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1.
为研究地铁施工风险耦合机理和地铁施工系统的脆弱性,提高地铁施工系统的安全性。结合脆弱性理论,归纳地铁施工安全风险因素,构建系统脆弱性模型;并对国内2008-2020年的地铁施工事故进行搜集整理,选取风险致因因素完整的130起事故,运用N-K模型计算不同耦合方式下的风险发生概率以及风险耦合值,获得影响系统脆弱性的关键风险耦合方式。结果表明:系统中的风险因素越多,事故发生的概率越大;人员因素、管理因素与环境因素完全耦合时,地铁施工安全系统脆弱性较大。研究明确系统中脆弱性的关键耦合风险,为地铁施工安全控制方面提供了参考价值。  相似文献   
2.
为研究灌浆波纹管连接和带榫头的灌浆波纹管连接两种预制拼装桥墩的抗震性能并对其在地震作用下的易损性进行评估,根据预制拼装桥墩墩底接缝的特点,通过拟静力试验研究,以墩顶漂移率为损伤指标,对其不同的损伤破坏状态进行描述,并确定了对应不同破坏等级的损伤量化指标限值Dcr、Dcy、Dcm和Dcu。采用有限元软件对现浇及预制拼装桥墩进行不同地震作用下的时程分析并建立概率地震需求模型,对其易损性进行评估,并通过改变轴压比、纵筋配筋率,来进一步研究这些参数对预制拼装桥墩易损性的影响。结果表明:虽然预制拼装桥墩与现浇桥墩大部分的破坏形式都为弯曲破坏,但是损伤状态因为接缝而存在差异;采用波纹管连接的预制拼装桥墩与现浇桥墩的地震易损性差别不大,抗震性能基本一致;有榫头构造的预制拼装桥墩在各级地震作用下发生四种损伤破坏的概率最低,这种构造形式的抗震性能优于平面接缝的预制拼装桥墩;轴压比、纵筋配筋率这两种参数对桥墩的易损性影响较大,随着轴压比的增大或配筋率的减小,桥墩的损伤概率增大。  相似文献   
3.
在洪水风险管理理论方面,明晰了洪水、洪水灾害、洪水风险的基本概念、内涵和要素构成,探讨了洪水韧性理念,并提出了狭义洪水韧性和广义洪水韧性。在洪水风险分析技术方面,集洪水淹没分析、洪水影响和损失评估于一体,完全自主研发耦合了降雨产流、一二维水动力模型、地下排水和LID(Low Impact Development)措施模块,实现了地面淹没、地下排水、道路行洪和地下空间进水的全过程同步模拟,支持对多类资产、多种淹没数据源的洪灾损失分钟级快速评估,适用于防洪保护区、蓄滞洪区、城市等多类型区域的洪水风险分析。该项技术已在我国洪水风险图编制、洪水风险评估、洪水影响评价、防洪预案编制、国土空间规划等领域得到广泛应用,为防洪减灾和洪水风险管理提供了有力的技术支撑,发挥了显著的经济和社会效益。  相似文献   
4.
Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.  相似文献   
5.
Peptide-based drugs are an attractive class of therapeutic agents, recently recognized by the pharmaceutical industry. These molecules are currently being used in the development of innovative therapies for diverse health conditions, including tropical diseases such as leishmaniasis. Despite its socioeconomic influence on public health, leishmaniasis remains long-neglected and categorized as a poverty-related disease, with limited treatment options. Peptides with antileishmanial effects encountered to date are a structurally heterogeneous group, which can be found in different natural sources—amphibians, reptiles, insects, bacteria, marine organisms, mammals, plants, and others—or inspired by natural toxins or proteins. This review details the biochemical and structural characteristics of over one hundred peptides and their potential use as molecular frameworks for the design of antileishmanial drug leads. Additionally, we detail the main chemical modifications or substitutions of amino acid residues carried out in the peptide sequence, and their implications in the development of antileishmanial candidates for clinical trials. Our bibliographic research highlights that the action of leishmanicidal peptides has been evaluated mainly using in vitro assays, with a special emphasis on the promastigote stage. In light of these findings, and considering the advances in the successful application of peptides in leishmaniasis chemotherapy, possible approaches and future directions are discussed here.  相似文献   
6.
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   
7.
Rapid development within the fields of both fragment-based drug discovery (FBDD) and medicinal targeting of RNA provides possibilities for combining technologies and methods in novel ways. This review provides an overview of fragment-based screening (FBS) against RNA targets, including a discussion of the most recently used screening and hit validation methods such as NMR spectroscopy, X-ray crystallography, and virtual screening methods. A discussion of fragment library design based on research from small-molecule RNA binders provides an overview on both the currently limited guidelines within RNA-targeting fragment library design, and future possibilities. Finally, future perspectives are provided on screening and hit validation methods not yet used in combination with both fragment screening and RNA targets.  相似文献   
8.
由于区块链不可窜改的特性,部署到区块链上的智能合约不可更改.为了提高合约的安全性,防止智能合约出现整数溢出、短地址攻击、伪随机等问题,在合约部署之前需对合约进行漏洞检测.针对智能合约的整数溢出漏洞利用符号执行进行分析研究,对现有符号执行方法进行调查发现检测速度较慢,从而提出一种自底向上求解约束的改进符号执行方法,并结合深度优先与广度优先进行路径选择从而提高符号执行的代码覆盖率.实验结果表明,改进符号执行在选取的100份含溢出漏洞的智能合约中检测正确率达84%,平均检测效率提高了20%,在中等规模智能合约中检测效率提升显著,检测结果正确率较高.  相似文献   
9.
近年来,窃密攻击成为了最严重的网络安全威胁之一.除了恶意软件,人也可以成为窃密攻击的实施主体,尤其是组织或企业的内部人员.由人实施的窃密很少留下明显的异常痕迹,给真实场景中攻击的及时发现和窃密操作的分析还原带来了挑战.提出了一个方法,将每个用户视为独立的主体,通过对比用户当前行为事件与其历史正常行为的偏差检测异常,以会话为单元的检测实现了攻击发现的及时性,采用无监督算法避免了对大量带标签数据的依赖,更能适用于真实场景.对算法检测为异常的会话,进一步提出事件链构建方法,一方面还原具体窃密操作,另一方面通过与窃密攻击模式对比,更精确地判断攻击.在卡内基梅隆大学的CERT内部威胁数据集上进行了实验,结果达到99%以上的准确率,且可以做到无漏报、低误报,证明了方法的有效性和优越性.  相似文献   
10.
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   
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