In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine.

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3-fold and >2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo

Comment mesurer les progrès de la lecture?

New observations of Neptune’s clouds in the near infrared were acquired in October 2013 with SINFONI on ESO’s Very Large Telescope (VLT) in Chile. SINFONI is an Integral Field Unit spectrometer returning a 64 × 64 pixel image with 2048 wavelengths. Image cubes in the J-band (1.09 – 1.41 μm) and H-band (1.43 – 1.87 μm) were obtained at spatial resolutions of 0.1″and 0.025″per pixel, while SINFONI’s adaptive optics provided an effective resolution of approximately 0.1″. Image cubes were obtained at the start and end of three successive nights to monitor the temporal development of discrete clouds both at short timescales (i.e. during a single night) as well as over the longer period of the three-day observing run. These observations were compared with similar H-band observations obtained in September 2009 with the NIFS Integral Field Unit spectrometer on the Gemini-North telescope in Hawaii, previously reported by Irwin et al., Icarus 216, 141-158, 2011, and previously unreported Gemini/NIFS observations at lower spatial resolution made in 2011. We find both similarities and differences between these observations, spaced over four years. The same overall cloud structure is seen with high, bright clouds visible at mid-latitudes (30 – 40°N,S), with slightly lower clouds observed at lower latitudes, together with small discrete clouds seen circling the pole at a latitude of approximately 60°S. However, while discrete clouds were visible at this latitude at both the main cloud deck level (at 2–3 bars) and in the upper troposphere (100–500mb) in 2009, no distinct deep (2–3 bar), discrete circumpolar clouds were visible in 2013, although some deep clouds were seen at the southern edge of the main cloud belt at 30–40°S, which have not been observed before. The nature of the deep sub-polar discrete clouds observed in 2009 is intriguing. While it is possible that in 2013 these deeper clouds were masked by faster moving, overlying features, we consider that it is unlikely that this should have happened in 2013, but not in 2009 when the upper-cloud activity was generally similar. Meanwhile, the deep clouds seen at the southern edge of the main cloud belt at 30 – 40°S in 2013, should also have been detectable in 2009, but were not seen. Hence, these observations may have detected a real temporal variation in the occurrence of Neptune’s deep clouds, pointing to underlying variability in the convective activity at the pressure of the main cloud deck at 2–3 bars near Neptune’s south pole and also in the main observable cloud belt at 30 – 40°S.</p

Outsourcing or efficiency? Investigating the decline in final energy consumption in the UK productive sectors

Over the past two decades reductions in the final energy consumption of the productive sectors (industry, public administration, commercial services and agriculture), have made important contributions to overall reductions in UK final energy consumption. This study investigates the drivers of the reductions in final energy consumption in the UK productive sectors between 1997 and 2013 using a decomposition analysis that incorporates two novel approaches. Firstly, it uses results from a multi-regional input-output model to investigate how much of the structural change in the economy has been driven by outsourcing production overseas. Secondly, it utilises energy conversion chain analysis to determine how much increases in the conversion efficiency from final energy to useful exergy have contributed to improvements in final energy intensity. In aggregate all energy savings from structural change are attributed to outsourcing. Improvements in the conversion efficiency produced savings of a similar size. However energy savings from both factors have stalled since 2009. Improvements in useful exergy intensity, the useful exergy used per unit of monetary output, provided the biggest share of energy savings, but these savings are concentrated in a few sectors and rarely lead to absolute reductions in final energy use. All of this suggests that a return to the rates of energy reduction seen between 2001 and 2009 should not be taken for granted and that active policy interventions might be required to achieve further reductions

An Essential Role for the Proximal but Not the Distal Cytoplasmic Tail of Glycoprotein M in Murid Herpesvirus 4 Infection

