全文获取类型
收费全文 | 868篇 |
免费 | 93篇 |
专业分类
961篇 |
出版年
2022年 | 8篇 |
2021年 | 17篇 |
2019年 | 8篇 |
2018年 | 8篇 |
2017年 | 7篇 |
2016年 | 21篇 |
2015年 | 17篇 |
2014年 | 16篇 |
2013年 | 27篇 |
2012年 | 44篇 |
2011年 | 48篇 |
2010年 | 27篇 |
2009年 | 30篇 |
2008年 | 36篇 |
2007年 | 37篇 |
2006年 | 29篇 |
2005年 | 34篇 |
2004年 | 24篇 |
2003年 | 22篇 |
2002年 | 20篇 |
2001年 | 18篇 |
2000年 | 29篇 |
1999年 | 21篇 |
1998年 | 13篇 |
1995年 | 13篇 |
1994年 | 11篇 |
1993年 | 9篇 |
1992年 | 9篇 |
1991年 | 8篇 |
1990年 | 10篇 |
1989年 | 13篇 |
1988年 | 18篇 |
1987年 | 7篇 |
1986年 | 14篇 |
1985年 | 20篇 |
1984年 | 19篇 |
1983年 | 22篇 |
1982年 | 13篇 |
1981年 | 15篇 |
1979年 | 11篇 |
1977年 | 14篇 |
1976年 | 10篇 |
1975年 | 14篇 |
1974年 | 8篇 |
1973年 | 7篇 |
1972年 | 20篇 |
1971年 | 12篇 |
1970年 | 6篇 |
1969年 | 11篇 |
1968年 | 14篇 |
排序方式: 共有961条查询结果,搜索用时 15 毫秒
91.
Complete and integrated pyrene degradation pathway in Mycobacterium vanbaalenii PYR-1 based on systems biology
下载免费PDF全文
![点击此处可从《Journal of bacteriology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Kim SJ Kweon O Jones RC Freeman JP Edmondson RD Cerniglia CE 《Journal of bacteriology》2007,189(2):464-472
Mycobacterium vanbaalenii PYR-1 was the first bacterium isolated by virtue of its ability to metabolize the high-molecular-weight polycyclic aromatic hydrocarbon (PAH) pyrene. We used metabolic, genomic, and proteomic approaches in this investigation to construct a complete and integrated pyrene degradation pathway for M. vanbaalenii PYR-1. Genome sequence analyses identified genes involved in the pyrene degradation pathway that we have proposed for this bacterium. To identify proteins involved in the degradation, we conducted a proteome analysis of cells exposed to pyrene using one-dimensional gel electrophoresis in combination with liquid chromatography-tandem mass spectrometry. Database searching performed with the M. vanbaalenii PYR-1 genome resulted in identification of 1,028 proteins with a protein false discovery rate of <1%. Based on both genomic and proteomic data, we identified 27 enzymes necessary for constructing a complete pathway for pyrene degradation. Our analyses indicate that this bacterium degrades pyrene to central intermediates through o-phthalate and the beta-ketoadipate pathway. Proteomic analysis also revealed that 18 enzymes in the pathway were upregulated more than twofold, as indicated by peptide counting when the organism was grown with pyrene; three copies of the terminal subunits of ring-hydroxylating oxygenase (NidAB2, MvanDraft_0817/0818, and PhtAaAb), dihydrodiol dehydrogenase (MvanDraft_0815), and ring cleavage dioxygenase (MvanDraft_3242) were detected only in pyrene-grown cells. The results presented here provide a comprehensive picture of pyrene metabolism in M. vanbaalenii PYR-1 and a useful framework for understanding cellular processes involved in PAH degradation. 相似文献
92.
