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  • Thesis

  • Active learning for sequential screening and classification of molecular and genomic data

    • Authors: Walker, Megon Jarmaine (2006)

  • Understanding molecular interactions is at the core of computational biology and includes problems such as characterizing protein-protein, protein-small molecule, protein-DNA, and Protein-RNA binding events. These interactions are often elucidated by expensive and time-consuming assays during which candidate binders are screened against a target. The main aim of this dissertation is to improve the speed, cost, and overall efficiency of screening assays in the context of drug design and molecular systems biology. Sequential screening is an iterative process of experimentation and model refinement. Target binding activity is determined for samples of putative binders, results are used to update a classification model, and subsequent binding experiments are performed based on knowledg...
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  • Algorithms for Representation and Discovery of Transcription Factor Binding Sites

    • Authors: Zaslavsky, Elena (2006)

  • A major objective in molecular biology is to understand how a genome encodes the information that speci es when and where a gene will be transcribed into its protein product. Mediating proteins, known as transcription factors, facilitate this process by interacting with the cell 's sDNA and the transcription machinery. It is of central importance to identify all sequence-speci c DNA binding sites of transcription factors. In this thesis, we consider two relevant computational problems. The first problem is to develop a representation for a group of known binding sites of a particular transcription factor, in order to facilitate recognition of other binding sites of the same protein. We evaluate the e ectiveness of several approaches commonly used for this problem, and show that the...
  • Thesis

  • Engineering Novel Fluorescent Proteins

    • Authors: Shaner, Nathan Christopher (2006)

  • Fluorescent proteins are intrinsically fluorescent, genetically encodable tags that can be expressed in many heterologous organisms. Originally cloned from jellyfish and corals, these proteins and their engineered derivatives have become ubiquitous tools in molecular and cell biology. While wild-type fluorescent proteins sometimes possess sufficiently beneficial properties to be used unmodified, many applications require improvements in brightness or photostability, reduction of oligomerization, or other specific properties that require additional engineering of the wild-type protein. This dissertation presents experiments drawn from the entire spectrum of fluorescent protein science, from the cloning of novel wild-type fluorescent proteins to the engineering of wavelength-shifted, ...
  • Thesis

  • Enhancements to hidden Markov models for gene finding and other biological applications

    • Authors: Vinar, Tomas (2006)

  • In this thesis, we present enhancements of hidden Markov models for the problem of finding genes in DNA sequences. Genes are the parts of DNA that serve as a template for synthesis of proteins. Thus. gene finding is a crucial step in the analysis of DNA sequencing data. Hidden Markov models are a key tool used in gene finding. Yhis thesis presents three methods for extending the capabilities of hidden Markov models to better capture the statistical properties of DNA sequences. In all three, we encounter limiting factors that lead to trade-offs between the model accuracy and those limiting factors. First. we build better models for recognizing biological signals in DNA sequences. Our new models capture non-adjacent dependencies within these signals. In this case. the main limiting ...
  • Thesis

  • Evidence combination in hidden Markov models for gene prediction

    • Authors: Brejova, Bronislava (2006)

  • This thesis introduces new techniques for finding genes in genomic sequences. Genes are regions of a genome encoding proteins of an organism. Identification of genes in a genome is an important step in the annotation process after a new genome is sequenced. The prediction accuracy of gene finding can be greatly improved by using experimental evidence. This evidence includes homologies between the genome and databases of known proteins, or evolutionary conservation of genomic sequence in different species. We propose a flexible framework to incorporate several different sources of such evidence into a gene finder based on a hidden Markov model. Various sources of evidence are expressed as partial probabilistic statements about the annotation of positions in the sequence, and these a...
  • Thesis

  • Peroxisome senescence and the role of catalase import in cellular aging

    • Authors: Koepke, Jay I. (2006)

  • Peroxisomes are ubiquitous subcellular organelles required for proper functioning of eukaryotic cells. They efficiently compartmentalize enzymes responsible for a number of essential cellular processes, including the metabolism of certain specific fatty acid chains via 13-oxidation. These and other oxidative reactions produce hydrogen peroxide, which is, in most instances, immediately processed in situ to water and oxygen. The responsible peroxidase is the heme-containing tetrameric enzyme, catalase. What has emerged during our investigation is that there are circumstances in which the tightly regulated balance of hydrogen peroxide producing and degrading activities in peroxisomes is upset - leading to the net production and accumulation of hydrogen peroxide and downstream reactive...
  • Thesis

  • Small molecule-based approach to chemistry and biology: Synthesis, measurement, and analysis

    • Authors: Kim, Young-kwon (2006)

  • Small molecules have long played important roles in the advancement of biology; however, little meta-insight has been gained during this period. This thesis presents two studies that aim to uncover the relationships between chemical space and biological measurement space. The first chapter comprises literature surveys of chemical descriptor space, biological measurement space (outputs), and analysis methods to link them. An emphasis on the role of diversity-oriented synthesis populating accessible chemical space (inputs) is offered. The second chapter describes the methodology that uses well-defined inputs provided by diversity-oriented synthesis and robust readouts from a series of chemical genetic modifier screenings. Subsequent multidimensional data analysis confirms the intuit...
  • Thesis

  • Structural Studies of Multi-Drug Resistance P-glycoprotein by Electron Microscopy

    • Authors: Lee, Jyh-Yeuan (2006)

  • Multi-drug resistance P-glycoprotein (Pgp), a member of the ATP-binding cassette transporter superfamily, is associated with multi-drug resistance in cancer chemotherapy. In addition to cancer cells, Pgp can be found in organs or normal tissues, such as blood-tissue barriers, gastrointestinal tract or kidney, where it provides protection against toxic or xenobiotic materials. This indicates that Pgp plays a dual role: one in drug resistance in cancer and one in detoxification in normal cells, and it is important to investigate the mechanism of Pgp for understanding multi-drug resistance in cancer and for elucidating its physiological functions. P-glycoprotein is a single polypeptide consisting of -1280 amino acids. The protein contains two cytoplamic nucleotide-binding domains (N...
  • Thesis

  • The Identification and Characterization of Proteins Required for Endocytosis in The Budding Yeast Saccharomyces Cerevisiae

    • Authors: Shaw, Jonathan D. (2006)

  • All eukaryotic cells are surrounded by a plasma membrane that segregates the interior of the cell from the extracellular environment. Transport to and from this membrane regulates homeostasis of the membrane itself, allows the import of material from the extracellular space, and provides a mechanism for communication with the outer environment. The process of endocytosis describes the internalization and subsequent transport of plasma membrane components and extracellular material. Endocytosis requires the coordinated activity of many protein factors, and the specific mechanisms employed by the cell for internalization remain only partially understood. The studies presented in this work focus on identifying novel proteins involved in endocytosis and characterizing their role in mem...