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1.
The calcium pump (sarco/endoplasmic reticulum Ca2+-ATPase, SERCA) plays a major role in calcium homeostasis in muscle cells by clearing cytosolic Ca2+ during muscle relaxation. Active Ca2+ transport by SERCA involves the structural transition from a low-Ca2+ affinity E2 state toward a high-Ca2+ affinity E1 state of the pump. This structural transition is accompanied by the countertransport of protons to stabilize the negative charge and maintain the structural integrity of the transport sites and partially compensate for the positive charges of the two Ca2+ ions passing through the membrane. X-ray crystallography studies have suggested that a hydrated pore located at the C-terminal domain of SERCA serves as a conduit for proton countertransport, but the existence and function of this pathway have not yet been fully characterized. We used atomistic simulations to demonstrate that in the protonated E2 state and the absence of initially bound water molecules, the C-terminal pore becomes hydrated in the nanosecond timescale. Hydration of the C-terminal pore is accompanied by the formation of water wires that connect the transport sites with the cytosol. Water wires are known as ubiquitous proton-transport devices in biological systems, thus supporting the notion that the C-terminal domain serves as a conduit for proton release. Additional simulations showed that the release of a single proton from the transport sites induces bending of transmembrane helix M5 and the interaction between residues Arg762 and Ser915. These structural changes create a physical barrier against full hydration of the pore and prevent the formation of hydrogen-bonded water wires once proton transport has occurred through this pore. Together, these findings support the notion that the C-terminal proton release pathway is a functional element of SERCA and also provide a mechanistic model for its operation in the catalytic cycle of the pump. 相似文献
2.
Shraddha Parate Vikas Kumar Danishuddin Jong Chan Hong Keun Woo Lee 《International journal of molecular sciences》2021,22(10)
Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer. 相似文献
3.
Dr. Laurent David Dr. Mark Wenlock Dr. Patrick Barton Dr. Andreas Ritzén 《ChemMedChem》2021,16(17):2669-2685
Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Å2 was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R2=0.92) with an experimental measure of hydrogen bond donor potential, Δlog Poct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility. 相似文献
4.
Vancha Harish Effi Haque Magdalena
miech Hiroaki Taniguchi Sarah Jamieson Devesh Tewari Anupam Bishayee 《International journal of molecular sciences》2021,22(9)
Xanthohumol (XH) is an important prenylated flavonoid that is found within the inflorescence of Humulus lupulus L. (Hop plant). XH is an important ingredient in beer and is considered a significant bioactive agent due to its diverse medicinal applications, which include anti-inflammatory, antimicrobial, antioxidant, immunomodulatory, antiviral, antifungal, antigenotoxic, antiangiogenic, and antimalarial effects as well as strong anticancer activity towards various types of cancer cells. XH acts as a wide ranging chemopreventive and anticancer agent, and its isomer, 8-prenylnaringenin, is a phytoestrogen with strong estrogenic activity. The present review focuses on the bioactivity of XH on various types of cancers and its pharmacokinetics. In this paper, we first highlight, in brief, the history and use of hops and then the chemistry and structure–activity relationship of XH. Lastly, we focus on its prominent effects and mechanisms of action on various cancers and its possible use in cancer prevention and treatment. Considering the limited number of available reviews on this subject, our goal is to provide a complete and detailed understanding of the anticancer effects of XH against different cancers. 相似文献
5.
Isabel Fernandes Cecília Melo-Alvim Raquel Lopes-Brs Miguel Esperana-Martins Luís Costa 《International journal of molecular sciences》2021,22(2)
Osteosarcoma (OS) is a rare condition with very poor prognosis in a metastatic setting. Basic research has enabled a better understanding of OS pathogenesis and the discovery of new potential therapeutic targets. Phase I and II clinical trials are already ongoing, with some promising results for these patients. This article reviews OS pathogenesis and new potential therapeutic targets. 相似文献
6.
