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Novel Targets For Mitochondrial Dysfunction Following Traumatic Brain Injury, Heather M. Yonutas

Theses and Dissertations--Neuroscience

Mitochondrial dysfunction is a phenomenon observed in models of Traumatic Brain Injury (TBI). Loss of mitochondrial bioenergetics can result in diminished cellular homeostasis leading to cellular dysfunction and possible cellular death. Consequently, the resultant tissue damage can manifest as functional deficits and/or disease states. Therapeutic strategies to target this mitochondrial dysfunction have been investigated for models TBI and have shown promising effects.

For this project, we tested the hypothesis that mitoNEET, a novel mitochondrial membrane protein, is a target for pioglitazone mediated neuroprotection. To test this, we used a severe Controlled Cortical Impact (CCI) injury model in mitoNEET null and …

Development In Normal Mixture And Mixture Of Experts Modeling, Meng Qi

Theses and Dissertations--Statistics

In this dissertation, first we consider the problem of testing homogeneity and order in a contaminated normal model, when the data is correlated under some known covariance structure. To address this problem, we developed a moment based homogeneity and order test, and design weights for test statistics to increase power for homogeneity test. We applied our test to microarray about Down’s syndrome. This dissertation also studies a singular Bayesian information criterion (sBIC) for a bivariate hierarchical mixture model with varying weights, and develops a new data dependent information criterion (sFLIC).We apply our model and criteria to birth- weight and gestational …

Multi-State Models With Missing Covariates, Wenjie Lou

Theses and Dissertations--Statistics

Multi-state models have been widely used to analyze longitudinal event history data obtained in medical studies. The tools and methods developed recently in this area require the complete observed datasets. While, in many applications measurements on certain components of the covariate vector are missing on some study subjects. In this dissertation, several likelihood-based methodologies were proposed to deal with datasets with different types of missing covariates efficiently when applying multi-state models.

Firstly, a maximum observed data likelihood method was proposed when the data has a univariate missing pattern and the missing covariate is a categorical variable. The construction of the …

Statistical Inference On Dynamical Systems, Hongyuan Wang

Theses and Dissertations--Statistics

The ordinary differential equation (ODE) is one representative and popular tool in modeling dynamical systems, which are widely implemented in physics, biology, economics, chemistry and biomedical sciences, etc. Because of the importance of dynamical systems in scientific studies, they are the main focuses of my dissertation.

The first chapter of the dissertation is introduction and literature review, which mainly focuses on numerical integration algorithms of ODEs that are difficult to solve analytically, as well as derivative-free optimization algorithms for the so-called inverse problem.

The second chapter is on the estimation method based on numerical solvers of differential equations. We start …

Gender Matters: Masculinities Among African American Men Farming In North Carolina, Marcus K. Bernard

Theses and Dissertations--Sociology

The residue of racism, institutional discrimination, and class warfare continue to displace constructions of masculinity for African-American men in farming by shifting the drive for success onto the sidewalk of survival. The shifting focus migrates from goals of economic and political gain to simply shielding masculinity through acts of providing for and protecting the family. African-American men’s failure to acknowledge these quandaries in Western society’s social structure entraps their masculine identity by keeping their focus on issues of race and social class which overshadow the broad gender transformations. The deceptive social forces underlying this social structure hurl African conditions are …

Improved Models For Differential Analysis For Genomic Data, Hong Wang

Theses and Dissertations--Statistics

This paper intend to develop novel statistical methods to improve genomic data analysis, especially for differential analysis. We considered two different data type: NanoString nCounter data and somatic mutation data. For NanoString nCounter data, we develop a novel differential expression detection method. The method considers a generalized linear model of the negative binomial family to characterize count data and allows for multi-factor design. Data normalization is incorporated in the model framework through data normalization parameters, which are estimated from control genes embedded in the nCounter system. For somatic mutation data, we develop beta-binomial model-based approaches to identify highly or lowly …

Biobehavioral Influences Of Anxiety, Depression, And Hostility Symptoms On Health-Related Outcomes In Patients With Heart Failure, Lynn P. Roser

Theses and Dissertations--Nursing

The incidence of heart failure (HF) has increased each year as more people are living longer with heart disease and other chronic conditions. Recently, there has been much interest in the psychological dimensions of HF and the influence psychological symptoms have on the health outcomes (e.g., self-care, rehospitalization, mortality and quality of life) of patients living with HF. Patients with HF frequently experience symptoms of anxiety, depression, and hostility that may be associated with poor health outcomes. The purpose of this dissertation was to examine how psychological variables influence health outcomes of patients with HF, how psychological variables change over …

