全文获取类型
收费全文 | 856篇 |
免费 | 106篇 |
国内免费 | 1篇 |
专业分类
963篇 |
出版年
2023年 | 7篇 |
2022年 | 15篇 |
2021年 | 27篇 |
2020年 | 8篇 |
2019年 | 14篇 |
2018年 | 23篇 |
2017年 | 16篇 |
2016年 | 31篇 |
2015年 | 60篇 |
2014年 | 59篇 |
2013年 | 68篇 |
2012年 | 74篇 |
2011年 | 65篇 |
2010年 | 31篇 |
2009年 | 41篇 |
2008年 | 44篇 |
2007年 | 49篇 |
2006年 | 53篇 |
2005年 | 41篇 |
2004年 | 45篇 |
2003年 | 41篇 |
2002年 | 31篇 |
2001年 | 13篇 |
2000年 | 9篇 |
1999年 | 18篇 |
1998年 | 8篇 |
1997年 | 6篇 |
1996年 | 5篇 |
1995年 | 6篇 |
1994年 | 7篇 |
1993年 | 4篇 |
1992年 | 4篇 |
1991年 | 3篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1985年 | 3篇 |
1984年 | 4篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1972年 | 2篇 |
1971年 | 1篇 |
1967年 | 1篇 |
1948年 | 1篇 |
1920年 | 1篇 |
排序方式: 共有963条查询结果,搜索用时 0 毫秒
101.
Oubrie A Kaptein A de Zwart E Hoogenboom N Goorden R van de Kar B van Hoek M de Kimpe V van der Heijden R Borsboom J Kazemier B de Roos J Scheffers M Lommerse J Schultz-Fademrecht C Barf T 《Bioorganic & medicinal chemistry letters》2012,22(1):613-618
Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series. 相似文献
102.
Lipoteichoic acid is an important microbe-associated molecular pattern of Lactobacillus rhamnosus GG
Claes Ingmar JJ Segers Marijke E Verhoeven Tine LA Dusselier Michiel Sels Bert F De Keersmaecker Sigrid CJ Vanderleyden Jos Lebeer Sarah 《Microbial cell factories》2012,11(1):1-8
Background
Receptors with a single transmembrane (TM) domain are essential for the signal transduction across the cell membrane. NMR spectroscopy is a powerful tool to study structure of the single TM domain. The expression and purification of a TM domain in Escherichia coli (E.coli) is challenging due to its small molecular weight. Although ketosteroid isomerase (KSI) is a commonly used affinity tag for expression and purification of short peptides, KSI tag needs to be removed with the toxic reagent cyanogen bromide (CNBr).Result
The purification of the TM domain of p75 neurotrophin receptor using a KSI tag with the introduction of a thrombin cleavage site is described herein. The recombinant fusion protein was refolded into micelles and was cleaved with thrombin. Studies showed that purified protein could be used for structural study using NMR spectroscopy.Conclusions
These results provide another strategy for obtaining a single TM domain for structural studies without using toxic chemical digestion or acid to remove the fusion tag. The purified TM domain of p75 neurotrophin receptor will be useful for structural studies. 相似文献103.
ABSTRACT: Macroautophagy (commonly abbreviated as autophagy) is an evolutionary conserved lysosome-directed vesicular trafficking pathway in eukaryotic cells that mediates the lysosomal degradation of intracellular components. The cytoplasmic cargo is initially enclosed by a specific double membrane vesicle, termed the autophagosome. By this means, autophagy either helps to remove damaged organelles, long-lived proteins and protein aggregates, or serves as a recycling mechanism for molecular building blocks. Autophagy was once invented by unicellular organisms to compensate the fluctuating external supply of nutrients. In higher eukaryotes, it is strongly enhanced under various stress conditions, such as nutrient and growth factor deprivation or DNA damage. The serine/threonine kinase Atg1 was the first identified autophagy-related gene (ATG) product in yeast. The corresponding nematode homolog UNC-51, however, has additional neuronal functions. Vertebrate genomes finally encode five closely related kinases, of which UNC-51-like kinase 1 (Ulk1) and Ulk2 are both involved in the regulation of autophagy and further neuron-specific vesicular trafficking processes. This review will mainly focus on the vertebrate Ulk1/2-Atg13-FIP200 protein complex, its function in autophagy initiation, its evolutionary descent from the yeast Atg1-Atg13-Atg17 complex, as well as the additional non-autophagic functions of its components. Since the rapid nutrient- and stress-dependent cellular responses are mainly mediated by serine/threonine phosphorylation, it will summarize our current knowledge about the relevant upstream signaling pathways and the altering phosphorylation status within this complex during autophagy induction. 相似文献
104.
