全文获取类型
收费全文 | 623篇 |
免费 | 55篇 |
国内免费 | 5篇 |
出版年
2023年 | 15篇 |
2022年 | 9篇 |
2021年 | 17篇 |
2020年 | 25篇 |
2019年 | 23篇 |
2018年 | 18篇 |
2017年 | 18篇 |
2016年 | 15篇 |
2015年 | 13篇 |
2014年 | 28篇 |
2013年 | 36篇 |
2012年 | 28篇 |
2011年 | 34篇 |
2010年 | 21篇 |
2009年 | 19篇 |
2008年 | 27篇 |
2007年 | 31篇 |
2006年 | 21篇 |
2005年 | 23篇 |
2004年 | 12篇 |
2003年 | 23篇 |
2002年 | 7篇 |
2001年 | 6篇 |
2000年 | 10篇 |
1999年 | 10篇 |
1998年 | 17篇 |
1997年 | 7篇 |
1996年 | 7篇 |
1995年 | 10篇 |
1994年 | 8篇 |
1993年 | 7篇 |
1992年 | 7篇 |
1991年 | 5篇 |
1988年 | 4篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 8篇 |
1984年 | 14篇 |
1983年 | 9篇 |
1982年 | 15篇 |
1981年 | 17篇 |
1980年 | 11篇 |
1979年 | 10篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1976年 | 5篇 |
1975年 | 5篇 |
1974年 | 6篇 |
1973年 | 4篇 |
1972年 | 3篇 |
排序方式: 共有683条查询结果,搜索用时 15 毫秒
31.
Kyeong-Ryeol Lee Soo In Sohn Jin Hee Jung Sun Hee Kim Kyung Hee Roh Jong-Bum Kim Mi Chung Suh Hyun Uk Kim 《Gene》2013
Fatty acid desaturase 2 (FAD2), which resides in the endoplasmic reticulum (ER), plays a crucial role in producing linoleic acid (18:2) through catalyzing the desaturation of oleic acid (18:1) by double bond formation at the delta 12 position. FAD2 catalyzes the first step needed for the production of polyunsaturated fatty acids found in the glycerolipids of cell membranes and the triacylglycerols in seeds. In this study, four FAD2 genes from amphidiploid Brassica napus genome were isolated by PCR amplification, with their enzymatic functions predicted by sequence analysis of the cDNAs. Fatty acid analysis of budding yeast transformed with each of the FAD2 genes showed that whereas BnFAD2-1, BnFAD2-2, and BnFAD2-4 are functional enzymes, and BnFAD2-3 is nonfunctional. The four FAD2 genes of B. napus originated from synthetic hybridization of its diploid progenitors Brassica rapa and Brassica oleracea, each of which has two FAD2 genes identical to those of B. napus. The BnFAD2-3 gene of B. napus, a nonfunctional pseudogene mutated by multiple nucleotide deletions and insertions, was inherited from B. rapa. All BnFAD2 isozymes except BnFAD2-3 localized to the ER. Nonfunctional BnFAD2-3 localized to the nucleus and chloroplasts. Four BnFAD2 genes can be classified on the basis of their expression patterns. 相似文献
32.
33.
Birte Arlt Guido Mastrobuoni Jasmin Wuenschel Kathy Astrahantseff Angelika Eggert Stefan Kempa Hedwig E. Deubzer 《Journal of enzyme inhibition and medicinal chemistry》2021,36(1):1282
The small-molecule inhibitor of phosphoglycerate dehydrogenase, NCT-503, reduces incorporation of glucose-derived carbons into serine in vitro. Here we describe an off-target effect of NCT-503 in neuroblastoma cell lines expressing divergent phosphoglycerate dehydrogenase (PHGDH) levels and single-cell clones with CRISPR-Cas9-directed PHGDH knockout or their respective wildtype controls. NCT-503 treatment strongly reduced synthesis of glucose-derived citrate in all cell models investigated compared to the inactive drug control and independent of PHGDH expression level. Incorporation of glucose-derived carbons entering the TCA cycle via pyruvate carboxylase was enhanced by NCT-503 treatment. The activity of citrate synthase was not altered by NCT-503 treatment. We also detected no change in the thermal stabilisation of citrate synthase in cellular thermal shift assays from NCT-503-treated cells. Thus, the direct cause of the observed off-target effect remains enigmatic. Our findings highlight off-target potential within a metabolic assessment of carbon usage in cells treated with the small-molecule inhibitor, NCT-503. 相似文献
34.
35.
36.
Mitochondrial uncoupling protein 2 (UCP2) is highly abundant in rapidly proliferating cells that utilize aerobic glycolysis, such as stem cells, cancer cells, and cells of the immune system. However, the function of UCP2 has been a longstanding conundrum. Considering the strict regulation and unusually short life time of the protein, we propose that UCP2 acts as a “signaling protein” under nutrient shortage in cancer cells. We reveal that glutamine shortage induces the rapid and reversible downregulation of UCP2, decrease of the metabolic activity and proliferation of neuroblastoma cells, that are regulated by glutamine per se but not by glutamine metabolism. Our findings indicate a very rapid (within 1?h) metabolic adaptation that allows the cell to survive by either shifting its metabolism to the use of the alternative fuel glutamine or going into a reversible, more quiescent state. The results imply that UCP2 facilitates glutamine utilization as an energetic fuel source, thereby providing metabolic flexibility during glucose shortage. The targeting UCP2 by drugs to intervene with cancer cell metabolism may represent a new strategy for treatment of cancers resistant to other therapies. 相似文献
37.