Psychological Distress And Cardiac Disease, Tracey Vitori

Theses and Dissertations--Nursing

The purpose of this dissertation was to evaluate the association of psychological distress with cardiac disease, events, and mortality. Specific aims were to: 1) to evaluate the association between hostility level and recurrence of acute coronary syndrome (ACS) and all-cause mortality in patients with coronary heart disease (CHD); 2) to evaluate the psychometric properties of the Brief Symptom Inventory (BSI) hostility and anxiety subscales in a group of incarcerated participants at high risk of cardiovascular disease; and 3) to evaluate the association of patient and caregiver psychological state with quality of life in both patient and caregiver, and postoperative complications …

Elucidating Proteasome Catalytic Subunit Composition And Its Role In Proteasome Inhibitor Resistance, Kimberly C. Carmony

Theses and Dissertations--Pharmacy

Proteasome inhibitors bortezomib and carfilzomib are FDA-approved anticancer agents that have contributed to significant improvements in treatment outcomes. However, the eventual onset of acquired resistance continues to limit their clinical utility, yet a clear consensus regarding the underlying mechanisms has not been reached.

Bortezomib and carfilzomib are known to target both the constitutive proteasome and the immunoproteasome, two conventional proteasome subtypes comprising distinctive sets of catalytic subunits. While it has become increasingly evident that additional, ‘intermediate’ proteasome subtypes, which harbor non-standard mixtures of constitutive proteasome and immunoproteasome catalytic subunits, represent a considerable proportion of the proteasome population in many cell …

Development Of Cocaine Hydrolase For Therapeutic Treatment Of Cocaine Abuse, Xiabin Chen

Theses and Dissertations--Pharmacy

Cocaine abuse is a world-wide public health and social problem without a U.S. Food and Drug Administration (FDA)-approved medication. An ideal anti-cocaine medication would accelerate cocaine metabolism producing biologically inactive metabolites by administration of an efficient cocaine-specific exogenous enzyme. Recent studies in our lab have led to discovery of the desirable, highly efficient human cocaine hydrolases (hCocHs) that can efficiently detoxify and inactivate cocaine without affecting normal functions of central nervous system (CNS). Preclinical and clinical data have demonstrated that these hCocHs are safe for use in humans and effective for accelerating cocaine metabolism. However, the actual therapeutic use of …

Towards Elucidation Of The Mechanism Of Biological Nanomotors, Zhengyi Zhao

Theses and Dissertations--Pharmacy

Biological functions such as cell mitosis, bacterial binary fission, DNA replication or repair, homologous recombination, Holliday junction resolution, viral genome packaging, and cell entry all involve biomotor-driven DNA translocation. In the past, the ubiquitous biological nanomotors were classified into two categories: linear and rotation motors. In 2013, we discovered a third type of biomotor, revolving motor without rotation. The revolving motion is further found to be widespread among many biological systems. In addition, the detailed sequential action mechanism of the ATPase ring in the phi29 dsDNA packaging motor has been elucidated: ATP binding induces a conformational entropy alternation of ATPase …

Development Of New Biological Nanopores And Their Application For Biosensing And Disease Detection, Shaoying Wang

Theses and Dissertations--Pharmacy

Nanopore technology has recently emerged as a new real-time single molecule sensing method. The current dominant technologies, such as mass spectrometry and immunoassay, for protein analysis is still slow and complex, which can’t meet the urgent need and fields of use. Development of a highly simple, portable and sensitive detection system for pathogen detection, disease diagnosis, and environmental monitoring is in great need. Membrane embedded Phi29 connector nanopore, the first protein nanopore coming from bacteriophage, was mainly focusing on DNA and RNA translocation in previous studies. Here, Phi29 connector nanopore was first time established for antibody detection by engineering Epithelial …

Rna Nanotechnology For Next Generation Targeted Drug Delivery, Fengmei Pi

Theses and Dissertations--Pharmacy

The emerging field of RNA nanotechnology is developing into a promising platform for therapeutically application. Utilizing the state-of-art RNA nanotechnology, RNA nanoparticles can be designed and constructed with controllable shape, size for both RNA therapeutics and chemical drug delivery. The high homogeneity in particle size and ease for RNA therapeutic module conjugation, made it feasible to explore versatile RNA nanoparticle designs for preclinical studies.

