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Articles 1 - 30 of 39
Full-Text Articles in Life Sciences
Phds, Stress, And Starvation: The Identification Of A New Rpd3 Deacetylase Complex Involved In The Yeast Oxidative Stress And Metabolism Pathways, Lindsey A. Baker
Phds, Stress, And Starvation: The Identification Of A New Rpd3 Deacetylase Complex Involved In The Yeast Oxidative Stress And Metabolism Pathways, Lindsey A. Baker
Student Theses and Dissertations
The cellular pathways that govern survival in the face of diverse stresses rely on gene expression changes as one mechanism to respond to or protect against internal and external threats. Because eukaryotic DNA is packaged into chromatin, these gene expression changes depend on the targeting of regulatory proteins to specifi c regions of the genome to alter chromatin structure, promoting or repressing transcription. One protein domain involved in targeting chromatin regulators is the plant homeodomain, or PHD fi nger, a module that preferentially interacts with either methylated or unmethylated lysines on histones, and has important functions in human health. Despite …
Analysis Of Behavior In Populations Of Swimming Microbes, David Jordan
Analysis Of Behavior In Populations Of Swimming Microbes, David Jordan
Student Theses and Dissertations
This work describes our work developing an experimental biological system to study patterns of behavioral variability. We selected motility as the behavior of in- terest because it is common throughout biology and can be recorded and analyzed relatively easily. We chose to work with a microbe, Tetrahymena thermophila, as a model organism for these studies; it is easy to grow in the laboratory in controlled con- ditions, has a relatively short generation time, and is large enough to for its motions to be easily imaged. To achieve the imaging, we developed a set of low cost digital video microscopes. Concurrently, …
Structural And Functional Studies Of Slo K+ Channels: Mechanisms Of Gating By Intracellular Signaling, Manuel D. Leonetti
Structural And Functional Studies Of Slo K+ Channels: Mechanisms Of Gating By Intracellular Signaling, Manuel D. Leonetti
Student Theses and Dissertations
Eukaryotic K+ channels from the SLO family (SLO1, SLO2 and SLO3) provide a link between intracellular signaling and the electrical activity of a cell. The opening and closing (gating) of the three different SLO homologs is controlled by the synergistic action of membrane voltage and specific intracellular cues: Ca2+ binding in SLO1, Na+ binding in SLO2 and pH increase in SLO3. It is known that intracellular signals activate SLO channels by acting on the large cytoplasmic domains (CTDs) of these proteins, which follows the transmembrane ionconduction pore. However, a molecular description of the mechanisms of intracellular gating in SLO channels …
Glia Delimit Shape Changes Of Sensory Neuron Receptive Endings In C. Elegans, Carl Procko
Glia Delimit Shape Changes Of Sensory Neuron Receptive Endings In C. Elegans, Carl Procko
Student Theses and Dissertations
Neuronal receptive endings such as dendritic spines and sensory protrusions are structurally remodeled by experience. How receptive endings acquire their remodeled shapes is not well understood. In response to environmental stressors, including starvation, crowding and high temperature, the nematode Caenorhabditis elegans enters a diapause state, termed dauer, which is accompanied by remodeling of sensory neuron receptive endings. Here, we demonstrate that sensory receptive endings of the AWC amphid neurons in dauer animals remodel in the confines of a compartment defined by the amphid sheath glial cells that envelop these endings. The glia remodel concomitantly with and independently of AWC receptive …
Dissecting Mammalian Replication-Independent Chromatin Assembly €“ Biochemical And Structural Studies On The H3.3-Specific Histone Chaperones Hira And Daxx, Simon Elsässer
Student Theses and Dissertations
Histones are architectural proteins that wrap approximately two turns of DNA around their octameric core structure, constituting the fundamental packaging unit of eukaryotic chromatin – the nucleosome. Beyond their structural role, they regulate virtually all processes that act on or depend on DNA, such as replication, gene expression and maintenance of centromeres and telomeres. Despite the high conservation of the four core histones, H3, H4, H2A and H2B, throughout all eukaryotes, histone variants have emerged with variable degree of divergence from their canonical counterparts. These variants are thought to expand the regulatory repertoire of chromatin. The histone replacement variant H3.3 …
