全文获取类型
收费全文 | 766篇 |
免费 | 59篇 |
出版年
2021年 | 7篇 |
2020年 | 9篇 |
2019年 | 9篇 |
2018年 | 10篇 |
2017年 | 20篇 |
2016年 | 10篇 |
2015年 | 33篇 |
2014年 | 27篇 |
2013年 | 41篇 |
2012年 | 51篇 |
2011年 | 58篇 |
2010年 | 37篇 |
2009年 | 38篇 |
2008年 | 53篇 |
2007年 | 50篇 |
2006年 | 46篇 |
2005年 | 41篇 |
2004年 | 37篇 |
2003年 | 34篇 |
2002年 | 24篇 |
2001年 | 9篇 |
2000年 | 9篇 |
1999年 | 8篇 |
1998年 | 10篇 |
1997年 | 6篇 |
1996年 | 12篇 |
1995年 | 6篇 |
1994年 | 5篇 |
1993年 | 16篇 |
1992年 | 4篇 |
1991年 | 8篇 |
1990年 | 9篇 |
1989年 | 7篇 |
1988年 | 8篇 |
1986年 | 5篇 |
1985年 | 3篇 |
1984年 | 4篇 |
1983年 | 4篇 |
1982年 | 5篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1977年 | 6篇 |
1976年 | 5篇 |
1975年 | 4篇 |
1971年 | 3篇 |
1969年 | 3篇 |
1968年 | 2篇 |
1967年 | 5篇 |
1963年 | 2篇 |
1959年 | 2篇 |
排序方式: 共有825条查询结果,搜索用时 31 毫秒
91.
Ande SR Kommoju PR Draxl S Murkovic M Macheroux P Ghisla S Ferrando-May E 《Apoptosis : an international journal on programmed cell death》2006,11(8):1439-1451
L-amino acid oxidase (LAAO) from the Malayan pit viper induces both necrosis and apoptosis in Jurkat cells. Cell death by
necrosis is attributed to H2O2 produced by oxidation of α-amino acids. In the presence of catalase that effectively scavenges H2O2, a switch to apoptosis is observed. The major factors contributing to apoptosis are proposed to be: (i) generation of toxic
intermediates from fetal calf serum (ii) binding and internalization of LAAO. The latter process appears to be mediated by
the glycan moiety of the enzyme as desialylation reduces cytotoxicity. D-amino acid oxidase (DAAO), which catalyzes the same
reaction as LAAO but lacks glycosylation, triggers necrosis as a consequence of H2O2 production but not apoptosis in the presence of catalase. Thus induction of cell death by LAAO appears to involve both the
generation of H2O2 and the molecular interaction of the glycan moiety of the enzyme with structures at the cell surface.
S. R. Ande, P. R. Kommoju contributed equally to this work. 相似文献
92.
93.
Caspases are a family of cysteine proteases that are essential in the initiation and execution of apoptosis and the proteolytic maturation of inflammatory cytokines such as IL-1beta and IL-18. Caspases can be subdivided into those that have a large prodomain and those that have not. In general, apoptotic and inflammatory signalling pathways are initiated when large-prodomain caspases are recruited to large protein complexes via homotypic interactions involving death domain folds. The formation of these specialised multimeric platforms involves three major functions: (1) the sensing of cellular stress, damage, infection or inflammation; (2) multimerisation of the platform; and (3) recruitment and conformational activation of caspases. In this overview we discuss the complexes implicated in the regulation of cell death and inflammatory processes such as the death-inducing signalling complex (DISC), the apoptosome, the inflammasomes and the PIDDosome. We describe their sensing functions, compositions and functional outcomes. Inhibitory protein families such as FLIPs and CARD-only proteins prevent the recruitment of caspases in these sensing complexes, avoiding inappropriate initiation of cell death or inflammation. 相似文献
94.
