An Investigation Of Entamoeba Histolytica Chitin Synthases And Other Encystation Factors In Early Encystation, John N. Talledo

All Theses

Entamoeba histolytica is a food-and-water-borne human protozoan pathogen that relies on a two-stage life cycle for successful proliferation outside of the host. E. histolytica exists in its dormant cyst form while outside of its host and converts to the motile trophozoite (amoeba) form in the small intestine. The trophozoites colonize the large intestine to cause symptomatic disease in ~10% of infections, resulting in ~100 million cases of amoebic dysentery each year. Trophozoites can convert back to the cyst form, which is shed in feces to continue the infection cycle.

Currently, there is a lack of understanding of the exact molecular …

Denisovan Introgression And Selection At Cntnap2 In Ancient And Modern American Populations, Matthew Barker

All Theses

The peopling of the Americas created new opportunities for genetic adaptation as ancient populations encountered novel environments across North and South America. Previous research has shown that segments of Indigenous American ancestry contain elevated proportions of Denisovan alleles. The gene CNTNAP2, which is involved in brain development and neuronal function, contains a Denisovan-derived haplotype that represents a candidate locus for adaptive introgression in admixed American populations. A Denisovan-derived core haplotype approximately 55 kb in length was identified within intron 13 of CNTNAP2. This haplotype is primarily found in admixed American populations and occurs rarely outside the Americas, and …

Modeling Repeated Evolution Of Polygenic Traits, Marshall N. Hoskins

All Theses

Understanding the genetic composition of adaptive evolution is a longstanding and primary goal of evolutionary genetics. Despite many advances in our knowledge of trait adaptation, it remains unclear how demographic changes and repeated selection might alter the expected genetic architecture of adaptation. We used forward-in-time genetic simulations to test and observe the effects of opposing, repeated selection regimes on a polygenic trait in populations with and without changes in demography to better understand the genetic alleles that underlie polygenic adaptation. To further illuminate how natural populations might evolve, we investigated the impact of mutation effect size, the role of dominant/recessive …

Sorghum Grain Secondary Metabolites And Underlying Genetics To Reduce Foodborne Pathogens In Poultry, Maria A. Conti

All Dissertations

The rise in antibiotic-resistant pathogens poses a threat to the poultry industry's ability to maintain animal health, prompting growing interest in alternatives to synthetic antibiotics. The use of non-tannin sorghum [Sorghum bicolor (L.) Moench] in poultry rations offers a valuable alternative, as this cereal grain has a high bioactive profile that can provide health benefits, including antimicrobial (AM) activity. The scope of this study was to examine the AM potential of non-tannin sorghum grain against Clostridium perfringens, a major foodborne pathogen that negatively impacts poultry health and production. To that end, the inhibitory effects of a non-tannin sorghum …

Precursor Rna Properties Driving Cryptic 3’ Splice Site Selection In Sf3b1 Mutant Malignancies, Austin A. Herbert

All Dissertations

SF3B1 is a core component of the spliceosome involved in branch point recognition and 3’ splice site selection. SF3B1 is commonly mutated in myelodysplastic syndromes and other blood cancers with the K700E mutation being the most frequent. This mutation of SF3B1 induces cryptic 3’ splice site activation in hundreds of genes. Introduction of such cryptic 3’ splice sites can shift the reading frame of protein coding transcripts, causing the transcript to be tagged for nonsense-mediated decay or resulting in the production of a truncated protein. Both these scenarios can lead to down-regulated protein expression. Sequence and structural properties of precursor …

Characterizing The Molecular Response Of Embryonic Zebra Finch To Acute Sound Playback, Saidat O. Adeniran-Obey Miss

All Theses

Auditory stimuli are important cues that influence developmental plasticity in animals and are important for development and adaptation to an ever-changing environment. In the zebra finch (Taeniopygia guttata), there is evidence of adaptive developmental reprogramming in response to a prenatal ‘heat call’. Embryos exposed to this heat call exhibit changes in growth rate post-hatch, increased heat resistance, and enhanced reproductive success at maturity. However, it has long been assumed that embryonic zebra finches cannot respond to sound due to the immaturity of their auditory system. These findings raise the critical question of whether late-stage zebra finch embryos can, …

Abnormal Trafficking And Processing Of Multiple Matrix Metalloproteinases Drive Cartilage Defects In Congenital Disorders Of Glycosylation, Chia-Lun Wu

All Dissertations

Congenital Disorders of Glycosylation (CDG) are rare metabolic diseases caused by defects in glycosylation. Despite identification of over 200 CDG types, the mechanisms linking glycosylation defects to diverse clinical phenotypes remain unclear. This dissertation uses zebrafish models of PMM2-CDG and STT3-CDG to redefine CDG pathogenesis, shifting from a simple glycan deficiency model to one involving disrupted cellular spatial organization.

