全文获取类型
收费全文 | 1246篇 |
免费 | 113篇 |
出版年
2021年 | 9篇 |
2018年 | 9篇 |
2017年 | 16篇 |
2016年 | 17篇 |
2015年 | 19篇 |
2014年 | 28篇 |
2013年 | 45篇 |
2012年 | 70篇 |
2011年 | 58篇 |
2010年 | 35篇 |
2009年 | 36篇 |
2008年 | 38篇 |
2007年 | 44篇 |
2006年 | 42篇 |
2005年 | 48篇 |
2004年 | 60篇 |
2003年 | 48篇 |
2002年 | 61篇 |
2001年 | 43篇 |
2000年 | 70篇 |
1999年 | 49篇 |
1998年 | 19篇 |
1997年 | 19篇 |
1996年 | 18篇 |
1995年 | 26篇 |
1994年 | 22篇 |
1993年 | 14篇 |
1992年 | 42篇 |
1991年 | 28篇 |
1990年 | 27篇 |
1989年 | 43篇 |
1988年 | 33篇 |
1987年 | 29篇 |
1986年 | 27篇 |
1985年 | 19篇 |
1984年 | 10篇 |
1983年 | 6篇 |
1982年 | 6篇 |
1981年 | 8篇 |
1980年 | 5篇 |
1979年 | 19篇 |
1978年 | 13篇 |
1977年 | 9篇 |
1976年 | 5篇 |
1974年 | 8篇 |
1972年 | 6篇 |
1971年 | 5篇 |
1970年 | 7篇 |
1969年 | 6篇 |
1968年 | 6篇 |
排序方式: 共有1359条查询结果,搜索用时 15 毫秒
81.
Ikuta M Kamata K Fukasawa K Honma T Machida T Hirai H Suzuki-Takahashi I Hayama T Nishimura S 《The Journal of biological chemistry》2001,276(29):27548-27554
Genetic alteration of one or more components of the p16(INK4A)-CDK4,6/cyclin D-retinoblastoma pathway is found in more than half of all human cancers. Therefore, CDK4 is an attractive target for the development of a novel anticancer agent. However, it is difficult to make CDK4-specific inhibitors that do not possess activity for other kinases, especially CDK2, because the CDK family has high structural homology. The three-dimensional structure of CDK2, particularly that bound with the inhibitor, has provided useful information for the synthesis of CDK2-specific inhibitors. The same approach used to make CDK4-specific inhibitors was hindered by the failure to obtain a crystal structure of CDK4. To overcome this problem, we synthesized a CDK4 mimic CDK2 protein in which the ATP binding pocket of CDK2 was replaced with that of CDK4. This CDK4 mimic CDK2 was crystallized both in the free and inhibitor-bound form. The structural information thus obtained was found to be useful for synthesis of a CDK4-specific inhibitor that does not have substantial CDK2 activity. Namely, the data suggest that CDK4 has additional space that will accommodate a large substituent such as the CDK4 selective inhibitor. Inhibitors designed to bind into this large cavity should be selective for CDK4 without having substantial CDK2 activity. This design principle was confirmed in the x-ray crystal structure of the CDK4 mimic CDK2 with a new CDK4 selective inhibitor bound. 相似文献
82.
Effects of nitric oxide on matrix metalloproteinase-2 production by rheumatoid synovial cells 总被引:9,自引:0,他引:9
Hirai Y Migita K Honda S Ueki Y Yamasaki S Urayama S Kamachi M Kawakami A Ida H Kita M Fukuda T Shibatomi K Kawabe Y Aoyagi T Eguchi K 《Life sciences》2001,68(8):913-920
Nitric oxide (NO) is a multifunctional messenger molecule generated from L-arginine by a family of enzymes, including nitric oxide synthase (NOS). This study was performed to examine whether NO modulates the production of matrix metalloproteinases (MMPs), which degrade all components of extracellular matrix (ECM), in rheumatoid synovial cells. We investigated the effects of exogenously generated NO by a NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), on the MMPs production by rheumatoid synovial cells. Culture media conditioned by SNAP-treated synovial cells were examined by gelatin zymography and immunoblot analysis. Incubation of synovial cells with SNAP resulted in gelatinase A production in a dose-dependent fashion. Furthermore, RT-PCR analysis demonstrated that MMP-2 mRNA expression was induced in SNAP-treated synovial cells. In contrast, SNAP did not influence the production of TIMP-1 and TIMP-2, which preferentially inhibit MMP-2, by rheumatoid synovial cells. Our data indicate that NO could modulate MMP production by rheumatoid synovial cells and therefore contribute to ECM degradation of articular components in RA. 相似文献
83.
Mitsuoka K Hirai T Murata K Miyazawa A Kidera A Kimura Y Fujiyoshi Y 《Journal of molecular biology》1999,286(3):861-882
Electron crystallography has the potential to visualise the charge status of atoms. This is due to the significantly different scattering factors of neutral and ionised atoms for electrons in the low-resolution range (typically less than 5 A). In previous work, we observed two different types of densities around acidic residues in the experimental (|Fo|) map of bacteriorhodopsin (bR), a light-driven proton pump. We suggested that these might reflect different states of the acidic residues; namely, the protonated (neutral) and the deprotonated (negatively charged) state. To evaluate the observed charge more quantitatively, we refined the atomic model for bR and eight surrounding lipids using our electron crystallographic data set between 8.0 and 3.0 A resolution, where the charge effect is small. The refined model yielded an R-factor of 23.7% and a free R-factor of 33.0%. To evaluate the effect of charges on the density map, we calculated a difference (|Fo|-|Fc|) map including data of a resolution lower than 8.0 A resolution, where the charge effect is significant. We found strong peaks in the difference map mainly in the backbone region of the transmembrane helices. We interpreted these peaks to come from the polarisation of the polar groups in the main chain of the alpha-helices and we examined this by assuming a partial charge of 0.5 for the peptide carbonyl groups. The resulting R and free R-factors dropped from 0.250 and 0.341 to 0.246 and 0.336, respectively. Furthermore, we also observed some strong peaks around some side-chains, which could be assigned to positively charged atoms. Thus, we could show that Asp36 and Asp102 are likely to interact with cations nearby. In addition, peaks found around the acidic residues Glu74, Glu194 and Glu212 have different features and might represent positive charges on polarised water molecules or hydroxonium ions. 相似文献
84.
