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Genomic Approaches For Pathway Identification In Regenerating Sensory Epithelia Of The Inner Ear, David Alvarado
Genomic Approaches For Pathway Identification In Regenerating Sensory Epithelia Of The Inner Ear, David Alvarado
All Theses and Dissertations (ETDs)
The inner ear utilizes sensory hair cells as mechano-electric transducers for sensing sound and balance. In mammals, these sensory hair cells lack the capacity for regeneration and if damaged lead to hearing or balance disorders. However, non-mammalian vertebrates such as birds maintain their regenerative abilities throughout their life. We completed a gene expression profiling time course of regenerating sensory epithelia: SE) in avian cochlea and utricle on a custom transcription factor microarray following damage by laser and chemical ablation and identified genes from known signaling cascades differentially expressed during SE regeneration. In the second study, we selected 27 of these …
Integrated Genomics Of Susceptiblity To Therapy-Related Leukemia, Patrick Cahan
Integrated Genomics Of Susceptiblity To Therapy-Related Leukemia, Patrick Cahan
All Theses and Dissertations (ETDs)
Therapy-related acute myeloid leukemia t-AML is a secondary, generally incurable, malignancy attributable to the chemotherapeutic treatment of an initial disease. Although there is a genetic component to susceptibility to therapy-related leukemias in mice, little is understood either about the contributing loci, or the mechanisms by which susceptibility factors mediate their effect. An improved understanding of susceptibility factors and the biological processes in which they act may lead to the development of t-AML prevention strategies. In this thesis work, we identified expression networks that are associated with t-AML susceptibility in mice. These networks are robust in that they emerge from distinct …
Growth Factor Delivery From Fibrin Matrics Containing Affinity-Based Delivery Systems To Treat Peripheral Nerve Injury, Matthew Wood
Growth Factor Delivery From Fibrin Matrics Containing Affinity-Based Delivery Systems To Treat Peripheral Nerve Injury, Matthew Wood
All Theses and Dissertations (ETDs)
This thesis work sought to develop a biomaterial to further the understanding of affinity-based delivery and to serve as a potential treatment for peripheral nerve injury. The use of an affinity-based delivery system: ABDS) with growth factors in a nerve guidance conduit: NGC) was hypothesized to promote nerve regeneration and functional recovery following a critical nerve defect. Evaluation of affinity-based delivery using peptides with varying binding affinity for heparin determined that peptide binding affinity for heparin affected the release rate and biological activity of nerve growth factor: NGF) in vitro. The ABDS presented biologically active NGF, which promoted neurite extension …
Genetic And Biochemical Properties Of Arabidopsis Rna Polymerases Iv And V, Jeremy Haag
Genetic And Biochemical Properties Of Arabidopsis Rna Polymerases Iv And V, Jeremy Haag
All Theses and Dissertations (ETDs)
RNA Polymerases IV and V: Pol IV and Pol V) are plant-specific enzyme complexes with subunit homology to RNA Polymerase II: Pol II). The largest subunits in Pol IV and Pol V, NRPD1 and NRPE1 respectively, share a second largest subunit, NRPD2/NRPE2. The evolutionarily conserved Metal A and Metal B binding sites are required for Pol IV and V in vivo function fitting the prediction that these are functional polymerases. The Defective Chloroplast and Leaves-like: DeCL) domain at the C-terminus of both NRPD1 and NRPE1 is also required for complementation but other domains in the NRPE1 CTD are largely dispensable. …
A New Quantitative Method For The Taxonomic Identification Of Tetrapods, Stephanie Kuster
A New Quantitative Method For The Taxonomic Identification Of Tetrapods, Stephanie Kuster
All Theses and Dissertations (ETDs)
The rarity of good fossil samples throughout geologic time frequently makes fossil identification difficult. This dissertation presents a new, multivariate, statistically validated method to identify tetrapods based on quantification of the shapes of microstructural features in cortical bone of the postcranial skeleton. The ultimate goal is to reduce the reliance on rare, near-complete fossil skeletons. The method is validated on a set of 15,745 mammalian microstructural features from eleven diverse species. An additional set of 21,122 microstructural features from one species serve to examine microstructural variation within a single skeleton. Microstructural measurements were made on thin-sections using optical microscopy. Initial …
