Molecular basis of cullin-3 (Cul3) ubiquitin ligase subversion by vaccinia virus protein A55.

BTB-Kelch proteins are substrate-specific adaptors for cullin-3 (Cul3) RING-box-based E3 ubiquitin ligases, mediating protein ubiquitylation for subsequent proteasomal degradation. Vaccinia virus encodes three BTB-Kelch proteins: A55, C2, and F3. Viruses lacking A55 or C2 have altered cytopathic effects in cultured cells and altered pathology in vivo Previous studies have shown that the ectromelia virus orthologue of A55 interacts with Cul3 in cells. We report that the N-terminal BTB-BACK (BB) domain of A55 binds directly to the Cul3 N-terminal domain (Cul3-NTD), forming a 2:2 complex in solution. We solved the structure of an A55BB/Cul3-NTD complex from anisotropic crystals diffracting to 2.3/3.7 Å resolution in the best/worst direction, revealing that the overall interaction and binding interface closely resemble the structures of cellular BTB/Cul3-NTD complexes, despite low sequence identity between A55 and cellular BTB domains. Surprisingly, despite this structural similarity, the affinity of Cul3-NTD for A55BB was stronger than for cellular BTB proteins. Glutamate substitution of the A55 residue Ile-48, adjacent to the canonical φX(D/E) Cul3-binding motif, reduced affinity of A55BB for Cul3-NTD by at least 2 orders of magnitude. Moreover, Ile-48 and the φX(D/E) motif are conserved in A55 orthologues from other poxviruses, but not in the vaccinia virus proteins C2 or F3. The high-affinity interaction between A55BB and Cul3-NTD suggests that, in addition to directing the Cul3-RING E3 ligase complex to degrade cellular/viral target proteins that are normally unaffected, A55 may also sequester Cul3 from cellular adaptor proteins, thereby protecting substrates of these cellular adaptors from ubiquitylation and degradation.Wellcome Trust, Royal Societ

Glacial melt under a porous debris layer

In this paper we undertake a quantitative analysis of the dynamic process by which ice underneath a dry porous debris layer melts. We show that the incorporation of debris-layer airflow into a theoretical model of glacial melting can capture the empirically observed features of the so-called Østrem curve (a plot of the melt rate as a function of debris depth). Specifically, we show that the turning point in the Østrem curve can be caused by two distinct mechanisms: the increase in the proportion of ice that is debris-covered and/or a reduction in the evaporative heat flux as the debris layer thickens. This second effect causes an increased melt rate because the reduction in (latent) energy used for evaporation increases the amount of energy available for melting. Our model provides an explicit prediction for the melt rate and the temperature distribution within the debris layer, and provides insight into the relative importance of the two effects responsible for the maximum in the Østrem curve. We use the data of Nicholson and Benn (2006) to show that our model is consistent with existing empirical measurements

Additive manufactured Poly("-caprolactone)-graphene scaffolds: Lamellar crystal orientation, mechanical properties and biological performance

Understanding the mechano–biological coupling mechanisms of biomaterials for tissue engineering is of major importance to assure proper scaffold performance in situ. Therefore, it is of paramount importance to establish correlations between biomaterials, their processing conditions, and their mechanical behaviour, as well as their biological performance. With this work, it was possible to infer a correlation between the addition of graphene nanoparticles (GPN) in a concentration of 0.25, 0.5, and 0.75% (w/w) (GPN0.25, GPN0.5, and GPN0.75, respectively) in three-dimensional poly("-caprolactone) (PCL)-based scaffolds, the extrusion-based processing parameters, and the lamellar crystal orientation through small-angle X-ray scattering experiments of extruded samples of PCL and PCL/GPN. Results revealed a significant impact on the scaffold’s mechanical properties to a maximum of 0.5% of GPN content, with a significant improvement in the compressive modulus of 59 MPa to 93 MPa. In vitro cell culture experiments showed the scaffold’s ability to support the adhesion and proliferation of L929 fibroblasts (fold increase of 28, 22, 23, and 13 at day 13 (in relation to day 1) for PCL, GPN0.25, GPN0.5, and GPN0.75, respectively) and bone marrow mesenchymal stem/stromal cells (seven-fold increase for all sample groups at day 21 in relation to day 1). Moreover, the cells maintained high viability, regular morphology, and migration capacity in all the different experimental groups, assuring the potential of PCL/GPN scaffolds for tissue engineering (TE) applications.info:eu-repo/semantics/publishedVersio

The polaroid image as photo-object

This article is part of a larger project on the cultural history of Polaroid photography and draws on research done at the Polaroid Corporate archive at Harvard and at the Polaroid company itself. It identifies two cultural practices engendered by Polaroid photography, which, at the point of its extinction, has briefly flared into visibility again. It argues that these practices are mistaken as novel but are in fact rediscoveries of practices that stretch back as many as five decades. The first section identifies Polaroid image-making as a photographic equivalent of what Tom Gunning calls the ‘cinema of attractions’. That is, the emphasis in its use is on the display of photographic technologies rather than the resultant image. Equally, the common practice, in both fine art and vernacular circles, of making composite pictures with Polaroid prints, draws attention from image content and redirects it to the photo as object

