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Full-Text Articles in Medicine and Health Sciences
The Role Of Ribosome Biogenesis In Exercise-Induced Skeletal Muscle Anabolism In Aging, Michael Stec
The Role Of Ribosome Biogenesis In Exercise-Induced Skeletal Muscle Anabolism In Aging, Michael Stec
All ETDs from UAB
Numerous chronic medical conditions, as well as normal aging result in a significant loss of skeletal muscle mass. This has profound effects on quality of life and can increase the risk of all-cause mortality. Currently, the most potent treatment for reversing the loss of muscle mass is resistance exercise training (RT); however, the human muscle fiber growth (hypertrophy) response to this treatment is quite variable, and older adults do not respond as favorably to this treatment as younger adults. The focus of this dissertation is to elucidate the role that ribosome biogenesis plays in regulating the RT-induced hypertrophic response. We …
The Role Of C-Reactive Protein In Acute Kidney Injury, Melissa A. Pegues
The Role Of C-Reactive Protein In Acute Kidney Injury, Melissa A. Pegues
All ETDs from UAB
Acute kidney injury (AKI), which manifests as an abrupt decline in renal function, occurs in ~1% of all hospitalization. Ischemia reperfusion injury (IRI), a common cause of AKI, can occur in any situation where blood flow to the kidney is significantly reduced such as hypertensive crisis, cardiovascular surgery, and inevitably during renal transplantation. Mortality from AKI is up to 80% due to incomplete knowledge of the pathogenesis of IRI and the lack of an effective therapy. It is thought that cellular damage as a result of hypoxia signals the release of proinflammatory cytokines that lead to a systemic inflammatory response. …
Regulation Of The Regulatory T Cell-Immunoglobulin A Pathway, Katie Lynn Alexander
Regulation Of The Regulatory T Cell-Immunoglobulin A Pathway, Katie Lynn Alexander
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A dysregulated immune response to the microbiota is a defined characteristic of Crohn's Disease (CD), a type of Inflammatory Bowel Disease (IBD). Understanding how homeo-stasis is maintained in the intestine despite the immense concentration of bacteria present is an active area of research. Regulatory T cells (Tregs) play an important role in mucosal tolerance by controlling inflammation and modulating immune responses initiated by T effector cells (Teffs). Tregs also provide vital survival factors to IgA+ B cells in the intes-tine in order to support Immunoglobulin A (IgA) responses as part of a protective Treg-IgA pathway, which functions to maintain mutualism …
Robust Production Of Mature Ribosomal Rna Is Directly Influenced By Multiple Steps Within The Transcription Cycle, Krysta Engel
Robust Production Of Mature Ribosomal Rna Is Directly Influenced By Multiple Steps Within The Transcription Cycle, Krysta Engel
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Cellular growth depends on the capacity for protein synthesis, and likewise ribosome biogenesis. Therefore, robust rRNA synthesis by RNA Polymerase I (Pol I) is a critical component of cell growth. The work reported in this dissertation highlights the contribution of polymerase domains and trans-acting proteins during rRNA synthesis and ribosome biogenesis. Eukaryotes utilize three homologous nuclear RNA polymerases (RNAPs) to express their genomes. The trigger loop (TL) is a well conserved region within the active site of multi-subunit RNAPs that plays a direct role during the nucleotide addition cycle. Analysis of Pol II TL mutants has suggested that catalysis is …
The Mechanism Of Small Molecule Viral Fusion Inhibitors, Michael Joseph Rowse
The Mechanism Of Small Molecule Viral Fusion Inhibitors, Michael Joseph Rowse
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All negative stranded RNA viruses (NSRV) have genomes encapsidated by oligomerized nucleoprotein (N). The N-RNA complex acts as the template for both transcription and replication. The crystal structure of the N protein from the model NSRV vesicular stomatitis virus (VSV) established the structural basis for the oligomerization of N-protein and the encapsidation of RNA. To determine how the structure of N protein changes in response to specific sequences of RNA, we developed a strategy to digest the random RNA encapsidated in the recombinant N-protein and reencapsidated specific RNA sequences. Poly-rA, poly-rC, poly-rU, and poly-rG sequences were encapsidated and co-crystallized with …
The Jak/Stat Pathway In Neuroinflammatory Diseases, Yudong Liu
The Jak/Stat Pathway In Neuroinflammatory Diseases, Yudong Liu
