全文获取类型
收费全文 | 5725篇 |
免费 | 509篇 |
国内免费 | 4篇 |
专业分类
6238篇 |
出版年
2023年 | 25篇 |
2022年 | 45篇 |
2021年 | 101篇 |
2020年 | 60篇 |
2019年 | 92篇 |
2018年 | 118篇 |
2017年 | 106篇 |
2016年 | 173篇 |
2015年 | 290篇 |
2014年 | 299篇 |
2013年 | 350篇 |
2012年 | 518篇 |
2011年 | 545篇 |
2010年 | 314篇 |
2009年 | 271篇 |
2008年 | 345篇 |
2007年 | 352篇 |
2006年 | 310篇 |
2005年 | 321篇 |
2004年 | 300篇 |
2003年 | 296篇 |
2002年 | 252篇 |
2001年 | 44篇 |
2000年 | 68篇 |
1999年 | 68篇 |
1998年 | 62篇 |
1997年 | 48篇 |
1996年 | 36篇 |
1995年 | 42篇 |
1994年 | 44篇 |
1993年 | 27篇 |
1992年 | 22篇 |
1991年 | 25篇 |
1990年 | 29篇 |
1989年 | 23篇 |
1988年 | 13篇 |
1987年 | 13篇 |
1986年 | 23篇 |
1985年 | 8篇 |
1984年 | 11篇 |
1983年 | 17篇 |
1982年 | 19篇 |
1981年 | 16篇 |
1980年 | 11篇 |
1979年 | 13篇 |
1978年 | 12篇 |
1977年 | 8篇 |
1976年 | 12篇 |
1975年 | 5篇 |
1973年 | 8篇 |
排序方式: 共有6238条查询结果,搜索用时 0 毫秒
61.
Phillipp Kirfel Marisa Skaljac Jens Grotmann Tobias Kessel Maximilian Seip Katja Michaelis Andreas Vilcinskas 《Archives of insect biochemistry and physiology》2020,103(3):e21614
Histone acetylation is an evolutionarily conserved epigenetic mechanism of eukaryotic gene regulation which is tightly controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). In insects, life-history traits such as longevity and fecundity are severely affected by the suppression of HAT/HDAC activity, which can be achieved by RNA-mediated gene silencing or the application of chemical inhibitors. We used both experimental approaches to investigate the effect of HAT/HDAC inhibition in the pea aphid (Acyrthosiphon pisum) a model insect often used to study complex life-history traits. The silencing of HAT genes (kat6b, kat7, and kat14) promoted survival or increased the number of offspring, whereas targeting rpd3 (HDAC) reduced the number of viviparous offspring but increased the number of premature nymphs, suggesting a role in embryogenesis and eclosion. Specific chemical inhibitors of HATs/HDACs showed a remarkably severe impact on life-history traits, reducing survival, delaying development, and limiting the number of offspring. The selective inhibition of HATs and HDACs also had opposing effects on aphid body weight. The suppression of HAT/HDAC activity in aphids by RNA interference or chemical inhibition revealed similarities and differences compared to the reported role of these enzymes in other insects. Our data suggest that gene expression in A. pisum is regulated by multiple HATs/HDACs, as indicated by the fitness costs triggered by inhibitors that suppress several of these enzymes simultaneously. Targeting multiple HATs or HDACs with combined effects on gene regulation could, therefore, be a promising approach to discover novel targets for the management of aphid pests. 相似文献
62.
63.
