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Excessive Complement Activation Due To Genetic Haploinsufficiency Of Regulators In Multiple Human Diseases, Michael Triebwasser

Arts & Sciences Graduate Student Theses and Dissertations

The complement system is an ancient and powerful form of innate immunity. The alternative pathway (AP), a positive feedback loop, is at the core of the complement system. Activating components and regulators of the AP are genetically implicated in atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). aHUS features kidney failure, and often affects young children, but may occur throughout life and can be precipitated by pregnancy. aHUS associated variants are extremely rare and are considered highly penetrant. At the opposite end of the spectrum, AMD affects the retina leading to loss of central vision with a late …

Guanine Nucleotide Synthesis And The Enteric Nervous System, Jonathan Ian Lake

Arts & Sciences Graduate Student Theses and Dissertations

There are currently no prevention strategies for Hirschsprung disease (HSCR), a potentially lethal birth defect caused by the failure of the enteric nervous system (ENS) to develop completely, resulting in an aganglionic segment of intestine. HSCR can result from one or a combination of partially-penetrant mutations in genes affecting the enteric neural crest-derived cells (ENCDCs) that colonize the intestine to form the ENS. While the genetics of HSCR and ENS development has been extensively studied, little is known about environmental risk factors for HSCR. To investigate maternal medication exposure as a possible HSCR risk factor, we conducted a chemical screen …

Functional Consequences Of Cd4+ T Cell Receptor Ligation In The Immune Response To Listeria Monocytogenes, Stephen Phillip Persaud

Arts & Sciences Graduate Student Theses and Dissertations

Interactions between the ab T cell receptor (TCR) and peptide-bound MHC molecules (pMHC) are highly specific and sensitive despite low affinities. The basis of TCR ligand specificity and its functional manifestations during protective immune responses are incompletely understood. To study this, we have generated two TCR transgenic mice called LLO56 and LLO118, which bear CD4+ T cells that recognize the same dominant epitope from the virulence factor Listeriolysin O (LLO) of Listeria monocytogenes. These TCRs were cloned from Listeria-infected B6 mice, and thus represent two solutions to recognizing the same pathogen-derived pMHC. LLO118 T cells expanded better than LLO56 during …

Ketone Body Metabolism Preserves Hepatic Function During Adaptation To Birth And In Overnutrition, David Graham Cotter

Arts & Sciences Graduate Student Theses and Dissertations

Mammalian ketone body metabolism partially oxidizes hepatic acyl-chains to ketone body intermediates, which can serve as alternative fuels in extrahapetic tissues during carbohydrate restricted states. Ketone body production (ketogenesis) occurs primarily in liver, due to hepatocyte-specific expression of the fate committing ketogenic enzyme, mitochondrial 3-hydroxymethylglutaryl-CoA synthase (HMGCS2). In contrast, the fate committing enzyme of ketone body oxidation, mitochondrial Succinyl-CoA:3-oxoacid CoA Transferase (SCOT), is expressed ubiquitously, except in liver. Here I demonstrate novel roles for ketone body metabolism during a classically ketogenic period, the transition to birth, and in a classically `non-ketogenic' state, overnutrition, using novel genetic mouse models, high-resolution measures …

Mass Spectrometry-Based Strategies For Biomolecular Structure Analysis: Steroid Metabolites Structures And Protein-Protein Interactions, Yuetian Yan

Arts & Sciences Graduate Student Theses and Dissertations

Mass spectrometry is an important method for studying the structure of both small molecules and large biomolecules (e.g., proteins). The majority of the applications prior to 1970 were focused on small molecules, owing to the limited ionization methods which posed difficulties in producing gas-phase ions for large biomolecules then. Beginning in the 1980's, with the introduction of new ionization methods (ESI and MALDI), the applications have gradually switched to biological science measuring large bioorganic molecules. Today, with the developing interest in metabolomics and proteomics, and ongoing improvement in MS-based techniques, mass spectrometry is extensively applied in the study of both …

How Gains And Losses Influence The Brain And Behavior: Relations To Age, Risk For Depression, And Individual Differences, Katherine R. Luking

Arts & Sciences Graduate Student Theses and Dissertations

Behavioral and neural response to rewards and punishments has been the subject of a growing literature with particular interest within developmental, psychopathology, and individual difference domains. There is now mounting evidence suggesting that adolescents show heightened response to reward relative to adults, and that adolescents with Major Depressive Disorder (MDD), elevated depressive symptoms, or at high-risk for depression show reduced response to reward. However, it is unclear whether similar relations between response to incentives and development/psychopathology are observed during childhood. Here we examine behavioral, neural (functional magnetic resonance imaging - fMRI), and self-reported responsiveness to gain and loss of rewards …

