Digital Commons Network^™

Diabetes Risk Status And Physical Activity In Pregnant Women: U.S. Brfss 2011, 2013, 2015, 2017, Bethany Rand

UNF Graduate Theses and Dissertations

Objective: We sought to examine differences in aerobic activity (AA) and muscle-strengthening activity (MSA) by diabetes risk status (DRS) among pregnant women in the United States.

Background: Pregnant women without complications are advised to engage in physical activity (PA) to mitigate adverse outcomes. Differences may exist among pregnant women of diverging diabetes status in meeting national PA recommendations.

Methods: The sample (n=9,597) included pregnant women ages 18-44, who participated in 2011, 2013, 2015, and 2017 Behavioral Risk Factor Surveillance System. Levels of DRS were: no diabetes (ND), high risk for diabetes (HRD) due to self-reported gestational diabetes or …

Biomarkers Of Inflammation In Heart Failure Patients With Reduced And Preserved Ejection Fractions: Multi-Ethnic Study Of Atherosclerosis, Michelle Lynne Stone

UNF Graduate Theses and Dissertations

Purpose Examine the relationships between high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and soluble tumor necrosis factor-α receptor-1 (sTNF-R1) and the cumulative risk of heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fractions in a diverse, population-based sample. Methods Study sample included 6,814 adult (45-84 years of age) men and women who participated in the Multi-Ethnic Study of Atherosclerosis and were free of cardiovascular disease at baseline. Cox regression was used to calculate the hazard ratios (HR) associated with elevated baseline hs-CRP (> 3-10 mg/L), IL-6 (> 75^th percentile) and sTNF-R1 (> 75^th percentile) and risk of overall …

Novel Mechanisms Of Nitric Oxide Activation In The Kidney, Randee Sedaka

All ETDs from UAB

Globally, adult sodium consumption has far exceeded daily intake recommendations, leading to one in ten cardiovascular deaths. Given the rise in hypertension prevalence, uncontrolled hypertension with antihypertensive medication use, and significant associations between high salt intake and high blood pressure, there is a need to better understand the mechanisms involved in hypertension. Nitric oxide synthase 1 (NOS1) is a well-established regulator of fluid and electrolyte balance in the renal collecting duct (CD) with highest activity in the inner medulla (IM). We previously reported that high salt (HS) intake stimulates CD endothelin B receptor (ETBR)/NOS1-dependent generation of NO, thereby inhibiting the …

Diurnal Dysfunction In Control Of Sodium Excretion In Diet-Induced Obesity, Reham Soliman

All ETDs from UAB

The renal endothelin system plays a key role in sodium excretion, particularly under high salt (HS) diet. HS stimulates renal endothelin-1 (ET-1), which binds and activates the endothelin receptor B (ETB) to excrete the excess salt. Loss of ETB receptor is linked to the development of hypertension under HS. Central clock genes are important in maintaining rhythmic patterns of sodium excretion and ET-1 is identified as a target for clock genes, including Period and Bmal1. ET-1 excretion follows a diurnal rhythm along with sodium excretion. Sexual dimorphism is evident in the diurnal regulation of endothelin-mediated natriuresis and its downstream targets. …

Mitochondrial Priming Of Tumor Initiating Cells Involves Repression Of Mitochondrial Fission Activity Towards Redox Regulation Of The Cell Cycle Regulator Cyclin E, Brian Spurlock

All ETDs from UAB

Mitochondrial dynamics primarily refers to the opposing fission or fusion events between individual mitochondria, which maintains steady-state mitochondrial morphology in cells. Fission and fusion activities maintain the energetics of normal and neoplastic stem cells. We developed the novel approach mito-SinCe2 to study the bidirectional relationship between mitochondrial dynamics and energetics. Application of this method led to the hypothesis that mitochondria-dependent ovarian tumor initiating cells interconvert between 3 states with distinct mitochondrial energetics/dynamics relationships. Cells in one state, characterized by high mitochondrial ROS and low fission activity, appear to be primed for self-renewal by mitochondria. We call these cells mitochondria-primed stem …

Toxin Secretion By Mycobacterium Tuberculosis, Uday Tak

All ETDs from UAB

Mycobacterium tuberculosis (Mtb) is a highly infectious airborne bacterial pathogen, and the causative agent of human tuberculosis. Mtb infects approximately one-third of the human population, and is responsible for more deaths than any other infectious disease in the history of mankind. Mtb is an intracellular pathogen and primarily infects myeloid cells, such as macrophages in the human lung. In macrophages, Mtb establishes a replication niche within membrane-bound vacuoles named phagosomes, while subverting immunity. The intracellular survival of Mtb depends on manipulation of host cellular processes through secreted effector proteins. Ultimately, this intracellular vacuole is ruptured by the type VII secretion …

