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Discrimination Against Immigrant Latina Mothers Associated With Pro-Inflammatory Gene Expression in Their Preschool-Aged Children.
Get PDFBackground: For immigrant mothers navigating the challenges of an unfamiliar sociopolitical landscape, the burden of discrimination extends beyond their personal experiences. Over time, cumulative exposure to discrimination may shape the environments in which young children grow and develop, with potential biological effects across the lifespan. Objectives: This cross-sectional observational study examined (1) whether maternal experiences of post-migration discrimination in the past year are associated with pro-inflammatory gene expression in their preschool-aged children, and (2) the potential contributing roles of maternal depressive symptoms and child body mass index (BMI). Methods: Immigrant Latina mothers completed sociodemographic and psychosocial measures (acculturation, discrimination, depressive symptoms). Buccal swabs were collected from children to assess mRNA expression of pro-inflammatory genes (IL-8, IL-1β), and child BMI was measured. Analyses included 70 mother-child dyads with ≥1 valid biomarker. We fit a multivariate model with correlated residuals across biomarkers to test associations between experiences of maternal discrimination and child gene expression. Results: Most mothers (69%) reported experiencing discrimination in the past year, primarily due to race or ancestry. Children whose mothers reported more frequent experiences of discrimination had higher IL-8 (B = .05, SE = .01, p < .001) and IL-1β (Β = .03, SE = .01, p = .03) mRNA expression. Associations persisted after adjusting for maternal depressive symptoms and child BMI. Conclusions: Early life experiences that devalue immigrants and their children may be critical predictors of health disparities that develop after migration. Cultivating welcoming environments for immigrant families may help support children's potential and broader community resilience
Teaching Cancer Survivors Coping Skills for Managing Fear of Recurrence: Insights From a Pilot Randomized Controlled Trial
Get PDFPurpose: Fear of cancer recurrence (FCR) is highly common and, if poorly managed, can be distressing and impairing. We developed a virtual, mind-body resiliency intervention for fear of cancer recurrence in survivorship (IN FOCUS), which was shown to be feasible and improved FCR post-intervention. This report aimed to describe coping processes associated with FCR and effects of IN FOCUS on coping over time. Method: A single-blinded, 2-arm, randomized controlled trial was conducted from July 2021 to March 2022 comparing IN FOCUS (8 weekly, 90-minute, synchronous virtual group classes teaching cognitive behavioral techniques, relaxation training, meditation, adaptive health behaviors, and positive psychology skills) to usual care (synchronous virtual community group support referral) among cancer survivors with non-metastatic disease and clinically elevated FCR (FCR Inventory severity ≥16). Measures included coping styles (Brief COPE) and perceived coping skills (Measure of Current Status-Part A). Intent-to-treat analyses with separate general linear mixed models were used to identify group-by-time effects (Cohen's d; 0.5 a medium effect, 0.8 a large effect) from baseline through 2 months and 5 months. Results: Sixty-four survivors enrolled (age M = 52 years, time since completing primary cancer treatment M = 5 years). By 5 months, survivors randomized to IN FOCUS (vs usual care) demonstrated multiple effects on coping in the medium to large range. Compared to usual care, IN FOCUS increased problem-focused coping, such as using instrumental support (d = 0.60), planning (d = 0.60), positive reframing (d = 0.48), and active coping (d = 0.45). Similarly, IN FOCUS improved emotion-focused coping, specifically venting (d = 0.70), acceptance (d = 0.58), humor (d = 0.50), and religion (d = 0.48). IN FOCUS also enhanced survivors' coping confidence (d = 0.79), relaxation skills (d = 0.57), and assertiveness (d = 0.46). Avoidance-focused coping and awareness of physical tension exhibited less robust changes by 5 months. Conclusions: Cancer survivors can enhance multiple aspects of coping with FCR through interventions such as IN FOCUS that teach mind-body resiliency techniques
Assessment of the functional and health-related needs of patients with metastatic breast cancer prior to initiation of cancer treatment
