Pennsylvania State University, The

NIH Research Projects · FY 2025 · 2025-01

Project Summary: Nanoplastics (plastic particles smaller than one micron) are ubiquitous in our environment. Nanoplastics are found in our food, drinking water, and even in the air we breathe. However, knowledge is just now emerging regarding the uptake and accumulation of nanoplastics into the body and how this may impact human health. Of particular concern is how nanoplastics may impact the brain. Exposure to airborne pollutants and toxins has been found to be a strong risk factor in the development of neurodegenerative disease, and interestingly, a decreased sense of smell (anosmia) has been found to be one of the best predictors of the development of neurodegenerative disease. This raises the possibility that nanoplastics can enter the brain via the olfactory system. The olfactory sensory neurons that line the nasal epithelium send direct axon projections into the brain, making the olfactory system a potential a conduit for inhaled foreign substances to enter the brain. In neurons, the active transport of vesicles and organelles down axons from the neuronal cell body to synapses is carried out by kinesin motor proteins that walk along microtubule tracks. The overarching hypothesis of the proposed work is that nanoplastics are taken up by neurons in the periphery, hijack the kinesin-microtubule axonal transport machinery, and are thereby rapidly transported into the brain. To test this model, we (neuroscientist Drew and biophysicist Hancock) will investigate plastic nanoparticle uptake in the mouse olfactory system in vivo and nanoparticle interactions with kinesin motor proteins in vitro. Our preliminary studies have shown that intranasal application of fluorescent polystyrene nanoparticles in mice results in nanoparticle uptake by olfactory sensory neurons and spreading to the olfactory bulb over just a few hours. This transport is far too rapid to be accounted for by diffusion, suggesting the possibility that the nanoparticles are actively transported by kinesins. It is known that kinesins can bind to plastic nanoparticles through their tail domain, which normally binds intracellular cargo. Using nanoplastics of different size, shape, and surface chemistry, we will use single-molecule microscopy experiments to investigate the rules governing the binding of kinesin-1, 2 and 3 family transport motors to plastic nanoparticles, and their resulting transport along microtubules. We hypothesize that the kinesin tail domain is inherently ‘sticky,’ and that binding to nanoparticle surfaces relieves the normal autoinhibition of these motors, which normally prevents their mislocalization in the absence of cargo. In parallel, we will use histology and in vivo microscopy to investigate the dynamics and the potential pathways that nanoparticles may use to enter the brain. These combined in vivo and in vitro experiments will provide a comprehensive understanding of nanoplastics uptake and transport in the olfactory system, and will test the important potential link between nanoplastics exposure and neurological disease.

NIH Research Projects · FY 2025 · 2024-12

Project Summary Holobionts assemble their microbial communities from a biosphere teeming with bacteria, viruses, and fungi, yet host-associated studies of microbial communities are largely dominated by bacteria-centric foci that overlook the kingdom-level diversity of bionts in hosts. Gut fungi in animal hosts interact with members of the gut bacteriome, respond to diets, and contribute to gut homeostasis, but can be difficult to study due to the relatively low biomass in the gut. Hence, the host genetic, evolutionary, and bacterial community factors that influence mycobiome form, function, and diversity are often overlooked but potentially indispensable for understanding the missing or less studied components of the holobiont. Such effects in humans have not, thus far, been investigated. While several gut bacteria are heritable, associate with human genetic variants, and codiverge with hominids, the potential genetic and evolutionary bases of the gut mycobiome remain enigmatic. Thus, the central hypothesis of this proposal is that genetic variants, gut bacterial genes and taxa, and/or hominid evolution shape the diversity and composition of human gut fungi. I will test this hypothesis with three specific aims. First, I will determine human genetic heritability of the gut mycobiome by sequencing the gut mycobiome of monozygotic and dizygotic twin participants in the TwinsUK cohort. Heritable gut bacteria and fungi will be compared for correlations in monozygotic compared to dizygotic twins that may suggest co-heritability (Aim 1). In Aim 2, I will investigate the number and types of mycobiome-associated human genetic variants in a genome-wide association analysis (GWAS) of the human gut mycobiome, and I will evaluate the number and types of bacterial taxa and functional genetic categories that underpin gut fungi variation using a microbiome-wide association test (MWAS). In Aim 3, I will evaluate if evolutionary history of humans and their closest hominid relatives influences the structure of the gut mycobiome via tests of topological congruency, co-diversification, and machine learning. Together, these analyses will break new ground on resolving experimental, quantitative, and conceptual themes of human gut fungi that may parallel those for human gut bacteria. The devised training plan to support my career development includes the assembly of a multi-institutional Postdoctoral Mentoring Committee, mentoring opportunities and training in higher education pedagogy, and scientific education outreach activities. The proposed research is carried out under the guidance of Dr. Seth Bordenstein and Dr. Emily Davenport at The Pennsylvania State University.

