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71.
Mycobacterium tuberculosis, along with other actinobacteria, harbours proteasomes in addition to members of the general bacterial repertoire of degradation complexes. In analogy to ubiquitination in eukaryotes, substrates are tagged for proteasomal degradation with prokaryotic ubiquitin‐like protein (Pup) that is recognized by the N‐terminal coiled‐coil domain of the ATPase Mpa (also called ARC). Here, we reconstitute the entire mycobacterial proteasome degradation system for pupylated substrates and establish its mechanistic features with respect to substrate recruitment, unfolding and degradation. We show that the Mpa–proteasome complex unfolds and degrades Pup‐tagged proteins and that this activity requires physical interaction of the ATPase with the proteasome. Furthermore, we establish the N‐terminal region of Pup as the structural element required for engagement of pupylated substrates into the Mpa pore. In this process, Mpa pulls on Pup to initiate unfolding of substrate proteins and to drag them toward the proteasome chamber. Unlike the eukaryotic ubiquitin, Pup is not recycled but degraded with the substrate. This assigns a dual function to Pup as both the Mpa recognition element as well as the threading determinant. 相似文献
72.
Verdorfer I Neubauer S Letzel S Angerer J Arutyunyan R Martus P Wucherer M Gebhart E 《Mutation research》2001,491(1-2):97-109
The suitability of a three-color fluorescence in situ suppression hybridization technique was examined for monitoring five different groups of individuals: 30 occupied in radiology, 26 occupied in nuclear medicine or radiation physics, 32 patients with breast cancer, 26 occupied with military waste disposal, all presumably exposed to low doses of radiation or chemical mutagens and a non-exposed control group (N=29). The average frequency of breaks constituting the various aberrations did not significantly differ between the groups of medical radiation appliers and the control group. However, breast tumor patients and military waste disposers, as groups, showed a higher aberration rate than did healthy controls. Stable rearrangements mainly characterized the groups of controls, tumor patients, and radiation appliers, while a higher proportion of unstable aberrations was found in the chemically exposed individuals. Individuals with an increased frequency of aberrations could be detected within each examined group, which clearly determined the average values of the whole group. With respect to interchromosomal distribution of the breakpoints constituting the found aberrations and the involvement of the labeled chromosomes in rearrangements, the observed values were very close to the expected ones in the controls. A rather similar trend of deviations from expectation was observed in all other groups. Chromosome 4 was slightly over-affected, while chromosome 2 was slightly underrepresented in all analyzed groups (except tumor patients). Rearrangements of the labeled chromosomes with the unlabeled ones exceeded expectation. In conclusion, chromosome painting if included in further attempts of human population monitoring will broaden the basis of argumentation with respect to health risks introduced by mutagen exposure. 相似文献
73.
Angerer WP 《Mutation research》2001,479(1-2):207-224
Fluctuation analysis has emerged as a valuable tool for the measurement of mutation rates in single-cell populations. In this paper, we show how to make fuller use of the information supplied by the outcome of a fluctuation experiment. We shall extend Lea and Coulson's theory of the Luria-Delbrück distribution so that it accounts for residual mutation, reduced plating efficiency of mutants, and phenotypic lag, and establish a unifying method for the evaluation of fluctuation experiments in these cases and discuss its limitations. It will be proved that not all factors that might influence the distribution of mutant colonies in a fluctuation experiment can, in effect, be determined simultaneously. Nevertheless, it will be shown that the fluctuation-analytic approach to the measurement of mutation rates may retain its value in comparison with (or may even be superior to) alternative methods. Finally, we give some numerical examples to illustrate our results. 相似文献
74.
Introns are generally believed to evolve too rapidly and too erratically to be of much use in phylogenetic reconstructions.
Few phylogenetically informative intron sequences are available, however, to ascertain the validity of this supposition. In
the present study the supposition was tested on the example of the mammalian class II major histocompatibility complex (Mhc) genes of the DRB family. Since the Mhc genes evolve under balancing selection and are believed to recombine or rearrange frequently, the evolution of their introns
could be expected to be particularly rapid and subject to scrambling. Sequences of intron 4 and 5 DRB genes were obtained from polymerase chain reaction-amplified fragments of genomic DNA from representatives of six eutherian
orders—Primates, Scandentia, Chiroptera, Dermoptera, Lagomorpha, and Insectivora. Although short stretches of the introns
have indeed proved to be unalignable, the bulk of the intron sequences from all six orders, spanning >85 million years (my)
of evolution, could be aligned and used in a study of the tempo and mode of intron evolution. The analysis has revealed the
Mhc introns to evolve at a rate similar to that of other genes and of synonymous sites of non-Mhc genes. No evidence of homogenization or large-scale scrambling of the intron sequences could be found. The Mhc introns apparently evolve largely by point mutations and insertions/deletions. The phylogenetic signals contained in the
intron sequences could be used to identify Scandentia as the sister group of Primates, to support the existence of the Archonta
superorder, and to confirm the monophyly of the Chiroptera.
