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Articles 1 - 18 of 18
Full-Text Articles in Life Sciences
Application Of Crispr/Cas9 Whole Genome Screens To Advance Macrophage Biology, Kevin Wanniarachchi
Application Of Crispr/Cas9 Whole Genome Screens To Advance Macrophage Biology, Kevin Wanniarachchi
Electronic Theses and Dissertations
Advances in CRISPR/Cas9 gene editing technologies present opportunities to better understand the contribution of individual genes to complex eukaryotic cellular processes. I have applied CRISPR whole genome screen technologies to inform further mechanistic understanding of macrophage fitness and neutral lipid metabolism. This work is important because macrophages play critical roles in immune function and are implicated as causative agents in disease states. Chapter One of this dissertation provides insights into how CRISPR genome screening technologies have improved biological discovery and key findings from their application and discusses how this technology can be implemented to advance the discovery of novel macrophage …
Modulatory Effects Of Deacetylated Sialic Acids On Breast Cancer Resistance Protein-Mediated Multidrug Resistance And Receptor Tyrosine Kinase-Targeted Therapy, Isaac Tuffour
Electronic Theses and Dissertations
Multidrug resistance (MDR) remains a major challenge in cancer treatment, accounting for over 90% of chemotherapeutic failures. Cancers utilize sugar residues to engage in multidrug resistance. The underlying mechanism of action involving glycans, specifically the glycan sialic acid (Sia) and its various functional group alterations, has not been explored. ATP-binding cassette (ABC) transporter proteins, key proteins utilized by cancers to engage in MDR pathways, contain Sias in their extracellular domains. Modulating the expression of acetylated-Sias on Breast Cancer Resistance Protein (BCRP), a significant ABC transporter implicated in MDR, in lung and colon cancer cells directly impacted the ability of cancer …
Characterization Of Parp1-Dependent Poly-Adp-Ribosylation Of Sprtn, Quincee Simonson
Characterization Of Parp1-Dependent Poly-Adp-Ribosylation Of Sprtn, Quincee Simonson
Electronic Theses and Dissertations
DNA-protein crosslinks (DPCs) are a type of DNA lesion that form when proteins become covalently linked to DNA. It is estimated that replicating cells experience approximately 6,000 DPCs per day per genome during exponential growth (Ruggiano & Ramadan, 2021). If left unrepaired, DPCs can be lethal to cells. For this reason, cells have evolved multiple pathways to repair or bypass DPCs to survive. One such pathway involves SPRTN, a nuclear metalloprotease that plays a key role in the repair of DPCs through direct proteolysis (Lopez-Mosqueda et al., 2016; Vaz et al., 2016). Once SPRTN degrades the bulky protein component of …
Identifying Adp-Ribosylation As The Biochemical Signal That Marks Dna-Protein Crosslinks For Sprtn-Dependent Proteolysis, Katelyn Hurley
Identifying Adp-Ribosylation As The Biochemical Signal That Marks Dna-Protein Crosslinks For Sprtn-Dependent Proteolysis, Katelyn Hurley
Electronic Theses and Dissertations
DNA-protein crosslinks (DPCs) form when proteins covalently attach to DNA. It is estimated that hundreds of DPCs form in our cells each day. Because these lesions are cytotoxic, mammalian cells have evolved multiple intricate repair systems to remove DPCs and restore genome integrity. One mechanism mammalian cells rely on for DPC repair is direct proteolysis by the metalloprotease, SPRTN. While it is known that SPRTN degrades a heterogenous array of DPCs, including both naturally occurring and chemically induced, how SPRTN selects DPCs amongst chromatin-associated proteins remains unknown. Our main objective is to determine how DPC repair is regulated. In Chapter …
Characterizing The Lir Domain Of Abin1 And Identifying Its Role As A Regulator Of Mitophagy, Andrew Rhiner
Characterizing The Lir Domain Of Abin1 And Identifying Its Role As A Regulator Of Mitophagy, Andrew Rhiner
Electronic Theses and Dissertations
A20 Inhibitor of NF-κB (ABIN1/TNIP1) is a known regulator of TNFα signaling induced cell death and inflammation. The regulatory activity has been attributed to ABIN1’s recruitment of the ubiquitin editing enzyme TNF-α-induced protein 3 (TNFAIP3/A20) to Receptor-interacting serine/threonine-protein kinase 1 (RIPK1). The regulation of RIPK1 by ABIN1 and A20 relies on a third player, linear ubiquitin chain assembly complex (LUBAC), which is involved in the recruitment of ABIN1 to RIPK1. Loss of LUBAC or ABIN1 is embryonic lethal, but loss of A20 is not embryonic lethal. The embryonic lethality due to loss of ABIN1, paired with the lack of lethality …
