全文获取类型
收费全文 | 249篇 |
免费 | 29篇 |
国内免费 | 4篇 |
出版年
2023年 | 1篇 |
2022年 | 4篇 |
2021年 | 5篇 |
2020年 | 6篇 |
2019年 | 7篇 |
2018年 | 11篇 |
2017年 | 8篇 |
2016年 | 9篇 |
2015年 | 18篇 |
2014年 | 14篇 |
2013年 | 11篇 |
2012年 | 27篇 |
2011年 | 15篇 |
2010年 | 15篇 |
2009年 | 6篇 |
2008年 | 21篇 |
2007年 | 11篇 |
2006年 | 9篇 |
2005年 | 9篇 |
2004年 | 9篇 |
2003年 | 7篇 |
2002年 | 6篇 |
2001年 | 8篇 |
2000年 | 6篇 |
1999年 | 3篇 |
1998年 | 3篇 |
1997年 | 4篇 |
1996年 | 3篇 |
1995年 | 4篇 |
1994年 | 4篇 |
1993年 | 1篇 |
1991年 | 2篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1970年 | 2篇 |
1969年 | 1篇 |
1966年 | 2篇 |
排序方式: 共有282条查询结果,搜索用时 15 毫秒
21.
Yiting Qiao Yunxin Pei Miao Luo Muthukumar Rajasekaran Kam M Hui Jianxiang Chen 《Experimental biology and medicine (Maywood, N.J.)》2021,246(12):1343
Cytokinesis, the final step of mitosis, is critical for maintaining the ploidy level of cells. Cytokinesis is a complex, highly regulated process and its failure can lead to genetic instability and apoptosis, contributing to the development of cancer. Human hepatocellular carcinoma is often accompanied by a high frequency of aneuploidy and the DNA ploidy pattern observed in human hepatocellular carcinoma results mostly from impairments in cytokinesis. Many key regulators of cytokinesis are abnormally expressed in human hepatocellular carcinoma, and their expression levels are often correlated with patient prognosis. Moreover, preclinical studies have demonstrated that the inhibition of key cytokinesis regulators can suppress the growth of human hepatocellular carcinoma. Here, we provide an overview of the current understanding of the signaling networks regulating cytokinesis, the key cytokinesis regulators involved in the initiation and development of human hepatocellular carcinoma, and their applications as potential diagnostic and therapeutic biomarkers. 相似文献
22.
Thu P. Huynh Sonali P. Barwe Seung J. Lee Ryan McSpadden Omar E. Franco Simon W. Hayward Robert Damoiseaux Stephen S. Grubbs Nicholas J. Petrelli Ayyappan K. Rajasekaran 《PloS one》2015,10(4)
Glucocorticoids are commonly used as palliative or chemotherapeutic clinical agents for treatment of a variety of cancers. Although steroid treatment is beneficial, the mechanisms by which steroids improve outcome in cancer patients are not well understood. Na,K-ATPase beta-subunit isoform 1 (NaK-β1) is a cell-cell adhesion molecule, and its expression is down-regulated in cancer cells undergoing epithelial-to mesenchymal-transition (EMT), a key event associated with cancer progression to metastatic disease. In this study, we performed high-throughput screening to identify small molecules that could up-regulate NaK-β1 expression in cancer cells. Compounds related to the glucocorticoids were identified as drug candidates enhancing NaK-β1 expression. Of these compounds, triamcinolone, dexamethasone, and fluorometholone were validated to increase NaK-β1 expression at the cell surface, enhance cell-cell adhesion, attenuate motility and invasiveness and induce mesenchymal to epithelial like transition of renal cell carcinoma (RCC) cells in vitro. Treatment of NaK-β1 knockdown cells with these drug candidates confirmed that these compounds mediate their effects through up-regulating NaK-β1. Furthermore, we demonstrated that these compounds attenuate tumor growth in subcutaneous RCC xenografts and reduce local invasiveness in orthotopically-implanted tumors. Our results strongly indicate that the addition of glucocorticoids in the treatment of RCC may improve outcome for RCC patients by augmenting NaK-β1 cell-cell adhesion function. 相似文献
23.
