全文获取类型
收费全文 | 1470篇 |
免费 | 74篇 |
国内免费 | 1篇 |
专业分类
1545篇 |
出版年
2023年 | 4篇 |
2022年 | 12篇 |
2021年 | 15篇 |
2020年 | 7篇 |
2019年 | 3篇 |
2018年 | 15篇 |
2017年 | 11篇 |
2016年 | 20篇 |
2015年 | 47篇 |
2014年 | 76篇 |
2013年 | 79篇 |
2012年 | 105篇 |
2011年 | 113篇 |
2010年 | 68篇 |
2009年 | 76篇 |
2008年 | 100篇 |
2007年 | 97篇 |
2006年 | 97篇 |
2005年 | 94篇 |
2004年 | 93篇 |
2003年 | 77篇 |
2002年 | 89篇 |
2001年 | 20篇 |
2000年 | 12篇 |
1999年 | 14篇 |
1998年 | 29篇 |
1997年 | 13篇 |
1996年 | 12篇 |
1995年 | 15篇 |
1994年 | 13篇 |
1993年 | 10篇 |
1992年 | 6篇 |
1991年 | 7篇 |
1990年 | 10篇 |
1989年 | 11篇 |
1988年 | 7篇 |
1987年 | 8篇 |
1986年 | 7篇 |
1985年 | 4篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1982年 | 9篇 |
1981年 | 6篇 |
1980年 | 7篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1976年 | 3篇 |
1975年 | 1篇 |
1974年 | 4篇 |
1971年 | 1篇 |
排序方式: 共有1545条查询结果,搜索用时 15 毫秒
71.
Mikó T Ligneau X Pertz HH Arrang JM Ganellin CR Schwartz JC Schunack W Stark H 《Bioorganic & medicinal chemistry》2004,12(10):2727-2736
Recent bioisoteric replacements in histamine H3 receptor ligands with an exchange of the imidazole moiety by a piperidino group as well as of the trimethylene chain in 4-((3-phenoxy)propyl)-lH-imidazole derivatives (proxifan class) by an alpha,alpha'-xylendiyl linker represents the starting point in the development of 1-(4-(phenoxymethyl)benzyl)piperidines as a new class of nonimidazole histamine H3 receptor antagonists. According to different strategies in optimization of imidazole-containing antagonists the central benzyl phenyl ether moiety was replaced by numerous other polar functionalities. Additionally, the ortho- and meta-analogues of the lead were synthesized to determine the influence of the position of the piperidinomethyl substituent. The new compounds were tested in an in vitro binding assay for their affinities for cloned human H3 receptors stably expressed in CHO-K1 cells and for their oral in vivo potencies brain in a functional screening assay in the brain of mice. Additionally, activities of selected compounds were determined in the guinea-pig ileum functional test model. In contrast to the analogues ortho-substituted compounds all other compounds maintained respectable affinities for the human H3 receptor (-log Ki values 6.3-7.5). Despite the results from other classes of compounds the 4-methyl substituted derivatives generally displayed higher affinities than the corresponding 4-chloro substituted compounds. In vivo only the inverse phenyl benzyl ether (3) showed worthwhile antagonist potencies. 相似文献
72.
Abergel C Nitschke W Malarte G Bruschi M Claverie JM Giudici-Orticoni MT 《Structure (London, England : 1993)》2003,11(5):547-555
The study of electron transfer between the copper protein rusticyanin (RCy) and the c(4)-cytochrome CYC(41) of the acidophilic bacterium Acidithiobacillus ferrooxidans has evidenced a remarkable decrease of RCy's redox potential upon complex formation. The structure of the CYC(41) obtained at 2.2 A resolution highlighted a specific glutamate residue (E121) involved in zinc binding as potentially playing a central role in this effect, required for the electron transfer to occur. EPR and stopped-flow experiments confirmed the strong inhibitory effect of divalent cations on CYC(41):RCy complex formation. A docking analysis of the CYC(41) and RCy structure allows us to propose a detailed model for the complex-induced tuning of electron transfer in agreement with our experimental data, which could be representative of other copper proteins involved in electron transfer. 相似文献
73.
