全文获取类型
收费全文 | 1510篇 |
免费 | 79篇 |
国内免费 | 1篇 |
出版年
2023年 | 4篇 |
2022年 | 10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 | 45篇 |
2014年 | 76篇 |
2013年 | 86篇 |
2012年 | 103篇 |
2011年 | 113篇 |
2010年 | 66篇 |
2009年 | 76篇 |
2008年 | 100篇 |
2007年 | 100篇 |
2006年 | 98篇 |
2005年 | 96篇 |
2004年 | 98篇 |
2003年 | 78篇 |
2002年 | 89篇 |
2001年 | 22篇 |
2000年 | 15篇 |
1999年 | 17篇 |
1998年 | 31篇 |
1997年 | 13篇 |
1996年 | 14篇 |
1995年 | 18篇 |
1994年 | 15篇 |
1993年 | 11篇 |
1992年 | 7篇 |
1991年 | 8篇 |
1990年 | 10篇 |
1989年 | 13篇 |
1988年 | 8篇 |
1987年 | 8篇 |
1986年 | 8篇 |
1985年 | 5篇 |
1984年 | 6篇 |
1983年 | 5篇 |
1982年 | 9篇 |
1981年 | 7篇 |
1980年 | 7篇 |
1979年 | 6篇 |
1978年 | 4篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1971年 | 2篇 |
排序方式: 共有1590条查询结果,搜索用时 46 毫秒
71.
Palmer G Burger D Mezin F Magne D Gabay C Dayer JM Guerne PA 《Arthritis research & therapy》2004,6(3):R181-R189
Leflunomide is an immunomodulatory agent used for the treatment of rheumatoid arthritis. In this study, we investigated the
effect of A77 1726 – the active metabolite of leflunomide – on the production of IL-1 receptor antagonist (IL-1Ra) by human
synovial fibroblasts and articular chondrocytes. Cells were incubated with A77 1726 alone or in combination with proinflammatory
cytokines. IL-1Ra production was determined by ELISA. A77 1726 alone had no effect, but in the presence of IL-1β or tumour
necrosis factor-α it markedly enhanced the secretion of IL-1Ra in synovial fibroblasts and chondrocytes. The effect of A77
1726 was greatest at 100 μmol/l. In synovial fibroblasts and de-differentiated chondrocytes, A77 1726 also increased IL-1β-induced
IL-1Ra production in cell lysates. Freshly isolated chondrocytes contained no significant amounts of intracellular IL-1Ra.
A77 1726 is a known inhibitor of pyrimidine synthesis and cyclo-oxygenase (COX)-2 activity. Addition of exogenous uridine
did not significantly modify the effect of A77 1726 on IL-1Ra production, suggesting that it was not mediated by inhibition
of pyrimidine synthesis. Indomethacin increased IL-1β-induced IL-1Ra secretion in synovial fibroblasts and de-differentiated
chondrocytes, suggesting that inhibition of COX-2 may indeed enhance IL-1β-induced IL-1Ra production. However, the stimulatory
effect of indomethacin was consistently less effective than that of A77 1726. A77 1726 increases IL-1Ra production by synovial
fibroblasts and chondrocytes in the presence of proinflammatory cytokines, and thus it may possess chondroprotective effects.
The effect of A77 1726 may be partially mediated by inhibition of COX-2, but other mechanisms likely concur to stimulate IL-1Ra
production. 相似文献
72.
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
73.
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
74.
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
75.
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
76.
Laurine E Lafitte D Grégoire C Sérée E Loret E Douillard S Michel B Briand C Verdier JM 《The Journal of biological chemistry》2003,278(32):29979-29986
The effect of neurosteroids is mediated through their membrane or nuclear receptors. However, no dehydroepiandrosterone (DHEA)-specific receptors have been evidenced so far in the brain. In this paper, we showed by isothermal titration calorimetry that the DHEA specifically binds to the dendritic brain microtubule-associated protein MAP2C with an association constant of 2.7 x 10(7) m-1 and at a molar ratio of 1:1. By partial tryptic digestions and mass spectrometry analysis, we found that the binding involved the N-terminal region of MAP2C. Interestingly, MAP2C displays homologies with 17 beta-hydroxysteroid dehydrogenase 1, an enzyme required for estrogen synthesis. Based on these sequence homologies and on the x-ray structure of the DHEA-binding pocket of 17 beta-hydroxysteroid dehydrogenase 1, we modeled the complex of DHEA with MAP2C. The binding of DHEA to MAP2C involved specific hydrogen bonds that orient the steroid into the pocket. This work suggests that DHEA can directly influence brain plasticity via MAP2C binding. It opens interesting ways for understanding the role of DHEA in the brain. 相似文献
77.