Dissecting The Molecular Mechanisms Underlying Synpase Development And Neuronal Functions In Caenorhabditis Elegans, Shuo Luo
All Theses and Dissertations (ETDs)
The development and function of the nervous system is under delicate regulation of diverse tissue-derived signals in multi-cellular organisms. In Dr. Nonet's lab, I am using the model organism Caenorhabditis elegans to ask two basic questions: 1) How do different tissues in an organism coordinate to regulate neural functions and behaviors? 2) What controls the development of synapse, the basic unit of the nervous system? These questions divide my dissertation into three parts, with the first two parts related to the first question and the third part to the second question. In the first part of this dissertation, I present …
Engineering The Optical Properties Of Gold Nanostructures For Biomedical Applications, Leslie Au
Engineering The Optical Properties Of Gold Nanostructures For Biomedical Applications, Leslie Au
All Theses and Dissertations (ETDs)
This research investigated the synthesis and optical properties of Au nanostructures with an aim to use them as imaging agents and photothermal transducers for the diagnosis and treatment of cancer. I have produced Au nanocages with hollow interiors and porous walls using the galvanic replacement reaction between Ag nanocubes and AuCl4-. I have engineered these Au nanocages to have localized surface plasmon resonance: LSPR) peaks in the near-infrared region with strong absorption. These optical properties allow for the imaging of biological tissues at deeper penetration and the photoablation of cancer. By replacing AuCl4- with AuCl2 …
Uropathogenic E. Coli Employ A Conserved Intracellular Infection Pathway That Can Be Inhibited By Novel Anti-Virulence Therapeutics, Corinne Cusumano
Uropathogenic E. Coli Employ A Conserved Intracellular Infection Pathway That Can Be Inhibited By Novel Anti-Virulence Therapeutics, Corinne Cusumano
All Theses and Dissertations (ETDs)
Urinary tract infections: UTIs) affect 13 million women annually in the United States and are predominately caused by uropathogenic Escherichia coli: UPEC). In a murine cystitis model, UPEC utilize a multistep pathogenic pathway in which they invade and form intracellular bacterial communities: IBCs) within bladder facet cells. Type 1 pili expressing the adhesin, FimH, are necessary for UPEC binding and invasion of urothelial cells and formation of IBCs. UPEC ultimately disperse from the IBC, many with filamentous morphology, and infect other host urothelial cells. Using a panel of UPEC clinical isolates, this work evaluates the conservation of the IBC pathway …
Mechanisms Of Feedback In The Visual System, Adam Eggebrecht
Mechanisms Of Feedback In The Visual System, Adam Eggebrecht
All Theses and Dissertations (ETDs)
Feedback is an ubiquitous feature of neural systems though there is little consensus on the roles of mechanisms involved with feedback. We set up an in vivo preparation to study and characterize an accessible and isolated feedback loop within the visual system of the leopard frog, Rana pipiens. We recorded extracellularly within the nucleus isthmi, a nucleus providing direct topographic feedback to the optic tectum, a nucleus that receives the vast majority of retinal output. The optic tectum and nucleus isthmi of the amphibian are homologous structures to the superior colliculus and parabigeminal nucleus in mammals, respectively. We formulated a …
Identification And Characterization Of Novel Astroviruses, Stacy Finkbeiner
Identification And Characterization Of Novel Astroviruses, Stacy Finkbeiner
All Theses and Dissertations (ETDs)
Approximately 1.8 million children die from diarrhea annually, and millions more suffer multiple episodes of nonfatal diarrhea. Despite the availability of improved molecular diagnostics to detect the known viral agents, the etiology of a large proportion of diarrheal cases is unknown. In fact, it is estimated that no causative agent can be identified in up to 40% of sporadic cases or in gastroenteritis outbreaks. Detection of novel or unexpected viruses is the first step in identifying agents that could potentially close the diagnostic gap and pave the way for the development of more comprehensive preventative measures and better treatments. This …
Accurate Docking Is Achieved By Decoupling Systematic Sampling From Scoring, Jianwen Feng
Accurate Docking Is Achieved By Decoupling Systematic Sampling From Scoring, Jianwen Feng