Understanding The Impact Of Diet And Obesity On Anti-Tumor Immunity And Therapeutic Efficacy In Kidney Cancer, Rachael Miller Orlandella

All ETDs from UAB

Obesity is regarded as a major risk factor for developing renal cell carcinoma (RCC). Advanced-stage RCC exhibits chemotherapeutic resistance, but is responsive to immunotherapies such as the immune checkpoint inhibitor anti-programmed cell death-1 (anti-PD-1). Despite some clinical successes, response rates remain low for anti-PD-1 monotherapy (20-30%). Preclinical evaluations of immunotherapeutic strategies typically use lean mice and do not account for patient comorbidities. This may explain the underwhelming success rates following clinical translation of new cancer treatments. Recent studies found that obesity was associated with favorable outcomes and responses to immunotherapy in melanoma. However, the effects of obesity on anti-tumor immunity …

Novel Hiv Adaptation Strategy Against Host Cd8 T Cell Immunity, Kai Qin

All ETDs from UAB

Since the 1980s, HIV infection has caused millions of death and tremendous economic losses worldwide. Despite great scientific advances, the only effective therapy to date, antiretroviral therapy (ART), merely delays disease progression yet cannot eradicate viral infection. Therefore, an effective HIV vaccine that can prevent the acquisition of infection would be a desirable alternative. The critical role of CD8 T-cell immunity in HIV infection has been well documented and therefore not surprisingly a great deal of effort has been focused on developing an effective CD8 T-cell based HIV vaccine. However, by far, such CD8 T-cell based HIV vaccine trials have …

Investigating The Roles Of The Renal Primary Cilium Through The Use Of Intravital Imaging, Dustin Zachary Revell

All ETDs from UAB

Primary cilia are small microtubule based appendages present on nearly every cell type in the mammalian body, and are highly conserved from organisms as simple as algae to humans. Cilia function as complex signaling centers integrating a variety of pathways and play critical roles throughout development and in maintaining homeostasis. Mutations to ciliary proteins in humans result in a wide array of diseases termed ciliopathies, which have a broad range of symptoms affecting nearly every organ in the body. Renal primary cilia are present on the apical side of tubular epithelium, where they project into the lumen and are thought …

T Cells In Synucleinopathies, Gregory Paul Williams

All ETDs from UAB

Synucleinopathies, which include Parkinson disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), are a collection of neurodegenerative diseases that are in major part defined by the presence of alpha-synuclein (α-syn) rich protein aggregates in the brain. Increasing evidence has highlighted a neuroinflammatory phenotype also associated with these synucleinopathies. This neuroinflammatory phenotype includes the activation of central nervous system (CNS) microglia, increased pro-inflammatory cytokines, and the infiltration of peripheral T cells into the CNS. We sought to further explore the T cell responses associated with PD and MSA. Using two preclinical mouse models of PD and MSA, …

Co-Factors In Fgf Signaling, Christopher Yanucil

All ETDs from UAB

The fibroblast growth factor (FGF) family consists of a group of proteins whose diverse biological functions are mediated by receptor tyrosine kinases, termed FGF receptors (FGFR) 1-4. While paracrine FGFs require heparin sulfate as a co-factor for FGFR bind-ing and signaling, it has been assumed that endocrine FGFs, such as FGF23, do not bind heparin but instead require klotho, a family of transmembrane proteins, as a co-receptor on specific target cells. FGF23 acts as bone-derived hormone that targets tubular epitheli-al cells in the kidney via FGFR1 and α-klotho to reduce renal phosphate uptake. In chron-ic kidney disease (CKD), the kidney …

Network-Based Analytics For Discovering Gene Modules And Biomarkers In Complex Diseases, Zongliang Yue

All ETDs from UAB

With rapidly increasing novel discoveries of associations between genomic data and complex disease phenotypes, the translation of those associations into knowledge and the identification of critical molecular mechanisms are essential to guild clinical decisions such as the diagnosis of symptomatic individuals, the prediction of disease risk, reproductive genetic counseling, and determining pharmacogenetic profiles for treatment. To decipher the genome of complex diseases, gene-centric analyses focus on detecting molecular mechanisms lead by driver genetics variants, abnormally expressed genes and high-abundance proteins through gene module construction. Additionally, the gene module construction approaches implement systems biology analysis to reveal the causative co-expressed gene …

