Digital Commons Network^™

Human Regulatory T Cells Control Inflammation From Effector T Cells In Prediabetes, Rui Liu

Theses and Dissertations--Pharmacy

Type 2 diabetes (T2D) is a chronic low-grade inflammatory disease. A T cell cytokine profile (Th17) from PBMCs can distinguish obese T2D from obese non-diabetes subjects. Individual T cell subsets interact with each other and the diverse subsets jointly determine overall inflammation. Cellular metabolism drives cytokine production of CD4⁺ T cells, and therefore contributes to inflammation in T2D. However, specific changes in metabolism and function of CD4⁺ T cells during the progression from lean healthy to obese and diabetic stages in people have not been clarified.

We hypothesize that human regulatory T cells (Treg) impact metabolism of effector …

Abc Transporters In Glioblastoma: Anticancer Drug Transport And Transporter Regulation At The Blood-Brain Barrier, Julia A. Schulz

Theses and Dissertations--Pharmacy

Glioblastoma is one of the deadliest cancers, with a median survival of only one year. Even after aggressive treatment consisting of surgical resection, radiation, and chemotherapy, most glioblastoma patients suffer from tumor recurrence within 6-9 months. One reason for treatment failure of anticancer drugs is the blood-brain barrier that protects the brain by impeding xenobiotic uptake from the blood. To this end, efflux transporters at the human blood-brain barrier, such as P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2), prevent many compounds, including anticancer drugs, from entering the brain. Thus far, approaches to deliver anticancer drugs across the blood-brain barrier …

Identification And Characterization Of Epitope Specific Immune Responses In Humans And Mice, David Henson

Theses and Dissertations--Pharmacy

Cardiovascular disease (CVD) is a major cause of morbidity and mortality around the world causing approximately 14% of total disease burden. A major factor in the progression to major CVD within patients is immune activation, which led to the study of various immune products as potential biomarkers for the prediction of cardiovascular events, including antigen-specific antibodies and immune complexes. One focus of this biomarker research is IgG autoantibodies targeting apolipoprotein A-I (ApoA-I), and several studies of these antibodies have found an association with increased CVD events. Based on the encouraging results from these studies and previous research which has identified …

Elucidating The Role Of The Tyrosine Phosphatase, Shp-2, In Regulation Of Pd-L1 Expression In Non-Small Lung Cancer Using Both Biochemical Analyses And Real-World Genomic Information, Keller Toral

Theses and Dissertations--Pharmacy

Immune checkpoint inhibitors (ICIs), especially those that target programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1), have been shown to provide substantial clinical benefit in many patients with non-small cell lung cancer (NSCLC). While these therapeutic agents can be highly effective in the correct context, the biological systems that malignant cells draft from normal activities of the cell are poorly characterized. Tumor cell-specific expression of PD-L1 is likely important for clinical benefit from PD-1 and PD-L1 inhibitors. It is known that PD-L1 is inappropriately expressed in many cancers harboring mutations in the RAS family of genes. …

Delineating The Biosynthesis Of Capuramycin-Type Antibiotics, Ashley L. Biecker

Theses and Dissertations--Pharmacy

New antibiotic scaffolds with novel drug targets are needed to combat the rise of drug-resistant, infectious microorganisms. The bacterial translocase I is a ubiquitous enzyme in the peptidoglycan biosynthetic pathway that has yet to be targeted by clinically used antibiotics. It catalyzes the transfer of N-acetylmuramoyl-pentapeptide to undecaprenylphosphate in order to generate lipid I during cell wall biosynthesis. A screening of bacterial translocase I inhibitors led to the discovery of the novel compound capuramycin and its analogues: A-500359s, A-503083s, and A-102395, produced by various species of actinomycetes. The capuramycins show potent activity against the bacterial translocase I with IC50s …

Multiple Proteinopathies And Their Role In Cognitive Impairment And Neurodegenerative Diseases, Shama D. Karanth

Theses and Dissertations--Epidemiology and Biostatistics

Most age-related neurodegenerative disorders are associated with the aggregation of misfolded and aberrant proteins. Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders and is highly prevalent in older adults. Neuropathologically, AD is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). Other misfolded proteins, including α-synuclein and transactive response DNA-binding protein 43 (TDP-43), are also commonly observed in aged brains. Aberrant α-synuclein has been associated with Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy, whereas TDP-43 has been associated with multiple neurological diseases, the most common of which was designated as limbic-predominant, …

Use Of Microscale Hydrophobic Surface Features For Integration Of 3d Cell Culture Into Multi-Functional Microfluidic Devices, Soroosh Torabi

