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61.
Impaired intervertebral disc formation in the absence of Jun 总被引:11,自引:0,他引:11
Behrens A Haigh J Mechta-Grigoriou F Nagy A Yaniv M Wagner EF 《Development (Cambridge, England)》2003,130(1):103-109
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Alexey E. Lyashkov Joachim Behar Edward G. Lakatta Yael Yaniv Victor A. Maltsev 《Biophysical journal》2018,114(5):1176-1189
Recent data suggest that cardiac pacemaker cell function is determined by numerous time-, voltage-, and Ca-dependent interactions of cell membrane electrogenic proteins (M-clock) and intracellular Ca cycling proteins (Ca-clock), forming a coupled-clock system. Many aspects of the coupled-clock system, however, remain underexplored. The key players of the system are Ca release channels (ryanodine receptors), generating local Ca releases (LCRs) from sarcoplasmic reticulum, electrogenic Na/Ca exchanger (NCX) current, and L-type Ca current (ICaL). We combined numerical model simulations with experimental simultaneous recordings of action potentials (APs) and Ca to gain further insight into the complex interactions within the system. Our simulations revealed a positive feedback mechanism, dubbed AP ignition, which accelerates the diastolic depolarization (DD) to reach AP threshold. The ignition phase begins when LCRs begin to occur and the magnitude of inward NCX current begins to increase. The NCX current, together with funny current and T-type Ca current accelerates DD, bringing the membrane potential to ICaL activation threshold. During the ignition phase, ICaL-mediated Ca influx generates more LCRs via Ca-induced Ca release that further activates inward NCX current, creating a positive feedback. Simultaneous recordings of membrane potential and confocal Ca images support the model prediction of the positive feedback among LCRs and ICaL, as diastolic LCRs begin to occur below and continue within the voltage range of ICaL activation. The ignition phase onset (identified within the fine DD structure) begins when DD starts to notably accelerate (~0.15 V/s) above the recording noise. Moreover, the timing of the ignition onset closely predicted the duration of each AP cycle in the basal state, in the presence of autonomic receptor stimulation, and in response to specific inhibition of either the M-clock or Ca-clock, thus indicating general importance of the new coupling mechanism for regulation of the pacemaker cell cycle duration, and ultimately the heart rate. 相似文献
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Benjamin Kupfer Koushik Majhi David A. Keller Yaniv Bouhadana Sven Rühle Hannah Noa Barad Assaf Y. Anderson Arie Zaban 《Liver Transplantation》2015,5(1)
Co3O4 is investigated as a light absorber for all‐oxide thin‐film photovoltaic cells because of its nearly ideal optical bandgap of around 1.5 eV. Thin film TiO2/Co3O4 heterojunctions are produced by spray pyrolysis of TiO2 as a window layer, followed by pulsed laser deposition of Co3O4 as a light absorbing layer. The photovoltaic performance is investigated as a function of the Co3O4 deposition temperature and a direct correlation is found. The deposition temperature seems to affect both the crystallinity and the morphology of the absorber, which affects device performance. A maximum power of 22.7 μW cm?2 is obtained at the highest deposition temperature (600 °C) with an open circuit photovoltage of 430 mV and a short circuit photocurrent density of 0.2 mA cm?2. Performing deposition at 600 °C instead of room temperature improves power by an order of magnitude and reduces the tail states (Urbach edge energy). These phenomena can be explained by larger grains that grows at high temperature, as opposed to many nucleation events that occur at lower temperature. 相似文献
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DNA double-strand breaks (DSBs) and other lesions occur frequently during cell growth and in meiosis. These are often repaired by homologous recombination (HR). HR may result in the formation of DNA structures called Holliday junctions (HJs), which need to be resolved to allow chromosome segregation. Whereas HJs are present in most HR events in meiosis, it has been proposed that in vegetative cells most HR events occur through intermediates lacking HJs. A recent screen in yeast has shown HJ resolution activity for a protein called Yen1, in addition to the previously known Mus81/Mms4 complex. Yeast strains deleted for both YEN1 and MMS4 show a reduction in growth rate, and are very sensitive to DNA-damaging agents. In addition, we investigate the genetic interaction of yen1 and mms4 with mutants defective in different repair pathways. We find that in the absence of Yen1 and Mms4 deletion of RAD1 or RAD52 have no further effect, whereas additional sensitivity is seen if RAD51 is deleted. Finally, we show that yeast cells are unable to carry out meiosis in the absence of both resolvases. Our results show that both Yen1 and Mms4/Mus81 play important (although not identical) roles during vegetative growth and in meiosis. 相似文献
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Next-generation sequencing is limited to short read lengths and by high error rates. We systematically analyzed sources of noise in the Illumina Genome Analyzer that contribute to these high error rates and developed a base caller, Alta-Cyclic, that uses machine learning to compensate for noise factors. Alta-Cyclic substantially improved the number of accurate reads for sequencing runs up to 78 bases and reduced systematic biases, facilitating confident identification of sequence variants. 相似文献
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The Functional Transfer of Genes From the Mitochondria to the Nucleus: The Effects of Selection,Mutation, Population Size and Rate of Self-Fertilization 下载免费PDF全文
