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Articles 1 - 26 of 26
Full-Text Articles in Life Sciences
Crystal Structure And Mechanism Of Lysine Specific Demethylase-1, Pete G. Stravropoulos
Crystal Structure And Mechanism Of Lysine Specific Demethylase-1, Pete G. Stravropoulos
Student Theses and Dissertations
The reversible methylation of specific lysine residues in histone tails is crucial in epigenetic gene regulation. LSD1, the first known lysine-specific demethylase, selectively removes monomethyl and dimethyl, but not trimethyl modifications of Lys4 or Lys9 of histone-3. Here, we present the crystal structure of LSD1 at 2.9-A resolution. LSD1 forms a highly asymmetric, closely packed domain structure from which a long helical 'tower' domain protrudes. The active site cavity is spacious enough to accommodate several residues of the histone tail substrate, but does not appear capable of recognizing the different methylation states of the substrate lysine. This supports the hypothesis …
The Role Of Gdf-3 In Patterning The Early Embryo, Ariel Levine
The Role Of Gdf-3 In Patterning The Early Embryo, Ariel Levine
Student Theses and Dissertations
The central aim of modern embryology is the resolution of the signaling pathways and transcriptional networks that direct embryonic development. After a century of rich experimental embryology, more recent molecular analyses of embryogenesis have revealed that communication between cells drives some of the most important events of development, including cell fate determination, growth, and morphogenesis. Among signaling factors, the TGF-β superfamily regulates all of these phenomena, and is the focus of this work. Despite significant progress in understanding the role of individual TGF-β ligands, their ultimate integration as a pathway is not fully understood and several ligands remain unexplored. In …
The Differential Contribution Of Striatonigral And Striatopallidal Neurons In Mediating Responses To Therapeutic Agents And Drugs Of Abuse: A Dual Role For Darpp-32, Helen S. Bateup
Student Theses and Dissertations
The basal ganglia are a set of subcortical structures which integrate information from diverse brain areas to coordinate vital behaviors including movement, reward, and motivational processes. The striatum is the main input center of the basal ganglia which sends projections to the output nuclei via two pathways, the direct striatonigral pathway and the indirect striatopallidal pathway. These two pathways work together to modulate behavior and imbalance of these pathways can have profound physiological consequences. DARPP-32 is a dual function kinase/phosphatase inhibitor which has been shown to be a key mediator of signaling in both striatonigral and triatopallidal neurons. A variety …
The Hu Syndrome: At The Intersection Of Cancer And Autoimmunity, Ilana J. Deluca
The Hu Syndrome: At The Intersection Of Cancer And Autoimmunity, Ilana J. Deluca
Student Theses and Dissertations
Paraneoplastic neurologic diseases (PNDs) arise when systemic malignancies express proteins normally restricted to neurons. Abnormal expression of a neuronal protein by tumor cells in the periphery results in an autoimmune response that then targets both the tumor and the nervous system. These diseases offer a unique opportunity to gain insight into the mechanisms behind both tumor immunity and neuronal autoimmunity. The Hu syndrome is an example of PND that affects patients with small cell lung cancer (SCLC). Hu patients are diagnosed by the presence of antibodies in the blood that recognize the HuD antigen. HuD is normally restricted in expression …
Conditional Protein Alleles And Regulation Of Bacterial Transcription: A Thesis In Two Acts, Edmund Ching Schwartz
Conditional Protein Alleles And Regulation Of Bacterial Transcription: A Thesis In Two Acts, Edmund Ching Schwartz
Student Theses and Dissertations
The use of small molecule modulators of protein function (drugs) has gained in popularity due to the speed and precision with which they can work. Unfortunately, a small molecule with the required specificity and potency is not always available. We have developed two methods to generate small molecule sensitive protein alleles without the need to screen for a new drug. In the first, which we term conditional protein splicing (CPS), an intein is split into two inactive fragments which are activated by heterodimerization. By fragmenting the target protein and fusing the pieces to this split intein, we were able to …
Proteomic, Bioinformatic And Functional Characterization Of The Nuclear Pore Complex Of The African Trypanosome, Jeffrey Allen Degrasse
