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Articles 1 - 12 of 12
Full-Text Articles in Life Sciences
Investigation Of The In Vivo Activity Of Ribosome-Targeting Peptides And Aminoglycosides In Escherichia Coli, Nisansala Sarangi Thilakarathne Muthunayake
Investigation Of The In Vivo Activity Of Ribosome-Targeting Peptides And Aminoglycosides In Escherichia Coli, Nisansala Sarangi Thilakarathne Muthunayake
Wayne State University Dissertations
The development of short peptides that specifically bind to higher-order structures of ribosomal RNA is one promising way to address the problem of antibiotic resistance. However, the poor correlation between in vitro and in vivo activities of these peptides is one of the major questions in antibiotic peptide research. Therefore, one of the main objectives of this dissertation work was to utilize a plasmid-based system to in vivo express ribosome-targeting peptides and study their direct inhibitory effects on bacteria. A specific plasmid system was optimized to in vivo express oncocin, a prolin-rich antimicrobial peptide and its variants in bacteria. Our …
Functional Study Of Smyd2 Glutathionylation In Cardiomyocytes, Dhanushka Nalin Perera Munkanatta Godage
Functional Study Of Smyd2 Glutathionylation In Cardiomyocytes, Dhanushka Nalin Perera Munkanatta Godage
Wayne State University Dissertations
Reactive oxygen species (ROS) are important signaling molecules that contribute to the etiology of multiple muscle-related diseases, including cardiomyopathy and heart failure. There is emerging evidence that cellular stress can lead to destabilization of sarcomeres, the contractile unit of muscle. However, it is not completely understood how cellular stress or ROS induce structural destabilization of sarcomeres or myofibrils. Protein glutathionylation is one of the major protein cysteine oxidative modifications that play an important role in redox signaling and oxidative stress. In this report, we used a clickable glutathione approach in a cardiomyocyte cell line, and found that SET and MYND …
Biochemical And Cellular Studies Of Apobec3 Family Dna-Cytosine Deaminases, Sachini Umedi Siriwardena
Biochemical And Cellular Studies Of Apobec3 Family Dna-Cytosine Deaminases, Sachini Umedi Siriwardena
Wayne State University Dissertations
The AID/APOBEC family of enzymes deaminate cytosines in single-stranded DNA to uracils leading to base substitutions and strand breaks. Members of APOBEC3 family in humans are induced by cytokines produced during the body's inflammatory response to infections and provide innate immunity against viruses. However, there is emerging consensus that these enzymes can cause mutations in the cellular genome depending on the physiological state of the cell and the phase of the cell cycle they are expressed. Since aberrant expression of APOBEC3B was recently identified as a possible source of cancer, we initiated a study to determine the maximally active catalytic …
Alternative Strategies To Inhibit Lysine Methyltransferases And Deubiquitinases In Human Cancers, Nicholas Spellmon
Alternative Strategies To Inhibit Lysine Methyltransferases And Deubiquitinases In Human Cancers, Nicholas Spellmon
Wayne State University Dissertations
X-ray crystallography is the gold standard method for imagining macromolecules to atomic resolution. Three dimensional data is central to understanding the molecular mechanism how DNA, RNA and proteins function in biological events. Structural insights into these events provide a molecular window to visualize how biological molecules influence human health. Visualizing the architecture of these molecules set the stage for rational and selective drug design. The following dissertation utilizes biochemical and biophysical tools, including X-ray crystallography, to shed light on poorly understood mechanisms related to SMYD2 activity and regulation, USP10 architecture and function, and PDZ-RhoGEF dimerization. SMYD2 is one member of …
Validating Functional Mechanisms For Non-Coding Genetic Variants Associated With Complex Traits, Cynthia Ann Kalita
Validating Functional Mechanisms For Non-Coding Genetic Variants Associated With Complex Traits, Cynthia Ann Kalita
Wayne State University Dissertations
Genome-wide association studies (GWAS) have identified a large number of genetic variants associated with disease as well as normal phenotypic variation for complex traits. However challenges remain in determining the functional relevance of human DNA sequence variants. Even after fine mapping, most variants are located in non-coding regions making it difficult to infer mechanisms linking individual genetic variants with the disease trait. In addition, we do not know under which environmental conditions the sequence variants have a functional impact, and whether they become one of many factors involved in complex phenotypes at the organismal level.
Chapter 1 describes computational methods …
Polarized Localization Microscopy (Plm) Detects Nanoscale Membrane Curvature And Induced Budding By Cholera Toxin Subunit B (Ctxb), Abir Kabbani
Wayne State University Dissertations
The curvature of biological membranes at the nanometer scale is critically important for vesicle trafficking, organelle morphology, and disease propagation. Many proteins and lipids interact with diverse curvature sensing and curvature generating mechanisms. Deciphering the molecular mechanisms of toxin-membrane interactions has been limited by the resolution and drawbacks of conventional experimental techniques. This study reveals the inherent membrane bending capability of cholera toxin subunit B (CTxB) through the development and implementation of Polarized Localization Microscopy (PLM). PLM is a pointillist optical imaging technique for the detection of nanoscale membrane curvature in correlation with single-molecule dynamics and molecular sorting.
