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Full-Text Articles in Medicine and Health Sciences
Investigating The Role Of Myristoylated Alanine Rich C Kinase Substrate's (Marcks's) Effector Domain In Lung And Brain Cancer Biology, Timothy D. Rohrbach
Investigating The Role Of Myristoylated Alanine Rich C Kinase Substrate's (Marcks's) Effector Domain In Lung And Brain Cancer Biology, Timothy D. Rohrbach
All ETDs from UAB
In this study, we investigated the role MARCKS's Effector Domain plays in lung and brain cancer biology. Initially, we identified that MARCKS was present in a range of lung cancer histologies including: squamous cell, adenocarcinoma, and normal lung tissues among others. In addition, lung adenocarcinoma patients with a mutation in the MARCKS gene correlated with decreased survival as determined by The Cancer Genome Atlas. In vitro studies identified that the phosphorylation status of MARCKS's Effector Domain was able to influence lung cancer radiation sensitivity. When MARCKS's Effector Domain was in a non-phosphorylated state, A549 lung cancer cell lines experienced increased …
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 …
Protumorigenic Role Of Cathelicidin-Related Antimicrobial Peptide In Chemotaxis And Differentiation Of Myeloid Lineage During Prostate Cancer Progression, Ha-Ram Cha
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A growing body of evidence indicates a positive correlation between the expression of human antimicrobial peptide leucine leucine 37 (LL-37) and the progression of epithelial cancers, including carcinomas of the breast, lung, ovary, and prostate. Although the molecular mechanisms for this correlation have not yet been clearly elucidated, the primary function of LL-37 as a chemotactic molecule for innate immune effector cells suggests its possible association in coordinating protumorigenic mechanisms mediated by tumor-infiltrating immune cells. Using a mouse model of epithelial prostate cancer (PCa), the present study identified a unique role for cathelicidin-related antimicrobial peptide (CRAMP), a murine orthologue of …
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 …
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
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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. …
An Nphp-4 Enhancer Mutagenesis Screen For Modifiers Of Cilia Phenotypes Reveals Novel Mks Alleles, Uncovers, A Specific Genetic Interaction Between Osm-3 And Nphp-4, And A Novel Ciliary Calcium Channel., Dawn Landis
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Nephronophthisis (NPHP) is a ciliopathy with diverse clinical features likely caused by genetic modifiers. To identify NPHP modifiers, a screen was conducted on nphp-4(tm925) mutant C. elegans to reveal mutations that exacerbate the NPHP ciliary defects. Ten loci were generated, five of which have now been identified. Three are mutations in ciliopathy genes mks-1, mks-2, and mks-5. The fourth allele (yhw66) is a missense mutation (S316F) in OSM-3, a kinesin required for cilia distal segment assembly. As in osm-3 null mutants, nphp-4(tm925);osm-3(yhw66) mutants lack distal segments, are dye-filing defective (Dyf), and have osmotic avoidance defects (OSM). The osm-3(yhw66) mutant alone …
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 …
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 …
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 …
Tau-Sh3 Interactions: Implications For Alzheimer's Disease, Jesse Nicholas Cochran
Tau-Sh3 Interactions: Implications For Alzheimer's Disease, Jesse Nicholas Cochran
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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 …
Glutamate And The Biology Of Malignant Glioma, Stephanie Marie Robert
Glutamate And The Biology Of Malignant Glioma, Stephanie Marie Robert
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Malignant gliomas are the most prevalent primary brain tumor. They are highly aggressive and lack effective treatment options. Standard therapy includes a combination of radiation, chemotherapy, and tumor resection; however, even with aggressive treatment, median patient survival remains a dismal 12 – 14 months after diagnosis. Research has focused on understanding the unique biological mechanisms involved in glioma growth and survival in an effort to design novel therapies to treat this devastating disease. In the unique environment of the brain, gliomas have developed the ability to grow and survive at the cost of the normal surrounding brain tissue. Glutamate, the …
