Digital Commons Network^™

Genetic And Epigenetic Determinants Of Transcription In The Divergent Eukaryote Leishmania Major, Britta Anderson

All Theses and Dissertations (ETDs)

Leishmania spp. and other trypanosomatid protozoa use a highly unusual mechanism to generate functional messenger RNAs (mRNAs) in which protein-coding genes are transcribed polycistronically. Here, transcription initiates primarily in divergent strand switch regions (dSSRs), where two polycistronic gene clusters are oriented head-to-head. These regions lack all known eukaryotic cis-regulatory elements, and it is not known how genetic and epigenetic factors cooperate to define dSSRs as regions of productive initiation. To quantitatively identify regulatory elements and to study the contribution of epigenetic factors to dSSR function, we combined genome-wide studies of chromatin structure with a focused interrogation of a single dSSR …

Contribution Of The Microenvironment In Bone Resident Cancer: The Role Of Thrombospondin-1 In Bone And Risk Loci Contributing To Multiple Myeloma, Sarah R. Amend

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Cancer growth in bone, a defining characteristic of multiple myeloma and common in many solid tumors including breast and prostate cancer, is characterized by the active participation of host microenvironment cells. Tumor cells stimulate the vicious cycle through stimulation of bone remodeling by osteoclasts and osteoblasts, resulting in increased release of growth factors and cytokines to further promote local tumor growth. Notably, cancer cells are unable to remodel bone independently, and require the metabolically active bone cells for this support.

A specific role for the bone microenvironment in mediating tumor growth was first discussed in 1889 with the introduction of …

Making Sense Of Unexpected Preferences, Gordon Alexander Arsenoff

All Theses and Dissertations (ETDs)

This dissertation includes three papers using quantitative models to sensibly describe what kinds of preferences political actors will or actually do hold when existing theory offers no insight. The first two papers use evolutionary game theory to predict ways in which politicians, artificially selected on the basis of good performance to remain in office, will in the long run diverge from instrumental rationality as ordinarily assumed in game theory. The first sets out a general principle for producing models of preference evolution in games as political models, namely, that the information about opponent preferences necessary for evolution of non-rational preferences …

Murine Cytomegalovirus Encodes Proteins That Regulate Viral Late Transcription, Travis Chapa

All Theses and Dissertations (ETDs)

Human Cytomegalovirus (HCMV) is a Beta-herpesvirus that causes severe disease in immuno-compromised individuals (including AIDS patients), and is the leading viral cause of congenital birth defects. Murine Cytomegalovirus (MCMV) is the primary surrogate model for HCMV, and resembles the human virus with respect to virion structure, genome organization, gene expression, tissue tropism, and clinical manifestations. In my graduate studies, I discovered the function of two novel MCMV proteins during in vitro infection. I demonstrated that ORF M79 encoded protein pM79, and ORF M92 encoded protein pM92. Both pM79 and pM92 have homologs in HCMV, and I showed that they regulate …

Dynamic Responses At The Barrier Epithelium, Katherine Beebe

All Theses and Dissertations (ETDs)

A fundamental question in biology is how cellular systems sense and respond to their environment. The environment is a changing parameter, and cellular life has evolved a multitude of interesting and adaptive ways to sense and respond to external changes. The GI tract is a particularly interesting tissue in which to examine this question. One of few barrier epithelia, the intestine is exposed to both the unique environment of the lumen and the internal environment of the organism. Cells of the intestine simultaneously function as barrier, digestive organ, and sensory organ. Additionally, in many metazoan animals these functions occur in …

Regulation Of Fluid-Phase Uptake In Podocytes By Albumin-Associated Lipids, Jun-Jae Chung

All Theses and Dissertations (ETDs)

I. Podocytes are specialized epithelial cells in the kidney glomerulus that play important structural and functional roles in maintaining the filtration barrier. In nephrotic syndrome, a major breakdown of the kidney filtration barrier associated with proteinuria, hyperlipidemia, and edema, podocytes undergo changes in morphology and appear to internalize serum proteins. We postulated that fluid-phase uptake by podocytes might play a role in maintaining the integrity of the filtration barrier. Using fluid-phase tracers, we show that podocytes in vivo actively internalize fluid from the serum and that the rate of internalization is enhanced when the filtration barrier is disrupted. In vitro …

