全文获取类型
收费全文 | 2415篇 |
免费 | 142篇 |
出版年
2023年 | 10篇 |
2022年 | 24篇 |
2021年 | 60篇 |
2020年 | 30篇 |
2019年 | 33篇 |
2018年 | 56篇 |
2017年 | 35篇 |
2016年 | 85篇 |
2015年 | 105篇 |
2014年 | 116篇 |
2013年 | 212篇 |
2012年 | 190篇 |
2011年 | 182篇 |
2010年 | 104篇 |
2009年 | 97篇 |
2008年 | 135篇 |
2007年 | 121篇 |
2006年 | 105篇 |
2005年 | 112篇 |
2004年 | 106篇 |
2003年 | 84篇 |
2002年 | 81篇 |
2001年 | 22篇 |
2000年 | 20篇 |
1999年 | 26篇 |
1998年 | 13篇 |
1997年 | 20篇 |
1996年 | 15篇 |
1995年 | 10篇 |
1994年 | 19篇 |
1993年 | 11篇 |
1992年 | 19篇 |
1991年 | 23篇 |
1990年 | 12篇 |
1989年 | 19篇 |
1988年 | 20篇 |
1987年 | 16篇 |
1986年 | 14篇 |
1985年 | 25篇 |
1984年 | 13篇 |
1983年 | 14篇 |
1982年 | 12篇 |
1979年 | 11篇 |
1977年 | 9篇 |
1976年 | 10篇 |
1975年 | 11篇 |
1973年 | 9篇 |
1971年 | 8篇 |
1970年 | 8篇 |
1969年 | 9篇 |
排序方式: 共有2557条查询结果,搜索用时 46 毫秒
91.
Akemi Shodai Toshifumi Morimura Akemi Ido Tsukasa Uchida Takashi Ayaki Rina Takahashi Soichiro Kitazawa Sakura Suzuki Mikako Shirouzu Takanori Kigawa Yutaka Muto Shigeyuki Yokoyama Ryosuke Takahashi Ryo Kitahara Hidefumi Ito Noriko Fujiwara Makoto Urushitani 《The Journal of biological chemistry》2013,288(21):14886-14905
Aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is a pathological signature of amyotrophic lateral sclerosis (ALS). Although accumulating evidence suggests the involvement of RNA recognition motifs (RRMs) in TDP-43 proteinopathy, it remains unclear how native TDP-43 is converted to pathogenic forms. To elucidate the role of homeostasis of RRM1 structure in ALS pathogenesis, conformations of RRM1 under high pressure were monitored by NMR. We first found that RRM1 was prone to aggregation and had three regions showing stable chemical shifts during misfolding. Moreover, mass spectrometric analysis of aggregated RRM1 revealed that one of the regions was located on protease-resistant β-strands containing two cysteines (Cys-173 and Cys-175), indicating that this region served as a core assembly interface in RRM1 aggregation. Although a fraction of RRM1 aggregates comprised disulfide-bonded oligomers, the substitution of cysteine(s) to serine(s) (C/S) resulted in unexpected acceleration of amyloid fibrils of RRM1 and disulfide-independent aggregate formation of full-length TDP-43. Notably, TDP-43 aggregates with RRM1-C/S required the C terminus, and replicated cytopathologies of ALS, including mislocalization, impaired RNA splicing, ubiquitination, phosphorylation, and motor neuron toxicity. Furthermore, RRM1-C/S accentuated inclusions of familial ALS-linked TDP-43 mutants in the C terminus. The relevance of RRM1-C/S-induced TDP-43 aggregates in ALS pathogenesis was verified by immunolabeling of inclusions of ALS patients and cultured cells overexpressing the RRM1-C/S TDP-43 with antibody targeting misfolding-relevant regions. Our results indicate that cysteines in RRM1 crucially govern the conformation of TDP-43, and aberrant self-assembly of RRM1 at amyloidogenic regions contributes to pathogenic conversion of TDP-43 in ALS. 相似文献
92.
Maki Seki Osamu Tsuruta Ryo Tatsumi Aki Soejima 《Bioorganic & medicinal chemistry letters》2013,23(14):4230-4234
A novel series of pyrrolidine derivatives as Na+ channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na+ channels. Structure–activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na+ channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke. 相似文献
93.
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
94.
95.
Ryo Higuchi Jason D. Vevea Theresa C. Swayne Robert Chojnowski Vanessa Hill Istvan R. Boldogh Liza A. Pon 《Current biology : CB》2013,23(23):2417-2422
- Download : Download high-res image (144KB)
- Download : Download full-size image
96.
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
97.
98.
Ryo Yamauchi Masahiro Kojima Masatoshi Isogai Koji Kato Yoshimitsu Ueno 《Bioscience, biotechnology, and biochemistry》2013,77(11):2847-2849
The NaCl concentration of the growth medium affected hydrogen production by Lyngbya sp. (No. 108) strain. Cells grown in medium containing 3% NaCl produced the most hydrogen. The carbohydrate content of this strain also increased with increasing NaCl concentration of the growth medium up to 720 fig/mg cells at 5 % NaCl. In the presence of 20 finlol/ml MFA (monofluoroacetic acid), inhibition of hydrogen production was observed. We extracted the glycogen from this nonheterocystous filamentous cyanobacterium, Lyngbya sp. (No. 108), and observed that glycogen and carbohydrate consumption of this strain is coincident with hydrogen production.These results led us to the conclusion that the reserve glycogen or other carbohydrate were used as sources of electron donors for hydrogen production, and that the NaCl concentration of the medium affected the hydrogen production by this strain. 相似文献
99.
Izuru Yamamoto Hideo Kamimura Ryo Yamamoto Seiroku Sakai Masayoshi Goda 《Bioscience, biotechnology, and biochemistry》2013,77(10):709-716
Toxicities of some nicotinoids as an insecticide were determined. 5′-methylnornicotine, a new synthetic isomer of nicotine, shows similar toxicity to nicotine. The essential moiety in nicotinoids molecule responsible for high toxicity may be 3-pyridylmethylamine group, the amino nitrogen of which must have high basicity (pKa′: 7.4~9.0). All nicotinoids of high toxicity are estimated to be largely as monocation at physiological pH of 7. 相似文献
100.
Ryo Yamauchi Tomoo Yamada Koji Kato Yoshimitsu Ueno 《Bioscience, biotechnology, and biochemistry》2013,77(12):2897-2902
Methyl eicosapentaenoate (methyl 5,8,11,14,17-eicosapentaenoate) was subjected to autoxidation and methylene blue sensitized photooxidation. Methyl eicosapentaenoate monohydroperoxides, the primary products of the autoxidation and photosensitized oxidation, were isolated by silica gel column chromatography, and characterized by ultraviolet, infrared and nuclear magnetic resonance spectra. The isomeric composition of the monohydroperoxides were determined by gas chromatography-mass spectrometry as follows: the 5-, 8-, 9-, 11-, 12-, 14-, 15- and 18-isomers (autoxidation), and the 5-, 6-, 8-, 9-, 11-, 12-, 14-, 15-, 17- and 18-isomers (photosensitized oxidation). Methyl eicosapentaenoate was readily oxidized both by autoxidation and by photosensitized oxidation. 相似文献