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  • Open Access English
    Authors: 
    Meisenberg, Cornelia; Pinder, Sarah I; Hopkins, Suzanna R; Wooller, Sarah K; Benstead-Hume, Graeme; Pearl, Frances M G; Jeggo, Penny A; Downs, Jessica A;
    Publisher: Cell Press
    Country: United Kingdom
    Project: UKRI | Mechanistic analysis of D... (MR/N02155X/1)

    Summary Cohesin subunits are frequently mutated in cancer, but how they function as tumor suppressors is unknown. Cohesin mediates sister chromatid cohesion, but this is not always perturbed in cancer cells. Here, we identify a previously unknown role for cohesin. We find that cohesin is required to repress transcription at DNA double-strand breaks (DSBs). Notably, cohesin represses transcription at DSBs throughout interphase, indicating that this is distinct from its known role in mediating DNA repair through sister chromatid cohesion. We identified a cancer-associated SA2 mutation that supports sister chromatid cohesion but is unable to repress transcription at DSBs. We further show that failure to repress transcription at DSBs leads to large-scale genome rearrangements. Cancer samples lacking SA2 display mutational patterns consistent with loss of this pathway. These findings uncover a new function for cohesin that provides insights into its frequent loss in cancer. Meisenberg et al. show that, in response to DNA double strand breaks (DSBs), cohesin is required to repress nearby transcription. This happens throughout interphase, regardless of whether a sister chromatid is present. Failure to repress transcription near a DNA DSB results in an increase in large-scale chromosome rearrangements. Highlights • Cohesin and PBAF repress gene transcription near DNA double-strand breaks (DSBs) • Transcriptional repression at DSBs requires cohesin and PBAF throughout interphase • Loss of DSB-induced gene repression leads to more large-scale genome alterations Graphical Abstract

  • Open Access English
    Authors: 
    Andrew Hook; Victor Court; Benjamin K. Sovacool; Steven Sorrell;
    Publisher: HAL CCSD
    Countries: France, France, United Kingdom

    Abstract Information and communication technologies (ICTs) increasingly enable employees to work from home and other locations (‘teleworking’). This study explores the extent to which teleworking reduces the need to travel to work and the consequent impacts on economy-wide energy consumption. The paper provides a systematic review of the current state of knowledge of the energy impacts of teleworking. This includes the energy savings from reduced commuter travel and the indirect impacts on energy consumption associated with changes in non-work travel and home energy consumption. The aim is to identify the conditions under which teleworking leads to a net reduction in economy-wide energy consumption, and the circumstances where benefits may be outweighed by unintended impacts. The paper synthesises the results of 39 empirical studies, identified through a comprehensive search of 9000 published articles. Twenty six of the 39 studies suggest that teleworking reduces energy use, and only eight studies suggest that teleworking increases, or has a neutral impact on energy use. However, differences in the methodology, scope and assumptions of the different studies make it difficult to estimate ‘average’ energy savings. The main source of savings is the reduced distance travelled for commuting, potentially with an additional contribution from lower office energy consumption. However, the more rigorous studies that include a wider range of impacts (e.g. non-work travel or home energy use) generally find smaller savings. Despite the generally positive verdict on teleworking as an energy-saving practice, there are numerous uncertainties and ambiguities about its actual or potential benefits. These relate to the extent to which teleworking may lead to unpredictable increases in non-work travel and home energy use that may outweigh the gains from reduced work travel. The available evidence suggests that economy-wide energy savings are typically modest, and in many circumstances could be negative or non-existent.

  • Open Access English
    Authors: 
    Lehmann, A R; Walicka, M; Griffths, D J; Murray, J M; Watts, F Z; McCready, S; Carr, A M;
    Publisher: American Society for Microbiology
    Country: United Kingdom

    The rad18 mutant of Schizosaccharomyces pombe is very sensitive to killing by both UV and ¿ radiation. We have cloned and sequenced the rad18 gene and isolated and sequenced its homolog from Saccharomyces cerevisiae, designated RHC18. The predicted Rad18 protein has all the structural properties characteristic of the SMC family of proteins, suggesting a motor function- the first implicated in DNA repair. Gene deletion shows that both rad18 and RHC18 are essential for proliferation. Genetic and biochemical analyses suggest that the product of the rad18 gene acts in a DNA repair pathway for removal of UV-induced DNA damage that is distinct from classical nucleotide excision repair. This second repair pathway involves the products of the rhp51 gene (the homolog of the RAD51 gene of S. cerevisiae) and the rad2 gene.

