Digital Commons Network^™

Investigations Of Interleukin-1 Alpha As A Novel Stroke Therapy In Experimental Ischemic Stroke, Kathleen Elizabeth Salmeron

Theses and Dissertations--Neuroscience

Stroke is a leading cause of death and disability worldwide. Although rapid recognition and prompt treatment have dropped mortality rates, most stroke survivors are left with permanent disability. Approximately 87% of all strokes result from the thromboembolic occlusion of the cerebrovasculature (ischemic strokes). Potential stroke therapeutics have included anti-inflammatory drugs, as well as many other targets with the goal of mitigating the acute and chronic inflammatory responses typically seen in an ischemic stroke. While these approaches have had great success in preclinical studies, their clinical translation has been less successful. Master inflammatory cytokines, such as IL-1, are of particular interest. …

Myosin-Xva Is Key Molecule In Establishing The Architecture Of Mechanosensory Stereocilia Bundles Of The Inner Ear Hair Cells, Shadan Hadi

Theses and Dissertations--Medical Sciences

Development of hair cell stereocilia bundles involves three stages: elongation, thickening, and supernumerary stereocilia retraction. Although Myo-XVa is known to be essential for stereocilia elongation, its role in retraction/thickening remains unknown. We quantified stereocilia numbers/diameters in shaker-2 mice (Myo15^sh2) that have deficiencies in “long” and “short” isoforms of myosin-XVa, and in mice lacking only the “long” myosin-XVa isoform (Myo15^ΔN). Our data showed that myosin-XVa is largely not involved in the developmental retraction of supernumerary stereocilia. In normal development, the diameters of the first (tallest)/second row stereocilia within a bundle are equal and grow simultaneously. …

Accounting For Matching Uncertainty In Photographic Identification Studies Of Wild Animals, Amanda R. Ellis

Theses and Dissertations--Statistics

I consider statistical modelling of data gathered by photographic identification in mark-recapture studies and propose a new method that incorporates the inherent uncertainty of photographic identification in the estimation of abundance, survival and recruitment. A hierarchical model is proposed which accepts scores assigned to pairs of photographs by pattern recognition algorithms as data and allows for uncertainty in matching photographs based on these scores. The new models incorporate latent capture histories that are treated as unknown random variables informed by the data, contrasting past models having the capture histories being fixed. The methods properly account for uncertainty in the matching …

Dual Lox/Cox Inhibition: A Novel Strategy To Prevent Neurovascular Leakage In Epilepsy, Brent S. Sokola

Theses and Dissertations--Pharmacy

Epilepsy affects 3.4 million patients in the USA and is characterized by recurring seizures. The blood-brain barrier is leaky in epilepsy and may contribute to seizure progression but the mechanisms which cause this leakage are not fully understood. We hypothesized that seizures trigger LOX- and COX-mediated blood-brain barrier leakage and that dual LOX/COX inhibition prevents barrier leakage in vivo. To test this hypothesis, we administered either the dual LOX/COX inhibitor licofelone or a combination of the 5-LOX inhibitor zileuton and the COX-2 inhibitor celecoxib to rats that experienced status epilepticus (SE). Serum and brain capillaries were isolated 48 hours …

The Impact Of Bioactive Phytosterol, Stigmasterol, On Cholesterol Elimination Pathways In Mice, Hannah C. Lifsey

Theses and Dissertations--Pharmacy

Despite advances in healthcare, cardiovascular disease (CVD) remains the leading cause of death in the United States. Elevated levels of plasma cholesterol are highly predictive of CVD and stroke and are the principal driver of atherosclerosis. Unfortunately, current cholesterol lowering agents, such as statins, are not known to reverse atherosclerotic disease once it has been established. In preclinical models, agonists of nuclear receptor, LXR, have been shown to reduce and reverse atherosclerosis. Phytosterols are bioactive non-cholesterol sterols that act as LXR agonists and regulate cholesterol metabolism and transport. We hypothesize that stigmasterol would act as an LXR agonist and alter …

Characterization And Engineering Of Human Proteins As Therapeutic Candidates, Kyungbo Kim

Theses and Dissertations--Pharmacy

Protein engineering has been a useful tool in the fight against human diseases. Human insulin was the first recombinant DNA-derived therapeutic protein (Humulin^®) approved by the US FDA in 1982. However, many of the early protein drugs were only recombinant versions of natural proteins with no modification of their primary amino acid sequence and most of them did not make optimal drug products mainly due to their short half-life or suboptimal affinity, leading to poor therapeutic efficacy. The difficulty in the large-scale production of some therapeutic proteins was another important issue. In the past three decades, different protein …

Alternatively Activated Macrophages In Pseudomonas Aeruginosa Pneumonia: Modulation Of The Nf-Κb Signaling Pathway And The Immunomodulatory Role Of Arginase-1, Dalia Haydar

Theses and Dissertations--Pharmacy

Background: Azithromycin polarizes macrophages into an alternative phenotype and promotes a regulated immunity. Arginase is an important effector of these macrophages believed to play an essential role in decreasing injury and promoting repair.

