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71.
The Tau/A152T mutation,a risk factor for frontotemporal‐spectrum disorders,leads to NR2B receptor‐mediated excitotoxicity 下载免费PDF全文
Astrid Sydow Frank JA Dennissen Zuzana Siskova Eckhard Mandelkow Eva‐Maria Mandelkow 《EMBO reports》2016,17(4):552-569
We report on a novel transgenic mouse model expressing human full‐length Tau with the Tau mutation A152T (hTauAT), a risk factor for FTD‐spectrum disorders including PSP and CBD. Brain neurons reveal pathological Tau conformation, hyperphosphorylation, mis‐sorting, aggregation, neuronal degeneration, and progressive loss, most prominently in area CA3 of the hippocampus. The mossy fiber pathway shows enhanced basal synaptic transmission without changes in short‐ or long‐term plasticity. In organotypic hippocampal slices, extracellular glutamate increases early above control levels, followed by a rise in neurotoxicity. These changes are normalized by inhibiting neurotransmitter release or by blocking voltage‐gated sodium channels. CA3 neurons show elevated intracellular calcium during rest and after activity induction which is sensitive to NR2B antagonizing drugs, demonstrating a pivotal role of extrasynaptic NMDA receptors. Slices show pronounced epileptiform activity and axonal sprouting of mossy fibers. Excitotoxic neuronal death is ameliorated by ceftriaxone, which stimulates astrocytic glutamate uptake via the transporter EAAT2/GLT1. In summary, hTauAT causes excitotoxicity mediated by NR2B‐containing NMDA receptors due to enhanced extracellular glutamate. 相似文献
72.
Yury T. Granja-Salcedo Carlos S. Ribeiro Júnior Raphael B. de Jesus Arturo S. Gomez-Insuasti Astrid R. Rivera Juliana D. Messana 《Archives of animal nutrition》2016,70(1):17-32
The aim of this study was to investigate the effect of different dietary levels of concentrate on feed intake, digestibility, ruminal fermentation and microbial population in steers. Eight Nellore steers fitted with ruminal cannulas were used in a double 4 × 4 Latin square design experiment. The dietary treatments consist of four different proportions of concentrate to roughage: 30:70, 40:60, 60:40 and 80:20% in the dry matter, resulting in Diets 30, 40, 60 and 80, respectively. The roughage was corn silage, and the concentrate was composed of corn, soybean meal and urea. Apparent digestibility of organic matter and crude protein showed a linear association with concentrate proportion (p = 0.01), but the increased concentrate levels did not affect the digestibility of fibre. The lowest ruminal pH-values were observed in animals fed with Diet 80, remaining below pH 6.0 from 6 h after feeding, while in the other diets, the ruminal pH was below 6.0 not before 12 h after feeding. After feeding Diet 80, the ammonia concentration in the rumen was significantly the highest. Higher dietary concentrate levels resulted in a linear increase of propionic acid concentrations, a linear reduction of the ratio acetic acid to propionic acid (p < 0.01) and a linear increased synthesis of microbial nitrogen (p < 0.001). The predicted production of methane was lower in diets with greater amounts of concentrate (p = 0.032). The population of methanogens, R. flavefaciens and R. albus decreased with higher concentrate levels, while the population of S. ruminantium increased (p < 0.05). The results indicate that greater amounts of concentrate do not decrease ruminal pH-values as much as expected and inhibit some cellulolytic bacteria without impairing the dry matter intake and fibre digestibility in Nellore steers. 相似文献
73.
Alan Walton Elisabeth Stes Nicolas Cybulski Michiel Van Bel Sabrina I?igo Astrid Nagels Durand Evy Timmerman Jefri Heyman Laurens Pauwels Lieven De Veylder Alain Goossens Ive De Smet Frederik Coppens Sofie Goormachtig Kris Gevaert 《The Plant cell》2016,28(1):6-16
Ubiquitination, the covalent binding of the small protein modifier ubiquitin to a target protein, is an important and frequently studied posttranslational protein modification. Multiple reports provide useful insights into the plant ubiquitinome, but mostly at the protein level without comprehensive site identification. Here, we implemented ubiquitin combined fractional diagonal chromatography (COFRADIC) for proteome-wide ubiquitination site mapping on Arabidopsis thaliana cell cultures. We identified 3009 sites on 1607 proteins, thereby greatly increasing the number of known ubiquitination sites in this model plant. Finally, The Ubiquitination Site tool (http://bioinformatics.psb.ugent.be/webtools/ubiquitin_viewer/) gives access to the obtained ubiquitination sites, not only to consult the ubiquitination status of a given protein, but also to conduct intricate experiments aiming to study the roles of specific ubiquitination events. Together with the antibodies recognizing the ubiquitin remnant motif, ubiquitin COFRADIC represents a powerful tool to resolve the ubiquitination maps of numerous cellular processes in plants. 相似文献
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75.
Thanks to the exponentially increasing number of publicly available bacterial genome sequences, one can now estimate the important contribution of integrated viral sequences to the diversity of bacterial genomes. Indeed, temperate bacteriophages are able to stably integrate the genome of their host through site‐specific recombination and transmit vertically to the host siblings. Lysogenic conversion has been long acknowledged to provide additional functions to the host, and particularly to bacterial pathogen genomes where prophages contribute important virulence factors. This review aims particularly at highlighting the current knowledge and questions about lysogeny in Salmonella genomes where functional prophages are abundant, and where genetic interactions between host and prophages are of particular importance for human health considerations. 相似文献
76.