Molecular Characterization Of A Novel, Highly Protective Combination Monoclonal Antibody Therapy Against Chikungunya Virus, Pankaj Pal

Arts & Sciences Graduate Student Theses and Dissertations

Chikungunya virus (CHIKV) is an Aedes mosquito-transmitted alphavirus that causes epidemics of a debilitating, often chronic polyarthritis in humans. Over five million people in Africa and Asia have been infected since 2005, and an outbreak occurred recently in Italy demonstrating the potential for a global epidemic. A strong antibody response is elicited during infection and the aim of this thesis was to develop a better understanding of how the humoral immune response can control CHIKV infection. We identified 230 new anti-CHIKV monoclonal antibodies (MAbs) and tested their ability to inhibit infection of strains representing all three CHIKV genotypes (East/Central/South African, …

Genetic And Cellular Studies Of The Podocyte In Focal Segmental Glomerulosclerosis, Haiyang Yu

Arts & Sciences Graduate Student Theses and Dissertations

The podocyte forms the outer layer of the filtration barrier in the glomerulus to prevent albumin leakage. Podocyte damage leads to focal segmental glomerulosclerosis (FSGS), a leading cause of chronic kidney disease. The cause of the majority of FSGS cases is unknown and referred to as sporadic FSGS. Genetic studies have identified genes as monogenic causes of FSGS in patients with a strong family history, but these cases account for only a small proportion of the FSGS population. Whether genetic susceptibility contributes to sporadic FSGS and which cellular process in the podocyte initiates the pathogenesis of FSGS are important questions …

Molecular Mechanisms Of Plasmodium Red Blood Cell Invasion, Brian Michael Malpede

Arts & Sciences Graduate Student Theses and Dissertations

The malaria parasite Plasmodium utilizes specialized proteins for adherence to cellular receptors in its mosquito vector and human host. Adherence is critical for parasite development, host cell traversal and invasion, and protection from vector and host immune mechanisms. These vital roles have identified several adhesins as vaccine candidates. A deficiency in current adhesin-based vaccines is induction of antibodies targeting non-conserved, non-functional, and decoy epitopes due to the use of full length proteins or binding domains. To alleviate the elicitation of non-inhibitory antibodies, conserved functional regions of proteins must be identified and exploited. Structural biology provides the tools necessary to achieve …

Regulation Of Host And Viral Rna Expression During Gammaherpesvirus Infection, Susan Priscilla Canny

Arts & Sciences Graduate Student Theses and Dissertations

Gammaherpesviruses are oncogenic viruses that establish latent infection and can periodically reactivate. Replication, reactivation from latency and gammaherpesvirus-mediated pathology are regulated by viral and host factors. Long-standing interests in the field include understanding viral gene expression and regulation during lytic and latent infection and the effects of chronic viral infection on the host. Murine gammaherpesvirus 68 (MHV68) is used to model features of human gammaherpesvirus biology.In this dissertation, I investigated: (1) the function of antisense viral transcripts; (2) Stat1 regulation of MHV68 gene 50 promoters; and (3) the effect of chronic infection on host gene expression. Our laboratory identified extensive …

Molecular And Computational Methods For Cellular State Control, Drew Groves Michael

Arts & Sciences Graduate Student Theses and Dissertations

The control of cellular state has many promising applications, including stem cell biology andregenerative medicine, biofuel production, and gene therapy. This dissertation demonstrates acomprehensive approach to cellular state control at the transcriptional level. We introduce anovel algorithm, NetSurgeon, which utilizes genome-wide gene regulatory networks to identifyinterventions that will force a cell toward a desired expression state. Following extensive insilico validation, we applied NetSurgeon to S. cerevisiae biofuel production, generatinginterventions designed to promote a fermentative state during xylose catabolism. Our selectedinterventions successfully promoted a fermentative transcriptional state and generated strainswith higher xylose import rates, improved xylose integration and increased ethanol productionrates. …

Neural Processing In The Three Layer Turtle Visual Cortex, Jeffrey Steven Pobst

Arts & Sciences Graduate Student Theses and Dissertations

In this thesis we investigate neural processing in turtle visual cortex. To this end, we characterize the nature of both spontaneous, ongoing neural activity as well as activity evoked by visual stimulation. Data are collected from whole brain eye-attached preparations, recording with extracellular and intracellular electrodes. We investigate the activity of action potentials as well as the slower local field potential activity.To investigate response properties, we explore spatial properties of receptive fields, temporal properties of spontaneous and evoked activity, response adaptation, and correlations between different types of activity as well as between activity recorded in different regions.To study the roles …

