全文获取类型
收费全文 | 14763篇 |
免费 | 1478篇 |
国内免费 | 831篇 |
专业分类
17072篇 |
出版年
2024年 | 51篇 |
2023年 | 300篇 |
2022年 | 323篇 |
2021年 | 450篇 |
2020年 | 525篇 |
2019年 | 824篇 |
2018年 | 665篇 |
2017年 | 690篇 |
2016年 | 645篇 |
2015年 | 596篇 |
2014年 | 758篇 |
2013年 | 1450篇 |
2012年 | 472篇 |
2011年 | 654篇 |
2010年 | 574篇 |
2009年 | 800篇 |
2008年 | 867篇 |
2007年 | 735篇 |
2006年 | 741篇 |
2005年 | 575篇 |
2004年 | 589篇 |
2003年 | 488篇 |
2002年 | 411篇 |
2001年 | 302篇 |
2000年 | 307篇 |
1999年 | 282篇 |
1998年 | 265篇 |
1997年 | 226篇 |
1996年 | 215篇 |
1995年 | 192篇 |
1994年 | 154篇 |
1993年 | 127篇 |
1992年 | 127篇 |
1991年 | 108篇 |
1990年 | 81篇 |
1989年 | 70篇 |
1988年 | 53篇 |
1987年 | 69篇 |
1986年 | 48篇 |
1985年 | 56篇 |
1984年 | 47篇 |
1983年 | 18篇 |
1982年 | 33篇 |
1981年 | 34篇 |
1980年 | 20篇 |
1979年 | 13篇 |
1978年 | 13篇 |
1977年 | 8篇 |
1976年 | 7篇 |
1973年 | 4篇 |
排序方式: 共有10000条查询结果,搜索用时 11 毫秒
31.
《Bioorganic & medicinal chemistry letters》2014,24(22):5330-5336
Free fatty acid receptor 1 (FFAR1) is a member of a previously characterized cluster of orphan G protein-coupled receptors (GPCRs). Later, this orphan receptor was identified as a target of medium- to long-chain free fatty acids in β-cells of the pancreas. Administration of FFAR1 agonists has been proved to potentiate glucose-stimulated insulin secretion from pancreatic β-cells. It was reported that some thiazolidinediones (TZDs), the best studied PPARγ agonists, are also able to stimulate FFAR1 in a dose-dependent manner. In the present study, a homology model of the human FFAR1 was constructed and inserted into a pre-equilibrated DPPC/TIP3P membrane system. This system was then simulated for 20 ns in complex with the FFAR1 agonist GW9085, as well as rosiglitazone and pioglitazone. We noticed that the salt bridge between Glu172 and Arg258 and the H bond between Glu145 and His153 could be responsible for the stabilization of the receptor in the inactive state. Moreover, we described for the first time the binding mode of TZDs in the binding site of FFAR1. The thiazolidinedione head forms a hydrogen bonding network with the critical polar residues in the binding site, Arg258 and Asn244, while the rest of the molecule is embedded into the receptor hydrophobic pocket. Based on this modeling study, we arrived at a proposal of the pharmacophore required for binding to both PPARγ and FFAR1. Insights gained from this investigation should provide future directions for the design of novel dual acting antidiabetic agents. 相似文献
32.
33.
Shubhandra Tripathi Akhil Kumar B. Sathish Kumar Arvind S. Negi 《Journal of biomolecular structure & dynamics》2016,34(6):1232-1240
Microtubule stabilizers provide an important mode of treatment via mitotic cell arrest of cancer cells. Recently, we reported two novel neolignans derivatives Cmp10 and Cmp19 showing anticancer activity and working as microtubule stabilizers at micromolar concentrations. In this study, we have explored the binding site, mode of binding, and stabilization by two novel microtubule stabilizers Cmp10 and Cmp19 using in silico molecular docking, molecular dynamics (MD) simulation, and binding free energy calculations. Molecular docking studies were performed to explore the β-tubulin binding site of Cmp10 and Cmp19. Further, MD simulations were used to probe the β-tubulin stabilization mechanism by Cmp10 and Cmp19. Binding affinity was also compared for Cmp10 and Cmp19 using binding free energy calculations. Our docking results revealed that both the compounds bind at Ptxl binding site in β-tubulin. MD simulation studies showed that Cmp10 and Cmp19 binding stabilizes M-loop (Phe272-Val288) residues of β-tubulin and prevent its dynamics, leading to a better packing between α and β subunits from adjacent tubulin dimers. In addition, His229, Ser280 and Gln281, and Arg278, Thr276, and Ser232 were found to be the key amino acid residues forming H-bonds with Cmp10 and Cmp19, respectively. Consequently, binding free energy calculations indicated that Cmp10 (?113.655 kJ/mol) had better binding compared to Cmp19 (?95.216 kJ/mol). This study provides useful insight for better understanding of the binding mechanism of Cmp10 and Cmp19 and will be helpful in designing novel microtubule stabilizers. 相似文献
34.
