全文获取类型
收费全文 | 567篇 |
免费 | 27篇 |
出版年
2024年 | 2篇 |
2023年 | 8篇 |
2022年 | 9篇 |
2021年 | 23篇 |
2020年 | 5篇 |
2019年 | 4篇 |
2018年 | 7篇 |
2017年 | 12篇 |
2016年 | 13篇 |
2015年 | 36篇 |
2014年 | 37篇 |
2013年 | 44篇 |
2012年 | 56篇 |
2011年 | 50篇 |
2010年 | 40篇 |
2009年 | 26篇 |
2008年 | 32篇 |
2007年 | 35篇 |
2006年 | 27篇 |
2005年 | 27篇 |
2004年 | 22篇 |
2003年 | 18篇 |
2002年 | 25篇 |
2001年 | 6篇 |
2000年 | 1篇 |
1999年 | 1篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1995年 | 3篇 |
1993年 | 3篇 |
1992年 | 4篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1982年 | 2篇 |
1962年 | 1篇 |
排序方式: 共有594条查询结果,搜索用时 31 毫秒
61.
In order for mutualism to evolve, some force must align the interests of the two interacting partners. Vertical transmission can fill this role, but it is still unknown whether mutualism can be stable when vertically transmitted symbionts can evolve toward horizontal transmission. In this article, we investigate how symbionts' transmission mode and virulence should evolve, depending on the relationship between these two traits. We show that pathogens that reduce their host's fecundity can have more complex evolutionary dynamics than those that increase mortality. In some cases, runaway evolution of virulence can drive the host population extinct. In most cases, evolutionary branching results in the differentiation of avirulent, vertically transmitted symbionts from virulent, contagious pathogens. The population of symbionts then becomes polymorphic, and because the least virulent symbionts are the most frequent, the average virulence of symbionts is much lower than it would be in a monomorphic population. When the link between transmission and virulence results from correlated mutational changes and not from fixed constraints, vertically transmitted symbionts do not simply lose virulence; they evolve toward mutualism. We show that the force that stabilizes mutualism in such situations is the competition for transmission between symbionts. 相似文献
62.
Studies have shown that mammalian cytochromes p450 participate in the metabolism of terpenes, yet their role in the biotransformation of farnesol, an endogenous 15-carbon isoprenol, is unknown. In this report, [(14)C]-farnesol was transformed to more polar metabolites by NADPH-supplemented mammalian microsomes. In experiments with microsomes isolated from acetone-treated animals, the production of one polar metabolite was induced, suggesting catalysis by CYP2E1. The metabolite was identified as (2E, 6E, 10E)-12-hydroxyfarnesol. In studies with purified CYP2E1, 12-hydroxyfarnesol was obtained as the major product of farnesol metabolism. Among a series of available human p450 enzymes, only CYP2C19 also produced 12-hydroxyfarnesol. However, in individual human microsomes, CYP2E1 was calculated to contribute up to 62% toward total 12-hydroxyfarnesol production, suggesting CYP2E1 as the major catalyst. Mammalian cells expressing CYP2E1 demonstrated further farnesol metabolism to alpha,omega-prenyl dicarboxylic acids. Since such acids were identified in animal urine, the data suggest that CYP2E1 could be an important regulator of farnesol homeostasis in vivo. In addition, CYP2E1-dependent 12-hydroxyfarnesol formation was inhibited by pharmacological alcohol levels. Given that farnesol is a signaling molecule implicated in the regulation of tissue and cell processes, the biological activity of ethanol may be mediated in part by interaction with CYP2E1-dependent farnesol metabolism. 相似文献
63.
