全文获取类型
收费全文 | 339篇 |
免费 | 47篇 |
出版年
2021年 | 3篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 6篇 |
2016年 | 7篇 |
2015年 | 8篇 |
2014年 | 12篇 |
2013年 | 13篇 |
2012年 | 20篇 |
2011年 | 12篇 |
2010年 | 14篇 |
2009年 | 8篇 |
2008年 | 16篇 |
2007年 | 18篇 |
2006年 | 19篇 |
2005年 | 16篇 |
2004年 | 19篇 |
2003年 | 10篇 |
2002年 | 12篇 |
2001年 | 11篇 |
2000年 | 12篇 |
1999年 | 12篇 |
1998年 | 6篇 |
1995年 | 7篇 |
1994年 | 5篇 |
1992年 | 6篇 |
1991年 | 9篇 |
1990年 | 6篇 |
1989年 | 9篇 |
1988年 | 8篇 |
1987年 | 6篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1980年 | 5篇 |
1979年 | 3篇 |
1978年 | 4篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1975年 | 5篇 |
1974年 | 2篇 |
1973年 | 5篇 |
1972年 | 2篇 |
1971年 | 3篇 |
1969年 | 2篇 |
1968年 | 2篇 |
1925年 | 3篇 |
排序方式: 共有386条查询结果,搜索用时 31 毫秒
71.
Background
There is only one established drug binding site on sodium channels. However, drug binding of sodium channels shows extreme promiscuity: ∼25% of investigated drugs have been found to potently inhibit sodium channels. The structural diversity of these molecules suggests that they may not share the binding site, and/or the mode of action. Our goal was to attempt classification of sodium channel inhibitors by measuring multiple properties of inhibition in electrophysiology experiments. We also aimed to investigate if different properties of inhibition correlate with specific chemical properties of the compounds.Methodology/Principal Findings
A comparative electrophysiological study of 35 compounds, including classic sodium channel inhibitors (anticonvulsants, antiarrhythmics and local anesthetics), as well as antidepressants, antipsychotics and neuroprotective agents, was carried out using rNav1.2 expressing HEK-293 cells and the QPatch automatic patch-clamp instrument. In the multi-dimensional space defined by the eight properties of inhibition (resting and inactivated affinity, potency, reversibility, time constants of onset and offset, use-dependence and state-dependence), at least three distinct types of inhibition could be identified; these probably reflect distinct modes of action. The compounds were clustered similarly in the multi-dimensional space defined by relevant chemical properties, including measures of lipophilicity, aromaticity, molecular size, polarity and electric charge. Drugs of the same therapeutic indication typically belonged to the same type. We identified chemical properties, which were important in determining specific properties of inhibition. State-dependence correlated with lipophilicity, the ratio of the neutral form of molecules, and aromaticity: We noticed that the highly state dependent inhibitors had at least two aromatic rings, logP>4.0, and pKa<8.0.Conclusions/Significance
The correlations of inhibition properties both with chemical properties and therapeutic profiles would not have been evident through the sole determination of IC50; therefore, recording multiple properties of inhibition may allow improved prediction of therapeutic usefulness. 相似文献72.
73.
Seema S. Lakdawala Yicong Wu Peter Wawrzusin Juraj Kabat Andrew J. Broadbent Elaine W. Lamirande Ervin Fodor Nihal Altan-Bonnet Hari Shroff Kanta Subbarao 《PLoS pathogens》2014,10(3)
Reassortment of influenza viral RNA (vRNA) segments in co-infected cells can lead to the emergence of viruses with pandemic potential. Replication of influenza vRNA occurs in the nucleus of infected cells, while progeny virions bud from the plasma membrane. However, the intracellular mechanics of vRNA assembly into progeny virions is not well understood. Here we used recent advances in microscopy to explore vRNA assembly and transport during a productive infection. We visualized four distinct vRNA segments within a single cell using fluorescent in situ hybridization (FISH) and observed that foci containing more than one vRNA segment were found at the external nuclear periphery, suggesting that vRNA segments are not exported to the cytoplasm individually. Although many cytoplasmic foci contain multiple vRNA segments, not all vRNA species are present in every focus, indicating that assembly of all eight vRNA segments does not occur prior to export from the nucleus. To extend the observations made in fixed cells, we used a virus that encodes GFP fused to the viral polymerase acidic (PA) protein (WSN PA-GFP) to explore the dynamics of vRNA assembly in live cells during a productive infection. Since WSN PA-GFP colocalizes with viral nucleoprotein and influenza vRNA segments, we used it as a surrogate for visualizing vRNA transport in 3D and at high speed by inverted selective-plane illumination microscopy. We observed cytoplasmic PA-GFP foci colocalizing and traveling together en route to the plasma membrane. Our data strongly support a model in which vRNA segments are exported from the nucleus as complexes that assemble en route to the plasma membrane through dynamic colocalization events in the cytoplasm. 相似文献
74.
75.