105.
Michiel van Breugel Paulo van Breugel Patrick A. Jansen Miguel Martínez-Ramos Frans Bongers 《Plant Ecology》2012,213(1):25-34
Competition between neighboring plants plays a major role in the population dynamics of tree species in the early phases of
humid tropical forest succession. We evaluated the relative importance of above- versus below-ground competition during the
first years of old-field succession on soil with low fertility in Southern Mexico, using the premise that competition for
light is size-asymmetric, unlike competition for nutrients. Plant growth is thus expected to be disproportionally impeded
by larger neighbors. We studied how growth and survival of 3.5–5.5 m tall saplings of Cecropia peltata and Trichospermum mexicanum, two pioneer species that dominate the secondary forests in the study region, varied with the abundance and size of neighboring
trees in 1–2 year old secondary vegetation. We found that local neighborhood basal area varied 10-fold (3 to 30 cm2 m-2) and explained most of the variation in diameter and height growth of the target saplings. Most growth variables were strongly
affected by the neighbors bigger than the focal trees with no significant additive effect of the smaller neighbors, indicating
asymmetric competition. Smaller neighbors did have a small but significant additive effect on the diameter growth of Cecropia saplings and stem slenderness of Trichospermum saplings. We conclude that competition for light was more important than belowground competition in this initial phase of
moist tropical forest successional, despite the low soil fertility. 相似文献
106.
Anna Gaertner Baerbel Klauke Ines Stork Karsten Niehaus Gesa Niemann Jan Gummert Hendrik Milting 《PloS one》2012,7(10)
Background
Although numerous sequence variants in desmoglein-2 (DSG2) have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), the functional impact of new sequence variations is difficult to estimate.Methodology/Principal Findings
To test the functional consequences of DSG2-variants, we established an expression system for the extracellular domain and the full-length DSG2 using the human cell line HT1080. We established new tools to investigate ARVC-associated DSG2 variations and compared wild-type proteins and proteins with one of the five selected variations (DSG2-p.R46Q, -p.D154E, -p.D187G, -p.K294E, -p.V392I) with respect to prodomain cleavage, adhesion properties and cellular localisation.Conclusions/Significance
The ARVC-associated DSG2-p.R46Q variation was predicted to be probably damaging by bioinformatics tools and to concern a conserved proprotein convertase cleavage site. In this study an impaired prodomain cleavage and an influence on the DSG2-properties could be demonstrated for the R46Q-variant leading to the classification of the variant as a potential gain-of-function mutant. In contrast, the variants DSG2-p.K294E and -p.V392I, which have an arguable impact on ARVC pathogenesis and are predicted to be benign, did not show functional differences to the wild-type protein in our study. Notably, the variants DSG2-p.D154E and -p.D187G, which were predicted to be damaging by bioinformatics tools, had no detectable effects on the DSG2 protein properties in our study. 相似文献107.
