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221.
R J Mayer J L Adams M J Bossard T A Berkhout 《The Journal of biological chemistry》1991,266(30):20070-20078
A 32-carboxylic acid derivative of lanosterol (SKF 104976) was found to be a potent inhibitor of lanosterol 14 alpha-demethylase (14 alpha DM). 14 alpha DM activity in a Hep G2 cell extract was inhibited 50% by 2 nM SKF 104976. Exposure of intact cells to similar concentrations of the compound resulted in the inhibition of incorporation of [14C]acetate into cholesterol with concomitant accumulation of lanosterol as well as a 40-70% decrease in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) activity. SKF 104976 did not effect low density lipoprotein uptake and degradation in Hep G2 cells, suggesting that HMGR and low density lipoprotein receptor activity were not coordinately regulated under these conditions. Reduction of the flux of carbon units in the sterol synthetic pathway by as much as 80% did not alter the suppressing effect of SKF 104976 on HMGR activity. However, under conditions where sterol synthesis was almost completely blocked by lovastatin, HMGR activity was not suppressed by SKF 104976. Mevalonate, at concentrations that did not decrease HMGR activity, was able to restore the inhibiting effect of SKF 104976 on HMGR activity. The rapid inhibition (2-3 h) of HMGR activity by SKF 104976 to 30-60% of the level in controls was not dependent on the initial amount of HMGR enzyme present. These findings suggest that upon inhibition of 14 alpha DM by SKF 104976, a mevalonate-derived precursor regulates HMGR activity, even when the sterol synthetic rate is considerably reduced and when HMGR protein levels are very high. In Hep G2 cells, formation of oxylanostenols from [3H]mevalonate reached a maximum between 1 and 10 nM SKF 104976 and was negligible at higher concentrations. This result suggests that oxylanostenols are not the key mediators of the modulation of HMGR in Hep G2 cells upon 14 alpha DM inhibition. 相似文献
222.
Down modulation of HIV-1 gene expression using a procaryotic RNA-binding protein. 总被引:3,自引:1,他引:2 下载免费PDF全文
The coat protein of the single stranded RNA bacteriophages acts as a translational repressor by binding with high affinity to a target RNA that encompasses the ribosomal binding site of the replicase gene. We have expressed this procaryotic RNA-binding protein in mammalian cells. Using the coat protein binding site attached to the HIV-1 5' leader RNA, we tested for the biological effect of co-expressed bacteriophage protein. We found that HIV-1 LTR-directed expression within this context was inhibited in trans by the coat protein. This example suggests the feasibility of using procaryotic RNA-binding proteins as genetic modulators in eucaryotic cells. 相似文献
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Testing the covarion hypothesis of molecular evolution 总被引:14,自引:8,他引:6
The covarion hypothesis of molecular evolution states that the fixation of
mutations may alter the probability that any given position will fix the
next change. Tests of this hypothesis using the divergence of real
sequences are compromised because models of rate variation among sites
(e.g., the gamma version of the one-parameter equation) predict sequence
divergence values similar to those for the covarion process. This study
therefore focuses on the extent to which the varied and unvaried codons of
two well-diverged taxa are the same, because fewer are expected by the
covarion hypothesis than by the gamma model. The data for these tests are
the protein sequences of Cu, Zn superoxide dismutase (SOD) for mammals and
plants. Simulation analyses show that the covarion hypothesis makes better
predictions about the frequencies of varied and unhit positions in common
between these two taxa than does the gamma version of the one-parameter
model. Furthermore, the analysis of SOD tertiary structure demonstrates
that mammal and plant variabilities are distributed differently on the
protein. These results support the conclusions that the variable and
invariable codons of mammal and plant SODs are different and that the
covarion model explains the evolution of this protein better than the gamma
version of the one-parameter process. Unlike other models, the covarion
hypothesis accounts for rate fluctuations among positions over time, which
is an important parameter of molecular evolution.
相似文献
226.
Sterigmatocystin (STG) is a toxic metabolite produced by severalAspergillus species. Because of its toxic and carcinogenic properties the occurrence of STG in food is considered to represent a potential
hazard to man. The present study was designed to investigate following points:
相似文献
1 | A survey of STG incidence in Ras cheese on local markets. Ras cheese samples were collected from Cairo, Giza and Kalubia governorates. Thirty five percent of the samples contained the toxin with a mean value of 22.23 μg /kg |
2 | Fate of STG contaminating milk during Ras cheese processing. Milk was artificially contaminated with 125 μg/kg and processed into Ras cheese. Eighty percent of the toxin was distributed into the curd and 20% into the whey. Cheese ripening effected toxin content and the effect was temperature dependent. At 6°C: toxin concentration was slightly affected; at 20°C the toxin was reduced by 16% after 90 days when low toxin concentration was used. |
3 | Formation of STG byA versicolor mold on Ras cheese. Ras cheese blocks were contaminated with spores of the mold. Toxin production started after 45 days of ripening and reached a maximum at 90 days and then declined. Cow’s milk favoured toxin production over buffaloe’s. Aged cheese inhibited toxin production. |
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RNAi efficiency is influenced by local RNA structure of the target sequence. We studied this structure-based resistance in detail by targeting a perfect RNA hairpin and subsequently destabilized its tight structure by mutation, thereby gradually exposing the target sequence. Although the tightest RNA hairpins were completely resistant to RNAi, we observed an inverse correlation between the overall target hairpin stability and RNAi efficiency within a specific thermodynamic stability (ΔG) range. Increased RNAi efficiency was shown to be caused by improved binding of the siRNA to the destabilized target RNA hairpins. The mutational effects vary for different target regions. We find an accessible target 3′ end to be most important for RNAi-mediated inhibition. However, these 3′ end effects cannot be reproduced in siRNA-target RNA-binding studies in vitro, indicating the important role of RISC components in the in vivo RNAi reaction. The results provide a more detailed insight into the impact of target RNA structure on RNAi and we discuss several possible implications. With respect to lentiviral-mediated delivery of shRNA expression cassettes, we present a ΔG window to destabilize the shRNA insert for vector improvement, while avoiding RNAi-mediated self-targeting during lentiviral vector production. 相似文献
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