Medicine and Health Sciences Commons^™

Expression Of The Influenza Protein M2 During Viral Infection Inhibits Cftr Activity, James David Londino

All ETDs from UAB

The purpose of these dissertation studies was to 1) determine whether influenza infection alters CFTR activity in polarized epithelium; 2) measure CFTR expression and activity in cells co-expressing influenza M2 protein; and 3) examine the role of M2 on the alteration of CFTR during viral infection. We determined that infection of polarized primary epithelial cells with influenza decreases CFTR expression and activity. In addition, individual cells infected with influenza had decreased CFTR conductance as measured by whole-cell patch clamp. We also found that the influenza ion channel, matrix protein 2 (M2), alone reduced CFTR expression and activity. M2 is expressed …

Three‐Dimensional Brain Mri For Dbs Patients Within Ultra‐Low Radiofrequency Power Limits, Subhendra N. Sarkar, Efstathios Papavassiliou, David Hackney, David Alsop, Ananth Madhuranthakam, Ludy Shih, Reed Busse, Susan Laruche, Rafeeque Bhadelia

Publications and Research

Background: For patients with deep brain stimulators (DBS), local absorbed radiofrequency (RF) power is unknown and is much higher than what the system estimates. We developed a comprehensive, highquality brain magnetic resonance imaging (MRI) protocol for DBS patients utilizing three-dimensional (3D) magnetic resonance sequences at very low RF power. Methods: Six patients with DBS were imaged (10 sessions) using a transmit/receive head coil at 1.5 Tesla with modified 3D sequences within ultra-low specific absorption rate (SAR) limits (0.1 W/kg) using T2, fast fluid-attenuated inversion recovery (FLAIR) and T1- weighted image contrast. Tissue signal and tissue contrast from the low-SAR images …

An Investigation Of Nurbs-Based Deformable Image Registration, Travis J. Jacobson

Theses and Dissertations

Deformable image registration (DIR) is an essential tool in medical image processing. It provides a means to combine image datasets, allowing for intra-subject, inter-subject, multi-modality, and multi-instance analysis, as well as motion detection and compensation. One of the most popular DIR algorithms models the displacement vector field (DVF) as B-splines, a sum of piecewise polynomials with coefficients that enable local shape control. B-splines have many advantageous properties in the context of DIR, but they often struggle to adequately model steep local gradients and discontinuities. This dissertation addresses that limitation by proposing the replacement of conventional B-splines with a generalized formulation …

Comparison Of Two Different Sprint Interval Training Work-To-Rest Ratios On Acute Metabolic And Inflammatory Responses, Christopher R. Harnish

Theses and Dissertations

High intensity exercise is believed to yield greater results on health and human performance than moderate intensity exercise. Extensive research indicates that not only do high-intensity interval training (HIT) and sprint interval training (SIT) produce significant improvements in cardiovascular fitness and disease, they may be more effective at improving long-term metabolic function, including insulin sensitivity (Si), by producing more mitochondria. Moreover, compliance rates for HIT and SIT participation are reported to be the same or better than traditional moderate intensity exercise. Because lack of time is often cited as major hindrance to exercise participation, SIT is also seen as a …

Analysis Of The Role Of Astrocyte Elevated Gene-1 In Normal Liver Physiology And In The Onset And Progression Of Hepatocellular Carcinoma, Chadia L. Robertson

Theses and Dissertations

First identified over a decade ago, Astrocyte Elevated Gene-1 (AEG-1) has been studied extensively due to early reports of its overexpression in various cancer cell lines. Research groups all over the globe including our own have since identified AEG-1 overexpression in cancers of diverse lineages including cancers of the liver, colon, skin, prostate, breast, lung, esophagus, neurons and neuronal glia as compared to matched normal tissue. A comprehensive and convincing body of data currently points to AEG-1 as an essential component, critical to the progression and perhaps onset of cancer. AEG-1 is a potent activator of multiple pro-tumorigenic signal transduction …

Isolation And Characterization Of Multipotent Lung Stem Cells From P53 Mutant Mice Models, Venkat Sundar Gadepalli

Theses and Dissertations

Recent advances in understanding lung biology have shown evidence for the existence of resident lung stem cells. Independent studies in identifying and characterizing these somatic lung stem cells have shown the potential role of these cells in lung repair and regeneration. Understanding the functional characteristics of these tissue resident stem/progenitor cells has gained much importance with increasing evidence of cancer stem cells, cells in a tumor tissue with stem cell characteristics. Lung cancer is most commonly characterized by loss of p53 function which results in uncontrolled cell divisions. Incidence of p53 point mutations is highest in lung cancer, with a …

