全文获取类型
收费全文 | 1014篇 |
免费 | 59篇 |
国内免费 | 2篇 |
专业分类
1075篇 |
出版年
2023年 | 6篇 |
2021年 | 7篇 |
2019年 | 5篇 |
2018年 | 14篇 |
2017年 | 9篇 |
2016年 | 18篇 |
2015年 | 30篇 |
2014年 | 30篇 |
2013年 | 34篇 |
2012年 | 35篇 |
2011年 | 57篇 |
2010年 | 34篇 |
2009年 | 27篇 |
2008年 | 47篇 |
2007年 | 48篇 |
2006年 | 30篇 |
2005年 | 48篇 |
2004年 | 43篇 |
2003年 | 51篇 |
2002年 | 46篇 |
2001年 | 49篇 |
2000年 | 31篇 |
1999年 | 25篇 |
1998年 | 16篇 |
1997年 | 9篇 |
1996年 | 6篇 |
1995年 | 9篇 |
1994年 | 7篇 |
1993年 | 7篇 |
1992年 | 30篇 |
1991年 | 25篇 |
1990年 | 30篇 |
1989年 | 26篇 |
1988年 | 18篇 |
1987年 | 15篇 |
1986年 | 14篇 |
1985年 | 18篇 |
1984年 | 10篇 |
1983年 | 10篇 |
1982年 | 11篇 |
1981年 | 5篇 |
1980年 | 7篇 |
1979年 | 6篇 |
1978年 | 14篇 |
1976年 | 6篇 |
1974年 | 6篇 |
1972年 | 4篇 |
1970年 | 4篇 |
1969年 | 8篇 |
1965年 | 5篇 |
排序方式: 共有1075条查询结果,搜索用时 0 毫秒
991.
Human alpha(1)-acid glycoprotein (AGP), which is comprised of 183 amino acid residues and 5 carbohydrate chains, is a major plasma protein that binds to basic and neutral drugs as well as to steroid hormones. It has a beta-sheet-rich structure in aqueous solution. Our previous findings suggest that AGP forms an alpha-helix structure through an interaction with biomembranes. We report herein on a study of the mechanism of alpha-helix formation in AGP using various modified AGPs. The disulfide reduced AGP (R-AGP) was extensively unfolded, whereas asialylated AGP (A-AGP) maintained the native structure. Intriguingly, reduced and asialylated AGP (RA-AGP) increased the alpha-helix content as observed in the presence of biomembrane models, and showed a significant decrease in ligand binding capacity. This suggests that AGP has an innate tendency to form an alpha-helix structure, and disulfide bonds are a key factor in the conformational transition between the beta-sheet and alpha-helix structures. However, RA-AGP with all histidine residues chemically modified (HRA-AGP) was found to lose the intrinsic ability to form an alpha-helix structure. Furthermore, disulfide reduction of the H172A mutant expressed in Pichia pastoris also caused a similar loss of folding ability. The present results indicate that disulfide bonds and the C-terminal region, including H172 of AGP, play important roles in alpha-helix formation in the interaction of the protein with biomembranes. 相似文献
992.
Ken-ichi Honjoh Kanae Matsuura Takeshi Machida Koutarou Nishi Miki Nakao Tomoki Yano Takahisa Miyamoto Masayoshi Iio 《Amino acids》2010,38(4):1173-1183
Taurine is known to function as a protectant against various stresses in animal cells. In order to utilize taurine as a compatible
solute for stress tolerance of yeast, isolation of cDNA clones for genes encoding enzymes involved in biosynthesis of taurine
was attempted. Two types of cDNA clones corresponding to genes encoding cysteine dioxygenase (CDO1 and CDO2) and a cDNA clone
for cysteine sulfinate decarboxylase (CSD) were isolated from Cyprinus carpio. Deduced amino acid sequences of the two CDOs and that of CSD showed high similarity to those of CDOs and those of CSDs from
other organisms, respectively. The coding regions of CDO1, CDO2, and CSD were subcloned into an expression vector, pESC-TRP, for Saccharomyces cerevisiae. Furthermore, to enhance the efficiency of synthesis of taurine in S. cerevisiae, a CDO–CSD fusion was designed and expressed. Expression of CDO and CSD proteins, or the CDO–CSD fusion protein was confirmed by Western
blot analysis. HPLC analysis showed that the expression of the proteins led to enhancement of the accumulation level of hypotaurine,
a precursor of taurine, rather than taurine. The yeast cells expressing corresponding genes showed tolerance to oxidative
stress induced by menadione, but not to freezing–thawing stress. 相似文献
993.
Akinori Nishi Ayako Ishii Aki Takahashi Toshihiko Shiroishi Tsuyoshi Koide 《Mammalian genome》2010,21(9-10):477-485
The activity of mice in their home cage is influenced greatly by the cycle of light and dark. In addition, home-cage activity shows remarkable time-dependent changes that result in a prominent temporal pattern. The wild-derived mouse strain MSM/Ms (MSM) exhibits higher total activity in the home cage than does C57BL/6 (B6), a commonly used laboratory strain. In addition, there is a clear strain difference in the temporal pattern of home-cage activity. This study aimed to clarify the genetic basis of strain differences in the temporal pattern of home-cage activity between MSM and B6. Through the comparison of temporal patterns of home-cage activity between B6 and MSM, the pattern can be classified into five temporal components: (1) resting phase, (2) anticipation phase, (3) 1st phase, (4) 2nd phase, and (5) 3rd phase. To identify quantitative trait loci (QTLs) involved in these temporal components, we used consomic strains established from crosses between B6 and MSM. Five consomic strains, for Chrs 2T (telomere), 3, 4, 13, and 14, showed significantly higher total activity than B6. In contrast, the consomic strains of Chrs 6C (centromere), 7T, 9, 11, and 15 were less active than B6. This indicates that multigenic factors regulate the total activity. Further analysis showed an impact of QTLs on the temporal components of home-cage activity. The present data showed that each temporal component was regulated by different combinations of multigenic factors, with some overlap. These temporal component-related QTLs are important to understand fully the genetic mechanisms that underlie home-cage activity. 相似文献
994.
Tomoharu Tsukada Kazuhiko Tamaki Jun Tanaka Toshiyuki Takagi Taishi Yoshida Akira Okuno Takeshi Shiiki Mizuki Takahashi Takahide Nishi 《Bioorganic & medicinal chemistry letters》2010,20(9):2938-2941
For the purpose of reducing the strong CYP3A4 inhibitory potency of diamide prodrug 4, cyclic prodrugs of tricyclic-based FBPase inhibitors were synthesized. Extensive SAR studies led to the discovery of pyridine-containing cyclic prodrug 20, which strongly inhibited glucose production in monkey hepatocytes and also showed weak CYP3A4 inhibitory potency. 相似文献
995.
K.C. Agarwal Vidisha Sharma Nishi Shakya Suman Gupta 《Bioorganic & medicinal chemistry letters》2009,19(18):5474-5477
4-(Substituted-benzylidine)-2-substituted-5,6-dihydrobenzo[h]quinazoline (5a–p) and 4-(substituted-benzylidine)-2-substituted-3, 4, 5, 6-tetrahydrobenzo[h]quinazoline (6a–p) have been synthesized from 2-(substituted-benzylidine)tetralone-1(3a–d) and several substituted guanidine sulfates(4a–d).These compounds were tested for their in vitro antileishmanial activity. The compounds 6i, 6f, 6g show promising antileishmanial activity against Leishmania donovani. 相似文献
996.
Takeo Kasagami In-Hae Kim Hsing-Ju Tsai Kosuke Nishi Bruce D. Hammock Christophe Morisseau 《Bioorganic & medicinal chemistry letters》2009,19(6):1784-1789
We investigated N-adamantyl-N′-phenyl urea derivatives as simple sEH inhibitors. Salicylate ester derivatives have high inhibitory activities against human sEH, while the free benzoic acids are less active. The methyl salicylate derivative is a potent sEH inhibitor, which also has high metabolic and chemical stabilities; suggesting that such inhibitors are potential lead molecule for bioactive compounds acting in vivo. 相似文献
997.
Kayoko Nishi Hirokazu Inoue Joachim B. Schnier Robert H. Rice 《Journal of cellular biochemistry》2009,106(1):63-72
To understand the relationship between permanent cell cycle exit and differentiation the immortalized keratinocyte cell line, SIK and the squamous cell carcinoma, SCC9 were compared during differentiation induced by anchorage‐deprivation. The SIK cells when placed in suspension culture promptly lost almost all ability to reinitiate growth by 2 days concomitantly expressing the differentiation specific proteins, transglutaminase (TGK) and involucrin. These cells rapidly underwent G1 cell cycle arrest with complete disappearance of phosphorylated RB. In contrast SCC9 cells neither showed TGK expression nor increase in involucrin. They decreased their colony‐forming ability much more slowly, which coordinated well with a gradual decrease in phosphorylated RB, demonstrating the significant resistance to loss of colony‐forming ability and cell cycle exit. In accordance, cyclin D1, a positive regulator of cyclin‐dependent kinase (CDK) 4/6 which phosphorylates RB decreased drastically in anchorage deprived SIK but not in SCC9 cells. Endogenous cyclin D1 knockdown in SCC9 cells by siRNA enhanced loss of the colony‐forming ability during anchorage‐deprivation. Conversely enforced expression of cyclin D1 in SIK cells and in another immortalized keratinocyte cell line, HaCaT, partly prevented loss of their colony‐forming abilities. Cyclin D1 overexpression antagonized Keratin 10 expression in suspended HaCaT cells. The result demonstrates the importance of cyclin D1 down regulation for proper initiation of keratinocyte differentiation. J. Cell. Biochem. 106: 63–72, 2009. © 2008 Wiley‐Liss, Inc. 相似文献
998.
Deficiencies in brain serotonergic neurotransmission, which is in part associated with the alteration of brain serotonin (5-HT) receptors, have been proposed as part of a neurochemical imbalance in affective disorders, including depression. The drugs used for the treatment of these disorders generally act through and/or on the serotonergic system. Different animal models of depression have provided researchers with tools to obtain a better understanding of drug actions and possibilities to obtain insight into the neurochemical bases of these disorders. The measurements of the 5-HT1A and 5-HT1B receptor densities in a rat model of depression, Flinders sensitive line (FSL) rats, and comparisons with Sprague–Dawley (SPD) and Flinders resistant line (FRL) rats, are reported here. The receptor sites were quantified by autoradiography in more than 25 distinct brain regions known to have relatively large densities of respective sites. Some brain regions (e.g., dental gyrus, septal nucleus) were divided into several parts, according to previously known subdivisions, because of a substantial heterogeneity of these receptors. The densities in the FSL rats (“depressed” rats) were compared statistically to those in the SPD rats. In addition, comparisons were made to the densities in the FRL rats (rats not showing depressive symptoms). Comparisons were performed with the SPD and FRL rats because both of these strains have been used as control animals in studies of FSL rats. The results show that the densities of 5-HT1A receptors are not significantly different between the FSL and SPD rats, but they are significantly different from the FRL rats. 5-HT1A receptor density is significantly higher in the FRL rats than the SPD rats. The 5-HT1B receptors were significantly greater in the FSL rats than in either the SPD or FRL rats. In addition, the FRL rats have 5-HT1B receptor densities significantly lower in many brain regions than the SPD rats. The data presented here, in addition to previously reported differences in regional synthesis between these strains and the effect of acute citalopram on synthesis, suggest that SPD rats are likely a more appropriate control than FRL rats, when studies of FSL rats are performed with drugs acting directly or indirectly on, or through, the brain serotonergic system. However, comparisons, particularly of neurochemical and/or biological parameters in FRL rats, may reveal new insight into the alterations of 5-HT neurotransmission in this animal model of depression and possibly human depression, as well as the elevation of symptoms with treatments. The data also suggest that there could be a different fraction of 5-HT1A receptors in high and low affinity states in these strains, as well as the possibility of different intracellular signalling. 相似文献
999.
Tanaka N Goto M Kawasaki A Sasano T Eto K Nishi R Sugasawa K Abe S Saitoh H 《Cell biochemistry and function》2010,28(7):604-612
A multifunctional calcium‐binding protein, centrin‐1, is specifically expressed in male germ cells, certain neurons and ciliated cells. We identified centrin‐1 as a protein interacting with SUMO‐2/3 using yeast two‐hybrid screening of a mouse testicular cDNA library. In bead halo assays, the interaction between centrin‐1 and SUMO‐2/3 was reduced in the presence of EGTA and facilitated by the addition of CaCl2. immunostaining of seminiferous tubules in 35‐day‐old mouse testes revealed that cells in the layer containing spermatogonia showed colocalization of SUMO‐2/3 with centrin‐1 in cytoplasmic spots. Identification of centrin‐1 as the EGTA‐sensitive SUMO‐2/3‐interacting protein indicates the possible role of calcium in modulating the centrin‐1–SUMO‐2/3 interaction and suggests the importance of this interaction in mouse testis. Copyright © 2010 John Wiley & Sons, Ltd. 相似文献
1000.
An efficient in vitro propagation is described for Spondias mangifera Willd., a medicinally important tree, using nodal explants obtained from 4-week-old seedlings. The frequency of shoot regeneration
from seedling node was affected by various concentrations of BAP and successive transfer of mother explant. MS (Murashige
and Skoog, Physiol Plant 15:473–497, 1962) medium supplemented with 1.0 mg l−1 of 6-benzylaminopurine (BAP) was optimal for shoot multiplication. Upon this medium, highest number of shoots (about 10.6)
per explants was obtained after fourth subculture of mother explants. Half-strength MS medium containing IAA (1.0 mg l−1) was most effective for rooting of shoots. Regenerated plantlets were successfully acclimatized and transferred into soil
with 80–90% survival rate. The regenerated plants were morphologically uniform and exhibited similar growth characteristics
and vegetative morphology to the mother plants. This is the first report on micropropagation of S. mangifera, which can be applied for further genetic transformation assays and pharmaceutical purposes. 相似文献