Wip1 Phage Specificity For B. Anthracis, Sherry Kan
Wip1 Phage Specificity For B. Anthracis, Sherry Kan
Student Theses and Dissertations
Bacteriophage-based diagnostics and therapeutics have been recognized as tools to combat bacterial infections for nearly a century. Wip1 is a recently isolated phage that infects Bacillus anthracis, the notorious biothreat pathogen and gram-positive bacterium that causes anthrax disease. The current standard for identifying suspected B. anthracis involves testing for Wγ phage sensitivity. However, studies have shown that the narrow Wip1 host range is even more specific to B. anthracis than that of Wγ, suggesting that Wip1 may be a superior diagnostic tool. Wip1’s high specificity to B. anthracis is likely mediated by the initial recognition and binding of the virus …
Genetic Variation In Neurotransmitter Receptors Generates Behavioral Diversity, Andres Bendesky
Genetic Variation In Neurotransmitter Receptors Generates Behavioral Diversity, Andres Bendesky
Student Theses and Dissertations
Variation in behavior among individuals is both remarkable and of great significance to society. People differ in locomotor skills, in sleep patterns, in their willingness to take risks, and in how they relate to other people. Whereas diversity enriches society, extreme behavioral deviations can be pathological, so it is important to identify the causes of behavioral variability. It is clear that both the environment and genetics contribute to behavioral diversity in all animals, but the nature of the specific genes involved is only beginning to emerge. The nematode worm Caenorhabditis elegans is a good animal model to study the genetic …
Efforts Toward Production Of Novel Natural Products From Uncultured Soil Microbes, Jacob Joseph Banik
Efforts Toward Production Of Novel Natural Products From Uncultured Soil Microbes, Jacob Joseph Banik
Student Theses and Dissertations
The isolation of small molecule natural products from bacteria has led to the identification of many of the antibiotics currently in use today. Within the last 25 years, in fact, natural products (and their derivatives) account for almost three quarters of all antibiotic discoveries (Newman and Cragg). The discovery of novel natural product antibiotics, however, has witnessed a significant drop in numbers over this time period, suggesting that new sources of small molecules may be necessary to keep up with the need for new antibacterial compounds (Newman and Cragg). Due to the emergence of bacteria resistant to commonly used antibiotics, …
The Extent And Nature Of Chromosomal Rearrangements In B Lymphocytes, Isaac Andrew Klein
The Extent And Nature Of Chromosomal Rearrangements In B Lymphocytes, Isaac Andrew Klein
Student Theses and Dissertations
Chromosomal rearrangements, including translocations, require formation and joining of DNA double strand breaks (DSBs). These events disrupt the integrity of the genome and are frequently involved in producing leukemias, lymphomas and sarcomas. Mature B cell lymphomas are unique among tumors in that they frequently carry clonal recurrent translocations. This may be the result of Activation Induced Cytidine Deaminase (AID) expression, which introduces a heretofore uncharacterized array of rearrangements. Despite the importance of these events, current understanding of their genesis is limited. To examine the origins of chromosomal rearrangements we developed Translocation Capture Sequencing (TC-Seq), a method to document chromosomal rearrangements …
Chemical Reporters For Investigating Lipidated Proteins At The Host-Pathogen Interface, Guillaume Charron
Chemical Reporters For Investigating Lipidated Proteins At The Host-Pathogen Interface, Guillaume Charron
Student Theses and Dissertations
Lipidation of proteins regulates many cellular processes such as signaling transduction and membrane sorting by modulating protein localization and proteinprotein interactions. As such, defects in protein lipidation can render host cells more susceptible to microbial infection and are also associated with a variety of human diseases ranging from cancer to neurological disorders. Moreover, viral and bacterial pathogens can exploit and modulate the host lipidation machinery to enhance infection. Robust biochemical methods for characterizing lipidated proteins are therefore important for understanding fundamental physiology and disease mechanisms. In this thesis, I report the development of alkyne-lipid chemical reporters that afford more sensitive …
