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Investigating Smooth Muscle Myosin Dynamics And Assembly In Physiology And Pathology, Maggie Bennett
Investigating Smooth Muscle Myosin Dynamics And Assembly In Physiology And Pathology, Maggie Bennett
Dissertations
Vascular smooth muscle cells (SMCs) surround many blood vessels throughout the body,where they dynamically alter vessel diameter to regulate blood pressure, provide structural integrity, and absorb shock on a beat-to-beat timescale. As smooth muscle function fails, profound vascular disease ensues, often with tragic results- even death. Smooth muscle myosin 2 (SM2) is the dominant motor protein that actuates contractility and allows SMCs to perform these vital functions. To function, SM2 monomers dynamically assemble into filaments, which upon SMC activation, associate with filamentous actin to drive contractility. Despite the critical contribution of SM2 to SMC function, foundational aspects of SM2 assembly …
Investigating The Impact Of Nonenzymatic Lysine Acetylation On The Function Of The Bacterial Ribosome, Sarah Caldwell Feid
Investigating The Impact Of Nonenzymatic Lysine Acetylation On The Function Of The Bacterial Ribosome, Sarah Caldwell Feid
Dissertations
An under-investigated target of lysine acetylation is the bacterial ribosome. Although lysine acetylations on the ribosome are common and conversed in diverse bacterial species, little work has been done to understand how lysine acetylation affects the bacterial ribosome. The goal of this work is to determine if lysine acetylation has functional impact on the bacterial ribosome.I have identified in vitro and in vivo effects of nonenzymatic, AcP-dependent lysine acetylation on translation and the ribosome. In vitro acetylation of transcription-translation reactions causes a translation-specific defect that is unaffected by the addition of the CobB deacetylase. This suggests certain AcP-sensitive residues that …
Role Of Micrornas In Intestinal Inflammation And Barrier Homeostasis After Alcohol And Burn Injury, Caroline J. Herrnreiter
Role Of Micrornas In Intestinal Inflammation And Barrier Homeostasis After Alcohol And Burn Injury, Caroline J. Herrnreiter
Dissertations
MicroRNAs are small noncoding RNA molecules that negatively regulate gene expression. Within the intestinal epithelium, miRNAs play a critical role in gut homeostasis and aberrant miRNA expression has been implicated in various disorders associated with intestinal inflammation and barrier disruption. In this study, we sought to profile changes in intestinal epithelial cell miRNA expression after alcohol and burn injury and elucidate their impact on inflammation and barrier integrity. In a more targeted approach, we began by focusing on anti-inflammatory miRNAs that, when downregulated, could exacerbate inflammation and result in intestinal barrier disruption. Using a mouse model of acute ethanol intoxication …
Characterization Of Mroq-Dependent Regulation Of Staphylococcus Aureus Quorum Sensing, Madison Ruth Stock
Characterization Of Mroq-Dependent Regulation Of Staphylococcus Aureus Quorum Sensing, Madison Ruth Stock
Dissertations
Gram-positive bacteria produce small autoinducing peptides (AIPs), which act to regulate expression of genes that promote adaptive traits including virulence. The Gram-positive pathogen Staphylococcus aureus generates a cyclic AIP that controls expression of virulence factors via the accessory gene regulatory (Agr) system. S. aureus strains belong to one of four Agr groups (I, II, III, and IV), and each group harbors allelic variants of AgrD, the precursor of AIP. In a prior screen for S. aureus virulence factors, the Alonzo lab identified MroQ, a putative peptidase. A ΔmroQ mutant closely resembled a Δagr mutant and had significant defects in AIP …
Identification Of Conditions That Promote Biofilm Formation By Vibrio Fischeri And Elucidation Of The Underlying Signal Transduction Pathway, Courtney Noelle Dial
Identification Of Conditions That Promote Biofilm Formation By Vibrio Fischeri And Elucidation Of The Underlying Signal Transduction Pathway, Courtney Noelle Dial
