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61.
Qiaoqiao Xu Shanshan Huang Mingke Song Chuan-En Wang Sen Yan Xudong Liu Marta A. Gaertig Shan Ping Yu He Li Shihua Li Xiao-Jiang Li 《The Journal of cell biology》2013,202(7):1123-1138
Many genetic mouse models of Huntington’s disease (HD) have established that mutant huntingtin (htt) accumulates in various subcellular regions to affect a variety of cellular functions, but whether and how synaptic mutant htt directly mediates HD neuropathology remains to be determined. We generated transgenic mice that selectively express mutant htt in the presynaptic terminals. Although it was not overexpressed, synaptic mutant htt caused age-dependent neurological symptoms and early death in mice as well as defects in synaptic neurotransmitter release. Mass spectrometry analysis of synaptic fractions and immunoprecipitation of synapsin-1 from HD CAG150 knockin mouse brains revealed that mutant htt binds to synapsin-1, a protein whose phosphorylation is critical for neurotransmitter release. We found that polyglutamine-expanded exon1 htt binds to the C-terminal region of synapsin-1 to reduce synapsin-1 phosphorylation. Our findings point to a critical role for synaptic htt in the neurological symptoms of HD, providing a new therapeutic target. 相似文献
62.
de Melo AC d'Avila-Levy CM Branquinha MH Vermelho AB 《Experimental parasitology》2002,102(3-4):150-156
The extracellular metalloproteinases of the insect trypanosomatid Crithidia guilhermei were characterized through the incorporation of different protein substrates (gelatin, casein, haemoglobin, and bovine serum albumin) into SDS-PAGE. Two gelatinases (60 and 80 kDa) showed ability to degrade casein as well and a 67-kDa enzyme presented the broadest specificity since it was also able to degrade casein and haemoglobin. Besides the 67-kDa extracellular proteinases detected on haemoglobin-SDS-PAGE, a 43-kDa haemoglobinase was only observed with this substrate. All C. guilhermei proteinases were incapable of using bovine serum albumin. C. guilhermei was also grown in four different culture media and the best proteinase production was reached using yeast extract-peptone medium containing glucose as the major carbon source. The results point to the importance of the use of distinct culture media and proteinaceous substrates on the characterization of extracellular proteolytic activities in trypanosomatids, since alterations in growth conditions and methods of detection could lead to distinct proteolytic profiles. 相似文献
63.
64.
Bruce E. Maryanoff Michael J. Costanzo Ricahrd P. Shank James J. Schupsky Marta E. Ortegon Jeffry L. Vaught 《Bioorganic & medicinal chemistry letters》1993,3(12):2653-2656
Exploration structure-activity relationships surrounding the clinically effective antiepileptic drug topiramate (1) led to a series of potent anticonvulsants with a 4,5-cyclic sulfate or 4,5-cycli sulfite functionality. Key derivative 2 (RWJ-37947) is ca. 8 times more potent than topiramate in mice; it also features a long duration of action and a very favorable neurotoxicity index. 相似文献
65.
Background
In gene expression studies a key role is played by the so called "pre-processing", a series of steps designed to extract the signal and account for the sources of variability due to the technology used rather than to biological differences between the RNA samples. At the moment there is no commonly agreed gold standard pre-processing method and each researcher has the responsibility to choose one method, incurring the risk of false positive and false negative features arising from the particular method chosen. 相似文献66.
The present work proposes new boundaries for the current submediterranean territories of the Iberian Peninsula, defining them
at the smallest scale attempted to date. The boundaries proposed are not sharp divisions but somewhat ‘gradual’, reflecting
the transitional nature of the territories they encompass. Climate change predictions were used to estimate how the distribution
of these submediterranean regions might change in the near future. The maps constructed are based on the distribution of marcescent
Quercus species—trees that characterise the submediterranean plant landscape where they form the main forest communities. To determine
their climatic range, the distribution of different types of Iberian oak forest was represented in ‘climate diagrams’ (ordination
diagrams derived from principal components analysis), both in terms of individual species and groups of species based on leaf
ecophysiological type, i.e. marcescent (Submediterranean), sclerophyllous (Mediterranean), semideciduous (Mediterranean) and
deciduous (Eurosiberian). The climate range of each type of forest was determined, and the means of representative climate
variables are analysed by one way ANOVA. The variables differentiating the forest groups were also examined by discriminant
analysis. The range of the climate variables found to be associated with the majority of marcescent forests was used to determine
the distribution of territories throughout the Peninsula with the same conditions (i.e. whether marcescent forests were present
or not), thus providing a map of the Iberian submediterranean territories. Predictions of climate change were used to investigate
possible climate-induced modifications in the boundaries of these territories in the near future. The patterns obtained show
dramatic reductions in the extension of the Iberian submediterranean environment. Submediterranean conditions will probably
disappear from the areas where they currently reign, and it seems unlikely that any new, large submediterranean areas will
form by displacement towards higher altitudes. The outlook for the unique submediterranean vegetation of the Iberian Peninsula
is gloomy.
