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Building Tools For Improved Modulation Of The Human Gabaa Receptor, A Central Nervous System Target For The Treatment Of Anxiety, Garrett Edward Zinck

Theses and Dissertations--Pharmacy

In the U.S., anxiety is recognized as an increasing range of mentally and physically debilitating psychiatric health disorders with significant economic repercussions. Over the last 20 years, several novel anti-anxiety therapies have entered the drug development pipeline, but none have made it to market.

The work in this dissertation focused on structurally modifying valerenic acid (VA), a structurally unique carboxylated sesquiterpene acid found in Valeriana officinalis. VA is putatively reported to have allosteric modulatory activity of the human GABA_A receptor, a ligand-gated ion channel responsible for attenuating neurotransmissions. Structural modeling of VA’s GABA_A receptor interaction suggests that …

Studies Toward The Development Of An Improved Countermeasure For Synthetic Opioid Overdose, Sidnee L. Hedrick

Theses and Dissertations--Pharmacy

One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to fully reverse fentanyl-induced respiratory depression, rendering …

Response Of Dopaminergic System To Cocaine Exposure, Recovery After Cocaine Abstinence, And Impact Of A Long-Acting Cocaine Hydrolase, Jing Deng

Theses and Dissertations--Pharmacy

Cocaine produces its physiological effects by targeting multiple proteins in the central nervous system, particularly by binding with dopamine transporter (DAT) to block the normal dopamine (DA) recycling process. This process along with the pleasure feeling would wear off shortly after the abstinence from the drug. However, chronic cocaine use is associated with neuroadaptations in the dopaminergic system, including increases in the density of DAT on plasma membrane of dopaminergic neurons. Given the critical role of DAT in neurotransmission, various studies have been carried out on animal models to learn its structure, function, and distribution. Long-standing evidence supports that DAT …

Liposomal Technologies To Improve Gene Delivery, David Nardo Padron

Theses and Dissertations--Pharmacy

Lipid based nanoparticles (LBNs) are used in myriad applications in medicine from small molecule drug delivery to mRNA vaccines. A major contributing factor to the development of the field has been the ongoing development of novel compounds that retain the functionality of natural lipids but expand upon them through inclusion of functional moieties that can be applied to specific scientific and biomedical questions. In the body of this dissertation, an extensive overview of LBNs is provided, focusing primarily on their use in immune modulation. The research presented herein begins with the synthesis of a novel class of lipids based on …

The Relative Contribution Of Liver And Intestine In Reverse Cholesterol Transport, Rupinder Kaur

Theses and Dissertations--Pharmacy

Despite decades of advances in research, death due to cardiometabolic disease remains the largest contributor to mortality in the US. While present therapies oppose “forward cholesterol transport,” and atherosclerotic plaque progression, they do not remove cholesterol from established atherosclerotic plaques. Reverse cholesterol transport (RCT) is the active process of mobilizing peripheral cholesterol for excretion through the hepatobiliary (transhepatic cholesterol elimination, THCE) or intestinal (transintestinal cholesterol elimination, TICE) pathways. Currently, there are no clinically approved therapeutics that target RCT. Elucidation of the mechanisms that govern RCT and TICE, and the subsequent identification of novel targets is of importance. The present work …

Development Of Accurate And Efficient Computational Methodologies For Predicting Protein-Ligand And Protein-Protein Binding Free Energies, Alexander Hamilton Williams

Theses and Dissertations--Pharmacy

Computational modeling is an invaluable tool in the drug discovery process either for small ligand or protein therapeutics. The widespread availability of protein X-Ray Crystal and Cryo-Electron Microscopy (Cryo-EM) structures has allowed for more accurate molecular dynamics (MD) simulations that are not reliant on methods such as homology modeling, which may produce structures that require significant computational time to demonstrate their stability. In this thesis we describe several novel methodologies for the computationally efficient modeling of protein/ligand and protein/protein complexes that may be employed within both large-scale virtual screenings and lead compound optimization. These methodologies may also be utilized in …

Development Of Zafirlukast Derivatives Active Against Porphyromonas Gingivalis, Kaitlind C. Howard

Theses and Dissertations--Pharmacy

Periodontal diseases are inflammatory diseases that can lead to damage of the soft tissue and bone supporting the teeth. Gingivitis is the reversible early stage of gum disease, which consist of gums that bleed when brushing or flossing teeth. When left untreated, the preventable but irreversible late stage of periodontal disease, periodontitis, can lead teeth to loosen or even fall out. Oral bacterial species, such as the Gram-negative anaerobic pathogen Porphyromonas gingivalis trigger these inflammatory diseases through oral dysbiosis. P. gingivalis is a keystone pathogen, meaning that the damage caused by P. gingivalis is not proportional to its abundance. Treatment …