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Dysregulation of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway is critically involved in the pathogenesis of multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE). Suppressor Of Cytokine Signaling (SOCS) proteins are the negative regulators of the JAK/STAT pathway. To determine the role of SOCS3 in myeloid cells in EAE, mice with conditional SOCS3 deletion in myeloid cells (LysMCre-SOCS3fl/fl) were created and tested. LysMCre-SOCS3fl/fl mice develop a severe, non-resolving atypical form of disease, characterized by lesions and extensive neutrophil and other inflammatory cell infiltrates in the cerebellum and brainstem, elevated STAT activation, elevated cytokine, chemokine and iNOS expression, and prominent …
A New Form Of Rod Photoreceptor Light Adaptation, Alex S. Mckeown
A New Form Of Rod Photoreceptor Light Adaptation, Alex S. Mckeown
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In the first step in light perception, rod and cone photoreceptors convert photon absorption into an electrical impulse that is transmitted through the visual pathway. While the biochemistry and the signaling physiology have largely been defined in dark-adapted, isolated mammalian rods, there are still unanswered questions regarding photoreceptor light adaptation processes that involve extracellular components. In particular, the proteins of the interphotoreceptor matrix have not been considered in the studies of rod signaling and adaptation. This thesis details a new form of light adaptation, now known as adaptive potentiation (AP), in which extracellular components act on rods to transiently increase …
Structural Implications Of P22 Bacteriophage Coat Protein A-Domain Modifications, David Samuel Morris
Structural Implications Of P22 Bacteriophage Coat Protein A-Domain Modifications, David Samuel Morris
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Modification of virus capsids as target-specific delivery devices has become highly popularized in recent years and P22 bacteriophage has been proposed as a potential candidate for development of a targeting drug delivery system. As a proof of concept for our system, we hypothesized that the A-domain of P22 coat protein could be utilized to alter the binding affinity of virus-like procapsids for biological targets. Addition of acidic residues to the A-domain revealed that this could be accomplished through the quarternary localization of charged residues in three-dimensional space without interrogating procapsid assembly. Further manipulations implemented in vivo were performed to examine …
Functional Role Of Mepe In Tooth Mineralization: Mediation By Tgf-Beta1, Angela Gullard
Functional Role Of Mepe In Tooth Mineralization: Mediation By Tgf-Beta1, Angela Gullard
All ETDs from UAB
Transforming growth factor-β1 (TGF-β1) is one of the most abundant cytokines of the dentin-pulp complex that regulates a broad range of biological processes related to matrix synthesis and ultimately tooth formation, including secretion and mineralization of the dentin extracellular matrix (DECM). TGF-β1 mediates odontoblast cytodifferentiation from precursor dental pulp cells, being up-regulated in odontoblasts and then incorporated into the DECM as a reservoir that can be utilized in times of mechanical, chemical, or bacterial insult. Formation of the DECM is modulated by the actions of small integrin-binding ligand N-linked glycoproteins (SIBLINGs), which include DMP-1, DSPP, BSP, SPP1, and MEPE, with …
Tau-Sh3 Interactions: Implications For Alzheimer's Disease, Jesse Nicholas Cochran
Tau-Sh3 Interactions: Implications For Alzheimer's Disease, Jesse Nicholas Cochran
All ETDs from UAB
Alzheimer’s disease (AD) is the most common neurodegenerative disease and with Americans’ increasing longevity it is becoming an epidemic. There are currently no effective treatments for this disorder. Abnormalities of tau track more closely with cognitive decline than the most studied therapeutic target in AD, amyloid-beta, but the optimal strategy for targeting tau has not yet been identified. Based on considerable preclinical data from AD models, we hypothesize that interactions between tau and SH3 domain–containing proteins are pathogenic in AD. Genetically reducing either tau or tau interactants has beneficial effects relevant to AD. Here, we describe a drug screen for …
The Mspa Nanopore As A Sensor For Dna Sequencing, Mikhail Pavlenok
The Mspa Nanopore As A Sensor For Dna Sequencing, Mikhail Pavlenok