The transfer of mitochondrial genes to the nucleus is a recurrent and consistent feature of eukaryotic genome evolution. Although many theories have been proposed to explain such transfers, little relevant data exist. The observation that clonal and self-fertilizing plants transfer more mitochondrial genes to their nuclei than do outcrossing plants contradicts predictions of major theories based on nuclear recombination and leaves a gap in our conceptual understanding how the observed pattern of gene transfer could arise. Here, with a series of deterministic and stochastic simulations, we show how epistatic selection and relative mutation rates of mitochondrial and nuclear genes influence mitochondrial-to-nuclear gene transfer. Specifically, we show that when there is a benefit to having a mitochondrial gene present in the nucleus, but absent in the mitochondria, self-fertilization dramatically increases both the rate and the probability of gene transfer. However, absent such a benefit, when mitochondrial mutation rates exceed those of the nucleus, self-fertilization decreases the rate and probability of transfer. This latter effect, however, is much weaker than the former. Our results are relevant to understanding the probabilities of fixation when loci in different genomes interact.GENOMIC investigations of obligate intracellular endosymbionts (Moran and Wernegreen 2000; Akman et al. 2002; Tamas et al. 2002; Wernegreen et al. 2002; Klasson and Andersson 2004; Foster et al. 2005) reveal a reduction in genome size and number of protein-coding genes compared to their free-living relatives (Charles et al. 1999; Gil et al. 2002; Wernegreen et al. 2002; Moran 2003; Van Ham et al. 2003; Klasson and Andersson 2004; Khachane et al. 2007). Similarly, mitochondria—ancient obligate intracellular symbionts of eukaryotes—have retained very few protein-coding genes (Boore 1999; Adams et al. 2002) [Reclinomonas americanas is at the extreme of retention of mitochondrial genes (Lang et al. 1997)]. Understanding the process of gene loss in mitochondria and other endosymbionts is a major research focus of mitochondrial and endosymbiont genomics (Moran 2003; Timmis et al. 2004; Khachane et al. 2007; Bock and Timmis 2008).The loss of endosymbiont genes can be complete, in which lost genes are absent from the host–endosymbiont complex, a substitution, in which a nuclear allele functions in place of the lost symbiont gene, or a functional transfer of an endosymbiont gene to the nucleus, followed by its loss (Adams and Palmer 2003). Such “functional transfer” involves the relocation of a mitochondrial gene to the nucleus, its acquisition of a promoter, successful targeting to the mitochondria for proper function, and the eventual loss of the gene from the mitochondrial genome altogether. Although this process is probably quite complex and requires numerous evolutionary modifications (Murcha et al. 2005), there is evidence that some mitochondrial genes are preadapted to functional transfer as they contain signals that target them to the mitochondria before functional transfer to the nucleus (Ueda et al. 2008a). The complex evolution of rps16 is an illuminating case of both functional gene transfer and substitution. In some lineages, the mitochondrial rps16 is functionally expressed in the nucleus but absent from the mitochondria (functional transfer) while in a subset of taxa, the chloroplast copy is also absent and the nuclear gene is also targeted to the chloroplast [substitution (Ueda et al. 2008b)].A number of evolutionary scenarios have been proposed to account for the massive loss of genes from endosymbionts. A subset of models argues that endosymbiont gene loss is a neutral or nearly neutral process. Since endosymbiosis reduces the strength of selection on genes that are unnecessary or redundant in an obligate intracellular environment, these genes may be quickly lost by the neutral fixation of a deletion or other loss-of-function mutations. Moreover, even when selection favors the retention of genes in endosymbionts, such selection may be ineffective because of reduction in effective population size due to recurrent bottlenecking (Rispe and Moran 2000). Additionally, frequent input of functional endosymbiont genes into the nucleus makes symbiont genes redundant, exacerbating gene loss via functional transfer (Berg and Kurland 2000).An alternative class of explanations views the loss of mitochondrial genes (be it complete loss, substitution, or functional transfer) as an adaptive process. The “mitochondrial competition theory” argues that mitochondrial genomes that either do not contain or do not express a given allele have a replicative advantage over other mitochondria, providing a within-host selective advantage to mitochondrial gene loss (Albert et al. 1996; Selosse et al. 2001; Yamauchi 2005). The “benefits of sex” model posits that the genomic diploid nuclear environment (diploid, sexual) is in some way preferable (e.g., as an escape from Muller''s ratchet or Hill–Robertson interference) to a haploid asexual mitochondrial environment (Blanchard and Lynch 2000). The epistatic model (Wade and Goodnight 2006) does not advance a specific or consistent benefit to transfer, but posits that transfer is explicitly a process of coevolution between mitochondrial and nuclear genomes, where fitness is a function of the gene combination rather than of either gene separately.Because few species are currently undergoing mitochondrial to nuclear gene transfer, these alternative hypotheses are difficult to distinguish with direct experimentation. However, the distribution of transferred genes across lineages allows for evaluation of the alternative hypotheses. For example, self-pollination reduces the rate of heteroplasmy and consequently the opportunity for competition among genetically distinct mitochondria. Thus, the mitochondrial competition theory predicts an excess of transfer events in sexual, outcrossing lineages, with high degrees of “paternal leakage.” Similarly, frequent self-fertilization diminishes the benefits of sex, and thus the benefits of sex hypothesis predicts fewer transfers in selfing and clonally reproducing plants than in outcrossing taxa. The epistatic model makes the opposite prediction. Selfing and clonal reproduction maintain cyto-nuclear gene combinations and increase the response to selection on epistatic combinations, potentially encouraging transfer. On the other hand, outcrossing tends to break apart adaptive cyto-nuclear gene combinations, potentially decreasing the amount of adaptive transfer in outcrossing lineages.Plant lineages with high levels of self-fertilization or asexual reproduction transfer more mitochondrial genes to their nuclei than predominantly sexual and outcrossing lineages (Brandvain et al. 2007). This result is consistent with predictions of the epistatic model and is contrary to predictions of the mitochondrial competition or benefits of sex models. More specific predictions allowing further empirical tests require more detailed theoretical investigations of the gene transfer process. Here, we investigate the roles of mutation, selection, and random drift in gene transfer using both deterministic models and stochastic simulations to refine and extend predictions of patterns of functional mitochondrial to nuclear gene transfer. 相似文献