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Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR 总被引:9,自引:0,他引:9
Bell DW Gore I Okimoto RA Godin-Heymann N Sordella R Mulloy R Sharma SV Brannigan BW Mohapatra G Settleman J Haber DA 《Nature genetics》2005,37(12):1315-1316
Somatic activating mutations in EGFR identify a subset of non-small cell lung cancer that respond to tyrosine kinase inhibitors. Acquisition of drug resistance is linked to a specific secondary somatic mutation, EGFR T790M. Here we describe a family with multiple cases of non-small cell lung cancer associated with germline transmission of this mutation. Four of six tumors analyzed showed a secondary somatic activating EGFR mutation, arising in cis with the germline EGFR mutation T790M. These observations implicate altered EGFR signaling in genetic susceptibility to lung cancer. 相似文献
85.
Localized Ca2+ and calcium-activated potassium conductances in terminals of a barnacle photoreceptor
Calcium channels are found in the presynaptic terminals of neurones, where they have a key role in synaptic transmission. They are also found in the somata of many cells, in dendrites and along a few axons. In no cell is the actual distribution of these channels known in detail, because there are no known toxins or other agents suitable for labelling calcium channels, and the current through these channels is usually too small to be quantified with extracellular electrodes. However, several experiments have suggested that the density of the channels is less in the axon than in the cell body or terminal region. Here we have used the indicator dye Arsenazo III in conjunction with an array of photodetectors to examine the spatial influx of calcium in the presynaptic terminal region of the giant barnacle, Balanus nubilus. In these cells, calcium entry occurs in a restricted region less than 50 micron in length, which corresponds closely to the region of synaptic contact with second-order cells. Outside this area the magnitude of calcium entry is reduced at least 50-fold. With reasonable assumptions it follows that the calcium channel density is equally localized. In addition, we demonstrate that these cells have a calcium-activated potassium conductance. Since calcium entry is restricted to the synaptic zone, this conductance must be effective only in this region. 相似文献
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McKern NM Lawrence MC Streltsov VA Lou MZ Adams TE Lovrecz GO Elleman TC Richards KM Bentley JD Pilling PA Hoyne PA Cartledge KA Pham TM Lewis JL Sankovich SE Stoichevska V Da Silva E Robinson CP Frenkel MJ Sparrow LG Fernley RT Epa VC Ward CW 《Nature》2006,443(7108):218-221
The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding. 相似文献
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D J Henner D V Goeddel H Heyneker K Itakura D Yansura M Ross G Miozzari 《Nature》1999,399(6734):297-298
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Jackie S Bodnar Aurobindo Chatterjee Lawrence W Castellani David A Ross Jeffrey Ohmen James Cavalcoli Chenyan Wu Katherine M Dains Joe Catanese Michael Chu Sonal S Sheth Kanti Charugundla Peter Demant David B West Pieter de Jong Aldons J Lusis 《Nature genetics》2002,30(1):110-116
Familial combined hyperlipidemia (FCHL, MIM-144250) is a common, multifactorial and heterogeneous dyslipidemia predisposing to premature coronary artery disease and characterized by elevated plasma triglycerides, cholesterol, or both. We identified a mutant mouse strain, HcB-19/Dem (HcB-19), that shares features with FCHL, including hypertriglyceridemia, hypercholesterolemia, elevated plasma apolipoprotein B and increased secretion of triglyceride-rich lipoproteins. The hyperlipidemia results from spontaneous mutation at a locus, Hyplip1, on distal mouse chromosome 3 in a region syntenic with a 1q21-q23 FCHL locus identified in Finnish, German, Chinese and US families. We fine-mapped Hyplip1 to roughly 160 kb, constructed a BAC contig and sequenced overlapping BACs to identify 13 candidate genes. We found substantially decreased mRNA expression for thioredoxin interacting protein (Txnip). Sequencing of the critical region revealed a Txnip nonsense mutation in HcB-19 that is absent in its normolipidemic parental strains. Txnip encodes a cytoplasmic protein that binds and inhibits thioredoxin, a major regulator of cellular redox state. The mutant mice have decreased CO2 production but increased ketone body synthesis, suggesting that altered redox status down-regulates the citric-acid cycle, sparing fatty acids for triglyceride and ketone body production. These results reveal a new pathway of potential clinical significance that contributes to plasma lipid metabolism. 相似文献
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Part of all of the difference in the ability of ACTH1-24, and a fluorescent-labeled ACTH1-24 to activate lipolysis in fat cells can be accounted for by label-related binding to albumin present in the assay medium. 相似文献