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EFFECTS OF ACUTE THC CHALLENGE ON BEHAVIOR AND NEUROINFLAMMATION IN HIV-1 TG26 MICE VARY BASED ON HIV STATUS, CHRONIC THC HISTORY, AND SEX
Get PDFΔ9-tetrahydrocannabinol (THC) has been studied for its neuroprotective benefits and its ability to improve HIV-1-related symptoms in clinical and preclinical models. Research has demonstrated THC’s antinociceptive, hypothermic, and anxiolytic effects; however, chronic THC administration may result in tolerance to these effects following acute administration of THC, and HIV status may further influence these effects. Thus, the present study investigated the effects of an acute THC challenge after chronic THC exposure on behavioral and neuroinflammatory measures using the HIV-1 Tg26 neuroHIV mouse model. HIV-1 Tg26 transgenic (Tg26+/−, n=32(16f)) mice and their control littermates (Tg26−/−, n=31(16f)) received subcutaneous injections of vehicle solution or THC (3mg/kg), once a day, 5 days per week, for 90 days. After a 7-day drug-free period, all mice were given a high dose of THC (10mg/kg; intraperitoneally), and behavioral and neuroinflammatory measures were collected. Results suggest that female mice may develop tolerance to some chronic THC effects and that tolerance development may depend on HIV genotype.Master of Art
ADVANCED MACHINE LEARNING AND ARTIFICIAL INTELLIGENCE METHODS FOR SPATIAL OMICS
Get PDFSpatial transcriptomics (ST) technology has revolutionized our understanding of biological systems by enabling the simultaneous measurement of gene expression and the preservation of spatial localization within tissues. Given this enriched data source, the central question in spatial omics analysis becomes: How can we efficiently utilize all this information and what important biological question can we answer? In this dissertation, we aim to develop ML and AI methods to address the pressing biological problems in spatial omics data analysis. In the first section, we present POLARIS, a versatile ST analysis method that can perform cell type deconvolution, identify anatomical or functional layer-wise differentially expressed (LDE) genes, and enable cell composition inference from histology images. POLARIS employs transfer learning to extract meaningful features from images of each spot and its surroundings. These features are then input into a deep neural network guided by Bayesian posterior probabilities to estimate cell compositions. This integration significantly enhances accuracy, and allows for predicting cell-type proportions in unmeasured regions and applying to new histology images without corresponding gene expression data. In the second section, we propose StarTrail, a novel ML method that leverage spatial gradients for spatial omics data. StarTrail investigates where and how does the omics feature change through spatial gradients, which map the rate of change of omics features across spatial positions. This approach allows us to identify zones of rapid change, characterized by high spatial gradients, which often correspond to critical biological junctures such as interfaces between lesional/diseased and healthy/normal tissues or regions with distinct functions. StarTrail, filling important gaps in current literature, enables deeper insights into tissue spatial architecture. In the third section, we introduce the Nearest Neighbor Derivative Process (NNDP), a scalable Gaussian Process framework that jointly models spatial processes and their derivatives, resulting a time complexity reduction from to . NNDP improves StarTrail in the second section by providing less hyper-parameter tuning, more theoretical support. NNDP robustly and accurately estimates spatial derivatives in various simulated spatial patterns and real data analysis.Doctor of Philosoph
ASSESSING CROWDSOURCED OSINT: THE EFFECTIVENESS AND OBJECTIVITY OF X’S COMMUNITY NOTES AGAINST DISINFORMATION
Get PDFThe use of crowdsourced open-source intelligence (OSINT) may be valuable in countering the rapid spread of disinformation campaigns. This study examines the effectiveness of X’s Community Notes using a mixed-methods approach to assess how quickly disinformation is detected and whether corrections are influenced by bias or grounded in truth-seeking. Automated OSINT tools were used to collect Community Notes, followed by tonal analysis to detect bias. Findings show that most disinformation was identified within 24 hours, suggesting crowdsourced OSINT enables timely responses. However, about one-third of Community Notes showed negative tonal bias, raising concerns about impartiality. While the results highlight the potential of crowdsourced OSINT for rapid fact-checking, they also reveal limitations in neutrality and accessibility. The study concludes by calling for improved methods and institutional guidance to increase the reliability of crowdsourced OSINT in fighting disinformation.Master of Art
USING ENDOMETRIAL ORGANOIDS TO CHARACTERIZE PERSISTENT DES-INDUCED UTERLINE EPITHELIAL CHANGES
