Akt-dependent regulation of NF- B is controlled by mTOR and Raptor in association with IKK

While NF-κB is considered to play key roles in the development and progression of many cancers, the mechanisms whereby this transcription factor is activated in cancer are poorly understood. A key oncoprotein in a variety of cancers is the serine–threonine kinase Akt, which can be activated by mutations in PI3K, by loss of expression/activity of PTEN, or through signaling induced by growth factors and their receptors. A key effector of Akt-induced signaling is the regulatory protein mTOR (mammalian target of rapamycin). We show here that mTOR downstream from Akt controls NF-κB activity in PTEN-null/inactive prostate cancer cells via interaction with and stimulation of IKK. The mTOR-associated protein Raptor is required for the ability of Akt to induce NF-κB activity. Correspondingly, the mTOR inhibitor rapamycin is shown to suppress IKK activity in PTEN-deficient prostate cancer cells through a mechanism that may involve dissociation of Raptor from mTOR. The results provide insight into the effects of Akt/mTOR-dependent signaling on gene expression and into the therapeutic action of rapamycin

'Education, education, education' : legal, moral and clinical

This article brings together Professor Donald Nicolson's intellectual interest in professional legal ethics and his long-standing involvement with law clinics both as an advisor at the University of Cape Town and Director of the University of Bristol Law Clinic and the University of Strathclyde Law Clinic. In this article he looks at how legal education may help start this process of character development, arguing that the best means is through student involvement in voluntary law clinics. And here he builds upon his recent article which argues for voluntary, community service oriented law clinics over those which emphasise the education of students

The WiggleZ Dark Energy Survey: Survey Design and First Data Release

The WiggleZ Dark Energy Survey is a survey of 240,000 emission line galaxies in the distant universe, measured with the AAOmega spectrograph on the 3.9-m Anglo-Australian Telescope (AAT). The target galaxies are selected using ultraviolet photometry from the GALEX satellite, with a flux limit of NUV<22.8 mag. The redshift range containing 90% of the galaxies is 0.2<z<1.0. The primary aim of the survey is to precisely measure the scale of baryon acoustic oscillations (BAO) imprinted on the spatial distribution of these galaxies at look-back times of 4-8 Gyrs. Detailed forecasts indicate the survey will measure the BAO scale to better than 2% and the tangential and radial acoustic wave scales to approximately 3% and 5%, respectively. This paper provides a detailed description of the survey and its design, as well as the spectroscopic observations, data reduction, and redshift measurement techniques employed. It also presents an analysis of the properties of the target galaxies, including emission line diagnostics which show that they are mostly extreme starburst galaxies, and Hubble Space Telescope images, which show they contain a high fraction of interacting or distorted systems. In conjunction with this paper, we make a public data release of data for the first 100,000 galaxies measured for the project.Comment: Accepted by MNRAS; this has some figures in low resolution format. Full resolution PDF version (7MB) available at http://www.physics.uq.edu.au/people/mjd/pub/wigglez1.pdf The WiggleZ home page is at http://wigglez.swin.edu.au

Current challenges in software solutions for mass spectrometry-based quantitative proteomics

This work was in part supported by the PRIME-XS project, grant agreement number 262067, funded by the European Union seventh Framework Programme; The Netherlands Proteomics Centre, embedded in The Netherlands Genomics Initiative; The Netherlands Bioinformatics Centre; and the Centre for Biomedical Genetics (to S.C., B.B. and A.J.R.H); by NIH grants NCRR RR001614 and RR019934 (to the UCSF Mass Spectrometry Facility, director: A.L. Burlingame, P.B.); and by grants from the MRC, CR-UK, BBSRC and Barts and the London Charity (to P.C.

COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): statistical and economic analysis plan for a randomised controlled trial.

BACKGROUND: Dissociative seizures (DSs), also called psychogenic non-epileptic seizures, are a distressing and disabling problem for many patients in neurological settings with high and often unnecessary economic costs. The COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES) trial is an evaluation of a specifically tailored psychological intervention with the aims of reducing seizure frequency and severity and improving psychological well-being in adults with DS. The aim of this paper is to report in detail the quantitative and economic analysis plan for the CODES trial, as agreed by the trial steering committee. METHODS: The CODES trial is a multicentre, pragmatic, parallel group, randomised controlled trial performed to evaluate the clinical effectiveness and cost-effectiveness of 13 sessions of cognitive behavioural therapy (CBT) plus standardised medical care (SMC) compared with SMC alone for adult outpatients with DS. DISCUSSION: The objectives and design of the trial are summarised, and the aims and procedures of the planned analyses are illustrated. The proposed analysis plan addresses statistical considerations such as maintaining blinding, monitoring adherence with the protocol, describing aspects of treatment and dealing with missing data. The formal analysis approach for the primary and secondary outcomes is described, as are the descriptive statistics that will be reported. This paper provides transparency to the planned inferential analyses for the CODES trial prior to the extraction of outcome data. It also provides an update to the previously published trial protocol and guidance to those conducting similar trials. TRIAL REGISTRATION: ISRCTN registry ISRCTN05681227 (registered on 5 March 2014); ClinicalTrials.gov NCT02325544 (registered on 15 December 2014)