Mitochondrial uncoupling proteins (UCPs) play a central role in adaptive thermogenesis in mammals. The UCPs dissipate the proton gradient formed through respiration without ATP synthesis, and the freed energy is readily converted to heat, helping the animals to maintain their body temperature in cold environments. Recently, it was found that UCPs also function in plant mitochondria. Subsequently, a cDNA clone encoding a UCP in potato was isolated. Whereas the UCP gene constitutes a multigene family in mammals, only a single cDNA sequence has been reported so far for the potato UCP. Moreover, it has been recently suggested that Arabidopsis has only a single nuclear gene for UCP. Here we report the existence of another UCP gene in the Arabidopsis genome, showing for the first time the occurrence of a multigene family for the protein in higher plants. A cDNA analysis of this gene showed that the novel isoform possesses all typical features reported for known UCPs. However, the new gene, unlike the other gene in Arabidopsis and the gene in potato, did not appear to respond to low temperature. 相似文献
85.
86.
The genetic variation of Japanese isolates of Coxiella burnetii, the agent of Q fever, was found for the first time. Forty-nine out of 72 isolates had the chronic pattern of the isocitrate hydrogenase gene. Sequence analysis revealed that the isolates have a specific nucleotide sequence. The putative amino acid sequence was the same as that of chronic reference strains. These results suggest the variation of C. burnetii isolates in Japan. 相似文献
87.
Coxiella burnetii is the agent of the worldwide zoonosis, Q fever. The in vitro susceptibility to tetracycline and fluoroquinolones of Japanese isolates of C. burnetii was evaluated for the first time. The MICs against Japanese isolates were almost the same as the MICs against the foreign reference isolates. The results suggest that the common antibiotics therapy for Q fever used in other countries is also effective for Japanese Q fever patients. 相似文献
88.
Funatogawa K Hayashi S Shimomura H Yoshida T Hatano T Ito H Hirai Y 《Microbiology and immunology》2004,48(4):251-261
Helicobacter pylori is a major etiological agent in gastroduodenal disorders. In this study, we isolated 36 polyphenols and 4 terpenoids from medicinal plants, and investigated their antibacterial activity against H. pylori in vitro. All hydrolyzable tannins tested demonstrated promising antibacterial activity against H. pylori. Monomeric hydrolyzable tannins revealed especially strong activity. Other compounds demonstrated minimal antibacterial activity with a few exceptions. A monomeric hydrolyzable tannin, Tellimagrandin I demonstrated time- and dose-dependent bactericidal activity against H. pylori in vitro. On the other hand, hydrolyzable tannins did not affect the viability of MKN-28 cells derived from human gastric epithelium. Hydrolyzable tannins, therefore, have potential as new and safe therapeutic regimens against H. pylori infection. Furthermore, we investigated effects of hydrolyzable tannins on lipid bilayer membranes. All the hydrolyzable tannins tested demonstrated dose-dependent membrane-damaging activity. However, it remains to be elucidated whether their membrane-damaging activity directly contributes to their antibacterial action. 相似文献
89.
90.
Genetic variations at urotensin II and urotensin II receptor genes and risk of type 2 diabetes mellitus in Japanese 总被引:1,自引:0,他引:1
Suzuki S Wenyi Z Hirai M Hinokio Y Suzuki C Yamada T Yoshizumi S Suzuki M Tanizawa Y Matsutani A Oka Y 《Peptides》2004,25(10):1803-1808
Urotensin II is among the most potent vasoactive hormones known and the urotensin II (UTS2) gene is localized to 1p36-p32, one of the regions reported to show possible linkage with type 2 diabetes in Japanese. When we surveyed genetic polymorphisms in the UTS2 and urotensin II receptor (GPR14) gene, we identified two SNPs with amino acid substitutions (designated T21M and S89N and an SNP in the promotor region (-605G>A) of the UTS2 gene, and two SNPs in the non-coding region of the GPR14 gene. We then studied these three SNPs in the UTS2 gene and two SNPs in the GPR14 gene in 152 Japanese subjects with type 2 diabetes mellitus and two control Japanese populations. The allele frequency of 89N was significantly higher in type 2 diabetic patients than in both elderly normal subjects (P = 0.0018) and subjects with normal glucose tolerance (P = 0.0011), whereas the allele frequency of T21M and -605G>A in the UTS2 gene and those of two SNPs in the GPR14 gene were essentially identical in these three groups. Furthermore, in the subjects with normal glucose tolerance, 89N was associated with significantly higher insulin levels on oral glucose tolerance test, suggesting reduced insulin sensitivity in subjects with 89N. These results strongly suggest that subjects with S89N in the UTS2 gene are more insulin-resistant and thus more susceptible to type 2 diabetes mellitus development. 相似文献