NIH Research Projects · FY 2025 · 2024-11

Project Summary / Abstract The American Physiological Society’s Integrative Physiology of Exercise (IPE) conference is the preeminent scientific meeting for researchers in human performance and integrative exercise physiology. Planning for the next biennial meeting is underway with a proposed Fall 2024 meeting venue at Penn State’s main campus to be held in conjunction with the 50th Anniversary of Noll Laboratory, the Nation’s first and oldest free-standing research institute dedicated to the study of exercise and environmental physiology. This two-day conference will focus on the future of human performance and aging research, and other hot topics within integrative physiology. The program will start with a historical marker dedication and welcome reception followed by two days of research presentations and poster sessions on a range of topics including, but not limited to: The history of human performance research at Noll Lab; Effects of aging and physical activity on cardiovascular structure and function; Thermoregulation and blood pressure regulation in women across the lifespan; Aging and working in a hotter world; Lessons in resistance training and hypertrophy: update on molecular mechanisms; Exercise and experiments of nature; Climate change and kidney vulnerability in outdoor workers; Mechanisms of vascular endothelial insulin resistance and therapeutic targets for intervention; Exercise, energy balance, and reproductive health; Exercise and related strategies to counteract the health consequences of high dietary salt; Update on the molecular transducers of physical activity consortium (MoTrPAC); The role of physical activity and exercise in precision health; Modulators of oxygen supply–demand balance that influence endurance performance limits; The potential of artificial intelligence in human performance and integrative physiology research. Special sessions are also planned for 1) professional guidance for trainees, 2) an expert panel discussion of current research challenges and future opportunities for the field, and 3) a thought- provoking/engaging presentation open to the public. Based on previous in-person attendance at IPE conferences we anticipate that this conference will attract approximately 300 attendees, of which over 50% will be students. This application requests funds to defray travel and registration costs (junior investigators, underrepresented minorities, individuals with childcare/family responsibilities) and travel expenses (airfare, hotel, registration) for session speakers as determined by need.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT The opioid epidemic is a critical public health crisis in the United States; over 100 Americans die each day from an opioid overdose. To date, there are few effective treatments for individuals suffering from opioid use disorder. Critically, there is considerable data that demonstrates that men and women differ on opioid use characteristics. For example, women appear to progress more quickly from initial use to problematic use than men. Although this and other sex differences in opioid use characteristics have been reported, neuroimaging studies of opioid abusers have been mostly limited to males. Additionally, human neuroimaging studies have examined functional connectivity after chronic opioid exposure; thus, it is unclear if baseline differences in brain connectivity predict opioid misuse. This project addresses these unanswered questions by examining sex differences in neural mechanisms that underlie opioid use. We will examine circuitry-based changes utilizing resting-state functional magnetic resonance imaging (rsfMRI) in awake, non-anesthetized mice. This method allows for the longitudinal assessment of brain activity and drug behaviors in the same animal. In Aim 1, adult male and female C57BL/6J mice will undergo rsfMRI to characterize baseline resting-state functional connectivity (RSFC). Mice will then be allowed to voluntarily consume morphine. These data will allow us to determine if RSFC is a biomarker capable of predicting an individual’s vulnerability to initial opioid consumption. In Aim 2, the same mice will have a second rsfMRI to characterize post-drug RSFC. These data will allow us to determine if there are sex differences in morphine-induced changes in RSFC. The long-term goal of this work is to develop targeted treatments that could aid individuals suffering from opioid use disorder.

NIH Research Projects · FY 2024 · 2024-09

Project Summary/Abstract The proposed study is a longitudinal mixed methods social network analysis (MMSNA) of a novel peer-led community-based reentry program aimed at a vulnerable population: older men transitioning from prison after completing long (10+ years) sentences. The Cumberland House Reentry Program departs from traditional community corrections programs by immersing older, previously incarcerated (OPI) men into a peer-run house designed to build and enhance peer and community social ties. This previously untested program relies on the principles of network alteration and provides a case study for examining interpersonal mechanisms underlying a behavioral health program. With a MMSNA research design, we propose collecting both (1) dynamic sociocentric network data of house residents and staff and (2) qualitative data of health and interpersonal relationships. We then analyze if, when, how, and why the program performs as expected. Moreover, we leverage implementation science to document program fidelity and implementation, key NIH priorities. Such research permits the translation of basic science results into realistic future network interventions by documenting how to deliver similar interventions at scale that supports effectiveness. With the assistance of internal seed funding, our interdisciplinary team has studied the program's development and delivery from its outset, providing preliminary results and a unique opportunity to evaluate the implementation process in real time. Such research is extremely rare and allows us to document the real-world contextual factors that may drive effectiveness, or alternatively, result in null or even iatrogenic effects for health and other reentry outcomes. To evaluate program impacts for long-term health and criminal justice outcomes (e.g., rearrest and reincarceration), we will request a matched sample of untreated older, previously incarcerated men through the PSU Criminal Justice Research Center from the Pennsylvania Department of Corrections (PADOC). Our sample and its matched counterpart will be linked to open source (e.g., arrest data from the Administration Offices of Pennsylvania Courts) and restricted access healthcare data (Medicare/Medicaid service records) through the PSU Data Accelerator and compared at 6- and 12-months post-prison release. Results will provide a comprehensive evaluation of a network-based program applicable to future network interventions aimed at vulnerable older adults experiencing challenging life course transitions.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Young-adult alcohol misuse is a public health problem causing thousands of assaults, injuries, and deaths each year. Both college and non-college adults frequently report high drink counts (e.g.,10+ drinks) and many alcohol-related consequences. Approximately 13% meet criteria for past-year alcohol use disorder (AUD) and problems associated with AUDs frequently continue into midlife. Although measurement of drinking is necessary for assessing these risks, concerns have been raised about exclusive reliance on self-reported drink counts, especially on heavier drinking nights. Our pilot work supports this concern, showing that over 12 weekend days: 1) 70% of the sample reported blackouts (55% reporting multiple blackouts), and 2) the rate of blackout was 1 in every 3 drinking days. These and associated impairments may affect the accuracy of self-reported drinking and lead to underestimation of the links between alcohol consumption and outcomes (consequences and AUD). To address this concern, we have used objective watchband-like transdermal alcohol concentration (TAC) biosensors in our studies. TAC assesses alcohol use in near real-time and records the manner in which alcohol is being consumed through continuous measurement of alcohol intoxication. TAC features from the rising portion of the curve for each drinking day – rise rate, peak, and rise duration – capture dynamic aspects of drinking behavior that standard drink counts do not. Our pilot data provide evidence that TAC features predict consequences and are associated with baseline AUD. These findings are promising, but they are limited to small samples over short time spans (1-4 weeks). These short time spans limit generalizability of TAC effect size estimates and have prevented prospective tests of TAC features as predictors of outcomes that develop over long time spans (i.e., AUD). The proposed research addresses these gaps using a large-scale measurement burst design consisting of eight 14-day bursts across two years among 500 young adults (ages 19-22) who frequently engage in heavy episodic drinking. Aim 1 will examine TAC features as predictors of alcohol-related consequences, relative to EMA self-reports. Aim 2 will assess AUD using DSM criteria at baseline, 12, and 24 months and focus on examining the contribution of TAC features, relative to EMA self-reports, in predicting AUD. The scientific premise of our research is fully supported by the literature and our past studies. Together, these warrant further study of how well TAC features can predict: 1) event level alcohol-related consequences, and 2) AUDs. Our approach uses a rigorous longitudinal and multimodal measurement burst design to address these significant gaps in the field.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY This project will study how exposure to climatic variability (i.e., temperature and precipitation anomalies) during different phases of the life course, from early childhood through adulthood, affect older adults’ health, economic status, and migration behaviors. We draw on data from the Indonesian and Mexican Family Life Surveys to measure three health outcomes (body mass index, hemoglobin, and blood pressure), consumption expenditures, and lifetime migration status among adults aged 50+ years in Indonesia (~36,000 observations from ~17,000 individuals) and Mexico (~19,400 observations from ~13,100 individuals). We link these demographic records to high-resolution climate data, and measure individuals’ climate exposures during early childhood (ages -1 to 5), adolescence (ages 12 to 18), and early adulthood (ages 19 to 25). We fit a series of fixed effects regression models to measure the independent effects of climate exposures during the three focal critical periods, while controlling for relevant demographic characteristics and spatial and temporal confounders. We then evaluate whether and how climate effects vary by age, sex, and rural (urban) residence at birth, all of which we expect to be correlated with climate vulnerability. Our third set of analyses evaluate whether exposure to recurring shocks from early childhood through adulthood have compounding and (or) cumulative effects on health in older adulthood. We also perform a series of supplemental analyses that test the robustness of our findings to alternative data and measurement decisions and compare the effects of earlier-life and contemporaneous shocks on health in later life. This study provides new evidence about the links between climate change and older adults’ demographic and health outcomes in the developing world, where the severity of climate change and extent of population aging are expected to increase in the decades ahead.