Hypothesis: Decreases in inflammation in response to Pseudomonas aeruginosa (PA) pneumonia achieved by polarizing macrophages to an alternative phenotype is dependent upon the production of arginase.

Methods: Requirement of arginase was examined by pharmacological inhibition using S-(2-boronoethyl)- l-cysteine (BEC) or l-norvaline and by infecting arginase-1 conditional knock-out mice (Arg1^flox/flox;Lyz2-cre (Arg1^Δm)) with PA intratracheally. Arg1^ΔM and control Arg1^flox/flox mice were then …

Discovery Of New Antimicrobial Options And Evaluation Of Aminoglycoside Resistance Enzyme-Associated Resistance Epidemic, Selina Y. L. Holbrook

Theses and Dissertations--Pharmacy

The extensive and sometimes incorrect and noncompliant use of various types of antimicrobial agents has accelerated the development of antimicrobial resistance (AMR). In fact, AMR has become one of the greatest global threat to human health in this era. The broad-spectrum antibiotics aminoglycosides (AGs) display excellent potency against most Gram-negative bacteria, mycobacteria, and some Gram-positive bacteria, such as Staphylococcus aureus. The AG antibiotics amikacin, gentamicin, kanamycin, and tobramycin are still commonly prescribed in the U.S.A. for the treatment of serious infections. Unfortunately, bacteria evolve to acquire resistance to AGs via four different mechanisms: i) changing in membrane permeability to …

Development And Preclinical Evaluation Of Long-Lasting Cocaine Hydrolases For Cocaine Overdose And Cocaine Use Disorder Treatment, Ting Zhang

Theses and Dissertations--Pharmacy

Cocaine is a plant-based illicit drug commonly involved in substance use disorder. Although cocaine overdose and cocaine use disorders cause adverse health consequences to individuals and the economic burden on their family and society, there are no FDA (Food and Drug Administration) approved medications for treatment. Recently, it has been recognized that delivery of cocaine hydrolase (CocH) is a promising therapeutic strategy. Human butyrylcholinesterase (hBChE), the primary enzyme involved in cocaine metabolism in human, have advantages over other candidates for the development of CocH. Previous studies in our laboratory have designed and characterized hBChE mutants that have ~4,000-fold improved catalytic …

Using The Qbest Equation To Evaluate Ellagic Acid Safety Data: Generating A Qnoael With Confidence Levels From Disparate Literature, Cynthia Rose Dickerson

Theses and Dissertations--Pharmacy

QBEST, a novel statistical method, can be applied to the problem of estimating the No Observed Adverse Effect Level (NOAEL or QNOAEL) of a New Molecular Entity (NME) in order to anticipate a safe starting dose for beginning clinical trials. The NOAEL from QBEST (called the QNOAEL) can be calculated using multiple disparate studies in the literature and/or from the lab. The QNOAEL is similar in some ways to the Benchmark Dose Method (BMD) used widely in toxicological research, but is superior to the BMD in some ways. The QNOAEL simulation generates an intuitive curve that is comparable to the …

Investigation Of Environmental Cadmium Sources In Eastern Kentucky, Elizabeth Maher

Theses and Dissertations--Mining Engineering

Utilizing data collected by the University of Kentucky Lung Cancer Research Initiative (LCRI), this study investigated potential mining-related sources for the elevated levels of cadmium in Harlan and Letcher counties. Statistical analyses for this study were conducted utilizing SAS. A number of linear regression models and logarithmic models were used to evaluate the significance of the data. The linear regression models consisted of both simple and multivariate types, with the simple models seeking to establish significance between the potential sources and urine cadmium levels and the multivariate models seeking both to identify any statistically significant linear relationships between source types …

NoX Formation In Light-Hydrocarbon, Premixed Flames, Robert T. Hughes

Theses and Dissertations--Mechanical and Aerospace Engineering

This study explores the reactions and related species of NO_x pollutants in methane flames in order to understand their production and consumption during the combustion process. To do this, several analytical simulations were run to explore the behavior of nitrogen species in the pre-flame, post- flame, and reaction layer regions. The results were then analyzed in order to identify all "steady-state" species in the flame as well as the determine all the unnecessary reactions and species that are not required to meet a defined accuracy. The reductions were then applied and proven to be viable.

