Digital Commons Network^™

S. Gordonii-Produced Hydrogen Peroxide Modulates Mir-663a And Ccl20 Expression In Oral Epithelial Cells, Marshall Houston Maynard

Theses and Dissertations--Medical Sciences

The mechanisms through which a persistent recognition of commensal bacteria by oral epithelial cells (OECs) mitigates an uncontrolled inflammatory response of the oral mucosa remain unknown. CCL20 secretion by OECs in response to pathogenic bacteria is regulated by S. gordonii (Sg)-induced miR-663a; nevertheless, the mechanisms involved in these Sg-modulated responses remain to be elucidated. Since Sg is a hydrogen peroxide (H₂O₂) producer, and H₂O₂ has been shown to stimulate miRNA expression, we hypothesized that H₂O₂ could be involved in Sg-induced miR663a and CCL20 responses. Expression of miR663a …

Application Of Genetic Techniques To Investigate Chlamydia Trachomatis Type Iii Secretion Effector Biology, Gabrielle Keb

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Chlamydia trachomatis is the causative agent of the most reported bacterial sexually transmitted disease in the United States. The establishment of an intracellular niche within mucosal epithelium is sufficient to drive immunopathology and disease sequela. As obligate intracellular bacteria, Chlamydia spp. have evolved numerous mechanisms for establishing an intracellular growth environment. The type III secretion system (T3SS) delivers effector proteins to the host cytosol and is essential for C. trachomatis invasion and development. The effectors TmeA, TmeB, and TarP, are all secreted during C. trachomatis invasion. TarP and TmeA have been associated with manipulation of actin networks and are …

Carnosic Acid Differentially Modulates The Nrf2- Antioxidant Response In Male And Female Mice Following Experimental Traumatic Brain Injury, Jacob A. Dunkerson

Theses and Dissertations--Neuroscience

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Each year, an estimated 2.8 million Americans are diagnosed with a TBI due to falling, motor vehicle collisions, gun violence, and sports related concussions. Although inflicted by a single event, the post-traumatic effects of TBI often develop into a life-long disease. Survivors often experience cognitive decline, memory loss, emotional instability, changes in personality, and physical disabilities. A single TBI, and more-so repetitive TBI's, place an individual at a greater risk of developing chronic neurological disorders, such as dementia or Alzheimer’s disease, earlier in life. …

Examining Human Apoe Genotype And Sex As Modulators Of Respiratory Plasticity In The Presence And Absence Of Spinal Cord Injury, Lydia Ella Strattan

Theses and Dissertations--Neuroscience

There are over 17,000 new spinal cord injuries (SCIs) every year in the Unites States alone. Almost 60% of these injuries occur at the cervical level, potentially leading to loss of function in a variety of sensory and motor systems including upper and lower limbs, respiratory, and autonomics. In addition to the physical and emotional costs, individuals who experience these higher level injuries also face a massive financial burden, incurring over $1 million in expenses during the first year after injury in addition to substantial yearly costs for the rest of their lifetime. A myriad of therapeutic approaches targeting plasticity …

Characterizing The Physiology And Genetics Of Contact Dependent Growth Inhibiton Systems In Burkholderia Species, Alice Elizabeth Oates

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Contact-dependent growth inhibition (CDI) systems mediate interbacterial competition. The genes encoding these systems are widespread among Gram-negative bacteria, including Burkholderia pathogens. CDI systems of Burkholderia species are composed of two-partner secretion pathway proteins and function to deliver the toxic C-terminus of a polymorphic surface-exposed exoprotein BcpA (Burkholderia CDI protein A) to the cytoplasm of neighboring recipient bacteria upon cell-cell contact. Specific outer and inner membrane proteins facilitate BcpA translocation both out of the donor bacterium and into the recipient cell cytoplasm. Most Burkholderia species-specific CDI translocation factors in recipient cells are unknown. BcpA intoxication functions as a mechanism by …

Dimension Reduction Techniques In Regression, Pei Wang

Theses and Dissertations--Statistics

Because of the advances of modern technology, the size of the collected data nowadays is larger and the structure is more complex. To deal with such kinds of data, sufficient dimension reduction (SDR) and reduced rank (RR) regression are two powerful tools. This dissertation focuses on these two tools and it is composed of three projects. In the first project, we introduce a new SDR method through a novel approach of feature filter to recover the central mean subspace exhaustively along with a method to determine the dimension, two variable selection methods, and extensions to multivariate response and large p …

Interactions Of Post-Pks Enzymes Of The Mithramycin Biosynthetic Pathway, Ryan Wheeler

Theses and Dissertations--Pharmacy

Combinatorial biosynthesis is a powerful tool for generating new, more active drug analogues to combat disease. But in order for combinatorial biosynthesis to be employed to its full potential, a deep understanding of the enzymes that produce the parent molecule must be had. The goals of the work presented in this thesis are to characterize the reaction catalyzed by MtmW, the final enzyme in the mithramycin (MTM) biosynthetic pathway, and to discover the interaction between MtmW and MtmOIV.

MtmW is an aldol-ketoreductase responsible for reducing the most distal carbonyl on the MTM pentyl side chain. It forms an octamer that …

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 …

Investigation Of The Biosynthesis Of The Nucleoside Antibiotic Sphaerimicin, Jonathan Overbay

Theses and Dissertations--Pharmacy

Antibiotic-resistance has become a widespread problem in the United States and across the globe. Meanwhile, new antibiotics are entering the clinic at an alarmingly low rate. Highly-modified nucleosides, a class of natural products often produced by actinobacteria, target MraY bacterial translocase I. MraY is a clinically unexploited enzyme target that is ubiquitous and essential to peptidoglycan cell wall biosynthesis. The nucleoside antibiotics known vary in efficacy and the functionalities contributing to improved activity is poorly understood. Sphaerimicin, a newly discovered modified nucleoside, has potent inhibitory activity with an IC50 of 13.65 nM against MraY. In general, sphaerimicin is primarily effective …

Examining Childhood Outcomes In Neonatal Abstinence Syndrome, Kailyn Conner

Theses and Dissertations--Pharmacy

Rates of neonatal abstinence syndrome have been rising over the past several years, alongside rising rates of opioid use disorder, propelled by the continuing Opioid Epidemic ravaging the country. Children born withdrawing from opioids they were exposed to in utero have known health complications through the first year of life that have been studied in the current literature. Less is known, however, about the outcomes these children face in childhood. As many of these children are progressing to childhood, there is an urgent need for healthcare system to prepare to handle the health needs of these children; outcomes related to …

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 …