One vital module for therapeutic RNA nanoparticle design is RNA aptamer, which can enable the RNA nanoparticles find its specific target for targeted drug delivery. A system of screening divalent RNA aptamers for cancer cell targeting …

Investigating Mechanisms Determining Cancer Cell Sensitivity To Carfilzomib And Novel Strategies To Overcome Resistance, Lin Ao

Theses and Dissertations--Pharmacy

Proteasome inhibitors (PIs) are a class of FDA-approved anti-cancer agents which includes the first-generation PI bortezomib (BTZ) and second-generation carfilzomib (CFZ). Drug resistance is a major challenge in PI therapy with no solution currently available. While a few resistance mechanisms had been proposed for BTZ, little was known about CFZ resistance before the start of our studies. In this dissertation work, we investigated multiple mechanisms contributing to CFZ resistance—alterations in the drug transporter activity, metabolic stability, and proteasome activity profiles—and evaluated potential strategies to overcome CFZ resistance.

We observed marked upregulation of the drug efflux transporter P-glycoprotein (P-gp) in our …

Rna As A Unique Polymer To Build Controllable Nanostructures For Nanomedicine And Nanotechnology, Hui Li

Theses and Dissertations--Pharmacy

RNA nanotechnology is an emerging field that involves the design, construction and functionalization of nanostructures composed mainly of RNA for applications in biomedical and material sciences. RNA is a unique polymer with structural simplicity like DNA and functional diversity like proteins. A variety of RNA nanostructures have been reported with different geometrical structures and functionalities. This dissertation describes the design and construction of novel two-dimensional and three-dimensional self-assembled RNA nanostructures with applications in therapeutics delivery, cancer targeting and immunomodulation. Firstly, by using the ultra-stable pRNA three-way junction motif with controllable angles and arm lengths, tetrahedral architectures composed purely of RNA …

Maternal Allostatic Load During Pregnancy: Predicting Length Of Gestation, Molly E. M. Sayre

Theses and Dissertations--Social Work

Allostatic load, or the “wear and tear” on the body due to stress, is thought to have a negative impact on length of pregnancy and contribute to health disparities in preterm birth. However, the magnitude of the effect on birth outcomes is unknown, in part due to questions of timing of measurement of allostatic load during pregnancy. This study used linear regression analysis of data from 156 pregnant women to test whether allostatic load is a predictor of length of gestation in the study sample, finding that third trimester allostatic load predicted length of gestation among women with full-term births. …

Identifying The Trauma Recovery Needs Of Maltreated Children: An Examination Of Child Welfare Workers' Effectiveness In Screening For Traumatic Stress, Adrienne Whitt-Woosley

Theses and Dissertations--Social Work

Children in the child welfare system comprise a group characterized by their exposure to trauma via experiences of maltreatment, under circumstances presenting multiple risk factors for traumatic stress. High rates of posttraumatic stress have been observed in this population. However, there is currently no standard for the universal screening of children in child welfare for trauma exposure and traumatic stress. The purpose of this study was to analyze the trauma experiences of a sample of maltreated children and examine whether child welfare workers are effective screeners of traumatic stress symptoms with children from their caseloads. Method: A sample of children …

Cryogenic Processing Of Al 7050-T7451 Alloy For Improved Surface Integrity, Bo Huang

Theses and Dissertations--Mechanical and Aerospace Engineering

Al 7050-T7451 alloy with good combinations of strength, stress corrosion cracking resistance and toughness, is used broadly in the aerospace/aviation industry for fatigue-critical airframe structural components. However, it is also considered as a highly anisotropic alloy as the crack growth behavior along the short transverse direction is very different from the one in the long transverse direction, due to the inhomogeneous microstructure with the elongated grains distributed in the work material used in the sheet/plate applications. Further processes on these materials are needed to improve its mechanical and material properties and broaden its applications.

