全文获取类型
收费全文 | 848篇 |
免费 | 94篇 |
出版年
2021年 | 15篇 |
2018年 | 6篇 |
2017年 | 12篇 |
2016年 | 10篇 |
2015年 | 18篇 |
2014年 | 27篇 |
2013年 | 37篇 |
2012年 | 36篇 |
2011年 | 31篇 |
2010年 | 37篇 |
2009年 | 22篇 |
2008年 | 34篇 |
2007年 | 45篇 |
2006年 | 30篇 |
2005年 | 38篇 |
2004年 | 27篇 |
2003年 | 19篇 |
2002年 | 36篇 |
2001年 | 28篇 |
2000年 | 31篇 |
1999年 | 21篇 |
1998年 | 16篇 |
1997年 | 7篇 |
1996年 | 15篇 |
1994年 | 6篇 |
1993年 | 6篇 |
1992年 | 12篇 |
1991年 | 19篇 |
1990年 | 14篇 |
1989年 | 10篇 |
1988年 | 8篇 |
1987年 | 13篇 |
1986年 | 15篇 |
1985年 | 7篇 |
1984年 | 15篇 |
1983年 | 13篇 |
1982年 | 6篇 |
1981年 | 8篇 |
1980年 | 10篇 |
1979年 | 11篇 |
1978年 | 13篇 |
1977年 | 9篇 |
1976年 | 6篇 |
1974年 | 8篇 |
1973年 | 13篇 |
1972年 | 7篇 |
1970年 | 5篇 |
1969年 | 11篇 |
1967年 | 5篇 |
1963年 | 5篇 |
排序方式: 共有942条查询结果,搜索用时 31 毫秒
101.
The evolution of cytoplasmic incompatibility types: integrating segregation, inbreeding and outbreeding 下载免费PDF全文
Cytoplasmic incompatibility (CI) is a reproductive incompatibility induced by maternally transmitted bacteria of the genera Wolbachia and Cardinium. In the simplest form of CI, offspring from infected males and uninfected females suffer from increased mortality. However, it has been noted that crosses between males and females carrying different strains of infection are often also incompatible. The evolutionary processes leading to the emergence of new CI-compatibility types are still not resolved. Here, we develop a model that extends previous theoretical approaches by including segregation of bacterial strains during transmission as well as a continuum of breeding systems ranging from inbreeding (complete sib mating) to outbreeding (complete sib-mating avoidance). Our results demonstrate that (1) with segregation of strains, evolution is unlikely to lead to new CI types that co-occur as a double infection with the preexisting one, (2) inbreeding substantially hampers the evolution of new CI types, and (3) outbreeding facilitates the evolution of new CI types. Our model also provides a hypothesis on the evolutionary origin of CI. 相似文献
102.
Fehér T Bogos B Méhi O Fekete G Csörgo B Kovács K Pósfai G Papp B Hurst LD Pál C 《Molecular biology and evolution》2012,29(10):3153-3159
Although both genotypes with elevated mutation rate (mutators) and mobilization of insertion sequence (IS) elements have substantial impact on genome diversification, their potential interactions are unknown. Moreover, the evolutionary forces driving gradual accumulation of these elements are unclear: Do these elements spread in an initially transposon-free bacterial genome as they enable rapid adaptive evolution? To address these issues, we inserted an active IS1 element into a reduced Escherichia coli genome devoid of all other mobile DNA. Evolutionary laboratory experiments revealed that IS elements increase mutational supply and occasionally generate variants with especially large phenotypic effects. However, their impact on adaptive evolution is small compared with mismatch repair mutator alleles, and hence, the latter impede the spread of IS-carrying strains. Given their ubiquity in natural populations, such mutator alleles could limit early phase of IS element evolution in a new bacterial host. More generally, our work demonstrates the existence of an evolutionary conflict between mutation-promoting mechanisms. 相似文献
103.