The Diversity Of Cortical Interneurons, Miho Nakajima
The Diversity Of Cortical Interneurons, Miho Nakajima
Student Theses and Dissertations
The cortex is involved in diverse higher cognitive processes including decision making,motor planning, sensory discrimination, and memory consolidation. The cortical interneurons are key elements of the cortical system. These interneurons stabilize networks, but at the same time they also add non-linear effects to the excitatory system to make the cortical network more dynamic. To achieve this, cortical interneurons form a very heterogeneous group, making it hard to classify them without markers. We took a BACtrap approach performing translating ribosome affinity purifications on transgenic mice with Bacterial artificial chromosome, for systematic discovery of markers for different cell types. First, we generated …
Conserved And Novel Properties Of Clathrin-Mediated Endocytosis In Dictyostelium Discoideum, Laura Macro
Conserved And Novel Properties Of Clathrin-Mediated Endocytosis In Dictyostelium Discoideum, Laura Macro
Student Theses and Dissertations
The protein clathrin mediates one of the major pathways of endocytosis from the extracellular milieu and plasma membrane. Clathrin functions with a network of interacting accessory proteins, one of which is the adaptor complex AP-2, to co-ordinate vesicle formation. Disruption of genes involved in clathrin-mediated endocytosis causes embryonic lethality in multicellular animals suggesting that clathrin-mediated endocytosis is a fundamental cellular process. However, loss of clathrin-mediated endocytosis genes in single cell eukaryotes, such as S.cerevisiae (yeast), does not cause lethality, suggesting that clathrin may convey specific advantages for multicellularity. Furthermore, the spatiotemporal dynamics and requirements for individual components of the clathrin-mediated …
The Gluk4 Kainate Receptor Subunit Regulates Mood, Memory And Excitotoxic Neurodegeneration, Emily Rhodes Lowry
The Gluk4 Kainate Receptor Subunit Regulates Mood, Memory And Excitotoxic Neurodegeneration, Emily Rhodes Lowry
Student Theses and Dissertations
Though the GluK4 kainate receptor subunit shows limited homology and a restricted expression pattern relative to other kainate receptor subunits, its ablation results in distinct behavioral and molecular phenotypes. To study the function of GluK4, I generated a global GluK4 knockout mouse line by crossing a germline-expressed cre transgenic mouse line with a GluK4-floxed mouse line in which exon 16 of GRIK4, the gene encoding GluK4, was flanked by lox-P sites (floxed). Thorough characterization of GluK4 expression in the resulting knockout mice using RT-PCR and a custom-designed anti-GluK4 antibody revealed that GRIK4 mRNA expression persisted though GluK4 protein expression was …
Exploring Synaptic Vesicle Exocytosis, Pablo Ariel
Exploring Synaptic Vesicle Exocytosis, Pablo Ariel
Student Theses and Dissertations
The strength of a synapse is an important variable that will affect the function of neural circuits. This thesis develops optical techniques to study determinants of presynaptic efficiency. Our methods are largely based on a chimera of a pH-sensitive variant of the green fluorescent protein and the vesicular glutamate transporter. This reporter is incorporated into synaptic vesicles and increases its fluorescence when those vesicles fuse with the presynaptic membrane. Using this reporter, we measure the size of the primed pool of vesicles (n), a privileged subset of synaptic vesicles which are docked at the active zone and can immediately fuse …
Characterization Of The Central Cavity Of A Potassium Channel: Helix Dipoles, Conformational Plasticity And Inhibition, Disan Schold Davis
Characterization Of The Central Cavity Of A Potassium Channel: Helix Dipoles, Conformational Plasticity And Inhibition, Disan Schold Davis
Student Theses and Dissertations
Potassium channels are important for regulating the flow of potassium ions across semi-permeable cell membranes in an efficient and selective manner. Potassium channels form a conduction pore comprised of a selectivity filter responsible for the strong preference for potassium, and a water-filled central cavity that contributes to rapid conduction by lowering the energy barrier for potassium ions to cross the low dielectric membrane environment. In the high resolution structure of the potassium channel KcsA, a hydrated potassium ion was observed in the central cavity. It was proposed that some electrostatic stabilization for this potassium ion may come from the backbone …
