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Full-Text Articles in Medical Sciences
Human Cytomegalovirus Ul97 Kinase Activity Modifies Cell Cycle Checkpoint Regulators, Rachel Brooke Gill
Human Cytomegalovirus Ul97 Kinase Activity Modifies Cell Cycle Checkpoint Regulators, Rachel Brooke Gill
All ETDs from UAB
Human cytomegalovirus (CMV) infection results in destructive infections in neonates and immunocompromised individuals. Being the primary congenital infection in the United States, it can often result in permanent neurological deficits in infants. The current therapies for CMV infections all target the viral DNA polymerase and also have dose-limiting toxicities. Isolates resistant to ganciclovir (GCV), the therapy of choice, can sometimes overwhelm immunocompromised hosts. Better therapies for this infection are required. The CMV UL97 kinase is a key enzyme in the treatment of CMV infection because it phosphorylates GCV. Additionally, maribavir (MBV) specifically inhibits UL97 kinase activity and inhibits viral replication. …
Role Of The Cystine/Glutamate Exchanger In Glioma Cell Biology, Toyin Adeyemi Ogunrinu
Role Of The Cystine/Glutamate Exchanger In Glioma Cell Biology, Toyin Adeyemi Ogunrinu
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Changes in the glioma microenvironment including oxygen (O2) levels, supply of amino acid such as L-glutamate and L-cystine and glutathione (GSH) concentrations play a critical role in glioma biology. Previous data from our laboratory and others have implicated the L-cystine/L-glutamate exchanger, system xc- in the invasion and proliferation of cancers including glioma. The central aim of this dissertation was to characterize the contribution of L-cystine uptake, GSH synthesis and L-glutamate release to migration and proliferation of glioma cells. In my first study, I examined the role of system xc- mediated L-glutamate release on glioma migration. I show that activation of …
Ecology And Transmission Of Eastern Equine Encephalitis Virus In The Southeastern United States, Gregory Scott White
Ecology And Transmission Of Eastern Equine Encephalitis Virus In The Southeastern United States, Gregory Scott White
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The virus Eastern Equine Encephalitis virus (EEEV) is a highly pathogenic arthropod-borne virus (arbovirus) present in the US. The virus is listed as a reportable illness to the Centers of Disease Control and Prevention (CDC) and is also listed as a select agent by Human Health and Services (HHS). Studies on EEEV starting back in the 1930's have determined many important facets of the ecology, transmission and evolution of the virus. It is understood that in many endemic foci, the mosquito Culiseta melanura is the primary enzootic vector of the virus. EEEV is thus maintained in an enzootic cycle between …
Expanding Genetic Analysis Of Patients With A Neurofibromatosis Type 1-Like Phenotype, Emily Spencer
Expanding Genetic Analysis Of Patients With A Neurofibromatosis Type 1-Like Phenotype, Emily Spencer
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Neurofibromatosis Type 1, a common autosomal dominant disorder with neuro-cardio- facio-cutaneous presentation, is caused by mutations in the NF1 gene, a negative regulator of RAS-MAPK signaling. The presentation of NF1 is overlapping, yet clinically distinct from other diseases of RAS-MAPK signaling. An RNA-based comprehensive approach for mutation detection identifies an NF1 alteration in over 95% of non-founder NF1 patients with a classical NF1 presentation. However, no NF1 mutation was identified in 54.2% of the 2432 patients referred for molecular diagnostics due to the presence one or more NF1 related sign between August 2003 and July 2007. In order to clarify …
Molecular Piracy In The Mobilization Of Staphylococcus Aureus Pathogenicity Island 1, Michael Spilman
Molecular Piracy In The Mobilization Of Staphylococcus Aureus Pathogenicity Island 1, Michael Spilman
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Staphylococcus aureus bacteriophage 80α is a temperate, double-stranded DNA phage that serves as a "helper" phage for the mobilization of several S. aureus pathogenicity islands (SaPIs), including SaPI1. When mobilized by 80α, SaPI1 genomes are packaged into smaller phage-like transducing particles composed of 80α capsid (gp47), scaffolding (gp46) and portal (gp42) proteins. In this dissertation, I utilize electron microscopy and biochemistry to tease apart the structural and genetic controls and consequences of SaPI1 as a molecular pirate. More specifically, I show that two SaPI1 proteins shift assembly from 63-nm, T = 7 icosahedral capsids to 47-nm, T = 4 capsids, …
