全文获取类型
收费全文 | 1241篇 |
免费 | 105篇 |
国内免费 | 1篇 |
出版年
2023年 | 8篇 |
2022年 | 9篇 |
2021年 | 24篇 |
2019年 | 17篇 |
2018年 | 23篇 |
2017年 | 16篇 |
2016年 | 19篇 |
2015年 | 50篇 |
2014年 | 60篇 |
2013年 | 81篇 |
2012年 | 87篇 |
2011年 | 80篇 |
2010年 | 52篇 |
2009年 | 44篇 |
2008年 | 72篇 |
2007年 | 66篇 |
2006年 | 77篇 |
2005年 | 47篇 |
2004年 | 48篇 |
2003年 | 32篇 |
2002年 | 34篇 |
2001年 | 23篇 |
2000年 | 29篇 |
1999年 | 29篇 |
1998年 | 14篇 |
1997年 | 15篇 |
1996年 | 13篇 |
1995年 | 13篇 |
1994年 | 16篇 |
1993年 | 10篇 |
1992年 | 25篇 |
1991年 | 16篇 |
1990年 | 18篇 |
1989年 | 15篇 |
1988年 | 11篇 |
1985年 | 8篇 |
1983年 | 11篇 |
1982年 | 6篇 |
1979年 | 6篇 |
1977年 | 8篇 |
1976年 | 6篇 |
1975年 | 8篇 |
1974年 | 7篇 |
1973年 | 7篇 |
1972年 | 11篇 |
1971年 | 9篇 |
1970年 | 6篇 |
1969年 | 7篇 |
1967年 | 6篇 |
1966年 | 9篇 |
排序方式: 共有1347条查询结果,搜索用时 20 毫秒
211.
The efficient and rapid synthesis of novel azetidin-2-ones 4a–j has been established. Thus, both microwave and conventional condensation 2-{(1H-benzimidazol)-ylthio}-N′-2-(substituted phenyl) hydrazide with chloroacetylchloride were carried out in DMF-benzene solvent in the presence of Et3N catalyst. The microwave synthesis route afforded better yield with short time. The novel heterocycles were characterized by elemental analysis and spectral features. Some of the produced compounds were screened for their antimicrobial activity. 相似文献
212.
213.
Selection pressures on proteins are usually measured by comparing homologous nucleotide sequences (Zuckerkandl and Pauling 1965). Recently we introduced a novel method, termed volatility, to estimate selection pressures on proteins on the basis of their synonymous codon usage (Plotkin and Dushoff 2003; Plotkin et al. 2004). Here we provide a theoretical foundation for this approach. Under the Fisher-Wright model, we derive the expected frequencies
of synonymous codons as a function of the strength of selection on amino acids, the mutation rate, and the effective population
size. We analyze the conditions under which we can expect to draw inferences from biased codon usage, and we estimate the
time scales required to establish and maintain such a signal. We find that synonymous codon usage can reliably distinguish
between negative selection and neutrality only for organisms, such as some microbes, that experience large effective population
sizes or periods of elevated mutation rates. The power of volatility to detect positive selection is also modest—requiring
approximately 100 selected sites—but it depends less strongly on population size. We show that phenomena such as transient
hyper-mutators can improve the power of volatility to detect selection, even when the neutral site heterozygosity is low.
We also discuss several confounding factors, neglected by the Fisher-Wright model, that may limit the applicability of volatility
in practice.
Electronic Supplementary Material Electronic Supplementary material is available for this article at
and accessible for authorised users.
[Reviewing Editor: Dr. Lauren Meyers] 相似文献
214.
Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus 总被引:7,自引:0,他引:7
Levenson JM Roth TL Lubin FD Miller CA Huang IC Desai P Malone LM Sweatt JD 《The Journal of biological chemistry》2006,281(23):15763-15773
DNA (cytosine-5) methylation represents one of the most widely used mechanisms of enduring cellular memory. Stable patterns of DNA methylation are established during development, resulting in creation of persisting cellular phenotypes. There is growing evidence that the nervous system has co-opted a number of cellular mechanisms used during development to subserve the formation of long term memory. In this study, we examined the role DNA (cytosine-5) methyltransferase (DNMT) activity might play in regulating the induction of synaptic plasticity. We found that the DNA within promoters for reelin and brain-derived neurotrophic factor, genes implicated in the induction of synaptic plasticity in the adult hippocampus, exhibited rapid and dramatic changes in cytosine methylation when DNMT activity was inhibited. Moreover, zebularine and 5-aza-2-deoxycytidine, inhibitors of DNMT activity, blocked the induction of long term potentiation at Schaffer collateral synapses. Activation of protein kinase C in the hippocampus decreased reelin promoter methylation and increased DNMT3A gene expression. Interestingly, DNMT activity is required for protein kinase C-induced increases in histone H3 acetylation. Considered together, these results suggest that DNMT activity is dynamically regulated in the adult nervous system and that DNMT may play a role in regulating the induction of synaptic plasticity in the mature CNS. 相似文献
215.
The serine protease thrombin plays multiple roles in many important physiological processes, especially coagulation, where it functions as both a pro- and anticoagulant. The polyanionic glycosaminoglycan heparin modulates thrombin's activity through binding at exosite II. Sucrose octasulfate (SOS) is often used as a surrogate for heparin, but it is not known whether it is an effective heparin mimic in its interaction with thrombin. We have characterized the interaction of SOS with thrombin in solution and determined a crystal structure of their complex. SOS binds thrombin with a K(d) of ~1.4 μM, comparable to that of the much larger polymeric heparin measured under the same conditions. Nonionic (hydrogen bonding) interactions make a larger contribution to thrombin binding of SOS than to heparin. SOS binding to exosite II inhibits thrombin's catalytic activity with high potency but with low efficacy. Analytical ultracentrifugation shows that bovine and human thrombins are monomers in solution in the presence of SOS, in contrast to their complexes with heparin, which are dimers. In the X-ray crystal structure, two molecules of SOS are bound nonequivalently to exosite II portions of a thrombin dimer, in contrast to the 1:2 stoichiometry of the heparin-thrombin complex, which has a different monomer association mode in the dimer. SOS and heparin binding to exosite II of thrombin differ on both chemical and structural levels and, perhaps most significantly, in thrombin inhibition. These differences may offer paths to the design of more potent exosite II binding, allosteric small molecules as modulators of thrombin function. 相似文献
216.
Zebrafish embryos have not been cryopreserved due to their structural limitations. Although embryo survival rates have been used as the measured outcome for most of the cryopreservation protocols studied, there are very limited data available at the molecular level. This study focused on the effect of chilling and subsequent warming on gene expression of sox2, sox3 and sox19a which play vital roles in the development of zebrafish embryos. A quantitative RT-PCR approach was used to investigate gene expression following chilling at 0 °C for up to 180 min. The effect on gene expression was also studied during a 180 min warming period after chilling for 30 or 60 min. There were significant decreases in sox2 (up to 4-fold) and sox3 (up to 3-fold) expressions following chilling. Significant increases in gene expressions of sox2 (up to 2-fold), sox3 (up to 33-fold) and sox19a (up to 25-fold) were observed during warming in the embryos that had been chilled for 30 min. Similarly, significant increases were observed in sox2 (up to 3-fold) and sox3 (up to 2-fold) during warming in embryos that had been chilled for 60 min. These increases may be explained by compensation for the suppression observed during chilling and/or to activate repair mechanisms or maintain homeostasis. 相似文献
217.
Fluorescent amplified fragment length polymorphism (FAFLP) analysis was applied to genetically fingerprint 'working culture control strains' used by accredited food microbiology laboratories. A working culture control strain is defined as a subculture from a strain initially obtained from an authenticated source [such as the National Collection of Type Cultures (NCTC)] that is maintained for use with routine testing within the laboratory. Working culture control strains from eight food examination laboratories, representing four bacterial species, were analysed by FAFLP; these were Salmonella Nottingham, Staphylococcus aureus, Listeria monocytogenes and Bacillus cereus. The resultant FAFLP profiles of the eight working culture control strains for each of these species were compared against the appropriate freeze-dried ampoules obtained directly from NCTC. FAFLP results demonstrated that within 50% of working cultures analysed, several laboratories were routinely using working cultures that were genetically different from the original reference NCTC strains. This study highlights the need for laboratories to review the protocols used to process and maintain control strains and working cultures, with a potential view to utilize single-use quality control materials. 相似文献
218.