The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy 总被引:1,自引:0,他引:1
Eckermann K Mocanu MM Khlistunova I Biernat J Nissen A Hofmann A Schönig K Bujard H Haemisch A Mandelkow E Zhou L Rune G Mandelkow EM 《The Journal of biological chemistry》2007,282(43):31755-31765
Neurofibrillary lesions are characteristic for a group of human diseases, named tauopathies, which are characterized by prominent intracellular accumulations of abnormal filaments formed by the microtubule-associated protein Tau. The tauopathies are accompanied by abnormal changes in Tau protein, including pathological conformation, somatodendritic mislocalization, hyperphosphorylation, and aggregation, whose interdependence is not well understood. To address these issues we have created transgenic mouse lines in which different variants of full-length Tau are expressed in a regulatable fashion, allowing one to switch the expression on and off at defined time points. The Tau variants differ by small mutations in the hexapeptide motifs that control the ability of Tau to adopt a beta-structure conformation and hence to aggregate. The "pro-aggregation" mutant DeltaK280, derived from one of the mutations observed in frontotemporal dementias, aggregates avidly in vitro, whereas the "anti-aggregation" mutant DeltaK280/PP cannot aggregate because of two beta-breaking prolines. In the transgenic mice, the pro-aggregation Tau induces a pathological conformation and pre-tangle aggregation, even at low expression levels, the anti-aggregation mutant does not. This illustrates that abnormal aggregation is primarily controlled by the molecular structure of Tau in vitro and in the organism. Both variants of Tau become mislocalized and hyperphosphorylated independently of aggregation, suggesting that localization and phosphorylation are mainly a consequence of increased concentration. These pathological changes are reversible when the expression of Tau is switched off. The pro-aggregation Tau causes a strong reduction in spine synapses. 相似文献
77.
Bernd Gruhn Joerg Seidel Felix Zintl Raymonda Varon Holger Tönnies Heidemarie Neitzel Astrid Bechtold Holger Hoehn Detlev Schindler 《Orphanet journal of rare diseases》2007,2(1):1-8
Cirrhotic cardiomyopathy is the term used to describe a constellation of features indicative of abnormal heart structure and function in patients with cirrhosis. These include systolic and diastolic dysfunction, electrophysiological changes, and macroscopic and microscopic structural changes. The prevalence of cirrhotic cardiomyopathy remains unknown at present, mostly because the disease is generally latent and shows itself when the patient is subjected to stress such as exercise, drugs, hemorrhage and surgery. The main clinical features of cirrhotic cardiomyopathy include baseline increased cardiac output, attenuated systolic contraction or diastolic relaxation in response to physiologic, pharmacologic and surgical stress, and electrical conductance abnormalities (prolonged QT interval). In the majority of cases, diastolic dysfunction precedes systolic dysfunction, which tends to manifest only under conditions of stress. Generally, cirrhotic cardiomyopathy with overt severe heart failure is rare. Major stresses on the cardiovascular system such as liver transplantation, infections and insertion of transjugular intrahepatic portosystemic stent-shunts (TIPS) can unmask the presence of cirrhotic cardiomyopathy and thereby convert latent to overt heart failure. Cirrhotic cardiomyopathy may also contribute to the pathogenesis of hepatorenal syndrome. Pathogenic mechanisms of cirrhotic cardiomyopathy are multiple and include abnormal membrane biophysical characteristics, impaired β-adrenergic receptor signal transduction and increased activity of negative-inotropic pathways mediated by cGMP. Diagnosis and differential diagnosis require a careful assessment of patient history probing for excessive alcohol, physical examination for signs of hypertension such as retinal vascular changes, and appropriate diagnostic tests such as exercise stress electrocardiography, nuclear heart scans and coronary angiography. Current management recommendations include empirical, nonspecific and mainly supportive measures. The exact prognosis remains unclear. The extent of cirrhotic cardiomyopathy generally correlates to the degree of liver insufficiency. Reversibility is possible (either pharmacological or after liver transplantation), but further studies are needed. 相似文献
78.
Evangelos Papadopoulos Martin Billeter Astrid Gräslund Alexios Vlamis-Gardikas 《Biomolecular NMR assignments》2007,1(2):217-219
The 131 residues protein encoded by the open reading frame ygiT of E. coli contains two characteristic domains: a zinc finger protein-like structure with two CxxC motives at its N-terminus and a helix-turn-helix
(HTH) motif at its C-terminus. We report the backbone and side chain 1H, 13C, and 15N resonances assignment of YgiT. 相似文献
79.
80.
Protein phosphorylation is a ubiquitous post-translational modification critical to many cellular processes. Large-scale unbiased characterization of phosphorylation status remains a major technical challenge in proteomics. In the present work, we evaluate and optimize titania-based affinity enrichment for global profiling of phosphopeptides from complex biological mixtures. We demonstrate that inclusion of glutamic acid in the sample loading buffer substantially reduced nonspecific binding of nonphosphorylated peptides to the titania while retaining the high binding affinity for phosphopeptides. The reduction in nonspecific peptide binding enhanced overall phosphopeptide recovery, ranging from 22 to 85%, and led to substantial improvement in large-scale global profiling. In addition, we observed that the overall identification of phosphopeptides was significantly enhanced by neutral loss-triggered MS (3) scans and respective use of multiple charge- and mass-dependent filtering criteria for MS (2) and MS (3) spectra. In conjunction with strong-cation exchange chromatography (SCX) for prefractionation, a total of 4002 distinct phosphopeptides were identified from SKBr3 breast cancer cells at false-positive rates of 3.7% and 5.5%, respectively, for singly and doubly phosphorylated peptides. 相似文献