NC van der Weerd MP Grooteman ML Bots MA van den Dorpel CH den Hoedt AH Mazairac MJ Nubé EL Penne CA Gaillard JF Wetzels ET Wiegerinck DW Swinkels PJ Blankestijn PM Ter Wee;CONTRAST Investigators 《PloS one》2012,7(7):e39783
Hepcidin-25, the bioactive form of hepcidin, is a key regulator of iron homeostasis as it induces internalization and degradation of ferroportin, a cellular iron exporter on enterocytes, macrophages and hepatocytes. Hepcidin levels are increased in chronic hemodialysis (HD) patients, but as of yet, limited information on factors associated with hepcidin-25 in these patients is available. In the current cross-sectional study, potential patient-, laboratory- and treatment-related determinants of serum hepcidin-20 and -25, were assessed in a large cohort of stable, prevalent HD patients. Baseline data from 405 patients (62% male; age 63.7 ± 13.9 [mean SD]) enrolled in the CONvective TRAnsport STudy (CONTRAST; NCT00205556) were studied. Predialysis hepcidin concentrations were measured centrally with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patient-, laboratory- and treatment related characteristics were entered in a backward multivariable linear regression model. Hepcidin-25 levels were independently and positively associated with ferritin (p<0.001), hsCRP (p<0.001) and the presence of diabetes (p = 0.02) and inversely with the estimated glomerular filtration rate (p = 0.01), absolute reticulocyte count (p = 0.02) and soluble transferrin receptor (p<0.001). Men had lower hepcidin-25 levels as compared to women (p = 0.03). Hepcidin-25 was not associated with the maintenance dose of erythropoiesis stimulating agents (ESA) or iron therapy. In conclusion, in the currently studied cohort of chronic HD patients, hepcidin-25 was a marker for iron stores and erythropoiesis and was associated with inflammation. Furthermore, hepcidin-25 levels were influenced by residual kidney function. Hepcidin-25 did not reflect ESA or iron dose in chronic stable HD patients on maintenance therapy. These results suggest that hepcidin is involved in the pathophysiological pathway of renal anemia and iron availability in these patients, but challenges its function as a clinical parameter for ESA resistance. 相似文献
108.
Michiel G. J. Balvers Kitty C. M. Verhoeckx Sabina Bijlsma Carina M. Rubingh Jocelijn Meijerink Heleen M. Wortelboer Renger F. Witkamp 《Metabolomics : Official journal of the Metabolomic Society》2012,8(6):1130-1147
It is well established that dietary intake of n-3 fatty acids is associated with anti-inflammatory effects, and this has been linked to modulation of the oxylipin and endocannabinoid metabolomes. However, the amount of data on specific tissue effects is limited, and it is not known how inflammation affects this relation. In the present study we systematically explored the combined effects of n-3 fatty acid diets and inflammation on the in vivo endocannabinoid and oxylipin metabolomes using a multicompartment, detailed targeted lipidomics approach. Male C57BL/6 mice received diets containing 0, 1, or 3?% w/w fish oil (FO) for 6?weeks, after which 2?mg/kg LPS or saline was administered i.p. Levels of endocannabinoids/N-acylethanolamines (NAEs) and oxylipins, covering n-3 and n-6 fatty acid derived compounds, were determined in plasma, liver, ileum and adipose tissue using LC?CMS/MS. FO generally increased ??n-3?? NAEs and oxylipins at the expense of compounds derived from other fatty acids, affecting all branches of the oxylipin metabolome. LPS generally increased levels of endocannabinoids/NAEs and oxylipins, with opposing effects across plasma and tissues. Multivariate data analysis revealed that separation between diet groups in the saline treated groups was primarily explained by decreases in other than n-3 derived compounds. In the LPS treated groups, the separation was primarily explained by increases in n-3 derived compounds. In conclusion, FO caused marked changes in the n-3 to n-6 balance of the endocannabinoid and oxylipin metabolomes, with specific effects depending on inflammatory status. 相似文献
109.
110.
Gross G van der Meulen J Snel J van der Meer R Kleerebezem M Niewold TA Hulst MM Smits MA 《FEMS immunology and medical microbiology》2008,54(2):215-223
Host-microorganism interactions in the intestinal tract are complex, and little is known about specific nonpathogenic microbial factors triggering host responses in the gut. In this study, mannose-specific interactions of Lactobacillus plantarum 299v with jejunal epithelium were investigated using an in situ pig Small Intestinal Segment Perfusion model. The effects of L. plantarum 299v wild-type strain were compared with those of two corresponding mutant strains either lacking the gene encoding for the mannose-specific adhesin (msa) or sortase (srtA; responsible for anchoring of cell surface proteins like Msa to the cell wall). A slight enrichment of the wild-type strain associated with the intestinal surface could be observed after 8 h of perfusion when a mixture of wild-type and msa-mutant strain had been applied. In contrast to the mutant strains, the L. plantarum wild-type strain tended to induce a decrease in jejunal net fluid absorption compared with control conditions. Furthermore, after 8 h of perfusion expression of the host gene encoding pancreatitis-associated protein, a protein with proposed bactericidal properties, was found to be upregulated by the wild-type strain only. These observations suggest a role of Msa in the induction of host responses in the pig intestine. 相似文献