全文获取类型
收费全文 | 2132篇 |
免费 | 137篇 |
专业分类
2269篇 |
出版年
2023年 | 7篇 |
2022年 | 22篇 |
2021年 | 41篇 |
2020年 | 27篇 |
2019年 | 34篇 |
2018年 | 54篇 |
2017年 | 28篇 |
2016年 | 67篇 |
2015年 | 97篇 |
2014年 | 96篇 |
2013年 | 164篇 |
2012年 | 184篇 |
2011年 | 164篇 |
2010年 | 93篇 |
2009年 | 90篇 |
2008年 | 137篇 |
2007年 | 125篇 |
2006年 | 125篇 |
2005年 | 99篇 |
2004年 | 111篇 |
2003年 | 97篇 |
2002年 | 89篇 |
2001年 | 21篇 |
2000年 | 13篇 |
1999年 | 13篇 |
1998年 | 26篇 |
1997年 | 13篇 |
1996年 | 19篇 |
1995年 | 13篇 |
1994年 | 18篇 |
1993年 | 23篇 |
1992年 | 14篇 |
1991年 | 13篇 |
1990年 | 20篇 |
1989年 | 4篇 |
1988年 | 10篇 |
1987年 | 5篇 |
1986年 | 4篇 |
1985年 | 14篇 |
1984年 | 7篇 |
1983年 | 7篇 |
1982年 | 7篇 |
1981年 | 12篇 |
1980年 | 5篇 |
1979年 | 10篇 |
1978年 | 7篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1971年 | 2篇 |
1968年 | 2篇 |
排序方式: 共有2269条查询结果,搜索用时 0 毫秒
191.
Regulation of translation is required for dendritic cell function and survival during activation 下载免费PDF全文
Lelouard H Schmidt EK Camosseto V Clavarino G Ceppi M Hsu HT Pierre P 《The Journal of cell biology》2007,179(7):1427-1439
In response to inflammatory stimulation, dendritic cells (DCs) have a remarkable pattern of differentiation (maturation) that exhibits specific mechanisms to control antigen processing and presentation. Here, we show that in response to lipopolysaccharides, protein synthesis is rapidly enhanced in DCs. This enhancement occurs via a PI3K-dependent signaling pathway and is key for DC activation. In addition, we show that later on, in a manner similar to viral or apoptotic stress, DC activation leads to the phosphorylation and proteolysis of important translation initiation factors, thus inhibiting cap-dependent translation. This inhibition correlates with major changes in the origin of the peptides presented by MHC class I and the ability of mature DCs to prevent cell death. Our observations have important implications in linking translation regulation with DC function and survival during the immune response. 相似文献
192.
Giovanna Lalatta-Costerbosa Maurizio Mazzoni Paolo Clavenzani Giovanni Di Guardo Gemma Mazzuoli Giuseppe Marruchella Luigi De Grossi Umberto Agrimi Roberto Chiocchetti 《The journal of histochemistry and cytochemistry》2007,55(4):387-401
Until now, significant differences in the neurochemical pattern of enteric neurons have been demonstrated in all species studied; however, some strong similarities also occur across species, such as the occurrence of nitric oxide synthase immunoreactivity (NOS-IR) in inhibitory motor neurons to muscle. In consideration of the insufficient data regarding the enteric nervous system (ENS) of sheep, we investigated the myenteric plexus and submucosal plexus of the ovine ileum. Since the pivotal role of the ENS in the early pathogenesis of sheep scrapie, the "prototype" of prion diseases, has been suggested, we have focused our observations also on the host's PrP genotype. We have studied the morphology and distribution of NOS-IR neurons and their relationships with the enteric glia in whole-mount preparations and in cryostat sections. NOS-IR neurons, always encircled by glial processes, were located in both plexuses. Many NOS-IR fibers were seen in the circular muscle layer, in the submucosa, and in the mucosa. In the submucosa they were close to the lymphoid tissue. No differences in the distribution and percentage of NOS-IR fibers and neurons were observed among sheep carrying different PrP genotype, thus making unlikely their contribution in the determinism of susceptibility/resistance to scrapie infection. 相似文献
193.
