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Full-Text Articles in Medical Sciences
Mcmv Induced Cerebellar Maldevelopment, Thadeus B. Koontz
Mcmv Induced Cerebellar Maldevelopment, Thadeus B. Koontz
All ETDs from UAB
Congenital Human Cytomegalovirus (HCMV) infection represents a significant cause of morbidity and mortality in infants and children. While most of the systemic damage incurred by the infant in the course of the infection resolves without permanent consequence, the pathological manifestations of infection in the central nervous system (CNS) are often permanent. Children born with congenital HCMV infection may exhibit hearing loss and cognitive impairment in various degrees. These neurological disabilities are correlated with pathological findings in various permutations including infection of the inner ear, ventricular calcifications, ventriculomegaly, microgyria, lissencephaly, and cerebellar hypoplasia. To develop a therapeutic or preventive strategy, HCMV …
Bacillus Anthracis Spore-Host Interactions, Melissa K. Swiecki
Bacillus Anthracis Spore-Host Interactions, Melissa K. Swiecki
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The use of Bacillus anthracis as a bioweapon depends on the dispersal of its spores into the environment, entrance into the body, spore uptake by human host cells, germination of the spores in the host and the pathological consequences of the virulence factors produced by the vegetative cells. Prior to 2001, very little was known about the mechanisms of spore entry into the host, including targeting cell types at airway, digestive and skin surfaces, potential spore receptors on these cells and spore encounters with cellular and humoral elements of the innate and adaptive immune systems. To this end, we have …
Cd8+ T-Lymphocytes And The Control Of Cytomegalovirus Infection Of The Newborn Central Nervous System, Glenn Robert Burgner Bantug
Cd8+ T-Lymphocytes And The Control Of Cytomegalovirus Infection Of The Newborn Central Nervous System, Glenn Robert Burgner Bantug
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Congenital HCMV infection of the developing brain is the leading viral cause of mental retardation and sensorineural hearing loss. To elucidate the pathogenesis of congenital HCMV CNS infections, we developed a small animal model of CMV infection where newborn Balb/c mice are peripherally inoculated with murine cytomegalovirus. In this model we observed transient deficits in cerebellar/hindbrain development as well as the recruitment of peripheral immune effector cells to the CNS parenchyma. CD8+ T-lymphocytes were the predominant mononuclear cellular infiltrates in the brain and immune-depletion of CD8+ cells resulted in increased viral genome copy numbers in the CNS. CD8+ T-lymphocytes exhibited …
Localization And Function Of G2e3, William Samuel Brooks
Localization And Function Of G2e3, William Samuel Brooks
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A microarray study was performed which identified G2E3 as a novel, putative ubiquitin ligase that was both G2/M-specific in expression and down regulated at the transcriptional level following DNA damage by γ-irradiation. The initial characterization of this protein is described herein. G2E3 is composed of three PHD/RING (plant homoedomain/really interesting new gene) domains within its amino-terminal half and a carboxy-terminal HECT (homologous to E6AP carboxy-terminus) domain. G2E3 is regulated in part by its subcellular localization. The protein normally resides within the nucleoplasm of cultured cells and distinctly within the nucleolus of HeLa cells. G2E3 is a nucleo-cytoplasmic shuttling protein with …
Loss Of Pias3 Expression In Glioblastoma Multiforme Tumors:Implications For Stat-3 Activation And Gene Expression, Emily Claire Brantley
Loss Of Pias3 Expression In Glioblastoma Multiforme Tumors:Implications For Stat-3 Activation And Gene Expression, Emily Claire Brantley
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Glioblastoma multiforme (GBM) is the most common form of cancer in the central nervous system in adults. Because of the infiltrative and aggressive nature of GBM, current treatments including surgical resection, radiation and chemotherapy provide little benefit to patients diagnosed with this tumor. Median survival, after treatment, is less than one year. Despite advances in the basic understanding of cancer biology, this poor prognosis has remained virtually unchanged for several decades. Given the continuing difficulty of clinical treatment of GBMs, a molecular appreciation of relevant signaling pathways has grown. Signal Transducers and Activators of Transcription (STATs) function to activate gene …
