全文获取类型
收费全文 | 5039篇 |
免费 | 308篇 |
专业分类
5347篇 |
出版年
2024年 | 8篇 |
2023年 | 37篇 |
2022年 | 103篇 |
2021年 | 171篇 |
2020年 | 132篇 |
2019年 | 134篇 |
2018年 | 210篇 |
2017年 | 155篇 |
2016年 | 241篇 |
2015年 | 324篇 |
2014年 | 350篇 |
2013年 | 384篇 |
2012年 | 433篇 |
2011年 | 416篇 |
2010年 | 306篇 |
2009年 | 222篇 |
2008年 | 256篇 |
2007年 | 246篇 |
2006年 | 227篇 |
2005年 | 174篇 |
2004年 | 145篇 |
2003年 | 114篇 |
2002年 | 113篇 |
2001年 | 62篇 |
2000年 | 41篇 |
1999年 | 61篇 |
1998年 | 30篇 |
1997年 | 20篇 |
1996年 | 11篇 |
1995年 | 16篇 |
1994年 | 13篇 |
1993年 | 8篇 |
1992年 | 16篇 |
1991年 | 19篇 |
1990年 | 11篇 |
1989年 | 13篇 |
1988年 | 10篇 |
1987年 | 8篇 |
1986年 | 8篇 |
1985年 | 5篇 |
1984年 | 8篇 |
1983年 | 8篇 |
1982年 | 8篇 |
1981年 | 5篇 |
1980年 | 7篇 |
1979年 | 7篇 |
1976年 | 5篇 |
1971年 | 5篇 |
1970年 | 4篇 |
1969年 | 5篇 |
排序方式: 共有5347条查询结果,搜索用时 0 毫秒
161.
Migueleti DL Smetana JH Nunes HF Kobarg J Zanchin NI 《The Journal of biological chemistry》2012,287(7):4853-4862
PP2A is the main serine/threonine-specific phosphatase in animal cells. The active phosphatase has been described as a holoenzyme consisting of a catalytic, a scaffolding, and a variable regulatory subunit, all encoded by multiple genes, allowing for the assembly of more than 70 different holoenzymes. The catalytic subunit can also interact with α4, TIPRL (TIP41, TOR signaling pathway regulator-like), the methyl-transferase LCMT-1, and the methyl-esterase PME-1. Here, we report that the gene encoding the catalytic subunit PP2Acα can generate two mRNA types, the standard mRNA and a shorter isoform, lacking exon 5, which we termed PP2Acα2. Higher levels of the PP2Acα2 mRNA, equivalent to the level of the longer PP2Acα mRNA, were detected in peripheral blood mononuclear cells that were left to rest for 24 h. After this time, the peripheral blood mononuclear cells are still viable and the PP2Acα2 mRNA decreases soon after they are transferred to culture medium, showing that generation of the shorter isoform depends on the incubation conditions. FLAG-tagged PP2Acα2 expressed in HEK293 is catalytically inactive. It displays a specific interaction profile with enhanced binding to the α4 regulatory subunit, but no binding to the scaffolding subunit and PME-1. Consistently, α4 out-competes PME-1 and LCMT-1 for binding to both PP2Acα isoforms in pulldown assays. Together with molecular modeling studies, this suggests that all three regulators share a common binding surface on the catalytic subunit. Our findings add important new insights into the complex mechanisms of PP2A regulation. 相似文献
162.
Eukaryotic cells have developed a diverse repertoire of Rab GTPases to regulate vesicle trafficking pathways. Together with their effector proteins, Rabs mediate various aspects of vesicle formation, tethering, docking and fusion, but details of the biological roles elicited by effectors are largely unknown. Human Rab6 is involved in the trafficking of vesicles at the level of Golgi via interactions with numerous effector proteins. We have previously determined the crystal structure of Rab6 in complex with DENND5, alternatively called Rab6IP1, which comprises two RUN domains (RUN1 and RUN2) separated by a PLAT domain. The structure of Rab6/RUN1-PLAT (Rab6/R1P) revealed the molecular basis for Golgi recruitment of DENND5 via the RUN1 domain, but the functional role of the RUN2 domain has not been well characterized. Here we show that a soluble DENND5 construct encompassing the RUN2 domain binds to the N-terminal region of sorting nexin 1 by surface plasmon resonance analyses. 相似文献
163.