NIH Research Projects · FY 2025 · 2024-09

The increasing salinity of groundwater is a key emerging global environmental health risk factor for hundreds of millions of adults, including in the United States. Droughts, saltwater intrusion, and anthropogenic effects are exacerbating the salinization of drinking water sources. Drinking water salinity increases concerns about water safety. Further, recent evidence suggests that it may affect body water homeostasis, negatively impact kidney function, and increase blood pressure (BP) and risk of hypertension. In hot settings, physiological water needs increase, yet water scarcity and salinity make it harder to meet those needs. However, aside from guidelines for palatability, which are important as they may signify individual concerns, there are currently no established health standards for maximum water salinity (unlike dietary salt). Much of the research examining drinking water salinity has done so cross-sectionally, retrospectively, or in settings where other factors such as health-protecting salts may confound the relationship. Further, in examining chronic kidney disease of unknown origin, studies examine water quality or heat stress, without integrating co-exposures. Thus, it is hard to know how drinking water salinity affects hydration, kidney function, and hypertension and whether effects are due to salinity or other factors. A critical step toward understanding and mitigating the health risks of water salinity is to establish evidence-based relationships between water salinity and health using a longitudinal design in a real world hot setting with variation in water salinity levels due to seasonality, hydrology, and a desalination system. This research proposes to test the central hypothesis that drinking water salinity is detrimental to hydration, kidney function, and BP longitudinally. The specific aims of the project are: (1) To identify seasonal variation in drinking water salinity and individual hydration status, water turnover, and water insecurity; (2) To test how drinking water salinity affects kidney function and injury over time; and (3) To test how drinking water salinity affects systolic and diastolic BP and hypertension longitudinally, and whether these BP changes affect kidney health. The research will expand an ongoing longitudinal study to leverage a natural experiment created by a new water desalination system that provides variation in drinking water salinity levels across communities. This longitudinal study will enroll 600 adults (300 men, 300 women; 50% aged 18-45; 50% aged 45+) with seasonal (dry and rainy) assessments across 3 years to have within-participant, repeated measures analysis. The research will integrate environmental measures of water quality (in-field and laboratory assessment of water salinity, ionic composition, and heavy metals) and heat stress (wet bulb globe temperatures, heat illness), socio-ecologic assessments (in-depth multi-modal measurements of water and food insecurity, socio-demographics, diet, mobility, and stressors), and health measures using point-of-care and gold-standard laboratory methods (biomarkers of hydration, water turnover, kidney function/injury, and BP). The results will inform policy and EPA and WHO recommendations about drinking water salinity levels for human health and potential mitigation with water desalination in all affected areas.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY About 25% of daily care interactions between staff and residents in long-term care including Assisted Living Facilities (ALFs) comprise of poor care interactions. Individuals with Alzheimer’s disease and related dementias (ADRD) are especially at risk for poor care interactions related to ineffective staff approaches such as negative touching, being overprotective, and lack of verbal or non-verbal contact during care. Poor care interactions have a negative impact on both resident and staff well-being and therefore, need to be replaced with positive care interactions. Use of positive care approaches such as identifying resident’s abilities and preferences, understanding resident’s responses and non-verbal cues, appreciating resident’s effort, managing self-responses to resident, and using a calm and respectful approach can promote positive care interactions in ALFs and further improve outcomes for both residents (e.g., less behavioral distress) and staff (e.g., greater competence in dementia care). Yet, we continue to see poor care interactions in ALFs due to resident’s ADRD-related communication challenges and behaviors, staff’s limited knowledge and skills in caring for residents with ADRD, and organization’s limited support and engagement in initiating and sustaining positive approaches. Therefore, the purpose of this study is to pilot test the Promoting Positive Care Interactions (PPCI) intervention with the goal of establishing a feasible and culturally responsive approach to optimize care interactions between staff (nursing, activity, housekeeping, and dining service) and residents with ADRD in ALFs, and further improve select resident, staff, and organizational outcomes. PPCI is a theory-based four-step intervention consisting of 1) stakeholder engagement in developing facility specific goals; (2) environment and policy assessments; (3) flexible staff education; and (4) ongoing mentorship, motivation, and support (in-person visits and text messages) for staff to optimize care interactions in ALFs. Aim 1 will examine the feasibility and acceptability of PPCI. We will also explore the cultural responsiveness of PPCI. Aim 2 will test the preliminary efficacy of PPCI on select resident outcomes (primary: quality of life; secondary: agitation, resistiveness to care), staff outcomes (primary: quality of care interactions; secondary: knowledge, perceived competence related to care and communication, stress, relationship quality), and organizational outcomes (environment and policies). Aim 1 will use a convergent parallel mixed-method design with surveys and focus groups completed at six months. For Aim 2, repeated (resident, staff, and facility) measures will be evaluated at baseline and six months. Data will be analyzed using mixed methods for aim 1 and count models for aim 2. This study will support to establish a feasible and culturally responsive approach to optimize care interactions and further improve ADRD care in ALFs. Findings will inform future implementation of PPCI.

