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71.
Atsuko Fukazawa Carmen Alonso Kiyotaka Kurachi Sonal Gupta Cammie F. Lesser Beth Ann McCormick Hans-Christian Reinecker 《PLoS pathogens》2008,4(11)
Shigella flexneri has evolved the ability to modify host cell function with intracellular active effectors to overcome the intestinal barrier. The detection of these microbial effectors and the initiation of innate immune responses are critical for rapid mucosal defense activation. The guanine nucleotide exchange factor H1 (GEF-H1) mediates RhoA activation required for cell invasion by the enteroinvasive pathogen Shigella flexneri. Surprisingly, GEF-H1 is requisite for NF-κB activation in response to Shigella infection. GEF-H1 interacts with NOD1 and is required for RIP2 dependent NF-κB activation by H-Ala-D-γGlu-DAP (γTriDAP). GEF-H1 is essential for NF-κB activation by the Shigella effectors IpgB2 and OspB, which were found to signal in a NOD1 and RhoA Kinase (ROCK) dependent manner. Our results demonstrate that GEF-H1 is a critical component of cellular defenses forming an intracellular sensing system with NOD1 for the detection of microbial effectors during cell invasion by pathogens. 相似文献
72.
Sodium fluoride inhibited carbachol, 5-hydroxytryptamine and noradrenaline stimulated formation of inositol phosphates in rat cerebral cortex. For example, carbachol (1 mM) induced a 337% increase of inositol phosphates above basal in 30 min which was reduced to 69% in the presence of NaF (10 mM). The IC50 for NaF was approximately 1.5 mM and inhibition was mediated by a decrease in maxima of the carbachol dose response curve rather than a shift to the right. This inhibitory action was not mimicked by NaBr or NaI, or by agents which increase cAMP. Inhibition did not appear to result from a toxic action of NaF since it had no effect on the formation of inositol phosphates by high K+; moreover, in higher concentrations NaF stimulated phospholipase C activity. Since fluoride ions are known to activate G-proteins in the concentrations used in this study, these results may indicate the existence of a novel G-protein linked to receptor inhibition of phospholipase C. 相似文献
73.
Alzheimer's disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme 总被引:5,自引:0,他引:5
Eckman EA Watson M Marlow L Sambamurti K Eckman CB 《The Journal of biological chemistry》2003,278(4):2081-2084
The abnormal accumulation of beta-amyloid (Abeta) in the brain is an early and invariant feature in Alzheimer's disease (AD) and is believed to play a pivotal role in the etiology and pathogenesis of the disease. As such, a major focus of AD research has been the elucidation of the mechanisms responsible for the generation of Abeta. As with any peptide, however, the degree of Abeta accumulation is dependent not only on its production but also on its removal. In cell-based and in vitro models we have previously characterized endothelin-converting enzyme-1 (ECE-1) as an Abeta-degrading enzyme that appears to act intracellularly, thus limiting the amount of Abeta available for secretion. To determine the physiological significance of this activity, we analyzed Abeta levels in the brains of mice deficient for ECE-1 and a closely related enzyme, ECE-2. Significant increases in the levels of both Abeta40 and Abeta42 were found in the brains of these animals when compared with age-matched littermate controls. The increase in Abeta levels in the ECE-deficient mice provides the first direct evidence for a physiological role for both ECE-1 and ECE-2 in limiting Abeta accumulation in the brain and also provides further insight into the factors involved in Abeta clearance in vivo. 相似文献
74.
75.
A process-orientated design and performance assessment methodology for passive mine water treatment systems 总被引:1,自引:0,他引:1
The aim of this paper is the development of a methodology for assessing the iron removal efficiency of passive mine water treatment settling lagoons and reed beds. Previous work in the design and sizing of coal mine drainage lagoons and wetlands has focussed on the use of standard hydraulic residence times or using the 10 g m−2 d−1 metric, these criteria have been applied without regard to the fundamental physical and chemical processes controlling iron removal in the system, namely the pH dependent rates of Fe(II) oxidation and physical settling of the particulate Fe(III). In this study field water quality data have been collected from lagoons and reed beds. These data are examined alongside data from the UK Coal Authority database and combined with simple mathematical formulations to provide a framework through which to understand passive treatment schemes from a process-orientated perspective. It is demonstrated that for the sites studied reed beds are more efficient for iron removal. This paper recommends that judgements of iron removal performance should be based on a derived treatment efficiency index (?) and that the modelling approach espoused in this paper should be used when designing passive mine water treatment schemes. 相似文献
76.
