全文获取类型
收费全文 | 29391篇 |
免费 | 4159篇 |
国内免费 | 2163篇 |
专业分类
化学 | 25126篇 |
晶体学 | 136篇 |
力学 | 2262篇 |
综合类 | 76篇 |
数学 | 1456篇 |
物理学 | 6657篇 |
出版年
2024年 | 70篇 |
2023年 | 416篇 |
2022年 | 1150篇 |
2021年 | 1178篇 |
2020年 | 1762篇 |
2019年 | 1427篇 |
2018年 | 1150篇 |
2017年 | 1042篇 |
2016年 | 1817篇 |
2015年 | 1566篇 |
2014年 | 1715篇 |
2013年 | 2383篇 |
2012年 | 1609篇 |
2011年 | 1750篇 |
2010年 | 1507篇 |
2009年 | 1670篇 |
2008年 | 1642篇 |
2007年 | 1584篇 |
2006年 | 1428篇 |
2005年 | 1206篇 |
2004年 | 1088篇 |
2003年 | 930篇 |
2002年 | 1572篇 |
2001年 | 563篇 |
2000年 | 468篇 |
1999年 | 469篇 |
1998年 | 484篇 |
1997年 | 336篇 |
1996年 | 264篇 |
1995年 | 244篇 |
1994年 | 196篇 |
1993年 | 140篇 |
1992年 | 110篇 |
1991年 | 99篇 |
1990年 | 85篇 |
1989年 | 67篇 |
1988年 | 65篇 |
1987年 | 64篇 |
1986年 | 92篇 |
1985年 | 43篇 |
1984年 | 33篇 |
1983年 | 24篇 |
1982年 | 27篇 |
1981年 | 14篇 |
1980年 | 15篇 |
1979年 | 23篇 |
1978年 | 18篇 |
1976年 | 15篇 |
1972年 | 12篇 |
1957年 | 11篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
111.
The interactions of [Pt(CNN)(4-dpt)]PF(6), (1; 4-dpt=2,4-diamino-6-(4-pyridyl)-1,3,5-triazine, HCNN=6-phenyl-2,2'-bipyridine) with double-stranded DNA, poly(dA-dT)(2), and poly(dG-dC)(2) were examined by spectroscopic, electrophoretic, and hydrodynamic methods. The spectroscopic data were analyzed with McGhee, van't Hoff, and Gibbs-Helmholtz equations. In a comparative study, [Pt(CNN)(py)]PF(6) (2; py=pyridine) was prepared and the nature of its binding towards DNA was investigated [preliminary results: ChemBioChem 2003, 4, 62-68]. For reactions with calf thymus DNA at 20 degrees C, the intrinsic binding constants for 1 and 2 are (4.6+/-0.2)x10(5) and (2.3+/-0.3)x10(4) mol(-1) dm(3), respectively. Results of DNA-binding reactions revealed that 1 and 2 preferentially bind to the AT sequence of duplex DNA. Intercalation is the preferred binding mode for 2, whereas both intercalation and minor-groove binding are observed for 1. Complex 1 is cytotoxic against a number of carcinoma cell lines, including KB-3-1, CNE-3, and HepG2, and remains potent against multidrug- or cisplatin-resistant KB-V-1 and CNE1 cell lines, for which the resistance ratios are 1.6 and 1.5, respectively. Importantly, 1 is almost an order of magnitude less toxic to the normal cell line CCD-19Lu (IC(50)=176+/-1.7 microM) and it selectively induced apoptosis leading to cancer cell death with less than 5 % detectable necrosis. 相似文献
112.
Denis J. Evans 《Journal of statistical physics》1979,20(5):547-555
Nonequilibrium molecular dynamics calculations are used to show that polyatomic fluids can support antisymmetric stress. In a homogeneous system where the time dependence of vorticity is a step function, it is shown that the rate at which intrinsic angular velocity approaches its steady-state value ( = 1/2 × u) is determined by the magnitude of the antisymmetric part of the pressure tensor. 相似文献
113.
114.
