全文获取类型
收费全文 | 8078篇 |
免费 | 628篇 |
国内免费 | 15篇 |
出版年
2022年 | 63篇 |
2021年 | 103篇 |
2020年 | 60篇 |
2019年 | 78篇 |
2018年 | 84篇 |
2017年 | 87篇 |
2016年 | 215篇 |
2015年 | 314篇 |
2014年 | 352篇 |
2013年 | 432篇 |
2012年 | 515篇 |
2011年 | 517篇 |
2010年 | 352篇 |
2009年 | 297篇 |
2008年 | 447篇 |
2007年 | 398篇 |
2006年 | 416篇 |
2005年 | 393篇 |
2004年 | 347篇 |
2003年 | 370篇 |
2002年 | 343篇 |
2001年 | 92篇 |
2000年 | 76篇 |
1999年 | 83篇 |
1998年 | 78篇 |
1997年 | 79篇 |
1996年 | 59篇 |
1995年 | 52篇 |
1994年 | 73篇 |
1993年 | 67篇 |
1992年 | 82篇 |
1991年 | 64篇 |
1990年 | 55篇 |
1989年 | 57篇 |
1988年 | 51篇 |
1987年 | 51篇 |
1985年 | 46篇 |
1984年 | 72篇 |
1983年 | 52篇 |
1982年 | 63篇 |
1981年 | 73篇 |
1980年 | 73篇 |
1979年 | 46篇 |
1978年 | 76篇 |
1977年 | 55篇 |
1976年 | 55篇 |
1975年 | 46篇 |
1974年 | 40篇 |
1973年 | 51篇 |
1972年 | 37篇 |
排序方式: 共有8721条查询结果,搜索用时 15 毫秒
991.
CP Gómez M Tiemi Shio P Duplay M Olivier A Descoteaux 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(5):2203-2210
The process of phagocytosis and phagosome maturation involves the recruitment of effector proteins that participate in phagosome formation and in the acidification and/or fusion with various endocytic vesicles. In the current study, we investigated the role of the Src homology region 2 domain-containing phosphatase 1 (SHP-1) in phagolysosome biogenesis. To this end, we used immortalized bone marrow macrophages derived from SHP-1-deficient motheaten mice and their wild-type littermates. We found that SHP-1 is recruited early and remains present on phagosomes for up to 4 h postphagocytosis. Using confocal immunofluorescence microscopy and Western blot analyses on purified phagosome extracts, we observed an impaired recruitment of lysosomal-associated membrane protein 1 in SHP-1-deficient macrophages. Moreover, Western blot analyses revealed that whereas the 51-kDa procathepsin D is recruited to phagosomes, it is not processed into the 46-kDa cathepsin D in the absence of SHP-1, suggesting a defect in acidification. Using the lysosomotropic agent LysoTracker as an indicator of phagosomal pH, we obtained evidence that in the absence of SHP-1, phagosome acidification was impaired. Taken together, these results are consistent with a role for SHP-1 in the regulation of signaling or membrane fusion events involved in phagolysosome biogenesis. 相似文献
992.
Hepatitis A virus (HAV) has previously been reported to bind to human red blood cells through interaction with glycophorin A. Residue K221 of VP1 and the surrounding VP3 residues are involved in such an interaction. This capsid region is specifically recognized by the monoclonal antibody H7C27. A monoclonal antibody-resistant mutant with the mutation G1217D has been isolated. In the present study, the G1217D mutant was characterized physically and biologically in comparison with the parental HM175 43c strain. The G1217D mutant is more sensitive to acid pH and binds more efficiently to human and rat erythrocytes than the parental 43c strain. In a rat model, it is eliminated from serum more rapidly and consequently reaches the liver with a certain delay compared to the parental 43c strain. In competition experiments performed in vivo in the rat model, the G1217D mutant was efficiently outcompeted by the parental 43c strain. Only in the presence of antibodies reacting specifically with the parental 43c strain could the G1217D mutant outcompete the parental 43c strain in serum, although the latter still showed a remarkable ability to reach the liver. Altogether, these results indicate that the G1217D mutation induces a low fitness phenotype which could explain the lack of natural antigenic variants of the glycophorin A binding site. 相似文献
993.
The EcoRV DNA methyltransferase methylates the first adenine in the GATATC recognition sequence. It is presumed that methylation proceeds by a nucleotide flipping mechanism but no crystal structure is available to confirm this. A popular solution-phase assay for nucleotide flipping employs the fluorescent adenine analogue, 2-aminopurine (2AP), substituted at the methylation target site; a substantial increase in fluorescence intensity on enzyme binding indicates flipping. However, this appeared to fail for M.EcoRV, since 2AP substituted for the non-target adenine in the recognition sequence showed a much greater intensity increase than 2AP at the target site. This anomaly is resolved by recording the fluorescence decay of 2AP which shows that the target 2AP is indeed flipped by the enzyme, but its fluorescence is quenched by interaction with aromatic residues in the catalytic site, whereas bending of the duplex at the non-target site alleviates inter-base quenching and exposes the 2AP to solvent. 相似文献
994.
