Long Non-Coding Rna Meg3 Deficiency Impairs Glucose Homeostasis And Insulin Signaling By Inducing Cellular Senescence Of Hepatic Endothelium In Obesity, 2021 University of Nebraska-Lincoln
Long Non-Coding Rna Meg3 Deficiency Impairs Glucose Homeostasis And Insulin Signaling By Inducing Cellular Senescence Of Hepatic Endothelium In Obesity, Xiao Cheng, Mohamed Sham Shihabudeen Haider Ali, Matthew Moran, Martonio Ponte Viana, Sarah L. Schlichte, Matthew C. Zimmerman, Oleh Khalimonchuk, Mark W. Feinberg, Xinghui Sun
Department of Biochemistry: Faculty Publications
Obesity-induced insulin resistance is a risk factor for diabetes and cardiovascular disease. However, the mechanisms underlying endothelial senescence in obesity, and how it impacts obesity-induced insulin resistance remain incompletely understood. In this study, transcriptome analysis revealed that the long non-coding RNA (lncRNA) Maternally expressed gene 3 (Meg3) is one of the top differentially expressed lncRNAs in the vascular endothelium in diet-induced obese mice. Meg3 knockdown induces cellular senescence of endothelial cells characterized by increased senescence-associated β–galactosidase activity, increased levels of endogenous superoxide, impaired mitochondrial structure and function, and impaired autophagy. Moreover, Meg3 knockdown causes cellular senescence of hepatic endothelium in …
Targeting The Phgdh-Mtor Metabolic Axis In Osteosarcoma, 2021 Washington University in St. Louis
Targeting The Phgdh-Mtor Metabolic Axis In Osteosarcoma, Richa Rathore
Arts & Sciences Electronic Theses and Dissertations
Altering cellular energy metabolism has been highlighted as one of the emerging hallmarks of cancer. The reprogramming of bioenergetic pathways towards enhanced glycolysis, rather than the mitochondrial oxidative phosphorylation indicative of normal cells, results in increased biomass production and is associated with the activation of various oncogenes. The increased or decreased expression of key metabolic enzymes has been identified as a potential family of biomarkers that could serve as the targets for novel metabolic-based therapies in cancer.
The serine, glycine, and one-carbon (SGOC) metabolism pathway consists of a series of enzymes and metabolites that drive protein and lipid production, enhanced …
Uncovering The Roles And Evolved Sequence Grammar Of Hypervariable Intrinsically Disordered Proteins In Bacterial Cell Division, 2021 Washington University in St. Louis
Uncovering The Roles And Evolved Sequence Grammar Of Hypervariable Intrinsically Disordered Proteins In Bacterial Cell Division, Megan Cohan
McKelvey School of Engineering Theses & Dissertations
Across all domains of life, a defining hallmark of the onset of cell division is the formation of a cytokinetic ring at the center of the cell. Cell division is a tightly controlled process that involves various regulatory factors that modulate the assembly of the cytokinetic ring. In rod-shaped bacteria, the ring is termed the Z-ring after the protein FtsZ, which is foundational to ring formation and is the bacterial homolog of tubulin. Like tubulin, FtsZ is an assembling GTPase, where GTP binding promotes the cooperative assembly into FtsZ polymers that laterally associate to form bundles. While the GTPase domain …
Homeostatic T Cell Receptor Interactions With Self-Peptide Tune Cd4+ T Cell Function, 2021 Washington University in St. Louis
Homeostatic T Cell Receptor Interactions With Self-Peptide Tune Cd4+ T Cell Function, Juliet Marie Bartleson
Arts & Sciences Electronic Theses and Dissertations
Homeostatic T Cell Receptor Interactions with Self-Peptide Tune CD4+ T Cell Function
by
Juliet Marie Bartleson
Doctor of Philosophy in Biology and Biomedical Sciences
Immunology
Washington University in St. Louis, 2021
Professor Paul M. Allen, Chair