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Nanopore sequencing is a novel and promising DNA sequencing method. This single molecule technique is capable of long reads, retains epigenetic information, and is inexpensive and fast. In this method ionic current is measured while single-stranded DNA is electrophoretically translocated through a nanometer-scale pore. Each passing nucleotide blocks current with characteristic amplitude and duration which are used to identify DNA sequence. MspA is the primary porin of M. smegmatis and mediates the diffusion of small, hydrophilic nutrients across the outer membrane. MspA is an octameric, channel-forming protein and represents the founding member of a new class of mycobacterial outer membrane …
C-Reactive Protein, Autoimmunity, And Inflammation In The Central Nervous System, Tyler T. Wright
C-Reactive Protein, Autoimmunity, And Inflammation In The Central Nervous System, Tyler T. Wright
All ETDs from UAB
C-reactive protein (CRP) is an acute phase reactant whose blood concentration rises in response all types of inflammation. And while CRP is widely used as a clinical marker of inflammation, it has several biological functions, e.g. activation of the classical complement cascade and binding Fcγ receptors in order to mediate multiple immune processes. The full extent of CRP’s physiological activities has not yet been fully elucidated, but there is significant evidence to establish that CRP plays an important role in the onset and progression of autoimmune disease. Seminal work from our lab showed that human CRP, hepatically expressed in transgenic …
The Characterization Of Human Cytosolic Sulfotransferase 1a1: Interactions With 17Α-Ethinylestradiol, Katie Jo Glowacki
The Characterization Of Human Cytosolic Sulfotransferase 1a1: Interactions With 17Α-Ethinylestradiol, Katie Jo Glowacki
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Human cytosolic sulfotransferases (SULTs) are a family of Phase II conjugating enzymes that facilitate the transfer of a sulfonate moiety from 3’phosphoadenosine 5’phosphosulfate (PAPS) to hydroxyl or amine groups of acceptor substrates. SULT1A1, located in many tissues throughout the human body including the liver, is important in the metabolism of many endogenous, exogenous, xenobiotic, and drug compounds. The majority of substrates for SULT1A1 are small neutral phenols including 1-naphthol and acetaminophen; however, SULT1A1 sulfates larger compounds including 17β-estradiol (E2) and raloxifene. SULT1A1 conjugates E2 with a Km of 2.3 µM and the structure of E2 is almost identical to the …
Bioenergetics As A Biomarker Of Health And Disease, Philip Kramer
Bioenergetics As A Biomarker Of Health And Disease, Philip Kramer
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The increasing prevalence of metabolic syndrome, diabetes, atherosclerosis, and many other diseases only recently associated with aberrant metabolism, have led to a de-mand for clinical assays to determine a patient’s mitochondrial health. With the rapidly growing interest in personalized medicine, such an assay would ideally be able to capture the metabolic changes associated with oxidative stress, inflammation, and therapy of a patient in a swift and non-invasive manner. Short of tissue biopsies, this burgeoning field of Translational Bioenergetics has had minimal success in obtaining sufficient human cells and the means to assess them both accurately and swiftly. The purpose of …
Role Of Macrophages In The Cardiomyopathy Associated With Obesity And Type 2 Diabetes, Mehak Goel
Role Of Macrophages In The Cardiomyopathy Associated With Obesity And Type 2 Diabetes, Mehak Goel
All ETDs from UAB
Obesity is a state of chronic low-grade systemic inflammation that, along with type 2 diabetes (T2D), increases the risk of developing cardiovascular disease (CVD). Despite the wealth of information on the link between macrophages and cytokines in adipose tissue and peripheral insulin resistance, their role in the pathogenesis of diabetic cardiomyopathy and cardiac diastolic dysfunction is unclear. We hypothesized that activated immune cell mediators, in particular monocytes and macrophages, are fundamental drivers of diet-induced obesity and diabetic cardiomyopathy. Herein, firstly, a diet-induced model of diabetic cardiomyopathy was developed in C57BL/6 mice by feeding a high fat diet (HFD, 45% kcal …
Obesity Weighs Down Memory: Emerging Insights Into The Epigentic Basis Of Obesity-Induced Memory Impairment In Adult Mice, Frankie Darryn Heyward
Obesity Weighs Down Memory: Emerging Insights Into The Epigentic Basis Of Obesity-Induced Memory Impairment In Adult Mice, Frankie Darryn Heyward
All ETDs from UAB