Dissertations
Biofilms are communities of microorganisms that have intrinsically antimicrobial properties and are difficult to treat in the clinical setting. The marine bacterium Vibrio fischeri efficiently colonizes its symbiotic squid host, Euprymna scolopes, by producing a transient biofilm dependent on the symbiosis polysaccharide (SYP), making it the perfect model system to study biofilm dynamics. In vitro, however, wild-type (WT) strain ES114 fails to form SYP – dependent biofilms. Instead, genetically engineered strains, such as those lacking the negative regulator BinK, have been developed to study SYP biofilms. Historically, V. fischeri has been grown using LBS, a complex medium containing tryptone and …
Dynamic Control Of The Cardiac Calcium Pump, Sean Robert Cleary
Dynamic Control Of The Cardiac Calcium Pump, Sean Robert Cleary
Dissertations
The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) sequesters Ca2+ into the endoplasmic reticulum of cells to establish a reservoir for Ca2+ signaling. In the heart, the activity of this transporter is tightly controlled via direct interactions with two competing regulatory micropeptides: phospholamban (PLB) and dwarf open reading frame (DWORF). PLB inhibits SERCA, while DWORF activates SERCA. These competing interactions determine cardiac performance by modulating the Ca2+ signals that drive the contraction/relaxation cycle. Previous studies indicated these SERCA-micropeptide interactions are Ca2+-sensitive; SERCA binds PLB more avidly at low cytoplasmic [Ca2+] but binds DWORF better when [Ca2+] is high. Here, FRET-microscopy demonstrated that this …
Distinct Roles For Free Fatty Acid Receptor 3 (Ffar3) In Vagal And Spinal Afferents Regulating Energy Balance And Glucose Homeostasis, Tyler M. Cook
Distinct Roles For Free Fatty Acid Receptor 3 (Ffar3) In Vagal And Spinal Afferents Regulating Energy Balance And Glucose Homeostasis, Tyler M. Cook
Dissertations
energy balance, glucose homeostasis, gut-brain axis, microbiome, nutrient sensing, satiety
Elucidating The Mechanisms Underlying How Vmp1 Regulates Inflammatory Responses, Stephanie Zack
Elucidating The Mechanisms Underlying How Vmp1 Regulates Inflammatory Responses, Stephanie Zack
Dissertations
autophagy, inflammation, mitochondria, NLRP3 inflammasome, SERCA, VMP1
The Role Of Gut Microbiome And Scfa Butyrate In The Development Of Obesity Associated Pre-Hfpef, Jomana Hatahet
The Role Of Gut Microbiome And Scfa Butyrate In The Development Of Obesity Associated Pre-Hfpef, Jomana Hatahet
Dissertations
No abstract provided.
Structural And Transient Kinetic Analysis On Mechanism-Based Inactivators Of Human Ornithine Aminotransferase, Arseniy Butrin
Structural And Transient Kinetic Analysis On Mechanism-Based Inactivators Of Human Ornithine Aminotransferase, Arseniy Butrin
Dissertations
HCC, Hepatocellular carcinoma, MBI, Mechanism-based inactivator, OAT, Ornithine Aminotransferase
The Roles Of A Probiotic Exopolysaccharide In Breast Cancer, Mai Rachel Nguyen
The Roles Of A Probiotic Exopolysaccharide In Breast Cancer, Mai Rachel Nguyen
Dissertations
breast cancer, exopolysaccharide, probiotic
Investigating The Bactericidal Activity Of Lactobacillus Crispatus Cell-Free-Supernatant, Omar Majed Abdul-Rahim
Investigating The Bactericidal Activity Of Lactobacillus Crispatus Cell-Free-Supernatant, Omar Majed Abdul-Rahim
Dissertations
Antimicrobial-resistant (AMR) microorganisms are an increasingly seriousproblem worldwide, accounting for thousands of fatalities annually. The current literature on combating AMR pathogens often centers on commensal microbes such as Lactobacillus species, which are most frequently found in asymptomatic ‘healthy’ patients and are believed to elicit protective effects. In this dissertation, I sought to investigate the protective effect of Lactobacillus crispatus, utilizing our vast collection of clinical isolates. Previous work from our lab had found that cell-free-supernatant (CFS) of L. crispatus is robustly bactericidal, and that this killing activity does not depend on hydrogen peroxide or lactic acid. We identified phenyl-lactic acid …
