全文获取类型
收费全文 | 1814篇 |
免费 | 196篇 |
国内免费 | 2篇 |
出版年
2021年 | 17篇 |
2019年 | 15篇 |
2017年 | 15篇 |
2016年 | 24篇 |
2015年 | 54篇 |
2014年 | 68篇 |
2013年 | 74篇 |
2012年 | 87篇 |
2011年 | 86篇 |
2010年 | 52篇 |
2009年 | 50篇 |
2008年 | 63篇 |
2007年 | 60篇 |
2006年 | 59篇 |
2005年 | 72篇 |
2004年 | 65篇 |
2003年 | 60篇 |
2002年 | 81篇 |
2001年 | 68篇 |
2000年 | 56篇 |
1999年 | 46篇 |
1998年 | 22篇 |
1997年 | 26篇 |
1996年 | 18篇 |
1995年 | 20篇 |
1994年 | 23篇 |
1993年 | 32篇 |
1992年 | 33篇 |
1991年 | 41篇 |
1990年 | 30篇 |
1989年 | 33篇 |
1988年 | 26篇 |
1987年 | 33篇 |
1986年 | 24篇 |
1985年 | 24篇 |
1984年 | 20篇 |
1983年 | 22篇 |
1981年 | 14篇 |
1980年 | 20篇 |
1978年 | 18篇 |
1977年 | 19篇 |
1976年 | 14篇 |
1975年 | 14篇 |
1974年 | 24篇 |
1973年 | 16篇 |
1972年 | 16篇 |
1971年 | 16篇 |
1970年 | 22篇 |
1968年 | 15篇 |
1967年 | 22篇 |
排序方式: 共有2012条查询结果,搜索用时 31 毫秒
61.
62.
Elena Sugrue Nicholas J. Fraser Davis H. Hopkins Paul D. Carr Jeevan L. Khurana John G. Oakeshott Colin Scott Colin J. Jackson 《Applied and environmental microbiology》2015,81(7):2612-2624
The amidohydrolase superfamily has remarkable functional diversity, with considerable structural and functional annotation of known sequences. In microbes, the recent evolution of several members of this family to catalyze the breakdown of environmental xenobiotics is not well understood. An evolutionary transition from binuclear to mononuclear metal ion coordination at the active sites of these enzymes could produce large functional changes such as those observed in nature, but there are few clear examples available to support this hypothesis. To investigate the role of binuclear-mononuclear active-site transitions in the evolution of new function in this superfamily, we have characterized two recently evolved enzymes that catalyze the hydrolysis of the synthetic herbicides molinate (MolA) and phenylurea (PuhB). In this work, the crystal structures, mutagenesis, metal ion analysis, and enzyme kinetics of both MolA and PuhB establish that these enzymes utilize a mononuclear active site. However, bioinformatics and structural comparisons reveal that the closest putative ancestor of these enzymes had a binuclear active site, indicating that a binuclear-mononuclear transition has occurred. These proteins may represent examples of evolution modifying the characteristics of existing catalysts to satisfy new requirements, specifically, metal ion rearrangement leading to large leaps in activity that would not otherwise be possible. 相似文献
63.
Meshail Okla Wei Wang Inhae Kang Anjeza Pashaj Timothy Carr Soonkyu Chung 《The Journal of biological chemistry》2015,290(44):26476-26490
Adaptive thermogenesis is the cellular process transforming chemical energy into heat in response to cold. A decrease in adaptive thermogenesis is a contributing factor to obesity. However, the molecular mechanisms responsible for the compromised adaptive thermogenesis in obese subjects have not yet been elucidated. In this study we hypothesized that Toll-like receptor 4 (TLR4) activation and subsequent inflammatory responses are key regulators to suppress adaptive thermogenesis. To test this hypothesis, C57BL/6 mice were either fed a palmitate-enriched high fat diet or administered with chronic low-dose LPS before cold acclimation. TLR4 stimulation by a high fat diet or LPS were both associated with reduced core body temperature and heat release. Impairment of thermogenic activation was correlated with diminished expression of brown-specific markers and mitochondrial dysfunction in subcutaneous white adipose tissue (sWAT). Defective sWAT browning was concomitant with elevated levels of endoplasmic reticulum (ER) stress and autophagy. Consistently, TLR4 activation by LPS abolished cAMP-induced up-regulation of uncoupling protein 1 (UCP1) in primary human adipocytes, which was reversed by silencing of C/EBP homologous protein (CHOP). Moreover, the inactivation of ER stress by genetic deletion of CHOP or chemical chaperone conferred a resistance to the LPS-induced suppression of adaptive thermogenesis. Collectively, our data indicate the existence of a novel signaling network that links TLR4 activation, ER stress, and mitochondrial dysfunction, thereby antagonizing thermogenic activation of sWAT. Our results also suggest that TLR4/ER stress axis activation may be a responsible mechanism for obesity-mediated defective brown adipose tissue activation. 相似文献
64.
