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Full-Text Articles in Life Sciences
The Origin Of Multiple Sclerosis Revisited: The Case For A Soluble Toxin, Kareem Rashid Rumah
The Origin Of Multiple Sclerosis Revisited: The Case For A Soluble Toxin, Kareem Rashid Rumah
Student Theses and Dissertations
After nearly two hundred years of scientific inquiry, the cause of Multiple Sclerosis (MS) remains unknown. Although generally considered an autoimmune disease, recent pathological findings have challenged the longstanding autoimmune view of MS. Indeed, lesions that are just hours past their initial onset display evidence of cellular degeneration in the absence of an inflammatory infiltrate. This seminal finding begs the fundamental question, if immune cells do not participate in early tissue damage in MS, what is the mysterious triggering agent? In the first half of this thesis, I will propose that a soluble bacterial toxin, Clostridium perfringens epsilon toxin (ETX), …
Forces Generated By Cell Intercalculation Tow Epidermal Sheets In Mammalian Tissue Morphogenesis, Evan Heller
Forces Generated By Cell Intercalculation Tow Epidermal Sheets In Mammalian Tissue Morphogenesis, Evan Heller
Student Theses and Dissertations
Underlying the dramatic tissue movements of development—the bending, folding, squeezing, pushing, pulling, mass movements, and individual movements—are processes of cell migration. Throughout our lives, cell migration plays a role in the maintenance and regeneration of our tissues, and even in the development and progression of disease. To carry out the complex tasks of development and tissue morphogenesis, cells must coordinate their behaviors and migrate collectively. Insights into these collective behaviors have come from elegant studies of gastrulation movements in model organisms such as flies, frogs, and fish, uncovering conserved cellular and molecular mechanisms. However, the extent to which these mechanisms …
Identification Of A Microrna Network That Regulates Melanoma Metastasis And Angiogenesis By Targeting Apoe, Nora Pencheva
Identification Of A Microrna Network That Regulates Melanoma Metastasis And Angiogenesis By Targeting Apoe, Nora Pencheva
Student Theses and Dissertations
Metastatic melanoma, a prevalent and deadly form of skin cancer, remains an aggressive clinical outcome that lacks effective preventative and/or curative therapeutics. Patients diagnosed with advanced metastatic melanoma face a dreaded 10-year survival rate of less than 10%. By performing in vivo selection for highly metastatic melanoma cells, we systematically identified three microRNAs (miRNAs) that promoted metastasis across multiple mutationally diverse human melanoma subtypes. These miRNAs were found to promote metastasis by enhancing the invasive capacity of melanoma cells and also by allowing melanoma cells to recruit endothelial cells into the metastatic niche, leading to enhanced metastatic angiogenesis. Importantly, the …
Causes And Consequences Of Genetic Robustness And Fragility In Hiv-1 Proteins, Suzannah J. Rihn
Causes And Consequences Of Genetic Robustness And Fragility In Hiv-1 Proteins, Suzannah J. Rihn
Student Theses and Dissertations
Genetic robustness describes a capacity to maintain function in the face of mutation. RNA viruses, like human immunodeficiency virus-1 (HIV-1), experience extremely high mutations rates in vivo, which contribute to the evolvability that permits HIV-1 to evade immune defenses. However, the compact nature of the HIV-1 viral genome, in which small or overlapping proteins are often multifunctional and essential, often necessitates a strong pressure to conserve functional roles, which is at opposition with immunological pressures to diversify. Under such conditions, and in consideration of the relatively rapid replication cycle of HIV-1, natural selection for robustness would be predicted to be …
Functional And Structural Studies Of The Human Voltage-Gated Proton Channel, James Anthony Letts
Functional And Structural Studies Of The Human Voltage-Gated Proton Channel, James Anthony Letts
Student Theses and Dissertations
The activity of voltage-gated cation channels underlies the action potentials that allow for neuronal signaling and muscle contraction. The canonical family of voltage-gated K+, Na+ and Ca2+ channels has been the subject of extensive electrophysiological, biophysical, genetic, biochemical and structural characterization since the 1950s. These channels all share a conserved six-transmembrane helix topology (S1-S6) in which the first four transmembrane helices (S1-S4) form the regulatory voltage-sensor domain and the last two transmembrane helices (S5 and S6) comprise the ion-conducting pore domain. It was thought that all voltage-gated cation channels shared this conserved domain architecture. However, this scheme was challenged by …
Taming A Potent Mutator: Identification And Characterization Of Novel Mechanisms Of Regulating Antibody Diversification In B-Lymphocytes, Rebecca Kyle Delker
Taming A Potent Mutator: Identification And Characterization Of Novel Mechanisms Of Regulating Antibody Diversification In B-Lymphocytes, Rebecca Kyle Delker
Student Theses and Dissertations
