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91.
92.
Normal and expanded Huntington's disease gene alleles produce distinguishable proteins due to translation across the CAG repeat. 总被引:7,自引:1,他引:6
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F. Persichetti C. M. Ambrose P. Ge S. M. McNeil J. Srinidhi M. A. Anderson B. Jenkins G. T. Barnes M. P. Duyao L. Kanaley et al. 《Molecular medicine (Cambridge, Mass.)》1995,1(4):374-383
BACKGROUND: An expanded CAG trinucleotide repeat is the genetic trigger of neuronal degeneration in Huntington's disease (HD), but its mode of action has yet to be discovered. The sequence of the HD gene places the CAG repeat near the 5' end in a region where it may be translated as a variable polyglutamine segment in the protein product, huntingtin. MATERIALS AND METHODS: Antisera directed at amino acid stretches predicted by the DNA sequence upstream and downstream of the CAG repeat were used in Western blot and immunohistochemical analyses to examine huntingtin expression from the normal and the HD allele in lymphoblastoid cells and postmortem brain tissue. RESULTS: CAG repeat segments of both normal and expanded HD alleles are indeed translated, as part of a discrete approximately 350-kD protein that is found primarily in the cytosol. The difference in the length of the N-terminal polyglutamine segment is sufficient to distinguish normal and HD huntingtin in a Western blot assay. CONCLUSIONS: The HD mutation does not eliminate expression of the HD gene but instead produces an altered protein with an expanded polyglutamine stretch near the N terminus. Thus, HD pathogenesis is probably triggered by an effect at the level of huntingtin protein. 相似文献
93.
Abnormal bone growth and selective translational regulation in basic fibroblast growth factor (FGF-2) transgenic mice. 总被引:15,自引:2,他引:13
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J D Coffin R Z Florkiewicz J Neumann T Mort-Hopkins G W Dorn nd P Lightfoot R German P N Howles A Kier B A O'Toole et al. 《Molecular biology of the cell》1995,6(12):1861-1873
Basic fibroblast growth factor (FGF-2) is a pleiotropic growth factor detected in many different cells and tissues. Normally synthesized at low levels, FGF-2 is elevated in various pathologies, most notably in cancer and injury repair. To investigate the effects of elevated FGF-2, the human full-length cDNA was expressed in transgenic mice under control of a phosphoglycerate kinase promoter. Overexpression of FGF-2 caused a variety of skeletal malformations including shortening and flattening of long bones and moderate macrocephaly. Comparison by Western blot of FGF-2 transgenic mice to nontransgenic littermates showed expression of human FGF-2 protein in all major organs and tissues examined including brain, heart, lung, liver, kidney, spleen, and skeletal muscle; however, different molar ratios of FGF-2 protein isoforms were observed between different organs and tissues. Some tissues preferentially synthesize larger isoforms of FGF-2 while other tissues produce predominantly smaller 18-kDa FGF-2. Translation of the high molecular weight isoforms initiates from unconventional CUG codons and translation of the 18-kDa isoform initiates from an AUG codon in the FGF-2 mRNA. Thus the Western blot data from the FGF-2 transgenic mice suggest that tissue-specific expression of FGF-2 isoforms is regulated translationally. 相似文献
94.
PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. 总被引:36,自引:6,他引:30
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![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
R Dhand I Hiles G Panayotou S Roche M J Fry I Gout N F Totty O Truong P Vicendo K Yonezawa et al. 《The EMBO journal》1994,13(3):522-533
Phosphatidylinositol 3-kinase (PI 3-kinase) has a regulatory 85 kDa adaptor subunit whose SH2 domains bind phosphotyrosine in specific recognition motifs, and a catalytic 110 kDa subunit. Mutagenesis of the p110 subunit, within a sequence motif common to both protein and lipid kinases, demonstrates a novel intrinsic protein kinase activity which phosphorylates the p85 subunit on serine at a stoichiometry of approximately 1 mol of phosphate per mol of p85. This protein-serine kinase activity is detectable only upon high affinity binding of the p110 subunit with its unique substrate, the p85 subunit. Tryptic phosphopeptide mapping revealed that the same major peptide was phosphorylated in p85 alpha both in vivo in cultured cells and in the purified recombinant enzyme. N-terminal sequence and mass analyses were used to identify Ser608 as the major phosphorylation site on p85 alpha. Phosphorylation of the p85 subunit at this serine causes an 80% decrease in PI 3-kinase activity, which can subsequently be reversed upon treatment with protein phosphatase 2A. These results have implications for the role of inter-subunit serine phosphorylation in the regulation of the PI 3-kinase in vivo. 相似文献
95.
Immortalization of multipotent growth-factor dependent hemopoietic progenitors from mice transgenic for GATA-1 driven SV40 tsA58 gene. 总被引:2,自引:0,他引:2
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L A Cairns S Crotta M Minuzzo E Moroni F Granucci S Nicolis R Schiró L Pozzi B Giglioni P Ricciardi-Castagnoli et al. 《The EMBO journal》1994,13(19):4577-4586
96.
