全文获取类型
收费全文 | 31218篇 |
免费 | 2344篇 |
国内免费 | 2266篇 |
专业分类
35828篇 |
出版年
2024年 | 65篇 |
2023年 | 435篇 |
2022年 | 1072篇 |
2021年 | 1757篇 |
2020年 | 1158篇 |
2019年 | 1555篇 |
2018年 | 1416篇 |
2017年 | 991篇 |
2016年 | 1428篇 |
2015年 | 1979篇 |
2014年 | 2377篇 |
2013年 | 2588篇 |
2012年 | 2822篇 |
2011年 | 2540篇 |
2010年 | 1484篇 |
2009年 | 1373篇 |
2008年 | 1612篇 |
2007年 | 1421篇 |
2006年 | 1163篇 |
2005年 | 908篇 |
2004年 | 749篇 |
2003年 | 714篇 |
2002年 | 541篇 |
2001年 | 485篇 |
2000年 | 460篇 |
1999年 | 430篇 |
1998年 | 265篇 |
1997年 | 254篇 |
1996年 | 253篇 |
1995年 | 229篇 |
1994年 | 218篇 |
1993年 | 150篇 |
1992年 | 199篇 |
1991年 | 179篇 |
1990年 | 126篇 |
1989年 | 98篇 |
1988年 | 81篇 |
1987年 | 69篇 |
1986年 | 39篇 |
1985年 | 44篇 |
1984年 | 24篇 |
1983年 | 30篇 |
1982年 | 16篇 |
1981年 | 18篇 |
1980年 | 7篇 |
1979年 | 5篇 |
1965年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Wenzheng Zhang Sheng Fu Xuefeng Liu Xuelian Zhao Wenchi Zhang Wei Peng Congying Wu Yuanyuan Li Xuemei Li Mark Bartlam Zong-Hao Zeng Qimin Zhan Zihe Rao 《蛋白质与细胞》2011,2(10):814
The human Gadd45 protein family plays critical roles in DNA repair, negative growth control, genomic stability, cell cycle checkpoints and apoptosis. Here we report the crystal structure of human Gadd45, revealing a unique dimer formed via a bundle of four parallel helices, involving the most conserved residues among the Gadd45 isoforms. Mutational analysis of human Gadd45 identified a conserved, highly acidic patch in the central region of the dimer for interaction with the proliferating cell nuclear antigen (PCNA), p21 and cdc2, suggesting that the parallel dimer is the active form for the interaction. Cellular assays indicate that: (1) dimerization of Gadd45 is necessary for apoptosis as well as growth inhibition, and that cell growth inhibition is caused by both cell cycle arrest and apoptosis; (2) a conserved and highly acidic patch on the dimer surface, including the important residues Glu87 and Asp89, is a putative interface for binding proteins related to the cell cycle, DNA repair and apoptosis. These results reveal the mechanism of self-association by Gadd45 proteins and the importance of this self-association for their biological function. 相似文献
992.
本研究旨在探讨长QT综合征(long QT syndromes,LQTS)室性心律失常发生的性别差异及其电生理机制,初步观察了不同性别兔LQT2模型左心事原已存在的电生理异质性和心事复极动力学的特征。实验分为3组,上下常组以标准台氏液灌流;LQT2模型组给予含100gmol/L dl-sotalol的台式液灌流;LQT2模型+低钾组给了含3.0mmol/LKCl、100μmol/L dl-sotalol的台式液灌流。采用冠状动脉旋支灌注兔左室心肌楔形组织块标本,应用浮置玻璃微电极记录技术进行记录。给予基础刺激周长(basic cycle length,BCL)为500、l000和2000ms的S1刺激,同步记录心事肌内膜侧、外膜侧细胞动作电位,并记录跨壁心电图:在BCL为500和1000ms时加用S2程序刺激以记录动作电位时程(action potential duration,APD)恢复曲线。研究发现:在不同刺激频率时,3组实验雌兔心肌细胞的跨壁复极化离散(transmural dispersion of repolarization,TDR)、APD恢复曲线斜率均大于雄兔,有显著性差异(P〈0.05),并呈频率依赖性;LQT2模型组及LQT2模型+低钾组雌雄兔TDR、APD恢复曲线斜率较正常组明显增人(P〈0.01)。BCL为1000ms时,LQT2模型组雌兔7例中1例发生尖端扭转性窀性心动过速(torsade de pointes,TdP);LQT2模型+低钾组雌兔7例中5例诱发TdP,雄兔7例中2例诱发TdP,有显著性差异(P〈0.05)。结果提示:LQT2模型心肌原已存在的电生理异质性和动态异质性均有明显的性别差异,并≯频率依赖性。存LQT2模型中,TDR以及APD恢复曲线斜率的增大可能是雌性动物较雄性更易发生尖端扭转性心律失常的原因。 相似文献
993.
