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1.
Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer’s disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aβ fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aβ disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aβ fibril via the π–π interactions. Moreover, docking scores correlate well with the ThT EC50 values. Molecular dynamic simulations revealed that biflavonoids decrease the content of β-sheet in Aβ fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aβ fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aβ fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer’s disease.  相似文献   
2.
随着科学技术的快速发展与进步,当今社会要求学生学习知识水平越来越高,要求其学习范围更为广泛。因此目前学生仅依凭英语课堂学习还远远不够,很多时候根本无法适应社会发展的需要,所以培养学生自学能力就显得非常重要。由此提出开发一款英语自学系统为英语爱好者提供自学英语平台。文章立足于Web网络,依托B/C结构,应用ASP.NET和数据库进行相互融入技术;然后从功能模块,数据库等设计详细分析本系统设计;最后从聊天室、BBS论坛、以及留言板等方面来实现本系统的在线沟通与交流,从而完成了本系统研究。该系统不但能使学生学习英语不受时空限制,而且对于提升他们学习英语效果与使用英语能力均有很大帮助。  相似文献   
3.
Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by 1H,15N HSQC NMR to bind in the small hydrophobic P0 pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.  相似文献   
4.
The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.  相似文献   
5.
包玄  陈红梅  肖清 《计算机应用》2021,41(8):2406-2411
兴趣点(POI)推荐可以帮助用户发现其没有访问过但可能感兴趣的地点,是重要的基于位置的服务之一。时间在POI推荐中是一个重要因素,而现有POI推荐模型并没有较好地考虑时间因素,因此通过考虑时间因素来提出融入时间的POI协同推荐(TUCF)算法,从而提高POI推荐的效果。首先,分析基于位置的社交网络(LBSN)的用户签到数据,以探索用户签到的时间关系;然后,利用时间关系对用户签到数据进行平滑处理,以融入时间因素并缓解数据稀疏性;最后,根据基于用户的协同过滤方法,在不同时间推荐不同POI给用户。在真实签到数据集上的实验结果表明,与基于用户的协同过滤(U)算法相比,TUCF算法的精确率和召回率分别提高了63%和69%;与具有平滑增强时间偏好的协同过滤(UTE)算法相比,TUCF算法的精确率和召回率分别提高了8%和12%;并且TUCF算法的平均绝对误差(MAE)比U算法和UTE算法分别减小了1.4%和0.5%。  相似文献   
6.
Despite the existing arsenal of anti-cancer drugs, 10 million people die each year worldwide due to cancers; this highlights the need to discover new therapies based on innovative modes of action against these pathologies. Current chemotherapies are based on the use of cytotoxic agents, targeted drugs, monoclonal antibodies or immunotherapies that are able to reduce or stop the proliferation of cancer cells. However, tumor eradication is often hampered by the presence of resistant cells called cancer stem-like cells or cancer stem cells (CSCs). Several strategies have been proposed to specifically target CSCs such as the use of CSC-specific antibodies, small molecules able to target CSC signaling pathways or drugs able to induce CSC differentiation rendering them sensitive to classical chemotherapy. These latter compounds are the focus of the present review, which aims to report recent advances in anticancer-differentiation strategies. This therapeutic approach was shown to be particularly promising for eradicating tumors in which CSCs are the main reason for therapeutic failure. This general view of the chemistry and mechanism of action of compounds inducing the differentiation of CSCs could be particularly useful for a broad range of researchers working in the field of anticancer therapies as the combination of compounds that induce differentiation with classical chemotherapy could represent a successful approach for future therapeutic applications.  相似文献   
7.
Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is causally related to fibrotic diseases, including idiopathic pulmonary fibrosis. The identification of Compounds that interfere with the HSP47-collagen interaction is essential for the development of relevant therapeutics. Herein, we prepared human HSP47 as a soluble fusion protein expressed in E. coli and established an assay system for HSP47 inhibitor screening. We screened a natural and synthetic Compound library established at Nagasaki University. Among 1023 Compounds, 13 exhibited inhibitory activity against human HSP47, of which three inhibited its function in a dose-dependent manner. Epigallocatechin-3-O-gallate, one of these three Compounds, is a typical polyphenol Compound derived from tea leaves. Structurally related Compounds were synthesized and examined for their activity, revealing a hydroxyl group at A-ring position 5 as important for its activity. The present findings provide valuable insight for the development of natural product-derived therapeutics for fibrotic diseases, including idiopathic pulmonary fibrosis.  相似文献   
8.
The substantial increase in DNA sequencing efforts has led to a rapid expansion of available sequences in glycoside hydrolase families. The ever-increasing sequence space presents considerable opportunities for the search for enzymes with novel functionalities. In this work, the sequence-function space of glycoside hydrolase family 94 (GH94) was explored in detail, using a combined approach of phylogenetic analysis and sequence similarity networks. The identification and experimental screening of unknown clusters led to the discovery of an enzyme from the soil bacterium Paenibacillus polymyxa that acts as a 4-O-β-d -glucosyl-d -galactose phosphorylase (GGalP), a specificity that has not been reported to date. Detailed characterization of GGalP revealed that its kinetic parameters were consistent with those of other known phosphorylases. Furthermore, the enzyme could be used for production of the rare disaccharides 4-O-β-d -glucosyl-d -galactose and 4-O-β-d -glucosyl-l -arabinose. Our current work highlights the power of rational sequence space exploration in the search for novel enzyme specificities, as well as the potential of phosphorylases for rare disaccharide synthesis.  相似文献   
9.
杨威亚  余正涛  高盛祥  宋燃 《计算机应用》2021,41(10):2879-2884
针对汉越跨语言新闻话题发现任务中汉越平行语料稀缺,训练高质量的双语词嵌入较为困难,而且新闻文本一般较长导致双语词嵌入的方法难以很好地表征文本的问题,提出一种基于跨语言神经主题模型(CL-NTM)的汉越新闻话题发现方法,利用新闻的主题信息对新闻文本进行表征,将双语语义对齐转化为双语主题对齐任务。首先,针对汉语和越南语分别训练基于变分自编码器的神经主题模型,从而得到单语的主题抽象表征;然后,利用小规模的平行语料将双语主题映射到同一语义空间;最后,使用K-means方法对双语主题表征进行聚类,从而发现新闻事件簇的话题。实验结果表明,所提方法相较于面向中英文的隐狄利克雷分配主题改进模型(ICE-LDA)在Macro-F1值与主题一致性上分别提升了4个百分点与7个百分点,可见所提方法可有效提升新闻话题的聚类效果与话题可解释性。  相似文献   
10.
搜索引擎作为互联网主要应用之一,能够根据用户需求从互联网资源中检索并返回有效信息。然而,得到的返回列表往往包含广告和失效网页等噪声信息,而这些信息会干扰用户的检索与查询。针对复杂的网页结构特征和丰富的语义信息,提出了一种基于注意力机制和集成学习的网页黑名单判别方法,并采用本方法构建了一种基于集成学习和注意力机制的卷积神经网络(EACNN)模型来过滤无用的网页。首先,根据网页上不同种类的HTML标签数据,构建多个基于注意力机制的卷积神经网络(CNN)基学习器;然后,采用基于网页结构特征的集成学习方法对不同基学习器的输出结果执行不同的权重计算,从而实现EACNN的构建;最后,将EACNN的输出结果作为网页内容分析结果,从而实现网页黑名单的判别。所提方法通过注意力机制来关注网页语义信息,并通过集成学习的方式引入网页结构特征。实验结果表明,与支持向量机(SVM)、K近邻(KNN)、CNN、长短期记忆(LSTM)网络、GRU、结合注意力机制的卷积神经网络(ACNN)等基线模型相比,所提模型在所构建的面向地理信息领域的判别数据集上具有最高的准确率(0.97)、召回率(0.95)和F1分值(0.96),验证了EACNN在网页黑名单判别工作中的优势。  相似文献   
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