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Tolerance Intervals For Various Regression Models, Xitong Zhou

Theses and Dissertations--Statistics

Among statistical intervals, confidence intervals and prediction intervals are well-known and commonly used. In many applications, the problem becomes finding an interval that covers at least a certain proportion $P$ of the population for a characteristic of interest with a specified confidence level $(1-\alpha)$. And such interval is named a $P$-content, $(1-\alpha)$-confidence Tolerance Interval (TI). The topic of the dissertation is the utility of tolerance intervals for various regression models. We begin with a discussion of tolerance intervals for linear and nonlinear regression models. We then propose a bootstrap method of constructing TIs for Tobit regression to deal with censored …

Investigating The Use Of Mpges-1 Inhibitors For The Treatment Of Abdominal Aortic Aneurysms, Lauren M. Weaver

Theses and Dissertations--Pharmacy

The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease is a deadly, permanent ballooning of the aortic artery. It often goes undiagnosed until a late stage where associated rupture has a high mortality rate. Surgery is the only option available to patients, but it is risky. There are currently no FDA-approved pharmacological treatments for AAA available. Historically, drugs that have been examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments have been unable to reach the clinic, stalling out in pre-clinical studies. Exceedingly few murine studies have …

Effectiveness Of A Long-Acting Cocaine Hydrolase In Metabolizing Cocaine And Its Physiologically Active Metabolites, Linyue Shang

Theses and Dissertations--Pharmacy

Cocaine is a widely abused, hepatotoxic drug without an FDA-approved pharmacotherapy specific for cocaine addiction or overdose. Cocaine-induced toxicity in animals and humans is due to its multiple physiological effects on the central nervous system, cardiovascular system, etc. The toxicity of cocaine is highly complex, as its metabolites also contribute to the toxicity. Notably, the combination of cocaine and alcohol is common among drug users and can produce additional metabolites. Some of the metabolites are more toxic than cocaine itself. Hence, to develop an ideal therapeutic candidate, the candidate should not only account for cocaine but should also detoxify other …

Self-Assembled Ternary Polypeptide Nanoparticles With Improved Biostability For Drug Delivery In Cancer Therapy, Preye Mike Agbana

Theses and Dissertations--Pharmacy

Cancer remains a real and present threat to global health. In the United States, according to cancer statistics, almost 40% of people will be diagnosed with cancer at some point in their lifetime. Conventional chemotherapy has become the mainstay for cancer treatment option. However, chemotherapeutic agents are plagued with problems such as poor aqueous solubility, chemical degradation, Bio instability, and off-site toxicity due to non-specificity. New drug modalities are needed to tackle the ever-growing burden on cancer. In recent times, the promise of nanotechnology has aided to develop drug delivery vehicles to facilitate the administration of potent chemotherapeutics. Nanoformulations such …

Developing A Biocatalytic Toolbox To Aid In Understanding Nucleoside Antibiotics, Jasmine Brianna Woods

Theses and Dissertations--Pharmacy

Antibiotic resistance happens when bacteria develop the ability to survive medications that normally terminate them. Instead, these super germs are able to survive in the body and produce a community of antibiotic resistance germs which can cause human fatalities. It is important to discover and develop new compounds and molecules that will improve this clinical obstacle. This research focused on analyzing the biosynthesis that incorporates distinctive chemical characteristic of various nucleoside antibiotics, ß-hydroxy amino acids and α-methyl-amino acids. ß-hydroxy amino acids and α-methyl-amino acids are considered an important class of industrially useful compounds, particularly for pharmaceutical development, and are found …

New Tools For Biocatalysis: Studies On The Carminomycin 4-O-Methyltransferase Dnrk, Elnaz Jalali

Theses and Dissertations--Pharmacy

Methyltransferases (MTs) are ubiquitous enzymes commonly involved in biosynthesis and regulation. The fundamental goal of this thesis was to explore the permissive nature of methyltransferases and leverage this unique biocatalytic feature to develop a new platform for chemoselective intramolecular cyclization reactions. To realize this ambitious goal, this thesis project set out to probe the substrate specificity of multiple natural product tailoring enzymes (MTs and glycosyltransferases), identify model substrates common to multiple such tailoring enzymes and subsequently establish multi-enzyme tandem reactions that would set the stage for a subsequent chemoselective intramolecular cyclization reaction. Chapter One highlights current state of the art …

Mitochondria As Causes Of And Therapeutic Targets In Chronic Post-Sepsis Skeletal Muscle Weakness, Meagan Scott Kingren