A preponderance of evidence has established that obesity contributes to memory impairments in mid-age adults. Empirical evidence has revealed that diet-induced obesity contributes to memory impairments in adult rodents. Precisely how obesity disrupts memory remains an open question. Bourgeoning data indicate that molecular epigenetic mechanisms mediate the changes in gene transcription that are necessary for hippocampus-dependent memory consolidation. Epigenetic mechanisms, such as DNA methylation, stably regulate gene expression without affecting the DNA sequence. Moreover, DNA methylation of memory-related genes with in the hippocampus is indispensible for memory formation. There is recent evidence of obesity-induced aberrantions in DNA methylation both peripherally …
Decoding Nf1 Intragenic Copy-Number Changes, Meng-Chang Hsiao
Decoding Nf1 Intragenic Copy-Number Changes, Meng-Chang Hsiao
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Genomic rearrangements may cause both Mendelian and complex disorders. Currently, several major mechanisms causing genomic rearrangements have been proposed such as non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR). However, to what extent these mechanisms contribute to gene-specific pathogenic copy-number changes (CNCs) remains understudied. Furthermore, only few studies resolved these pathogenic alterations at the nucleotide-level. Accordingly, our aim was to explore which mechanisms contribute to a large, unique set of locus-specific non-recurrent genomic rearrangements causing the genetic neurocutaneous disorder neurofibromatosis type 1 (NF1). Through breakpoint-spanning PCR as well as …
Mechanisms Of Resistance To Oncolytic Herpes Simplex Viruses In Malignant Peripheral Nerve Sheath Tumors, Joshua Douglas Jackson
Mechanisms Of Resistance To Oncolytic Herpes Simplex Viruses In Malignant Peripheral Nerve Sheath Tumors, Joshua Douglas Jackson
All ETDs from UAB
Malignant peripheral nerve sheath tumors (MPNSTs) are rare but highly aggressive cancer of the peripheral nervous tissue. Median patient survival is approximately two years following diagnosis due in part to the ineffective options for treatment. As an alternative therapeutic approach to conventional radio- and chemotherapy, oncolytic herpes simplex viruses type-1 (oHSVs) have been proposed to treat MPNSTs. These oHSVs have been shown safe in clinical trials with associated tumor regression. However, there is evidence that resistance to the therapy should be anticipated in a subset of patients. Therefore, the goal of this dissertation has been to identify the primary obstacles …
Zebrafish Wnt9b Patterns The First Pharyngeal Arch Into D-I-V Domains And Promotes Anterior-Medial Outgrowth, Henry Jackson
Zebrafish Wnt9b Patterns The First Pharyngeal Arch Into D-I-V Domains And Promotes Anterior-Medial Outgrowth, Henry Jackson
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The secondary mouth and its associated face and jaws were an important evolutionary adaptation in the vertebrate lineage. The secondary mouth is formed from facial prominences including the fronto-nasal prominence and the 1st pharyngeal-arch derived maxillary and mandibular prominence. Cranial neural crest cells within these prominences give rise to the connective tissues of face and jaws, and strict spatio-temporal regulation of cranial neural crest cell fate patterning and subsequent prominence outgrowth is vital to normal facial development. Oral-facial clefting (OFC) is a common morbid human birth disorder characterized by disrupted oral and craniofacial morphogenesis. Our previous studies demonstrate that a …
Changes In Gene Expression During Nitrogen Starvation Are Mediated By Targeted Degradation Of Translation And Mrna Decay Factors In Saccharomyces Cerevisiae, Shane Patrick Kelly
Changes In Gene Expression During Nitrogen Starvation Are Mediated By Targeted Degradation Of Translation And Mrna Decay Factors In Saccharomyces Cerevisiae, Shane Patrick Kelly
All ETDs from UAB
Autophagy is the cellular mechanism of recruitment and decay of cytoplasmic molecules, proteins, and organelles that are obsolete for a particular growth condition. Autophagic degradation is distinct from proteasomal degradation by the formation of a de-novo double membrane which engulfs its cargo to be delivered for degradation to the yeast vacuole. Once thought to be only a general phenomenon of bulk decay, several autophagic pathways have demonstrated selectivity. In the following work we show that during nitrogen starvation (a potent inducer of autophagy) in the yeast Saccharomyces cerevisiae, a subset of translation factors are degraded selectively and rapidly. We go …
Gene Replacement Therapy For Sickle Cell Disease, Chao Li