Lysosomes are membrane-bound organelles that contain acid hydrolases that degrade cellular proteins, lipids, nucleic acids, and oligosaccharides, and are important for cellular maintenance and protection against age-related decline. Lysosome related organelles (LROs) are specialized lysosomes found in organisms from humans to worms, and share many of the features of classic lysosomes. Defective LROs are associated with human immune disorders and neurological disease. Caenorhabditis elegans LROs are the site of concentration of vital dyes such as Nile red as well as age-associated autofluorescence. Even though certain short-lived mutants have high LRO Nile red and high autofluorescence, and other long-lived mutants have low LRO Nile red and low autofluorescence, these two biologies are distinct. We identified a genetic pathway that modulates aging-related LRO phenotypes via serotonin signaling and the gene kat-1, which encodes a mitochondrial ketothiolase. Regulation of LRO phenotypes by serotonin and kat-1 in turn depend on the proton-coupled, transmembrane transporter SKAT-1. skat-1 loss of function mutations strongly suppress the high LRO Nile red accumulation phenotype of kat-1 mutation. Using a systems approach, we further analyzed the role of 571 genes in LRO biology. These results highlight a gene network that modulates LRO biology in a manner dependent upon the conserved protein kinase TOR complex 2. The results implicate new genetic pathways involved in LRO biology, aging related physiology, and potentially human diseases of the LRO. 相似文献
65.
The molecular weight of the genomes of the blue-green algaeAnacystis nidulans andAnabaena cylindrica have been estimated as 2.27×109 and 2.47×109 daltons respectively from the renaturation kinetics of DNA. Thus the genomes of these organisms are similar in size to that ofEscherichia coli K-12, (2.40×109 daltons) measured by the same technique. No evidence was obtained of repeated sequences in the DNA of the two blue-green algae. 相似文献
66.
67.
68.
69.
70.
Nine isoforms of voltage-gated sodium channels (NaV) have been characterized and in excitable tissues they are responsible for the initiation and conduction of action potentials. For primary afferent neurons residing in dorsal root ganglia (DRG), individual neurons may express multiple NaV isoforms extending the neuron’s functional capabilities. Since expression of NaV isoforms can be differentially regulated by neurotrophic factors we have examined the functional consequences of exposure to either nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) on action potential conduction in outgrowing cultured porcine neurites of DRG neurons. Calcium signals were recorded using the exogenous intensity based calcium indicator Fluo-8®, AM. In 94 neurons, calcium signals were conducted along neurites in response to electrical stimulation of the soma. At an image acquisition rate of 25 Hz it was possible to discern calcium transients in response to individual electrical stimuli. The peak amplitude of electrically-evoked calcium signals was limited by the ability of the neuron to follow the stimulus frequency. The stimulus frequency required to evoke a half-maximal calcium response was approximately 3 Hz at room temperature. In 13 of 14 (93%) NGF-responsive neurites, TTX-r NaV isoforms alone were sufficient to support propagated signals. In contrast, calcium signals mediated by TTX-r NaVs were evident in only 4 of 11 (36%) neurites from somata cultured in GDNF. This establishes a basis for assessing action potential signaling using calcium imaging techniques in individual cultured neurites and suggests that, in the pig, afferent nociceptor classes relying on the functional properties of TTX-r NaV isoforms, such as cold-nociceptors, most probably derive from NGF-responsive DRG neurons. 相似文献