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The Effects Of Cannabidiol On Brain Temperature In Treatment-Resistant Epilepsy, Ayushe A. Sharma Jan 2023

The Effects Of Cannabidiol On Brain Temperature In Treatment-Resistant Epilepsy, Ayushe A. Sharma

All ETDs from UAB

Epilepsy affects over 70 million people worldwide with a global incidence of 2.4 million new cases per year. In many of these patients, neuroinflammation (NI) is a key pathological contributor to focal seizure generation and maintenance. Sustained NI degrades the blood–brain barrier, leads to neuronal death, and ultimately decreases seizure threshold. Finding ways to image and treat NI is especially important for the >30% of patients with treatment-resistant epilepsy (TRE) who cannot achieve seizure freedom with standard antiseizure medications. Cannabidiol (CBD) effectively reduces seizure frequency and severity in many TRE patients, although its antiepileptic effects remain poorly understood. Atypically high …

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Perceptionf Of Multipurpose Prevention Technologies Aimed At Hiv/Sti/Unintended Pregnancy Among African American Women In The Deep South, Kristina Wilbekin Walker Jan 2023

Perceptionf Of Multipurpose Prevention Technologies Aimed At Hiv/Sti/Unintended Pregnancy Among African American Women In The Deep South, Kristina Wilbekin Walker

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Sexual and reproductive health (SRH) needs for women are not being met globally. In addition to efforts towards providing widespread access to currently available contraceptives and sexually transmitted infection (STI) treatment or prevention products, another focus is the development of multipurpose prevention technologies (MPTs). These MPTs are combination methods that prevent pregnancy, and protect against HIV and/or additional STIs. The objective of this dissertation research was to assess factors related to sexual and reproductive decision-making that may influence interest in MPTs and inform MPT implementation strategies for African and African American (AA) women. The first aim of this research, I …

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Interactions Between Pseudomonas Aeruginosa And The Oral Commensal Streptococcus Salivarius, Sara Noelle Stoner Jan 2023

Interactions Between Pseudomonas Aeruginosa And The Oral Commensal Streptococcus Salivarius, Sara Noelle Stoner

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The cystic fibrosis airway is a polymicrobial environment often dominated by opportunistic pathogens such as Pseudomonas aeruginosa, a leading cause of lung function decline and mortality in persons with CF. Commensal streptococcal colonization has been associated with stable CF lung function in multiple studies. However, few studies have examined interactions between P. aeruginosa and commensals as well as their impact on P. aeruginosa airway infections. In the first half of this work, we studied interactions between P. aeruginosa and the oral commensal Streptococcus salivarius within a biofilm setting. We found that S. salivarius biofilm formation is promoted by the non-mucoid …

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Mediation Analysis Using Marginalized Zero-Inflated Poisson Model, Andrew Sims Jan 2023

Mediation Analysis Using Marginalized Zero-Inflated Poisson Model, Andrew Sims

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Mediation analysis has become exponentially more popular over the last decade as researchers are interested in establishing mechanistic pathways for intervention. Standard statistical methods emphasize quantifying and testing whether a specific exposure impacts a particular health outcome. Mediation analysis addresses the question ‘How is the exposure causing the outcome?’ by examining the extent to which an intermediate variable, called a mediator, influences the relationship between an exposure and an outcome. While multiple mediation strategies exist, the counterfactual approach to mediation allows for mediation effects to be estimated directly with nonlinearities and interactions. The counterfactual approach allows for the effect of …

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Investigating The P53 Tumor-Suppressive Network And The Dynamics/Mechanism Of P53 Loss Of Heterozygosity, Jun Wang Jan 2023

Investigating The P53 Tumor-Suppressive Network And The Dynamics/Mechanism Of P53 Loss Of Heterozygosity, Jun Wang