Characterization And Functional Analysis Of Usp14, Stephen Lewis Crimmins
Characterization And Functional Analysis Of Usp14, Stephen Lewis Crimmins
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The ubiquitin proteasome system (UPS) is essential for regulated protein degrada-tion, a requirement for numerous neuronal process, including vesicle cycling, neuro-transmitter release, spine morphology, and synaptic plasticity. Better understanding of UPS function in neurons will increase our knowledge of neurological diseases caused by alterations in ubiquitin signaling. I utilized the ataxia (axJ) mice as a tool to study the UPS in the nervous system. The axJ mice have lowered expression of ubiquitin-specific protease 14 (Usp14) in all tissues; this decreased expression results from an intracisternal-A particle insertion into Usp14. The axJ mice are phenotypically indistinguishable from wild type littermates at …
The Role Of The Cytoskeleon In Achr Clustering, G Clement Dobbins
The Role Of The Cytoskeleon In Achr Clustering, G Clement Dobbins
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The human brain contains billions of neurons which are designed to receive and integrate a range of electrical and biochemical signals. The ability to convey information between these cells depends on synapses. A precise apposition between the pre and post synapse must exist for efficient transmission to occur. The neuromuscular junction (NMJ) has become a model for studying synaptogenesis. Although much is known about the steps in NMJ formation, only recently have there been insights into the mechanism behind NMJ development. Much of this research has focused on how acetylcholine receptors (AChRs) at the postsynapse form clusters directly apposed to …
Visualizing The Function And Migration Of T Cells, Kari J. Dugger
Visualizing The Function And Migration Of T Cells, Kari J. Dugger
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Lymphocytes are highly mobile cells that can travel throughout the body in response to a multitude of stimuli. Identifying lymphocyte trafficking patterns in vivo is essential for a complete understanding of immune function. Cell-cell and cell-tissue interactions in immune development and in lymphocyte response to stimuli can be comprehended with these investigations. Although the location of cell populations in various tissues at any given point in time may be investigated by techniques such as flow cytometry and immunofluorescence, these methods are not easily used in the assessment of dynamic cell migration patterns in vivo. In the past years, technologies for …
A Study Into The Protein/Protein Interactions Involved In Hiv-1 Capsid Assembly, Chanel Catherine Douglas
A Study Into The Protein/Protein Interactions Involved In Hiv-1 Capsid Assembly, Chanel Catherine Douglas
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The aim of this work was to build an understanding of the protein/protein interactions involved in HIV-1 capsid assembly as it relates to the condensation of capsid within the virion. This was undertaken in an attempt to (i) understand how capsid subunits recognize and interact with each other, (ii) gain insight into the protein-protein interactions involved in the process, and (iii) determine if the protein-protein interactions involved in virus cap-sid assembly can be used as a target for viral inhibition. Within this dissertation you will find two approaches to this investigation. The first examines the role of electrostatics in the …
The Role Of Chloride In The Volume Regulation Of Human Glioma Cells, Nola Jean Ernest
The Role Of Chloride In The Volume Regulation Of Human Glioma Cells, Nola Jean Ernest
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According to the Central Brain Tumor Registry of the United States, the most common primary brain tumors are gliomas, tumors composed of cells of glial origin, most commonly astrocytes and oligodendrocytes. The most aggressive of these tumors are characterized by hyperproliferation, marked cellular and nuclear atypia, extensive infiltration into surrounding normal brain tissue, and large areas of cell and tissue death. Previous data published by our lab and others suggest that these biological processes may involve regulated cell volume changes. Using cell volume regulation in the presence of an anisosmotic challenge as a model for cell swelling and shrinkage, cell …
Protease Dysregulation: Role In Neutrophilic Inflammation In Cystic Fibrosis, Amit Gaggar
