Crystal structure of the ligand-free G-protein-coupled receptor opsin

In the G-protein-coupled receptor (GPCR) rhodopsin, the inactivating ligand 11-cis-retinal is bound in the seven-transmembrane helix (TM) bundle and is cis/trans isomerized by light to form active metarhodopsin II. With metarhodopsin II decay, all-trans-retinal is released, and opsin is reloaded with new 11-cis-retinal. Here we present the crystal structure of ligand-free native opsin from bovine retinal rod cells at 2.9 ?ngstr?m (A) resolution. Compared to rhodopsin, opsin shows prominent structural changes in the conserved E(D)RY and NPxxY(x)(5,6)F regions and in TM5-TM7. At the cytoplasmic side, TM6 is tilted outwards by 6-7 A, whereas the helix structure of TM5 is more elongated and close to TM6. These structural changes, some of which were attributed to an active GPCR state, reorganize the empty retinal-binding pocket to disclose two openings that may serve the entry and exit of retinal. The opsin structure sheds new light on ligand binding to GPCRs and on GPCR activation.     

Tibetan plateau river incision inhibited by glacial stabilization of the Tsangpo gorge

A considerable amount of research has focused on how and when the Tibetan plateau formed in the wake of tectonic convergence between India and Asia. Although far less enquiry has addressed the controls on river incision into the plateau itself, widely accepted theory predicts that steep fluvial knick points (river reaches with very steep gradients) in the eastern Himalayan syntaxis at the southeastern plateau margin should erode rapidly, driving a wave of incision back into the plateau. Preservation of the plateau edge thus presents something of a conundrum that may be resolved by invoking either differential rock uplift matching erosional decay, or other mechanisms for retarding bedrock river incision in this region where high stream power excludes the potential for aridity as a simple limit to dissection of the plateau. Here we report morphologic evidence showing that Quaternary depression of the regional equilibrium line altitude, where long-term glacier mass gain equals mass loss, was sufficient to repeatedly form moraine dams on major rivers: such damming substantially impeded river incision into the southeastern edge of the Tibetan plateau through the coupled effects of upstream impoundment and interglacial aggradation. Such glacial stabilization of the resulting highly focused river incision centred on the Tsangpo gorge could further contribute to initiating and accentuating a locus of rapid exhumation, known as tectonic anaeurysm.     

Smart Cities and M<Superscript>3</Superscript>: Rapid Research,Meaningful Metrics and Co-Design

The research described in this paper is undertaken under the banner of the smart city, a concept that captures the way urban spaces are re-made by the incursion of new technology. Much of smart is centred on converting everyday activities into data, and using this data to generate knowledge mediated by technology. Ordinary citizens, those that may have their lives impacted by the technology, usually are not properly involved in the ‘smartification’ process. Their perceptions, concerns and expectations should inform the conception and development of smart technologies at the same extent. How to engage general public with smart cities research is the central challenge for the Making Metrics Meaningful (MMM) project. Applying a rapid participatory method, ‘Imagine’ over a five-month period (March – July) the research sought to gain insights from the general public into novel forms of information system innovation. This brief paper describes the nature of the accelerated research undertaken and explores some of the themes which emerged in the analysis. Generic themes, beyond the remit of an explicit transport focus, are developed and pointers towards further research directions are discussed. Participatory methods, including engaging with self-selected transport users actively through both picture creation and programmatically specific musical ‘signatures’ as well as group discussion, were found to be effective in eliciting users’ own concerns, needs and ideas for novel information systems.     

Standards of evidence and causality in regulatory science: Risk and benefit assessment

In this paper we analyze the Russo-Williamson Thesis (RWT) as a standard of evidence in regulatory science, in risk as well as benefit assessment. In our analysis we take account of the recent controversies that have taken place in regulation with respect to the evidentiary requirements necessary for regulatory decision making. RWT's main point is that not only probabilistic but also mechanistic evidence is necessary for being able to infer the existence of causal links. We ask in which way RWT could have an impact upon current decision making about subjecting to regulation (or, to the contrary, leaving them unregulated) certain chemical substances, food stuffs, health claims, and other typical objects of regulation. We show that the application of RWT resolves some of the problems posed by current standards of evidence. RWT makes it possible to determine with higher accuracy if a particular substance should be subjected to regulation or not, even though under certain circumstances RWT itself may turn into a source of regulatory error. The adequacy of RWT as a standard of evidence depends on the precise manner of its application to regulation (particularly the consideration of mechanistic evidence as a complementary or necessary requirement), as well as the assessment of its non-epistemic consequences.     

Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations

Sulindac is a non-selective inhibitor of cyclooxygenases (COX) used to treat inflammation and pain. Additionally, non-COX targets may account for the drug’s chemo-preventive efficacy against colorectal cancer and reduced gastrointestinal toxicity. Here, we demonstrate that the pharmacologically active metabolite of sulindac, sulindac sulfide (SSi), targets 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of proinflammatory leukotrienes (LTs). SSi inhibited 5-LO in ionophore A23187- and LPS/fMLP-stimulated human polymorphonuclear leukocytes (IC₅₀ ≈ 8–10 μM). Importantly, SSi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC₅₀ = 18.7 μM). SSi was 5-LO-selective as no inhibition of related lipoxygenases (12-LO, 15-LO) was observed. The sulindac prodrug and the other metabolite, sulindac sulfone (SSo), failed to inhibit 5-LO. Mechanistic analysis demonstrated that SSi directly suppresses 5-LO with an IC₅₀ of 20 μM. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy.     

Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome

ARC syndrome (OMIM 208085) is an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity. Platelet dysfunction is common. Affected infants do not thrive and usually die in the first year of life. To elucidate the molecular basis of ARC, we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC. VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion.     

Discovery of five irregular moons of Neptune

Each giant planet of the Solar System has two main types of moons. 'Regular' moons are typically larger satellites with prograde, nearly circular orbits in the equatorial plane of their host planets at distances of several to tens of planetary radii. The 'irregular' satellites (which are typically smaller) have larger orbits with significant eccentricities and inclinations. Despite these common features, Neptune's irregular satellite system, hitherto thought to consist of Triton and Nereid, has appeared unusual. Triton is as large as Pluto and is postulated to have been captured from heliocentric orbit; it traces a circular but retrograde orbit at 14 planetary radii from Neptune. Nereid, which exhibits one of the largest satellite eccentricities, is believed to have been scattered from a regular satellite orbit to its present orbit during Triton's capture. Here we report the discovery of five irregular moons of Neptune, two with prograde and three with retrograde orbits. These exceedingly faint (apparent red magnitude m(R) = 24.2-25.4) moons, with diameters of 30 to 50 km, were presumably captured by Neptune.