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Tumor suppressor gene TP53 is the most frequently mutated gene across human cancers (~50%). Patients with Li-Fraumeni syndrome (LFS) who carry germline p53 mutations exhibit a diverse spectrum of childhood- and adult-onset malignancies. Despite over 40 years of dedicated studies to understand the role of p53 in tumor prevention, there are still many unanswered questions regarding the underlying mechanisms of p53. Previous studies have supported the notion that p53 exerts its tumor-suppressive function through its transcriptional activities. Therefore, strategies to enhance p53’s functions in tumor suppression via manipulating of downstream target gene activities in cancers show promising. To better investigate …

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Cis-Regulatory Elements: Relevance For Alzheimer's Disease, Brianne Brazell Rogers Jan 2023

Cis-Regulatory Elements: Relevance For Alzheimer's Disease, Brianne Brazell Rogers

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Alzheimer’s disease (AD) is the most common neurodegenerative disease, currently affecting more than six million Americans with limited treatment options. Identifying genetics contributors to neurodegenerative diseases has contributed critical insights into potential disease mechanisms. The majority of disease-associated genetic variants are located in non-coding regions, likely in regulatory elements, and affect the expression of target genes whose function contributes to neurodegeneration. Here, I performed a case-control study utilizing nuclei from dorsolateral prefrontal cortex postmortem tissue to correlate chromatin accessibility with gene expression and nominate 40,831 AD-specific candidate cis-regulatory elements. Additionally, work in this dissertation nominates ZEB1 and MAFB as candidate …

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Imaging Nanoscale Plasma Membrane Dynamics Reveals Diversity In Clathrin-Coated Vesicle Formation, Tomasz Jacek Nawara Jan 2023

Imaging Nanoscale Plasma Membrane Dynamics Reveals Diversity In Clathrin-Coated Vesicle Formation, Tomasz Jacek Nawara

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Clathrin-mediated endocytosis (CME) is an essential cellular process facilitating the internalization of a variety of cargo. Clathrin polymerization and changes in plasma membrane architecture and composition are necessary steps to mediate the formation of clathrin-coated vesicles (CCVs). However, simultaneous analysis of clathrin dynamics and membrane structure in living cells is challenging due to the limited axial resolution of fluorescence microscopes and the heterogeneity of CME. This has fueled conflicting models of vesicle assembly and obscured the roles of flat clathrin assemblies. Here we use Simultaneous Two-wavelength Axial Ratiometry (STAR) microscopy to bridge this critical knowledge gap by quantifying the nanoscale …

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Structural Characterization Of Autoreactive Igg Fabs In The Context Of Iga Nephropathy, Jordan Lingo Jan 2023

Structural Characterization Of Autoreactive Igg Fabs In The Context Of Iga Nephropathy, Jordan Lingo

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IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world, yet there is no cure and treatment options are limited. Advances in understanding of the molecular basis of this pathology may lead to potential novel therapeutics, but there is still much we don’t know about the disease and the underlying biology. The current paradigm explaining the molecular stages leading to IgAN is called the “multi-hit hypothesis,” which involves the following four hits: (1) Elevated levels of circulating IgA1 with some O-linked glycans deficient in galactose moieties (galactose-deficient IgA1, Gd-IgA1). (2) Circulating IgG autoantibodies (autoAbs) specific to the Gd-IgA1 …

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T-Bet Regulates The Maintenance And Asc Differentiation Potential Of The Lymph Node And Lung Memory B Cell Compartments, Christopher A. Risley Jan 2023

T-Bet Regulates The Maintenance And Asc Differentiation Potential Of The Lymph Node And Lung Memory B Cell Compartments, Christopher A. Risley

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Although human memory B cells (Bmem), including extrafollicular DN2 cells and CD27+ effector Bmem (eBmem), express T-bet, its role in Bmem biology is not understood. We characterized transcriptionally distinct clusters of mature, somatically mutated nucleoprotein (NP)-specific Bmem in LNs of influenza-infected mice. None of the Bmem expressed plasma cell (PC) lineage commitment factors, but one cluster was significantly enriched for Tbx21+ cells that exhibited a molecular signature similar to the previously described human T-bet+ eBmem. Metabolic reprogramming, protein synthesis and the mTOR-dependent unfolded protein response gene networks were all upregulated in Tbx21+ NP+ mouse Bmem. Using constitutive and inducible models …