Bizat N Hermel JM Humbert S Jacquard C Créminon C Escartin C Saudou F Krajewski S Hantraye P Brouillet E 《The Journal of biological chemistry》2003,278(44):43245-43253
The role of caspases and calpains in neurodegeneration remains unclear. In this study, we focused on these proteases in a rat model of Huntington's disease using the mitochondrial toxin 3-nitropropionic acid (3NP). Results showed that 3NP-induced death of striatal neurons was preceded by cytochrome c redistribution, transient caspase-9 processing, and activation of calpain, whereas levels of the active/processed form of caspase-3 remained low and were even reduced as compared with control animals. We evidenced here that this decrease in active caspase-3 levels could be attributed to calpain activation. Several observations supported this conclusion. 1) Pharmacological blockade of calpain in 3NP-treated rats increased the levels of endogenous processed caspase-9 and caspase-3. 2) Cell-free extracts prepared from the striatum of 3NP-treated rats degraded in vitro the p34 and p20 subunits of active recombinant caspase-9 and caspase-3, respectively. 3) This degradation of p34 and p20 could be mimicked by purified mu-calpain and was prevented by calpain inhibitors. 4) mu-Calpain produced a loss of the DEVDase (Asp-Glu-Val-Asp) activity of active caspase-3. 5) Western blot analysis and experiments with 35S-radiolabeled caspase-3 showed that mu-calpain cleaved the p20 subunit of active caspase-3 near its catalytic site. 6) mu-Calpain activity was selectively inhibited (IC50 of 100 mum) by a 12 amino acid peptide corresponding to the C terminus of p20. Our results showed that calpain can down-regulate the caspase-9/caspase-3 cell death pathway during neurodegeneration due to chronic mitochondrial defects in vivo and that this effect may involve, at least in part, direct cleavage of the caspase-3 p20 subunit. 相似文献
78.
Orelle C Dalmas O Gros P Di Pietro A Jault JM 《The Journal of biological chemistry》2003,278(47):47002-47008
ATP-binding cassette (ABC) proteins constitute one of the widest families in all organisms, whose P-glycoprotein involved in resistance of cancer cells to chemotherapy is an archetype member. Although three-dimensional structures of several nucleotide-binding domains of ABC proteins are now available, the catalytic mechanism triggering the functioning of these proteins still remains elusive. In particular, it has been postulated that ATP hydrolysis proceeds via an acid-base mechanism catalyzed by the Glu residue adjacent to the Walker-B motif (Geourjon, C., Orelle, C., Steinfels, E., Blanchet, C., Deléage, G., Di Pietro, A., and Jault, J. M. (2001) Trends Biochem. Sci. 26, 539-544), but the involvement of such residue as the catalytic base in ABC transporters was recently questioned (Sauna, Z. E., Muller, M., Peng, X. H., and Ambudkar, S. V. (2002) Biochemistry, 41, 13989-14000). The equivalent glutamate residue (Glu504) of a half-ABC transporter involved in multidrug resistance in Bacillus subtilis, BmrA (formerly known as YvcC), was therefore mutated to Asp, Ala, Gln, Ser, and Cys residues. All these mutants were fully devoid of ATPase activity, yet they showed a high level of vanadate-independent trapping of 8-N3-alpha-32P-labeled nucleotide(s), following preincubation with 8-N3-[alpha-32P]ATP. However, and in contrast to the wild-type enzyme, the use of 8-N3-[gamma-32P]ATP unequivocally showed that all the mutants trapped exclusively the triphosphate form of the analogue, suggesting that they were not able to perform even a single hydrolytic turnover. These results demonstrate that Glu504 is the catalytic base for ATP hydrolysis in BmrA, and it is proposed that equivalent glutamate residues in other ABC transporters play the same role. 相似文献
79.
Conjugated linoleic acids (CLA) have recently been recognized to reduce body fat and plasma lipids in some animals. This study demonstrated that the steatosis accompanying the fat loss induced by trans-10,cis-12-C(18:2) (CLA2) and not cis-9,trans-11-C(18:2) (CLA1) isomer in C57BL/6j mice was not due to an alteration of the liver lipoprotein production that was even increased. The 3-fold decrease in plasma triacylglycerol contents and the induction of mRNA expression of low-density lipoprotein receptors concomitantly observed in CLA2-fed mice suggested an increase in the lipoprotein clearance at the level of the liver itself. CLA1 feeding produced similar but attenuated effects on triglyceridaemia only. 相似文献
80.
Somerville RP Longpre JM Jungers KA Engle JM Ross M Evanko S Wight TN Leduc R Apte SS 《The Journal of biological chemistry》2003,278(11):9503-9513
We demonstrate that in humans, two metalloproteases, ADAMTS-9 (1935 amino acids) and ADAMTS-20 (1911 amino acids) are orthologs of GON-1, an ADAMTS protease required for gonadal morphogenesis in Caenorhabditis elegans. ADAMTS-9 and ADAMTS-20 have an identical modular structure, are distinct in possessing 15 TSRs and a unique C-terminal domain, and have a similar gene structure, suggesting that they comprise a new subfamily of human ADAMTS proteases. ADAMTS20 is very sparingly expressed, although it is detectable in epithelial cells of the breast and lung. However, ADAMTS9 is highly expressed in embryonic and adult tissues, and therefore we characterized the ADAMTS-9 protein further. Although the ADAMTS-9 zymogen has many proprotein convertase processing sites, pulse-chase analysis, site-directed mutagenesis, and amino acid sequencing demonstrated that maturation to the active form occurs by selective proprotein convertase (e.g. furin) cleavage of the Arg(287)-Phe(288) bond. Although lacking a transmembrane sequence, ADAMTS-9 is retained near the cell surface as well as in the ECM of transiently transfected COS-1 and 293 cells. COS-1 cells transfected with ADAMTS9 (but not vector-transfected cells) proteolytically cleaved bovine versican and aggrecan core proteins at the Glu(441)-Ala(442) bond of versican V1 and the Glu(1771)-Ala(1772) bond of aggrecan, respectively. In contrast, the ADAMTS-9 catalytic domain alone was neither localized to the cell surface nor able to confer these proteolytic activities on cells, demonstrating that the ancillary domains of ADAMTS-9, including the TSRs, are required both for specific extracellular localization and for its versicanase and aggrecanase activities. 相似文献