UTMB Health SHARED (Univ. of Texas Medical Branch at Galveston)
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p53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer's Disease
No full textThe transcription factor, p53, is critical for many important cellular functions involved in genome integrity, including cell cycle control, DNA damage response, and apoptosis. Disruption of p53 results in a wide range of disorders including cancer, metabolic diseases, and neurodegenerative diseases. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by protein aggregates that contribute to disease pathology. Although p53 is known to aggregate, its propensity to aggregate in AD has never been assessed. Moreover, AD neuropathology includes lethal cell cycle re-entry, excessive DNA damage, and abnormal cell death which are all controlled by p53. Here, we show p53 forms oligomers and fibrils in human AD brain, but not control brain. p53 oligomers can also be detected in htau, P301L, and Tg2576 mouse models. Additionally, we demonstrate that p53 interacts with tau, specifically tau oligomers, in AD brain and can be recapitulated by in vitro exogenous tau oligomer treatment in C57BL/6 primary neurons. p53 oligomers also colocalize, potentially seeding, endogenous p53 in primary neurons. Lastly, we demonstrate that in the presence of DNA damage, phosphorylated p53 is mislocalized outside the nucleus and p53-mediated DNA damage responders are significantly decreased in AD brain. Control brain shows a healthy DNA damage response, indicating a loss of nuclear p53 function in AD may be due to p53 aggregation and/or interactions with tau oligomers. Given the critical role of p53 in cellular physiology, the disruption of this crucial transcription factor may set an irreversible course towards neurodegeneration in AD and potentially other tauopathies, warranting further investigation.
A cross-national comparison of the effect of diabetes on the cognitive function of older adults- The case of Mexico and the United States
No full textOlder adults in Mexico and the U.S. have aged under different socioeconomic and epidemiologic contexts. Poorer aging conditions in Mexico impact cognitive function and chronic disease burden. In Mexico, diabetes prevalence is similar to that in the U.S., but the diabetes-related mortality is higher. As diabetes impacts cognitive function, the greater diabetes burden in Mexico may negatively impact the cognitive function of older adults to a greater extent compared to the U.S. Thus, the objective of this dissertation is to measure the effect of diabetes on the cognitive trajectory of older adults in Mexico and the U.S at one cross-section and over time. Two nationally representative cohorts of older adults 50 years and older were used to study Mexico and the U.S., the Mexican Health and Aging Study (MHAS) and the Health and Retirement Study (HRS), respectively. The outcome of interest was cognitive function, measured with a total cognitive score, by cognitive domain, and categorized into dementia vs. normal cognition. The main independent variable was self-reported diabetes status. A cross-sectional analysis was conducted to assess how diabetes impacts cognitive function in the 2012 waves of the MHAS and HRS. Two longitudinal analyses were conducted using the 2001, 2003, 2012, and 2015 MHAS waves, and the 2000, 2002, 2012, and 2014 HRS waves. First, mixed-effect linear models were used to test the impact of diabetes on the cognitive trajectory in both countries. Second, GEE models were used to test if the risk of dementia associated with diabetes differed between countries. Compared to those without diabetes, the results showed that those with diabetes had lower cognitive scores in the 2012 cross-section in both countries. Diabetes also predicted greater cognitive decline over time in both countries, for both memory and non-memory domains. Further, having diabetes increased the risk of dementia at age 65, but the dementia risk did not differ by diabetes status after age 80 in both countries. Independent of diabetes status, the probability of dementia over time was greater in Mexico compared to the U.S. However, the risk of dementia associated with diabetes was similar between the two countries
Structural Basis For Poliovirus Cloverleaf-Mediated Regulation Of Genome Replication
No full textPoliovirus is a member of the Enterovirus genus, members of which are characterized by small, non-enveloped capsids containing short, positive-sense single-stranded RNA genomes. During the viral replication cycle, it is critical that the virus generates the appropriate amounts of viral proteins and genomic RNA. Upon entry in the cell, the viral genome is first used as a template for translation of viral genes and then as a template for genome replication. Regulation of these two processes is mediated by a series of six stem-loops in the 3’ untranslated region of the genomic RNA. Stem-loops II-VI comprise an internal ribosomal entry sequence (IRES), which makes cap-independent translation possible. Stem-loop I, also known as the cloverleaf, serves as a switch to shut off translation, and promote negative strand RNA synthesis. The cloverleaf has previously been shown to form a three-component complex with the viral protein product 3CD (a fusion of 3C protease and 3D RNA polymerase) and host-protein Poly-C binding Protein 2. The formation of this complex is critical for the initiation of negative-strand RNA synthesis. In order to investigate the function and role of the cloverleaf, we report the X-ray crystal structure of the poliovirus cloverleaf RNA. Additionally, we report binding studies and conceptual modeling to characterize the interaction between the cloverleaf RNA, 3CD and Poly-C Binding Protein 2