Mature CD4+ T cells circulate throughout peripheral secondary lymphoid organs using their T cell receptor (TCR) to surveil peptide presented on major histocompatibility complex class II molecules (pMHC) in search of cognate, antigenic peptide. In the absence of an immune challenge, however, the TCR is continuously interacting with self-pMHC, which induces a relatively weak TCR signal known as tonic signaling. These homeostatic TCR:self-pMHC interactions …
Protein Synthesis Adaptation To The Au-Rich Transcriptome Of Plasmodium Falciparum, 2021 Washington University in St. Louis
Protein Synthesis Adaptation To The Au-Rich Transcriptome Of Plasmodium Falciparum, Jessey Lee Erath
Arts & Sciences Electronic Theses and Dissertations
The process of protein synthesis whereby a messenger RNA is decoded into an amino acid chainis conserved among the domains. Fastidious protein synthesis is necessary for organism survival. However, exceptions negatively affecting the mRNA translation cycle – inadvertently or by design – may occur. Polyadenosine tracts are one such motif causing ribosomal stalling and frameshifting in almost all organisms tested thus far; save Plasmodium spp. Thus, with ~60% of their protein-coding genome harboring polyadenosine tracts, the elucidation of such paradigm-breaking adaptations enabling Plasmodium spp. to translate this typically problematic motif without issue is salient from both basic science and clinical …
Understanding The Molecular Mechanisms Of Photoferrotrophy And Phototrophic Extracellular Electron Uptake, 2021 Washington University in St. Louis
Understanding The Molecular Mechanisms Of Photoferrotrophy And Phototrophic Extracellular Electron Uptake, Dinesh Gupta
Arts & Sciences Electronic Theses and Dissertations
Several anoxygenic phototrophs grow by utilizing soluble iron or insoluble mixed-valence iron minerals (such as rust) as electron donors to fix carbon dioxide using light energy, a process called photoferrotrophy. Photoferrotrophs can also use electron donors such as poised electrodes that serve as proxies for rust via phototrophic extracellular electron uptake (EEU). Despite the recognition that these two related microbial processes contribute to various biogeochemical cycles such as iron and carbon, the electron uptake mechanisms underlying photoferrotrophy and phototrophic EEU are poorly understood. To address the key knowledge gaps in our understanding of these microbial metabolisms, here we characterized Rhodopseudomonas …
The Role Of Mature Secretory Cells In Gastrointestinal Regeneration, 2021 Washington University in St. Louis
The Role Of Mature Secretory Cells In Gastrointestinal Regeneration, Megan Deanna Radyk
Arts & Sciences Electronic Theses and Dissertations
Differentiated cells exhibit the ability to adjust their cell fate and become more progenitor-like after wide-scale tissue injury. This inherent cell plasticity is shown across many tissues and organisms and is a conserved behavior that ensures organ function even in a chronic injury setting. At the tissue level, the change in cell fate from a differentiated cell to one with more progenitor properties can be identified as metaplasia. Importantly, metaplasias, like Spasmolytic Polypeptide-Expressing Metaplasia (SPEM) in the stomach and Acinar-to-Ductal Metaplasia (ADM) in the pancreas, are risk factors for the development of adenocarcinoma. Thus, understanding the cellular and molecular mechanisms …
Understanding And Exploiting Protein Allostery And Dynamics Using Molecular Simulations, 2021 Washington University in St. Louis
Understanding And Exploiting Protein Allostery And Dynamics Using Molecular Simulations, Sukrit Singh
Arts & Sciences Electronic Theses and Dissertations
Protein conformational landscapes contain much of the functionally relevant information that is useful for understanding biological processes at the chemical scale. Understanding and mapping out these conformational landscapescan provide valuable insight into protein behaviors and biological phenomena, and has relevance to the process of therapeutic design.