Get PDFPurpose To identify needs of metastatic breast cancer patients prior to starting a new systemic treatment. Methods Fifty patients with newly diagnosed, recurrent, or progressive metastatic breast cancer completed an electronic survey which included patient-reported outcome measures of function (PROMIS Cancer Function Brief 3D profile), quality of life (FACT-G), exercise (Godin Leisure-Time exercise questionnaire), and diet (REAP-S); demographic information; and self-reported use of or referral to specific resources at the cancer center prior to beginning a new systemic oncologic treatment. Results Prior to starting a new treatment for metastatic breast cancer, patients reported mild functional impairment (PROMIS Cancer Function Brief 3D profile mean score: 42.1) and low quality of life (FACT-G: 50%) along with low diet quality (REAP-S mean score: 29). Fifty-two percent of patients were sedentary (Godin Leisure-Time exercise questionnaire) and major barriers to exercise were pain (38%) and fatigue (34%); however, patients expressed a high level of interest (86%) in improving their ability to tolerate cancer treatment by addressing these areas. Conclusion Patients with new or recurrent metastatic breast cancer face health-related issues including sedentary behavior, poor diet, and limitations including pain and fatigue that can be addressed in prehabilitative efforts prior to starting a new oncologic treatment
On the Estimation of Controllability Metrics in Ordinal Vector Autoregressive Models
Get PDFThe quantification of symptom importance in psychological disorders is a central problem in clinicalscience. Many diverse methods have been proposed to tackle this problem, and one such technique isthrough the application of control theory to psychological time series. In this approach, the evolution ofmultiple time-varying indices (such as symptoms and behaviors) across time is treated as a dynamicalsystem and symptom importance is quantified through the controllability gramian of the underlyingsystem. Existing work, however, assumes that individual indices are measured on continuous scales.This is in contrast to the inherent ordinal nature of most psychological measures. In this regard, it islargely unknown how effectively we can recover the true underlying gramian when ordinal measures areof interest, especially in small sample regimes. In this work, we study the relevance and recoverability of the controllability gramian obtained byestimating (ordinal) vector autoregressive models in an SEM framework. This is done in 3 parts. Inthe first part, we demonstrate that controllability metrics obtained from the gramian provide distinctinformation vis-a-vis traditional symptom metrics obtained from graph theory. Secondly, we studied ifordinal modeling techniques using polychoric correlations improve upon a naive treatment of ordinaldata as continuous variables when estimating the controllability gramian. Lastly, we examined how wellwe can recover the difference in gramian values in pre-post intervention designs. Results indicate that,unless the length of the observed time-series is unreasonably large, the use of polychoric correlationsprovided little benefit relative to the naive approach of assuming continuous responses. Furthermore, wefound that accurate estimation of differences in the gramian in a pre-post setting can be challenging, withthe results varying depending on the metric used.Master of Art
Branched-Chain Amino Acids in Metabolic Programming from Genetic and Early-Life Perspectives
Get PDFBranched-chain amino acids (BCAAs) are essential amino acids that play critical roles in protein synthesis, energy production, and metabolic regulation. While BCAAs are vital for maintaining metabolic health, chronic elevations in circulating BCAA levels have been consistently associated with metabolic disorders, including obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM). Despite extensive research, it remains unclear whether elevated plasma BCAA concentrations are a cause or consequence of metabolic dysfunction. Moreover, the tissue-specific regulation of BCAA metabolism and the long-term consequences of altered BCAA exposure during early life remain incompletely understood.To address these gaps, we investigated the mechanistic regulation of systemic BCAA levels and their contribution to metabolic disease susceptibility. Utilizing T2DM-associated ankyrin-B mutant mouse models characterized by elevated circulating BCAA levels prior to the onset of obesity and insulin resistance, we demonstrated that impaired BCAA catabolism in white adipose tissue (WAT) leads to systemic BCAA accumulation by disrupting the surface localization of the Alanine, Serine, Cysteine Transporter 2 (ASCT2) in adipocytes, resulting in diminished BCAA uptake. These findings establish WAT as a critical regulator of systemic BCAA homeostasis and metabolic health.In a separate study, we examined the