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   11110篇
  免费   647篇
  国内免费   93篇
  2023年   139篇
  2022年   115篇
  2021年   197篇
  2020年   208篇
  2019年   267篇
  2018年   310篇
  2017年   226篇
  2016年   246篇
  2015年   285篇
  2014年   655篇
  2013年   765篇
  2012年   379篇
  2011年   695篇
  2010年   517篇
  2009年   578篇
  2008年   575篇
  2007年   603篇
  2006年   524篇
  2005年   609篇
  2004年   455篇
  2003年   315篇
  2002年   328篇
  2001年   163篇
  2000年   179篇
  1999年   179篇
  1998年   147篇
  1997年   140篇
  1996年   144篇
  1995年   157篇
  1994年   137篇
  1993年   160篇
  1992年   129篇
  1991年   129篇
  1990年   122篇
  1989年   85篇
  1988年   90篇
  1987年   71篇
  1986年   58篇
  1985年   64篇
  1984年   178篇
  1983年   104篇
  1982年   100篇
  1981年   82篇
  1980年   66篇
  1979年   66篇
  1978年   26篇
  1977年   26篇
  1976年   14篇
  1975年   13篇
  1973年   9篇
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
1.
Chronic hepatitis is a major cause of liver cancer, so earlier treatment of hepatitis might be reducing liver cancer incidence. Hepatitis can be induced in mice by treatment with Concanavalin A (Con A); the resulting liver injury causes significant CD4+ T cell activation and infiltration. In these T cells, Roquin, a ring-type E3 ubiquitin ligase, is activated. To investigate the role of Roquin, we examined Con A-induced liver injury and T cell infiltration in transgenic (Tg) mice overexpressing Roquin specifically in T cells. In Roquin Tg mice, Con A treatment caused greater increases in both the levels of liver injury enzymes and liver tissue apoptosis, as revealed by TUNEL and H&E staining, than wild type (WT) mice. Further, Roquin Tg mice respond to Con A treatment with greater increases in the T cell population, particularly Th17 cells, though Treg cell counts are lower. Roquin overexpression also enhances increases in pro-inflammatory cytokines, including IFN-γ, TNF-α and IL-6, upon liver injury. Furthermore, Roquin regulates the immune response and apoptosis in Con A induced hepatitis via STATs, Bax and Bcl2. These findings suggest that over-expression of Roquin exacerbates T-cell mediated hepatitis.  相似文献   
2.
Epithelial–mesenchymal transition (EMT) is associated with pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF). In this study, we investigated EMT of human pulmonary epithelial-derived cells (A549). A549 cells was either cultured by itself or co-cultured with THP-1 macrophages under normoxic (21% O2) and hypoxic (2% O2) conditions. We evaluated the presence of EMT by determining the expression of EMT markers, E-cadherin, vimentin, and fibronectin. To determine the role of TGF-β1 and IL-1β in EMT of the A549 cells, we analyzed the effects of blocking their activity with TGF-β1 inhibitor or IL-1β neutralizing antibody respectively. The A549 cells presented EMT when they were co-cultured with THP-1 macrophages. The EMT of the A549 cells co-cultured with THP-1 macrophages was exacerbated under hypoxia. In addition, the EMT were prevented by the addition of TGF-β1 type I receptor kinase inhibitor. The hypoxic condition increased the mRNA levels of TGF-β1 in A549 cells and THP-1 macrophages and that of IL-1β in THP-1 macrophages when each cells were co-cultured. Anti-IL-1β neutralizing antibody attenuated TGF-β1 secretion in co-culture media under hypoxic conditions. Thus, the IL-1β from THP-1 macrophages up-regulated the TGF-β1 from A549 cells and THP-1 macrophages, and then the TGF-β1 from both cells induced and promoted the EMT of A549 cells when they were co-cultured under hypoxia. Together, these results demonstrate that the interaction between type II pneumocytes and macrophages under hypoxia is necessary for the development of pulmonary fibrosis.  相似文献   
3.
Transforming growth factor-β (TGF-β) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-β signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our study was to determine the effect of TGF-β pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2f/f) and their corresponding wild-type background mice (MyhCre.Tgfbr2WT/WT) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-β signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process.  相似文献   
4.
Genome-wide association studies (GWAS) have identified over 70 loci associated with type 2 diabetes (T2D). Most genetic variants associated with T2D are common variants with modest effects on T2D and are shared with major ancestry groups. To what extent the genetic component of T2D can be explained by common variants relies upon the shape of the genetic architecture of T2D. Fine mapping utilizing populations with different patterns of linkage disequilibrium and functional annotation derived from experiments in relevant tissues are mandatory to track down causal variants responsible for the pathogenesis of T2D.  相似文献   
5.
We have analyzed the cell wall of the radio-resistant bacterium Deinococcus radiodurans. Unexpectedly, the bacterial envelope appears to be organized in different complexes of high molecular weight. Each complex is composed of several proteins, most of which are coded by genes of unknown function and the majority are constituents of the inner/outer membrane system. One of the most abundant complexes is constituted by the gene DR_0774. This protein is a type of secretin which is a known subunit of the homo-oligomeric channel that represents the main bulk of the type IV piliation family. Finally, a minor component of the pink envelope consists of several inner-membrane proteins. The implications of these findings are discussed.  相似文献   
6.
