全文获取类型
收费全文 | 3868篇 |
免费 | 29篇 |
国内免费 | 47篇 |
专业分类
系统科学 | 63篇 |
丛书文集 | 75篇 |
教育与普及 | 215篇 |
理论与方法论 | 17篇 |
现状及发展 | 307篇 |
研究方法 | 524篇 |
综合类 | 2741篇 |
自然研究 | 2篇 |
出版年
2021年 | 6篇 |
2017年 | 6篇 |
2016年 | 8篇 |
2014年 | 14篇 |
2013年 | 16篇 |
2012年 | 246篇 |
2011年 | 319篇 |
2010年 | 103篇 |
2009年 | 89篇 |
2008年 | 356篇 |
2007年 | 305篇 |
2006年 | 363篇 |
2005年 | 377篇 |
2004年 | 203篇 |
2003年 | 215篇 |
2002年 | 175篇 |
2001年 | 130篇 |
2000年 | 217篇 |
1999年 | 83篇 |
1998年 | 43篇 |
1997年 | 21篇 |
1996年 | 18篇 |
1995年 | 8篇 |
1994年 | 13篇 |
1993年 | 14篇 |
1992年 | 13篇 |
1991年 | 18篇 |
1990年 | 14篇 |
1989年 | 31篇 |
1988年 | 14篇 |
1987年 | 12篇 |
1986年 | 18篇 |
1985年 | 15篇 |
1984年 | 18篇 |
1983年 | 14篇 |
1982年 | 18篇 |
1981年 | 17篇 |
1980年 | 10篇 |
1979年 | 11篇 |
1971年 | 15篇 |
1970年 | 24篇 |
1966年 | 11篇 |
1960年 | 6篇 |
1959年 | 30篇 |
1958年 | 62篇 |
1957年 | 43篇 |
1956年 | 43篇 |
1955年 | 49篇 |
1954年 | 35篇 |
1948年 | 17篇 |
排序方式: 共有3944条查询结果,搜索用时 375 毫秒
911.
Stagg SM Gürkan C Fowler DM LaPointe P Foss TR Potter CS Carragher B Balch WE 《Nature》2006,439(7073):234-238
Endomembranes of eukaryotic cells are dynamic structures that are in continuous communication through the activity of specialized cellular machineries, such as the coat protein complex II (COPII), which mediates cargo export from the endoplasmic reticulum (ER). COPII consists of the Sar1 GTPase, Sec23 and Sec24 (Sec23/24), where Sec23 is a Sar1-specific GTPase-activating protein and Sec24 functions in cargo selection, and Sec13 and Sec31 (Sec13/31), which has a structural role. Whereas recent results have shown that Sec23/24 and Sec13/31 can self-assemble to form COPII cage-like particles, we now show that Sec13/31 can self-assemble to form minimal cages in the absence of Sec23/24. We present a three-dimensional reconstruction of these Sec13/31 cages at 30 A resolution using cryo-electron microscopy and single particle analysis. These results reveal a novel cuboctahedron geometry with the potential to form a flexible lattice and to generate a diverse range of containers. Our data are consistent with a model for COPII coat complex assembly in which Sec23/24 has a non-structural role as a multivalent ligand localizing the self-assembly of Sec13/31 to form a cage lattice driving ER cargo export. 相似文献
912.
Kämper J Kahmann R Bölker M Ma LJ Brefort T Saville BJ Banuett F Kronstad JW Gold SE Müller O Perlin MH Wösten HA de Vries R Ruiz-Herrera J Reynaga-Peña CG Snetselaar K McCann M Pérez-Martín J Feldbrügge M Basse CW Steinberg G Ibeas JI Holloman W Guzman P Farman M Stajich JE Sentandreu R González-Prieto JM Kennell JC Molina L Schirawski J Mendoza-Mendoza A Greilinger D Münch K Rössel N Scherer M Vranes M Ladendorf O Vincon V Fuchs U Sandrock B Meng S Ho EC Cahill MJ Boyce KJ Klose J 《Nature》2006,444(7115):97-101
Ustilago maydis is a ubiquitous pathogen of maize and a well-established model organism for the study of plant-microbe interactions. This basidiomycete fungus does not use aggressive virulence strategies to kill its host. U. maydis belongs to the group of biotrophic parasites (the smuts) that depend on living tissue for proliferation and development. Here we report the genome sequence for a member of this economically important group of biotrophic fungi. The 20.5-million-base U. maydis genome assembly contains 6,902 predicted protein-encoding genes and lacks pathogenicity signatures found in the genomes of aggressive pathogenic fungi, for example a battery of cell-wall-degrading enzymes. However, we detected unexpected genomic features responsible for the pathogenicity of this organism. Specifically, we found 12 clusters of genes encoding small secreted proteins with unknown function. A significant fraction of these genes exists in small gene families. Expression analysis showed that most of the genes contained in these clusters are regulated together and induced in infected tissue. Deletion of individual clusters altered the virulence of U. maydis in five cases, ranging from a complete lack of symptoms to hypervirulence. Despite years of research into the mechanism of pathogenicity in U. maydis, no 'true' virulence factors had been previously identified. Thus, the discovery of the secreted protein gene clusters and the functional demonstration of their decisive role in the infection process illuminate previously unknown mechanisms of pathogenicity operating in biotrophic fungi. Genomic analysis is, similarly, likely to open up new avenues for the discovery of virulence determinants in other pathogens. 相似文献
913.