We have applied a quantitative structure-activity relationship (QSAR) approach to analyze the chemical parameters that determine the relative sensitivity of olfaction and nasal chemesthesis to a common set of volatile organic compounds (VOCs). We used previously reported data on odor detection thresholds (ODTs) and nasal pungency thresholds (NPTs) from 64 VOCs belonging to 7 chemical series (acetate esters, carboxylic acids, alcohols, aliphatic aldehydes, alkylbenzenes, ketones, and terpenes). The analysis tested whether NPTs could be used to separate out "selective" chemosensory effects (i.e., those resting on the transfer of VOCs from the gas phase to the receptor phase) from "specific" chemosensory effects in ODTs. Previous work showed that selective effects overwhelmingly dominate chemesthetic potency whereas both selective and specific effects control olfactory potency. We conclude that it is indeed possible to use NPTs to separate out selective from specific effects in ODTs. Among the series studied, aldehydes and acids, except for formic acid, show clear specific effects in their olfactory potency. Furthermore, for VOCs whose odor potency rests mainly on selective effects, we have developed a QSAR equation that can predict their ODTs based on their NPTs. 相似文献
93.
Boddey JA Day CJ Flegg CP Ulrich RL Stephens SR Beacham IR Morrison NA Peak IR 《Cellular microbiology》2007,9(2):514-531
94.
Silicon has gradually been recognized to be an essential trace element in the normal metabolism of higher animals, and the role of silicon in the human body has aroused interests in the biomedical community. In fact, the interactions between silicon-based devices and the human body such as biosensors and microelectromechanical systems (MEMS) often suffer from poor biocompatibility. In this work, hydrogen plasma immersion ion implantation (H-PIII) is conducted to improve the bioactivity or bone conductivity of silicon. In order to investigate the formation mechanism of bone-like apatite on the surface of the hydrogen implanted silicon wafer, two comparative experiments, hydrogenation and argon bombardment, are performed. The H-PIII sample exhibits an amorphous surface consisting of Si-H bonds. After immersion in simulated body fluids, a negatively charged surface containing the functional group ([triple bond]Si-O-) is produced and bone-like apatite is observed to nucleate and grow on the surface. The surface of the H-PIII silicon wafer favors the adhesion and growth of osteoblast cells and good cytocompatibility may be inferred. 相似文献
95.
Initial gene vector dosing for studying symptomatology of amyotrophic lateral sclerosis in non‐human primates
下载免费PDF全文
![点击此处可从《Journal of medical primatology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
96.
Luis J. García-Rodríguez Giacomo De?Piccoli Vanessa Marchesi Richard C. Jones Ricky D. Edmondson Karim Labib 《Nucleic acids research》2015,43(18):8830-8838
Defects during chromosome replication in eukaryotes activate a signaling pathway called the S-phase checkpoint, which produces a multifaceted response that preserves genome integrity at stalled DNA replication forks. Work with budding yeast showed that the ‘alternative clamp loader’ known as Ctf18-RFC acts by an unknown mechanism to activate the checkpoint kinase Rad53, which then mediates much of the checkpoint response. Here we show that budding yeast Ctf18-RFC associates with DNA polymerase epsilon, via an evolutionarily conserved ‘Pol ϵ binding module’ in Ctf18-RFC that is produced by interaction of the carboxyl terminus of Ctf18 with the Ctf8 and Dcc1 subunits. Mutations at the end of Ctf18 disrupt the integrity of the Pol ϵ binding module and block the S-phase checkpoint pathway, downstream of the Mec1 kinase that is the budding yeast orthologue of mammalian ATR. Similar defects in checkpoint activation are produced by mutations that displace Pol ϵ from the replisome. These findings indicate that the association of Ctf18-RFC with Pol ϵ at defective replication forks is a key step in activation of the S-phase checkpoint. 相似文献
97.
