全文获取类型
收费全文 | 2637篇 |
免费 | 133篇 |
出版年
2022年 | 16篇 |
2021年 | 34篇 |
2020年 | 22篇 |
2019年 | 20篇 |
2018年 | 52篇 |
2017年 | 41篇 |
2016年 | 63篇 |
2015年 | 90篇 |
2014年 | 98篇 |
2013年 | 183篇 |
2012年 | 144篇 |
2011年 | 125篇 |
2010年 | 86篇 |
2009年 | 79篇 |
2008年 | 137篇 |
2007年 | 159篇 |
2006年 | 126篇 |
2005年 | 146篇 |
2004年 | 129篇 |
2003年 | 130篇 |
2002年 | 106篇 |
2001年 | 59篇 |
2000年 | 73篇 |
1999年 | 60篇 |
1998年 | 28篇 |
1997年 | 30篇 |
1996年 | 19篇 |
1995年 | 29篇 |
1994年 | 14篇 |
1993年 | 23篇 |
1992年 | 44篇 |
1991年 | 35篇 |
1990年 | 28篇 |
1989年 | 30篇 |
1988年 | 25篇 |
1987年 | 32篇 |
1986年 | 26篇 |
1985年 | 26篇 |
1984年 | 21篇 |
1983年 | 15篇 |
1982年 | 15篇 |
1981年 | 10篇 |
1980年 | 11篇 |
1979年 | 10篇 |
1977年 | 12篇 |
1976年 | 10篇 |
1975年 | 12篇 |
1974年 | 16篇 |
1972年 | 15篇 |
1971年 | 10篇 |
排序方式: 共有2770条查询结果,搜索用时 203 毫秒
81.
Susumu Hara Shigeki Arawaka Hiroyasu Sato Youhei Machiya Can Cui Asuka Sasaki Shingo Koyama Takeo Kato 《Molecular biology of the cell》2013,24(11):1649-1660
Most α-synuclein (α-syn) deposited in Lewy bodies, the pathological hallmark of Parkinson disease (PD), is phosphorylated at Ser-129. However, the physiological and pathological roles of this modification are unclear. Here we investigate the effects of Ser-129 phosphorylation on dopamine (DA) uptake in dopaminergic SH-SY5Y cells expressing α-syn. Subcellular fractionation of small interfering RNA (siRNA)–treated cells shows that G protein–coupled receptor kinase 3 (GRK3), GRK5, GRK6, and casein kinase 2 (CK2) contribute to Ser-129 phosphorylation of membrane-associated α-syn, whereas cytosolic α-syn is phosphorylated exclusively by CK2. Expression of wild-type α-syn increases DA uptake, and this effect is diminished by introducing the S129A mutation into α-syn. However, wild-type and S129A α-syn equally increase the cell surface expression of dopamine transporter (DAT) in SH-SY5Y cells and nonneuronal HEK293 cells. In addition, siRNA-mediated knockdown of GRK5 or GRK6 significantly attenuates DA uptake without altering DAT cell surface expression, whereas knockdown of CK2 has no effect on uptake. Taken together, our results demonstrate that membrane-associated α-syn enhances DA uptake capacity of DAT by GRKs-mediated Ser-129 phosphorylation, suggesting that α-syn modulates intracellular DA levels with no functional redundancy in Ser-129 phosphorylation between GRKs and CK2. 相似文献
82.
83.
Yoshiyuki Yabe Yasuo Koyama Makiya Nishikawa Yoshinobu Takakura Mitsuru Hashida 《Free radical research》2013,47(4):265-274
To explore the possibility of using catalase for the treatment of reactive oxygen species (ROS)-mediated injuries, the pharmacokinetics of bovine liver catalase (CAT) labeled with 111In was investigated in mice. At a dose of 0.1 mg/kg, more than 70% of 111In-CAT was recovered in the liver within 10 min after intravenous injection. In addition, 111In-CAT was predominantly recovered from the parenchymal cells (PC) in the liver. Increasing the dose retarded the hepatic uptake of 111In-CAT, suggesting saturation of the uptake process. This cell-specific uptake could not be inhibited by coadministration of various compounds which are known to be taken up by liver PC, indicating that the uptake mechanism of CAT by PC is very specific to this compound. The preventive effect of CAT on a hepatic ischemia/reperfusion injury was examined in mice by measuring the GOT and GPT levels in plasma. A bolus injection of CAT at 5 min prior to the reperfusion attenuated the increase in the levels of these indicators in a dose-dependent manner. These results suggest that catalase can be used for various hepatic injuries caused by ROS. 相似文献
84.
