Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase

Cysteinyl leukotrienes are key mediators in inflammation and have an important role in acute and chronic inflammatory diseases of the cardiovascular and respiratory systems, in particular bronchial asthma. In the biosynthesis of cysteinyl leukotrienes, conversion of arachidonic acid forms the unstable epoxide leukotriene A4 (LTA4). This intermediate is conjugated with glutathione (GSH) to produce leukotriene C4 (LTC4) in a reaction catalysed by LTC4 synthase: this reaction is the key step in cysteinyl leukotriene formation. Here we present the crystal structure of the human LTC4 synthase in its apo and GSH-complexed forms to 2.00 and 2.15 A resolution, respectively. The structure reveals a homotrimer, where each monomer is composed of four transmembrane segments. The structure of the enzyme in complex with substrate reveals that the active site enforces a horseshoe-shaped conformation on GSH, and effectively positions the thiol group for activation by a nearby arginine at the membrane-enzyme interface. In addition, the structure provides a model for how the omega-end of the lipophilic co-substrate is pinned at one end of a hydrophobic cleft, providing a molecular 'ruler' to align the reactive epoxide at the thiol of glutathione. This provides new structural insights into the mechanism of LTC4 formation, and also suggests that the observed binding and activation of GSH might be common for a family of homologous proteins important for inflammatory and detoxification responses.     

The sources of sodium escaping from Io revealed by spectral high definition imaging

On Jupiter's moon Io, volcanic plumes and evaporating lava flows provide hot gases to form an atmosphere that is subsequently ionized. Some of Io's plasma is captured by the planet's strong magnetic field to form a co-rotating torus at Io's distance; the remaining ions and electrons form Io's ionosphere. The torus and ionosphere are also depleted by three time-variable processes that produce a banana-shaped cloud orbiting with Io, a giant nebula extending out to about 500 Jupiter radii, and a jet close to Io. No spatial constraints exist for the sources of the first two; they have been inferred only from modelling the patterns seen in the trace gas sodium observed far from Io. Here we report observations that reveal a spatially confined stream that ejects sodium only from the wake of the Io-torus interaction, together with a visually distinct, spherically symmetrical outflow region arising from atmospheric sputtering. The spatial extent of the ionospheric wake that feeds the stream is more than twice that observed by the Galileo spacecraft and modelled successfully. This implies considerable variability, and therefore the need for additional modelling of volcanically-driven, episodic states of the great jovian nebula.     

Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon

Self-renewal and differentiation are cardinal features of stem cells. Asymmetric cell division provides one fundamental mechanism by which stem cell self-renewal and differentiation are balanced. A failure of this balance could lead to diseases such as cancer. During asymmetric division of stem cells, factors controlling their self-renewal and differentiation are unequally segregated between daughter cells. Numb is one such factor that is segregated to the differentiating daughter cell during the stem-cell-like neuroblast divisions in Drosophila melanogaster, where it inhibits self-renewal. The localization and function of Numb is cell-cycle-dependent. Here we show that Polo (ref. 13), a key cell cycle regulator, the mammalian counterparts of which have been implicated as oncogenes as well as tumour suppressors, acts as a tumour suppressor in the larval brain. Supernumerary neuroblasts are produced at the expense of neurons in polo mutants. Polo directly phosphorylates Partner of Numb (Pon, ref. 16), an adaptor protein for Numb, and this phosphorylation event is important for Pon to localize Numb. In polo mutants, the asymmetric localization of Pon, Numb and atypical protein kinase C are disrupted, whereas other polarity markers are largely unaffected. Overexpression of Numb suppresses neuroblast overproliferation caused by polo mutations, suggesting that Numb has a major role in mediating this effect of Polo. Our results reveal a biochemical link between the cell cycle and the asymmetric protein localization machinery, and indicate that Polo can inhibit progenitor self-renewal by regulating the localization and function of Numb.     