Murid herpesvirus-4 (MuHV-4) provides a tractable model with which to define common, conserved features of gamma-herpesvirus biology. The multi-membrane spanning glycoprotein M (gM) is one of only 4 glycoproteins that are essential for MuHV-4 lytic replication. gM binds to gN and is thought to function mainly secondary envelopment and virion egress, for which several predicted trafficking motifs in its C-terminal cytoplasmic tail could be important. We tested the contribution of the gM cytoplasmic tail to MuHV-4 lytic replication by making recombinant viruses with varying C-terminal deletions. Removing an acidic cluster and a distal YXXΦ motif altered the capsid distribution somewhat in infected cells but had little effect on virus replication, either in vitro or in vivo. In contrast, removing a proximal YXXΦ motif as well completely prevented productive replication. gM was still expressed, but unlike its longer forms showed only limited colocalization with co-transfected gN, and in the context of whole virus appeared to support gN expression less well. We conclude that some elements of the gM cytoplasmic tail are dispensible for MuHV-4 replication, but the tail as a whole is not

The outcomes of midline versus medio-lateral episiotomy

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Ontogeny of juvenile freshwater pearl mussels, Margaritifera margaritifera (Bivalvia: Margaritiferidae).

The gills of juvenile freshwater bivalves undergo a complex morphogenesis that may correlate with changes in feeding ecology, but ontogenic studies on juvenile mussels are rare. Scanning electron microscopy was used to examine the ultrastructure and ontogeny of 117 juvenile freshwater pearl mussels (Margaritifera margaritifera) ranging in age from 1–44 months and length from 0.49–8.90 mm. Three stages of gill development are described. In Stage 1 (5–9 inner demibranch filaments), only unreflected inner demibranch filaments were present. In Stage 2 (9–17 inner demibranch filaments), inner demibranch filaments began to reflect when shell length exceeded 1.13 mm, at 13–16 months old. Reflection began in medial filaments and then proceeded anterior and posterior. In Stage 3 (28–94 inner demibranch filaments), outer demibranch filaments began developing at shell length > 3.1 mm and about 34 months of age. The oral groove on the inner demibranch was first observed in 34 month old specimens > 2.66 mm but was never observed on the outer demibranch. Shell length (R2 = 0.99) was a better predictor of developmental stage compared to age (R2 = 0.84). The full suite of gill ciliation was present on filaments in all stages. Interfilamentary distance averaged 31.3 μm and did not change with age (4–44 months) or with size (0.75–8.9 mm). Distance between laterofrontal cirri couplets averaged 1.54 μm and did not change significantly with size or age. Labial palp primordia were present in even the youngest individuals but ciliature became more diverse in more developed individuals. Information presented here is valuable to captive rearing programmes as it provides insight in to when juveniles may be particularly vulnerable to stressors due to specific ontogenic changes. The data are compared with two other recent studies of Margaritifera development.N/

GWAS on retinal vasculometry phenotypes.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa

GWAS on retinal vasculometry phenotypes.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa

Circulating soluble Fas levels and risk of ovarian cancer

BACKGROUND: Dysregulation of apoptosis, specifically overexpression of soluble Fas (sFas), has been proposed to play a role in the development of ovarian cancer. The main objective of the present study was to evaluate serum sFas as a potential biomarker of ovarian cancer risk. METHODS: The association between serum sFas levels and the risk of ovarian cancer was examined in a case-control study nested within three prospective cohorts in New York (USA), Umeå (Sweden), and Milan (Italy). Case subjects were 138 women with primary invasive epithelial ovarian cancer diagnosed between 2 months and 13.2 years after the initial blood donation. Control subjects were 263 women who were free of cancer, and matched the case on cohort, menopausal status, age, and enrollment date. Serum sFas levels were determined using a quantitative sandwich enzyme immunoassay. RESULTS: Serum sFas levels were similar in women subsequently diagnosed with ovarian cancer (median, 6.5 ng/mL; range, 4.4 – 10.2) and in controls (median, 6.8 ng/mL; range, 4.5 – 10.1). Statistically significant trends of increasing serum sFas with age were observed among cases (r = 0.39, p < 0.0001) and controls (r = 0.42, p < 0.0001). Compared to women in the lowest third, women in the highest third of serum sFas were not at increased risk of ovarian cancer after adjustment for potential confounders (odd ratio (OR), 0.87; 95% confidence interval (CI), 0.42 – 1.82). CONCLUSION: The results suggest that serum sFas may not be a suitable marker for identification of women at increased risk of ovarian cancer