全文获取类型
收费全文 | 2882篇 |
免费 | 192篇 |
国内免费 | 1篇 |
出版年
2021年 | 20篇 |
2019年 | 17篇 |
2018年 | 23篇 |
2017年 | 19篇 |
2016年 | 47篇 |
2015年 | 72篇 |
2014年 | 80篇 |
2013年 | 161篇 |
2012年 | 129篇 |
2011年 | 145篇 |
2010年 | 89篇 |
2009年 | 100篇 |
2008年 | 130篇 |
2007年 | 166篇 |
2006年 | 137篇 |
2005年 | 134篇 |
2004年 | 122篇 |
2003年 | 119篇 |
2002年 | 140篇 |
2001年 | 127篇 |
2000年 | 117篇 |
1999年 | 100篇 |
1998年 | 48篇 |
1997年 | 32篇 |
1996年 | 19篇 |
1995年 | 29篇 |
1994年 | 23篇 |
1993年 | 24篇 |
1992年 | 49篇 |
1991年 | 60篇 |
1990年 | 57篇 |
1989年 | 56篇 |
1988年 | 57篇 |
1987年 | 26篇 |
1986年 | 35篇 |
1985年 | 36篇 |
1984年 | 23篇 |
1983年 | 27篇 |
1982年 | 32篇 |
1981年 | 16篇 |
1980年 | 13篇 |
1979年 | 16篇 |
1978年 | 25篇 |
1977年 | 29篇 |
1976年 | 17篇 |
1975年 | 16篇 |
1974年 | 15篇 |
1973年 | 16篇 |
1969年 | 12篇 |
1968年 | 13篇 |
排序方式: 共有3075条查询结果,搜索用时 18 毫秒
991.
Yukiko Doi Hideyuki Takeuchi Hiroshi Horiuchi Taketo Hanyu Jun Kawanokuchi Shijie Jin Bijay Parajuli Yoshifumi Sonobe Tetsuya Mizuno Akio Suzumura 《PloS one》2013,8(4)
The neurodegenerative processes that underlie Alzheimer''s disease are mediated, in part, by soluble oligomeric amyloid β, a neurotoxic protein that inhibits hippocampal long-term potentiation, disrupts synaptic plasticity, and induces the production of reactive oxygen species. Here we show that the sphingosine-1-phosphate (S1P) receptor (S1PR) agonist fingolimod phosphate (FTY720-P)-a new oral drug for multiple sclerosis-protects neurons against oligomeric amyloid β-induced neurotoxicity. We confirmed that primary mouse cortical neurons express all of the S1P receptor subtypes and FTY720-P directly affects the neurons. Treatment with FTY720-P enhanced the expression of brain-derived neurotrophic factor (BDNF) in neurons. Moreover, blocking BDNF-TrkB signaling with a BDNF scavenger, TrkB inhibitor, or ERK1/2 inhibitor almost completely ablated these neuroprotective effects. These results suggested that the neuroprotective effects of FTY720-P are mediated by upregulated neuronal BDNF levels. Therefore, FTY720-P may be a promising therapeutic agent for neurodegenerative diseases, such as Alzheimer''s disease. 相似文献
992.
Jiro Kikuchi Naoya Shibayama Satoshi Yamada Taeko Wada Masaharu Nobuyoshi Tohru Izumi Miyuki Akutsu Yasuhiko Kano Kanako Sugiyama Mio Ohki Sam-Yong Park Yusuke Furukawa 《PloS one》2013,8(4)
The proteasome is a proteolytic machinery that executes the degradation of polyubiquitinated proteins to maintain cellular homeostasis. Proteasome inhibition is a unique and effective way to kill cancer cells because they are sensitive to proteotoxic stress. Indeed, the proteasome inhibitor bortezomib is now indispensable for the treatment of multiple myeloma and other intractable malignancies, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. To resolve these problems, we attempted to develop orally bioavailable proteasome inhibitors with distinct mechanisms of action and identified homopiperazine derivatives (HPDs) as promising candidates. Biochemical and crystallographic studies revealed that some HPDs inhibit all three catalytic subunits (ß 1, ß 2 and ß 5) of the proteasome by direct binding, whereas bortezomib and other proteasome inhibitors mainly act on the ß5 subunit. Proteasome-inhibitory HPDs exhibited cytotoxic effects on cell lines from various hematological malignancies including myeloma. Furthermore, K-7174, one of the HPDs, was able to inhibit the growth of bortezomib-resistant myeloma cells carrying a ß5-subunit mutation. Finally, K-7174 had additive effects with bortezomib on proteasome inhibition and apoptosis induction in myeloma cells. Taken together, HPDs could be a new class of proteasome inhibitors, which compensate for the weak points of conventional ones and overcome the resistance to bortezomib. 相似文献
993.