Gene Replacement Therapy For Sickle Cell Disease, Chao Li
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Sickle Cell Disease (SCD) is a devastating inherited disorder resulting from a single DNA base pair (bp) mutation in the sixth codon of the β-globin gene. It causes severe tissue damage that can result in strokes, splenic infarction, kidney failure, liver and lung disorders, painful crises, and other complications. Currently, the only cure for the disease is allogenic stem cell transplantation, which is only available to limited patients with histocompatible donors. In order to overcome this limitation, CRISPR/Cas enhanced gene correction in sickle patient iPS and CD34+ hematopoietic stem/progenitor cells as a therapy strategy was explored. Keratinocytes from skin biopsies …
Gaba(A) Receptor Trafficking And Localization In Schizophrenia, Toni Marie Mueller
Gaba(A) Receptor Trafficking And Localization In Schizophrenia, Toni Marie Mueller
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Mechanisms underlying the complex etiology of schizophrenia have long been a subject of scientific inquiry. Early investigations focused on identifying functional deficits in dopaminergic and glutamatergic neurotransmission, but evidence for disrupted GABAergic signaling has also emerged. Recent studies from our lab have identified disrupted N-glycosylation of glutamate receptor and transporter subunits and abnormal subcellular distribution of glutamate receptor subunits, suggesting a potential functional consequence of perturbed N-glycosylation in schizophrenia. N-glycosylation is the posttranslational enzymatic attachment of an oligosaccharide precursor to a protein. This modification plays a significant role in protein processing in the ER and Golgi, and is known to …
A Novel Role For Usp14 In Regulating Non-Proteolytic Ubiquitin Signaling, Jada Hallengren Vaden
A Novel Role For Usp14 In Regulating Non-Proteolytic Ubiquitin Signaling, Jada Hallengren Vaden
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Loss of the deubiquitinating enzyme (DUB) USP14 in the ataxia (axJ) mice leads to altered neuromuscular junction (NMJ) structure, reduced synaptic transmission at the NMJ, and decreased mobility. However, the types of processes that USP14 regulates in the nervous system remain unclear. Because association with the proteasome stimulates USP14's ubiquitin hydrolase activity, it is thought to act primarily on proteasomal substrates. Therefore, one way for USP14 to support nervous system function is by modulating protein turnover. While a number of studies done in yeast and immortalized cell lines demonstrate that loss or inhibition of USP14 alters proteasome function, there is …
Characterization Of The Gtpase Rac1 As An Electrophilic-Sensitive Protein In Vascular Cells, Stephanie Brook Wall
Characterization Of The Gtpase Rac1 As An Electrophilic-Sensitive Protein In Vascular Cells, Stephanie Brook Wall
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The GTPase Rac1 is a protein which has been shown to be dysregulated in the context of a number of inflammatory diseases including atherosclerosis. Rac1 responds to extracellular signals and is involved in cellular cytoskeletal rearrangement, reactive oxygen species generation and cell cycle progression. When activated Rac1 interacts with effector proteins on the plasma membrane. This activation has recently been shown to be modulated by redox signaling via an active site cysteine. However, it is not known whether other redox signaling compounds can modulate Rac1 activity. An important redox signaling mediator is the electrophilic lipid, 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2). This lipid …
Socs3 Deficiency In Myeloid Cells Promotes Tumor Development, Hao Yu
Socs3 Deficiency In Myeloid Cells Promotes Tumor Development, Hao Yu
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STAT3 signaling is a major intrinsic pathway for cancer inflammation owing to its frequent activation in malignant cells, and key role in regulating many genes crucial for inflammation in the tumor microenvironment. Persistently activated STAT3 increases tumor cell proliferation, survival, and invasion while suppressing anti-tumor immunity. Suppressor Of Cytokine Signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway, and generally function as tumor suppressors. The absence of SOCS3 in particular leads to heightened activation of the STAT3 transcription factor. In the present study, we demonstrate that genetic deletion of SOCS3 specifically in myeloid cells significantly enhances tumor growth, which …
Intestinal Microbiota And Its Role In Mucosal And Systemic Immune Responses, Qing Zhao