Autoinhibition of the platelet-derived growth factor beta-receptor tyrosine kinase by its C-terminal tail 总被引:2,自引:0,他引:2
Chiara F Bishayee S Heldin CH Demoulin JB 《The Journal of biological chemistry》2004,279(19):19732-19738
In this report, we investigated the role of the C-terminal tail of the platelet-derived growth factor (PDGF) beta-receptor in the control of the receptor kinase activity. Using a panel of PDGF beta-receptor mutants with progressive C-terminal truncations, we observed that deletion of the last 46 residues, which contain a proline- and glutamic acid-rich motif, increased the autoactivation velocity in vitro and the V(max) of the phosphotransfer reaction, in the absence of ligand, as compared with wild-type receptors. By contrast, the kinase activity of mutant and wild-type receptors that were pre-activated by treatment with PDGF was comparable. Using a conformation-sensitive antibody, we found that truncated receptors presented an active conformation even in the absence of PDGF. A soluble peptide containing the Pro/Glu-rich motif specifically inhibited the PDGF beta-receptor kinase activity. Whereas deletion of this motif was not enough to confer ligand-independent transforming ability to the receptor, it dramatically enhanced the effect of the weakly activating D850N mutation in a focus formation assay. These findings indicate that allosteric inhibition of the PDGF beta-receptor by its C-terminal tail is one of the mechanisms involved in keeping the receptor inactive in the absence of ligand. 相似文献
64.
65.
A short peptide at the amino terminus of the Sendai virus C protein acts as an independent element that induces STAT1 instability
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The Sendai virus C protein acts to dismantle the interferon-induced cellular antiviral state in an MG132-sensitive manner, in part by inducing STAT1 instability. This activity of C maps to the first 23 amino acids (C(1-23)) of the 204-amino-acid (aa)-long protein (C(1-204)). C(1-23) was found to act as an independent viral element that induces STAT1 instability, since this peptide fused to green fluorescent protein (C(1-23)/GFP) is at least as active as C(1-204) in this respect. This peptide also induces the degradation of C(1-23)/GFP and other proteins to which it is fused. Most of C(1-204), and particularly its amino-terminal half, is predicted to be structurally disordered. C(1-23) as a peptide was found to be disordered by circular dichroism, and the first 11 aa have a strong potential to form an amphipathic alpha-helix in low concentrations of trifluoroethanol, which is thought to mimic protein-protein interaction. The critical degradation-determining sequence of C(1-23) was mapped by mutation to eight residues near its N terminus: (4)FLKKILKL(11). All the large hydrophobic residues of (4)FLKKILKL(11), plus its ability to form an amphipathic alpha-helix, were found to be critical for STAT1 degradation. In contrast, C(1-23)/GFP self-degradation did not require (8)ILKL(11), nor the ability to form an alpha-helix throughout this region. Remarkably, C(1-23)/GFP also stimulated C(1-204) degradation, and this degradation in trans required the same peptide determinants as for STAT1. Our results suggest that C(1-204) coordinates its dual activities of regulating viral RNA synthesis and counteracting the host innate antiviral response by sensing both its own intracellular concentration and that of STAT1. 相似文献
66.
We describe two roles for the Rad50 protein in telomere maintenance and the protection of chromosome ends. Using fluorescence in situ hybridisation (FISH) and fibre-FISH analyses, we show that absence of AtRad50 protein leads to rapid shortening of a subpopulation of chromosome ends and subsequently chromosome-end fusions lacking telomeric repeats. In the absence of telomerase, mutation of atrad50 has a synergistic effect on the number of chromosome end fusions. Surprisingly, this 'deprotection' of the shortened telomeres does not result in increased exonucleolytic degradation, but in a higher proportion of anaphase bridges containing telomeric repeats in atrad50/tert plants, compared to tert mutant plants. Absence of AtRad50 thus facilitates the action of recombination on these shortened telomeres. We propose that this protective role of Rad50 protein on shortened telomeres results from its action in constraining recombination to sister chromatids and thus avoiding end-to-end interactions. 相似文献
67.