相似文献
Helios Sainz-OlleroEmail: |
67.
68.
Deborah Long June Swinburne Marta Martin Kate Wilson Eva Sundberg Karen Lee George Coupland 《Molecular & general genetics : MGG》1993,241(5-6):627-636
The Ac/Ds transposon system of maize shows low activity in Arabidopsis. However, fusion of the CaMV 35S promoter to the transposase gene (35S::TPase) increases the abundance of the single Ac mRNA encoded by Ac and increases the frequency of Ds excision. In the experiments reported here it is examined whether this high excision frequency is associated with efficient re-insertion of the transposon. This was measured by using a Ds that carried a hygromycin resistance gene (HPT) and was inserted within a streptomycin resistance gene (SPT). Excision of Ds therefore gives rise to streptomycin resistance, while hygromycin resistance is associated with the presence of a transposed Ds or with retention of the element at its original location. Self-fertilisation of most individuals heterozygous for Ds and 35S::TPase produced many streptomycin-resistant (strepr) progeny, but in many of these families a small proportion of strepr seedlings were also resistant to hygromycin (hygr). Nevertheless, 70% of families tested did give rise to at least one strepr, hygr seedling, and over 90% of these individuals carried a transposed Ds. In contrast, the Ac promoter fusion to the transposase gene (Ac::TPase) produced fewer streprhygr progeny, and only 53% of these carried a transposed Ds. However, a higher proportion of the strepr seedlings were also hygr than after activation by 35S::TPase. We also examined the genotype of strepr, hygr seedlings and demonstrated that after activation by 35S::TPase many of these were homozygous for the transposed Ds, while this did not occur after activation by Ac::TPase. From these and other data we conclude that excisions driven by 35S::TPase usually occur prior to floral development, and that although a low proportion of strepr progeny plants inherit a transposed Ds, those that do can be efficiently selected with an antibiotic resistance gene contained within the element. Our data have important implications for transposon tagging strategies in transgenic plants and these are discussed. 相似文献
69.
Urs Duthaler Michael Weber Lorenz Hofer Carlos Chaccour Marta Maia Pie Müller Stephan Krhenbühl Felix Hammann 《PLoS pathogens》2021,17(3)
Mosquitoes are vectors of major diseases such as dengue fever and malaria. Mass drug administration of endectocides to humans and livestock is a promising complementary approach to current insecticide-based vector control measures. The aim of this study was to establish an insect model for pharmacokinetic and drug-drug interaction studies to develop sustainable endectocides for vector control. Female Aedes aegypti mosquitoes were fed with human blood containing either ivermectin alone or ivermectin in combination with ketoconazole, rifampicin, ritonavir, or piperonyl butoxide. Drug concentrations were quantified by LC-MS/MS at selected time points post-feeding. Primary pharmacokinetic parameters and extent of drug-drug interactions were calculated by pharmacometric modelling. Lastly, the drug effect of the treatments was examined. The mosquitoes could be dosed with a high precision (%CV: ≤13.4%) over a range of 0.01–1 μg/ml ivermectin without showing saturation (R2: 0.99). The kinetics of ivermectin were characterised by an initial lag phase of 18.5 h (CI90%: 17.0–19.8 h) followed by a slow zero-order elimination rate of 5.5 pg/h (CI90%: 5.1–5.9 pg/h). By contrast, ketoconazole, ritonavir, and piperonyl butoxide were immediately excreted following first order elimination, whereas rifampicin accumulated over days in the mosquitoes. Ritonavir increased the lag phase of ivermectin by 11.4 h (CI90%: 8.7–14.2 h) resulting in an increased exposure (+29%) and an enhanced mosquitocidal effect. In summary, this study shows that the pharmacokinetics of drugs can be investigated and modulated in an Ae. aegypti animal model. This may help in the development of novel vector-control interventions and further our understanding of toxicology in arthropods. 相似文献