92 research outputs found

    Constrained patterns of covariation and clustering of HIV-1 non-nucleoside reverse transcriptase inhibitor resistance mutations

    Get PDF
    Objectives:We characterized pairwise and higher order patterns of non-nucleoside reverse transcriptase inhibi-tor (NNRTI)-selected mutations because multiple mutations are usually required for clinically significant resist-ance to second-generation NNRTIs. Patients and methods: We analysed viruses from 13039 individuals with sequences containing at least one of 52 published NNRTI-selected mutations, including 1133 viruses from individuals who received efavirenz but no other NNRTI and 1510 viruses from individuals who received nevirapine but no other NNRTI. Of the 17 reported etravirine resistance-associated mutations (RAMs), Y181C/I/V, L100I, K101P and M230L were considered major based on published in vitro susceptibility data

    Modern agglutinated foraminifera from the Hovgård ridge, fram strait, west of Spitsbergen: Evidence for a deep bottom current

    Get PDF
    Deep-water agglutinated foraminifera on the crest of the Hovgârd Ridge, west of Spitsbergen, consist mostly of large tubular astrorhizids. At a boxcore station collected from the crest of Hovgârd Ridge at a water depth of 1169 m, the sediment surface was covered with patches of large (1 mm diameter) tubular forms, belonging mostly to the species Astrorhiza crassatina Brady, with smaller numbers of Saccorhiza, Hyperammina, and Psammosiphonella. Non-tubutar species consisted mainly of opportunistic forms, such as Psammosphaera and Reophax. The presence of large suspension-feeding tubular genera as well as opportunistic forms point to the presence of deep currents at this locality that are strong enough to disturb the benthic fauna. This is confirmed by data obtained from sediment echosounding, which exhibit lateral variation in relative sedimentation rates within the Pleistocene sedimentary drape covering the ridge, indicative of winnowing in a south-easterly direction

    A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

    Get PDF
    The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

    Effusive and explosive volcanism on the ultraslow-spreading Gakkel Ridge, 85°E

    Get PDF
    Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 13 (2012): Q10005, doi:10.1029/2012GC004187.We use high-definition seafloor digital imagery and multibeam bathymetric data acquired during the 2007 Arctic Gakkel Vents Expedition (AGAVE) to evaluate the volcanic characteristics of the 85°E segment of the ultraslow spreading Gakkel Ridge (9 mm yr−1 full rate). Our seafloor imagery reveals that the axial valley is covered by numerous, small-volume (order ~1000 m3) lava flows displaying a range of ages and morphologies as well as unconsolidated volcaniclastic deposits with thicknesses up to 10 cm. The valley floor contains two prominent volcanic lineaments made up of axis-parallel ridges and small, cratered volcanic cones. The lava flows appear to have erupted from a number of distinct source vents within the ~12–15 km-wide axial valley. Only a few of these flows are fresh enough to have potentially erupted during the 1999 seismic swarm at this site, and these are associated with the Oden and Loke volcanic cones. We model the widespread volcaniclastic deposits we observed on the seafloor as having been generated by the explosive discharge of CO2 that accumulated in (possibly deep) crustal melt reservoirs. The energy released during explosive discharge, combined with the buoyant rise of hot fluid, lofted fragmented clasts of rapidly cooling magma into the water column, and they subsequently settled onto the seafloor as fall deposits surrounding the source vent.We gratefully acknowledge the financial support of the National Aeronautics and Space Administration, the National Science Foundation (N.S.F.), the International Polar Year 2007–2008, and Woods Hole Oceanographic Institution; and the graduate support provided by N.S.F., the NDSEG Fellowship, and WHOI Deep Ocean Exploration Institute.2013-04-0

    Irish cardiac society - Proceedings of annual general meeting held 20th & 21st November 1992 in Dublin Castle

    Get PDF

    Sistemas nacionais de inteligência: origens, lógica de expansão e configuração atual

    Full text link

    Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

    Get PDF
    Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification
    corecore