Epigenetic Regulation In Cancer And Development, Theodore Busby

All ETDs from UAB

Feedback loops between cellular cues and changes in gene expression mediate the interactions between a multitude of regulatory events that promote development and cancer. Vesicular trafficking is an important process in carrying out signaling events by transporting receptors and ligands to and from the cell surface. GBF1 and BIG1 are large guanine-exchange factors (GEFs) that activate GTPase mediated shuttling of cargo through the Golgi apparatus. This dissertation demonstrates that GBF1 localizes to the cytoplasmic membrane in glioblastoma multiform cells to maintain cell shape and promote migration. Reports have shown that BIG1translocates to the nucleus is hepatocyte carcinoma cell lines in …

Enhancer Rnas As Regulators Of Gene Expression And Neuronal Function, Nancy Verena Nicole Carullo

All ETDs from UAB

Genomic enhancers are cis-regulatory elements in the DNA that exhibit spatial and temporal control over intricate gene expression programs shaping fate and function of heterogeneous cell populations in the developing and adult brain. In addition to their role in cellular development and maintenance, enhancer activity drives transcriptional changes in response to stimulation. Active enhancers are subject to bidirectional transcription that yields non-coding enhancer RNAs (eR-NAs). However, the functional role of eRNAs in transcriptional regulation remains controversial. Therefore, we used primary neuronal cultures to investigate en-hancers and eRNAs in the rat genome. We identified and verified enhancer-gene pairs, characterized their response …

Il-17 Producing Cd4 T Cells In Spontaneous Germinal Center And Autoantibody Formation In Murine Lupus, Huixian Hong

All ETDs from UAB

IL-23 promotes autoimmune disease, including Th17 CD4 T-cell development and autoantibody (autoAb) production. Here, we show that a deficiency of the p19 component of IL-23 in the autoimmune BXD2 (BXD2-p19−/−) mouse leads to a shift of the follicular T-helper cell program from Tfh-IL-17 to Tfh-IFN-ɣ. Although the germinal center (GC) size and the number of GC B cells remained the same, BXD2-p19−/− mice exhibited a lower class-switch recombination (CSR) in the GC B cells, leading to lower serum levels of IgG2b. Single-cell transcriptomics analysis of GC B cells revealed that while Ifngr1, Il21r and Il4r genes exhibited a synchronized expression …

Pharmacodynamic Responses And Efficacies Associated With Lrrk2 Inhibition, Kaela Kelly

All ETDs from UAB

Parkinson’s disease (PD) is an age-related, progressive, movement disorder pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of proteinaceous aggregates, termed Lewy bodies, that are largely comprised of αSynuclein (αSyn). Missense mutations in the leucine-rich repeat kinase (LRRK2) gene are the most common genetic cause of PD and lead to gain-of-function increases in kinase activity. The G2019S-LRRK2 mutation is the most frequent mutation and elevates kinase activity by ~2-3 fold. Genetic and biochemical evidence suggest elevated LRRK2 kinase activity plays a pathogenic role in the development of PD, implicating LRRK2 …

Protective Host Responses During Acute And Chronic Lung Exposure To Aspergillus Fumigatus, Joseph Mackel

All ETDs from UAB

Aspergillus fumigatus is an environmental airborne fungus that acts as both an opportunistic pathogen and an allergen. In immunocompromised hosts, A. fumigatus can germinate in the lung, cause tissue damage and pneumonia, and disseminate to other organs, causing a disease termed invasive aspergillosis (IA). In severe asthma, sensitization to fungi such as A. fumigatus is associated with more severe disease. Determination of host and fungal factors that drive immunoprotection versus immunopathogenesis in both of these settings will ultimately enable therapeutic modulation of immune responses to improve disease outcomes. In this body of work, we build on recent findings that implicate …

Gp44, A Minor Protein With A Major Role In Bacteriophage 80Α Infection, Keith Allen Manning

All ETDs from UAB

Bacteriophage 80α is a temperate double-stranded DNA phage that infects Staphylococcus aureus and is capable of mobilizing a variety of mobile genetic elements named S. aureus Pathogenicity Islands. The capsid of the mature virion is composed of subunits of the capsid protein, portal protein, and a minor capsid protein gp44 as well as packaged phage genomic DNA. The loss of the gp44 protein completely eliminates the phage titer of 80α but does not eliminate the transduction of the pathogenicity islands. In this dissertation, I show that the minor capsid protein is primarily active in a post-ejection role. Without gp44 the …

The Role Of The Β-Catenin Signaling Pathway In Modulating The Nucleolar Proteome Of Triple Negative Breast Cancer, Shannon E. Meier

