Molecular Biology Commons^™

Epigenetic Implications In Inorganic Arsenic-Mediated Carcinogenesis, Meredith Eckstein

Theses and Dissertations--Molecular and Cellular Biochemistry

Chronic, low dose exposure to inorganic arsenic (iAs) is a public health concern throughout the world, contributing to the development of many diseases, including lung cancer. Several mechanisms for iAs-mediated carcinogenesis have been proposed, of which the production of reactive oxygen species and formation of chromosomal aberrations are the most studied. Another equally important, yet less studied mechanism is dysregulation of epigenetic marks. “Epigenetics” refers to changes that occur on the DNA and chromatin that do not alter base pair identity, but alter compaction, expression, and regulation of specific DNA sequences. There are several types of epigenetic marks including histone …

The Role Of Manganese In Streptococcus Sanguinis, Tanya M. Puccio

Theses and Dissertations

Streptococcus sanguinis is primarily associated with oral health as a commensal bacterium. As an opportunistic pathogen, S. sanguinis is capable of colonizing heart valve vegetations, leading to the disease infective endocarditis. Previous studies from our lab have identified the high-affinity manganese transporter SsaACB as important for endocarditis virulence. The impact that manganese depletion has on S. sanguinis had never been evaluated and a secondary manganese transporter has not been identified. Thus, we employed the use of a fermentor to control large-scale growth over time and depleted manganese in an ΔssaACB mutant using a metal chelator, EDTA. The changes in …

Synthesis And The Genetic Encoding Of Novel Lysine Post-Translational Modifications, Sahan A. Galbada Liyanage

Theses and Dissertations

Post-translational modifications (PTMs) play a significant role in regulating cell signaling and regulating the inner cellular environment. The study of PTMs and their primary biological functions is critical for the development of new medicines targeting the pathways and biomolecules responsible for the PTMs.

Previous studies revealed the direct coupling of the β -hydroxybutyryl lysine (K_BHB) modification with the gene expression. K_BHB in histone proteins links metabolism to epigenetics and gene expression and enables to study in-depth, how cell metabolism controls the gene expression and vice versa. Similar novel histone modification, K_Lac, attracts a special interest …

The Balancing Act Of Cytokinin In Environmental Stress Tolerance, Sumudu Sandeepani Karunadasa

Theses and Dissertations--Plant and Soil Sciences

Cytokinin, long known as a phytohormone that regulates plant growth and development, has been recently recognized as an important regulator of stress responses. However, our current knowledge about the mechanisms by which cytokinin regulates stress responses is fragmentary, as many of the studies in this field yielded conflicting results. Most of the work described here has focused on analyses of the molecular mechanisms of cytokinin-dependent regulation of growth and development under stress conditions, with an emphasis on the role of cytokinin-dependent regulation of protein synthesis in development and stress tolerance.

One of the important contributions of this study is the …

The Impact Of Aging And Mechanical Injury On Alveolar Epithelial And Macrophage Responses In Acute Lung Injury And Inflammation, Michael S. Valentine

Theses and Dissertations

Patients with severe lung pathologies, such as Acute Respiratory Distress Syndrome (ARDS), often require mechanical ventilation as a clinical intervention; however, this procedure frequently exacerbates the original pulmonary issue and produces an exaggerated inflammatory response that potentially leads to sepsis, multisystem organ failure, and mortality. This acute lung injury (ALI) condition has been termed Ventilator-Induced Lung Injury (VILI). Alveolar overdistension, cyclic atelectasis, and biotrauma are the primary injury mechanisms in VILI that lead to the loss of alveolar barrier integrity and pulmonary inflammation. Stress and strains during mechanical ventilation are believed to initiate alveolar epithelial mechanotransduction signaling mechanisms that contribute …

Investigation Of Glutamate Carboxypeptidase Ii Roles In The Folate Cycle Dependent Reproduction And Development Of Caenorhabditis Elegans, Jessica M. Derham