Little is known about the influence of genetic architecture on local adaptation. We investigated the genetic architecture of the rapid contemporary evolution of mouthparts, the flight polymorphism and life history traits in the soapberry bug Jadera haematoloma (Hemiptera) using laboratory selection. The mouthparts of these seed‐feeding bugs have adapted in 40–50 years by decreasing in length following novel natural selection induced by a host switch to the seeds of an introduced tree with smaller fruits than those of the native host vine. Laboratory selection on beak length in both an ancestral population feeding on the native host and a derived population feeding on the introduced host reveals genetic variance allowing a rapid response (heritabilities of 0.51–0.87) to selection for either longer or shorter beaks. This selection resulted in reverse evolution by restoring long beaks in the derived population and forward evolution by re‐creating short beaks in the ancestral bugs. There were strong genetic correlations (0.68–0.84) in both populations between beak lengths and the frequency of flight morphs, with short beaks associated with short wings. The results reveal a genetically interrelated set of adaptive multivariate traits including both beak length and flight morph. This suite of traits reflects host plant patchiness and seeding phenology. Weaker evidence suggests that egg mass and early egg production may be elements of the same suite. Reversible or forward evolution thus may occur in a broad set of genetically correlated multivariate traits undergoing rapid contemporary adaptation to altered local environments. 相似文献
35.
A Lacoursière-Roussel DG Bock ME Cristescu F Guichard P Girard P Legendre CW McKindsey 《Molecular ecology》2012,21(17):4227-4241
The relative importance of multiple vectors to the initial establishment, spread and population dynamics of invasive species remains poorly understood. This study used molecular methods to clarify the roles of commercial shipping and recreational boating in the invasion by the cosmopolitan tunicate, Botryllus schlosseri. We evaluated (i) single vs. multiple introduction scenarios, (ii) the relative importance of shipping and boating to primary introductions, (iii) the interaction between these vectors for spread (i.e. the presence of a shipping-boating network) and (iv) the role of boating in determining population similarity. Tunicates were sampled from 26 populations along the Nova Scotia, Canada, coast that were exposed to either shipping (i.e. ports) or boating (i.e. marinas) activities. A total of 874 individuals (c. 30 per population) from five ports and 21 marinas was collected and analysed using both mitochondrial cytochrome c oxidase subunit I gene (COI) and 10 nuclear microsatellite markers. The geographical location of multiple hotspot populations indicates that multiple invasions have occurred in Nova Scotia. A loss of genetic diversity from port to marina populations suggests a stronger influence of ships than recreational boats on primary coastal introductions. Population genetic similarity analysis reveals a dependence of marina populations on those that had been previously established in ports. Empirical data on marina connectivity because of boating better explains patterns in population similarities than does natural spread. We conclude that frequent primary introductions arise by ships and that secondary spread occurs gradually thereafter around individual ports, facilitated by recreational boating. 相似文献
36.
Kevin J. S. Zollman Carl T. Bergstrom Simon M. Huttegger 《Proceedings. Biological sciences / The Royal Society》2013,280(1750)
Costly signalling theory has become a common explanation for honest communication when interests conflict. In this paper, we provide an alternative explanation for partially honest communication that does not require significant signal costs. We show that this alternative is at least as plausible as traditional costly signalling, and we suggest a number of experiments that might be used to distinguish the two theories. 相似文献
37.
Dicoumarol derivatives were synthesized in the InCl3 catalyzed pseudo three-component reactions of 4-hydroxycoumarin with aromatic aldehydes in excellent yields. The reactions were performed in water under microwave irradiation. All synthesized compounds were characterized using NMR, IR, and UV–Vis spectroscopy, as well as with TD-DFT. Obtained dicoumarols were subjected to evaluation of their in vitro lipid peroxidation and soybean lipoxygenase inhibition activities. It was shown that five of ten examined compounds (3e, 3h, 3b, 3d, 3f) possess significant potential of antilipid peroxidation (84–97%), and that compounds 3b, 3e, 3h provided the highest soybean lipoxygenase (LOX-Ib) inhibition (IC50 = 52.5 µM) and 3i somewhat lower activity (IC50 = 55.5 µM). The bioactive conformations of the best LOX-Ib inhibitors were obtained by means of molecular docking and molecular dynamics. It was shown that, within the bioactive conformations interior to LOX-Ib active site, the most active compounds form the pyramidal structure made of two 4-hydroxycoumarin cores and a central phenyl substituent. This form serves as a spatial barrier which prevents LOX-Ib Fe2+/Fe3+ ion activity to generate the coordinative bond with the C13 hydroxyl group of the α-linoleate. It is worth pointing out that the most active compounds 3b, 3e, 3h and 3i can be candidates for further examination of their in vitro and in vivo anti-inflammatory activity and that molecular modeling study results provide possibility to screen bioactive conformations and elucidate the mechanism of dicoumarols anti-LOX activity. 相似文献
38.
Dissipative particle dynamics (DPD) was carried out to study systems containing gold atoms, organic ether (oligohydroquinonyl ether terminated with a thiol group) and organic solvents. The components in the simulated system are very different in size and chemical nature. Our simulation showed that the reproduction of the macroscopic experimental phase separation, properly dividing the polymeric molecule into beads, selecting the size of gold bead, and choosing the appropriate interaction parameters between beads are crucial. In addition, the solvent effect was the dominant factor for the formation of spherical aggregates of Au atoms and organic ether molecules. We report the interaction strengths between the solvent and gold clusters. Our work has demonstrated that DPD methods can be applied to the study of complex meso-scale systems. 相似文献
39.
40.