Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors.

Hyaline Fibromatosis Syndrome (HFS) is a human genetic disease caused by mutations in the anthrax toxin receptor 2 (or cmg2) gene, which encodes a membrane protein thought to be involved in the homeostasis of the extracellular matrix. Little is known about the structure and function of the protein or the genotype-phenotype relationship of the disease. Through the analysis of four patients, we identify three novel mutants and determine their effects at the cellular level. Altogether, we show that missense mutations that map to the extracellular von Willebrand domain or the here characterized Ig-like domain of CMG2 lead to folding defects and thereby to retention of the mutated protein in the endoplasmic reticulum (ER). Mutations in the Ig-like domain prevent proper disulphide bond formation and are more efficiently targeted to ER-associated degradation. Finally, we show that mutant CMG2 can be rescued in fibroblasts of some patients by treatment with proteasome inhibitors and that CMG2 is then properly transported to the plasma membrane and signalling competent, identifying the ER folding and degradation pathway components as promising drug targets for HFS

Coevolution of variability models and related software artifacts

Variant-rich software systems offer a large degree of customization, allowing users to configure the target system according to their preferences and needs. Facing high degrees of variability, these systems often employ variability models to explicitly capture user-configurable features (e.g., systems options) and the constraints they impose. The explicit representation of features allows them to be referenced in different variation points across different artifacts, enabling the latter to vary according to specific feature selections. In such settings, the evolution of variability models interplays with the evolution of related artifacts, requiring the two to evolve together, or coevolve. Interestingly, little is known about how such coevolution occurs in real-world systems, as existing research has focused mostly on variability evolution as it happens in variability models only. Furthermore, existing techniques supporting variability evolution are usually validated with randomly-generated variability models or evolution scenarios that do not stem from practice. As the community lacks a deep understanding of how variability evolution occurs in real-world systems and how it relates to the evolution of different kinds of software artifacts, it is not surprising that industry reports existing tools and solutions ineffective, as they do not handle the complexity found in practice. Attempting to mitigate this overall lack of knowledge and to support tool builders with insights on how variability models coevolve with other artifact types, we study a large and complex real-world variant-rich software system: the Linux kernel. Specifically, we extract variability-coevolution patterns capturing changes in the variability model of the Linux kernel with subsequent changes in Makefiles and C source code. From the analysis of the patterns, we report on findings concerning evolution principles found in the kernel, and we reveal deficiencies in existing tools and theory when handling changes captured by our patterns

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Performance of Long Ladders for the LHCb Silicon Tracker

The LHCb Silicon Tracker uses detector ladders with readout strips with an effective length of up to 36,cm. Kapton interconnect cables of up to 54,cm in length are employed in between silicon sensors and front-end readout hybrids. Fast front-end readout electronics with a shaping time of around 25,ns are employed to avoid pile-up of events from consecutive LHC bunch crossings. An extensive measurement program as well as simulations have been carried out to study the expected noise performance of these detectors. Presented at the 14th International Workshop on Vertex Detectors, Chuzenji Lake, Nikko, Japan, November 7-11, 2005 Proceedings submitted for publication in Nucl. Instr. and Meth.

Quantitative imaging of concentrated suspensions under flow

We review recent advances in imaging the flow of concentrated suspensions, focussing on the use of confocal microscopy to obtain time-resolved information on the single-particle level in these systems. After motivating the need for quantitative (confocal) imaging in suspension rheology, we briefly describe the particles, sample environments, microscopy tools and analysis algorithms needed to perform this kind of experiments. The second part of the review focusses on microscopic aspects of the flow of concentrated model hard-sphere-like suspensions, and the relation to non-linear rheological phenomena such as yielding, shear localization, wall slip and shear-induced ordering. Both Brownian and non-Brownian systems will be described. We show how quantitative imaging can improve our understanding of the connection between microscopic dynamics and bulk flow.Comment: Review on imaging hard-sphere suspensions, incl summary of methodology. Submitted for special volume 'High Solid Dispersions' ed. M. Cloitre, Vol. xx of 'Advances and Polymer Science' (Springer, Berlin, 2009); 22 pages, 16 fig

Radiation Monitoring System for the LHCb Inner Tracker

The performance requirements and the design of the Radiation Monitoring System (RMS) for the LHCb Inner Tracker are presented. Details of the Metal Foil Detector technology employed for the RMS are described, along with results from tests of RMS prototypes

3-Deazaneplanocin A (DZNep), an Inhibitor of the Histone Methyltransferase EZH2, Induces Apoptosis and Reduces Cell Migration in Chondrosarcoma Cells

