Summary Objectives Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and ...Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed. Methods We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory. Results Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC50 and high selectivity index. Additionally, ribavirin and interferons also exhibited in-vitro anti-MERS-CoV activity. The serum concentrations achievable at therapeutic doses of mycophenolic acid and interferon-β1b were 60–300 and 3–4 times higher than the concentrations at which in-vitro anti-MERS-CoV activities were demonstrated, whereas that of ribavirin was ∼2 times lower. Combination of mycophenolic acid and interferon-β1b lowered the EC50 of each drug by 1–3 times. Conclusions Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.
Genome editing with targeted nucleases and DNA donor templates homologous to the break site has proven challenging in human hematopoietic stem and progenitor cells (HSPCs), and particularly in the ...most primitive, long-term repopulating cell population. Here we report that combining electroporation of zinc finger nuclease (ZFN) mRNA with donor template delivery by adeno-associated virus (AAV) serotype 6 vectors directs efficient genome editing in HSPCs, achieving site-specific insertion of a GFP cassette at the CCR5 and AAVS1 loci in mobilized peripheral blood CD34
HSPCs at mean frequencies of 17% and 26%, respectively, and in fetal liver HSPCs at 19% and 43%, respectively. Notably, this approach modified the CD34
CD133
CD90
cell population, a minor component of CD34
cells that contains long-term repopulating hematopoietic stem cells (HSCs). Genome-edited HSPCs also engrafted in immune-deficient mice long-term, confirming that HSCs are targeted by this approach. Our results provide a strategy for more robust application of genome-editing technologies in HSPCs.
Jira 8 Administration Cookbook, Third Edition, is a collection of helpful recipes that will enable you to configure Jira applications with ease. The book includes all the new features of Jira 8 that ...provides better prioritizing capabilities, enhanced visibility, and the ability to customize Jira application to meet your needs.
We aimed to investigate the longitudinal change in the number of surgically operated myopic traction maculopathies (MTM) cases at a tertiary eye centre.
A retrospective study of all consecutive cases ...of surgically operated MTM over 12 years (2009-2020) was conducted in a myopia prevalent region. We compared outcomes among three groups: (1) myopic macular hole (MH), (2) myopic macular hole with retinal detachment (MHRD), and (3) myopic foveoschisis with retinal detachment (MFRD).
Fifty-one cases were included in the study (8 cases of MH, 33 cases of MHRD and 10 cases of MFRD). The overall mean age was 63.8 +/- 8.7 with a female preponderance (2:1). The mean age of the MH group (58.6) was significantly younger than the MHRD group (64.2) and MFRD group (66.6) (p = 0.02). Subgroup analysis using ATN classification did not show its correlation with both visual improvement and anatomical success. When comparing the first 6-year period (2009-2014) with the second 6-year period (2015-2020), there was a significant increase in the number of cases (p = 0.01).
We observe an increase in the number of surgically operated MTM. This follows the trend of the global rise in the prevalence of myopia and baby boomers entering retirement.
Jira 8 Essentials covers in detail all the necessary features required to manage modern enterprise Jira projects. You will learn how to easily upgrade to the latest version of Jira, manage processes ...and issues using agile methodologies, and implement the Jira Services Desk, among many others.
Aging is accompanied with loss of tissue homeostasis and accumulation of cellular damages. As one of the important metabolic centers, liver shows age-related dysregulation of lipid metabolism, ...impaired detoxification pathway, increased inflammation and oxidative stress response. However, the mechanisms for these age-related changes still remain unclear. In the fruit fly, Drosophila melanogaster, liver-like functions are controlled by two distinct tissues, fat body and oenocytes. Compared to fat body, little is known about how oenocytes age and what are their roles in aging regulation. To characterize age- and stress-regulated gene expression in oenocytes, we performed cell-type-specific ribosome profiling (RiboTag) to examine the impacts of aging and oxidative stress on oenocyte translatome in Drosophila.