Calcium Dynamics Of Glial Cells And Genetic Influences On Behavior Of The Nematode Caenorhabditis Elegans, Randy Franklin Stout
Calcium Dynamics Of Glial Cells And Genetic Influences On Behavior Of The Nematode Caenorhabditis Elegans, Randy Franklin Stout
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A major challenge in neuroscience is understanding how the different neural cell types work together to process information and produce a behavioral output. Glial cells of the human brain have long been thought to act as support for the fundamental cell to cell communication at the core of cognition: neuronal synaptic communication. Research over the past several decades measuring glial activity and experimentally controlling glial cells in rodent model systems has shown that the two macroglia sub-types of glial cells (astrocytes and oligodendrocytes) have active roles in establishment, maintenance, and modulation of synaptic communication in the mammalian brain. Much of …
The Role Of The Classical Nf-Kb Pathway In Hsc Self-Renewal And Acute Myeloid Leukemia, Robert Jason Flynn
The Role Of The Classical Nf-Kb Pathway In Hsc Self-Renewal And Acute Myeloid Leukemia, Robert Jason Flynn
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Acute myeloid leukemia (AML) comprises approximately 25% of newly diagnosed cases of leukemia each year. The constitutive activation of the classical NF-κB signaling pathway has been observed in up to 70% of AML cases, and could be due to mutations upstream involving the PI3K-Akt cascade, which is also constitutively active in a majority of cases. In mice, constitutive activation of Akt either through deletion of the negative regulator of PI3K-Akt, PTEN, or by expression of Myr-Akt induces rapid stem cell loss along with a lethal, transplantable myeloproliferative disorder and AML. These studies show that constitutive Akt and NF-κB signaling distinguish …
The Study Of Intracellular Signaling Pathways In Schizophrenia, Adam Funk
The Study Of Intracellular Signaling Pathways In Schizophrenia, Adam Funk
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INTRACELLULAR SIGNALING AND INTEGRATION ABNORMALITIES IN SCHIZOPHRENIA Adam J. Funk DEPARTMENT OF NEUROBIOLOGY ABSTRACT The pathophysiology of schizophrenia is complex and diverse, with many classes of receptors, neurotransmitters, and brain regions implicated in this illness. The many hypotheses proposed have yet to fully explain the heterogeneity of the genetic, postmor-tem, and clinical evidence. It is the goal of this dissertation to integrate the current hy-potheses of schizophrenia into a unified hypothesis of abnormal intracellular signaling and signal integration. Inconsistencies in genetic and postmortem findings suggest that the development of schizophrenia is multifaceted, and the heterogeneity of symptoms supports the hypothesis …
Characterization Of Tbx20 Isoforms And Protein Interactions In Heart Development, Paige Debenedittis
Characterization Of Tbx20 Isoforms And Protein Interactions In Heart Development, Paige Debenedittis
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Proper cardiogenesis is critical for the development of vertebrates. Abnormalities in cardiogenesis can lead to congenital heart defects (CHDs), which occur in approximately 1% of live births. The cardiac transcription factor network contains different transcription factor families which direct the expression of critical cardiac genes. Determining how the cardiac transcription factors are regulated will provide insight in the mechanisms of cardiogenesis and CHDs. The T-box (TBX) transcription factor family is an ancient gene family important for development. Several TBX genes are expressed within the developing heart and play critical roles in differentiation, proliferation, and morphogenesis. One important TBX protein is …
Oxidative Stress And Xanthine Oxidase In Acute And Chronic Cardiac Volume Overload In Rats, James Douglas Gladden
Oxidative Stress And Xanthine Oxidase In Acute And Chronic Cardiac Volume Overload In Rats, James Douglas Gladden
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Mechanisms of left ventricular dysfunction in cardiac volume overload (VO) are not well understood and there is no medical therapy. Cardiac VO is marked by eccentric remodeling and contractile dysfunction ultimately resulting in cardiac failure. Oxidative stress is implicated in the pathophysiology of heart failure and recent evidence suggests xanthine oxidase (XO) plays a role in VO. To study VO, we used a rat model of aortocaval fistula (ACF). ACF results in early diastolic stress on the left ventricle (LV) and recapitulates the progressive nature of heart failure with contractile function being initially maintained and then depressed by 6 weeks. …