Eukaryotic protein mimicry as an infection strategy for Ehrlichia chaffeensis
No full textEhrlichia chaffeensis (E. ch.) expresses the TRP120 multifunctional effector on the surface of infectious dense-cored ehrlichiae which is known to play a role in phagocytic entry, but a cognate host receptor has not been identified. We recently reported that E. ch. activates canonical Wnt signaling in monocytes to promote bacterial uptake and intracellular survival and that TRP120 was involved in this activation event. To identify the specific mechanism of pathway activation, we hypothesized that TRP120 is a Wnt signaling ligand mimetic that initiates Wnt pathway activity through direct interaction with the Wnt pathway Frizzled (Fzd) family of receptors. In this study, we used immunofluorescence microscopy to demonstrate very strong colocalization between E. ch. and Fzd2, 4, 5, 7, and 9, as well as coreceptor LRP5 1-3 h post infection. Direct binding between TRP120 and multiple Fzd receptors was further confirmed by ELISA and surface plasmon resonance (SPR). Interfering RNA knockdown of Wnt receptors, coreceptors, and signaling pathway components significantly reduced E. ch. infection demonstrating complex and redundant interactions are involved in Wnt pathway exploitation. We utilized in silico approaches to identify a repetitive short linear motif (SLiM) in TRP120 that is homologous to Wnt ligands and used mutant SLiM peptides and an α-TRP120-Wnt-SLiM antibody to demonstrate that the TRP120 Wnt SLiM activates the canonical Wnt pathway and promotes E. ch. infection. This document reports the first example of bacterial mimicry of Wnt pathway ligands and investigates a pathogenic mechanism with potential for targeting by antimicrobial therapeutics
Hepatitis C Virus infection: ROS, cell death sensitization, and the antiviral effect of an antioxidant
No full textHepatitis C Virus infection: ROS, cell death sensitization, and
the antiviral effect of an antioxidan
Employee Assistance Program and Occupational Health Providers’Perceptions and Experiences with Intimate Partner Violence in the Workplace: A Grounded Theory Study
No full textAbstract:Title: Employee Assistance Program and Occupational Health Providers’ Experiences and Perceptions of Intimate Partner Violence in the WorkplacePurpose/Significance: Employee Assistance Program/Occupational Health Providers(“providers”) are often the first point of contact for employees, both victims and perpetrators, affected by intimate partner violence (IPV). This Classical Grounded Theory (CGT) study explored providers’ experiences and perceptions of working with employees in IPV relationships. This study advances the mission of the Southern Nursing Research Society by communicating research findings related to a persistent social and health issue: IPV.Methods: CGT (Glaser, 1978) guided the study. Semi-structured interviews were conducted with ten providers from across the United States. The interviews were analyzed using constant comparison and open coding to identify categories and concepts within transcripts to ultimately reveal a substantive theory grounded in the study data. The study and resulting substantive theory adhered to Glaser’s (1978) criteria for trustworthiness: Fit, work, relevance and modifiability
Investigating Mechanisms of Nucleoside Reverse Transcriptase Inhibitor Induced Sensory Neuropathy
No full textThe success of antiretroviral therapy (ART) has generally improved the survival of HIV-infected patients. However, patients on ART whose HIV disease is well controlled show peripheral sensory neuropathy (PSN), supporting the idea that the ART may cause PSN. Although the nucleoside reverse transcriptase inhibitors (NRTIs) used in the ART are thought to contribute to PSN, the mechanisms underlying the PSN induced by NRTIs are unclear. This is partly due to the lack of a good model for mechanistic investigations. In this study, we developed a Drosophila model and modified a mouse model of NRTI-induced PSN that recapitulates the salient features observed in patients undergoing ART: PSN and nociception sensitization. Furthermore, through modified expression screening of both genomic and mitochondrial genes we have identified several effectors that inhibit or exacerbate the NRTI-induced PSN phenotype. The most promising candidate identified was nicotinamide mononucleotide adenylyltransferease (NMNAT) which at increased levels inhibits the NRTI-induced PSN and nociception sensitization in our model. Further characterization revealed that ubiquitous upregulation of catalytically competent NMNAT was required for its neuroprotection against NRTI-induced PSN. From this, we utilized the Drosophila and mouse models to investigate the effects of NAD+ precursor coadministration with NRTI. The mouse model allowed for extended testing from which we determined vitamin B3 exhibits potential to both inhibit and rescue NRTI-induced PSN. Therefore, our models developed here provide a robust platform to elucidate the pathogenic mechanisms of painful PSN induced by chronic exposure to NRTIs, and our findings provide insight into the effectors of NRTI-induced PSN and potentially provide vitamin B3 as a readily implementable, accessible, and inexpensive cotreatment with ART that could improve the quality of life for patients
