Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer.

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency1-5. Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and identified MAGOH and MAGOHB, core members of the splicing-dependent exon junction complex, as top-ranked paralog dependencies6-8. MAGOHB is the top gene dependency in cells with hemizygous MAGOH deletion, a pervasive genetic event that frequently occurs due to chromosome 1p loss. Inhibition of MAGOHB in a MAGOH-deleted context compromises viability by globally perturbing alternative splicing and RNA surveillance. Dependency on IPO13, an importin-β receptor that mediates nuclear import of the MAGOH/B-Y14 heterodimer9, is highly correlated with dependency on both MAGOH and MAGOHB. Both MAGOHB and IPO13 represent dependencies in murine xenografts with hemizygous MAGOH deletion. Our results identify MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and suggest a rationale for targeting the MAGOHB-IPO13 axis in cancers with chromosome 1p deletion

Identification of Melatonin-Regulated Genes in the Ovine Pituitary Pars Tuberalis, a Target Site for Seasonal Hormone Control

The pars tuberalis (PT) of the pituitary gland expresses a high density of melatonin (MEL) receptors and is believed to regulate seasonal physiology by decoding changes in nocturnal melatonin secretion. Circadian clock genes are known to be expressed in the PT in response to the decline (Per1) and onset (Cry1) of MEL secretion, but to date little is known of other molecular changes in this key MEL target site. To identify transcriptional pathways that may be involved in the diurnal and photoperiod-transduction mechanism, we performed a whole genome transcriptome analysis using PT RNA isolated from sheep culled at three time points over the 24-h cycle under either long or short photoperiods. Our results reveal 153 transcripts where expression differs between photoperiods at the light-dark transition and 54 transcripts where expression level was more globally altered by photoperiod (all time points combined). Cry1 induction at night was associated with up-regulation of genes coding for NeuroD1 (neurogenic differentiation factor 1), Pbef / Nampt (nicotinamide phosphoribosyltransferase) , Hif1α (hypoxia-inducible factor-1α), and Kcnq5 (K channel) and down-regulation of Rorβ, a key clock gene regulator. Using in situ hybridization, we confirmed day-night differences in expression for Pbef / Nampt, NeuroD1, and Rorβ in the PT. Treatment of sheep with MEL increased PT expression for Cry1, Pbef / Nampt, NeuroD1, and Hif1α, but not Kcnq5. Our data thus reveal a cluster of Cry1-associated genes that are acutely responsive to MEL and novel transcriptional pathways involved in MEL action in the PT

Search for direct stau production in events with two hadronic tau-leptons in root s=13 TeV pp collisions with the ATLAS detector

A search for the direct production of the supersymmetric partners ofτ-leptons (staus) in final stateswith two hadronically decayingτ-leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of139fb−1, recorded with the ATLAS detector at the LargeHadron Collider at a center-of-mass energy of 13 TeV. No significant deviation from the expected StandardModel background is observed. Limits are derived in scenarios of direct production of stau pairs with eachstau decaying into the stable lightest neutralino and oneτ-lepton in simplified models where the two staumass eigenstates are degenerate. Stau masses from 120 GeV to 390 GeV are excluded at 95% confidencelevel for a massless lightest neutralino

Clinical presentation and outcomes of peripartum cardiomyopathy in the Middle East: a cohort from seven Arab countries