The Quetiapine Active Metabolite N-Desalkylquetiapine And The Neurotensin Nts1 Receptor Agonist Pd149163 Exhibit Antidepressant-Like Effects On Operant Responding In Male Rats, Todd M. Hillhouse, Zachary Shankland, Katelin S. Matazel, Ashley Keiser, Adam J. Prus

Journal Articles

Major depressive disorder (MDD) is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that are apparent following one week of quetiapine treatment, and it is possible that the active metabolite N-Desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS₁ receptor agonist PD149163 are suggestive of antidepressant efficacy, but the effects of a NTS …

A Potential Mechanism For Extracellular Matrix Induction Of Breast Cancer Cell Normality, Robert D. Bruno, Gilbert H. Smith

School of Medical Diagnostics & Translational Sciences Publications

Extracellular matrix proteins from embryonic mesenchyme have a normalizing effect on cancer cells in vitro and slow tumor growth in vivo. This concept is suggestive of a new method for controlling the growth and spread of existing cancer cells in situ and indicates the possibility that extracellular proteins and/or embryonic mesenchymal fibroblasts may represent a fertile subject for study of new anti-cancer treatments.

A Nonrigid Registration Method For Correcting Brain Deformation Induced By Tumor Resection, Yixun Liu, Chengjun Yao, Fotis Drakopoulos, Jinsong Wu, Liangfu Zhou, Nikos Chrisochoides

Computer Science Faculty Publications

Purpose: This paper presents a nonrigid registration method to align preoperative MRI with intraoperative MRI to compensate for brain deformation during tumor resection. This method extends traditional point-based nonrigid registration in two aspects: (1) allow the input data to be incomplete and (2) simulate the underlying deformation with a heterogeneous biomechanical model.

Methods: The method formulates the registration as a three-variable (point correspondence, deformation field, and resection region) functional minimization problem, in which point correspondence is represented by a fuzzy assign matrix; Deformation field is represented by a piecewise linear function regularized by the strain energy of a heterogeneous biomechanical …

Heterogeneous Immunological Landscapes And Medieval Plague : An Invitation To A New Dialogue Between Historians And Immunologists., Fabian Crespo, Matthew B. Lawrenz

Faculty and Staff Scholarship

Efforts to understand the differential mortality caused by plague must account for many factors, including human immune responses. In this essay we are particularly interested in those people who were exposed to the Yersinia pestis pathogen during the Black Death, but who had differing fates—survival or death—that could depend on which individuals (once infected) were able to mount an appropriate immune response as a result of biological, environmental, and social factors. The proposed model suggests that historians of the medieval world could make a significant contribution to the study of human health, and especially the role of human immunology in …

Gender Differences In High Sensitivity C - Reactive Protein And Self-Reported Muscle Strengthening Activity Among U.S. Adults, Michael R. Richardson

UNF Graduate Theses and Dissertations

Objectives: We sought to examine the gender differences between C - reactive protein (CRP) and muscle strengthening activity (MSA) in U.S. adults (≥20 years of age)

Background: Elevated levels of CRP have been shown to be associated with an increase in risk of cardiovascular disease (CVD). Studies analyzing the relationship between physical activity (PA) and CRP by gender have produced mixed results.

Methods: The sample (n=9,135) included participants in the 1999-2004 National Health and Nutrition Examination Survey (NHANES). Three categories of reported MSA participation were created: no MSA (referent group), some MSA (≥1 to/wk), and meeting the …

Osteoblast And Odontoblast Specific Regulatory Actions Of Runx2 For The Development Of Mineralized Tissues, Mitra Darice Adhami

All ETDs from UAB

The Runx2 transcription factor is necessary for commitment and differentiation of mesenchymal cells into the chondroblasts, osteoblasts and odontoblasts. Runx2 induces the expression of several key genes involved in mineralization of both the bone and dentin matrices. Global Runx2-null mice are completely void of mineralized tissue and do not express osteoblast markers, indicating that Runx2 is required for commitment to the osteoblast lineage. Tooth development in Runx2-null mice is arrested in the bell stage, prior to the differentiation of odontoblasts. Thus, Runx2 is essential for development of osteoblast and odontoblast lineages. However, the functional requirements of Runx2 after commitment to …

