38 research outputs found

    ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation

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    Two side-by-side papers report that the transcription elongation factor ELOF1 drives transcription-coupled repair and prevents replication stress.Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. DNA damage-induced binding of the TCR-specific repair factor CSB to RNA polymerase II (RNAPII) triggers RNAPII ubiquitylation of a single lysine (K1268) by the CRL4(CSA) ubiquitin ligase. How CRL4(CSA) is specifically directed towards K1268 is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to K1268, revealing ELOF1 as a specificity factor that binds and positions CRL4(CSA) for optimal RNAPII ubiquitylation. Drug-genetic interaction screening also revealed a CSB-independent pathway in which ELOF1 prevents R-loops in active genes and protects cells against DNA replication stress. Our study offers key insights into the molecular mechanisms of TCR and provides a genetic framework of the interplay between transcriptional stress responses and DNA replication.Cancer Signaling networks and Molecular Therapeutic

    DPHL: A DIA Pan-human Protein Mass Spectrometry Library for Robust Biomarker Discovery

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    To address the increasing need for detecting and validating protein biomarkers in clinical specimens, mass spectrometry (MS)-based targeted proteomic techniques, including the selected reaction monitoring (SRM), parallel reaction monitoring (PRM), and massively parallel data-independent acquisition (DIA), have been developed. For optimal performance, they require the fragment ion spectra of targeted peptides as prior knowledge. In this report, we describe a MS pipeline and spectral resource to support targeted proteomics studies for human tissue samples. To build the spectral resource, we integrated common open-source MS computational tools to assemble a freely accessible computational workflow based on Docker. We then applied the workflow to generate DPHL, a comprehensive DIA pan-human library, from 1096 data-dependent acquisition (DDA) MS raw files for 16 types of cancer samples. This extensive spectral resource was then applied to a proteomic study of 17 prostate cancer (PCa) patients. Thereafter, PRM validation was applied to a larger study of 57 PCa patients and the differential expression of three proteins in prostate tumor was validated. As a second application, the DPHL spectral resource was applied to a study consisting of plasma samples from 19 diffuse large B cell lymphoma (DLBCL) patients and 18 healthy control subjects. Differentially expressed proteins between DLBCL patients and healthy control subjects were detected by DIA-MS and confirmed by PRM. These data demonstrate that the DPHL supports DIA and PRM MS pipelines for robust protein biomarker discovery. DPHL is freely accessible at https://www.iprox.org/page/project.html?id=IPX0001400000

    Search for neutral resonances decaying into a Z boson and a pair of b jets or τ leptons

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    A search is performed for a new resonance decaying into a lighter resonance and a Z boson. Two channels are studied, targeting the decay of the lighter resonance into either a pair of oppositely charged τ leptons or a bb‾ pair. The Z boson is identified via its decays to electrons or muons. The search exploits data collected by the CMS experiment at a centre-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 19.8 fb −1 . No significant deviations are observed from the standard model expectation and limits are set on production cross sections and parameters of two-Higgs-doublet models

    Search for massive WH resonances decaying into the l nu b(b)over-bar final state at root s=8 TeV

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    Peer reviewe

    Forward-backward asymmetry of Drell-Yan lepton pairs in pp collisions at root s=8 TeV

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    Peer reviewe

    Search for R-parity violating decays of a top squark in proton–proton collisions at √s=8 TeV

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    The results of a search for a supersymmetric partner of the top quark (top squark), pair-produced in proton–proton collisions at View the MathML sources=8 TeV, are presented. The search, which focuses on R-parity violating, chargino-mediated decays of the top squark, is performed in final states with low missing transverse momentum, two oppositely charged electrons or muons, and at least five jets. The analysis uses a data sample corresponding to an integrated luminosity of 19.7 fb−1 collected with the CMS detector at the LHC in 2012. The data are found to be in agreement with the standard model expectation, and upper limits are placed on the top squark pair production cross section at 95% confidence level. Assuming a 100% branching fraction for the top squark decay chain, View the MathML sourcet˜→tχ˜1±,χ˜1±→ℓ±+jj, top squark masses less than 890 (1000) GeV for the electron (muon) channel are excluded for the first time in models with a single nonzero R-parity violating coupling View the MathML sourceλijk′(i,j,k≤2)(i,j,k≤2), where i,j,ki,j,k correspond to the three generations

    Measurement of the Zγ→νν‾γ production cross section in pp collisions at s=8 TeV and limits on anomalous ZZγ and Zγγ trilinear gauge boson couplings

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    An inclusive measurement of the Zγ→νν‾γ production cross section in pp collisions at s=8TeV is presented, using data corresponding to an integrated luminosity of 19.6 fb −1 collected with the CMS detector at the LHC. This measurement is based on the observation of events with large missing energy and with a single photon with transverse momentum above 145 GeV and absolute pseudorapidity in the range |η|<1.44 . The measured Zγ→νν‾γ production cross section, 52.7±2.1 (stat)±6.4 (syst)±1.4 (lumi) fb , agrees well with the standard model prediction of 50.0−2.2+2.4 fb . A study of the photon transverse momentum spectrum yields the most stringent limits to date on the anomalous ZZγ and Zγγ trilinear gauge boson couplings

    CMS Collaboration

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    Search for supersymmetry in events with soft leptons, low jet multiplicity, and missing transverse energy in proton-proton collisions at root s=8 TeV

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    Peer reviewe

    Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

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    Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries
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