Electrical Sensing In Non-Excitable Cells To Promote Galvanotaxis And Tissue Survival, Anyesha Sarkar
Electrical Sensing In Non-Excitable Cells To Promote Galvanotaxis And Tissue Survival, Anyesha Sarkar
Electronic Theses and Dissertations
Weak DC fields have been shown to induce polarity, cell migration and cell proliferation in 2D cultures in vitro. To understand the mechanism by which non-excitable cells sense such weak EFs, we have investigated the mechanism of cathode-directed water flow (electro-osmosis) in the boundary layer of cells by reducing it with neutral, viscous polymers. Our results indicate that low molecular weight polymers decrease cathodal migration and promote anodal migration in a concentration dependent manner. High molecular weight polymers do not affect directionality and can be explained using porosity and hydraulic permeability between the polymers. These results provide the first evidence …
In Situ Analysis Of Line-1 Promoter Activity Using Lacz Transgenic Mice, Partha Sarathi Saha
In Situ Analysis Of Line-1 Promoter Activity Using Lacz Transgenic Mice, Partha Sarathi Saha
Electronic Theses and Dissertations
Apart from an evolutionary role, transposable elements have been implicated in animal development and also in pathophysiology. Non-LTR retrotransposons– LINE-1, Alu and SVA - are responsible for over 120 cases of human genetic diseases as heritable insertions, and are emerging as an important etiological factor for cancer and neurological disorders as somatic mutations. It is estimated that among the total number of 500,000 LINE-1s presents in the human genome, 80-100 LINE-1s remain competent for retrotransposition. Retrotransposition is only possible when LINE-1 is expressed. Because LINE-1 transcription is regulated by its 5’UTR promoter, it is essential to understand the spatiotemporal control …
The Role And Molecular Mechanisms Of Wss1 In Preserving Genomic Stability, Daniel Kwesi Sam
The Role And Molecular Mechanisms Of Wss1 In Preserving Genomic Stability, Daniel Kwesi Sam
Electronic Theses and Dissertations
Cells are constantly under threat from both exogenous and endogenous sources of DNA damage. Eukaryotic organisms, however, possess conserved mechanisms that accurately and faithfully respond to DNA damage. The inability to effectively remove DNA lesions can lead to an accumulation of mutations which can compromise cellular viability. The DNA damage response is conserved from bacteria to eukaryotic organisms and have been well characterized, however, how covalently crosslinked proteins are removed from DNA remains enigmatic This thesis provides genetic and biochemical evidence implicating Wss1, a yeast metalloprotease in genome maintenance. We have identified SUMOylation to be an important signal that mediates …
Crispr/Cas9 Whole Genome Screens Reveal Novel Regulators Of Endocytic Processes In Macrophages, Jared Wollman
Crispr/Cas9 Whole Genome Screens Reveal Novel Regulators Of Endocytic Processes In Macrophages, Jared Wollman
Electronic Theses and Dissertations
Macrophages maintain tissue homeostasis by identifying and eliminating threats within their tissue microenvironment. Pattern recognition receptors allow macrophages to recognize and internalize specific ligands while macropinocytosis allows the internalization of all extracellular solutes from their environment. Without pattern recognition receptors, pathogens may grow unchecked if they cannot be detected, and without macropinocytosis, macrophages struggle to detect and move around their environment. This thesis presents the results of CRISPR/Cas9 whole-genome screens used to identify the regulators of both endocytosis (Chapter 2) and macropinocytosis (Chapter 3). In Chapter 2, we report genes regulating dextran uptake in primary murine macrophages and reveal Mrc1-mediated …
Exploring The Properties Of Chitin For Promoting Tissue Engineering And Repair, M. Jahir Raihan
Exploring The Properties Of Chitin For Promoting Tissue Engineering And Repair, M. Jahir Raihan
Electronic Theses and Dissertations
No abstract provided.
