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51.
The amino-terminal region of the membrane-anchored subunit of influenza virus hemagglutinin, the fusion peptide, is crucial for membrane fusion of this virus. The peptide is extruded from the interior of the protein and inserted into the lipid bilayer of the target membrane upon induction of a conformational change in the protein by low pH. Although the effects of several mutations in this region on the fusion behavior and the biophysical properties of the corresponding peptides have been studied, the structural requirements for an active fusion peptide have still not been defined. To probe the sensitivity of the fusion peptide structure and function to small hydrophobic perturbations in the middle of the hydrophobic region, we have individually replaced the alanine residues in positions 5 and 7 with smaller (glycine) or bulkier (valine) hydrophobic residues and measured the extent of fusion mediated by these hemagglutinin constructs as well as some biophysical properties of the corresponding synthetic peptides in lipid bilayers. We find that position 5 tolerates a smaller and position 7 a larger hydrophobic side chain. All peptides contained segments of alpha-helical (33-45%) and beta-strand (13-16%) conformation as determined by CD and ATR-FTIR spectroscopy. The order parameters of the peptide helices and the lipid hydrocarbon chains were determined from measurements of the dichroism of the respective infrared absorption bands. Order parameters in the range of 0.0-0.6 were found for the helices of these peptides, which indicate that these peptides are most likely aligned with their alpha-helices at oblique angles to the membrane normal. Some (mostly fusogenic) peptides induced significant increases of the order parameter of the lipid hydrocarbon chains, suggesting that the lipid bilayer becomes more ordered in the presence of these peptides, possibly as a result of dehydration at the membrane surface. 相似文献
52.
W Fiers S Neirynck T Deroo X Saelens W M Jou 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2001,356(1416):1961-1963
Soluble, recombinant forms of influenza A virus haemagglutinin and neuraminidase have been produced in cells of lower eukaryotes, and shown in a mouse model to induce complete protective immunity against a lethal virus challenge. Soluble neuraminidase, produced in a baculovirus system, consisted of tetramers, dimers and monomers. Only the tetramers were enzymatically active. The immunogenicity decreased very considerably in the order tetra > di > mono. Therefore, we fused the head part of the neuraminidase gene to a tetramerizing leucine zipper sequence; the resulting product was enzymatically active, tetrameric neuraminidase. The protective immunity induced by this engineered neuraminidase, however, remained fairly strain-specific. A third influenza A virus protein, the M2 protein, has only 23 amino acids exposed on the outer membrane surface. This extracellular part, M2e, has been remarkably conserved in all human influenza A strains since 1933. By fusing the M2e sequence to hepatitis B virus core protein, we could obtain highly immunogenic particles that induced complete, strain-independent, long-lasting protection in mice against a lethal viral challenge. Native M2 is a tetrameric protein and this conformation of the M2e part can also be mimicked by fusing this sequence to a tetramerizing leucine zipper. The potential of the resulting protein as a vaccine candidate remains to be evaluated. 相似文献
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K. Isensee M. Amon A. Galaparti X. Ligneau J.-C. Camelin M. Capet J.-C. Schwartz H. Stark 《Bioorganic & medicinal chemistry letters》2009,19(8):2172-2175
Fluorine substituents have become a widespread and important component in drug design and development. Here, the synthesis of fluorine containing compounds and some corresponding precursor molecules are presented for potential isotope labelling as well as their data obtained with in vitro and in vivo screenings. The compounds vary in the basic centres (piperidine or pyrrolidine) and are fluoro substituted in different positions of the basic alicyclic moiety. Pharmacological evaluation resulted in ligands with high affinities at hH3 receptor in the nanomolar and subnanomolar concentration range and some with high antagonist in vivo potencies. 相似文献
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Wanwisa Dejnirattisai Daming Zhou Helen M. Ginn Helen M.E. Duyvesteyn Piyada Supasa James Brett Case Yuguang Zhao Thomas S. Walter Alexander J. Mentzer Chang Liu Beibei Wang Guido C. Paesen Jose Slon-Campos César López-Camacho Natasha M. Kafai Adam L. Bailey Rita E. Chen Baoling Ying Gavin R. Screaton 《Cell》2021,184(8):2183-2200.e22
60.
Man Lung Yeung Jade Lee Lee Teng Lilong Jia Chaoyu Zhang Chengxi Huang Jian-Piao Cai Runhong Zhou Kwok-Hung Chan Hanjun Zhao Lin Zhu Kam-Leung Siu Sin-Yee Fung Susan Yung Tak Mao Chan Kelvin Kai-Wang To Jasper Fuk-Woo Chan Zongwei Cai Susanna Kar Pui Lau Kwok-Yung Yuen 《Cell》2021,184(8):2212-2228.e12