Theses and Dissertations from UMD
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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM
More information is available at Theses and Dissertations at University of Maryland Libraries.
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Item Exploration of Lithium Ion Binding to Magnesium Bound Adenosine Triphosphate and Its Implications for Bipolar Disorder(2015) Briggs, Katharine Therese; Marino, John P.; Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Lithium carbonate, a drug for the treatment of Bipolar Disorder, provides mood stability to treat an illness that causes recurrent episodes of mania and/or depression. The mechanism by which lithium acts to elicit these psychological changes remains unknown. Interestingly, this small bio-active salt has been shown to reduce the risk of suicide, and appears to lower the incidence of Alzheimer’s disease. It has been proposed that lithium inhibits magnesium-dependent enzymes; however, there is no consensus as to how this occurs. Based on high resolution 7Li, 23Na, and 31P T1 and Paramagnetic Relaxation Enhancement (PRE) Nuclear Magnetic Resonance (NMR) methods, which can be used to characterize the association of lithium (Li+) at magnesium (Mg2+)-phosphorus chelation sites, we have identified a ATP•Mg•Li complex. The lithium binding affinity to form this complex is relatively high compared to other monovalent cations, with a Kd < 1 mM, and biologically relevant considering that at the typical dosing of Li+, physiological concentrations of Mg and ATP are in the 0.6 – 2.5 mM range. This has led us to propose a mechanism of action for lithium based on the formation of Mg•Li-complexes at dehydrated magnesium-phosphate sites and perhaps a role for ATP•Mg as a physiological carrier for Li+. To test this model experimentally in the context of relevant ATP-protein binding sites, we have used NMR methods to characterize the formation of the complex at ATP binding sites on albumin. Similarly, we initiated studies investigating the relevance of the ATP•Mg•Li complex to a class of purinergic receptor proteins (P2XR), since they are stimulated by purine agonists and have been implicated in Bipolar Disorder.Item THE IDENTIFICATION AND CHARACTERIZATION OF AN INTRINSIC CD39/A2R-BASED REGULATORY MECHANISM THAT GOVERNS MACROPHAGE ACTIVATION RESPONSES(2014) Cohen, Heather Bloom; Mosser, David M; Cell Biology & Molecular Genetics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Macrophages are acutely sensitive to changes within their environment and can readily develop into a variety of activation states important for both the progression and resolution of inflammation. In response to immunological threats, macrophages must be able to effectively clear infections without sacrificing the integrity of the affected tissue. Thus, these cells must successfully balance their activation responses in order to preserve tissue function and the overall health of the host. The failure to properly regulate macrophage activation responses often manifests in the clinic in a variety of disease scenarios including sepsis, chronic inflammatory disorders, and cutaneous Leishmaniasis. While many factors that drive the initiation of macrophage activation are known, it remains unclear what governs the transition to an immunosuppressive state. This study reveals that macrophages can control their own activation status through the coordination between the ecto-ATPase, CD39, and the adenosine 2a and 2b receptors (A2Rs). The first part of this work shows that soon after toll-like receptor (TLR) stimulation, macrophages secrete and convert ATP into immunosuppressive adenosine via CD39. Moreover, we show that CD39 on macrophages is necessary to induce regulatory macrophage development and prevent severe immunopathology in a mouse model of septic shock. The next sets of data demonstrate that TLR activation also enhances A2bR expression, thus completing the CD39-initiated autoregulatory circuit to limit inflammatory macrophage responses. The second part of this work demonstrates that the chronic inflammatory disease-asociated cytokine, IFN-gamma, prevents TLR-induced A2bR expression and consequently promotes the hyper-production of inflammatory cytokines by macrophages thereby revealing a novel mechanism by which IFN-gamma; maintains overactive macrophages. The final chapter illustrates that while the A2bR is the dominant adenosine receptor mediating the inhibition of inflammatory cytokine production, A2aR signaling inhibits nitric oxide generation and that its expression may be hijacked by intracellular parasites to evade innate host defense mechanisms. Thus, this study demonstrates that inflammatory macrophage activation is inherently transient and that macrophages can reprogram themselves. These results culminate in the discovery of a novel immunomodulatory mechanism reliant on macrophage purinergic signaling and offer new targets and strategies to more effectively treat myriad inflammatory and infectious diseases.Item The effect of freezing rate on striped bass (Morone saxatilis) spermatozoa(2013) Frankel, Tyler Edward; Woods, Lewis C; Animal Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Several studies have attempted to determine the optimal freezing rate for the cryopreservation of striped bass spermatozoa. In this study, the effects of freezing rate (-10, -15, -20 and -40oC/min) on sperm quality was examined utilizing Sybr-14/Propidium Iodide staining to confirm membrane integrity, a luciferin-luciferase assay to estimate ATP concentration and a Hamilton-Thorne CEROSTM system to characterize sperm motion. Males (n=12) were sampled once a week for five weeks. Samples were extended, cryo-protected using a 7.5% (v/v) dimethyl sulfoxide solution, and frozen using a controlled-rate freezer. Samples were stored in liquid nitrogen for 49 days and re-evaluated post-thaw. Sperm cryopreserved at -40oC per minute resulted in: total motility (10.06%), progressive motility (7.14%), ATP concentration (0.86 pmol/million cells), and sperm viability (56.5%); which were greater (P < 0.05) than the slower rates. Results demonstrate that -40oC/minute was the optimal freezing rate among those tested for the cryopreservation of striped bass spermatozoa.Item Coordinating Demand Fulfillment With Supply Across A Dynamic Supply Chain(2006-04-25) Chen, Maomao; Ball, Michael; Decision and Information Technologies; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Today, technology enables companies to extend their reach in managing the supply chain and operating it in a coordinated fashion from raw materials to end consumers. Order promising and order fulfillment have become key supply chain capabilities which help companies win repeat business by promising orders competitively and reliably. In this dissertation, we study two issues related to moving a company from an Available to Promise (ATP) philosophy to a Profitable to Promise (PTP) philosophy: pseudo order promising and coordinating demand fulfillment with supply. To address the first issue, a single time period analytical ATP model for n confirmed customer orders and m pseudo orders is presented by considering both material constraints and production capacity constraints. At the outset, some analytical properties of the optimal policies are derived and then a particular customer promising scheme that depends on the ratio between customer service level and profit changes is presented. To tackle the second issue, we create a mathematical programming model and explore two cases: a deterministic demand curve or stochastic demand. A simple, yet generic optimal solution structure is derived and a series of numerical studies and sensitivity analyses are carried out to investigate the impact of different factors on profit and fulfilled demand quantity. Further, the firm's optimal response to a one-time-period discount offered by the supplier of a key component is studied. Unlike most models of this type in the literature, which define variables in terms of single arc flows, we employ path variables to directly identify and manipulate profitable and non-profitable products. Numerical experiments based on Toshiba's global notebook supply chain are conducted. In addition, we present an analytical model to explore balanced supply. Implementation of these policies can reduce response time and improve demand fulfillment; further, the structure of the policies and our related analysis can give managers broad insight into this general decision-making environment.