Kazumasa Aoyagi Siranoush Shahrzad Yutaka Kuzure Akio Koyama Ko Nakamura Kazuharu Ienaga 《Free radical research》2013,47(6):487-496
Puromycin aminonucleoside (PAN) has been known to induce proteinuria. The increased generation of reactive oxygen species (ROS) has been implicated in this toxicity of PAN. We have reported that PAN increases the synthesis of methylguanidine (MG) and creatol which are the products of the reaction of creatinine and the hydroxyl radical in isolated rat hepatocytes. However, the mechanism for the increased ROS induced by PAN is still unclear. In this paper, we investigate the role of protein kinase C (PKC) on the PAN induced reactive oxygen generation in isolated rat hepatocytes. Isolated hepatocytes were incubated in Krebs-Henseleit bicarbonate buffer containing 3% BSA, 16.6 mM creatinine and tested reagents. MG and creatol were determined by high-performance liquid chromatography using 9,10-phenanthrenequinone for the post-labeling. PAN increased MG and creatol synthesis in isolated rat hepatocytes by 60%. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), a PKC inhibitor, at 10 and 100 μM significantly inhibited MG and creatol synthesis with or without PAN. The inhibition rate is dose dependent from 10 to 100 μM. H1004, a reagent used as control for H-7, did not affect (at 10 μM) or increased little (at 100 μM) the synthesis of MG and creatol. Ro31-8425, a potent PKC inhibitor, significantly inhibited (at 10 μM) MG synthesis in the presence of PAN. PKC in the membrane fraction, a marker of PKC activation, increased over the initial concentration by a factor of 1.65-fold at 60 min incubation and 2.16-fold at 120 min with PAN, while it changed little without PAN. These results indicate that PAN activates PKC resulting in increased hydroxyl radical generation in isolated rat hepatocytes. 相似文献
85.
Kohji Ichimori Naoto Fukuyama Hiroe Nakazawa Yasuaki Aratani Hideki Koyama Shunya Takizawa 《Free radical research》2013,47(5):481-489
Myeloperoxidase (MPO) catalyzes a nitration reaction to form nitrotyrosine in the presence of high nitrite, the metabolite of NO. Human leukocyte was shown to cause phenolic nitration using released MPO as a catalyst in the presence of nitrite. It opposes our previous finding that inhibition of MPO was essential for phenol nitration in human leukocyte study. To clarify the role of MPO, we utilized MPO-deficient human leukocytes and MPO-knockout mice. Even in the absence of exogenously added nitrite, high nitration product was observed in MPO-deficient leukocytes. In liver subjected to ischemia/reperfusion injury, a significantly higher amount of nitrotyrosine was produced in MPO-knockout mice than in normal mice. These results clearly demonstrate that MPO inhibits the accumulation of nitration products in vivo . Further experiments showed that MPO could degrade nitrotyrosine in the presence of glutathione. Thus, MPO-induced degradation of nitration products may cause the underestimation of the nitration product generated in vivo . We conclude that MPO may act predominantly to scavenge nitrotyrosine under physiological nitrite condition, and protect against injurious effect of nitrotyrosine. 相似文献
86.
Elisabet Safont Teresa Vegas-vilarrúbia Valentí Rull Bruce K. Holst Otto Huber Shingo Nozawa 《分类学与生物多样性》2013,11(4):327-344
The Guayana Highlands (GH) constitute a highly diverse, but relatively poorly studied Neotropical biome, comprised of ~50 flat-topped mountain summits (called tepuis). Previous studies based on warming forecasts for the region suggested that an upward displacement of environmental conditions of 500–700 m could occur by 2100, potentially resulting in the extinction of c. 50% of its endemic flora due to total habitat loss. To assess the ecological responses of the species to climate change, and select the appropriate conservation measures, long-term monitoring of the GH plant communities will be necessary. In this study, the baseline state for future comparisons was established for the best explored tepui in terms of its flora, Roraima-tepui (2810 m), through a floristic characterization of its different vegetation types. We also identified the environmental gradients underlying the major plant communities, and assessed the effects of human activities on the chemistry of soils and water at three field camps. Our results yielded five main community types: three meadows, one shrubland, and one forest, with their corresponding diagnostic species. The herbaceous communities were mainly influenced by the presence of flat sandy soils, with varying flooding capacity. Shrublands and forests were characterized by irregular organic soils with very low pH. Finally, pH values below 3 were measured on an organic soil of a field camp, although further studies will be necessary to attribute this deviation to human activities. 相似文献
87.
