UMD Theses and Dissertations

Permanent URI for this collectionhttp://hdl.handle.net/1903/3

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 given thesis/dissertation in DRUM.

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    EXPLORING THE EFFECTS OF PHYSIOLOGICAL ENVIRONMENT ON AMYLOID AGGREGATION
    (2022) Sahoo, Abhilash; Matysiak, Silvina; Biophysics (BIPH); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Molecular level self-assembly/aggregation processes are common in biomolecular systems. Specifically, aggregation of protein molecules results in formation of amyloid deposits, that has been associated with neuronal dysfunction leading up to neurodegeneration. The protein aggregation is often influenced by several external physiological features, which can modulate this pathological process in a specific or non-specific manner. This thesis aims to elucidate the role of such factors in amyloid aggregation in the context of neurodegeneration. As test cases, we have focused on different fragments of Amyloid-beta peptide and Huntingtin protein and explored common interaction schemes in the presence of phospholipid membranes, solvated glucose molecules and added trailing sequences. Phospholipid membranes, composed of a heterogeneous distribution of lipid molecules, serve as packaging envelopes in cellular systems. But several studies have suggested a role of cellular membranes in abetting protein aggregation in neurodegenerative diseases. The first section of this thesis explores Amyloid-beta 16-22 aggregation in the presence of membranes. Lipid membranes have been shown to modulate peptide aggregation in a charge dependent manner with anionic membranes promoting faster peptide aggregation into ordered fibrillar structures compared to zwitterionic membranes. In this work, we evaluate the role of this electrostatic membrane headgroup charge on Amyloid-beta 16-22 peptide aggregation with model lipid membranes composed of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine) lipids. Beyond, membrane charge, membrane's physical organization can also affect peptide-peptide and peptide-membrane interactions. Here, we have curated the effects of applied surface-tension, as a proxy for membrane curvature, on peptide fibrillation propensities. Apart from ordered structures such as membranes, solvated small molecules are a large class of molecules that can affect aggregation patterning by affecting peptides through both specific and non-specific interactions. The second section of this thesis explores Amyloid-beta 16-22 aggregation in varying hyperglycemic conditions, to draw correlations between Alzheimer's disease and type 2 diabetes. Here, we discovered that the glucose prefers partitioning onto the aggregate-water interface in a specific manner, leading to a loss in rotational entropy that propels peptide aggregation. In the final section, we discuss the case of pathological peptide aggregation in the case of Huntington's disease. Broadly, Huntinting protein's N-terminal region which consists of 17-residue N-terminal domain (N17) and the following Glutamine repeat tract (Poly-Q) are our objects of interest and associated with pathological aggregation. The aggregation landscape of N17 is analyzed in presence of added different lengths of trailing Poly-Q tract and the presence of curved membranes. We have approached our research through a computational lens using molecular dynamics simulations. To address the relevant concerns of large spatio-temporal scales necessary to study peptide aggregation systems with molecular simulations, we have developed a coarse-grained forcefield (ProMPT: Protein Model with Polarizability and Transferability) that uses reduced spatial resolution to accelerate phase-space exploration. The forcefield can capture secondary and tertiary folding of protein structures with minimal constraints, and is transferable across biomolecular systems without a need for re-parametrization. My dissertation presents a holistic picture of peptide aggregation and various physiological factors that affect it, with biomolecular simulation across multiple scales.
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    Rapid Harvest of Algae for Biofuel Production with the Aggregating Bacterium Bacillus sp. strain RP1137.
    (2014) Powell, Ryan Joseph; Hill, Russell T; Marine-Estuarine-Environmental Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Algal biofuels represent one of the most promising means of sustainably replacing liquid fuels. However significant challenges remain before algal based fuels become competitive with fossil fuels. One of the largest challenges is the ability to harvest the algae in an economic and low energy manner. In this dissertation I describe the isolation of the bacterium, Bacillus sp. strain RP1137, which can rapidly aggregate several algae that are candidates for biofuel production. This bacterium aggregates algae in a pH dependent and reversible manner and retains its aggregation ability after paraformaldehyde fixation. The optimal ratio of bacteria to algae is described as well as the robustness of aggregation at different salinities and temperatures. Aggregation is dependent on the presence of calcium or magnesium ions and likely occurs via charge neutralization through binding of calcium ions to the cell surface of both algae and bacteria. I show charge neutralization occurs at least in part through binding of calcium to negatively charged teichoic acid residues. A comparison of the aggregation efficiency of RP1137, Bacillus megaterium QM B1551 and Bacillus subtilis SMY showed that RP1137 and B1551 are equally efficient at aggregating algae while SMY does not aggregate algae. The genome of RP1137 was sequenced to understand the molecular underpinning of the mechanism of aggregation. The difference in aggregation phenotypes between the three bacilli was used to inform a genomic comparison which revealed two putative proteins that are predicted to be bound to the cell wall and are found only in RP1137 and B1551 but not SMY. This work characterizes the conditions under which Bacillus sp. RP1137 aggregates algae and the mechanism by which that aggregation occurs.