Chidambaram Parameswari Rajasekaran Sripriya Karuppannan Veluthambi 《In vitro cellular & developmental biology. Plant》2010,46(5):395-402
In an analysis of 339 independent T
0 transgenic rice lines generated by Agrobacterium-mediated transformation, albino plants appeared in the T
1 generation in two single-copy transgenic lines, O54 and O36 and in one double-copy transgenic line, C18. While the T
0 plants of these three lines were green, albino and green plants emerged in a 1:3 ratio in the T
1 generation. The albino phenotype segregated as a monogenic recessive trait. Southern blot analysis of the green and albino
plants in the T
1 generation confirmed that the albino trait and the T-DNA insertion events were unlinked. Segregation of the albino trait
from the transgenic trait in the lines O54 and O36 was confirmed in T
2 and T
3 generations, respectively. Homozygous transgenic plants free from the albino trait were also identified. In the double-copy
transgenic line C18, we genetically separated the two transgenic loci, out-segregated the albino locus from both transgene
loci, and identified homozygous plants for each of the transgenic events by Southern blot analysis in the T
1 generation itself. Thus, we demonstrate that when an albino trait appears in the T
1 generation and is unlinked to a transgene locus, the albino locus can be segregated from the transgene locus and homozygous
transgenic lines free from albinos can be established. 相似文献
24.
Mason T. MacDonald Rajasekaran R. Lada Alex I. Martynenko Martine Dorais Steeve Pepin Yves Desjardins 《Trees - Structure and Function》2010,24(5):879-886
Post-harvest needle abscission is a major challenge for Christmas tree and greenery industries. It was hypothesized that ethylene
triggers abscission in balsam fir. Three experiments were conducted to test this hypothesis. In experiment 1, 70 balsam fir
branches were collected, placed in water, and ethylene evolution was observed over time. In experiment 2, a 2 × 5 factorial
experiment was designed to determine the effect of exogenous ethylene and an ethylene receptor blocker, 1-methylcyclopropene
(1-MCP), on needle abscission. In experiment 3, a 2 × 6 factorial experiment was designed to determine the effect of exogenous
ethylene and an ethylene inhibitor, aminoethoxyvinylglycine (AVG), on needle abscission. It was found that ethylene evolution
was the highest 1–2 days prior to needle abscission, which was consistent in untreated branches and branches exposed to exogenous
ethylene. Exposure to exogenous ethylene significantly decreased needle retention by 63%. When ethylene receptors were blocked
by 1-MCP, needle retention increased by 147% despite the presence of ethylene and increased by 73% in the absence of ethylene
when compared to the respective controls. When endogenous ethylene synthesis was inhibited by AVG, there was no improvement
in needle retention in the presence of ethylene, but there was a 113% increase in needle retention in the absence of exogenous
ethylene. Ethylene is strongly implicated as the signal triggering abscission in root-detached balsam fir. 相似文献
25.
Mohan B Rajasekaran Sue A Mitchell Rohanah Hussain Simon C Andrews 《Biochemical and biophysical research communications》2010,398(3):366-371
The EfeM protein is a component of the putative EfeUOBM iron-transporter of Pseudomonas syringae pathovar syringae and is thought to act as a periplasmic, ferrous-iron binding protein. It contains a signal peptide of 34 amino acid residues and a C-terminal ‘Peptidase_M75’ domain of 251 residues. The C-terminal domain contains a highly conserved ‘HXXE’ motif thought to act as part of a divalent cation-binding site. In this work, the gene (efeM or ‘Psyr_3370’) encoding EfeM was cloned and over-expressed in Escherichia coli, and the mature protein was purified from the periplasm. Mass spectrometry confirmed the identity of the protein (MW 27,772 Da). Circular dichroism spectroscopy of EfeM indicated a mainly α-helical structure, consistent with bioinformatic predictions. Purified EfeM was crystallised by hanging-drop vapor diffusion to give needle-shaped crystals that diffracted to a resolution of 1.6 Å. This is the first molecular study of a peptidase M75 domain with a presumed iron transport role. 相似文献
26.