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Intent-To-Treat Versus Per Protocol Analysis Of A Crossover Feeding Trial: Effect Of Dietary Sodium On Obstructive Sleep Apnea, Gabrielle Gloston Jan 2023

Intent-To-Treat Versus Per Protocol Analysis Of A Crossover Feeding Trial: Effect Of Dietary Sodium On Obstructive Sleep Apnea, Gabrielle Gloston

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Obstructive sleep apnea (OSA) is a common form of sleep disordered breathing that leads to poor daytime functioning. It is strongly associated with hypertension (HTN) and apneic events in individuals with OSA can drive blood pressure (BP) surges at night. Treating OSA with continuous positive airway pressure (CPAP) has led to reductions in day- and nighttime BP and treatment of HTN has also been reported to have beneficial effects on OSA severity. Dietary sodium has long been implicated in HTN and dietary sodium restriction improves BP levels. Recently, dietary sodium restriction was found to reduce OSA severity in men with …

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Examining Associations Between Sources Of Stress And Experimental Pain Sensitivity In Pediatric Patients With Functional Abdominal Pain Disorders, Corinne Taylor Evans Jan 2023

Examining Associations Between Sources Of Stress And Experimental Pain Sensitivity In Pediatric Patients With Functional Abdominal Pain Disorders, Corinne Taylor Evans

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Functional abdominal pain disorders (FAPDs) are one of the most common pain complaints among children and adolescents. Research demonstrates a relationship between multiple sources of stress and pain responses. However, research has not yet explored the role of stress in pain processing and sensitivity in youth with FAPDs. Thus, the present study aimed to examine associations between biopsychosocial sources of stress and experimental pain sensitivity in pediatric patients with FAPDs. Additionally, racial differences in clinical and experimental pain responses were explored. Analytical findings did not support hypotheses as the biological, social, and psychological sources of stress did not predict experimental …

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Adverse Childhood Experiences And Chronic Low Back Pain In Adulthood: Roles Of Emotion Regulation And Socioeconomic Status, Pavithra Andrea Thomas Jan 2023

Adverse Childhood Experiences And Chronic Low Back Pain In Adulthood: Roles Of Emotion Regulation And Socioeconomic Status, Pavithra Andrea Thomas

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Adverse childhood experiences (ACEs) can have profound deleterious effects on physical health and psychological functioning in adulthood. ACEs may be a social determinant of chronic pain development and severity in adulthood; however, little research to date has investigated the psychological processes that might underlie this association. Emotion regulation, an established transdiagnostic risk factor underlying psychopathological conditions, may be a potential mediator of the relationship between ACEs and pain. Lower socioeconomic status is associated with greater risk of ACEs and poor chronic pain outcomes, yet research has not clarified the role of subjective versus objective determinants of socioeconomic factors within these …

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Impact Of Malaria Rapid Diagnostic Test On The Receipt Of Antimalarials Among Children Aged 6-59 Months In Nigeria From 2010 To 2021, Sandra Chibuzor Olisakwe Jan 2023

Impact Of Malaria Rapid Diagnostic Test On The Receipt Of Antimalarials Among Children Aged 6-59 Months In Nigeria From 2010 To 2021, Sandra Chibuzor Olisakwe

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Background: Nigeria has the highest malaria burden globally, and antimalarials have been commonly used to treat malaria without parasitological confirmation. In 2012, Nigeria implemented RDTs to reduce use of antimalarials for those without malaria and to increase the use of artemisinin-combination therapies (ACTs) for malaria treatment. In this study, we examined trends in antimalarial receipt among children aged 6-59 months during a 12-year period of increasing RDT availability. Methods: We conducted a cross-sectional analysis using nationally representative Nigeria Malaria Indicator Survey (NMIS) data from 2010 (before RDT implementation), 2015, and 2021. NMIS surveys used histidine-rich protein 2 (HRP2)- based RDTs …

