全文获取类型
收费全文 | 2890篇 |
免费 | 274篇 |
国内免费 | 46篇 |
专业分类
电工技术 | 17篇 |
综合类 | 41篇 |
化学工业 | 1318篇 |
金属工艺 | 51篇 |
机械仪表 | 73篇 |
建筑科学 | 60篇 |
矿业工程 | 12篇 |
能源动力 | 64篇 |
轻工业 | 275篇 |
水利工程 | 35篇 |
石油天然气 | 23篇 |
武器工业 | 3篇 |
无线电 | 161篇 |
一般工业技术 | 492篇 |
冶金工业 | 279篇 |
原子能技术 | 72篇 |
自动化技术 | 234篇 |
出版年
2024年 | 11篇 |
2023年 | 102篇 |
2022年 | 52篇 |
2021年 | 178篇 |
2020年 | 134篇 |
2019年 | 112篇 |
2018年 | 110篇 |
2017年 | 97篇 |
2016年 | 92篇 |
2015年 | 116篇 |
2014年 | 136篇 |
2013年 | 247篇 |
2012年 | 135篇 |
2011年 | 183篇 |
2010年 | 136篇 |
2009年 | 166篇 |
2008年 | 130篇 |
2007年 | 135篇 |
2006年 | 128篇 |
2005年 | 124篇 |
2004年 | 85篇 |
2003年 | 71篇 |
2002年 | 65篇 |
2001年 | 55篇 |
2000年 | 32篇 |
1999年 | 32篇 |
1998年 | 44篇 |
1997年 | 33篇 |
1996年 | 32篇 |
1995年 | 34篇 |
1994年 | 29篇 |
1993年 | 19篇 |
1992年 | 16篇 |
1991年 | 14篇 |
1990年 | 16篇 |
1989年 | 13篇 |
1988年 | 11篇 |
1987年 | 15篇 |
1986年 | 14篇 |
1985年 | 13篇 |
1984年 | 13篇 |
1983年 | 9篇 |
1982年 | 6篇 |
1981年 | 4篇 |
1975年 | 2篇 |
1963年 | 1篇 |
1962年 | 1篇 |
1961年 | 2篇 |
1959年 | 1篇 |
1956年 | 1篇 |
排序方式: 共有3210条查询结果,搜索用时 15 毫秒
1.
Dr. Jie Zang Dr. Fei Ye Dr. Sara M. Ø. Solbak Dr. Lars J. Høj Prof. Mingjie Zhang Prof. Anders Bach 《ChemMedChem》2021,16(6):949-954
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
2.
药物相互作用改变了剂量效应关系,可能会降低疗效或增加毒性,是临床应用中合并用药治疗时重要的考虑因素。预测具有临床意义的药物相互作用是药物研发过程中获益风险评估的重要环节。本文概述了药物研发过程中药物相互作用研究的目的和意义,体内和体外研究的主要内容;梳理分析了2020年国家药品监督管理局(National Medical Products Administration, NMPA)和美国食品药品监督管理局(Food and Drug Administration, FDA)批准上市的新药药物相互作用研究情况,旨在为我国药物研发过程中药物相互作用研究及其监管审评提供参考。 相似文献
3.
Verena B. K. Kunig Dr. Marco Potowski Dr. Mateja Klika Škopić Dr. Andreas Brunschweiger 《ChemMedChem》2021,16(7):1048-1062
Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug-like compounds on any site, can give important stimuli to drug-development projects. For instance, inhibition of protein–protein interactions usually depends on the identification of protein surface binders. DNA-encoded chemical libraries (DELs) allow scanning of protein surfaces with large chemical space. Encoded library selection screens uncovered several protein–protein interaction inhibitors and compounds binding to the surface of G protein-coupled receptors (GPCRs) and kinases. The protein surface-binding chemotypes from DELs are predominantly chemically modified and cyclized peptides, and functional small-molecule peptidomimetics. Peptoid libraries and structural peptidomimetics have been less studied in the DEL field, hinting at hitherto less populated chemical space and suggesting alternative library designs. Roughly a third of bioactive molecules evolved from smaller, target-focused libraries. They showcase the potential of encoded libraries to identify more potent molecules from weak, for example, fragment-like, starting points. 相似文献
4.
5.
《International Journal of Hydrogen Energy》2022,47(79):33765-33780
This work investigates selective Ni locations over Ni/CeZrOx–Al2O3 catalysts at different Ni loading contents and their influences on reaction pathways in ethanol steam reforming (ESR). Depending on the Ni loading contents, the added Ni selectively interacts with CeZrOx–Al2O3, resulting in the stepwise locations of Ni over CeZrOx–Al2O3. This behavior induces a remarkable difference in hydrogen production and coke formation in ESR. The selective interaction between Ni and CeZrOx for 10-wt.% Ni generates more oxygen vacancies in the CeZrOx lattice. The Ni sites near the oxygen vacancies enhance reforming via steam activation, resulting in the highest hydrogen production rate of 1863.0 μmol/gcat·min. In contrast, for 15 and 20-wt.% Ni, excessive Ni is additionally deposited on Al2O3 after the saturation of Ni–CeZrOx interactions. These Ni sites on Al2O3 accelerate coking from the ethylene produced on the acidic sites, resulting in a high coke amount of 19.1 mgc/gcat·h (20Ni/CZ-Al). 相似文献
6.