Modulating The Cxcl12/Cxcr4 Axis In The Pulmonary Vasculature By Adenoviral Vector-Mediated Delivery Of Soluble Cxcr4 (Scxcr4): A Prophylactic Approach To The Prevention Of Cancer Metastasis To The Lung, Anand Chandrasekaran Annan

All ETDs from UAB

The results also indicate that in situ nests were cooler than egg corral nests but still

Francisella Tularensis Lvs Invasion Of Primary Murine Macrophages And Mtor Signaling, Michael Warren Edwards

All ETDs from UAB

Francisella tularensis is an intracellular pathogen and the etiologic agent of tularemia. Because virulent strains cause morbidity and lethality in human, the attenuated live vaccine strain (LVS) has been used to study F. tularensis pathogenesis in murine models, since the disease in mice resembles human tularemia. Despite growing knowledge about host responses to Francisella infection, there is scarce information on the cell signaling events involved in Francisella host cell entry and in early immune re-sponses. Therefore, the purpose of this dissertation was to assess the involvement of the mammalian target of rapamycin (mTOR) in these processes. First, we evaluated the …

The Role Of Wnt5a In Tumor Suppression And Differentiation, Stephanie Easter

All ETDs from UAB

TGF-beta and the Wnt signaling pathways play key roles in regulating ductal growth and branching morphogenesis in the mammary gland. Disruption to this signaling can cause deregulation of the normal mammary stem cell population and foster an environment favorable for tumorigenesis and recurrence. Recent studies show that TGF-beta up-regulates expression of the non-canonical Wnt, Wnt5a, in the mammary gland and that Wnt5a antagonizes canonical Wnt/beta-catenin signaling in mammary epithelial cells. Canonical Wnt/beta-catenin signaling has been strongly implicated in expanding the mammary stem/progenitor cell pool. Here, we test the hypothesis that Wnt5a suppresses the expansion of the mammary stem and progenitor …

Mitochondrial Genetics And Cellular Metabolism Regulate Tumorigenicity And Metastatic Potential, Kyle Paul Feeley

All ETDs from UAB

Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors combine to influence an individual's predilection for breast cancer and related metastatic tumor formation. The genetic component, in particular, has become the focus of many emergent studies. A renewed focus on cancer metabolism and the Warburg effect has similarly cast a spotlight on the role, if any, of the mitochondrion in directing disease progression. Analysis of the direct contribution of mitochondrial DNA on tumorigenicity is made possible through the use of mitochondrial-nuclear exchange (MNX) mice in which nuclei from normal FVB mice (the background strain of the tg: …

Mitochondrial Dysfunction In Response To Neurotoxins And The Role Of Mitophagy, Samantha Giordano

All ETDs from UAB

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Two major factors in both familial and sporadic PD are mitochondrial dysfunction and insufficient autophagy. My thesis research focuses on the interplay between these activities in PD. To investigate the common and differential effects of PD-inducing neurotoxins on mitochondrial bioenergetics and their relationships to cell survival, we used an in vitro culture system, differentiated dopaminergic SH-SY5Y neuroblastoma cells. We found that the neurotoxins rotenone, 1-methyl-4- phenylyridinium (MPP+) and 6-hydroxydopamine (6-OHDA), decreased mitochondrial respiration and induced cell death in these cells. The extent and characteristics of mitochondrial dysfunction in response to …

Regulation Of Skeletal Muscle Plasticity Using Engineered Configurations Of The Transcription Factors Myod And E12, Vladimir Grubisic

All ETDs from UAB

Skeletal muscle fibers, although terminally differentiated, can change their features, such as contraction speed and endurance, and throughout adult life in response to variety of stimuli, like exercise. This process is called plasticity and is mainly regulated by the type of nerve activity. Over the past several decades, research has shown that the properties of myofibers are also determined during muscle development. Ultimately, the change in phenotype requires a change in gene expression which is, in turn, regulated by transcription factors (TFs). Basic helix-loop-helix (bHLH) TFs regulate myogenesis and the central role belongs to the myogenic differentiation 1 (MyoD), often …

Determining The Role Of Neuregulin-1 And Its Erbb Receptors In The Pathogenesis Of Malignant Peripheral Nerve Sheath Tumors, Stephanie Brosius