Dissecting Synaptic Vesicle Endocytosis, Moritz Armbruster
Dissecting Synaptic Vesicle Endocytosis, Moritz Armbruster
Student Theses and Dissertations
Synaptic vesicle endocytosis is critical for ensuring rapid local recycling of synaptic vesicles to enable ongoing neuronal activity. We utilized the sensitivity and robustness of the pHluorin assay of synaptic vesicle recycling to probe the control of endocytosis spatially and in response to varying stimulation conditions. We examined the role of the large GTPases dynamin 1 and dynamin 3 in synaptic vesicle endocytosis; which have been thought to be essential for the ssion of budding vesicles from the plasma membrane. Dynamin 1, 3 and 1/3 double knockouts indicated that there is redundant presynaptic function of the proteins. Loss of either …
Chemical Reporters For Bacterial Pathogenesis And Beyond, Markus Grammel
Chemical Reporters For Bacterial Pathogenesis And Beyond, Markus Grammel
Student Theses and Dissertations
Microbial infection involves complex and dynamic interplay of host defense and pathogen virulence pathways that requires new methods for mechanistic investigation. Towards this goal, I have developed chemical reporters of nucleic acid and protein synthesis and posttranslational modifications to explore their functions in bacterial pathogenesis as well as basic biological pathways. Initially, I developed amino acid chemical reporters that allow the cell-selective labeling of bacterial proteomes to facilitate the analysis of bacterial protein expression during infection of host cells. These reporters are based on unnatural amino acids that are incorporated into the bacterial proteome instead of methionine or phenylalanine when …
Protein Phosphatase 1 At The Kinetochore Regulates Chromosome Segregation, Jessica Scott Rosenberg
Protein Phosphatase 1 At The Kinetochore Regulates Chromosome Segregation, Jessica Scott Rosenberg
Student Theses and Dissertations
Two regulatory mechanisms exist to ensure proper chromosome segregation in mitosis. First, improper kinetochore-microtubule attachments are destabilized through the error correction machinery. Second, the spindle assembly checkpoint (SAC) delays anaphase onset until all kinetochores have achieved bioriented microtubule attachments. Both of these mechanisms are mediated by several centromeric and kinetochore kinases, including Aurora B. Protein Phosphatase 1 (PP1) plays a counteracting role to Aurora B to stabilize kinetochore-microtubule attachments and silence the SAC. The regulation of PP1 to modulate these functions, however, remains enigmatic. Using the biochemical tools available in the Xenopus egg extract system, I show here that PP1 …
The Neural Circuit For Behavioral Responses To Pheromone And Social Behavior In Caenorhabditis Elegans, Heeun Jang
The Neural Circuit For Behavioral Responses To Pheromone And Social Behavior In Caenorhabditis Elegans, Heeun Jang
Student Theses and Dissertations
Social behavior is a widespread phenomenon across species from microorganisms to humans. Chemical communication using pheromones is particularly interesting for its versatile use in many organisms, and has been studied at both molecular and circuit levels. However, the central issue of how genes and molecular components contribute to neural circuits that eventually lead to complex social behaviors remains unclear. Using the nematode model organism Caenorhabditis elegans, I have examined two behavioral responses to pheromones, pheromone avoidance and pheromoneregulated social aggregation behavior, at genetic and circuit levels. The known C. elegans pheromones are a set of related compounds called ascarosides. Specific …
Variability In Singing And In Song In The Zebra Finch, Cameron Wellock
Variability In Singing And In Song In The Zebra Finch, Cameron Wellock
Student Theses and Dissertations
Variability is a defining feature of the oscine song learning process, reflected in song and in the neural pathways involved in song learning. For the zebra finch, juveniles learning to sing typically exhibit a high degree of vocal variability, and this variability appears to be driven by a key brain nucleus. It has been suggested that this variability is a necessary part of a trial-Ââ€and-Ââ€error learning process in which the bird must search for possible improvements to its song. Our work examines the role this variability plays in learning in two ways: through behavioral experiments with juvenile zebra finches, and …