Winfried Neuhaus Fabian Samwer Steffen Kunzmann Ralf M. Muellenbach Michael Wirth Christian P. Speer Norbert Roewer Carola Y. Förster 《Differentiation; research in biological diversity》2012
The blood–air barrier in the lung consists of the alveolar epithelium, the underlying capillary endothelium, their basement membranes and the interstitial space between the cell layers. Little is known about the interactions between the alveolar and the blood compartment. The aim of the present study was to gain first insights into the possible interplay between these two neighbored cell layers. We established an in vitro Transwell model of the alveolar epithelium based on human cell line H441 and investigated the influence of conditioned medium obtained from human lung endothelial cell line HPMEC-ST1.6R on the barrier properties of the H441 layers. As control for tissue specificity H441 layers were exposed to conditioned medium from human brain endothelial cell line hCMEC/D3. Addition of dexamethasone was necessary to obtain stable H441 cell layers. Moreover, dexamethasone increased expression of cell type I markers (caveolin-1, RAGE) and cell type II marker SP-B, whereas decreased the transepithelial electrical resistance (TEER) in a concentration dependent manner. Soluble factors obtained from the lung endothelial cell line increased the barrier significantly proven by TEER values and fluorescein permeability on the functional level and by the differential expression of tight junctional proteins on the molecular level. In contrast to this, soluble factors derived from brain endothelial cells weakened the barrier significantly. In conclusion, soluble factors from lung endothelial cells can strengthen the alveolar epithelium barrier in vitro, which suggests communication between endothelial and epithelial cells regulating the integrity of the blood–air barrier. 相似文献
995.
JI García-Plazaola R Esteban B Fernández-Marín I Kranner A Porcar-Castell 《Photosynthesis research》2012,113(1-3):89-103
Thermal dissipation of excitation energy is a fundamental photoprotection mechanism in plants. Thermal energy dissipation is frequently estimated using the quenching of the chlorophyll fluorescence signal, termed non-photochemical quenching. Over the last two decades, great progress has been made in the understanding of the mechanism of thermal energy dissipation through the use of a few model plants, mainly Arabidopsis. Nonetheless, an emerging number of studies suggest that this model represents only one strategy among several different solutions for the environmental adjustment of thermal energy dissipation that have evolved among photosynthetic organisms in the course of evolution. In this review, a detailed analysis of three examples highlights the need to use models other than Arabidopsis: first, overwintering evergreens that develop a sustained form of thermal energy dissipation; second, desiccation tolerant plants that induce rapid thermal energy dissipation; and third, understorey plants in which a complementary lutein epoxide cycle modulates thermal energy dissipation. The three examples have in common a shift from a photosynthetically efficient state to a dissipative conformation, a strategy widely distributed among stress-tolerant evergreen perennials. Likewise, they show a distinct operation of the xanthophyll cycle. Expanding the list of model species beyond Arabidopsis will enhance our knowledge of these mechanisms and increase the synergy of the current studies now dispersed over a wide number of species. 相似文献
996.
Violle C Enquist BJ McGill BJ Jiang L Albert CH Hulshof C Jung V Messier J 《Trends in ecology & evolution》2012,27(4):244-252
Despite being recognized as a promoter of diversity and a condition for local coexistence decades ago, the importance of intraspecific variance has been neglected over time in community ecology. Recently, there has been a new emphasis on intraspecific variability. Indeed, recent developments in trait-based community ecology have underlined the need to integrate variation at both the intraspecific as well as interspecific level. We introduce new T-statistics ('T' for trait), based on the comparison of intraspecific and interspecific variances of functional traits across organizational levels, to operationally incorporate intraspecific variability into community ecology theory. We show that a focus on the distribution of traits at local and regional scales combined with original analytical tools can provide unique insights into the primary forces structuring communities. 相似文献
997.
Joaquin M Gubern A González-Nuñez D Josué Ruiz E Ferreiro I de Nadal E Nebreda AR Posas F 《The EMBO journal》2012,31(13):2952-2964
The p57(Kip2) cyclin-dependent kinase inhibitor (CDKi) has been implicated in embryogenesis, stem-cell senescence and pathologies, but little is known of its role in cell cycle control. Here, we show that p57(Kip2) is targeted by the p38 stress-activated protein kinase (SAPK). Phosphorylation of p57(Kip2) at T143 by p38 enhances its association with and inhibition of Cdk2, which results in cell-cycle delay upon stress. Genetic inactivation of the SAPK or the CDKi abolishes cell-cycle delay upon osmostress and results in decreased cell viability. Oxidative stress and ionomycin also induce p38-mediated phosphorylation of p57 and cells lacking p38 or p57 display reduced viability to these stresses. Therefore, cell survival to various stresses depends on p57 phosphorylation by p38 that inhibits CDK activity. Together, these findings provide a novel molecular mechanism by which cells can delay cell cycle progression to maximize cell survival upon stress. 相似文献
998.
Susanne Roth Mobarak Abu Mraheil Winfried Barchet Jan Böttcher Torsten Hain Sergej Geiger Yoshihiro Hayakawa Jörg H Fritz Filiz Civril Karl‐Peter Hopfner Christian Kurts Jürgen Ruland Gunther Hartmann Trinad Chakraborty Percy A Knolle 《The EMBO journal》2012,31(21):4153-4164
Immunity against infection with Listeria monocytogenes is not achieved from innate immune stimulation by contact with killed but requires viable Listeria gaining access to the cytosol of infected cells. It has remained ill‐defined how such immune sensing of live Listeria occurs. Here, we report that efficient cytosolic immune sensing requires access of nucleic acids derived from live Listeria to the cytoplasm of infected cells. We found that Listeria released nucleic acids and that such secreted bacterial RNA/DNA was recognized by the cytosolic sensors RIG‐I, MDA5 and STING thereby triggering interferon β production. Secreted Listeria nucleic acids also caused RIG‐I‐dependent IL‐1β‐production and inflammasome activation. The signalling molecule CARD9 contributed to IL‐1β production in response to secreted nucleic acids. In conclusion, cytosolic recognition of secreted bacterial nucleic acids by RIG‐I provides a mechanistic explanation for efficient induction of immunity by live bacteria. 相似文献
999.
1000.