Dr. Qian Wang Xinli Fan Nannan Jing Han Zhao Dr. Lijia Yu Prof. Xinjing Tang 《Chembiochem : a European journal of chemical biology》2021,22(11):1901-1907
Small interfering RNA (siRNA) can effectively silence target genes through Argonate 2 (Ago2)-induced RNA interference (RNAi). It is very important to control siRNA activity in both spatial and temporal modes. Among different masking strategies, photocaging can be used to regulate gene expression through light irradiation with spatiotemporal and dose-dependent resolution. Many different caging strategies and caging groups have been reported for light-activated siRNA gene silencing. Herein, we describe a novel caging strategy that increases the blocking effect of RISC complex formation/process through host/guest (including ligand/receptor) interactions, thereby enhancing the inhibition of caged siRNA activity until light activation. This strategy can be used as a general approach to design caged siRNAs for the photomodulation of gene silencing of exogenous and endogenous genes. 相似文献
7.
Svetlana Kononova Ekaterina Litvinova Timur Vakhitov Maria Skalinskaya Stanislav Sitkin 《International journal of molecular sciences》2021,22(8)
The growth in the number of chronic non-communicable diseases in the second half of the past century and in the first two decades of the new century is largely due to the disruption of the relationship between the human body and its symbiotic microbiota, and not pathogens. The interaction of the human immune system with symbionts is not accompanied by inflammation, but is a physiological norm. This is achieved via microbiota control by the immune system through a complex balance of pro-inflammatory and suppressive responses, and only a disturbance of this balance can trigger pathophysiological mechanisms. This review discusses the establishment of homeostatic relationships during immune system development and intestinal bacterial colonization through the interaction of milk glycans, mucins, and secretory immunoglobulins. In particular, the role of fucose and fucosylated glycans in the mechanism of interactions between host epithelial and immune cells is discussed. 相似文献
8.
9.
Zhi-Bi Zhang Yuan-Ling Xia Guang-Heng Dong Yun-Xin Fu Shu-Qun Liu 《International journal of molecular sciences》2021,22(4)
Cold-adapted enzymes feature a lower thermostability and higher catalytic activity compared to their warm-active homologues, which are considered as a consequence of increased flexibility of their molecular structures. The complexity of the (thermo)stability-flexibility-activity relationship makes it difficult to define the strategies and formulate a general theory for enzyme cold adaptation. Here, the psychrophilic serine hydroxymethyltransferase (pSHMT) from Psychromonas ingrahamii and its mesophilic counterpart, mSHMT from Escherichia coli, were subjected to μs-scale multiple-replica molecular dynamics (MD) simulations to explore the cold-adaptation mechanism of the dimeric SHMT. The comparative analyses of MD trajectories reveal that pSHMT exhibits larger structural fluctuations and inter-monomer positional movements, a higher global flexibility, and considerably enhanced local flexibility involving the surface loops and active sites. The largest-amplitude motion mode of pSHMT describes the trends of inter-monomer dissociation and enlargement of the active-site cavity, whereas that of mSHMT characterizes the opposite trends. Based on the comparison of the calculated structural parameters and constructed free energy landscapes (FELs) between the two enzymes, we discuss in-depth the physicochemical principles underlying the stability-flexibility-activity relationships and conclude that (i) pSHMT adopts the global-flexibility mechanism to adapt to the cold environment and, (ii) optimizing the protein-solvent interactions and loosening the inter-monomer association are the main strategies for pSHMT to enhance its flexibility. 相似文献
10.
Corey R. Nelson Tyler Mrozowich Sean M. Park Simmone Dsouza Amy Henrickson Justin R. J. Vigar Hans-Joachim Wieden Raymond J. Owens Borries Demeler Trushar R. Patel 《International journal of molecular sciences》2021,22(1)
Rift Valley fever virus (RVFV) is a mosquito-transmitted virus from the Bunyaviridae family that causes high rates of mortality and morbidity in humans and ruminant animals. Previous studies indicated that DEAD-box helicase 17 (DDX17) restricts RVFV replication by recognizing two primary non-coding RNAs in the S-segment of the genome: the intergenic region (IGR) and 5′ non-coding region (NCR). However, we lack molecular insights into the direct binding of DDX17 with RVFV non-coding RNAs and information on the unwinding of both non-coding RNAs by DDX17. Therefore, we performed an extensive biophysical analysis of the DDX17 helicase domain (DDX17135–555) and RVFV non-coding RNAs, IGR and 5’ NCR. The homogeneity studies using analytical ultracentrifugation indicated that DDX17135–555, IGR, and 5’ NCR are pure. Next, we performed small-angle X-ray scattering (SAXS) experiments, which suggested that DDX17 and both RNAs are homogenous as well. SAXS analysis also demonstrated that DDX17 is globular to an extent, whereas the RNAs adopt an extended conformation in solution. Subsequently, microscale thermophoresis (MST) experiments were performed to investigate the direct binding of DDX17 to the non-coding RNAs. The MST experiments demonstrated that DDX17 binds with the IGR and 5’ NCR with a dissociation constant of 5.77 ± 0.15 µM and 9.85 ± 0.11 µM, respectively. As DDX17135–555 is an RNA helicase, we next determined if it could unwind IGR and NCR. We developed a helicase assay using MST and fluorescently-labeled oligos, which suggested DDX17135–555 can unwind both RNAs. Overall, our study provides direct evidence of DDX17135–555 interacting with and unwinding RVFV non-coding regions. 相似文献