164.
The goal of this research was to use the sequential probability ratio test to establish a sequential sampling plan for Aphis gossypii Glover and Frankliniella schultzei Trybom infesting cotton. Field work was conducted at the agricultural experimental station of the Universidade Federal da Grande Dourados during the 2003/2004 and 2004/2005 agricultural years. Aphid colonies and individual thrips in the sampling area were counted and their numbers were recorded. The spatial distribution pattern of A. gossypii and F. schultzei in the cotton culture was aggregated. Sequential sampling plans were developed for aphids and thrips with type I and type II errors set at 0.1, common Kc = 0.6081 (aphids) and = 0. 9449 (thrips), and safety and management levels of 20% (aphids) and 40% (thrips) of infested plants. The sampling plans resulted in two decision boundaries for each species, as follows: the upper boundary, indicating when management (population control) is recommended: S1 = 4.6546 + 0.2849n (aphids), and S1 = 3.6514 + 0.1435n (thrips); and the lower boundary, indicating when population control is not necessary: S0 = -4.6546 + 0.2849n (aphids) and S0 = - 3.6514 + 0.1435n (thrips). The highest probability of error when making a decision was 3% for aphids and 2% for thrips, respectively. The maximum number of samples required to reach a decision was 63 for aphids and 95 for thrips. 相似文献
165.
166.
Sj?gren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder characterized by ichthyosis, mental retardation, spasticity, and deficient activity of fatty aldehyde dehydrogenase (FALDH). FALDH is an enzyme component of fatty alcohol:NAD oxidoreductase (FAO), which is necessary for fatty alcohol metabolism. To better understand the biochemical basis for the cutaneous symptoms in this disease, we investigated lipid metabolism in cultured keratinocytes from SLS patients. Enzyme activities of FALDH and FAO in SLS cells were <10% of normal. SLS keratinocytes accumulated 45-fold more fatty alcohol (hexadecanol, octadecanol, and octadecenol) than normal, whereas wax esters and 1-O-alkyl-2,3-diacylglycerols were increased by 5.6-fold and 7.5-fold, respectively. SLS keratinocytes showed a reduced incorporation of radioactive octadecanol into fatty acid (24% of normal) and triglyceride (13% of normal), but incorporation into wax esters and 1-O-alkyl-2,3-diacylglycerol was increased by 2.5-fold and 2.8-fold, respectively. Our results indicate that FALDH deficiency in SLS keratinocytes causes the accumulation and diversion of fatty alcohol into alternative biosynthetic pathways. The striking lipid abnormalities in cultured SLS keratinocytes are distinct from those seen in fibroblasts and may be related to the stratum corneum dysfunction and ichthyosis in SLS. 相似文献
167.
