全文获取类型
收费全文 | 363篇 |
免费 | 36篇 |
出版年
2023年 | 2篇 |
2022年 | 7篇 |
2021年 | 15篇 |
2020年 | 3篇 |
2019年 | 7篇 |
2018年 | 9篇 |
2017年 | 9篇 |
2016年 | 13篇 |
2015年 | 26篇 |
2014年 | 28篇 |
2013年 | 28篇 |
2012年 | 37篇 |
2011年 | 34篇 |
2010年 | 23篇 |
2009年 | 25篇 |
2008年 | 24篇 |
2007年 | 16篇 |
2006年 | 16篇 |
2005年 | 19篇 |
2004年 | 8篇 |
2003年 | 7篇 |
2002年 | 5篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1995年 | 1篇 |
1994年 | 3篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1990年 | 1篇 |
1988年 | 2篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1977年 | 1篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 2篇 |
1970年 | 1篇 |
1967年 | 1篇 |
1966年 | 1篇 |
1961年 | 1篇 |
1942年 | 1篇 |
1939年 | 1篇 |
排序方式: 共有399条查询结果,搜索用时 31 毫秒
101.
Lekse Jaclyn Xia Li Stark Jeffrey Morrow Jason D. May James M. 《Molecular and cellular biochemistry》2001,226(1-2):89-95
The antioxidant activity of several plant catechol derivatives was tested in buffer, plasma, and human erythrocytes. In buffer, chlorogenic acid (CGA), caffeic acid (CA), and dihydrocaffeic acid (DCA) reduced ferric iron equally well in the ferric reducing antioxidant power (FRAP) assay. Low concentrations of the polyphenols enhanced the ability of plasma to reduce ferric iron by about 10%. In plasma, lipid hydroperoxide and F2-isoprostane formation induced by a water-soluble free radical initiator were reduced by CGA at concentrations as low as 20 M. During incubation at 37°C, human erythrocytes took up DCA, but not CGA, and intracellular DCA enhanced the ability of erythrocytes to reduce extracellular ferricyanide. When intact erythrocytes were exposed to oxidant stress generated by liposomes containing small amounts of lipid hydroperoxides, extracellular CGA at a concentration of 5 M decreased both lipid peroxidation in the liposomes, and spared -tocopherol in erythrocyte membranes. These results suggest that the catechol structure of these compounds convey the antioxidant effect in plasma and in erythrocytes. 相似文献
102.
103.
Daniel F. Vatner Jaclyn Snikeris Violeta Popov Rachel J. Perry Yasmeen Rahimi Varman T. Samuel 《PloS one》2015,10(10)
Thyroid hormone mimetics are alluring potential therapies for diseases like dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and insulin resistance. Though diiodothyronines are thought inactive, pharmacologic treatment with 3,5- Diiodo-L-Thyronine (T2) reportedly reduces hepatic lipid content and improves glucose tolerance in fat-fed male rats. To test this, male Sprague Dawley rats fed a safflower-oil based high-fat diet were treated with T2 (0.25 mg/kg-d) or vehicle. Neither 10 nor 30 days of T2 treatment had an effect on weight, adiposity, plasma fatty acids, or hepatic steatosis. Insulin action was quantified in vivo by a hyperinsulinemic-euglycemic clamp. T2 did not alter fasting plasma glucose or insulin concentration. Basal endogenous glucose production (EGP) rate was unchanged. During the clamp, there was no difference in insulin stimulated whole body glucose disposal. Insulin suppressed EGP by 60% ± 10 in T2-treated rats as compared with 47% ± 4 suppression in the vehicle group (p = 0.32). This was associated with an improvement in hepatic insulin signaling; insulin stimulated Akt phosphorylation was ~2.5 fold greater in the T2-treated group as compared with the vehicle-treated group (p = 0.003). There was no change in expression of genes thought to mediate the effect of T2 on hepatic metabolism, including genes that regulate hepatic lipid oxidation (ppara, carnitine palmitoyltransferase 1a), genes that regulate hepatic fatty acid synthesis (srebp1c, acetyl coa carboxylase, fatty acid synthase), and genes involved in glycolysis and gluconeogenesis (L-pyruvate kinase, glucose 6 phosphatase). Therefore, in contrast with previous reports, in Sprague Dawley rats fed an unsaturated fat diet, T2 administration failed to improve NAFLD or whole body insulin sensitivity. Though there was a modest improvement in hepatic insulin signaling, this was not associated with significant differences in hepatic insulin action. Further study will be necessary before diiodothyronines can be considered an effective treatment for NAFLD and dyslipidemia. 相似文献
104.
