A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome

DNA topoisomerases are required to resolve DNA topological stress. Despite this essential role, abortive topoisomerase activity generates aberrant protein-linked DNA breaks, jeopardising genome stability. Here, to understand the genomic distribution and mechanisms underpinning topoisomerase-induced DNA breaks, we map Top2 DNA cleavage with strand-specific nucleotide resolution across the S. cerevisiae and human genomes—and use the meiotic Spo11 protein to validate the broad applicability of this method to explore the role of diverse topoisomerase family members. Our data characterises Mre11-dependent repair in yeast and defines two strikingly different fractions of Top2 activity in humans: tightly localised CTCF-proximal, and broadly distributed transcription-proximal, the latter correlated with gene length and expression. Moreover, single nucleotide accuracy reveals the influence primary DNA sequence has upon Top2 cleavage—distinguishing sites likely to form canonical DNA double-strand breaks (DSBs) from those predisposed to form strand-biased DNA single-strand breaks (SSBs) induced by etoposide (VP16) in vivo

Meiotic DSB patterning: A multifaceted process

Meiosis is a specialized two-step cell division responsible for genome haploidization and the generation of genetic diversity during gametogenesis. An integral and distinctive feature of the meiotic program is the evolutionarily conserved initiation of homologous recombination (HR) by the developmentally programmed induction of DNA double-strand breaks (DSBs). The inherently dangerous but essential act of DSB formation is subject to multiple forms of stringent and self-corrective regulation that collectively ensure fruitful and appropriate levels of genetic exchange without risk to cellular survival. Within this article we focus upon an emerging element of this control—spatial regulation—detailing recent advances made in understanding how DSBs are evenly distributed across the genome, and present a unified view of the underlying patterning mechanisms employed

Chemostratigraphy of Upper Carboniferous (Pennsylvanian) sequences from the Southern North Sea (United Kingdom)

Important gas reservoirs occur in the Upper Carboniferous coal measures and red beds of the Southern North Sea. The thick red beds of the Boulton and Ketch formations are difficult to correlate, due to poor internal seismic definition, repetitive e-log signatures, and their barren nature. Although the underlying coal measures of the Westoe, Cleaver, and Caister Formations have better seismic resolution and contain palynomorphs, coals that die out laterally and the lack of diagnostic taxa over certain intervals contribute to their correlation being problematical. However, the application of chemostratigraphy to more than sixty wells from numerous fields in UK Quadrants 44 and 49, as well as from Dutch sector Blocks E, F, and K, allows the establishment of an independent, robust, detailed correlation framework for the aforesaid red beds and coal measures. Presented in this paper are correlative chemostratigraphic reference sections for the Caister, Westoe, Cleaver, Ketch, Boulton, and Step Graben formations. The chemostratigraphic zonations erected for these formations are based on variations in silty claystone geochemistry that can be tied to changes in provenance, climate, and depositional environment. In addition, the zonations are supported by stratigraphic changes in sandstone and coal geochemistry, the geochemical correlation of tonsteins and marine bands, and the recognition of different types of paleosol in the above formations. The chemostratigraphic correlation framework enables specific broad intervals ("packages") to be correlated between fields and is also used to constrain seismic correlations with a view to highlighting potential exploration targets. Furthermore, the same framework allows much thinner intervals ("units" and "subunits") to be correlated within fields: these smaller-scale correlations enhance reservoir correlations with respect to the development of fields such as Boulton, Schooner, Tyne, Ketch, and Topaz. In addition to using inorganic geochemical data to characterize and correlate sedimentological packages, data can also used to identify and correlate marker horizons and surfaces (tonsteins, coals, marine bands, major paleosols), which may be highly correlative low-diachrony surfaces, which greatly enhance the overall validity of the stratigraphic correlation scheme

The simulation of action disorganisation in complex activities of daily living

Action selection in everyday goal-directed tasks of moderate complexity is known to be subject to breakdown following extensive frontal brain injury. A model of action selection in such tasks is presented and used to explore three hypotheses concerning the origins of action disorganisation: that it is a consequence of reduced top-down excitation within a hierarchical action schema network coupled with increased bottom-up triggering of schemas from environmental sources, that it is a more general disturbance of schema activation modelled by excessive noise in the schema network, and that it results from a general disturbance of the triggering of schemas by object representations. Results suggest that the action disorganisation syndrome is best accounted for by a general disturbance to schema activation, while altering the balance between top-down and bottom-up activation provides an account of a related disorder - utilisation behaviour. It is further suggested that ideational apraxia (which may result from lesions to left temporoparietal areas and which has similar behavioural consequences to action disorganisation syndrome on tasks of moderate complexity) is a consequence of a generalised disturbance of the triggering of schemas by object representations. Several predictions regarding differences between action disorganisation syndrome and ideational apraxia that follow from this interpretation are detailed

Factors associated with the effectiveness and reach of NHS Stop Smoking Services for pregnant women in England

