Medicine and Health Sciences Commons^™

The Effect Of Hamstring Lengthening On Pelvic Tilt And Lumbar Lordosis, Michael Scott Braman

Theses and Dissertations (ETD)

A direct correlation between hamstring tightness and severity of lower back pain (LBP) has been previously reported. Hamstring contraction creates knee flexion, hip extension and posterior pelvic tilt. Posterior pelvic tilt causes the lumbar spine to flatten (hypolordosis) which places pressure on the anterior structures of the spine, including the intervertebral disc. This increased pressure may predispose individuals to disc degeneration and associated pain. For this reason, hamstring stretching is often prescribed to alleviate LBP, however, the effect of hamstring lengthening on the kinematics of the lumbar spine and pelvis is not well understood. Accurate measurement of lumbar spine movement …

A Subject Specific Surface Electromyography Model For Estimating L4/L5 Compressive Loading, Pablo Joaquin Dopico

Theses and Dissertations (ETD)

Introduction: Low Back Pain (LBP) is a leading cause of activity limitation worldwide and results in 149 million lost work days annually in the United States. The total costs of LBP are estimated to be $100 to $200 billion annually. Specific causes of LBP account for less than 15% of LBP cases. Heavy loading of the lumbar spine and tight hamstrings have been identified as risk factors for LBP. Tight hamstrings pull the pelvis posteriorly and reduce the lordosis of the spine, resulting in increased loading of the lumbar vertebral bodies of the spine. While this mechanism has been described, …

Medication Nonadherence, Health Care Utilization, And Safemed Care Transitions Model Impact In Super-Utilizers, Satya Surbhi

Theses and Dissertations (ETD)

BACKGROUND: Super-utilizers are individuals with disproportionately high inpatient and emergency department (ED) use, and mostly have multiple chronic conditions and use multiple concurrent medications. They place a substantial burden on the U.S. healthcare system and have become the focus of policy initiatives aimed at reducing their disproportionate inpatient and ED use. Medication management is critical for these patients since nonadherence to essential chronic medications is associated with poor health outcomes, and higher health care utilization and costs. OBJECTIVES: This dissertation employed a three empirical research papers approach to study the following aims: (1) the prevalence and patterns of medication nonadherence …

Regulation Of Cancer Metastasis By Protein Kinase D1: A Global Regulatory Cascade, Aditya Ganju

Theses and Dissertations (ETD)

Protein Kinase D1 (PKD1) is a serine threonine kinase which is downregulated in Prostate, Breast and Colon Cancer. It functions as a tumor suppressor in different cancer cells. Downregulation of PKD1 is known to be associated with aggressiveness of the cancer. PKD1 is known to regulate many key oncogenic signaling pathways such as E-cadherin, β-catenin and Androgen Receptor signaling pathways. Aberrant expression of these oncogenic pathways leads to transformation of cells from normal to malignant phenotype, thereby leading to increased proliferation, growth and metastasis to distant organs of these cancer cells. Literature evidence also points to the fact that E-cadherin …

Endosomal Trafficking As A Determinant Of Antifungal Tolerance In The Pathogenic Fungus Candida Albicans, Arturo Luis Luna

Theses and Dissertations (ETD)

Several important antifungal drugs inhibit the synthesis of ergosterol, a lipid that modulates the thickness, fluidity and permeability of fungal cell membranes. These include the azole antifungals, which block ergosterol biosynthesis by inhibiting lanosterol demethylase (Erg11p). The resulting depletion of cellular ergosterol and the accumulation of ‘toxic’ sterol intermediates are both thought to cause plasma membrane dysfunction and ultimately growth arrest. However, the effects of ergosterol depletion upon the function of intracellular membranes and organelles are not well described. The purpose of this study was to characterize the effects of azole treatment upon the integrity of the Candida albicans vacuole, …

Examining The Associations Between Depressive Symptoms, Body Mass Index, And Physical Activity Self-Efficacy In African American Mother-Child Dyads, Y'Esha Vonyae Williams

Theses and Dissertations (ETD)

In recent decades the prevalence of childhood and adult depression and obesity has increased worldwide. Multiple factors influence the onset of both depression and obesity. Individual manifestations of depressive symptomatology and health-related problems associated with obesity vary; however, genetics and environmental and psychological factors have been implicated as correlates. Consequently, both disorders can ultimately interfere with individuals’ activities of daily living and decrease their quality of life. African American women are known to have a higher prevalence of obesity and more severe depressive symptoms in comparison to Caucasian women. Likewise, African American children are more obese and experience many factors …