Received: 26 October 1998 / Accepted: 21 December 1998 相似文献
75.
Nishinakamura R Matsumoto Y Matsuda T Ariizumi T Heike T Asashima M Yokota T 《Developmental biology》1999,216(2):481-490
Stat3 is one of the main signaling components of cytokine receptors, including gp130. Here we show that activation of cytokine receptor gp130 resulted in a dramatic ventralization of Xenopus embryos and that the ventralization correlated well with Stat3 activation potential of the receptor. This finding led to identification of Xenopus Stat3 (Xstat3), which showed a 95% homology to its murine and human counterparts, at the amino acid level, and was expressed from the one-cell stage throughout development. The mechanism of gp130/XStat3-mediated ventralization proved to be independent of BMP-4. gp130/Xstat3 stimulation inhibited Smad2-induced ectopic axis formation in embryos and Smad2-dependent luciferase activity. A dominant-negative Stat3, in contrast, dorsalized Xenopus embryos, resulting in ectopic axis formation. We propose that Stat3-mediated signaling has the capacity to modify dorsoventral patterning in the early development of Xenopus. 相似文献
76.
Bauer Paul J.; Schauf Heike; Schwarzer Andreas; Brown Joel E. 《American journal of physiology. Cell physiology》1999,276(3):C558
Na+/Ca2+exchange has been investigated in squid(Loligopealei) rhabdomeric membranes.Ca2+-containing vesicles have beenprepared from purified rhabdomeric membranes by extrusion throughpolycarbonate filters of 1-µm pore size. After removal of externalCa2+, up to 90% of the entrappedCa2+ could be specificallyreleased by the addition of Na+;this finding indicates that most of the vesicles containedNa+/Ca2+exchanger. The Na+-inducedCa2+ efflux had a half-maximumvalue (K1/2) of~44 mM and a Hill coefficient of ~1.7. The maximalNa+-inducedCa2+ efflux was ~0.6 nmolCa2+ · s1 · mgprotein1. SimilarNa+-inducedCa2+ effluxes were measured ifK+ was replaced withLi+ orCs+. Vesicles loaded withCa2+ byNa+/Ca2+exchange also released this Ca2+byNa+/Ca2+exchange, suggesting thatNa+/Ca2+exchange operated in both forward and reverse modes. Limited proteolysis by trypsin resulted in a rate ofCa2+ efflux enhanced byapproximately fivefold when efflux was activated with 95 mM NaCl. For vesicles subjected to limited proteolysis by trypsin,Na+/Ca2+exchange was characterized by aK1/2 of ~25 mMand a Hill coefficient of 1.6. For these vesicles, the maximalNa+-inducedCa2+ efflux was about twice asgreat as in control vesicles. We conclude thatNa+/Ca2+exchange proteins localized in rhabdomeric membranes mediate Ca2+ extrusion in squid photoreceptors. 相似文献
77.
78.
79.
Cottrell SE Distler J Goodman NS Mooney SH Kluth A Olek A Schwope I Tetzner R Ziebarth H Berlin K 《Nucleic acids research》2004,32(1):e10
DNA methylation-based biomarkers have been discovered that could potentially be used for the diagnosis of cancer by detection of circulating, tumor-derived DNA in bodily fluids. Any methylation detection assay that would be applied to these samples must be capable of detecting small amounts of tumor DNA in the presence of background normal DNA. We have developed a real-time PCR assay, called HeavyMethyl, that is well suited for this application. HeavyMethyl uses methylation-specific oligonucleotide blockers and a methylation-specific probe to achieve methylation-specific amplification and detection. We tested the assays on unmethylated and artificially methylated DNA in order to determine the limit of detection. After careful optimization, our glutathione-S-transferase pi1 and Calcitonin assays can amplify as little as 30 and 60 pg of methylated DNA, respectively, and neither assay amplifies unmethylated DNA. The Calcitonin assay showed a highly significant methylation difference between normal colon and colon adenocarcinomas, and methylation was also detected in serum DNA from colon cancer patients. These assays show that HeavyMethyl technology can be successfully employed for the analysis of very low concentrations of methylated DNA, e.g. in serum of patients with tumors. 相似文献
80.