The Energetic Particle Detector (EPD) Investigation and the Energetic Ion Spectrometer (EIS) for the Magnetospheric Multiscale (MMS) Mission

Abstract The Energetic Particle Detector (EPD) Investigation is one of 5 fields-and-particles investigations on the Magnetospheric Multiscale (MMS) mission. MMS comprises 4 spacecraft flying in close formation in highly elliptical, near-Earth-equatorial orbits targeting understanding of the fundamental physics of the important physical process called magnetic reconnection using Earth’s magnetosphere as a plasma laboratory. EPD comprises two sensor types, the Energetic Ion Spectrometer (EIS) with one instrument on each of the 4 spacecraft, and the Fly’s Eye Energetic Particle Spectrometer (FEEPS) with 2 instruments on each of the 4 spacecraft. EIS measures energetic ion energy, angle and elemental compositional distributions from a required low energy limit of 20 keV for protons and 45 keV for oxygen ions, up to \u3e0.5 MeV (with capabilities to measure up to \u3e1 MeV). FEEPS measures instantaneous all sky images of energetic electrons from 25 keV to \u3e0.5 MeV, and also measures total ion energy distributions from 45 keV to \u3e0.5 MeV to be used in conjunction with EIS to measure all sky ion distributions. In this report we describe the EPD investigation and the details of the EIS sensor. Specifically we describe EPD-level science objectives, the science and measurement requirements, and the challenges that the EPD team had in meeting these requirements. Here we also describe the design and operation of the EIS instruments, their calibrated performances, and the EIS in-flight and ground operations. Blake et al. (The Flys Eye Energetic Particle Spectrometer (FEEPS) contribution to the Energetic Particle Detector (EPD) investigation of the Magnetospheric Magnetoscale (MMS) Mission, this issue) describe the design and operation of the FEEPS instruments, their calibrated performances, and the FEEPS in-flight and ground operations. The MMS spacecraft will launch in early 2015, and over its 2-year mission will provide comprehensive measurements of magnetic reconnection at Earth’s magnetopause during the 18 months that comprise orbital phase 1, and magnetic reconnection within Earth’s magnetotail during the about 6 months that comprise orbital phase 2

Precise Radial Velocities of Giant Stars II. Pollux and its Planetary Companion

It has long been speculated that the observed periodic radial velocity pattern for the K giant Pollux might be explained in terms of an orbiting planetary companion. We have collected 80 high-resolution spectra for Pollux at Lick Observatory yielding precise radial velocities with a mean error of 3.8 m/s, providing the most comprehensive and precise data set available for this star. Our data confirm the periodicity previously seen in the radial velocities. We derive a period of 589.7+/-3.5 days and, assuming a primary mass of 1.86 M_Sun, a minimum companion mass of 2.9+/-0.3 M_Jup, consistent with earlier determinations. No evidence for any periodicities is visible in our analysis of the shapes of the spectral lines via the bisector method, so that we conclude that evidence is accumulating and compelling for a planet around Pollux. However, some last doubt remains about this interpretation, because non-radial pulsations which might be present in giant stars could in principle also explain the observed radial velocities, while the accompanying bisector variations might be too small to be detectable with current data.Comment: 13 pages, 4 figures, accepted by Ap

MPPUPM Pantau Harga Makanan

Majlis Perwakilan Pelajar Universiti Putra Malaysia (MPPUPM) giat memantau harga makanan yang dikatakan meningkat dengan ketara sehingga menimbulkan kegelisahan mahansiswa

Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C

Background Eltrombopag is a new, orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis. We evaluated its ability to increase platelet counts and facilitate treatment for hepatitis C virus (HCV) infection in patients with thrombocytopenia associated with HCV-related cirrhosis. Methods Seventy-four patients with HCV-related cirrhosis and platelet counts of 20,000 to less than 70,000 per cubic millimeter were randomly assigned to receive eltrombopag (30, 50, or 75 mg daily) or placebo daily for 4 weeks. The primary end point was a platelet count of 100,000 per cubic millimeter or more at week 4. Peginterferon and ribavirin could then be initiated, with continuation of eltrombopag or placebo for 12 additional weeks. Results At week 4, platelet counts were increased to 100,000 per cubic millimeter or more in a dose-dependent manner among patients for whom these data were available: in 0 of the 17 patients receiving placebo, in 9 of 12 (75%) receiving 30 mg of eltrombopag, in 15 of 19 (79%) receiving 50 mg of eltrombopag, and in 20 of 21 (95%) receiving 75 mg of eltrombopag (P\u3c0.001). Antiviral therapy was initiated in 49 patients (in 4 of 18 patients receiving placebo, 10 of 14 receiving 30 mg of eltrombopag, 14 of 19 receiving 50 mg of eltrombopag, and 21 of 23 receiving 75 mg of eltrombopag) while the administration of eltrombopag or placebo was continued. Twelve weeks of antiviral therapy, with concurrent receipt of eltrombopag or placebo, were completed by 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, and 75 mg of eltrombopag, respectively, and by 6% of patients in the placebo group. The most common adverse event during the initial 4 weeks was headache; thereafter, the adverse events were those expected with interferon-based therapy. Conclusions Eltrombopag therapy increases platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis, thereby permitting the initiation of antiviral therapy. (ClinicalTrials.gov number, NCT00110799.