Pike) and MOTS-s and geroscience (Dr. Lee). Aim 1: Does MOTS-c protect against APOE4-associated aging phenotypes? We test the hypothesis that MOTS-c will improve systemic and neural outcomes in the contexts of aging and APOE4 genotype. Studies will test the ability of MOTS-c to prevent vs treat APOE4-associated phenotypes. We will also test the prediction that inhibition of endogenous MOTS-c will exacerbate aging outcomes, especially with APOE4 genotype. Aim 2: Does MOTS-c treatment provide protection/treatment against Alzheimer pathology in an APOE- dependent manner? The second aim is conceptually parallel to Aim 1 but with a focus on MOTS-c and APOE genotype in the context of AD pathology. These studies will be conducted in male and female APOE3 vs APOE4 AD mice and tau mice to determine potential sex differences and at two different ages to consider efficacies for both the prevention and treatment. As in Aim 1, we will also consider the effects of inhibiting endogenous MOTS- c. Aim 3: Does MOTS-c reprogram aging APOE4 macrophages/microglia to protect from Alzheimer pathology? We investigate the hypothesis that a primary mechanism by which MOTS-c protects against APOE4 phenotypes is reprogramming of monocyte-derived macrophages and microglia at both transcriptional and functional levels. Studies will test whether MOTS-c-programmed macrophages/microglia are poised to clear A more effectively and resolve inflammatory phenotypes that can impede neuronal homeostasis. Completion of the proposed studies will yield preclinical data that define the interactions and underlying mechanisms among MOTS-c, APOE genotype, sex, age, and intervention timing, relationships that are essential to the effective clinical translation of this novel mitochondrial-derived peptide approach to combat cognitive decline and AD.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT There is an unmet medical need to develop new therapeutic strategies for Alzheimer’s disease (AD). Brain lymphatic vasculature is (re)discovered at the interface between skull and brain (meninges) and is a pathogenic factor for AD. We recently found that meningeal lymphatic dysfunction drives neurocognitive defects in craniosynostosis disorder and established three independent approaches to activate brain lymphatics (Cell, 2021, PMID: 33417861; Cell Stem Cell, 2023, PMID: 37863055). The goal of this proposal is to determine whether craniosynostosis is a risk factor for AD and how our multiplex brain lymphatic activation approaches can be re-deployed to mitigate AD. These three approaches include the transcranial delivery of VEGF-C recombinant protein, intra-cisterna magna (i.c.m.) injection of AAV1-VEGF-C gene, and MSC implantation. They are derived from our investigation of skull-brain communication via skull mesenchymal stem cells (MSCs) and meningeal lymphatic endothelial cells (LECs) crosstalk in health and craniosynostosis. Craniosynostosis is a major craniofacial skull disorder characterized by the premature skull bone fusion due to suture MSC loss coupled with neurocognitive defects. Our meningeal lymphatic investigation in Twist1+/- craniosynostosis mice provides a foundational framework for structural and functional studies of brain lymphatics. Further mechanistic studies revealed that skull MSCs directly promote LEC growth via VEGF-C signaling. Preliminary data identified an abnormal buildup of amyloid β in Twist1+/- mouse brain, which is further exacerbated in the background of 5xFAD mouse model of AD. We are in a unique position to re-deploy these discoveries and multiplex tools to promote brain lymphatics as a therapeutic treatment for AD. We hypothesize that craniosynostosis is a risk factor for AD due to its impaired meningeal lymphatics, and lymphatic activation by multiplex approaches can promote brain fluid homeostasis and waste clearance, mitigating AD-like pathologies and behaviors. The successful outcome of this study will determine the efficacy of individual brain lymphatic activation approaches in promoting brain fluid homeostasis and waste clearance to mitigate AD pathogenesis.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Adverse birth outcomes, including prematurity and low birthweight, are a persistent public health problem in the United States. They affect nearly half a million newborns each year and contribute to long-term health challenges like cardiovascular disease and cognitive impairment. Risk for adverse birth outcomes is differentially distributed across the population and disproportionately high in low-income households. Past research suggests this discrepancy at birth is at least partially attributable to differing social and environmental exposures during the prenatal period, including differences in housing stability and affordability. Housing insecurity, or limited access to safe, affordable housing, is a common material hardship in low- income households, forcing many into unstable housing