Natsuko Tsujino Tomomi Tsunematsu Motokazu Uchigashima Kohtarou Konno Akihiro Yamanaka Kazuto Kobayashi Masahiko Watanabe Yoshimasa Koyama Takeshi Sakurai 《PloS one》2013,8(7)
Narcolepsy patients often suffer from insomnia in addition to excessive daytime sleepiness. Narcoleptic animals also show behavioral instability characterized by frequent transitions between all vigilance states, exhibiting very short bouts of NREM sleep as well as wakefulness. The instability of wakefulness states in narcolepsy is thought to be due to deficiency of orexins, neuropeptides produced in the lateral hypothalamic neurons, which play a highly important role in maintaining wakefulness. However, the mechanism responsible for sleep instability in this disorder remains to be elucidated. Because firing of orexin neurons ceases during sleep in healthy animals, deficiency of orexins does not explain the abnormality of sleep. We hypothesized that chronic compensatory changes in the neurophysiologica activity of the locus coeruleus (LC) and dorsal raphe (DR) nucleus in response to the progressive loss of endogenous orexin tone underlie the pathological regulation of sleep/wake states. To evaluate this hypothesis, we examined firing patterns of serotonergic (5-HT) neurons and noradrenergic (NA) neurons in the brain stem, two important neuronal populations in the regulation of sleep/wakefulness states. We recorded single-unit activities of 5-HT neurons and NA neurons in the DR nucleus and LC of orexin neuron-ablated narcoleptic mice. We found that while the firing pattern of 5-HT neurons in narcoleptic mice was similar to that in wildtype mice, that of NA neurons was significantly different from that in wildtype mice. In narcoleptic mice, NA neurons showed a higher firing frequency during both wakefulness and NREM sleep as compared with wildtype mice. In vitro patch-clamp study of NA neurons of narcoleptic mice suggested a functional decrease of GABAergic input to these neurons. These alterations might play roles in the sleep abnormality in narcolepsy. 相似文献
88.
Climate-induced warming of the Arctic tundra is expected to increase nutrient availability to soil microbes, which in turn may accelerate soil organic matter (SOM) decomposition. We increased nutrient availability via fertilization to investigate the microbial response via soil enzyme activities. Specifically, we measured potential activities of seven enzymes at four temperatures in three soil profiles (organic, organic/mineral interface, and mineral) from untreated native soils and from soils which had been fertilized with nitrogen (N) and phosphorus (P) since 1989 (23 years) and 2006 (six years). Fertilized plots within the 1989 site received annual additions of 10 g N⋅m-2⋅year-1 and 5 g P⋅m-2⋅year-1. Within the 2006 site, two fertilizer regimes were established – one in which plots received 5 g N⋅m-2⋅year-1 and 2.5 g P⋅m-2⋅year-1 and one in which plots received 10 g N⋅m-2⋅year-1 and 5 g P⋅m-2⋅year-1. The fertilization treatments increased activities of enzymes hydrolyzing carbon (C)-rich compounds but decreased phosphatase activities, especially in the organic soils. Activities of two enzymes that degrade N-rich compounds were not affected by the fertilization treatments. The fertilization treatments increased ratios of enzyme activities degrading C-rich compounds to those for N-rich compounds or phosphate, which could lead to changes in SOM chemistry over the long term and to losses of soil C. Accelerated SOM decomposition caused by increased nutrient availability could significantly offset predicted increased C fixation via stimulated net primary productivity in Arctic tundra ecosystems. 相似文献
89.
Shutaro Ishimura Masato Furuhashi Yuki Watanabe Kyoko Hoshina Takahiro Fuseya Tomohiro Mita Yusuke Okazaki Masayuki Koyama Marenao Tanaka Hiroshi Akasaka Hirofumi Ohnishi Hideaki Yoshida Shigeyuki Saitoh Tetsuji Miura 《PloS one》2013,8(11)
Objective
Fatty acid-binding proteins (FABPs) are a family of 14-15-kDa proteins, and some FABPs have been to be used as biomarkers of tissue injury by leak from cells. However, recent studies have shown that FABPs can be secreted from cells into circulation. Here we examined determinants and roles of circulating FABPs in a general population.Methods
From the database of the Tanno-Sobetsu Study, a study with a population-based cohort design, data in 2011 for 296 subjects on no medication were retrieved, and FABP1∼5 in their serum samples were assayed.Results
Level of FABP4, but not the other isoforms, showed a gender difference, being higher in females than in males. Levels of all FABPs were negatively correlated with estimated glomerular filtration rate (eGFR), but a distinct pattern of correlation with other clinical parameters was observed for each FABP isoform; significant correlates were alanine aminotransferase (ALT), blood pressure (BP), and brain natriuretic peptide (BNP) for FABP1, none besides eGFR for FABP2, age, BP, and BNP for FABP3, age, waist circumference (WC), BP, BNP, lipid variables, high-sensitivity C-reactive protein (hsCRP), and HOMA-R for FABP4, and age, WC, BP, ALT, BNP, and HOMA-R for FABP5. FABP4 is the most strongly related to metabolic markers among FABPs. In a multivariate regression analysis, FABP4 level was an independent predictor of HOMA-R after adjustment of age, gender, WC, BP, HDL cholesterol, and hsCRP.Conclusions
Each FABP isoform level showed a distinct pattern of correlation with clinical parameters, although levels of all FABPs were negatively determined by renal function. Circulating FABP4 appears to be a useful biomarker for detecting pre-clinical stage of metabolic syndrome, especially insulin resistance, in the general population. 相似文献90.
Keisuke Kirita Genichiro Ishii Rie Matsuwaki Yuki Matsumura Shigeki Umemura Shingo Matsumoto Kiyotaka Yoh Seiji Niho Koichi Goto Hironobu Ohmatsu Yuichiro Ohe Kanji Nagai Atsushi Ochiai 《PloS one》2013,8(12)