long-term metabolic effects of early-life exposure to elevated BCAA levels through maternal dietary manipulation. Male offspring from dams fed a BCAA-enriched diet during pregnancy and lactation exhibited persistent hyperglycemia in adulthood, an effect exacerbated by subsequent high-fat diet (HFD) feeding. Notably, maternal BCAA overconsumption attenuated HFD-induced adiposity in the offspring, associated with enhanced lipolysis in WAT without a corresponding rise in circulating free fatty acids, alongside increased hepatic gluconeogenesis. These results suggest that altered adipose-liver metabolic crosstalk contributes to the persistent hyperglycemia in the offspring.Collectively, this work provides new mechanistic insight into the regulation of systemic BCAA metabolism, identifies white adipose tissue as a key site of BCAA degradation, and demonstrates that both genetic and dietary disruptions in BCAA homeostasis contribute to the development of metabolic disease.Doctor of Philosoph
PRENATAL CORTICOSTERONE TREATMENT IMPACTS HIPPOCAMPAL DEVELOPMENT AND ADULT BEHAVIOR: A FOCUS ON AREA CA2
Get PDFPrenatal stress is a risk factor for several neurodevelopmental and neuropsychiatric disorders. During heightened periods of stress, Glucocorticoids such as cortisol and corticosterone (CORT) are produced. These stress-signaling hormones bind to their receptors, the glucocorticoid and mineralocorticoid receptors, where they act as transcription factors to regulate gene expression in their target tissues, including the brain. Within the brain is the hippocampus, which is enriched with MRs beginning early in prenatal development, making it a viable target for circulating stress hormones associated with prenatal stress. Area CA2 is present in the hippocampus of many mammalian species and has the highest expression of MRs in thebrain. Interestingly, conditional genetic deletion of MRs in mice eliminates expression of CA2-specific molecular markers, alters CA2’s synaptic plasticity profile, and impairs social behavior, indicating a critical role of MR function in CA2’s identity. Yet to be determined is how prenatal treatment with the stress hormone and MR agonist, CORT, affects the expression of CA2’s molecular profile, its connectivity to other brain regions, and related behaviors. To investigate this, I treated pregnant dams with CORT or a vehicle in their home-cage drinking water and examined the resulting offspring at different developmental stages. Our findings suggest that stress experienced in the prenatal environment alters the connectivity of area CA2 to other areas of the brain. In addition, prenatal CORT disrupts the brain’s hormonal profile and impacts novelty-reactivity and anxiety-like behaviors in sex-specific ways during adulthood.Doctor of Philosoph
CONTRIBUTION OF THE GUT MICROBIOME TO OBESITY-DRIVEN TRIPLE-NEGATIVE BREAST CANCER
Get PDFBreast cancer (BC) is the leading cause of death in women in the United States, where the triple-negative BC (TNBC) subtype is particularly fatal, partially due to its resistance to standard treatments. The global prevalence of obesity has tripled since 1975. As obesity is an established risk factor for BC, including the TNBC subtype, preclinical mouse models are crucial for elucidating mechanisms underlying the obesity-cancer link. Mounting evidence suggests gut microbial communities are implicated in obesity and cancer, with gut dysbiosis commonly observed in these conditions. Given its malleability, the gut microbiota is an appealing therapeutic target for obesity and cancer. Short-chain fatty acids (SCFAs), particularly butyrate, reduce obesity-associated adiposity and confer anti-cancer effects, making them promising for improving BC therapy. In Chapter 2, we sought to establish and characterize a new transplantable mouse model of TNBC on a C57BL/6 background. We successfully developed four readily tumorigenic claudin-low TNBC cell lines—B6TAg1.02, B6TAg2.03, B6TAg2.10, and B6TAg2.51— from tumors generated from C3-TAg transgenic C57BL/6 mice (B6TAg) and confirmed that the tumors that formed from the three most transcriptionally distinct B6TAg cell lines were enhanced by obesity. In Chapter 3, we characterized the gut microbiota from the same control and DIO mice from Chapter 2 and found that the gut microbiotas were compositionally distinct. Because SCFA-producing microbes support intestinal health, we tested whether SCFA supplementation influenced tumor progression in the B6TAg1.02 cell line. While butyrate supplementation increased cytotoxicity in vitro, our in vivo study revealed no statistically significant reductions in tumor volume and mass in our TNBC model. Finally, we tested whether butyrate supplementation could reduce body weight or tumor outcomes in DIO mice injected with the B6TAg1.02 cell line; however, we observed no statistically significant reduction in tumor volume and mass. The results from this dissertation provide researchers with new TNBC cell lines to investigate the complex interactions between obesity and TNBC in human-relevant cell lines of BC. Unsurprisingly, we demonstrate that diet had the biggest effect on the gut microbiota in our mouse model of TNBC. Future work is needed to understand how butyrate impacts tumor outcomes in TNBC.Doctor of Philosoph