Masters Theses

Glutamate Carboxypeptidase II (GCPII) is a transmembrane, zinc metallopeptidase that is expressed in a wide range of organisms, including roundworms, mice, and humans. In humans, GCPII is primarily expressed in the prostate, kidneys, small intestine, and central nervous system. Within the small intestine, the expected function of GCPII is to aid in the absorption of dietary folate from the intestinal lumen. GCPII cleaves excess glutamates from folate to yield monoglutamated folate which is then readily transported into the enterocyte. Folate can then be used through the one carbon metabolic cycle for the synthesis of nucleotides, conversion of homocysteine to methionine, …

A Bioinformatic Approach To Exploring Land Plant Evolution, Lauren Margaret Orton

Graduate Research Theses & Dissertations

Today, researchers are inundated with an overwhelming amount of data due to advances in DNA sequencing technologies. This has benefited the fields of both bioinformatics and phylogenomics substantially. With the ability to increase sampling at both the taxonomic and molecular levels, we are now able to produce robust phylogenomic reconstructions and better discern relationships between taxa.

The goals of this dissertation are in two distinct parts: 1) to advance the understanding of land plant terrestrialization and evolution through examination of the closest relative to the land plant lineage, a species of green algae; and 2) to explore evolution among a …

A Role For Mek3 In The Oncogenesis Of Acute Lymphocytic Leukemia: Inactivation Of Mapk P38 Promotes Cell Proliferation Through Enhanced Degradation Of Mutant Mek3, Yoshira Marie Ayala-Marin

Open Access Theses & Dissertations

In the United States, pediatric leukemia has the second-highest cancer mortality rate in Hispanic children, especially Acute Lymphocytic Leukemia (ALL). While treatment of ALL has improved overall the five-year survival rate of ~90 %, not everyone has benefited. Twenty percent of them will experience relapse, and from these, 30 - 50 % will die. Unfortunately, the cause behind these dreadful statistics is poorly understood due to the complex etiology of this disease. Thereby, it is essential to identify potential oncogenic proteins that promote ALL so that new strategies can be developed to diagnose and treat this cancer. Whole Exome Sequencing …

Synthesis, Characterization, And Biological Activity Of Imidazolium Salts, David Weader

Williams Honors College, Honors Research Projects

Nonmuscle invasive bladder cancer (NMIBC) inflicts thousands of Americans annually, and is typically treated with the immunotherapy BCG. However, due to a BCG shortage, there is a new need for novel treatments of NMIBC. Addressing this issue, several imidazolium salt derivatives were synthesized and characterized with the intent of treatment within the bladder. These imidazolium salts were tested against different human bladder cancer cell lines in vitro to determine their reactivity and cytotoxicity. Among these results are GI50 concentrations for each drug, which is the concentration of drug needed to see growth inhibition in 50% of treated cells. Previous published …

The Effects Of Signaling Molecules To Agrobacterium Tumefaciens Tumorigenesis At Plant Wound Sites, Nicole Walker

Honors Theses

Agrobacterium tumefaciens can live independently within soil before infecting its host (McCullen and Binns, 2006). The bacterium infects the plant through the rhizosphere, an area of soil along the plant root surface which contains microorganisms, making up the “external metabolome” (Bais et al. 2006). As these bacteria live in the rhizosphere, they are exposed to a multitude of chemical signals. These chemical signals include several conditions that must be met before the virulence machinery is expressed. These conditions include signaling from phenols and sugars as well as low PO4 levels and low pH. Upon wounding, sugars and phenols are released …

Archaeosine Modification Of Archaeal Trna - A Role In Structural Stabilization, Ben Turner, Brett W. Burkhart, Katrin Weidenbach, Robert Ross, Patrick A. Limbach, Ruth A. Schmitz, Valérie De Crécy-Lagard, Kenneth M. Stedman, Thomas J. Santangelo, Dirk Iwata-Reuyl