ObjectiveGrowing evidences indicate that the histone methyltransferase EZH2 (enhancer of zeste homolog 2) may be an appropriate therapeutic target in some tumors. Indeed, a high expression of EZH2 is correlated with poor prognosis and metastasis in many cancers. In addition, 3-Deazaneplanocin A (DZNep), an S-adenosyl-L homocysteine hydrolase inhibitor which induces EZH2 protein depletion, leads to cell death in several cancers and tumors. The aim of this study was to determine whether an epigenetic therapy targeting EZH2 with DZNep may be also efficient to treat chondrosarcomas.MethodsEZH2 expression was determined by immunohistochemistry and western-blot. Chondrosarcoma cell line CH2879 was cultured in the presence of DZNep, and its growth and survival were evaluated by counting adherent cells periodically. Apoptosis was assayed by cell cycle analysis, Apo2.7 expression using flow cytometry, and by PARP cleavage using western-blot. Cell migration was assessed by wound healing assay.ResultsChondrosarcomas (at least with high grade) highly express EZH2, at contrary to enchondromas or chondrocytes. In vitro, DZNep inhibits EZH2 protein expression, and subsequently reduces the trimethylation of lysine 27 on histone H3 (H3K27me3). Interestingly, DZNep induces cell death of chondrosarcoma cell lines by apoptosis, while it slightly reduces growth of normal chondrocytes. In addition, DZNep reduces cell migration.ConclusionThese results indicate that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach to treat chondrosarcomas

Influence of IFNL3/4 polymorphisms on the incidence of cytomegalovirus infection after solid-organ transplantation

Background. Polymorphisms in the interferon-λ (IFNL) 3/4 region have been associated with reduced hepatitis C virus clearance. We explored the role of such polymorphisms on the incidence of CMV infection in solid-organ transplant (SOT) recipients. Methods. Caucasian patients participating in the Swiss Transplant Cohort Study in 2008-2011 were included. A novel functional TT/-G polymorphism (rs368234815) in the CpG region upstream of IFNL3 was investigated. Results. A total of 840 SOT recipients at risk for CMV were included, among whom 373 (44%) received antiviral prophylaxis. The 12-months cumulative incidence of CMV replication and disease were 0.44 and 0.08, respectively. Patient homozygous for the minor rs368234815 allele (-G/-G) tended to have a higher cumulative incidence of CMV replication (SHR=1.30 [95%CI 0.97-1.74], P=0.07) compared to other patients (TT/TT or TT/-G). The association was significant among patients followed by a preemptive approach (SHR=1.46 [1.01-2.12], P=0.047), especially in patients receiving an organ from a seropositive donor (D+, SHR=1.92 [95%CI 1.30-2.85], P=0.001), but not among those who received antiviral prophylaxis (SHR=1.13 [95%CI 0.70-1.83], P=0.6). These associations remained significant in multivariate competing risk regression models. Conclusions. Polymorphisms in the IFNL3/4 region influence susceptibility to CMV replication in SOT recipients, particularly in patients not receiving antiviral prophylaxi

Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition

In birds, as in mammals, one pair of chromosomes differs between the sexes. In birds, males are ZZ and females ZW. In mammals, males are XY and females XX. Like the mammalian XY pair, the avian ZW pair is believed to have evolved from autosomes, with most change occurring in the chromosomes found in only one sex—the W and Y chromosomes1, 2, 3, 4, 5. By contrast, the sex chromosomes found in both sexes—the Z and X chromosomes—are assumed to have diverged little from their autosomal progenitors2. Here we report findings that challenge this assumption for both the chicken Z chromosome and the human X chromosome. The chicken Z chromosome, which we sequenced essentially to completion, is less gene-dense than chicken autosomes but contains a massive tandem array containing hundreds of duplicated genes expressed in testes. A comprehensive comparison of the chicken Z chromosome with the finished sequence of the human X chromosome demonstrates that each evolved independently from different portions of the ancestral genome. Despite this independence, the chicken Z and human X chromosomes share features that distinguish them from autosomes: the acquisition and amplification of testis-expressed genes, and a low gene density resulting from an expansion of intergenic regions. These features were not present on the autosomes from which the Z and X chromosomes originated but were instead acquired during the evolution of Z and X as sex chromosomes. We conclude that the avian Z and mammalian X chromosomes followed convergent evolutionary trajectories, despite their evolving with opposite (female versus male) systems of heterogamety. More broadly, in birds and mammals, sex chromosome evolution involved not only gene loss in sex-specific chromosomes, but also marked expansion and gene acquisition in sex chromosomes common to males and females.National Science Foundation (U.S.)Howard Hughes Medical Institut

Evidence for oxygenic photosynthesis half a billion years before the Great Oxidation Event

The early Earth was characterized by the absence of oxygen in the ocean–atmosphere system, in contrast to the well-oxygenated conditions that prevail today. Atmospheric concentrations first rose to appreciable levels during the Great Oxidation Event, roughly 2.5–2.3 Gyr ago. The evolution of oxygenic photosynthesis is generally accepted to have been the ultimate cause of this rise, but it has proved difficult to constrain the timing of this evolutionary innovation. The oxidation of manganese in the water column requires substantial free oxygen concentrations, and thus any indication that Mn oxides were present in ancient environments would imply that oxygenic photosynthesis was ongoing. Mn oxides are not commonly preserved in ancient rocks, but there is a large fractionation of molybdenum isotopes associated with the sorption of Mo onto the Mn oxides that would be retained. Here we report Mo isotopes from rocks of the Sinqeni Formation, Pongola Supergroup, South Africa. These rocks formed no less than 2.95 Gyr ago in a nearshore setting. The Mo isotopic signature is consistent with interaction with Mn oxides. We therefore infer that oxygen produced through oxygenic photosynthesis began to accumulate in shallow marine settings at least half a billion years before the accumulation of significant levels of atmospheric oxygen