Protease Dysregulation: Role In Neutrophilic Inflammation In Cystic Fibrosis, Amit Gaggar
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Cystic fibrosis (CF) is a lethal disorder characterized by abnormal epithelial ion transport; this disorder is characterized by an ongoing airway remodeling and neutrophilic inflammation. Much of the airway remodeling is due to activation of a group of enzymes known as proteases; human neutrophil elastase (HNE) is a prominent protease found in the CF airway. While specific cytokines/chemokines are well-known for their role in the inflammation seen in CF, it is unknown how the protease-rich environment in CF lung disease influences airway inflammation. Recently, our group has characterized a novel collagen-derived fragment, proline-glycine-proline (PGP), which causes neutrophil influx through mechanisms …
Protein Interaction And Cell Surface Trafficking Differences Between Wild-Type And Δf508 Cystic Fibrosis Transmembrane Conductance Regulator, Rebecca F. Goldstein
Protein Interaction And Cell Surface Trafficking Differences Between Wild-Type And Δf508 Cystic Fibrosis Transmembrane Conductance Regulator, Rebecca F. Goldstein
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Cystic fibrosis (CF) is caused by mutation of one protein, the cystic fibrosis transmembrane conductance regulator (CFTR), which normally functions as a chloride channel at the apical surface of epithelial cells. The most common CFTR mutation results in the deletion of a single amino acid (phenylalanine) at position 508, which causes the protein to fold improperly. The ΔF508 CFTR is a temperature-sensitive (TS) processing mutant: At the restrictive temperature, 37°C, ΔF508 CFTR misfolds in the endoplasmic reticulum (ER) and is degraded, but at the permissive temperature, 27°C, it is “rescued” from degradation (rΔF508). In particular, rΔF508 CFTR folds correctly enough …
Molecular Determinants Of Picrotoxin Inhibition, Brian E. Erkkila
Molecular Determinants Of Picrotoxin Inhibition, Brian E. Erkkila
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PTX is a non-competitive antagonist of many LGICs, and its site of action is believed to be within the ion-conducting pore. This study will examine, through the use of mutagenesis, electrophysiology and homology modeling, the binding interaction between the LGIC receptors and the PTX molecule. The data provides evidence that an interaction between the PTX molecule and uncharged polar amino acids at the 6’ level of the M2 transmembrane domain are essential for PTX inhibition. While the work will focus on the γ-aminobutyric type A receptor, the pharmacological and structural relevance is attributable to the LGIC family as a whole.
A Role For P63 In The Regulati On Of Cell Cycle Progression And Cell Death, Eric Scott Helton
A Role For P63 In The Regulati On Of Cell Cycle Progression And Cell Death, Eric Scott Helton
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p63 is a member of the p53 family of transcription factors that is a critical regulator of epithelial development. Studies have shown that p63 does not appear to function as a classical tumor suppressor like p53. Instead, the expression pattern of p63 in cancers suggests that p63 retains the potential to function as either a tumor suppressor or an onco-protein. Here, we provide evidence describing the transcriptional activity of the p63 isoforms and provide mechanisms whereby p63 function is regulated in a context dependent manner. Our data shows that both the ΔNp63 and TAp63 variants retain the potential to regulate …
Regulation Of The Human Heme Oxygenase-1 Gene, Thomas D. Hock
Regulation Of The Human Heme Oxygenase-1 Gene, Thomas D. Hock
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The heme oxygenase-1 (HO-1) gene encodes a microsomal enzyme that catalyzes the conversion of heme to carbon monoxide, Iron, and biliverdin. HO-1 transcription is induced upon a plethora of cellular stresses including heme, heavy metal exposure, hy-poxia, oxidative stress and many others. The goal of this work was to explore the molecu-lar regulation of HO-1 transcription. Four DNase 1 hypersensitive sites are detected within the HO-1 promoter extending from ~-40bp to ~-9.2kb relative to the transcription start site. Dimethylsulfate (DMS) in vivo footprinting is shown for two regulatory re-gions and reveals nine protected guanines in all. Mutational analyses indicates that …
Quantitation Of Antiretrovirals In Alternative Matrices, Chantelle Bennetto Hood
Quantitation Of Antiretrovirals In Alternative Matrices, Chantelle Bennetto Hood
