Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Long-duration laboratory experiment of slow development of steady alternate bars

The current view is that migrating bars are the result of morphodynamic instability in straight or mildly-sinuous alluvial channels and are therefore an inevitable feature of alluvial river beds. Steady bars, instead, require some external forcing or specific morphodynamic conditions to develop. Yet, recent numerical tests showed that steady bars may develop as a result of spontaneous morphodynamic instability, just like migrating bars, without meeting the specific conditions. We investigated this possibility in the laboratory, following the temporal evolution of alternate bars in a straight flume with mobile bed. The experiment was run with a constant discharge for about 10 weeks. Initially, the bed topography was dominated by the presence of fast growing migrating bars. After three weeks, however, slowly growing, larger, steady bars emerged. These bars had the same wavelength as the ones that formed in another experimental test in which the flow was perturbed by the presence of a transverse plate. The experiment confirms the recent numerical results. Considering that the presence of steady alternate bars is a prerequisite for initiation of meandering, this is now shown to be an inherent feature of alluvial rivers.Hydraulic EngineeringCivil Engineering and Geoscience

Influence of blade deflections on wind turbine noise directivity

This paper establishes the effect of blade deflections on wind turbine noise directivity. Fast turn-around methods are used in a framework of integrated aeroelastic and aeroacoustic simulations: the blade element momentum theory is coupled with a RANS-informed Amiet's model for the aeroacoustic modelling of trailing-and leading-edge noise. This approach is applied to the NREL 5 MW wind turbine and the results of rigid and flexible blades are compared. The overall sound pressure level computed with flexible blades increases up to 13 dBA for listeners close to the rotor plane. This effect is attributed to the flapwise angular deflection of the wind turbine blade. Furthermore, the symmetry of the results with respect to the rotor plane is lost when the flapwise deflection is considered, indicating that the modelling of this rotation is of fundamental importance for the acoustic simulation. Aerodynamics, Wind Energy & Propulsio

CGILS: Results from the first phase of an international project to understand the physical mechanisms of low cloud feedbacks in single column models

CGILS—the CFMIP-GASS Intercomparison of Large Eddy Models (LESs) and single column models (SCMs)—investigates the mechanisms of cloud feedback in SCMs and LESs under idealized climate change perturbation. This paper describes the CGILS results from 15 SCMs and 8 LES models. Three cloud regimes over the subtropical oceans are studied: shallow cumulus, cumulus under stratocumulus, and well-mixed coastal stratus/stratocumulus. In the stratocumulus and coastal stratus regimes, SCMs without activated shallow convection generally simulated negative cloud feedbacks, while models with active shallow convection generally simulated positive cloud feedbacks. In the shallow cumulus alone regime, this relationship is less clear, likely due to the changes in cloud depth, lateral mixing, and precipitation or a combination of them. The majority of LES models simulated negative cloud feedback in the well-mixed coastal stratus/stratocumulus regime, and positive feedback in the shallow cumulus and stratocumulus regime. A general framework is provided to interpret SCM results: in a warmer climate, the moistening rate of the cloudy layer associated with the surface-based turbulence parameterization is enhanced; together with weaker large-scale subsidence, it causes negative cloud feedback. In contrast, in the warmer climate, the drying rate associated with the shallow convection scheme is enhanced. This causes positive cloud feedback. These mechanisms are summarized as the “NESTS” negative cloud feedback and the “SCOPE” positive cloud feedback (Negative feedback from Surface Turbulence under weaker Subsidence—Shallow Convection PositivE feedback) with the net cloud feedback depending on how the two opposing effects counteract each other. The LES results are consistent with these interpretations.Geoscience & Remote SensingCivil Engineering and Geoscience

Searches for violation of lepton flavour and baryon number in tau lepton decays at LHCb

