Digital Commons Network^™

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. …

Towards A Holistic Risk Model For Safeguarding The Pharmaceutical Supply Chain: Capturing The Human-Induced Risk To Drug Quality, Heather R. Campbell

Theses and Dissertations--Pharmacy

Counterfeit, adulterated, and misbranded medicines in the pharmaceutical supply chain (PSC) are a critical problem. Regulators charged with safeguarding the supply chain are facing shrinking resources for inspections while concurrently facing increasing demands posed by new drug products being manufactured at more sites in the US and abroad. To mitigate risk, the University of Kentucky (UK) Central Pharmacy Drug Quality Study (DQS) tests injectable drugs dispensed within the UK hospital. Using FT-NIR spectrometry coupled with machine learning techniques the team identifies and flags potentially contaminated drugs for further testing and possible removal from the pharmacy. Teams like the DQS are …

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 …

The Role Of Adverse Childhood Experiences (Aces) In The Military And Predicting Current Distress, Douglas A. Foote

Theses and Dissertations--Social Work

The United States has been in continuous military conflicts for the past two decades. The importance of having a fully capable fighting force is unquestionable, but too often, military units are not at full capacity due to service members (SMs) within a unit being unable to deploy due to mental health impediments. The surge of non-deployable SMs is a national security concern as it affects the SMs’ quality of life and Department of Defense’s (DoD) ability to fight today’s conflicts.

This study bolsters military ACE research because it sampled more female and officer participants compared to extant military ACE studies. …

Capture Of Respirable Dust Using Maintenance Free Impingement Screen, Neeraj Kumar Gupta

Theses and Dissertations--Mining Engineering

Dust produced during mining activities has a detrimental effect on both miners’ health and operations’ safety. There is no definitive treatment for coal miners’ pneumoconiosis (CWP), which is caused by prolonged inhalation of respirable dust. Elevated coal dust concentrations have also been shown to cause several disastrous explosions in the United States and worldwide, resulting in the death of miners and loss of operations. Flooded-bed dust scrubbers are used on all modern-day continuous miners. These devices cleanse the dust-laden air and assist in bringing fresh air towards the mining face. Scrubbers use a multi-layered fibrous screen to capture airborne particles. …

The Role Of Live Conifer Fuels In Crown Fires Spread, Adnan Darwish Ahmad

Theses and Dissertations--Mechanical and Aerospace Engineering

Live foliage for some tree and shrub species can support flaming fire spread at much higher moisture content than dead fuel materials. However, the role of live fuels in forest fires has been controversial in the past decades. Although ignition and spread statistical data for live and dead fuels exist in the literature, a clear understanding of the fundamental difference in the burning behavior is missing. To illuminate the role of live fuel on forest fire spreading, a laboratory ignition experiment was designed to examine the burning behavior of live Norway spruce needles. A schlieren-Infrared combined measurement apparatus was developed …

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 …

Redesigning Products To Optimize Sustainable Performance In Multi-Generational Closed-Loop Production For Advancing The Circular Economy, Buddhika Minendra Hapuwatte

Theses and Dissertations--Mechanical and Aerospace Engineering

Sustainable manufacturing and the circular economy concepts promote efficient and effective resource use to minimize the adverse economic, environmental, and social impacts of alarmingly increasing consumption rates. Product design is the key to implement these transformations in manufacturing. However, the currently available sustainable and circular design methods are not comprehensive and inadequate—especially for multi-generational products. Therefore, designing sustainable products optimized for circular and closed-loop production systems is a challenging task. The 6Rs concept introduced ‘Redesign’ to modify a product’s engineering specifications and allow sustainable utilization of the end-of-use resources from previous generations, thus closing the production loop. Therefore, the objective …

Cell And Biofilm Adhesion Strength Quantified By The Laser Spallation Technique Yields A Novel Biocompatibility Metric, The Adhesion Index, James Boyd

Theses and Dissertations--Mechanical and Aerospace Engineering

Implant associated infections are one of the leading causes of hospital acquired infections in the United States. Medical orthopedic implant devices are designed to improve adhesion of relevant cells within our body. In the case of orthopedic implants, osteoblast cells will adhere and allow for proper integration with the body’s bones. However, virulent bacteria will also adhere onto medical implants and proliferate into biofilms. Bacterial biofilms become extremely difficult to eradicate clinically as antibiotics are not as effective, resulting in severe infections or loss of implant. The aim of this research is to quantify the adhesion strength differential between relevant …

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 …

Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids To Predict Carboplatin Resistance, Justin W. Gorski

Theses and Dissertations--Clinical and Translational Science

The development of patient-derived tumor organoids (TOs) from epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine.