Post-Transcriptional Control Of Type I Interferon Genes By Ksrp In The Innate Immune Response Against Viral Infection, Wei-Jye Lin
Post-Transcriptional Control Of Type I Interferon Genes By Ksrp In The Innate Immune Response Against Viral Infection, Wei-Jye Lin
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Several strategies are used in eukaryotic cells in order to determine the gene expression level, including the transcriptional and post-transcriptional mechanisms. One of the post-transcriptional mechanisms is the regulation of mRNA stability, which varies considerably from one mRNA species to another. Previous studies have shown that inherently unstable mRNAs encoding cytokines and proto-oncogenes contain the AU-rich elements (AREs) in the 3' untranslated regions (UTRs). Their decay requires decay-promoting RNA-binding proteins that recognize the AREs and recruit mRNA decay machineries to facilitate the rapid decay of targeting mRNA. KH-type splicing regulatory protein (KSRP) was previously identified as an ARE decay promoting …
Erythropoiesis In The Absence Of Adult Hemoglobin, Shanrun Liu
Erythropoiesis In The Absence Of Adult Hemoglobin, Shanrun Liu
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The mammalian erythrocyte is a highly specialized blood cell that differentiates via an orderly series of committed progenitors in the bone marrow in a process termed erythropoiesis. During erythroid development, hemoglobin synthesis increases from early erythroid progenitors to mature enucleated red blood cells (RBCs). Although hemoglobin is the most extensively studied protein in history, the role, if any, that hemoglobin plays in erythroid development remains obscure. In this study, I ask the question what happens during erythropoiesis in the absence of hemoglobin. I demonstrate that my original hypothesis that excess free heme would accumulate in the absence of globin chain …
The Effects Of Simvastatin On Learning And Memory Mechanisms In Mice, Robert Mans
The Effects Of Simvastatin On Learning And Memory Mechanisms In Mice, Robert Mans
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Statins, a widely prescribed class of cholesterol-lowering drug, inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. Due to the identification of cholesterol as a risk factor for developing Alzheimer's disease (AD), a number of studies have examined whether statins are neuroprotective against developing AD or dementia. While some epidemiological studies do indicate a lower prevalence of AD in people taking statins, other reports are contradictory. A consensus has therefore not been reached regarding the neuroprotective effects of statin treatment. Aside from the well-characterized reduction in circulating cholesterol resulting from statin therapy, numerous cholesterol-independent, pleiotropic effects have been …
Gabaergic Signaling To Adult-Generated Neurons In Hippocampus, Sean Markwardt
Gabaergic Signaling To Adult-Generated Neurons In Hippocampus, Sean Markwardt
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In the central nervous system of adult mammals, new neurons are produced throughout life in at least two regions, the subventricular zone and dentate gyrus of the hippocampus. New neurons in the SVZ migrate via the rostral migratory stream and eventually participate in adaptive olfactory processes. In the dentate gyrus, a variety of physiological functions for continued addition of neurons have been proposed, but its role in normal or pathological conditions remains largely unclear. Neurogenesis in the dentate gyrus consists of the stepwise process of generating fully functional granule cells (GCs) from adult neural stem cells. Regulation of neurogenesis can …
Analysis Of Nphp Complex Genetic Interactions Associated With Human Cilia Disorders, Svetlana Viktorovna Masyukova
Analysis Of Nphp Complex Genetic Interactions Associated With Human Cilia Disorders, Svetlana Viktorovna Masyukova
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Primary cilia are antenna-like organelles that extend from the surface of almost all mammalian cell types. They regulate many signaling pathways and sense physical and chemical changes in the extracellular environment. Defects in primary cilia cause several human disorders of different severity collectively called ciliopathies, including nephronophthisis (NPHP), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). Numerous MKS, JBTS and NPHP genes have been identified but in most cases of these ciliopathies the genetic defect is unknown. Despite the fact that NPHP, JBTS and MKS patients present with distinct clinical features, they have mutations in identical genes. This can be explained …
