全文获取类型
收费全文 | 671篇 |
免费 | 33篇 |
出版年
2022年 | 3篇 |
2021年 | 4篇 |
2020年 | 4篇 |
2018年 | 7篇 |
2017年 | 7篇 |
2016年 | 8篇 |
2015年 | 12篇 |
2014年 | 17篇 |
2013年 | 112篇 |
2012年 | 45篇 |
2011年 | 36篇 |
2010年 | 23篇 |
2009年 | 30篇 |
2008年 | 35篇 |
2007年 | 32篇 |
2006年 | 36篇 |
2005年 | 49篇 |
2004年 | 38篇 |
2003年 | 28篇 |
2002年 | 28篇 |
2001年 | 4篇 |
1999年 | 4篇 |
1998年 | 12篇 |
1997年 | 6篇 |
1996年 | 2篇 |
1995年 | 2篇 |
1994年 | 2篇 |
1993年 | 4篇 |
1992年 | 5篇 |
1991年 | 8篇 |
1990年 | 4篇 |
1989年 | 5篇 |
1988年 | 9篇 |
1987年 | 6篇 |
1986年 | 7篇 |
1985年 | 3篇 |
1984年 | 6篇 |
1983年 | 7篇 |
1982年 | 8篇 |
1981年 | 9篇 |
1980年 | 4篇 |
1979年 | 7篇 |
1978年 | 5篇 |
1976年 | 2篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1971年 | 3篇 |
1968年 | 1篇 |
1967年 | 5篇 |
1961年 | 1篇 |
排序方式: 共有704条查询结果,搜索用时 15 毫秒
21.
22.
23.
Tomoyuki Yamanaka Asako Tosaki Masaru Kurosawa Kazunori Akimoto Tomonori Hirose Shigeo Ohno Nobutaka Hattori Nobuyuki Nukina 《PloS one》2013,8(12)
Cell polarity plays a critical role in neuronal differentiation during development of the central nervous system (CNS). Recent studies have established the significance of atypical protein kinase C (aPKC) and its interacting partners, which include PAR-3, PAR-6 and Lgl, in regulating cell polarization during neuronal differentiation. However, their roles in neuronal maintenance after CNS development remain unclear. Here we performed conditional deletion of aPKCλ, a major aPKC isoform in the brain, in differentiated neurons of mice by camk2a-cre or synapsinI-cre mediated gene targeting. We found significant reduction of aPKCλ and total aPKCs in the adult mouse brains. The aPKCλ deletion also reduced PAR-6β, possibly by its destabilization, whereas expression of other related proteins such as PAR-3 and Lgl-1 was unaffected. Biochemical analyses suggested that a significant fraction of aPKCλ formed a protein complex with PAR-6β and Lgl-1 in the brain lysates, which was disrupted by the aPKCλ deletion. Notably, the aPKCλ deletion mice did not show apparent cell loss/degeneration in the brain. In addition, neuronal orientation/distribution seemed to be unaffected. Thus, despite the polarity complex disruption, neuronal deletion of aPKCλ does not induce obvious cell loss or disorientation in mouse brains after cell differentiation. 相似文献
24.
25.
Masashi Kato Mayuko Y. Kumasaka Shoko Ohnuma Akio Furuta Yoko Kato Hossain U. Shekhar Michiyo Kojima Yasuko Koike Nguyen Dinh Thang Nobutaka Ohgami Thuy Bich Ly Xiaofang Jia Husna Yetti Hisao Naito Gaku Ichihara Ichiro Yajima 《PloS one》2013,8(6)
Health risk for well drinking water is a worldwide problem. Our recent studies showed increased toxicity by exposure to barium alone (≤700 µg/L) and coexposure to barium (137 µg/L) and arsenic (225 µg/L). The present edition of WHO health-based guidelines for drinking water revised in 2011 has maintained the values of arsenic (10 µg/L) and barium (700 µg/L), but not elements such as manganese, iron and zinc. Nevertheless, there have been very few studies on barium in drinking water and human samples. This study showed significant correlations between levels of arsenic and barium, but not its homologous elements (magnesium, calcium and strontium), in urine, toenail and hair samples obtained from residents of Jessore, Bangladesh. Significant correlation between levels of arsenic and barium in well drinking water and levels in human urine, toenail and hair samples were also observed. Based on these results, a high-performance and low-cost adsorbent composed of a hydrotalcite-like compound for barium and arsenic was developed. The adsorbent reduced levels of barium and arsenic from well water in Bangladesh and Vietnam to <7 µg/L within 1 min. Thus, we have showed levels of arsenic and barium in humans and propose a novel remediation system. 相似文献
26.