PLM combines …
Investigation Of The Saccharomyces Cerevisiae Gpi Transamidase: Insights Into Its Activity And Subunit-Subunit Interactions, Travis Ness
Wayne State University Dissertations
Glycosylphosphatidylinositol (GPI) anchoring of proteins is a eukaryotic, posttranslational
modification catalyzed by GPI transamidase (GPI-T). The Saccharomyces
cerevisiae GPI-T is composed of five membrane-bound subunits: Gaa1, Gpi8, Gpi16,
Gpi17, and Gab1. Structural and functional studies have been hindered by the
complexity of this enzyme. Conditions to purify the Gpi8:Gaa1:Gpi16 GPI-T heterotrimer
from yeast have been reported, but an understanding of the subunit functions,
interactions, and stoichiometry remain unclear. Furthermore, a reliable, quantitative, in
vitro assay for this important post-translational modification has remained elusive for
nearly three decades.
Our laboratory has developed an in vitro peptide cleavage assay that correlates
changes …
Carbohydrate-Based Inducers Of Cellular Stress For Targeting Cancer Cell Metabolism, Fidelis Ndombera
Carbohydrate-Based Inducers Of Cellular Stress For Targeting Cancer Cell Metabolism, Fidelis Ndombera
Wayne State University Dissertations
ABSTRACT
CARBOHYDRATE-BASED INDUCERS OF CELLULAR STRESS FOR TARGETING CANCER CELL METABOLISM
by
FIDELIS TOLOYI NDOMBERA
May 2018
Advisor: Dr. Young-Hoon Ahn
Major: Chemistry (Biochemistry)
Degree: Doctor of Philosophy
Metabolic reprogramming and redox control of cancer cells is vital for their proliferation, but also provides selective strategies for treating cancer. Increased generation of reactive oxygen species (ROS) and an intricate control of redox status in cancer cells relative to normal cells provide a basis for designing ROS-inducing anticancer agents. In my work, I designed, synthesized and evaluated carbohydrate-based small molecules for ROS-generation, cytotoxicity and redox signaling and stress response. Our data …
Chchd10, A Novel Bi-Organellar Regulator Of Cellular Metabolism: Implications In Neurodegeneration, Neeraja Purandare
Chchd10, A Novel Bi-Organellar Regulator Of Cellular Metabolism: Implications In Neurodegeneration, Neeraja Purandare
Wayne State University Dissertations
CHCHD10 (Coiled-coil Helix Coiled-coil Helix Domain containing protein 10) and MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1, also known as CHCHD2), have been shown by us to be stress regulators of mitochondrial function that act both in the mitochondria and in the nucleus. Both are members of the twin CX9C family, but CHCHD10 in particular, has been found in mutant form to be linked to a myriad of neurodegenerative conditions. In mitochondria, both activate cytochrome c oxidase (COX) whereas in the nucleus, both act as transcription regulators of a subset of genes that contain a 13-bp sequence termed as the oxygen …
Role Of Sirna Pathway In Epigenetic Modifications Of The Drosophila Melanogaster X Chromosome, Nikita Deshpande
Role Of Sirna Pathway In Epigenetic Modifications Of The Drosophila Melanogaster X Chromosome, Nikita Deshpande
Wayne State University Dissertations
Eukaryotic genomes are organized into large domains of coordinated regulation. The role of small RNAs in formation of these domains is largely unexplored. An extraordinary example of domain-wide regulation is X chromosome compensation in Drosophila melanogaster males. This process occurs by hypertranscription of genes on the single male X chromosome. Extensive research in this field has shown that the Male Specific Lethal (MSL) complex binds X-linked genes and modifies chromatin to increase expression. The components of this complex, and their actions on chromatin, are well studied. In contrast, the mechanism that results in exclusive recruitment to the X chromosome is …
Design, Synthesis, And Reactivity Of Homo- And Heterobimetallic Complexes Bridged By A Xanthene Linker, Thilini Samangi Hollingsworth
Design, Synthesis, And Reactivity Of Homo- And Heterobimetallic Complexes Bridged By A Xanthene Linker, Thilini Samangi Hollingsworth
Wayne State University Dissertations
Cooperative reactivity of bimettalics can be is observed in many different areas of chemistry and have been increasingly investigated because of the advantageous reactivity when compared to the corresponding mononuclear systems. The focus of my dissertation is on (1) investigation of the homobimetallic cooperativity in lactide polymerization catalysis; (2) investigation of the heterobimetallic cooperativity in the biomimetic studies of Mo-Cu carbon monoxide dehydrogenase (CODH) enzyme in order to make a functional model of its active site.
Three new main group bis(alkoxide) complexes Mg(OR)2(THF)2, Zn(Cl)(μ2-OR)2Li(THF) and In(OR)2(μ2-Cl)2Li(THF)2 featuring bulky alkoxide [OCtBu2Ph] were synthesized serve as metal alkoxide precursors for bimetallic lactide …
Methionine Sulfoximine: A Novel Anti Inflammatory Agent, Tyler Peters
Methionine Sulfoximine: A Novel Anti Inflammatory Agent, Tyler Peters
Wayne State University Dissertations
ABSTRACT
METHIONINE SULFOXIMINE: A NOVEL ANTI-INFLAMMATORY AGENT
by
TYLER J. PETERS
October 2018
Advisor: William Brusilow
Major: Biochemistry and Molecular Biology
Degree: Doctor of Philosophy
The glutamine synthetase inhibitor methionine sulfoximine (MSO), shown previously to prevent death caused by an inflammatory liver response in mice, was tested on in vitro production of cytokines by mouse peritoneal macrophages triggered with lipopolysaccharide (LPS). MSO significantly reduced the production of Interleukin 6 (IL-6) and Tumor Necrosis Factor Alpha (TNFα) at 4 and 6 hours after LPS-treatment. This reduction did not result from decreased transcription of IL-6 and TNFα genes, and therefore appeared to …