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The human immunodeficiency virus (HIV) pandemic is a growing concern, affecting almost 40 million people worldwide. Treatment for HIV infection consists of highly active antiretroviral therapy (HAART) to block different steps in the viral lifecycle, ultimately reducing HIV RNA to undetectable levels in the plasma. However, HIV RNA can be detected in numerous reservoirs outside of the blood despite the use of HAART. Therefore, measurement of antiretroviral (ARV) drugs in other biological matrices is important to broaden our understanding of HIV transmission, the development of viral resistance with sub-optimal ARV exposure, and fetal and neonatal drug exposure. This work describes …
Prostate Cancer Chemoprevention With Genistein And Resveratrol In Models Of Spontaneously Developing Prostate Cancer, Curt E. Harper
Prostate Cancer Chemoprevention With Genistein And Resveratrol In Models Of Spontaneously Developing Prostate Cancer, Curt E. Harper
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Prostate cancer is the second leading cause of cancer-related death among men in the United States. The goal of this research was to investigate the potential of three nutriceutical polyphenols, genistein, resveratrol, and epigallocatechin-3-gallate (EGCG), to suppress prostate cancer. Cancer chemoprevention and mechanism of action studies were carried out in transgenic models of prostate cancer. In TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, resveratrol suppressed poorly differentiated tumors by 86%, whereas EGCG suppressed precancerous lesions, but failed to prevent late-stage prostate cancer. Agents that were chemopreventive in the TRAMP model were subsequently evaluated alone, and in combination, in the …
Characterization Of A Global Regulatory Pathway In Streptococcus Pneumoniae, Greer E. Kaufman
Characterization Of A Global Regulatory Pathway In Streptococcus Pneumoniae, Greer E. Kaufman
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Streptococcus pneumoniae is a versatile organism that adapts to many different environments in the host. S. pneumoniae can asymptomatically colonize the nasopharynx of humans. However, dissemination of the bacterium from the nasopharynx to different locations in the body can lead to invasive diseases such as pneumonia, bacteremia, and meningitis. How S. pneumoniae modulates factors that are important for survival in these niches has not been well characterized. In the studies described here, we propose that S. pneumoniae may modulate gene expression in these niches by sensing the different glu-cose concentrations via carbon catabolite control protein A (CcpA). Initially we characterized …
On The Immunological Roles Of Tlt2 And Hsh2, R Glenn King
On The Immunological Roles Of Tlt2 And Hsh2, R Glenn King
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The evolution of multicellular organisms necessitated the ability to detect and remove harmful parasitic microorganisms from the host. This simple requirement for self non-self discrimination has evolved in vertebrates into an elaborate system consisting of a variety of effector mechanisms to perform this process. The immune system is often described as consisting of two distinct yet complimentary components, the innate and adaptive immune systems. It is now recognized that the immune system relies on the highly coordinated interplay between a variety of cell types which cooperate to maintain the health of the organism. The work outlined in this dissertation addresses …
The Effect Of The Aml1-Eto Translocation On Cell Cycle Tumor Suppressor Gene Function, Rose Marie Ko
The Effect Of The Aml1-Eto Translocation On Cell Cycle Tumor Suppressor Gene Function, Rose Marie Ko
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The t(8;21)(q22;q22) AML1-ETO translocation is one of the most frequent translocations in acute myeloid leukemia (AML), occurring in approximately 12% of cases. Our laboratory has generated a mouse model in which AML1-ETO is expressed in hematopoietic progenitor cells using a retroviral vector and assayed using bone marrow transplantation. Animals transplanted with AML1-ETO-expressing cells failed to develop leukemia. However, AML1-ETO promoted significant expansion of immature myeloid cells suggesting a “pre-leukemic” state that requires secondary mutations for disease progression. In addition, analysis of cell cycle kinetics in AML1-ETOexpressing myeloid progenitor cells showed that AML1- ETO slowed G1 to S phase progression compared …
The Role Of Complement In The Clearance Of Streptococcus Pneumoniae Through Immune Adherence, Jie Li
