首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   502篇
  免费   38篇
  国内免费   15篇
  555篇
  2023年   2篇
  2022年   5篇
  2021年   10篇
  2020年   12篇
  2019年   11篇
  2018年   14篇
  2017年   8篇
  2016年   5篇
  2015年   29篇
  2014年   25篇
  2013年   46篇
  2012年   41篇
  2011年   37篇
  2010年   20篇
  2009年   27篇
  2008年   30篇
  2007年   27篇
  2006年   22篇
  2005年   24篇
  2004年   19篇
  2003年   8篇
  2002年   14篇
  2001年   14篇
  2000年   9篇
  1999年   7篇
  1998年   5篇
  1997年   5篇
  1996年   2篇
  1995年   8篇
  1993年   3篇
  1992年   6篇
  1991年   6篇
  1990年   5篇
  1989年   3篇
  1988年   3篇
  1987年   4篇
  1986年   2篇
  1985年   12篇
  1984年   3篇
  1983年   2篇
  1982年   2篇
  1981年   3篇
  1980年   2篇
  1979年   1篇
  1978年   2篇
  1977年   1篇
  1976年   3篇
  1975年   1篇
  1973年   3篇
  1972年   1篇
排序方式: 共有555条查询结果,搜索用时 15 毫秒
91.
We used satellite tags to record the patterns of depth utilisation for four ocean sunfish (Mola mola) and two leatherback turtles (Dermochelys coriacea) moving in broadly the same area off South Africa. Individuals were tracked for between 2 and 8 months and dive data relayed via satellite. For all the sunfish and one of the turtles, we received binned data on depth distribution, while for the second turtle we received individual dive profiles along with the proportion of time spent diving. Leatherback turtles dived almost exclusively within the upper 200 m, spending only 0.6 and 0.2% of their time > 200 m. There were times when sunfish likewise occupied these relatively shallow depths. However, there were also protracted periods when sunfish spent the majority of their time much deeper, with one individual remaining around 500 m for many hours at a time. These results suggest that sunfish sometimes exploit deeply distributed prey which is beyond the foraging range of leatherback turtles. We conclude that while both species are believed to feed predominantly on gelatinous zooplankton, the fact that sunfish do not need to come to the surface to breathe means that they can occupy an expanded vertical niche compared to the leatherback turtle.  相似文献   
92.