Proteomic, Bioinformatic And Functional Characterization Of The Nuclear Pore Complex Of The African Trypanosome, Jeffrey Allen Degrasse
Student Theses and Dissertations
The eukaryotic genome, and its associated proteins, is intricately packaged and sequestered within the boundary of a double membrane, known as the nuclear envelope (NE). Transport across the NE is mediated by large protein assemblages known as nuclear pore complexes (NPCs). Yeast and vertebrate NPCs are comprised of about 30 proteins, termed nucleoporins (Nups), which are present in multiple copies. The origins and evolution of the nucleus and NPC are not yet clear, although it seems likely that the nucleus arose only once in eukaryotic evolution. To further our understanding of the evolution of the NPC, we characterized the NPC …
A Structural And Biochemical Analysis Of The Drosophila Protein Period, Heather Anne King
A Structural And Biochemical Analysis Of The Drosophila Protein Period, Heather Anne King
Student Theses and Dissertations
Circadian clocks regulate changes in behavior and physiology that occur with a period of approximately 24 hours and are based on negative feedback loops. The molecular components of circadian clocks are conserved among animals, and a key element in all such clocks is the protein Period (PER), a circadian transcription inhibitor. The stable production, posttranslational modification, and nuclear translocation of PER all contribute to the timing of the clock. This work describes the synthesis and purification of various Drosophila PER fragments for biochemical and crystallographic analysis. Several stable PER fragments are identified, including one crystallizable fragment. The structure of the …
Dividing The Preplate: Characterization Of Neuronal Subpopulations In The Early Murine Cerebral Cortex, Hilleary Botts Osheroff
Dividing The Preplate: Characterization Of Neuronal Subpopulations In The Early Murine Cerebral Cortex, Hilleary Botts Osheroff
Student Theses and Dissertations
The preplate is a transient layer of the developing cerebral cortex which is comprised of the earliest generated cortical neurons. Preplate neurons are a heterogenous population of future Cajal-Retzius neurons and future subplate neurons, which are derived from multiple sources of progenitors. During the formation of the cortical layers, the preplate is split into an upper marginal zone and the lower subplate layer by the radial migration of projection neurons from the cortical ventricular zone. Cajal-Retzius and subplate neurons have important developmental functions in regulating radial migration and in pioneering corticofugal projections. The genetic mechanisms of preplate neuron specification are …
Visualizing Dendritic Cells In Vivo, Randall L. Lindquist
Visualizing Dendritic Cells In Vivo, Randall L. Lindquist
Student Theses and Dissertations
Cell:cell interactions are critical at all stages of the immune response, yet relatively little is known about their dynamics in vivo. We set out to visualize in intact, living lymphoid tissue the physiological role of dendritic cells in tolerance and immunity; this was achieved by intravital microscopy of fluorescently-labeled DCs and lymphocytes in the inguinal lymph nodes. We generated mice that specifically expressed EYFP in their dendritic cells and observed their behavior in living LNs; we found that in the steady state, DCs formed sessile networks and largely restricted their movements to probing with their dendrites. We next observed dendritic …
Cracking The Odor Code: Molecular And Cellular Deconstruction Of The Olfactory Circuit Of Drosophila Larvae, Kenta Asahina
Cracking The Odor Code: Molecular And Cellular Deconstruction Of The Olfactory Circuit Of Drosophila Larvae, Kenta Asahina
Student Theses and Dissertations
The Drosophila larva offers a powerful model system to investigate the general principles by which the olfactory system processes behaviorally relevant sensory stimuli. The numerically reduced larval olfactory system relieves the formidable molecular and cellular complexity found in other organisms. This thesis presents a study in four parts that investigates molecular and neuronal mechanisms of larval odor coding. First, the larval odorant receptor (OR) repertoire was characterized. ORs define the olfactory receptive range of an animal. Each of the 21 larval olfactory sensory neurons (OSNs) expresses one or rarely two ORs, along with the highly conserved olfactory co-receptor Or83b. Second, …
Semi-Synthesis Of The Transcription Factor Smad2 Containing Caging Groups And Phosphoaminoacid Analogues, Michael Eric Hahn