All Theses and Dissertations (ETDs)
This dissertation discusses two main projects from my thesis work. The first project focuses on the development of a small molecule docking program, SKATE, for drug discovery. The second project focuses on the critical analysis of the thermal stability of a mini-protein, FSD-1. SKATE is a novel approach to small molecule docking. It removes any inter-dependence between sampling and scoring to improve docking accuracy. SKATE systematically and exhaustively samples a ligand's conformational, rotational and translational degrees of freedom, as constrained by a receptor pocket, to find sterically allowed poses. A total of 266 ligands were re-docked to their respective receptors …
A Quest For Meaning In Spontaneous Brain Activity - From Fmri To Electrophysiology To Complexity Science, Biyu He
All Theses and Dissertations (ETDs)
The brain is not a silent, complex input/output system waiting to be driven by external stimuli; instead, it is a closed, self-referential system operating on its own with sensory information modulating rather than determining its activity. Ongoing spontaneous brain activity costs the majority of the brain's energy budget, maintains the brain's functional architecture, and makes predictions about the environment and the future. I have completed three separate studies on the functional significance and the organization of spontaneous brain activity. The first study showed that strokes disrupt large-scale network coherence in the spontaneous functional magnetic resonance imaging: fMRI) signals, and that …
In Vivo Function Of Otopetrin 1 In The Vestibular Sensory Epithelium, Euysoo Kim
In Vivo Function Of Otopetrin 1 In The Vestibular Sensory Epithelium, Euysoo Kim
All Theses and Dissertations (ETDs)
Otopetrin family genes encode multi-transmembrane domain proteins with three highly conserved domains. In mice, three Otopetrin paralogues are found. One of its members, Otopetrin 1: Otop1) has been previously shown to be essential for the formation of otoconia in the vestibular system of the inner ear. Otoconia are calcium carbonate biominerals that are required for normal balance and the sensation of linear acceleration with respect to gravity. The mechanism by which OTOP1 mediates otoconia biosynthesis is not known, but the ability of OTOP1 to modulate [Ca2+]i in response to purinergic signals in heterologous systems suggest that OTOP1 may be involved …
Evolution Of Endosperm Starch Synthesis Pathway Genes In The Context Of Rice: Oryza Sativa) Domestication, Guoqin Yu
All Theses and Dissertations (ETDs)
The evolution of metabolic pathways is a fundamental but poorly understood aspect of evolutionary change. The rice endosperm starch biosynthetic pathway is one of the most thoroughly characterized biosynthesis pathways in plants, and starch is a trait that has evolved in response to strong selection during rice domestication and subsequent crop improvement. In this study, I have examined six key genes in the rice endosperm starch biosynthesis pathway to investigate the evolution of this pathway before rice domestication and during rice domestication. Oryza rufipogon is the wild ancestor of cultivated rice: Oryza sativa). Oryza sativa has five variety groups: aus, …
The Role Of Astrocyte Activation In Infantile Neuronal Ceroid Lipofuscinosis, Shannon Macauley-Rambach
The Role Of Astrocyte Activation In Infantile Neuronal Ceroid Lipofuscinosis, Shannon Macauley-Rambach
All Theses and Dissertations (ETDs)
Infantile neuronal ceroid lipofuscinoses: INCLs), or Batten Disease, is an inherited neurodegenerative lysosomal storage disorder affecting the central nervous system: CNS) during infancy or childhood. Hallmark pathological changes include accumulation of autofluorescent material, neuronal loss, cortical thinning, and brain atrophy, which ultimately lead to cognitive deficits, motor dysfunction, seizure activity, and blindness. INCL is the result of mutations in the CLN1 gene leading to a deficiency in the lysosomal enzyme, palmitoyl protein thioesterase 1: PPT1). A mouse model of INCL, the PPT1-deficient: PPT1-/-) mouse, was recently created by a targeted disruption in the CLN1 gene. The phenotype of the PPT1-/- …
A Role For The Ecdysone Response Gene E93 In Imaginaling Patterning During Metamorphosis, Xiaochun Mou
A Role For The Ecdysone Response Gene E93 In Imaginaling Patterning During Metamorphosis, Xiaochun Mou
All Theses and Dissertations (ETDs)