NIH Research Projects · FY 2025 · 2024-09

PROJECT ABSTRACT The proposed research will assess the impact adolescent friendship networks have on the psychosocial health of immigrant youth (i.e., the 1st and 2nd generation). Immigrant youth are a vulnerable population, with disproportionately high prevalence of adverse psychosocial health outcomes, including higher rates of mental health disorders, and lower sense of belonging, self-esteem, and wellbeing. Adolescence is a critical developmental stage, marked by the ascension in the complexity and importance of peer friendships. Although immigrant youth’s friendship networks look different from non-immigrant youth’s networks in a variety of ways, very little research have examined whether and how these friendship patterns and processes may explain the immigrant-based disparities in psychosocial health. This proposed research will bring more contemporary data to the forefront of research on immigrant youth’s school friendships, generate new and rare data on immigrant youth’s non-school friendships, and use advanced social network analytical methods to provide a more comprehensive examination of the impacts adolescent friendship networks have on the psychosocial health of immigrant youth. During the K99 phase, Dr. Khuu will focus on friendships developed in school, a major peer context shared by both immigrant and nonimmigrant youth. AIM 1 is to identify and understand differences in friendship patterns and processes between immigrant and nonimmigrant youth. AIM 2 is to compare measures of psychosocial health between these two groups and test whether differential friendship patterns and processes explain differences in psychosocial health. During the R00 phase, Dr. Khuu will leverage her training in survey design and network sampling methods as well as in adolescent development and psychosocial health to lead a new data collection effort on immigrant youth’s friendship networks extending beyond school. AIM 3 is to understand how the social contexts of friendships shape friendship patterns and composition. AIM 4 is to test the relationship between immigrant youth’s psychosocial health and these friendship measures. As a sub aim, Dr. Khuu will also take the opportunity to examine heterogeneity among immigrant youth, focusing particularly on the distinctions between refugee and non-refugee youth. Dr. Khuu’s career goal is to become a leading research authority on the friendships, health, and critical life outcomes of immigrant youth. The training and findings of the proposed research will position her favorably to pursue an R01 grant, enabling her to propose a more expansive, longitudinal study that explores the social integration and health of immigrant youth, with a specific focus on refugee youth, who have resettled in a diversity of new immigrant destinations in the United States.

NIH Research Projects · FY 2025 · 2024-09

Project Summary: Motor learning is fundamental for humans to become proficient in daily activities, such as self-care, work, and leisure. Two fundamental components of motor learning in humans, motor adaptation and skill learning, are critical for acquiring new activities. For example, when learning a new sport, such as pickleball, one adapts previously learned tennis skills (adaptation) while also learning components unique to the sport at hand (skill learning). This proposal details a set of studies aimed at understanding the functional neuroanatomy of these two learning processes. Converging evidence implicates a major role of posterior parietal cortex (PPC) in visuomotor learning. We have previously shown that left, but not right, posterior parietal lesions in stroke patients prevent motor adaptation with both the contralesional and ipsilesional arms, indicating that learning is lateralized to the left hemisphere. This proposal will utilize two types of non-invasive brain stimulation (NIBS) in humans to ask the following questions: Are there hemisphere-specific effects on the two types of motor learning?, and can learning and/or transfer be facilitated by excitatory stimulation to posterior parietal cortex? We will examine interlimb transfer of learning as a reflection of consolidation of effector-independent motor memories. Our overarching hypothesis is that HD-tDCS delivered exclusively to the left PPC will facilitate learning and/or transfer in each of the adaptation and skill learning tasks, and that this facilitation will be plausibly attributable to motor consolidation between trials. We will test these hypotheses through three aims that address 1) whether anodal high-definition transcranial direct current stimulation (HD-tDCS) delivered to left, but not right, posterior parietal cortex will facilitate visuomotor adaptation and interlimb transfer in both arms, 2) whether anodal HD-tDCS delivered to left, but not right, posterior parietal cortex will facilitate skill learning and interlimb transfer in both arms, and 3) whether double pulse TMS delivered to the left, but not the right, PPC, either prior to movement or during movement, will affect learning and transfer in both tasks. This last aim will help to elucidate the mechanisms underlying posterior parietal cortex mediated learning. Our pilot data strongly support a substantial effect of NIBS to the left PPC on distinct aspects of these two motor learning processes. The information gained from this study should prove essential for the optimal translation of non-invasive brain stimulation techniques to motor learning in rehabilitation. This proposal brings together the complimentary expertise of two research programs: Dr. Sainburg has developed the proposed behavioral paradigms, related software/hardware, and his team has expertise in the neural basis of motor control, learning, and lateralization. Dr. Tunik studies the neural foundations of visual-motor coordination for upper limb movements. His team has specific expertise in the brain stimulation techniques proposed. Both teams have been effectively working together for over a year.