Cation–π interaction is a non-covalent binding force that plays a significant role in protein stability and drug–receptor interactions. In this work, we have investigated the structural role of cation–π interactions in sugar-binding proteins (SBPs). We observed 212 cation–π interactions in 53 proteins out of 59 SBPs in dataset. There is an average one energetically significant cation–π interaction for every 66 residues in SBPs. In addition, Arg is highly preferred to form cation–π interactions, and the average energy of Arg-Trp is high among six pairs. Long-range interactions are predominant in the analyzed cation–π interactions. Comparatively, all interaction pairs favor to accommodate in strand conformations. The analysis of solvent accessible area indicates that most of the aromatic residues are found on buried or partially buried whereas cationic residues were found mostly on the exposed regions of protein. The cation–π interactions forming residues were found that around 43% of cation–π residues had highly conserved with the conservation score ≥6. Almost cationic and π-residues equally share in the stabilization center. Sugar-binding site analysis in available complexes showed that the frequency of Trp and Arg is high, suggesting the potential role of these two residues in the interactions between proteins and sugar molecules. Our observations in this study could help to further understand the structural stability of SBPs. 相似文献
27.
Benjamin IJ Guo Y Srinivasan S Boudina S Taylor RP Rajasekaran NS Gottlieb R Wawrousek EF Abel ED Bolli R 《American journal of physiology. Heart and circulatory physiology》2007,293(5):H3201-H3209
The abundantly expressed small molecular weight proteins, CRYAB and HSPB2, have been implicated in cardioprotection ex vivo. However, the biological roles of CRYAB/HSPB2 coexpression for either ischemic preconditioning and/or protection in situ remain poorly defined. Wild-type (WT) and age-matched ( approximately 5-9 mo) CRYAB/HSPB2 double knockout (DKO) mice were subjected either to 30 min of coronary occlusion and 24 h of reperfusion in situ or preconditioned with a 4-min coronary occlusion/4-min reperfusion x 6, before similar ischemic challenge (ischemic preconditioning). Additionally, WT and DKO mice were subjected to 30 min of global ischemia in isolated hearts ex vivo. All experimental groups were assessed for area at risk and infarct size. Mitochondrial respiration was analyzed in isolated permeabilized cardiac skinned fibers. As a result, DKO mice modestly altered heat shock protein expression. Surprisingly, infarct size in situ was reduced by 35% in hearts of DKO compared with WT mice (38.8 +/- 17.9 vs. 59.8 +/- 10.6% area at risk, P < 0.05). In DKO mice, ischemic preconditioning was additive to its infarct-sparing phenotype. Similarly, infarct size after ischemia and reperfusion ex vivo was decreased and the production of superoxide and creatine kinase release was decreased in DKO compared with WT mice (P < 0.05). In permeabilized fibers, ADP-stimulated respiration rates were modestly reduced and calcium-dependent ATP synthesis was abrogated in DKO compared with WT mice. In conclusion, contrary to expectation, our findings demonstrate that CRYAB and HSPB2 deficiency induces profound adaptations that are related to 1) a reduction in calcium-dependent metabolism/respiration, including ATP production, and 2) decreased superoxide production during reperfusion. We discuss the implications of these disparate results in the context of phenotypic responses reported for CRYAB/HSPB2-deficient mice to different ischemic challenges. 相似文献
28.
