Host-Pathogen Interactions In A Changing World: Microbes, Mucosal Defenses, And Multiple Hosts, Brandon C. Labumbard

Graduate Doctoral Dissertations

As fungal diseases continue to emerge, research increasingly focuses on host-microbiome interactions and links to disease. Certain skin-associated microbes may benefit hosts by protecting them from invading pathogens. Seasonal changes in the host environment can also result in shifts in the microbial community and pathogen virulence – potentially influencing disease dynamics. I investigated how cutaneous microbial communities differ across hosts, seasons, and Batrachochytrium dendrobatidis (Bd) infection status by sequencing the microbial communities of 1,100 leopard frogs at five locations across the US. Percent anti-Bd function varied seasonally and with Bd infection status. Bacterial communities also varied across locations and time. …

Characterizing The Function Of B Cells That Accumulate In The Inflamed Central Nervous System In Anti-Myelin Autoimmunity, Lika Chowdhury

Electronic Thesis and Dissertation Repository

While the role of autoimmune T cells has been extensively studied in anti-myelin

autoimmunity, little is known about the function of B cells in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). B cells form clusters with T cells in the meninges directly adjacent to demyelinating lesions. Previous studies have shown that disease progression is dependent on the depletion of specific populations of B cells, but it is not clear which contributes to pathology or how. The purpose of this thesis is to characterize the population of meningeal B cells to determine how they differ …

Data-Driven Biomarker Panel Discovery In Ovarian Cancer Using Heterogenous Data Fusion On Exosomal And Non-Exosomal Microrna Expression Data, Paritra Mandal

All Dissertations

Ovarian cancer (OC) is an aggressive gynecological cancer and is currently the 5th leading cause of deaths due to cancer in women. High mortality rates are attributable to the vague pathogenesis and asymptomatic nature of the early stages. The development of a liquid biopsy for routine OC screening could help identify the disease at an earlier stage, making treatments more likely to be effective thereby increasing survival rates. Exosomes, small (~100nm) extracellular vesicles present in body fluids, have been shown to contain cancer-progression, onset, and related factors, making them good candidates for use in liquid biopsies. However, to date, only …

Isolation Of Drug-Sensitive Eimeria Species From Wild Turkey Feces And Development Of A Model Bioshuttle Program For Eimeria Meleagrimitis For Domestic Turkeys, Maria Carolina Trujillo Peralta

Graduate Theses and Dissertations

The objective of this thesis was to determine the anticoccidial profile of Eimeria spp. derived from wild turkeys. These drug-sensitive Eimeria spp. have potential to be used as vaccine candidates to control coccidiosis in commercial turkeys. Chapter two consists of a brief literature review focused on coccidiosis in turkeys. Chapter three addresses the methodologies utilized to isolate, recover, and speciate Eimeria recovered from wild turkey feces in the eastern two-thirds of the United States. From this, we successfully obtained single oocyst-derived stocks for E. meleagrimitis, E. dispersa, E. meleagridis, E. gallopavonis, and E. adenoeides. Chapter four describes the experiment conducted …

Med12 Is A Critical Regulator Of Neural Crest Lineage And Nervous System Myelination, Fatma Betul Aksoy Yasar

Dissertations & Theses (Open Access)

The Mediator complex (MED) is a multi-subunit protein complex integral to the eukaryotic transcription machinery. MED12 is a Cdk8- regulatory kinase module subunit directly implicated in human disease and is genetically altered in neurological disease and cancer. Numerous attempts at generating an in vivo system to study the role of Med12 failed due to embryonic lethality associated with germline or developmental disruption of Med12 gene. To understand the cellular and molecular processes associated with its role in disease, we generated multiple mouse models with targeted depletion of MED12 in distinct cellular lineages. Our genetically engineered models with induced and conditional …

Differential Impacts Of Hhv-6a Versus Hhv-6b Infection In Differentiated Human Neural Stem Cells, Elham Bahramian

Graduate Theses and Dissertations

Within the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there areonly three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscores the conclusion that HHV-6A and HHV-6B are distinct viruses of the β-herpesvirinae. Despite these viruses being implicated as causative agents in …

Identification Of Possible Vectors For Histomoniasis In Turkeys On Commercial Farms In Arkansas And Oklahoma, Treva Dillon