Theses and Dissertations--Mechanical and Aerospace Engineering

3D cell culture and microfluidics both represent powerful tools for replicating critical components of the cell microenvironment; however, challenges involved in integration of the two and compatibility with standard tissue culture protocols still represent a steep barrier to widespread adoption. Here we demonstrate the use of engineered surface roughness in the form of microfluidic channels to integrate 3D cell-laden hydrogels and microfluidic fluid delivery. When a liquid hydrogel precursor solution is pipetted onto a surface containing open microfluidic channels, the solid/liquid/air interface becomes pinned at sharp edges such that the hydrogel forms the “fourth wall” of the channels upon solidification. …

Multiscale Finite Element Modeling Of Active Contraction In Striated Muscle, Charles Kurtis Mann

Theses and Dissertations--Mechanical and Aerospace Engineering

Greater than one in three American adults have at least one type of cardiovascular disease, a major cause of morbidity. Computational cardiac mechanics has become an important part of the research effort to understand the heart’s response to mechanical stimuli and as an extension, disease progression and potential therapies. To this end, the present work aims to extend these efforts by implementing a cell level contractile model in which active stress generation in muscle tissue is driven by half-sarcomere mechanics. This is accomplished by enhancing the MyoSim model of actin and myosin in order to produce a multiscale model. This …

Study Of Stress-Based Fiber Reorientation Law In A Finite Element Model Of Cardiac Tissue, Alexus Lori Rockward

Theses and Dissertations--Mechanical and Aerospace Engineering

Myofiber organization in the heart plays an important role in achieving and maintaining physiological cardiac function. In many cardiac disease states, myofibers and particularly cardiomyocytes are disorganized in chaotic patterns, a phenotype known broadly as myocardial disarray. In familial hypertrophic cardiomyopathy (HCM), this disorganization in the form of myocyte disarray is thought to contribute to impaired cardiac function and the development of arrhythmia during disease progression. However, the mechanisms regarding fiber reorientation in the heart are yet still unclear, and few adaptative laws have been created to explore these mechanisms. A stretch-based law was developed with the aim of achieving …

Effective Modulus Of Cracked Bodies: A Finite Element Analysis, Alan Thomas Varughese

Theses and Dissertations--Mechanical and Aerospace Engineering

This thesis considers how cracks in an elastic body can alter the body’s elastic properties. In the present study the elastic property of note is the elastic or young’s modulus. It is desired to investigate to what extent the number and orientation of cracks can cause a reduction in the elastic modulus. Because of the complex nature of the elastic fields resulting from multiple cracks interacting together in a finite geometry an analytical solution is not possible or considered. Rather the Finite Element Method is used to determine the elastic response to a body with many cracks. This provides a …

Precision Drug Delivery For Vancomycin Efficacy And Safety In Critically Ill Patients, Alexander Flannery

Theses and Dissertations--Clinical and Translational Science

Vancomycin is the most commonly prescribed antibiotic for hospitalized patients. Despite this fact and decades of clinical use, clinicians remain challenged to meet dosing targets of this narrow therapeutic index drug as well as minimize the risks of therapy, primarily nephrotoxicity. These concerns are magnified in critically ill patients given their severity. Accordingly, in a series of five clinical studies, we sought to identify optimal methods of vancomycin administration in critically ill patients to maximize efficacy and minimize nephrotoxicity via three techniques: use of continuous versus intermittent infusion, use of first-dose pharmacokinetic calculations to guide dosing, and use of loading …

Therapeutic Drug Monitoring Of Beta-Lactam Antibiotics In Critically Ill Patients With Sepsis, Melissa Thompson Bastin

Theses and Dissertations--Clinical and Translational Science

Sepsis is a devastating diagnosis affecting over 750,000 patients a year, accounting for approximately 10% of all hospital admissions, costs more than $50,000 per patient, and exceeds $17 billion annual spending. The mortality rate for sepsis remains unacceptably high: one out of every three patients diagnosed with sepsis dies. Sepsis physiology induces physiologic changes to drug pharmacokinetic (PK) parameters that alter the ability to achieve the goal pharmacodynamic (PD) target for beta-lactams of >4-fold unbound concentration above the minimum inhibitory concentration for 100% of the dosing interval (100% fT >4x MIC). Sepsis treatment such as volume resuscitation and vasopressor …

Genetic Mouse Models Of Liver Disease: Potential Roles Of Zhx2 (Afr1) And Afr2 In Damage And Regeneration, Courtney P. Turpin

