全文获取类型
收费全文 | 126628篇 |
免费 | 6873篇 |
国内免费 | 3970篇 |
出版年
2023年 | 1538篇 |
2022年 | 1537篇 |
2021年 | 3926篇 |
2020年 | 3172篇 |
2019年 | 4420篇 |
2018年 | 3732篇 |
2017年 | 2697篇 |
2016年 | 3211篇 |
2015年 | 5225篇 |
2014年 | 9700篇 |
2013年 | 10957篇 |
2012年 | 7285篇 |
2011年 | 8812篇 |
2010年 | 6491篇 |
2009年 | 6346篇 |
2008年 | 6529篇 |
2007年 | 6745篇 |
2006年 | 5317篇 |
2005年 | 4608篇 |
2004年 | 3684篇 |
2003年 | 2988篇 |
2002年 | 2677篇 |
2001年 | 1700篇 |
2000年 | 1406篇 |
1999年 | 1369篇 |
1998年 | 1246篇 |
1997年 | 975篇 |
1996年 | 990篇 |
1995年 | 1130篇 |
1994年 | 1027篇 |
1993年 | 944篇 |
1992年 | 883篇 |
1991年 | 832篇 |
1990年 | 708篇 |
1989年 | 665篇 |
1988年 | 630篇 |
1987年 | 529篇 |
1986年 | 472篇 |
1985年 | 889篇 |
1984年 | 1393篇 |
1983年 | 970篇 |
1982年 | 1161篇 |
1981年 | 1065篇 |
1980年 | 839篇 |
1979年 | 808篇 |
1978年 | 560篇 |
1977年 | 539篇 |
1976年 | 513篇 |
1975年 | 385篇 |
1973年 | 412篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
61.
《Neurochemistry international》1995,26(6):635-641
Acetylcholine synthesis from radiolabelled glucose was monitored in cerebral cortex cells isolated from brains of suckling and adult rats. Acetylcholine synthesis was found much higher in suckling animals, both in the absence and presence of acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7) inhibitor, paraoxon. Together with choline (20 μM), carnitine was found to stimulate acetylcholine synthesis in a synergistic way in cortex cells from adult rats (18%). Choline, however, was incapable of reversing an inhibitory effect exerted by carnitine on acetylcholine synthesis in cortex cells from suckling animals. Distribution of carnitine derivatives was found significantly different in the cells from young and old animals, the content of acetylcarnitine decreased with age with a corresponding increase of free carnitine. The observed differences in carnitine effect on acetylcholine synthesis suggested that high acetylcarnitine in cells capable of β-oxidation might be correlated with the lower level of acetylcholine synthesis. 相似文献
62.
Patricia B. Miller Hua Shen Neil R. Gilkes Douglas G. Kilburn Robert C. Miller Jr. Andrew G. Plaut R.Antony J. Warren 《FEMS microbiology letters》1992,92(2):199-203
The hinge in IgA1 and the linker in endoglucanase A (CenA) are quite similar. The IgA1 hinge is 18 amino acids long and contains only proline, threonine and serine. The linker in CenA is 27 amino acids long and contains only proline, threonine and a single serine. IgA proteases from Neisseria gonorrhoeae cleave Pro-Ser and Pro-Thr bonds within the IgA1 hinge sequence, but they do not attack CenA. When the linker sequence of CenA is replaced with the hinge sequence of IgA1, the hybrid polypeptide is susceptible to the N. gonorrhoeae proteases. It is cleaved within the hinge sequence at the same sites as IgA1. 相似文献
63.
《Bioorganic & medicinal chemistry》2020,28(24):115819
The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing’s sarcoma models. 相似文献
64.
65.
66.
67.
《Bioorganic & medicinal chemistry》2020,28(9):115437
NDM-1 can hydrolyze nearly all available β-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of 15N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae. 相似文献
68.
Many lung disease processes are characterized by structural and functional heterogeneity that is not directly appreciable with traditional physiological measurements. Experimental methods and lung function modeling to study regional lung function are crucial for better understanding of disease mechanisms and for targeting treatment. Synchrotron radiation offers useful properties to this end: coherence, utilized in phase-contrast imaging, and high flux and a wide energy spectrum which allow the selection of very narrow energy bands of radiation, thus allowing imaging at very specific energies. K-edge subtraction imaging (KES) has thus been developed at synchrotrons for both human and small animal imaging. The unique properties of synchrotron radiation extend X-ray computed tomography (CT) capabilities to quantitatively assess lung morphology, and also to map regional lung ventilation, perfusion, inflammation and biomechanical properties, with microscopic spatial resolution. Four-dimensional imaging, allows the investigation of the dynamics of regional lung functional parameters simultaneously with structural deformation of the lung as a function of time. This review summarizes synchrotron radiation imaging methods and overviews examples of its application in the study of disease mechanisms in preclinical animal models, as well as the potential for clinical translation both through the knowledge gained using these techniques and transfer of imaging technology to laboratory X-ray sources. 相似文献
69.
《Molecular cell》2020,77(5):1055-1065.e4
Download : Download video (66MB) 相似文献
70.
《Journal of structural biology》2020,209(1):107399
G-quadruplexes (G4) are secondary structures of nucleic acids that can form in cells and have diverse biological functions. Several biologically important proteins interact with G-quadruplexes, of which RHAU (or DHX36) – a helicase from the DEAH-box superfamily, was shown to bind and unwind G-quadruplexes efficiently. We report a X-ray co-crystal structure at 1.5 Å resolution of an N-terminal fragment of RHAU bound to an exposed tetrad of a parallel-stranded G-quadruplex. The RHAU peptide folds into an L-shaped α-helix, and binds to a G-quadruplex through π-stacking and electrostatic interactions. X-ray crystal structure of our complex identified key amino acid residues important for G-quadruplex-peptide binding interaction at the 3′-end G•G•G•G tetrad. Together with previous solution and crystal structures of RHAU bound to the 5′-end G•G•G•G and G•G•A•T tetrads, our crystal structure highlights the occurrence of a robust G-quadruplex recognition motif within RHAU that can adapt to different accessible tetrads. 相似文献