Examining An Implicit Mechanism Of Recognition Criterion Regulation, Justin Christopher Cox

All Theses and Dissertations (ETDs)

A variety of factors influence how we make decisions about our own memories. When judging a person on the street as novel or familiar, one appeals to an internal cutoff value known as a decision criterion; if an individual is less familiar than this criterion value, he is judged as new, and vice versa. A host of research has demonstrated that people can explicitly and judiciously update their decision criteria based on a variety of factors such as the prevalence of old and new items, rewards and punishments, and simple instructions. One oft overlooked variable that affects criterion placement and …

We Were Alway United, Except When We Were Not: Bivocal Memory And Georgia's Geopolitical Dilemma, Nino Batiashvili

All Theses and Dissertations (ETDs)

This study examines two distinct but mutually constitutive discursive genres on Georgian identity: one based in the voice of self-idealization and the other in self-condemnation. These two genres are embedded in historical conceptions and enact public debate on the country's geopolitical challenges. The ethnographic material I examine, unveils politically strained discursive terrain that unfolds as a "game of memory" between two visions of Georgian history, Georgian identity and Georgian geopolitics.

Throughout this study I examine how these two voices unfold through debates on historical memory and how they shape forms of political reasoning. On the basis of diverse textual and …

Effects Of Anion Excited States On Photodetachment Of Negative Ions, Diep Dao

All Theses and Dissertations (ETDs)

In this dissertation, effects of anion excited states on photodetachment of negative ions containing transition metals will be presented. Evidence of autodetachment (sudden change in photodetachment cross section and photoelectron agular distribution) is observed for diatomic (AgF-, CuF-) and triatomic (NiO₂-, CuOF-) anions. The mechanism of the autodetachment (vibrational or electronic autodetachment) is explored using ab initio calculation. EOM-CCSD calculation reveals a dipole bound anion state, which is responsible for vibrational autodetachment observed in AgF- detachment. Additionally, CAP/EOM-CCSD calculation and experimental data suggest the presence of shape resonances ([AgF-]* and [CuF-]*) which electronically autodetach to several vibrational levels …

Antisense Reduction Of The Protein Tau Attenuates Neuronal Hyperexcitability And Permits Clearance Of Intraneuronal Tau Accumulations In Vivo, Sarah Lorraine Devos

All Theses and Dissertations (ETDs)

The protein tau is a major contributor in some of the most prevalent neurodegenerative diseases, including the most common form of dementia, Alzheimer's Disease (AD). As a member of the microtubule-associated protein family, tau in enriched in the axons of mature and growing neurons, though under certain conditions, can become hyperphosphorylated and accumulate into toxic oligomeric species and aggregates. In the studies outlined here, we sought to directly target the protein tau using Antisense Oligonucleotides (ASOs) to reduce total expression of tau in vivo and assess if such a reduction could be therapeutically beneficial. To first test the feasibility of …

A Multidimensional Approach To The Study Of Social Anxiety And Friendships, Katya Christine Fernandez

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Despite its inherently interpersonal nature, the specific ways in which social anxiety symptoms interact with and impact friendships has not been well-studied. Research suggests that social anxiety, when compared with other psychological disorders, has a specific relationship with friendship impairment; however, the mechanisms that explain how this impairment functions over time are not well-understood. The current study sought to test whether interpersonal styles--dependence, avoidance, warmth, dominance, and emotional expressivity--mediate the relationship between social anxiety and both self- and friend-report friendship functioning over time. Participants consisted of undergraduate students who nominated a friend to participate in the study; both the participants …

The Regulation Of Glucose Metabolism During Osteoblast Differentiation, Emel Esen

All Theses and Dissertations (ETDs)

Differentiation and cell-specific functions are coupled with metabolic alterations to meet the needs of the cell. In this thesis, I have investigated the alterations of cellular metabolism in osteoblast-lineage cells in response to two different bone anabolic signals, WNT and PTH. I have further elucidated the mechanism underlying the metabolic changes, and have explored the functional importance of such changes for bone anabolism.