Background
Although social participation is a key determinant of health among older adults, few studies have focused on the association between social participation and dental health. This study examined the associations between social participation and dental health status in community-dwelling older Japanese adults.Methods and Findings
In 2010, self-administered postal questionnaires were distributed to all people aged ≥65 years in Iwanuma City, Japan (response rate, 59.0%). Data from 3,517 respondents were analyzed. Data on the number of remaining natural teeth, for determining the dental health status, and social participation were obtained using self-administered questionnaires. The number, type, and frequency of social activities were used to assess social participation. Social activities were political organizations or associations, industrial or professional groups, volunteer groups, senior citizens'' clubs, religious groups or associations, sports groups, neighborhood community associations, and hobby clubs. Using ordinal logistic regression, we calculated the odds ratios (OR) and 95% confidence intervals (95% CI) for an increase in category of remaining teeth based on the number, type, and frequency of social activities. Sex, age, marital status, current medical history, activity of daily living, educational attainment, and annual equivalent income were used as covariates. Of the respondents, 34.2% reported having ≥20 teeth; 27.1%, 10–19 teeth; 26.3%, 1–9 teeth; and 12.4%, edentulousness. Social participation appeared to be related with an increased likelihood of having a greater number of teeth in old age, even after adjusting for covariates (OR = 1.30, 95% CI = 1.10–1.53). Participation in sports groups, neighborhood community associations, or hobby clubs was significantly associated with having more teeth.Conclusions
Our results suggest a protective effect of social participation on dental health. In particular, participation in sports groups, neighborhood community associations, or hobby clubs might be a strong predictor for retaining more teeth in later life. 相似文献994.
Kenichi Hirano Tomohiro Ohgomori Kazuyoshi Kobayashi Fumiaki Tanaka Tomohiro Matsumoto Takamitsu Natori Yukihiro Matsuyama Kenji Uchimura Kazuma Sakamoto Hideyuki Takeuchi Akihiro Hirakawa Akio Suzumura Gen Sobue Naoki Ishiguro Shiro Imagama Kenji Kadomatsu 《PloS one》2013,8(6)
Biopolymers consist of three major classes, i.e., polynucleotides (DNA, RNA), polypeptides (proteins) and polysaccharides (sugar chains). It is widely accepted that polynucleotides and polypeptides play fundamental roles in the pathogenesis of neurodegenerative diseases. But, sugar chains have been poorly studied in this process, and their biological/clinical significance remains largely unexplored. Amyotrophic lateral sclerosis (ALS) is a motoneuron-degenerative disease, the pathogenesis of which requires both cell autonomous and non-cell autonomous processes. Here, we investigated the role of keratan sulfate (KS), a sulfated long sugar chain of proteoglycan, in ALS pathogenesis. We employed ALS model SOD1G93A mice and GlcNAc6ST-1−/− mice, which are KS-deficient in the central nervous system. Unexpectedly, SOD1G93AGlcNAc6ST-1−/− mice exhibited a significantly shorter lifespan than SOD1G93A mice and an accelerated appearance of clinical symptoms (body weight loss and decreased rotarod performance). KS expression was induced exclusively in a subpopulation of microglia in SOD1G93A mice, and became detectable around motoneurons in the ventral horn during the early disease phase before body weight loss. During this phase, the expression of M2 microglia markers was transiently enhanced in SOD1G93A mice, while this enhancement was attenuated in SOD1G93AGlcNAc6ST-1−/− mice. Consistent with this, M2 microglia were markedly less during the early disease phase in SOD1G93AGlcNAc6ST-1−/− mice. Moreover, KS expression in microglia was also detected in some human ALS cases. This study suggests that KS plays an indispensable, suppressive role in the early phase pathogenesis of ALS and may represent a new target for therapeutic intervention. 相似文献
995.