Carla B. Schubiger Lisa H. Orfe Ponnerassery S. Sudheesh Kenneth D. Cain Devendra H. Shah Douglas R. Call 《Applied and environmental microbiology》2015,81(2):658-665
Flavobacterium psychrophilum causes bacterial cold-water disease in multiple fish species, including salmonids. An autochthonous Enterobacter strain (C6-6) inhibits the in vitro growth of F. psychrophilum, and when ingested as a putative probiotic, it provides protection against injection challenge with F. psychrophilum in rainbow trout. In this study, low-molecular-mass (≤3 kDa) fractions from both Enterobacter C6-6 and Escherichia coli K-12 culture supernatants inhibited the growth of F. psychrophilum. The ≤3-kDa fraction from Enterobacter C6-6 was analyzed by SDS-PAGE, and subsequent tandem mass spectroscopy identified EcnB, which is a small membrane lipoprotein that is a putative pore-forming toxin. Agar plate diffusion assays demonstrated that ecnAB knockout strains of both Enterobacter C6-6 and E. coli K-12 no longer inhibited F. psychrophilum (P < 0.001), while ecnAB-complemented knockout strains recovered the inhibitory phenotype (P < 0.001). In fish experiments, the engineered strains (C6-6 ΔecnAB and C6-6 ΔecnAB<pET101::ecnAB>) and the wild-type strain (C6-6) were added to the fish diet every day for 38 days. On day 11, the fish were challenged by injection with a virulent strain of F. psychrophilum (CSF 259-93). Fish that were fed C6-6 had significantly longer survival than fish fed the ecnAB knockout strain (P < 0.0001), while fish fed the complemented knockout strain recovered the probiotic phenotype (P = 0.61). This entericidin is responsible for the probiotic activity of Enterobacter C6-6, and it may present new opportunities for therapeutic and prophylactic treatments against similarly susceptible pathogens. 相似文献
98.
Voltage-gated calcium channels are a family of integral membrane calcium-selective proteins found in all excitable and many nonexcitable cells. Calcium influx affects membrane electrical properties by depolarizing cells and generally increasing excitability. Calcium entry further regulates multiple intracellular signaling pathways as well as the biochemical factors that mediate physiological functions such as neurotransmitter release and muscle contraction. Small changes in the biophysical properties or expression of calcium channels can result in pathophysiological changes leading to serious chronic disorders. In humans, mutations in calcium channel genes have been linked to a number of serious neurological, retinal, cardiac, and muscular disorders. 相似文献
99.
Richards P Didszun C Campesan S Simpson A Horley B Young KW Glynn P Cain K Kyriacou CP Giorgini F Nicotera P 《Cell death and differentiation》2011,18(2):191-200
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the huntingtin protein (htt) that mediates formation of intracellular protein aggregates. In the brains of HD patients and HD transgenic mice, accumulation of protein aggregates has been causally linked to lesions in axo-dendritic and synaptic compartments. Here we show that dendritic spines - sites of synaptogenesis - are lost in the proximity of htt aggregates because of functional defects in local endosomal recycling mediated by the Rab11 protein. Impaired exit from recycling endosomes (RE) and association of endocytosed protein with intracellular structures containing htt aggregates was demonstrated in cultured hippocampal neurons cells expressing a mutant htt fragment. Dendrites in hippocampal neurons became dystrophic around enlarged amphisome-like structures positive for Rab11, LC3 and mutant htt aggregates. Furthermore, Rab11 overexpression rescues neurodegeneration and dramatically extends lifespan in a Drosophila model of HD. Our findings are consistent with the model that mutant htt aggregation increases local autophagic activity, thereby sequestering Rab11 and diverting spine-forming cargo from RE into enlarged amphisomes. This mechanism may contribute to the toxicity caused by protein misfolding found in a number of neurodegenerative diseases. 相似文献
100.
de las Heras A Cain RJ Bielecka MK Vázquez-Boland JA 《Current opinion in microbiology》2011,14(2):118-127
Listeria monocytogenes is the causative agent of listeriosis, a severe foodborne infection. These bacteria live as soil saprotrophs on decaying plant matter but also as intracellular parasites, using the cell cytosol as a replication niche. PrfA, a regulatory protein, integrates a number of environmental cues that signal the transition between these two contrasting lifestyles, activating a set of key virulence factors during host infection. While a number of details concerning the general mode of action of this virulence master switch have been elucidated, others remain unsolved. Recent work has revealed additional mechanisms that contribute to L. monocytogenes virulence modulation, often via cross-talk with PrfA, or by regulating new genes involved in host colonization. 相似文献