Graduate Theses and Dissertations

Histomonas meleagridis, is a parasitic protozoan, commonly found in the gallinaceous species of birds and is the causative agent of Blackhead disease. The cecal worm, known as Heteraskis gallinarum, acts as a vector in the spread of H. meleagridis in gallinaceous birds. H. meleagridis develops inside the cecal worm and in its eggs which allows H. meleagridis a method to survive in the environment. Blackhead disease causes high mortality rates in both chickens and turkeys; however, turkeys are noted to have a higher mortality rate compared to chickens. Molecular diagnostic testing such as PCR has been developed by creating primers …

Effects Of Home-Based High-Intensity Interval Training Versus Continuous Walking On Cognition In Overweight And Obese Women, Kelsey C. Bourbeau

Health, Exercise, and Sports Sciences ETDs

Objective: The purpose of the present study was to determine whether six weeks of home-based high-intensity interval training versus six weeks of moderate-intensity walking improves cognition, depression, and anxiety in women that are overweight or obese. Design: A randomized control trial design. Subjects: Twelve sedentary women characterized as overweight or obese were randomized into either a six-week home-based high-intensity interval training (HIIT, n = 6, 26.6 ± 8.9 years, 37.4 ± 4.9% body fat) group or a six-week moderate-intensity walking (Walk, n = 6, 22.5 ± 3.7 years, 40.2 ± 4.1% body fat) group. Main Measures: Pre- and post-intervention, participants …

Seeing The Big Picture: System Architecture Trends In Endoscopy And Led-Based Hyperspectral Subsystem Intergration, Craig M. Browning

<strong> Theses and Dissertations </strong>

Early-stage colorectal lesions remain difficult to detect. Early development of neoplasia tends to be small (less than 10 mm) and flat and difficult to distinguish from surrounding mucosa. Additionally, optical diagnosis of neoplasia as benign or malignant is problematic. Low rates of detection of these lesions allow for continued growth in the colorectum and increased risk of cancer formation. Therefore, it is crucial to detect neoplasia and other non-neoplastic lesions to determine risk and guide future treatment. Technology for detection needs to enhance contrast of subtle tissue differences in the colorectum and track multiple biomarkers simultaneously. This work implements one …

Optimization Of Clostridium Septicum Antigen Production And Evaluation Of Vaccine Administration Parameters For A Candidate Bacterin-Toxoid To Prevent Dermatitis In Commercial Turkeys, Aaron Forga

Graduate Theses and Dissertations

The objective of this thesis was to optimize the hemolytic activity of two isolates of Clostridium septicum to evaluate if hemolytic titer of C. septicum antigen at time of formalin inactivation corresponded to increased serum antibody titer to the C. septicum alpha-toxin of turkeys immunized with an experimental formalin inactivated bacterin-toxoid vaccine. Chapter 1 provides a brief overview of the thesis. Chapter 2 consists of a literature review focused on clostridial dermatitis, specifically C. septicum-associated dermatitis (cellulitis) that affects commercial turkeys. Chapter 3 outlines our attempts to optimize an experimental autogenous bacterin-toxoid vaccine as a potential strategy to mitigate clostridial …

Risk-Factor Induced Changes In The Breast Microenvironment Facilitate Inflammatory Breast Cancer Progression And Lymphovascular Invasion, Wintana Balema, Wintana Balema

Dissertations & Theses (Open Access)

Inflammatory breast cancer (IBC) is a rapidly progressing, rare and highly lethal form of breast cancer. IBC is a clinical diagnosis, requiring >1/3 involvement on the affected breast and/or skin by erythema, and disease onset of < 6 months. The clinical symptoms of IBC vary in severity and presentation, these include redness, warmth, skin thickening and bruised or pink/purple discoloration appearance and skin changes such as peau d’orange. These skin symptoms are not attributed to inflammation, rather IBC is characterized by florid lymphovascular tumor emboli clogging dermal lymphatics. This leads to “classic” symptoms of breast swelling and skin edema or discoloration. To date, unique genomic drivers which differentiate IBC from non-IBC invasive breast cancers have not been identified highlighting a role for the microenvironment. Several epidemiological studies have unveiled subtype-specific risk factors associated with IBC that are known to alter the microenvironment. Obesity is an established risk factor for all subtypes of IBC. Never-breastfeeding increases risk for developing the most aggressive, triple-negative IBC. Further, never breastfeeding is associated with later clinical stage and worse outcomes. We worked to model these overlapping risk factors to understand microenvironment changes that may lead to the lymphatic change’s indicative of IBC.