Background The UK National Health Service provides Stop Smoking Services for pregnant women (SSSP) but there is a lack of evidence concerning how these are best organised. This study investigates influences on services’ effectiveness and also on their propensity to engage pregnant smokers with support in stopping smoking. Methods Survey data collected from 121/141 (86%) of SSSP were augmented with data from Hospital Episode Statistics and the 2011 UK National Census. ‘Reach’ or propensity to engage smokers with support was defined as the percentage of pregnant smokers setting a quit date with SSSP support, and ‘Effectiveness’ as the percentage of women who set a quit date who also reported abstinence at four weeks later. A bivariate (i.e. two outcome variable) response Markov Chain Monte Carlo model was used to identify service-level factors associated with the Reach and Effectiveness of SSSP. Results Beta coefficients represent a percentage change in Reach and Effectiveness by the covariate. Providing the majority of one-to-one contacts in a clinic rather than at home increased both Reach (%) (β: 6.97, 95% CI: 3.34, 10.60) and Effectiveness (%) (β: 7.37, 95% CI: 3.03, 11.70). Reach of SSSP was also increased when the population served was more deprived (β for increase in Reach with a one unit increase in IMD score: 0.55, 95% CI: 0.25, 0.85), had a lower proportion of people with dependent children (β: -2.52, 95% CI: -3.82, −1.22), and a lower proportion of people in managerial or professional occupations (β: -0.31, 95% CI: -0.59, −0.03). The Effectiveness of SSSP was decreased in those areas that had a greater percentage of people >16 years with no educational qualifications (β: -0.51, 95% CI: -0.95, −0.07). Conclusions To engage pregnant smokers and to encourage them to quit, it may be more efficient for SSSP support to be focussed around clinics, rather than women’s homes. Reach of SSSP is inversely associated with disadvantage and efforts should be made to contact these women as they are less likely to achieve abstinence in the short and longer term

Final Protocol and Statistical Analysis Plan for the SNAP Trial - a randomised, double-blind, placebo-controlled trial of nicotine replacement therapy in pregnancy

This NIHR HTA-funded smoking, nicotine and pregnancy (SNAP) trial investigated whether or not nicotine replacement therapy (NRT) is effective, cost-effective and safe when used for smoking cessation by pregnant women. We randomised 1050 women who were between 12 and 24 weeks pregnant as they attended hospital for ante-natal ultrasound scans. Women received either nicotine or placebo transdermal patches with behavioural support. The primary outcome measure was biochemically-validated, self-reported, prolonged and total abstinence from smoking between a quit date (defined before randomisation and set within 2 weeks of this) and delivery. At 6 months after childbirth self-reported maternal smoking status was ascertained and 2 years after childbirth, self-reported maternal smoking status and the behaviour, cognitive development and respiratory symptoms of children born in the trial were compared in both groups. This repository contains the final approved version of the protocol plus the statistical analysis plan (SAP) for both outcomes at delivery and following the 2 year follow up period after birth

Search for the <i>bb </i>decay of the Standard Model Higgs boson in associated (<i>W/Z)H</i> production with the ATLAS detector

A search for the bb¯ decay of the Standard Model Higgs boson is performed with the ATLAS experiment using the full dataset recorded at the LHC in Run 1. The integrated luminosities used are 4.7 and 20.3 fb−1 from pp collisions at √s=7 and 8 TeV, respectively. The processes considered are associated (W/Z)H production, where W → eν/μν, Z → ee/μμ and Z → νν. The observed (expected) deviation from the background-only hypothesis corresponds to a significance of 1.4 (2.6) standard deviations and the ratio of the measured signal yield to the Standard Model expectation is found to be μ = 0.52 ± 0.32 (stat.) ± 0.24 (syst.) for a Higgs boson mass of 125.36 GeV. The analysis procedure is validated by a measurement of the yield of (W/Z)Z production with Z→bb¯ in the same final states as for the Higgs boson search, from which the ratio of the observed signal yield to the Standard Model expectation is found to be 0.74 ± 0.09 (stat.) ± 0.14 (syst.)

Robust Detection of Hierarchical Communities from Escherichia coli Gene Expression Data

Determining the functional structure of biological networks is a central goal of systems biology. One approach is to analyze gene expression data to infer a network of gene interactions on the basis of their correlated responses to environmental and genetic perturbations. The inferred network can then be analyzed to identify functional communities. However, commonly used algorithms can yield unreliable results due to experimental noise, algorithmic stochasticity, and the influence of arbitrarily chosen parameter values. Furthermore, the results obtained typically provide only a simplistic view of the network partitioned into disjoint communities and provide no information of the relationship between communities. Here, we present methods to robustly detect coregulated and functionally enriched gene communities and demonstrate their application and validity for Escherichia coli gene expression data. Applying a recently developed community detection algorithm to the network of interactions identified with the context likelihood of relatedness (CLR) method, we show that a hierarchy of network communities can be identified. These communities significantly enrich for gene ontology (GO) terms, consistent with them representing biologically meaningful groups. Further, analysis of the most significantly enriched communities identified several candidate new regulatory interactions. The robustness of our methods is demonstrated by showing that a core set of functional communities is reliably found when artificial noise, modeling experimental noise, is added to the data. We find that noise mainly acts conservatively, increasing the relatedness required for a network link to be reliably assigned and decreasing the size of the core communities, rather than causing association of genes into new communities.Comment: Due to appear in PLoS Computational Biology. Supplementary Figure S1 was not uploaded but is available by contacting the author. 27 pages, 5 figures, 15 supplementary file

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

BioTIME: A database of biodiversity time series for the Anthropocene.

MotivationThe BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.Main types of variables includedThe database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.Spatial location and grainBioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).Time period and grainBioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.Major taxa and level of measurementBioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.Software format.csv and .SQL