Addressing Ascertainment Bias In The Study Of Cardiovascular Disease Burden In Opioid Use Disorders - Application Of Natural Language Processing Of Electronic Health Records, Jade Huang Singleton

Theses and Dissertations--Epidemiology and Biostatistics

In the United States, the prevalence of long-term exposure to opioid drugs, for both medically and nonmedically indicated purposes, has increased considerably since the mid-1990’s. Concerns have emerged about the potential health effects of opioid use. There is also growing interest in other possible connections with opioid use including cardiovascular disease. Electronic health records (EHR) contain information about patient care in the form of structured codes and unstructured notes. Natural language processing (NLP) provides a tool for processing unstructured textual data in EHR clinical notes and extracts useful information for research with structured formats. The purpose of this dissertation was …

Energy And Economic Modeling Of Stillage Dewatering Processes In Kentucky Bourbon Distilleries, William Brennan

Theses and Dissertations--Mechanical and Aerospace Engineering

Stillage is a byproduct of alcohol distillation and must be managed in all distilleries to sustain operations. In the United States, fuel ethanol plants typically convert all stillage into Dried Distillers’ Grains with Solubles (DDGS). This process and its variations are well known. Typical stillage management approaches are not well known, however, for the Kentucky bourbon industry. A survey of stillage management approaches in operational bourbon distilleries was conducted. Process modeling was performed to evaluate the energy and economic considerations of the available stillage dewatering methods for a 7 Million Original Proof Gallon (MMOPG) distillery. Monte Carlo simulations were performed …

Formation Control With Bounded Controls And Collision Avoidance: Theory And Application To Quadrotor Unmanned Air Vehicles, Zachary S. Lippay

Theses and Dissertations--Mechanical and Aerospace Engineering

This dissertation presents new results on multi-agent formation control and applies the new control algorithms to quadrotor unmanned air vehicles. First, this dissertation presents a formation control algorithm for double-integrator agents, where the formation is time varying and the agents’ controls satisfy a priori bounds (e.g., the controls accommodate actuator saturation). The main analytic results provide sufficient conditions such that all agents converge to the desired time-varying relative positions with one another and the leader, and have a priori bounded controls (if applicable). We also present results from rotorcraft experiments that demonstrate the algorithm with time-varying formations and bounded controls. …

Numerical And Scaling Study On Application Of Inkjet Technology To Automotive Coating, Masoud Arabghahestani Dr.

Theses and Dissertations--Mechanical and Aerospace Engineering

A thorough literature review identified lack of precision control over quality of droplets generated by the currently available industrial sprayers and a growing need for higher quality droplets in the coating industry. Particularly, lack of knowledge and understanding in continuous inkjets (CIJ) and drop-on-demand (DOD) technologies is identified as significant. Motivated by these needs, this dissertation is dedicated to computational fluid dynamics (CFD) and scaling studies to improve existing inkjet technologies and develop new designs of efficient coating with single and/or multiple piezoelectric sensors to produce on-demand droplets. This dissertation study aims at developing a new DOD type coating technology, …

Novel Mechanism Of Endogenous Pancreatic Cancer Cell Expression Of Immune Checkpoint Programmed Cell-Death 1 Protein (Pd-1) Inducing Epithelial-To-Mesenchymal Transition (Emt) Through The Met Pathway And Promoting Cancer Progression In An Immune-Independent Process, Megan M. Harper

Theses and Dissertations--Clinical and Translational Science

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with few treatment options, necessitating an urgent need for novel therapeutics. Immuno-oncologic (IO) therapies have revolutionized anti-cancer regimens in the past decade but typically involve reactivation of adaptive immune responses. In particular, immune checkpoint PD-1 is traditionally expressed only on immune cells while PD-L1 (PD-1 ligand) is overexpressed on cancer cells. When tumor-endogenous PD-L1 binds the PD-1 receptor on T-cells, the immune cells undergo anergy resulting in self-tolerance and cancer cell immune evasion. However, contrary to standard dogma, we previously demonstrated tumor-endogenous PD-1 expression in PDAC. Our data indicated that …

Art Education In Medical Education: Benefits And Challenges, Sara K. Brown

Theses and Dissertations--Art and Visual Studies

Humanity is synergistic with art and medicine. Likewise, art education can be impactful throughout medical education. Art as a tool to develop the next generation of healthcare differs from the clinical goals of creative art therapies. Over the prior decade, many medical schools now provide curricular offerings in the arts and humanities. Less is known about the application in postgraduate medical settings. The focus of this thesis is to review the pairing of artist-educators with postgraduate medical training programs.