We identify a protease-dependent pathway underlying craniofacial cartilage defects. Specifically, defective proteolytic processing of N-cadherin, a key adhesion molecule in chondrogenesis, is a central driver of pathology. We further uncover an unconventional trafficking mechanism in which ER stress and altered secretory …

Unpacking Developmental Programming: A Conceptual And Historical Analysis In The Context Of Dohad, Andrea Gretchev, Heide S. Temples, Gillian England-Mason, Deborah Dewey, Sara M. Sarasua, Christopher Farrell, Vivian Haley-Zitlin

Publications

The Developmental Origins of Health and Disease (DOHaD) paradigm posits that early environmental factors may influence a child’s development and long-term health outcomes. Developmental programming (DP) is central to this paradigm, whereby specific early life exposures during critical periods of development are associated with changes to physiological and metabolic pathways, potentially predisposing individuals to disease. However, no standard definition of DP exists, and various terms have been used to describe similar processes. This analysis aimed to develop a conceptual definition for DP to inform interdisciplinary research, education, and practice. Walker and Avant’s eight-step method was employed to analyze the literature, …

Citrullus Amarus Drought Tolerance: An Above And Below Ground Analysis, Ben A. Hyland

All Theses

Ever rising environmental temperatures threaten global food security by worsening severity and increasing the occurrence of drought. Commercially cultivated watermelon (Citrullus lanatus), have reduced drought tolerance due to a narrow genetic base caused by breeding for desirable traits such as sweetness, size, and flesh/rind color. Comparatively, the crop wild relative desert watermelon variety (Citrullus amarus), while more drought tolerant than their commercially cultivated relatives (C. lanatus), still require large amounts of water to grow and produce reliable fruit yields. Watermelon root morphology plays a key role in their ability to tolerate drought, with more …

Purple Tomatoes Boost Nutrition Crop Value And Create New Opportunities For United States (U.S) Agriculture, Tariq Alam

Agronomic Crops

The agricultural landscape in the United States is continually evolving, with growers and the tomato industry seeking innovative ways to meet consumer demands while enhancing profitability. The introduction of both bioengineered and classically bred anthocyanins-enriched purple tomatoes presents a unique opportunity for U.S. growers to cultivate a high-value crop that appeals to niche markets and commands premium pricing. Bioengineered purple tomatoes achieve high anthocyanin levels through the introduction of snapdragon transcription factors, while classically bred 'Indigo Rose' purple tomatoes are developed via classical breeding methods, providing an alternative for consumers who prefer traditionally bred products. Specifically, the purple tomato holds …

Single Nuclei Transcriptomics Reveals Cellular Diversity In Tsc Subependymal Giant Cell Astrocytomas, Jennie C. Holmberg, Vijay Shankar, Rachel A. Lyman, Trudy F.C. Mackay, David M. Feliciano

Publications

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by benign growths called hamartomas that are a significant cause of morbidity and mortality. Hamartomas are found along the neurocutaneous axis including along the brain’s ventricles near the boundaries of the striatum. They can be categorized by size and include small subependymal nodules (SENs) or larger subependymal giant cell astrocytomas (SEGAs). Here, we describe a quantitative analysis of SEGA cell identities based on single nuclei RNA sequencing. SEGAs contain several cell types. In contrast to unaffected samples, SEGAs have pronounced vasculature, more endothelial cells, increased perivascular macrophages, less myelination, and altered …

Breeding Biofortified Protein Rich Organic Pulses For Better Human Health, Sonia Salaria

All Dissertations

Pulse crops are dry grains of legumes, the second most consumed plant crops in the world after cereals. These crops are one of the primary sources of plant-based protein and contain high concentrations of pre-biotic carbohydrates, minerals and vitamins. Recognizing the health benefits of pulses intake, their demands as sustainable food and changes in people’s diet preferences for plant-based protein have increased awareness for pulses consumption. With this scenario, improving the nutritional profile of pulse crops for rich nutrition has been an opportunity for breeders to explore and tailor the available germplasm to develop nutrient dense pulses. Furthermore, the genomic …

Alternative Therapeutics For Human Breast Cancer: Nutraceutical Underpinnings, In Vitro Metabolomic Profiling, Treatment Efficacy, And Contextual Ethical Implications, Aubrey A. Mattingly

