全文获取类型
收费全文 | 404篇 |
免费 | 22篇 |
国内免费 | 43篇 |
出版年
2023年 | 9篇 |
2022年 | 13篇 |
2021年 | 28篇 |
2020年 | 15篇 |
2019年 | 22篇 |
2018年 | 20篇 |
2017年 | 16篇 |
2016年 | 23篇 |
2015年 | 28篇 |
2014年 | 36篇 |
2013年 | 36篇 |
2012年 | 43篇 |
2011年 | 40篇 |
2010年 | 12篇 |
2009年 | 15篇 |
2008年 | 20篇 |
2007年 | 23篇 |
2006年 | 12篇 |
2005年 | 13篇 |
2004年 | 16篇 |
2003年 | 8篇 |
2002年 | 7篇 |
2000年 | 1篇 |
1999年 | 3篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1996年 | 2篇 |
1995年 | 2篇 |
1990年 | 1篇 |
1989年 | 1篇 |
排序方式: 共有469条查询结果,搜索用时 31 毫秒
411.
Barta TE Veal JM Rice JW Partridge JM Fadden RP Ma W Jenks M Geng L Hanson GJ Huang KH Barabasz AF Foley BE Otto J Hall SE 《Bioorganic & medicinal chemistry letters》2008,18(12):3517-3521
Hsp90 maintains the conformational stability of multiple proteins implicated in oncogenesis and has emerged as a target for chemotherapy. We report here the discovery of a novel small molecule scaffold that inhibits Hsp90. X-ray data show that the scaffold binds competitively at the ATP site on Hsp90. Cellular proliferation and client assays demonstrate that members of the series are able to inhibit Hsp90 at nanomolar concentrations. 相似文献
412.
Two microtubule-associated proteins of the Arabidopsis MAP65 family function differently on microtubules 下载免费PDF全文
The organization and dynamics of microtubules are regulated by microtubule-associated proteins, or MAPs. In Arabidopsis (Arabidopsis thaliana), nine genes encode proteins of the evolutionarily conserved MAP65 family. We proposed that different MAP65s might have distinct roles in the interaction with microtubules. In this study, two AtMAP65 proteins, AtMAP65-1 and AtMAP65-6, were chosen to test this hypothesis in vitro. Although both fusion proteins were able to cosediment with microtubules in vitro, different properties on tubulin polymerization and microtubule bundling were observed. AtMAP65-1 was able to promote tubulin polymerization, enhance microtubule nucleation, and decrease the critical concentration for tubulin polymerization. It also induced the formation of large microtubule bundles by forming cross-bridges between microtubules evenly along the whole length of microtubules. In the presence of AtMAP65-1, microtubule bundles were more resistant to cold and dilution treatments. AtMAP65-6, however, demonstrated no activity in promoting tubulin polymerization and stabilizing preformed microtubules. AtMAP65-6 induced microtubules to form a mesh-like network with individual microtubules. Cross-bridge-like interactions were only found at regional sites between microtubules. The microtubule network induced by AtMAP65-6 was more resistant to high concentration of NaCl than the bundles induced by AtMAP65-1. Purified monospecific anti-AtMAP65-6 antibodies revealed that AtMAP65-6 was associated with mitochondria in Arabidopsis cells. It was concluded that these two MAP65 proteins were targeted to distinct sites, thus performing distinct functions in Arabidopsis cells. 相似文献
413.
Jianping Liu Lifeng Pan 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2018,1865(10):1410-1422
Linear ubiquitin chain is a latest discovered type of poly-ubiquitin chain that is broadly involved in innate immune and inflammatory pathways. Dysfunctions in its assembly, recognition or disassembly are intimately related with numerous immunodeficiency or autoimmune diseases. Our understanding of the molecular mechanism for linear ubiquitin chain formation, recognition and disassembly has being significantly evolved in recent years, with particular contribution from the biochemical and structural characterizations of related proteins. Here, we focus on the relevant proteins for the synthesis, recognition and digestion of linear ubiquitin chain, and review recent findings to summarize currently known molecular mechanism from a perspective of structural biology. 相似文献
414.