Aims: Published data on the clinical presentation of peripartum cardiomyopathy (PPCM) are very limited particularly from the Middle East. The aim of this study was to examine the clinical presentation, management, and outcomes of patients with PPCM using data from a large multicentre heart failure (HF) registry from the Middle East. Methods and results: From February to November 2012, a total of 5005 consecutive patients with HF were enrolled from 47 hospitals in 7 Middle East countries. From this cohort, patients with PPCM were identified and included in this study. Clinical features, in-hospital, and 12 months outcomes were examined. During the study period, 64 patients with PPCM were enrolled with a mean age of 32.5 ± 5.8 years. Family history was identified in 11 patients (17.2%) and hypertension in 7 patients (10.9%). The predominant presenting symptom was dyspnoea New York Heart Association class IV in 51.6%, class III in 31.3%, and class II in 17.2%. Basal lung crepitations and peripheral oedema were the predominant signs on clinical examination (98.2% and 84.4%, respectively). Most patients received evidence-based HF therapies. Inotropic support and mechanical ventilation were required in 16% and 5% of patients, respectively. There was one in-hospital death (1.6%), and after 1 year of follow-up, nine patients were rehospitalized with HF (15%), and one patient died (1.6%). Conclusions: A high index of suspicion of PPCM is required to make the diagnosis especially in the presence of family history of HF or cardiomyopathy. Further studies are warranted on the genetic basis of PPCM.Gulf CARE is an investigator-initiated study conducted under the auspices of the Gulf Heart Association and funded by Servier, Paris, France, and (for centres in Saudi Arabia) by the Saudi Heart Association [The Deanship of Scientific Research at King Saud University, Riyadh, Saudi Arabia (Research Group Number RG-1436-013)]. This does not alter our adherence to policies on sharing data and materials, and the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Checkpoint-Dependent and -Independent Roles of Swi3 in Replication Fork Recovery and Sister Chromatid Cohesion in Fission Yeast

Multiple genome maintenance processes are coordinated at the replication fork to preserve genomic integrity. How eukaryotic cells accomplish such a coordination is unknown. Swi1 and Swi3 form the replication fork protection complex and are involved in various processes including stabilization of replication forks, activation of the Cds1 checkpoint kinase and establishment of sister chromatid cohesion in fission yeast. However, the mechanisms by which the Swi1–Swi3 complex achieves and coordinates these tasks are not well understood. Here, we describe the identification of separation-of-function mutants of Swi3, aimed at dissecting the molecular pathways that require Swi1–Swi3. Unlike swi3 deletion mutants, the separation-of-function mutants were not sensitive to agents that stall replication forks. However, they were highly sensitive to camptothecin that induces replication fork breakage. In addition, these mutants were defective in replication fork regeneration and sister chromatid cohesion. Interestingly, unlike swi3-deleted cell, the separation-of-functions mutants were proficient in the activation of the replication checkpoint, but their fork regeneration defects were more severe than those of checkpoint mutants including cds1Δ, chk1Δ and rad3Δ. These results suggest that, while Swi3 mediates full activation of the replication checkpoint in response to stalled replication forks, Swi3 activates a checkpoint-independent pathway to facilitate recovery of collapsed replication forks and the establishment of sister chromatid cohesion. Thus, our separation-of-function alleles provide new insight into understanding the multiple roles of Swi1-Swi3 in fork protection during DNA replication, and into understanding how replication forks are maintained in response to different genotoxic agents

10 Recommended core outcome domains for tendinopathy derived from a delphi of patients and health care professionals: the groningen ISTS2018 consensus

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Correlated long-range mixed-harmonic fluctuations measured in pp, p+Pb and low-multiplicity Pb+Pb collisions with the ATLAS detector

For abstract see published article

Performance of top-quark and W -boson tagging with ATLAS in Run 2 of the LHC

The performance of identification algorithms (“taggers”) for hadronically decaying top quarks and W bosons in pp collisions at √s=13 TeV recorded by the ATLAS experiment at the Large Hadron Collider is presented. A set of techniques based on jet shape observables are studied to determine a set of optimal cut-based taggers for use in physics analyses. The studies are extended to assess the utility of combinations of substructure observables as a multivariate tagger using boosted decision trees or deep neural networks in comparison with taggers based on two-variable combinations. In addition, for highly boosted top-quark tagging, a deep neural network based on jet constituent inputs as well as a re-optimisation of the shower deconstruction technique is presented. The performance of these taggers is studied in data collected during 2015 and 2016 corresponding to 36.1 fb −1 for the tt ¯ and γ+jet and 36.7 fb −1 −1 for the dijet event topologies