Human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) have been shown to compartmentalize within various tissues, including the brain. However, the evolution of viral quasispecies in the setting of drug abuse has not been characterized. The goal of this study was to examine viral evolution in the cerebral compartment of morphine-dependent and control macaques to determine its role in rapid disease progression. To address this issue, we analyzed the envelope (env) gene from proviral DNA in our SIV/SHIV macaque model of morphine-dependence and AIDS. Analyses of proviral DNA revealed a direct correlation between total genetic changes and survival time. However, the rate of evolution during disease progression was higher in morphine-dependent and rapid-progressor macaques than was the rate of evolution in the control animals. This study provides additional insight into SIV envelope variation in the CNS of morphine-dependent macaques and genotypes that may have evolved in the brain and contributed to disease progression.
Viral protein R (Vpr) is an accessory protein of HIV and SIV involved in the pathogenesis of viral infection. In this study, we monitored SIV evolution in the central nervous system and other organs from morphine-dependent and control animals by sequencing vpr in an attempt to understand the relationship between drug abuse, disease progression, and compartmentalization of viral evolution. Animals in the morphine group developed accelerated disease and died within twenty weeks post-infection. A unique mutation, R50G, was identified in the macaques that survived regardless of morphine exposure. Functional studies revealed that the R50G mutation exhibited altered cellular localization and decreased the expression levels of both IL-6 and IL-8. Our results, therefore, suggest that sequence changes within the SIV/17E-Fr vpr occur regardless of drug abuse but correlate with survival, and that they alter disease progression rates by affecting Vpr functions.
Recently, epigenetic factors, including histone modifications, and environmental factors have shown to play an active role in endometriosis. We have recently shown that the levels of histone de‐acetylates (HDACs) are higher and that histone acetylation marks are decreased in endometriosis lesions. Also, stress contribute to the development of higher number of lesions and inflammatory parameters are exacerbated. Psychological stress has shown to cause changes in the epigenome. We sought to test the hypothesis that in endometriotic tissue from rats exposed to stress, histone acetylation is modulated, which would impact gene expression and lead to higher severity of symptoms. This randomized controlled study consists of two groups of rats, both with surgically induced endometriosis: the experimental group, which was exposed to a 10‐day swim stress protocol and a control group, which was not exposed to stress. On day 60, all rats were sacrificed and examined for the presence of endometriotic vesicles, which were processed for protein extraction and western blot analysis for HDACs, and for acetylated H3K9 and H4K8, as well as the housekeeping gene GAPDH. Densitometry and statistical analyses were performed to the bands. We have standardized the conditions for Western blot analysis of HDAC2 (57kD), H3K9ac and H3K8ac (~20Kd). Our preliminary results identified a specific HDAC2 band, which is expressed at the highest level by a rat exposed to stress, characterized by higher number of lesions and worse inflammatory parameters. Next, we will conduct Western Blot for HDACs and histone marks in both groups and will evaluate possible correlations between protein levels and inflammatory parameters in this rat model. These studies may produce evidence in support of a possible role of stress in modulation of epigenetic markers in endometriosis. Due to the fact that HDACs can be targeted using inhibitors, which can become potential new therapies, these results have a high translational potential. Grant Funding Source: Supported by: NIH Grant #R25GM096955 and (NCCAM) #3 NC1R15AT006373.
OBJECTIVES/SPECIFIC AIMS: The goal of this study is to assess how quality of life scores change in menopausal women before and after implementation of this aid. In addition, we are also interested in 2 process evaluation objectives: (1) determine if MyChart, the patient portal, is an effective way for this patient population to provide insight their quality of life to their providers and (2) to evaluate providers use of and reactions to the decision support tool. METHODS/STUDY POPULATION: This project is a collaboration between University of Rochester Medical Center and S.U.N.Y. Upstate Medical University. Participants were recruited through Upstate’s Family Medicine and OB/GYN practices via a MyChart invitation sent by the practices. Participating patients will be asked to complete a survey, through MyChart, every 3 months for 18 months. Participating health providers will be trained to use the decision support tool and participate in 3 interviews with the researchers to gain insight into the usefulness and effectiveness of the tool. RESULTS/ANTICIPATED RESULTS: Of the 465 eligible women, 117 women responded to our MyChart invitation to join our study. Of these, 105 agreed to participate and 98 met eligibility criteria. Only half of the women currently enrolled in our study had spoken to a provider about menopause related symptoms (56.1%) prior to study enrollment. DISCUSSION/SIGNIFICANCE OF IMPACT: The goal of this study is to improve menopause related symptoms in women, thus increasing their quality of life, but it will also provide important process evaluation for using EPIC and MyChart for future research studies.
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