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Western populations collectively responded to historically contingent, society-wide developments in the 19th and 20th centuries by reducing births to record-low levels. However, a minority of Westerners, largely ethnic sectarian religions, have maintained pre-transition fertility levels despite exposure to contexts that motivate fertility decline. How have these populations—conspicuous among them being the Amish—maintained high birth rates? Decades of sporadic research suggest that high birth and low attrition rates explain the unabated 20-25 year Amish population doubling time. Yet, it is less clear why Amish women maintain high birth rates and, perhaps more revealing, why births vary so widely among them, with community-level completed birth rates ranging from approximately 4 to 12. Occasional cross-sectional studies suggest that multiple variables—including household head occupation, religious differences, and individual status— predict Amish birth rates, but what these results mean, exactly, remains educated guesswork. This project overcomes past barriers and delivers new knowledge by making two ground-breaking contributions to Amish demography research. First, this project develops a large population-wide, time-sensitive dataset that will permanently transition Amish demography research from limited, single-site, cross-sectional analyses to full-scale, continent-wide, time-sensitive analyses. This transition will substantially advance the scope and interpretability of statistical predictors of births. This longitudinal database pulls information from Amish-produced population record books that provide extensive documentation of vital events, sociocultural information, and geocodable addresses at the household level. These geographically referenced data will then be linked to publically available contextual data. The launch-point for this database is my cross-sectional Amish population dataset, which incorporates 71 current record books with information about 54,731 unique Amish households (estimated at about 270,000 individuals), covering approximately 89.6% of all Amish in North America. The proposed longitudinal database will use all editions of three major directory sets, piloting the process of eventually incorporating all editions of all Amish directories. Second, this project will validate the data by testing population growth explanations, beginning with articulation of population structure trends over time. This project will then test the relative influence of competing fertility theories by disentangling the effects of Amish-internal versus external structural-cultural forces. Namely, are birth differences more the product of Amish-internal differences in spite of contextual socioeconomic development or is birth variation more the product of relative isolation from society-wide structures in spite of Amish internal demarcations? To test these competing theories, I will employ this project’s internally linked, geographically referenced pilot longitudinal database in time-sensitive analyses. To achieve these project goals, I propose a research and training program that will enable me to apply conventional and recent advancements in time-sensitive statistical analysis, fertility theory, and relational database design and management. In so doing, I will quickly achieve researcher independence in preparation for career-long management, ongoing development, and analysis of a population database that has sprawling potential to address many demography and population health questions.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Adoptive cellular immunotherapies are an established therapeutic weapon in the fight against cancer. However, there is a large variability in anti-tumor responses and toxicity between patients, due primarily to differences in immune cell trafficking to tumor and lymph tissues. This has urged the development of surveillance tools that can monitor adoptive immune cell tissue migration in vivo to inform treatment regimens, empower interpretation of therapeutic outcomes, and aid in the early detection of adverse events. To address this technologic need, our goal is to develop nano-scale contrast agents that enable continuous and high-fidelity ultrasound (US) imaging of immune cells in deep tissues, employing tumoricidal chimeric antigen receptor macrophages (CAR-M) as an exemplary cellular model. Fundamental to this strategy is our development of phase-changing peptide nanoemulsions (NPep) that are rapidly internalized and persist within macrophages for multiple days and can generate echogenic bubble imaging nuclei on-demand without compromising cell viability. Our recent studies show these capabilities allow NPeps to provide real-time and long-term monitoring of macrophages in tissues using diagnostic B-mode and Doppler US imaging. Additional studies demonstrate NPeps provide a distinctive Doppler ‘twinkling’ feature that permits unparalleled spatiotemporal resolution of contrast-enhanced features from the tissue background to improve imaging resolution and identification of cellular locale. Bringing together a multi-disciplinary team of materials scientists, ultrasound imaging experts, and immunologists, our objective is to rationally tune NPep design to improve Doppler twinkling in cells (Aim 1), controllably modulate macrophage behavior in situ via US release of immunostimulants loaded into the NPep carrier (Aim 2), and demonstrate non- invasive, real-time, high contrast, and continuous imaging of NPep-labeled CAR-M intratumoral migration and persistence in vivo (Aim 3). To achieve this, in aim 1 we perform multiplexed imaging of NPep formulations with varying emulsion size and surface tension, two parameters linked to particle US response, to establish design rules that can be used to improve the consistency, power, and duration of NPep Doppler twinkling. Aim 2 will evaluate changes in macrophage viability, phenotype, and phagocytic function after uptake of NPep contrast agents, as well as demonstrate our ability to productively modulate anti-tumor behavior via US-actuated intracellular release of a loaded PPARγ agonist demonstrated to stimulate tumoricidal responses. In aim 3, we evaluate the potential of this tool to provide real-time and long-term monitoring of adoptive CAR-M infiltration into xenograft neuroblastoma tumors, as an exemplary in vivo model, using standard diagnostic US imaging modalities. Collectively, this work will provide the foundation for a clinically relevant tool that can be broadly adopted by the oncology community for real-time deep tissue imaging of adoptive cellular immunotherapies.

