全文获取类型
收费全文 | 141篇 |
免费 | 0篇 |
国内免费 | 1篇 |
专业分类
理论与方法论 | 2篇 |
现状及发展 | 29篇 |
研究方法 | 20篇 |
综合类 | 89篇 |
自然研究 | 2篇 |
出版年
2017年 | 1篇 |
2014年 | 1篇 |
2012年 | 4篇 |
2011年 | 8篇 |
2010年 | 4篇 |
2009年 | 4篇 |
2008年 | 9篇 |
2007年 | 4篇 |
2006年 | 5篇 |
2005年 | 5篇 |
2004年 | 8篇 |
2003年 | 4篇 |
2002年 | 4篇 |
2001年 | 8篇 |
2000年 | 9篇 |
1999年 | 3篇 |
1994年 | 2篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1984年 | 4篇 |
1983年 | 1篇 |
1982年 | 3篇 |
1981年 | 1篇 |
1980年 | 4篇 |
1979年 | 7篇 |
1978年 | 2篇 |
1976年 | 4篇 |
1975年 | 3篇 |
1973年 | 2篇 |
1971年 | 5篇 |
1970年 | 2篇 |
1968年 | 1篇 |
1967年 | 3篇 |
1966年 | 2篇 |
1965年 | 2篇 |
排序方式: 共有142条查询结果,搜索用时 0 毫秒
71.
Bacterial targets and antibiotics: genome-based drug discovery 总被引:2,自引:0,他引:2
The requirement for novel classes of antibiotics to combat the emergence of resistant and multi-resistant bacteria has coincided with the completion sequencing of a number of bacterial genomes. The in silico analysis of these genomes coupled with innovative genetic manipulation has already led to the identification of conserved essential (either in vitro or in vivo, depending on the methodology) genes that are potential targets for antibacterial research. New technologies, made possible by access to the genomic sequences, are capable of simultaneously quantifying almost the entire complement of gene products synthesised by bacterial cells. These technologies are opening up the way for the analysis of expression patterns elicited in cells in response to changes in their environment. The integration of these technologies into the drug discovery process is still in its infancy and the potential wealth of information, some of it already available, has yet to be fully realised. 相似文献
72.
73.
74.
Endfeet of retinal glial cells have higher densities of ion channels that mediate K+ buffering 总被引:4,自引:0,他引:4
A major function of glial cells in the central nervous system is to buffer the extracellular potassium concentration, [K+]o. A local rise in [K+]o causes potassium ions to enter glial cells, which have membranes that are highly permeable to K+; potassium then leaves the glial cells at other locations where [K+]o has not risen. We report here the first study of the individual ion channels mediating potassium buffering by glial cells. The patch-clamp technique was employed to record single channel currents in Müller cells, the radial glia of the vertebrate retina. Those cells have 94% of their potassium conductance in an endfoot apposed to the vitreous humour, causing K+ released from active retinal neurones to be buffered preferentially to the vitreous. Recordings from patches of endfoot and cell body membrane show that a single type of inward-rectifying K+ channel mediates potassium buffering at both cell locations. The non-uniform density of K+ conductance is due to a non-uniform distribution of one type of K+ channel, rather than to the cell expressing high conductance channels at the endfoot and low conductance channels elsewhere on the cell. 相似文献
75.
76.
Corey DP García-Añoveros J Holt JR Kwan KY Lin SY Vollrath MA Amalfitano A Cheung EL Derfler BH Duggan A Géléoc GS Gray PA Hoffman MP Rehm HL Tamasauskas D Zhang DS 《Nature》2004,432(7018):723-730
Mechanical deflection of the sensory hair bundles of receptor cells in the inner ear causes ion channels located at the tips of the bundle to open, thereby initiating the perception of sound. Although some protein constituents of the transduction apparatus are known, the mechanically gated transduction channels have not been identified in higher vertebrates. Here, we investigate TRP (transient receptor potential) ion channels as candidates and find one, TRPA1 (also known as ANKTM1), that meets criteria for the transduction channel. The appearance of TRPA1 messenger RNA expression in hair cell epithelia coincides developmentally with the onset of mechanosensitivity. Antibodies to TRPA1 label hair bundles, especially at their tips, and tip labelling disappears when the transduction apparatus is chemically disrupted. Inhibition of TRPA1 protein expression in zebrafish and mouse inner ears inhibits receptor cell function, as assessed with electrical recording and with accumulation of a channel-permeant fluorescent dye. TRPA1 is probably a component of the transduction channel itself. 相似文献
77.
