首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   3519篇
  免费   322篇
  国内免费   71篇
  2023年   59篇
  2022年   70篇
  2021年   93篇
  2020年   99篇
  2019年   123篇
  2018年   149篇
  2017年   107篇
  2016年   117篇
  2015年   107篇
  2014年   184篇
  2013年   211篇
  2012年   148篇
  2011年   218篇
  2010年   138篇
  2009年   185篇
  2008年   179篇
  2007年   199篇
  2006年   176篇
  2005年   178篇
  2004年   167篇
  2003年   123篇
  2002年   106篇
  2001年   63篇
  2000年   72篇
  1999年   81篇
  1998年   69篇
  1997年   62篇
  1996年   68篇
  1995年   55篇
  1994年   48篇
  1993年   44篇
  1992年   33篇
  1991年   24篇
  1990年   14篇
  1989年   11篇
  1988年   14篇
  1987年   9篇
  1986年   4篇
  1985年   8篇
  1984年   16篇
  1983年   9篇
  1982年   10篇
  1981年   14篇
  1980年   6篇
  1979年   6篇
  1978年   6篇
  1977年   10篇
  1976年   5篇
  1974年   4篇
  1972年   5篇
排序方式: 共有3912条查询结果,搜索用时 31 毫秒
1.
N-Glycosylation is an important post-translational modification of proteins, which mainly occurs in the endoplasmic reticulum (ER). Glycoproteins that are unable to fold properly are exported to the cytosol for degradation by a cellular system called ER-associated degradation (ERAD). Once misfolded glycoproteins are exported to the cytosol, they are subjected to deglycosylation by peptide:N-glycanase (PNGase) to facilitate the efficient degradation of misfolded proteins by the proteasome. Interestingly, the ortholog of PNGase in some filamentous fungi was found to be an inactive deglycosylating enzyme. On the other hand, it has been shown that in filamentous fungi genomes, usually two different fungi-specific endo-β-N-acetylglucosamidases (ENGases) can be found; one is predicted to be localized in the cytosol and the other to have a signal sequence, while the functional importance of these enzymes remains to be clarified. In this study the ENGases of the filamentous fungus Trichoderma atroviride was characterized. By heterologous expression of the ENGases Eng18A and Eng18B in Saccharomyces cerevisiae, it was found that both ENGases are active deglycosylating enzymes. Interestingly, only Eng18B was able to enhance the efficient degradation of the RTL protein, a PNGase-dependent ERAD substrate, implying the involvement of this enzyme in the ERAD process. These results indicate that T. atroviride Eng18B may deglycosylate misfolded glycoproteins, substituting the function of the cytoplasmic PNGase in the ERAD process.  相似文献   
2.
Interleukin-33 is a newly described member of the interleukin-1 family. Recent research suggests that IL-33 is increased in lungs and plays a critical role in chronic airway inflammation in cigarette smoke-induced chronic obstructive pulmonary disease (COPD) mice. To determine the role of IL-33 in systemic inflammation, we induced COPD mice models by passive cigarette smoking and identified the IL-33 expression in bronchial endothelial cells and peripheral blood mononuclear cells (PBMCs) of them. After isolation, PBMCs were cultured and stimulated in vitro. We measured expressions of interleukin-6 and interleukin-8 in PBMCs in different groups. The expression of IL-33 in bronchial endothelial cells and PBMCs of COPD mice were highly expressed. Stimulated by cigarette smoke extract (CSE), the expression of IL-6 and IL-8 were induced and enhanced by IL-33. PBMCs of COPD mice produced more IL-6 and IL-8 stimulated by CSE and IL-33. Expression of IL-6 and IL-8 were decreased when stimulated by IL-33 together with soluble ST2. The mRNA production of ST2 in IL-33 stimulated PBMCs was increased. Being pretreated with several kinds of MAPK inhibitors, the secretions of IL-6 and IL-8 in PBMCs did not decrease except for the p38 MAPK inhibitor. We found that IL-33 could induce and enhance the expression of IL-6 and IL-8 in PBMCs of COPD mice via p38 MAPK pathway, and it is a promoter of the IL-6 and IL-8 production in systemic inflammation in COPD mice.  相似文献   
3.
Sticholysin I (St I) is a pore-forming toxin (PFT) produced by the Caribbean Sea anemone Stichodactyla helianthus belonging to the actinoporin protein family, a unique class of eukaryotic PFT exclusively found in sea anemones. As for actinoporins, it has been proposed that the presence of sphingomyelin (SM) and the coexistence of lipid phases increase binding to the target membrane. However, little is known about the role of membrane structure and dynamics (phase state, fluidity, presence of lipid domains) on actinoporins' activity or which regions of the membrane are the most favorable platforms for protein insertion. To gain insight into the role of SM on the interaction of St I to lipid membranes we studied their binding to monolayers of phosphatidylcholine (PC) and SM in different proportions. Additionally, the effect of acyl chain length and unsaturation, two features related to membrane fluidity, was evaluated on St I binding to monolayers. This study revealed that St I binds and penetrates preferentially and with a faster kinetic to liquid-expanded films with high lateral mobility and moderately enriched in SM. A high content of SM induces a lower lateral diffusion and/or liquid-condensed phases, which hinder St I binding and penetration to the lipid monolayer. Furthermore, the presence of lipid domain borders does not appear as an important factor for St I binding to the lipid monolayer.  相似文献   
4.
