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991.
992.
Wang J Soisson SM Young K Shoop W Kodali S Galgoci A Painter R Parthasarathy G Tang YS Cummings R Ha S Dorso K Motyl M Jayasuriya H Ondeyka J Herath K Zhang C Hernandez L Allocco J Basilio A Tormo JR Genilloud O Vicente F Pelaez F Colwell L Lee SH Michael B Felcetto T Gill C Silver LL Hermes JD Bartizal K Barrett J Schmatz D Becker JW Cully D Singh SB 《Nature》2006,441(7091):358-361
Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity. 相似文献
993.
Goldraij A Kondo K Lee CB Hancock CN Sivaguru M Vazquez-Santana S Kim S Phillips TE Cruz-Garcia F McClure B 《Nature》2006,439(7078):805-810
Pollen-pistil interactions are crucial for controlling plant mating. For example, S-RNase-based self-incompatibility prevents inbreeding in diverse angiosperm species. S-RNases are thought to function as specific cytotoxins that inhibit pollen that has an S-haplotype that matches one of those in the pistil. Thus, pollen and pistil factors interact to prevent mating between closely related individuals. Other pistil factors, such as HT-B, 4936-factor and the 120 kDa glycoprotein, are also required for pollen rejection but do not contribute to S-haplotype-specificity per se. Here we show that S-RNase is taken up and sorted to a vacuolar compartment in the pollen tubes. Antibodies to the 120 kDa glycoprotein label the compartment membrane. When the pistil does not express HT-B or 4936-factor, S-RNase remains sequestered, unable to cause rejection. Similarly, in wild-type pistils, compatible pollen tubes degrade HT-B and sequester S-RNase. We suggest that S-RNase trafficking and the stability of HT-B are central to S-specific pollen rejection. 相似文献
994.
995.
996.
Himalayan tectonics explained by extrusion of a low-viscosity crustal channel coupled to focused surface denudation. 总被引:77,自引:0,他引:77
Recent interpretations of Himalayan-Tibetan tectonics have proposed that channel flow in the middle to lower crust can explain outward growth of the Tibetan plateau, and that ductile extrusion of high-grade metamorphic rocks between coeval normal- and thrust-sense shear zones can explain exhumation of the Greater Himalayan sequence. Here we use coupled thermal-mechanical numerical models to show that these two processes-channel flow and ductile extrusion-may be dynamically linked through the effects of surface denudation focused at the edge of a plateau that is underlain by low-viscosity material. Our models provide an internally self-consistent explanation for many observed features of the Himalayan-Tibetan system. 相似文献
997.
Xianhua Li Hanwen Zhou Shijiang Ding Chi-Yu Lee Renjie Zhang Yeming Zhang Wenchun Ge 《科学通报(英文版)》2000,45(10):956-960
A number of metamorphosed mafic rocks occurred within the Paleozoic strata in the Chenxing and Bangxi regions at the northern
side of the Changjiang-Qionghai Fault in Central Hainan Island. These metamorphosed mafic rocks are tholeiites in chemistry.
They are characterized by extreme depletion of Th, Nb, Ta and LREEs, resembling the depleted N-type mid-ocean ridge basalts
(MORB). Field relations suggest that the protolith of the metamorphosed mafic rocks were likely formed in Paleozoic. These
metamorphosed mafic rocks with N-type MORB geochemical features were probably the remnants of the Paleo-Tethys oceanic crust. 相似文献
998.
借助TGA-MS技术研究了煤中的氯含量(高氯、中氯、低氯煤)对煤在燃烧时氯的析出特征的影响.MS的结果表明,HCl第一个析出峰是一个热作用过程,这部分氯是以离子状态存在于煤的内表面上,第二个HCl析出峰与煤的变质程度有关,而氯则是与煤的有机结构相连,当煤燃烧时,以HCl形式与CO2、SO2、H2O一起析出.第三个HCl析出峰是由于煤中无机氯化物而导致的. 相似文献
999.
Neurotransmitter release at many central synapses is initiated by an influx of calcium ions through P/Q-type calcium channels, which are densely localized in nerve terminals. Because neurotransmitter release is proportional to the fourth power of calcium concentration, regulation of its entry can profoundly influence neurotransmission. N- and P/Q-type calcium channels are inhibited by G proteins, and recent evidence indicates feedback regulation of P/Q-type channels by calcium. Although calcium-dependent inactivation of L-type channels is well documented, little is known about how calcium modulates P/Q-type channels. Here we report a calcium-dependent interaction between calmodulin and a novel site in the carboxy-terminal domain of the alpha1A subunit of P/Q-type channels. In the presence of low concentrations of intracellular calcium chelators, calcium influx through P/Q-type channels enhances channel inactivation, increases recovery from inactivation and produces a long-lasting facilitation of the calcium current. These effects are prevented by overexpression of a calmodulin-binding inhibitor peptide and by deletion of the calmodulin-binding domain. Our results reveal an unexpected association of Ca2+/calmodulin with P/Q-type calcium channels that may contribute to calcium-dependent synaptic plasticity. 相似文献
1000.
Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster 总被引:28,自引:0,他引:28
Dews M Homayouni A Yu D Murphy D Sevignani C Wentzel E Furth EE Lee WM Enders GH Mendell JT Thomas-Tikhonenko A 《Nature genetics》2006,38(9):1060-1065
Human adenocarcinomas commonly harbor mutations in the KRAS and MYC proto-oncogenes and the TP53 tumor suppressor gene. All three genetic lesions are potentially pro-angiogenic, as they sustain production of vascular endothelial growth factor (VEGF). Yet Kras-transformed mouse colonocytes lacking p53 formed indolent, poorly vascularized tumors, whereas additional transduction with a Myc-encoding retrovirus promoted vigorous vascularization and growth. In addition, VEGF levels were unaffected by Myc, but enhanced neovascularization correlated with downregulation of anti-angiogenic thrombospondin-1 (Tsp1) and related proteins, such as connective tissue growth factor (CTGF). Both Tsp1 and CTGF are predicted targets for repression by the miR-17-92 microRNA cluster, which was upregulated in colonocytes coexpressing K-Ras and c-Myc. Indeed, miR-17-92 knockdown with antisense 2'-O-methyl oligoribonucleotides partly restored Tsp1 and CTGF expression; in addition, transduction of Ras-only cells with a miR-17-92-encoding retrovirus reduced Tsp1 and CTGF levels. Notably, miR-17-92-transduced cells formed larger, better-perfused tumors. These findings establish a role for microRNAs in non-cell-autonomous Myc-induced tumor phenotypes. 相似文献