Jens H. W. Pahl S. Eriaty N. Ruslan Kitty M. C. Kwappenberg Monique M. van Ostaijen-ten Dam Maarten J. D. van Tol Arjan C. Lankester Marco W. Schilham 《Cancer immunology, immunotherapy : CII》2013,62(7):1235-1247
Osteosarcoma and Ewing’s sarcoma tumor cells are susceptible to IL15-induced or antibody-mediated cytolytic activity of NK cells in short-term cytotoxicity assays. When encountering the tumor environment in vivo, NK cells may be in contact with tumor cells for a prolonged time period. We explored whether a prolonged interaction with sarcoma cells can modulate the activation and cytotoxic activity of NK cells. The 40 h coculture of NK cells with sarcoma cells reversibly interfered with the IL15-induced expression of NKG2D, DNAM-1 and NKp30 and inhibited the cytolytic activity of NK cells. The inhibitory effects on receptor expression required physical contact between NK cells and sarcoma cells and were independent of TGF-β. Five days pre-incubation of NK cells with IL15 prevented the down-regulation of NKG2D and cytolytic activity in subsequent cocultures with sarcoma cells. NK cell FcγRIIIa/CD16 receptor expression and antibody-mediated cytotoxicity were not affected after the coculture. Inhibition of NK cell cytotoxicity was directly linked to the down-regulation of the respective NK cell-activating receptors. Our data demonstrate that the inhibitory effects of sarcoma cells on the cytolytic activity of NK cells do not affect the antibody-dependent cytotoxicity and can be prevented by pre-activation of NK cells with IL15. Thus, the combination of cytokine-activated NK cells and monoclonal antibody therapy may be required to improve tumor targeting and NK cell functionality in the tumor environment. 相似文献
64.
Stéphanie B. N. Serre Henrik B. Krarup Jens Bukh Judith M. Gottwein 《Journal of virology》2013,87(23):12776-12793
Alpha interferon (IFN-α) is an essential component of innate antiviral immunity and of treatment regimens for chronic hepatitis C virus (HCV) infection. Resistance to IFN might be important for HCV persistence and failure of IFN-based therapies. Evidence for HCV genetic correlates of IFN resistance is limited. Experimental studies were hampered by lack of HCV culture systems. Using genotype (strain) 1a(H77) and 3a(S52) Core-NS2 JFH1-based recombinants, we aimed at identifying viral correlates of IFN-α resistance in vitro. Long-term culture with IFN-α2b in Huh7.5 cells resulted in viral spread with acquisition of putative escape mutations in HCV structural and nonstructural proteins. Reverse genetic studies showed that primarily amino acid changes I348T in 1a(H77) E1 and F345V/V414A in 3a(S52) E1/E2 increased viral fitness. Single-cycle assays revealed that I348T and F345V/V414A enhanced viral entry and release, respectively. In assays allowing viral spread, these mutations conferred a level of IFN-α resistance exceeding the observed fitness effect. The identified mutations acted in a subtype-specific manner but were not found in genotype 1a and 3a patients, who failed IFN-α therapy. Studies with HCV recombinants with different degrees of culture adaptation confirmed the correlation between viral fitness and IFN-α resistance. In conclusion, in vitro escape experiments led to identification of HCV envelope mutations resulting in increased viral fitness and conferring IFN-α resistance. While we established a close link between viral fitness and IFN-α resistance, identified mutations acted via different mechanisms and appeared to be relatively specific to the infecting virus, possibly explaining difficulties in identifying signature mutations for IFN resistance. 相似文献
65.
Yíngyún Caì Shu?qìng Yú Steven Mazur Lián D?ng Krisztina Janosko Téngfēi Zhāng Marcel A. Müller Lisa E. Hensley Sina Bavari Peter B. Jahrling Sheli R. Radoshitzky Jens H. Kuhn 《Journal of virology》2013,87(24):13930-13935
Ocozocoautla de Espinosa virus (OCEV) is a novel, uncultured arenavirus. We found that the OCEV glycoprotein mediates entry into grivet and bat cells through transferrin receptor 1 (TfR1) binding but that OCEV glycoprotein precursor (GPC)-pseudotyped retroviruses poorly entered 53 human cancer cell lines. Interestingly, OCEV and Tacaribe virus could use bat, but not human, TfR1. Replacing three human TfR1 amino acids with their bat ortholog counterparts transformed human TfR1 into an efficient OCEV and Tacaribe virus receptor. 相似文献
66.