Theses and Dissertations--Pharmacology and Nutritional Sciences

The liver is the largest internal organ in mammals and responsible for carrying out various processes, including lipid and carbohydrate metabolism, detoxification of chemicals, and production of serum proteins. Liver damage, which can be caused by a variety of agents including viral infection, environmental toxins, alcohol and excessive dietary fats, can cause dysregulation of these critical functions, leading to worsening liver pathophysiology and impacting health. However, the liver has the remarkable ability to regenerate when damaged. Hepatocytes, which comprise a majority of liver cells, are relatively quiescent under healthy conditions. Upon injury, remaining hepatocytes can proliferate to recover from liver …

The Gestation Of Health: Environmental Insults, Behavioral Interventions, And Protective Mechanisms, Brittany Breon Rice

Theses and Dissertations--Pharmacology and Nutritional Sciences

Diabetes remains a leading cause of death nationwide despite pharmacological advances. Recent etiological investigations of the disease detail the role of perinatal exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs), in enhancing disease susceptibility. Polychlorinated biphenyl 126, a coplanar PCB, elicits its toxic effects through the aryl-hydrocarbon receptor and the disruption of endocrine signaling. The goal of this dissertation was to focus on delineating the differences in the developmental windows of diabetes susceptibility respective to the timing of PCB126 exposure and to understand the influence of maternal exercise and nuclear-factor erythroid-2-related factor 2 (Nrf2) expression in combating the negative …

The Role Of Microtubule-Associated Protein Tau In Neuronal Excitability And Epileptogenesis, Ryan A. Cloyd

Theses and Dissertations--Physiology

Tauopathies, including Alzheimer’s disease (AD), are devastating diseases with an immense burden on society which is predicted to increase in coming decades. In addition to progressive loss of memory and cognitive function, patients with tauopathies have a 6-10 fold increase in lifetime risk for seizures, and many are diagnosed with epilepsy. The presence of epileptiform activity on electroencephalogram (EEG) recordings from patients with AD predicts faster cognitive decline compared to patients without abnormal EEG readings. Electrophysiological measurements in murine models of AD have identified neuronal hyperexcitability. Furthermore, reducing tau phosphorylation or expression confers seizure resistance in animal epilepsy models. Although …

Novel Mammalian Models For Understanding And Treating Spinal Cord Injury, Michael B. Orr

Theses and Dissertations--Physiology

Spinal cord injury (SCI) is devastating and often leaves the injured individual with persistent dysfunction. The injury persists because humans have poor wound repair and there are no pharmacologic treatments to induce wound repair after SCI. The continued efforts to discover therapeutic targets and develop treatments heavily relies on animal models. The purpose of this project is to develop and study novel mammalian models of SCI to provide insights for the development and effective implementation of SCI therapies.

Lab mice (Mus musculus) are a powerful tool for recapitulating the progression and persistent damage evident in human SCI, but …

Metabolic And Electrophysiological Effects Of Fibroblast Growth Factor 19 In The Dorsal Vagal Complex, Jordan Wean

Theses and Dissertations--Physiology

The dorsal vagal complex (DVC) is an important homeostatic regulatory center located in the hindbrain that alters vagal parasympathetic activity in response to central, viscerosensory, and humoral cues. Within the DVC, second-order sensory neurons in the nucleus tractus solitarius (NTS) integrate ascending vagal sensory input with descending regulatory inputs from higher brain areas and respond to circulating hormones and glucose. In turn, the NTS projects to the dorsal motor nucleus of the vagus (DMV) which is comprised of cholinergic motor neurons and regulates gastric motility, hepatic glucose production, and pancreatic hormone release functions, among others.

Fibroblast growth factor 19 (FGF19) …

The Roles Of The Actin Network And Co-Opted Host Factors In Tbsv Replication, Melissa Gabriela Molho Medina

Theses and Dissertations--Plant Pathology

Positive-stranded (+) RNA viruses are the largest family of viruses that infect plants, causing important economic losses in different crops. Tomato bushy stunt virus (TBSV), a small positive-stranded RNA virus, has emerged as a model virus to study virus-host interactions. TBSV encodes for only five proteins, therefore, to infect the host cell TBSV co-opts selected host components and subverts specific molecular pathways.