Light-Harvesting, Redox Control, And Biomimicry Of The Photosynthetic Antennas Of Green Sulfur Bacteria, Gregory Scott Orf

Arts & Sciences Graduate Student Theses and Dissertations

The green sulfur bacteria (class Chlorobea) are obligately anaerobic photoautotrophic prokaryotes. Members of this bacterial class are found in anoxic, sulfur- or iron-rich environments such as hydrothermal vents and hot springs. These bacteria are champions of lowlight adaptation, with some species being able to thrive photosynthetically on less than eight photons hr-1 per pigment. We have studied the two photosynthetic antenna complexes from these organisms that are responsible for light capture: the chlorosome and the Fenna-Matthews-Olson (FMO) protein.In regards to the chlorosome, we studied, using steady-state and time-resolved spectroscopic methods, the effect of incorporation of an expected, but as-yet-undiscovered-in-nature, light-harvesting …

Single-Chain Rankl Provides Insights Into Rank Receptor Oligomerization And A Novel Approach To Osteoclast Inhibition, Julia Therese Warren

Arts & Sciences Graduate Student Theses and Dissertations

Osteoporosis is a skeletal disease characterized by bone resorption in excess of bone formation. The osteoclast is the sole bone resorbing cell and therefore provides an important avenue for novel therapeutic development. The mature osteoclast is derived from the monocyte/macrophage lineage, and its proper differentiation and function requires the interaction of receptor activator of NF-kB Ligand (RANKL) with its receptor RANK. RANKL exists as a homotrimer, with classical models of receptor activation assuming trimeric clustering of receptor as necessary for signal transduction. We have designed a novel single-chain RANKL (scRANKL) construct to test the assumption that the recruitment of three …

Kinematic Modeling Of The Determinants Of Diastolic Function, Leonid Shmuylovich

Arts & Sciences Graduate Student Theses and Dissertations

Multiple modalities are routinely used in clinical cardiology to determine cardiovascular function, and many of the indexes derived from these modalities are causally interconnected. A correlative approach to cardiovascular function however, where indexes are correlated to disease presence and progression, fails to fully capitalize on the information content of the indexes.Causal quantitative modeling of cardiovascular physiology on the other hand offers a predictive rather than accommodative approach to cardiovascular function determination. In this work we apply a kinematic modeling approach to understanding diastolic function. We discuss novel insights related to the physiological determinants of diastolic function, and define novel causal …

Molecular And Epigenetic Regulation Of Stem Cell Radiosensitivity, Keith Michael Jacobs

Arts & Sciences Graduate Student Theses and Dissertations

Normal tissue injury resulting from ionizing radiation (IR) during cancer radiotherapy has been attributed to reduced regenerative capacity of stem cell compartments. Utilizing multiple in vivo tissue niches and primary culture models, we demonstrate that normal stem cells are highly radiosensitive while their isogenic, directly differentiated progeny are radioresistant. Stem cell dropout is therefore likely responsible for the resulting radiation injury in these niches. This differential radiosensitivity is independent of proliferation status, and increased IR-induced apoptosis in stem cells is more broadly distributed across the cell cycle.We elucidate that stem cells exhibit an attenuated DDR resulting in aberrant cell cycle …

Melittin-Derived Peptides For Sirna Delivery: Mechanisms Of Efficient Cytoplasmic Release, Kirk Kohwa Hou

Arts & Sciences Graduate Student Theses and Dissertations

The development of small molecules as therapeutic agents for targeted disease treatment is unable to keep up with the rapid expansion of databases cataloguing disease-causing proteins enabled by high throughput analysis of patient samples. As an alternative, the use of small interfering RNA (siRNA) provides a simple means of efficiently and specifically silencing the expression of these pathogenic proteins without the need for screening and development required of small molecules. Unfortunately, the delivery of siRNA is not trivial, and existing technology is characterized by either poor siRNA transfection efficiency or induction of cytotoxicity. Detailed work by many groups has supported …

Ion Interactions At The Mineral-Water Interface During Biogeochemical Iron And Manganese Cycling, Margaret A. G. Hinkle

Arts & Sciences Graduate Student Theses and Dissertations

The biogeochemical cycling of iron and manganese involves the reductive dissolution and oxidative precipitation of Fe(III) and Mn(IV/III) oxides. Biogenic Fe(III) and Mn(IV/III) oxides are often characterized by high surface areas and therefore high sorptive capacities. As a result, these minerals can substantially alter the chemistry of natural waters and the availability of micronutrients in soils and sediments by scavenging trace metals. Recent research indicates that the adsorption of aqueous Fe(II) onto Fe(III) oxides involves oxidative adsorption, electron transfer, and subsequent reductive dissolution at another surface site [a process collectively referred to as `electron transfer-atom exchange' (ET-AE)]. Aqueous Mn(II) adsorption …

