A magnetar powering the ordinary monster GRB 130427A?

We present the analysis of the extraordinarily bright Gamma-Ray Burst (GRB) 130427A under the hypothesis that the GRB central engine is an accretion-powered magnetar. In this framework, initially proposed to explain GRBs with precursor activity, the prompt emission is produced by accretion of matter onto a newly-born magnetar, and the observed power is related to the accretion rate. The emission is eventually halted if the centrifugal forces are able to pause accretion. We show that the X-ray and optical afterglow is well explained as the forward shock emission with a jet break plus a contribution from the spin-down of the magnetar. Our modelling does not require any contribution from the reverse shock, that may still influence the afterglow light curve at radio and mm frequencies, or in the optical at early times. We derive the magnetic field ($B\sim 10^{16}$ G) and the spin period ($P\sim 20$ ms) of the magnetar and obtain an independent estimate of the minimum luminosity for accretion. This minimum luminosity results well below the prompt emission luminosity of GRB 130427A, providing a strong consistency check for the scenario where the entire prompt emission is the result of continuous accretion onto the magnetar. This is in agreement with the relatively long spin period of the magnetar. GRB 130427A was a well monitored GRB showing a very standard behavior and, thus, is a well-suited benchmark to show that an accretion-powered magnetar gives a unique view of the properties of long GRBs.Comment: 5 pages, 1 figure, accepted for publication in MNRAS Letter

Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol

Introduction: Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12–15% of patients with SSc and accounts for 30– 40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc- PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH. Methods and analysis: This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken. Ethics and dissemination: Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals.Alicia Calderone, Wendy Stevens, David Prior, Harshal Nandurkar, Eli Gabbay, Susanna M Proudman, Trevor Williams, David Celermajer, Joanne Sahhar, Peter K K Wong, Vivek Thakkar, Nathan Dwyer, Jeremy Wrobel, Weng Chin, Danny Liew, Margaret Staples, Rachelle Buchbinder, Mandana Nikpou

Cellular responses of Candida albicans to phagocytosis and the extracellular activities of neutrophils are critical to counteract carbohydrate starvation, oxidative and nitrosative stress

Acknowledgments We thank Alexander Johnson (yhb1D/D), Karl Kuchler (sodD/D mutants), Janet Quinn (hog1D/D, hog1/cap1D/D, trx1D/D) and Peter Staib (ssu1D/D) for providing mutant strains. We acknowledge helpful discussions with our colleagues from the Microbial Pathogenicity Mechanisms Department, Fungal Septomics and the Microbial Biochemistry and Physiology Research Group at the Hans Kno¨ll Institute (HKI), specially Ilse D. Jacobsen, Duncan Wilson, Sascha Brunke, Lydia Kasper, Franziska Gerwien, Sea´na Duggan, Katrin Haupt, Kerstin Hu¨nniger, and Matthias Brock, as well as from our partners in the FINSysB Network. Author Contributions Conceived and designed the experiments: PM HW IMB AJPB OK BH. Performed the experiments: PM CD HW. Analyzed the data: PM HW IMB AJPB OK BH. Wrote the paper: PM HW OK AJPB BH.Peer reviewedPublisher PD

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

Funding: This work was funded by the European Research Council [http://erc.europa.eu/], AJPB (STRIFE Advanced Grant; C-2009-AdG-249793). The work was also supported by: the Wellcome Trust [www.wellcome.ac.uk], AJPB (080088, 097377); the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk], AJPB (BB/F00513X/1, BB/K017365/1); the CNPq-Brazil [http://cnpq.br], GMA (Science without Borders fellowship 202976/2014-9); and the National Centre for the Replacement, Refinement and Reduction of Animals in Research [www.nc3rs.org.uk], DMM (NC/K000306/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Dr. Elizabeth Johnson (Mycology Reference Laboratory, Bristol) for providing strains, and the Aberdeen Proteomics facility for the biotyping of S. cerevisiae clinical isolates, and to Euroscarf for providing S. cerevisiae strains and plasmids. We are grateful to our Microscopy Facility in the Institute of Medical Sciences for their expert help with the electron microscopy, and to our friends in the Aberdeen Fungal Group for insightful discussions.Peer reviewedPublisher PD

A Variable-Density Absorption Event in NGC 3227 mapped with Suzaku and Swift

The morphology of the circumnuclear gas accreting onto supermassive black holes in Seyfert galaxies remains a topic of much debate. As the innermost regions of Active Galactic Nuclei (AGN) are spatially unresolved, X-ray spectroscopy, and in particular line-of-sight absorption variability, is a key diagnostic to map out the distribution of gas. Observations of variable X-ray absorption in multiple Seyferts and over a wide range of timescales indicate the presence of clumps/clouds of gas within the circumnuclear material. Eclipse events by clumps transiting the line of sight allow us to explore the properties of the clumps over a wide range of radial distances from the optical/UV Broad Line Region (BLR) to beyond the dust sublimation radius. Time-resolved absorption events have been extremely rare so far, but suggest a range of density profiles across Seyferts. We resolve a weeks-long absorption event in the Seyfert NGC 3227. We examine six Suzaku and twelve Swift observations from a 2008 campaign spanning 5 weeks. We use a model accounting for the complex spectral interplay of three differently-ionized absorbers. We perform time-resolved spectroscopy to discern the absorption variability behavior. We also examine the IR-to-X-ray spectral energy distribution (SED) to test for reddening by dust. The 2008 absorption event is due to moderately-ionized ($\log \xi\sim 1.2-1.4$) gas covering 90% of the line of sight. We resolve the density profile to be highly irregular, in contrast to a previous symmetric and centrally-peaked event mapped with RXTE in the same object. The UV data do not show significant reddening, suggesting that the cloud is dust-free. The 2008 campaign has revealed a transit by a filamentary, moderately-ionized cloud of variable density that is likely located in the BLR, and possibly part of a disk wind.Comment: Accepted for publication by A&