All Dissertations

Breast cancer remains one of the most prevalent diseases worldwide, yet therapeutic equity is still lacking. Standard treatments including surgery, radiotherapy, chemotherapy, and long-term hormone therapy. These approaches are often accompanied by significant side effects. While newer methods such as immunotherapy and targeted therapies have emerged, chemotherapy protocols and incorporation have remained largely unchanged in the past decades. In this context, nutraceuticals represent an alternative or adjuvant to therapy worthy of exploration. The reviewed literature highlights the anti-carcinogenic activity in selected nutraceuticals, marjoram, thyme and persimmon, considering their phytochemical constituents and secondary metabolites. Metabolomic profiling using the Biolog Phenotype Mammalian …

A Review On Treatment, Prevention, And Research Of Worldwide Parasitic Disease: Toxoplasmosis, Hannah Skinner

All Theses

Toxoplasmosis is a worldwide, yet often overlooked, parasitic disease caused by the protozoan parasite, Toxoplasma gondii. The parasite is capable of infecting humans and almost all warm-blooded vertebrates. Over a million people are infected in the United States with toxoplasmosis each year. Most infections are asymptomatic but severe cases can lead to vision impairment, neurological disorders, and congenital birth defects. T. gondii is transmitted through undercooked meat, infected feline feces, or contaminated water and soil. The burden of T. gondii infection is most notable in livestock, felines, and immunocompromised humans. Despite being a widespread disease, toxoplasmosis is neglected in …

African Sleeping Sickness: From Basic Biology To Future Directions, Riddhi R. Patel

All Theses

African Sleeping Sickness is a Neglected Tropical Disease (NTD) which poses a significant health risk to impoverished populations in 36 Sub-Saharan African countries. It is a devastating disease caused by the protozoan parasite Trypanosoma brucei, which is transmitted to mammals via the bite of infected tsetse flies. The disease manifests in two stages: the hemolymphatic stage and the meningoencephalitic stage. In the latter stage, it invades the Central Nervous System (CNS) and can be fatal if left untreated. It is caused by morphologically indistinguishable species of Trypanosoma brucei in both humans and animals, where in humans it is known as …

Chromosome Evolution Model Reveals Hidden Variation In Karyotype-Driven Speciation In Ferns, Thomas Buchloh

All Theses

Because karyotype change commonly generates reproductive isolation between diverging species, rapid karyotype evolution, like that seen in plants, may increase the total rate of diversification. However, few studies have investigated this predicted relationship. Tests of this prediction have identified a positive correlation between the rate of karyotype change (specifically whole genome duplications) and diversification, but tests have been restricted to relatively small and young clades. Fortunately, novel macroevolutionary models have recently become available to investigate patterns of karyotype evolution in large phylogenies, providing new opportunity to investigate variation in karyotype driven diversification. Ferns are one of the most karyotype rich …

A Stakeholder-Informed Conceptual Framework For Evaluating Genomics In Precision Oncology, Julie A. Wiedower

All Dissertations

This dissertation explores the value of genomic testing in precision oncology with an emphasis on how US payers conceptualize and prioritize elements of value. This research aims to address gaps in understanding payer perspectives and proposes a stakeholder-informed framework for evaluating genomic testing in oncology. To achieve this aim, the presented research investigates payer perspectives, value-based cancer care priorities, and the conceptual understanding of the value of a genetic diagnosis to establish a framework for value with the payer audience in mind. Chapter 1 outlines relevant background information relating to the genomic revolution and challenges in translating genomic testing technologies …

The Genomic Landscape And Prognostic Impact Of Kras, Stk11, And Smarca4 Mutations And Co-Mutations On Survival Outcomes In Non-Small Cell Lung Cancer, Peter Manolakos

All Dissertations

Non-small lung cancer (NSCLC) accounts for 85% of lung cancer cases, and Kirsten rat sarcoma viral oncogene homolog (KRAS), Serine/Threonine Kinase 11 (STK11), and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations and co-mutations have been increasingly recognized for their potential prognostic significance. However, clear knowledge gaps remain regarding which treatments should be selected for patients who present clinically with KRAS/STK11 or KRAS/SMARCA4 co-mutations, as outlined in Chapter 1. Despite significant clinical development advancements in immunotherapy and targeted therapy, a deeper understanding of the influence of these genomic …

Perspectives On Clinical Oncogenomics: Secondary Germline Variants Associated With Tumor Genomic Profiling In Community Cancer Care And Advanced Practitioner Oncogenomic Proficiency, Sarah Moncado

All Dissertations

Precision medicine in oncology is defined by the sequencing of tumor genomic variants that can be used to identify targeted treatment for patients. Secondary pathogenic and likely pathogenic germline variants (P/LPGVs) can incidentally be detected on tumor genomic profiling (TGP). With the rise in precision medicine over the past 15 years, secondary P/LPGVs on TGP have been an increasingly important clinical issue. However, there are factors that can lead to misidentification and underreporting of P/LPGVs. Germane to this clinical practice issue is healthcare provider oncogenomic literacy and proficiency.