Intermittent Hypoxemia In Preterm Infants, Elie G. Abu Jawdeh

Theses and Dissertations--Clinical and Translational Science

Intermittent hypoxemia (IH) is defined as episodic drops in oxygen saturation (SpO₂). Virtually all preterm infants have IH events. Extremely preterm infants have hundreds of IH events per day. The extent of IH is not apparent clinically as accurately documenting cardiorespiratory events for day-to-day patient care management is challenging. High resolution pulse oximeters with 2 second averaging time are currently the ideal methods to measure IH. We have developed novel methods and processes to accurately and efficiently calculate an IH profile that reflects to spectrum of the problem.

The natural progression of IH is dynamic. There is low …

Parent-Implemented Language Intervention With Young Children From Low-Ses Environments Who Have Language Impairment, Courtney Allison Hatcher

Theses and Dissertations--Rehabilitation Sciences

In this study, the author examined the effects of training four parents from low-socioeconomic environments to use Enhanced Milieu Teaching (EMT) with their young children with language impairment. The investigator used a modified Teach-Model-Coach-Review method to teach parents to use the following EMT strategies during 8-10 individualized, home-based sessions: matched turns, expansions, time delays and milieu teaching prompts. A single-case multiple-baseline design across-behaviors replicated across four parent/child dyads was used to evaluate the parents' use of the EMT strategies. Child language outcomes were also assessed using pre- and post-intervention language samples. All parents learned and demonstrated use of each language …

Vitamin D Works Through The Lipid Droplet Protein Plin2 To Augment Mitochondrial Function In Skeletal Muscle, David M. Schnell

Theses and Dissertations--Pharmacology and Nutritional Sciences

Vitamin D has been connected with increased intramyocellular lipid (IMCL) mitochondrial function in skeletal muscle. It is also shown to prevent lipotoxicity in several tissues, but this has not yet been examined in skeletal muscle. Perilipin 2 (PLIN2), a lipid droplet protein upregulated with vitamin D treatment, is integral to managing IMCL capacity and lipid oxidation in skeletal muscle. Increased lipid storage and oxidation is associated with increased tolerance to a hyperlipidic environment and resistance to lipotoxicity. Therefore, I hypothesized that vitamin D increases β-oxidation and lipid turnover though a PLIN2 mediated mechanism, thereby preventing lipotoxicity.

This hypothesis was divided …

Pcb Disruption Of Gut And Host Health: Implications Of Prebiotic Nutritional Intervention, Jessie Baldwin Hoffman

Theses and Dissertations--Pharmacology and Nutritional Sciences

Exposure to environmental pollutants poses numerous risk factors for human health, including increasing incidence of cardiovascular disease and diabetes. Persistent organic pollutants, such as polychlorinated biphenyls (PCBs) have been strongly linked to the development of these chronic inflammatory diseases and the primary route of exposure is through consumption of contaminated food products. Thus, the gastrointestinal tract is susceptible to the greatest levels of these pollutants and is an important facet to study.

The first two hypotheses of this dissertation tested that exposure to PCBs disrupts gut microbiota directly (in vitro) and within a whole body system. PCB exposure …

The Prebiotic Inulin Beneficially Modulates The Gut-Brain Axis By Enhancing Metabolism In An Apoe4 Mouse Model, Jared D. Hoffman

Theses and Dissertations--Pharmacology and Nutritional Sciences

Alzheimer’s disease (AD) is the most common form of dementia and a growing disease burden that has seen pharmacological interventions primarily fail. Instead, it has been suggested that preventative measures such as a healthy diet may be the best way in preventing AD. Prebiotics are one such potential measure and are fermented into metabolites by the gut microbiota and acting as gut-brain axis components, beneficially impact the brain. However, the impact of prebiotics in AD prevention is unknown. Here we show that the prebiotic inulin increased multiple gut-brain axis components such as scyllo-inositol and short chain fatty acids in the …

Role Of Sex Chromosomes In Sexual Dimorphism Of Angii-Induced Abdominal Aortic Aneurysms, Yasir Alsiraj

Theses and Dissertations--Pharmacology and Nutritional Sciences

Abdominal aortic aneurysms (AAAs), a permanent dilation in the abdominal region of the aorta, is a highly sexually dimorphic disease. AAAs prevalence is ranging from 4-10 fold higher in males than females. Defining the mechanistic basis for reduced (in females) or increased (in males) AAA formation and progression may uncover potential therapeutic targets. The majority of studies examining sexual dimorphism focus on the role of sex hormones. However, genes residing on sex chromosomes, in addition to sex hormones, may contribute to sexual dimorphism of AAAs. For example, the X chromosome contains about 5% of the whole genome, but the role …