全文获取类型
收费全文 | 5255篇 |
免费 | 291篇 |
国内免费 | 121篇 |
出版年
2024年 | 2篇 |
2023年 | 50篇 |
2022年 | 47篇 |
2021年 | 94篇 |
2020年 | 97篇 |
2019年 | 118篇 |
2018年 | 136篇 |
2017年 | 127篇 |
2016年 | 112篇 |
2015年 | 168篇 |
2014年 | 261篇 |
2013年 | 348篇 |
2012年 | 141篇 |
2011年 | 214篇 |
2010年 | 175篇 |
2009年 | 225篇 |
2008年 | 279篇 |
2007年 | 298篇 |
2006年 | 273篇 |
2005年 | 237篇 |
2004年 | 243篇 |
2003年 | 216篇 |
2002年 | 192篇 |
2001年 | 124篇 |
2000年 | 137篇 |
1999年 | 133篇 |
1998年 | 119篇 |
1997年 | 151篇 |
1996年 | 104篇 |
1995年 | 101篇 |
1994年 | 84篇 |
1993年 | 97篇 |
1992年 | 88篇 |
1991年 | 69篇 |
1990年 | 73篇 |
1989年 | 64篇 |
1988年 | 56篇 |
1987年 | 41篇 |
1986年 | 25篇 |
1985年 | 40篇 |
1984年 | 33篇 |
1983年 | 21篇 |
1982年 | 20篇 |
1981年 | 12篇 |
1980年 | 9篇 |
1979年 | 7篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1976年 | 3篇 |
排序方式: 共有5667条查询结果,搜索用时 15 毫秒
101.
Sviatoslav N Bagriantsev R��mi Peyronnet Kimberly A Clark Eric Honor�� Daniel L Minor Jr 《The EMBO journal》2011,30(17):3594-3606
Members of the K2P potassium channel family regulate neuronal excitability and are implicated in pain, anaesthetic responses, thermosensation, neuroprotection, and mood. Unlike other potassium channels, K2Ps are gated by remarkably diverse stimuli that include chemical, thermal, and mechanical modalities. It has remained unclear whether the various gating inputs act through separate or common channel elements. Here, we show that protons, heat, and pressure affect activity of the prototypical, polymodal K2P, K2P2.1 (KCNK2/TREK‐1), at a common molecular gate that comprises elements of the pore‐forming segments and the N‐terminal end of the M4 transmembrane segment. We further demonstrate that the M4 gating element is conserved among K2Ps and is employed regardless of whether the gating stimuli are inhibitory or activating. Our results define a unique gating mechanism shared by K2P family members and suggest that their diverse sensory properties are achieved by coupling different molecular sensors to a conserved core gating apparatus. 相似文献
102.
Erika Chavira-Suárez Alejandro Sandoval Ricardo Felix Mónica Lamas 《Biochemical and biophysical research communications》2011,404(2):678
Normal vision depends on the correct function of retinal neurons and glia and it is impaired in the course of diabetic retinopathy. Müller cells, the main glial cells of the retina, suffer morphological and functional alterations during diabetes participating in the pathological retinal dysfunction. Recently, we showed that Müller cells express the pleiotropic protein potassium channel interacting protein 3 (KChIP3), an integral component of the voltage-gated K+ channels KV4. Here, we sought to analyze the role of KChIP3 in the molecular mechanisms underlying hyperglycemia-induced phenotypic changes in the glial elements of the retina. The expression and function of KChIp3 was analyzed in vitro in rat Müller primary cultures grown under control (5.6 mM) or high glucose (25 mM) (diabetic-like) conditions. We show the up-regulation of KChIP3 expression in Müller cell cultures under high glucose conditions and demonstrate a previously unknown interaction between the KV4 channel and KChIP3 in Müller cells. We show evidence for the expression of a 4-AP-sensitive transient outward voltage-gated K+ current and an alteration in the inactivation of the macroscopic outward K+ currents expressed in high glucose-cultured Müller cells. Our data support the notion that induction of KChIP3 and functional changes of KV4 channels in Müller cells could exert a physiological role in the onset of diabetic retinopathy. 相似文献
103.