NIH Research Projects · FY 2025 · 2024-09

Background-related interpersonal challenges can negatively impact many youth, contributing to increased vulnerability for depression, anxi ety, and conduct problems. Caregiver-child communication that fosters pride in one’s background and equips youth with the skills to cope with these experiences can help offset their harmful impact. However, not all youth receive these messages, as some parents avoid such discussions with their children, and others may feel stressed by them or lack the skills and confidence needed for effective communication. Using intervention mapping, the current study will further develop and refine the Video-feedback Intervention to Promote Background-Related Communication Competency (VIP-BCC) to strengthen parents’ motivation to engage in these conversations with their children and build their competency in doing so (improved skills and confidence, decreased stress). Leveraging advances in communication-focused theory and intervention approaches in video feedback and motivational interviewing, VIP-BCC currently comprises three sessions: Session 1 is an ecologically-focused assessment of parents’ communications practices, assessed with parent- and youth-reported surveys and videotaped observation of parent-adolescent conversations. Session 2 involves an interview with the parent to build rapport, explore parents’ concerns and challenges, and obtain additional information to assist with tailoring the feedback session. During Session 3, parents and family coaches review clips from videotaped interaction tasks. Video feedback highlights parents’ communication strengths and encourages them to reflect on missed opportunities for promoting pride in their child’s background and supporting the development of coping skills to navigate challenging social experiences related to that background. Data from questionnaires and interviews are also used to punctuate strengths and highlight concerns. During Phase 1 (Aim 1), we will iteratively refine VIP-BCC in partnership with advisory boards of youth, parents, and family coaches, as well as expert researchers and clinicians, who will review Draft 1 of the intervention manual and materials. Feedback will be used to guide the development of Draft 2. We will reconvene the advisory boards and experts to provide feedback on the revised draft and guide further curriculum refinements for Draft 3. The refined intervention will be tested with five parents of 10-14-year-old youth to identify gaps in the curriculum and obstacles to implementation that can be addressed prior to a larger pilot. In Phase 2 (Aim 2), we will conduct a proof-of-concept single-arm trial with families to assess the feasibility, acceptability, and preliminary efficacy of VIP-BCC. Intervention effects on parents’ motivation and competency in engaging in background-related communication, as well as youth coping, self-concept development, mental health, and conduct problems, will be assessed. As one of the first studies to develop and test an intervention centered on promoting pride in one’s background through enhanced caregiver-child communication, this project has the potential to yield lasting benefits for youth well-being and development.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Offspring of mothers with depression are 2 to 3 times more likely than offspring of never-depressed mothers to develop anxiety and depressive disorders. Meta-analytic work shows that relations between maternal depression and offspring internalizing symptoms are stronger in younger than older children, highlighting the critical need to study causal risk mechanisms early in development among these high-risk (HR) youth to develop targeted prevention efforts. Across studies, HR youth are characterized by alterations within the NIMH Research Domain Criteria (RDoC) construct of Positive Valence Systems (PVS). Specifically, reduced reward responsiveness (RR), a PVS subconstruct, is consistently observed across behavioral and brain units in HR youth and predicts internalizing symptoms during adolescence, suggesting that reduced RR represents a key vulnerability marker to target with prevention efforts for HR youth. Yet, previous research in this area has focused predominantly on adolescent samples despite increasing evidence that PVS impairments are apparent in preschool-aged youth across internalizing disorders. Prior studies examining PVS function in HR samples are also largely limited by a single PVS assessment, limiting our understanding of how maternal depression impacts both overall levels and trajectories of PVS function in offspring during early development. To address these gaps, we will use an innovative, multimodal, accelerated longitudinal design to chart trajectories of PVS function across early childhood in a large sample (N=450) of biological offspring of mothers with and without depression histories recruited across two sites. Children, ages 4-6 at baseline, will complete developmentally sensitive tasks evoking neural (event-related potentials) and behavioral indicators of RR to tangible and social rewards at baseline and 1- and 2-year follow-ups, resulting in trajectories of PVS function from 4 to 8 years. We will assess factors that protect against or exacerbate alterations in PVS development to identify HR youth who could most benefit from PVS-related interventions. Specifically, our data suggest that maternal positive emotion behaviors (i.e., positive affect, parenting, and socialization) can buffer against maternal depression effects on child PVS function, whereas exposure to early life adversity (ELA), particularly deprivation experiences, potentiates effects. Thus, maternal positive emotion behaviors and child ELA exposure at individual and community-levels will be assessed at every time point, along with parent and clinician-rated assessments of child’s internalizing symptoms and disorders. This unique design will allow us to examine the effects of maternal depression on overall PVS levels and developmental trajectories in offspring during early childhood (Aim 1), test PVS function as a mechanism of maternal depression effects on early-emerging internalizing symptoms (Aim 2) and examine key risk and protective factors that moderate effects of maternal depression on child PVS function (Aim 3). Findings from the project may lead to novel PVS prevention efforts that could be delivered during early child development to break intergenerational risk cycles more effectively.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract A unifying theme of this research is to determine how RNA structure and RNA-binding proteins regulate gene expression by affecting the activity of RNA polymerase (RNAP) or by affecting ribosome access to the mRNA. Critical mechanistic insight into these processes will be obtained through studies in Escherichia coli and Bacillus subtilis. We previously developed a transcriptomics 3' end-mapping method called Term-seq to identify >1,500 intrinsic terminators in Bacillus subtilis. Many of these terminators are in 5' leader regions, some of which have been shown to regulate gene expression by attenuation/antitermination mechanisms. Another transcriptomics method that was developed by Philip Bevilacqua and Sarah Assmann at Penn State called Structure-seq is used to probe the structure of RNA in vivo. Structure-seq will be used to develop a method for protein-RNA footprinting in vivo, while both Structure-seq and Term-seq will be used for the discovery of novel RNA-based gene regulatory mechanisms. CsrA is a conserved RNA-binding protein that in E. coli binds to and regulates hundreds of mRNAs by affecting their translation and decay. Since CsrA binds to numerous RNA targets in E. coli many of which have been verified in vitro, we will use Structure-seq to develop a method for genome-wide protein-RNA footprinting in E. coli using CsrA-RNA interaction as a testbed. These footprinting studies will then be extended to a conserved RNA helicase called DeaD. Of particular importance, the footprinting methods will be applicable to essentially any organism or cell type. Another discovery-based theme of this research will combine Structure-seq with Term-seq to identify new RNA-based gene regulatory mechanisms at an unprecedented scale. We will identify regulatory mechanisms that respond to metabolites and stresses such as high temperature, and then determine the underlying molecular mechanisms of regulation. This supplement will provide Dr. Gulshan Ara the opportunity to re-enter into a productive career path towards scientific independence. The experimental plan will augment her existing experience in RNA biochemistry and also extend her expertise into microbiology, transcriptomics, bioinformatics, and RNA-based gene regulatory studies.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Nearly 7 million Americans suffer from Alzheimer’s disease (AD), and this number is only projected to rise as the US population continues to age at an unprecedented rate. Aging remains the single greatest risk factor for the development of AD, but how aging affects the molecular mechanisms underlying memory remains incompletely understood. For instance, aging is often accompanied by memory inflexibility—the inability to update previously formed memories to reflect new information—but minimal research has examined the molecular and cellular mechanisms of memory updating and less still has looked at how these mechanisms change with age. This proposal will use a newly developed memory updating paradigm called the Objects in Updated Locations (OUL) task to probe the epigenetic and cellular mechanisms underlying age-related memory updating deficits in mice. In this proposal, we investigate a specific epigenetic mechanism, the activity of histone deacetylase 3 (HDAC3), in age-related memory updating deficits. HDAC3 is an epigenetic inhibitor of gene expression that is abundant in the aged hippocampus and plays a well-characterized role in the formation of new memories. However, the role of HDAC3 in memory updating is unexplored. We hypothesize that HDAC3 is repressing the expression of genes necessary for proper memory updating in the aged hippocampus and thereby preventing allocation of the update information to the same neurons used to encode the original memory. In Aim 1, I will investigate how neuronal ensemble dynamics during memory updating change with age and whether this process is affected by HDAC3 inhibition in old mice. In Aim 2, I will use RNA-sequencing to identify which genes are dysregulated by HDAC3 during memory updating in the aged hippocampus. Together, these aims will identify important epigenetic and cellular mechanisms underlying the effects of age on memory updating. These results will provide a critical conceptual advance in our understanding of age-related memory deficits and are a necessary step in developing therapeutics to prevent or treat disorders of memory such as AD.

