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71.
Nuclear protein import is mediated mainly by the transport factor importin-beta that binds cytoplasmic cargo, most often via the importin-alpha adaptor, and then transports it through nuclear pore complexes. This active transport is driven by disassembly of the import complex by nuclear RanGTP. The switch I and II loops of Ran change conformation with nucleotide state, and regulate its interactions with nuclear trafficking components. Importin-beta consists of 19 HEAT repeats that are based on a pair of antiparallel alpha-helices (referred to as the A- and B-helices). The HEAT repeats stack to yield two C-shaped arches, linked together to form a helicoidal molecule that has considerable conformational flexibility. Here we present the structure of full-length yeast importin-beta (Kap95p or karyopherin-beta) complexed with RanGTP, which provides a basis for understanding the crucial cargo-release step of nuclear import. We identify a key interaction site where the RanGTP switch I loop binds to the carboxy-terminal arch of Kap95p. This interaction produces a change in helicoidal pitch that locks Kap95p in a conformation that cannot bind importin-alpha or cargo. We suggest an allosteric mechanism for nuclear import complex disassembly by RanGTP. 相似文献
72.
Implications for prediction and hazard assessment from the 2004 Parkfield earthquake 总被引:5,自引:0,他引:5
Bakun WH Aagaard B Dost B Ellsworth WL Hardebeck JL Harris RA Ji C Johnston MJ Langbein J Lienkaemper JJ Michael AJ Murray JR Nadeau RM Reasenberg PA Reichle MS Roeloffs EA Shakal A Simpson RW Waldhauser F 《Nature》2005,437(7061):969-974
Obtaining high-quality measurements close to a large earthquake is not easy: one has to be in the right place at the right time with the right instruments. Such a convergence happened, for the first time, when the 28 September 2004 Parkfield, California, earthquake occurred on the San Andreas fault in the middle of a dense network of instruments designed to record it. The resulting data reveal aspects of the earthquake process never before seen. Here we show what these data, when combined with data from earlier Parkfield earthquakes, tell us about earthquake physics and earthquake prediction. The 2004 Parkfield earthquake, with its lack of obvious precursors, demonstrates that reliable short-term earthquake prediction still is not achievable. To reduce the societal impact of earthquakes now, we should focus on developing the next generation of models that can provide better predictions of the strength and location of damaging ground shaking. 相似文献
73.
Alpha-farnesene in the natural coating of apples 总被引:1,自引:0,他引:1
74.
Hepatitis B virus genes and their expression in E. coli. 总被引:66,自引:0,他引:66
M Pasek T Goto W Gilbert B Zink H Schaller P MacKay G Leadbetter K Murray 《Nature》1979,282(5739):575-579
A composite DNA sequence of regions of hepatitis B virus, determined from a series of recombinant plasmids, reveals the genes for the surface antigen and the core antigen of the virus. The sequence of the core antigen shows it to be a DNA binding protein. The core antigen gene is expressed in Escherichia coli and when injected into rabbits the bacterial product induces antibodies which react with core antigen isolated from human sources. 相似文献
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76.
Johannessen CM Boehm JS Kim SY Thomas SR Wardwell L Johnson LA Emery CM Stransky N Cogdill AP Barretina J Caponigro G Hieronymus H Murray RR Salehi-Ashtiani K Hill DE Vidal M Zhao JJ Yang X Alkan O Kim S Harris JL Wilson CJ Myer VE Finan PM Root DE Roberts TM Golub T Flaherty KT Dummer R Weber BL Sellers WR Schlegel R Wargo JA Hahn WC Garraway LA 《Nature》2010,468(7326):968-972
Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ~600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies. 相似文献
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Growing axons can be guided by a number of different cues: adhesive substrates, diffusible factors, electrical fields and even factors intrinsic to the neurone itself have all been shown to affect axon orientation and outgrowth in vitro. However, in most intact systems it has proved difficult to test directly the role played by these putative guidance cues. Here, we describe a system, the developing wing of the fruitfly, in which we have tested simultaneously two putative guidance mechanisms, physical constraints to axon growth (channels) and the position of neuronal somata (guideposts), using surgical techniques. We show that pioneer sensory axons can navigate correctly and form their normal stereotyped pattern of axon bundles in wing fragments that apparently lack both physical and neural cues. This technique allows access to the surface along which neuronal pathfinding takes place, making possible a wide range of experimental manipulations on the developing system. 相似文献
79.
M McDonald M Bayliss BA Benson RJ Foley J Ruel P Sullivan S Veilleux KA Aird ML Ashby M Bautz G Bazin LE Bleem M Brodwin JE Carlstrom CL Chang HM Cho A Clocchiatti TM Crawford AT Crites T de Haan S Desai MA Dobbs JP Dudley E Egami WR Forman GP Garmire EM George MD Gladders AH Gonzalez NW Halverson NL Harrington FW High GP Holder WL Holzapfel S Hoover JD Hrubes C Jones M Joy R Keisler L Knox AT Lee EM Leitch J Liu M Lueker D Luong-Van A Mantz DP Marrone JJ McMahon J Mehl SS Meyer ED Miller 《Nature》2012,488(7411):349-352
In the cores of some clusters of galaxies the hot intracluster plasma is dense enough that it should cool radiatively in the cluster's lifetime, leading to continuous 'cooling flows' of gas sinking towards the cluster centre, yet no such cooling flow has been observed. The low observed star-formation rates and cool gas masses for these 'cool-core' clusters suggest that much of the cooling must be offset by feedback to prevent the formation of a runaway cooling flow. Here we report X-ray, optical and infrared observations of the galaxy cluster SPT-CLJ2344-4243 (ref. 11) at redshift z = 0.596. These observations reveal an exceptionally luminous (8.2?×?10(45)?erg?s(-1)) galaxy cluster that hosts an extremely strong cooling flow (around 3,820 solar masses a year). Further, the central galaxy in this cluster appears to be experiencing a massive starburst (formation of around 740 solar masses a year), which suggests that the feedback source responsible for preventing runaway cooling in nearby cool-core clusters may not yet be fully established in SPT-CLJ2344-4243. This large star-formation rate implies that a significant fraction of the stars in the central galaxy of this cluster may form through accretion of the intracluster medium, rather than (as is currently thought) assembling entirely via mergers. 相似文献
80.