Theses and Dissertations--Pharmacology and Nutritional Sciences

Sepsis, or the organ damage that ensues after the body fails to properly contain a local infection, is the leading cause of in-patient hospitalization in the United States. Advances in critical care medicine over the last 20 years have enabled most sepsis patients to survive the life-threatening dysregulated immune response. However, a majority of survivors report chronic weakness and fatigue years after sepsis, and the cause of this weakness remains largely unknown. This dissertation work focused first on elucidating the major causes of post-sepsis muscle weakness (Aim 1). This aim involved a time-course study to determine when muscle weakness was …

Maternal Occupation And Pediatric Brain Cancer In Kentucky, Mary Elizabeth Begley

Theses and Dissertations--Epidemiology and Biostatistics

Pediatric brain cancer is a rare and potentially deadly diagnosis that affects children in Kentucky at a higher incidence than those nationally. Limited exposures in children early in life to warrant the development and progression of brain cancer point to the role parental exposures experienced in the period prior to conception and throughout pregnancy may play in its development. Many of these exposures may be experienced through occupation.

Data on a subset of pediatric brain cancer cases in Kentucky was compared to all cases diagnosed in the state from 1995 to 2019. Survey data of the study sample was collected …

Assessment Of Air Overpressure From Blasting Using Computational Fluid Dynamics, Cecilia Estefania Aramayo

Theses and Dissertations--Mining Engineering

Air overpressure is a shock wave that occurs when explosives detonate and travel through the air. This can cause damage and annoyance in mining blasts, making it a significant concern for the surroundings of the operation. Currently, the cube root scale distance is used to predict air overpressure, but this method has limitations. To accurately determine air overpressure behavior, a new method is needed. Computational fluid dynamics (CFD) is a reliable and advanced technique that can simulate and solve complex physical problems, including the behavior of air overpressure. In this thesis, two techniques, the bursting balloon, and total pressure boundary, …

Multiscale Modeling Of Cardiac Growth And Baroreflex Control, Hossein Sharifi

Theses and Dissertations--Mechanical and Aerospace Engineering

The heart functions within a complex system that adapts its function to any alteration in loading via several mechanisms. For example, the baroreflex is a short-term feedback loop that modulates the heart's function on a beat-to-beat basis to control arterial pressure. On the other hand, cardiac growth is a long-term adaptive response that occurs over weeks or months in response to changes in left ventricular loading. Understanding the mechanisms that drive ventricular growth and biological remodeling is critical to improving patient care. Multiscale models of the cardiovascular system have emerged as effective tools for investigating G&R, offering the ability to …

Assessment Of The Interplay Between Regional Β-Amyloid Burden And White Matter Hyperintensities On Cognition And Default Mode Network In Clinically Normal Older Participants, Doaa G. Ali

Theses and Dissertations--Clinical and Translational Science

Objective: Alzheimer’s disease (AD) and subcortical vascular dementia are considered the most common pathologic contributors to dementia in the aging population. Both frequently coexist in over 80% of community dwelling adults with dementia. The neuropathological development of AD arguably begins with β-amyloid (Aβ) deposition in the brain. This series of studies aims to test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in preclinical AD (pAD) (study1). Since mixed dementia is widely recognized as the norm rather than the exception, the second study aimed to explore the …

Enhancing Dna-Damaging Therapy Through The Inhibition Of Dntp Synthesis Using A Synergistic Drug Combination To Treat Pancreatic Neuroendocrine Neoplasms, Jennifer Castle Md

Theses and Dissertations--Clinical and Translational Science

Despite clinical advances, pancreatic neuroendocrine neoplasms (pNEN) remain a difficult clinical entity to treat and can carry a poor prognosis. Systemic therapy is used to treat pNENs which are not amenable to surgical resection. Peptide receptor radionuclide therapy, a form of radiation therapy (RT) and cisplatin are two different forms of DNA-damaging therapy in current use to treat pNENs. However, their efficacy remains poor as single agents. This study aimed to increase the sensitivity of pNENs to the DNA-damaging agents, RT and cisplatin, by inhibiting deoxynucleotide triphosphate (dNTP) synthesis. Triapine, a ribonucleotide reductase inhibitor (RNRi), and ataxia telangiectasia and Rad3-related …

