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   3384篇
  免费   235篇
  国内免费   53篇
耳鼻咽喉   14篇
儿科学   86篇
妇产科学   40篇
基础医学   458篇
口腔科学   66篇
临床医学   196篇
内科学   513篇
皮肤病学   81篇
神经病学   242篇
特种医学   52篇
外科学   577篇
综合类   221篇
预防医学   98篇
眼科学   29篇
药学   511篇
中国医学   293篇
肿瘤学   195篇
  2023年   46篇
  2022年   58篇
  2021年   89篇
  2020年   102篇
  2019年   210篇
  2018年   265篇
  2017年   152篇
  2016年   69篇
  2015年   86篇
  2014年   199篇
  2013年   233篇
  2012年   192篇
  2011年   202篇
  2010年   139篇
  2009年   126篇
  2008年   183篇
  2007年   140篇
  2006年   127篇
  2005年   99篇
  2004年   94篇
  2003年   73篇
  2002年   84篇
  2001年   86篇
  2000年   64篇
  1999年   52篇
  1998年   50篇
  1997年   39篇
  1996年   46篇
  1995年   48篇
  1994年   35篇
  1993年   32篇
  1992年   34篇
  1991年   18篇
  1990年   19篇
  1989年   22篇
  1988年   18篇
  1987年   15篇
  1986年   14篇
  1985年   21篇
  1984年   21篇
  1983年   8篇
  1982年   10篇
  1981年   10篇
  1980年   8篇
  1979年   5篇
  1978年   6篇
  1977年   6篇
  1976年   3篇
  1975年   5篇
  1974年   6篇
排序方式: 共有3672条查询结果,搜索用时 15 毫秒
1.
《Drug discovery today》2022,27(3):808-821
Tyrosine kinases are enzymes that can transfer a phosphate group from ATP to a specific protein tyrosine, serine or threonine residue within a cell, operating as a switch that can turn ‘on’ and ‘off’ causing different physiological alterations in the body. Mutated kinases have been shown to display an equilibrium shift toward the activated state. Types I–III have been studied intensively leading to drugs like imatinib (type II), cobimetinib (type III), among others. It is the same scenario for types V–VII; however, there is a lacuna in information regarding type IV inhibitors, although recently some advances have surfaced. This review aims to accumulate the knowledge gained so far about type IV inhibitors.  相似文献   
2.
目的 基于分子动力学模拟和实验评价揭示黄芪甲苷对HepG2细胞的作用机制。方法 构建“药物-疾病”网络药理图,分析黄芪甲苷(AS-IV)作用于肝细胞癌(HCC)的核心基因,筛选关键信号通路,建立“药物-靶点”分子动力学模型;体外实验检测HepG2细胞迁移、增殖、侵袭能力;流式细胞术检测HepG2细胞周期及凋亡;qRT-PCR检测核心基因相对表达量。结果 AS-IV作用于HCC核心靶点为VEGFA;体外实验结果显示:与对照组比较,高浓度AS-IV对HepG2细胞的迁移、侵袭和增殖活力具有抑制作用,能阻滞HepG2细胞从G1期向G2期转移,促进其凋亡,可下调VEGFA mRNA表达,上调TGF-β1 mRNA表达。结论 AS-IV可能通过多靶点、多通路抑制肝癌细胞的增殖。  相似文献   
3.
目的: 研究黄芪甲苷对大鼠脑缺血后小胶质细胞/巨噬细胞M1/M2极化及炎症反应的影响。方法: 将48只大鼠随机分为手术对照组、模型对照组和黄芪甲苷组。采用线栓法建立大鼠大脑中动脉阻塞模型。黄芪甲苷组造模后即刻腹腔注射黄芪甲苷(40 mg/kg),随后1次/d,连续给药3 d。各组术后第1、3天采用改良的神经损伤严重程度评分(mNSS)和角试验进行神经功能评价;术后第3天采用2,3,5-氯化三苯基四氮唑染料(TTC)染色检测脑梗死体积;实时逆转录PCR检测M1型小胶质细胞/巨噬细胞表面标志物CD86、诱导型一氧化氮合酶(iNOS)和促炎因子TNF-α、IL-1β、IL-6的mRNA表达,以及M2型小胶质细胞/巨噬细胞表面标志物CD206、精氨酸酶1(Arg-1)、类几丁质酶3样分子1/2(YM1/2)及抗炎因子IL-10、TGF-β的mRNA表达;免疫荧光双标记法检测脑缺血周边区CD16/32/Iba1和CD206/Iba1的表达。结果: 与模型对照组比较,黄芪甲苷组mNSS分值降低、右转次数减少(P < 0.05或P < 0.01),脑梗死体积减小(P < 0.01),M1型小胶质细胞/巨噬细胞标志物CD86、iNOS、TNF-α、IL-1β和IL-6的mRNA表达下调(均P < 0.01),M2型小胶质细胞/巨噬细胞标志物CD206、Arg-1、YM1/2、IL-10和TGF-β的mRNA表达上调(均P < 0.01),脑缺血区CD16/32+/Iba1+细胞数量减少(P < 0.05),CD206+/Iba1+细胞数量增加(P < 0.01)。结论: 黄芪甲苷对大鼠脑缺血损伤有保护作用,可能与促进小胶质细胞/巨噬细胞从M1型向M2型转化、抑制炎症反应有关。  相似文献   
4.
