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Full-Text Articles in Life Sciences

A Forward Genetics Approach To Identify Molecular Drivers Of Liver Cancer Using Sleeping Beauty Mouse Models, Jesse Daniel Riordan Dec 2013

A Forward Genetics Approach To Identify Molecular Drivers Of Liver Cancer Using Sleeping Beauty Mouse Models, Jesse Daniel Riordan

Theses and Dissertations

Each year liver cancer kills more than half a million people, making it the third

leading cause of cancer-related death worldwide. Annual incidence continues to rise steadily, both domestically and globally, increasing the burden of this disease. Advancements in the ability to obtain detailed molecular profiles of tumors have led to the successful development of targeted therapies for a number of different cancers. Unfortunately, however, the molecular pathogenesis of liver cancer is poorly understood relative to many other types of malignancies. Thus, the identification of factors contributing to the development and progression of liver tumors is a major goal of ...


Characterization Of Cis-Acting Partners Within The Cytomegalovirus Major Immediate-Early Enhancer That Strengthen Mie Gene Expression And Viral Fitness, Courtney Searcey Galle Dec 2013

Characterization Of Cis-Acting Partners Within The Cytomegalovirus Major Immediate-Early Enhancer That Strengthen Mie Gene Expression And Viral Fitness, Courtney Searcey Galle

Theses and Dissertations

Human cytomegalovirus infects approximately 50% of adults in the United States and in most cases is asymptomatic. However, in the case of immune compromised persons such as AIDS patients, transplant patients, and newborn babies, life threatening CMV disease can occur. The HCMV major immediate-early enhancer functions as a master regulatory switch, whose activation is essential for the expression of the major IE transactivating proteins, IE1 p72 and IE2 p86. While critical to the viral lifecycle, regulation of MIE enhancer activation is very complex and not yet fully understood. I characterized the role of cis-acting partners within the MIE enhancer that ...


Cell Biological Defects In Juvenile Neuronal Ceroid Lipofuscinosis, Mark Schultz Dec 2013

Cell Biological Defects In Juvenile Neuronal Ceroid Lipofuscinosis, Mark Schultz

Theses and Dissertations

Mutations in the CLN3 gene cause Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), a form of Batten disease that is grouped within the broad class of lysosomal storage diseases. JNCL displays a primary central nervous system phenotype characterized by rapid onset blindness, wide spread brain atrophy and reversal of learned abilities with death occurring 10-20 years after symptom onset. The mechanisms underlying these phenotypes are not known. CLN3 encodes CLN3, a protein with no known molecular function. CLN3 is expressed at very low levels natively in most cells, and is highly hydrophobic.

Similar to other lysosomal storage diseases, it is difficult to ...


The Molecular Mechanisms Of Pitx2 In Tooth Development And Enamel Defects In Axenfeld-Rieger Syndrome, Xiao Li Dec 2013

The Molecular Mechanisms Of Pitx2 In Tooth Development And Enamel Defects In Axenfeld-Rieger Syndrome, Xiao Li

Theses and Dissertations

Patients with Axenfeld-Rieger Syndrome (ARS) present various dental abnormalities. ARS is genetically associated with mutations in the PITX2 gene, which encodes one of the earliest transcription factors to initiate tooth development. Thus, Pitx2 has long been considered as an upstream regulator of the transcriptional hierarchy in tooth development. However, it is unclear how its mutant forms cause ARS dental anomalies. In this report, we outline the transcriptional mechanism that is defective in ARS. We demonstrate that during normal tooth development Pitx2 activates Amelogenin (Amel) expression, whose product is required for enamel formation, and that this regulation is perturbed by missense ...


Endothelial Agonists Stimulate Vwf Release In Vitro And Trigger Ttp In Vivo, Gilbert Van Schaeffer Dec 2013

Endothelial Agonists Stimulate Vwf Release In Vitro And Trigger Ttp In Vivo, Gilbert Van Schaeffer

Theses and Dissertations

Von Willebrand factor (VWF) is a plasma glycoprotein that can bind collagen at a wound site as well as circulating platelets. VWF forms high molecular weight multimers (>20,000 kDa). VWF can also form VWF strings that appear to be attached to the endothelial surface and are capable of binding platelets. These strings are only observed in vitro and in vivo in the absence of the VWF-cleaving protease ADAMTS13. Deficiency in ADAMTS13 results in thrombotic thrombocytopenic purpura (TTP), a clotting disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, renal dysfunction, neurological dysfunction and fever. Patients suffering from TTP demonstrate VWF-and platelet-rich ...


