排序方式: 共有283条查询结果,搜索用时 31 毫秒
51.
Earth science: the rise and growth of Tibet 总被引:1,自引:0,他引:1
52.
Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the neuroparalytic syndrome of botulism. With a lethal dose of 1 ng kg(-1), they pose a biological hazard to humans and a serious potential bioweapon threat. BoNTs bind with high specificity at neuromuscular junctions and they impair exocytosis of synaptic vesicles containing acetylcholine through specific proteolysis of SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors), which constitute part of the synaptic vesicle fusion machinery. The molecular details of the toxin-cell recognition have been elusive. Here we report the structure of a BoNT in complex with its protein receptor: the receptor-binding domain of botulinum neurotoxin serotype B (BoNT/B) bound to the luminal domain of synaptotagmin II, determined at 2.15 A resolution. On binding, a helix is induced in the luminal domain which binds to a saddle-shaped crevice on a distal tip of BoNT/B. This crevice is adjacent to the non-overlapping ganglioside-binding site of BoNT/B. Synaptotagmin II interacts with BoNT/B with nanomolar affinity, at both neutral and acidic endosomal pH. Biochemical and neuronal ex vivo studies of structure-based mutations indicate high specificity and affinity of the interaction, and high selectivity of BoNT/B among synaptotagmin I and II isoforms. Synergistic binding of both synaptotagmin and ganglioside imposes geometric restrictions on the initiation of BoNT/B translocation after endocytosis. Our results provide the basis for the rational development of preventive vaccines or inhibitors against these neurotoxins. 相似文献
53.
Environmental and genetic aberrations lead to neural tube closure defects (NTDs) in 1 out of every 1,000 births. Mouse and frog models for these birth defects have indicated that Van Gogh-like 2 (Vangl2, also known as Strabismus) and other components of planar cell polarity (PCP) signalling might control neurulation by promoting the convergence of neural progenitors to the midline. Here we show a novel role for PCP signalling during neurulation in zebrafish. We demonstrate that non-canonical Wnt/PCP signalling polarizes neural progenitors along the anteroposterior axis. This polarity is transiently lost during cell division in the neural keel but is re-established as daughter cells reintegrate into the neuroepithelium. Loss of zebrafish Vangl2 (in trilobite mutants) abolishes the polarization of neural keel cells, disrupts re-intercalation of daughter cells into the neuroepithelium, and results in ectopic neural progenitor accumulations and NTDs. Remarkably, blocking cell division leads to rescue of trilobite neural tube morphogenesis despite persistent defects in convergence and extension. These results reveal a function for PCP signalling in coupling cell division and morphogenesis at neurulation and indicate a previously unrecognized mechanism that might underlie NTDs. 相似文献
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Androutsellis-Theotokis A Leker RR Soldner F Hoeppner DJ Ravin R Poser SW Rueger MA Bae SK Kittappa R McKay RD 《Nature》2006,442(7104):823-826
56.
Fracture behavior and microstructure analysis of Al2O3–MgO–CaO castables for steel-ladle purging plugs
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Three different castables based on the Al2O3–MgO–CaO system were prepared as steel-ladle purging plug refractories: corundum- based low-cement castable (C-LCC), corundum-spinel-based low-cement castable (C-S-LCC), and corundum-spinel no-cement castable (C-S-NCC) (hydratable alumina (ρ-Al2O3) bonded). The fracture behavior at room temperature was tested by the method of “wedge-splitting” on samples pre-fired at different temperatures; the specific fracture energy G′f and notched tensile strength σNT were obtained from these tests. In addition, the Young’s modulus E was measured by the method of resonance frequency of damping analysis (RFDA). The thermal stress resistance parameter R′′′′ calculated using the values of G′f, σNT, and E was used to evaluate the thermal shock resistance of the materials. According to the microstructure analysis results, the sintering effect and the bonding type of the matrix material were different among these three castables, which explains their different fracture behaviors. 相似文献
57.
Sven Herrmann Katharina T. Huber Vincent Moulton Andreas Spillner 《Journal of Classification》2012,29(3):321-340
A k-dissimilarity D on a finite set X, |X|????k, is a map from the set of size k subsets of X to the real numbers. Such maps naturally arise from edgeweighted trees T with leaf-set X: Given a subset Y of X of size k, D(Y ) is defined to be the total length of the smallest subtree of T with leaf-set Y . In case k?=?2, it is well-known that 2-dissimilarities arising in this way can be characterized by the so-called ??4-point condition??. However, in case k?>?2 Pachter and Speyer (2004) recently posed the following question: Given an arbitrary k-dissimilarity, how do we test whether this map comes from a tree? In this paper, we provide an answer to this question, showing that for k????3 a k-dissimilarity on a set X arises from a tree if and only if its restriction to every 2?k-element subset of X arises from some tree, and that 2?k is the least possible subset size to ensure that this is the case. As a corollary, we show that there exists a polynomial-time algorithm to determine when a k-dissimilarity arises from a tree. We also give a 6-point condition for determining when a 3-dissimilarity arises from a tree, that is similar to the aforementioned 4-point condition. 相似文献
58.
Knabl J Witschi R Hösl K Reinold H Zeilhofer UB Ahmadi S Brockhaus J Sergejeva M Hess A Brune K Fritschy JM Rudolph U Möhler H Zeilhofer HU 《Nature》2008,451(7176):330-334
Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics. 相似文献
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Proteome survey reveals modularity of the yeast cell machinery 总被引:4,自引:0,他引:4
Gavin AC Aloy P Grandi P Krause R Boesche M Marzioch M Rau C Jensen LJ Bastuck S Dümpelfeld B Edelmann A Heurtier MA Hoffman V Hoefert C Klein K Hudak M Michon AM Schelder M Schirle M Remor M Rudi T Hooper S Bauer A Bouwmeester T Casari G Drewes G Neubauer G Rick JM Kuster B Bork P Russell RB Superti-Furga G 《Nature》2006,440(7084):631-636
Protein complexes are key molecular entities that integrate multiple gene products to perform cellular functions. Here we report the first genome-wide screen for complexes in an organism, budding yeast, using affinity purification and mass spectrometry. Through systematic tagging of open reading frames (ORFs), the majority of complexes were purified several times, suggesting screen saturation. The richness of the data set enabled a de novo characterization of the composition and organization of the cellular machinery. The ensemble of cellular proteins partitions into 491 complexes, of which 257 are novel, that differentially combine with additional attachment proteins or protein modules to enable a diversification of potential functions. Support for this modular organization of the proteome comes from integration with available data on expression, localization, function, evolutionary conservation, protein structure and binary interactions. This study provides the largest collection of physically determined eukaryotic cellular machines so far and a platform for biological data integration and modelling. 相似文献