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991.
Sébastien L. Degorce Rana Anjum Keith S. Dillman Lisa Drew Sam D. Groombridge Christopher T. Halsall Eva M. Lenz Nicola A. Lindsay Michele F. Mayo Jennifer H. Pink Graeme R. Robb James S. Scott Stephen Stokes Yafeng Xue 《Bioorganic & medicinal chemistry》2018,26(4):913-924
We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib. 相似文献
992.
Kitashova Anastasia Schneider Katja Fürtauer Lisa Schröder Laura Scheibenbogen Tim Fürtauer Siegfried Nägele Thomas 《Photosynthesis research》2021,147(1):49-60
Photosynthesis Research - Photosynthesis and carbohydrate metabolism of higher plants need to be tightly regulated to prevent tissue damage during environmental changes. The intracellular position... 相似文献
993.
994.
Lisa G. Pell Genevieve M.C. Gasmi-Seabrook Philipp Neudecker Voula Kanelis Diane Bona Aled M. Edwards Alan R. Davidson Karen L. Maxwell 《Journal of molecular biology》2010,403(3):468-479
Immunoglobulin (Ig)-like domains are found frequently on the surface of tailed double-stranded DNA bacteriophages, yet their functional role remains obscure. Here, we have investigated the structure and function of the C-terminal Ig-like domain of gpV (gpVC), the tail tube protein of phage λ. This domain has been predicted through sequence similarity to be a member of the bacterial Ig-like domain 2 (Big_2) family, which is composed of more than 1300 phage and bacterial sequences. Using trypsin proteolysis, we have delineated the boundaries of gpVC and have shown that its removal reduces the biological activity of gpV by 100-fold; thus providing a definitive demonstration of a functional role for this domain. Determination of the solution structure of gpVC by NMR spectroscopy showed that it adopts a canonical Ig-like fold of the I-set class. This represents the first structure of a phage-encoded Ig-like domain and only the second structure of a Big_2 domain. Structural and sequence comparisons indicate that the gpVC structure is more representative of both the phage-encoded Big_2 domains and Big_2 domains in general than the other available Big_2 structure. Bioinformatics analyses have identified two conserved clusters of residues on the surface of gpVC that may be important in mediating the function of this domain. 相似文献
995.
Pseudomonas aeruginosa phosphorylcholine phosphatase (PchP) catalyzes the hydrolysis of phosphorylcholine, which is produced by the action of hemolytic
phospholipase C on phosphatidylcholine or sphyngomielin, to generate choline and inorganic phosphate. Among divalent cations,
its activity is dependent on Mg2+ or Zn2+. Mg2+ produced identical activation at pH 5.0 and 7.4, but Zn2+ was an activator at pH 5.0 and became an inhibitor at pH 7.4. At this higher pH, very low concentrations of Zn2+ inhibited enzymatic activity even in the presence of saturating Mg2+ concentrations. Considering experimental and theoretical physicochemical calculations performed by different authors, we
conclude that at pH 5.0, Mg2+ and Zn2+ are hexacoordinated in an octahedral arrangement in the PchP active site. At pH 7.4, Mg2+ conserves the octahedral coordination maintaining enzymatic activity. The inhibition produced by Zn2+ at 7.4 is interpreted as a change from octahedral to tetrahedral coordination geometry which is produced by hydrolysis of
the
[ \textZn 2+ \textL 2 - 1 \textL 20 ( \textH 2 \textO ) 2 ] \left[ {{\text{Zn}}^{ 2+ } {\text{L}}_{ 2}^{ - 1} {\text{L}}_{ 2}^{0} \left( {{\text{H}}_{ 2} {\text{O}}} \right)_{ 2} } \right] complex. 相似文献
996.
Lisa C Willcocks Paul A Lyons Andrew J Rees Kenneth GC Smith 《Arthritis research & therapy》2010,12(1):202
The aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis has not been well defined. Here
we review two factors which may play a role in the pathogenesis of the disease: genetics and infection. In particular, we
discuss the role of autoantibodies to LAMP-2, which may arise following infection with Gram-negative bacteria, and may contribute
to the development of ANCA-associated systemic vasculitis in genetically susceptible individuals. 相似文献
997.
