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121.
The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function,brain perfusion,and glucose metabolism 下载免费PDF全文
Gernot Kleinberger Matthias Brendel Eva Mracsko Benedikt Wefers Linda Groeneweg Xianyuan Xiang Carola Focke Maximilian Deußing Marc Suárez‐Calvet Fargol Mazaheri Samira Parhizkar Nadine Pettkus Wolfgang Wurst Regina Feederle Peter Bartenstein Thomas Mueggler Thomas Arzberger Irene Knuesel Axel Rominger Christian Haass 《The EMBO journal》2017,36(13):1837-1853
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD‐like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock‐in mouse model for the disease‐associated Trem2 p.T66M mutation. Consistent with a loss‐of‐function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p.T66M mutation. Trem2 p.T66M knock‐in mice show delayed resolution of inflammation upon in vivo lipopolysaccharide stimulation and cultured macrophages display significantly reduced phagocytic activity. Immunohistochemistry together with in vivo TSPO small animal positron emission tomography (μPET) demonstrates an age‐dependent reduction in microglial activity. Surprisingly, perfusion magnetic resonance imaging and FDG‐μPET imaging reveal a significant reduction in cerebral blood flow and brain glucose metabolism. Thus, we demonstrate that a TREM2 loss‐of‐function mutation causes brain‐wide metabolic alterations pointing toward a possible function of microglia in regulating brain glucose metabolism. 相似文献
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We have studied a small isolated population of black grouse (Tetrao tetrix) in the Netherlands to examine the impact of isolation and reduction in numbers on genetic diversity. We compared the genetic diversity in the last extant Dutch population with Dutch museum samples and three other black grouse populations (from England, Austria and Norway, respectively) representing isolated and continuous populations. We found significantly lower allelic richness, observed and expected heterozygosities in the present Dutch population compared to the continuous populations (Austria and Norway) and also to the historical Dutch population. However, using a bottleneck test on each population, signs of heterozygosity excess were only found in the likewise isolated English population despite that strong genetic drift was evident in the present Dutch population in comparison to the reference populations, as assessed both in pairwise F(ST)and STRUCTURE analyses. Simulating the effect of a population reduction on the Dutch population from 1948 onwards, using census data and with the Dutch museum samples as a model for the genetic diversity in the initial population, revealed that the loss in number of alleles and observed heterozygosity was according to genetic drift expectations and within the standard error range of the present Dutch population. Thus, the effect of the strong decline in the number of grouse on genetic diversity was only detectable when using a reference from the past. The lack of evidence for a population reduction in the present Dutch population by using the program bottleneck was attributed to a rapidly found new equilibrium as a consequence of a very small effective population size. 相似文献
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The ancestors of rock ptarmigan Lagopus muta originated in the Beringia area well before the disruption of the Beringian land bridge. They spread westwards to Siberia and eastwards to the North American arctic and Greenland. The distribution of rock ptarmigan has been affected by glaciations restricting it to geographically limited refugia. Today the species has a circumpolar distribution in arctic tundra and alpine habitats, with up to 30 subspecies recognised based on morphological characters. We sequenced the mitochondrial control region for 72 individuals and genotyped 69 individuals for 12 microsatellite loci to investigate neutral genetic variation within and among five rock ptarmigan populations, Greenland, Iceland, Scandinavia, Svalbard and Taimyr. Genetic structure among the studied samples was high, overall FST estimated from microsatellite loci was 0.18 and only one out of 16 mtDNA haplotypes was found in more than one population. Genetic variation ( h, π, He , allelic richness) was slightly lower in the Svalbard population than in other populations, suggesting a low effective population size, possibly due to isolation following colonisation. An unrooted network and a phylogenetic tree showed that the Scandinavian population has diverged from the other populations by at least ten mutational steps, probably due to independent colonisation of Europe and subsequent long-term isolation, and rules out Scandinavia as a source for colonisation of Svalbard. Alignment with partial control region sequences from other studies showed that the haplotype that was central in our network and found on Svalbard and in Taimyr, most likely corresponds to a haplotype found in Siberia, Alaska and the Canadian Arctic, but not in Greenland, Scandinavia and Iceland. This suggests an eastern origin of rock ptarmigan in Svalbard, although this question cannot be settled conclusively. 相似文献
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Background
Repeat-rich regions such as centromeres receive less attention than their gene-rich euchromatic counterparts because the former are difficult to assemble and analyze. Our objectives were to 1) map all ten centromeres onto the maize genetic map and 2) characterize the sequence features of maize centromeres, each of which spans several megabases of highly repetitive DNA. Repetitive sequences can be mapped using special molecular markers that are based on PCR with primers designed from two unique "repeat junctions". Efficient screening of large amounts of maize genome sequence data for repeat junctions, as well as key centromere sequence features required the development of specific annotation software. 相似文献129.
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Fargol Mazaheri Nicolas Snaidero Gernot Kleinberger Charlotte Madore Anna Daria Georg Werner Susanne Krasemann Anja Capell Dietrich Trümbach Wolfgang Wurst Bettina Brunner Sebastian Bultmann Sabina Tahirovic Martin Kerschensteiner Thomas Misgeld Oleg Butovsky Christian Haass 《EMBO reports》2017,18(7):1186-1198