The Role Of Complement In The Clearance Of Streptococcus Pneumoniae Through Immune Adherence, Jie Li
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Streptococcus pneumoniae is the most frequently isolated pathogen causing bacteremia in young children and elderly adults. Complement-dependent opsonophagocytosis is thought to be essential to eliminate pneumococci from the circulation. Pneumococci are reported to attach to erythrocytes through immune adherence (IA), a complement and antibody- dependent process that facilitates phagocytosis of pneumococci. In these studies we have determined that protein (chapter 1) and polysaccharide (chapter 2) virulence factors of pneumococci can interfere with this process and that antibody to pneumococci can enhance this process. Using PspA and/or PspC negative strains and complement-deficient mouse sera, we demonstrated that PspA inhibits complement C1q …
Directing Akt And Gsk3ss: Molecular Insights Into Cell Signaling And Survival, Gordon P. Meares
Directing Akt And Gsk3ss: Molecular Insights Into Cell Signaling And Survival, Gordon P. Meares
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Proper regulation of survival signaling is critical for all organisms. One important signaling cascade involved in the coordinated effort to control signals influencing cell fate is the phosphatidylinositol 3-kinase (PI3K)-Akt-glycogen synthase kinase 3β (GSK3β) signaling cascade. Following activation by growth factors the PI3K-Akt pathway promotes cell survival and, cell death is facilitated following inhibition of Akt. Many factors influence the function of the Akt-GSK3β signaling dyad, including phosphorylation, protein complex formation and subcellular localization. Previous work had demonstrated that the 90kDa heat shock protein, HSP90, directly binds and stabilizes Akt. Furthermore, several heat shock proteins including HSP90 and HSP105 can …
Primer Selection Of E. Coli Trna Lys,3 By Human Immunodeficiency Virus Type-1, Anna Mcculley
Primer Selection Of E. Coli Trna Lys,3 By Human Immunodeficiency Virus Type-1, Anna Mcculley
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Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). HIV replication includes the notable process of reverse transcription, a conversion of RNA to DNA. Reverse transcription is initiated from a primer by a viral enzyme, reverse transcriptase. The primer, tRNALys,3, is selected from the cytoplasm of an infected cell, annealed via the 3’ terminal 18-nucleotides to the viral primer binding site (PBS), and used in a subsequent infection. The mechanism of primer selection has not been determined although numerous studies have been performed. This has been hampered by the challenge of tRNALys,3 manipulation in the cell and …
The Function Of Hiv-1 A-Loop On Primer Selection, Na Ni
The Function Of Hiv-1 A-Loop On Primer Selection, Na Ni
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Reverse transcription is the hallmark of retroviruses, such as HIV-1. A cellular tRNA bound to the primer binding site region (PBS) is used for initiation of reverse transcription. HIV-1 specially selects tRNALys3 as primer, although changing the PBS can force HIV-1 to use alternative tRNAs as a primer. However, HIV-1 reverts back to use tRNALys3 following in vitro replication. The A-loop, located upstream of PBS, interacts with the anti-codon of primer tRNA. The inclusion of A-loop modification has been shown to stabilize the utilization of some alternative tRNAs. The studies in this dissertation focus on further defining the role of …
Regulation Of Vertebrate Gastrulation By Erbb Signaling, Shuyi Nie
Regulation Of Vertebrate Gastrulation By Erbb Signaling, Shuyi Nie
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ErbB receptor tyrosine kinases have long been implicated in cancer formation and progression by regulating cell division, migration, and survival. ErbBs are also essential in multiple processes during invertebrate development; however, their activities during vertebrate embryogenesis are not well understood. For functional characterization of ErbB signaling during vertebrate development, frog model Xenopus laevis was used in our studies. The expression pattern and the general activities of ErbB receptors during early frog development were first analyzed and results shown that ErbBs regulate gastrulation, somite organization and head patterning. As gastrulation is the first major morphogenetic event in vertebrate development, I focused …
Surveying The Chromosomal Supercoiling Levels In Rapidly Growing Wild Type And Gyrase Mutant Strains Of Salmonella Enterica Serovar Typhimurium With Γδ Resolvase-Mediated Recombination Assay, Zhenhua Pang