One such program is ArtsCAFE (Arts Connect Around Food and Enrichment), an intercollegiate project fusing experienced arts educators with medical educators …

A Study Of The Analysis Of Hemp-Derived Oil Products: Development Of A Method For The Analysis Of Phytocannabinoids In Medicinal Products, Erin Johnson

Theses and Dissertations--Pharmacology and Nutritional Sciences

Human interactions with cannabis have a history spanning millennia as a source of fiber, food, and medicine. The plant came across Asia, Europe, and Africa with the movements of people and travelers eventually coming to the Americas with European explorers. In colonizing North America, cannabis fiber was key to the production of canvas and ropes for ships. Although fiber was the driver for cannabis production in the United States, medicinal uses were prevalent and propelled the eventual regulations. The Pure Food and Drug Act of 1906 mandated accurate labeling on drugs such as cannabis followed by the Marihuana Tax Act …

Modeling The Effects Of Adverse Childhood Experiences Using A Mouse Model Of Neglect: Mechanisms Of Adiposity Expansion In Females, Jacqueline Leachman

Theses and Dissertations--Pharmacology and Nutritional Sciences

Adverse childhood experiences (ACEs) are an independent risk factor for chronic disease, including obesity and metabolic syndrome. We have previously shown that a mouse model of early life stress, maternal separation and early weaning (MSEW), exacerbates high-fat diet (HF)-induced obesity only in adult female mice. In agreement, the analysis of several cohorts of participants exposed to ACEs have shown that women are more susceptible to develop obesity than men. Therefore, the aim of this study was to investigate the link between early life stress and obesity in pre-clinical and clinical settings. Male and female MSEW mice fed 1 week a …

Apoe Genotype And Cerebral Glucose Metabolism: A Multi-Omics Approach, Holden C. Williams

Theses and Dissertations--Physiology

Apolipoprotein E (APOE) is encoded by the APOE gene, present in humans as three main isoforms (E2, E3, and E4). E4 carriers face up to a 15-fold increased risk for developing late-onset Alzheimer’s disease (AD), while E2 carriers are protected. Understanding the risk conferred by E4 has been an extensive research focus for nearly three decades, but the exact mechanism has yet to be proven. Many studies have demonstrated attenuated roles of E4 in classical hallmarks of AD, notably amyloid processing and neurofibrillary formation, which normally present later in disease progression. How APOE influences hallmarks that present much earlier are …

Regulation Of Skeletal Muscle Plasticity By The Gut Microbiome, Taylor R. Valentino

Theses and Dissertations--Physiology

Recent evidence suggests that the gut microbiome could play a role in skeletal muscle plasticity, providing novel treatments for muscle wasting diseases and/or performance enhancements. I first sought to determine if the gut microbiome is necessary for skeletal muscle adaptation to exercise. Forty-two, four-month old, female C57Bl/6J underwent nine weeks of weighted wheel running or remained in cage with a locked wheel, without or without the administration of antibiotics (treated). In response to wheel running, I found that antibiotic depletion of the microbiome led to a blunted hypertrophic response in the soleus muscle as measured by normalized muscle wet weight …

Immunoregulatory Receptor Genetics, Expression, And Splicing Studies In Alzheimer’S Disease, Benjamin C. Shaw

Theses and Dissertations--Physiology

Microglia are the resident immune cells of the brain, undertaking many critical tissue maintenance functions such as immune surveillance and phagocytosis. Microglial dysfunction has recently been identified as a multi-stage signature of many neurodegenerative diseases, including late-onset Alzheimer’s Disease (LOAD). Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in over thirty genes that modulate risk of developing LOAD. In the central nervous system, roughly half of these LOAD-associated genes are primarily expressed in microglia. The proteins encoded by these genes include cell surface receptors that contain either immunomodulatory tyrosine-phosphorylated activating motifs (ITAMs) or inhibitory motifs (ITIMs), including TREM2 …

Nutritional Status In Critical Care Of Covid-19 Patients, Dolph Lewis Davis Iii

Theses and Dissertations--Nutrition and Food Systems

Critical care nutrition is a poorly researched, and such a sudden pandemic event requiring manipulation of nutritional status via propofol-induced sedation for mechanical ventilation is potentially impactful on patient outcomes. This paper seeks to provide context to the impact of critical care protocols on the nutritional status of obese patients suffering from COVID-19.