Yixiong Wang Lixia Chen Feng Zhao Zhihui Liu Jianqiang Li Feng Qiu 《Journal of Molecular Catalysis .B, Enzymatic》2011,68(1):83-88
Microbial transformation of neoandrographolide (1), was performed by Mucor spinosus (AS 3.2450). Ten metabolites were obtained and identified as 14-deoxyandrographolide (2), 17,19-dihydroxy-8,13-ent-labdadien-16,15-olide (3), 3,14-dideoxyandrographolide (4), 7β-hydroxy-3,14-dideoxyandrographolide (5), 17,19-dihydroxy-7,13-ent-labdadien-16,15-olide (6), 8(17),13-ent-labdadien-16,15-olid-19-oic acid (7), 8α,17β-epoxy-3,14-dideoxyandrographolide (8), 8β,17,19-trihydroxy-ent-labd-13-en-16, 15-olide (9), phlogantholide-A (10), 19-[(β-d-glucopyranosyl)oxy]-19-oxo-ent-labda-8(17),13-dien-16,15-olide (11) by spectroscopic and chemical means. Among them, products 3, 5, 6, 8 and 9 were characterized as new compounds. The inhibitory effects of compounds 1–11 on nitric oxide production in lipopolysaccharide-activated macrophages were evaluated and their preliminary structure–activity relationships (SAR) were discussed. 相似文献
994.
FUNDC1 regulates mitochondrial dynamics at the ER–mitochondrial contact site under hypoxic conditions 下载免费PDF全文
Wen Li Haixia Zhuang Xingliang Zhang Hao Chen Shupeng Li Yue Yang Yue Lu Jingjing Wang Runzhi Zhu Liangqing Zhang Senfang Sui Ning Tan Bin Zhao Jingjing Zhang Longxuan Li Du Feng 《The EMBO journal》2016,35(13):1368-1384
In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called mitophagy. The ER–mitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells. 相似文献
995.
Virulent Mycobacterium bovis Beijing Strain Activates the NLRP7 Inflammasome in THP-1 Macrophages 总被引:1,自引:0,他引:1
Yang Zhou Syed Zahid Ali Shah Lifeng Yang Zhongqiu Zhang Xiangmei Zhou Deming Zhao 《PloS one》2016,11(4)
Mycobacterium bovis is the causative agent of tuberculosis in a wide range of mammals, including humans. Macrophages are the first line of host defense. They secrete proinflammatory cytokines, such as interleukin-1 beta (IL-1β), in response to mycobacterial infection, but the underlying mechanisms by which human macrophages are activated and release IL-1β following M. bovis infection are poorly understood. Here we show that the ‘nucleotide binding and oligomerization of domain-like receptor (NLR) family pyrin domain containing 7 protein’ (NLRP7) inflammasome is involved in IL-1β secretion and caspase-1 activation induced by M. bovis infection in THP-1 macrophages. NLRP7 inflammasome activation promotes the induction of pyroptosis as well as the expression of tumor necrosis factor alpha (TNF-α), Chemokine (C-C motif) ligand 3 (CCL3) and IL-1β mRNAs. Thus, the NLRP7 inflammasome contributes to IL-1β secretion and induction of pyroptosis in response to M. bovis infection in THP-1 macrophages. 相似文献
996.
Fang‐Jie Zhao 《Molecular microbiology》2016,100(6):928-930
Microorganisms have evolved various mechanisms to detoxify arsenic, an ubiquitous environmental toxin. Known mechanisms include arsenite efflux, arsenate reduction followed by arsenite efflux and arsenite methylation. In this issue, Chen et al. describe a novel mechanism for arsenate detoxification via synergistic interaction of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) and a major facilitator superfamily protein (ArsJ). They propose that GAPDH catalyzes the formation of 1‐arseno‐3‐phosphoglycerate, which is then extruded out of the cell by ArsJ. The significance of this pathway and questions for further research are discussed. 相似文献
997.