Get PDFPrenatal exposure of diethylstilbestrol (DES), a synthetic estrogen, caused female reproductive abnormalities that lead to infertility and increased cancer risks. In mice, neonatal DES exposure induces similar reproductive dysfunction seen in human prenatal exposure. Neonatal mouse DES exposure causes aberrant gene expression and estrogen dependent alterations to the uterine epigenome and persist into adulthood. In particular, these changes result in altered epithelial cell differentiation which develops into adenocarcinoma later in life. The uterine glandular and luminal epithelium goes through cyclic regeneration and is replenished from a population of resident adult stem cells. Thus, we hypothesized that early DES exposure alters the endometrial stem cell and progenitor populations which causes aberrant epithelial differentiation. To study the persistent effects of DES, CD-1 mice were exposed to a daily dose of DES at 1mg/kg from post-natal day (PND) 1-5 and uteri were collected prior to puberty on postnatal day 16 (PND16). An epithelial enriched cell population was isolated for RNA-seq analysis or cultured into endometrial organoids – designed for optimal stem and progenitor cell survival and expansion. Using bulk RNA-seq, we found that at PND16, the epithelial enriched cell population had characteristic DES induced phenotype in tissue (Ltf and Six1 upregulation). Endometrial organoids were able to capture similar DES effects from the in vivo exposure such as aberrant Wnt signaling pathway and basal cell marker expression. To further understand how epithelial cells are altered, single cell RNA and ATAC sequencing was done using both PND16 whole uterine tissue and PND16-derived endometrial organoids. DES-exposed uteri samples had completely different transcriptional landscape compared to the control. The epithelial population of CON and DES exhibited different characteristics. We found that the endometrial organoid culture was entirely epithelial. Subpopulations included stem cell/progenitor, glandular/secretory, and basal cells in both control and DES. There were no stem cell population and fewer progenitor populations identified in DES-exposed organoids. These early findings suggest that neonatal DES exposure alters endometrial progenitor renewal capacity and epithelial differentiation.Master of Scienc
Elucidating the diet of sharks through DNA analysis of fecal matter
Get PDFOne-third of shark species are currently threatened with extinction, and their populations continue to decline. Despite their ecological importance, basic natural history information such as diet, range, and life cycle remains largely unknown for many species. Traditionally, shark diet reconstruction has relied on morphological identification of stomach contents. While widely used, this method often limits prey identification to coarse taxonomic levels and is prone to error due to subtle morphological similarities among prey items. In this dissertation, I employ DNA-based methods to quantify shark diet with higher taxonomic resolution. DNA barcoding more than doubled the number of prey items identified to the species level compared to morphological analysis, and dietary composition differed significantly between methods for all sampled shark species: Atlantic sharpnose (Rhizoprionodon terraenovae), blacknose (Carcharhinus acronotus), blacktip (Carcharhinus limbatus), and bonnethead (Sphyrna tiburo) (Chapter 1). Metabarcoding fecal DNA collected with cloacal swabs represented the corresponding prey DNA from the metabarcoded stomach contents and no significant differences in taxonomic richness or diversity were found between these two sample types (Chapter 2). In North Carolina, Atlantic sharpnose and blacknose sharks had the largest dietary overlap, with both species relying on the same two most frequently consumed prey taxa, i.e., prawns (Penaeus spp.) and spot (Leiostomus xanthurus). Bonnetheads and blacktips had the least amount of overlap between all shark species, where blacktips fed mainly on menhaden (Brevoortia spp.) and prawns while bonnetheads primarily consumed Atlantic blue crab (Callinectes sapidus) (Chapter 3). Prey taxa richness of the juvenile blacktip in the Galapagos was highest among sharks sampled in the bays of San Cristobal, possibly due to geographic variation in prey availability (Chapter 4). Thoburn’s mullet (Mugil thoburni), was the most common prey taxa identified in the diet of both the scalloped hammerhead (Sphyrna lewini) and blacktip sharks in the Galapagos. However, blacktips had a broader dietary niche, reflecting a more generalist feeding strategy (Chapter 5). Using metabarcoding techniques on non-lethal fecal samples to expand our understanding of shark diets can improve our ability to predict how disruptions in food web structure and prey availability may impact shark survival and conservation efforts.Doctor of Philosoph
HOME-BASED EXERCISE REDUCES CELL VIABILITY IN LNCAP BUT NOT PC-3 CELLS AND APPEARS TO MODERATED BY INFLAMMATION, EXERCISE ADHERENCE, CARDIORESPIRATORY FITNESS, AND BODY FAT
Get PDFAcute and chronic exercise reduce in vitro PC cell viability; however, no home-based interventions have been investigated on PC cell kinetics. This study aimed to evaluate a 12-week multimodal home-based exercise intervention in mCRPC patients on inflammation and in vitro PC cell viability.Decreased viability was observed at POST in LNCaP, but not PC-3 cells, at 96h (-9.6%, p=0.020), but not 72h. PC-3 viability was reduced in serum from individuals with higher VO2peak (-11.5%, p=0.053), lower percent body fat (-9.2%, p=0.044), and higher adherences to total (- 9.6%, p=0.037) and RT (-9.3%, p=0.046). LNCaP viability was reduced at POST with serum from individuals with low TNFa (-22.0%, p<0.001) and after controlling for CRP (-10.3%, p=0.023).Our findings contribute new information on the effects of home-based exercise on PC cells in vitro. These data partially support that exercise is protective against PC, especially with respect to androgen sensitive PC.Master of Art
Modifiers of PM2.5 Associated Health Effects in Vulnerable Populations