Osteoblasts, the principal bone-forming cells, are differentiated from mesenchymal progenitor cells through sequential stages. These stages are identifiable by molecular markers, cell morphology and location. Transcription factors and developmental signals important for osteoblast differentiation have been studied …

Multi- Modal Characterization Of Left Ventricular Diastolic Filling Physiology, Erina Ghosh

All Theses and Dissertations (ETDs)

Multiple modalities are clinically used to quantify cardiovascular function. Most clinical indexes derived from these modalities are empirically derived or correlation- based rather than causality based. Hence these indexes don't provide insight into cardiac physiology and the mechanism of dysfunction. Our group has previously developed and validated a mathematical model using a kinematic paradigm of suction- initiated ventricular filling to understand the mechanics of early transmitral flow and the associated physiology/ pathophysiology. The model characterizes the kinematics of early transmitral flow analogous to a damped simple harmonic oscillator with lumped parameters- ventricular stiffness, ventricular viscoelasticity/ relaxation and ventricular load.

The …

Absolute Quantitation For Mr Molecular Imaging Of Angiogenesis, Matthew John Goette

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Medical imaging is undergoing a transition from an art that is used to make static images of human physiology into a scientific tool that employs advanced techniques to measure clinically relevant data. Recently, the role of magnetic resonance imaging in cardiovascular and oncological research has grown, largely due to the implementation of new quantitative techniques in the clinic. Magnetic resonance imaging (MRI) and spectroscopy (MRS) are particularly rich in their capability to quantify both physiology and disease via biomarker detection. While this is true for many applications of MRI in cardiovascular and oncological research, 19F MR molecular imaging is particularly …

Procedural Postures: The Influence Of Legal Change On Strategic Litigants And Judges, Morgan Willey Hazelton

All Theses and Dissertations (ETDs)

A wealth of scholarship indicates that rational individuals should modify their actions to maximize benefits as conditions change. Participants in litigation are faced with a multitude of opportunities to make decisions regarding if and how they will engage the legal system. Despite this fact, the potential for strategic behavior by litigants is often ignored by researchers due to difficulties in capturing such activity. To the extent that existing studies have focused on outcomes to the exclusion of litigant behavior, they have potentially produced biased results in considering the impact of changes in law, such as Supreme Court decisions. Thus, in …

Phase-Space Distributions Of Galactic Dark Matter Halos And Implications For Detection, Daniel Robert Hunter

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This work focuses on models of galactic dark matter halos and observational prospects. We investigate the impact of careful computation of the phase-space density and velocity distribution of weakly-interacting massive particles, a major class of dark matter particle candidates, in the Milky Way. In particular, the possibility of a non-trivial velocity-dependence in the self-annihilation cross-section from the Sommerfeld effect is considered in indirect detection; we derive an upper limit on the local velocity dispersion and examine the significance of local anisotropy in the local dark matter distribution in direct detection efforts.

Asset Holdings And Undernutrition Of Young Children: Evidence From China Health And Nutrition Survey, Minchao Jin

All Theses and Dissertations (ETDs)

Undernutrition is an underlying determinant of 45% of all childhood deaths annually, resulting in 3.1 million deaths to children less than five years globally (Black et al., 2013). The adverse effects of undernutrition, especially chronic undernutrition, could cause impaired physical growth, mental development retardation, low productivity and poverty during adulthood, and undernutrition of next generation. Worldwide, over 200 million children are undernourished (Black et al., 2013). Thus, there is an imperative to identify effective preventive actions or interventions for child undernutrition. Studies have documented links between undernutrition and low income, but few has tackling the causation from assets to child …

Dapk3 Suppresses Mammary Acini Morphogenesis And Is Required For Mouse Development, Brandon Kocher

All Theses and Dissertations (ETDs)