Dissecting The Physiological Roles Of Ulk1/2 In The Mouse Brain, Bo Wang

Theses and Dissertations (ETD)

Mammalian UNC-51–like kinases 1 and 2 (ULK1 and ULK2), Caenorhabditis elegans UNC-51 and Drosophila melanogaster Atg1 are redundant serine/threonine kinases that regulate flux through the autophagy pathway in response to various types of cellular stress. C. elegans UNC-51 and D. melanogaster Atg1 also promote axonal growth and defasciculation, and disruption of these genes results in defects in axon guidance in invertebrates. Germline Ulk1/2-deficient mice die perinatally. Therefore, we used a conditional-knockout approach to investigate the roles of ULK1/2 in the brain. Mice lacking Ulk1 and Ulk2 in their central nervous systems (CNS) showed defects in axonal pathfinding and defasciculation affecting …

The Nucleolar Protein Nucleophosmin Undergoes Liquid-Liquid Phase Separation With Arginine-Rich Nucleolar Proteins Through Weak, Multivalent Electrostatic Interactions, Jaclyn Alicia Cika

Theses and Dissertations (ETD)

Nucleoli are nuclear membrane-less organelles that are the sites for ribosome biogenesis and serve as sensors of cellular stress. Weak, multivalent protein-protein interactions and interactions between disordered, low complexity domains (LCDs) and rRNA have been shown to promote liquid-liquid phase separation (LLPS) in vitro, suggesting a basis for the liquid-like behavior of nucleoli. Nucleophosmin (NPM1), a multifunctional and highly abundant nucleolar protein, exhibits structural features associated with LLPS suggesting a role in nucleolar organization. Specifically, NPM1 forms a pentamer through its N-terminal oligomerization domain and can bind to rRNA through its C-terminal nucleic acid binding domain. Multiple acidic tracts throughout …

Environmental Signaling Through The Target Of Rapamycin Complex 1 (Torc1) And The Regulation Of Epigenetic Mechanisms, Jason J. Workman

Theses and Dissertations (ETD)

The gene expression profile of a eukaryotic cell is responsive to a variety of extracellular stimuli, including nutrient availability, which allows cells to toggle between anabolism and catabolism based on the favorability of their environment. Much of this information is relayed through signaling complexes, such as the target of rapamycin complex 1 (TORC1), to downstream chromatin modifying enzymes. These enzymes impact the gene regulatory process through altered histone post-translation modifications, changes in chromatin structure, and docking of chromatin regulatory complexes. Yet, despite preliminary studies suggesting that TORC1 affects epigenetic mechanisms, including histone H3 lysine 56 acetylation (H3K56ac), almost nothing is …

Role Of Occludin In The Regulation Of Epithelial Tight Junctions, Bhargavi Manda

Theses and Dissertations (ETD)

Tight junctions (TJ) constitute the primary component of epithelial barrier function, a disruption of which is involved in the pathogenesis of many gastrointestinal, pulmonary and renal diseases. Occludin is the major transmembrane protein of TJ, a deletion of which leads to a complex phenotype including chronic inflammation in several epithelial tissues of occludin deficient mice and poor TJ integrity in epithelial cell lines. Its down regulation was seen in Crohn’s disease, tumors of the colon, brain, endometrium and breast cancer. Occludin is also known to be a target that enables Hepatitis C Virus infection and bacterial pathogenesis. But the specific …

Multipronged Approach To Study Glaucoma-Associated Phenotypes, Sumana Rameshbabu Chintalapudi

Theses and Dissertations (ETD)

Glaucoma refers to a group of conditions characterized by death of RGCs, increase in intraocular pressure is usually a precursor to glaucoma and irreversible optic neuropathy leads to visual impairment and blindness. Recent advances have seen a surge of new ideas and technologies to aid in the early detection, efficacious treatments and neuroprotection. Despite advances we face several challenges in understanding the pathophysiology of glaucoma. One of the many challenges scientists and ophthalmologists are facing is, to better understand IOP, its role in glaucomatous damage and design safer, more predictable IOP-lowering therapies. Another challenge is to find a practical method …

Neuroanatomical Maps And Taste Reactivity To Sweet, Umami, And Bitter Taste In The Pbn Of C57bl/6j Mice, Jennifer Marie Saputra

Theses and Dissertations (ETD)

Humans can distinguish at least five different taste qualities, sour, salty, bitter, sweet, and umami (the savory taste of certain amino acids). In neuroscience research, behavioral testing is used to measure the ability of rodents (including inbred mice) to discriminate between the different taste qualities. Taste reactivity and two-bottle preference are behavioral tests that are utilized to investigate different aspects of taste. These tests involve either voluntary or forced consumption of taste stimuli, respectively. Either test can be used to infer the preference and palatability of the stimulus consumed by an animal.

