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101.
Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells 总被引:1,自引:0,他引:1
Although interleukin-2 (IL-2) was initially characterized as the primary T-cell growth factor following in vitro activation, less is known about its role in shaping T-cell responses to acute infections in vivo. The use of IL-2- or IL-2-receptor-deficient mice is problematic owing to their early development of autoimmunity, attributable to the central role of IL-2 in the generation, maintenance and function of CD4+CD25+ regulatory T cells. To bypass these inherent difficulties, we have studied the effect of IL-2 on T-cell responses to acute infections by adopting a mixed chimaera strategy in which T cells lacking the high-affinity IL-2 receptor could be studied in an otherwise healthy mouse containing a full complement of regulatory T cells. Here we show that although IL-2 signalling to pathogen-specific CD8+ T cells affects the number of developing effector and memory cells very little, it is required for the generation of robust secondary responses. This is not due to an altered T-cell-receptor repertoire development or selection, and does not reflect an acute requirement for IL-2 during secondary activation and expansion. Rather, we demonstrate a previously unappreciated role for IL-2 during primary infection in programming the development of CD8+ memory T cells capable of full secondary expansion. These results have important implications for the development of vaccination or immunotherapeutic strategies aimed at boosting memory T-cell function. 相似文献
102.
Kash JC Tumpey TM Proll SC Carter V Perwitasari O Thomas MJ Basler CF Palese P Taubenberger JK García-Sastre A Swayne DE Katze MG 《Nature》2006,443(7111):578-581
The influenza pandemic of 1918-19 was responsible for about 50 million deaths worldwide. Modern histopathological analysis of autopsy samples from human influenza cases from 1918 revealed significant damage to the lungs with acute, focal bronchitis and alveolitis associated with massive pulmonary oedema, haemorrhage and rapid destruction of the respiratory epithelium. The contribution of the host immune response leading to this severe pathology remains largely unknown. Here we show, in a comprehensive analysis of the global host response induced by the 1918 influenza virus, that mice infected with the reconstructed 1918 influenza virus displayed an increased and accelerated activation of host immune response genes associated with severe pulmonary pathology. We found that mice infected with a virus containing all eight genes from the pandemic virus showed marked activation of pro-inflammatory and cell-death pathways by 24 h after infection that remained unabated until death on day 5. This was in contrast with smaller host immune responses as measured at the genomic level, accompanied by less severe disease pathology and delays in death in mice infected with influenza viruses containing only subsets of 1918 genes. The results indicate a cooperative interaction between the 1918 influenza genes and show that study of the virulence of the 1918 influenza virus requires the use of the fully reconstructed virus. With recent concerns about the introduction of highly pathogenic avian influenza viruses into humans and their potential to cause a worldwide pandemic with disastrous health and economic consequences, a comprehensive understanding of the global host response to the 1918 virus is crucial. Moreover, understanding the contribution of host immune responses to virulent influenza virus infections is an important starting point for the identification of prognostic indicators and the development of novel antiviral therapies. 相似文献
103.
Geochemical and sedimentological evidence suggest that the rapid climate warming oscillations of the last ice age, the Dansgaard-Oeschger cycles, were coupled to fluctuations in North Atlantic meridional overturning circulation through its regulation of poleward heat flux. The balance between cold meltwater from the north and warm, salty subtropical gyre waters from the south influenced the strength and location of North Atlantic overturning circulation during this period of highly variable climate. Here we investigate how rapid reorganizations of the ocean-atmosphere system across these cycles are linked to salinity changes in the subtropical North Atlantic gyre. We combine Mg/Ca palaeothermometry and oxygen isotope ratio measurements on planktonic foraminifera across four Dansgaard-Oeschger cycles (spanning 45.9-59.2 kyr ago) to generate a seawater salinity proxy record from a subtropical gyre deep-sea sediment core. We show that North Atlantic gyre surface salinities oscillated rapidly between saltier stadial conditions and fresher interstadials, covarying with inferred shifts in the Tropical Atlantic hydrologic cycle and North Atlantic overturning circulation. These salinity oscillations suggest a reduction in precipitation into the North Atlantic and/or reduced export of deep salty thermohaline waters during stadials. We hypothesize that increased stadial salinities preconditioned the North Atlantic Ocean for a rapid return to deep overturning circulation and high-latitude warming by contributing to increased North Atlantic surface-water density on interstadial transitions. 相似文献
104.