Approaches To Study Small Molecule Inhibitors And Their Targets, Sarah Anne Wacker
Approaches To Study Small Molecule Inhibitors And Their Targets, Sarah Anne Wacker
Student Theses and Dissertations
Bioactive small molecules are valuable tools to understand and manipulate biological pathways. In order to be effective as either probes for understanding cell biology or as clinical drugs, the small molecule’s mechanism of action must be characterized. However, identifying a small molecule’s target and characterizing its interaction with that target remain major challenges in the chemical biology field. In this thesis, I describe methods to improve the process of drug target identification and binding site characterization. In order to identify the target of a small molecule, I have developed an approach in which multiple drug resistant clones are isolated and …
Vocal Handedness: The Emergence Of Lateralization At Fledging, Rudy Bellani
Vocal Handedness: The Emergence Of Lateralization At Fledging, Rudy Bellani
Student Theses and Dissertations
Adult waterslager canaries produce the majority of their song under the control of the left hemisphere / left syringeal half. Unilateral section of the left treacheosyringeal nerve results in near complete loss of song while right denervation affects only a subset of call elements. This strong asymmetry for the production of a learned vocalization is reminiscent of the left hemisphere control for language in humans and provides a potentially powerful animal model to study lateralized behaviors in the vertebrate brain. ! Earlier work on another songbird, the European chaffinch, Friungilla crebes, suggested that the onset of lateralized vocalizations occured before …
Structure Function Analysis Of Adenosine Deaminase Acting On Trna (Adat2) From Trypanosoma Brucei, Miller Marshall
Structure Function Analysis Of Adenosine Deaminase Acting On Trna (Adat2) From Trypanosoma Brucei, Miller Marshall
Student Theses and Dissertations
tRNA is edited at the wobble position of the anticodon to accommodate the degeneracy of the genetic code. The enzymes responsible for deamination of adenosine 34 to inosine are found in all organisms and in all but a few cases are essential for life. In bacteria the reaction is carried out by the homodimeric adenosine deaminase acting on tRNA (ADAT) and modifies only tRNAarg, whereas in eukarya the enzyme is the ADAT2/3 heterodimer, which performs the same reaction on all tRNA molecules with adenosine at position 34. Despite a similar evolutionary origin, the characteristics of these two enzymes are significantly …
The Application Of Functional Metagenomics To Natural Products Research, Jeffrey William Craig
The Application Of Functional Metagenomics To Natural Products Research, Jeffrey William Craig
Student Theses and Dissertations
The study of bacterial natural products offers important insights into the physiologies and behaviors of individual species of bacteria as well as the contributions of these organisms to complex microbial communities. Such information frequently has important downstream applications in medicine, industry, agriculture, biotechnology, basic sciences and applied microbiology. The majority of bacteria found in nature cannot be cultivated in a laboratory setting, however, leaving a wealth of genetic and chemical diversity unexplored by traditional microbiological methods. Culture-independent approaches for studying diverse microbial populations affords indirect access to these resources. Within the wide array of culture-independent approaches currently in use (collectively …
Progress Towards Integrated Models Of Hcv Dynamics, Thomas S. Oh
Progress Towards Integrated Models Of Hcv Dynamics, Thomas S. Oh
Student Theses and Dissertations
Hepatitis C virus is a small, enveloped positiveâ€strand RNA member of the Flaviviridae and the etiological agent of a global epidemic of chronic hepatitis C. One of the salient features of HCV is a complex regulatory scheme involving numerous viral and cellular components and which may be the key to its striking success in initiating and maintaining decadesâ€long chronic disease in infected individuals. Lacking any known latent or integrated form, HCV must persist through ongoing RNA replication, immune evasion, and infection of naïve cells. HCV is a highlyâ€studied virus, and many details of its life cycle have been worked out; …
Mechanisms That Ensure The Proper Terminal Structure Of Mammalian Telomeres, Peng Wu
Mechanisms That Ensure The Proper Terminal Structure Of Mammalian Telomeres, Peng Wu