Background  

Numerous proteins can be converted to amyloid-like fibrils to increase cytotoxicity and induce apoptosis, but the methods generally require a high concentration of protein, vigorous shaking, or fibril seed. As well, the detailed mechanism of the cytotoxic effects is not well characterized. In this study, we have developed a novel process to convert native proteins into the fibrillar form. We used globular bovine serum albumin (BSA) as a model protein to verify the properties of the fibrillar protein, investigated its cellular effects and studied the signaling cascade induced by the fibrillar protein.  相似文献   
93.
PhnP is a phosphodiesterase that plays an important role within the bacterial carbon-phosphorus lyase (CP-lyase) pathway by recycling a "dead-end" intermediate, 5-phospho-α-d-ribosyl 1,2-cyclic phosphate, that is formed during organophosphonate catabolism. As a member of the metallo-β-lactamase superfamily, PhnP is most homologous in sequence and structure to tRNase Z phosphodiesterases. X-ray structural analysis of PhnP complexed with orthovanadate to 1.5 ? resolution revealed this inhibitor bound in a tetrahedral geometry by the two catalytic manganese ions and the putative general acid residue H200. Guided by this structure, we probed the contributions of first- and second-sphere active site residues to catalysis and metal ion binding by site-directed mutagenesis, kinetic analysis, and ICP-MS. Alteration of H200 to alanine resulted in a 6-33-fold decrease in k(cat)/K(M) with substituted methyl phenylphosphate diesters with leaving group pK(a) values ranging from 4 to 8.4. With bis(p-nitrophenyl)phosphate as a substrate, there was a 10-fold decrease in k(cat)/K(M), primarily the result of a large increase in K(M). Moreover, the nickel ion-activated H200A PhnP displayed a bell-shaped pH dependence for k(cat)/K(M) with pK(a) values (pK(a1) = 6.3; pK(a2) = 7.8) that were comparable to those of the wild-type enzyme (pK(a1) = 6.5; pK(a2) = 7.8). Such modest effects are counter to what is expected for a general acid catalyst and suggest an alternate role for H200 in this enzyme. A Br?nsted analysis of the PhnP reaction with a series of substituted phenyl methyl phosphate esters yielded a linear correlation, a β(lg) of -1.06 ± 0.1, and a Leffler α value of 0.61, consistent with a synchronous transition state for phosphoryl transfer. On the basis of these data, we propose a mechanism for PhnP.  相似文献   
94.
Do NQ  Lim KW  Teo MH  Heddi B  Phan AT 《Nucleic acids research》2011,39(21):9448-9457
G-rich oligonucleotides T30695 (or T30923), with the sequence of (GGGT)(4), and T40214, with the sequence of (GGGC)(4), have been reported to exhibit anti-HIV and anticancer activity. Here we report on the structure of a dimeric G-quadruplex adopted by a derivative of these sequences in K(+) solution. It comprises two identical propeller-type parallel-stranded G-quadruplex subunits each containing three G-tetrad layers that are stacked via the 5'-5' interface. We demonstrated control over the stacking of the two monomeric subunits by sequence modifications. Our analysis of possible structures at the stacking interface provides a general principle for stacking of G-quadruplexes, which could have implications for the assembly and recognition of higher-order G-quadruplex structures.  相似文献   
95.
Bacterial polysaccharides are known to induce the immune response in macrophages. Here we isolated a novel extracellular polysaccharide from the biofilm of Thermus aquaticus YT-1 and evaluated its structure and immunomodulatory effects. The size of this polysaccharide, TA-1, was deduced by size-exclusion chromatography as 500 kDa. GC-MS, high performance anion-exchange chromatography with pulsed amperometric detection, electrospray ionization-MS/MS, and NMR revealed the novel structure of TA-1. The polysaccharide is composed of tetrasaccharide-repeating units of galactofuranose, galactopyranose, and N-acetylgalactosamine (1:1:2) and lacked acidic sugars. TA-1 stimulated macrophage cells to produce the cytokines TNF-α and IL-6. Screening of Toll-like receptors and antibody-blocking experiments indicated that the natural receptor of TA-1 in its immunoactivity is TLR2. Recognition of TA-1 by TLR2 was confirmed by TA-1 induction of IL-6 production in peritoneal macrophages from wild-type mice but not from TLR2(-/-) mice. TA-1, as a TLR2 agonist, could possibly be used as an adjuvant and could enhance cytokine release, which increases the immune response. Furthermore, TA-1 induced cytokine release is dependent on MyD88/TIRAP.  相似文献   
96.

Background:

Household devices (e.g., television, car, computer) are common in high income countries, and their use has been linked to obesity and type 2 diabetes mellitus. We hypothesized that device ownership is associated with obesity and diabetes and that these effects are explained through reduced physical activity, increased sitting time and increased energy intake.

Methods:

We performed a cross-sectional analysis using data from the Prospective Urban Rural Epidemiology study involving 153 996 adults from high, upper-middle, lower-middle and low income countries. We used multilevel regression models to account for clustering at the community and country levels.

Results:

Ownership of a household device increased from low to high income countries (4% to 83% for all 3 devices) and was associated with decreased physical activity and increased sitting, dietary energy intake, body mass index and waist circumference. There was an increased odds of obesity and diabetes with the ownership of any 1 household device compared to no device ownership (obesity: odds ratio [OR] 1.43, 95% confidence interval [CI] 1.32–1.55; diabetes: OR 1.38, 95% CI 1.28–1.50). Ownership of a second device increased the odds further but ownership of a third device did not. Subsequent adjustment for lifestyle factors modestly attenuated these associations. Of the 3 devices, ownership of a television had the strongest association with obesity (OR 1.39, 95% CI 1.29–1.49) and diabetes (OR 1.33, 95% CI 1.23–1.44). When stratified by country income level, the odds of obesity and diabetes when owning all 3 devices was greatest in low income countries (obesity: OR 3.15, 95% CI 2.33–4.25; diabetes: OR 1.97, 95% CI 1.53–2.53) and decreased through country income levels such that we did not detect an association in high income countries.