First, we investigated the association of a “classic” triad of clinical IBC signs with overall survival among patients to demonstrate the most overt clinical findings of lymphatic involvement were impacting prognosis. We evaluated a triad of IBC signs, including swollen involved breast, nipple change, and diffuse skin change, using breast medical photographs from patients enrolled on a prospective IBC registry. We reported that the …

Ankyrin Dependent Mitochondrial Function And Bioenergetics In The Heart, Janani Subramaniam, Janani Subramaniam

Dissertations & Theses (Open Access)

ANK2 mutations in patients are associated with numerous arrhythmias, cardiomyopathies, and other heart defects. In the heart, AnkB, the protein encoded by ANK2, clusters relevant ion channels and cell adhesion molecules in several important domains; however, its role at Mitochondria Associated ER/SR Membranes (MAMs) has yet to be investigated. MAMs are crucial to mitochondrial function and metabolism and are signaling hubs implicated in various cardiac pathologies. Among several functions, these sites mediate the direct transfer of calcium from the ER/SR to the mitochondria to modulate ATP synthesis. Given that mitochondrial function and energy production are paramount to cardiovascular heath, …

Investigating The Pi3k/Akt/Atm Pathway, Telomeric Dna Damage, T Cell Death, And Crispr/Cas9-Mediated Gene Editing During Acute And Chronic Hiv Infection, Sushant Khanal

Electronic Theses and Dissertations

Human Immunodeficiency Virus (HIV) infection initiates major metabolic and cell- survival complications. Anti-retroviral therapy (ART) is the current approach to suppress active HIV replication to a level of undetected viral load, but it is not a curative approach. Newer and sophisticated gene editing technologies could indeed be a potent antiviral therapy to achieve a clinical sterilization/cure of HIV infection. Chronic HIV patients, even under a successful ART regimen, exhibit a low-grade inflammation, immune senescence, premature aging, telomeric DNA attrition, T cell apoptosis, and cellular homeostasis. In this dissertation, we investigated CD4 T cell homeostasis, degree of T cell apoptosis, an …

Comparison Of The Humoral Immune Response Following Both Bacterial Challenge And Rnai Of Major Factors On Proliferation Of Bartonella Quintana In The Human Louse, Jake Zina

Masters Theses

Human body lice, Pediculus humanus humanus, and head lice, Pediculus humanus capitis, have been hematophagous ectoparasites of humans for thousands of years. Despite being ecotypes, only body lice are known to transmit bacterial diseases to humans, and it appears that lower humoral and cellular immune responses allow body lice to possess a higher vector competence. We previously observed that the transcription level of the defensin 1 gene was up-regulated only in head lice following oral challenge of Bartonella quintana, a causative agent of trench fever, and also that body lice excreted more viable B. quintana in their …

Prenatal Choline Supplementation During Maternal Obesity Alters Offspring Response To Western Diets, Hunter W. Korsmo

Dissertations, Theses, and Capstone Projects

Maternal obesity has led to an increase in adverse offspring developmental outcomes and a greater risk for long-term metabolic diseases. Choline, a semi-essential nutrient, can be incorporated into phosphatidylcholine (PC) as well as sphingomyelin (SM) and donate its labile methyl group for the remethylation of homocysteine after choline is oxidized to betaine. Prenatal choline insufficiency has been related to maternal obesity and metabolic diseases, such as metabolic associated fatty liver disease (MAFLD). Choline may interact with maternal obesity to influence the programming offspring.

Chapter 1 presents an introduction of choline and the various clinical outcomes associated with choline supplementation during …

Using A One Health Approach For The Assessment Of Rabies Control In Rural Victoria Falls, Zimbabwe, Ryan Lapenna

Electronic Thesis and Dissertation Repository

Rabies, a viral zoonotic disease, is widespread in Zimbabwe, with human fatalities reported annually in the country. To supplement the Government’s effort on rabies control, the Victoria Falls Wildlife Trust and Veterinarians for Animal Welfare Zimbabwe have joined forces to carry out dog rabies vaccinations in rural communities adjacent to the major tourist attraction of The Victoria Falls. A One Health approach was used to 1) determine the level of protective rabies antibodies among a sample of rural dogs and 2) collect information and describe the knowledge, attitudes, and practices related to rabies among dog owners. In 2020, blood was …

Infection And Transmission Determinants Of Flea-Borne Rickettsioses, Hanna J. Laukaitis

<strong> Theses and Dissertations </strong>

The genus Rickettsia is comprised of Gram-negative, obligate intracellular bacteria that are spread by hematophagous arthropods. Elucidating the factors conferring rickettsial virulence has perplexed investigators for decades, complicated by the lack of efficient genetic tools necessary to uncover rickettsial- and vector-specific factors contributing to persistence. The advent of transposon mutagenesis has enabled the field to make vast developments in uncovering novel rickettsial mechanisms utilized in various host backgrounds. Thus, the aim of this study was to generate Rickettsia felis transposon mutants and characterize novel phenotypes associated with genetic disruption in an arthropod background. Distribution of rickettsiae is reliant on the …