Tyrosine phosphorylation of CD45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase. 总被引:11,自引:1,他引:10
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M Autero J Saharinen T Pessa-Morikawa M Soula-Rothhut C Oetken M Gassmann M Bergman K Alitalo P Burn C G Gahmberg et al. 《Molecular and cellular biology》1994,14(2):1308-1321
Src family protein tyrosine kinases (PTKs) play an essential role in antigen receptor-initiated lymphocyte activation. Their activity is largely regulated by a negative regulatory tyrosine which is a substrate for the activating action of the CD45 phosphotyrosine phosphatase (PTPase) or, conversely, the suppressing action of the cytosolic p50csk PTK. Here we report that CD45 was phosphorylated by p50csk on two tyrosine residues, one of them identified as Tyr-1193. This residue was not phosphorylated by T-cell PTKs p56lck and p59fyn. Tyr-1193 was phosphorylated in intact T cells, and phosphorylation increased upon treatment with PTPase inhibitors, indicating that this tyrosine is a target for a constitutively active PTK. Cotransfection of CD45 and csk into COS-1 cells caused tyrosine phosphorylation of CD45 in the intact cells. Tyrosine-phosphorylated CD45 bound p56lck through the SH2 domain of the kinase. Finally, p50csk-mediated phosphorylation of CD45 caused a severalfold increase in its PTPase activity. Our results show that direct tyrosine phosphorylation of CD45 can affect its activity and association with Src family PTKs and that this phosphorylation could be mediated by p50csk. If this is also true in the intact cells, it adds a new dimension to the physiological function of p50csk in T lymphocytes. 相似文献
97.
The rad16 gene of Schizosaccharomyces pombe: a homolog of the RAD1 gene of Saccharomyces cerevisiae. 总被引:6,自引:2,他引:4
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A M Carr H Schmidt S Kirchhoff W J Muriel K S Sheldrick D J Griffiths C N Basmacioglu S Subramani M Clegg A Nasim et al. 《Molecular and cellular biology》1994,14(3):2029-2040
The rad10, rad16, rad20, and swi9 mutants of the fission yeast Schizosaccharomyces pombe, isolated by their radiation sensitivity or abnormal mating-type switching, have been shown previously to be allelic. We have cloned DNA correcting the UV sensitivity or mating-type switching phenotype of these mutants and shown that the correcting DNA is encompassed in a single open reading frame. The gene, which we will refer to as rad16, is approximately 3 kb in length, contains seven introns, and encodes a protein of 892 amino acids. It is not essential for viability of S. pombe. The predicted protein is the homolog of the Saccharomyces cerevisiae RAD1 protein, which is involved in an early step in excision-repair of UV damage from DNA. The approximately 30% sequence identity between the predicted proteins from the two yeasts is distributed throughout the protein. Two-hybrid experiments indicate a strong protein-protein interaction between the products of the rad16 and swi10 genes of S. pombe, which mirrors that reported for RAD1 and RAD10 in S. cerevisiae. We have identified the mutations in the four alleles of rad16. They mapped to the N-terminal (rad10), central (rad20), and C-terminal (rad16 and swi9) regions. The rad10 and rad20 mutations are in the splice donor sequences of introns 2 and 4, respectively. The plasmid correcting the UV sensitivity of the rad20 mutation was missing the sequence corresponding to the 335 N-terminal amino acids of the predicted protein. Neither smaller nor larger truncations were, however, able to correct its UV sensitivity. 相似文献
98.
Effects of Methane Metabolism on Nitrification and Nitrous Oxide Production in Polluted Freshwater Sediment 总被引:4,自引:2,他引:2
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We report the effect of CH4 and of CH4 oxidation on nitrification in freshwater sediment from Hamilton Harbour, Ontario, Canada, a highly polluted ecosystem. Aerobic slurry experiments showed a high potential for aerobic N2O production in some sites. It was suppressed by C2H2, correlated to NO3- production, and stimulated by NH4+ concentration, supporting the hypothesis of a nitrification-dependent source for this N2O production. Diluted sediment slurries supplemented with CH4 (1 to 24 μM) showed earlier and enhanced nitrification and N2O production compared with unsupplemented slurries (≤1 μM CH4). This suggests that nitrification by methanotrophs may be significant in freshwater sediment under certain conditions. Suppression of nitrification was observed at CH4 concentrations of 84 μM and greater, possibly through competition for O2 between methanotrophs and NH4+ -oxidizing bacteria and/or competition for mineral N between these two groups of organisms. In Hamilton Harbour sediment, the very high CH4 concentrations (1.02 to 6.83 mM) which exist would probably suppress nitrification and favor NH4+ accumulation in the pore water. Indeed, NH4+ concentrations in Hamilton Harbour sediment are higher than those found in other lakes. We conclude that the impact of CH4 metabolism on N cycling processes in freshwater ecosystems should be given more attention. 相似文献
99.
100.