All ETDs from UAB

Previously, abnormal nucleoli were noted as indicators of cancerous lesions andused as a pathologic readout of neoplasia. Nucleolar hypertrophy and increased nucleolar number have been correlated with increased breast cancer (BC) mortality rates. Although various functions of the nucleolus have been investigated, it remains widely understudied in the context of cancer. The nucleolus was initially thought to be solely the site of ribosome biogenesis. However, over half of the proteins found in the nucleolus are associated with other biological functions. It is evident that the nucleolus plays major roles in stress response, DNA repair, and critical cellular aspects that influence …

Advancing Single Cell And Crispr/Dcas9 Technologies For The Study Of Reward Learning And Addiction, Corey Grant Duke

All ETDs from UAB

Drug addiction is a chronic relapsing condition inflicting tremendous harm to individuals and society with ineffective treatment options available to most people. Drugs of abuse elevate dopamine levels in a brain region known as the nucleus accumbens (NAc), and activate gene programs considered essential for producing lasting synaptic and cell state changes which underlie the generation of addictive behavior. These gene expression changes remain poorly understood due to a complex heterogenous cellular architecture, and the rapidly fluctuating nature of the transcriptional processes themselves which make investigation difficult. Recent technical advances increase access to both profiling and manipulating these transcriptional changes …

Deficiency Of Tumor Suppressor Merlin Induces Metabolic Reprogramming In Breast Cancer, Mateus Mota

All ETDs from UAB

The tumor suppressor Merlin is encoded by Neurofibromin 2 (NF2) gene. Merlin is predominantly located in the cell cortex where regulates cell proliferation by mediating cell contact-dependent growth inhibition. Metastatic breast cancer tissues presented with a remarkable loss of Merlin protein, revealing clinical relevance of Merlin. In order to examine the cellular effect of Merlin deficiency, breast cancer cell lines were silenced for NF2. Additionally, to assess the impact of Merlin loss at the organismal level, a mammary-specific NF2 knockout mouse mammary tumor model was engineered. Merlin deficiency induced a metabolic shift from mitochondrial oxidative phosphorylation to aerobic glycolysis. Furthermore, …

Protective Effects Of Thioredoxin Reductase Inhibition In The Murine Lung: The Regulation And Contribution Of Heme Oxygenase-1, Katelyn Louise Dunigan-Russell

All ETDs from UAB

Endogenous antioxidant responses defend the lung against oxygen toxicity. In premature neonates, oxygen toxicity and impaired antioxidant defenses contribute to the development of bronchopulmonary dysplasia (BPD), the leading cause of long-term morbidity among premature infants. In adults, oxygen toxicity and impaired antioxidant defense contributes to the pathogenesis of acute lung injury (ALI). Acute Respiratory Distress Syndrome (ARDS), a severe form of ALI, can cause permeant lung damage and mortality. Our lab has established that pharmacologic thioredoxin reductase-1 (TXNRD1) inhibition attenuates lung injury in murine BPD and ALI models. The protective effects of TXNRD1 inhibition are mediated by the activation of …

Immunopathogenesis In Fungal Asthma, Matthew Stephen Godwin

All ETDs from UAB

Asthma patients are increasingly presenting with asthma that is more difficult to control and treat than in years past. A subset of these patients who are sensitive to fungal species are described as having severe asthma with fungal sensitization (SAFS). Given the severity of disease, there is ever increasing interest in identifying the immune processes underlying SAFS disease pathology and the development of novel therapeutics to improve management. While sensitivity to multiple fungal species has been described in SAFS, none is more common than Aspergillus fumigatus. Here, we describe two previously unrecognized contributors to the amelioration of disease pathology in …

C-Reactive Protein Subverts The Myeloid Lineage: Implications For Renal Injury, Rachel Jimenez

All ETDs from UAB

C-reactive protein (CRP) is an evolutionarily conserved pattern recognition molecule that was first characterized for its participation in the acute phase response to bacterial infection. In the last 90 years, knowledge of CRP biology in innate immunity has expanded significantly. CRP is known to bind and activate the classical pathway of complement, to opsonize bacteria and inflamed tissue, and to modulate myeloid cell functions. CRP is normally present in the blood at low levels with its biosynthesis and serum concentration rapidly rises upon systemic inflammation. For example, high levels of serum CRP are found following acute kidney injury (AKI) in …

Understanding And Targeting Glucose Transporter 3 In Glioblastoma, Catherine Jeanne Libby

