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

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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

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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 …

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

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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 …

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

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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

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

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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

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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

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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 …

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

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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

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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

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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

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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

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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

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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 …

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

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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

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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

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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 …

Single Cell Pharmacodynamic Modeling Of Cancer Cell Lines, Arnab Mutsuddy

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Cancer is one of the leading causes of disease related death worldwide. Since the discovery of the genomic origins of cancer, targeted therapy has been developed towards specific mutations implicated for oncogenic transformation. However, current standard-of-care for mapping cancer patients to efficacious drug combination is often inadequate. The pathophysiology of tumor progression relies on the dysregulation of biomolecular pathways of which the topology and the dynamics challenge prognosis. Moreover, the overall genomic instability involved in disease states and the resulting inter-patient as well as intra-tumoral heterogeneity challenge rationalization of therapy and clinical decision-making. It highlights the need for the use …

Communication Of Oncology Genomics: Patients, Providers, And Artificial Intelligence, Lisa Stewart

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ABSTRACT This dissertation comprises five chapters concentrated on the communication of molecular profiling (MP) results between patients with cancer and oncology providers. Chapter I introduces MP and describes the significance of this testing. Chapter II is a state-of-the-art literature review focused on cancer patients’ expectations, knowledge, attitudes, satisfaction, and concerns regarding MP. Nineteen articles were reviewed, and findings revealed gaps in the communication process between patients and clinicians. Chapter III is a case study entitled “A Case for Caution: Patient Use of Artificial Intelligence.” In this case, pitfalls become apparent when a patient utilizes an artificial intelligence (AI) chatbot as …

A Systems Genetics Approach To Drosophila Melanogaster Models Of Rare And Common Neurodevelopmental Disorders, Rebecca Macpherson

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Fetal Alcohol Spectrum Disorders are a group of disorders resulting from prenatal alcohol exposure, presenting with neurodevelopmental and facial abnormalities of varying severity. SSRIDDs and CdLS are rare disorders of chromatin modification, resulting in patients with a wide range of craniofacial, digit and/or neurodevelopmental abnormalities. All of these disorders have a wide range of clinical phenotypes and disease severity, yet the role of potential genetic modifiers and gene-gene or gene-environment interactions in disease pathogenesis is largely unknown and cannot be studied in humans. Insufficient numbers of patients with a single rare disorder prevent investigation of genetic factors beyond the focal …

Perspectives On The Application Of Pharmacogenomics In Patient Care, Erika Meaddough

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Pharmacogenomics, the study of the genetic contribution to inter-individual differences in drug response, has great potential for realizing the goals of precision medicine: the right drug, for the right patient, at the right time. However, application in the clinical setting, through the use of pharmacogenetic testing, still has not gained widespread acceptance. This work describes multiple aspects of pharmacogenomics, which drive current research in this field.

Chapter I is an introduction to pharmacogenomics. Regulatory agencies and professional organizations across the globe provide information about gene-drug interactions that could lead to adverse drug reactions, and/or therapeutic failure. Risks for poor health …

Elucidating Mechanisms Of Rad51 Regulation During The Replication Stress Response, Alexandra Hawks

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The genome must be accurately and efficiently replicated each cell cycle to ensure there is not accumulation of mutations or structural rearrangements. When an active replication fork stalls, there are multiple DNA damage tolerance (DTT) pathways that can act to both protect integrity of DNA at the fork and restart replication. RAD51, a vital recombinase, works with HLTF, ZRANB3, and SMARCAL1 or FBH1 to regress stalled replication forks. RAD51 is loaded and stabilized onto the replication fork to protect the newly synthesized DNA from degradation. RAD51 is also active during the template switching DDT pathway. This pathway can be utilized …

Investigating The Potential Of A Cell-Based Gene Editing Therapy For Inherited Metabolic Liver Disease, Ilayda Ates

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Inherited metabolic diseases (IMDs) affecting the liver are relatively rare but collectively have a prevalence of 1 in 800 live births. These diseases result from autosomal recessive single-gene mutations, leading to organ dysfunction and potentially fatal consequences if left untreated. One potential therapeutic strategy for IMDs of the liver involves using CRISPR-Cas9-induced loss of function mutations. However, translating this approach into the clinic is limited by the need for safe and effective CRISPR delivery methods. Adeno-associated viral vectors (AAVs), commonly used for CRISPR delivery, are associated with significant safety and efficacy concerns, including risks for immunogenicity, off-target mutagenesis, and genotoxicity …

An Overview Of Risk Factors For Neural Tube Defects And An Investigation Within South Carolina, Lucy Pulliam

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Neural tube defects (NTDs) are congenital anomalies that affect both the morbidity and mortality of infants worldwide. Inadequate levels of the vitamin folate in women during early pregnancy have been shown to be a risk factor for NTDs. Recent efforts to ensure adequate folate intake in mothers have been helpful in reducing but not eliminating NTDs. This dissertation examines additional risk factors for NTDs as possible focus areas for decreasing NTD occurrence.