You-Gang Zhang Xia-Xia Liu Jian-Cheng Zong Yang-Teng-Jiao Zhang Rong Dong Na Wang Zhi-Hui Ma Li Li Shang-Long Wang Yan-Ling Mu Song-Song Wang Zi-Min Liu Li-Wen Han 《Molecules (Basel, Switzerland)》2022,27(13)
Phytotherapy offers obvious advantages in the intervention of Coronary Artery Disease (CAD), but it is difficult to clarify the working mechanisms of the medicinal materials it uses. DGS is a natural vasoprotective combination that was screened out in our previous research, yet its potential components and mechanisms are unknown. Therefore, in this study, HPLC-MS and network pharmacology were employed to identify the active components and key signaling pathways of DGS. Transgenic zebrafish and HUVECs cell assays were used to evaluate the effectiveness of DGS. A total of 37 potentially active compounds were identified that interacted with 112 potential targets of CAD. Furthermore, PI3K-Akt, MAPK, relaxin, VEGF, and other signal pathways were determined to be the most promising DGS-mediated pathways. NO kit, ELISA, and Western blot results showed that DGS significantly promoted NO and VEGFA secretion via the upregulation of VEGFR2 expression and the phosphorylation of Akt, Erk1/2, and eNOS to cause angiogenesis and vasodilation. The result of dynamics molecular docking indicated that Salvianolic acid C may be a key active component of DGS in the treatment of CAD. In conclusion, this study has shed light on the network molecular mechanism of DGS for the intervention of CAD using a network pharmacology-driven strategy for the first time to aid in the intervention of CAD. 相似文献
115.
Mingfei Ji Zongtao Chai Jie Chen Gang Li Qiang Li Miao Li Yelei Ding Shaoyong Lu Guanqun Ju Jianquan Hou 《Molecules (Basel, Switzerland)》2022,27(13)
Small ubiquitin-related modifier (SUMO)-specific protease 1 (SENP1) is a cysteine protease that catalyzes the cleavage of the C-terminus of SUMO1 for the processing of SUMO precursors and deSUMOylation of target proteins. SENP1 is considered to be a promising target for the treatment of hepatocellular carcinoma (HCC) and prostate cancer. SENP1 Gln597 is located at the unstructured loop connecting the helices α4 to α5. The Q597A mutation of SENP1 allosterically disrupts the hydrolytic reaction of SUMO1 through an unknown mechanism. Here, extensive multiple replicates of microsecond molecular dynamics (MD) simulations, coupled with principal component analysis, dynamic cross-correlation analysis, community network analysis, and binding free energy calculations, were performed to elucidate the detailed mechanism. Our MD simulations showed that the Q597A mutation induced marked dynamic conformational changes in SENP1, especially in the unstructured loop connecting the helices α4 to α5 which the mutation site occupies. Moreover, the Q597A mutation caused conformational changes to catalytic Cys603 and His533 at the active site, which might impair the catalytic activity of SENP1 in processing SUMO1. Moreover, binding free energy calculations revealed that the Q597A mutation had a minor effect on the binding affinity of SUMO1 to SENP1. Together, these results may broaden our understanding of the allosteric modulation of the SENP1−SUMO1 complex. 相似文献
116.
Lin Li Hongliang Wang Jun Ye Yankun Chen Renyun Wang Dujia Jin Yuling Liu 《Molecules (Basel, Switzerland)》2022,27(14)
Surface charge polarity and density influence the immune clearance and cellular uptake of intravenously administered lipid nanoparticles (LNPs), thus determining the efficiency of their delivery to the target. Here, we modified the surface charge with ascorbyl palmitate (AsP) used as a negatively charged lipid. AsP-PC-LNPs were prepared by dispersion and ultrasonication of AsP and phosphatidylcholine (PC) composite films at various ratios. AsP inserted into the PC film with its polar head outward. The pKa for AsP was 4.34, and its ion form conferred the LNPs with negative surface charge. Zeta potentials were correlated with the amount and distribution of AsP on the LNPs surface. DSC, Raman and FTIR spectra, and molecular dynamics simulations disclosed that AsP distributed homogeneously in PC at 1–8% (w/w), and there were strong hydrogen bonds between the polar heads of AsP and PC (PO2−), which favored LNPs’ stability. But at AsP:PC > 8% (w/w), the excessive AsP changed the interaction modes between AsP and PC. The AsP–PC composite films became inhomogeneous, and their phase transition behaviors and Raman and FTIR spectra were altered. Our results clarified the mechanism of surface charge modification by AsP and provided a rational use of AsP as a charged lipid to modify LNP surface properties in targeted drug delivery systems. Furthermore, AsP–PC composites were used as phospholipid-based biological membranes to prepare paclitaxel-loaded LNPs, which had stable surface negative charge, better tumor targeting and tumor inhibitory effects. 相似文献
117.
新型含氮螯合树脂的制备及其吸附性能 总被引:1,自引:0,他引:1
以三甘醇和苯磺酰氯为原料,二乙烯三胺为交联剂合成了新型含氮螯合树脂(5),其结构经IR表征.讨论了Ni2 浓度和pH对5吸附容量的影响.动力学研究表明,5对Ni2 的吸附速率符合鲛岛公式. 相似文献
118.