NIH Research Projects · FY 2026 · 2024-09

Project Summary Nucleic acid aptamers (aptamers) have been used as therapeutic agents or delivery ligands for various biomedical applications such as regenerative medicine, cancer therapy, molecular biosensing, cell delivery, detoxification, anti-inflammation, anti-coagulation, etc. However, the success of these applications largely depends on the discovery and delivery of high-affinity and high-specificity aptamers, which remains challenging today. Therefore, the objective of this project is to study an innovative method for aptamer selection and truncation, and to further examine the efficiency of in vivo aptamer delivery in regulating inflammation. We will work on four specific aims to achieve the objective. In the first three aims, we will focus on aptamer selection and truncation. Notably, while these three aims are related to one another, the proposed research activities in these aims can be conducted independently. After the selection and truncation of high-quality aptamers, we will examine microneedle-mediated aptamer delivery for local, defined treatment of inflammation using an animal model. The success of this project will not only lead to the development of a technological platform for therapeutic aptamer discovery, but also pave a new way of fighting against inflammatory cytokines in the treatment of complicated immune disorders.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract This proposal will exploit the unique and latent features of radical-mediated migrations to underpin new synthetic transformations designed to facilitate the discovery and manufacture of medicines. Using this approach, we aim to make significant advances in olefin difunctionalizations and stereoselective α-functionalizations of carbonyls. These reaction classes have enormous potential in pharmaceutical synthesis, but technical complications with their transition-metal catalysts have restricted the products they can directly access. To address these limitations, we will develop new conceptual platforms that promote these transformations and are compatible with medicinally valuable motifs that have heretofore presented challenges. In the context of olefin alkyl–arylation and amino–arylation, we have shown that a radical-migration-based design affords clear improvements over established strategies. Using this approach, our alkyl–arylation protocol enables (1) the use of mono- to tetrasubstituted olefins without activating or directing groups, (2) alkylation with diversifiable partners, (3) the formation of quaternary benzylic centers, (4) the broad use of N-rich heteroaromatic groups, and (5) good diastereocontrol. All five of these key outcomes are nearly unprecedented in metal-catalyzed alkyl–arylations of unbiased olefins, and they result directly from the method’s radical-migration-based design. Amino–arylation features similar advantages. Future work will comprehensively demonstrate the utility of these methods, develop more accessible reagents, and the introduce a further suite of amino–functionalization reactions. We will also translate this open-shell approach to the stereoselective α-functionalization of carbonyls. In this setting, we will develop and implement simple ‘chiral chaperones’ that are well-poised to deliver aromatics and other key functional groups to the α-position of carbonyl compounds after a radical-generation step. Since these transformations have struggled to introduce N-rich heteroaryl groups stereoselectively – a task for which radical- mediated migrations hold particular promise – this approach will unlock access to a broad range of stereodefined carbonyls bearing these privileged pharmacophores, in addition to α- and β-amino acids.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract: Phase transitions are emerging as a fundamental organizational principle for gene regulation. Transcription is organized into diverse higher-order structures called transcriptional condensates: Pol II associates into dynamic foci that rapidly assemble and disassemble concomitant with mRNA production, while the nucleolus maintains a tri-partite layered structure that supports the steady stream of rRNA. However, little is known how and why the flow of gene expression is organized across disparate condensates in the mitochondria. For example, within the mitochondrial matrix, the mitochondrial (mt-) genome and its RNA products are not diffuse but are packaged by proteins into distinct droplet-like structures called mt-nucleoids or mtRNA granules, respectively. Within the framework of biomolecular phase transitions, the vision of the research program will be to investigate how biomolecules involved in mitochondrial gene regulation self- organize into higher-order, functional structures in the mt-matrix and how anomalies to these biophysical processes contribute to mitochondrial (dys)function. The goals for the next five years are to identify the biomolecular interactions underlying the immiscibility of mt-condensates using in vivo and in vitro systems and supported by theoretical modeling. Using super-resolution light microscopy, we will perform biophysical experiments on the organization and dynamics of the components within mt-condensates. We will complement these microscopy experiments with next-generation sequencing approaches to identify the biomolecular networks underlying the biophysical behavior. Next, using our established in vitro mt-transcriptional system, we will study the interplay between phase coexistence and resulting transcriptional activity. We will support these experiments by performing analogous perturbations in live cells within the phase transition framework, allowing us to directly connect phase behavior to the flow of gene expression. Finally, this proposal will elucidate how the structure-function relationships of mt-condensates contribute to mitochondrial (dys)function in live cells. Overall, this research program will apply ideas from thermodynamics and polymer physics to uncover the biophysical principles underlying the flow of gene expression across these disparate condensates within the mt-matrix. This work will shed light on the functional consequences of the canonical organization of mt-condensates and how anomalies contribute to dysfunction, with implications for disease processes. By harnessing mitochondrial biology, we will uncover structure-function relationships of transcriptional condensates, which will pave the way for developing entirely new strategies to precisely target these structures in the pursuit of improving human health.

NIH Research Projects · FY 2025 · 2024-09

Project Abstract: Air pollutants such as nanoplastics have been identified to increase risks for neurodegenerative diseases such as Alzheimer’s disease and related dementias (ADRDs). Studies have found that these pollutants can enter the central nervous system (CNS), however how this happens has not been fully characterized. Olfactory sensory neurons (OSNs) are neurons whose cell bodies are found within the nasal epithelium, sending projections though the cribiform plate and onto the olfactory bulbs (OBs) within the CNS. These neurons endogenously sense compounds in the air to transmit information to the CNS and form a potential direct route for nanoplastics to travel from the nose to the brain. The purpose of this proposal is to characterize the nose-to-brain pathway that nanoplastics can be transported into the brain, whether sex, inflammation, age, or known genetic risk factors for cognitive decline and ADRDs (APOE3/4) influence this pathway, and how microglial dynamics change in vitro, after intranasal nanoplastic exposure. The first set of experiments will use advanced histological techniques and confocal microscopy to investigate the cells involved in this pathway and whether sex, age, genotype and inflammation alter the rate of nanoplastic uptake. The second set of experiments will focus on understanding microglial dynamics after intranasal exposure to nanoplastics through 2-photon microscopy and utilizing antibody staining to further investigate microglial dynamics. Age, sex, genotype, and inflammation will be observed to determine their influence on nanoplastic uptake into the CNS.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Protecting children through the primary prevention of child abuse and neglect (CAN) is a major priority given that an estimated 1 in 7 children are affected each year in the U.S. and the societal cost of CAN is of over $400 billion. Even though there are many evidence-based programs to prevent abuse, reduce harm, and treat trauma, there remain numerous barriers for policymakers to craft scientifically-informed policies to protect children. Accordingly, we propose an experimental study of a formal, theory-based approach for supporting policymakers’ use of scientific evidence that does not involve lobbying—the Research-to-Policy Collaboration (RPC) Model. The RPC fosters productive engagement between the policy and research communities by implementing systematic capacity building and outreach strategies. Previous experimental work on the RPC demonstrated the ability of this model to increase engagement between researchers and policymakers, increase policymakers’ value for research evidence, and improve their use of scientific evidence in their policymaking. We propose a state-level randomized controlled trial of the RPC (N = 30 state legislatures) that will evaluate the model’s ability to improve engagement between state policymakers and the science community, build policymakers’ awareness and value of CAN research, and subsequently increase their use of research evidence throughout the policymaking process. To accomplish this, we will test three specific research aims. Aim 1 will assess historical and current use of research evidence in state legislation pertaining to policies to protect children and provide equitable service delivery. This will involve qualitative coding of bills introduced by state legislatures over the last five years. Aim 2 will compare the frequency and quality of engagement with CAN researchers between the intervention and control conditions. Additionally, we will assess how the RPC model influences policymakers’ value and awareness of CAN research and evidence-based programs over time using a validated survey across three time points. Aim 3 will evaluate the effectiveness of the RPC on legislators’ actual use of research in legislation by observing and quantifying changes in legislator behavior related to research use. Improving the use of scientific information in policymaking can reduce population-level CAN and protect children by increasing the availability of evidence-based prevention programs and policies.