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A gyrase mutant strain (gyrB652) has severe growth defect at 42°C. The survival at high temperature is dependent on DNA repair proteins. The purified mutant gyrase was assayed for supercoiling acitivity and quinolone-induced DNA cleavage activity. The results suggested that the mutant enzyme is not temperature-sensitive, but has slower kinetics than the wild type gyrase. The DNA supercoiling levels at multiple chromosomal loci in exponential phase cells were monitored with γδ resolvase-mediated recombination assay. The wild type cells showed homogenous supercoiling levels throughout most of the chromosome. But the superhelicity at dif locus was significantly lower than the other loci. …
The Role Of Complement In Experimental Autoimmune Uveitis, Russell W. Read
The Role Of Complement In Experimental Autoimmune Uveitis, Russell W. Read
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The complement system has been increasingly implicated in the pathophysiology of autoimmune disease. Complement expression in the normal human eye had not been previously completely defined. We performed immunohistochemical studies for membrane complement proteins in normal human retina to provide a baseline for future studies. We found expression of the anaphylatoxin receptors, CD55, and CD59 in the inner retina and CD46 in a polarized fashion on the retinal pigment epithelium. Previous studies in uveitis have shown activated fragments of complement in human eyes with uveitis and animal models have shown an effect on disease by complement depletion with cobra venom …
Pathogenesis And Therapeutic Potential Of Plasmacytoid Dendritic Cells In Siv/Shiv-Infected Macaques, R Keith Reeves Ii
Pathogenesis And Therapeutic Potential Of Plasmacytoid Dendritic Cells In Siv/Shiv-Infected Macaques, R Keith Reeves Ii
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Plasmacytoid dendritic cells (pDCs) are among the first responders during acute viral infections and are the primary producers of IFN-α, a cytokine known to inhibit viral replication and to activate natural killer (NK) cells. In HIV patients pDCs are decreased in number, are dysfunctional, and can harbor HIV-1 proviruses. However, since the time of transmission is usually unknown, pDC-virus interactions immediately after exposure to HIV remain unclear. Using the SIV/SHIV-macaque model, we showed that an acute and sustained loss of blood pDCs occurred during SIVmac239 infections, and when compared to those from naïve controls, pDCs were also significantly reduced in …
The Characterization Of The Subcellular Localization Of Bile Acid Coa: N-Acyltransferase, Nathan Allen Styles
The Characterization Of The Subcellular Localization Of Bile Acid Coa: N-Acyltransferase, Nathan Allen Styles
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The liver plays a central role in metabolism. It controls protein metabolism through deamination and transamination of amino acids, removal of ammonia through urea synthesis, synthesis of non-essential amino acids and synthesis of the majority of plasma proteins such as albumin. The liver regulates blood glucose levels through glyconeogenesis and glyconeolysis of glycogen, as well as gluconeogenesis from amino acids. It regulates fat metabolism through oxidation of triglycerides and fatty acids, as well as synthesis of cholesterol, lipoproteins, and phospholipids. Furthermore, the liver is the only site of formation of bile acids and their conjugates, physiologically important compounds that solubilize …
Genetic And Epigenetic Regulation Of Dihydropyrimidinase And Beta-Ureidopropionase In Individuals With Altered Uracil Catabolism And Normal Dihydro Pyrimidine Dehydrogenase Enzyme Activity, Holly Reed Thomas
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There remain a number of patients presenting with 5-fluorouracil (5-FU) toxicity despite normal dihydropyrimidine dehydrogenase (DPD) enzyme activity, suggesting possible deficiencies in the two enzymes downstream of DPD in the uracil catabolic pathway: dihydropyrimidinase (DHP), encoded by the DPYS gene, or β-ureidopropionase (BUP-1), encoded by the UPB1 gene. Unlike DPD, which is expressed in peripheral blood mononuclear cells (PBMCs), DHP and BUP-1 enzyme activity is detected in only the liver and kidney, thus requiring an invasive biopsy for determination of activity. This dissertation, therefore, focuses on the role of the genetic and epigenetic regulation of DPYS and UPB1. The genetic …