The Effects Of Hpa Axis Genetic Variation And Early Life Stress On Cortisol Levels In Preschool Age Children And On Amygdala And Hippocampus Volumes, Reactivity, And Connectivity At School Age, David Pagliaccio

Arts & Sciences Graduate Student Theses and Dissertations

Internalizing psychopathology has been linked to increased cortisol reactivity and alterations in limbic brain structure and function, yet the mechanisms underlying these alterations are unclear. One key hypothesis is that stress plays a major causal role in these mechanisms. Animal studies find that chronic stress or glucocorticoid administration lead to alterations in hippocampal and amygdala structure and function. Relatedly, life stress is a major risk factors for depression while candidate gene studies have related variation in hypothalamic-pituitary-adrenal (HPA) axis genes to increased prevalence and severity of depression. The present work tested the hypothesis that genetic profile scores combining variance across …

Viral And Innate Immune Factors Controlling Disease Susceptibility During Chikungunya Virus Infection, Anjali Rohatgi

Arts & Sciences Graduate Student Theses and Dissertations

Chikungunya virus (CHIKV) is a re-emerging pathogen that causes a high fever, painful arthritis and a macular rash. The current outbreak began in Kenya in 2004 and spread throughout the Indian Ocean area and Southeast Asia, infecting millions. During this outbreak, more severe disease manifestations, including lethality, were reported for the first time. To understand one possible reason for this change in severity, we explored the impact of genetic changes in the virus on disease pathogenesis. In addition, we dissected the role of type I interferon (IFN) subtypes in CHIKV infection. From these studies, we have gained important insight into …

The Attentional Control Of Reading: Insights From Behavior, Imaging And Development, Sarah Ihnen

Arts & Sciences Graduate Student Theses and Dissertations

The process by which the initially attention-requiring task of transforming scribbles into meaningful concepts eventually becomes facile remains a central riddle of cognitive neuroscience. This body of work represents an effort to provide forward movement in answering the question of how attentional control mediates the process of reading, both by considering different stages of reading competence (development) and by seeking convergence between types of evidence (behavior and imaging).Inspired by a study published by Balota and colleagues in 2000, the paradigm used throughout this work involves comparing a simple speeded reading task vs. a regularize ("sound out") task (Balota et al. …

The Intrinsic Apoptotic Cascade In Hematopoiesis And Susceptibility To Therapy-Related Leukemia, Elise Peterson Lu

Arts & Sciences Graduate Student Theses and Dissertations

Apoptosis and the DNA damage response have been implicated in hematopoietic development and differentiation, as well as in the pathogenesis of myelodysplastic syndrome (MS) and leukemia. However, the specific roles of direct mediators of apoptosis, such as caspases, in hematopoiesis and leukemogenesis have not been elucidated. In order to address this, we studied the effects of loss of Caspase-9, the initiator caspase of the intrinsic apoptotic cascade, and Apaf1, the key component of the apoptosome, on fetal and adult hematopoiesis. We first found that loss of these key regulators has significant effects on the hematopoietic stem and progenitor compartment, with …

Understanding Escherichia Coli Urinary Tract Infection: A Niche Perspective, Drew Joel Schwartz

Arts & Sciences Graduate Student Theses and Dissertations

Urinary tract infections (UTIs) are among the most common bacterial infections worldwide, costing greater than $2 billion in healthcare costs and lost wages yearly in America alone. The lifetime risk for a woman exceeds 50% with 25-40% of these suffering recurrent infections. Two of the most important risk factors for recurrent UTI are prior UTIs and sexual intercourse. Over 80% of UTIs are caused by uropathogenic Escherichia coli (UPEC), which binds and invades superficial facet cells lining the bladder surface. UPEC expresses extracellular fibers called type 1 pili with a terminal mannose-binding adhesin, FimH, which interacts with mannosylated uroplakin residues …

The U1a/U2b"/Snf Family Of Rna Binding Proteins: Evolution Of Rna Binding Specificity And Contributions Of Heterotropic Linkage To Snrnp Protein Partitioning, Sandra Gisela Williams

Arts & Sciences Graduate Student Theses and Dissertations

The U1A/U2B"/SNF is a family of RNA binding proteins that is a highly conserved throughout eukaryotes. These proteins are found in the U1 and/or U2 splicing snRNPs (small nuclear ribonucleoprotein particles). In humans, U1A and U2B" specifically bind to the U1 and U2 snRNAs, respectively. The Drosophila genome codes for SNF, an essential protein that localizes to both the U1 and U2 snRNP. While a specific splicing functions for these proteins have not been determined, their conserved snRNP localization suggests an important splicing-related function.The difference in protein number and partitioning between Drosophila and humans suggested that these proteins may use …

