全文获取类型
收费全文 | 3034篇 |
免费 | 256篇 |
专业分类
3290篇 |
出版年
2023年 | 11篇 |
2022年 | 30篇 |
2021年 | 42篇 |
2020年 | 23篇 |
2019年 | 34篇 |
2018年 | 47篇 |
2017年 | 39篇 |
2016年 | 74篇 |
2015年 | 112篇 |
2014年 | 162篇 |
2013年 | 146篇 |
2012年 | 189篇 |
2011年 | 221篇 |
2010年 | 154篇 |
2009年 | 135篇 |
2008年 | 161篇 |
2007年 | 176篇 |
2006年 | 175篇 |
2005年 | 118篇 |
2004年 | 154篇 |
2003年 | 146篇 |
2002年 | 141篇 |
2001年 | 56篇 |
2000年 | 57篇 |
1999年 | 52篇 |
1998年 | 45篇 |
1997年 | 32篇 |
1996年 | 35篇 |
1995年 | 20篇 |
1994年 | 24篇 |
1993年 | 26篇 |
1992年 | 37篇 |
1991年 | 27篇 |
1990年 | 31篇 |
1989年 | 32篇 |
1988年 | 26篇 |
1987年 | 18篇 |
1986年 | 26篇 |
1985年 | 31篇 |
1984年 | 21篇 |
1983年 | 20篇 |
1982年 | 18篇 |
1981年 | 12篇 |
1980年 | 8篇 |
1979年 | 24篇 |
1978年 | 22篇 |
1977年 | 10篇 |
1976年 | 12篇 |
1974年 | 6篇 |
1972年 | 11篇 |
排序方式: 共有3290条查询结果,搜索用时 15 毫秒
81.
82.
Maingret F Coste B Hao J Giamarchi A Allen D Crest M Litchfield DW Adelman JP Delmas P 《Neuron》2008,59(3):439-449
Small-conductance Ca2+-activated K+ (SK) channels are widely expressed in neuronal tissues where they underlie post-spike hyperpolarizations, regulate spike-frequency adaptation, and shape synaptic responses. SK channels constitutively interact with calmodulin (CaM), which serves as Ca2+ sensor, and with protein kinase CK2 and protein phosphatase 2A, which modulate their Ca2+ gating. By recording coupled activities of Ca2+ and SK2 channels, we showed that SK2 channels can be inhibited by neurotransmitters independently of changes in the activity of the priming Ca2+ channels. This inhibition involvesSK2-associated CK2 and results from a 3-fold reduction in the Ca2+ sensitivity of channel gating. CK2phosphorylated SK2-bound CaM but not KCNQ2-bound CaM, thereby selectively regulating SK2 channels. We extended these observations to sensory neurons by showing that noradrenaline inhibits SK current and increases neuronal excitability in aCK2-dependent fashion. Hence, neurotransmitter-initiated signaling cascades can dynamically regulate Ca2+ sensitivity of SK channels and directly influence somatic excitability. 相似文献
83.
Background
In the past decades the rapid growth of molecular diagnostics (based on either traditional PCR or isothermal amplification technologies) meet the demand for fast and accurate testing. Although isothermal amplification technologies have the advantages of low cost requirements for instruments, the further improvement on sensitivity, speed and robustness is a prerequisite for the applications in rapid pathogen detection, especially at point-of-care diagnostics. Here, we describe and explore several strategies to improve one of the isothermal technologies, helicase-dependent amplification (HDA). 相似文献84.
Cellular aging is characterized by the build-up of oxidatively modified protein that results, at least in part, from impaired redox homeostasis associated with the aging process. Protein degradation and repair are critical for eliminating oxidized proteins from the cell. Oxidized protein degradation is mainly achieved by the proteasomal system and it is now well established that proteasomal function is generally impaired with age. Specific enzymatic systems have been identified which catalyze the regeneration of cysteine and methionine following oxidation within proteins. Protein-bound methionine sulfoxide diastereoisomers S and R are repaired by the combined action of the enzymes MsrA and MsrB that are subsequently regenerated by thioredoxin/thioredoxin reductase. Importantly, the peptide methionine sulfoxide reductase system has been implicated in increased longevity and resistance to oxidative stress in different cell types and model organisms. In a previous study, we reported that peptide methionine sulfoxide reductase activity as well as gene and protein expression of MsrA are decreased in various organs as a function of age. More recently, we have shown that gene expression of both MsrA and MsrB2 (Cbs-1) is decreased during replicative senescence of WI-38 fibroblasts, and this decline is associated with an alteration in catalytic activity and the accumulation of oxidized protein. In this review, we will address the importance of protein maintenance in the aging process as well as in replicative senescence, with a special focus on regulation of the peptide methionine sulfoxide reductase systems. 相似文献
85.
86.
