全文获取类型
收费全文 | 1536篇 |
免费 | 99篇 |
国内免费 | 2篇 |
出版年
2023年 | 8篇 |
2022年 | 28篇 |
2021年 | 45篇 |
2020年 | 21篇 |
2019年 | 35篇 |
2018年 | 40篇 |
2017年 | 35篇 |
2016年 | 66篇 |
2015年 | 69篇 |
2014年 | 80篇 |
2013年 | 110篇 |
2012年 | 111篇 |
2011年 | 154篇 |
2010年 | 54篇 |
2009年 | 70篇 |
2008年 | 96篇 |
2007年 | 81篇 |
2006年 | 73篇 |
2005年 | 70篇 |
2004年 | 55篇 |
2003年 | 51篇 |
2002年 | 53篇 |
2001年 | 23篇 |
2000年 | 19篇 |
1999年 | 14篇 |
1998年 | 14篇 |
1997年 | 10篇 |
1996年 | 8篇 |
1995年 | 5篇 |
1994年 | 4篇 |
1993年 | 8篇 |
1992年 | 5篇 |
1991年 | 4篇 |
1990年 | 5篇 |
1989年 | 7篇 |
1988年 | 4篇 |
1987年 | 7篇 |
1985年 | 5篇 |
1984年 | 8篇 |
1983年 | 3篇 |
1981年 | 5篇 |
1979年 | 4篇 |
1978年 | 5篇 |
1977年 | 10篇 |
1976年 | 5篇 |
1975年 | 9篇 |
1974年 | 15篇 |
1973年 | 6篇 |
1971年 | 4篇 |
1968年 | 3篇 |
排序方式: 共有1637条查询结果,搜索用时 31 毫秒
101.
Bhave G Nadin BM Brasier DJ Glauner KS Shah RD Heinemann SF Karim F Gereau RW 《The Journal of biological chemistry》2003,278(32):30294-30301
The metabotropic glutamate receptors (mGluRs) have been predicted to have a classical seven transmembrane domain structure similar to that seen for members of the G-protein-coupled receptor (GPCR) superfamily. However, the mGluRs (and other members of the family C GPCRs) show no sequence homology to the rhodopsin-like GPCRs, for which this seven transmembrane domain structure has been experimentally confirmed. Furthermore, several transmembrane domain prediction algorithms suggest that the mGluRs have a topology that is distinct from these receptors. In the present study, we set out to test whether mGluR5 has seven true transmembrane domains. Using a variety of approaches in both prokaryotic and eukaryotic systems, our data provide strong support for the proposed seven transmembrane domain model of mGluR5. We propose that this membrane topology can be extended to all members of the family C GPCRs. 相似文献
102.
Simonin Marie-Agnes; Bordji Karim; Boyault Sandrine; Bianchi Arnaud; Gouze Elvire; Becuwe Philippe; Dauca Michel; Netter Patrick; Terlain Bernard 《American journal of physiology. Cell physiology》2002,282(1):C125
This work demonstrated the constitutive expressionof peroxisome proliferator-activated receptor (PPAR)- and PPAR-in rat synovial fibroblasts at both mRNA and protein levels. A decrease in PPAR- expression induced by 10 µg/ml lipopolysaccharide (LPS) was observed, whereas PPAR- mRNA expression was not modified. 15-Deoxy-12,14-prostaglandin J2(15d-PGJ2) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (80%) and inducible nitric oxide synthase (iNOS) mRNA expression (80%), whereas troglitazone (10 µM) only inhibited iNOS mRNA expression (50%). 15d-PGJ2 decreasedLPS-induced interleukin (IL)-1 (25%) and tumor necrosis factor(TNF)- (40%) expression. Interestingly, troglitazone stronglydecreased TNF- expression (50%) but had no significant effect onIL-1 expression. 15d-PGJ2 was able to inhibitDNA-binding activity of both nuclear factor (NF)-B and AP-1.Troglitazone had no effect on NF-B activation and was shown toincrease LPS-induced AP-1 activation. 15d-PGJ2 andtroglitazone modulated the expression of LPS-induced iNOS, COX-2, andproinflammatory cytokines differently. Indeed, troglitazone seems tospecifically target TNF- and iNOS pathways. These results offer newinsights in regard to the anti-inflammatory potential of the PPAR-ligands and underline different mechanisms of action of15d-PGJ2 and troglitazone in synovial fibroblasts. 相似文献
103.
Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway 总被引:16,自引:0,他引:16
Schmidlin F Amadesi S Dabbagh K Lewis DE Knott P Bunnett NW Gater PR Geppetti P Bertrand C Stevens ME 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(9):5315-5321
Trypsin and mast cell tryptase can signal to epithelial cells, myocytes, and nerve fibers of the respiratory tract by cleaving proteinase-activated receptor 2 (PAR2). Since tryptase inhibitors are under development to treat asthma, a precise understanding of the contribution of PAR2 to airway inflammation is required. We examined the role of PAR2 in allergic inflammation of the airway by comparing OVA-sensitized and -challenged mice lacking or overexpressing PAR2. In wild-type mice, immunoreactive PAR2 was detected in airway epithelial cells and myocytes, and intranasal administration of a PAR2 agonist stimulated macrophage infiltration into bronchoalveolar lavage fluid. OVA challenge of immunized wild-type mice stimulated infiltration of leukocytes into bronchoalveolar lavage and induced airway hyperreactivity to inhaled methacholine. Compared with wild-type animals, eosinophil infiltration was inhibited by 73% in mice lacking PAR2 and increased by 88% in mice overexpressing PAR2. Similarly, compared with wild-type animals, airway hyperreactivity to inhaled methacholine (40 micro g/ml) was diminished 38% in mice lacking PAR2 and increased by 52% in mice overexpressing PAR2. PAR2 deletion also reduced IgE levels to OVA sensitization by 4-fold compared with those of wild-type animals. Thus, PAR2 contributes to the development of immunity and to allergic inflammation of the airway. Our results support the proposal that tryptase inhibitors and PAR2 antagonists may be useful therapies for inflammatory airway disease. 相似文献
104.
Bouazoune K Mitterweger A Längst G Imhof A Akhtar A Becker PB Brehm A 《The EMBO journal》2002,21(10):2430-2440
Drosophila Mi-2 (dMi-2) is the ATPase subunit of a complex combining ATP-dependent nucleosome remodelling and histone deacetylase activities. dMi-2 contains an HMG box-like region, two PHD fingers, two chromodomains and a SNF2-type ATPase domain. It is not known which of these domains contribute to nucleosome remodelling. We have tested a panel of dMi-2 deletion mutants in ATPase, nucleosome mobilization and nucleosome binding assays. Deletion of the chromodomains impairs all three activities. A dMi-2 mutant lacking the chromodomains is incorporated into a functional histone deacetylase complex in vivo but has lost nucleosome-stimulated ATPase activity. In contrast to dHP1, dMi-2 does not bind methylated histone H3 tails and does not require histone tails for nucleosome binding. Instead, the dMi-2 chromodomains display DNA binding activity that is not shared by other chromodomains. Our results suggest that the chromodomains act at an early step of the remodelling process to bind the nucleosome substrate predominantly via protein-DNA interactions. Furthermore, we identify DNA binding as a novel chromodomain-associated activity. 相似文献
105.
We investigated the occurrence of gene conversions between paralogous sequences of Salmoninae derived from ancestral tetraploidization
and their effect on the evolutionary history of DNA sequences. A microsatellite with long flanking regions (750 bp) including
both coding and noncoding sequences was analyzed. Microsatellite size polymorphism was used to detect the alleles of both
paralogous counterparts and infer linkage arrangement between loci. DNA sequencing of seven Salmoninae species revealed that
paralogous sequences were highly differentiated within species, especially for noncoding regions. Ten gene conversion events
between paralogous sequences were inferred. While these events appears to have homogenized regions of otherwise highly differential
paralogous sequences, they amplified the differentiation among orthologous sequences. Their effects were larger on coding
than on noncoding regions. As a consequence, noncoding sequences grouped by orthologous lineages in phylogenetic trees, whereas
coding regions grouped by taxa. Based upon these results, we present a model showing how gene conversion events may also result
in the PCR amplification of nonorthologous sequences in different taxa, with obvious complications for phylogenetic inferences,
comparative mapping, and population genetic studies.
Received: 11 October 2000 / Accepted: 18 September 2001 相似文献
106.
107.
Determinants of the recognition of enteroviral cloverleaf RNA by coxsackievirus B3 proteinase 3C
下载免费PDF全文
![点击此处可从《RNA (New York, N.Y.)》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The initiation of enteroviral positive-strand RNA synthesis requires the presence of a functional ribonucleoprotein complex containing a cloverleaf-like RNA secondary structure at the 5' end of the viral genome. Other components of the ribonucleoprotein complex are the viral 3CD proteinase (the precursor protein of the 3C proteinase and the 3D polymerase), the viral 3AB protein and the cellular poly(rC)-binding protein 2. For a molecular characterization of the RNA-binding properties of the enteroviral proteinase, the 3C proteinase of coxsackievirus B3 (CVB3) was bacterially expressed and purified. The recombinant protein is proteolytically active and forms a stable complex with in vitro-transcribed cloverleaf RNA of CVB3. The formation of stable complexes is also demonstrated with cloverleaf RNA of poliovirus (PV) 1, the first cloverleaf of bovine enterovirus (BEV) 1, and human rhinovirus (HRV) 2 but not with cloverleaf RNA of HRV14 and the second cloverleaf of BEV1. The apparent dissociation constants of the protein:RNA complexes range from approx. 1.7 to 4.6 microM. An electrophoretic mobility shift assay with subdomain D of the CVB3 cloverleaf demonstrates that this RNA is sufficient to bind the CVB3 3C proteinase. Binding assays using mutated versions of CVB3 and HRV14 cloverleaf RNAs suggest that the presence of structural features rather than a defined sequence motif of loop D are important for 3C proteinase-RNA interaction. 相似文献
108.
