Structural insights into RNA processing by the human RISC-loading complex.

Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

The Coyote-Proof Pasture Experiment

Few scientific experiments have influenced more land than one conducted in the Wallowa Mountains of eastern Oregon by the US Department of Agriculture’s Bureau of Plant Industry and US Forest Service in 1907–1909. Four square miles of land were enclosed with a “coyote-proof fence,” guarded by a hunter, and stocked with an untended band of sheep. Data were collected on vegetation and sheep performance inside and outside the fence, and two years later success was declared. By 1910, the Forest Service had wrested range research from the Bureau of Plant Industry, subordinating the emerging field to timber production and fire suppression for decades to come. The young scientist who conducted the experiment, James Jardine, was promoted to Inspector of Grazing for the fledgling Forest Service, while his Wallowa collaborator, Arthur Sampson, went on to become “the father” of range science. The model of range management that they pioneered was applied across the US West and, later, on many rangelands in the developing world. Fencing and predator control are now generally viewed as unrelated management practices, but in the Forest Service model they were intimately connected. A critical physical geography of the Wallowa experiment reveals that the institutional context in which it occurred was more important than the findings themselves, and that although the results appeared to be scientifically rigorous and ecological, the methods were weak and the real criteria for “success” were economic. The high costs of fencing could be justified only if they were offset by a reduction in labor costs for herders. But without herders to guard the livestock, predators would have to be eliminated. Enormous public subsidies were required to implement the model, which continues to affect rangelands around the world

Slicer and the Argonautes

Though they started out as somewhat mysterious components of the RNAi effector complexes, Argonaute proteins have since taken center stage in RNAi gene silencing. They interact with small RNAs to effect gene silencing in all RNAi-related pathways known so far. We will review the dramatic advances in our understanding of the role of the Argonautes in RNAi through studies of their structure and function