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Expression Of St6gal1 Imparts Stem-Like Cell Behaviors, Thereby Promoting Neoplasia, Sejal Sanjay Shinde Jan 2023

Expression Of St6gal1 Imparts Stem-Like Cell Behaviors, Thereby Promoting Neoplasia, Sejal Sanjay Shinde

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Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal malignancies with a five-year survival of ~10%. Recent studies in the US population suggest PDAC as the fourth leading cause of cancer-related deaths in 2022. ST6 β-galactoside α2,6-sialyltransferase (ST6GAL1) is a glycosyltransferase which is known to be upregulated in cancer. It acts as a master regulator of a cell by being the predominant sialyltransferase catalyzing the addition of a bulky negatively charged sialic acid to the galactose sugar in an α2,6-linkage. Due to this, the sialic acid changes the structure and function of cell surface receptor proteins and regulates signal …

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Investigating The Effects Of Immune Checkpoint Inhibition And Combined Treatment With Evofosfamide On The Tumor Microenvironment Through Hypoxia Imaging, Kaytlyn Carter Mcneal Jan 2023

Investigating The Effects Of Immune Checkpoint Inhibition And Combined Treatment With Evofosfamide On The Tumor Microenvironment Through Hypoxia Imaging, Kaytlyn Carter Mcneal

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Colorectal cancer (CRC) is a prevalent and deadly cancer worldwide. While immunotherapy, particularly immune checkpoint inhibition, shows promise in various cancers, its efficacy in CRC and other tumor types is limited. Hypoxia, characterized by inadequate tissue oxygenation, critically drives cancer progression, promoting tumor growth, metastasis, chemotherapy resistance, and poor prognosis. Evofosfamide, a hypoxia-activating prodrug, is being evaluated in clinical trials for combined use with checkpoint blockade as a potential therapeutic strategy. This study investigates the impact of hypoxia on immune checkpoint inhibition, evofosfamide, and combination therapy, while utilizing non-invasive molecular imaging to develop analytical methods for quantifying and characterizing tumor …

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Comparison Of Crown Fracture And Wear Resistence Of Resin 3d Printed Permanent Crown And Other Restorative Materials, Victor Moncada Jan 2023

Comparison Of Crown Fracture And Wear Resistence Of Resin 3d Printed Permanent Crown And Other Restorative Materials, Victor Moncada

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Statement of Problem: The resin for 3D printing permanent crowns is a recently approved material with limited literature evidence to support its in vitro properties. Comparing the mechanical properties such as fracture load (N) and wear resistance for 3D printing permanent restorations resins would represent a very good reference to consider future clinical decisions. Purpose: To investigate the fracture load (N) and wear resistance of the resins for 3D printing permanent crowns available in the U.S. dental market and to compare amongst them using lithium disilicate as a reference. Materials and Methods: for the crown fracture test, the experimental design …

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Respiratory Symptoms And Psychological Distress In Farmers Living With Copd, Prasert Kham-Ai Jan 2023

Respiratory Symptoms And Psychological Distress In Farmers Living With Copd, Prasert Kham-Ai

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Farmers are susceptible to both Chronic Obstructive Pulmonary Disease (COPD) and psychological distress. It is known that psychological distress is associated with increased respiratory symptoms and triggers COPD exacerbation. Therefore, farmers who have COPD may experience worsening respiratory symptoms as a result of psychological distress. Since no known studies revealed the association between the frequency of respiratory symptoms and the level of psychological distress among farmers with COPD, this study aimed to explore (1) the frequency of respiratory symptoms and the level of psychological distress, (2) the factors related to increased respiratory symptoms and psychological distress, and (3) the association …

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The Molecular And Structural Basis Of B Cell Epitope Targeting In Transplant Rejection, John T. Killian Jan 2023

The Molecular And Structural Basis Of B Cell Epitope Targeting In Transplant Rejection, John T. Killian