Isabel Olmos Calvo Eszter Fodor Dorottya Kardos Istvn Hornyk Adl Hinsenkamp Olga Kuten-Pella Zsuzsanna Gyevnr Gbor Erdlyi Tams Brdos Tams Mirk Paukovits Krisztin Magos Gyrgy Bres Stefan Nehrer Zsombor Lacza 《Current issues in molecular biology》2021,43(2):637
The serum fraction of platelet-rich fibrin (hyperacute serum) has been shown to improve cartilage cell proliferation in in vitro osteoarthritic knee joint models. We hypothesize that hyperacute serum may be a potential regenerative therapeutic for osteoarthritic knees. In this study, the cytokine milieu at the synovial fluid of osteoarthritic knee joints exposed to hyperacute serum intraarticular injections was investigated. Patients with knee osteoarthritis received three injections of autologous hyperacute serum; synovial fluid was harvested before each injection and clinical monitoring was followed-up for 6 months. Forty osteoarthritic-related cytokines, growth factors and structural proteins from synovial fluid were quantified and analysed by Multivariate Factor Analysis. Hyperacute serum provided symptomatic relief regarding pain and joint stability for OA patients. Both patients “with” and “without effusion knees” had improved VAS, KOOS and Lysholm-Tegner scores 6 months after of hyperacute serum treatment. Synovial fluid analysis revealed two main clusters of proteins reacting together as a group, showing strong and significant correlations with their fluctuation patterns after hyperacute serum treatment. In conclusion, hyperacute serum has a positive effect in alleviating symptoms of osteoarthritic knees. Moreover, identified protein clusters may allow the prediction of protein expression, reducing the number of investigated proteins in future studies. 相似文献
76.
Hannah T Baddock Sanja Brolih Yuliana Yosaatmadja Malitha Ratnaweera Marcin Bielinski Lonnie
P Swift Abimael Cruz-Migoni Haitian Fan Jeremy R Keown Alexander P Walker Garrett
M Morris Jonathan
M Grimes Ervin Fodor Christopher
J Schofield Opher Gileadi Peter
J McHugh 《Nucleic acids research》2022,50(3):1484
The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14–nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14–nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14–nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3′-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14–nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12–nsp7–nsp8 (nsp12–7–8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14–nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14–nsp10, including the known SARS-CoV-2 major protease (Mpro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment. 相似文献
77.
The effects of whole-body X-irradiation with a dose of (7 Gray) were studied on the time course of systemic responses (fever, leukocytosis, serum coeruloplasmin concentration) in turpentine-induced inflammation and on the acute-phase reaction (coeruloplasmin, haptoglobin and seromucoid) produced by various stressful conditions (turpentine-abscess, immobilization, restraint conditions). Results showed that in the irradiated animals the lack of the leukocytic and febrile response to turpentine administration was accompanied by a normal coeruloplasmin response. Therefore, we have concluded to the involvement of more than one mediator in the development of systemic reactions accompanying inflammation. The leukopenia induced by whole-body irradiation could not prevent the development or reduce the magnitude of the acute-phase response in any of the models analysed. This observation appears to make doubtful the exclusive role of leukocytes in the mediation of the acute-phase reaction. 相似文献
78.
Summary Direct selection for recombinants by supplemented minimal media from polyethylene-glycol (PEG)-induced fusion of protoplasts of polyauxotrophic strains of B. megaterium revealed striking physiological influences on the yield of recombinants. Cytoplasmic state of the protoplasts to be fused, rather than genetic events, determined the number of colonies obtained on the selection media. It is suggested that the physiological effects primarily influenced the ability of the fused protoplasts to revert to bacillary form. 相似文献
79.
The complete nucleotide sequence of Citrus limon 26S rDNA has been determined. The sequence has been aligned with large ribosomal RNA (L-rRNA) sequences of Escherichia coli, Saccharomyces cerevisiae and Oryza sativa. Nine extensive expansion segments in dicot 26S rRNA relative to E. coli 23S rRNA have been identified and compared with analogous segments of monocot, yeast, amphibian and human L-rRNAs. A secondary structure model for lemon 26S rRNA has been derived based on the refined model of E. coli 23S rRNA. It has been compared with other eukaryotic L-rRNAs models in terms of location of functionally important regions. Origin and evolution of L-rRNA expansion segments are discussed. 相似文献
80.
Raman spectroscopic elucidation of DNA backbone conformations for poly(dG-dT).poly(dA-dC) and poly(dA-dT).poly(dA-dT) in CsF solution 总被引:3,自引:0,他引:3
Raman spectra have been recorded for poly(dG-dT) · poly(dA-dC) and poly(dA-dT) · poly(dA-dT) in low salt and at high concentrations of CsF. Poly(dG-dT) · poly(dA-dC) shows no change in the 682-cm?1 guanine mode, demonstrating the absence of the Z-structure at high salt. The 790-cm?1 phosphodiester symmetric stretch, however, shifts up 5 cm?1 in 4.3M CsF, suggesting a slight conformational change, associated with ion binding or hydration changes. Poly(dA-dT) · poly(dA-dT) shows an additional broad band at 816 cm?1, attributed to the phosphodiester modes associated with the C3′-endo deoxyribose units in the alternating B-structure. In this case, both the 841- and the 816-cm?1 asymmetric phosphodiester stretches, associated with the C2′- and C3′-endo units, shift down on addition of CsF in a sequential manner. Correlation of this sequence with that previously observed for the two 31P-nmr resonances, establishes that the phosphodiester stretching frequencies depend on the conformation of the 5′-sugar, and not on the 3′-sugar. 相似文献