Drosophila melanogaster E93 is an early ecdysone response gene that encodes a pipsqueak domain transcription factor. E93 is induced by ecdysone at the end of larval development, and directs the death and elimination of several larval tissues during metamorphosis. Although E93 has been considered a dedicated regulator of larval cell death, I have found that E93 is also widely expressed in imaginal tissues during metamorphosis, where it is required for the proper patterning of many adult structures. Our working hypothesis is that E93 functions in imaginal tissues as a metamorphosis-specific cofactor that determines the pupa-specific action of numerous other transcription …
Flap Endonuclease 1 Ensures Telomere Replication And Stability, Abhishek Saharia
Flap Endonuclease 1 Ensures Telomere Replication And Stability, Abhishek Saharia
All Theses and Dissertations (ETDs)
Telomeres, protein-DNA structures that distinguish the end of a chromosome from a bona fide DNA double strand break, are integral to genomic stability. High fidelity replication of telomeres is indispensable for their stability. Telomere replication is a challenging task that is completed through the coordinated actions of telomere binding proteins and DNA replication and repair proteins in ways that are not well understood. This work focuses on delineating the function of one DNA replication and repair protein, Flap Endonulcease 1: FEN1), in telomere replication and maintenance. I demonstrate that FEN1 is essential for the efficient replication of telomeres through its …
The Mechanisms And Roles Of Feedback Loops For Visual Processing, Jing Shao
The Mechanisms And Roles Of Feedback Loops For Visual Processing, Jing Shao
All Theses and Dissertations (ETDs)
Signal flow in the brain is not unidirectional; feedback represents a key element in neural signal processing. To address the question on how do neural feedback loops work in terms of synapses, microcircuitry, and systems dynamics, we developed a chick midbrain slice preparation to study and characterize one important feedback loop within the avian visual system: isthmotectal feedbackloop. The isthmotectal feedback loop consists of the optic tectum: OT) and three nucleus isthmi: Imc, Ipc and SLu. The tectal layer 10 neurons project to ipsilateral Imc, Ipc and SLu in a topographic way. In turn Ipc and SLu send back topographical: …
Role And Regulation Of Escrt-Iii In Multivesiculr Body Biogenesis, Soomin Shim
Role And Regulation Of Escrt-Iii In Multivesiculr Body Biogenesis, Soomin Shim
All Theses and Dissertations (ETDs)
Endosomal sorting complex required for transports: ESCRT) machinery responsible for multivesicular body: MVB) biogenesis is essential for receptor downregulation, viral budding and cytokinesis. ESCRT-III is a large polymer built from related ESCRT-III proteins that is thought to help generate intralumenal vesicles: ILVs) within the MVB. How ESCRT-III functions is poorly understood. Although ESCRT-III assembles on the endosomal membrane, its components are predominantly soluble in the cytoplasm. I found that the transition between these two states is controlled by autoinhibitory domains within ESCRT-III proteins, which I identified by structure/ function analysis in four human ESCRT-III proteins - Charged multivesicular body protein2A: …
Identification And Characterization Of A Xylosylphosphotransferase Of Cryptococcus Neoformans, Morgann Reilly
Identification And Characterization Of A Xylosylphosphotransferase Of Cryptococcus Neoformans, Morgann Reilly
All Theses and Dissertations (ETDs)
Cryptococcus neoformans is an environmental yeast and an opportunistic pathogen capable of causing a meningoencephalitis in human hosts. The organism produces an extensive polysaccharide capsule that is unique among pathogenic fungi and absolutely required for its virulence. Work in the Doering laboratory on the capsule and other glycoconjugates of C. neoformans has focused on the identification of glycosyltransferases, enzymes that catalyze the transfer of a sugar moiety from an active donor to a specific acceptor, creating a particular linkage. Previous work demonstrated that xylose residues, derived from the nucleotide sugar UDP-xylose, are necessary for cryptococcal virulence. An assay to detect …
Systemic Levels Of G-Csf And Il-6 Determine The Angiogenic Potential Of Bone Marrow Resident Monocytes, Alyssa Gregory
Systemic Levels Of G-Csf And Il-6 Determine The Angiogenic Potential Of Bone Marrow Resident Monocytes, Alyssa Gregory
All Theses and Dissertations (ETDs)