All ETDs from UAB

Malignant peripheral nerve sheath tumors (MPNSTs) are the most common cause of death in patients with neurofibromatosis type-1. These aggressive, Schwann cell-derived tumors have no treatment beyond surgical resection. Developing targeted chemotherapeutics remains crucial to improving patient survival. The Schwann cell mitogen neuregulin-1 (NRG1) was shown to mediate the migration, proliferation and survival of MPNSTs. Furthermore, overexpression of NRG1 in Schwann cells (P0-GGF beta 3 mice) on an outbred C57BL/6J x SJL/J background induced the formation of neurofibromas and MPNSTs similar to human disease, yet these mice have intact neurofibromin. To determine if NRG1 acts within the same signaling cascade …

Cd5-Dependent Ck2 Activation Is Critical For The Maintenance Of B-1a B Cells, Kevin S. Cashman

All ETDs from UAB

CD5 has classically been shown to act as a negative regulator of antigen receptor signaling, however recent evidence has discerned that the CD5 molecule contains a previously undefined cytoplasmic domain which constitutively binds inactive CK2 and facilitates its activation through CD5 ligation. With the development of a mouse model which contains a micro-deletion knock-in form of CD5 which lacks the amino acids necessary to facilitate this CD5-CK2 interaction, it is now understood that CD5 plays a more significant role in cellular physiology than previously appreciated. T cells from this mouse model show increased AICD and dysregulation in T helper subset …

Recognition Of Hiv-1 Cryptic Epitopes During Infection And Following Vaccination, Anne Bet

All ETDs from UAB

Cryptic epitopes (CE) are a unique set of human leukocyte antigen class I (HLA-I)-restricted peptides that are encoded by alternative reading frames (ARFs) of genes. During human immunodeficiency virus-1 (HIV-1) infection, CE translated from either sense or antisense transcripts elicit epitope-specific CD8 T cell responses. Previous studies using simian immunodeficiency virus (SIV)-vaccinated animals have shown that an increased breadth of CD8 T cell responses is correlated with controlling viral replication, therefore stressing the potential clinical benefit of vaccine-induced T cell responses to a diverse set of viral epitopes. Yet, the genetic profiles and immunological significance of CE remain poorly understood. …

The Modulation Of High Density Lipoprotein Metabolism In Systemic Lupus Erythematosus, Leland Latham Black

All ETDs from UAB

Apolipoprotein A-I (ApoA-I), the major lipid-binding protein of high-density lipoprotein (HDL), can suppress inflammation and autoimmunity in hypercholesterolemic mice by modulating cellular cholesterol homeostasis and lipid oxidation. However, the cellular and molecular mechanisms involved are poorly understood, and whether ApoA-I or ApoA-I mimetic peptides can similarly exert immunosuppressive effects or improve inflammatory organ disease in SLE under normolipidemic conditions remains unresolved. We therefore first took a genetic approach in which bone marrow from SLE-prone Sle123 mice was transferred into wild-type, ApoA-I knockout (ApoA-I-/-) and ApoA-I transgenic (ApoA-Itg) mice. Transgenic expression of ApoA-I suppressed CD4+ T and B lymphocyte activation, reduced …

The Role Of The Developing Microbiome In Mucosal Defense Of The Neonatal Gut, Emily G. Blosser

All ETDs from UAB

Neonatal late-onset sepsis is invasive infection occurring after the first 48 hours of life, and one of the leading causes of death among preterm infants in the United States and abroad. Infections with Gram-negative bacteria, such as Klebsiella pneumonia, occurring when bacteria translocate across premature gut epithelium into the bloodstream, can be particularly severe. Preterm infants in the neonatal intensive care unit undergo intense antibiotic regimens due to high risk of infection. Paradoxically, prolonged exposure of preterm infants to empiric antibiotic therapy early in the hospital stay is associated with increased risk of intestinal infection and death after adjustment for …

Development Of A Patient-Derived Xenograft Model Of Ovarian Cancer To Characterize The Chemotherapy Resistant Population, Zachary Christopher Dobbin

All ETDs from UAB

Ovarian cancer while the second most common gynecologic malignancy is the most commons cause of death due to a gynecologic malignancy and the fifth most common cause of death to cancer in women. In 2014, there will be an expected 21,980 cases and 14,270 deaths. Unfortunately, the five-year survival for ovarian cancer is only 40% and this has barely increased over the past 30 years. New approaches need to be developed in order to study ovarian cancer and identify methods of overcoming chemotherapy resistance. This dissertation presents the work conducted in the development of a patient-derived xenograft model of ovarian …

The Role Of The Planar Cell Polarity Pathway In The Second Heart Field During Outflow Tract Morphogenesis, Tanvi Sinha