Semi-Synthesis Of The Transcription Factor Smad2 Containing Caging Groups And Phosphoaminoacid Analogues, Michael Eric Hahn
Student Theses and Dissertations
Post-translational modification (PTM) of a protein refers to any chemical change that occurs to the protein after its ribosomal synthesis. The seemingly endless number of PTMs can endow proteins with new functionalities that are not present in the unmodified proteins. In order to study the functions of PTMs on a given protein, it is often necessary to have access to pure preparations of the modified protein and its analogues. Traditional biological methods frequently do not allow for the isolation of significant amounts of pure modified proteins, therefore chemical methods are often employed in this regard. Protein semi-synthesis is a chemical …
Structural Analysis Of Cycle Inhibiting Factor From Pathogenic Escherichia Coli, Yun-Yuan Hsu
Structural Analysis Of Cycle Inhibiting Factor From Pathogenic Escherichia Coli, Yun-Yuan Hsu
Student Theses and Dissertations
Bacterial pathogens have evolved a sophisticated arsenal of virulence factors to modulate host cell biology. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) use a type III protein secretion system (T3SS) to inject microbial proteins into host cells. These translocated proteins possess a diverse array of biochemical activities, reprogramming eukaryotic cell biochemistry to serve the requirements of the pathogen. Examples of translocated effector proteins hijacking essential host functions such as cytoskeleton assembly, vesicular transport, and apoptosis are numerous (Galan and Wolf-Watz, 2006). However, until recently, less progress had been made with bacteria that also possess virulence mechanisms that target the …
Dendritic Cell Regulation Of Peripheral Tolerance In Polyclonal T Cell Repertoires, Revati F. Masilamani
Dendritic Cell Regulation Of Peripheral Tolerance In Polyclonal T Cell Repertoires, Revati F. Masilamani
Student Theses and Dissertations
Dendritic cells (DCs) play a pivotal role in determining whether the outcome of the immune system's encounter with antigen will be immunity or tolerance. Using an antibody against the DEC-205 receptor, antigens have been delivered specifically to DCs in vivo. Under steady state conditions, such presentation of antigen leads to peripheral tolerance in transgenic T cells, either by deletion, anergy or the induction of regulatory T cells. We wanted to examine whether delivery of autoantigens to DCs using this approach, could be used to tolerize autoreactive polyclonal T cells, thereby preventing autoimmunity in mouse models. We succeeded in inducing tolerance …
Further Insight Into The Two Functions Of Telomeres: Determining The Role Of Tankyrase1 In Telomere Length Regulation And Tin2 In Telomere Protection, Jill Donigian
Student Theses and Dissertations
Tankyrase1 is a multifunctional poly(ADP-ribose) polymerase that can localize to telomeres through its interaction with the shelterin component TRF1. Tankyrase1 poly(ADP-ribosyl)ates TRF1 in vitro, and its nuclear overexpression leads to loss of TRF1 and telomere elongation, suggesting that tankyrase1 is a positive regulator of telomere length. In agreement with this proposal, we showed that tankyrase1 RNA interference results in telomere shortening proportional to the level of knockdown, while a tankyrase1-resistant form of TRF1 enforced normal telomere length control. Thus, in human cells, tankyrase1 appears to act upstream of TRF1, promoting telomere elongation through the removal of TRF1. This pathway appears …
Discovery Of The First Endogenous Gain Of Function Mutation In Drosophila Ras1 As A Dominant Suppressor Of Apoptosis, Christopher Gafuik
Discovery Of The First Endogenous Gain Of Function Mutation In Drosophila Ras1 As A Dominant Suppressor Of Apoptosis, Christopher Gafuik
Student Theses and Dissertations
The development of multicellular organisms requires a tight coordination of cell proliferation, cell differentiation and cell death in order to correctly specify cell fate and number. According to the trophic theory of survival, this is achieved in part by a competition between cells in a tissue for a limited number of extracellular survival factors. Cells that do not receive sufficient quantities of these survival cues engage a default cell death program and are thereby eliminated. This ‘social control’ of cell survival ensures the integrity of tissues by matching the correct number of different cell types to each other. Apoptosis is …
Small Molecules As Probes For Cell Division And Intracellular Transport, Ulf Peters