Biology Faculty Publications and Presentations

Archaeosine (G+) is a structurally complex modified nucleoside found quasi-universally in the tRNA of Archaea and located at position 15 in the dihydrouridine loop, a site not modified in any tRNA outside of the Archaea. G+ is characterized by an unusual 7-deazaguanosine core structure with a formamidine group at the 7-position. The location of G+ at position 15, coupled with its novel molecular structure, led to a hypothesis that G+ stabilizes tRNA tertiary structure through several distinct mechanisms. To test whether G+ contributes to tRNA stability and define the biological role of G+, we investigated the consequences of introducing targeted …

Evaluating A Culprit: A Review Of The Biochemical Mechanisms Of Non-Celiac Gluten Intolerance, Callie Cinque

Honors Theses

Non-Celiac Gluten Intolerance (NCGI) has evaded biological and chemical mechanisms since it was first reported in 1978. Celiac Disease, a multi-system immune mediated disorder has long served as the most similar counterpart to NCGI. Less cases of celiac disease are going undiagnosed reflecting an improvement on sensitive and decisive diagnostic tools. However, NCGI has been significantly growing as a diagnosis over the past decade with little match or similarity to the markers found in celiac disease patients. Critical evaluation of NCGI theories, experimentation, and existing hypotheses is necessary. This review seeks to synthesize multiple disciplines of gluten research and enhance …

Application Of Β-Chloroenals: One-Pot Syntheses To Create Highly Variable, Functional, And Biologically Interesting Molecules, Julia Powell Siewert

Honors Theses

Pyrroles and pyrazoles are privileged structures which provide a molecular framework found in many different classes of bioactive compounds, thus rendering their syntheses useful in pharmaceutical drug development. Additionally, being able to selectively create these molecules with interesting substituents allows for different pharmacological and biological activities, such as antitumor and antibiotic effects. Our group has used β-chloroenals in the application of many different unique synthetic strategies in the past, and here I show that chloroenals can be used to synthesize novel 1,2,5 trisubstituted pyrroles as well as 1,5 di- and 1,4,5 trisubstituted pyrazoles in fewer steps and with milder conditions …

A Novel Pool Of Microparticle Cholesterol Is Elevatedin Rheumatoid Arthritis But Not In Systemic Lupus Erythematosus Patients, Shuai Shuai Hu, Brenton L. Cavanagh, Robert Harrington, Muddassar Ahmad, Grainne Kearns, Steve Meaney, Claire Wynne

Articles

Microparticles are sub-micron, membrane-bound particles released from virtually allcells and which are present in the circulation. In several autoimmune disorders their amountand composition in the circulation is altered. Microparticle surface protein expression has beenexplored as a differentiating tool in autoimmune disorders where the clinical pictures can overlap.Here, we examine the utility of a novel lipid-based marker—microparticle cholesterol, present in allmicroparticles regardless of cellular origin—to distinguish between rheumatoid arthritis (RA) andsystemic lupus erythematosus (SLE). We first isolated a series of microparticle containing lipoproteindeficient fractions from patient and control plasma. There were no significant differences in thesize, structure or protein content of …

Optimisation Of Estrogen Receptor Subtype-Selectivity Of A 4-Aryl-4h-Chromene Scaffold Previously Identified By Virtual Screening, Miriam Carr, Andrew Knox, Daniel Nevin, Niamh O'Boyle, Shu Wang, Billy Egan, Thomas Mccabe, Brendan Twamley, Daniela Zisterer, David Lloyd, Mary Meegan

Articles

4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and β with low nanomolar affinity and <20-fold selectivity for α over β and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERβ (compound 42; 170-fold selectivity).

