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861.
Charles R. Harrington John M. D. Storey Scott Clunas Kathleen A. Harrington David Horsley Ahtsham Ishaq Steven J. Kemp Christopher P. Larch Colin Marshall Sarah L. Nicoll Janet E. Rickard Michael Simpson James P. Sinclair Lynda J. Storey Claude M. Wischik 《The Journal of biological chemistry》2015,290(17):10862-10875
Alzheimer disease (AD) is a degenerative tauopathy characterized by aggregation of Tau protein through the repeat domain to form intraneuronal paired helical filaments (PHFs). We report two cell models in which we control the inherent toxicity of the core Tau fragment. These models demonstrate the properties of prion-like recruitment of full-length Tau into an aggregation pathway in which template-directed, endogenous truncation propagates aggregation through the core Tau binding domain. We use these in combination with dissolution of native PHFs to quantify the activity of Tau aggregation inhibitors (TAIs). We report the synthesis of novel stable crystalline leucomethylthioninium salts (LMTX®), which overcome the pharmacokinetic limitations of methylthioninium chloride. LMTX®, as either a dihydromesylate or a dihydrobromide salt, retains TAI activity in vitro and disrupts PHFs isolated from AD brain tissues at 0.16 μm. The Ki value for intracellular TAI activity, which we have been able to determine for the first time, is 0.12 μm. These values are close to the steady state trough brain concentration of methylthioninium ion (0.18 μm) that is required to arrest progression of AD on clinical and imaging end points and the minimum brain concentration (0.13 μm) required to reverse behavioral deficits and pathology in Tau transgenic mice. 相似文献
862.
Meckel–Gruber syndrome (MKS) is a severe autosomal recessively inherited disorder characterized by developmental defects of
the central nervous system that comprise neural tube defects that most commonly present as occipital encephalocele. MKS is
considered to be the most common syndromic form of neural tube defect. MKS is genetically heterogeneous with six known disease
genes: MKS1, MKS2/TMEM216, MKS3/TMEM67, RPGRIP1L, CEP290, and CC2D2A with the encoded proteins all implicated in the correct function of primary cilia. Primary cilia are microtubule-based organelles
that project from the apical surface of most epithelial cell types. Recent progress has implicated the involvement of cilia
in the Wnt and Shh signaling pathways and has led to an understanding of their role in normal mammalian neurodevelopment.
The aim of this review is to provide an overview of the molecular genetics of the human disorder, and to assess recent insights
into the etiology and molecular cell biology of severe ciliopathies from mammalian animal models of MKS. 相似文献
863.
Mäthger LM Lohmann KJ Limpus CJ Fritsches KA 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2011,366(1565):757-762
Sea turtles undertake long migrations in the open ocean, during which they rely at least partly on magnetic cues for navigation. In principle, sensitivity to polarized light might be an additional sensory capability that aids navigation. Furthermore, polarization sensitivity has been linked to ultraviolet (UV) light perception which is present in sea turtles. Here, we tested the ability of hatchling loggerheads (Caretta caretta) to maintain a swimming direction in the presence of broad-spectrum polarized light. At the start of each trial, hatchling turtles, with their magnetic sense temporarily impaired by magnets, successfully established a steady course towards a light-emitting diode (LED) light source while the polarized light field was present. When the LED was removed, however, hatchlings failed to maintain a steady swimming direction, even though the polarized light field remained. Our results have failed to provide evidence for polarized light perception in young sea turtles and suggest that alternative cues guide the initial migration offshore. 相似文献
864.
865.
In this issue of Molecular Cell, Lopez et?al. (2011) examine the caspase-recruitment domain (CARD) of c-IAP1 to reveal an intriguing mechanism in which conformational changes of the CARD determine c-IAP1's ubiquitin ligase activity, with implications for regulation of cell proliferation and survival by the IAPs. 相似文献
866.
Taminau J Steenhoff D Coletta A Meganck S Lazar C de Schaetzen V Duque R Molter C Bersini H Nowé A Weiss Solís DY 《Bioinformatics (Oxford, England)》2011,27(22):3204-3205
Microarray technology has become an integral part of biomedical research and increasing amounts of datasets become available through public repositories. However, re-use of these datasets is severely hindered by unstructured, missing or incorrect biological samples information; as well as the wide variety of preprocessing methods in use. The inSilicoDb R/Bioconductor package is a command-line front-end to the InSilico DB, a web-based database currently containing 86 104 expert-curated human Affymetrix expression profiles compiled from 1937 GEO repository series. The use of this package builds on the Bioconductor project's focus on reproducibility by enabling a clear workflow in which not only analysis, but also the retrieval of verified data is supported. 相似文献
867.
868.
The 2011 German E. coli O104:H4 outbreak resulted in thousands of cases of enterohaemorrhagic illness, with approximately 25% of these progressing to develop haemolytic uraemic syndrome (HUS). This high rate of progression to HUS was the first indicator that the bacterial cause of illness was not a typical enterohaemorrhagic E. coli (EHEC) strain. Collaborative bioinformatic analysis while the outbreak was still in progress indicated that the O104:H4 strain was in fact an enteroaggregative E. coli (EAEC) strain which had acquired genes for the production of Shiga - like toxin. 相似文献
869.
We previously reported that global deletion of insulin receptor substrate protein 1 (Irs1) extends lifespan and increases resistance to several age-related pathologies in female mice. However, no effect on lifespan was observed in male Irs1 null mice. We suggested at the time that the lack of any effect in males might have been due to a sample size issue. While such lifespan studies are essential to our understanding of the aging process, they are generally based on survival curves derived from single experiments, primarily due to time and economic constraints. Consequently, the robustness of such findings as a basis for further investigation has been questioned. We have therefore measured lifespan in a second, separate cohort of Irs1 null female mice, and show that, consistent with our previous finding, global deletion of Irs1 significantly extends lifespan in female mice. In addition, an augmented and completed study demonstrates lifespan extension in male Irs1 null mice. Therefore, we show that reduced IRS1-dependent signalling is a robust mechanism through which mammalian lifespan can be modulated. 相似文献
870.
Lauck M Hyeroba D Tumukunde A Weny G Lank SM Chapman CA O'Connor DH Friedrich TC Goldberg TL 《PloS one》2011,6(4):e19056