全文获取类型
收费全文 | 1289篇 |
免费 | 58篇 |
出版年
2022年 | 8篇 |
2021年 | 7篇 |
2020年 | 9篇 |
2019年 | 8篇 |
2018年 | 22篇 |
2017年 | 15篇 |
2016年 | 31篇 |
2015年 | 29篇 |
2014年 | 38篇 |
2013年 | 66篇 |
2012年 | 65篇 |
2011年 | 78篇 |
2010年 | 49篇 |
2009年 | 48篇 |
2008年 | 88篇 |
2007年 | 95篇 |
2006年 | 84篇 |
2005年 | 100篇 |
2004年 | 91篇 |
2003年 | 81篇 |
2002年 | 92篇 |
2001年 | 9篇 |
2000年 | 5篇 |
1999年 | 6篇 |
1998年 | 17篇 |
1997年 | 14篇 |
1996年 | 22篇 |
1995年 | 13篇 |
1994年 | 18篇 |
1993年 | 17篇 |
1992年 | 16篇 |
1991年 | 14篇 |
1990年 | 11篇 |
1989年 | 5篇 |
1988年 | 8篇 |
1987年 | 5篇 |
1986年 | 4篇 |
1985年 | 4篇 |
1984年 | 6篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 2篇 |
1980年 | 8篇 |
1979年 | 2篇 |
1978年 | 9篇 |
1977年 | 4篇 |
1976年 | 2篇 |
1975年 | 3篇 |
1974年 | 3篇 |
1973年 | 2篇 |
排序方式: 共有1347条查询结果,搜索用时 156 毫秒
101.
Shinji Sudoh Yuuki Kawamura Shinji Sato §Rong Wang ‡Takaomi C. Saido †Fumitaka Oyama Yoshiyuki Sakaki Hiroto Komano Katsuhiko Yanagisawa 《Journal of neurochemistry》1998,71(4):1535-1543
Abstract: Mutations in the presenilin genes PS1 and PS2 cause the most common form of early-onset familial Alzheimer's disease. The influence of PS1 mutations on the generation of endogenous intracellular amyloid β-protein (Aβ) species was assessed using a highly sensitive immunoblotting technique with inducible mouse neuro-blastoma (Neuro 2a) cell lines expressing the human wild-type (wt) or mutated PS1 (M146L or Δexon 10). The induction of mutated PS1 increased the intracellular levels of two distinct Aβ species ending at residue 42 that were likely to be Aβ1–42 and its N-terminally truncated variant(s) Aβx-42. The induction of mutated PS1 resulted in a higher level of intracellular Aβ1–42 than of intracellular Aβx-42, whereas extracellular levels of Aβ1–42 and Aβx-42 were increased proportionally. In addition, the intracellular generation of these Aβ42 species in wt and mutated PS1 -induced cells was completely blocked by brefeldin A, whereas it exhibited differential sensitivities to monensin: the increased accumulation of intracellular Aβx-42 versus inhibition of intracellular Aβ1–42 generation. These data strongly suggest that Aβx-42 is generated in a proximal Golgi, whereas Aβ1–42 is generated in a distal Golgi and/or a post-Golgi compartment. Thus, it appears that PS1 mutations enhance the degree of 42-specific γ-secretase cleavage that occurs in the normal β-amyloid precursor protein processing pathway (a) in the endoplasmic reticulum or the early Golgi apparatus prior to β-secretase cleavage or (b) in the distinct sites where Aβx-42 and Aβ1–42 are generated. 相似文献
102.
Hideko Kambe-Honjoh Shoji Hata Keisuke Ohsumi Katsuhiko Kitamoto 《Biotechnology Techniques》1998,12(2):91-95
A novel bioassay system for estimating concentrations of several heavy metal ions was carried out with yeast mutants which are highly sensitive to heavy metal ions. The method does not need an atomic adsorption spectrometer or other special equipment. It is suitable for screening of microorganisms that efficiently remove heavy metal ions from aqueous solution. 相似文献
103.
Riki Okita Diana Wolf Koichiro Yasuda Ai Maeda Takuro Yukawa Shinsuke Saisho Katsuhiko Shimizu Yoshiyuki Yamaguchi Mikio Oka Eiichi Nakayama Andreas Lundqvist Rolf Kiessling Barbara Seliger Masao Nakata 《PloS one》2015,10(10)
IntroductionSeveral cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti-tumor immunity remains largely unknown.MethodsThis study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis.ResultsWe demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a.ConclusionIn keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells. 相似文献
104.
105.
Hyeon-Ki Kim Masayuki Konishi Masaki Takahashi Hiroki Tabata Naoya Endo Shigeharu Numao Sun-Kyoung Lee Young-Hak Kim Katsuhiko Suzuki Shizuo Sakamoto 《PloS one》2015,10(9)
Purpose
To compare the effects of endurance exercise performed in the morning and evening on inflammatory cytokine responses in young men.Methods
Fourteen healthy male participants aged 24.3 ± 0.8 years (mean ± standard error) performed endurance exercise in the morning (0900–1000 h) on one day and then in the evening (1700–1800 h) on another day with an interval of at least 1 week between each trial. In both the morning and evening trials, the participants walked for 60 minutes at approximately 60% of the maximal oxygen uptake () on a treadmill. Blood samples were collected to determine hormones and inflammatory cytokines at pre-exercise, immediately post exercise, and 2 h post exercise.Results
Plasma interleukin (IL)-6 and adrenaline concentrations were significantly higher immediately after exercise in the evening trial than in the morning trial (P < 0.01, both). Serum free fatty acids concentrations were significantly higher in the evening trial than in the morning trial at 2 h after exercise (P < 0.05). Furthermore, a significant correlation was observed between the levels of IL-6 immediately post-exercise and free fatty acids 2 h post-exercise in the evening (r = 0.68, P < 0.01).Conclusions
These findings suggest that the effect of acute endurance exercise in the evening enhances the plasma IL-6 and adrenaline concentrations compared to that in the morning. In addition, IL-6 was involved in increasing free fatty acids, suggesting that the evening is more effective for exercise-induced lipolysis compared with the morning. 相似文献106.