Therapeutic Efficacy Of Umbilical Cordderived Stem Cells For Diabetes Mellitus: A Meta-Analysis Study, Dina H. Kassem, Mohamed M. Kamal

Pharmacy

Background: Stem cell therapy provides great hope for patients with diabetes mellitus (DM). DM is a seriously alarming metabolic disease characterized by hyperglycemia and β cell dysfunction. Efficient novel therapeutic modalities to treat DM are indeed warranted. Stem cells (SC) derived from the umbilical cord specifically provide several advantages and unique characteristics being a readily available non-invasive source, with an additional credit for their banking potential. This meta-analysis study aims to provide a focused assessment for therapeutic efficacy of umbilical cord (UC)-derived SC-transplantation, namely Wharton’s jelly mesenchymal stem cells (WJMSCs) and umbilical cord blood (UCB) for DM. Methods: The clinical …

“C1orf150”: A Novel Regulator Of Jak2 Kinase, And Candidate Tumor Suppressor In Human Blood Cell Progenitors, Tyler M. Wade

Honors Theses and Capstones

Erythropoietin (EPO) is an essential growth factor for red blood cell (RBC) production. In response to anemia, hypoxia-sensing cells in the kidney express and release EPO. EPO then acts in bone marrow to drive RBC formation from erythroid progenitors. Upon binding to its cell surface receptor, EPO triggers a JAK2 kinase signaling cascade for progenitor cell growth. Our lab has discovered a novel regulator of JAK2, “C1ORF150” (“150”). “150” is conserved in H sapiens and primates and is a new orthologue of the B-cell receptor adaptor protein and tumor marker, HGAL. Using a shRNA knockdown approach, I investigated the actions …

Effect Of Mptp On Α-Synuclein Spreading, Accumulation And Toxicity In Mice With Intrastriatal Innoculation Of Human Α-Synuclein Preformed Fibril, Madiha Mohieldin Merghani

Theses

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder, characterized by abnormal accumulation of interneuronal inclusions of α-synuclein (α-syn) known as Lewy bodies (LBs) and Lewy neurites (LNs), and significant loss of dopamine neurons in the substantia nigra pars compacta (SNc) region of the brain. Recent evidence suggests that intrastriatal inoculation of α-syn Preformed Fibril (PFF) into mice induces PD-like LBs and LNs pathology formed by aggregated α-syn in anatomically interconnected brain regions which needs several months of incubation to develop the pathology. In the present study, we have evaluated the effect of different doses of 1-methyl, 4-phenyl, …

A Proteomic Analysis Of Corydoras Sterbai Secretions And Tissues, Erik Powell Wictor

University of the Pacific Theses and Dissertations

Defensive mechanisms vary widely in the animal kingdom ranging from physical defenses like spines to chemical defenses such as toxins. Toxins in these secretions and tissues can fluctuate from enzymes to lipids to uncharacterized chemicals. Next generation -omics technology and mass spectrometry are extremely important in analyzing these samples because of their ability to distinguish minute amounts of toxic substance within a complicated sample. The goal of this experiment was to look at secretions and tissues from Corydoras sterbai. All samples in this study were proteolyzed using a mixture of Trypsin and Lys-C, fractionated, and run through nanoLC-MS/MS analysis using …

Outlier Profiles Of Atomic Structures Derived From X-Ray Crystallography And From Cryo-Electron Microscopy, Lin Chen, Jing He, Angelo Facchiano

Computer Science Faculty Publications

Background: As more protein atomic structures are determined from cryo-electron microscopy (cryo-EM) density maps, validation of such structures is an important task. Methods: We applied a histogram-based outlier score (HBOS) to six sets of cryo-EM atomic structures and five sets of X-ray atomic structures, including one derived from X-ray data with better than 1.5 Å resolution. Cryo-EM data sets contain structures released by December 2016 and those released between 2017 and 2019, derived from resolution ranges 0–4 Å and 4–6 Å respectively. Results: The distribution of HBOS values in five sets of X-ray structures show that HBOS is sensitive distinguishing …