Get PDFFine particulate matter (PM2.5) exposure is a global health issue linked to increased mortality, cardiovascular problems, and hospital visits. The impact of PM2.5 varies based on factors like clinical condition, age, social determinants of health, location, and medication use. This study examines how clinical conditions and medication impact PM2.5 outcomes in patients with COVID-19 and heart failure (HF). PM2.5 is associated with cardiovascular issues, causing dysfunction through various pathways. One area not fully explored is how commonly prescribed medications affect sensitivity to PM2.5, especially in patients with cardiovascular disease who typically have high medication usage. We focused on HF patients due to their heightened sensitivity to PM2.5 and significant medication use, specifically examining β-blockers, ACE inhibitors, and ARBs.Our findings indicate that these medications reduce the impact of short-term PM2.5 exposure on vital signs in HF patients and an animal model. We also looked into adding environmental data to predict 30-day readmissions in COVID-19 patients, considering the connections between PM2.5, social determinants of health, and readmissions. These studies aim to enhance our understanding of the link between the environment and health, identify mechanisms by which PM2.5 causes vascular dysfunction, and reveal how environmental pollutants and socioeconomic factors influence health outcomes.Doctor of Philosoph
Integration of Optical Maps and Short-Read Sequencing Data in Genomic Investigation
Get PDFShort-read sequencing takes randomly fragmented DNA segments and retrieves the corresponding nucleobase sequence from them, yielding short sequences that can be assembled into longer contigs. Optical mapping performs a similar task, taking long DNA fragments and measuring the distances between their occurrences of specific sequence motifs to create restriction maps. Despite the similar strategy these methods employ, the data they yield is very different; short-read sequencing produces shorter and more accurate sequence-level information, while optical mapping produces much longer maps that only carry barcode-style patterns of restriction sites in the genome. While optical mapping dates back to the early 1990s and short-read sequencing to the late 1970s, it is only in the past decade that both have enjoyed notable commercial availability at the same time. As the two methods produce highly complementary data, integrating them can yield benefits where one source of data provides information the other is missing. This integration takes two forms: the creation of methods that directly use both types of data, and the creation of research environments where both types of data are well-supported. I present two tools to facilitate the latter: Rekit, an open-source optical map aligner and simulator; and a coverage browser for detecting copy number variations in Collaborative Cross mouse strains. In service of the former goal, I also present two versions of a classifier model that use short-read sequence and optical map data from the same sample to detect certain classes of structural variant in the mouse genome.Doctor of Philosoph
Individualism, Neoliberalism, and International Influence in the Push for Family Planning Programs in Romania, 1990-1995
Get PDFAfter the Romanian Revolution in December 1989, abortion once again became legal following years of extreme pronatalist policies. As women rushed to obtain abortions, the maternal mortality rate skyrocketed due to the unsafe conditions the abortions were performed in. International organizations, such as the World Health Organization, the World Bank, and the International Planned Parenthood Federation, were moved to take action. This thesis examines how the international organizations advocated for women to stop using abortion as a primary form of birth control, and for the newly-formed Romanian government to spread information about family planning programs and other forms of contraception. Through an analysis of reports and other publications from international organizations, this thesis explores how this push for family planning programs was part of a larger movement for neoliberal institutions across the former East Bloc.Master of Art
Advances in Germanium Detector Signal Modeling with GPU Computing and Deep Learning Techniques
Get PDFThe Large Enriched Germanium Experiment for Neutrinoless Double-Beta Decay (LEGEND) collaboration is searching for neutrinoless double-beta (0νββ) decay in Ge-76 using modular strings of enriched germanium detectors. Pulse shape simulations (PSS) are essential for modeling the analysis techniques used to distinguish signal events from multi-site and surface event backgrounds, and for generating reliable simulations of energy spectra. Together, these capabilities are critical for identifying the sources of background in current experiments and projecting background levels in future searches. Two longstanding obstacles have hindered reliable PSS: incomplete models of charge collection from surface event interactions and the complexity of replicating the detector’s electronic response. This dissertation addresses both issues using advanced computational techniques. EH-Drift is a novel simulation of charge carriers in germanium that incorporates surface drift, diffusion, and self-repulsion to model surface events. EH-Drift accurately simulates the passivated surface events while reproducing the experimental results from Germanium detector test stands. Using parallel computing on GPUs EH-Drift achieves 62.5x run-time improvement over CPU implementations, making their use for L-200 background modeling computationally feasible. Cyclic Positional U-Net (CPU-Net) is a neural network architecture that performs translations of simulated pulses so that they closely resemble measured detector signals. Using a CycleGAN framework, this Ad-hoc Translation Network learns a data-driven mapping between simulated and measured pulses with high fidelity and computational efficiency. Using data from an HPGe detector, we show that (CPU-Net) effectively captures and reproduces critical pulse shape features, allowing more realistic simulations without detector-specific tuning.Doctor of Philosoph