Small but crucial : the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans

Peer reviewedPublisher PD

Infrastructure for Detector Research and Development towards the International Linear Collider

The EUDET-project was launched to create an infrastructure for developing and testing new and advanced detector technologies to be used at a future linear collider. The aim was to make possible experimentation and analysis of data for institutes, which otherwise could not be realized due to lack of resources. The infrastructure comprised an analysis and software network, and instrumentation infrastructures for tracking detectors as well as for calorimetry.Comment: 54 pages, 48 picture

Paleomagnetism of Middle Miocene Volcanic Rocks in the Mojave-Sonora Desert Region of Western Arizona and Southeastern California

Paleomagnetic directions have been obtained from 190 early to middle Miocene (12–20 Ma) mafic volcanic flows in 16 mountain ranges in the Mojave-Sonora desert region of western Arizona and southeastern California. These flows generally postdate early Miocene tectonic deformation accommodated by low-angle normal faults but predate high-angle normal faulting in the region. After detailed demagnetization experiments, 179 flows yielded characteristic directions interpreted as original thermal remanent magnetizations (TRM). Because of the episodic nature of basaltic volcanism in this region, the 179 flows yielded only 65 time-distinct virtual geomagnetic poles (VGPs). The angular dispersion of the 65 VGPs is consistent with the angular dispersion expected for a data set that has adequately averaged geomagnetic secular variation. The paleomagnetic pole calculated from the 65 cooling unit VGPs is located at 85.5°N, 108.9° within a 4.4° circle of 95% confidence. This pole is statistically indistinguishable (at 95% confidence) from reference poles calculated from rocks of similar age in stable North America and from a paleomagnetic pole calculated from rocks of similar age in Baja California. The coincidence of paleomagnetic poles from the Mojave-Sonora desert region with reference poles from the stable continental interior indicates that (1) significant vertical axis net tectonic rotations have not accompanied post-middle Miocene high-angle normal faulting in this region; (2) there has been no detectable post-middle Miocene latitudinal transport of the region; and (3) long-term nondipole components of the middle Miocene geomagnetic field probably were no larger than those of the recent (0–5 Ma) geomagnetic field. In contrast, paleomagnetic data indicate vertical axis rotations of similar age rocks in the Transverse Ranges, the Eastern Transverse Ranges, and the Mojave Block. We speculate that a major structural discontinuity in the vicinity of the southeastward projection of the Death Valley fault zone separates western areas affected by vertical axis rotations from eastern areas that have not experienced such rotations

Patient preferences and willingness-to-pay for a home or clinic based program of chronic heart failure management: findings from the which? trial

BACKGROUND Beyond examining their overall cost-effectiveness and mechanisms of effect, it is important to understand patient preferences for the delivery of different modes of chronic heart failure management programs (CHF-MPs). We elicited patient preferences around the characteristics and willingness-to-pay (WTP) for a clinic or home-based CHF-MP. METHODOLOGY/PRINCIPAL FINDINGS A Discrete Choice Experiment was completed by a sub-set of patients (n = 91) enrolled in the WHICH? trial comparing home versus clinic-based CHF-MP. Participants provided 5 choices between hypothetical clinic and home-based programs varying by frequency of nurse consultations, nurse continuity, patient costs, and availability of telephone or education support. Participants (aged 71±13 yrs, 72.5% male, 25.3% NYHA class III/IV) displayed two distinct preference classes. A latent class model of the choice data indicated 56% of participants preferred clinic delivery, access to group CHF education classes, and lower cost programs (p<0.05). The remainder preferred home-based CHF-MPs, monthly rather than weekly visits, and access to a phone advice service (p<0.05). Continuity of nurse contact was consistently important. No significant association was observed between program preference and participant allocation in the parent trial. WTP was estimated from the model and a dichotomous bidding technique. For those preferring clinic, estimated WTP was ≈AU$9-20 per visit; however for those preferring home-based programs, WTP varied widely (AU$15-105). CONCLUSIONS/SIGNIFICANCE Patient preferences for CHF-MPs were dichotomised between a home-based model which is more likely to suit older patients, those who live alone, and those with a lower household income; and a clinic-based model which is more likely to suit those who are more socially active and wealthier. To optimise the delivery of CHF-MPs, health care services should consider their patients’ preferences when designing CHF-MPs.Jennifer A. Whitty, Simon Stewart, Melinda J. Carrington, Alicia Calderone, Thomas Marwick, John D. Horowitz, Henry Krum, Patricia M. Davidson, Peter S. Macdonald, Christopher Reid, Paul A. Scuffha

Novel, synergistic antifungal combinations that target translation fidelity

There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8 fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone