全文获取类型
收费全文 | 666篇 |
免费 | 54篇 |
国内免费 | 2篇 |
出版年
2021年 | 7篇 |
2020年 | 5篇 |
2019年 | 11篇 |
2018年 | 11篇 |
2017年 | 9篇 |
2016年 | 18篇 |
2015年 | 25篇 |
2014年 | 32篇 |
2013年 | 37篇 |
2012年 | 41篇 |
2011年 | 28篇 |
2010年 | 24篇 |
2009年 | 23篇 |
2008年 | 19篇 |
2007年 | 30篇 |
2006年 | 28篇 |
2005年 | 30篇 |
2004年 | 28篇 |
2003年 | 24篇 |
2002年 | 13篇 |
2001年 | 12篇 |
2000年 | 18篇 |
1999年 | 15篇 |
1998年 | 6篇 |
1993年 | 7篇 |
1992年 | 12篇 |
1991年 | 7篇 |
1990年 | 8篇 |
1989年 | 11篇 |
1987年 | 11篇 |
1986年 | 11篇 |
1985年 | 15篇 |
1984年 | 6篇 |
1983年 | 5篇 |
1982年 | 5篇 |
1981年 | 7篇 |
1980年 | 4篇 |
1979年 | 6篇 |
1978年 | 4篇 |
1977年 | 8篇 |
1976年 | 11篇 |
1975年 | 6篇 |
1974年 | 11篇 |
1973年 | 9篇 |
1972年 | 4篇 |
1971年 | 4篇 |
1970年 | 8篇 |
1969年 | 6篇 |
1968年 | 6篇 |
1966年 | 6篇 |
排序方式: 共有722条查询结果,搜索用时 31 毫秒
81.
Handzlik J Szymańska E Wójcik R Dela A Jastrzębska-Więsek M Karolak-Wojciechowska J Fruziński A Siwek A Filipek B Kieć-Kononowicz K 《Bioorganic & medicinal chemistry》2012,20(14):4245-4257
The study is focused on a series of 5-arylidenehydantoin derivatives with a phenylpiperazine-hydroxypropyl fragment at N3 of the hydantoin ring. The compounds were assessed on their affinity for α(1)-adrenoceptors and evaluated in functional bioassays for their antagonistic properties. Crystal structures of (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)imidazolidine-2,4-dione (7) and hydrochloride of (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (10a) were solved using the X-ray diffraction method. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) were used to predict 3D structure of compounds 5a-18a using a crystal structure of 7. SAR analysis was performed on the basis of Barbaro's pharmacophore model and structural properties of previously investigated α(1)-adrenoceptor antagonists possessing a hydantoin fragment. Most of the compounds exhibited significant affinities for α(1)-ARs in nanomolar range (40-290 nM). The highest activities (K(i)<75 nM) were observed for compounds possessing a 2-alkoxyphenylpiperazine fragment and two methoxy substituents at the benzylidene moiety. The results indicated that chemical properties, number and positions of substituents at the 5-arylidene fragment influenced the power of α(1)-affinities as follows: 3,4-di CH(3)O>2,4-di CH(3)O>4-Cl>2,3-di CH(3)O>H>4-N(CH(3))(2). 相似文献
82.
M Miyamoto Y Tsuboi K Honda M Kobayashi K Takamiya RL Huganir M Kondo M Shinoda BJ Sessle A Katagiri D Kita I Suzuki Y Oi K Iwata 《PloS one》2012,7(8):e44055
To evaluate the involvement of trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) GluR2 and GluR3 subunits in an acute inflammatory orofacial pain, we analyzed nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK) and Fos expression in Vi/Vc, Vc and C1/C2 in GluR2 delta7 knock-in (KI), GluR3 delta7 KI mice and wild-type mice. We also studied Vc neuronal activity to address the hypothesis that trafficking of GluR2 and GluR3 subunits plays an important role in Vi/Vc, Vc and C1/C2 neuronal activity associated with orofacial inflammation in these mice. Late nocifensive behavior was significantly depressed in GluR2 delta7 KI and GluR3 delta7 KI mice. In addition, the number of pERK-immunoreactive (IR) cells was significantly decreased bilaterally in the Vi/Vc, Vc and C1/C2 in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice at 40 min after formalin injection, and was also significantly smaller in GluR3 delta7 KI compared to GluR2 delta7 KI mice. The number of Fos protein-IR cells in the ipsilateral Vi/Vc, Vc and C1/C2 was also significantly smaller in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice 40 min after formalin injection. Nociceptive neurons functionally identified as wide dynamic range neurons in the Vc, where pERK- and Fos protein-IR cell expression was prominent, showed significantly lower spontaneous activity in GluR2 delta7 KI and GluR3 delta7 KI mice than wild-type mice following formalin injection. These findings suggest that GluR2 and GluR3 trafficking is involved in the enhancement of Vi/Vc, Vc and C1/C2 nociceptive neuronal excitabilities at 16-60 min following formalin injection, resulting in orofacial inflammatory pain. 相似文献
83.