Tetsurou Muroi Takaaki Kokuzawa Yoshihiko Kihara Ryuichi Kobayashi Nobutaka Hirano Hideo Takahashi Mitsuru Haruki 《Applied microbiology and biotechnology》2013,97(9):4039-4048
Serine-type phage integrases catalyze unidirectional site-specific recombination between the attachment sites, attP and attB, in the phage and host bacterial genomes, respectively; these integrases and DNA target sites function efficiently when transferred into heterologous cells. We previously developed an in vivo site-specific genomic integration system based on actinophage TG1 integrase that introduces ~2-kbp DNA into an att site inserted into a heterologous Escherichia coli genome. Here, we analyzed the TG1 integrase-mediated integrations of att site-containing ~10-kbp DNA into the corresponding att site pre-inserted into various genomic locations; moreover, we developed a system that introduces ~10-kbp DNA into the genome with an efficiency of ~104 transformants/μg DNA. Integrations of attB-containing DNA into an attP-containing genome were more efficient than integrations of attP-containing DNA into an attB-containing genome, and integrations targeting attP inserted near the replication origin, oriC, and the E. coli “centromere” analogue, migS, were more efficient than those targeting attP within other regions of the genome. Because the genomic region proximal to the oriC and migS sites is located at the extreme poles of the cell during chromosomal segregation, the oriC–migS region may be more exposed to the cytosol than are other regions of the E. coli chromosome. Thus, accessibility of pre-inserted attP to attB-containing incoming DNA may be crucial for the integration efficiency by serine-type integrases in heterologous cells. These results may be beneficial to the development of serine-type integrases-based genomic integration systems for various bacterial species. 相似文献
27.
28.
Ryo C. Yanagita Hiroaki Kamachi Masayuki Kikumori Harukuni Tokuda Nobutaka Suzuki Kiyotake Suenaga Hiroshi Nagai Kazuhiro Irie 《Bioorganic & medicinal chemistry letters》2013,23(15):4319-4323
Debromoaplysiatoxin (DAT) is a tumor promoter isolated from sea hare and exhibits anti-proliferative activity against several cancer cell lines. To clarify key residues that are responsible for its tumor-promoting activity, we focused on the chiral methoxy group in the side chain, whose role had not yet been discussed or examined before. Demethoxy-DAT (8) was derived from DAT and we evaluated its tumor-promoting activity, anti-proliferative activity, and ability to bind to protein kinase C (PKC) isozymes. Compound 8 showed somewhat weaker tumor-promoting activity than that of DAT both in vitro and in vivo, but showed higher anti-proliferative activity against several cancer cell lines. Although the affinity to novel PKC isozymes of 8 was comparable to that of DAT, the affinity to conventional PKC isozymes decreased slightly. These results suggest that the methoxy group of DAT is one of the key residues critical for tumor-promoting activity but not for anti-proliferative activity. Since the methoxy group has little influence on the molecular hydrophobicity, this is the first report showing that structural factors other than hydrophobicity in the side chain of DAT affected its biological activities. 相似文献
29.
Ryosuke Misu Shinya Oishi Shohei Setsuda Taro Noguchi Masato Kaneda Hiroaki Ohno Barry Evans Jean-Marc Navenot Stephen C. Peiper Nobutaka Fujii 《Bioorganic & medicinal chemistry letters》2013,23(9):2628-2631
Kisspeptins, endogenous peptide ligands for GPR54, play an important role in GnRH secretion. Since in vivo administration of kisspeptins induces increased plasma LH levels, GPR54 agonists hold promise as therapeutic agents for the treatment of hormonal secretion diseases. To facilitate the design of novel potent GPR54 ligands, residues in kisspeptins that involve in the interaction with GPR54 were investigated by kisspeptin-based photoaffinity probes. Herein, we report the design and synthesis of novel kisspeptin-based photoaffinity probes, and the application to crosslinking experiments for GPR54-expressing cells. 相似文献
30.
Hiroaki Kamachi Keisuke Tanaka Ryo C. Yanagita Akira Murakami Kazuma Murakami Harukuni Tokuda Nobutaka Suzuki Yu Nakagawa Kazuhiro Irie 《Bioorganic & medicinal chemistry》2013,21(10):2695-2702
We have recently developed a simplified analog of aplysiatoxin (aplog-1) as an activator of protein kinase C (PKC) with anti-proliferative activity like bryostain 1. To identify sites in aplog-1 that could be readily modified to optimize therapeutic performance and to develop a molecular probe for examining the analog’s mode of action, substituent effects on the phenol ring were systematically examined. Whereas hydrophilic acetamido derivatives were less active than aplog-1 in inhibiting cancer cell growth and binding to PKCδ, introduction of hydrophobic bromine and iodine atoms enhanced both biological activities. The anti-proliferative activity was found to correlate closely with molecular hydrophobicity, and maximal activity was observed at a log P value of 4.0–4.5. On the other hand, an induction test with Epstein–Barr virus early antigen demonstrated that these derivatives have less tumor-promoting activity in vitro than aplog-1 regardless of the hydrophobicity of their substituents. These results would facilitate rapid preparation of molecular probes to examine the mechanism of the unique biological activities of aplog-1. 相似文献