Identifying Critical Genes For Cholesterol Metabolism In Macrophages Using Crispr-Cas9 Whole-Genome Screens, Kevin Wanniarachchi
Identifying Critical Genes For Cholesterol Metabolism In Macrophages Using Crispr-Cas9 Whole-Genome Screens, Kevin Wanniarachchi
Electronic Theses and Dissertations
Macrophage foam cells contribute to atherosclerotic plaque formation, a pathology that underlies heart disease, peripheral arterial disease and stroke. Foam cells form when macrophages take up excessive amounts of low-density lipoprotein (LDL) leading to elevated cellular levels of neutral lipids, which are packaged into lipid droplet organelles. Despite the high public health priority motivating research of cardiovascular disease processes, current understanding of macrophage cholesterol metabolism including mechanisms of LDL uptake, cholesterol trafficking, lipid droplet biogenesis, lipid droplet degradation and cholesterol efflux is limited. Here, we implemented a CRISPR-Cas9 whole genome screening strategy to identify critical genes regulating macrophage cholesterol metabolism. …
Investigation Of Intergroup Bias In Two Neuromaturationally Distinct Age Cohorts: An Erp Study, Reuven M. Hanna
Investigation Of Intergroup Bias In Two Neuromaturationally Distinct Age Cohorts: An Erp Study, Reuven M. Hanna
Electronic Theses and Dissertations
Currently, sociological investigation of adolescent behavior focuses on the intersection of biography, history, and structure to explain adolescent risk-taking, reward-seeking, impulsivity, novelty-seeking and peer-salience. However, the preponderance of the evidence points away from social ecology and to a significant neuromaturational restructuring event between the 12th and 25th years of life as the root of adolescent behavioral tendencies. As a result, sociological social psychology can benefit from engaging in basic research using neuroscience methods. The present study expands the dual systems model of brain development to account for maturational changes in the social brain network as a way to explain social …
Mechanisms By Which Mechanotransduction Promotes Proliferation In Keratinocytes, Chhavi Chaudhary
Mechanisms By Which Mechanotransduction Promotes Proliferation In Keratinocytes, Chhavi Chaudhary
Electronic Theses and Dissertations
Chronic wounds are wounds that do not heal within 30 days and often they can last over a year. Interference in any of the wound healing stages may hinder the process. Some of the local and systemic factors such as infection, old age, diabetes, AIDS, and the regular application of corticoids may also have negative effects on the healing process. Cell proliferation is an important phase in epidermal wound healing in which surviving epithelial cells replicate independently into daughter cells through mitosis and maintain a balance between cell growth and cell loss during the cell cycle. Physical and chemical stimuli …
Identification Of Macropinocytosis Regulating Proteins And Signaling From Macropinosomes, Louise Monga
Identification Of Macropinocytosis Regulating Proteins And Signaling From Macropinosomes, Louise Monga
Electronic Theses and Dissertations
Understanding macrophage cell biology is important due to macrophages key roles in human health and diseases including proper immune function, wound healing, atherosclerosis, and cancer. Despite their importance, relatively little is understood about macrophage activation, growth factor signaling, and cytoskeletal regulation. This thesis presents data from investigations into mechanisms of macrophage growth factor signaling and actin polymerization for ruffling and macropinocytosis. Alt-R CRISPR-Cas9 method and dextran uptake assay were used to knock out individual genes (SHP-1, Lyn, Syk, BTK, Vav1) and determine their role in macropinocytosis and CSF-1R signaling. Dextran uptake was disrupted in SHP-1 and Lyn targeted knockout cells, …