The Role Of Nitric Oxide In Inter- And Intra- Cellular Signaling In Plant Defense, Fan Xia

Theses and Dissertations--Plant Pathology

Plants have evolved a sophisticated immune system to defend themselves against pathogens. This immune response can be triggered in response to pathogen-associated molecular patterns (PAMP) or specialized effectors that are recognized by the plant resistance (R) proteins. The latter, commonly referred to as effector-triggered immunity (ETI), is well known to induce broad-spectrum resistance throughout the plants. This phenomenon known as systemic acquired resistance (SAR) is regulated by several chemical signals including salicylic acid (SA), and free radical nitric oxide (NO) and reactive oxygen species (ROS). These signals operate in two parallel branches with NO/ROS functioning downstream of pipecolic acid (Pip) …

An Examination Of Organic Options In Tomato Systems And Their Use As Alternatives To Copper-Based Products, Erica Ann Fealko

Theses and Dissertations--Plant Pathology

Organic farming is an ever-increasing segment of tomato production. Currently, limited information is available which directly compares conventional to organic treatment programs for disease control in tomato production. Furthermore, many methods available rely on the use of copper products which may be contribute to high Cu levels in agricultural soils. In this study, the efficacies of current conventional and organic methods were compared. In addition, newer disease-control programs, with and without copper were examined, which potentially could reduce over-reliance on copper products.

Standard organic and conventional spray programs were conducted over a four year period targeting two pathogens, Alternaria tomatophila …

Identifying Bisphosphonate Protein Biomarkers In Equine Sera Using Mass Spectrometry Methods, Malinda Jayne Alison Porter

Theses and Dissertations--Veterinary Science

Bone resorptive diseases affect humans and horses, alike. Examples of these diseases include osteoporosis, Paget’s disease, and osteogenesis imperfecta in humans, and navicular disease in the horse (Mitchell et al., 2019; Suva et al., 2021). Bisphosphonates are used to treat these diseases, and may remain in the bone for several years after administration, demonstrating the need for newer drug testing methods.

The purpose of the discovery phase of this study was to use blood samples of in-training horses which had been given an initial administration of the bisphosphonate tiludronate and identify protein biomarkers that changed in response to this class …

The Effect Of Intra-Articular Corticosteroids On The Systemic Messenger Rna Response In An Equine Experimental Inflammation Model, Emma Elaine Partridge

Theses and Dissertations--Veterinary Science

Intra-articular (IA) corticosteroids are regularly used in equine athletes for the control of joint inflammation. The goal of this study was to utilize an acute synovitis inflammation model to determine the residual effects of IA betamethasone and triamcinolone acetonide on various inflammatory parameters and lameness.

Five mixed-breed, 2-year-old horses were randomly allocated to an IA treatment of the radiocarpal joint with 9 mg of either betamethasone or triamcinolone acetonide. Two weeks following treatment, horses were injected with 1μg of lipopolysaccharide (LPS) diluted in 1 mL of 0.9% sterile saline. Following LPS injection, horses were crossed-over and both sets of injections …

Dissecting The Role Of Actin-Myosin Motor And Calcium – Based Organelle Secretion In Motility Of Sarcocystis Neurona, Parul Suri

Theses and Dissertations--Veterinary Science

Sarcocystis neurona is a protozoan parasite that causes a rare neurological disorder in horses called Equine Protozoal Myeloencephalitis (EPM). Apicomplexa use actin-myosin based motor and organelle secretion to interact with the host cell and invade it. Despite the importance of motility and invasion-needed factors, the mechanisms by which S. neurona employs host cell association strategies to interact remains largely undefined. To address this knowledge gap, we hypothesize that just like other Apicomplexa, S. neurona utilizes actin polymerization for substrate-dependent gliding. Moreover, we also hypothesize that micronemes of S. neurona secrete proteins that are calcium-dependent. Based on previous studies in T. …

