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
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Item EFFECTS OF PCB EXPOSURE ON HEPATIC GENE EXPRESSION AND ENZYME ACTIVITY IN AVIAN SPECIES(2014) Bohannon, Meredith Ena; Ottinger, Mary Ann; Marine-Estuarine-Environmental Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Polychlorinated biphenyls (PCBs) are a class of anthropogenic chemical compounds used by industry from the 1940s until the 1970s. Two General Electric plants at Fort Edward and Hudson Falls, NY contaminated the Hudson River by disposing roughly 604,500 kg of PCBs into the waterway during that time. This research focused on using whole-genome screening to find novel biochemical responses in laboratory and wild birds that are exposed to PCB mixtures relevant to the Hudson River. We used two PCB congener profiles, found in spotted sandpiper eggs and in tree swallow eggs from the Hudson River area of concern. We also tested PCB 126 and PCB 77 singly, since both have very high avian TEQs compared to other PCB congeners. Microarray technology was used to assess the spotted sandpiper mixture in Japanese quail. Pathways of interest were identified and qPCR was performed on a suite of genes to assess the response levels of Japanese quail that were exposed to both mixtures as well as the single congeners. Ethoxyresorufin-O-deethylase (EROD) was assessed in Japanese quail with all treatments, and in tree swallow and bluebird populations at the Hudson River site, and at three reference sites. Major findings from the microarray study revealed that the pathways for xenobiotic metabolism, oxidative damage, endocrine disruption, and energy balance were all impacted with PCB exposure. For the four compounds tested with both sexes, EROD activity increased in laboratory birds for seven of those eight sex/compound combinations. Cytochrome P450 1A4 and cytochrome P450 1A5 were the most consistently responsive genes for all sex/compound combinations. All other genes showed varied responses that changed with concentration, compound, and sex, however there were few differences seen at the level of significance (p<0.05). EROD exhibited mild response to PCB exposure in wild birds, with significant (p<0.05) differential expression in environmentally exposed birds at the Hudson River across years, 2006-2008. In summary, this research demonstrates that xenobiotic metabolism remains a highly responsive pathway with PCB exposure and that this pathway responds to PCB mixtures in a manner that does not mirror the toxic equivalency of the component PCBs.Item KNOWLEDGE DISCOVERY FROM GENE EXPRESSION DATA: NOVEL METHODS FOR SIMILARITY SEARCH, SIGNATURE DETECTION, AND CONFOUNDER CORRECTION(2012) Licamele, Louis; Getoor, Lise; Computer Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Gene expression microarray data is used to answer a variety of scientific questions. For example, it can be used for gaining a better understanding of a drug, segmenting a disease, and predicting an optimal therapeutic response. The amount of gene expression data publicly available is extremely large and continues to grow at an increasing rate. However, this rapid growth of gene expression data from laboratories across the world has not fully achieved its potential impact on the scientific community. This shortcoming is due to the fact that the majority of the data has been gathered under varying conditions, and there is no principled way for combining and fully utilizing related data. Even within a closely controlled gene expression experiment, there are confounding factors that may mask the true signatures when analyzed with current methods. Therefore, we are interested in three core tasks that we believe are important for improving the utilization of gene array data: similarity search, signature detection, and confounder correction. We have developed novel methods that address each of these tasks. In this work, we first address the similarity search problem. More specifically, we propose methods which overcome experimental barriers in pariwise gene expression similarity calculations. We introduce a method, which we refer to as indirect similarity, which, unlike previous approaches, uses all of the information in a database to better inform the similarity calculation of a pair of gene expression profiles. We demonstrate that our method is more robust and better able to cope with experimental barriers such as vehicle and batch effects. We evaluate the ability of our method to retrieve compounds with similar therapeutic effects in two independent datasets. We evaluate the recall ability of our approach and show that our method results in an improvement of 97.03% and 49.44% respectively over existing state of the art approaches. The second problem we focus on is signature detection. Gene expression experiments are performed to test a specific hypothesis. Generally, this hypothesis is that there is some genetic signature common in a group of samples. Current methods try to find the differentially expressed genes within a group of samples using a variety of methods, however, they all are parametric. We introduce a nonparametric approach to group profile creation which we refer to as the Weighted Influence Model - Rank of Ranks method. For every probe on the microarray, the average rank is calculated across all members of a group. These average ranks are then re-ranked to form the group profile. We demonstrate the ability of our group profile method to better understand a disease and the underlying mechanism common to its treatments. Additionally, we demonstrate the predictive power of this group profile to detect novel drugs that could treat a particular disease. This method leads the detection of robust group signatures even with unknown confounding effects. The final problem that we address is the challenge of removing known (annotated) confounding effects from gene expression profiles. We propose an extension to our non-parametric gene expression profile method to correct for observed confounding effects. This correction is performed on ranked lists directly, and it provides a robust alternative to parametric batch profile correction methods. We evaluate our novel profile subtraction method on two real world datasets, comparing against several state-of-the-art parametric methods. We demonstrate an improvement in group signature detection using our method to remove confounding effects. Additionally, we show that in a dataset with the true group assignments removed and only the confounding effects labelled, our profile subtraction method allows for the discovery of the true groups. We evaluate the robustness of our methods using a gene expression profile generator that we developed.Item TRANSCRIPT PROFILING AS A METHOD TO STUDY FRUIT MATURATION, TREE-RIPENING, AND THE ROLE OF "TREE FACTOR" IN 'GALA' AND 'FUJI' APPLES(2005-04-20) Lin, Shu-fei; Walsh, Christopher S; Plant Science and Landscape Architecture (PSLA); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)'Gala' and 'Fuji' are two high-quality apple (Malus domestica Borkh) cultivars. Their fruits mature and tree-ripen over a long period of time, and are resistant to pre-harvest drop. "Tree factor," a putative inhibitor of system 2 ethylene production is hypothesized to account for differences in ethylene production between attached and detached apple fruits. Three years of field data revealed two distinct patterns of maturation and ripening behavior in these two cultivars. 'Gala,' an early cultivar, demonstrated a typical positive "tree factor." Studies of the ripening pattern of 'Fuji' apple, which is a late-maturing cultivar, did not. 'Fuji' data were confounded by cold weather in the late fall. The natural progression of tree-ripening did not lead to the high concentrations of internal ethylene routinely measured in stored fruits. The stimulation of ethylene found in picked 'Gala' fruits ripened in the orchard might be explained by wounding stress coupled with a loss of nutrients and the water stress. Our alternative explanation for "tree factor" is the effect of continued termination of the phloem and xylem connection. The strength of the "tree factor" declined as 'Gala' fruit maturity progressed. Therefore, the "tree factor" tends to be more obvious in fruits with shorter growing period that mature during warm weather. To investigate differential gene expression that accompanies maturation and tree ripening, we used cDNA-AFLP (Amplified Fragment Length Polymorphism) to identify changes in transcript profiling during tree-ripening, and in the ripening of harvested fruits. Two hundred differentially-expressed transcript-derived fragments were isolated from 'Gala.' Ripening-related genes including those known to function in the key processes of defense and stress, cell wall degradation, pigment production and aroma biosynthesis were identified. Clones similar to housekeeping genes involved in protein biosynthesis and degradation, intracellular trafficking and sorting, cell structure and mobility, and metabolism-associated genes were also isolated. Expression patterns of these transcript-derived fragments were verified by using a different 'Gala' sample set on microarray and/or Northern blots. Our study supports the hypothesis that many ripening processes are under transcriptional control and that most of these differentially-expressed genes are highly conserved in fruits.