The material with ultra-fine or nano …

Diffusion-Mediated Deposition Of Proteins, Ruiqian Zhan

Theses and Dissertations--Mechanical and Aerospace Engineering

Gradients of proteins play a prominent role in many biological processes, from development of multicellular organisms to chemical signaling in the immune system. Deposition of surface gradients is a way to permanently modifying a surface’s properties, resulting in the creation of novel materials which have widespread applications in biologically relevant fields, such as directed cell growth, production of biocompatible implantable materials, and creation of functional biosensors. These types of surfaces can also be used as an ex vivo tool to help understand many biological processes by mimicking the environment in gradient-related phenomena in a controllable way. However, despite the large …

The Role Of Fat Grafting And Adipose-Derived Stem Cells In Breast Reconstruction, Krishna S. Vyas

Theses and Dissertations--Clinical and Translational Science

Fat grafting is a common surgical procedure that involves the transfer of fat from one area of the body to another in order to improve contour deformities, such as in breast reconstruction. Advantages of the technique include using autologous tissue rather than a foreign body and the added benefit of having liposuction to remove fat from an undesirable location. Although adipose tissue could be the ideal soft tissue filler, fat grafting is plagued by tremendous variability in long-term retention, with volume survival rates of 20-80%, resulting in suboptimal outcomes and repetitive procedures.

The mechanisms contributing to long-term fat graft survival …

A Study On Student Learning In Higher Education: Art Exhibition Motivation, Olivia M. Lussi

Theses and Dissertations--Art and Visual Studies

This study explored whether non-majors at the University of Kentucky, were more motivated in a particular course when their finished project was introduced to the public through an art exhibition. The problem being addressed that since the passing of Senate Bill One in 2009 the high school art requirement in Kentucky is met by “allowing a foreign language course, career and technical education course, or a computer technology or programming course to meet the arts and humanities requirement for high school graduation” (Wilson et al., 2016, para. 1). A mixed methods approach with an action research design was used for …

The Role Of Pxr And Ikkβ Signaling In Cardiometabolic Disease, Robert N. Helsley

Theses and Dissertations--Pharmacology and Nutritional Sciences

Cardiovascular disease (CVD) is the leading cause of death worldwide and is partially attributed to perturbations in lipid metabolism. Xenobiotics, such as pharmaceutical drugs and environmental chemicals, have been associated with increased risk of CVD in multiple large-scale human population studies, but the underlying mechanisms remain poorly defined. We and others have identified several xenobiotics as potent agonists for the pregnane X receptor (PXR), a nuclear receptor that can be activated by numerous drugs as well as environmental and dietary chemicals. However, the role of PXR in mediating the pathophysiological effects of xenobiotic exposure in humans and animals remains elusive. …

The Role Of The Ace2/Ang-(1-7)/Masr Axis In The Development Of Obesity-Hypertension In Male And Female Mice, Yu Wang

Theses and Dissertations--Pharmacology and Nutritional Sciences

Obesity is strongly associated with hypertension and cardiovascular diseases. An activated renin-angiotensin system (RAS) has long been suggested as a critical contributor to elevated blood pressure with obesity. Angiotensin II (AngII), the main effector of an activated RAS, can be catabolized by angiotensin-converting enzyme 2 (ACE2) to form angiotensin-(1-7) (Ang-(1-7)), which, acting through the mas receptor (MasR), has been shown to oppose the effects of an activated RAS. Therefore, further understanding of the mechanisms of this counter-regulatory arm, called the ACE2/Ang-(1-7)/MasR axis, may lead to new therapies for obesity-induced hypertension. Previously, we demonstrated that differences in the regulation of ACE2 …

Effects Of Mammalian Target Of Rapamycin Inhibition On Circuitry Changes In The Dentate Gyrus Of Mice After Focal Brain Injury, Corwin R. Butler

Theses and Dissertations--Physiology

Post-traumatic epilepsy is a common outcome of severe traumatic brain injury (TBI). The development of spontaneous seizures after traumatic brain injury generally follows a latent period of little to no symptoms. The series of events occurring in this latent period are not well understood. Additionally, there is no current treatment to prevent the development of epilepsy after TBI (i.e. antiepileptogenics). One cell signaling pathway activated in models of TBI and in models of epilepsy is the mammalian target of rapamycin (mTOR). mTOR activity is sustained for weeks after the initial insult in models of TBI, and the inhibition of mTOR …

Protein Kinase A And Epac Mediate Chronic Pain After Injury: Prolonged Inhibition By Endogenous Y1 Receptors In Dorsal Horn, Weisi Fu