Anna Makri Stamatia Bellou Maria Birkou Konstantinos Papatrehas Dimitrios Bokas Seraphim Papanikolaou George Aggelis 《Engineering in Life Science》2011,11(1):52-58
Tetraselmis sp. and Nannochloropsis oculata, cultivated in industrial‐scale bioreactors, produced 2.33 and 2.44% w/w lipid (calculated as the sum of fatty acid methyl esters) in dry biomass, respectively. These lipids contained higher amounts of neutral lipids and glycolipids plus sphingolipids, than phospholipids. Lipids of Tetraselmis sp. were characterized by the presence of eicosapentaenoic acid (that was located mainly in phospholipids), and octadecatetraenoic acid (that was equally distributed among lipid fractions), while these fatty acids were completely absent in N. oculata lipids. Additionally, lipids produced by 16 newly isolated strains from Greek aquatic environments (cultivated in flask reactors) were studied. The highest percentage of lipids was found in Prorocentrum triestinum (3.69% w/w) while the lowest in Prymnesium parvum (0.47% w/w). Several strains produced lipids rich in eicosapentaenoic and docosahexaenoic acids. For instance, docosahexaenoic acid was found in high percentages in lipids of Amphidinium sp. S1, P. parvum, Prorocentrum minimum and P. triestinum, while lipids produced by Asterionella sp. (?) S2 contained eicosapentaenoic acid in high concentration. These lipids, containing ω‐3‐long‐chain polyunsaturated fatty acids, have important applications in the food and pharmaceutical industries and in aquaculture. 相似文献
104.
目的:基于阿尔茨海默病微阵列基因表达数据,分析研究微阵列基因表达数据预处理的新的有效方法。方法:首先采用标准差滤波、FSC(特征记分准则)和WPT-SAM(小波包变换-微阵列数据显著性分析)方法对微阵列基因表达数据进行预处理,比较处理后获得的基因数和FDR值;然后采用分类聚类方法对处理后的数据进行分类聚类和分层决策聚类,比较分类聚类结果。结果:标准差滤波和FSC方法获得的初筛基因数据较WPT-SAM方法多,但FDR值也高、后续分类聚类结果较WPT-SAM方法差。结论:WPT-SAM方法在预处理微阵列基因表达数据中,是比较灵活理想的分析方法。 相似文献
105.
目的:比较蛇床子素对不同钙通道亚型的作用差异。方法:首先在tsA201细胞上瞬时转染Cavl.2,Cav1.3,Cav2.2e[37a],和Cav2.2e[37b]通道,然后采用全细胞膜片钳技术,记录tsA201细胞上的钙电流,并观察蛇床子素对各种钙通道亚型的影响。结果:蛇床子素可以浓度依赖性抑制Cav1.2和Cav1.3电流,抑制的半有效浓度分别为162.1μmol·L-1和56.2μmol·L-1.此外,蛇床子素对Cav2.2通道也有一定的抑制作用,在300μmol·L-1。的浓度下,抑制38%的Cav2.2e[37a]电流和61%的Cav2.2e[37b]电流,蛇床子素对钙电流的抑制是快速可逆的。蛇床子素在各个测试电位水平均能抑制上述四种钙通道电流,但不改变电流的激活阂值和最大峰值电流的激活电压。结论:蛇床子素以浓度依赖的方式抑制多种钙通道亚型并表现出不同的亲和力。 相似文献
106.
目的:检测脊神经切断大鼠背根节(DRG)神经元重复放电能力和钠电流的变化,并研究介导其电流变化的钠通道亚型的表达情况。方法:脊神经切断术后2~8d慢性痛大鼠模型背根节急性分离,对中等直径DRG神经元运用全细胞膜片钳技术记录神经元放电和钠电流的变化。对背根节神经元进行RT-PCR检测,分析其钠通道亚型的表达情况。结果:电流钳下,实验组DRG神经元在电流刺激下产生重复放电,而对照组神经元多诱发单个动作电位,电压钳记录发现实验组背根节神经元快钠电流和持续性钠电流幅值均明显大于对照组,PCR结果显示,Nav1.3、Nav1.7和Nav1.8通道亚型mRNA表达显著增高。结论:钠通道介导了脊神经受损模型的DRG神经元兴奋性增高,持续性钠电流可能通过调节阈下膜电位振荡的产生调节神经元兴奋性。 相似文献
107.
双孔钾离子通道是一种背景钾离子通道,广泛分布于各种兴奋和非兴奋细胞中,并具有许多重要的生理功能。TASK-1是双孔钾离子通道家族的重要一员,它对缺氧和细胞外酸化敏感,参与形成心肌动作电位平台期,调节呼吸、肺动脉平滑肌收缩和醛固酮的分泌,并且是麻醉剂的作用靶点,人们不断对其进行研究并取得了很多重要结果,本文将概述双孔钾通道TASK-1的研究进展。 相似文献
108.
