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111.
DNA mismatch repair ensures genomic integrity on DNA replication. Recognition of a DNA mismatch by a dimeric MutS protein initiates a cascade of reactions and results in repair of the newly synthesized strand; however, details of the molecular mechanism remain controversial. Here we present the crystal structure at 2.2 A of MutS from Escherichia coli bound to a G x T mismatch. The two MutS monomers have different conformations and form a heterodimer at the structural level. Only one monomer recognizes the mismatch specifically and has ADP bound. Mismatch recognition occurs by extensive minor groove interactions causing unusual base pairing and kinking of the DNA. Nonspecific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. The interleaved nucleotide-binding sites are located far from the DNA. Mutations in human MutS alpha (MSH2/MSH6) that lead to hereditary predisposition for cancer, such as hereditary non-polyposis colorectal cancer, can be mapped to this crystal structure. 相似文献
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113.
Evidence from Sardinian basalt geochemistry for recycling of plume heads into the Earth's mantle 总被引:1,自引:0,他引:1
Gasperini D Blichert-Toft J Bosch D Del Moro A Macera P Télouk P Albarède F 《Nature》2000,408(6813):701-704
Up to 10 per cent of the ocean floor consists of plateaux--regions of unusually thick oceanic crust thought to be formed by the heads of mantle plumes. Given the ubiquitous presence of recycled oceanic crust in the mantle source of hotspot basalts, it follows that plateau material should also be an important mantle constituent. Here we show that the geochemistry of the Pleistocene basalts from Logudoro, Sardinia, is compatible with the remelting of ancient ocean plateau material that has been recycled into the mantle. The Sr, Nd and Hf isotope compositions of these basalts do not show the signature of pelagic sediments. The basalts' low CaO/Al2O3 and Ce/Pb ratios, their unradiogenic 206Pb and 208Pb, and their Sr, Ba, Eu and Pb excesses indicate that their mantle source contains ancient gabbros formed initially by plagioclase accumulation, typical of plateau material. Also, the high Th/U ratios of the mantle source resemble those of plume magmas. Geochemically, the Logudoro basalts resemble those from Pitcairn Island, which contain the controversial EM-1 component that has been interpreted as arising from a mantle source sprinkled with remains of pelagic sediments. We argue, instead, that the EM-1 source from these two localities is essentially free of sedimentary material, the geochemical characteristics of these lavas being better explained by the presence of recycled oceanic plateaux. The storage of plume heads in the deep mantle through time offers a convenient explanation for the persistence of chemical and mineralogical layering in the mantle. 相似文献
114.
Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons 总被引:11,自引:0,他引:11
de la Monte SM Neely TR Cannon J Wands JR 《Cellular and molecular life sciences : CMLS》2000,57(10):1471-1481
Neuronal loss and neuritic/cytoskeletal lesions (synaptic disconnection and proliferation of dystrophic neurites) represent
major dementia-associated abnormalities in Alzheimer’s disease (AD). This study examined the role of oxidative stress as a
factor contributing to both the cell death and neuritic degeneration cascades in AD. Primary neuron cultures were treated
with H2O2 (9–90 μM) or desferrioxamine (2–25 μM) for 24 h and then analyzed for viability, mitochondrial mass, mitochondrial function,
and pro-apoptosis and sprouting gene expression. H2O2 treatment causes free-radical injury and desferrioxamine causes hypoxia-type injury without free radical generation. The
H2O2-treated cells exhibited sustained viability but neurite retraction, impaired mitochondrial function, increased levels of
the pro-apoptosis gene product CD95/Fas, reduced expression of N2J1-immunoreactive neuronal thread protein and synaptophysin,
and reduced distribution of mitochondria in neuritic processes. Desferrioxamine treatment resulted in dose-dependent neuronal
loss associated with impaired mitochondrial function, proliferation of neurites, and reduced expression of GAP-43, which has
a role in path-finding during neurite outgrowth. The results suggest that oxidative stress can cause neurodegeneration associated
with enhanced susceptibility to apoptosis due to activation of pro-apoptosis genes, neurite retraction (synaptic disconnection),
and impaired transport of mitochondria to cell processes where they are likely required for synaptic function. In contrast,
hypoxia-type injury causes neuronal loss with proliferation of neurites (sprouting), impaired mitochondrial function, and
reduced expression of molecules required to form and maintain synaptic connections. Since similar abnormalities occur in AD,
both oxidative stress and hypoxic injury can contribute to AD neurodegeneration.
Received 24 May 2000; received after revision 7 July 2000; accepted 27 July 2000 相似文献
115.
Identification of genes that modify ataxin-1-induced neurodegeneration 总被引:55,自引:0,他引:55
116.
Laurent de Sutter 《Foundations of Science》2013,18(2):327-329
Are we to get rid with representation after all? Since World War II, political philosophy seems to have devoted itself to either the intellectual sabotage of representation, or its defence against all evidence. Nobody seems to have thought that the problem with political representation might be the fact that the way it was thought was by no means correct. Considered as a fundamental principle of Western democracies, it might be at the very level of what a principle implies that representation must be reloaded. For instance, by admitting that as a principle representation is not something that precedes what for which it provides ground (the government, the State, etc.)—but something that follows, that constitutes the final product of representation itself. 相似文献
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