Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese

We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10(-4)) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10(-10); FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10(-8)) and 3p11.2 (rs2055109; P = 3.94 × 10(-8)). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10(-7)). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations.     

No supernovae associated with two long-duration gamma-ray bursts

It is now accepted that long-duration gamma-ray bursts (GRBs) are produced during the collapse of a massive star. The standard 'collapsar' model predicts that a broad-lined and luminous type Ic core-collapse supernova accompanies every long-duration GRB. This association has been confirmed in observations of several nearby GRBs. Here we report that GRB 060505 (ref. 10) and GRB 060614 (ref. 11) were not accompanied by supernova emission down to limits hundreds of times fainter than the archetypal supernova SN 1998bw that accompanied GRB 980425, and fainter than any type Ic supernova ever observed. Multi-band observations of the early afterglows, as well as spectroscopy of the host galaxies, exclude the possibility of significant dust obscuration and show that the bursts originated in actively star-forming regions. The absence of a supernova to such deep limits is qualitatively different from all previous nearby long-duration GRBs and suggests a new phenomenological type of massive stellar death.     

Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10?1? and P = 4.1 × 10??, respectively).     

Crystal structure of the µ-opioid receptor bound to a morphinan antagonist

Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled μ-opioid receptor (μ-OR) in the central nervous system. Here we describe the 2.8?? crystal structure of the mouse μ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the μ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.     

Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.     

A volcanic environment for bedrock diagenesis at Meridiani Planum on Mars

Exposed bedrocks at Meridiani Planum on Mars display chemical and mineralogical evidence suggesting interaction with liquid water. On the basis of morphological observations as well as high abundances of haematite and sulphate minerals, the rocks have been interpreted as sediments that were deposited in a shallow body of briny water with subsequent evaporation leaving behind the sulphate minerals. The iron-sulphur mineralization at Meridiani has also been inferred to be analogous to that produced during oxidative weathering of metal sulphide minerals, such as occurs at acid mine drainage sites. Neither of these interpretations, however, is consistent with the chemical composition of the rocks. Here we propose an alternative model for diagenesis of Meridiani bedrock that involves deposition of volcanic ash followed by reaction with condensed sulphur dioxide- and water-bearing vapours emitted from fumaroles. This scenario does not require prolonged interaction with a standing body of surface water and may have occurred at high temperatures. Consequently, the model invokes an environment considerably less favourable for biological activity on Mars than previously proposed interpretations.     

The Application of Critical Systems Thinking to Enhance the Effectiveness of a University Information System

Faced with the common problem of dissatisfaction with the outcome of investments in information systems (IS), the IS community has long sought ways to improve information systems development (ISD). This paper reports on action research (AR) that sought to improve the effectiveness a UK university’s student record system (SRS), which had exhibited persistent problems. Critical systems thinking (CST) is seen to have value for ISD and was used to guide the AR. In the first stage of this research, the issues with the initial design of the SRS were identified to have largely resulted from insufficient elicitation of the underlying assumptions about, and perspectives on, complex organisational issues. The second stage centred on examining the situation from an “ought” perspective analysing what should be done and how, in order to develop creative solutions to the problems uncovered. The third stage involved recommending solutions to address the problems identified in order to improve the effectiveness of the SRS. Overall, the AR indicates that CST enables those involved to view the design and implementation of the SRS as a holistic system, critically reflect upon broad and complex human, technological and organisational issues from different perspectives, and thereby identify creative solutions. The main contribution of this research is in generating support for an ISD intervention guided by CST. The results of, and the understanding developed from, this intervention are likely to be relevant to the problems that frequently occur in similar situations.     

A Theoretical Framework for Facilitating Methodological Choice

Total Systems Intervention, in a recent version, facilitates the intervention process via three modes: problem solving, critical reflection, and critical review. Of these modes, there has been relatively little attention paid to the critical review mode, the purpose of which is to assess the value of different methodologies within a given problem situation. This paper takes as its basis the only major work in this area and seeks to build on this in order to improve the mixing of methodologies within a single intervention.