Morphine-6-beta-d-glucuronide (M6G) is an active metabolite of morphine with high analgesic potency despite a low blood-brain barrier (BBB) permeability. The aim of the study was to elucidate its transport mechanism across the BBB. We first checked if M6G was effluxed by the P-glycoprotein (P-gp), as previously reported by others. Second, we investigated the role of anionic transporters like the multidrug resistance-associated protein mrp1 and the glucose transporter GLUT-1. The brain uptake of [14C]M6G was measured by the in situ brain perfusion technique in wild-type and deficient mice [mdr1a(-/-) and mrp1(-/-)], with and without probenecid, digoxin, PSC833 or d-glucose. No difference was found between P-gp and mrp1 competent and deficient mice. The brain uptake of [14C]M6G co-perfused with probenecid in wild-type mice was not significantly different from that found in group perfused with [14C]M6G alone. The co-perfusion of [14C]M6G with digoxin or PSC833 was responsible of a threefold decrease of its uptake in mdr1a competent and deficient mice, suggesting that another transporter than P-gp and sensitive to digoxin and PSC833, may be involved. The co-perfusion of [14C]M6G with d-glucose revealed a threefold decrease in M6G uptake. In conclusion, P-gp and mrp1 are not involved in the transport of M6G at the BBB level in contrast to GLUT-1 and a digoxin-sensitive transporter (probably oatp2), which can actively transport M6G but with a weak capacity. 相似文献
74.
It has been shown (Cambillau, C., and Claverie, J. M. (2000) J. Biol. Chem. 275, 32383-32386) that a large difference between the proportions of charged versus polar (non-charged) amino acids (CvP-bias) was an adequate, if empirical, signature of the proteome of hyperthermophilic organisms (T(growth) >80 degrees C). Since that study, the number of available microbial genomes has more than doubled, raising the possibility that the simple CvP-bias rule might no longer hold. Taking advantage of the new sequence data, we re-analyzed the genomes of 9 fully sequenced thermophiles, 9 hyperthermophiles, and 53 mesothermophile microorganisms to identify the genomic correlates of hyperthermostability on a wider data set. Our new results confirm that the CvP-bias previously identified on a much smaller data set still holds. Moreover, we show that it is an optimal criterion, in the sense that it corresponds to the most discriminating factor between hyperthermophilic and mesothermophilic microorganisms in a principal component analysis. In parallel, we evaluated two other recently proposed correlates of hyperthermostability, the proteome average pI and the dinucleotide statistical index (Kawashima, T., Amano, N., Koike, H., Makino, S., Higuchi, S., Kawashima-Ohya, Y., Watanabe, K., Yamazaki, M., Kanehori, K., Kawamoto, T., Nunoshiba, T., Yamamoto, Y., Aramaki, H., Makino, K., and Suzuki, M. (2000) Proc. Natl. Acad. Sci. 97, 14257-14262). We show that the CvP-bias is the sole criterion that is able to clearly discriminate hyperthermophile from mesothermophile microorganisms on a global genomic basis. 相似文献
75.
Todeschini AR Girard MF Wieruszeski JM Nunes MP DosReis GA Mendonca-Previato L Previato JO 《The Journal of biological chemistry》2002,277(48):45962-45968
Trypanosoma cruzi, the protozoan parasite responsible for Chagas' disease, expresses on its surface an uncommon membrane-bound sialidase, known as trans-sialidase. trans-Sialidase is the product of a multigene family encoding both active and inactive proteins. We report here that an inactive mutant of trans-sialidase physically interacts with CD4(+) T cells. Using a combination of flow cytometry and immunoprecipitation techniques, we identified the sialomucin CD43 as a counterreceptor for trans-sialidase on CD4(+) T cells. Using biochemical, immunological, and spectroscopic approaches, we demonstrated that the inactive trans-sialidase is a sialic acid-binding protein displaying the same specificity required by active trans-sialidase. Taken together, these results suggest that inactive members of the trans-sialidase family can physically interact with sialic acid-containing molecules on host cells and could play a role in host cell/T. cruzi interaction. 相似文献
76.
77.
Proliferative generation of mammalian auditory hair cells in culture 总被引:18,自引:0,他引:18
Malgrange B Belachew S Thiry M Nguyen L Rogister B Alvarez ML Rigo JM Van De Water TR Moonen G Lefebvre PP 《Mechanisms of development》2002,112(1-2):79-88
Hair cell (HC) and supporting cell (SC) productions are completed during early embryonic development of the mammalian cochlea. This study shows that acutely dissociated cells from the newborn rat organ of Corti, developed into so-called otospheres consisting of 98% nestin (+) cells when plated on a non-adherent substratum in the presence of either epidermal growth factor (EGF) or fibroblast growth factor (FGF2). Within cultured otospheres, nestin (+) cells were shown to express EGF receptor (EGFR) and FGFR2 and rapidly give rise to newly formed myosin VIIA (+) HCs and p27(KIP1) (+) SCs. Myosin VIIA (+) HCs had incorporated bromodeoxyuridine (BrdU) demonstrating that they were generated by a mitotic process. Ultrastructural studies confirmed that HCs had differentiated within the otosphere, as defined by the presence of both cuticular plates and stereocilia. This work raises the hypothesis that nestin (+) cells might be a source of newly generated HCs and SCs in the injured postnatal organ of Corti. 相似文献
78.
79.
80.