Student Theses and Dissertations
The telomeric single-stranded 3’ overhang, a conserved feature at the ends of linear chromosomes, is thought to contribute to the important functions of end protection and telomere length homeostasis. Here, I investigated the mechanism by which the overhang is generated and maintained at mammalian telomeres. First, I evaluated the terminal chromatin structure of mouse telomeres using conventional micrococcal nuclease (MNase) assays and a novel method to examine the terminal nucleosomes adjacent to the telomeric overhang. In wild type mouse embryonic fibroblasts (MEFs), the telomeric overhang was protected from MNase digestion of chromatin in nuclei. In addition, the induction of various …
The Expression Of The Zinc Finger Transcription Factor Zdc Defines The Classical Dendritic Cell Lineage, Matthew M. Meredith
The Expression Of The Zinc Finger Transcription Factor Zdc Defines The Classical Dendritic Cell Lineage, Matthew M. Meredith
Student Theses and Dissertations
Classical dendritic cells (cDCs) are a critical component of the immune system due to their roles in the maintenance of immune tolerance and the induction of adaptive immune responses. However, distinguishing cDCs from other myeloid populations is complicated by the lack of highly specific cDC markers. For example, high expression of the integrin CD11c is used to define cDCs, but this marker is also expressed at lower levels by plasmacytoid dendritic cells, monocyte and macrophage subsets, and some lymphocytes. Similarly, the use of the CD11c promoter to drive the expression of different reporters in cDCs likewise affects these additional populations. …
Develoment And Application Of Chemical Strategies To Study Protein Fatty-Acylation In Eukaryotes, Mingzi Zhang
Develoment And Application Of Chemical Strategies To Study Protein Fatty-Acylation In Eukaryotes, Mingzi Zhang
Student Theses and Dissertations
Reversible S-palmitoylation confers spatiotemporal control of protein function by modulating protein stability, trafficking and activity as well as protein-protein and membrane-protein associations. While it is evident that palmitoylation is regulated in vivo, mechanisms that mediate cellular stimuli-driven changes of the lipid modification are not understood. Furthermore, the requirement for substrate specificity among the highly redundant palmitoyl acyltransferases (PATs) remains unresolved. To study the regulation of PATs and palmitoylomes, I developed bioorthogonal chemical strategies for improved analysis of dynamic palmitoylation in mammalian cells. I showed that alkyne-functionalized fatty acids, in conjunction with azido-fluorophores, provide the most sensitive detection of acylated proteins …
Structure And Organization Of Nuclear Pore Proteins, Claire Atkinson
Structure And Organization Of Nuclear Pore Proteins, Claire Atkinson
Student Theses and Dissertations
The nuclear pore complex (NPC) is a large macromolecular assembly that controls the flow of molecules between the nucleus and the cytoplasm. Elucidating the structure and organization of this complex will be crucial to understanding the mechanism of nucleocytoplasmic transport, but due to its size, the NPC presents a challenge to structure determination. There are electron microscopy (EM) structures of the entire NPC, and high resolution crystal structures of some of the individual components have been solved, but the arrangement of proteins within the overall complex remains unknown. An approach to solving structures of macromolecular complexes is to fit high …
Induction Of Innate And Adaptive Immunity In Vivo By Selective Antibody Targeting Of Poly Da:Dt And Antigen To Dendritic Cells, Scott A. Barbuto
Induction Of Innate And Adaptive Immunity In Vivo By Selective Antibody Targeting Of Poly Da:Dt And Antigen To Dendritic Cells, Scott A. Barbuto
Student Theses and Dissertations
Dendritic cells (DCs) have been shown to be efficient and specialized in antigen presentation, but innate stimuli have not been selectively delivered to determine if these cells alone can integrate innate and adaptive immunity in vivo. Here we illustrate a novel method using expressed protein ligation (EPL) to attach the immune stimulant, poly dA:dT, to the DC uptake receptor, DEC205 (DEC). We will show that inoculation of α- DEC-poly dA:dT fusion monoclonal antibodies (mAbs) is sufficient to induce rapid innate cytokine production by DCs. Adaptive T cell immunity is also elicited when the fusion mAb is given in combination with …