Jens Tilsner Olga Linnik Marion Louveaux Ian M. Roberts Sean N. Chapman Karl J. Oparka 《The Journal of cell biology》2013,201(7):981-995
Plant viruses use movement proteins (MPs) to modify intercellular pores called plasmodesmata (PD) to cross the plant cell wall. Many viruses encode a conserved set of three MPs, known as the triple gene block (TGB), typified by Potato virus X (PVX). In this paper, using live-cell imaging of viral RNA (vRNA) and virus-encoded proteins, we show that the TGB proteins have distinct functions during movement. TGB2 and TGB3 established endoplasmic reticulum–derived membranous caps at PD orifices. These caps harbored the PVX replicase and nonencapsidated vRNA and represented PD-anchored viral replication sites. TGB1 mediated insertion of the viral coat protein into PD, probably by its interaction with the 5′ end of nascent virions, and was recruited to PD by the TGB2/3 complex. We propose a new model of plant virus movement, which we term coreplicational insertion, in which MPs function to compartmentalize replication complexes at PD for localized RNA synthesis and directional trafficking of the virus between cells. 相似文献
67.
Arun T. John Peter Jens Lachmann Meenakshi Rana Madeleine Bunge Margarita Cabrera Christian Ungermann 《The Journal of cell biology》2013,201(1):97-111
Membrane microcompartments of the early endosomes serve as a sorting and signaling platform, where receptors are either recycled back to the plasma membrane or forwarded to the lysosome for destruction. In metazoan cells, three complexes, termed BLOC-1 to -3, mediate protein sorting from the early endosome to lysosomes and lysosome-related organelles. We now demonstrate that BLOC-1 is an endosomal Rab-GAP (GTPase-activating protein) adapter complex in yeast. The yeast BLOC-1 consisted of six subunits, which localized interdependently to the endosomes in a Rab5/Vps21-dependent manner. In the absence of BLOC-1 subunits, the balance between recycling and degradation of selected cargoes was impaired. Additionally, our data show that BLOC-1 is both a Vps21 effector and an adapter for its GAP Msb3. BLOC-1 and Msb3 interacted in vivo, and both mutants resulted in a redistribution of active Vps21 to the vacuole surface. We thus conclude that BLOC-1 controls the lifetime of active Rab5/Vps21 and thus endosomal maturation along the endocytic pathway. 相似文献
68.
69.
70.
Lydia R. Durant Spyridon Makris Cornelia Maaike Voorburg Jens Loebbermann Cecilia Johansson Peter J. M. Openshaw 《Journal of virology》2013,87(20):10946-10954
During viral infection, inflammation and recovery are tightly controlled by competing proinflammatory and regulatory immune pathways. Respiratory syncytial virus (RSV) is the leading global cause of infantile bronchiolitis, which is associated with recurrent wheeze and asthma diagnosis in later life. Th2-driven disease has been well described under some conditions for RSV-infected mice. In the present studies, we used the Foxp3DTR mice (which allow specific conditional depletion of Foxp3+ T cells) to investigate the functional effects of regulatory T cells (Tregs) during A2-strain RSV infection. Infected Treg-depleted mice lost significantly more weight than wild-type mice, indicating enhanced disease. This enhancement was characterized by increased cellularity in the bronchoalveolar lavage (BAL) fluid and notable lung eosinophilia not seen in control mice. This was accompanied by abundant CD4+ and CD8+ T cells exhibiting an activated phenotype and induction of interleukin 13 (IL-13)- and GATA3-expressing Th2-type CD4+ T cells that remained present in the airways even 14 days after infection. Therefore, Treg cells perform vital anti-inflammatory functions during RSV infection, suppressing pathogenic T cell responses and inhibiting lung eosinophilia. These findings provide additional evidence that dysregulation of normal immune responses to viral infection may contribute to severe RSV disease. 相似文献