Theses and Dissertations--Physiology

Inflammation or nerve injury sensitizes several populations of nociceptive neurons in the dorsal horn of the spinal cord, including those that express the neuropeptide Y (NPY) Y1 receptor (Y1R). Our overall hypothesis is that after tissue or nerve injury, these Y1R-expressing neurons enter a state of latent sensitization (LS) that contributes to vulnerability to the development of chronic pain; furthermore, LS is under the tonic inhibitory control of endogenous Y1R signaling. First, we evaluated the intracellular signaling pathways that become activated in Y1R-expressing neurons and participate in LS. To do this, we established behavioral models of inflammatory or neuropathic pain, …

Regulation Of Uv-Protective Pathways Downstream Of The Melanocortin 1 Receptor In Melanocytes, Erin M. Wolf Horrell

Theses and Dissertations--Physiology

Malignant cutaneous melanoma is the deadliest form of skin cancer, and a majority of melanoma diagnoses are a result of exposure to ultraviolet (UV) radiation. UV radiation causes DNA damage, which if not repaired correctly via nucleotide excision repair (NER) can result in mutations and melanomagenesis. The melanocortin 1 receptor (MC1R) is a G_s protein coupled receptor located on melanocyte plasma membranes and is involved in protecting the skin from UV induced damage. MC1R signaling results in the activation of two protective pathways: 1) induction of eumelanin synthesis downstream of micropthalmia-associated transcription factor (MITF) and 2) acceleration of NER …

Co-Morbid Symptoms Of Depression And Anxiety And Bio-Behavioral Response To Stress In Patients With Heart Failure, Abdullah S. Alhurani

Theses and Dissertations--Nursing

Heart failure (HF) is a major public health problem throughout the world. It accounts for one death certificate among nine in the United States. Heart failure and sudden death combined are responsible for the largest number of deaths in America. The total costs of HF in the United States are estimated to be $37 billion each year. Despite substantial medical and surgical advances related to treatment of HF, it remains a very costly condition with high mortality and morbidity rates. Although biological factors contribute to high morbidity and mortality in HF, there are many unexplored psychosocial factors that also likely …

Molecular And Biochemical Signaling Underlying Arabidopsis-Bacterial/Virus/Fungal Interactions, Mohamed H. El-Shetehy

Theses and Dissertations--Plant Pathology

Systemic acquired resistance (SAR) is a form of inducible defense response triggered upon localized infection that confers broad-spectrum disease resistance against secondary infections. Several factors are known to regulate SAR and these include phenolic phytohormone salicylic acid (SA), phosphorylated sugar glycerol-3-phosphate (G3P), and dicarboxylic acid azelaic acid (AzA). This study evaluated a role for free radicals nitric oxide (NO) and reactive oxygen species (ROS) in SAR. Normal accumulation of both NO and ROS was required for normal SAR and mutations preventing NO/ROS accumulation and/or biosynthesis compromised SAR. A role for NO and ROS was further established using pharmacological approaches. Notably, …

Differential Gene Expression In Equine Cartilaginous Tissues And Induced Chondrocytes, Emma N. Adam

Theses and Dissertations--Veterinary Science

Degenerative joint disease, or osteoarthritis, is a major cause of lameness and morbidity in horses, humans, and dogs. There are no truly satisfactory cures for this widespread problem and current treatments all have limitations or unwanted side effects.

New cell-based strategies to repair joint surface lesions have generated a high level of interest, but have yet to achieve the full restoration of articular cartilage structure and function. Currently used therapy cells include autologous chondrocytes and adult mesenchymal cells such as bone marrow derived cells and adipose derived cells. Unfortunately, the resultant repair tissue is biomechanically inferior fibrocartilage. A critical gap …

Hormonal And Nutritional Regulation Of Molting, Metamorphosis, And Reproduction In Bed Bugs, Cimex Lectularius, Hemant Gujar

Theses and Dissertations--Entomology

The bed bug, Cimex lectularius is an obligate hematophagous ectoparasite that feeds on humans. The increase in travel and development of insecticide resistance to commercially available insecticides have enabled the bed bug population to resurge, causing economical and psychological trauma to the human population. Lack of knowledge about the basic molecular biology of bed bugs has motivated us to study the key aspects of molting, metamorphosis, and reproduction. A blood meal triggers expression of various genes that enable bed bugs to molt or undergo metamorphosis. Molting and metamorphosis in bed bugs are regulated by two key hormones: 20-hydroxyecdysone (20E) and …