A scoping review was conducted to evaluate the variability of the prevalence …

A Drosophila Model Of Mucopolysacchridosis Iiia, Rebecca Bishop

All Theses

Mucopolysaccharidosis IIIA (MPS IIIA) is a rare lysosomal storage disorder that arises from inability to break down heparan sulfate (HS) because of mutations in the N-sulfoglucosamine sulfohydrolase (SGSH) gene. We used a deletion mutant of the Drosophila melanogaster Sgsh gene along with three point mutations analogous to mutations observed in patients (S64W, L89P, S301P) to show an increase in the average percent of area with lysosomal puncta in the fly brains of our mutants using Lysotracker. RNA sequencing of brains of mutant and control flies showed 441 (Knockout), 337 (S64W), 155 (L89P), and 96 (S301P) differentially expressed …

Bap1: Genotype-Phenotype Correlation, Variant Classification, And Treatment Efficacy, Elizabeth Hobbs

All Dissertations

BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21.3 and encodes a deubiquitinase enzyme (DUB) involved in DNA repair, cell cycle and metabolism, and apoptosis. BAP1 pathogenic germline variants are primarily associated with a familial cancer syndrome, Tumor Predisposition Syndrome 1 (TPDS1), but new missense variants have been linked to a neurodevelopmental disorder known as Kury-Isidor Syndrome (KURIS). Patients with TPDS1 variants have an increased risk for developing cancers, such as uveal and cutaneous melanomas, mesothelioma, and renal cell carcinoma, at an earlier age with lower thresholds for environmental exposures, mainly UV rays and asbestos, compared …

Characterizing Mechanisms Of Dna Repair And Genome Stability, Joshua Turner

All Dissertations

Every day our cells are bombarded with DNA lesions that threaten the stability of our genome. To help maintain genomic integrity our cells evolved to have a network of enzymes dedicated to repairing DNA lesions. Upon encountering a site of DNA damage, a cell recruits enzymes that remodel the stalled replication fork by reannealing the newly synthesized DNA together known as fork regression. Loss of fork regression activity has been shown to promote replication stress resistance after induced DNA damage. In this thesis, I discuss the role F-Box Helicase 1 (FBH1) plays in fork regression and how FBH1 promotes the …

Advancing Substance Use Disorder Treatment Using Genomics And Metabolomics, Lindsey Contella

All Dissertations

Advancing our understanding of genetic, metabolic, and environmental factors in substance use disorder (SUD) could lead to more effective therapies. In 2022, 16.5% of the U.S. population was diagnosed with SUD, yet current treatments lack efficacy for all patients, making a precision medicine approach crucial. This dissertation explores SUD's relationship with tryptophan (TRP) metabolism through the kynurenine pathway (KP) as a potential therapeutic target. Chapter I reviews current knowledge on SUD and KP. Chapter II identifies how SUD alters KP metabolite concentrations, identifying a reduced concentration of the neuroprotective metabolite, kynurenic acid (KA) and elevated concentrations of the neurotoxic metabolite, …

Behavior In Phelan-Mcdermid Syndrome: Clinical Characteristics, Genetic And Metabolic Contributions, And Evaluation Of Behavioral Assessment Tools, Emily Payne

All Dissertations

Phelan-McDermid syndrome (PMS) is characterized by genetic and phenotypic variability with varying levels of developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), speech delay, minor dysmorphic features, and behavioral issues. Genetic causes of PMS involve deletions in the 22q13.3 region or pathogenic/likely pathogenic variants in SHANK3. Due to the significant heterogeneity and complexities seen in individuals with PMS, there are numerous challenges surrounding research, accurate diagnoses, assessments, and the creation of treatments. Behavioral issues are present in the majority of individuals with PMS, including lower levels of adaptive behavioral skills needed for daily functioning, disruptive behaviors, restricted and …