MicroRNAs (miRNAs) have emerged as key regulators of gene expression. Intragenic miRNAs account for ~50% of mammalian miRNAs. Classic studies reported that they are usually coexpressed with host genes. Here, using genome-wide miRNA and gene expression profiles from five sample sets, we show that evolutionarily conserved ('old') intragenic miRNAs tend to be coexpressed with host genes, but non-conserved ('young') ones rarely do so. This result is robust: in all sample sets, the coexpression rate of young miRNAs is significantly lower than that of conserved ones even after controlling for abundance. As a result, although young miRNAs dominate in human genome, the majority of intragenic miRNAs that show coexpression with host genes are phylogenetically old ones. For younger miRNAs, extrapolation of their expression profiles from those of their host genes should be treated with caution. We propose a model to explain this phenomenon in which the majority of young miRNAs are unlikely to be coexpressed with host genes; however, for some fraction of young miRNAs coexpression with their host genes, initially imbued by chromatin level effects, is advantageous and these are the ones likely to embed into the system and evolve ever higher levels of coexpression, possibly by evolving piggybacking mechanisms. 相似文献
104.
Mehlmer N Parvin N Hurst CH Knight MR Teige M Vothknecht UC 《Journal of experimental botany》2012,63(4):1751-1761
Calcium has long been acknowledged as one of the most important signalling components in plants. Many abiotic and biotic stimuli are transduced into a cellular response by temporal and spatial changes in cellular calcium concentration and the calcium-sensitive protein aequorin has been exploited as a genetically encoded calcium indicator for the measurement of calcium in planta. The objective of this work was to generate a compatible set of aequorin expression plasmids for the generation of transgenic plant lines to measure changes in calcium levels in different cellular subcompartments. Aequorin was fused to different targeting peptides or organellar proteins as a means to localize it to the cytosol, the nucleus, the plasma membrane, and the mitochondria. Furthermore, constructs were designed to localize aequorin in the stroma as well as the inner and outer surface of the chloroplast envelope membranes. The modular set-up of the plasmids also allows the easy replacement of targeting sequences to include other compartments. An additional YFP-fusion was included to verify the correct subcellular localization of all constructs by laser scanning confocal microscopy. For each construct, pBin19-based binary expression vectors driven by the 35S or UBI10 promoter were made for Agrobacterium-mediated transformation. Stable Arabidopsis lines were generated and initial tests of several lines confirmed their feasibility to measure calcium signals in vivo. 相似文献
105.
Busby JN Landsberg MJ Simpson RM Jones SA Hankamer B Hurst MR Lott JS 《Journal of molecular biology》2012,415(2):359-371
Yersinia entomophaga MH96 is a native New Zealand soil bacterium that secretes a large ABC-type protein toxin complex, Yen-Tc, similar to those produced by nematode-associated bacteria such as Photorhabdus luminescens. Y. entomophaga displays an exceptionally virulent pathogenic phenotype in sensitive insect species, causing death within 72 h of infection. Because of this phenotype, there is intrinsic interest in the mechanism of action of Yen-Tc, and it also has the potential to function as a novel class of biopesticide. We have identified genes that encode chitinases as part of the toxin complex loci in Y. entomophaga MH96, P. luminescens, Photorhabdus asymbiotica and Xenorhabdus nematophila. Furthermore, we have shown that the secreted toxin complex from Y. entomophaga MH96 includes two chitinases as an integral part of the complex, a feature not described previously in other ABC toxins and possibly related to the severe disease caused by this bacterium. We present here the structure of the Y. entomophaga MH96 Chi1 chitinase, determined by X-ray crystallography to 1.74 Å resolution, and show that a ring of five symmetrically arranged lobes on the surface of the Yen-Tc toxin complex structure, as determined by single-particle electron microscopy, provides a good fit to the Chi1 monomer. We also confirm that the isolated chitinases display endochitinase activity, as does the complete toxin complex. 相似文献
106.
Direct and indirect consequences of meiotic recombination: implications for genome evolution 总被引:1,自引:0,他引:1
There is considerable variation within eukaryotic genomes in the local rate of crossing over. Why is this and what effect does it have on genome evolution? On the genome scale, it is known that by shuffling alleles, recombination increases the efficacy of selection. By contrast, the extent to which differences in the recombination rate modulate the efficacy of selection between genomic regions is unclear. Recombination also has direct consequences on the origin and fate of mutations: biased gene conversion and other forms of meiotic drive promote the fixation of mutations in a similar way to selection, and recombination itself may be mutagenic. Consideration of both the direct and indirect effects of recombination is necessary to understand why its rate is so variable and for correct interpretation of patterns of genome evolution. 相似文献
107.