A Novel Role For Prolyl-Hydroxylase 3 Gene Silencing In Epithelial-To-Mesenchymal-Like Transition, Trenton Lane Place Dec 2013

A Novel Role For Prolyl-Hydroxylase 3 Gene Silencing In Epithelial-To-Mesenchymal-Like Transition, Trenton Lane Place

Theses and Dissertations

The ability of cells to sense oxygen is a highly evolved process that facilitates adaptations to the local oxygen environment and is critical to energy homeostasis. In vertebrates, this process is largely controlled by three intracellular prolyl-4-hydroxylases (PHD 1-3). These related enzymes share the ability to hydroxylate the hypoxia-inducible transcription factor (HIF), and therefore control the transcription of genes involved in metabolism and vascular recruitment. However, it is becoming increasingly apparent that proline-4-hydroxylation controls much more than HIF signaling, with PHD3 emerging as the most unique and functionally diverse of the PHD isoforms. In fact, PHD3-mediated hydroxylation has recently been ...


Studies Of Proliferating Cell Nuclear Antigen Mutant Proteins Defective In Translesion Synthesis And Mismatch Repair, Lynne Margaret Dieckman Jul 2013

Studies Of Proliferating Cell Nuclear Antigen Mutant Proteins Defective In Translesion Synthesis And Mismatch Repair, Lynne Margaret Dieckman

Theses and Dissertations

Proliferating cell nuclear antigen (PCNA) is a versatile protein involved in all pathways of DNA metabolism. It is best known as a processivity factor for classical polymerases, which synthesize DNA on non-damaged templates during DNA replication (ex: pol δ). Non-classical polymerases, on the other hand, are those that synthesize DNA on damaged templates (ex: pol η). PCNA also functions in repair, recombination, and most other DNA-dependent cellular processes. A number of separation of function mutant PCNA proteins have been identified, suggesting that PCNA could be a valuable target to manipulate DNA metabolism. This thesis focuses on the study of PCNA ...


Understanding The Contribution Of Individual Zinc Fingers To A Multi-Functional, Polydactyl Transcription Factor, Ryan M. Baxley Jul 2013

Understanding The Contribution Of Individual Zinc Fingers To A Multi-Functional, Polydactyl Transcription Factor, Ryan M. Baxley

Theses and Dissertations

Suppressor of Hairy-wing [Su(Hw)] is a twelve zinc-finger (ZF), DNA binding transcription factor. Su(Hw) has been well characterized as critical component of the gypsy insulator complex, required for the enhancer blocking and the barrier activity of the insulator. In addition to gypsy, Su(Hw) localizes to ~3,000 binding sites in the Drosophila genome, with association to a subset of sites required for female germline development. Loss of Su(Hw) results in activation of a developmental checkpoint and apoptosis at mid- oogenesis, with a critical role during oogenesis in down-regulation of neural genes. Studies of Su(Hw) function ...


Fhit Inactivation Combined With Cigarette Smoke Enhances The Oxidative Stress Response, Jennifer A. Boylston Jul 2013

Fhit Inactivation Combined With Cigarette Smoke Enhances The Oxidative Stress Response, Jennifer A. Boylston

Theses and Dissertations

The FHIT gene is located on the most fragile site in the human genome. FHIT gene deletions are among the earliest and most frequent events in carcinogenesis, particularly in carcinogen-exposed tissue. Previous work in mouse and cell culture models established FHIT to be an authentic tumor suppressor. Re-expression of FHIT in cell culture causes cell death via initiation of apoptosis, but the precise mechanism underlying this process is unclear. It is well established that cellular transition from normal to transformed occurs in multiple steps and requires the accumulation of several genetic changes. Relying on the compelling phenotype of tumor development ...