A benzene extract of the trunk of an Aniba species (Lauraceae) contained benzyl benzoate, benzyl salicylate, sitosterol and the neolignans (2S,3S,3aR)-3a-allyl-5-methoxy-3-methyl-2-piperonyl-2,3,3a,6-tetrahydro-6-oxobenzofuran (burchellin); (2S,3S,3aR)-3a-allyl-5-methoxy-3-methyl-2-veratryl-2,3,3a,6-tetrahydro-6-oxobenzofuran; (2S,3S,3aR)-3a-allyl-5,7-dimethoxy-3-methyl-2-veratryl-2,3,3a,6-tetrahydro-6-oxobenzofuran; (2S,3S,5S)-5-allyl-5-methoxy-3-methyl-2-veratryl-2,3,5,6-tetrahydro-6-oxo-benzofuran; (2R,3R)-7-methoxy-3-methyl-5-propenyl-2-veratryl-2,3-dihydrobenzofuran; rel-(1R,5R,6R,7R,8S)-1-allyl-8-hydroxy-3-methoxy-7-methyl-4-oxo-6-piperonylbicyclo[3,2,1]oct-2-ene (guianin); rel-(1S,5S,6S,7R,8R)-1-allyl-8-hydroxy-3,5-dimethoxy-7-methyl-4-oxo-6-piperonylbicyclo[3,2,1]oct-2-ene; rel-(1S,5S,6S,7R,8R)-8-acetoxy-1-allyl-3-hydroxy-5-methoxy-7-methyl-4-oxo-6-piperonyl-bicyclo[3,2,1]oct-2-ene; rel-1S,5S,6S,7R,8R)-8-acetoxy-3,5-dimethoxy-7-methyl-4-oxo-6-piperonylbicyclo[3,2,1]oct-2-ene; rel-(1R,5S,6R,7R)-1-allyl-3-methoxy-7-methyl-4,8-dioxo-6-piperonylbicyclo[3,2,1]oct-2-ene. 相似文献
168.
169.
Inactivation of the adenosine A(2A) receptor (A(2A)R) consistently protects against ischemic brain injury and other neural insults, but the relative contribution of A(2A)Rs on peripheral inflammatory cells versus A(2A)Rs expressed on neurons and glia is unknown. We created a chimeric mouse model in which A(2A)Rs on bone marrow-derived cells (BMDCs) were selectively inactivated or reconstituted by bone marrow transplantation. Selective reconstitution of A(2A)Rs on BMDCs (A(2A)R knockout mice transplanted with wild-type bone marrow cells) largely reinstates ischemic brain injury in global A(2A)R knockout mice. Conversely, selective inactivation of A(2A)Rs on BMDCs (wild-type mice transplanted with A(2A)R knockout bone marrow cells) attenuates infarct volumes and ischemia-induced expression of several proinflammatory cytokines in the brain, but exacerbates ischemic liver injury. These results indicate that the A(2A)R-stimulated cascade in BMDCs is an important modulator of ischemic brain injury and that ischemic brain and liver injuries are regulated distinctly by A(2A)Rs on BMDCs. 相似文献
170.
Silva EM Guillermo LV Ribeiro-Gomes FL De Meis J Pereira RM Wu Z Calegari-Silva TC Seabra SH Lopes UG Siegel RM Dosreis GA Lopes MF 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(10):6314-6321
During Trypanosoma cruzi infection, T cells up-regulate caspase-8 activity. To assess the role of caspase-8 in T cell-mediated immunity, we investigated the effects of caspase-8 inhibition on T cells in viral FLIP (v-FLIP) transgenic mice. Compared with wild-type controls, increased parasitemia was observed in v-FLIP mice infected with T. cruzi. There was a profound decrease in expansion of both CD4 and CD8 T cell subsets in the spleens of infected v-FLIP mice. We did not find differences in activation ratios of T cells from transgenic or wild-type infected mice. However, the numbers of memory/activated CD4 and CD8 T cells were markedly reduced in v-FLIP mice, possibly due to defective survival. We also found decreased production of IL-2 and increased secretion of type 2 cytokines, IL-4 and IL-10, which could enhance susceptibility to infection. Similar, but less pronounced, alterations were observed in mice treated with the caspase-8 inhibitor, zIETD. Furthermore, blockade of caspase-8 by zIETD in vitro mimicked the effects observed on T. cruzi infection in vivo, affecting the generation of activated/memory T cells and T cell cytokine production. Caspase-8 is also required for NF-kappaB signaling upon T cell activation. Blockade of caspase-8 by either v-FLIP expression or treatment with zIETD peptide decreased NF-kappaB responses to TCR:CD3 engagement in T cell cultures. These results suggest a critical role for caspase-8 in the establishment of T cell memory, cell signaling, and regulation of cytokine responses during protozoan infection. 相似文献