A link between large mantle melting events and continent growth seen in osmium isotopes

Although Earth's continental crust is thought to have been derived from the mantle, the timing and mode of crust formation have proven to be elusive issues. The area of preserved crust diminishes markedly with age, and this can be interpreted as being the result of either the progressive accumulation of new crust or the tectonic recycling of old crust. However, there is a disproportionate amount of crust of certain ages, with the main peaks being 1.2, 1.9, 2.7 and 3.3 billion years old; this has led to a third model in which the crust has grown through time in pulses, although peaks in continental crust ages could also record preferential preservation. The 187Re-187Os decay system is unique in its ability to track melt depletion events within the mantle and could therefore potentially link the crust and mantle differentiation records. Here we employ a laser ablation technique to analyse large numbers of osmium alloy grains to quantify the distribution of depletion ages in the Earth's upper mantle. Statistical analysis of these data, combined with other samples of the upper mantle, show that depletion ages are not evenly distributed but cluster in distinct periods, around 1.2, 1.9 and 2.7 billion years. These mantle depletion events coincide with peaks in the generation of continental crust and so provide evidence of coupled, global and pulsed mantle-crust differentiation, lending strong support to pulsed models of continental growth by means of large-scale mantle melting events.     

14种高原植物抑制植物病原菌活性的初步研究

采用生长速率法检测了11科14种高原植物的乙醇提取物对6种植物病原真茵的抑制活性.实验结果显示,在样品的作用浓度为1 mg/mL时,香青、铁线莲、露蕊乌头的乙醇提取物对苹果腐烂病原茵有明显的抑制作用,抑制率分别为77.10%、68.14%、67.53%;香青、露蕊乌头、金露梅、木鳖子对苹果炭疽病原茵也有值得关注的抑制作...     

Cryptic genetic variation promotes rapid evolutionary adaptation in an RNA enzyme

Cryptic variation is caused by the robustness of phenotypes to mutations. Cryptic variation has no effect on phenotypes in a given genetic or environmental background, but it can have effects after mutations or environmental change. Because evolutionary adaptation by natural selection requires phenotypic variation, phenotypically revealed cryptic genetic variation may facilitate evolutionary adaptation. This is possible if the cryptic variation happens to be pre-adapted, or "exapted", to a new environment, and is thus advantageous once revealed. However, this facilitating role for cryptic variation has not been proven, partly because most pertinent work focuses on complex phenotypes of whole organisms whose genetic basis is incompletely understood. Here we show that populations of RNA enzymes with accumulated cryptic variation adapt more rapidly to a new substrate than a population without cryptic variation. A detailed analysis of our evolving RNA populations in genotype space shows that cryptic variation allows a population to explore new genotypes that become adaptive only in a new environment. Our observations show that cryptic variation contains new genotypes pre-adapted to a changed environment. Our results highlight the positive role that robustness and epistasis can have in adaptive evolution.     

A dynamic early East Antarctic Ice Sheet suggested by ice-covered fjord landscapes

The first Cenozoic ice sheets initiated in Antarctica from the Gamburtsev Subglacial Mountains and other highlands as a result of rapid global cooling ～34 million years ago. In the subsequent 20 million years, at a time of declining atmospheric carbon dioxide concentrations and an evolving Antarctic circumpolar current, sedimentary sequence interpretation and numerical modelling suggest that cyclical periods of ice-sheet expansion to the continental margin, followed by retreat to the subglacial highlands, occurred up to thirty times. These fluctuations were paced by orbital changes and were a major influence on global sea levels. Ice-sheet models show that the nature of such oscillations is critically dependent on the pattern and extent of Antarctic topographic lowlands. Here we show that the basal topography of the Aurora Subglacial Basin of East Antarctica, at present overlain by 2-4.5?km of ice, is characterized by a series of well-defined topographic channels within a mountain block landscape. The identification of this fjord landscape, based on new data from ice-penetrating radar, provides an improved understanding of the topography of the Aurora Subglacial Basin and its surroundings, and reveals a complex surface sculpted by a succession of ice-sheet configurations substantially different from today's. At different stages during its fluctuations, the edge of the East Antarctic Ice Sheet lay pinned along the margins of the Aurora Subglacial Basin, the upland boundaries of which are currently above sea level and the deepest parts of which are more than 1?km below sea level. Although the timing of the channel incision remains uncertain, our results suggest that the fjord landscape was carved by at least two iceflow regimes of different scales and directions, each of which would have over-deepened existing topographic depressions, reversing valley floor slopes.