Role Of Autophagy In Aortic Aneurysms, Aida Javidan

Theses and Dissertations--Pharmacology and Nutritional Sciences

Abdominal Aortic Aneurysms (AAAs) are permanent dilations of the abdominal aorta with greater than 80% mortality after rupture. Currently, there are no proven non-surgical therapeutics to blunt expansion or rupture, which highlights the need to gain mechanistic insights into AAA formation. AAA formation involves a complex process of destruction of aortic media through activation of matrix metalloproteinases (MMPs), loss of smooth muscle cells, degradation of extracellular matrix proteins like elastin and collagen, and inflammation. Autophagy is a well-conserved cellular process whereby damaged cytoplasmic organelles and long-lived proteins are degraded. Cellular autophagic activity is usually low under normal conditions but can …

The Role Of High Mobility Group Box-1 Pathobiology In Angiotensin Ii-Induced Abdominal Aortic Aneurysms, Shayan Mohammadmoradi

Theses and Dissertations--Pharmacology and Nutritional Sciences

Abdominal aortic aneurysms (AAAs) are permanent luminal dilations of the vessel wall that can result in rupture and death. There is currently no evidence-based treatment to prevent or attenuate the development of this devastating condition. Although vascular inflammation is known to be one of the hallmarks of AAA, underlying mechanisms that initiate inflammatory pathways in the aorta are not clearly known. High-mobility group box 1 (HMGB1), a highly conserved nonhistone DNA-binding nuclear protein, may contribute to vascular diseases. Since whole-body genetic deletion of HMGB1 is embryonic lethal, pharmacological approaches have been used to manipulate HMGB1 in mice. However, it remains …

Age- And Sex-Dependent Alterations In Primary Somatosensory Neuronal Calcium Network Dynamics During Locomotion, Sami L. Case

Theses and Dissertations--Pharmacology and Nutritional Sciences

Over the past 30 years, the calcium (Ca2+) hypothesis of brain aging has provided clear evidence that hippocampal neuronal Ca2+ dysregulation is a key biomarker of aging. Indeed, age-dependent Ca2+-mediated changes in intrinsic excitability, synaptic plasticity, and activity have helped identify some of the mechanisms engaged in memory and cognitive decline. However, much of this work has been done at the single-cell level, mostly in slice preparations, and in restricted structures of the brain. Recently, our lab identified age- and Ca2+-related neuronal network dysregulation in the cortex of the anesthetized animal. Still, investigations in the awake animal are needed to …

Relative Adrenal Insufficiency In Sepsis, Dan Hao

Theses and Dissertations--Pharmacology and Nutritional Sciences

Sepsis is a leading cause of death in children. Glucocorticoid (GC) therapy had been strongly recommended for the pediatric sepsis (grade 1A). However, the recommendation was changed to grade 2C in 2020 due to weak evidence. Relative adrenal insufficiency (RAI) is a condition characterized by impaired inducible glucocorticoid (iGC) production in response to stress. It develops in 32.8% of pediatric septic patients. Unfortunately, little is known about the pathogenesis of RAI in pediatric sepsis, and whether GC therapy should be based on the status of RAI is controversial. In this study, we utilized 21-day-old SF1CreSRBI^fl/fl mice as the first …

High Cholesterol Diet Induces Sudden Death In Mice With Impaired Reverse Cholesterol Transport, Misa Ito

Theses and Dissertations--Pharmacology and Nutritional Sciences

Unexplained sudden death continues to be a major public health crisis as AHA reports that 1,000 people suffer sudden cardiac arrest each day in the U.S. with only 10% surviving. A number of ongoing challenges hinder to understand the sudden death. Thus, investigating underlined mechanisms of sudden death is urgent. Unexpectedly, I found a high cholesterol diet (HCD)-induced sudden death preclinical model. Although HCD is associated with a higher risk of cardiovascular disease (CVD) and the subendothelial lipoprotein retention theory is well established for atherosclerosis development, these theories cannot explain the sudden death in my model because atherosclerosis and CVD …

Age-Associated Increase Of Gamma Delta T Cells In Visceral Adipose Tissue And Mechanisms Of Their Accumulation, Sujata Mukherjee

Theses and Dissertations--Pharmacology and Nutritional Sciences

Chronic systemic inflammation, known as inflammaging is considered a hallmark of aging and associated diseases. While adipose tissue has long been considered only as a caloric reservoir regulating systemic energy homeostasis, research in the past couple of decades substantiate its endocrine function to secrete an array of inflammatory mediators and hormones, which have physiological effects on multiple organ systems, and contribute to inflammaging. Redistribution of adipose tissue from subcutaneous to visceral depots, changes in the immune profile and the chronic inflammatory state are among the major sources of adipose tissue dysfunction with aging.