Intestinal Microbiota And Its Role In Mucosal And Systemic Immune Responses, Qing Zhao
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Host-microbiota mutualism is established with long-term co-evolution. The abundant and diverse microbes colonizing on the surface of the host’s body, especially those in the gastrointestinal (GI) tract, play an essential role in the development and maturation of the host’s immune system. Failure of intestinal microbial control may lead to the development of an array of autoimmune diseases, including inflammatory bowel disease (IBD). As a well-recognized inflammation mediator, Th17 cells are actually among the most abundant effector CD4+ T cells in the normal adult gut. What the role of intestinal Th17 cells is under steady state conditions and how the intestinal …
Transient-State Kinetic Analysis Of The Rna Polymerase I Nucleotide Incorporation Mechanism, Francis Dean Appling
Transient-State Kinetic Analysis Of The Rna Polymerase I Nucleotide Incorporation Mechanism, Francis Dean Appling
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The diversity of enzymes and the reactions which they catalyze is enormous. Careful study of enzymatic reaction mechanisms has taught us a great deal about chemical reactivity and has given us insight into the chemical and physical basis of life. One particularly ubiquitous class of enzymes, the RNA polymerases, are expressed in all forms of life. RNA polymerases are central components of nucleic acid metabolism and display a variety of distinctive enzymatic features; two points which solicit their thorough study. The central theme of this dissertation is the use of kinetic techniques to describe enzymatic reaction mechanisms. Although the main …
The I507-Atc→Att Silent Codon Change Contributes To The Misfolding Of ∆F508 Cftr, Vedrana Bali
The I507-Atc→Att Silent Codon Change Contributes To The Misfolding Of ∆F508 Cftr, Vedrana Bali
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Synonymous codon changes (SCCs) do not alter the amino acid sequence of proteins, but may significantly change the phenotype. The frequency of synonymous codons is species- and gene-specific, described as codon usage bias (CUB). Over the past 50 years, research has shown that SCCs affect protein biogenesis, development of human disorders and the function of recombinant proteins developed for therapeutic applications. However, the molecular mechanisms by which SCCs alter the function of gene products are not completely understood. In Chapter 2 we summarize present knowledge in this field. The most common cause of cystic fibrosis (CF) is the deletion of …
Energy Metabolism Of Platelets During Activation, Oxidative Stress And Storage, Saranya Ravi
Energy Metabolism Of Platelets During Activation, Oxidative Stress And Storage, Saranya Ravi
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The principal function of platelets is to regulate hemostasis, and dysfunction of platelet aggregation or activation can lead to either excessive thrombotic or hemorrhagic complications. It has been shown that the ability to generate ATP and exposure to oxidative stress can affect platelet thrombotic potential. While platelet metabolism has been extensively studied, the importance of substrate availability and metabolic plasticity in regulating aggregation under physiological or pathological conditions is not well understood. In this dissertation, we examined the reliance of platelets on different metabolic substrates, the importance of ATP production for aggregation in response to thrombin stimulation, metabolic stress following …
Exploiting The Glioblastoma Tumor Microenvironment For Enhanced Oncolytic Herpes Simplex Virus Therapy, Tyrel Talbert Smith
Exploiting The Glioblastoma Tumor Microenvironment For Enhanced Oncolytic Herpes Simplex Virus Therapy, Tyrel Talbert Smith
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Gliomas are the most common and fatal malignancy of the adult central nervous system. The need for new therapeutic options is clear, as standard of care therapies only extend median survival 12-14 months beyond diagnosis. Conditionally replication-competent oncolytic herpes simplex type-1 viruses (oHSV) have emerged as promising therapeutics for treating malignant gliomas. However, two factors that contribute to the dismal prognosis of malignant gliomas, immunosuppression and invasive growth, are also thought to limit virotherapeutic efficacy. We examined these factors in tumor microenvironments to explore novel strategies to treat malignant gliomas with oHSV for improved therapeutic response. In a Phase 1b …