Drosophila Model Of Cocaine Use Disorder, Jeffrey Hatfield

All Dissertations

Cocaine use disorder (CUD) is a major public health challenge. While the primary mechanism of action of cocaine has been well characterized, and family studies have identified a strong genetic component, the specific genetic factors that influence susceptibility to development of CUD remain poorly understood. Genetic studies of cocaine use disorder are difficult in humans, but can be readily performed in Drosophila, where environment, genetic background, and cocaine exposure can be controlled. Drosophila exhibit behavioral and transcriptomic responses to cocaine, which binds to the dopamine transporter in fruit flies as it does in humans. Here, we use Drosophila to …

Quantifying Effects Of Partial Genetic Backgrounds To Decode Genetic Drivers Of Clinical Phenotypes, Rini Pauly

All Dissertations

Understanding partial genetic backgrounds illuminates the genetic architecture of complex traits and diseases, revealing how diverse genetic backgrounds contribute to phenotypic diversity. With this approach we could advance personalized medicine by identifying population-specific variants affecting drug metabolism, tailoring medical treatments to individual genetic profiles. Additionally, it offers evolutionary insights into human history, shedding light on past migrations and the spread of genetic traits. This research leverages cutting-edge statistical genetics techniques and novel machine learning approaches to efficiently analyze extensive population genomic datasets, distilling complex admixture signals into meaningful genetic markers.

The study introduces Admix-AI, an innovative convolutional neural network-based tool …

Regulation Of Serpina1 Mrna Expression By Environmental Conditions In Hepatocyte Cells, Fnu Jiamutai

All Theses

The SERPINA1 gene encodes the critical protease inhibitor α-1-antitrypsin (A1AT). A1AT represses neutrophil elastase activity to protect lung tissue from inflammatory damage. A deficiency in α-1-antitrypsin can lead to chronic obstructive pulmonary disease (COPD). Pathogenic genetic variants in SERPINA1 are also associated with A1AT protein misfolding and liver cirrhosis. The regulatory mechanisms of SERPINA1 expression are not well understood, but previous studies suggest that alternative polyadenylation in the 3' untranslated region (3'UTR) affects A1AT protein expression. In this study, we used the liver cancer cell line HepG2 to determine how environmental conditions influence SERPINA1 mRNA expression and post-transcriptional regulation. We …

Elucidating The Roles Of Septin Proteins In Thermotolerance And Cell Wall Integrity In Cryptococcus Neoformans, Stephani S. Martinez Barrera

All Dissertations

Cryptococcus neoformans is a globally distributed fungal pathogen responsible for causing cryptococcal meningitis in immunocompromised individuals. This pathogenic yeast must adapt to changes in temperature upon entering the human host. Septin proteins are conserved filament-forming GTPases that assemble as higher-order complexes at the cell cortex to support cytokinesis and morphogenesis in fungal and animal cells. In C. neoformans, four septin homologs (Cdc3, Cdc10, Cdc11, and Cdc12) assemble at the mother-bud neck, contributing to cytokinesis through poorly understood mechanisms. C. neoformans strains lacking the septins Cdc3 or Cdc12 are viable at 25°C, but fail to proliferate at 37°C, and are …

Exploring Equity In Introductory Biology Genetics Education, Sandy G. Phillips-Long

All Dissertations

The dissertation “Exploring Equity in Introductory Biology Genetics Education” delved into the critical examination of equity within undergraduate genetics education. Chapter One outlined the background, significance, research framework, and manuscripts included in this study. Chapter Two was a scoping review that provided an overview of the current pedagogical approaches in undergraduate genetics education. It identified six active learning pedagogies: Course-based Undergraduate Research Experience (CURE); group work; case-based learning; inquiry-based learning; Virtual Reality (VR); and Consider, Read, Elucidate the hypothesis, Analyze and interpret the data, and Think of the next Experiment (CREATE). Chapter Three was a systematic literature review investigating pedagogical …

Genomic Data Science Approaches For Understanding Human Diseases, Snehal Shah

All Dissertations

The intricate interplay of genetic predisposition, environmental influences, and lifestyle acts as the multifactorial landscape of diseases. Understanding this complexity presents a significant challenge. Molecular insights into disease mechanisms, particularly the interactions of DNA, RNA, and proteins with environmental and lifestyle factors, have revolutionized disease diagnosis, prognosis, and treatment. High-throughput technologies, such as next-generation sequencing, generate large amounts of molecular data, holding a wealth of knowledge. These datasets unveil the roles of genes and their interactions with various factors through analysis, shedding light on previously unknown molecular mechanisms underlying disease pathogenesis. Furthermore, they facilitate the discovery of biomarkers crucial for …