B Cells In The Gut Associated Lymphoid Tissue (Galt), Ameera Bukhari
B Cells In The Gut Associated Lymphoid Tissue (Galt), Ameera Bukhari
Dissertations
The gut-associated lymphoid tissue (GALT) is the largest mass of lymphoid tissue in the body, and it is a unique line of defense where immune cells are in constant contact with gut commensals and pathogens. B lymphocytes constitute most of the lymphatic tissues of the gastrointestinal (GI) tract and they play a critical role in protecting from infections, promoting tolerance, and shaping microbiota in the gut through the production of immunoglobulins (Ig). Previous studies on GALT B cells in human showed that large B cell clones in the body partition into two broad networks: one includes the blood, bone marrow, …
The Role Of Glycogen Synthase Kinase 3 Β (Gsk-3Β) At The Cardiac Myofilament, Marisa Jean Stachowski
The Role Of Glycogen Synthase Kinase 3 Β (Gsk-3Β) At The Cardiac Myofilament, Marisa Jean Stachowski
Dissertations
Altered kinase activity and localization is gaining appreciation as a mechanism contributing to cardiovascular disease. Previous work suggests that the kinase glycogen synthase kinase 3 β (GSK-3β) regulates contractile function of the myofilament, but this work was performed in vitro. The goal of this work was to investigate GSK-3β’s in vivo role in regulating myofilament function, the mechanisms involved, and the translational relevance in disease. GSK-3β’s myofilament localization was confirmed in wild type mouse and human tissue via western blot of myofilament enriched tissue and immunofluorescence. These experiments also revealed that GSK-3β phosphorylated at Y216 binds to the z-disc. We …
Abl2 Promotes Alcohol-Associated Liver Disease Via Ppar Gamma Regulation, Gregory Malnassy
Abl2 Promotes Alcohol-Associated Liver Disease Via Ppar Gamma Regulation, Gregory Malnassy
Dissertations
Alcohol-associated liver disease (AALD) is an umbrella term for a spectrum of diseases resulting from chronic alcohol (e.g. ethanol) abuse ranging in severity from reversible conditions such as alcohol-induced steatosis to advanced and largely irreversible liver pathologies including alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). AALD is one of the primary causes of chronic liver disease worldwide and accounts for 44% of liver disease deaths in the United States. Drinking rates, both in the United States and globally, have increased year over year for the past three decades, a trend which has resulted in significantly …
Elucidating The Role Of Kmt2d In Her2+ Breast Cancer, Emily Ma
Elucidating The Role Of Kmt2d In Her2+ Breast Cancer, Emily Ma
Dissertations
Breast cancer is the second leading cause of cancer-related deaths among women in the US. Histone modifications are common epigenetic changes that have been implicated in several breast cancers, including HER2+ breast cancers. Current therapies, such as trastuzumab, block the HER2 receptor to reduce tumor growth. Unfortunately, HER2+ breast cancers have found ways to overcome these therapies, leading to tumor resistance, metastases, and poor survival outcomes. A better understanding of the underlying mechanisms contributing to HER2+ breast cancer resistance may lead to the discovery of novel therapeutic strategies to improve patient outcomes.One prognostic marker for poor survival in women with …
Characterizing Galectin And Lysosomal Rupture's Role In Spreading Parkinson Disease Pathology, Kevin Burbidge
Characterizing Galectin And Lysosomal Rupture's Role In Spreading Parkinson Disease Pathology, Kevin Burbidge
Dissertations
The misfolding and subsequent accumulation of alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD). Several lines of evidence suggest pathological α-syn spread cell-to-cell via a "prion-like" mechanism. Furthermore, this pathological α-syn is capable of "seeding" further misfolding of non-pathological α-syn, converting them to the pathological form. While a vast body of both genetic and experimental evidence indicates that α-syn is critical to PD development, how α-syn induces progressive neuronal dysfunction and cell death remains unclear.Autophagy, conventional for macroautophagy, is the primary degradation pathway for α-syn aggregates. Autophagy also influences the unconventional secretion of both pathological and non-pathological …