Star formation rates in luminous quasars at 2 <z< 3

We investigate the relation between star formation rates (M ˙ s M˙s ) and AGN properties in optically selected type 1 quasars at 2 < z < 3 using data from Herschel and the SDSS. We find that M ˙ s M˙s remains approximately constant with redshift, at 300 ± 100 M⊙ yr−1. Conversely, M ˙ s M˙s increases with AGN luminosity, up to a maximum of ∼ 600 M⊙ yr−1, and with C IV FWHM. In context with previous results, this is consistent with a relation between M ˙ s M˙s and black hole accretion rate (M ˙ bh M˙bh ) existing in only parts of the z−M ˙ s −M ˙ bh z−M˙s−M˙bh plane, dependent on the free gas fraction, the trigger for activity, and the processes that may quench star formation. The relations between M ˙ s M˙s and both AGN luminosity and C IV FWHM are consistent with star formation rates in quasars scaling with black hole mass, though we cannot rule out a separate relation with black hole accretion rate. Star formation rates are observed to decline with increasing C IV equivalent width. This decline can be partially explained via the Baldwin effect, but may have an additional contribution from one or more of three factors; Mi is not a linear tracer of L2500, the Baldwin effect changes form at high AGN luminosities, and high C IV EW values signpost a change in the relation between M ˙ s M˙s and M ˙ bh M˙bh . Finally, there is no strong relation between M ˙ s M˙s and Eddington ratio, or the asymmetry of the C IV line. The former suggests that star formation rates do not scale with how efficiently the black hole is accreting, while the latter is consistent with C IV asymmetries arising from orientation effects

Primed T Cell Responses to Chemokines Are Regulated by the Immunoglobulin-Like Molecule CD31

CD31, an immunoglobulin-like molecule expressed by leukocytes and endothelial cells, is thought to contribute to the physiological regulation T cell homeostasis due to the presence of two immunotyrosine-based inhibitory motifs in its cytoplasmic tail. Indeed, loss of CD31 expression leads to uncontrolled T cell-mediated inflammation in a variety of experimental models of disease and certain CD31 polymorphisms correlate with increased disease severity in human graft-versus-host disease and atherosclerosis. The molecular mechanisms underlying CD31-mediated regulation of T cell responses have not yet been clarified. We here show that CD31-mediated signals attenuate T cell chemokinesis both in vitro and in vivo. This effect selectively affects activated/memory T lymphocytes, in which CD31 is clustered on the cell membrane where it segregates to the leading edge. We provide evidence that this molecular segregation, which does not occur in naïve T lymphocytes, might lead to cis-CD31 engagement on the same membrane and subsequent interference with the chemokine-induced PI3K/Akt signalling pathway. We propose that CD31-mediated modulation of memory T cell chemokinesis is a key mechanism by which this molecule contributes to the homeostatic regulation of effector T cell immunity

First results from the DEAP-3600 dark matter search with argon at SNOLAB

This paper reports the first results of a direct dark matter search with the DEAP-3600 single-phase liquid argon (LAr) detector. The experiment was performed 2 km underground at SNOLAB (Sudbury, Canada) utilizing a large target mass, with the LAr target contained in a spherical acrylic vessel of 3600 kg capacity. The LAr is viewed by an array of PMTs, which would register scintillation light produced by rare nuclear recoil signals induced by dark matter particle scattering. An analysis of 4.44 live days (fidicial exposure of 9.87 tonne days) of data taken during the initial filling phase demonstrates the best electronic recoil rejection using pulse-shape discrimination in argon, with leakage <1.2X107 (90% C.L.) between 15 and 31 keVee. No candidate signal events are observed, which results in the leading limit on WIMP-nucleon spin-independent cross section on argon, <1.21044 cm2 for a 100 GeV/c2 WIMP mass (90% C.L.)

Design and construction of the DEAP-3600 dark matter detector

The Dark matter Experiment using Argon Pulse-shape discrimination (DEAP) has been designed for a direct detection search for particle dark matter using a single-phase liquid argon target. The projected cross section sensitivity for DEAP-3600 to the spin-independent scattering of Weakly Interacting Massive Particles (WIMPs) on nucleons is 10−46cm2 for a 100 GeV/c2 WIMP mass with a fiducial exposure of 3 tonne-years. This paper describes the physical properties and construction of the DEAP-3600 detector

Search for dark matter with a 231-day exposure of liquid argon using DEAP-3600 at SNOLAB

DEAP-3600 is a single-phase liquid argon (LAr) direct-detection dark matter experiment, operating 2 km underground at SNOLAB (Sudbury, Canada). The detector consists of 3279 kg of LAr contained in a spherical acrylic vessel. This paper reports on the analysis of a 758  tonne⋅day exposure taken over a period of 231 live-days during the first year of operation. No candidate signal events are observed in the WIMP-search region of interest, which results in the leading limit on the WIMP-nucleon spin-independent cross section on a LAr target of 3.9×10−45  cm2 (1.5×10−44  cm2) for a 100  GeV/c2 (1  TeV/c2) WIMP mass at 90% C.L. In addition to a detailed background model, this analysis demonstrates the best pulse-shape discrimination in LAr at threshold, employs a Bayesian photoelectron-counting technique to improve the energy resolution and discrimination efficiency, and utilizes two position reconstruction algorithms based on the charge and photon detection time distributions observed in each photomultiplier tube