Macrophage Microrna And Mrna Responses To Stimulation Of Tlrs Or Upon Infection With Leishmania Infantum Chagasi, Erik Bruce Wendlandt Jul 2013

Macrophage Microrna And Mrna Responses To Stimulation Of Tlrs Or Upon Infection With Leishmania Infantum Chagasi, Erik Bruce Wendlandt

Theses and Dissertations

Leishmania are obligate intracellular protozoan parasites that are inoculated into human skin while a sand fly vector takes a blood meal with the resulting disease coined leishmaniasis. The twenty plus species of Leishmania known to cause human disease are found throughout tropical and subtropical regions of the world. Leishmaniasis affects at least eighty-eight countries with three hundred and fifty million people at risk for infection, resulting in an estimated seventy thousand deaths annually. Different species of Leishmania have developed distinct methods for host defense evasion, leading to a wide spectrum of pathologies within humans.

Prior studies of macrophage infections with ...


Gb Virus C Interactions With Hiv: Effects On Immunoactivation And Mechanisms Of Immunomodulation, Nirjal Bhattarai May 2013

Gb Virus C Interactions With Hiv: Effects On Immunoactivation And Mechanisms Of Immunomodulation, Nirjal Bhattarai

Theses and Dissertations

GB virus C (GBV-C) is a lymphotropic human virus which was recently assigned to a new genus Pegivirus within the Flaviviridae family. GBV-C infection is found worldwide, and viremia prevalence is about 1% to 4% in healthy blood donors and up to 42% in HIV-infected individuals. In clinical studies, GBV-C coinfection is associated with prolonged survival of HIV-infected individuals. GBV-C infection modestly alters T cell homeostasis in vivo through various mechanisms, including modulation of chemokine and cytokine release and receptor expression, and by diminution of T cell activation, proliferation and apoptosis, all of which may contribute to improved HIV clinical ...


Taking Shape : Regulating Mitochondria Morphology Through Alternative Splicing And Phosphorylation Of Fission Factor Proteins, Theodore James Wilson May 2013

Taking Shape : Regulating Mitochondria Morphology Through Alternative Splicing And Phosphorylation Of Fission Factor Proteins, Theodore James Wilson

Theses and Dissertations

Mitochondria are important cellular organelles whose functions include generation of ATP, sequestration and release of pro-apoptotic molecules and calcium buffering. Mitochondria function is tightly linked to organelle morphology, which exits in a dynamic spectrum between a highly interconnected/fused mitochondria network to a punctate/fragmented scattering of individual mitochondrion. A family of large GTPase enzymes modulates this spectrum, with fusion catalyzed through the actions of mitofusin 1 and 2 (Mfn1/2) on the outer mitochondria membrane (OMM) and optic atrophy 1 (Opa1) causing fusion of the inner mitochondria membrane (IMM). On the other end of the spectrum, fragmentation is catalyzed ...


Loss Of Acid Sensing Ion Channel-1a And Bicarbonate Administration Attenuate The Severity Of Traumatic Brain Injury, Terry Yin May 2013

Loss Of Acid Sensing Ion Channel-1a And Bicarbonate Administration Attenuate The Severity Of Traumatic Brain Injury, Terry Yin

Theses and Dissertations

Traumatic brain injury (TBI) is a common cause of morbidity and mortality in people of all ages. Following the acute mechanical insult, TBI evolves over the ensuing minutes and days. Understanding the secondary factors that contribute to TBI might suggest therapeutic strategies to reduce the long-term consequences of brain trauma. To assess secondary factors that contribute to TBI, we studied a lateral fluid percussion injury (FPI) model in mice. Following FPI, the brain cortex became acidic, consistent with data from humans following brain trauma. Administering HCO3- after FPI prevented the acidosis and reduced the extent of neurodegeneration. Because acidosis can ...


Mechanisms Of Microrna Evolution, Regulation And Function: Computational Insight, Biological Evaluation And Practical Application, Ryan Michael Spengler May 2013

Mechanisms Of Microrna Evolution, Regulation And Function: Computational Insight, Biological Evaluation And Practical Application, Ryan Michael Spengler

Theses and Dissertations

MicroRNAs (miRNAs) are an abundant and diverse class of small, non-protein coding RNAs that guide the post-transcriptional repression of messenger RNA (mRNA) targets in a sequence-specific manner. Hundreds, if not thousands of distinct miRNA sequences have been described, each of which has the potential to regulate a large number of mRNAs. Over the last decade, miRNAs have been ascribed roles in nearly all biological processes in which they have been tested. More recently, interest has grown in understanding how individual miRNAs evolved, and how they are regulated. In this work, we demonstrate that Transposable Elements are a source for novel ...