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 Sialyltransferase St6gal-I Promotes A Cancer Stem Cell Phenotype, Matthew Jonathan Schultz
The Sialyltransferase St6gal-I Promotes A Cancer Stem Cell Phenotype, Matthew Jonathan Schultz
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Alterations in tumor cell glycosylation have been observed for decades, but the functional consequences of specific glycosyltransferase activity are not well understood. This dissertation focuses on the role of the sialyltransferase ST6Gal-I in driving ovarian and pancreatic cancer development. ST6Gal-I adds a negatively-charged sialic acid sugar in an alpha 2-6 linkage to select receptors, which can alter their function. We show that ST6Gal-I protein is upregulated in ovarian and pancreatic cancers but not expressed in normal epithelial tissue from these organs. ST6Gal-I expression in ovarian cancer correlates with decreased progression-free and overall survival, and we present evidence that ST6Gal-I expression …
Role Of Vapb/Als8 Signaling Through Lar Receptor, Jessica Lindsey Winek Schultz
Role Of Vapb/Als8 Signaling Through Lar Receptor, Jessica Lindsey Winek Schultz
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In humans, a P56S point mutation in the VAPB/ALS8 MSP domain is associated with amyotrophic lateral sclerosis (ALS) and late-onset spinal muscular atrophy (SMA). The N-terminal MSP domain is cleaved from the C-terminus, and secreted through an unknown, nonconventional manner. The P56S mutation inhibits secretion of the MSP domain. We use Caenorhabditis elegans to study live secretion of VPR-1, as well as to understand vMSP receptor signaling in muscle and gonad. To study the secretion mechanism of VPR-1 we created a transgenic line of C. elegans with a fluorescently tagged VPR-1. Using this model, we were able to visualize live …
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 …
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 …
Bcla As An Adjunct To Current Bacillus Anthracis Vaccination And Therapy Protocols, Juan Bosco Rodriguez Barrantes
Bcla As An Adjunct To Current Bacillus Anthracis Vaccination And Therapy Protocols, Juan Bosco Rodriguez Barrantes
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Bacillus anthracis (Ba) is a Gram,-positive zoonotic bacterium that causes inhala- tional, cutaneous and intestinal Anthrax Disease. Although the infectious form of Ba is its endospore (spore), only the tripartite toxin-producing vegetative bacteria causes disease pathology. While current vaccination strategies target the Protective Antigen (PA) com- ponent of this toxin, vaccine-elicited immunity to the spore form of Ba is lacking. How- ever, vaccines targeting spore components of Ba have the potential to neutralize the in- fectious form of Ba. We sought to determine if antibodies elicited through immunization with the main antigenic component of the spore surface- Bacillus collagen-like protein …
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 …
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
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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 …
G Protein-Coupled Inwardly-Rectifying Potassium (Girk) Chanels Mediate Entrainment Of Circadian Rhythms, Lauren Marie Hablitz
G Protein-Coupled Inwardly-Rectifying Potassium (Girk) Chanels Mediate Entrainment Of Circadian Rhythms, Lauren Marie Hablitz
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Circadian rhythms are 24-hour cycles in biological and behavioral processes. These cycles enable an organism to predict changes in its environment, like changes in food availability and seasonality. Although endogenously driven, these rhythms can entrain or synchronize to daily changes in the environment, allowing the animal to adapt. One way entrainment occurs is shifts in circadian phase following the presentation of nonphotic, or non-light, stimuli, such as exercise, arousal, or stress at certain times of day. The molecular mechanisms underlying nonphotic entrainment are poorly understood - specifically, how nonphotic cues alter excitability within the suprachiasmatic nucleus (SCN) of the hypothalamus, …
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
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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 …
Caenorhabditis Elegans Sperm Chemotaxis, Hieu Dinh Hoang
Caenorhabditis Elegans Sperm Chemotaxis, Hieu Dinh Hoang
