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831.
Ahluwalia J Tinker A Clapp LH Duchen MR Abramov AY Pope S Nobles M Segal AW 《Nature》2004,427(6977):853-858
Neutrophil leukocytes have a pivotal function in innate immunity. Dogma dictates that the lethal blow is delivered to microbes by reactive oxygen species (ROS) and halogens, products of the NADPH oxidase, whose impairment causes immunodeficiency. However, recent evidence indicates that the microbes might be killed by proteases, activated by the oxidase through the generation of a hypertonic, K+-rich and alkaline environment in the phagocytic vacuole. Here we show that K+ crosses the membrane through large-conductance Ca2+-activated K+ (BK(Ca)) channels. Specific inhibitors of these channels, iberiotoxin and paxilline, blocked oxidase-induced 86Rb+ fluxes and alkalinization of the phagocytic vacuole, whereas NS1619, a BK(Ca) channel opener, enhanced both. Characteristic outwardly rectifying K+ currents, reversibly inhibited by iberiotoxin, were demonstrated in neutrophils and eosinophils and the expression of the alpha-subunit of the BK channel was confirmed by western blotting. The channels were opened by the combination of membrane depolarization and elevated Ca2+ concentration, both consequences of oxidase activity. Remarkably, microbial killing and digestion were abolished when the BK(Ca) channel was blocked, revealing an essential and unexpected function for this K+ channel in the microbicidal process. 相似文献
832.
Despite over a century of applying organic synthesis to the search for drugs, we are still far from even a cursory examination of the vast number of possible small molecules that could be created. Indeed, a thorough examination of all 'chemical space' is practically impossible. Given this, what are the best strategies for identifying small molecules that modulate biological targets? And how might such strategies differ, depending on whether the primary goal is to understand biological systems or to develop potential drugs? 相似文献
833.
834.
Predicting the consequences of species loss is critically important, given present threats to biological diversity such as habitat destruction, overharvesting and climate change. Several empirical studies have reported decreased ecosystem performance (for example, primary productivity) coincident with decreased biodiversity, although the relative influence of biotic effects and confounding abiotic factors has been vigorously debated. Whereas several investigations focused on single trophic levels (for example, grassland plants), studies of whole systems have revealed multiple layers of feedbacks, hidden drivers and emergent properties, making the consequences of species loss more difficult to predict. Here we report functionally important organisms and considerable biocomplexity in a sedimentary seafloor habitat, one of Earth's most widespread ecosystems. Experimental field measurements demonstrate how the abundance of spatangoid urchins--infaunal (in seafloor sediment) grazers/deposit feeders--is positively related to primary production, as their activities change nutrient fluxes and improve conditions for production by microphytobenthos (sedimentatry microbes and unicellular algae). Declines of spatangoid urchins after trawling are well documented, and our research linking these bioturbators to important benthic-pelagic fluxes highlights potential ramifications for productivity in coastal oceans. 相似文献
835.
Surface science is an important and well-established branch of materials science involving the study of changes in material properties near a surface or interface. A fundamental issue has been atomic reconstruction: how the surface lattice symmetry differs from the bulk. 'Correlated-electron compounds' are materials in which strong electron-electron and electron-lattice interactions produce new electronic phases, including interaction-induced (Mott) insulators, many forms of spin, charge and orbital ordering, and (presumably) high-transition-temperature superconductivity. Here we propose that the fundamental issue for the new field of correlated-electron surface/interface science is 'electronic reconstruction': how does the surface/interface electronic phase differ from that in the bulk? As a step towards a general understanding of such phenomena, we present a theoretical study of an interface between a strongly correlated Mott insulator and a band insulator. We find dramatic interface-induced electronic reconstructions: in wide parameter ranges, the near-interface region is metallic and ferromagnetic, whereas the bulk phase on either side is insulating and antiferromagnetic. Extending the analysis to a wider range of interfaces and surfaces is a fundamental scientific challenge and may lead to new applications for correlated electron materials. 相似文献
836.
Stephens P Hunter C Bignell G Edkins S Davies H Teague J Stevens C O'Meara S Smith R Parker A Barthorpe A Blow M Brackenbury L Butler A Clarke O Cole J Dicks E Dike A Drozd A Edwards K Forbes S Foster R Gray K Greenman C Halliday K Hills K Kosmidou V Lugg R Menzies A Perry J Petty R Raine K Ratford L Shepherd R Small A Stephens Y Tofts C Varian J West S Widaa S Yates A Brasseur F Cooper CS Flanagan AM Knowles M Leung SY Louis DN Looijenga LH Malkowicz B Pierotti MA Teh B Chenevix-Trench G 《Nature》2004,431(7008):525-526
The protein-kinase family is the most frequently mutated gene family found in human cancer and faulty kinase enzymes are being investigated as promising targets for the design of antitumour therapies. We have sequenced the gene encoding the transmembrane protein tyrosine kinase ERBB2 (also known as HER2 or Neu) from 120 primary lung tumours and identified 4% that have mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. ERBB2 inhibitors, which have so far proved to be ineffective in treating lung cancer, should now be clinically re-evaluated in the specific subset of patients with lung cancer whose tumours carry ERBB2 mutations. 相似文献
837.
Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR 总被引:5,自引:0,他引:5
838.
839.
Plzf is required in adult male germ cells for stem cell self-renewal 总被引:21,自引:0,他引:21
Buaas FW Kirsh AL Sharma M McLean DJ Morris JL Griswold MD de Rooij DG Braun RE 《Nature genetics》2004,36(6):647-652
840.