Role Of Calcium-Activated Potassium Channels In Glioblastoma Volume Regulation, Michael Bryan Mcferrin
Role Of Calcium-Activated Potassium Channels In Glioblastoma Volume Regulation, Michael Bryan Mcferrin
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The most common and most malignant gliomas are the Grade IV Glioblastoma Multiforme (GBM), characterized by a highly proliferative tumor mass and extremely invasive phenotype that allows for profuse dispersal of tumor cells throughout the brain. GBM cells must specifically regulate their cell volume to thrive within the edematous tumor mass and infiltrate throughout the tortuous extracellular spaces of the brain. These rapid and directed volume changes are governed by the controlled flux of potassium and chloride ions across the cell membrane, which move osmotically obliged water. The goal of this dissertation was to investigate the role of calcium-activated potassium …
Killer Immunoglobulin-Like Receptors And Human Leukocyte Polymorphisms In Hiv-1 Pathogenesis, Aimee Marie Merino
Killer Immunoglobulin-Like Receptors And Human Leukocyte Polymorphisms In Hiv-1 Pathogenesis, Aimee Marie Merino
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Human leukocyte antigen (HLA) molecules influence the adaptive and innate immune responses through interactions with cytotoxic T lymphocytes and natural killer cells (NK). HLA influence the activation state of NK through direct binding to killer immunoglobulin-like receptors (KIR) and presentation of HLA-derived peptides to NKG2 receptors. Activated NK can kill HIV-infected cells through direct cytolysis and release cytokines that influence other aspects of the immune system. Variations in KIR gene content and allelic variants have been associated with autoimmunity, transplantation success, and infectious diseases such as hepatitis C and HIV/AIDS. We investigated the impact of KIR genes and potential KIR-HLA …
The Role Of Cd19 In Follicular Dendritic Cell Activation, Riley Croom Myers
The Role Of Cd19 In Follicular Dendritic Cell Activation, Riley Croom Myers
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Germinal Centers (GC) are organized foci in secondary lymphoid organs of birds and mammals and are the principle sites of memory B cell generation and plasma cell formation. GC concentrate antigen within follicles to facilitate recognition by responding B cells to promote somatic hypermutation and affinity maturation. Follicular dendritic cells (FDC) reside within the light zones of GC and serve to facilitate B cell interactions with antigen, as well as B cell selection, proliferation, and survival. The work contained within this dissertation addresses the collaborative interactions between B cells and FDC. FDC within an active, GC-containing follicle express an array …
Exopolysaccharide: A Multi-Faceted Role In Mycoplasma Pulmonis, Jeffrey R. Bolland
Exopolysaccharide: A Multi-Faceted Role In Mycoplasma Pulmonis, Jeffrey R. Bolland
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The recently characterized exopolysaccharide of Mycoplasma pulmonis, EPS-I, has been identified as modulating the susceptibility to complement-mediated lysis and binding to host mucosal epithelium. M. pulmonis produces family of size- and phase-variable lipoproteins called Vsa. Previous evidence has strongly demonstrated that the length of the tandem repeat region of the M. pulmonis Vsa protein is associated with the susceptibility to the host innate immune system through complement-mediated lysis. Mycoplasmas producing a long form of Vsa, containing about 40 repeats, are resistant complement whereas strains that produce the short form of Vsa, 5 repeats or fewer, are susceptible. Furthermore, the size …
Mitochondrial Genetics And Function In Cardiovascular Disease Susceptibility, Jessica L. Brenneman
Mitochondrial Genetics And Function In Cardiovascular Disease Susceptibility, Jessica L. Brenneman
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While progress has been made in understanding the development and progression of cardiovascular disease (CVD), the mechanisms of CVD risk and initiation are not completely understood. It is widely accepted that CVD is the result of a combination of genetic and environmental factors but it is not known why some populations with otherwise similar risk factors appear more susceptible to CVD than others. It is also known that different strains of laboratory mice have distinct susceptibilities to CVD development. For example, C3H mice are resistant to diet induced atherogenesis whereas C57 animals are susceptible. We have also found that the …
Role Of Ras Proteins In Malignant Peripheral Nerve Sheath Tumors, Nicole Marie Brossier
Role Of Ras Proteins In Malignant Peripheral Nerve Sheath Tumors, Nicole Marie Brossier