无瓣海桑和白骨壤是我国红树林造林中较具代表性的两种植物,通过对10龄无瓣海桑纯林、10龄白骨壤纯林、6龄无瓣海桑纯林和6龄白骨壤纯林的调查分析发现:1)无瓣海桑和白骨壤植株根系水平分布的半径和地下根系垂直深度均随树龄的增加而增加,其中10龄无瓣海桑和白骨壤植株的水平分布半径分别为30.6 m和3.85 m,6龄无瓣海桑和白骨壤植株的水平分布半径为9.47 m和2.23 m; 10龄和6龄无瓣海桑和白骨壤植株的地下根系分布深度分别为60 cm和40 cm; 2)无瓣海桑和白骨壤植株地表呼吸根系密度、高度、基径的分布范围会随其树龄的增加而增加,但其根系密度、高度和基径总体表现为由树冠向外逐渐减小; 3)无瓣海桑和白骨壤植株地下根系主要分别于0—20 cm表层,地下根系密度随树龄的增加而增多,具体如10龄无瓣海桑和白骨壤根系分布深度为60 cm,其中76.3%和77.6%根系分布于0—20 cm深度; 6龄无瓣海桑和白骨壤根系分布深度为40 cm,其中91.9%和91.6%根系集中于0—20 cm土层。这些结果能为进一步理解红树林的促淤保滩功能提供新启示。 相似文献
415.
Adaptive evolution to a high purine and fat diet of carnivorans revealed by gut microbiomes and host genomes 下载免费PDF全文
Lifeng Zhu Qi Wu Cao Deng Mengjie Zhang Chenglin Zhang Hua Chen Guoqing Lu Fuwen Wei 《Environmental microbiology》2018,20(5):1711-1722
Carnivorous members of the Carnivora reside at the apex of food chains and consume meat‐only diets, rich in purine, fats and protein. Here, we aimed to identify potential adaptive evolutionary signatures compatible with high purine and fat metabolism based on analysis of host genomes and symbiotic gut microbial metagenomes. We found that the gut microbiomes of carnivorous Carnivora (e.g., Felidae, Canidae) clustered in the same clade, and other clades comprised omnivorous and herbivorous Carnivora (e.g., badgers, bears and pandas). The relative proportions of genes encoding enzymes involved in uric acid degradation were higher in the gut microbiomes of meat‐eating carnivorans than plant‐eating species. Adaptive amino acid substitutions in two enzymes, carnitine O‐palmitoyltransferase 1 (CPT1A) and lipase F (LIPF), which play a role in fat digestion, were identified in Felidae‐Candidae species. Carnivorous carnivorans appear to endure diets high in purines and fats via gut microbiomic and genomic adaptations. 相似文献
416.
DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death 下载免费PDF全文
Chaosi Li Di Wang Wei Wu Wei Yang Syed Zahid Ali Shah Ying Zhao Yuhan Duan Lu Wang Xiangmei Zhou Deming Zhao Lifeng Yang 《Aging cell》2018,17(1)
Mitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases. Dynamin‐like protein 1 (DLP1) is one of the key regulators of mitochondrial fission. In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction in neurons using in vitro and in vivo prion disease models. Mitochondria became fragmented and redistributed from axons to soma, correlated with increased mitochondrial DLP1 expression in murine primary neurons (N2a cells) treated with the prion peptide PrP106–126 in vitro as well as in prion strain‐infected hamster brain in vivo. Suppression of DLP1 expression by DPL1 RNAi inhibited prion‐induced mitochondrial fragmentation and dysfunction (measured by ADP/ATP ratio, mitochondrial membrane potential, and mitochondrial integrity). We also demonstrated that DLP1 RNAi is neuroprotective against prion peptide in N2a cells as shown by improved cell viability and decreased apoptosis markers, caspase 3 induced by PrP106–126. On the contrary, overexpression of DLP1 exacerbated mitochondrial dysfunction and cell death. Moreover, inhibition of DLP1 expression ameliorated PrP106–126‐induced neurite loss and synaptic abnormalities (i.e., loss of dendritic spine and PSD‐95, a postsynaptic scaffolding protein as a marker of synaptic plasticity) in primary neurons, suggesting that altered DLP1 expression and mitochondrial fragmentation are upstream events that mediate PrP106–126‐induced neuron loss and degeneration. Our findings suggest that DLP1‐dependent mitochondrial fragmentation and redistribution plays a pivotal role in PrPSc‐associated mitochondria dysfunction and neuron apoptosis. Inhibition of DLP1 may be a novel and effective strategy in the prevention and treatment of prion diseases. 相似文献
417.