5.
6.
7.
8.
Cardiovascular disease (CAD) is a devastating illness, but to date there are limited means of predicting a person''s coronary stenosis severity and their prognosis. The study was performed to investigate the relationship between dipeptidyl peptidase 4(DPP4) gene polymorphisms and serum lipid profiles, as well as the severity of coronary artery stenosis in patients with CAD and type 2 diabetes (T2DM) for the first time.Herein, 201 patients with CAD and T2DM were enrolled in the Department of Cardiology, Shandong Provincial Qianfoshan Hospital. DPP4 rs3788979 and rs7608798 single nucleotide polymorphisms (SNPs) were genotyped. The general information of all patients was collected, and the associations between DPP4 SNPs and lipid profiles were detected. At the same time, association between SNP polymorphisms and the degree of coronary artery stenosis were analyzed.There was a significant difference in apolipoprotein B (ApoB) levels (P = .011) for the rs3788979 polymorphism, while no difference was identified in other blood lipids or with other mutations. SNP mutation of A to G in rs3788979 was associated with a reduced percentage of severe coronary artery stenosis in female patients (P = .023) as well as those with nosmoking (P = .030), nodrinking (P = 0.007), and nocardiovascular family history (P = 0.015).G allele of rs3788979 is associated with a reduced ApoB level. Besides, we suggest that G allele in rs3788979 may have a cardioprotective effect and prove to be a useful and specific measure when predicting a patient''s coronary stenosis severity if diagnosed with CAD and T2DM.  相似文献   
9.
BackgroundLaparoscopic central bisectionectomy (Couinaud's segment IV, V, and VIII) needs exposure of the RHV and MHV on the surface of the remnant and the resecting side, respectively. Avoiding venous injury is mandatory and laparoscopy-specific cranio-caudal approach to hepatic veins might be helpful [1]. We present this procedure in performing laparoscopic central bisectionectomy.PatientA 45-year-old female was admitted to our hospital with a 6 cm HCC in the segment VIII and IV. Her comorbid disease was non-cirrhotic HBV hepatitis (Child-Pugh grade A) and diabetes (untreated).MethodAfter cholecystectomy, G4 branches were dissected and cut by extra- or intra-hepatic approach. Hilar plate was dissected and the Gant was encircled and occluded by a vascular clip. Afterwards, exposure of the MHV was started at its root on IVC [2,3] and extended in cranio-caudal direction [1]. After sufficient space was obtained around the Gant, the Gant and the MHV were cut. Parenchymal transection between right anterior and right posterior sections was also started form the root of the RHV to its cranio-caudal direction. Liver resection was finished with full exposure of the RHV.ResultsThe operating time was 380 minutes, and the blood loss volume was 30 ml. Postoperative CT image showed exposure of the RHV and umbilical portion of Glissonean branch, and no fluid retention.ConclusionLaparoscopy-specific cranio-caudal approach to hepatic veins may be useful to avoid split injury of venous branches [4], especially if the hepatectomy requires complete exposure of hepatic vein, such as central bisectionectomy.  相似文献   
10.
Motility is ubiquitous in prokaryotic organisms including the photosynthetic cyanobacteria where surface motility powered by type 4 pili (T4P) is common and facilitates phototaxis to seek out favorable light environments. In cyanobacteria, chemotaxis-like systems are known to regulate motility and phototaxis. The characterized phototaxis systems rely on methyl-accepting chemotaxis proteins containing bilin-binding GAF domains capable of directly sensing light, and the mechanism by which they regulate the T4P is largely undefined. In this study we demonstrate that cyanobacteria possess a second, GAF-independent, means of sensing light to regulate motility and provide insight into how a chemotaxis-like system regulates the T4P motors. A combination of genetic, cytological, and protein–protein interaction analyses, along with experiments using the proton ionophore carbonyl cyanide m-chlorophenyl hydrazine, indicate that the Hmp chemotaxis-like system of the model filamentous cyanobacterium Nostoc punctiforme is capable of sensing light indirectly, possibly via alterations in proton motive force, and modulates direct interaction between the cyanobacterial taxis protein HmpF, and Hfq, PilT1, and PilT2 to regulate the T4P motors. Given that the Hmp system is widely conserved in cyanobacteria, and the finding from this study that orthologs of HmpF and T4P proteins from the distantly related model unicellular cyanobacterium Synechocystis sp. strain PCC6803 interact in a similar manner to their N. punctiforme counterparts, it is likely that this represents a ubiquitous means of regulating motility in response to light in cyanobacteria.