Brother, Help Thyself: The Construction of a Gay and Bisexual Men's Health Movement before HIV/AIDS
No full textThis project traces the formation and development of a gay and bisexual men’s health movement before HIV/AIDS (1981-1996). The project is an effort to consider the lives and contributions of gay and bisexual men between the Second World War and the HIV/AIDS period. The creation and management of health and clinical programs formed by and directed toward gay and bisexual men are examined. There is particular attention given to the Whitman-Walker Clinic in Washington, DC, and to similar clinical and community outreach programs in selected urban communities in North America. Through archival research methods, the project addresses the intersection of postwar science, public health, and biomedicine with human sexuality, gender, class, and race. This draws from research and publications in a number of humanities and social science disciplines to critique health politics and activism in response to medical discrimination, health disparities, and the pathology of homosexuality. The work of philosophers Michel Foucault and Guy Hocquenghem offers insights into a larger context of sexuality and Western political and health social movements. The project is intended to place the gay and lesbian health movement alongside the histories of the women’s health movement and African American health initiatives of the postwar decades. This work contributes to a growing dialogue among historians about this overlooked period of medical history and establishes new points of intersection between gay health activists and the association of disease to this stigmatized population
The Relationship Between Gastrointestinal Disease and Post-traumatic Stress Disorder in United States Military Veterans
No full textThis study examined relationship between gastrointestinal disease (GI
Disease) and post-traumatic stress disorder (PTSD) in United States Military Veterans. Based upon literature and clinical practice data sources from the US Veterans Administration, GI disease and PTSD were hypothesized to be positively
correlated in Veterans. The specific aims of the study were to determine the frequency with which: 1) GI Disease and PTSD are diagnosed co-morbidities; 2) a diagnosis of GI Disease accompanies a diagnosis of PTSD; and, 3) a diagnosis of PTSD
accompanies a diagnosis of a GI Disease. The methodology was a retrospective, correlational design using data collect from the Department of Veteran’s Affairs Patient Database. Findings were that PTSD is bi-directionally correlated with the GI
diseases of gastroesophageal reflux disease (GERD), peptic ulcer disease, functional dyspepsia, Crohn’s disease, diverticular disease, and irritable bowel syndrome (IBS), and the symptoms of constipation and nausea/vomiting within Veterans who served during wartime periods. The study also found that PTSD is not correlated with
ulcerative colitis in Veterans
Interrogation of Neuromedin U Receptor 2/Neuromedin U as a Novel Therapeutic Target for the Treatment of Obesity
No full textObesity is a growing public health concern, with 42.4% of the adult population considered obese. Obesity has many comorbidities associated with it, including diabetes, cancer, and heart disease. These comorbidities increase the likelihood of mortality and increase the individual medical costs of the obese population. Obesity is a disease commonly characterized by an overconsumption of energy dense foods leading to an increase in adiposity. The rate at which obesity is growing has demanded a better understanding of the disease and better pharmacotherapies. Currently, the pharmacotherapies available to treat obesity have modest efficacy which highlights the need for more effective pharmacotherapies to treat obesity. The identification of key neural pathways that play a role in food consumption have helped highlight the Neuromedin U Receptor 2 (NMUR2) as a promising target that can regulate body weight and food intake. NMUR2 is activated by the endogenous ligand, Neuromedin U (NMU), which then causes a downstream signaling cascade that leads to neuronal activation or inhibition. This dissertation aims to explore the role of the NMUR2/NMU signaling complex in vitro and identify the physiological role of NMU when examined in the neural pathways in which regulate food intake and body weight. Once identifying NMU as a mediator of food intake and body weight, we then explored the effect of small molecule NMUR2 agonists and their ability to decrease body weight, adiposity, and improve metabolic measures in diet induced obese animals