Small Molecules As Probes For Cell Division And Intracellular Transport, Ulf Peters
Student Theses and Dissertations
Cell-permeable small molecules that can act on their targets on fast time scales are powerful probes of cell division mechanisms and intracellular transport processes. Phenotype-based screens with chemical libraries have been used to identify such inhibitors. However, probes for most proteins are still not available, and the requirements on compound collections to yield such probes are not well understood. Here I present two approaches to find and use such probes. First, in an attempt to find probes for cell division, I have shown that a small collection of 100 diaminopyrimidines yielded a range of cell division phenotypes, including changes in …
A Novel Phosphorylation Site In The Telomeric Protein Trf2 Is Regulated By The Atr Kinase And Plays A Role In Relieving Replication Stress At The Telomere, Kristina Hoke
Student Theses and Dissertations
Phosphatidyl inositol 3-kinase-like kinases (PIKKs) have a well documented function at yeast telomeres. Although several lines of evidence suggest that members of the PIKK family also play a role in vertebrate telomere biology, little is known about their specific functions. We report that the human shelterin component, TRF2, overexpressed in 293T cells, is phosphorylated on serine 368 (S368) in a caffeine and wortmannin sensitive manner. Phosphorylation is induced by hydroxyurea (HU) and ultraviolet (UV) radiation but not Ionizing Radiation (IR). Knockdown studies indicate that ATR is the primary kinase responsible for TRF2 S368 phosphorylation, while the mTOR kinase is implicated …
Histone Modifications In Trypanosoma Brucei, Veena Mandava
Histone Modifications In Trypanosoma Brucei, Veena Mandava
Student Theses and Dissertations
Trypanosoma brucei maintains an infection in its mammalian host by switching its surface antigen, thus evading host antibodies, in a process known as antigenic variation. Variant surface glycoproteins (VSG), the surface antigen, are expressed from genes located at as many as 20 Expression Sites (ES), which are present in subtelomeric regions of several chromosomes. How trypanosomes maintain monoallelic expression of VSG is a major question in trypanosome biology. Several theories have been proposed, including the presence of an Expression Site Body (a dedicated ‘transcription factory’), regulation of RNA elongation, and some kind of transcriptionally restrictive chromatin structure at inactive ES. …
Cellular And Molecular Mechanisms Underlying Leptin’S Metabolic Effects, Amandeep Singh
Cellular And Molecular Mechanisms Underlying Leptin’S Metabolic Effects, Amandeep Singh
Student Theses and Dissertations
Obesity is rapidly increasing in prevalence, and has become one of the leading contributors to poor health in the world. Increased body weight by necessity must be a result of increased nutrient intake relative to total energy expenditure. While many have focused on the importance of caloric consumption in determining weight, it is increasingly clear that differences in energy expenditure, basal metabolic rates and/or adaptive thermogenesis are also important variables that contribute to human obesity. The experiments in this thesis start off by demonstrating that a significant portion of leptin-mediated weight loss is the result of an increase in energy …
Role Of Aid And Microrna-155 In C-Myc-Igh Translocations, Yair Dorsett
Role Of Aid And Microrna-155 In C-Myc-Igh Translocations, Yair Dorsett
Student Theses and Dissertations
Chromosome translocations between oncogenes and the immunoglobulin (Ig) region spanning the variable (V), diversity (D) and joining (J) genes (Ig V-JH region) are found in a number of mature B cell lymphomas in humans and mice. The breakpoints are frequently adjacent to the recombination signal sequences (RSSs) targeted by recombinase activating genes 1 and 2 (RAG1/2) during antigen receptor assembly in pre- B cells, suggesting that these translocations might be the result of aberrant V(D)J recombination. However, in mature B cells undergoing AID dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double strand break make up 6% …
Dendritic Cells In Normal And Inflamed Human Skin, Lisa C. Zaba
Dendritic Cells In Normal And Inflamed Human Skin, Lisa C. Zaba
Student Theses and Dissertations