The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation 总被引:1,自引:0,他引:1
Parker LH Schmidt M Jin SW Gray AM Beis D Pham T Frantz G Palmieri S Hillan K Stainier DY De Sauvage FJ Ye W 《Nature》2004,428(6984):754-758
Vascular development is a complex but orderly process that is tightly regulated. A number of secreted factors produced by surrounding cells regulate endothelial cell (EC) differentiation, proliferation, migration and coalescence into cord-like structures. Vascular cords then undergo tubulogenesis to form vessels with a central lumen. But little is known about how tubulogenesis is regulated in vivo. Here we report the identification and characterization of a new EC-derived secreted factor, EGF-like domain 7 (Egfl7). Egfl7 is expressed at high levels in the vasculature associated with tissue proliferation, and is downregulated in most of the mature vessels in normal adult tissues. Loss of Egfl7 function in zebrafish embryos specifically blocks vascular tubulogenesis. We uncover a dynamic process during which gradual separation and proper spatial arrangement of the angioblasts allow subsequent assembly of vascular tubes. This process fails to take place in Egfl7 knockdown embryos, leading to the failure of vascular tube formation. Our study defines a regulator that controls a specific and important step in vasculogenesis. 相似文献
78.
Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia 总被引:83,自引:0,他引:83
Davis JB Gray J Gunthorpe MJ Hatcher JP Davey PT Overend P Harries MH Latcham J Clapham C Atkinson K Hughes SA Rance K Grau E Harper AJ Pugh PL Rogers DC Bingham S Randall A Sheardown SA 《Nature》2000,405(6783):183-187
The vanilloid receptor-1 (VR1) is a ligand-gated, non-selective cation channel expressed predominantly by sensory neurons. VR1 responds to noxious stimuli including capsaicin, the pungent component of chilli peppers, heat and extracellular acidification, and it is able to integrate simultaneous exposure to these stimuli. These findings and research linking capsaicin with nociceptive behaviours (that is, responses to painful stimuli in animals have led to VR1 being considered as important for pain sensation. Here we have disrupted the mouse VR1 gene using standard gene targeting techniques. Small diameter dorsal root ganglion neurons isolated from VR1-null mice lacked many of the capsaicin-, acid- and heat-gated responses that have been previously well characterized in small diameter dorsal root ganglion neurons from various species. Furthermore, although the VR1-null mice appeared normal in a wide range of behavioural tests, including responses to acute noxious thermal stimuli, their ability to develop carrageenan-induced thermal hyperalgesia was completely absent. We conclude that VR1 is required for inflammatory sensitization to noxious thermal stimuli but also that alternative mechanisms are sufficient for normal sensation of noxious heat. 相似文献
79.
Malaria susceptibility and CD36 mutation 总被引:1,自引:0,他引:1
Aitman TJ Cooper LD Norsworthy PJ Wahid FN Gray JK Curtis BR McKeigue PM Kwiatkowski D Greenwood BM Snow RW Hill AV Scott J 《Nature》2000,405(6790):1015-1016
80.
A chemical switch for inhibitor-sensitive alleles of any protein kinase 总被引:32,自引:0,他引:32
Bishop AC Ubersax JA Petsch DT Matheos DP Gray NS Blethrow J Shimizu E Tsien JZ Schultz PG Rose MD Wood JL Morgan DO Shokat KM 《Nature》2000,407(6802):395-401
Protein kinases have proved to be largely resistant to the design of highly specific inhibitors, even with the aid of combinatorial chemistry. The lack of these reagents has complicated efforts to assign specific signalling roles to individual kinases. Here we describe a chemical genetic strategy for sensitizing protein kinases to cell-permeable molecules that do not inhibit wild-type kinases. From two inhibitor scaffolds, we have identified potent and selective inhibitors for sensitized kinases from five distinct subfamilies. Tyrosine and serine/threonine kinases are equally amenable to this approach. We have analysed a budding yeast strain carrying an inhibitor-sensitive form of the cyclin-dependent kinase Cdc28 (CDK1) in place of the wild-type protein. Specific inhibition of Cdc28 in vivo caused a pre-mitotic cell-cycle arrest that is distinct from the G1 arrest typically observed in temperature-sensitive cdc28 mutants. The mutation that confers inhibitor-sensitivity is easily identifiable from primary sequence alignments. Thus, this approach can be used to systematically generate conditional alleles of protein kinases, allowing for rapid functional characterization of members of this important gene family. 相似文献