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Malignant peripheral nerve sheath tumors (MPNSTs) arising in patients with neurofibromatosis type I (NF1) are null for the tumor suppressor neurofibromin, a negative regulator of signaling from both classic Ras (H-Ras, N-Ras and K-Ras) and R-Ras (R-Ras, R-Ras2/TC21, M-Ras/R-Ras3) subfamily members. Treatment of these tumors with Ras-targeted agents such as farnesyltransferase inhibitors has proven unsuccessful, likely due to the inability of these agents to successfully target all of the Ras isoforms regulated by neurofibromin. Thus, determining which Ras isoforms are critical for MPNST pathogenesis would be of therapeutic value. In this dissertation, we first review the clinical manifestations of NF1 …
Identification And Characterization Of Novel Adenosine Cleavage Enzymes In Mycobacteria, Kajal Buckoreelall
Identification And Characterization Of Novel Adenosine Cleavage Enzymes In Mycobacteria, Kajal Buckoreelall
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Tuberculosis (TB) is one of the leading infectious diseases in the world. An estimated one third of the world's population is infected with Mycobacterium tuberculosis, the causative pathogen of TB. With the emergence of drug resistant strains of the mycobacterium, and the HIV-TB coinfection epidemic, TB remains a global health emergency. Purine metabolism is an essential cellular component to all living cells. Previous studies have shown that differences exist between mycobacterial and human purine metabolism. One of the differences was in the metabolism of adenosine (Ado), whose cleavage was observed in mycobacterial cells whereas Ado cleavage is inefficient in human …
The Sodium-Potassium-Chloride Cotransporter In Glioma Biology, Brian R. Haas
The Sodium-Potassium-Chloride Cotransporter In Glioma Biology, Brian R. Haas
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The most common malignant primary brain tumor, gliomas usually derive from glial cells including oligodendrocytes and astrocytes. These tumors are characterized by high rates of proliferation and aberrant migration which make them notoriously difficult to treat using standard treatment paradigms such as chemotherapy and radiation. In order for glioma cells to migrate into the surrounding brain tissue, they must undergo rapid and dynamic volume changes. Previous work published by the Sontheimer laboratory and others indicates glioma utilize the flux of ions across the cell membrane to aid in volume changes associate with cell migration. In this dissertation, I show the …
Determining The Functional Role Of Trem-Like Transcript 2 In The Innate Immune Response, Matthew Martin Halpert
Determining The Functional Role Of Trem-Like Transcript 2 In The Innate Immune Response, Matthew Martin Halpert
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TLT2 is one of four receptors conserved between mouse and human within the TREM locus, and is expressed on B cells, macrophages, and neutrophils. TLT2 ligation on murine macrophages induces the production of chemokines and growth factors, as evidenced by ex vivo treatment with anti-TLT2 mAbs. This treatment did not lead to the upregulation of activation markers such as CD69 or costimulatory molecules such as CD80 and CD86, indicating a specific response following TLT2 ligation. This is recapitulated in vivo following injection of anti-TLT2 mAbs resulting in the production of chemokines and growth factors, which ultimately lead to enhanced neutrophil …
Ampa Receptor Trafficking In Schizophrenia, John Hammond
Ampa Receptor Trafficking In Schizophrenia, John Hammond
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The glutamate hypothesis of schizophrenia is based primarily on NMDA receptor dysfunction. Recent studies have led to an expansion of this hypothesis to include AMPA receptors which are essential for neurotransmission through NMDA receptors. Examination of total AMPA receptor protein expression in schizophrenia has been inconsistent and led to examination of AMPA receptor interacting proteins and trafficking and subcellular localization of the receptors. AMPA receptors are highly trafficked from the endoplasmic reticulum to the synapse and in a complex system of endosomes. Alterations in the subcellular localization of these receptors may be a part of the underlying pathophysiology of schizophrenia. …
Bone Morphogenetic Protein Signaling Pathways During Mouse Heart Development: Roles For Chd7 And Mycn, Cristina Harmelink
Bone Morphogenetic Protein Signaling Pathways During Mouse Heart Development: Roles For Chd7 And Mycn, Cristina Harmelink