The Effects Of Cannabidiol On Senior Equine Health, Shelley Turner

Theses and Dissertations--Veterinary Science

Cannabis sativa L., has been revealed to produce hundreds of phytocannabinoids, of which cannabidiol (CBD) is one of the most desired. It has been revealed that CBD can potentially treat inflammation and act as an analgesic in humans without psychoactive effects of delta-9-tetrahydrocannabinol (THC). Recently, there has been interest in understanding the potential health benefits of CBD for horses. With an increasing senior horse population (< 15 years old), alternatives to the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as phenylbutazone, firocoxib, and flunixin meglumine, are desired as these common anti-inflammatory treatments have negative side effects. Because senior horses may have chronic low-grade inflammation, termed inflamm-aging, they are a natural model to investigate the efficacy of CBD on inflammatory responses as well as other health parameters. Given this interest, and due to the lack of research conducted on CBD in the horse, the overall objective of this dissertation work was to conduct both basic and applied research investigating the effects of CBD on equine immune function and health. The first objective was to determine the in vitro effects of CBD as an anti-inflammatory. Peripheral blood mononuclear cells (PBMCs) from senior horses were cultured in vitro with increasing concentrations of pure CBD dissolved in dimethyl sulfoxide (DMSO). These cells were …

The Microbiome Of The Equine Roundworm, Parascaris Spp., Jennifer Lynn Cain

Theses and Dissertations--Veterinary Science

Parasitic nematodes, including the large roundworms colloquially known as ascarids, affect the health and well-being of livestock animals worldwide. The equine ascarid, Parascaris spp., was the first ascarid parasite to develop wide-spread anthelmintic drug resistance, with other species slowly following suit. There are no new classes of anthelmintics currently in development, and a solution to the ever-increasing prevalence of resistance is desperately needed. The microbiome has been shown to be an important factor in the fitness and health of many organisms and changes to microbiome composition have been associated with a plethora of diseases. The microbiome is also important to …

Evaluating Restoration Outcomes: Red Spruce Reforestation In The West Virginia Highlands, Benjamin Rhodes

Theses and Dissertations--Forestry and Natural Resources

Red spruce (Picea rubens) is the keystone species of the red spruce-northern hardwood forest, a unique high-elevation plant community that supports hundreds of animal species in the Central Appalachians. These forests were devastated by the Industrial Logging Era of the late 1800s and early 1900s, and they remain in a degraded and fragmented state. Current restoration efforts include red spruce plantings on old field sites and reclaimed coal mines. This project seeks to aid those efforts by evaluating restoration outcomes for vegetation and soils along a ten-year chronosequence. Specifically, the study aims to determine whether restoration site soils …

Spatial Ecology Of Rocky Mountain Elk (Cervus Canadensis Nelsoni) Cows In Southeastern Kentucky, Nathan Dennis Hooven

Theses and Dissertations--Forestry and Natural Resources

The elk (Cervus canadensis) was extirpated from its range in eastern North America by the end of the 1800s, prompting several U.S. states and Canadian provinces to begin translocation programs with the goal of reestablishing elk populations. While eastern elk managers have relied on information from western herds to guide population and habitat management, there is a need for region-specific research on the spatial ecology and habitat associations of translocated elk given the stark differences in landscape, climate, predator communities, and harvest regimes across the continent. While the Kentucky elk reintroduction is one of the best documented programs …

The Response Of Beef Cattle To Disturbances From Unmanned Aerial Vehicles (Uavs), Gabriel Abdulai

Theses and Dissertations--Biosystems and Agricultural Engineering

Unmanned aerial vehicles (UAVs) are increasingly becoming common in animal agriculture. However, research regarding the impact of UAV disturbance on animal wellbeing is lacking or limited. The goal of this study was to investigate the effect of UAV flights on beef cattle by measuring cattle heart and movement rate when introduced to single or multiple UAV flights. A total of 16 -18 crossbred beef heifers were introduced to different flights patterns at between 5 and 9 m above ground level (AGL) at approximately 1 to 2 m/s horizontal velocity for 4 weeks with flights repeated 3 days per week. Results …

Lignin Valorization Via Reductive Depolymerization Using Promoted Nickel Catalysts And Sub- And Supercritical Methanol, Julia Parker

Theses and Dissertations--Biosystems and Agricultural Engineering

While lignin has been regarded as the most promising renewable feedstock for the sustainable manufacture of aromatic compounds, lignin valorization is necessary to improve the economic viability of biorefineries. Reductive catalytic fractionation (RCF), which combines delignification and lignin depolymerization into a single stage while maintaining the structure and integrity of the cellulose component, has evolved as an effective method for processing biomass. The ability of Cu and Fe to promote the performance of a 20% Ni/alumina catalyst when converting native lignin to alkylphenols by RCF in sub- and supercritical methanol was tested. The effectiveness of lignin extraction as measured by …