Psoriasis is a skin disease originally thought to be a primary keratinocyte differentiation and maturation disease. Several T cell targeted theraputics were found to reverse disease, and thus subsequent research has focussed on the adaptive immune system, particularly effector CD8+ T cells infiltrating the epidermis. Recent studies, however, show that inhibitors of tumor necrosis factor (TNF) are also effective therapeutics. Activated dendritic cells (DCs) produce large ammounts of TNF which acts in an autocrine loop to increase DC maturation. Thus, TNF inhibitors may inhibit DC maturation and downstream T cell activation. This thesis elucidates DC subsets present in normal human …
Structural And Computational Studies Of Rna Polymerase, William J. Lane
Structural And Computational Studies Of Rna Polymerase, William J. Lane
Student Theses and Dissertations
Although the multi-subunit RNA Polymerase (RNAP) structures have revolutionized our understanding of transcription, we still do not fully understand the molecular details of bacterial promoter recognition and melting. In addition, our understanding is generally limited to highly conserved elements of the structure, with little focus on the bacterial lineage-specific domain insertions. Furthermore, we lack information about the hidden functional residue networks that underlie the activities of this complex multi-subunit molecular machine. By combining structural and computational methods we: (1) Used X-ray crystallography to investigate promoter -35 element recognition by domain 4 of the Group IV sigma factors, revealing that conserved …
The Apollo Nuclease Binds To Trf2 And Protects, Megan Van Overbeek
The Apollo Nuclease Binds To Trf2 And Protects, Megan Van Overbeek
Student Theses and Dissertations
Members of the β-CASP family of proteins are involved in DNA repair and RNA processing. We identified a member of this family of enzymes, hSNM1B/Apollo, in complex with the telomere binding proteins TRF2/Rap1. Due to its low abundance at telomeres, we consider Apollo to be a telomere accessory factor, and not part of the core telomere protein complex, shelterin. Apollo localizes to telomeres by interacting directly with the TRFH domain of TRF2. Structural analysis of this interaction revealed an interface in the TRFH domain of TRF2 that is predicted to be shared by numerous accessory factors recruited to the telomere …
Bioluminescence-Based High Precision Bacterial Growth Rate Measurements And Their Potential Application In Quantifying Deleterious Effects Of High Mutation Rates, Sri Ram
Student Theses and Dissertations
The genomic mutation rate of wild-type Escherichia coli is 3 10 per generation, a value that is shared by many DNA-based microbes and viruses. A majority of clinical isolates of E. coli also have a mutation rate that is close to the wild-type value. These findings raise the possibility that the observed mutation rate is constrained by some universal evolutionary forces. In many laboratory settings, however, strains with high mutation rate (mutator strains) have been shown to outcompete otherwise isogenic wildtype cells. These results have been explained by positing that mutators offer a short-term benefit in the form of …
Tuning Of The Active Hair Bundle, Omar Ahmad
Tuning Of The Active Hair Bundle, Omar Ahmad
Student Theses and Dissertations
The organs of the inner ear rely upon a population of several thousand sensory hair cells to amplify and transduce acoustic, seismic, and kinesthetic signals. Each hair cell detects mechanical disturbances by means of its hair bundle, a motile organelle consisting of actin-filled, villous projections (called stereocilia) endowed with assemblies (called adaptation motors) of mechano-sensitive ion channels and myosin molecules that power both spontaneous and evoked movements. Active hair-bundle motility serves two functions: it mechanically amplifies sensory stimuli; and it regulates their transduction into electrical signals that drive the hair-cell synapse. To characterize these two functions, we consider here a …
Identification Of Loss Of Specific Fmrp-Rna Interactions As A Cause Of Fragile X Syndrome, Julie B. Zang
Identification Of Loss Of Specific Fmrp-Rna Interactions As A Cause Of Fragile X Syndrome, Julie B. Zang
Student Theses and Dissertations
Fragile X Syndrome presents with a clinical picture of moderate to severe mental retardation and behavioral abnormalities including autistic features resulting from the loss of function of a RNA-binding protein, Fragile X mental retardation protein (FMRP). This work is devoted to the understanding of functional roles of FMRP in normal neuronal development and in the pathogenesis of the Fragile X Syndrome. Particularly it focuses on the study of FMRP RNA binding properties, using both mouse models and biochemical analyses. The disease is usually caused by a triplet repeat expansion in the 5’UTR of the FMR1 gene leading to loss of …