Investigating The Roles Of Lipids In Staphylococcus Aureus Infection, Xi Chen
Investigating The Roles Of Lipids In Staphylococcus Aureus Infection, Xi Chen
Dissertations
The Gram-positive bacterium Staphylococcus aureus is a major threat to public health and causes a multitude of infections, ranging from mild skin and soft infection, to more severe diseases including sepsis, osteomyelitis and infective endocarditis. As a successful pathogen, S. aureus employs various mechanisms to invade host tissues, evade immune responses, and survive in the host environment. One critical adaptive trait of S. aureus that promotes virulence and survival is the ability to maintain membrane homeostasis via flexible modifications to its lipid composition in response to the surrounding lipid environment. Phospholipids are the major component of the bacterial membrane and …
Il-27 Signaling In The Maintenance Of Intestinal Barrier Following Ethanol Intoxication And Burn Injury, Marisa Luck
Il-27 Signaling In The Maintenance Of Intestinal Barrier Following Ethanol Intoxication And Burn Injury, Marisa Luck
Dissertations
Roughly half of burn patients that are hospitalized in the United States each year have detectable blood alcohol levels. Alcohol intoxication at the time of burn injury leads to worse outcomes, including longer hospital stays, increased rates of infection, and death. One of the severe consequences of intoxication and burn injury is the disruption of the gastrointestinal (GI) tract, which houses the largest reservoir of bacteria in the human body. Leakiness of the gut barrier can contribute to inflammation, infection, or sepsis from gut-derived microbes. Interleukin-27 (IL-27) is a cytokine that has shown some beneficial effects in other models of …
Understanding The Role Of Lipids Derived From The Gut Microbes In A Mouse Model Of Obesity-Induced Peripheral Pain, Raiza Rafael-Bonomo Hardy
Understanding The Role Of Lipids Derived From The Gut Microbes In A Mouse Model Of Obesity-Induced Peripheral Pain, Raiza Rafael-Bonomo Hardy
Dissertations
The increase in obesity has been accompanied by a rise in the prevalence of painful peripheral neuropathy. Recently, studies have suggested a role for gut microbiome in the development of some peripheral pain, including chemotherapy- induced pain and fibromyalgia. In the present dissertation, we showed that modulation of gut microbiome in obese mice alleviated neuropathic indices, concurrent with changes in immune cell profile within the peripheral nerve system. We demonstrated that fecal transplantation from lean to obese mice decreased obesity-induced pain and restored nerve density in the skin. These improvements were accompanied by changes in peripheral nerve system gene expression, …
F Plasmids In Escherichia Coli Decrease Permissivity To Coliphage, Cesar Eber Montelongo Hernandez
F Plasmids In Escherichia Coli Decrease Permissivity To Coliphage, Cesar Eber Montelongo Hernandez
Dissertations
The urinary tract contains a community of bacteria called the urinary microbiota (urobiota) thatmay be relevant to health; the genomic component of the urobiota is the urinary microbiome (urobiome). Urinary bacteria have been associated with both asymptomatic states and disease conditions, such as urinary tract infection (UTI), overactive bladder (OAB), and urge urinary incontinence (UUI). Some bacteria, such as E. coli, are considered urinary pathogens (uropathogens) but also can be commensals. Bacteriophage (phage) are ubiquitous in nature and likely shape bacterial populations in every niche; thus, phage may be one factor that modulates the urobiota. Phages have a specific host …
Comparative Studies On Biochemical And Pharmacological Profiles Of Unfractionated Heparins & Their Depolymerized Derivatives From Bovine, Ovine And Porcine Origins, Ahmed Kouta