Background
Trypanosoma cruzi is a parasitic protist that causes Chagas disease, which is prevalent in Latin America. Because of the unavailability of an effective drug or vaccine, and because about 8 million people are infected with the parasite worldwide, the development of novel drugs demands urgent attention. T. cruzi infects a wide variety of mammalian nucleated cells, with a preference for myocardial cells. Non-dividing trypomastigotes in the bloodstream infect host cells where they are transformed into replication-capable amastigotes. The amastigotes revert to trypomastigotes (trypomastigogenesis) before being shed out of the host cells. Although trypomastigote transformation is an essential process for the parasite, the molecular mechanisms underlying this process have not yet been clarified, mainly because of the lack of an assay system to induce trypomastigogenesis in vitro.Methodology/Principal Findings
Cultivation of amastigotes in a transformation medium composed of 80% RPMI-1640 and 20% Grace’s Insect Medium mediated their transformation into trypomastigotes. Grace’s Insect Medium alone also induced trypomastigogenesis. Furthermore, trypomastigogenesis was induced more efficiently in the presence of fetal bovine serum. Trypomastigotes derived from in vitro trypomastigogenesis were able to infect mammalian host cells as efficiently as tissue-culture-derived trypomastigotes (TCT) and expressed a marker protein for TCT. Using this assay system, we demonstrated that T. cruzi inositol 1,4,5-trisphosphate receptor (TcIP3R)—an intracellular Ca2+ channel and a key molecule involved in Ca2+ signaling in the parasite—is important for the transformation process.Conclusion/Significance
Our findings provide a new tool to identify the molecular mechanisms of the amastigote-to-trypomastigote transformation, leading to a new strategy for drug development against Chagas disease. 相似文献107.
Shoichiro Ozaki Etsuko Ebisui Kozo Hamada Jun-Ichi Goto Akinobu Z. Suzuki Akiko Terauchi Katsuhiko Mikoshiba 《Bioorganic & medicinal chemistry letters》2010,20(3):1141-1144
Aryl β-aminoethyl ketones were discovered as potent inhibitors of tissue transglutaminase. Heteroaryl-like thiophene groups and N-benzyl N-t-butyl aminoethyl group are critical to the strong inhibitory activity of aryl β-aminoethyl ketones. 相似文献
108.
Yasuyo Seshime Praveen Rao Juvvadi Katsuhiko Kitamoto Yutaka Ebizuka Takamasa Nonaka Isao Fujii 《Bioorganic & medicinal chemistry letters》2010,20(16):4785-4788
As a novel superfamily of type III polyketide synthases in microbes, four genes csyA, csyB, csyC, and csyD, were found in the genome of Aspergillus oryzae, an industrially important filamentous fungus. In order to analyze their functions, we carried out the overexpression of csyA under the control of α-amylase promoter in A. oryzae and identified 3,5-dihydroxybenzoic acid (DHBA) as the major product. Feeding experiments using 13C-labeled acetates confirmed that the acetate labeling pattern of DHBA coincided with that of orcinol derived from orsellinic acid, a polyketide formed by the condensation and cyclization of four acetate units. Further oxidation of methyl group of orcinol by the host fungus could lead to the production of DHBA. Comparative molecular modeling of CsyA with the crystal structure of Neurospora crassa 2′-oxoalkylresorcylic acid synthase indicated that CsyA cavity size can only accept short-chain acyl starter and tetraketide formation. Thus, CsyA is considered to be a tetraketide alkyl-resorcinol/resorcylic acid synthase. 相似文献
109.
Yanli Mao Zhiguo Shang Yosuke Imai Ryugo Tero Motohiko Tanaka Naoki Yamamoto Katsuhiko Yanagisawa 《生物化学与生物物理学报:生物膜》2010,1798(6):1090-5929
Ganglioside GM1 mediates the amyloid beta (Aβ) aggregation that is the hallmark of Alzheimer's disease (AD). To investigate how ganglioside-containing lipid bilayers interact with Aβ, we examined the interaction between Aβ40 and supported planar lipid bilayers (SPBs) on mica and SiO2 substrates by using atomic force microscopy, fluorescence microscopy, and molecular dynamics computer simulations. These SPBs contained several compositions of sphingomyelin, cholesterol, and GM1 and were treated at physiological salt concentrations. Surprisingly high-speed Aβ aggregation of fibril formations occurred at all GM1 concentrations examined on the mica surface, but on the SiO2 surface, only globular agglomerates formed and they formed slowly. At a GM1 concentration of 20 mol%, unique triangular regions formed on the mica surface and the rapidly formed Aβ aggregations were observed only outside these regions. We have found that some unique surface-induced phase separations are induced by the GM1 clustering effects and the strong interactions between the GM1 head group and the water layer adsorbed in the ditrigonal cavities on the mica surface. The speed of Aβ40 aggregation and the shape of the agglomerates depend on the molecular conformation of GM1, which varies depending on the substrate materials. We identified the conformation that significantly accelerates Aβ40 aggregation, and we think that the detailed knowledge about the GM1 molecular conformation obtained in this work will be useful to those investigating Aβ-GM1 interactions. 相似文献
110.
Clara Salaheddin Yoshimitsu Takakura Masako Tsunashima Barbara Stranzinger Oliver Spadiut Montarop Yamabhai Clemens K Peterbauer Dietmar Haltrich 《Microbial cell factories》2010,9(1):57