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Survival of animal species depends on fertilization, the union of an egg and a sperm. The sperm's ability to find an egg quickly allows it to pass on male genetic material. It is challenging to record sperm targeting or guidance efficiency and motility in utero. We use the Caenorhabditis elegans model organism to study sperm guidance, primarily because its epidermis is transparent, allowing the observation of live fluorescent sperm in the hermaphrodite uterus. Using genome-editing techniques, genetic analyses, fluorescent microscopy, and mass spectrometry, we aim to address the following two questions: how hermaphrodites regulate sperm motility in the uterus, and …
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 …
Innate Immunity Mechanisms In Parkinson Disease, Mark Moehle
Innate Immunity Mechanisms In Parkinson Disease, Mark Moehle
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Parkinson disease (PD) is a late onset, progressive neurodegenerative movement disorder with cardinal symptoms of tremor at rest, bradykinesia, postural instability, and rigidity. These motor symptoms of PD are caused by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). However, despite PDs first modern observation in 1817, little is understood about the causes and molecular mechanisms behind dopaminergic neuron loss. The relatively weak understanding of pathological mechanisms has hindered the development of treatments to slow or halt the progression of PD. However, recently, mounting evidence from post-mortem, imaging, and retrospective studies suggest an important role …
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 Heme Oxygenase-1-Mediated Protection Against Tissue Injury, Travis David Hull
Mechanisms Of Heme Oxygenase-1-Mediated Protection Against Tissue Injury, Travis David Hull
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Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in the catabolism of heme, which is released by necrotic cells in injured tissue. HO-1 expression is protective in cardiac and renal injury because it coordinates the degradation of pro-oxidant heme with the generation of equimolar quantities of iron (Fe2+) and the cytoprotective mole-cules carbon monoxide and biliverdin. While many studies have demonstrated that HO-1 expression is protective in numerous disease states, relatively few have examined the specific cellular compartment(s) through which HO-1 expression confers its protective effects. Our objective was to define the cellular compartments in which HO-1 expression is critical to …
Characterizing The Nuclear Import And Functions Of Cystin, The Ciliary Protein Disrupted In The Cpk Mouse Model Of Recessive Polycystic Kidney Disease, Jacob Asher Watts
Characterizing The Nuclear Import And Functions Of Cystin, The Ciliary Protein Disrupted In The Cpk Mouse Model Of Recessive Polycystic Kidney Disease, Jacob Asher Watts
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Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is a ma-jor cause of pediatric morbidity and mortality. Typically, orthologous animal models are the mainstay for pathogenic studies of human diseases. However, gene-targeting of Pkhd1, the mouse ortholog of the ARPKD gene, results in mutants with little or no kidney disease. In contrast, disruption of the non-orthologous gene, Cys1, in the cpk mouse model closely phenocopies human ARPKD. We speculate that this phenotypic similarity suggests that the Pkhd1 and Cys1 genes encode proteins (FPC and cystin, respectively) that share, at least in part, common molecular pathways. Our laboratory, as well as …
Nonsense Suppression In A Cftr Mouse Model And Analysis Of Animo Acids Inserted At Cftr Premature Termination Codons In Mammalian Cells, Xiaojiao Xue
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A nonsense mutation introduces a premature terminations codon (PTC) into an open reading frame (ORF) upstream of a normal stop codon and results in truncated protein production. In frame PTCs account for ~11% of all mutations that cause human genetic diseases. To treat PTC-associated disorders, one approach is to use drugs that facilitate the insertion of amino acids carried by near-cognate aminoacyl-tRNAs at PTCs. Aminoglycosides were shown to suppress nonsense mutations and restore full-length protein production. This process is also termed as readthrough. However, their low efficiency and their potential to induce ototoxicity and nephrotoxicity limits their long-term application for …
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 …
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
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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 …