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Malikotsi A. Qhobosheane Anél Petzer Jacobus P. Petzer Lesetja J. Legoabe 《Bioorganic & medicinal chemistry》2018,26(20):5531-5537
In the present study, a series of fourteen 2-mercapto-4(3H)-quinazolinone derivatives was synthesised and evaluated as potential inhibitors of the human monoamine oxidase (MAO) enzymes. Quinazolinone is the oxidised form of quinazoline, and although this class has not yet been extensively explored as MAO inhibitors, it has been shown to possess a wide variety of biological activities. Among the quinazolinone derivatives investigated, seven compounds (IC50?<?1?µM) proved to be potent and specific MAO-B inhibitors, with the most potent inhibitor, 2-[(3-iodobenzyl)thio]quinazolin-4(3H)-one, exhibiting an IC50 value of 0.142?μM. Further investigation showed that this inhibitor is a reversible and competitive inhibitor of MAO-B with a Ki value of 0.068?µM. None of the test compounds were MAO-A inhibitors. Analysis of the structure-activity relationships (SARs) for MAO-B inhibition shows that substitution on the C2 position of quinazolinone with a benzylthio moiety bearing a Cl, Br or I on the meta position yields the most potent inhibitors of the series. In contrast, substitution with the unsubstituted benzylthio moiety (IC50?=?3.03?µM) resulted in significantly weaker inhibition activity towards MAO-B. This study suggests that quinazolinones are promising leads for the development of selective MAO-B inhibitors which may be used for the treatment of neurodegenerative disorders such as Parkinson’s disease. 相似文献
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Juhas M Power PM Harding RM Ferguson DJ Dimopoulou ID Elamin AR Mohd-Zain Z Hood DW Adegbola R Erwin A Smith A Munson RS Harrison A Mansfield L Bentley S Crook DW 《Genome biology》2007,8(11):R237-14
Background
A major part of horizontal gene transfer that contributes to the diversification and adaptation of bacteria is facilitated by genomic islands. The evolution of these islands is poorly understood. Some progress was made with the identification of a set of phylogenetically related genomic islands among the Proteobacteria, recognized from the investigation of the evolutionary origins of a Haemophilus influenzae antibiotic resistance island, namely ICEHin1056. More clarity comes from this comparative analysis of seven complete sequences of the ICEHin1056 genomic island subfamily.Results
These genomic islands have core and accessory genes in approximately equal proportion, with none demonstrating recent acquisition from other islands. The number of variable sites within core genes is similar to that found in the host bacteria. Furthermore, the GC content of the core genes is similar to that of the host bacteria (38% to 40%). Most of the core gene content is formed by the syntenic type IV secretion system dependent conjugative module and replicative module. GC content and lack of variable sites indicate that the antibiotic resistance genes were acquired relatively recently. An analysis of conjugation efficiency and antibiotic susceptibility demonstrates that phenotypic expression of genomic island-borne genes differs between different hosts.Conclusion
Genomic islands of the ICEHin1056 subfamily have a longstanding relationship with H. influenzae and H. parainfluenzae and are co-evolving as semi-autonomous genomes within the 'supragenomes' of their host species. They have promoted bacterial diversity and adaptation through becoming efficient vectors of antibiotic resistance by the recent acquisition of antibiotic resistance transposons. 相似文献114.
115.
Luis Clepf Passos Marianne Araújo Soares Mariana Abreu Costa JP Michaud Brenda Carolina Freire Geraldo Andrade Carvalho 《Biocontrol Science and Technology》2017,27(9):1082-1095
In order to aid the integration of biological and chemical controls for the tomato leaf miner, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae), this study evaluated the relative toxicity of five insecticides to the leaf miner predator Macrolophus basicornis (Stal) (Hemiptera: Miridae). The insecticides evaluated were teflubenzuron, abamectin, chlorantraniliprole, chlorfenapyr, and cartap hydrochloride, all of which are recommended for control of T. absoluta in Brazil. Nymphs and adults of M. basicornis were exposed to tomato leaves treated with the insecticides, under laboratory and greenhouse conditions. The overall mortality caused by the products in both situations was recorded, and the survival of congeneric groups was analysed using the Weibull model. The persistence of the insecticides was also evaluated and they were categorised into toxicity classes proposed by the International Organisation for Biological Control (IOBC) based on predator mortality and persistence. Abamectin and chlorfenapyr were toxic to M. basicornis nymphs and adults in all bioassays. Cartap hydrochloride was slightly harmful to adults in laboratory assays, but harmful to nymphs, and moderately harmful under greenhouse conditions. Chlorantraniliprole and teflubenzuron were harmless in most assays, except when nymphs were exposed in the laboratory, where they were moderately and slightly harmful, respectively. Chlorantraniliprole and teflubenzuron should be preferred insecticides for use in tomato leaf miner IPM programmes that aim to conserve M. basicornis populations. 相似文献
116.
We have studied the functional effects of extracellular Cd(2+) on human ether-a-go-go-related gene (HERG) encoded K(+) channels. Low concentrations (10-200 &mgr;M) of extracellular Cd(2+) increased outward currents through HERG channels; 200 &mgr;M Cd(2+) more than doubled HERG currents and altered current kinetics. Cd(2+) concentrations up to 200 &mgr;M did not change the voltage dependence of channel activation, but shifted the voltage dependence of inactivation to more depolarized membrane potentials. Cd(2+) concentrations >/=500 &mgr;M shifted the voltage dependence of channel activation to more positive potentials. These results are consistent with a somewhat specific ability of Cd(2+) to destabilize the inactivated state. We tested the hypothesis that channel inactivation is essential for Cd(2+)-induced increases in HERG K(+) currents, using a double point mutation (G628C/S631C) that diminishes HERG inactivation (Smith, P. L., T. Baukrowitz, and G. Yellen. 1996. Nature (Lond.). 379:833-836). This inactivation-removed mutant is insensitive to low concentrations of Cd(2+). Thus, Cd(2+) had two distinct effects on HERG K(+) channels. Low concentrations of Cd(2+) caused relatively selective effects on inactivation, resulting in a reduction of the apparent rectification of the channel and thereby increasing HERG K(+) currents. Higher Cd(2+) concentrations affected activation gating as well, possibly by a surface charge screening mechanism or by association with a lower affinity site. 相似文献
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Y Novik LM Ryan DG Haller R Asbury JP Dutcher A Schutt 《Cancer immunology, immunotherapy : CII》1999,16(4):261-266
The study was a Phase II randomized study to evaluate the efficacy of new agents for the treatment of advanced gastric carcinoma.
Patients were randomized to receive single agent chemotherapy with mitoxantrone, etoposide, aclacinomycin-A or spirogermanium.
The patients were stratified by prior use of chemotherapy, prior doxorubicin use and ECOG performance status. Patients with
a history of cardiac disease or prior doxorubicin exceeding a dose of 400 mg/m2 were restrictively randomized to sopirogermanium or etoposide only. One hundred and fourteen patients were registered for
the study. Among 98 evaluable patients there were only two partial responses (both in the etoposide arm), and one complete
response in the mitoxantrone arm. The median survival on the study was 3.3 months. One hundred and six patients were analyzable
for toxicity. There were four treatment-related deaths and four life-threatening toxicities. Because of low response rates
and relatively high toxicities the studied compounds were not deemed worth further investigation for advanced gastric cancer. 相似文献
120.