The first agmatine/cadaverine aminopropyl transferase: biochemical and structural characterization of an enzyme involved in polyamine biosynthesis in the hyperthermophilic archaeon Pyrococcus furiosus 下载免费PDF全文
Cacciapuoti G Porcelli M Moretti MA Sorrentino F Concilio L Zappia V Liu ZJ Tempel W Schubot F Rose JP Wang BC Brereton PS Jenney FE Adams MW 《Journal of bacteriology》2007,189(16):6057-6067
We report here the characterization of the first agmatine/cadaverine aminopropyl transferase (ACAPT), the enzyme responsible for polyamine biosynthesis from an archaeon. The gene PF0127 encoding ACAPT in the hyperthermophile Pyrococcus furiosus was cloned and expressed in Escherichia coli, and the recombinant protein was purified to homogeneity. P. furiosus ACAPT is a homodimer of 65 kDa. The broad substrate specificity of the enzyme toward the amine acceptors is unique, as agmatine, 1,3-diaminopropane, putrescine, cadaverine, and sym-nor-spermidine all serve as substrates. While maximal catalytic activity was observed with cadaverine, agmatine was the preferred substrate on the basis of the k(cat)/K(m) value. P. furiosus ACAPT is thermoactive and thermostable with an apparent melting temperature of 108 degrees C that increases to 112 degrees C in the presence of cadaverine. Limited proteolysis indicated that the only proteolytic cleavage site is localized in the C-terminal region and that the C-terminal peptide is not necessary for the integrity of the active site. The crystal structure of the enzyme determined to 1.8-A resolution confirmed its dimeric nature and provided insight into the proteolytic analyses as well as into mechanisms of thermal stability. Analysis of the polyamine content of P. furiosus showed that spermidine, cadaverine, and sym-nor-spermidine are the major components, with small amounts of sym-nor-spermine and N-(3-aminopropyl)cadaverine (APC). This is the first report in Archaea of an unusual polyamine APC that is proposed to play a role in stress adaptation. 相似文献
194.
Biftu T Feng D Qian X Liang GB Kieczykowski G Eiermann G He H Leiting B Lyons K Petrov A Sinha-Roy R Zhang B Scapin G Patel S Gao YD Singh S Wu J Zhang X Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2007,17(1):49-52
Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin. 相似文献
195.
Kowalchick JE Leiting B Pryor KD Marsilio F Wu JK He H Lyons KA Eiermann GJ Petrov A Scapin G Patel RA Thornberry NA Weber AE Kim D 《Bioorganic & medicinal chemistry letters》2007,17(21):5934-5939
Various beta-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is demonstrated. 相似文献
196.
Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors
Gao YD Feng D Sheridan RP Scapin G Patel SB Wu JK Zhang X Sinha-Roy R Thornberry NA Weber AE Biftu T 《Bioorganic & medicinal chemistry letters》2007,17(14):3877-3879
Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4. 相似文献
197.
Biftu T Scapin G Singh S Feng D Becker JW Eiermann G He H Lyons K Patel S Petrov A Sinha-Roy R Zhang B Wu J Zhang X Doss GA Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2007,17(12):3384-3387
Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile. 相似文献
198.
Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state 总被引:2,自引:0,他引:2
Brown BD Gentner B Cantore A Colleoni S Amendola M Zingale A Baccarini A Lazzari G Galli C Naldini L 《Nature biotechnology》2007,25(12):1457-1467
We have shown previously that transgene expression can be suppressed in hematopoietic cells using vectors that are responsive to microRNA (miRNA) regulation. Here we investigate the potential of this approach for more sophisticated control of transgene expression. Analysis of the relationship between miRNA expression levels and target mRNA suppression suggested that suppression depends on a threshold miRNA concentration. Using this information, we generated vectors that rapidly adjust transgene expression in response to changes in miRNA expression. These vectors sharply segregated transgene expression between closely related states of therapeutically relevant cells, including dendritic cells, hematopoietic and embryonic stem cells, and their progeny, allowing positive/negative selection according to the cells' differentiation state. Moreover, two miRNA target sites were combined to restrict transgene expression to a specific cell type in the liver. Notably, the vectors did not detectably perturb endogenous miRNA expression or regulation of natural targets. The properties of miRNA-regulated vectors should allow for safer and more effective therapeutic applications. 相似文献
199.
200.
Three-dimensional reconstruction of bovine brain V-ATPase by cryo-electron microscopy and single particle analysis 总被引:1,自引:0,他引:1
Bovine V-ATPase from brain clathrin-coated vesicles was investigated by cryo-electron microscopy and single particle analysis. Our studies revealed great flexibility of the central linker region connecting V1 and V0. As a consequence, the two sub-complexes were processed separately and the resulting volumes were merged computationally. We present the first three-dimensional (3D) map of a V-ATPase obtained from cryo-electron micrographs. The overall resolution was estimated 34 Å by Fourier shell correlation (0.5 cutoff). Our 3D reconstruction shows a large peripheral stalk and a smaller, isolated peripheral density, suggesting a second, less well-resolved peripheral connection. The 3D map reveals new features of the large peripheral stator and of the collar-like density attached to the membrane domain. Our analyses of the membrane domain indicate the presence of six proteolipid subunits. In addition, we could localize the V0 subunit a flanking the large peripheral stalk. 相似文献