Here, we utilize TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high grade serous epithelial ovarian cancer tumor organoids from tissue obtained during debulking surgery (2 neoadjuvant carboplatin exposed, 4 chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1 and 0.1µM). Cell viability curves and resultant EC50 values were determined …

Comparison Of Implant-Retained Overdenture And Conventional Complete Denture In The Edentulous Mandible: A Survey Study To Measure Patients' Satisfaction And Quality Of Life In Dental School Clinical Environment, Ahmad Kutkut

Theses and Dissertations--Clinical and Translational Science

Patient satisfaction and quality of life are integral parts of assessing the quality of oral health care. Current aging population trends suggest a growing need to understand the effects of edentulism on oral health and quality of life. As the proportion of aged Americans expands, there will be an increased need to understand treatment options and patient communication strategies. In addition, as new treatment options and innovative technologies emerge, it will be essential to understand patients' concerns and identify best practices associated with denture treatments' individual fit and function. Advanced denture treatments can now be fabricated using CAD/CAM digital denture …

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 …

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) …

Development Of A Robust Linac-Based Radiosurgery Program For Multiple Brain Metastases & Estimation The Radiobiological Response Of Indirect Cell Kill, Allison Palmiero

Theses and Dissertations--Radiation Medicine

Accurate and precise delivery of Stereotactic Radiosurgery (SRS) using Gamma Knife (GK) unit by Leksell is a gold standard for multiple intracranial lesions. SRS provides less brain toxicity compared to whole brain radiotherapy techniques historically used. However, these treatments are limited in availability and are accompanied by long treatment times with painful, intolerable headframe fixation. With advancements in linear accelerator (Linac) based SRS, multiple brain lesions can be treated separately with individual isocenters or, more recently, altogether with a single isocenter multi-target (SIMT) volumetric modulated arc therapy (VMAT) technique. SIMT methods reduce the challenges of treating patients with GK by …

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 …

Characteristics Of Cercospora Nicotianae With Reduced Sensitvity To Azoxystrobin, William Barrett Barlow

Theses and Dissertations--Plant Pathology

Burley and dark tobacco production are important to agriculture in Kentucky, worth $145.1 and $94.4 million in 2020, respectively. The price received for a tobacco crop is influenced by leaf quality, determined by multiple characteristics including leaf damage. Frogeye leaf spot (FLS), caused by Cercospora nicotianae, has historically been a minor disease of tobacco. However, when FLS infections reach the upper canopy of tobacco, lesions are seen as damage that negatively influence leaf quality. Fungicides are regularly used to manage foliar diseases of tobacco, and the only systemic fungicide active ingredient labeled for tobacco is azoxystrobin. Azoxystrobin belongs to the …

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 …

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 …

Sustainability And Economics Of White Oak (Quercus Alba) Timber Supply In Kentucky, Gaurav Dhungel

Theses and Dissertations--Forestry and Natural Resources

Sustained timber supply relies upon balanced forest age distribution, where the level of harvesting and mortality is compensated by regeneration and growth among younger age classes. However, current forest inventory trends from the white oak growing region reveal sustainability threat from declining white oak regeneration and recruitment leading to disproportionate inventory structure. Consequently, there exists growing concern among stakeholders on long-term sustainability of white oak timber and its economic implications, particularly in Kentucky, because of the significance of the species to the state’s economy. This research aims to examine past and current inventory levels of white oak in Kentucky using …

The Impacts Of Imazapic On Garlic Mustard And Non-Target Forest Floor Vegetation In Central Kentucky’S Hardwood Forests, Pavan Kumar Podapati

Theses and Dissertations--Forestry and Natural Resources

Alliaria petiolata is an invasive biennial herb that poses a substantial threat to various ecosystems across the United States. Imazapic herbicide can control A. petiolata infestations, but there is limited peer-reviewed data on impacts of pre-emergent imazapic spraying to forest floor communities. This research examined the impacts of pre-emergent imazapic (0.84 kg/ha) with Pentra-Bark® surfactant on ground cover of A. petiolata and the spring perennials Claytonia virginica and Erigenia bulbosa. Experimental populations in randomized blocks within two forest stands in central Kentucky received the following treatments at 0.84 kg ai/ha: imazapic with Pentra-Bark®, glyphosate with Pentra-Bark®, Pentra-Bark® alone, and …

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 …

Evaluating The Biotic Condition Of Restored Streams In Kentucky’S Inner Bluegrass Region, Charles Cole Crankshaw

Theses and Dissertations--Biosystems and Agricultural Engineering

Numerous stream restoration projects have been implemented in Kentucky’s Inner Bluegrass region to offset anthropogenic impacts. These projects range from full channel realignments to volunteer-led riparian installations. To assess the ability of said projects to restore stream habitat and biota, full restoration (n=12) and riparian (n=6) sites were compared to reference (n=6) and disturbed (n=12) sites using RBP and SVAP protocols, macroinvertebrate samples, and geomorphology. General trends for SVAP, RBP, and BI scores, starting with highest habitat or biotic quality, were reference sites, full and riparian restoration sites, then disturbed sites. The number of EPT taxa, another indicator of biological …

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 …