The Comic Grotesque: Troubling The Body Politic In American Graphic Satire From World War I To The Great Depression, Bryna Rae Campbell

Arts & Sciences Graduate Student Theses and Dissertations

This dissertation examines the comic grotesque as a strategy of critical engagement within the thriving field of U.S. graphic satire from World War I through the Great Depression. During this period, artists across the political spectrum were using disruptive bodily forms, along with references to pain, vulgar associations and crude techniques, to challenge political authority, undermine attempts to smooth over political turbulence, and address communal anxieties about social tensions and the direction of the nation. Emerging in the context of record unemployment rates, the explosion of political radicalism, dramatic shifts of gender and class power dynamics, and emerging threats of …

The Roles Of Mist1 And Rab26 In Zymogenic (Chief) Cell Differentiation And Subcellular Organization, Ramon Jin

Arts & Sciences Graduate Student Theses and Dissertations

Little is known about how differentiating cells reorganize their cellular structure to perform specialized physiological functions. Specifically, exocrine cells like pancreatic acinar and zymogenic chief cells have a highly developed secretory architecture that is rapidly established upon differentiation. What is known in these cells is that the evolutionarily conserved transcription factor MIST1 is required for final maturation. We hypothesized that MIST1 directly regulates specific subcellular components that facilitate functional maturation of secretory cells.We show that MIST1 binds to conserved CATATG E-boxes to activate transcription of 6 genes, including the small GTPases RAB26 and RAB3D. We next demonstrate that RAB26 and …

Wheelchair Training Program For New Manual Wheelchair Users, Kerri Ann Morgan

Arts & Sciences Graduate Student Theses and Dissertations

Manual wheelchairs are commonly used for everyday mobility among people with lower limb impairments, including persons with spinal cord injury (SCI). Manual wheelchair users often experience pain and chronic overuse injuries in their upper extremities, limiting their mobility and their ability to complete daily activities. The repetitive trauma of propelling a wheelchair may be a contributing factor to upper extremity pain and injury. The anatomy of the upper extremities is not designed for the number of repetitions and the amount of force involved in everyday wheelchair propulsion. Research has been conducted to identify recommendations for decreasing the number of repetitions …

Four Projects Awarded Funding Through Amc21 Multi-Investigator Grants, Kendra Carter

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Aversive Stimuli Drive Drug Seeking In A State Of Low Dopamine Tone, Robert C. Twining, Daniel S. Wheeler, Amanda L. Ebben, Andre J. Jacobsen, Mykel A. Robble, John R. Mantsch, Robert A. Wheeler

Biological Sciences Faculty Research and Publications

Background

Stressors negatively impact emotional state and drive drug seeking, in part, by modulating the activity of the mesolimbic dopamine system. Unfortunately, the rapid regulation of dopamine signaling by the aversive stimuli that cause drug seeking is not well characterized. In a series of experiments, we scrutinized the subsecond regulation of dopamine signaling by the aversive stimulus, quinine, and tested its ability to cause cocaine seeking. Additionally, we examined the midbrain regulation of both dopamine signaling and cocaine seeking by the stress-sensitive peptide, corticotropin releasing factor (CRF).

Methods

Combining fast-scan cyclic voltammetry with behavioral pharmacology, we examined the effect of …

Tailoring Plasmonic Enhanced Upconversion In Single Nayf4:Yb3+/Er3+ Nanocrystals, Ya-Lan Wang, Nasim Mohammadi Estrakhri, Amber Johnson, Hai-Yang Li, Li-Xiang Xu, Zhenyu Zhang, Andrea Alù, Qu-Quan Wang, Chih-Kang (Ken) Shih

Engineering Faculty Articles and Research

By using silver nanoplatelets with a widely tunable localized surface plasmon resonance (LSPR) and their corresponding local field enhancement, here we show large manipulation of plasmonic enhanced upconversion in NaYF4:Yb³⁺/Er³⁺ nanocrystals at the single particle level. In particular, we show that when the plasmonic resonance of silver nanolplatelets is tuned to 656 nm, matching the emission wavelength, an upconversion enhancement factor ~5 is obtained. However, when the plasmonic resonance is tuned to 980 nm, matching the nanocrystal absorption wavelength, we achieve an enhancement factor of ~22 folds. The precise geometric arrangement between fluorescent nanoparticles and silver nanoplatelets …