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Bone Morphogenetic Protein (BMP) signaling pathways are imperative for proper heart development. BMP ligands bind serine threonine kinase receptors, which activate intracellular receptor-regulated SMAD proteins. SMAD1, SMAD5, and SMAD8 transduce BMP signals from the cytoplasm to the nucleus, where they regulate transcription. We have investigated two aspects of BMP signaling during mouse cardiogenesis: identifying SMAD1-interacting proteins and exploring the roles of a known BMP target, Mycn, in the developing myocardium. Chromodomain helicase DNA binding protein 7 (CHD7) is a highly conserved transcription factor that promotes protein synthesis, proliferation, and differentiation. Haploinsufficiency for CHD7 causes CHARGE syndrome, a developmental disorder characterized …
The Role Of Mitochondrial Oxidative Stress In Cardiovascular Disease Development, Corey Michael Harrison
The Role Of Mitochondrial Oxidative Stress In Cardiovascular Disease Development, Corey Michael Harrison
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An estimated 70 million Americans have one or more types of cardiovascular disease (CVD). Although the sequence of events leading to CVD are still controversial, there is a general consensus that atherosclerotic lesions result from oxidative stress associated with risk factor. For this study, it was hypothesized that endogenous mitochondrial oxidative stress would influence susceptibility to atherogenesis and mitochondrial damage mediated by CVD risk factor exposure. To test this hypothesis, atherosclerotic lesion formation, oxidant stress, and mitochondrial DNA damage were assessed in hypercholestoremic mice (apolipoprotein E null - apoE -/- SOD2 +/+) and mice with significantly decreased levels of the …
In Vivo Analysis Of The Natural Diversity Of The Igr Ires Family And Characterization Of The Role Of Ribosomal Protein S25 In Ires-Mediated Translation, Marla Ilene Hertz
In Vivo Analysis Of The Natural Diversity Of The Igr Ires Family And Characterization Of The Role Of Ribosomal Protein S25 In Ires-Mediated Translation, Marla Ilene Hertz
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Translation of the majority of eukaryotic mRNAs is initiated upon recognition of its 5' cap structure by translation initiation factors in so-called cap-dependent translation. Cap-dependent translation is repressed during cell stress and translation initiation by internal ribosome entry sites (IRESs) predominates. IRESs, located in the 5' untranslated region of specific mRNAs, recruit the ribosome independent of the 5' cap and are essential regulatory elements in many RNA viruses and cellular messages. The dysregulation of cellular IRESs has been linked to cancer because they regulate the expression of genes involved in growth, development and stress response. In comparison to cap-dependent translation, …
The Role Of Ll-37 In Prostate Cancer And Its Potential As A Therapeutic Target, Jonathan Adam Hensel
The Role Of Ll-37 In Prostate Cancer And Its Potential As A Therapeutic Target, Jonathan Adam Hensel
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LL-37 is the only cathelicidin-derived anti-microbial peptide in humans and has been shown to stimulate proliferation, angiogenesis, cellular migration and inhibit apoptosis, in addition to serving as a chemoattractant for leukocytes. It is produced primarily by epithelial cells and leukocytes, and has recently been discovered to be over-expressed in breast, ovarian and lung cancers. Based on these findings, we compared levels of LL-37 expression in benign and cancerous human prostate tissues. Results of this investigation demonstrated that LL-37 is increasingly over-expressed in primary prostate tumors in a grade dependent manner and in metastatic lesions. Since the physiological mechanisms of LL-37 …
Protein Modifications And The Response To Oxidized Lipids In Cardiovascular Cells, Ashlee Higdon
Protein Modifications And The Response To Oxidized Lipids In Cardiovascular Cells, Ashlee Higdon
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Free radical catalyzed oxidation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid is increased in cardiovascular disease states, including atherosclerosis and heart failure. Oxidized lipids have been extensively studied and found to recapitulate several key steps in atherogenesis. However, clinical trials with antioxidants such as alpha-tocopherol have been less promising than originally predicted. Now appreciated as more than just biomarkers of disease, lipid peroxidation products have been shown to have roles in pathogenesis as well as physiology. Of particular interest are reactive lipid species that possess electrophilic carbonyls enabling them to act in a receptor-independent manner. To date, the …