Auweter SD Fasan R Reymond L Underwood JG Black DL Pitsch S Allain FH 《The EMBO journal》2006,25(1):163-173
The Fox-1 protein regulates alternative splicing of tissue-specific exons by binding to GCAUG elements. Here, we report the solution structure of the Fox-1 RNA binding domain (RBD) in complex with UGCAUGU. The last three nucleotides, UGU, are recognized in a canonical way by the four-stranded beta-sheet of the RBD. In contrast, the first four nucleotides, UGCA, are bound by two loops of the protein in an unprecedented manner. Nucleotides U1, G2, and C3 are wrapped around a single phenylalanine, while G2 and A4 form a base-pair. This novel RNA binding site is independent from the beta-sheet binding interface. Surface plasmon resonance analyses were used to quantify the energetic contributions of electrostatic and hydrogen bond interactions to complex formation and support our structural findings. These results demonstrate the unusual molecular mechanism of sequence-specific RNA recognition by Fox-1, which is exceptional in its high affinity for a defined but short sequence element. 相似文献
95.
Quantification of Campylobacter Species Cross-Contamination during Handling of Contaminated Fresh Chicken Parts in Kitchens 下载免费PDF全文
Petra Luber Sigrid Brynestad Daniela Topsch Kathrin Scherer Edda Bartelt 《Applied microbiology》2006,72(1):66-70
Numerous outbreak investigations and case-control studies for campylobacteriosis have provided evidence that handling Campylobacter-contaminated chicken products is a risk factor for infection and illness. There is currently extremely limited quantitative data on the levels of Campylobacter cross-contamination in the kitchen, hindering risk assessments for the pathogen commodity combination of Campylobacter and chicken meat. An exposure assessment needs to quantify the transfer of the bacteria from chicken to hands and the kitchen environment and from there onto ready-to-eat foods. We simulated some typical situations in kitchens and quantified the Campylobacter transfer from naturally contaminated chicken parts most commonly used in Germany. One scenario simulated the seasoning of five chicken legs and the reuse of the same plate for cooked meat. In another, five chicken breast filets were cut into small slices on a wooden board where, without intermediate cleaning, a cucumber was sliced. We also investigated the transfer of the pathogen from chicken via hands to a bread roll. The numbers of Campylobacter present on the surfaces of the chicken parts, hands, utensils, and ready-to-eat foods were detected by using Preston enrichment and colony counting after surface plating on Karmali agar. The mean transfer rates from legs and filets to hands were 2.9 and 3.8%. The transfer from legs to the plate (0.3%) was significantly smaller (P < 0.01) than the percentage transferred from filets to the cutting board and knife (1.1%). Average transfer rates from hands or kitchen utensils to ready-to-eat foods ranged from 2.9 to 27.5%. 相似文献
96.
97.
Chang JS Ocvirk S Berger E Kisling S Binder U Skerra A Lee AS Haller D 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(3):1510-1520
Endoplasmic reticulum (ER) unfolded protein responses (UPR) are implicated in the pathogenesis of inflammatory bowel disease. Cytotoxic CD8αβ(+) intraepithelial lymphocytes (IEL) contribute to the development of Crohn's disease-like ileitis in TNF(ΔARE/+) mice. In this study, we characterized the role of ER-UPR mechanisms in contributing to the disease-associated phenotype of cytotoxic IEL under conditions of chronic inflammation. Inflamed TNF(ΔARE/+) mice exhibited increased expression of Grp78, ATF6, ATF4, and spliced XBP1 in CD8αβ(+) IEL but not in CD8αα(+) IEL or in lamina propria lymphocytes. Chromatin immunoprecipitation analysis in CD8αβ(+) T cells showed selective recruitment of ER-UPR transducers to the granzyme B gene promoter. Heterozygous Grp78(-/+) mice exhibited an attenuated granzyme B-dependent cytotoxicity of CD8αβ(+) T cells against intestinal epithelial cells, suggesting a critical activity of this ER-associated chaperone in maintaining a cytotoxic T cell phenotype. Granzyme B-deficient CD8αβ(+) T cells showed a defect in IL-2-mediated proliferation in Grp78(-/+) mice. Adoptively transferred Grp78(-/+) CD8αβ(+) T cells had a decreased frequency of accumulation in the intestine of RAG2(-/-) recipient mice. The tissue pathology in TNF(ΔARE/+) × Grp78(-/+) mice was similar to TNF(ΔARE/+) mice, even though the cytotoxic effector functions of CD8αβ(+) T cells were significantly reduced. In conclusion, ER stress-associated UPR mechanisms promote the development and maintenance of the pathogenic cytotoxic CD8αβ(+) IEL phenotype in the mouse model of Crohn's disease-like ileitis. 相似文献
98.