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HLA-reactive antibodies (HLA-Abs) to mismatched polymorphic HLA molecules are one of the major barriers to successful organ transplantation. However, key knowledge gaps remain surrounding the immunology of the anti-HLA B cell response in transplant rejection. This lack of understanding regarding the phenotype and specificity of the anti- HLA B cell response means that the field cannot develop optimal therapies to treat B-cell mediated donor-specific responses and that it lacks the tools to optimally match donors and recipients to prevent rejection events. Therefore, this dissertation aimed to explore the clinical factors associated with the formation of donor-specific antibodies and the molecular …

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A Prospective Randomized Clinical Trial To Compare Side Access Mucosal Releasing Incision (Samri) And Sulcular Tunnel Access And Root Coverage Procedures With Coronally Advanced Flap And Acellular Dermal Matrix (Adm) To Treat Teeth With Gingival Recession And Lack Of Adequate Keratinized Tissue. A Pilot Study, Wangsoo Lee Jan 2023

A Prospective Randomized Clinical Trial To Compare Side Access Mucosal Releasing Incision (Samri) And Sulcular Tunnel Access And Root Coverage Procedures With Coronally Advanced Flap And Acellular Dermal Matrix (Adm) To Treat Teeth With Gingival Recession And Lack Of Adequate Keratinized Tissue. A Pilot Study, Wangsoo Lee

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Aims. The aim of this prospective, randomized, blinded, controlled clinical trial was to compare clinical and patient-centered outcomes of Cairo recession type 1 (RT1) gingival recession defects treated with acellular dermal matrix (ADM) grafts and either Side Access Mucosal Releasing Incision (SAMRI) or Sulcular Tunnel Access (STA) techniques with coronal flap advancement (CAF). Methods. 11 patients, 22 surgical procedures and 81 gingival recession defect sites with Cairo RT1 gingival recession and £ 2mm of keratinized tissue at each site were randomly divided into two groups (A: SAMRI, B: STA) and were treated and evaluated for 12 months post-surgically. Clinical measurements …

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Understanding Molecular Mechanisms Of Glioblastoama Resistance To Design Novel Combinatorial Therapies, Amber B. Jones Jan 2023

Understanding Molecular Mechanisms Of Glioblastoama Resistance To Design Novel Combinatorial Therapies, Amber B. Jones

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Treatment options for the universally lethal brain tumor, glioblastoma (GBM), are severely limited and often unsuccessful in fully eradicating the disease. Extremely aggressive in nature, GBM cells often implore suppressive mechanisms to evade therapeutic detection which aids in the dismal 15-month median survival rate. Facilitating disease severity and more importantly, disease recurrence, are the immunosuppressive and chemoresistant phenotypes of GBM cells. Specifically, the DNA alkylating agent, temozolomide (TMZ) possesses lymphodepleting properties shunting robust immune cell infiltration into an immunologically cold tumor microenvironment. Additionally, through inherent or acquired mechanisms, GBM tumors commonly become resistant to the DNA damaging effects of TMZ …

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The Long Non-Coding Rna Neat1 Mediates Astrocyte Gene Expression And Hippocampus-Dependent Memory In Aging And Alzheimer's Disease, Ashleigh Burns Irwin Jan 2023

The Long Non-Coding Rna Neat1 Mediates Astrocyte Gene Expression And Hippocampus-Dependent Memory In Aging And Alzheimer's Disease, Ashleigh Burns Irwin

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Dysregulation of long non-coding RNAs (lncRNAs) is increasingly associated with cognitive dysfunction and neurodegenerative disorders such as Alzheimer’s disease (AD). The highly evolutionarily conserved lncRNA Nuclear-Enriched Abundant Transcript 1 (NEAT1) is expressed not only in a tissue- and temporally-specific manner, but also celltype specific manner. Despite the predominance of NEAT1 in glial populations, and the significant role astrocytes play in memory, relatively little is known about Neat1 regulation of astrocyte transcriptomics during age-related memory. Here, we report a crucial role of the lncRNA Neat1 in astrocyte dysfunction and memory deficits associated with both normal aging and AD. Expression of Neat1 …