Ziad Fajloun Nicolas Andreotti Mohamed Fathallah Jean‐Marc Sabatier Michel De Waard 《Journal of peptide science》2011,17(3):200-210
Maurotoxin (MTX) is a 34‐residue toxin that was isolated initially from the venom of the scorpion Scorpio maurus palmatus. Unlike the other toxins of the α‐KTx6 family (Pi1, Pi4, Pi7, and HsTx1), MTX exhibits a unique disulfide bridge organization of the type C1? C5, C2? C6, C3? C4, and C7? C8 (instead of the conventional C1? C5, C2? C6, C3? C7, and C4? C8, herein referred to as Pi1‐like) that does not prevent its folding along the classic α/β scaffold of scorpion toxins. MTXPi1 is an MTX variant with a conventional pattern of disulfide bridging without any primary structure alteration of the toxin. Here, using MTX and/or MTXPi1 as models, we investigated how the type of folding influences toxin recognition of the Shaker B potassium channel. Amino acid residues of MTX that were studied for Shaker B recognition were selected on the basis of their homologous position in charybdotoxin, a three disulfide‐bridged scorpion toxin also active on this channel type. These residues favored either an MTX‐ or MTXPi1‐like folding. Our data indicate clearly that Lys23 and Tyr32 (two out of ten amino acid residues studied) are the most important residues for Shaker B channel blockage by MTX. For activity on SKCa channels, the same amino acid residues also affect, directly or indirectly, the recognition of SK channels. The molecular modeling technique and computed docking indicate the existence of a correlation between the half cystine pairings of the mutated analogs and their activity on the Shaker B K+ channel. Overall, mutations in MTX could, or could not, change the reorganization of disulfide bridges of this molecule without affecting its α/β scaffold. However, changing of the peptide backbone (cross linking disulfide bridges from MTX‐like type vs MTXPi1‐like type) appears to have less impact on the molecule activity than mutation of certain key amino acids such as Lys23 and Tyr32 in this toxin. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
109.
SO_2对胸主动脉血管平滑肌细胞钾离子通道的影响 总被引:1,自引:0,他引:1
为了探讨二氧化硫(SO2)引起大鼠血管平滑肌的降压机制,采用急性酶分离法分离大鼠单个血管平滑肌细胞,运用全细胞膜片钳技术记录平滑肌细胞外向钾电流(IKv),观察SO2及其衍生物对平滑肌细胞膜钾电流的作用,从离子通道角度研究SO2对血压的影响。结果发现:SO2衍生物可使外向IKv显著增大,10μmol/L SO2衍生物可使电流-电压曲线(I-V曲线)显著上移,即增大IKv,且呈一定的电压依赖性,并且,SO2衍生物可使IKv增大呈现出剂量-效应关系。当使用5 mmol/L 4-氨基吡啶(4-AP)抑制IKv后,加入10μmol/L SO2衍生物,IKv有一定程度增加。TEA能抑制SO2衍生物对IKv的增大效应。10μmol/L SO2衍生物可使IKv的激活曲线显著向超极化方向移动,但并不影响其斜率因子。说明SO2衍生物作用于血管平滑肌细胞,可引起外向钾电流幅度增大,使钾电流提前激活,这是SO2及其衍生物降压的作用机制之一;TEA、4-AP对SO2衍生物引起的血管平滑肌细胞钾电流的增大具有拮抗作用。 相似文献
110.
采用膜片钳内面向外式记录技术,研究急性分离成年大鼠海马CAl区锥体神经元外向整流氯离子通道的氧化还原调控。发现细胞内侧给予氧化剂DTNB(5,5'-dithiobis-2-nitrobenzoic acid),可显著减弱氯通道的活动,IC50值为(28.05±2.42)μmol/L;还原剂DTT(dithiothreitol)对氯通道没有明显影响,但可逆转DTNB引起的抑制效应。说明DTNB不改变通道电导,其引起的通道活动减弱是由氯通道关闭时间延长而开放时间缩短所致。研究还发现,另一对氧化型和还原型谷胱甘肽具有与DTNB和DTT同样的效应。本研究结果显示,成年大鼠海马CA1区锥体神经元外向整流氯通道可以被细胞内氧化还原剂所调控。 相似文献