Beclin 1, a subunit of the class III phosphatidylinositol 3-kinase complex, is a tumour suppressor with a central role in endocytic trafficking, cytokinesis and the cross-regulation between autophagy and apoptosis. Interestingly, not only reduced expression but also overexpression of Beclin 1 is correlated with cancer development and metastasis. Thus it seems necessary for the cell to balance the protein levels of Beclin 1. In the present study we describe a regulatory link between Beclin 1 and the ubiquitin ligase Nedd4 (neural-precursor-cell-expressed developmentally down-regulated 4). We establish Nedd4 as a novel binding partner of Beclin 1 and demonstrate that Nedd4 polyubiquitinates Beclin 1 with Lys11- and Lys63-linked chains. Importantly, Nedd4 expression controls the stability of Beclin 1, and depletion of the Beclin 1-interacting protein VPS34 causes Nedd4-mediated proteasomal degradation of Beclin 1 via Lys11-linked polyubiquitin chains. Beclin 1 is thus the first tumour suppressor reported to be controlled by Lys11-linked polyubiquitination. 相似文献
99.
Maisch T Shimizu T Isbary G Heinlin J Karrer S Klämpfl TG Li YF Morfill G Zimmermann JL 《Applied and environmental microbiology》2012,78(12):4242-4247
Candida albicans is one of the main species able to form a biofilm on almost any surface, causing both skin and superficial mucosal infections. The worldwide increase in antifungal resistance has led to a decrease in the efficacy of standard therapies, prolonging treatment time and increasing health care costs. Therefore, the aim of this work was to demonstrate the applicability of atmospheric plasma at room temperature for inactivating C. albicans growing in biofilms without thermally damaging heat-sensitive materials. This so-called cold atmospheric plasma is produced by applying high voltage to accelerate electrons, which ionize the surrounding air, leading to the production of charged particles, reactive species, and photons. A newly developed plasma device was used, which exhibits a large plasma-generating surface area of 9 by 13 cm (117 cm(2)). Different time points were selected to achieve an optimum inactivation efficacy range of ≥3 log(10) to 5 log(10) reduction in CFU per milliliter, and the results were compared with those of 70% ethanol. The results obtained show that contact-free antifungal inactivation of Candida biofilms by cold atmospheric plasma is a promising tool for disinfection of surfaces (and items) in both health care settings and the food industry, where ethanol disinfection should be avoided. 相似文献
100.
Claes IJ Schoofs G Regulski K Courtin P Chapot-Chartier MP Rolain T Hols P von Ossowski I Reunanen J de Vos WM Palva A Vanderleyden J De Keersmaecker SC Lebeer S 《PloS one》2012,7(2):e31588
Lactobacillus rhamnosus GG (LGG) produces two major secreted proteins, designated here Msp1 (LGG_00324 or p75) and Msp2 (LGG_00031 or p40), which have been reported to promote the survival and growth of intestinal epithelial cells. Intriguingly, although each of these proteins shares homology with cell wall hydrolases, a physiological function that correlates with such an enzymatic activity remained to be substantiated in LGG. To investigate the bacterial function, we constructed knock-out mutants in the corresponding genes aiming to establish a genotype to phenotype relation. Microscopic examination of the msp1 mutant showed the presence of rather long and overly extended cell chains, which suggests that normal daughter cell separation is hampered. Subsequent observation of the LGG wild-type cells by immunofluorescence microscopy revealed that the Msp1 protein accumulates at the septum of exponential-phase cells. The cell wall hydrolyzing activity of the Msp1 protein was confirmed by zymogram analysis. Subsequent analysis by RP-HPLC and mass spectrometry of the digestion products of LGG peptidoglycan (PG) by Msp1 indicated that the Msp1 protein has D-glutamyl-L-lysyl endopeptidase activity. Immunofluorescence microscopy and the failure to construct a knock-out mutant suggest an indispensable role for Msp2 in priming septum formation in LGG. 相似文献