We show that aging and oxidant paraquat significantly increased the levels of reactive oxygen species (ROS) in adult oenocytes of Drosophila, and aged oenocytes exhibited reduced sensitivity to paraquat treatment. Through RiboTag sequencing, we identified 3324 and 949 differentially expressed genes in oenocytes under aging and paraquat treatment, respectively. Aging and paraquat exhibit both shared and distinct regulations on oenocyte translatome. Among all age-regulated genes, oxidative phosphorylation, ribosome, proteasome, fatty acid metabolism, and cytochrome P450 pathways were down-regulated, whereas DNA replication and immune response pathways were up-regulated. In addition, most of the peroxisomal genes were down-regulated in aged oenocytes, including genes involved in peroxisomal biogenesis factors and fatty acid beta-oxidation. Many age-related mRNA translational changes in oenocytes are similar to aged mammalian liver, such as up-regulation of innate immune response and Ras/MAPK signaling pathway and down-regulation of peroxisome and fatty acid metabolism. Furthermore, oenocytes highly expressed genes involving in liver-like processes (e.g., ketogenesis).
Our oenocyte-specific translatome analysis identified many genes and pathways that are shared between Drosophila oenocytes and mammalian liver, highlighting the molecular and functional similarities between the two tissues. Many of these genes were altered in both oenocytes and liver during aging. Thus, our translatome analysis provide important genomic resource for future dissection of oenocyte function and its role in lipid metabolism, stress response and aging regulation.
Background. Neurocognitive impairment remains prevalent, despite combination antiretroviral therapy (cART). Differences between changes in cerebral function and alternative cARTs have not been ...prospectively assessed. Methods. Treatment-naive, HIV-1–infected individuals randomly allocated to commence cART (tenofovir-emtricitabine plus either efavirenz arm 1, atazanavir-ritonavir arm 2, or zidovudine-abacavir arm 3) were eligible. Cerebral function tests included neurocognitive testing and assessment of cerebral metabolites using proton magnetic resonance spectroscopy in several anatomical voxels, including right frontal white matter and right basal ganglia, at baseline and after 48 weeks. N-acetylaspartate–to–creatine (NAA/Cr) ratios were calculated. Both the differences between changes in neurocognitive function and NAA/Cr ratios over 48 weeks and the study arms (arm 1 vs arm 2; arm 1 vs arm 3) were assessed. Results. Thirty subjects completed study procedures (9, 9, and 12 subjects in arms 1, 2, and 3, respectively). Mean CD4+ cell counts ( lusmn; standard deviation) were 218 lusmn;87 cells/ µL at baseline and 342 lusmn;145 cells/ µL at week 48. The mean plasma HIV-1 RNA level was µ50 copies/mL for 28 of the 30 subjects at week 48. Over 48 weeks, greater improvements in identification reaction time (P=.04) and executive function (P=.02) were observed in arm 3, compared with arm 1 (0.03, inus;0.30, inus;0.50 log10 ms change in identification reaction time, in arms 1, 2, and 3, respectively). Increases in the NAA/Cr ratio were observed in all voxels (maximum 38% in right basal ganglia), with greater increases observed in arm 1 than in arm 2 (P=.03) in frontal white matter (30%, inus;7%, and 0% change in the NAA/Cr ratio, in arms 1, 2, and 3, respectively). Conclusions. To our knowledge, this is the first study to prospectively describe different changes in cerebral function testing parameters between different cARTs. Greater improvements in neuronal recovery (NAA/Cr ratio) were observed for recipients of tenofovir-emtricitabine plus efavirenz (arm 1), and greater improvements in neurocognitive function testing were observed for recipients of tenofovir-emtricitabine plus zidovudine-abacavir (arm 3).
Dietary restriction (DR) is one of the most robust lifespan-extending interventions in animals. The beneficial effects of DR involve a metabolic adaptation toward increased triglyceride usage. The ...regulatory mechanism and the tissue specificity of this metabolic switch remain unclear. Here, we show that the IRE1/XBP1 endoplasmic reticulum (ER) stress signaling module mediates metabolic adaptation upon DR in flies by promoting triglyceride synthesis and accumulation in enterocytes (ECs) of the Drosophila midgut. Consistently, IRE1/XBP1 function in ECs is required for increased longevity upon DR. We further identify sugarbabe, a Gli-like zinc-finger transcription factor, as a key mediator of the IRE1/XBP1-regulated induction of de novo lipogenesis in ECs. Overexpression of sugarbabe rescues metabolic and lifespan phenotypes of IRE1 loss-of-function conditions. Our study highlights the critical role of metabolic adaptation of the intestinal epithelium for DR-induced lifespan extension and explores the IRE1/XBP1 signaling pathway regulating this adaptation and influencing lifespan.
