Mantle updrafts and mechanisms of oceanic volcanism.

Convection in an isolated planet is characterized by narrow downwellings and broad updrafts--consequences of Archimedes' principle, the cooling required by the second law of thermodynamics, and the effect of compression on material properties. A mature cooling planet with a conductive low-viscosity core develops a thick insulating surface boundary layer with a thermal maximum, a subadiabatic interior, and a cooling highly conductive but thin boundary layer above the core. Parts of the surface layer sink into the interior, displacing older, colder material, which is entrained by spreading ridges. Magma characteristics of intraplate volcanoes are derived from within the upper boundary layer. Upper mantle features revealed by seismic tomography and that are apparently related to surface volcanoes are intrinsically broad and are not due to unresolved narrow jets. Their morphology, aspect ratio, inferred ascent rate, and temperature show that they are passively responding to downward fluxes, as appropriate for a cooling planet that is losing more heat through its surface than is being provided from its core or from radioactive heating. Response to doward flux is the inverse of the heat-pipe/mantle-plume mode of planetary cooling. Shear-driven melt extraction from the surface boundary layer explains volcanic provinces such as Yellowstone, Hawaii, and Samoa. Passive upwellings from deeper in the upper mantle feed ridges and near-ridge hotspots, and others interact with the sheared and metasomatized surface layer. Normal plate tectonic processes are responsible both for plate boundary and intraplate swells and volcanism.

Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes.

The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.

Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile.

We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).

Evidence for mantle plumes?

Geophysical hotspots have been attributed to partially molten asthenosphere, fertile blobs, small-scale convection and upwellings driven by core heat. Most are short-lived or too close together to be deeply seated, and do not have anomalous heat flow or temperature; many are related to tectonic features. Bourdon et al. investigate the dynamics of mantle plumes from uranium-series geochemistry and interpret their results as evidence for thermal plumes. Here we show why alternative mechanisms of upwelling and melting should be considered.