The Diversity and Anti-Microbial Activity of Endophytic Actinomycetes Isolated from Medicinal Plants in Panxi Plateau,China 总被引:1,自引:0,他引:1
Ke Zhao Petri Penttinen Tongwei Guan Jing Xiao Qiang Chen Jun Xu Kristina Lindström Lili Zhang Xiaoping Zhang Gary A. Strobel 《Current microbiology》2011,62(1):182-190
Traditional Chinese medicinal plants are sources of biologically active compounds, providing raw material for pharmaceutical,
cosmetic and fragrance industries. The endophytes of medicinal plants participate in biochemical pathways and produce analogous
or novel bioactive compounds. Panxi plateau in South-west Sichuan in China with its unique geographical and climatological
characteristics is a habitat of a great variety of medicinal plants. In this study, 560 endophytic actinomycetes were isolated
from 26 medicinal plant species in Panxi plateau. 60 isolates were selected for 16S rDNA-RFLP analysis and 14 representative
strains were chosen for 16S rDNA sequencing. According to the phylogenetic analysis, seven isolates were Streptomyces sp., while the remainder belonged to genera Micromonospora, Oerskovia, Nonomuraea, Promicromonospora and Rhodococcus. Antimicrobial activity analysis combined with the results of amplifying genes coding for polyketide synthetase (PKS-I, PKS-II)
and nonribosomal peptide synthetase (NRPS) showed that endophytic actinomycetes isolated from medicinal plants in Panxi plateau
had broad-spectrum antimicrobial activity and potential natural product diversity, which further proved that endophytic actinomycetes
are valuable reservoirs of novel bioactive compounds. 相似文献
998.
M. Wang Z. Peng L. Wang J. Zhao J. Che G. Xia 《Russian Journal of Plant Physiology》2011,58(1):133-141
The protoplasts of tall fescue (Festuca arundinacea Schreb.) were fused with those of Bupleurum scorzonerifolium Willd. The latter were irradiated with UV at an intensity of 380 μW/cm2 for 0 s (combination I), 30 s (combination II), and 60 s (combination III) before fusion. Putative hybrid calli, leaves,
and shoots were generated from the fusion products. They were recognized as somatic hybrids by a combined analysis of chromosome
numbers, isozyme, RAPD, and 5S rDNA spacer sequence. The hybrid calli with morphogenetic ability and leaves/shoots differentiation
had the B. scorzonerifolium phenotype, whether they were derived from symmetric fusion (UV 0 s) or asymmetric fusion (UV 30 s/60 s). Cytological tests
revealed that these hybrids contained the complete set (12) of B. scorzonerifolium chromosomes and 0–4 partner tall fescue chromosomes. The tall fescue chromosomes were rapidly eliminated in combinations
II and III, but gradually lost in combination I. It was noted that the green leaves and shoots were produced earlier, and
the differentiation frequency was higher in combinations II and III than in combination I, which corresponded to the speed
of elimination of the tall fescue chromosomes in the hybrids. Therefore, UV irradiation can indirectly promote elimination
of tall fescue chromosomes and hybrid differentiation. B. scorzonerifolium can repel partner chromosomes with mechanism that differs from UV. 相似文献
999.
The antifungal activity and mechanism of fengycin in the presence and absence of commercial surfactin against Rhizopus stolonifer were investigated. The MIC (minimal inhibitory concentration) of fengycin without commercial surfactin added was 0.4 mg/ml
while the MIC of fengycin with commercial surfactin added was 2.0 mg/ml. Fengycin acted on cell membrane and cellular organs
and inhibited DNA synthesis. The antifungal effect of fengycin was reduced after commercial surfactin was added. All these
results suggest that the fungal cell membrane may be the primary target of fengycin action and commercial surfactin may reduce
the antifungal activity of fengycin. 相似文献
1000.
Impact of microbial transformation of food on health - from fermented foods to fermentation in the gastro-intestinal tract 总被引:2,自引:0,他引:2
van Hylckama Vlieg JE Veiga P Zhang C Derrien M Zhao L 《Current opinion in biotechnology》2011,22(2):211-219
Fermentation of food components by microbes occurs both during certain food production processes and in the gastro-intestinal tract. In these processes specific compounds are produced that originate from either biotransformation reactions or biosynthesis, and that can affect the health of the consumer. In this review, we summarize recent advances highlighting the potential to improve the nutritional status of a fermented food by rational choice of food-fermenting microbes. The vast numbers of microbes residing in the human gut, the gut microbiota, also give rise to a broad array of health-active molecules. Diet and functional foods are important modulators of the gut microbiota activity that can be applied to improve host health. A truly multidisciplinary approach is required to increase our understanding of the molecular mechanisms underlying health beneficial effects that arise from the interaction of diet, microbes and the human body. 相似文献