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    Relative roles of aggregation, competition, and predation in the North American invasion of the Asian Bush mosquito, Aedes japonicus
    (2012) Freed, Thomas Z.; Leisnham, Paul T; Environmental Science and Technology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    The success of an invasion can be mediated by biological interactions (e.g. competition and predation). The newly invasive mosquito Aedes japonicus has established in the range of the competitively superior resident mosquito Aedes albopictus and the predatory indigenous mosquito Toxorhynchites rutilus. I tested the hypotheses that intraspecific aggregation, fluctuating resources, or keystone predation are facilitating the invasion of A. japonicus into the range of A. albopictus. Populations of A. japonicus and A. albopictus were negatively correlated with each other and intraspecifically aggregated in field studies, suggesting that aggregation is facilitating coexistence. Resources showed a high amount of spatial variability, and A. japonicus populations were strongly associated with resource-rich containers, providing evidence for the fluctuating resource hypothesis. A laboratory experiment showed that predation suppresses A. japonicus populations to a greater extent than interspecific competition when all three species co-occur, and provided no evidence for keystone predation.
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    Data-Informed Calibration and Aggregation of Expert Judgment in a Bayesian Framework
    (2009) Shirazi, Calvin Homayoon; Mosleh, Ali; Reliability Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Historically, decision-makers have used expert opinion to supplement lack of data. Expert opinion, however, is applied with much caution. This is because judgment is subjective and contains estimation error with some degree of uncertainty. The purpose of this study is to quantify the uncertainty surrounding the unknown of interest, given an expert opinion, in order to reduce the error of the estimate. This task is carried out by data-informed calibration and aggregation of expert opinion in a Bayesian framework. Additionally, this study evaluates the impact of the number of experts on the accuracy of aggregated estimate. The objective is to determine the correlation between the number of experts and the accuracy of the combined estimate in order to recommend an expert panel size.
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    Molecularly Imprinted Polymers for the Recognition of Tobacco Viruses
    (2007-07-31) Bolisay, Linden De Venecia; Kofinas, Peter; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    The goal of this research is to elucidate the mechanism of virus recognition in molecularly imprinted polymers (MIPs) using already utilized techniques. The clinical relevance of this study relates to the development of a virus imprinted MIP, which would apply to the identification, classification, and removal of viruses. The separation of viruses and virus-like particles from various media represents an enormous challenge to the fields of medicine, healthcare, and biotechnology. Since virus MIPs must function in aqueous environments, our approach employs a more flexible non-covalent imprinting method which starts from a readily available polymer and utilizes an aqueous environment for both MIP synthesis and testing. Crosslinked polymers imprinted against Tobacco mosaic virus (TMV) via non-covalent interactions were synthesized using poly (allylamine hydrochloride) (PAA), epichlorohydrin (EPI), and TMV. The TMV imprinted polymer exhibited an increase affinity to the target virus compared to the control polymer and demonstrated a preferential affinity (imprinting factor of 2.1), based on shape, to the target virus compared to a non-target virus, Tobacco necrosis virus (TNV). In contrast, there was no significant increase in binding of the control polymer to either target or non-target virus. Once it was determined that virus imprinted polymers can be successfully synthesized having preferential binding to a targeted virus, the synthesis procedure was optimized to obtain better binding characteristics to the targeted virus. Efforts were made to avoid polymer-template aggregation in the MIP pre-polymerization mixture, and determine a proper wash solution by the ability to remove the templated virus from the crosslinked polymer. TMV imprinted hydrogels were synthesized using an optimized procedure and binding test performed on these MIPs to determine binding capacity, and more importantly, imprinting factor. The highest imprinting factor of 2.3 resulted from the MIP composed of 35 % PAA at pH 7, 15 %, ethylene glycol diglycidyl ether (EGDE), and 0.4 mg/mL TMV. The TMV imprinted hydrogels exhibited a lower binding capacity to TNV than when exposed to TMV. These results show that using optimized procedures, TMV MIPs with better shape selectivity can be achieved.