Single-nucleotide polymorphisms (SNPs) play a major role in the understanding of the genetic basis of many complex human diseases. Also, the genetics of human phenotype variation could be understood by knowing the functions of these SNPs. It is still a major challenge to identify the functional SNPs in a disease-related gene. In this work, we have analyzed the genetic variation that can alter the expression and the function of the BRCA1 gene using computational methods. Of the total 477 SNPs, 65 were found to be nonsynonymous (ns) SNPs. Among the 14 SNPs in the untranslated region, 4 were found in the 5' and 10 were found in the 3' untranslated region (UTR). It was found that 16.9% of the nsSNPs were damaging, by both the SIFT and the PolyPhen servers. The UTR Resource tool suggested that 2 of 4 SNPs in the 5' UTR and 3 of 10 SNPs in the 3' UTR might change the protein expression levels. We identified major mutations from proline to serine at positions 1776 and 1812 of the native protein of the BRCA1 gene. From a comparison of the stabilizing residues of the native and mutant proteins, we propose that an nsSNP (rs1800751) could be an important candidate for the breast cancer caused by the BRCA1 gene. 相似文献
29.
A novel conotoxin pl14a containing 25 amino acid residues with an amidated C-terminus from vermivorous cone snail, Conus planorbis belongs to J-conotoxin superfamily and this is the first conotoxin, which inhibits both nicotinic acetylcholine receptor subtypes and Kv1.6 channel. We have attempted through bioinformatics approaches to elucidate the extent of specificity of pl14a towards Kv1 channel subtypes (Kv1.1-Kv1.6). Our work provides rationale for the relatively high specificity and binding mode of pl14a to Kv1.6 channel. The pl14a peptide contains two types of structural elements, namely the putative dyad (Lys18 and Tyr19) and basic residue ring constituted of arginine residues. We have carried out in silico docking studies so as to assess the contribution of one or combination of both structural elements of pl14a in blocking of Kv1.6 channel. For this purpose, we have built by homology modelling, the theoretical 3D structure of Kv1.6 channel based on the available crystal structure of mammalian shaker Kv1.2 channel. Docking studies suggest that positively charged residues ring may be involved in the blocking mechanism of Kv1.6 channel. The models suggest that the peptide interacts with negatively charged extracellular loops and pore-mouth of the potassium channel and blocks the channel by covering the pore as a lid, akin to previously proposed blocking mechanism of kappaM-conotoxin RIIIK from Conus radiatus to Tsha1 potassium channel. The newly detected pharmacophore for pl14a interacting with Kv1.6 channel provides a pointer to experimental work to validate the observations made here. Based on differences in the number and distribution of the positively-charged residues in other conopeptides from the J-superfamily, we hypothesize different selectivity profiles against subtypes of the potassium channels for these conopeptides. 相似文献
30.
Kenneth F. Lyon Christy L. Strong Steve G. Schooler Richard J. Young Nervik Roy Brittany Ozar Mark Bachmeier II Sanguthevar Rajasekaran Martin R. Schiller 《Nucleic acids research》2015,43(13):6399-6412
Since the function of a short contiguous peptide minimotif can be introduced or eliminated by a single point mutation, these functional elements may be a source of human variation and a target of selection. We analyzed the variability of ∼300 000 minimotifs in 1092 human genomes from the 1000 Genomes Project. Most minimotifs have been purified by selection, with a 94% invariance, which supports important functional roles for minimotifs. Minimotifs are generally under negative selection, possessing high genomic evolutionary rate profiling (GERP) and sitewise likelihood-ratio (SLR) scores. Some are subject to neutral drift or positive selection, similar to coding regions. Most SNPs in minimotif were common variants, but with minor allele frequencies generally <10%. This was supported by low substation rates and few newly derived minimotifs. Several minimotif alleles showed different intercontinental and regional geographic distributions, strongly suggesting a role for minimotifs in adaptive evolution. We also note that 4% of PTM minimotif sites in histone tails were common variants, which has the potential to differentially affect DNA packaging among individuals. In conclusion, minimotifs are a source of functional genetic variation in the human population; thus, they are likely to be an important target of selection and evolution. 相似文献