An increasing concern affecting a growing aging population is working memory (WM) decline. Consequently, there is great interest in improving or stabilizing WM, which drives expanded use of brain training exercises. Such regimens generally result in temporary WM benefits to the trained tasks but minimal transfer of benefit to untrained tasks. Pairing training with neurostimulation may stabilize or improve WM performance by enhancing plasticity and strengthening WM-related cortical networks. We tested this possibility in healthy older adults. Participants received 10 sessions of sham (control) or active (anodal, 1.5 mA) tDCS to the right prefrontal, parietal, or prefrontal/parietal (alternating) cortices. After ten minutes of sham or active tDCS, participants performed verbal and visual WM training tasks. On the first, tenth, and follow-up sessions, participants performed transfer WM tasks including the spatial 2-back, Stroop, and digit span tasks. The results demonstrated that all groups benefited from WM training, as expected. However, at follow-up 1-month after training ended, only the participants in the active tDCS groups maintained significant improvement. Importantly, this pattern was observed for both trained and transfer tasks. These results demonstrate that tDCS-linked WM training can provide long-term benefits in maintaining cognitive training benefits and extending them to untrained tasks. 相似文献
105.
Jaclyn K. Mann John P. Barton Andrew L. Ferguson Saleha Omarjee Bruce D. Walker Arup Chakraborty Thumbi Ndung'u 《PLoS computational biology》2014,10(8)
Viral immune evasion by sequence variation is a major hindrance to HIV-1 vaccine design. To address this challenge, our group has developed a computational model, rooted in physics, that aims to predict the fitness landscape of HIV-1 proteins in order to design vaccine immunogens that lead to impaired viral fitness, thus blocking viable escape routes. Here, we advance the computational models to address previous limitations, and directly test model predictions against in vitro fitness measurements of HIV-1 strains containing multiple Gag mutations. We incorporated regularization into the model fitting procedure to address finite sampling. Further, we developed a model that accounts for the specific identity of mutant amino acids (Potts model), generalizing our previous approach (Ising model) that is unable to distinguish between different mutant amino acids. Gag mutation combinations (17 pairs, 1 triple and 25 single mutations within these) predicted to be either harmful to HIV-1 viability or fitness-neutral were introduced into HIV-1 NL4-3 by site-directed mutagenesis and replication capacities of these mutants were assayed in vitro. The predicted and measured fitness of the corresponding mutants for the original Ising model (r = −0.74, p = 3.6×10−6) are strongly correlated, and this was further strengthened in the regularized Ising model (r = −0.83, p = 3.7×10−12). Performance of the Potts model (r = −0.73, p = 9.7×10−9) was similar to that of the Ising model, indicating that the binary approximation is sufficient for capturing fitness effects of common mutants at sites of low amino acid diversity. However, we show that the Potts model is expected to improve predictive power for more variable proteins. Overall, our results support the ability of the computational models to robustly predict the relative fitness of mutant viral strains, and indicate the potential value of this approach for understanding viral immune evasion, and harnessing this knowledge for immunogen design. 相似文献
106.
Aline Rodrigues Hoffmann Adam P. Patterson Alison Diesel Sara D. Lawhon Hoai Jaclyn Ly Christine Elkins Stephenson Joanne Mansell J?rg M. Steiner Scot E. Dowd Thierry Olivry Jan S. Suchodolski 《PloS one》2014,9(1)
Background
Changes in the microbial populations on the skin of animals have traditionally been evaluated using conventional microbiology techniques. The sequencing of bacterial 16S rRNA genes has revealed that the human skin is inhabited by a highly diverse and variable microbiome that had previously not been demonstrated by culture-based methods. The goals of this study were to describe the microbiome inhabiting different areas of the canine skin, and to compare the skin microbiome of healthy and allergic dogs.Methodology/Principal Findings
DNA extracted from superficial skin swabs from healthy (n = 12) and allergic dogs (n = 6) from different regions of haired skin and mucosal surfaces were used for 454-pyrosequencing of the 16S rRNA gene. Principal coordinates analysis revealed clustering for the different skin sites across all dogs, with some mucosal sites and the perianal regions clustering separately from the haired skin sites. The rarefaction analysis revealed high individual variability between samples collected from healthy dogs and between the different skin sites. Higher species richness and microbial diversity were observed in the samples from haired skin when compared to mucosal surfaces or mucocutaneous junctions. In all examined regions, the most abundant phylum and family identified in the different regions of skin and mucosal surfaces were Proteobacteria and Oxalobacteriaceae. The skin of allergic dogs had lower species richness when compared to the healthy dogs. The allergic dogs had lower proportions of the Betaproteobacteria Ralstonia spp. when compared to the healthy dogs.Conclusions/Significance
The study demonstrates that the skin of dogs is inhabited by much more rich and diverse microbial communities than previously thought using culture-based methods. Our sequence data reveal high individual variability between samples collected from different patients. Differences in species richness was also seen between healthy and allergic dogs, with allergic dogs having lower species richness when compared to healthy dogs. 相似文献107.