While structural biology methods have been transformative in studying protein dynamics, they are limited by technicallimitations and have inherent resolution limits. Molecular dynamics (MD) simulations are a powerful tool for exploring conformational landscapes, and provide atomic-scale information that is useful in understanding protein behaviors. With recent advances in generating datasets of large timescale simulations …
Thermodynamics And Conformational Heterogeneity Of Recbcd Binding To Dna Ends, 2021 Washington University in St. Louis
Thermodynamics And Conformational Heterogeneity Of Recbcd Binding To Dna Ends, Linxuan Hao
Arts & Sciences Electronic Theses and Dissertations
E. coli RecBCD is crucial in initiating repair of double stranded (ds) DNA breaks. It is a heterotrimeric helicase and nuclease complex possessing two ATPase motors, RecB and RecD, and a regulatory subunit without ATPase activity, RecC. The RecB subunit also contains a 30kDa nuclease domain (RecBNuc) that, according to published structural data, is situated over 60Å away from the site of dsDNA binding. Surprisingly, we have shown in previous studies that deletion of RecBNuc to form RecBΔNucCD affects its dsDNA unwinding properties. The mechanism by which RecBNuc influences RecBCD dsDNA unwinding is unclear. In this thesis, equilibrium binding techniques, …
Molecular Strategies To Overcome Antibiotic Resistance, 2021 Washington University in St. Louis
Molecular Strategies To Overcome Antibiotic Resistance, Luting Fang
Arts & Sciences Electronic Theses and Dissertations
Antibiotics have greatly reduced the number of deaths caused by infectious diseases for the last 70 years, but as a result of overuse, antimicrobial resistance emerged. Resistance is the major reason why most traditional antibiotics currently have reduced clinical efficacy. However, there is still a drive to overcome this resistance in a variety of ways. There are two main avenues of research to overcome resistance; to discover and develop new drug candidates acting on new targets and pathways, and to determine the mechanisms of antibiotic resistance in order to combat it through multi-drug therapies, bringing back the effectiveness of antibiotics …
Mass Spectrometry-Based Strategies In Protein Higher Order Structure Analysis: Fundamentals And Applications In Protein-Ligand Interactions, 2021 Washington University in St. Louis
Mass Spectrometry-Based Strategies In Protein Higher Order Structure Analysis: Fundamentals And Applications In Protein-Ligand Interactions, Xiaoran Liu
Arts & Sciences Electronic Theses and Dissertations
Protein ligand interaction is a fundamental question in biology and biochemistry, and many approaches including X-ray crystallography, nuclear magnetic resonance, cryogenic electron microscopy, mass spectroscopy (MS), infrared spectroscopy, circular dichroism, fluorescence spectroscopy and many others have been applied to address this question. Among these techniques, mass spectroscopy has the advantage of high throughput, low sample amount requirement, and mid-to-high spatial resolution. One of the MS-based approaches is protein footprinting, which utilizes labeling reagents to map the solvent accessible surface of the protein of interest thus deliver structural information. Irreversible labeling is represented by covalent labeling and radical labeling, in which …
Prodrug Activation In Staphylococci And The Implications For Antimicrobial Development, 2021 Washington University in St. Louis
Prodrug Activation In Staphylococci And The Implications For Antimicrobial Development, Justin J. Miller
Arts & Sciences Electronic Theses and Dissertations