conditions and making health-related needs, like food and healthcare, more difficult to access and afford. Pregnancy is an especially vulnerable time for households to experience housing insecurity given the sensitivity of the mother and the developing fetus to environmental stress. A growing body of evidence links prenatal experiences of housing insecurity to adverse birth outcomes. For decades, the flagship policy solution to housing insecurity in the U.S. has been federal housing assistance. Administered by the U.S. Department of Housing and Urban Development (HUD), housing assistance programs provide stable, affordable housing to nearly 10 million individuals each year, including 5 million families. By reducing exposure to housing insecurity, housing assistance may play a critical role in reducing risk of adverse birth outcomes. Few studies, however, have investigated the impact of housing assistance on neonatal health and current estimates of an association with children's health are mixed, with roughly half of the analyses indicating no association and a quarter indicating negative health impacts. Many scholars attribute this inconclusive evidence base to a persistent set of methodological and empirical limitations, including selection effects, measurement error, effect heterogeneity, and mechanism ambiguity. To address these research gaps, our proposed study seeks to evaluate the impact of prenatal housing assistance on risk for adverse birth outcomes using a novel linkage of HUD administrative records for 2002- 2021 with California birth certificate data for 2004-2019. Our specific aims are the following: (1) To estimate the effect of prenatal housing assistance on birth outcomes, using quasi-experimental methods; (2) To determine if the effect of housing assistance on birth outcomes varies according to (a) category of assistance or (b) prenatal timing of assistance; and (3) To explore the role of neighborhood quality and maternal health behavior in mediating the relationship between prenatal housing assistance and birth outcomes. As government and health systems increasingly invest in the "promise" of affordable housing as preventive care, this project will generate a unique set of data and insights into the effects of housing assistance on neonatal health.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY HIV-related stigma and discrimination operate at multiple socioecological levels and are known obstacles to optimal health and HIV outcomes. In Zambia, some boarding school environments can be characterized by a culture of physical, verbal, and sexual abuse strongly linked to stigma and discrimination. Despite this, little data exists on the impact of HIV-related stigma or stigma reduction interventions within school settings, with even less attention to boarding schools. This study responds to the challenges of making Zambian boarding schools safe, stigma-free havens with reduced risk behaviors and improved health outcomes for learners, teachers, and support staff – both those living with HIV and those who are not. Building on evidence that addressing HIV stigma and discrimination can disrupt the cycle of violence that is both cause and consequence of HIV risk and vulnerability, this study’s objective is to pilot test and evaluate a ‘total school approach’ to addressing HIV-related stigma and discrimination in boarding schools, embedded in a safeguarding framework. We will co-create stigma reduction intervention packages with learners, teachers, staff, people living with HIV and other key stakeholders at two boarding schools in Zambia. Learners, teachers, and staff will be trained to then deliver trainings to at least 80% of each school’s population. For Aim 1, we will conduct a formative phase to adapt a ‘total facility approach’ for addressing stigma and discrimination in healthcare to the Zambian boarding school setting, and to co-create an intervention package, that uses a safeguarding approach, with the participating school communities. For Aim 2, we will carry out a paired pre- post study to pilot test the impact of the intervention on stigma and discrimination and broader safeguarding measures. We will implement a pre-post study design with outcomes measured through repeat paired surveys before and after the intervention. For Aim 3, a mixed-methods process evaluation will explore how the school environment affects its population’s attitudes and behaviors and seek to understand implementation barriers and facilitators with a view to informing sustainability and scale-up. The primary outcome measures will be self- reported experience of abuse and stigmatizing attitudes relating to HIV. Mixed-methods approaches will provide insight into why different elements of the intervention worked/did not work and maximize learning about implementation of this approach to fostering a safe school environment, free from stigma and discrimination so as to improve HIV-related outcomes.