In order to understand the basis of taste …

Evaluating The Therapeutic Effect Of An Hsp90 Inhibitor In Mouse Models Of Alzheimer’S Disease, Bin Wang

Theses and Dissertations (ETD)

The excessive accumulation of amyloid peptides (Aβ) represents one major pathological hallmark of Alzheimer’s disease (AD), which is most notably characterized by synaptic dysfunction. Strategies targeting heat shock protein 90 (Hsp90) inhibition have been widely investigated in the treatment of cancer for over two decades. Its application in the treatment of neurodegenerative diseases however, has emerged more recently in the last decade. The role of the Hsp90 chaperone in clearing misfolded protein aggregates has been well established (in vitro only), but its function in synaptic activity remains elusive.

In our study, we utilized a widely used Hsp90 inhibitor, 17-AAG …

The Roles Of Nuclear Receptor Nr4a1 In Cancer Cell Proliferation And Skeletal Muscle Differentiation, Alexa Farmer

Theses and Dissertations (ETD)

Nuclear receptors (NRs) constitute a major class of drug targets in the treatment of various cancer types. NRs respond to cellular signals and become activated upon ligand binding to transcriptionally modulate expression of target genes. NR4A1 (Nur77) is a member of the NR4A family of nuclear receptors and displays an oncogenic profile in many cancer models. It is often upregulated in adult solid malignancies and is known to promote cell proliferation and survival. Knockdown studies of NR4A1 in cancer cell lines results in decreased cell growth and angiogenesis and increased apoptosis, suggesting NR4A1 is an oncogenic protein. Due to the …

Antibiotic Drug Discovery With An Eye Towards Overcoming Drug Resistance, Daniel Towner Hoagland

Theses and Dissertations (ETD)

As a species, humans have become ever reliant on the use of antibiotics to facilitate our everyday lives. The widespread emergence of resistance to currently used antibiotics is commonly attributed to an over use in our society. Such resistance, coupled with a lack of innovation and production of novel antibiotic drugs, threatens to return humanity to an era similar to one before the discovery of the first antibiotics. The need to find new agents to be used in this fight is paramount, as well as learning from our recent failures to produce such compounds. This document will highlight my efforts …

Discoveries Of Targets And Novel Agents For The Treatment Of Ischemic Retinopathy And Neovascular Disease, Jordan Javad Toutounchian

Theses and Dissertations (ETD)

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are among the most common causes of blindness in adults. Vision loss can occur during the advanced stages of DR and AMD as a consequence of unregulated and dysfunctional growth of new blood vessels, or neovascularization (NV) in the retina or choroid. NV can also be triggered by numerous other ocular insults and diseases including radiation retinopathy (RR) and retinal vein occlusion. These latter cases are generally less common but, like DR and AMD, they are characterized by an initial injury, chronic inflammation, and ischemia which perpetuates episodes of retinal neovascularization (RNV). …

Repeated Zolpidem Treatment Effects On Sedative Tolerance, Withdrawal, Mrna Levels, And Protein Expression, Brittany T. Wright

Theses and Dissertations (ETD)

Zolpidem and benzodiazepines (BZs) potentiate the inhibitory action of gamma-Aminobutyric acid (GABA) by allosterically binding to GABAA receptors (GABAAR). Prolonged use of GABAAR positive allosteric modulators (PAM) can lead to behavioral tolerance, the diminished response to the same drug dose with repeated use, and withdrawal, a group of symptoms that occur due to abrupt end of drug treatment. Zolpidem is a short-acting, non-BZ GABAAR PAM whose potential for tolerance and withdrawal is unclear. Zolpidem demonstrates sedative efficacy similar to BZs and has become a main treatment of insomnia in lieu of BZs. Zolpidem replaced BZs due to lower incidences of …

Assessing The Role Of Faith-Based Organizations In Health Promotion, Troylyn Braud Francis

Theses and Dissertations (ETD)

Objective: The objective of this analysis was to evaluate the relationship between organizational readiness (OR) and weight loss and physical activity outcomes among faith-based organizations (FBOs).

