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Specific 3H-sulpiride binding to rat striatal membranes shows an absolute requirement for the presence of sodium ions in the incubation buffer. Potassium, rubidium and caesium ions were unable to initiate specific 3H-sulpiride binding in a sodium free buffer, and lithium ionscould only partially replace sodium ions. Specific 3H-spiperone binding was unaffected by variation of the cation content of the incubation buffer. The alteration in 3H-sulpiride binding caused by sodium and lithium ions was due predominantly to an increase in the number of available binding sites, rather than to altered receptor affinity. Sodium ions may be essential for the accessability of 3H-sulpiride to a single site labelled also by 3H-spiperone. However, the Ki value for sulpiride displacement of 3H-spiperone in the presence of sodium ions was 20 times greater than the KD value for 3H-sulpiride binding. So, 3H-sulpiride may interact with a highly sodium dependent binding site distinct from that labelled by 3H-spiperone. 相似文献
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Purification and characterization of phytochrome from oat seedlings 总被引:19,自引:0,他引:19
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Catalysis of the phytochrome dark reaction by reducing agents 总被引:6,自引:0,他引:6
75.
McCoull W Addie MS Birch AM Birtles S Buckett LK Butlin RJ Bowker SS Boyd S Chapman S Davies RD Donald CS Green CP Jenner C Kemmitt PD Leach AG Moody GC Gutierrez PM Newcombe NJ Nowak T Packer MJ Plowright AT Revill J Schofield P Sheldon C Stokes S Turnbull AV Wang SJ Whalley DP Wood JM 《Bioorganic & medicinal chemistry letters》2012,22(12):3873-3878
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship. 相似文献
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Maria Jose Cabello-Lobato Matthew Jenner Metztli Cisneros-Aguirre Kira Brüninghoff Zac Sandy Isabelle
C da
Costa Thomas
A Jowitt Christian
M Loch Stephen
P Jackson Qian Wu Henning
D Mootz Jeremy
M Stark Matthew
J Cliff Christine
K Schmidt 《Nucleic acids research》2022,50(8):4732
SUMOylation is critical for numerous cellular signalling pathways, including the maintenance of genome integrity via the repair of DNA double-strand breaks (DSBs). If misrepaired, DSBs can lead to cancer, neurodegeneration, immunodeficiency and premature ageing. Using systematic human proteome microarray screening combined with widely applicable carbene footprinting, genetic code expansion and high-resolution structural profiling, we define two non-conventional and topology-selective SUMO2-binding regions on XRCC4, a DNA repair protein important for DSB repair by non-homologous end-joining (NHEJ). Mechanistically, the interaction of SUMO2 and XRCC4 is incompatible with XRCC4 binding to three other proteins important for NHEJ-mediated DSB repair. These findings are consistent with SUMO2 forming a redundant NHEJ layer with the potential to regulate different NHEJ complexes at distinct levels including, but not limited to, XRCC4 interactions with XLF, LIG4 and IFFO1. Regulation of NHEJ is not only relevant for carcinogenesis, but also for the design of precision anti-cancer medicines and the optimisation of CRISPR/Cas9-based gene editing. In addition to providing molecular insights into NHEJ, this work uncovers a conserved SUMO-binding module and provides a rich resource on direct SUMO binders exploitable towards uncovering SUMOylation pathways in a wide array of cellular processes. 相似文献
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Lee CY Jenner AM Halliwell B 《Biochemical and biophysical research communications》2004,320(3):696-702
Reliable MS-based methods have been developed for the measurement of free and esterified F2-isoprostanes. However, prior to sample analysis several steps of purification, including solid-phase extraction followed by TLC or HPLC, are usually required, making it tedious to analyze large sample numbers, e.g., for population studies. We report a quick sample purification method using anion exchange solid phase extraction (SPE), which is highly selective for acidic compounds. Urine and hydrolyzed plasma of healthy individuals were acidified before SPE extraction, washed with 4 different solvent mixtures and finally eluted with ethyl acetate. The eluted samples were first derivatized with pentafluorobenzyl bromide followed by a second derivatization with bis-(trimethylsilyl)trifluoroacetamide. F2-isoprostanes were analyzed by GC-MS-NCI. The method was highly sensitive; the limit of detection at 5:1 signal-to-noise ratio was 0.037 ng/ml and 0.007 ng/mg creatinine for plasma and urine, respectively. Anion exchange SPE extraction for F2-isoprostane showed recovery of 55-65% and high linearity for concentration 0-1.0 ng/ml for urine (CV=4.08%, r2=0.990) and 0-0.5 ng/ml for plasma (CV=4.07%, r2=0.998). Fasting for 6h significantly increased plasma F2-isoprostanes levels, which has implications for the design of intervention studies using this biomarker. 相似文献
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