108.
Cristina Giogha Nichollas E. Scott Tania Wong Fok Lung Georgina L. Pollock Marina Harper Ethan D. Goddard-Borger Jaclyn S. Pearson Elizabeth L. Hartland 《PLoS pathogens》2021,17(6)
During infection, enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) directly manipulate various aspects of host cell function through the translocation of type III secretion system (T3SS) effector proteins directly into the host cell. Many T3SS effector proteins are enzymes that mediate post-translational modifications of host proteins, such as the glycosyltransferase NleB1, which transfers a single N-acetylglucosamine (GlcNAc) to arginine residues, creating an Arg-GlcNAc linkage. NleB1 glycosylates death-domain containing proteins including FADD, TRADD and RIPK1 to block host cell death. The NleB1 paralogue, NleB2, is found in many EPEC and EHEC strains but to date its enzymatic activity has not been described. Using in vitro glycosylation assays combined with mass spectrometry, we found that NleB2 can utilize multiple sugar donors including UDP-glucose, UDP-GlcNAc and UDP-galactose during glycosylation of the death domain protein, RIPK1. Sugar donor competition assays demonstrated that UDP-glucose was the preferred substrate of NleB2 and peptide sequencing identified the glycosylation site within RIPK1 as Arg603, indicating that NleB2 catalyses arginine glucosylation. We also confirmed that NleB2 catalysed arginine-hexose modification of Flag-RIPK1 during infection of HEK293T cells with EPEC E2348/69. Using site-directed mutagenesis and in vitro glycosylation assays, we identified that residue Ser252 in NleB2 contributes to the specificity of this distinct catalytic activity. Substitution of Ser252 in NleB2 to Gly, or substitution of the corresponding Gly255 in NleB1 to Ser switches sugar donor preference between UDP-GlcNAc and UDP-glucose. However, this switch did not affect the ability of the NleB variants to inhibit inflammatory or cell death signalling during HeLa cell transfection or EPEC infection. NleB2 is thus the first identified bacterial Arg-glucose transferase that, similar to the NleB1 Arg-GlcNAc transferase, inhibits host protein function by arginine glycosylation. 相似文献
109.
Katalin Szlavecz Melissa McCormick Lijun Xia Jaclyn Saunders Taylan Morcol Dennis Whigham Timothy Filley Csaba Csuzdi 《Biological invasions》2011,13(5):1165-1182
In many mid-Atlantic forests where both native and non-native earthworms exist, it is the non-native species that are the
dominant component of the soil macrofauna. Few earthworm ecology studies, however, focus attention on these forest systems
in order to determine the relative ecological roles and potential interactions of the native and non-native earthworms. In
a series of field samplings and experimental manipulations we collected data on the effects of earthworms on below-and aboveground
ecosystem processes. Earthworm abundance and the ecological processes measured were dynamic in space and time across the range
of study sites. Leaf litter decay rates doubled at sites that had abundant non-native earthworms. Earthworms also altered
the abundance of soil fungi, the activity of extracellular enzymes, soil respiration, and the growth of tree seedlings but
the effects varied among sites depending on differences in land-use history and forest age. Red oak seedling growth was less
at sites that had abundant earthworms but tulip poplar and red maple seedlings grew equally well with and without abundant
earthworms. These preliminary results suggest that non-native earthworms have significant ecosystem effects, even in forests
where native earthworms still occur. Land use history, however, plays an important role in determining what those effects
will be, and these effects are likely to be dynamic, depending on the abundance of non-native earthworms. 相似文献
110.
Coulthard LG Costello J Robinson B Shiels IA Taylor SM Woodruff TM 《Arthritis research & therapy》2011,13(2):R42