Sara?Cheek Yuan?Qi S?Sri?Krishna Lisa?N?Kinch Nick?V?GrishinEmail author 《BMC bioinformatics》2004,5(1):197
Background
Inference of remote homology between proteins is very challenging and remains a prerogative of an expert. Thus a significant drawback to the use of evolutionary-based protein structure classifications is the difficulty in assigning new proteins to unique positions in the classification scheme with automatic methods. To address this issue, we have developed an algorithm to map protein domains to an existing structural classification scheme and have applied it to the SCOP database. 相似文献998.
Groen AC Cameron LA Coughlin M Miyamoto DT Mitchison TJ Ohi R 《Current biology : CB》2004,14(20):1801-1811
BACKGROUND: The regulated assembly of microtubules is essential for bipolar spindle formation. Depending on cell type, microtubules nucleate through two different pathways: centrosome-driven or chromatin-driven. The chromatin-driven pathway dominates in cells lacking centrosomes. RESULTS: Human RHAMM (receptor for hyaluronic-acid-mediated motility) was originally implicated in hyaluronic-acid-induced motility but has since been shown to associate with centrosomes and play a role in astral spindle pole integrity in mitotic systems. We have identified the Xenopus ortholog of human RHAMM as a microtubule-associated protein that plays a role in focusing spindle poles and is essential for efficient microtubule nucleation during spindle assembly without centrosomes. XRHAMM associates both with gamma-TuRC, a complex required for microtubule nucleation and with TPX2, a protein required for microtubule nucleation and spindle pole organization. CONCLUSIONS: XRHAMM facilitates Ran-dependent, chromatin-driven nucleation in a process that may require coordinate activation of TPX2 and gamma-TuRC. 相似文献
999.
Dick GJ Podell S Johnson HA Rivera-Espinoza Y Bernier-Latmani R McCarthy JK Torpey JW Clement BG Gaasterland T Tebo BM 《Applied and environmental microbiology》2008,74(9):2646-2658
Microbial Mn(II) oxidation has important biogeochemical consequences in marine, freshwater, and terrestrial environments, but many aspects of the physiology and biochemistry of this process remain obscure. Here, we report genomic insights into Mn(II) oxidation by the marine alphaproteobacterium Aurantimonas sp. strain SI85-9A1, isolated from the oxic/anoxic interface of a stratified fjord. The SI85-9A1 genome harbors the genetic potential for metabolic versatility, with genes for organoheterotrophy, methylotrophy, oxidation of sulfur and carbon monoxide, the ability to grow over a wide range of O(2) concentrations (including microaerobic conditions), and the complete Calvin cycle for carbon fixation. Although no growth could be detected under autotrophic conditions with Mn(II) as the sole electron donor, cultures of SI85-9A1 grown on glycerol are dramatically stimulated by addition of Mn(II), suggesting an energetic benefit from Mn(II) oxidation. A putative Mn(II) oxidase is encoded by duplicated multicopper oxidase genes that have a complex evolutionary history including multiple gene duplication, loss, and ancient horizontal transfer events. The Mn(II) oxidase was most abundant in the extracellular fraction, where it cooccurs with a putative hemolysin-type Ca(2+)-binding peroxidase. Regulatory elements governing the cellular response to Fe and Mn concentration were identified, and 39 targets of these regulators were detected. The putative Mn(II) oxidase genes were not among the predicted targets, indicating that regulation of Mn(II) oxidation is controlled by other factors yet to be identified. Overall, our results provide novel insights into the physiology and biochemistry of Mn(II) oxidation and reveal a genome specialized for life at the oxic/anoxic interface. 相似文献
1000.
Terry D. Oberley Janice L. Schultz Larry W. Oberley 《Free radical biology & medicine》1994,16(6):741-751
Antioxidant enzyme (AE) activities were studied in normal hamster kidney proximal tubules and in estrogen-induced hamster kidney cancer. In vivo, kidney tumor had lower activities of manganese superoxide dismutase (MnSOD), copper, zinc superoxide dismutase, catalase, and glutathione peroxidase than kidney proximal tubules. Differences in AE activities were, in general, maintained in tissue culture, with AE activities remaining low in tumor cells compared to normal cells. Normal proximal tubular cells showed significant induction of MnSOD activity as a function of time in culture of following exposure to diethylstilbestrol, a synthetic estrogen, while MnSOD activity remained low in tumor cells under these conditions. Our results suggest that antioxidant enzymes, particularly MnSOD, are regulated differently in estrogen-induced hamster kidney tumor cells than in normal kidney proximal tubular cells, demonstrating that cancers arising from hormonal influence have similar AE profiles to those previously described in cancers arising from viral or chemical etiologies. 相似文献