Intestinal Microbiota Analysis Of Broiler Chickens Under Necrotic Enteritis Challenge And Tributyrin Supplementation, Taylor Nicole Mckinney

Graduate Theses and Dissertations

Poultry is a staple protein source for most of the planet. Until recently, antibiotic growth promoters (AGPs) were used to prevent illnesses in commercial chicken production. Currently, this is not possible due to regulations and consumer concern, but without such a preventative, diseases like necrotic enteritis (NE) have reemerged, posing a threat to bird health, and ultimately, our food source. Necrotic enteritis is a severe gastrointestinal disease caused by the gram-positive pathogen, Clostridium perfringens. Clinical features of this disease are diarrhea, intestinal lesions, and death, with a high transmission rate. In a subclinical form, growth performance is diminished and is …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations & Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Identifying A Glucocorticoid-Activated Gpcr That Rapidly And Non-Genomically Increases Camp Levels In Mammalian Cells, Francisco Nunez

Pharmaceutical Sciences (PhD) Dissertations

Glucocorticoids (GCs) are steroid hormones that regulate diverse physiological processes. Synthetic versions of GCs are commonly used to treat inflammatory diseases such as asthma by modulating gene expression to suppressing several inflammatory activities. However, it is estimated that 5-10% of asthmatics are unresponsive to GCs, which may be explained by receptor desensitization and/or the presence of a neutrophilic endotype. One understudied phenomenon of GCs is their ability to induce rapid, non-genomic actions. For example, GCs can acutely modulate calcium concentrations levels, induce smooth muscle relaxation and modulate nitric oxide synthase activity, within minutes and sometimes seconds, which is too rapid …

Histomonosis In Turkeys – Factors Influencing Transmission, Pathogenesis, And The Search For Prophylactic Or Therapeutic Compounds, Thainá Landim De Barros

Graduate Theses and Dissertations

The incidence of histomonosis has been increasing in poultry since the ban of prophylactic and therapeutic compounds. Histomonosis is caused by the protozoa Histomonas meleagridis. The objective of this dissertation was to investigate factors impacting the pathogenesis and transmission of histomonosis and to evaluate compounds that could potentially prevent or reduce the severity of histomonosis in turkeys. In the first study, the effect of sodium chlorate and sodium nitrate on reducing histomonads growth was tested in vitro and added to a basal turkey diet. A decrease in the growth of histomonads in vitro was observed, but no in vivo effect …

Radioluminescence Based Biochemical Sensing And Imaging Strategies To Measure Local Drug Release And Ph, Gretchen B. Schober

All Dissertations

In this dissertation we describe methods for measuring infection relevant biochemical analytes using radioluminescent and ultrasound luminescent materials. Films and nanoparticles fabricated with europium doped gadolinium oxysulfide (Gd₂O₂S:Eu³⁺) are used to quantitatively measure radiolabeled pharmaceutical concentration, specifically tritium labeled vancomycin (³H-vancomycin). Europium and dysprosium doped strontium aluminate is used to fabricate an ultrasound modulated, pH sensing film. These methods are indicated for theranostic evaluation of implant associated infection. Bacterial biofilms are inherently resistant to traditional antibiotic treatment and can coat biomedical implants. These biofilm related infections are difficult or impossible to eradicate …

Unraveling The Effects Of Aerobic Exercise And Erk5 Signaling In The Solid Tumor Microenvironment Using Murine Models, Hannah Savage

Dissertations & Theses (Open Access)

Solid tumors are comprised of multiple cell types which communicate and work together to promote tumor progression. Advances in the treatment of solid tumors have armed clinicians with more efficacious pharmacologic agents and combinations. However, a focus on drug adjuvants in the treatment of solid cancer has left gaps in knowledge regarding non-pharmacologic treatment adjuvants, like aerobic exercise. The current dissertation investigates pharmacologic and non-pharmacologic based approaches to remodel the solid tumor microenvironment landscape and alter therapeutic efficacy. We disassemble compartments of the tumor microenvironment, including tumor vasculature and immune infiltrate, using mouse models and single cell techniques, to elucidate …

Development Of Graphical Models And Statistical Physics Motivated Approaches To Genomic Investigations, Yashwanth Lagisetty

Dissertations & Theses (Open Access)