NIH Research Projects · FY 2026 · 2024-08

ABSTRACT Recent research emphasizes the opportunities of using neurotechnology earlier in the disease progression. However, earlier use of neurotechnology also raises significant ethical concerns. There are trade-offs and uncertainties involved in deciding to offer and undergo advanced neurotechnology treatments earlier in the disease progression. This has changed the ethical decision-making landscape for patients and treating clinicians. For patients, it can be challenging to assimilate clinical information and make risk–benefit trade-offs to select the most appropriate treatment. For clinicians it can be challenging to decide when in the disease progression is best to discuss with patient’s advanced neurotechnologies as therapies. While the literature addresses the opportunities that early use of neurotechnologies can bring, there is limited research on ethical concerns and decisional needs around their earlier use among patients, caregivers, and clinicians, and lack of support in decision-making about early use of neurotechnology. This proposed study addresses those significant gaps by (1) identifying neuroethical issues around shared-decision making (SDM) associated with the early use of neurotechnology, and (2) developing and testing a patient-centered decision aid (PtDA) for advanced neurotechnology that can be used at different disease stages. Using a pragmatic neuroethics framework together with the International Patient Decision Aids Standards (IPDAS) Collaboration guidelines our goal is to develop a tool to support SDM and the responsible use of these interventions in different stages of disease progression. To achieve this goal, our established, transdisciplinary research team, guided by a distinguished Steering Group, will answer two questions: (1) Are there any relevant differences in ethical issues and decisional needs when considering advanced neurotechnologies earlier in the disease progression vs. in advanced disease stages? (2) What impact does a PtDA about advanced neurotechnologies have on decision-making about this type of interventions (whether and timing), knowledge and attitudes about them, decision conflict, decision satisfaction/regret, and patient perceived involvement in care? To answer these questions, we will analyze data from interviews and validated instruments (Aims 1-3). We will examine key neuroethical concerns and decisional needs among patients, caregivers and clinicians (Aim 1). These results will inform the development of a PtDA (Aim 1). We will then evaluate comprehensibility and acceptability of PtDA (Aim 2) and evaluate small-scale efficacy and feasibility (Aims 3). The significance of this work lies in the in-depth new knowledge it will generate regarding specific neuroethical concerns and decisional needs raised by the earlier use of neurotechnology among patients and clinicians. Responding to the BRAIN Initiative imperatives, our PtDA will support SDM and ethical use of advanced neurotechnology at different disease stages.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY This project will measure how exposures to climatic variability (i.e., temperature and precipitation anomalies) during early-life and adolescence affect the fertility, health, migration, and socioeconomic statuses of working- age adults. We use data from the Indonesian and Mexican Family Life Surveys to measure women’s fertility (children ever born) and adults’ lifetime migration, body mass index, education, and consumption expenditures among 15-49 year-old individuals in Indonesia (~115,000 observations from 51,000 individuals) and Mexico (~60,000 observations from 41,000 individuals). We then link these demographic records to high-resolution climate data, and measure individuals’ climate exposures during early childhood (ages -1 to 4) and adolescence (ages 9 to 14). We fit a series of country-specific regression models that measure the effects of climate exposures during each critical period on the focal outcomes, controlling for individual characteristics and both birthplace and birth-year fixed effects. We then evaluate whether and how climate effects differ by individuals’ age, sex, parental education, parental mortality, and rural (or urban) residence at birth. The third analyses compare the effects of early-life and adolescent shocks with the impacts of contemporaneous shocks that occurred just prior to when the focal outcomes were measured. These analyses also account for the potential compounding or accumulation of impacts from repeated shocks. Our main analyses are complemented by a series of robustness checks. Overall, we provide new insights into the links between climate change and working-age adults’ wellbeing in middle-income, developing contexts.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY One in four children in the United States (US) has at least one immigrant parent—more than a third of whom came to the US from Mexico more than any other country of origin. Children of Mexican immigrants, in particular those without documentation status, are exposed to psychosocial stress through their parents and yet, nationally-representative analyses of how structural factors affect child dietary acculturation or obesity. Mexican American children/adolescents experience disparities in obesity as compared to either their non- Hispanic Whites or Mexican peers. The tapestry of state and local level immigration policy climates in the US provides an opportunity to study their impact on immigrant families, both short and long-term. We will address this research gap, by analyzing a novel data set of immigration policy climates linked to nationally- representative data, to apply quasi-experimental and longitudinal methods. Aim 1 will study how the Illegal Immigration Reform and Immigrant Responsibility Act Section 287(g), a local-federal immigration enforcement program, initiation affects measures of child diet and obesity in the year following implementation, as compared to the same locality the year prior to implementation. Then Aim 2 will expand the focus to include other immigration enforcement programs (e.g. Secure Communities) and types of immigrant inclusion/exclusion in state level policies (e.g. public health and welfare benefits, higher education, employment, and identifications) across 10 years. We focus on children of Mexican immigrants given their obesity disparities and demographic importance, but also compare our results to children of other immigrants, US-born Mexican Americans and other US-born parents. Anticipated findings of this work will advance our understanding of population-level structural determinants of obesity in Mexican American children, before weight trajectories have been set or comorbidities arise, and may inform public health interventions for this vulnerable population.