Dissertations
Heparin and heparin related drugs have remained the anticoagulant of choice for medical and surgical indications. These drugs are comprised of poly-component sulfated chains of varying length and biophysical structure with direct and indirect pharmacological effects. Heparins produce their therapeutic effects by multiple mechanisms involving both the cellular and humoral targets. These drugs represent natural products which are isolated from mammalian tissue rich in mast cells. Currently used heparin and LMWHs are obtained from porcine mucosal tissue. Other animal sources including bovine and ovine tissues also provide additional sources for the manufacturing of heparins. While there may be microchemical and …
Investigating The Effects Of Tgf-Β On T Cell Activation-Induced Cell Death, Christina Rose Cunha
Investigating The Effects Of Tgf-Β On T Cell Activation-Induced Cell Death, Christina Rose Cunha
Dissertations
Achieving immune homeostasis requires the functions and numbers of suppressive regulatory T cells (Tregs) and effector conventional T cells (conv T) to be balanced and precisely controlled. A decrease in Treg numbers is associated with autoimmune diseases such as type I diabetes and multiple sclerosis, while Treg numbers are increased in the tumor microenvironment. Conversely, an increase in conv inflammatory T cells in the tumor microenvironment is associated with better outcomes for cancer patients. Thus, maintaining the appropriate balance between Treg and conventional T cell populations is essential for controlling immune responses against non-self and self-antigens, as well as tumor …
Molecular Determinants Of Fetal Tolerance And The Transition To Adult Immunity, Yi Wei Lim
Molecular Determinants Of Fetal Tolerance And The Transition To Adult Immunity, Yi Wei Lim
Dissertations
The perinatal immune system is highly tolerogenic and is phenotypically and functionally distinct from the adult immune system. This tolerogenic nature is a double-edged sword for newborns. While it is beneficial to prevent excessive inflammation against the vast array of foreign antigens encountered after birth, it also causes a lack of immune responses to life-threatening infections. My dissertation research aims to investigate the mechanisms by which perinatal T cells contribute to immune tolerance in infants. A deeper understanding of the nature of the perinatal immune system will provide pivotal knowledge to develop safe and effective strategies to protect infants from …
The Role Of The Co-Chaperone Protein Bcl-2-Associated Athanogene 3 (Bag3) At The Cardiomyocyte Sarcomere, Thomas Gwynn Martin
The Role Of The Co-Chaperone Protein Bcl-2-Associated Athanogene 3 (Bag3) At The Cardiomyocyte Sarcomere, Thomas Gwynn Martin
Dissertations
The co-chaperone protein Bcl-2-associated athanogene-3 (BAG3) is a central mediator of cellular protein quality control through autophagy. In the heart, decreased BAG3 activity through mutation or decreased expression are linked to dilated cardiomyopathy (DCM). Unfortunately, though clinical data indicates BAG3 mutations are a definitive cause of DCM, few mechanistic studies had been performed to decipher the fundamental role of BAG3 in cardiomyocytes. However, several studies suggested BAG3 was involved in maintenance of the sarcomere, the molecular contractile structure in muscle cells. The goals of this dissertation were to: 1. Determine the functional significance of BAG3 for the sarcomere, 2. Identify …
Cardioprotective Extracellular Vesicles Derived-Micrornas: Sorting Mechanisms And Functions, Anh P. Phan
Cardioprotective Extracellular Vesicles Derived-Micrornas: Sorting Mechanisms And Functions, Anh P. Phan
Dissertations