Over the past decade several lines of research have indicated that DAPK3, a member of the serine/threonine death associated protein kinase (DAPK) family, plays an important role in various signaling pathways important to tissue homeostasis and mammalian biology. Considered to be a putative tumor suppressor, the molecular mechanisms by which DAPK3 exerts its tumor suppressor functions are not fully understood. Furthermore, unlike other DAPK family members, DAPK3 has received little attention regarding its physiological roles in vivo due to the lack of knockout animals. To address these gaps in our fundamental understanding of DAPK3 we

utilized the MCF10A 3D tumorigenesis …

Micrornas In Als: Defining Cell-Type Specific Expression, Developing Methods To Modulate Micrornas In Vivo, And Identifying Novel Therapeutic Targets, Erica Danielle Koval

All Theses and Dissertations (ETDs)

Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neuromuscular disease with no adequate therapies. MicroRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS model SOD1G93A rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. Generation of mice that express a GFP-tagged miRNA processing protein behind cell-type specific promoters allowed for the identification of miRNA expression patterns …

Reconceptualizing Social Impairment Using Informant Report, Erin Marie Lawton

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Psychological disorders would not be considered as such if they did not result in some form of dysfunction. Yet, the assessment of impairment remains considerably flawed. Typical instruments used to measure impairment are susceptible to criterion contamination (e.g., explicitly confounding symptoms with impairment, as a result of mood-biased responses involved in self report). Additionally, individuals with personality pathology seem likely to underreport impairment, either due to a lack of insight or because of the manifestations of impairment assessed. The current project aimed to demonstrate the concurrent validity of a newly-developed, informant-reported measure of social impairment (the Scale of Unpleasant Relational …

The Role Of Hspa9 In Mouse Hematopoiesis And Il-7 Receptor Signaling, Kilannin Krysiak

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HSPA9 was previously identified as a candidate gene in a commonly deleted region (CDR) associated with myelodysplastic syndrome (MDS), a clonal hematopoietic stem cell disorder. Cytogenetic abnormalities occur in ~50% of MDS patients and an interstitial deletion or loss of chromosome 5 containing HSPA9 is the most common, occurring in up to 25% of patients. In order to understand the role of HSPA9 in hematopoiesis and disease development, we created an Hspa9 knockout mouse model. We characterized hematopoiesis of heterozygous mice (Hspa9+/-), which have a 50% reduction in Hspa9 expression, modeling the heterozygous loss of HSPA9 and 50% reduction in …

Studies Of Seismic Sources In Antarctica Using An Extensive Deployment Of Broadband Seismographs, Amanda Colleen Lough

All Theses and Dissertations (ETDs)

This dissertation is the first comprehensive study reporting the seismicity of Antarctica utilizing year-round recordings from autonomous instruments installed on the continent itself. I first examine the general seismic nature of the continent using locally deployed seismographs in both East Antarctica and West Antarctica. I detect and locate seismic events using the traditional first arriving impulsive P and S waves as well as events classified as 'slow' earthquakes with no impulsive P-waves. I find evidence of tectonic events in East Antarctica (representing intraplate earthquakes within a stable craton), icequake events in the Transantarctic Mountains (associated with active alpine glaciers), and …

Host-Microbial Interactions That Modulate Luminal Iga, Clara Moon

All Theses and Dissertations (ETDs)

IgA is the most abundant immunoglobulin produced in the body, most of which can be found at mucosal sites such as the intestine where it plays an important role at a critical intersection between the host immune system and the microbiota. In the work detailed here, I sought to investigate IgA delivery and stability using in vitro and in vivo methods. First, I developed a primary intestinal epithelial monolayer system, and utilized this system to evaluate factors that modulate IgA transcytosis. In vivo, I interrogated baseline levels of fecal IgA in WT mice and surprisingly observed a binary phenotype in …

Dual Roles Of Interferon Stimulated Gene-15 During Respiratory Virus Infection, David James Morales

All Theses and Dissertations (ETDs)

ISG15 is a diubiquitin-like posttranslational modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins have been identified as targets of ISG15 conjugation after interferon stimulation, and a number of viral proteins have been shown to be modified by ISG15 during infection. Given the known importance of posttranslational protein modification in the regulation of cellular biology, understanding how ISG15 affects the interferon response and virus replication has been of considerable interest. ISG15 deficient mice have previously been shown to exhibit increased susceptibility to a number of different viruses, including influenza A and …