Yaniv Loewenstein Domenico Raimondo Oliver C Redfern James Watson Dmitrij Frishman Michal Linial Christine Orengo Janet Thornton Anna Tramontano 《Genome biology》2009,10(2):207-8
With many genomes now sequenced, computational annotation methods to characterize genes and proteins from their sequence are
increasingly important. The BioSapiens Network has developed tools to address all stages of this process, and here we review
progress in the automated prediction of protein function based on protein sequence and structure. 相似文献
77.
Acharya U Edwards MB Jorquera RA Silva H Nagashima K Labarca P Acharya JK 《The Journal of cell biology》2006,173(1):69-82
Scramblases are a family of single-pass plasma membrane proteins, identified by their purported ability to scramble phospholipids across the two layers of plasma membrane isolated from platelets and red blood cells. However, their true in vivo role has yet to be elucidated. We report the generation and isolation of null mutants of two Scramblases identified in Drosophila melanogaster. We demonstrate that flies lacking either or both of these Scramblases are not compromised in vivo in processes requiring scrambling of phospholipids. Instead, we show that D. melanogaster lacking both Scramblases have more vesicles and display enhanced recruitment from a reserve pool of vesicles and increased neurotransmitter secretion at the larval neuromuscular synapses. These defects are corrected by the introduction of a genomic copy of the Scramb 1 gene. The lack of phenotypes related to failure of scrambling and the neurophysiological analysis lead us to propose that Scramblases play a modulatory role in the process of neurotransmission. 相似文献
78.
M. Moorghen P. Ince Karen J. Finney A. J. Watson A. L. Harris 《In vitro cellular & developmental biology. Animal》1991,27(11):873-877
Summary The in-vitro effects of hydroxyurea 5-FU and 5-FUdR have been extensively studied in experimental systems employing cell-line
techniques. In this study we investigated the effects of these drugs on the levels of incorporation of labeled nucleosides
into DNA in explants of intact rat colonic mucosa maintained in organ culture. The effects of the nucleoside transport inhibitors
nitrobenzylthioinosine (NBMPR) and dipyridamole—which are modulators of antimetabolite cytotoxicity—on the incorporation of
tritiated thymidine [(3H]TdR) into DNA were also studied. The incorporation of tritiated TdR into DNA was reduced by hydroxyurea but was not altered
by either 5-FU or 5-FUdR. The levels of tritiated deoxyuridine were reduced by 5-FU and 5-FUdR in separate experiments; this
is in keeping with thymidylate synthase inhibition. NBMPR and dipyridamole also reduced 3H-TdR incorporation into DNA. These
results can be explained in terms of the known mechanisms of action of these drugs. This experimental model is therefore useful
in assessing the effects of antimetabolites and nucleoside transport inhibitors in intact colonic mucosa. 相似文献
79.
Beth A. Bouchard Matthew T. GisselMatthew F. Whelihan Kenneth G. MannSaulius Butenas 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Expression of tissue factor (TF) antigen and activity in platelets is controversial and dependent upon the laboratory and reagents used. Two forms of TF were described: an oxidized functional form and a reduced nonfunctional form that is converted to the active form through the formation of an allosteric disulfide. This study tests the hypothesis that the discrepancies regarding platelet TF expression are due to differential expression of the two forms.Methods
Specific reagents that recognize both oxidized and reduced TF were used in flow cytometry of unactivated and activated platelets and western blotting of whole platelet lysates. TF-dependent activity measurements were used to confirm the results.Results
Western blotting analyses of placental TF demonstrated that, in contrast to anti-TF#5, which is directed against the oxidized form of TF, a sheep anti-human TF polyclonal antibody recognizes both the reduced and oxidized forms. Flow cytometric analyses demonstrated that the sheep antibody did not react with the surface of unactivated platelets or platelets activated with thrombin receptor agonist peptide, PAR-1. This observation was confirmed using biotinylated active site-blocked factor (F)VIIa: no binding was observed. Likewise, neither form of TF was detected by western blotting of whole platelet lysates with sheep anti-hTF. Consistent with these observations, no FXa or FIXa generation by FVIIa was detected at the surface of these platelets. Similarly, no TF-related activity was observed in whole blood using thromboelastography.Conclusion and significance
Platelets from healthy donors do not express either oxidized (functional) or reduced (nonfunctional) forms of TF. 相似文献80.
Karl Deacon David Onion Rajendra Kumari Susan A. Watson Alan J. Knox 《The Journal of biological chemistry》2012,287(47):39967-39981