Asaad Khalid Mohnad Abdalla Maria Saeed Muhammad Nabeel Ghayur Surya Kant Kalauni Mohammed Albratty Hassan A. Alhazmi Mohammed Ahmed Mesaik Anwarul Hassan Gilani Zaheer Ul-Haq 《Molecules (Basel, Switzerland)》2022,27(11)
Acetylcholinesterase (AChE) inhibitors and calcium channel blockers are considered effective therapies for Alzheimer’s disease. AChE plays an essential role in the nervous system by catalyzing the hydrolysis of the neurotransmitter acetylcholine. In this study, the inhibition of the enzyme AChE by Sarcorucinine-D, a pregnane type steroidal alkaloid, was investigated with experimental enzyme kinetics and molecular dynamics (MD) simulation techniques. Kinetics studies showed that Sarcorucinine-D inhibits two cholinesterases—AChE and butyrylcholinesterase (BChE)—noncompetitively, with Ki values of 103.3 and 4.66 µM, respectively. In silico ligand-protein docking and MD simulation studies conducted on AChE predicted that Sarcorucinine-D interacted via hydrophobic interactions and hydrogen bonds with the residues of the active-site gorge of AChE. Sarcorucinine-D was able to relax contractility concentration-dependently in the intestinal smooth muscles of jejunum obtained from rabbits. Not only was the spontaneous spasmogenicity inhibited, but it also suppressed K+-mediated spasmogenicity, indicating an effect via the inhibition of voltage-dependent Ca2+ channels. Sarcorucinine-D could be considered a potential lead molecule based on its properties as a noncompetitive AChE inhibitor and a Ca2+ channel blocker. 相似文献
119.
Wei Zhu Fengming Wu Jindie Hu Wenjing Wang Jifeng Zhang Guoqing Guo 《Molecules (Basel, Switzerland)》2022,27(11)
Chlorogenic acid (CGA), an important metabolite in natural plant medicines such as honeysuckle and eucommia, has been shown to have potent antinociceptive effects. Nevertheless, the mechanism by which CGA relieves chronic pain remains unclear. α-amino-3-hydroxy-5-methyl-4-isooxazolpropionic acid receptor (AMPAR) is a major ionotropic glutamate receptor that mediates rapid excitatory synaptic transmission and its glutamate ionotropic receptor AMPA type subunit 1 (GluA1) plays a key role in nociceptive transmission. In this study, we used Western blot, surface plasmon resonance (SPR) assay, and the molecular simulation technologies to investigate the mechanism of interaction between CGA and AMPAR to relieve chronic pain. Our results indicate that the protein expression level of GluA1 showed a dependent decrease as the concentration of CGA increased (0, 50, 100, and 200 μM). The SPR assay demonstrates that CGA can directly bind to GluA1 (KD = 496 μM). Furthermore, CGA forms a stable binding interaction with GluA1, which is validated by molecular dynamics (MD) simulation. The binding free energy between CGA and GluA1 is −39.803 ± 14.772 kJ/mol, where van der Waals interaction and electrostatic interaction are the major contributors to the GluA1–CGA binding, and the key residues are identified (Val-32, Glu-33, Ala-36, Glu-37, Leu-48), which play a crucial role in the binding interaction. This study first reveals the structural basis of the stable interaction between CGA and GluA1 to form a binding complex for the relief of chronic pain. The research provides the structural basis to understand the treatment of chronic pain and is valuable to the design of novel drug molecules in the future. 相似文献
120.
Anthonny Cordero-Díaz Efren Robledo-Leal Eugenio Hernndez-Fernndez Emanuel Hernndez-Núez Mariana Elizondo-Zertuche Susana T. Lpez-Cortina 《Molecules (Basel, Switzerland)》2022,27(12)
The Scedosporium genus is an emerging pathogen with worldwide prevalence and high mortality rates that gives multidrug resistance to antifungals; therefore, pharmacological alternatives must be sought for the treatment of diseases caused by this fungus. In the present project, six new α-aminophosphates were synthesized by the Kabachnik–Fields multicomponent reaction by vortex agitation, and six new monohydrolyzed α-aminophosphonic acids were synthesized by an alkaline hydrolysis reaction. Antifungal activity was evaluated using the agar diffusion method as an initial screening to determine the most active compound compared to voriconazole; then it was evaluated against 23 strains of the genus Scedosporium following the M38-A2 protocol from CLSI (activity range: 648.76–700 µg/mL). Results showed that compound 5f exhibited the highest antifungal activity according to the agar diffusion method (≤1 mg/mL). Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay and it was shown that compound 5f exhibits a lower toxicity in comparison to voriconazole at the same concentration (1000 µM). A docking study was conducted afterwards, showing that the possible mechanism of action of the compound is through the inhibition of allosteric 14-α-demethylase. Taking these results as a basis, 5f is presented as a compound with attractive properties for further studies. 相似文献