Motility is ubiquitous in prokaryotic organisms, including both swimming motility in aqueous environments and twitching or gliding motility on solid surfaces, and enables these organisms to optimize their position in response to various environmental factors. Among the photosynthetic cyanobacteria, surface motility is widespread and facilitates phototaxis to seek out favorable light environments (1, 2), and, for multicellular filamentous cyanobacteria, plays a key role in dispersal as well as the establishment of nitrogen-fixing symbioses with eukaryotes (3) and the formation of supracellular structures (35).Current understanding of cyanobacterial surface motility at the molecular level has been informed primarily by studies of two model organisms, the unicellular strain Synechocystis sp. strain PCC6803 (herein Synechocystis) and the filamentous strain Nostoc punctiforme ATCC29133/PCC73102, where motility is exhibited only by differentiated filaments termed “hormogonia.” Motility in both organisms is powered by a type IV pilus (T4P) system where the ATPases PilB and PilT drive the extension and subsequent retraction, respectively, of pili which adhere to the substrate and pull the cells forward (for review, see ref. 6). In Synechocystis, the T4P motors are distributed throughout the entire cell, allowing a 360 ° range of motion (7), whereas in N. punctiforme they are confined to rings at the cell poles (8), resulting in movement only along the long axis of the filament. Comparative genomics implies that this mechanism of motility is widely conserved among cyanobacteria (9).Both Synechocystis and N. punctiforme employ chemotaxis-like systems to regulate motility. One of these systems, the Hmp chemotaxis-like system of N. punctiforme (3, 10), and its orthologous counterpart, the Pil chemotaxis-like system of Synechocystis (11), includes homologs to the canonical Escherichia coli chemotaxis complex (for review, see ref. 12), including the histidine kinase CheA, the adaptor protein CheW, the response regulator CheY, and the methyl-accepting chemotaxis protein MCP. These systems are essential for motility in their respective organisms and appear to regulate the T4P motors, although there are distinct differences in the phenotypes for inactivation of the components from each. In Synechocystis, null mutations either enhance or reduce the level of surface piliation (11), whereas in N. punctiforme they disrupt the coordinated polarity, but not the overall level of piliation, and affect various other aspects of hormogonium development (3, 10). In N. punctiforme, the subcellular localization of this system has been determined and has been found arrayed in static, bipolar rings similar to the T4P motors (3). However, the signals that are perceived by the MCPs and the precise mechanism by which these systems modulate T4P activity is currently undefined.Recently, an additional component of the Hmp system, HmpF, was characterized (9). HmpF is a predicted coiled-coil protein and is ubiquitous to, but confined within, the cyanobacterial lineage (9). It is essential for accumulation of surface pili and exhibits dynamic, unipolar localization to the leading poles of most cells in hormogonium filaments (9). Based on these findings, a model has been proposed where the localization of HmpF is regulated by the other components of the Hmp system, and in turn, the unipolar accumulation of HmpF leads to the activation of the T4P motors on one side of the cell to facilitate directional movement.A second chemotaxis-like system in each organism, the Ptx system of N. punctiforme (13) and the Pix system of Synechocystis (14, 15), is essential for positive phototaxis. These systems contain MCPs with cyanobacteriochrome sensory domains capable of perceiving light (for review, see ref. 16). Disruption of the Pix system results in negative phototaxis under light conditions that normally produce a positive phototactic response (14). Several other proteins containing cyanobacteriochromes, and one containing a BLUF domain, also modulate phototaxis in Synechocystis (for review, see ref. 6). In N. punctiforme, disruption of the Ptx system abolishes the phototactic response completely, resulting in uniform movement in all directions regardless of the light conditions (13), and there are currently no other proteins reported to modulate phototaxis. More recently, a motile, wild isolate of the model unicellular cyanobacterium Synechococcus elongatus sp. PCC7942 was shown to possess a chemotaxis-like system that modulates phototaxis in a manner similar to that of the N. punctiforme Ptx system (17). How these systems influence T4P activity to facilitate phototaxis is also currently unknown.There is also a substantial body of literature on motility and phototaxis in cyanobacteria, primarily based on observational studies of various filamentous strains, that predates the development of genetically tractable model organisms (for review, see ref. 18). These reports suggested that the photosystems may serve a sensory role in modulating phototaxis and that proton motive force (PMF) powers motility (19, 20), a finding that is inconsistent with the theory that cyanobacteria possess a common T4P-based gliding motor driven by ATP hydrolysis. In this study, we help reconcile this historical data with more recent molecular studies by providing evidence that the Hmp chemotaxis-like system senses light, possibly indirectly through alterations in PMF, and in turn modulates the interaction of HmpF with the T4P base to activate the motors.  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