Identifying genes involved in disease pathology has been a goal of genomic research since the early days of the field. However, as technology improves and the body of research grows, we are faced with more questions than answers. Among these is the pressing matter of our incomplete understanding of the genetic underpinnings of complex diseases. Many hypotheses offer explanations as to why direct and independent analyses of variants, as done in genome-wide association studies (GWAS), may not fully elucidate disease genetics. These range from pointing out flaws in statistical testing to invoking the complex dynamics of epigenetic processes. In the …

A Theoretical Perspective On Parasite-Host Coevolution With Alternative Modes Of Infection, George N. Shillcock

Electronic Thesis and Dissertation Repository

We investigate how natural selection shapes the coevolution of parasitism. We discuss the antagonism fuelled by parasites’ necessity to transmit to novel hosts, and host’s desire to minimise virulence. In support, we build a mathematical model which considers the epidemiology and life-history trade-offs faced by an obligate microparasite and its host. Our model allows parasites to be transmitted to new hosts via direct contact (horizontally) or from parent to offspring during birth (vertically). We test the hypothesis that vertical transmission causes virulence to diminish in the long run, and contrary to widely accepted views, find that vertical transmission need not …

The Role Of Reactive Oxygen Species In The Accumulation Of Driver Mutations In B Cell Acute Lymphoblastic Leukemia, Mia P. Sams

Electronic Thesis and Dissertation Repository

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with recurrent mutations and high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine was tested for its ability to prolong lifespan of a mouse model of B-ALL and reduce frequency of mutations. Mice treated with 1g/L of N-acetylcysteine in drinking water were found to have delayed onset of B-ALL at 11 weeks of age and changes in gene expression relating to B cell development, calcium-apoptosis signaling, and pathways in cancer, although no differences in lifespan were observed. Tumours from treated …

Quality Of Life For Women With Chronic Lyme Disease: A Socioeconomic Investigation, Dale M. Jones

Doctoral Dissertations

This is a mixed methods investigation of how chronic Lyme disease, including Lyme-like diseases and co-infections, affects the quality of life of women who have chronic Lyme. Both quantitative and qualitative methods were used during three phases of research: a 91-question survey instrument followed by focus group discussions and written narratives. The research considered the socioeconomic impact on quality of life in five areas: obtaining a diagnosis, relationships and personal support systems, struggles with the medical system, the ability to work, and access to treatment. There were 500 responses to the survey, of which 373 were analyzed; 11 participants in …

Utility Of The Motivation To Change Lifestyle And Health Behaviors For Dementia Risk Reduction Scale (Mclhb-Drr) Based On A North American Sample, Angelina E. Witbeck

Dissertations

As the population ages, the prevalence rates of dementia continue to increase. Without a cure or promising treatment for dementia, the best course of lowering the prevalence rates of dementia is through preventative measures. Through an electronic survey, the study utilized the MCLHB-DRR scale to determine whether (1) gender, age, educational background, and socioeconomic status will impact the motivational factors to change lifestyle and health behaviors to reduce the risk of developing dementia and (2) direct experiences with individuals that have a dementia diagnosis are likely to impact one's motivational factors to change lifestyle and health behaviors to reduce the …

Primary Cilia Of The Cardiac Neural Crest & Hedgehog-Mediated Mechanisms Of Congenital Heart Disease, Lindsey A. Fitzsimons

Electronic Theses and Dissertations

Elimination of primary cilia in cardiac neural crest cell (CNCC) progenitors is hypothesized to cause a variety of congenital heart defects (CHDs), including atrioventricular septal defects, and malformations of the developing cardiac outflow tract. We present an in vivo model of CHD resulting from the conditional elimination of primary cilia from CNCC using multiple, Wnt1:Cre-loxP, neural crest-specific systems, targeting two distinctive, but critical, primary cilia structural genes: Intraflagellar transport protein 88 (Ift88) or kinesin family member 3A (Kif3a). CNCC loss of primary cilia leads to widespread CHD, where homozygous mutant embryos (MUT) display a variety of outflow tract malformations, septation …

How Environmental Change Will Impact Mosquito-Borne Diseases, Arsal Khan

Master's Projects and Capstones

Mosquitos, the most lethal species throughout human history, are the most prevalent source of vector-borne diseases and therefore a major global health burden. Mosquito-borne disease incidence is expected to shift with environmental change. These changes can be predicted using species distribution models. With the wide variety of methods used for models, consensus for improving accuracy and comparability is needed. A comparative analysis of three recent modeling approaches revealed that integrating modeling techniques compensates for trade-offs associated with a singular approach. An area that represents a critical gap in our ability to predict mosquito behavior in response to changing climate factors, …