Methods: Data for this study were collected in two phases. Phase I data were based on a feasibility study and targeted African-American individuals (N = 55) who participated in an obesity prevention program. The intervention was accomplished in two stages, which included a 10-week core period followed by a 6-month maintenance period. Phase II data were based on key informant interviews that were conducted with community health leaders (CHLs) (N=6) from participating …

Super-Utilization: The New Perfect Storm Of Health Reform, Jill Diane Nault

Theses and Dissertations (ETD)

This three-essay dissertation was focused on geographic variation of super-utilization, or the disproportionately high healthcare utilization and costs attributed to a small sub-set of the inpatient population. For purposes of this research, super-utilization was operationalized as high repeat utilization (HRU) and referred to inpatient utilization and inpatient readmission expenditures attributed to beneficiaries with four or more 30-day readmissions per year. The overall purpose of the research was to identify geographic areas at increased risk for HRU. These areas corresponded to where beneficiaries live and were aligned with the geographically-bound healthcare delivery systems. Each essay employed an observational study design using …

Investigating The Regulation And Function Of The Nr4a Nuclear Receptors In Cancer, Jordan A. Beard

Theses and Dissertations (ETD)

The nuclear receptor (NR) superfamily represents a structurally-conserved group of ligand-regulated transcription factors. These proteins have critical roles in various physiological and pathological processes, including cancer, and have been targets of drug therapy. The orphan NR subfamily 4A (NR4A), which includes the NR4A1 (Nur77), NR4A2 (Nurr1), and NR4A3 (Nor-1) genes, has been implicated in adult solid tumors and has been characterized as pro-tumorigenic mediator of cell proliferation, transformation, migration, and drug resistance. Alternatively, in leukemia, NR4A1 and NR4A3 have been described as tumor suppressors in hematologic malignancies. Members of the NR4A family are commonly overexpressed in cancer and this has …

Examining The Roles Of Gabaa Receptor Subtypes In Anxiety And Anxiolysis: Focusing On The Basolateral Amygdala, Yudong Gao

Theses and Dissertations (ETD)

The investigation of the differential roles GABA_A receptor (GABA_AR) subtypes play in mediating various behaviors such as fear and anxiety was an intriguing research topic over the past decade. At present, most evidence suggests that benzodiazepine (BZ)-induced anxiolysis is primarily mediated by GABA_ARs containing the α2-subunit (α2-subtype). However, there is conflicting evidence as to whether α1- and α3-subtypes might also be involved in BZ-induced anxiolysis. In an attempt to further discern the role played by different α-subtype GABA_ARs in BZ-induced anxiolysis both systemically and within the basolateral amygdala (BLA), a brain region crucial …

Interaction Between Two E3 Ligases, Nedd8ylated Cullin And Hhari, Kheewoong Baek

Theses and Dissertations (ETD)

RBR (RING1-in between RING-RING2) is a special type of E3 ubiquitin ligase containing three zinc-binding RING (Really Interesting New Gene) domains, while adopting mechanisms of HECT (Homologous to E6-AP Carboxyl Terminus) for substrate ubiquitination. Most well known RBRs include Parkin and HOIP, which are associated with Parkinson’s disease and innate immune deficiency. However, it is not well known how the RBR proteins gain activity, as they are known to be autoinhibited. Here I show that a specific F430A, E431A, E503A triple mutation of RBR protein HHARI (Human homologue of Ariadne) and its interaction with NEDD8ylated cullin RING ligase can both …

Pten Signaling In Regulatory T Cells And Inflammatory Disease, Sharad Krishna Shrestha

Theses and Dissertations (ETD)

Regulatory T (Treg) cells suppress CD4+ T cell responses during homeostasis and inflammation to prevent autoimmunity and other immune disorders. Although the transcriptional and epigenetic programs impacting Treg cell function have been extensively studied, the signaling and metabolic pathways underlying Treg stability and function are not fully understood. In this study, we determined the role of the phosphatase PTEN in Treg cells. We found that specific depletion of PTEN in Treg cells results in excessive TH1 and T follicular helper cells (TFH) responses, associated with elevated germinal center (GC) B cells and spontaneous development of autoimmune and lymphoproliferative disease in …

Regulation Of Irf-3-Dependent Innate Immune Signaling Pathway By The Plpro Domain Of Non-Structural Protein 3 (Nsp3) Of Severe Acute Respiratory Syndrome (Sars) Coronavirus, Sandra Nicole Lester

Theses and Dissertations (ETD)

The induction of Type I Interferons (IFNs) is a powerful and rapid innate defense mechanism against viral infection, and many viruses have developed elaborate strategies to overcome the antiviral effects of IFN, ensuring their survival and replication. Severe acute respiratory syndrome coronavirus (SARS-CoV) is a highly pathogenic virus that causes severe lung disease in humans and is associated with high mortality rates. SARS-CoV, like all other successful viruses, encode proteins that counteract the innate immune response. A number of reports have indicated the papain-like protease (PLpro) domain of SARS-CoV Non-Structural Protein 3 (NSP3) as a powerful interferon antagonist, by suppressing …