Antibiotic resistance is an increasing concern for global health care, with some estimates suggesting that 10 million people will die from antibiotic resistant infections in the year 2050. Fueling this prospect, few antimicrobials are being actively developed and recently commercial entities have fled from the development of new anti-infectives. New antimicrobials and drug development strategies are urgently needed to revitalize this critical pipeline. While many putative antibiotics demonstrate promising in vitro potency, they routinely fail in vivo due to poor drug-like properties (e.g. oral bioavailability, serum-half life, toxicity) resulting in overly expensive drug development pipelines. Fortunately, drug-like properties can be …
Measuring And Manipulating Tension-Dependent Behavior Of Mechanosensitive Ion Channels, 2021 Washington University in St. Louis
Measuring And Manipulating Tension-Dependent Behavior Of Mechanosensitive Ion Channels, Angela M. Schlegel
Arts & Sciences Electronic Theses and Dissertations
Mechanical forces play critical roles throughout the lives of all organisms and, as such, diverse arrays of mechanotransduction systems have evolved to detect and initiate responses to force. Many mechanotransduction systems consist of mechanosensitive (MS) ion channels, membrane pores that open in response to sufficient mechanical force. My dissertation focuses on both the study and application of force-dependent conformational changes of MS channels. I tested whether charged pore-lining residues R326 and D327 of the Arabidopsis thaliana mitochondrial MS channel MSL1 function in inward rectification or gating kinetics. Mutating these residues showed no effect on MSL1 rectification; however, these residues are …
Implications And Applications Of Transfer Rna Variants That Mistranslate The Genetic Code, 2021 The University of Western Ontario
Implications And Applications Of Transfer Rna Variants That Mistranslate The Genetic Code, Matthew D. Berg
Electronic Thesis and Dissertation Repository
Genetic information is passed from DNA to RNA to protein through the processes of transcription and translation. Transfer RNAs (tRNA) are the adaptors that bring amino acids to the growing polypeptide chain during translation and decode the three base codons that define protein sequence. Mistranslation occurs when an amino acid different from what is specified by the genetic code is inserted into a protein. tRNA variants cause mistranslation by decreasing the accuracy of amino acid charging or by altering decoding at the ribosome. My goal was to characterize mistranslating tRNA variants, identify their effects on cells and determine mechanisms used …
Arginase 1 Insufficiency Precipitates Amyloid-Β Deposition And Hastens Behavioral Impairment In A Mouse Model Of Amyloidosis, 2021 University of Kentucky
Arginase 1 Insufficiency Precipitates Amyloid-Β Deposition And Hastens Behavioral Impairment In A Mouse Model Of Amyloidosis, Chao Ma, Jerry B. Hunt, Maj-Linda B. Selenica, Awa Sanneh, Leslie A. Sandusky-Beltran, Mallory Watler, Rana Daas, Andrii Kovalenko, Huimin Liang, Devon Placides, Chuanhai Cao, Xiaoyang Lin, Michael B. Orr, Bei Zhang, John C. Gensel, David J. Feola, Marcia N. Gordon, Dave Morgan, Paula C. Bickford, Daniel C. Lee
Sanders-Brown Center on Aging Faculty Publications
Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1 …
Design Of Fibril Forming Collagen Mimetic Peptides: Heterotrimers And Nucleation Domains, 2021 CUNY Hunter College
Design Of Fibril Forming Collagen Mimetic Peptides: Heterotrimers And Nucleation Domains, Sally Tan
Theses and Dissertations
This paper attempts to design collagen mimetic peptides where the triple-helical region mimics that of human Type I Collagen. With consideration for chain selection and chain register, we utilize the NC2 domain of heterotrimeric Type IX Collagen as a nucleation domain for triple-helix folding.