Manival X Charron C Fourmann JB Godard F Charpentier B Branlant C 《Nucleic acids research》2006,34(3):826-839
In archaeal rRNAs, the isomerization of uridine into pseudouridine (Ψ) is achieved by the H/ACA sRNPs and the minimal set of proteins required for RNA:Ψ-synthase activity is the aCBF5–aNOP10 protein pair. The crystal structure of the aCBF5–aNOP10 heterodimer from Pyrococcus abyssi was solved at 2.1 Å resolution. In this structure, protein aNOP10 has an extended shape, with a zinc-binding motif at the N-terminus and an α-helix at the C-terminus. Both motifs contact the aCBF5 catalytic domain. Although less efficiently as does the full-length aNOP10, the aNOP10 C-terminal domain binds aCBF5 and stimulates the RNA-guided activity. We show that the C-terminal domain of aCBF5 (the PUA domain), which is wrapped by an N-terminal extension of aCBF5, plays a crucial role for aCBF5 binding to the guide sRNA. Addition of this domain in trans partially complement particles assembled with an aCBF5ΔPUA truncated protein. In the crystal structure, the aCBF5–aNOP10 complex forms two kinds of heterotetramers with parallel and perpendicular orientations of the aNOP10 terminal α-helices, respectively. By gel filtration assay, we showed that aNOP10 can dimerize in solution. As both residues Y41 and L48 were needed for dimerization, the dimerization likely takes place by interaction of parallel α-helices. 相似文献
68.
Adriana Villella Jean-Baptiste Peyre Toshiro Aigaki Jeffrey C. Hall 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2006,192(12):1253-1269
In context of the semi-sterility exhibited by Drosophila males expressing certain mating-enabling fruitless (fru) mutant genotypes, we examined the transfer of seminal fluid using a transgene that encodes the Sex Peptide (SP) oligopeptide
fused to Green Fluorescent Protein (GFP). We found that this fusion construct expresses SP-GFP in a valid manner within accessory
glands of the male reproductive system in normal and fru-mutant males. Transfer of SP-GFP to live females was readily detectable during and after copulation. With respect to the
pertinent combinations of fru mutations, we demonstrated that these abnormal genotypes cause males to transmit mating-related materials in two aberrant
ways: one involving whether any seminal-fluid entities are transferred at all during a given mating; the other revealing an
intriguing aspect of these fruitless effects, such that the mutations in question cause males to transfer female-affecting materials in a manner that varies among
copulations. In this regard, certain mutant males that do not transfer SP nevertheless are able to transfer sperm: a fru-mated female possessing no GFP who was not fecund initially could produce progeny when seminal-fluid proteins were subsequently
supplied by mating with a male that was spermless owing to the effects of a tudor mutation. 相似文献
69.
Manneville JB Etienne-Manneville S 《Biology of the cell / under the auspices of the European Cell Biology Organization》2006,98(9):557-565
Centrosome positioning is tightly controlled throughout the cell cycle and probably shares common regulatory mechanisms with spindle-pole positioning. In this article, we detail the possible mechanisms controlling centrosome and spindle positioning in various organisms both in interphase and mitotic cells, and discuss recent findings showing how microtubule plus-end-associated proteins interact with the cell cortex. We suggest that microtubule plus-end complexes simultaneously regulate microtubule dynamics and microtubule anchoring at the cell periphery to allow proper centrosome and spindle-pole positioning. 相似文献
70.
In this article, we model analytically the evolution of mutation rate in asexual organisms. Three selective forces are present. First, everything else being equal, individuals with higher mutation rate have a larger fitness, thanks to the energy and time saved by not replicating DNA accurately. Second, as a flip side, the genome of these individuals is replicated with errors that may negatively affect fitness. Third, and conversely, replication errors have a potential benefit if beneficial mutations are to be generated. Our model describes the fate of modifiers of mutation rate under the three forces and allows us to predict the long-term evolutionary trajectory of mutation rate. We obtain three major results. First, in asexuals, the needs for both adaptation and genome preservation are not evolutionary forces that can stabilize mutation rate at an intermediate optimum. When adaptation has a significant role, it primarily destabilizes mutation rate and yields the emergence of strong-effect mutators. Second, in contrast to what is usually believed, the appearance of modifiers with large mutation rate is more likely when the fitness cost of each deleterious mutation is weak, because the cost of replication errors is then paid after a delay. Third, in small populations, and even if adaptations are needed, mutation rate is always blocked at the minimum attainable level, because the rate of adaptation is too slow to play a significant role. Only populations whose size is above a critical mass see their mutation rate affected by the need for adaptation. 相似文献