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141.
142.
Betaglycan binds inhibin and can mediate functional antagonism of activin signalling 总被引:12,自引:0,他引:12
Lewis KA Gray PC Blount AL MacConell LA Wiater E Bilezikjian LM Vale W 《Nature》2000,404(6776):411-414
Activins and inhibins, structurally related members of the TGF-beta superfamily of growth and differentiation factors, are mutually antagonistic regulators of reproductive and other functions. Activins bind specific type II receptor serine kinases (ActRII or IIB) to promote the recruitment and phosphorylation of the type I receptor serine kinase, ALK4 (refs 7-9), which then regulates gene expression by activating Smad proteins. Inhibins also bind type II activin receptors but do not recruit ALK4, providing a competitive model for the antagonism of activin by inhibin. Inhibins fail to antagonize activin in some tissues and cells, however, suggesting that additional components are required for inhibin action. Here we show that the type III TGF-beta receptor, betaglycan, can function as an inhibin co-receptor with ActRII. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing ActRII and betaglycan. Inhibin also forms crosslinked complexes with both recombinant and endogenously expressed betaglycan and ActRII. Finally, betaglycan confers inhibin sensitivity to cell lines that otherwise respond poorly to this hormone. The ability of betaglycan to facilitate inhibin antagonism of activin provides a variation on the emerging roles of proteoglycans as co-receptors modulating ligand-receptor sensitivity, selectivity and function. 相似文献
143.
Gray JE Holroyd GH van der Lee FM Bahrami AR Sijmons PC Woodward FI Schuch W Hetherington AM 《Nature》2000,408(6813):713-716
Stomatal pores on the leaf surface control both the uptake of CO2 for photosynthesis and the loss of water during transpiration. Since the industrial revolution, decreases in stomatal numbers in parallel with increases in atmospheric CO2 concentration have provided evidence of plant responses to changes in CO2 levels caused by human activity. This inverse correlation between stomatal density and CO2 concentration also holds for fossil material from the past 400 million years and has provided clues to the causes of global extinction events. Here we report the identification of the Arabidopsis gene HIC (for high carbon dioxide), which encodes a negative regulator of stomatal development that responds to CO2 concentration. This gene encodes a putative 3-keto acyl coenzyme A synthase--an enzyme involved in the synthesis of very-long-chain fatty acids. Mutant hic plants exhibit up to a 42% increase in stomatal density in response to a doubling of CO2. Our results identify a gene involved in the signal transduction pathway responsible for controlling stomatal numbers at elevated CO2. 相似文献
144.
George RE Sanda T Hanna M Fröhling S Luther W Zhang J Ahn Y Zhou W London WB McGrady P Xue L Zozulya S Gregor VE Webb TR Gray NS Gilliland DG Diller L Greulich H Morris SW Meyerson M Look AT 《Nature》2008,455(7215):975-978
Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease. 相似文献