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•ECs of the Drosophila intestine require IRE1/XBP1 for higher lipid turnover upon DR•This metabolic adaptation is required for DR-mediated lifespan extension•The IRE1/XBP1 module regulates lipid turnover by inducing Sugarbabe•Sugarbabe is required for metabolic adaptation and increased longevity upon DR
A metabolic switch that enhances triglyceride utilization mediates the protective effects of dietary restriction (DR), which extends the health span in multiple species. Luis et al. find that intestinal cells respond to DR by increasing lipid synthesis via the IRE1/XBP1/sugarbabe signaling module, thus extending longevity in Drosophila.
Explore Jira Software to manage your projects proficientlyAbout This BookPlan and manage projects effortlessly with Jira Software by integrating it with other applicationsImprove your team's ...performance with Scrum and Kanban, together with agile methodologyEasy-to-follow learning guide to install Jira Software and understand how it fits in with Atlassian JiraWho This Book Is ForIf you want to get started with Jira Software and learn how to run your Jira projects the agile way, then this is the perfect book for you. You will need to be familiar with the basics of Jira, both from an end user's and an administrator's perspective. Experience with workflows, custom fields, and other administrative functions of Jira will be useful.What You Will LearnUnderstand the basics and agile methodologies of Jira softwareUse Jira Software in a Scrum environmentManage and run Jira Software projects beyond the out of box Scrum and Kanban wayCombine Scrum and Kanban and use other project management options beyond just agileCustomize Jira Software's various features and options as per your requirementsWork with Jira Agile offline, and plan and forecast projects with agile portfolioIntegrate Jira Agile with Confluence and BitbucketIn DetailJira Software is an agile project management tool that supports any agile methodology, be it scrum, Kanban, or your own unique flavour. From agile boards to reports, you can plan, track, and manage all your agile software development projects from a single tool. Jira Software brings the power of agile methodology to Atlassian Jira.This second edition of JIRA Agile Essentials, will help you dive straight into the action, exploring critical agile terminologies and concepts in the context of Jira Software. You will learn how to plan, track, and release great software. This book will teach you how to install and run Jira Software and set it up to run with Scrum and Kanban. It will also teach you to use Jira Software your way and run projects beyond the out-of-box Scrum and Kanban way, including a hybrid approach of both the methodologies and other options that come with Jira Software. Later, you will learn how to integrate it with the tools you are already using and enhance Jira with add-ons such as Confluence. You will learn to stay connected with your team from anywhere to ensure great development. Jira Software has numerous deployment options in the cloud, on your own infrastructure, or at a massive scale. You will be introduced to Bitbucket, Atlassian's distributed version control system, which integrates seamlessly with Jira, allowing your team to work within the two applications as one harmonious environment.With this practical guide, you will develop a great working knowledge of Jira Software and your project management will become much more efficient.Style and approachThis practical book explains Jira Software with the help of detailed examples in a step-by- step manner.
Among various infectious diseases, HIV/AIDS is considered to be one of the most stigmatizing conditions. Using a prospective design, the present study attempted to test the attributional pathway from ...perceived control to responsibility to self-blame and finally to self-stigmatization, and to examine the social and psychological sequelae of stigma among a sample of 119 people with HIV/AIDS (PWHA) in Hong Kong. Structural equation modeling findings showed that the model had good fit to the data. Although the linkage between the attributions of control, responsibility, and blame was confirmed, the relationship of blame to self-stigma was not significant. Self-stigma was found to dampen social support and lead to psychological distress half a year later. The present study challenged the adequacy of attributional factors in understanding self-stigmatization and demonstrated the impact of stigma on psychological adjustment among PWHA.
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