Recent studies have demonstrated the efficacy of hematopoietic cell-based therapies in promoting therapeutic angiogenesis for a wide variety of vascular syndromes, however the cell populations responsible and the mechanisms involved are poorly understood. Using a mouse model of hindlimb ischemia, we previously showed that an adoptive transfer of donor monocytes significantly enhanced revascularization. Monocytes are a widely heterogeneous cell population and differences in the ability of various monocyte subsets to mediate revascularization have not been previously investigated. Using the hindlimb ischemia model we demonstrate that an adoptive transfer of inflammatory: CX3CR loGr-1+), but not resident: CX3CR1hiGr-1-) monocytes, significantly enhances revascularization …
Coordinate Interstitial Deletions Of Retinoblastoma (Rb1) And Neurobeachin (Nbea) Genes On Chromosome 13 In Mgus And Multiple Myeloma, Julie O'Neal
All Theses and Dissertations (ETDs)
ABSTRACT OF THE DISSERTATION Coordinate interstitial deletions of Retinoblastoma: RB1) and Neurobeachin: NBEA) genes on chromosome 13 in monoclonal gammopathy of undetermined significance: MGUS) and multiple myeloma By Julie O'Neal Doctor of Philosophy in Biology and Biomedical Sciences: Molecular and Cellular Biology) Washington University in Saint Louis, 2009 Assistant Professor Michael H. Tomasson, Chair Numeric or structural chromosomal abnormalities are detected in nearly all patients with plasma cell dyscrasias, including primary amyloidosis, monoclonal gammopathy of undetermined significance: MGUS) and multiple myeloma: MM). Chromosome 13 deletions, most frequently monosomy 13, are detected in 10- 20% of MM cases by routine cytogenetics …
Functional Significance Of Glycoprotein Clearance By The Asialoglycoprotein Receptor And The Mannose/Galnac-4-So4 Receptor, Lindsay Steirer Taylor
Functional Significance Of Glycoprotein Clearance By The Asialoglycoprotein Receptor And The Mannose/Galnac-4-So4 Receptor, Lindsay Steirer Taylor
All Theses and Dissertations (ETDs)
Glycosylation plays an important role in many biological functions. Two highly abundant, carbohydrate-specific, endocytic receptors reside in parenchymal and endothelial cells of the liver. Our lab has shown that the asialoglycoprotein receptor: ASGR) is capable of clearing glycoproteins bearing terminal Siaalpha2,6GalNAc as well as ones bearing terminal Gal/ GalNAc and that the Mannose/GalNAc-4-SO4 receptor: MR) is capable of clearing glycoproteins bearing terminal GalNAc-4-SO4. I am taking a genetic approach identifying endogenous ligands for the ASGR and the MR in vivo and establishing the biologic significance of clearing these glycoproteins from the blood. A number of glycosylated hormones such as luteinizing …
Microbial Diversity And Geochemical Energy Sources Of Tutum Bay, Ambitle Island, Papua New Guinea, An Arsenic-Rich, Shallow-Sea Hydrothermal System, Nancy Akerman
All Theses and Dissertations (ETDs)
I investigate the hydrothermal system located in Tutum Bay, Ambitle Island, Papua New Guinea, a shallow-sea system ~5 - 10 meters below sea level that is arsenic-rich. Hydrothermal vents in the bay expel fluids with arsenite: AsIII) concentrations as high as 950 μg/L. To determine the role that Tutum Bay microorganisms might play in mediating As-redox reactions, three approaches were used: analyzing the geochemical environment for energy sources, characterizing the archaeal community composition of the sediments, and conducting culture-dependent As-cycling experiments. The second chapter of this dissertation discusses an energetic study of potential chemolithotrophic metabolic reactions, including As-redox reactions. Results …
Medial Temporal Lobe Structure And Function, Meghana Karnik
Medial Temporal Lobe Structure And Function, Meghana Karnik
All Theses and Dissertations (ETDs)
Medial Temporal Lobe Structure and Function by Meghana Sunil Karnik Doctor of Philosophy in Biology and Biomedical Sciences: Neuroscience) Washington University in St. Louis, 2009 Professor John G. Csernansky, Chairperson My main goal was to examine the relationship between brain structure and function, specifically medial temporal lobe structure and episodic memory, in various groups of subjects who had schizophrenia, were at risk for schizophrenia because of genetic and disease influences, or who were healthy, in order to explore the influence of genetic and disease influences on brain structure-function relationships. Most of what is known about the neural structures thought to …
Computational And Experimental Investigation Of Allosteric Communication In The Transcriptional Regulator Nikr, Michael Bradley