Firstly, I performed a proteomic screening using Arabidopsis proteins. I found that TBSV viral replication proteins interact with 88 host proteins, including the ubiquitin-conjugating enzyme 2 (Ubc2), fructose 1,6 biphosphate aldolase (Fba1), and several members of the Hps70 …

Seeing Double With Cannabis: Heteroploid Populations In Bipolaris Gigantea, Causal Agent Of Bipolaris Leaf Spot, Desiree Szarka

Theses and Dissertations--Plant Pathology

Bipolaris leaf spot (BLS) disease emerged with the reintroduction of hemp as a crop in the United States following more than 60 years of prohibition. The causal agent was identified as Bipolaris gigantea (=Drechslera gigantea), a known minor pathogen of monocots which causes devastating disease on hemp. BLS has been confirmed throughout Kentucky and reported in 15 states. Morphology and growth characteristics of isolates from eight counties across Kentucky were similar with the exception of some isolates producing protoperithecial-like structures. Phylogenetic and whole genome analysis indicated that some isolates were haploid, containing a single allele at each gene …

Maturation Of Equine Proximal Sesamoid Bones In Thoroughbred Horses, Angela Maria Mangine

Theses and Dissertations--Veterinary Science

Proximal sesamoid bone (PSB) injuries account for approximately 50% of all fatal catastrophic musculoskeletal injuries in Thoroughbred racehorses. In addition, PSB fractures are not uncommon in Thoroughbred foals and yearlings as a result of energetic or intense free exercise. The ability to interpret some PSB pathology assessments, however, is more difficult given the limited information published on the normal development and maturation of these paired sesamoid bones. In addition, the level of normal variation in PSB morphological and structural parameters within the Thoroughbred population as a function of age, body size, gender, and inter-animal variation are not well documented, complicating …

Structural Adaptation Of Equine Proximal Sesamoid Bones To High-Speed Exercise, Kathryn Mary Babiarz

Theses and Dissertations--Veterinary Science

Proximal sesamoid bone (PSB) fractures are one of the most commonly reported catastrophic musculoskeletal injuries (CMI) in Thoroughbred racing. Despite the seriousness of these injuries, an understanding of the structural changes that occur normally within PSBs in response to the biomechanical forces of high-speed exercise and how they relate to pathological events leading to fracture remain limited. To address this critical knowledge gap, PSBs from Thoroughbred horses were analyzed with both computed tomography (CT) and microcomputed tomography (µCT) to assess their morphological and structural parameters. Comparisons were made using samples from the left and right forelimbs of Thoroughbreds of both …

An Assessment Of The Carrier State And A Novel Marker Of Leptospira And Abortion In Central Kentucky Horses, Gloria Louise Gellin

Theses and Dissertations--Veterinary Science

Leptospirosis is a reemerging zoonotic infection of worldwide importance and affects all mammals. The bacterium is transmitted to animals and humans by urine, fetal membranes and body fluids. Leptospira shedding in the urine contaminates both soil and water, exposing both humans and animals to the bacterium. Leptospirosis in horses can cause abortion and is one of the etiologies of equine recurrent uveitis which can lead to blindness. Equine leptospiral abortion in Central Kentucky is primarily caused by serovar Pomona, with occasional cases attributed to serovar Grippotyphosa. There are a few reports in the literature attributing abortion to serovar Bratislava in …

Muscle Mass And Immune Function In The Senior Horse, Alisa Christina Herbst

Theses and Dissertations--Veterinary Science

Senior horses (≥ 15 years) represent up to one-third of the global equine population, and the proportion of old horses (≥ 20 years) in the U.S. has been steadily increasing. Aging is associated with a loss of skeletal muscle mass in horses, and while age-related muscle loss is comparingly well characterized in humans, little is currently known concerning underlying mechanisms, adverse outcomes, or the prevalence of low muscle mass in senior horses. One factor proposed to play a role in the development of age-related muscle atrophy in humans is inflamm-aging, a low-grade inflammation that affects elderly people and that has …

Vole Population Dynamics In Cover Crops Transitioning To Soybeans With Integrated Pest Management By Habitat Modification, Jena L. Nierman

Theses and Dissertations--Forestry and Natural Resources

The use of cover crops has been a wildly used method in rotational row crop production. Cover crops have minimized soil runoff and aided in maintaining nutrients in agricultural fields. Increased use of cover crops has seen a corresponding increase in the amount of damage done to soybeans by voles. Currently, there are no mitigation methods that successfully decrease vole populations in agricultural fields. The use of habitat manipulation as an integrated pest management solution has not been studied as a practical solution for vole population management. During 2019 and 2020, I tested the impacts of various cover crop termination …

Quantifying The Source And Pathway Of Dissolved Reactive Phosphate In Karst Drainage Of The Inner-Bluegrass, Cory Radcliff