Aury JM Jaillon O Duret L Noel B Jubin C Porcel BM Ségurens B Daubin V Anthouard V Aiach N Arnaiz O Billaut A Beisson J Blanc I Bouhouche K Câmara F Duharcourt S Guigo R Gogendeau D Katinka M Keller AM Kissmehl R Klotz C Koll F Le Mouël A Lepère G Malinsky S Nowacki M Nowak JK Plattner H Poulain J Ruiz F Serrano V Zagulski M Dessen P Bétermier M Weissenbach J Scarpelli C Schächter V Sperling L Meyer E Cohen J Wincker P 《Nature》2006,444(7116):171-178
The duplication of entire genomes has long been recognized as having great potential for evolutionary novelties, but the mechanisms underlying their resolution through gene loss are poorly understood. Here we show that in the unicellular eukaryote Paramecium tetraurelia, a ciliate, most of the nearly 40,000 genes arose through at least three successive whole-genome duplications. Phylogenetic analysis indicates that the most recent duplication coincides with an explosion of speciation events that gave rise to the P. aurelia complex of 15 sibling species. We observed that gene loss occurs over a long timescale, not as an initial massive event. Genes from the same metabolic pathway or protein complex have common patterns of gene loss, and highly expressed genes are over-retained after all duplications. The conclusion of this analysis is that many genes are maintained after whole-genome duplication not because of functional innovation but because of gene dosage constraints. 相似文献
914.
915.
PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
Day CL Kaufmann DE Kiepiela P Brown JA Moodley ES Reddy S Mackey EW Miller JD Leslie AJ DePierres C Mncube Z Duraiswamy J Zhu B Eichbaum Q Altfeld M Wherry EJ Coovadia HM Goulder PJ Klenerman P Ahmed R Freeman GJ Walker BD 《Nature》2006,443(7109):350-354
Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection. 相似文献
916.
Bredemeyer AL Sharma GG Huang CY Helmink BA Walker LM Khor KC Nuskey B Sullivan KE Pandita TK Bassing CH Sleckman BP 《Nature》2006,442(7101):466-470
The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving lymphocyte antigen receptor loci. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs. However, defects in these pathways of the DNA damage response cannot fully account for the phenotypes of ATM deficiency. Here, we show that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during lymphocyte antigen receptor gene assembly. When coupled with the cell-cycle checkpoint and pro-apoptotic activities of ATM, these findings provide a molecular explanation for the increase in lymphoid tumours with translocations involving antigen receptor loci associated with ataxia-telangiectasia. 相似文献
917.
Any state of matter is classified according to its order, and the type of order that a physical system can possess is profoundly affected by its dimensionality. Conventional long-range order, as in a ferromagnet or a crystal, is common in three-dimensional systems at low temperature. However, in two-dimensional systems with a continuous symmetry, true long-range order is destroyed by thermal fluctuations at any finite temperature. Consequently, for the case of identical bosons, a uniform two-dimensional fluid cannot undergo Bose-Einstein condensation, in contrast to the three-dimensional case. However, the two-dimensional system can form a 'quasi-condensate' and become superfluid below a finite critical temperature. The Berezinskii-Kosterlitz-Thouless (BKT) theory associates this phase transition with the emergence of a topological order, resulting from the pairing of vortices with opposite circulation. Above the critical temperature, proliferation of unbound vortices is expected. Here we report the observation of a BKT-type crossover in a trapped quantum degenerate gas of rubidium atoms. Using a matter wave heterodyning technique, we observe both the long-wavelength fluctuations of the quasi-condensate phase and the free vortices. At low temperatures, the gas is quasi-coherent on the length scale set by the system size. As the temperature is increased, the loss of long-range coherence coincides with the onset of proliferation of free vortices. Our results provide direct experimental evidence for the microscopic mechanism underlying the BKT theory, and raise new questions regarding coherence and superfluidity in mesoscopic systems. 相似文献
918.
A recurring question in developmental biology has been whether localized determinants play any role in mammalian preimplantation development. This is a controversial issue that brings back the idea of prepatterning and is explored further by Plusa et al., who claim it is the first cleavage of the mouse zygote that predicts the blastocyst axis, rather than the animal pole or sperm entry point, as previously suggested. However, other evidence indicates that the blasotcyst axis is not predetermined and there is no prepatterning in the mouse egg. Here we investigate the origin of these different views and conclude that they arise from differences in the data themselves and in their interpretation. 相似文献
919.
Ant queens are among the most long-lived insects known. They mate early in adult life and maintain millions of viable sperm in their sperm storage organ until they die many years later. Because they never re-mate, the reproductive success of queens is ultimately sperm-limited, but it is not known what selective forces determine the upper limit to sperm storage. Here we show that sperm storage carries a significant cost of reduced immunity during colony founding. Newly mated queens of the leaf-cutting ant Atta colombica upregulate their immune response shortly after completing their nest burrow, probably as an adaptive response to a greater exposure to pathogens in the absence of grooming workers. However, the immune response nine days after colony founding is negatively correlated with the amount of sperm in the sperm storage organ, indicating that short-term survival is traded off against long-term reproductive success. The immune response was lower when more males contributed to the stored sperm, indicating that there might be an additional cost of mating or storing genetically different ejaculates. 相似文献
920.
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