A sand culture experiment assessed whether gibberellic acid(GA3) could alleviate the adverse effects of salt stress on thegrowth, ion accumulation and photosynthetic capacity of two spring wheatcultivars, Barani-83 (salt sensitive) and SARC-I (salt tolerant).Three-week-oldplants of both cultivars were exposed to 0, 100 and 200 molm–3 NaCl in Hoagland's nutrient solution. Threeweeks after the initiation of salt treatments, half of the plants of eachcultivar were sprayed overall with 100 mg L–1GA3 solution. Plants were harvested 3 weeks after theapplication of GA3. Fresh and dry weights of shoots and roots, plantheight and leaf area were decreased with increasing supply of salt, butgibberellic acid treatment caused a significant ameliorative effect on both thecultivars with respect to these growth attributes. However, GA3caused no significant change in grain yields but increased grain size in boththe cultivars. Saline growth medium caused a marked increase in theconcentrations of Na+ and Cl– in shoots androots of both the lines. However, with the application of GA3accumulation of Na+ and Cl– was enhanced inboth shoots and roots of both wheat lines, but more ions accumulated in saltsensitive Barani-83 than in salt tolerant SARC-1. Net CO2assimilation rate (A) of both wheat lines decreased consistently withincreasingsupply of NaCl, but application of GA3 alleviated the effect of saltstress on this variable in both the cultivars. However, the ameliorative effectof the hormone was more pronounced in Barani-83 than in SARC-1. Althoughwater-use efficiency (A/E=CO2assimilation/transpiration) and intrinsic water use efficiency(A/gs=CO2 assimilation/stomatalconductance) decreased significantly with increasing salt concentration of thegrowth medium in both the cultivars, GA3 was more effective inenhancing both the water-use attributes in Barani-83 than in SARC-1. Overall,GA3 treatment stimulated the vegetative growth of both cultivars ofwheat under salt stress, but it caused a slight reduction in grain yield.GA3 treatment enhanced the accumulation of Na+ andCl– in both shoots and roots of wheat plants under saltstress.It also caused a significant increase in photosynthetic capacity in both linesat the vegetative stage under both saline and non-saline media. 相似文献
109.
Asthenozoospermia in mice with targeted deletion of the sperm mitochondrion-associated cysteine-rich protein (Smcp) gene
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Nayernia K Adham IM Burkhardt-Göttges E Neesen J Rieche M Wolf S Sancken U Kleene K Engel W 《Molecular and cellular biology》2002,22(9):3046-3052
The sperm mitochondria-associated cysteine-rich protein (SMCP) is a cysteine- and proline-rich structural protein that is closely associated with the keratinous capsules of sperm mitochondria in the mitochondrial sheath surrounding the outer dense fibers and axoneme. To investigate the function of SMCP, we generated mice with a targeted disruption of the gene Smcp by homologous recombination. Homozygous mutant males on a mixed genetic background (C57BL/6J x 129/Sv) are fully fertile, while they are infertile on the 129/Sv background, although spermatogenesis and mating are normal. Homozygous Smcp(-/-) female mice are fertile on both genetic backgrounds. Electron microscopical examination demonstrated normal structures of sperm head, mitochondria, and tail. In vivo experiments with sperm of Smcp(-/-) 129/Sv mice revealed that the migration of spermatozoa from the uterus into the oviduct is reduced. This result is supported by the observation that sperm motility as determined by the computer-assisted semen analysis system (CASA) is significantly affected as compared to wild-type spermatozoa. In vitro fertilization assays showed that Smcp-deficient spermatozoa are able to bind to the oocyte but that the number of fertilized eggs is reduced by more than threefold relative to the wild-type control. However, removal of the zona pellucida resulted in an unaffected sperm-egg fusion which was monitored by the presence of pronuclei and generation of blastocyts. These results indicate that the infertility of the male Smcp(-/-) mice on the 129/Sv background is due to reduced motility of the spermatozoa and decreased capability of the spermatozoa to penetrate oocytes. 相似文献
110.
von der Haar T Hughes JM Manjarul Karim M Ptushkina M McCarthy JE 《Biochemical Society transactions》2002,30(2):155-162
Translation initiation in eukaryotes is a complicated process involving some of the largest cellular structures, the ribosomes, together with approx. 11 initiation factors, and a poorly characterized set of other proteins. The concerted action of all these components ultimately results in the formation of an 80 S ribosomal complex on the AUG codon of an mRNA, which is competent to start polypeptide production. In this brief overview, we describe the strategies developed by our laboratory to apply surface plasmon resonance (SPR)-based technology to the problem of elucidating kinetic aspects of substeps within the translation-initiation reaction. We then review how other groups have used similar SPR-based techniques to study related interactions. 相似文献