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排序方式: 共有451条查询结果,搜索用时 15 毫秒
91.
2020 computing: science in an exponential world 总被引:2,自引:0,他引:2
92.
Pepys MB Hirschfield GM Tennent GA Gallimore JR Kahan MC Bellotti V Hawkins PN Myers RM Smith MD Polara A Cobb AJ Ley SV Aquilina JA Robinson CV Sharif I Gray GA Sabin CA Jenvey MC Kolstoe SE Thompson D Wood SP 《Nature》2006,440(7088):1217-1221
Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury. 相似文献
93.
Amber provides an effective medium for conservation of soft-bodied microorganisms, but finds older than 135 million years are very rare and have not so far contained any microbial inclusions. Here we describe 220-million-year-old droplets of amber containing bacteria, fungi, algae and protozoans that are assignable to extant genera. These inclusions provide insight into the evolution and palaeoecology of Lower Mesozoic microorganisms: it seems that the basal levels of food webs of terrestrial communities (biocoenoses) have undergone little or no morphological change from the Triassic to the Recent. 相似文献
94.
Alexander P.M. van den Bosch 《Foundations of Science》1999,4(4):483-495
How can new drug lead suggestions beinferred from neurophysiological models? This paperaddresses this question based on a case study ofresearch into Parkinson's disease at the GroningenUniversity Department of Pharmacy. It is argued thatneurophysiological box-and-arrow models can beunderstood as qualitative differential equationmodels. An inference task is defined to helpunderstand and possibly aid the discovery andexplanation of new drug lead suggestions. 相似文献
95.
Primitive chondritic meteorites contain material (presolar grains), at the level of a few parts per million, that predates the formation of our Solar System. Astronomical observations and the chemical composition of the Sun both suggest that silicates must have been the dominant solids in the protoplanetary disk from which the planets of the Solar System formed, but no presolar silicates have been identified in chondrites. Here we report the in situ discovery of presolar silicate grains 0.1-1 microm in size in the matrices of two primitive carbonaceous chondrites. These grains are highly enriched in 17O (delta17O(SMOW) > 100-400 per thousand ), but have solar silicon isotopic compositions within analytical uncertainties, suggesting an origin in an oxygen-rich red giant or an asymptotic giant branch star. The estimated abundance of these presolar silicates (3-30 parts per million) is higher than reported for other types of presolar grains in meteorites, consistent with their ubiquity in the early Solar System, but is about two orders of magnitude lower than their abundance in anhydrous interplanetary dust particles. This result is best explained by the destruction of silicates during high-temperature processing in the solar nebula. 相似文献
96.
97.
Shachaf CM Kopelman AM Arvanitis C Karlsson A Beer S Mandl S Bachmann MH Borowsky AD Ruebner B Cardiff RD Yang Q Bishop JM Contag CH Felsher DW 《Nature》2004,431(7012):1112-1117
Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy. 相似文献
98.
Clathrin-coated pits invaginate from specific membrane compartments and pinch off as coated vesicles. These vesicles then uncoat rapidly once released. The Hsc70 molecular chaperone effects the uncoating reaction, and is guided to appropriate locations on clathrin lattices by the J-domain-containing co-chaperone molecule auxilin. This raises the question of how a local event such as ATP hydrolysis by Hsc70 can catalyse a global disassembly. Here, we have used electron cryomicroscopy to determine 12-A-resolution structures of in-vitro-assembled clathrin coats in association with a carboxy-terminal fragment of auxilin that contains both the clathrin-binding region and the J domain. We have located the auxilin fragment by computing differences between these structures and those lacking auxilin (described in an accompanying paper). Auxilin binds within the clathrin lattice near contacts between an inward-projecting C-terminal helical tripod and the crossing of two 'ankle' segments; it also contacts the terminal domain of yet another clathrin 'leg'. It therefore recruits Hsc70 to the neighbourhood of a set of critical interactions. Auxilin binding produces a local change in heavy-chain contacts, creating a detectable global distortion of the clathrin coat. We propose a mechanism by which local destabilization of the lattice promotes general uncoating. 相似文献
99.
100.
Structure of the ESCRT-II endosomal trafficking complex 总被引:1,自引:0,他引:1
The multivesicular-body (MVB) pathway delivers transmembrane proteins and lipids to the lumen of the endosome. The multivesicular-body sorting pathway has crucial roles in growth-factor-receptor downregulation, developmental signalling, regulation of the immune response and the budding of certain enveloped viruses such as human immunodeficiency virus. Ubiquitination is a signal for sorting into the MVB pathway, which also requires the functions of three protein complexes, termed ESCRT-I, -II and -III (endosomal sorting complex required for transport). Here we report the crystal structure of the core of the yeast ESCRT-II complex, which contains one molecule of the Vps protein Vps22, the carboxy-terminal domain of Vps36 and two molecules of Vps25, and has the shape of a capital letter 'Y'. The amino-terminal coiled coil of Vps22 and the flexible linker leading to the ubiquitin-binding NZF domain of Vps36 both protrude from the tip of one branch of the 'Y'. Vps22 and Vps36 form nearly equivalent interactions with the two Vps25 molecules at the centre of the 'Y'. The structure suggests how ubiquitinated cargo could be passed between ESCRT components of the MVB pathway through the sequential transfer of ubiquitinated cargo from one complex to the next. 相似文献