Bertrand L Ginion A Beauloye C Hebert AD Guigas B Hue L Vanoverschelde JL 《American journal of physiology. Heart and circulatory physiology》2006,291(1):H239-H250
Diabetic hearts are known to be more susceptible to ischemic disease. Biguanides, like metformin, are known antidiabetic drugs that lower blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in muscle. Part of these metabolic effects is thought to be mediated by the activation of AMP-activated protein kinase (AMPK). In this work, we studied the relationship between AMPK activation and glucose uptake stimulation by biguanides and oligomycin, another AMPK activator, in both insulin-sensitive and insulin-resistant cardiomyocytes. In insulin-sensitive cardiomyocytes, insulin, biguanides and oligomycin were able to stimulate glucose uptake with the same efficiency. Stimulation of glucose uptake by insulin or biguanides was correlated to protein kinase B (PKB) or AMPK activation, respectively, and were additive. In insulin-resistant cardiomyocytes, where insulin stimulation of glucose uptake was greatly reduced, biguanides or oligomycin, in the absence of insulin, induced a higher stimulation of glucose uptake than that obtained in insulin-sensitive cells. This stimulation was correlated with the activation of both AMPK and PKB and was sensitive to the phosphatidylinositol-3-kinase/PKB pathway inhibitors. Finally, an adenoviral-mediated expression of a constitutively active form of AMPK increased both PKB phosphorylation and glucose uptake in insulin-resistant cardiomyocytes. We concluded that AMPK activators, like biguanides and oligomycin, are able to restore glucose uptake stimulation, in the absence of insulin, in insulin-resistant cardiomyocytes via the additive activation of AMPK and PKB. Our results suggest that AMPK activation could restore normal glucose metabolism in diabetic hearts and could be a potential therapeutic approach to treat insulin resistance. 相似文献
87.
émilie Boudreau Sarah Labib Anne T. Bertrand Valérie Decostre Pierrette M. Bolongo Nicolas Sylvius Gisèle Bonne Frédérique Tesson 《PloS one》2012,7(9)
A-type lamins A and C are nuclear intermediate filament proteins in which mutations have been implicated in multiple disease phenotypes commonly known as laminopathies. A few studies have implicated sumoylation in the regulation of A-type lamins. Sumoylation is a post-translational protein modification that regulates a wide range of cellular processes through the attachment of small ubiquitin-related modifier (sumo) to various substrates. Here we showed that laminopathy mutants result in the mislocalization of sumo1 both in vitro (C2C12 cells overexpressing mutant lamins A and C) and in vivo (primary myoblasts and myopathic muscle tissue from the LmnaH222P
/H222P mouse model). In C2C12 cells, we showed that the trapping of sumo1 in p.Asp192Gly, p.Gln353Lys, and p.Arg386Lys aggregates of lamin A/C correlated with an increased steady-state level of sumoylation. However, lamin A and C did not appear to be modified by sumo1. Our results suggest that mutant lamin A/C alters the dynamics of sumo1 and thus misregulation of sumoylation may be contributing to disease progression in laminopathies. 相似文献
88.
Anne Zanchi Luc Tappy Kim-Anne Lê Murielle Bortolotti Nicolas Theumann Georges Halabi Thierry Gauthier Claudine Mathieu Sylvie Tremblay Pauline Coti Bertrand Michel Burnier Daniel Teta 《PloS one》2014,9(10)
Background
Fat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity.Trial Design
This was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects.Methods
At the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored.Results
Four months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63×10−3 to 0.76×10−3. This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP.Conclusions/Limitations
Pioglitazone significantly changes the visceral-subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation.Trial Registration
ClinicalTrial.gov NCT01253928相似文献89.
Lakard B Magnin D Deschaume O Vanlancker G Glinel K Demoustier-Champagne S Nysten B Jonas AM Bertrand P Yunus S 《Biosensors & bioelectronics》2011,26(10):4139-4145
A potentiometric biosensor based on urease was developed for the quantitative determination of urea concentration in aqueous solutions for biomedical applications. The urease was either physisorbed onto an electrodeposited polyaniline film (PANI), or immobilized on a layer-by-layer film (LbL) assembled over the PANI film, that was obtained by the alternate deposition of charged polysaccharides (carboxymethylpullulan (CMP) and chitosan (CHI)). In the latter case, the urease (Urs) enzyme was either physically adsorbed or covalently grafted to the LbL film using carbodiimide coupling reaction. Potentiometric responses of the enzymatic biosensors were measured as a function of the urea concentration in aqueous solutions (from 10(-6) to 10(-1) mol L(-1) urea). Very high sensitivity and short response time were observed for the present biosensor. Moreover, a stability study showed a higher stability over time for the potentiometric response of the sensor with the enzyme-grafted LbL film, testifying for the protective nature of the polysaccharide coating and the interest of covalent grafting. 相似文献
90.
1. The initial formation of arginine phosphate by arginine kinase was studied in the time range 2.8--50 ms by the quenched-flow method. 2. A transient burst phase of product formation was obtained, the amplitude of which was temperature-dependent. At 35 degrees C it was 0.64 mol arginine phosphate/mol arginine kinase and at 12 degrees C, 0.25 mol/mol. 3. These results show that for the reaction pathway of arginine kinase the rate-limiting step follows the formation of arginine phosphate on the enzyme. This is in contrast to the creatine kinase reaction where no transient phase was observed [Engelborghs, Y., Marsh, A. & Gutfreund, H. (1975) Biochem. J. 151, 47--50]. 4. The rate-limiting step on the arginine kinase reaction pathway is only slightly affected by temperature: the change in Kcat with temperature is due to a change of an equilibrium constant pertaining to at least two previous steps. 相似文献