Often the needs of an organism exceed the number of genes in the genome. Thus, modification of the genes, themselves, or of the gene products is necessary. This becomes particularly important in cells of the immune system, which have to combat a virtually infinite array of foreign pathogens. Blymphocytes, the mediators of humoral immunity, have developed extensive mechanisms of gene diversification collectively known as antibody diversification. Antibody diversification, a set of processes necessary for an organism to mount a specific and robust immune response, relies on Activation Induced Cytidine Deaminase (AID) to initiate two of such processes: Somatic Hypermutation (SHM) …
Genome-Wide Characterization Of The Effects Of Nucleic Acid Modifying Enzymes: Cytidine Deaminases And Dna Methylation, Eric Luke Fritz
Genome-Wide Characterization Of The Effects Of Nucleic Acid Modifying Enzymes: Cytidine Deaminases And Dna Methylation, Eric Luke Fritz
Student Theses and Dissertations
Activation-induced cytidine deaminase (AID) is essential for two processes of immunoglobulin diversification in germinal center B cells: somatic hypermutation (SHM), in which mutations are introduced into immunoglobulin (Ig) genes, and class-switch recombination (CSR), in which genomic constant regions are recombined to encode antibodies of different isotypes. Both of these processes require AID-catalyzed C-to-U lesions at the Ig loci, which are resolved to generate point mutations or double-stranded DNA breaks in the cases of SHM and CSR, respectively. Despite over a decade of intense study, a number of open issues remain surrounding AID. The diversity of findings regarding AID’s role in …
High Resolution Maps Of The Vasculature Of An Entire Organ, Oppenheim N. Jacob
High Resolution Maps Of The Vasculature Of An Entire Organ, Oppenheim N. Jacob
Student Theses and Dissertations
The structure of vascular networks represents a great, unsolved problem in anatomy. Network geometry and topology differ dramatically from left to right and person to person as evidenced by the superficial venation of the hands and the vasculature of the retinae. Mathematically, we may state that there is no conserved topology in vascular networks. Efficiency demands that these networks be regular on a statistical level and perhaps optimal. We have taken the first steps towards elucidating the principles underlying vascular organization, creating the rst map of the hierarchical vasculature (above the capillaries) of an entire organ. Using serial blockface microscopy …
Coordinating Stem Cell Behavior In The Hair Follicle, Chiung-Ying Chang
Coordinating Stem Cell Behavior In The Hair Follicle, Chiung-Ying Chang
Student Theses and Dissertations
Tissue stem cells perform important functions throughout an organism’s life. They generate new cells to replenish cells that are lost during normal wear and tear or in response to acute injury. Remarkably, hair follicles naturally undergo repetitive cycles of regeneration and degeneration, a process that is accomplished with the support of stem cells within the hair follicles. It is this feature that makes this miniorgan an attractive model system to study stem cell biology. Interestingly, hair follicle is home to two distinct stem cell populations: epithelial hair follicle stem cells (HFSCs), which contribute to the formation of hair shafts, and …
Identification Of A Functional Hotspot On Ubiquitin Required For Stimulation Of Methyltransferase Activity On Chromatin, Matthew Thomas Holt
Identification Of A Functional Hotspot On Ubiquitin Required For Stimulation Of Methyltransferase Activity On Chromatin, Matthew Thomas Holt
Student Theses and Dissertations
Histone post-translational modifications modulate chromatin structure and function either by directly altering the intrinsic physical properties of the chromatin fiber or by nucleating the recruitment and activity of a host of transacting nuclear factors. Histone ubiquitylation is one class of histone PTMs where the 76 amino acid protein, ubiquitin, is ligated to the ε-nitrogen of a lysine amino acid residue within the histone substrate. 36 unique ubiquitin sites across the 4 canonical histones have been annotated, with 7 of these sites associated with chromatin-templated processes. One such modification, the ubiquitylation of Histone H2B at lysine 120 (H2B-Ub) is enriched at …
Abdominal-B Neurons Control Drosophila Virgin Female Receptivity, Jennifer J. Bussell
Abdominal-B Neurons Control Drosophila Virgin Female Receptivity, Jennifer J. Bussell
Student Theses and Dissertations
To choose their mates, male and female vinegar flies (Drosophila melanogaster) perform a duet of stereotyped, sexually dimorphic courtship behaviors, a suite of sensory back-and-forth that offers an excellent model for studying the neural circuitry of complex behavior (Dickson, 2008). However, the study of Drosophila courtship has focused overwhelmingly on the male, and little is known about how the female evaluates male courtship to decide whether to mate and how she executes that decision by slowing down and opening vaginal plates, a process known as receptivity. To expand the mechanistic understanding of Drosophila receptivity, we set out to identify neurons …
Studies Of A Novel Phage Lytic Enzyme, Plyss2, Daniel B. Gilmer
Studies Of A Novel Phage Lytic Enzyme, Plyss2, Daniel B. Gilmer
Student Theses and Dissertations