Theses and Dissertations--Biosystems and Agricultural Engineering

In the Midwestern U.S. seasonal hypoxia experienced in the Gulf of Mexico and harmful algal blooms in inland freshwater ponds, lakes, and rivers are partly fueled by dissolved orthophosphate loadings from disturbed landscapes. Efforts to reduce dissolved reactive phosphate (DRP) loadings have had varying levels of success and have led to insufficient water quality improvements. Inefficiencies in conservation strategies can stem from poor understanding of phosphate source and flow pathway dynamics. This study focused on monitoring sources and flow pathways of dissolved reactive P in a karst agroecosystem with phosphatic limestone. We collected event water samples at the Camden Creek …

Extraction Of Micro- And Nano-Plastic Particles From Water Using Hydrophobic Natural Deep Eutectic Solvents, Jameson R. Hunter

Theses and Dissertations--Biosystems and Agricultural Engineering

The production of plastic and the amount of waste plastic that enters the environment increases every year. Synthetic polymers will gradually break down into particles on the micro- and nano-scale. The micro- and nano-plastics pose a significant ecological harm by transporting toxic chemicals and causing inflammation and cellular damage when ingested. Two common plastics are polyethylene terephthalate (PET) and Polystyrene (PS), and a newer bioplastic polylactic acid (PLA) that has become a popular alternative. Deep eutectic solvents are a recently discovered solvent composed of a hydrogen bond donor and hydrogen bond acceptor and have been proposed as a cheaper alternative …

Characterization And Upgrade Of Endocarp Biomass Derived Lignin To Value Added Products, Makua Vin-Nnajiofor

Theses and Dissertations--Biosystems and Agricultural Engineering

Lignin is an abundant biopolymer and a promising source of feedstock for high-value chemicals and energy materials, however, application methods of lignin into valuable products is yet to be fully explored. This study explores the valorization of lignin derived from lignin-rich endocarp biomass through the development of lignin-derived electrode materials. The chemical composition and cellular structure of the endocarps were characterized using HPLC and scanning electron microscopy (SEM) imaging. Mechanical properties of walnut and peach endocarps and preprocessing requirements were investigated using nanoindentation and specific energy consumption during grinding. Next, lignin was extracted from endocarps using deep eutectic solvent and …

Modeling Energy Flows In Floating In-Pond Raceways Utilizing Solar Power Back-Up, Bo Smith

Theses and Dissertations--Biosystems and Agricultural Engineering

The In-pond Raceway (IPR) is a novel option for production aquaculture, depending on water moving devices to provide constant flow. Device failure may result in catastrophic fish loss, requiring power backup systems to mitigate risk in case of power outages. Because these systems must be dependable and many suitable locations are remote, off-grid solar photovoltaic (PV) systems with battery storage have been considered since they eliminate need for utility power. Such systems can be hard to size and expensive. This study modeled system requirements using an energy balance to determine whether systems could withstand varying loads based on climatological conditions. …

Southern Pine Beetle-Specific Rna Interference Demonstrates No Effects On Nontarget Insects, Hannah Marie Hollowell

Theses and Dissertations--Entomology

The endemic southern pine beetle (SPB), Dendroctonus frontalis Zimmermann, is a highly destructive bark beetle that has devastated coniferous forests of the southern United States for decades. Traditional management strategies have been unable to respond effectively to largescale SPB outbreaks, prompting exploration of novel techniques including RNA interference (RNAi). Double-stranded RNAs (dsRNAs) are effective at triggering gene silencing and inducing mortality in SPB, but determining delivery methods and demonstrating specificity of the treatments is necessary before this technology may progress to deployment.

I evaluated three SPB-specific dsRNAs on model nontarget insects to assess potential lethal effects, sublethal effects such as …

Distribution And Diversity Of Heliothine And Other Lepidopteran Nudiviruses, Emrah Ozel

Theses and Dissertations--Entomology

Helicoverpa zea nudivirus 2 (HzNV-2) is the only known sterilizing and sexually-transmitted insect virus and causes pathological symptoms in H. zea reproductive tissues. HzNV-2 has features that make it a candidate as a H. zea (corn earworm) control agent, such as the ability to cause asymptomatic (latent) and symptomatic (lytic) infections and the ability to influence mating behavior of its host to favor virus spread. HzNV pathology has been studied and its genome sequenced, however, its prevalence in natural populations is largely unknown. In this study, we developed and used a low-cost PCR-based molecular survey to investigate HzNV-2 prevalence and …