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Organizational Climate And Its Association With Eth Perceived Permanence Of An Evidence-Based Decision-Aid For Patients With Lupus, Aizhan Karabukayeva Jan 2023

Organizational Climate And Its Association With Eth Perceived Permanence Of An Evidence-Based Decision-Aid For Patients With Lupus, Aizhan Karabukayeva

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It is increasingly evident that seemingly good ideas do not always result in changes in practice, and it is challenging to sustain evidence-based innovations, even if they are backed by substantial research. Long-term use of innovations seems more likely where favorable contextual conditions are in place, yet relatively little empirical research has taken up the question of how evidence-based practices are sustained and become established in day-to-day practice. This question of sustainability is crucial if the gains in patient care that derive from organizational innovations are to be maintained. The purpose of this dissertation was to examine the relationship between …

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Physical Activity Promotion In Persons Newly Diagnosed With Multiple Sclerosis, Le Thao Trinh Huynh Jan 2023

Physical Activity Promotion In Persons Newly Diagnosed With Multiple Sclerosis, Le Thao Trinh Huynh

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Multiple sclerosis (MS) is a prevalent immune-mediated, neurodegenerative disorder, affecting approximately 1 million people in the United States. MS onset is commonly between 20 and 40 years of age, and persons with MS often live a long life with the disease resulting from the early initiation of disease-modifying therapies and comorbidity-managing approaches. Notably, physical activity is promising for disease modification and symptoms and comorbidity management in MS. Yet, physical activity has been initiated quite late during the disease course. Further, early MS could be a “window of opportunity” for initiating physical activity to maximize its health benefits for symptom management …

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An Examination Of Clinical Pain Severity, Sleep Quality, And Neighborhood Disadvantage In A Racially/Ethically Diverse Sample Of Adults With Symptomatic Knee Osteoarthritis, Cesar Emmanuel Gonzalez Jan 2023

An Examination Of Clinical Pain Severity, Sleep Quality, And Neighborhood Disadvantage In A Racially/Ethically Diverse Sample Of Adults With Symptomatic Knee Osteoarthritis, Cesar Emmanuel Gonzalez

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Knee osteoarthritis (OA) is often accompanied by insomnia symptoms, character-ized by difficulty falling asleep, maintaining sleep, or both. Among individuals with knee OA, up to 31% report significant difficulty falling asleep, 81% have difficulties staying asleep, and up to 77% report any sleep problem. However, the sleep and pain relationship has also rarely been evaluated using objective and subjective sleep measures. Thus, this study attempted to characterize objective and subjective sleep variables in a diverse sam-ple of individuals with symptomatic knee OA. Further, the impact of objective and sub-jective sleep quality on clinical pain severity, movement-evoked pain, and physical func-tion …

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Application Of Machine Learning And Network Approaches To Prioritize Safe And Efficacious Drug Repurposing Candidates, Jennifer L. Fisher Jan 2023

Application Of Machine Learning And Network Approaches To Prioritize Safe And Efficacious Drug Repurposing Candidates, Jennifer L. Fisher

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Only ten percent of drugs in clinical trials are ultimately approved by the Food and Drug Administration (FDA). With many diseases and disorders needing therapeutic options, computational drug repurposing methodologies are great alternatives to some drug discovery methods due to quicker FDA approval and lower cost. We sought to gain insights to improve the identification of drug repurposing candidates that will be safe and effective to increase the success of computational drug repurposing approaches. In regards to identifying safe drug candidates, pharmacovigilance studies of adverse event case reports identified that women are more likely to experience an adverse event, and …

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International Graduate Students In A Master Of Public Health Program: A Mixed Methods Study To Identify Challenges And Needed Supports, Melinda S. Harrison Jan 2023

International Graduate Students In A Master Of Public Health Program: A Mixed Methods Study To Identify Challenges And Needed Supports, Melinda S. Harrison