  • Open Access
    Authors: 
    Duncan Farrah; Aprajita Verma; Seb Oliver; Michael Rowan-Robinson; Richard G. McMahon;
    Publisher: Oxford University Press (OUP)
    Country: United Kingdom

    We present Hubble Space Telescope Wide Field Planetary Camera 2 I-band imaging for a sample of nine hyperluminous infrared galaxies (HLIRGs) spanning a redshift range 0.45 < z < 1.34. Three of the sample have morphologies showing evidence for interactions and six are quasi-stellar objects (QSOs). Host galaxies in the QSOs are detected reliably out to z ∼ 0.8. The detected QSO host galaxies have an elliptical morphology with scalelengths spanning 6.5 < re (kpc) < 88 and absolute k-corrected magnitudes spanning −24.5 < MI < −25.2. There is no clear correlation between the infrared (IR) power source and the optical morphology. None of the sources in the sample, including F15307+3252, shows any evidence for gravitational lensing. We infer that the IR luminosities are thus real. Based on these results, and previous studies of HLIRGs, we conclude that this class of object is broadly consistent with being a simple extrapolation of the ULIRG population to higher luminosities; ULIRGs being mainly violently interacting systems powered by starbursts and/or active galactic nuclei. Only a small number of sources, the infrared luminosities of which exceed 1013 L⊙, are intrinsically less luminous objects that have been boosted by gravitational lensing.

  • Publication . Article . Preprint . 1999
    Open Access English
    Authors: 
    Axel Schwope; M. S. Catalán; Klaus Beuermann; Andre Metzner; Robert Connon Smith; D. Steeghs;
    Country: United Kingdom

    (abridged abstract) We present multi-epoch high-resolution spectroscopy and photoelectric polarimetry of the long-period polar (AM Herculis star) QQ Vul. The blue emission lines show several distinct components, the sharpest of which can unequivocally be assigned to the illuminated hemisphere of the secondary star and used to trace its orbital motion. This narrow emission line can be used in combination with NaI-absorption lines from the photosphere of the companion to build a stable long-term ephemeris for the star: inferior conjunction of the companion occurs at HJD = 2448446.4710(5) + E 0.15452011(11). MNRAS, in press (15 pages), see also http://www.aip.de/~preprint/preprints/1999/1999_049.html and http://www.aip.de/~preprint/preprints/1999/1999_048.html

  • Publication . Article . 2020
    Open Access
    Authors: 
    Peter Newell;
    Publisher: Wiley
    Country: United Kingdom

    In a context of climate emergency and calls from the IPCC for “transformative systemic change,” we need to revisit the role of business in helping to accelerate responses to climate crisis. The scale and depth of the challenges facing business have intensified in ways which force us to refocus our research on questions of urgency and speed, as well as the growing need for new and alternative business models and a fundamental re‐balancing of the economy. There is a large literature dealing with business responses to climate change from a range of perspectives and disciplines covering issues such as corporate strategy and public policy engagement. But I argue that the question of the nature and speed of change now required, and whether there are historical and contemporary precedents for accelerated transitions within and beyond business, must assume a more central place in our research. This must be alongside growing efforts to understand how business will adapt to climate chaos. This conclusion implies a closer engagement and cross‐fertilization of ideas with scholars of sustainability transitions, for example. Here, there is growing interest in the question of how to accelerate transitions, but where greater attention is required to the role of business actors.

  • Publication . Book . 2021
    Open Access English
    Authors: 
    Nicholls, Daniel; Cantone, Bernardo; Dacre, Nicholas; Eggleton, David; Gkogkidis, Vasilis;
    Publisher: Association for Project Management
    Country: United Kingdom

    The Dynamic Conditions for Project Success 2021 report builds on the Conditions for Project Success 2015 findings and can be used at an organisational level to set up projects for success from the outset. \ud \ud In 2015, Association for Project Management published a report which sought to identify the core factors which lead to project success. These conditions, subject to the situation and the judgement of the project professional, can be implemented with any project, programme or portfolio and help to best ensure project success. However, despite widespread usage we identified at the end of this research that dynamic conditions at the organisational, professional, and socio-economic levels existed that could help to shape successful project-based organisations.\ud \ud With this in mind and through a commissioned tender APM sought with the Universities of Sussex and Southampton to further develop the findings of the 2015 report by investigating these organisational, professional, and socio-economic dynamic conditions that can enhance project outcomes.