Computational And Experimental Investigation Of Allosteric Communication In The Transcriptional Regulator Nikr, Michael Bradley
All Theses and Dissertations (ETDs)
The Ni2+ and DNA binding protein NikR is involved in nickel regulation in Escherichia coli through transcriptional repression of the NikABCDE nickel permease. NikR is a homotetramer and each chain contains both a DNA binding ribbon-helix-helix: RHH) domain and a Ni2+ binding regulatory ACT: aspartokinase, chorismate mutase, TyrA) fold. Work herein combines computational modeling of NikR structure with experimental studies aimed at understanding allosteric communication between the ACT and RHH domains. Hydrogen/deuterium exchange mass spectrometry shows a Ni2+ specific NikR conformational change relative to bound Cu2+, Co2+, and Zn2+. Concurrent coordination geometry and in vivo repressor function studies show that …
A Phenotypic And Genetic Characterization Of The Cell Adhesion Molecules Echinoid And Friend-Of-Echinoid In The Directed Cell Movements Of Ommatidial Rotation During Drosophila Eye Development., Jennifer Fetting
All Theses and Dissertations (ETDs)
Correct development of multicellular organisms relies on the precise patterning of cells, which must respond to and interpret specific cues that instruct the cells to differentiate and often undergo directed cell movements and rearrangements to give rise to functional tissues and organs. Differential adhesion between the stationary and mobile cells permits and promotes these cellular movements, effecting patterning of cells and tissues. During Drosophila eye development, groups of cells, the ommatidial precursors, undergo a 90° rotational movement within a matrix of stationary cells, providing the cell motility readout of tissue polarity. The mechanisms that regulate ommatidial rotation are not well …
Expression Analysis And Stem Cell Engineering, Cara Rieger
Expression Analysis And Stem Cell Engineering, Cara Rieger
All Theses and Dissertations (ETDs)
The overall goal of the thesis was to develop tools to advance Investigations of stem cells in tissue engineering therapeutics for neurodegenerative disease and spinal cord injury. Two tools to characterize cell fate and a tool to separate a subset of neural cells were developed and evaluated. In the first study, a digital PCR technology, called polonies, was applied to measure mRNA from several key stem cell genes in small numbers of ES cells. Due to its properties, we hypothesized that polonies would be uniquely poised to profile stem cells. Polonies were counted for Oct3 in a sample of 10 …
Modeling And Identification Of Differentially Regulated Genes Using Transcriptomics And Proteomics Data, Thanura Elvitigala
Modeling And Identification Of Differentially Regulated Genes Using Transcriptomics And Proteomics Data, Thanura Elvitigala
All Theses and Dissertations (ETDs)
Photosynthetic organisms are complex dynamical systems, showing a remarkable ability to adapt to different environmental conditions for their survival. Mechanisms underlying the coordination between different cellular processes in these organisms are still poorly understood. In this dissertation we utilize various computational and modeling techniques to analyze transcriptomics and proteomics data sets from several photosynthetic organisms. We try to use changes in expression levels of genes to study responses of these organisms to various environmental conditions such as availability of nutrients, concentrations of chemicals in growth media, and temperature. Three specific problems studied here are transcriptomics modifications in photosynthetic organisms under …
Aggregation & Localization Of A Disease-Associated Prion Protein (Prp) Mutant, Andrea Rhonda Medrano
Aggregation & Localization Of A Disease-Associated Prion Protein (Prp) Mutant, Andrea Rhonda Medrano
All Theses and Dissertations (ETDs)
ABSTRACT OF THE DISSERTATION Aggregation & Localization of a Disease-Associated Prion Protein: PrP) Mutant by Andrea Rhonda Zaragoza Medrano Doctor of Philosophy in Biology and Biomedical Sciences: Genetics) Washington University in St. Louis, 2009 Professor David A. Harris, Chairperson Prion protein: PrP) is a GPI-anchored sialoglycoprotein involved in the pathogenesis of infectious and inherited forms of transmissible spongiform encephalopathies: TSEs). A nine-octapeptide insertional mutation in the prion protein: PrP) causes a fatal neurodegenerative disorder in both humans and transgenic mice. To determine the precise cellular localization of this mutant PrP: designated PG14), we have generated transgenic mice expressing PG14-EGFP, a …