Extracellular vesicles (EVs) are nano-size membrane bound vesicles that are derived from the fusion of multivesicular endosomes with the plasma membranes. EVs have important roles in intercellular communication through the transfer of their unique cargoes including RNA, DNA and protein molecules to recipient cells. Mesenchymal stem cell (MSC)-derived EVs have been shown to reduce infarct size and reduce the progress of heart failure after cardiac ischemia/reperfusion (I/R) injury in animal models. Small non-coding RNAs such as microRNA (miRNA) have been indicated as one of the active components that mediate the beneficial effects of MSC-derived EVs. However, the selective packaging mechanisms …
Analysis Of Regulatory Mechanisms For T Cell Activation, Aleksandra Vuchkovska
Analysis Of Regulatory Mechanisms For T Cell Activation, Aleksandra Vuchkovska
Dissertations
The primary function of the immune system is to seek and eliminate altered or unhealthy cells. T cells are a major component of the immune response and mediate their functions by recognizing specific antigens that allow elimination of infected or neoplastic cells. To avoid inappropriate activation and subsequent immune injuries, T cells have evolved strategies to discriminate self from non-self, or healthy from altered and infected. These strategies rely on the activation of receptors that restrict the T cell response. CD33rSiglecs are a family of mostly inhibitory receptors that bind to sialic acids. Siglecs respond to specific sialic acid patterns …
Identification And Characterization Of Calcium As A Biofilm Promoting Signal By Vibrio Fischeri, Alice Hannah Tischler
Identification And Characterization Of Calcium As A Biofilm Promoting Signal By Vibrio Fischeri, Alice Hannah Tischler
Dissertations
The marine bacterium, V. fischeri actively engages in an exclusive partnership in the light organ of its squid host, Euprymna scolopes. A critical step in this colonization process is the formation of a bacterial aggregate, or biofilm, which is a community of bacteria embedded within a protective extracellular matrix. While V. fischeri readily forms biofilms in nature, genetic overexpression must be utilized to achieve biofilm formation in the laboratory. Recent work investigating media composition led myself and others to evaluate how seawater salts impacted growth and biofilm formation in a number of mutant backgrounds, leading to the identification of calcium …
Selectivity For Allosteric Effectors Of Bacterial Adp-Glucose Pyrophosphorylase: Structural And Functional Studies, Mashael Alghamdi
Selectivity For Allosteric Effectors Of Bacterial Adp-Glucose Pyrophosphorylase: Structural And Functional Studies, Mashael Alghamdi
Dissertations
The biosynthesis of the intracellular polysaccharide in bacteria and plants, glycogen and starch, respectively, controlled by the key regulatory step that catalyzed by ADP-Glucose Pyrophosphorylase (ADP-Glc PPase). ADP-Glc PPase is an allosteric enzyme regulated by metabolites produced of the principle carbon assimilation pathway in each organism. Agrobacterium tumefaciens enzyme activated by fructose 6-phosphate (Fru6P) and pyruvate, whereas Escherichia coli enzyme activated by fructose 1,6-bisphosphate (FBP), and both enzymes inhibited by AMP. Here, we targeted the allosteric regulation of the A. tumefaciens enzyme, examined some residues that may impact the regulation mechanism (Ser72, His71, Arg75, Ser351, Ser334, Arg368, Asn350, and Asp291), …
Investigating The Mechanism Of The Coronavirus Endoribonuclease In Antagonizing Innate Immune Signaling, Matthew Hackbart
Investigating The Mechanism Of The Coronavirus Endoribonuclease In Antagonizing Innate Immune Signaling, Matthew Hackbart
Dissertations
Coronaviruses (CoVs) are positive-sense RNa viruses that can emerge from endemic reservoirs and infect zoonotically, causing significant morbidity and mortality. CoVs encode an endoribonuclease (EndoU) that cleaves RNa in biochemical assays, but the target and function of EndoU activity during viral replication was not known. My work focused on characterizing the functions of EndoU during infection. I report that EndoU is an innate immune antagonist. to function as an immune antagonist, EndoU cleaves the 5'-Poly-Uridines from Negative-sense viral RNA, termed PUN RNA, which is the product of polyA-templated RNa synthesis. Using a virus containing an EndoU catalytic-inactive mutation, I detected …