Experimental And Computational Observations Of Immunogenic Cobalt Porphyrin Lipid Bilayers: Nanodomain-Enhanced Antigen Association., 2021 Western University
Experimental And Computational Observations Of Immunogenic Cobalt Porphyrin Lipid Bilayers: Nanodomain-Enhanced Antigen Association., Jasmin Federizon, Conrard Giresse Tetsassi Feugmo, Wei-Chiao Huang, Xuedan He, Kazutoyo Miura, Aida Razi, Joaquin Ortega, Mikko Karttunen, Jonathan F Lovell
Chemistry Publications
Cobalt porphyrin phospholipid (CoPoP) can incorporate within bilayers to enable non-covalent surface-display of antigens on liposomes by mixing with proteins bearing a polyhistidine tag (his-tag); however, the mechanisms for how this occurs are poorly understood. These were investigated using the his-tagged model antigen Pfs25, a protein antigen candidate for malaria transmission-blocking vaccines. Pfs25 was found to associate with the small molecule aquocobalamin, a form of vitamin B12 and a cobalt-containing corrin macrocycle, but without particle formation, enabling comparative assessment. Relative to CoPoP liposomes, binding and serum stability studies indicated a weaker association of Pfs25 to aquocobalamin or cobalt nitrilotriacetic acid …
Modeling The Bidirectional Glutamine/ Ammonium Conversion Between Cancer Cells And Cancer-Associated Fibroblasts, 2021 University of Wisconsin - Milwaukee
Modeling The Bidirectional Glutamine/ Ammonium Conversion Between Cancer Cells And Cancer-Associated Fibroblasts, Peter Hinow, Gabriella Pinter, Wei Yan, Shizhen Emily Wang
Mathematical Sciences Faculty Articles
Like in an ecosystem, cancer and other cells residing in the tumor microenvironment engage in various modes of interactions to buffer the negative effects of environmental changes. One such change is the consumption of common nutrients (such as glutamine/Gln) and the consequent accumulation of toxic metabolic byproducts (such as ammonium/NH4). Ammonium is a waste product of cellular metabolism whose accumulation causes cell stress. In tumors, it is known that it can be recycled into nutrients by cancer associated fibroblasts (CAFs). Here we present monoculture and coculture growth of cancer cells and CAFs on different substrates: glutamine and ammonium. …
Time-Resolved Sans Reveals Pore-Forming Peptides Cause Rapid Lipid Reorganization, 2021 University of Windsor
Time-Resolved Sans Reveals Pore-Forming Peptides Cause Rapid Lipid Reorganization, Michael H.L. Nguyen, Mitchell Dipasquale, Brett W. Rickeard, Caesar G. Yip, Kaity N. Greco, Elizabeth G. Kelley, Drew Marquardt
Chemistry and Biochemistry Publications
Cells depend on proper lipid transport and their precise distribution for vital cellular function. Disruption of such lipid organization can be initiated by external agents to cause cell death. Here, we investigate two antimicrobial pore-forming peptides, alamethicin and melittin, and their influence on lipid intervesicular exchange and transverse lipid diffusion (i.e. flip-flop) in model lipid vesicles. Small angle neutron scattering (SANS) and a strategic contrast matching scheme show the mixing of two isotopically distinct dimyristoylphosphocholine (DMPC) vesicle populations is promoted upon the addition of high (1/40) and low (1/150, 1/1000) peptide-to-lipid (P/L) molar ratios. Parsing out the individual exchange and …
Self-Assembled Thermoresponsive Nanogel From Grafted Hyaluronic Acid As A Biocompatible Delivery Platform For Curcumin With Enhanced Drug Loading And Biological Activities, 2021 University of South Carolina
Self-Assembled Thermoresponsive Nanogel From Grafted Hyaluronic Acid As A Biocompatible Delivery Platform For Curcumin With Enhanced Drug Loading And Biological Activities, Jittima Amie Luckanagul, Pahweenvaj Ratnatilaka Na Bhuket, Chawanphat Muangnoi, Pranee Rojsitthisak, Qian Wang, Pornchai Rojsitthisak
Faculty Publications
A hyaluronic acid-grafted poly(N-isopropylacrylamide) (HA-pNIPAM) was synthesized as a polymeric nanogel platform for encapsulation and delivery of hydrophobic bioactive compounds using curcumin as a model drug. As demonstrated by transmission electron microscopy and dynamic light scattering techniques, the HA-pNIPAM was simply assembled into spherical nano-sized particles with the thermoresponsive behavior. The success of curcumin aqueous solubilization was confirmed by fluorescent spectroscopy. The resulting nanogel formulation enhanced the aqueous solubility and uptake into NIH-3T3 cells of curcumin. This nanogel formulation also demonstrates cytocompatibility against NIH-3T3 cells, which deems it safe as a delivery vehicle. Moreover, the formulation has a slight skin-protection …