All ETDs from UAB

Glioblastoma (GBM) is the most common adult primary malignant brain tumor with a median survival of about 15 months, even after aggressive treatment. Treatment of GBM is difficult for multiple reasons including the location of the tumor, tumor invasiveness, and the high degree of both inter-and intra-tumoral heterogeneity. Contributing to intratumoral heterogeneity are highly tumorigenic, stem-like tumor cells, with the capacity to self-renew and propagate the tumor, termed brain tumor initiating cells (BTICs). BTICs are also commonly therapy resistant, highly invasive, and metabolically plastic with elevated expression of glucose transporter 3 (GLUT3) allowing them to preferentially survive in low nutrient …

Copper Dependent Inhibitors Subvert Common Resistance Mechanisms In Staphylococcus Aureus And Inhibit Crucial Metabolic Pathways, Cameron Crawford

All ETDs from UAB

The effective antibiotic pool is shrinking with antibiotic resistance a constant problem that threatens to make our current therapies obsolete. To combat this, new drug screening methodologies are required since the traditional drug screens are offering limited results or only improvements upon current treatments. This work expands upon the idea that transition metal toxicity can be preferentially targeted towards bacteria. Specifically, the focus is on copper dependent inhibitors that quickly work to eliminate Staphylococcus aureus. S. aureus is a particularly threatening bacteria with high strain variability, a litany of survival and virulence factors, and multiple drug resistance mechanisms that are …

Rna Polymerase I Elongation Kinetics: A Biochemical And Global Study Of A Cancer Therapeutic Target, Catherine Elizabeth Scull

All ETDs from UAB

My graduate research has focused on understanding the elongation kinetics of RNA polymerase I (Pol I), the enzyme responsible for synthesizing ribosomal RNA (rRNA), and defining how inhibition of ribosome biogenesis may be used as a cancer therapeutic strategy. Here, I have defined key biophysical features of Pol I and I have expanded the field’s understanding of Pol I elongation by: 1) characterizing the enzymatic properties of Pol I by mutational analysis of the polymerase itself, and by 2) elucidating the role of DNA sequence on Pol I arrest and nucleolytic cleavage activity. In recent years, Pol I has become …

Association Of A Repetitive Manual Task On Inflammatory Biomarker Expression, Heart Rate Variability And Rating Of Perceived Exertion, Daniel Conde

Open Access Theses & Dissertations

The National Institute for Occupational Safety and Health (NIOSH) defines work related musculoskeletal disorders (WMSDs) as a group of disorders involving muscles, tendons, and nerves. The WMSDs symptoms are considered the most common occupational disease, causing limitations in daily activities. Even though there is an association between repetitive manual tasks involving short work cycles, force demanding tasks, and the development of WMSDs, the specific cause of the physiological changes over a long period of time is a cause of debate. The study of mechanisms underlying the physiological changes is essential for the early detection, diagnosis, and appropriate management of WMSDs.

Identification Of A Novel Single Amino Acid Substitution (V666g) Of Jak1 From A Patient With Acute Lymphoblastic Leukemia Impairs Jak3 Mediated Il-2 Signaling, Alice Hernandez Grant

Open Access Theses & Dissertations

The Janus kinase (JAK) family, notably JAK1, JAK2 and JAK3 are recognized as oncogenic drivers in high risk Acute Lymphoblastic Leukemia (ALL). The bulk of activating JAK mutations are thought to occur within functional hot-spots across Janus Homology (JH) domains. The most frequently mutated regions is the JH2 pseudo-kinase, which provides a negative regulatory role to the adjacent catalytically active JH1 kinase domain. Despite the prevalence of JAK activating mutations and a need for new therapeutic inhibitors, there is a lack of understanding in the allosteric regulation of JAK kinases. Here we sought to identify mutations involved in driving ALL …

Isolation And Characterization Of Α-Gal-Containing Extracellular Vesicles (Evs) From Three Major Genotypes Of Trypanosoma Cruzi: Potential Biomarkers Of Chagas Disease, Nasim Karimi Hosseini

Open Access Theses & Dissertations

Chagas disease (ChD) is a neglected tropical disease (NTD) caused by the protozoan parasite, Trypanosoma cruzi. It is transmitted by the insect-vector triatomine (popular known as kissing bug), blood transfusion, organ transplantation, congenitally, and contaminated foods and juices. T. cruzi has evolved several strategies to invade the host cells, including the release extracellular vesicles (EVs), which assist pathogen survival and its replication within the host. T. cruzi is covered with highly glycosylated surface molecules such as glycoproteins and glycolipids, which are shown to be involved in the interaction with host immune cells. These molecules are highly immunogenic and reactive with …