Mayumi Miyazawa-Onami Koh Takeuchi Toshiaki Takano Toshihiko Sugiki Ichio Shimada Hideo Takahashi 《Journal of biomolecular NMR》2013,57(3):297-304
The production of stable isotope-labeled proteins is critical in structural analyses of large molecular weight proteins using NMR. Although prokaryotic expression systems using Escherichia coli have been widely used for this purpose, yeast strains have also been useful for the expression of functional eukaryotic proteins. Recently, we reported a cost-effective stable isotope-labeled protein expression using the hemiascomycete yeast Kluyveromyces lactis (K. lactis), which allow us to express exogenous proteins at costs comparable to prokaryotic expression systems. Here, we report the successful production of highly deuterated (>90 %) protein in the K. lactis system. We also examined the methyl-selective 1H, 13C-labeling of Ile, Leu, and Val residues using commonly used amino acid precursors. The efficiency of 1H- 13C-incorporation varied significantly based on the amino acid. Although a high level of 1H-13C-incorporation was observed for the Ile δ1 position, 1H, 13C-labeling rates of Val and Leu methyl groups were limited due to the mitochondrial localization of enzymes involved in amino acid biosynthesis and the lack of transporters for α-ketoisovalerate in the mitochondrial membrane. In line with this notion, the co-expression with branched-chain-amino-acid aminotransferase in the cytosol significantly improved the incorporation rates of amino acid precursors. Although it would be less cost-effective, addition of 13C-labeled valine can circumvent problems associated with precursors and achieve high level 1H, 13C-labeling of Val and Leu. Taken together, the K. lactis system would be a good alternative for expressing large eukaryotic proteins that need deuteration and/or the methyl-selective 1H, 13C-labeling for the sensitive detection of NMR resonances. 相似文献
996.
Naomichi Iso Haruo Mizuno Takahide Saito Hiromi Takeuchi Yoshio Suyama Shiro Kawamura 《Bioscience, biotechnology, and biochemistry》2013,77(9):1871-1875
The 2% solution of a natto mucin behaved as a thixotropic flow at pH 5.7, although the flow of the same concentration was apparently Newtonian at pH 4.3. In the 6% solution the viscometric behavior at pH 4.3 was almost the same as that at pH 5.7. The results can be explained in terms of the conformational change of the molecule according to the pH change; that is, the mucin molecule is randomly coiled at pH 5.7 and a rod-like molecule at pH 4.3. The conformational change was shown by means of the electron microscope. 相似文献
997.
Yoshio Furutani Tomio Takeuchi Hamao Umezawa 《Bioscience, biotechnology, and biochemistry》2013,77(9):1587-1592
Inhibition mechanism of rat cerebral cortex cyclic nucleotide phosphodiesterases (PDE) by reticulol was investigated. The inhibition of PDE by reticulol was not reduced in the presence of excess PDE activating factor (PAF) or/and Ca2+ ion. Reticulol showed lower Ki values for Ca2+-PAF dependent PDE than for Ca2+ independent PDE. 相似文献
998.
Yoshio Furutani Hiroshi Naganawa Tomio Takeuchi Hamao Umezawa 《Bioscience, biotechnology, and biochemistry》2013,77(7):1179-1183
Besides reticulol, the strain MD611-C6 produced two compounds which inhibited cyclic nucleotide phosphodiesterases [EC 3.1.4. C.] These substances were isolated and their structures were elucidated to be 8-hydroxy-6, 7-dimethoxy-3-hydroxymethyIisocoumarin (II) and 6, 8-dihyroxy-7-methoxy-3-hydroxymethylisocoumarin (III). Concentrations of II and III for 50% inhibition of cAMP phosphodiesterase were 3.97 × 10?4m and 1.26 × 10?8m, respectively. 相似文献
999.
Yoshiki Kumada Tomio Takeuchi Hamao Umezawa 《Bioscience, biotechnology, and biochemistry》2013,77(5):869-876
A dehydrodicaffeic acid dilactone-forming enzyme was purified from the mycelia of a mushroom, Inonotus sp. K-1410 by calcium acetate treatment, ammonium sulfate precipitation and column chromatography on Sephadex G-100, DEAE-Sephadex A-50 and caffeic acid-bound AH-Sepharose 4B. The enzyme was purified about 1200-fold from a crude extract and shown to be almost completely homogeneous by polyacrylamide gel electrophoresis. The molecular weight of this enzyme was estimated by gel filtration on Sephadex G-100 to be approximately 39,000. The optimal pH for the enzymic conversion of caffeic acid to dehydrodicaffeic acid dilactone is around 6.0. The enzyme is stable up to 60°C and preincubation of the enzyme at 40°C for 10 min gives 1.5-fold activation compared with preincubation at 0°C. The optimal temperature for the enzyme reaction is 40°C. 相似文献
1000.
Takeuchi Hisanao Tadauchi Nobuo Keiichiro Muramatsu 《Bioscience, biotechnology, and biochemistry》2013,77(12):2417-2419
A proteinaceous inhibitor of auxin-induced ethylene synthesis by mungbean hypocotyls was purified from mungbean seeds by chromatography on CM-Sephadex C–50 and gel filtration on Sephadex G–200. The molecular weight was estimated to be about 89,000 by gel filtration on Sephadex G–200. The inhibitory protein consisted of two subunits with molecular weights of about 58,000 and 31,000. 相似文献