Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10?? and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.     

The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.     

On the elimination of chlorprothixene in rat and man

Zusammenfassung Die Ausscheidung des neuen Neuroleptikums, Chlorprothixen, bei Menschen und Ratten wurde in Urin, Galle und Faeces untersucht und als einziges Abbauprodukt Chlorprothixen-Sulfoxyd gefunden. Ausscheidungsprodukte in % der verabreichten Dosis: Beim Menschen (orale Verabreichung) im Urin: 5–29% Sulfoxyd, Faeces: 0–41% unveränderter Stoff + Sulfoxyd. Bei der Ratte (orale oder parenterale Verabreichung) im Urin: bis zu 5% Sulfoxyd, Faeces: 1–7% Sulfoxyd, keine unveränderte Substanz, Galle: bis zu 24% Sulfoxyd.     

Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate

The second messenger hydrogen peroxide is required for optimal activation of numerous signal transduction pathways, particularly those mediated by protein tyrosine kinases. One mechanism by which hydrogen peroxide regulates cellular processes is the transient inhibition of protein tyrosine phosphatases through the reversible oxidization of their catalytic cysteine, which suppresses protein dephosphorylation. Here we describe a structural analysis of the redox-dependent regulation of protein tyrosine phosphatase 1B (PTP1B), which is reversibly inhibited by oxidation after cells are stimulated with insulin and epidermal growth factor. The sulphenic acid intermediate produced in response to PTP1B oxidation is rapidly converted into a previously unknown sulphenyl-amide species, in which the sulphur atom of the catalytic cysteine is covalently linked to the main chain nitrogen of an adjacent residue. Oxidation of PTP1B to the sulphenyl-amide form is accompanied by large conformational changes in the catalytic site that inhibit substrate binding. We propose that this unusual protein modification both protects the active-site cysteine residue of PTP1B from irreversible oxidation to sulphonic acid and permits redox regulation of the enzyme by promoting its reversible reduction by thiols.     

A very energetic supernova associated with the gamma-ray burst of 29 March 2003

Over the past five years evidence has mounted that long-duration (>2 s) gamma-ray bursts (GRBs)-the most luminous of all astronomical explosions-signal the collapse of massive stars in our Universe. This evidence was originally based on the probable association of one unusual GRB with a supernova, but now includes the association of GRBs with regions of massive star formation in distant galaxies, the appearance of supernova-like 'bumps' in the optical afterglow light curves of several bursts and lines of freshly synthesized elements in the spectra of a few X-ray afterglows. These observations support, but do not yet conclusively demonstrate, the idea that long-duration GRBs are associated with the deaths of massive stars, presumably arising from core collapse. Here we report evidence that a very energetic supernova (a hypernova) was temporally and spatially coincident with a GRB at redshift z = 0.1685. The timing of the supernova indicates that it exploded within a few days of the GRB, strongly suggesting that core-collapse events can give rise to GRBs, thereby favouring the 'collapsar' model.     

Esterase activity of leucocyte proteins and their labelling with radioactive diisopropylfluorophosphate

Résumé Après électrophorèse en gélose des protéines extraites de leucocytes humains, l'activité estérasique des fractions fut comparée à leur affinité pour DFP³². Les deux méthodes montraient trois fractions actives, tant en leucocytes normaux qu'en leucocytes de leucémie myéloïde.     

A back-propagation programmed network that simulates response properties of a subset of posterior parietal neurons

Neurons in area 7a of the posterior parietal cortex of monkeys respond to both the retinal location of a visual stimulus and the position of the eyes and by combining these signals represent the spatial location of external objects. A neural network model, programmed using back-propagation learning, can decode this spatial information from area 7a neurons and accounts for their observed response properties.