Regulation And Inhibition Of Pro-Tumorigenic Microenvironments, Elise Oster Alspach

All Theses and Dissertations (ETDs)

Age is the number one risk factor for the development of cancer. While accumulation of epithelial cell mutations is a driving factor for this risk, the role that the tumor microenvironment plays in this process is now well established. Indeed, seminal work has shown that tumorigenic cells unable to grow in xenografts can form tumors when supportive stromal cells are present. Work by many laboratories has demonstrated that a wide variety of cells including endothelial cells, immune cells, the extracellular matrix and fibroblasts can all assume a pro-tumorigenic phenotype.

Like cancer-associated fibroblasts (CAFs), senescent cells promote all stages of tumor …

Motivational Strategies, Conditional Welfare And Distributive Justice, Cristian Perez

All Theses and Dissertations (ETDs)

In this dissertation I examine the normative implications of different motivational strategies when applied to address the behavioral obstacles of various redistributive schemes, in particular, in the case of income redistribution policies and the provision of essential services. I intend to show that negative inducements can have some advantages with reference to other motivational instruments. For example, negative inducements are often the main motivational strategies behind conditional welfare policies. I argue against the view that conditional welfare policies are always hostile to the poor and the less fortunate. Moreover, I explain why redistributive schemes whose benefits are tied to specified …

Software Defined Application Delivery Networking, Subharthi Paul

All Theses and Dissertations (ETDs)

In this thesis we present the architecture, design, and prototype implementation details of AppFabric. AppFabric is a next generation application delivery platform for easily creating, managing and controlling massively distributed and very dynamic application deployments that may span multiple datacenters.

Over the last few years, the need for more flexibility, finer control, and automatic management of large (and messy) datacenters has stimulated technologies for virtualizing the infrastructure components and placing them under software-based management and control; generically called "Software-defined Infrastructure" (SDI). However, current applications are not designed to leverage this dynamism and flexibility offered by SDI and they mostly depend …

Coping With Intimate Partners' Substance Use And Gambling Problems: The Role Of Intimate Partner Violence (Ipv), Megan Petra

All Theses and Dissertations (ETDs)

Intimate partners of the estimated 30.6 million United States residents with substance and/or gambling problems (SGP) experience significant stress, such as disrupted family life, financial trouble, and increased risk for related problems such as intimate partner violence (IPV). This results in considerable distress and physical/mental health problems. Though SGP are often chronic, the treatment rate is low, and there is little help available for intimate partners of those with untreated SGP. Before we can create effective assistance and empowerment programs for intimate partners of people with SGP, we must understand the function of coping and social support in the task …

Characterization Of A Novel Npc1i1061t Knock-In Mouse Model Of Niemann-Pick Type C1 Disease, Maria A. Praggastis

All Theses and Dissertations (ETDs)

Niemann-Pick Type C (NPC) disease is a fatal pediatric cholesterol storage disease that is caused by mutations in either the npc1 or npc2 genes. Loss of function of either gene results in toxic storage of free cholesterol in the lysosomes due to a cholesterol trafficking defect. In humans the free cholesterol accumulation leads to Purkinje cell loss in the cerebellum and is accompanied by neurodegenerative symptoms that include ataxia, vertical supranuclear gaze palsy, and decreased motor function. Most NPC1 patients succumb to the disease within the first two decades of life.

The most prevalent mutation, NPC1I1061T, resides within the cysteine-rich …

In Vivo Functions Of Inhibitory Immunoreceptors During Viral Infection, Aaron Rapaport

All Theses and Dissertations (ETDs)

CD8+ T cells and NK cells are two effector cells of the mammalian immune system that rely on activating and inhibitory immunoreceptors to determine the outcome of an interaction with a target cell. An infected or transformed target cell can upregulate a variety of ligands that bind to activating receptors. Activating signals within an effector cell can then elicit responses that kill the target directly by lysing it or indirectly by secreting cytokines and chemokines that attract and activate other immune cells. In contrast, a healthy target cell can maintain expression of ligands for inhibitory receptors that restrain effector cell …