Interpretation:

The ownership of household devices increased the likelihood of obesity and diabetes, and this was mediated in part by effects on physical activity, sitting time and dietary energy intake. With increasing ownership of household devices in developing countries, societal interventions are needed to mitigate their effects on poor health.The increasing global prevalence of obesity and type 2 diabetes mellitus has been driven predominantly by increases in high income countries.1,2 However, increases are expected in low and middle income countries, due in part to rapid development and industrialization.Proximal determinants of obesity and diabetes include energy expenditure and intake;35 however, the upstream factors are complex and entail numerous environmental factors. Of these, the increased use of common household devices (e.g., televisions, cars, computers) has been linked to increased sitting, decreased physical activity, obesity, metabolic syndrome and diabetes.612 Time spent watching television has also been linked to poor diet13 and increased caloric intake.14 However, these findings are based on studies in high income countries where the ownership of these devices is common.15,16 In low and middle income countries, such household devices are less prevalent, but their prevalence is rapidly increasing. Studies in countries with greater variability in the ownership of household devices are needed to understand the full effect of owning such devices on the risk of obesity and diabetes.We hypothesized that the ownership of a television, car or computer would be associated with an increased risk of obesity and diabetes and that these effects would be explained by reduced physical activity, increased sitting time and increased energy intake.  相似文献   
97.
To be able to colonize its host, invading Salmonella enterica serovar Typhimurium must disrupt and severely affect host-microbiome homeostasis. Here we report that S. Typhimurium induces acute infectious colitis by inhibiting peroxisome proliferator-activated receptor gamma (PPARγ) expression in intestinal epithelial cells. Interestingly, this PPARγ down-regulation by S. Typhimurium is independent of TLR-4 signaling but triggers a marked elevation of host innate immune response genes, including that encoding the antimicrobial peptide lipocalin-2 (Lcn2). Accumulation of Lcn2 stabilizes the metalloproteinase MMP-9 via extracellular binding, which further aggravates the colitis. Remarkably, when exposed to S. Typhimurium, Lcn2-null mice exhibited a drastic reduction of the colitis and remained protected even at later stages of infection. Our data suggest a mechanism in which S. Typhimurium hijacks the control of host immune response genes such as those encoding PPARγ and Lcn2 to acquire residence in a host, which by evolution has established a symbiotic relation with its microbiome community to prevent pathogen invasion.  相似文献   
98.
99.
As one of the largest gene families, F-box domain proteins have been found to play important roles in abiotic stress responses via the ubiquitin pathway. TaFBA1 encodes a homologous F-box protein contained in E3 ubiquitin ligases. In our previous study, we found that the overexpression of TaFBA1 enhanced drought tolerance in transgenic plants. To investigate the mechanisms involved, in this study, we investigated the tolerance of the transgenic plants to oxidative stress. Methyl viologen was used to induce oxidative stress conditions. Real-time PCR and western blot analysis revealed that TaFBA1 expression was up-regulated by oxidative stress treatments. Under oxidative stress conditions, the transgenic tobacco plants showed a higher germination rate, higher root length and less growth inhibition than wild type (WT). The enhanced oxidative stress tolerance of the transgenic plants was also indicated by lower reactive oxygen species (ROS) accumulation, malondialdehyde (MDA) content and cell membrane damage under oxidative stress compared with WT. Higher activities of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and peroxidase (POD), were observed in the transgenic plants than those in WT, which may be related to the upregulated expression of some antioxidant genes via the overexpression of TaFBA1. In others, some stress responsive elements were found in the promoter region of TaFBA1, and TaFBA1 was located in the nucleus, cytoplasm and plasma membrane. These results suggest that TaFBA1 plays an important role in the oxidative stress tolerance of plants. This is important for understanding the functions of F-box proteins in plants’ tolerance to multiple stress conditions.  相似文献   
100.
Aluminum and zinc based sacrificial anodes are routinely used to provide corrosion protection to metals (typically steel) exposed to seawater, for example in steel pipelines and storage tanks. However, the high fouling rates experienced in South East Asia means that both the anodes and the metals to be protected rapidly become coated with macrofoulers, which could potentially prevent the anodes from being effective. The present study, involving exposure tests of up to 18 months, indicates that both aluminum and zinc sacrificial anodes remain effective even after being completely coated with biofouling. Furthermore, it was easier to remove the biofouling on the cathodically protected samples than on their unprotected counterparts, possibly due to the higher local pH produced by cathodic protection at the metal and seawater interface.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号