The PDGF (platelet-derived growth factor) family members are potent mitogens for cells of mesenchymal origin and serve as important regulators of cell migration, survival, apoptosis and transformation. Tumour-derived PDGF ligands are thought to function in both autocrine and paracrine manners, activating receptors on tumour and surrounding stromal cells. PDGF-C and -D are secreted as latent dimers, unlike PDGF-A and -B. Cleavage of the CUB domain from the PDGF-C and -D dimers is required for their biological activity. At present, little is known about the proteolytic processing of PDGF-C, the rate-limiting step in the regulation of PDGF-C activity. In the present study we show that the breast carcinoma cell line MCF7, engineered to overexpress PDGF-C, produces proteases capable of cleaving PDGF-C to its active form. Increased PDGF-C expression enhances cell proliferation, anchorage-independent cell growth and tumour cell motility by autocrine signalling. In addition, MCF7-produced PDGF-C induces fibroblast cell migration in a paracrine manner. Interestingly, PDGF-C enhances tumour cell invasion in the presence of fibroblasts, suggesting a role for tumour-derived PDGF-C in tumour-stromal interactions. In the present study, we identify tPA (tissue plasminogen activator) and matriptase as major proteases for processing of PDGF-C in MCF7 cells. In in vitro studies, we also show that uPA (urokinase-type plasminogen activator) is able to process PDGF-C. Furthermore, by site-directed mutagenesis, we identify the cleavage site for these proteases in PDGF-C. Lastly, we provide evidence suggesting a two-step proteolytic processing of PDGF-C involving creation of a hemidimer, followed by GFD-D (growth factor domain dimer) generation. 相似文献
108.
Skidmore J Atcha Z Boucherat E Castelletti L Chen DW Coppo FT Cutler L Dunsdon RM Heath BM Hutchings R Hurst DN Javed S Martin S Maskell ES Norton D Pemberton DJ Redshaw S Rutter R Sehmi SS Scoccitti T Temple HE Theobald P Ward RW Wilson DM 《Bioorganic & medicinal chemistry letters》2012,22(10):3560-3563
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement. 相似文献
109.
Hui Zheng Elizabeth A Pearsall Dow P Hurst Yuhan Zhang Ji Chu Yali Zhou Patricia H Reggio Horace H Loh Ping-Yee Law 《BMC cell biology》2012,13(1):1-18
Background
A cholesterol-palmitoyl interaction has been reported to occur in the dimeric interface of the ??2-adrenergic receptor crystal structure. We sought to investigate whether a similar phenomenon could be observed with ??-opioid receptor (OPRM1), and if so, to assess the role of cholesterol in this class of G protein-coupled receptor (GPCR) signaling.Results
C3.55(170) was determined to be the palmitoylation site of OPRM1. Mutation of this Cys to Ala did not affect the binding of agonists, but attenuated receptor signaling and decreased cholesterol associated with the receptor signaling complex. In addition, both attenuation of receptor palmitoylation (by mutation of C3.55[170] to Ala) and inhibition of cholesterol synthesis (by treating the cells with simvastatin, a HMG-CoA reductase inhibitor) impaired receptor signaling, possibly by decreasing receptor homodimerization and G??i2 coupling; this was demonstrated by co-immunoprecipitation, immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) analyses. A computational model of the OPRM1 homodimer structure indicated that a specific cholesterol-palmitoyl interaction can facilitate OPRM1 homodimerization at the TMH4-TMH4 interface.Conclusions
We demonstrate that C3.55(170) is the palmitoylation site of OPRM1 and identify a cholesterol-palmitoyl interaction in the OPRM1 complex. Our findings suggest that this interaction contributes to OPRM1 signaling by facilitating receptor homodimerization and G protein coupling. This conclusion is supported by computational modeling of the OPRM1 homodimer. 相似文献110.
Males in many taxa are known to exhibit behavioural plasticity in response to the perceived intensity of sperm competition, reflected in Drosophila melanogaster by increased copulation duration following prior exposure to a rival. We tested the prediction that males do not adjust their copulation effort in response to the presence of a competitor in Drosophila species where there is little or no sperm competition. Contrary to expectations, male plasticity in copulation duration was found in both Drosophila subobscura and Drosophila acanthoptera, species in which females rarely remate. These results are discussed in relation to the adaptive basis of plasticity in these species. 相似文献