Influenza Polymerase Activity Correlates with the Strength of Interaction between Nucleoprotein and PB2 through the Host-Specific Residue K/E627

The ribonucleoprotein (RNP) complex is the essential transcription-replication machinery of the influenza virus. It is composed of the trimeric polymerase (PA, PB1 and PB2), nucleoprotein (NP) and RNA. Elucidating the molecular mechanisms of RNP assembly is central to our understanding of the control of viral transcription and replication and the dependence of these processes on the host cell. In this report, we show, by RNP reconstitution assays and co-immunoprecipitation, that the interaction between NP and polymerase is crucial for the function of the RNP. The functional association of NP and polymerase involves the C-terminal ‘627’ domain of PB2 and it requires NP arginine-150 and either lysine-627 or arginine-630 of PB2. Using surface plasmon resonance, we demonstrate that the interaction between NP and PB2 takes place without the involvement of RNA. At 33, 37 and 41°C in mammalian cells, more positive charges at aa. 627 and 630 of PB2 lead to stronger NP-polymerase interaction, which directly correlates with the higher RNP activity. In conclusion, our study provides new information on the NP-PB2 interaction and shows that the strength of NP-polymerase interaction and the resulting RNP activity are promoted by the positive charges at aa. 627 and 630 of PB2

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The ATLAS inner detector trigger performance in pp collisions at 13 TeV during LHC Run 2

The design and performance of the inner detector trigger for the high level trigger of the ATLAS experiment at the Large Hadron Collider during the 2016-18 data taking period is discussed. In 2016, 2017, and 2018 the ATLAS detector recorded 35.6 fb$^{-1}$, 46.9 fb$^{-1}$, and 60.6 fb$^{-1}$ respectively of proton-proton collision data at a centre-of-mass energy of 13 TeV. In order to deal with the very high interaction multiplicities per bunch crossing expected with the 13 TeV collisions the inner detector trigger was redesigned during the long shutdown of the Large Hadron Collider from 2013 until 2015. An overview of these developments is provided and the performance of the tracking in the trigger for the muon, electron, tau and $b$-jet signatures is discussed. The high performance of the inner detector trigger with these extreme interaction multiplicities demonstrates how the inner detector tracking continues to lie at the heart of the trigger performance and is essential in enabling the ATLAS physics programme

The ATLAS inner detector trigger performance in pp collisions at 13 TeV during LHC Run 2

The design and performance of the inner detector trigger for the high level trigger of the ATLAS experiment at the Large Hadron Collider during the 2016-18 data taking period is discussed. In 2016, 2017, and 2018 the ATLAS detector recorded 35.6 fb$^{-1}$, 46.9 fb$^{-1}$, and 60.6 fb$^{-1}$ respectively of proton-proton collision data at a centre-of-mass energy of 13 TeV. In order to deal with the very high interaction multiplicities per bunch crossing expected with the 13 TeV collisions the inner detector trigger was redesigned during the long shutdown of the Large Hadron Collider from 2013 until 2015. An overview of these developments is provided and the performance of the tracking in the trigger for the muon, electron, tau and $b$-jet signatures is discussed. The high performance of the inner detector trigger with these extreme interaction multiplicities demonstrates how the inner detector tracking continues to lie at the heart of the trigger performance and is essential in enabling the ATLAS physics programme

Observation of electroweak production of two jets in association with an isolated photon and missing transverse momentum, and search for a Higgs boson decaying into invisible particles at 13 TeV with the ATLAS detector

This paper presents the measurement of the electroweak production of two jets in association with a $Z\gamma$ pair with the $Z$ boson decaying into two neutrinos. It also presents the search for invisible or partially invisible decays of a Higgs boson with a mass of 125 GeV produced through vector-boson fusion with a photon in the final state. These results use data from LHC proton-proton collisions at $\sqrt{s}$ = 13 TeV collected with the ATLAS detector corresponding to an integrated luminosity of 139 fb$^{-1}$. The event signature, shared by all benchmark processes considered for measurements and searches, is characterized by a significant amount of unbalanced transverse momentum and a photon in the final state, in addition to a pair of forward jets. For electroweak production of $Z\gamma$ in association with two jets, the background-only hypothesis is rejected with an observed (expected) significance of 5.2 (5.1) standard deviations. The measured fiducial cross-section for this process is 1.31$\pm$0.29 fb. Observed (expected) upper limit of 0.37 (0.34) at 95% confidence level is set on the branching ratio of a 125 GeV Higgs boson to invisible particles, assuming the Standard Model production cross-section. The signature is also interpreted in the context of decays of a Higgs boson to a photon and a dark photon. An observed (expected) 95% CL upper limit on the branching ratio for this decay is set at 0.018 (0.017), assuming the 125 GeV Standard Model Higgs boson production cross-section

Structure and function analysis of an antibody recognizing all influenza A subtypes

Influenza virus remains a threat because of its ability to evade vaccine-induced immune responses due to antigenic drift. Here, we describe the isolation, evolution, and structure of a broad-spectrum human monoclonal antibody (mAb), MEDI8852, effectively reacting with all influenza A hemagglutinin (HA) subtypes. MEDI8852 uses the heavy-chain VH6-1 gene and has higher potency and breadth when compared to other anti-stem antibodies. MEDI8852 is effective in mice and ferrets with a therapeutic window superior to that of oseltamivir. Crystallographic analysis of Fab alone or in complex with H5 or H7 HA proteins reveals that MEDI8852 binds through a coordinated movement of CDRs to a highly conserved epitope encompassing a hydrophobic groove in the fusion domain and a large portion of the fusion peptide, distinguishing it from other structurally characterized cross- reactive antibodies. The unprecedented breadth and potency of neutralization by MEDI8852 support its development as immunotherapy for influenza virus-infected humans