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The increase in international graduate students (IGSs) in the United States in recent years has created additional linguistic and cultural diversity in graduate programs, thus, spotlighting the existence of these students’ unmet challenges. Although much research has been conducted on the experiences of international students in U.S. higher education contexts, very little research has focused on IGSs’ transition experiences to and through academic and professional university programs by way of pathway language support programs. Applying activity theory, I designed and conducted this case study with explanatory sequential mixed methods to investigate IGSs’ experiences as they transitioned into and through a …

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Advanced Applications Of Existing Technology And Their Influence On Quality Outcomes In Federally Qualified Health Centers, Ali Riza Demirbas Jan 2023

Advanced Applications Of Existing Technology And Their Influence On Quality Outcomes In Federally Qualified Health Centers, Ali Riza Demirbas

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Increasing competition in the healthcare industry is compelling organizations to adopt new strategies to obtain and/or maintain a competitive advantage. To obtain a competitive advantage, healthcare organizations may need either more efficient processes or offer new or improved products and services through the utilization of these strategies. In competitive market environments, technological innovations can be a key competitive advantage to reduce expenses, improve quality, attract more customers, or a combination of all. All healthcare organizations can benefit from technological innovations, especially those with limited resources. One type of healthcare organization that highlights the disparity in resources is the Federally Qualified …

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Reduction Of Sphingomyelinases Associated With Progranulin Deficiency And Frontotemporal Dementia, Nicholas R. Boyle Jan 2023

Reduction Of Sphingomyelinases Associated With Progranulin Deficiency And Frontotemporal Dementia, Nicholas R. Boyle

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Frontotemporal dementia (FTD) is a leading cause of early-onset dementia and has a significant socioeconomic burden due to difficulties in diagnosis and delay to diagnosis. FTD is a clinically, pathologically, and genetically heterogeneous disorder. The pathological changes associated with FTD are termed frontotemporal lobar degeneration (FTLD). Protein aggregates are always present in FTLD, with >90% of cases presenting with either TDP-43 or tau pathology. Most cases of FTD are sporadic, but familial cases account for up to 25% of FTD. All familial FTD is inherited in an autosomal dominant fashion with most cases being caused by mutations in tau (MAPT), …

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Investigation Into The Structure And Function Of Tyrosyl-Dna Phosphodiesterase I'S N-Terminal Domain, Evan J. Brettrager Jan 2023

Investigation Into The Structure And Function Of Tyrosyl-Dna Phosphodiesterase I'S N-Terminal Domain, Evan J. Brettrager

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Tyrosyl-DNA phosphodiesterase I (Tdp1) is a eukaryotic DNA repair enzyme that removes adducts from DNA ends via hydrolysis of a phosphodiester bond. These adducts consist of damaged nucleotides or trapped protein-DNA complexes. Tdp1 hydrolyzes the phosphodiester bond utilizing two catalytic histidines and forming a Tdp1-DNA covalent intermediate. Mutations of these catalytic histidines have been shown to increase the stability of the Tdp1-DNA covalent intermediate and cause Topoisomerase I dependent toxicity in cells. We use these toxic Tdp1 mutant enzymes to study the function of Tdp1’s N-terminal domain (NTD). Full-length Tdp1 has proven difficult to purify due to degradation of the …

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Sialylation Of Epidermal Growth Factor Receptor By The Sialyltransferase St6gal1 Modulates Receptor Activity And Downstream Signaling, Katherine Ankenbauer Jan 2023

Sialylation Of Epidermal Growth Factor Receptor By The Sialyltransferase St6gal1 Modulates Receptor Activity And Downstream Signaling, Katherine Ankenbauer

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During the process of malignant transformation, cells have striking changes in their cell surface glycosylation. One of these changes is an enrichment for α2,6 sialic acid which is added by the sialyltransferase, ST6GAL1. ST6GAL1 is upregulated in numerous malignancies and acts by adding an α2,6 sialic acid onto receptors bound for the plasma membrane. This sialic acid, in turn, modulates the activity of the receptor by regulating conformation, clustering, and cell surface retention. The work presented in this dissertation focuses on how ST6GAL1-mediated sialylation of a specific cell surface receptor, epidermal growth factor receptor (EGFR), regulates many of its properties. …

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