Searches for the lepton flavour violating decay τ−→μ−μ+μ−τ−→μ−μ+μ− and the lepton flavour and baryon number violating decays sourceτ−→p¯μ+μ− and τ−→pμ−μ−τ−→pμ−μ− have been carried out using proton–proton collision data, corresponding to an integrated luminosity of 1.0 fb−11.0 fb−1, taken by the LHCb experiment at s=7 TeV. No evidence has been found for any signal, and limits have been set at 90%90% confidence level on the branching fractions: B(τ−→μ−μ+μ−)<8.0×10−8B(τ−→μ−μ+μ−)<8.0×10−8, B(τ−→p¯μ+μ−)<3.3×10−7 and B(τ−→pμ−μ−)<4.4×10−7B(τ−→pμ−μ−)<4.4×10−7. The results for the τ−→p¯μ+μ− and τ−→pμ−μ−τ−→pμ−μ− decay modes represent the first direct experimental limits on these channels

Measurement of the time-dependent CP asymmetry in B0 -> J/ψ KS0 decays

This Letter reports a measurement of the CP violation observables SJ/ψK0S and CJ/ψK0S in the decay channel B0→J/ψK0S performed with 1.0 fb−1 of pp collisions at s√=7 TeV collected by the LHCb experiment. The fit to the data yields SJ/ψK0S=0.73±0.07(stat)±0.04(syst) and CJ/ψK0S=0.03±0.09(stat)±0.01(syst). Both values are consistent with the current world averages and within expectations from the Standard Model

Measurement of the diffractive cross-section in deep inelastic scattering

Diffractive scattering of $\gamma^* p \to X + N$, where $N$ is either a proton or a nucleonic system with $M_N~<~4$~GeV has been measured in deep inelastic scattering (DIS) at HERA. The cross section was determined by a novel method as a function of the $\gamma^* p$ c.m. energy $W$ between 60 and 245~GeV and of the mass $M_X$ of the system $X$ up to 15~GeV at average $Q^2$ values of 14 and 31~GeV$^2$. The diffractive cross section $d\sigma^{diff} /dM_X$ is, within errors, found to rise linearly with $W$. Parameterizing the $W$ dependence by the form d\sigma^{diff}/dM_X \propto (W^2)^{(2\overline{\mbox{\alpha_{_{I\hspace{-0.2em}P}}}} -2)} the DIS data yield for the pomeron trajectory \overline{\mbox{\alpha_{_{I\hspace{-0.2em}P}}}} = 1.23 \pm 0.02(stat) \pm 0.04 (syst) averaged over $t$ in the measured kinematic range assuming the longitudinal photon contribution to be zero. This value for the pomeron trajectory is substantially larger than \overline{\mbox{\alpha_{_{I\hspace{-0.2em}P}}}} extracted from soft interactions. The value of \overline{\mbox{\alpha_{_{I\hspace{-0.2em}P}}}} measured in this analysis suggests that a substantial part of the diffractive DIS cross section originates from processes which can be described by perturbative QCD. From the measured diffractive cross sections the diffractive structure function of the proton F^{D(3)}_2(\beta,Q^2, \mbox{x_{_{I\hspace{-0.2em}P}}}) has been determined, where $\beta$ is the momentum fraction of the struck quark in the pomeron. The form F^{D(3)}_2 = constant \cdot (1/ \mbox{x_{_{I\hspace{-0.2em}P}}})^a gives a good fit to the data in all $\beta$ and $Q^2$ intervals with $a = 1.46 \pm 0.04 (stat) \pmComment: 45 pages, including 16 figure

Search for direct CP violation in D0 -> h- h+ modes using semileptonic B decays

15 pages, 4 figures - See paper for full list of authorsA search for direct CP violation in D0 -> h- h+ (where h=K or pi) is presented using data corresponding to an integrated luminosity of 1.0 fb^-1 collected in 2011 by LHCb in pp collisions at a centre-of-mass energy of 7 TeV. The analysis uses D0 mesons produced in inclusive semileptonic b-hadron decays to the D0 mu X final state, where the charge of the accompanying muon is used to tag the flavour of the D0 meson. The difference in the CP-violating asymmetries between the two decay channels is measured to be Delta A_CP = A_CP(K-K+) - A_CP(pi-pi+) = (0.49 +- 0.30 (stat) +- 0.14 (syst)) % . This result does not confirm the evidence for direct CP violation in the charm sector reported in other analyses