Streptococcus suis infects pigs worldwide and may be zoonotically transmitted to humans with a mortality rate of up to 20%. Methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pyogenes (group A streptococci – GrAS) cause potentially fatal human diseases. These are just three of the many Gram-positive pathogens for which resistance to leading antibiotics has emerged. The goal of this work was to develop a novel antimicrobial treatment to combat these and other antibiotic-resistant pathogens. We identified a novel bacteriophage lysin, derived from an S. suis phage termed PlySs2 (phage lysin from S. suis 2). This thesis is divided into four main …
Chromatin Control Of The Antiviral Response To Influenza, Jessica Sook Yuin Ho
Chromatin Control Of The Antiviral Response To Influenza, Jessica Sook Yuin Ho
Student Theses and Dissertations
A key development for our understanding of the mechanisms that control gene expression has been the finding that the histones recruit proteins with effector functions to chromatin. This is mediated primarily by post-translational modifications that occur on the histone N-terminal domains (“tails”). Single or combinations of histone tail modifications serve as scaffolds for protein complexes controlling transcription or co-transcriptional processes, thus impacting gene expression. Histone tail modifications are regulated by multiple, often overlapping pathways in the cell, and as such, present an important regulatory “node” through which the cell is able to integrate and respond to environmental signals. However, a …
The Neuropeptide Regulation Of Host-Seeking Behavior In Aedes Aegypti Mosquitoes, Jeff Liesch
The Neuropeptide Regulation Of Host-Seeking Behavior In Aedes Aegypti Mosquitoes, Jeff Liesch
Student Theses and Dissertations
Aedes aegypti mosquitoes are the principal vectors for several human diseases including Dengue Fever, which causes ~400 million cases and ~24,000 deaths per year (Bhatt et al., 2013; WHO, 2002). Novel strategies to combat mosquito-borne diseases are needed for A. aegypti and other mosquitoes such as the malaria vector Anopheles gambiae. Our goal was to discover new ways to interfere with the ability of a mosquito to locate a human host for a blood meal. Currently, the mechanistic basis of host-seeking and its regulation remain incompletely understood. Although it is known that mosquitoes require human odor cues to locate a …
Hiv Specific B Cell Response In Patients With Broadly Neutralizing Serum Activity, Johannes F. Scheid
Hiv Specific B Cell Response In Patients With Broadly Neutralizing Serum Activity, Johannes F. Scheid
Student Theses and Dissertations
Antibodies to conserved epitopes on the HIV surface protein gp140 can protect against infection in non-human primates, suggesting that vaccines that elicit such antibodies would be protective. Some HIV infected individuals develop high titers of broadly neutralizing IgG antibodies in their serum, but until recently very little was known about the specificity and activity of these antibodies. To characterize the broadly neutralizing memory antibody responses to HIV we cloned 1078 antibodies from HIV envelope binding memory B cells from eight HIV infected patients with broadly neutralizing antibodies. We found that in these patients, the B cell memory response to gp140 …
Exploration Of Cell Cycle-Specific Essential Gene Functions In The Microbial Plant Chlamydomonas Reinhardtii, Frej Tulin
Exploration Of Cell Cycle-Specific Essential Gene Functions In The Microbial Plant Chlamydomonas Reinhardtii, Frej Tulin
Student Theses and Dissertations
The cell cycle encompasses all the steps required for cell proliferation, and is normally tightly coupled to growth and division in all organisms. Much research has resulted in a well-supported model of eukaryotic cell cycle control. However, since most of this research has been carried out in yeast and animals (opisthokonts), it could in principle apply poorly to early-diverging groups of organisms, such as the green plants. Plant cell cycle research has largely followed a candidate strategy based on reverse genetics. These studies have a provided insights into plant cell cycle control, but are generally dependent upon sequence conservation between …
Mechanism And Evolutionary Origins Of Hiv-1 Virion Entrapment By Tetherin, Siddarth Venkatesh
Mechanism And Evolutionary Origins Of Hiv-1 Virion Entrapment By Tetherin, Siddarth Venkatesh
Student Theses and Dissertations
The cellular restriction factor, tetherin, prevents HIV-1 and other enveloped virus particles from being disseminated into the extracellular milieu by infiltrating their envelopes and by physically crosslinking them to the cell surface. However, the mechanisms underlying virion retention have not yet been fully delineated. In this body of work, we employed biochemical assays and engineered tetherin proteins to demonstrate conclusively that virion tethers are composed of the tetherin protein itself, and to elucidate the configuration and topology that tetherin adopts during virion entrapment. We demonstrated that tetherin dimers adopt an “axial” configuration, in which pairs of transmembrane domains or pairs …
The Structural And Biochemical Characterization Of Salmonella Host Specificity Determinant Gifsy-2 Gene E, Amanda C. Kohler
The Structural And Biochemical Characterization Of Salmonella Host Specificity Determinant Gifsy-2 Gene E, Amanda C. Kohler