MOLECULAR QTLS IN DISEASED TISSUE REVEAL GENETIC MECHANISMS OF INFLAMMATORY BOWEL DISEASE
Get PDFThe Inflammatory bowel diseases (IBDs), Crohn’s disease and ulcerative colitis are chronic inflammatory disorders that cause damage to the gastrointestinal tract. There is no cure for IBD. Current therapies treat inflammatory responses but do not target underlying causes. Research improving our understanding of underlying causes of IBD can lead to improved treatment of disease. While over 300 genomic loci have been associated with IBD by genome-wide association studies (GWAS), only a handful of these loci have known molecular mechanisms. Loci falling within non-coding regions suggests variants perturb regulatory mechanisms by altering transcription factor binding and local chromatin structure but identifying exact mechanisms and target genes remains challenging using GWAS alone. Mapping molecular quantitative trait loci associate traits such as gene expression (eQTL) and chromatin accessibility (caQTL) with genetic variants, provides evidence to functionally link variants to regulatory mechanisms and target genes. Furthermore, I hypothesize that mapping QTL in diseased tissue specifically will identify regulatory mechanisms active in disease. In the following chapters I show that mapping eQTL in IBD tissue uncovers novel potential target genes associated with IBD whose genetic signals in non-IBD tissue did not colocalize with GWAS. Additionally, I have performed the first caQTL mapping in colon tissue using both IBD and non-IBD samples. Combining these data sets together I have generated mechanistic hypotheses for regulatory variants associated with IBD including identifying regulatory variants, their predicted effects on chromatin accessibility and transcription factor (TF) binding, and their candidate target genes. Together, the results presented here provide novel insights into the functional role of variants contributing to the molecular pathogenesis of IBD that can be used to guide future functional validation studies.Doctor of Philosoph
Advancing the Use of Remote Sensing to Measure Water Quality and Detect Submerged Aquatic Vegetation and Marsh Habitat in Currituck Sound
Get PDFIn North Carolina (NC), there is a pressing need to understand the dynamics of coastal marshes and submerged aquatic vegetation (SAV), two habitats increasingly threatened by climate change. This issue is especially relevant in Currituck Sound, an oligohaline estuary of ecological and economic importance that has shown marked declines in both marsh and SAV area in recent years. SAV decline in the region has also been linked to declining water quality. Advances in remote sensing offer opportunities to examine trends in water quality and habitat conditions and to better understand the resilience of these coastal systems. Combining traditional field-based methods with innovative remote sensing techniques, this work has three aims: to evaluate remote sensing approaches for measuring colored dissolved organic matter (CDOM), to assess their ability to detect SAV presence or absence, and to explore large-scale relationships between SAV distribution and marsh habitat change, ultimately informing future monitoring and management.Master of Scienc
A Weak Null Structure for Multiple Speed Systems of Wave Equations
Get PDFWe consider the Cauchy problem in three spatial dimensions for a system of semilinear wave equations with two wave speeds. Hidano, Yokoyama, and Zha established a weak null condition that can be placed on the nonlinearities of a system of wave equations with multiple speeds to ensure its solutions exist globally in time. In this thesis, we present a new weak null structure with fewer conditions and demonstrate that it is sufficient for global existence. To do so, we will use a combination of the -weighted energy estimate used by Dafermos and Rodnianski and the ghost weight estimate of Alinhac. We also introduce a new local energy estimate to improve our control of the solutions. In order to close the argument, we rely on the spacetime Klainerman-Sobolev estimates of Metcalfe, Tataru, and Tohaneanu.Doctor of Philosoph