This dissertation is focused on identifying and …

Exploring The Efficacy Of Mir-33 Antagonism In Promoting Regression Of Intracranial Atherosclerosis In A Nonhuman Primate Model, Peter Hecker

Theses and Dissertations--Pharmacology and Nutritional Sciences

Atherosclerosis, characterized by lipid accumulation and arterial inflammation, is a major contributor to global morbidity and mortality. Despite significant progress in understanding atherosclerosis in extracranial arteries, the study of intracranial atherosclerosis (ICAS) has been relatively neglected, despite its crucial role in stroke and vascular cognitive impairment. Challenges related to ICAS, including its location within the cranium and limited availability of suitable animal models, have hindered research progress in this area. Although nonhuman primates (NHPs) are commonly used for studying extracranial atherosclerosis, a comprehensive understanding of ICAS pathophysiology in these animals is lacking. By subjecting NHPs to a high-fat/cholesterol diet, we …

The Role Of Renal-Derived Human Soluble Prorenin Receptor In Blood Pressure Regulation And Kidney Function, Gertrude Arthur

Theses and Dissertations--Pharmacology and Nutritional Sciences

The soluble prorenin receptor (sPRR) is a cleaved form of the full-length prorenin receptor (PRR). It has been demonstrated to activate the renin-angiotensin system (RAS) independent of its full-length receptor and mediate similar physiological and pathophysiological processes, albeit via different mechanisms.

The sPRR hormone, a component of RAS, has been identified as a plasma biomarker for hypertension and cardiovascular diseases in humans. In mice, sPRR infusion has been shown to mediate blood pressure elevation through competitive AT1R binding and activation. However, the biological contribution of renal-derived human sPRR to blood pressure regulation and kidney function remains unknown. Therefore, this study …

Sex Dimorphisms Of Aldosterone And High Salt Induced Aortic Aneurysms In Mice, Xufang Mu

Theses and Dissertations--Pharmacology and Nutritional Sciences

Aortic aneurysms, a permanent enlargement in the aorta, is a devastating disease with a high mortality rate after rupture. Aortic aneurysms exhibit strong sex dimorphisms: men are at higher risk than women while women experience worse outcomes if diagnosed. Currently, the only intervention is by open surgery or endovascular repair, and no drugs are approved for blunting the disease progression. This highlights the needs for mechanistic studies for sex-specific therapeutic targets.

Our lab established the mouse model in which mineralocorticoid receptor (MR) agonist aldosterone induces aortic aneurysms in the presence of high salt in male mice age-dependently, mimicking the aging …

The Influence Of Apoe Genotype On Lipid Droplet Dynamics, Cassi Friday

Theses and Dissertations--Physiology

Excess lipid droplet (LD) accumulation is associated with several pathological states, including neurodegenerative disorders such as Alzheimer’s disease (AD). However, the mechanism(s) by which changes in LD composition and dynamics may contribute to the pathophysiology of AD remains unclear. Apolipoprotein E (ApoE) is a droplet-related protein with a common variant (ApoE4) that confers the largest increase in genetic risk for late-onset AD. Interestingly, ApoE4 is associated with both increased neuroinflammation and excess LD accumulation. This dissertation work seeks to quantitatively profile the lipid and protein composition of LDs between the ‘neutral’ ApoE3 and ‘risk’ ApoE4 isoforms, in order to gain …

Effects Of Traumatic Brain Injury On The Intestinal Tract And Gut Microbiome, Anthony Desana

Theses and Dissertations--Physiology

Traumatic brain injury (TBI) initiates not only complex neurovascular and glial changes within the brain but also pathophysiological responses that extend beyond the central nervous system. The peripheral response to TBI has become an intensive area of research, as these systemic perturbations can induce dysfunction in multiple organ systems. As there are no approved therapeutics for TBI, it is imperative that we investigate the peripheral response to TBI to identify targets for future intervention. Of particular interest is the gastrointestinal (GI) system. Even in the absence of polytrauma, brain-injured individuals are at increased risk of suffering from GI-related morbidity and …

Clinical And Biological Factors Determine Spinal Cord Injury Outcomes: Liquor To Lipids, Ethan Glaser

Theses and Dissertations--Physiology

Spinal cord injuries (SCI) are debilitating and life altering events that can lead to permanent motor and sensory loss. SCI outcomes are impacted by both clinical factors such as blood alcohol content (BAC) at the time of injury as well as biological factors like the lipid-rich myelin debris that accumulates in the injury site. Both clinical and biological factors contribute to SCI recovery, impacting neuroinflammation, locomotor recovery, and histopathology. The purpose of the studies described here is to investigate the role of acute alcohol intoxication and intracellular lipid processing pathways on SCI outcomes in a rodent model.