Chapter Two and Chapter Three are literature reviews conducted to explore select factors associated with an increased risk of NTDs and how these factors may affect folate availability …

An Interdisciplinary Approach To Online Genetics Education, Pinar Ozmizrak

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This dissertation presents an interdisciplinary approach to online genetics education.

Chapter I provides an overview of remote education and a brief history of genetics. While the COVID-19 pandemic prompted a turn to emergency online education, exposure to this form of delivery has led to increased intentional online education.

Chapter II focuses on computer and technology use in healthcare by nursing students. This study investigated nursing students’ perspectives using a modified version of the Pretest for Attitudes Toward Computers in Healthcare (PATCH) assessment scale to explore students’ ideas about computers and technology in healthcare delivery. According to the PATCH scale, the …

Elucidating Acetate Metabolism: Identification Of Transporters And Enzymes Required For Acetate Utilization In The Fungal Pathogen Cryptococcus Neoformans, Perry L. Kezh

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Cryptococcus neoformans is the leading cause of fungal meningitis world-wide. While exposure to this environmental sporophyte is common during childhood, those who are immune compromised are at risk of infection. Following inhalation, this basidiomycetous fungus subsequently colonizes other organs though hematogenous dissemination, eventually crossing the blood brain barrier and colonizing the brain where it causes as cryptococcal meningitis. Changes in the availability of carbon sources stemming from the movement from soil to the lungs induce changes in fungal metabolism. Specifically, alveolar macrophages, which present a first line of defense against infection, provide a glucose-/amino acid-poor environment. As such, the use …

Assesment Of Structure, Function, And Microevolutionary Dynamics Of Extrachromosomal Circular Dna In Chinese Hamster Ovary Cells, Dylan Chitwood

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Chinese hamster ovary (CHO) cell lines are among the most popular expression hosts used in biopharmaceutical manufacturing due to relative ease of culture, capacity to perform human-like post-translational modifications, and non-susceptibility to viruses. However, the intrinsic plasticity of the CHO genome can lead to undesired genetic rearrangements, phenotypic shifts, reduced product quality, and early culture termination that prevents continuous biomanufacturing. A characteristic of plastic and unstable genomes that is poorly understood in CHO cells is extrachromosomal circular DNA (eccDNA). EccDNAs are focal amplifications of the genome that reside in the extranuclear space. These plasmid-like entities are structurally complex and are …

Methyltransferase, Glucose Adaptation, And Import Complex In Trypanosoma Brucei, Emily Knight

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Trypanosoma brucei is a kinetoplastid parasite responsible for human African trypanosomiasis (HAT) and nagana, a livestock wasting disease, which both endemic to sub-Saharan Africa. Unique to kinetoplastids are the specialized peroxisomes, named glycosomes, which compartmentalize the first several steps of glycolysis and gluconeogenesis, nucleotide sugar biosynthesis, and many other metabolic processes. Kinetoplastids are unique in that they have a single mitochondrion. In this work, I present the first study into SET domain proteins in any kinetoplastid parasites. We have characterized a predicted SET domain protein, TbSETD3, that localizes to the mitochondrion and a depletion of the protein results in growth …

Acetate Metabolism In The Fungal Pathogen Cryptococcus Neoformans, Oly Ahmed

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Cryptococcus neoformans is an environmental basidiomycetous fungus with a worldwide distribution and a wide range of habitats. Inhalation of the desiccated yeasts or spores of C. neoformans often leads to opportunistic pulmonary infections in immunocompromised individuals, and in severe cases causes lethal meningitis following hematogenous dissemination. During infection, depending on the tissue and disease state, the invading fungi experience a range of nutrient microenvironments within the host body. As a result, rapid metabolic adaptations geared towards efficient utilization of carbon sources alternative to glucose become one of the prime determinants of survival and growth for the pathogen. Incidentally, cryptococcal infection …

Diagnosis Of Urinary Tract Infections And Rapid Molecular Characterization Of Antibiotic Resistance, Mohammed Harris

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Urinary tract infections (UTIs) are one of the most common infectious clinical entities in both community and hospital settings. They have a broad range of clinical severity yet inflict large epidemiological burden of morbidity and mortality on patients and the healthcare system with billions of dollars in cost of treatment. Understanding what methods are optimal for diagnosing UTIs are critical to mitigate the marked impact and cost of these infections.

Chapter 1 and 2 in this work surveys the broad array of diagnostic modalities for UTIs and highlights their advantages and limitations in the context of the current standard of …