Student Theses and Dissertations
Salmonella enterica continues to be a significant public health concern, causing an estimated 93.8 million cases of non-typhoidal salmonellosis and 21 million cases of typhoid fever worldwide each year. There are thousands of Salmonella enterica serovars, some with a very specific host set, and others that cause disease in rodents, birds, livestock, domestic fowl, and humans alike. In recent years, there has been much progress in the delineation of Salmonella infection, with the goal of understanding Salmonella pathogenesis at the molecular level. Salmonella produces many different effector proteins capable of interacting with and altering numerous biological pathways in the host …
Stochastic Activation Of Enhancers In The Innate Immune Response By The Histone Demethylase Jmjd2d, Rohit Chandwani
Stochastic Activation Of Enhancers In The Innate Immune Response By The Histone Demethylase Jmjd2d, Rohit Chandwani
Student Theses and Dissertations
The architecture of chromatin is complex and plays a substantial role in all of the biological processes involving DNA. In particular, transcriptional activation depends on the interplay of dozens of chromatin modifiers to establish an epigenetic landscape permissive of gene transcription. Among the most dynamic histone modifications are the acetylation and methylation at histone 3 lysine 9, but the precise roles of their modifiers in conserved transcriptional programs remain unknown. Using the poly I:C-induced transcriptional response in MEFs as our model, we find that JMJD2d is a positive regulator of type I interferon responses. siRNA-depletion of the H3K9 demethylase JMJD2d …
Mutations In A Mechanosensitive Channel Enable Intravascular Metaststic Cell Survival, Paul William Furlow
Mutations In A Mechanosensitive Channel Enable Intravascular Metaststic Cell Survival, Paul William Furlow
Student Theses and Dissertations
Next-generation sequencing technology has revolutionized cancer biology by accelerating the unbiased discovery of mutations across human cancers 1-4. Despite this advance, it remains unknown whether there exist mutations that function specifically to drive steps in the metastatic cascade independent from, or perhaps even to the detriment of, tumor initiation and growth 5. The development and implementation of a discovery framework that integrates next-generation RNA-sequencing with in vivo selection, has identified recurrent non-synonymous amino acid mutations that are enriched in metastatic breast cancer cells and predicted to significantly alter protein function. The pro-metastatic role of one of these mutations—a nonsense alteration …
Rna Deregulation In Metastatic Breast Cancer, Christina Beate Marney
Rna Deregulation In Metastatic Breast Cancer, Christina Beate Marney
Student Theses and Dissertations
Breast cancer is the most commonly diagnosed and second highest cause of cancer-related mortality in women, with the majority of deaths associated with metastatic spread of tumors to distal organs. The metastatic process involves multiple sequential steps including invasion of the surrounding stroma, intravasation into lymph or blood vessels, survival during transport with successful evasion of the immune system, extravasation and final outgrowth in the new microenvironment. At each step cells acquire new properties through the alteration of gene expression profiles. While a great deal of effort has been made towards understanding the underlying genetic mutations associated with enhanced motility …
Split Inteins: From Mechanistic Studies To Novel Protein Engineering Technologies, Neel H. Shah
Split Inteins: From Mechanistic Studies To Novel Protein Engineering Technologies, Neel H. Shah
Student Theses and Dissertations
Inteins are auto-processing protein domains that carry out a post-translational process known as protein splicing. This process is characterized by excision of the intein (intervening protein) domain from within a larger polypeptide sequence with concomitant ligation of the flanking extein ( external protein) regions through a native peptide bond. Remarkably, a small subset of all inteins are naturally transcribed and translated as two fragments that efficiently associate and carry out the same biochemical process in trans, and these split inteins are potentially powerful tools for protein engineering. Recently, a split intein from …
Transcriptome-Wide Characterization Of Apobec1-Catalyzed Rna Editing Events In Macrophages, Claire Ellen Hamilton
Transcriptome-Wide Characterization Of Apobec1-Catalyzed Rna Editing Events In Macrophages, Claire Ellen Hamilton
Student Theses and Dissertations
RNA editing refers to the process by which the sequence of RNA is altered through the insertion, deletion or modification of specific nucleotides. Editing of mRNA transcripts can increase the informational complexity encoded by the genome by producing alternative protein isoforms through specific posttranscriptional RNA editing events. Additionally, RNA editing in non-coding regions of mRNA transcripts has been shown to influence gene expression in a tissue-specific manner. In mammals, mRNA editing serves a diverse set of biological roles in neuronal function, host defense and lipid metabolism. The major mRNA editors acting in mammals include the adenosine deaminases acting on RNA …