An elevated BAC …

Rewired Metabolism In Apoe4 Microglia: Implications For Inflammation And Neurodegeneration, Nicholas A. Devanney

Theses and Dissertations--Physiology

Among the earliest changes to occur in Alzheimer’s disease, metabolic dysfunction and chronic neuroinflammation are now known to be major driving forces in disease progression. The paradigm of ‘immunometabolism’ seeks to bridge these two facets, positing that metabolic transformations are indispensable in determining the response of immune cells, such as microglia – the brain’s resident immune population. Proinflammatory stimulation of microglia leads to a shift away from mitochondrial respiration towards a dramatic upregulation of the glycolysis pathway for energy production. This glycolytic burst provides microglia with a rapid supply of ATP, but comes at a cost, as utilizing glucose to …

Examining The Utility Of A Kentucky Fcs Cooperative Extension Curriculum On Community Members’ Healthy And Sustainable Diet-Related Behaviors, Catharine Pickford

Theses and Dissertations--Nutrition and Food Systems

Experts recommend individuals adopt healthy and sustainable dietary behaviors to improve human and environmental health. The objective of this study was to pilot a sustainable eating Family and Consumer Sciences (FCS) Cooperative Extension curriculum and evaluate the effectiveness of the lesson series by measuring participants’ changes in knowledge, perceptions, and intentions towards healthy and sustainable dietary behaviors as well as overall satisfaction with lessons. A five-lesson sustainable eating curriculum was developed with topics focused on: reducing food waste; eating more seasonal, local plant-based foods; varying protein sources; maintaining energy balance; and consuming fewer highly processed and packaged foods. To assess …

Portrayals Of Family Resilience In Webcomics During The Covid-19 Pandemic: A Thematic Analysis, Claire Catherine Heaney

Theses and Dissertations--Family Sciences

Families and couples were challenged with stresses unlike any other as individuals faced adversities from lockdowns, as well as fears derived from the coronavirus. During the pandemic, trends of webcomics became more popular, particularly comics that depicted characters in romantic relationships dealing with “the new normal.” In this project, I suggest that social media webcomics incorporated topics of coping. The purpose of this study was to examine webcomics that documented daily life situations during lockdowns and stress-buffering skills found in couples’ interactions when dealing with concerns. Utilizing Braun and Clarke’s (2006) thematic analysis, 585 romantic relationship webcomics posted from March …

Mechanisms Of Rnai In Insects, Jin Mo Koo

Theses and Dissertations--Entomology

RNA interference (RNAi) mechanism is found in many eukaryotes and animal cells, with its endogenous functions as defense against transposable elements and viruses, as well as post transcriptional regulation of gene expression. Since its first discovery, RNAi has contributed enormously as a reverse genetic tool for functional genomic studies. In application, RNAi is used in therapeutics, as well as agricultural crop and livestock protection. Yet, for the wider application of RNAi, improvement of its potency and delivery technologies is needed. Deeper mechanistic understanding of every step of RNAi, from cellular uptake of RNAi trigger molecule to targeted mRNA degradation is …

Costs And Benefits Of Integrating Poultry Into Cover Crop - Vegetable Rotations, Viktor Halmos

Theses and Dissertations--Entomology

Integrated livestock systems were once common leading up to the 20th century where livestock generated manure that was then used to fertilizer crop production in a closed- or semi-closed system. However, with the industrialization of agriculture in the mid to late 20th century, specialization drove simplified systems that segregated livestock from cropping systems. This segregation led to nutrient surpluses occurring in livestock operations, and nutrient demands in cropping systems creating a plethora of environmental issues. With the increased awareness of environmental issues, a renewed interest in integration has driven producers and researchers to experiment with integration again. For research, the …

The Role Of Map Kinases, Transcription Factors, Callose Binding Proteins In Systemic Acquired Resistance, Xinyu Yuan

Theses and Dissertations--Plant Pathology

Systemic acquired resistance (SAR) is a broad-spectrum disease resistance induced upon local infections that provides protection against secondary infections. Earlier work has shown that SAR is regulated by two parallel pathways, one of which is regulated by salicylic acid (SA), and the other one involves pipecolic acid (Pip), nitric oxide (NO), reactive oxygen species (ROS), azelaic acid (AzA), and glycerol-3-phosphate (G3P). Pip acts upstream of NO, ROS, AzA, and G3P in the local leaves but the distal accumulation of Pip depends on the biosynthesis and transport of SA and G3P.

Normal induction of SAR also requires mitogen-activated protein kinase (MPK) …