Identification Of Cdks As Novel Targets Of Aspirin And Its Metabolites: A Potential Role In Cancer Prevention, Rakesh Dachineni
Identification Of Cdks As Novel Targets Of Aspirin And Its Metabolites: A Potential Role In Cancer Prevention, Rakesh Dachineni
Electronic Theses and Dissertations
Background:
The pursuit of drugs that inhibit cyclin-dependent kinases (CDKs) has been an intense area of research for more than 15 years. Till date, although multiple CDK inhibitors have been identified and few are undergoing clinical trials, only two synthetic drugs have been approved by Food and Drug Administration (FDA) for use in the treatment of cancer. These two drugs are mainly used for the treatment of metastatic breast cancer in combination with other drugs; however they have toxicity associated with their use and extends patients life not more than 24 months. Therefore, there is an urgent need for …
Macropinosome Maturation Is A Clathrin Dependent Process In Bone Marrow Macrophages, Susmita Poudel
Macropinosome Maturation Is A Clathrin Dependent Process In Bone Marrow Macrophages, Susmita Poudel
Electronic Theses and Dissertations
Macrophages nonspecifically take up extracellular fluids, solutes and macromolecules by macropinocytosis. Understanding the mechanisms of macropinosome maturation will inform the study of lipid uptake, viral entry, antigen processing and presentation, as well as regulation of cell growth. Colony stimulating factor-1 receptor (CSF-1R) is internalized by small vesicle endocytosis, trafficked to nascent macropinosomes and degraded. These CSF-1R positive macropinosomes mature through a sequence similar to endosomes, progressing from EEA1 and Rab5 to Rab7 positive vesicles before fusing with lysosomes. Here we report the assembly of clathrin on internalized macropinosomes shown both by live-cell microscopy of cells expressing clathrin light chain-yellow fluorescent …
Lipid-Laden Macrophages Downregulate Akt Phosphorylation And Metabolize Lipid Droplets Via Autophagy, Rifat Sultana
Lipid-Laden Macrophages Downregulate Akt Phosphorylation And Metabolize Lipid Droplets Via Autophagy, Rifat Sultana
Electronic Theses and Dissertations
Macrophages contribute to plaque formation in atherosclerosis. Macrophages take up modified low-density lipoproteins and store excess cholesterol and triglycerides in lipid droplet organelles. Evidence of lipid-laden macrophages or “foam cells” is apparent on histology sections of diseased arteries, and this lipid-laden appearance can be recreated in cell culture upon exposure of cultured macrophages to acetylated LDL (Ac-LDL). Under nutrient stress, neutral lipids in lipid droplets are hydrolyzed by lipolysis, autophagy, or both. However, these processes are not well understood in macrophages. We created lipidladen macrophages by 24-h exposure to Ac-LDL and analyzed dynamics of lipid droplet metabolism following removal of …
Enhancing The Industrial Potential Of Filamentous Cyanobacteria, Tylor J. Johnson
Enhancing The Industrial Potential Of Filamentous Cyanobacteria, Tylor J. Johnson
Electronic Theses and Dissertations
The objectives of this project were to improve the industrial potential of filamentous N2-fixing cyanobacteria by increasing its biofuel tolerance, and to evaluate the economic feasibility and environmental impacts of a theoretical, cyanobacteria-based biofuel production facility. To develop a method to quantify filamentous cyanobacteria in dilute culture media, a dual-stained fluorescence assay was evaluated. While the viable cell stain (SYTO® 9) was accurate, the non-viable cell stain (propidium iodide) also bound to viable cells. Additional non-viable cell stains were evaluated, but none were accurate at quantifying viability. Thus we concluded that the viable cell stain SYTO® 9 is a reliable …