5.
目的探讨布拉氏酵母菌散对轮状病毒肠炎患儿血清白介素16(IL-6)和肿瘤坏死因子-α(TNF-α)水平的影响及疗效观察。方法选取轮状病毒肠炎患儿84例,随机分为两组(观察组42例和对照组42例)。两组患儿均予以调整饮食、静脉及口服补液、抗病毒及纠正水电解质及酸碱平衡紊乱等常规治疗。观察组患儿加用布拉氏酵母菌散剂治疗,其中〈12个月,0.125g/次,1次/d;≥12个月,0.25g/次,2Oc/a。对照组患儿除不予以布拉氏酵母菌散剂治疗,余治疗药物基本同观察组。治疗3d后,观察两组患儿治疗前后血清细胞因子IL-6和TNF-α水平,并探讨其疗效及不良反应情况。结果治疗3d后,两组患儿血清IL-6和TNF-α水平均比治疗前明显下降(P〈0.05或P〈0.01),且观察组较对照组下降更明显(P〈0.05);同时观察组患儿的临床总有效率(95.24%)明显好于对照组(78.57%)(X2=5.13,P〈0.05),两组患儿治疗期间无明显的药物不良反应发生。结论布拉氏酵母菌散治疗轮状病毒肠炎患儿疗效及安全性均较好,能降低血清细胞因子IL-6和TNF-α表达水平,抑制炎症及免疫反应过程。  相似文献   
6.
7.
8.
9.
张子为  胡云  李爱梅  徐郁  黄洪  郭万华 《生物磁学》2009,(19):3707-3709,3731
目的:通过PET/CT检查观察脂肪肝患者肝脏及其他组织对18F脱氧葡萄糖(18F-FDG)摄入变化,探讨脂肪肝与糖脂代谢的相关性。方法:36例做PET/CT的健康和2型糖尿病男性患者,分为对照组(n=18例);脂肪肝组(n=9例);糖尿病脂肪肝组(n=9例)。常规测血糖、血脂及肝肾功能。PET/CT测肝脏CT值和肝脏、肾皮质,骨骼肌组织18F-FDG的最大标准摄入值(SUVmax)及平均标准摄入值(SUVmean)。结果:1.糖尿病脂肪肝组的TG显著高于单纯脂肪肝组和正常对照组,P=0.0003,0.0000。单纯脂肪肝组的TG亦显著高于正常对照组,P=0.028。2.糖尿病脂肪肝组的肝脏18F-FDG的SUVmean和SUVmax显著高于正常对照组的SUVmean和SUVmax,P=0.0054,0.0133。单纯脂肪肝组的肝脏SUVmean和SUVmax亦高于正常对照组,但比较无统计学差异。脑皮质、肾皮质和骨骼肌组织的18F-FDG的SUVmean和SUVmax三组间比较无显著性差异。3.Spearman相关性分析发现FBG与TG显著正相关(r=0.59919,P=0.0004);FBG和TG与肝脏的CT值显著负相关(r=-0.55625,P=0.0004;r=-0.45739,P=0.0097)。结论:脂肪肝与空腹血糖和甘油三酯升高显著相关。脂肪肝及2型糖尿病脂肪肝患者肝脏对葡萄糖摄取增高。  相似文献   
10.
高危型人乳头瘤病毒(human papillomavirus,HPV)的E6基因在宫颈癌的发生中起关键作用,特异siRNA能有效抑制宫颈癌HeLa 细胞内HPV18 E6基因的表达,诱导肿瘤细胞凋亡.为进一步探讨HPV18 E6-siRNA诱导HeLa 细胞凋亡的分子机制,针对HPV18-E6基因设计siRNA序列,利用人源U6启动子为模板,经PCR表达框架法体外扩增,转染宫颈癌HeLa细胞抑制HPV18 -E6基因表达,从而诱导肿瘤细胞凋亡.对转染前后HeLa细胞总RNA样品进行荧光标记后,与Agilent Human 1A寡核苷酸芯片杂交、扫描、数据分析及标准化处理,确定表达差异的基因并经荧光定量PCR对部分基因进行验证,结合PANTHER数据分析系统,将这些基因按照生物学功能进行归类,查阅GenBank数据库及相关文献,对其结果进行深入分析及讨论.在检测的18 716个基因和EST中,共筛出差异表达基因359个,其中307个基因表达上调,52个基因表达下调,主要包括细胞周期相关基因CCNG1、p21;凋亡相关基因CASP4、CASP6、IGFBP3、DFFA;泛素蛋白酶解途径相关基因E6-AP、UBE2C;角化细胞分化相关基因KRT4、KRT6E、KRT18;抑癌基因RECK、VHL等.研究结果表明,HPV18 -E6基因抑制引起的细胞凋亡效应主要是通过P53信号途径和泛素蛋白酶解信号途径调节细胞周期相关基因和凋亡相关基因的表达,从而抑制HeLa细胞增殖、促进细胞凋亡.同时,抑癌基因的激活,角化细胞分化和免疫相关基因的表达上调,都说明了E6抑制后肿瘤细胞恶性转化程度的下降.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号