Fushan Shi Lifeng Yang Mohammed Kouadir Yang Yang Tianjian Ding Jihong Wang Xiangmei Zhou Xiaomin Yin Deming Zhao 《Journal of neurochemistry》2013,124(2):168-174
The cellular prion protein (PrPC) is a glycoprotein anchored by glycosylphosphatidylinositol (GPI) to the cell surface and is abundantly expressed in the central nervous system. Numerous studies have suggested a protective function for PrPC, including protection from ischemic and excitotoxic lesions and several apoptotic insults, and recent reports have shown that PrPC has a context‐dependent neuroprotective function. In this study, we investigated the effect of PPNP down‐regulation on various forms of microglial activation. We first examined the mRNA expression of PRNP upon exposure to IFN‐γ, IL‐4, or IL‐10 in BV2 microglia. We then analyzed the effect of si‐RNA‐mediated disruption of PRNP on different parameters of microglial activation in IFN‐γ‐, IL‐4‐, or IL‐10‐stimulated microglia. The results showed that PRNP mRNA expression was invariably down‐regulated in microglia upon exposure to IFN‐γ, IL‐4, or IL‐10. PRNP silencing prior to cytokines treatment reduced the responsiveness of microglia to INF‐γ treatment, significantly altered IL‐4‐induced microglial activation phenotype, and had no effect on IL‐10‐induced microglial activation. Together, these results support a role of PrPC in the modulation of the shift of microglia from a quiescent state to an activated phenotype and in the regulation of the microglial response during classical and alternative activation. 相似文献
418.
Zhipeng Wang Meng Fu Lifeng Wang Juanjuan Liu Yuhua Li Cord Brakebusch Qibing Mei 《The Journal of biological chemistry》2013,288(27):20093-20099
PAK1 plays an important role in proliferation and tumorigenesis, at least partially by promoting ERK phosphorylation of C-RAF (Ser-338) or MEK1 (Ser-298). We observed how that overexpression of a kinase-dead mutant form of PAK1 increased phosphorylation of MEK1/2 (Ser-217/Ser-221) and ERK (Thr-202/Tyr-204), although phosphorylation of B-RAF (Ser-445) and C-RAF (Ser-338) remained unchanged. Furthermore, increased activation of the PAK1 activator Rac1 induced the formation of a triple complex of Rac1, PAK1, and MEK1 independent of the kinase activity of PAK1. These data suggest that PAK1 can stimulate MEK activity in a kinase-independent manner, probably by serving as a scaffold to facilitate interaction of C-RAF. 相似文献
419.
In this work, a new signal amplified strategy based on target-induced strand release coupling cleavage of nicking endonuclease for the ultrasensitive detection of ochratoxin A (OTA) is reported. OTA aptamer (DNA1) and OTA aptamer complementary (DNA2) were immobilized onto a magnetic bead (MB). In the presence of OTA, DNA2 was dissociated and released from the MB. The released DNA2 then hybridized with DNA3, which was linked at the 5' terminus of the amplification template and can extend along the template in the presence of Phi 29 DNA polymerase. The formed double-stranded DNA was cleaved by nicking endonuclease Nb.BbvCI and produced a short single-stranded DNA. The cleaved DNA strand generated a new site by Phi 29 DNA polymerase and the process of extension and cleavage was cyclical. Thus, a amount of the short single-stranded DNA were produced. Using DNA and ABEI labeled carboxylic silica nanoparticles chemiluminescence (CL) probe, the short single-stranded DNA could be sensitively detected. The CL intensity (ΔI) versus the concentration of OTA was linear in the range from 1.0×10(-12) to 5.0×10(-8)gmL(-1). The detection limit was 3.0×10(-13)gmL(-1), and the RSD was 3.4% at 1.0×10(-10)gmL(-1) (n=7). The developed method has been applied to detect OTA in naturally contaminated wheat samples. Due to its simplicity, sensitivity and no need of specific recognition of aptamer for cleavage, this CL bioassay offers a promising approach for the detection of OTA and other biomolecules. 相似文献
420.
南方小花蝽在不同空间及笼罩条件下对西花蓟马的控制作用 总被引:2,自引:0,他引:2
利用小花蝽控制外来害虫西花蓟马越来越受到人们的重视。本文在室内研究了5种空间异质条件下南方小花蝽对西花蓟马的捕食作用,并研究了笼罩条件下4种比例释放南方小花蝽对西花蓟马的控制效果。结果表明,不同空间异质下,南方小花蝽对西花蓟马的功能反应均符合Holling Ⅱ圆盘方程;以瞬时攻击率和寻找效应为评价指标,发现南方小花蝽在小容器中的瞬时攻击率(a')最高,为0.9204,寻找效应最好;在大容器且空间异质最复杂的处理中的瞬时攻击率(a')最低,为0.6303,寻找效应最差。在笼罩条件下,以3:120和6:120比例释放南方小花蝽和西花蓟马,其控制效果差;以9:120的比例释放,5周后对西花蓟马成虫和若虫的控制效果分别达到74.70%和81.01%;以15:120比例释放,5周后对西花蓟马成虫和若虫的控制效果分别达到95.71%和89.02%。结果显示空间越小或异质性越简单,越利于南方小花蝽捕食西花蓟马。若实际生产中采用9:120的益害比例释放南方小花蝽,既可以达到对西花蓟马较好的控制效果,又相对节约成本。 相似文献