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   
7.
目的:观察西格列汀治疗对初发2 型糖尿病(T2DM)患者血浆丝氨酸蛋白酶抑制物(vaspin)水平的影响,探讨其与胰岛素抵 抗的关系。方法:60 例初发2 型糖尿病患者使用西格列汀治疗12 周,采用酶联免疫法测定正常人及T2DM患者使用西格列汀治 疗前后的血浆vaspin 水平, 分析血浆vaspin水平与体重指数(BMI)、腰臀比(WHR)、胰岛素抵抗指数(HOMA- IR )、胰岛素分泌指 数(HOMA- IS )、空腹血糖(FPG)、餐后2 小时血糖(2hPG)、糖化血红蛋白(HbA1C)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋 白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)等的关系。结果:2 型糖尿病组血浆vaspin 水平高于对照组(P< 0.05);2 型糖 尿病组经西格列汀治疗12 周后BMI、WHR、HbA1c、FPG 、2hPG、TG和HOMA-IR 显著下降(P<0.05),而HOMA-IS 显著升高 (P<0.05),同时西格列汀治疗后血浆vaspin 水平也显著降低(P<0.01),且vaspin 水平的降低与HOMA-IR 的改变呈明显正相 关。胰岛素抵抗指数及体重指数是影响血浆vaspin水平的独立相关因素。结论:西格列汀治疗能有效改善2 型糖尿病患者糖脂代 谢和胰岛素敏感性,降低血浆vaspin 水平。  相似文献   
8.
目的:探讨血清胃蛋白酶原Ⅰ/Ⅱ(PGⅠ/Ⅱ)、铁蛋白、肿瘤坏死因子-alpha联合检查诊断胃癌的临床意义。方法:选择2013 年5 月至2014 年10 月收治的胃病住院患者及健康体检者,根据胃镜及病理组织学结果,将其分良性胃病组、胃癌组以及健康组,比 较三组血清胃蛋白酶原Ⅰ/Ⅱ、铁蛋白及肿瘤坏死因子-alpha水平,分析血清胃蛋白酶原Ⅰ/Ⅱ(PGⅠ/Ⅱ)、铁蛋白、肿瘤坏死因子-alpha单 独和联合诊断胃癌的敏感性、特异性和准确性。结果:与健康组比较,良性胃病组以及胃癌组的血清PGⅠ/Ⅱ水平较低(P<0.05), 与良性胃病组比较,胃癌组血清PGⅠ/Ⅱ水平较低(P<0.05);与健康组比较,良性胃病组以及胃癌组的血清铁蛋白以及TNF-alpha水 平较高(P<0.05),与良性胃病组比较,胃癌组血清铁蛋白以及TNF-alpha水平较高(P<0.05)。PGⅠ/Ⅱ、铁蛋白以及TNF-alpha联合检测 诊断胃癌的敏感度以及准确度分别为88.4%以及83.1%,高于单一检测。结论:血清PGⅠ/Ⅱ、血清铁蛋白、肿瘤坏死因子-alpha联合 检测诊断胃癌的效能优于单一检测。  相似文献   
9.
肾素-血管紧张素-醛固酮系统起初被认为是较简单的神经体液调节机制之一。但是,这一想法随着RAAS阻滞剂:肾素阻滞剂、血管紧张素转换酶抑制剂(ACEI)、AT1受体拮抗剂及盐皮质激素受体拮抗剂的深入研究而受到挑战。因此,RAAS的组成、以上药物发挥作用的具体通路及副作用均得到重新定义。在RAAS阻滞剂的应用过程中,机体肾素水平升高,并刺激肾素原受体(即无活性的肾素前体,PRR),进而对机体造成不良影响。同理,在AT1受体拮抗剂的应用过程中,血浆血管紧张素II的水平升高,并与2型血管紧张素II(AT2)受体结合,进而对机体产生有利作用。此外,随着ACEI及ARB的应用,血管紧张素1-7水平升高,其与Mas受体结合,发挥心脏及肾脏保护的作用,还可通过刺激干细胞发挥组织修复作用。  相似文献   
10.
目的:通过研究山药水浸提物对α-葡萄糖苷酶的抑制作用,初步探索山药对2型糖尿病的预防和治疗作用。方法:对山药进行热水浸提,采用1:5的料液比,浸提温度90℃,时间2小时,超滤获得山药水浸提物,利用α-葡萄糖苷酶对淀粉降解反应建立酶活检测体系,通过检测酶反应产物分析山药水浸提物对α-葡萄糖苷酶的抑制作用,并计算IC50。结果:山药水浸提物对α-葡萄糖苷酶的抑制率大于46%,IC50值为1.9 g/ml。结论:山药水浸提物对α-葡萄糖苷酶的抑制作用提示山药可以作为肥胖或者2型糖尿病患者有效的一种药食同源食材,本实验结果为2型糖尿病高危人群及患者合理选择膳食结构提供新的科学依据。  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