All ETDs from UAB

Outflow Tract (OFT) malformations underlie a majority of congenital heart defects (CHD) in humans and are a leading cause of childhood mortality. The OFT, which gives rise to the aorta and pulmonary artery of the heart, relies on the contribution of the Second Heart Field (SHF) progenitors in the pharyngeal and the splanchnic mesoderm, outside of the initial heart. OFT morphogenesis requires highly regulated SHF development involving the proliferation, differentiation and deployment of the SHF progenitors to the heart. Extensive studies elegantly demonstrate how transcriptional networks integrating signaling input from multiple pathways finely balance the proliferation and differentiation of SHF …

Modulation Of The Immune Response To Aspergillus Fumigatus By Antibodies To Conserved Bacterial Polysaccharides, Emily Stefanov

All ETDs from UAB

The incidence of asthma, allergies and autoimmune diseases has increased dramatically in developed countries. The hygiene hypothesis postulates that excessively sanitary conditions lead to a lack of critical immune stimulation during early life, leading to inappropriate responses to self or harmless antigens later in life. Many bacteria and potential allergens share common polysaccharide epitopes. We investigated the ability of antibodies against these shared polysaccharides to dampen the immune response to the ubiquitous fungus and potent allergen, Aspergillus fumigatus. We found that antibodies against these polysaccharides, specifically of the IgM isotype, induced by neonatal bacterial immunization or passive antibody transfer, dampened …

Characterization Of Phosphatidylinositol 4,5-Bisphosphate Regulation Of The Electrogenic Na/Bicarbonate Cotransporter Nbce1, Ian Michael Thornell

All ETDs from UAB

The electrogenic Na/bicarbonate cotransporter (NBCe1) is an acid/base regulator that is also involved in coordinating epithelial ion transport. Splice variants of NBCe1 differ at their cytosolic amino- (N-) and/or carboxy- (C-) termini. These different cytosolic termini impart differential regulation for each variant. For example, the N-terminus of NBCe1-A is autostimulatory, whereas the N-terminus of NBCe1-B and -C is autoinhibitory. We examine the regulatory role of PIP2 for NBCe1 splice variants. In the first study of this dissertation, we characterize the effect of increasing PIP2 on the activity of NBCe1-A, -B, and -C expressed in Xenopus laevis oocytes. Injecting PIP2 stimulated …

Peripheral Neuropathy In The Teetering Mice Results From Mutation Of The Escrt Component Hrs, Jennifer Ashley Watson

All ETDs from UAB

The sorting and degradation of endocytosed cargo by the endosome regulates many cellular functions common to all cells. Neural cells appear to be particularly vulnerable to perturbation in endo-lysosomal transport, and several neurological disorders are caused by a primary deficit in this pathway. In this dissertation, I show that the spontaneously occurring neurological mutation teetering (tn) is a single nucleotide substitution in the endosomal cargo-sorting component hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs) that reduces the abundance of HRS. By 3 weeks of age, the tn mice exhibit heightened pain sensitivity, muscle weakness and reduced muscle size. The loss of …

Using Neuroimaging To Predict Treatment Response In Patients With Schizophrenia, Nathan Lyle Hutcheson

All ETDs from UAB

Schizophrenia is a severe debilitating mental illness that affects approximately 1% of people worldwide. Compared to healthy controls (HC), patients with schizophrenia (SZ) have memory deficits, specifically prominent disruptions in their episodic memory. These memory disruptions are thought to be caused by altered structure and function of areas within the memory network, specifically the prefrontal and temporal lobe including the hippocampus. Recently, identifying biomarkers of treatment response by using neuroimaging has become a prominent area of interest in schizophrenia. Biomarkers in schizophrenia could help by allowing for more efficient treatment using current method and also the development of novel treatments. …

Mechanisms Of At101 [(-)-Gossypol] Induced Cytotoxicity In Malignant Peripheral Nerve Sheath Tumors, Niroop Kaza

All ETDs from UAB

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive Schwann cell-derived sarcomas and are the leading cause of mortality in patients with neurofibromatosis type 1 (NF1). Current treatment modalities have been largely ineffective resulting in a high rate of MPNST recurrence and poor five year patient survival. This necessitates the exploration of alternative chemotherapeutic options for MPNST patients. By evading apoptosis and utilizing protective mechanisms such as autophagy, cancer cells develop resistance to chemo- and radio-therapy. The overall goal of my thesis studies is to evaluate chemotherapeutic agents that can modulate both apoptosis and autophagy, thus target both cell death pathways …