The hippocampus has long been known to be involved in spatial navigational learning in rodents, and in memory for events in rodents, primates and humans. A unifying property of both navigation and event memory is a requirement for dealing with temporally sequenced information. Reactivation of temporally sequenced memories for previous behavioural experiences has been reported in sleep in rats. Here we report that sequential replay occurs in the rat hippocampus during awake periods immediately after spatial experience. This replay has a unique form, in which recent episodes of spatial experience are replayed in a temporally reversed order. This replay is suggestive of a role in the evaluation of event sequences in the manner of reinforcement learning models. We propose that such replay might constitute a general mechanism of learning and memory. 相似文献
105.
106.
All organisations face the challenge of how to assess performance beyond current financial metrics. These challenges are felt especially strongly by social enterprises, organisations that use business methods to achieve social goals. Social enterprises need to evidence superior social outcomes, are normally accountable to a complex range of stakeholders and yet are often rated low to medium in terms of organisational capacity—thus whilst they have a great need for rounded measurement, they may in practice lack the ability to make use of the different approaches on offer. This paper examines the current and potential use of the conventional Balanced Scorecard model, by social enterprises. The Adventure Capital Fund provides case study evidence of extensive use of a modified Scorecard. The model used is dynamic, combining reflection on the organisation’s current position, ‘near term’ and long term issues. It aims to take a holistic and coherent view of the management of social enterprises. Experience to date suggests that the medium term snapshot provided by the Scorecard is the most valuable, allowing organisations and especially boards and senior executives to keep a ‘strategic grip’ in a period of rapid change and focus on those actions that have best chance of changing performance in the round. 相似文献
107.
Current approaches to reaction discovery focus on one particular transformation. Typically, researchers choose substrates based on their predicted ability to serve as precursors for the target structure, then evaluate reaction conditions for their ability to effect product formation. This approach is ideal for addressing specific reactivity problems, but its focused nature might leave many areas of chemical reactivity unexplored. Here we report a reaction discovery approach that uses DNA-templated organic synthesis and in vitro selection to simultaneously evaluate many combinations of different substrates for bond-forming reactions in a single solution. Watson-Crick base pairing controls the effective molarities of substrates tethered to DNA strands; bond-forming substrate combinations are then revealed using in vitro selection for bond formation, PCR amplification and DNA microarray analysis. Using this approach, we discovered an efficient and mild carbon-carbon bond-forming reaction that generates an enone from an alkyne and alkene using an inorganic palladium catalyst. Although this approach is restricted to conditions and catalysts that are at least partially compatible with DNA, we expect that its versatility and efficiency will enable the discovery of additional reactions between a wide range of substrates. 相似文献
108.
Systematic generation of high-resolution deletion coverage of the Drosophila melanogaster genome 总被引:1,自引:0,他引:1
Parks AL Cook KR Belvin M Dompe NA Fawcett R Huppert K Tan LR Winter CG Bogart KP Deal JE Deal-Herr ME Grant D Marcinko M Miyazaki WY Robertson S Shaw KJ Tabios M Vysotskaia V Zhao L Andrade RS Edgar KA Howie E Killpack K Milash B Norton A Thao D Whittaker K Winner MA Friedman L Margolis J Singer MA Kopczynski C Curtis D Kaufman TC Plowman GD Duyk G Francis-Lang HL 《Nature genetics》2004,36(3):288-292
In fruit fly research, chromosomal deletions are indispensable tools for mapping mutations, characterizing alleles and identifying interacting loci. Most widely used deletions were generated by irradiation or chemical mutagenesis. These methods are labor-intensive, generate random breakpoints and result in unwanted secondary mutations that can confound phenotypic analyses. Most of the existing deletions are large, have molecularly undefined endpoints and are maintained in genetically complex stocks. Furthermore, the existence of haplolethal or haplosterile loci makes the recovery of deletions of certain regions exceedingly difficult by traditional methods, resulting in gaps in coverage. Here we describe two methods that address these problems by providing for the systematic isolation of targeted deletions in the D. melanogaster genome. The first strategy used a P element-based technique to generate deletions that closely flank haploinsufficient genes and minimize undeleted regions. This deletion set has increased overall genomic coverage by 5-7%. The second strategy used FLP recombinase and the large array of FRT-bearing insertions described in the accompanying paper to generate 519 isogenic deletions with molecularly defined endpoints. This second deletion collection provides 56% genome coverage so far. The latter methodology enables the generation of small custom deletions with predictable endpoints throughout the genome and should make their isolation a simple and routine task. 相似文献
109.
110.