Novel Oncogenic Drivers In Pediatric Gliomagenesis, Alexander K. Diaz

Theses and Dissertations (ETD)

Pediatric high-grade gliomas (pHGGs), with a two-year survival rate of less than 20%, are some of the most aggressive human cancers. This dissertation begins with our analysis of 127 pHGGs, including brainstem (BS) and non-brainstem (NBS) tumors, from 118 patients using next-generation sequencing technologies. Nearly one-third of BS-HGGs, also known as diffuse intrinsic pontine gliomas (DIPGs), harbored somatic heterozygous missense mutations in ACVR1, coding for a receptor serine-threonine kinase involved in bone morphogenetic protein (BMP) signaling. These alterations led to gain-of-function as evidenced by increased phosphorylation of downstream targets in primary astrocytes and zebrafish embryo ventralization. Whole-genome sequencing and …

Mild Traumatic Brain Injury With Associated Visual System Dysfunction: Investigating Histopathology, Functional Correlates, And A Novel Therapeutic Immune Modulator, Natalie M. Guley

Theses and Dissertations (ETD)

Background. Traumatic brain injury (TBI) is a significant source of morbidity and mortality worldwide. Injuries associated with moderate to severe TBI can be profound, and have historically overshadowed the significant impact mild TBI (mTBI) can have on the lives of affected individuals. Mild TBI can manifest in a number of different ways, but one of the most significant and often debilitating is its impact on the visual system. In order to further investigate the underlying pathology of mTBI and test potential therapeutics, we developed a mouse model of mTBI induced by blast overpressure. In this model, a 50-60 psi …

Predictors Of Quality Of Life For African American Women Who Assist Persons Who Receive Dialysis, Shaquita A. Starks

Theses and Dissertations (ETD)

The purpose of this predictive correlational study was to describe predictors of quality of life (QoL) for African American women who were caregivers of persons with end stage renal disease (ESRD). Five purposes, derived from a review of literature and conceptual model, guided this study. First, the study described the association between demographic factors (i.e., education, employment, age, marital status), and QoL. Second, the study explored the relationship between stress and QoL. Third, the study described the association between depressive symptoms and QoL. Fourth, the study described the association between family health/happiness and QoL. Fifth, the study described the extent …

Modulation Of The Magnetic Properties Of Aqueous Metal Ions And The Bioelectrodynamic Effects On Cancerous And Noncancerous Cells, Marcy C. Purnell

Theses and Dissertations (ETD)

Bioelectrodynamics is the study of how electromagnetism affects the biophysical functions of living organisms by examining the effects on biochemical processing at the cellular level. The Cellular Energy Transfer Science (CETS) system modulates the magnetic behavior of aqueous metal ions by applying direct current (DC) with a Lorenz force to a hypotonic saline solution. This treated solution was then used to make growth media for cancerous and noncancerous cell lines in vitro. Exposure of cancerous and noncancerous cells to this media showed significant growth inhibition, cell cycle arrest, hyperpolarization of transmembrane potential and apoptosis of cancerous cells while not causing …

Assessment Of The Zoonotic Potential Of A Novel Bovine Influenza Virus, Laura Evelyn Eckard

Theses and Dissertations (ETD)

A novel orthomyxovirus was recently identified from pigs, with subsequent work suggesting the natural reservoir being bovine populations. The virus had genome characteristics most similar to influenza C viruses (ICV) but, due to the extent of sequence divergence, was proposed as a new genus, influenza D virus (IDV). Current literature on IDV has largely focused on the agricultural significance of the virus and provided evidence for the agricultural impact via observation of widespread prevalence and pathology in laboratory infected cattle. However, only one study, which identified 1.3% seroprevalence in a small cohort, has addressed the zoonotic potential of IDV to …

Hit Identification For Pkcζ Inhibitors: Structure-Based Optimization, Virtual Screening, And Biological Evaluation, Xiaoxin Wu

Theses and Dissertations (ETD)

Protein kinase C ζ (PKCζ) is believed to be a promising target for the treatment of some diseases, including inflammatory diseases, obesity and diabetes. Hit identification of PKCζ inhibitors was conducted by structure-based modification, virtual screening and biological evaluation. Among all the compounds selected and synthesized, compound JW-1-60A showed moderate activity against PKCζ at 30 μM and 100 μM. The molecular modeling studies showed that the binding mode of JW-1-61A was very close to the binding mode of JP-3-149, a reported PKCζ inhibitor with very potent activity, which might partially explain the moderate activity of JW-1-61A. Based on the structure …