气藏平均地层压力跟踪计算新方法 总被引:1,自引:0,他引:1
平均地层压力是产能评价和动态分析的基础,准确、快速获取平均地层压力对高效开发气藏意义重大。基于地层压力随时间变化的规律,分析了平均地层压力的变化规律。研究结果表明:平均地层压力等效点仅随时间发生改变,平均地层压力的下降速率等于或者近似等于井底流压的下降速率。从封闭弹性驱动气藏的物质平衡方程出发,考虑偏差系数和井底流压随平均地层压力的变化,推导建立了平均地层压力跟踪计算新方法,根据生产数据可迭代计算平均地层压力。方法验证结果显示,采气速度和采出程度共同影响模型的计算结果。应用实例表明,跟踪计算法与压力恢复试井和物质平衡法之间的相对误差均较小,满足工程计算精度要求,且跟踪计算法不需依托生产测试数据,节约了测试费用,避免了测试占产。 相似文献
7.
Polyvinylidene fluoride (PVDF) has several crystal forms of which the α-form is nonpolar, while the β-form is polar and has the highest piezoelectric constant. α PVDF, when stretched, transforms into the β form, which has wide applications in sensors and actuators. Steered molecular dynamics simulations are used to study the transformation of a single chain of PVDF from a trans–gauche conformation to an all trans one. The Helmholtz free energy change (∆F) is estimated using Jarzynski's equality. The transformation starts at the chain ends followed by the transformation of the remaining chain. The free energy change for the transformation is found to be always positive, indicating that the TGTG' form has higher thermodynamic stability than the all trans form throughout the studied temperature range. With increasing temperature, free energy change for the transformation increases monotonically. 相似文献
8.
采用有限元模拟和实验研究了挤压钛合金弯曲管件。通过实验验证了工件的形状和尺寸精度,并通过有限元模拟分析了工艺参数对挤出过程中变形体的平均压应力分布情况和挤出弯管件的曲率半径的影响规律。结果表明:有限元模拟中,弯管件的曲率半径误差为6.03%,弯管直径误差为3.82%;在靠近定径带处,平均压应力呈非均匀分布;在焊合腔内,靠近细分流孔区域的平均压应力小于靠近粗分流孔区域的平均压应力,平均压应力的大小顺序在通过粗、细分流孔前后相反;在模具结构固定不变时,弯管件的曲率半径随挤压速度的减小而增大,不随挤压温度的变化而变化。 相似文献
9.
Cellulose nanocrystals (CNCs) are a kind of sustainable nanoparticle from biomass, which are widely used as reinforcing filler and assembly building block for high-performance composites and function materials including biomaterial, optics, and so forth. Here, their unique advantages in material applications were reviewed based on their rod-like morphology, crystalline structure, dimension-related effects, and multi-level order structure. Then, we focused on the molecular engineering of CNCs, including the structure and physicochemical properties of their surface, along with surface modification methods and steric effects. We further discussed the performance-improvement and functionalization methods based on multi-component complex systems, together with the effects of surface molecular engineering on the performance and functions. Meanwhile, methods of optimizing orientation in uniaxial arrays were discussed along with those of enhancing photoluminescence efficiency via surface chemical modification and substance coordination. In the end, we prospected the design, development, and construction methods of new CNCs materials. 相似文献
10.
多普勒测风激光雷达通过分析系统回波信号的多普勒频移反演出风速,为提高风场探测精度,从稳频技术方面展开研究。在稳频过程中,分别采取措施消除激光频率的长期漂移和短期抖动。针对激光频率的长期漂移,设计并研制了种子激光器温控箱,通过水浴的控温方式大大减小了激光频率的长期漂移,将激光频率稳定在±50 MHz以内;针对激光频率的短期抖动,采用以碘分子吸收池为核心器件的稳频系统,通过半导体控温方式对碘分子吸收池精确控温,控温精度达0.03 ℃,提高了稳频精度,将激光频率进一步稳定在±8 MHz以内,满足±10 MHz以内的设计精度要求。通过搭建多普勒测风激光雷达系统,对发射激光稳频装置进行系统验证,连续4组风场观测结果表明:系统探测高度为17 km,绝大部分方差在4 m/s以下,满足测风激光雷达测量指标的要求。 相似文献