Mintu Desai Padma Rangarajan Janet L. Donahue Sarah P. Williams Eric S. Land Mihir K. Mandal Brian Q. Phillippy Imara Y. Perera Victor Raboy Glenda E. Gillaspy 《The Plant journal : for cell and molecular biology》2014,80(4):642-653
Inositol pyrophosphates are unique cellular signaling molecules with recently discovered roles in energy sensing and metabolism. Studies in eukaryotes have revealed that these compounds have a rapid turnover, and thus only small amounts accumulate. Inositol pyrophosphates have not been the subject of investigation in plants even though seeds produce large amounts of their precursor, myo‐inositol hexakisphosphate (InsP6). Here, we report that Arabidopsis and maize InsP6 transporter mutants have elevated levels of inositol pyrophosphates in their seed, providing unequivocal identification of their presence in plant tissues. We also show that plant seeds store a little over 1% of their inositol phosphate pool as InsP7 and InsP8. Many tissues, including, seed, seedlings, roots and leaves accumulate InsP7 and InsP8, thus synthesis is not confined to tissues with high InsP6. We have identified two highly similar Arabidopsis genes, AtVip1 and AtVip2, which are orthologous to the yeast and mammalian VIP kinases. Both AtVip1 and AtVip2 encode proteins capable of restoring InsP7 synthesis in yeast mutants, thus AtVip1 and AtVip2 can function as bonafide InsP6 kinases. AtVip1 and AtVip2 are differentially expressed in plant tissues, suggesting non‐redundant or non‐overlapping functions in plants. These results contribute to our knowledge of inositol phosphate metabolism and will lay a foundation for understanding the role of InsP7 and InsP8 in plants. 相似文献
219.
Tanay M. Desai Mariana Marin Christopher R. Chin George Savidis Abraham L. Brass Gregory B. Melikyan 《PLoS pathogens》2014,10(4)
Interferon-induced transmembrane proteins (IFITMs) inhibit infection of diverse enveloped viruses, including the influenza A virus (IAV) which is thought to enter from late endosomes. Recent evidence suggests that IFITMs block virus hemifusion (lipid mixing in the absence of viral content release) by altering the properties of cell membranes. Consistent with this mechanism, excess cholesterol in late endosomes of IFITM-expressing cells has been reported to inhibit IAV entry. Here, we examined IAV restriction by IFITM3 protein using direct virus-cell fusion assay and single virus imaging in live cells. IFITM3 over-expression did not inhibit lipid mixing, but abrogated the release of viral content into the cytoplasm. Although late endosomes of IFITM3-expressing cells accumulated cholesterol, other interventions leading to aberrantly high levels of this lipid did not inhibit virus fusion. These results imply that excess cholesterol in late endosomes is not the mechanism by which IFITM3 inhibits the transition from hemifusion to full fusion. The IFITM3''s ability to block fusion pore formation at a post-hemifusion stage shows that this protein stabilizes the cytoplasmic leaflet of endosomal membranes without adversely affecting the lumenal leaflet. We propose that IFITM3 interferes with pore formation either directly, through partitioning into the cytoplasmic leaflet of a hemifusion intermediate, or indirectly, by modulating the lipid/protein composition of this leaflet. Alternatively, IFITM3 may redirect IAV fusion to a non-productive pathway, perhaps by promoting fusion with intralumenal vesicles within multivesicular bodies/late endosomes. 相似文献
220.
Raquel González Meghna Desai Eusebio Macete Peter Ouma Mwaka A. Kakolwa Salim Abdulla John J. Aponte Helder Bulo Abdunoor M. Kabanywanyi Abraham Katana Sonia Maculuve Alfredo Mayor Arsenio Nhacolo Kephas Otieno Golbahar Pahlavan María Rupérez Esperan?a Sevene Laurence Slutsker Anifa Vala John Williamsom Clara Menéndez 《PLoS medicine》2014,11(9)