Intestinal lactase in the neonatal rat. Maturational changes in intracellular processing and brush-border degradation 总被引:2,自引:0,他引:2
R O Castillo A M Reisenauer L K Kwong K K Tsuboi R Quan G M Gray 《The Journal of biological chemistry》1990,265(26):15889-15893
The mechanism of decline in the catalytic activity of intestinal lactase during neonatal maturation has not been defined, but a shift in the lactase subunit synthesis from an active 130-kDa subunit to an inactive 100-kDa species has now been noted in the adult rat (Quan, R., Santiago, N. A., Tsuboi, K. K., and Gray, G. M. (1990) J. Biol. Chem. 265, 15882-15888). The subunit structure, synthesis, intracellular assembly, and subsequent degradation of lactase from the brush-border surface membrane was examined in 15-day-old pre-weaned and 30-day-old post-weaned intact rats. Lactase was labeled intraintestinally with [35S]methionine, isolated from Triton-solubilized membranes with monospecific polyclonal anti-lactase, and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. The protein-stained gel revealed subunits of 225 and 130 kDa, the latter species predominating in both the pre- and post-weaned state. The distinct adult-type 100-kDa moiety was present in post-weaned animals while only a trace of a slightly larger (approximately 110 kDa) species was observed in pre-weaned animals. Quantitation of radioactivity in newly synthesized lactase revealed an increasing prominence of the 100-kDa species in post-weaned rats (130/100 incorporation ratio: pre-weaned 6.2; post-weaned 3.3). Accumulation of newly labeled lactase in brush-border membranes after intraperitoneal [35S]methionine labeling was similar in both groups at 3 h. Despite these comparable rates of lactase synthesis, assembly and insertion in the pre- and post-weaned state, subsequent removal of the 130-kDa unit was more rapid in post-weaned animals (t1/2 = 11 h; pre-weaned t1/2 = 37 h). In intact rats, the neonatal maturational decline in lactase catalytic activities involves both a shift to production of the inactive 100-kDa subunit and increased membrane surface degradation of the active 130-kDa subunit. 相似文献
84.
85.
Dr. habil. B. Ceranka Dr. A. Dobek Dr. H. Kiełozewska 《Biometrical journal. Biometrische Zeitschrift》1987,29(4):455-460
The analysis of offsprings from the partial diallel crosses is presented. In considered type of crossing, p parental forms into H separate groups are devided. Single crosses among parental forms, from separate groups only, are performed. The analysis for experiments laid out in efficiency balanced block designs is given. 相似文献
86.
Effects of scale on interpreting life-history characteristics of ungulates and carnivores 总被引:1,自引:0,他引:1
Many life-history characteristics of large mammals are scale sensitive. We provide examples where varying temporal and spatial scales can affect interpretation of data concerning life-history characteristics in large herbivores and carnivores and offer recommendations for selecting the most appropriate sampling scale or scales. We also document that some animals make decisions concerning their spatial distribution at scales well beyond the size of the home range. Conversely, other decisions involving sexual segregation of sexes, or where to give birth, may be made at scales below the level of the habitat patch. Such differences in behaviour affect our understanding of habitat selection in large herbivores, and interpreting tradeoffs between acquiring essential resources and avoiding predators. Moreover, some landscape attributes may be selected at one scale, whereas other characteristics of the environment may be selected at another. We argue that even sophisticated models for explaining the ecology and behaviour of mammals benefit from framing specific hypotheses that are related to the to the life-history characteristics of those animals. We also believe that the failure to consider and select the most appropriate scale, or suite of scales, may lead to the mismanagement of critical natural resources. We forge relationships among scale, life-history characteristics of mammals, and biodiversity. Finally, we synthesize the literature on scale for large mammals and make recommendations for future research. 相似文献
87.
When nuclei isolated from rat liver in a low salt buffer were washed with 0.1 M NaCl solution, the supernatant showed a deoxyribonuclease (DNase) activity. The activity required Mg2+ and in addition spermine or spermidine, and its optimal pH was 7.2-7.4. The activity was higher on denatured (single stranded) DNA than on double-helical DNA. With both substrates the activity was highest at a polyamine concentration at which the DNA-polyamine complex began to precipitate. No Mg2++Ca2+ dependent DNase activity was detected in the preparation. 相似文献
88.
Katarzyna Szczepańska Tadeusz Karcz Magdalena Kotańska Agata Siwek Kamil J. Kuder Gniewomir Latacz Szczepan Mogilski Stefanie Hagenow Annamaria Lubelska Michał Sobolewski Holger Stark Katarzyna Kieć-Kononowicz 《Bioorganic & medicinal chemistry》2018,26(23-24):6056-6066
As a continuation of our search for novel histamine H3 receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2–25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H3 receptors (hH3R). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hH3R affinity (hH3R Ki?=?5.2–115?nM). Moreover introduction of carbonyl group containing residues in the lipophilic part of molecules instead of branched alkyl substituents resulted in increased affinity in correlation to previously described series, whereas propionyl derivatives showed slightly higher affinities than those of acetyl (16 and 22vs.4 and 10; hH3R Ki?=?5.2 and 15.4?nM vs. 10.2 and 115?nM, respectively). These findings were confirmed by molecular modelling studies, demonstrating multiple ligand-receptor interactions. Furthermore, pharmacological in vivo test results of compound 4 clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. Likewise, its protective action against hyperglycemia and the development of overweight has been shown. In order to estimate drug-likeness of compound 4, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. 相似文献
89.