  • Open Access English
    Authors: 
    Towler, Benjamin P; Jones, Christopher I; Viegas, Sandra C; Apura, Patricia; Waldron, Joseph A; Smalley, Sarah K; Arraiano, Cecilia M; Newbury, Sarah F;
    Publisher: Landes Bioscience
    Country: United Kingdom
    Project: EC | ST-FLOW (289326), UKRI | Function of the exoribonu... (BB/G002754/1), FCT | EXPL/BEX-BCM/1317/2013 (EXPL/BEX-BCM/1317/2013), UKRI | Epigenetic regulation of ... (BB/I021345/1)

    Dis3 is a highly conserved exoribonuclease which degrades RNAs in the 3'-5' direction. Mutations in Dis3 are associated with a number of human cancers including multiple myeloma and acute myeloid leukaemia. In this work, we have assessed the effect of a Dis3 knockdown on Drosophila imaginal disc development and on expression of mature microRNAs. We find that Dis3 knockdown severely disrupts the development of wing imaginal discs in that the flies have a "no wing" phenotype. Use of RNA-seq to quantify the effect of Dis3 knockdown on microRNA expression shows that Dis3 normally regulates a small subset of microRNAs, with only 11 (10.1%) increasing in level > 2-fold and 6 (5.5%) decreasing in level >2-fold. Of these microRNAs, miR-252-5p is increased 2.1-fold in Dis3-depleted cells compared to controls while the level of the miR-252 precursor is unchanged, suggesting that Dis3 can act in the cytoplasm to specifically degrade this mature miRNA. Furthermore, our experiments suggest that Dis3 normally interacts with the exosomal subunit Rrp40 in the cytoplasm to target miR-252-5p for degradation during normal wing development. Another microRNA, miR-982-5p, is expressed at lower levels in Dis3 knockdown cells, while the miR-982 precursor remains unchanged, indicating that Dis3 is involved in its processing. Our study therefore reveals an unexpected specificity for this ribonuclease towards microRNA regulation, which is likely to be conserved in other eukaryotes and may be relevant to understanding its role in human disease.

  • Open Access English
    Authors: 
    Brennan C Kahan; Karla Diaz-Ordaz; Kate Homer; Dawn Carnes; Martin Underwood; Stephanie Taylor; Stephen Bremner; Sandra Eldridge;
    Publisher: BioMed Central
    Country: United Kingdom

    BACKGROUND: The Coping with Persistent Pain, Effectiveness Research into Self-management (COPERS) trial assessed whether a group-based self-management course is effective in reducing pain-related disability in participants with chronic musculoskeletal pain. This article describes the statistical analysis plan for the COPERS trial. METHODS AND DESIGN: COPERS was a pragmatic, multicentre, unmasked, parallel group, randomised controlled trial. This article describes (a) the overall analysis principles (including which participants will be included in each analysis, how results will be presented, which covariates will be adjusted for, and how we will account for clustering in the intervention group); (b) the primary and secondary outcomes, and how each outcome will be analysed; (c) sensitivity analyses; (d) subgroup analyses; and (e) adherence-adjusted analyses. TRIAL REGISTRATION: ISRCTN24426731.

  • Open Access English
    Authors: 
    Annaliza Todd; Charlene Martin; Jenna Morgan; Esther Herbert; Mike Bradburn; Maria Burton; Malcolm W.R. Reed; Tim Chater; Kirsty Pemberton; Stephen J Walters; +7 more
    Publisher: Elsevier
    Country: United Kingdom

    Introduction\ud \ud Recruitment and retention are two of the most important factors in successfully running clinical trials. Many trials encounter problems with both, causing delays or preventing study progress. These issues are greater in older adults and patients with cancer.\ud \ud \ud \ud Materials and methods\ud \ud We assessed recruitment and retention in a large, multicentre, observational breast cancer study in older female patients (>70 years, N = 3440). Data collected by the Age Gap study were used to assess rates of, and reasons for, patients not being recruited or retained. Statistical analysis assessed the impact of age as a predictor of recruitment and retention.\ud \ud \ud \ud Results\ud \ud Between February 2013 and June 2018, 6876 patients were screened and 3456 were consented across 56 United Kingdom (UK) breast units. Reasons for non-recruitment included ineligibility, clinician issues, staffing resource issues, patients' lack of interest or time and trial burden. In comparison with the age demographics of patients with breast cancer in the UK, women aged 70–75 years were over-represented compared to older age groups. Logistic regression demonstrated that older age significantly reduced the odds of consent (OR = 0.96, CI: 0.938–0.982; p < 0.001). Multivariate analysis showed that age (p < 0.001), markers of poor functional ability (Eastern Cooperative Oncology Group Performance Status (p = 0.011)) and instrumental activities of daily living (p = 0.026) were significant predictors of withdrawal.\ud \ud \ud \ud Discussion\ud \ud This study has demonstrated that selection and attrition bias for age are apparent despite a range of ‘age friendly’ study design measures. Exploration of the underlying reasons for this and development of measures to address this should be the focus of further research.

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