Lars Milke Patrícia Ferreira Nicolai Kallscheuer Adelaide Braga Michael Vogt Jannick Kappelmann Joana Oliveira Ana Rita Silva Isabel Rocha Michael Bott Stephan Noack Nuno Faria Jan Marienhagen 《Biotechnology and bioengineering》2019,116(6):1380-1391
In recent years microorganisms have been engineered towards synthesizing interesting plant polyphenols such as flavonoids and stilbenes from glucose. Currently, the low endogenous supply of malonyl-CoA, indispensable for plant polyphenol synthesis, impedes high product titers. Usually, limited malonyl-CoA availability during plant polyphenol production is avoided by supplementing fatty acid synthesis-inhibiting antibiotics such as cerulenin, which are known to increase the intracellular malonyl-CoA pool as a side effect. Motivated by the goal of microbial polyphenol synthesis being independent of such expensive additives, we used rational metabolic engineering approaches to modulate regulation of fatty acid synthesis and flux into the tricarboxylic acid cycle (TCA cycle) in Corynebacterium glutamicum strains capable of flavonoid and stilbene synthesis. Initial experiments showed that sole overexpression of genes coding for the native malonyl-CoA-forming acetyl-CoA carboxylase is not sufficient for increasing polyphenol production in C. glutamicum. Hence, the intracellular acetyl-CoA availability was also increased by reducing the flux into the TCA cycle through reduction of citrate synthase activity. In defined cultivation medium, the constructed C. glutamicum strains accumulated 24 mg·L −1 (0.088 mM) naringenin or 112 mg·L −1 (0.49 mM) resveratrol from glucose without supplementation of phenylpropanoid precursor molecules or any inhibitors of fatty acid synthesis. 相似文献
38.
Aims: The aim of this study is to assess the antibacterial activity of sodium citrate against Streptococcus pneumoniae and several oral bacteria. Methods and Results: The antibacterial activity was determined by broth microdilution method. The results showed that although Enterocuccus faecium OB7084 and Klebsiella pneumoniae OB7088 had high tolerance to sodium citrate, several oral bacteria including Fusobacterium nucleatum JCM8532T, Streptococcus mutans JCM5705T and Strep. pneumoniae NBRC102642T were susceptible. Furthermore, the bactericidal activity of sodium citrate against Strep. pneumoniae NBRC102642T was not influenced by pH in the range of 5·0–8·0, whereas that of sodium lactate was weakened at neutral or weak alkaline pH. When Strep. pneumoniae NBRC102642T was treated with sodium citrate for 2 h, many burst cells were observed. However, addition of MgCl2 or CaCl2 to an assay medium weakened the antimicrobial activity although ZnCl2 or MnCl2 did not influence. Conclusions: Independent of pH, sodium citrate inhibited the growth of oral bacteria, which suggests that the mechanism is different from that of sodium lactate. Significance and Impact of the Study: The results presented in this study would be available for understanding the antimicrobial property of sodium citrate. 相似文献
39.
Hsp42 is the general small heat shock protein in the cytosol of Saccharomyces cerevisiae 总被引:4,自引:0,他引:4
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Haslbeck M Braun N Stromer T Richter B Model N Weinkauf S Buchner J 《The EMBO journal》2004,23(3):638-649
Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that prevent the unspecific aggregation of proteins. So far, Hsp26 was the only unambiguously identified member of the sHsp family in Saccharomyces cerevisiae. We show here that the sHsp system in the cytosol of S. cerevisiae consists of two proteins, Hsp26 and Hsp42. Hsp42 forms large dynamic oligomers with a barrel-like structure. In contrast to Hsp26, which functions predominantly at heat shock temperatures, Hsp42 is active as a chaperone under all conditions tested in vivo and in vitro. Under heat shock conditions, both Hsp42 and Hsp26 suppress the aggregation of one-third of the cytosolic proteins. This subset is about 90% overlapping for Hsp42 and Hsp26. The sHsp substrates belong to different biochemical pathways. This indicates a general protective function of sHsps for proteome stability in S. cerevisiae. Consistent with this observation, sHsp knockout strains show phenotypical defects. Taken together, our results define Hsp42 as an important player for protein homeostasis at physiological and under stress conditions. 相似文献
40.
Chronic hypoxia in development selectively alters the activities of key enzymes of glucose oxidative metabolism in brain regions 总被引:2,自引:0,他引:2
Lai JC White BK Buerstatte CR Haddad GG Novotny EJ Behar KL 《Neurochemical research》2003,28(6):933-940
The immature brain is more resistant to hypoxia/ischemia than the mature brain. Although chronic hypoxia can induce adaptive-changes on the developing brain, the mechanisms underlying such adaptive changes are poorly understood. To further elucidate some of the adaptive changes during postnatal hypoxia, we determined the activities of four enzymes of glucose oxidative metabolism in eight brain regions of hypoxic and normoxic rats. Litters of Sprague-Dawley rats were put into the hypoxic chamber (oxygen level maintained at 9.5%) with their dams starting on day 3 postnatal (P3). Age-matched normoxic rats were use as control animals. In P10 hypoxic rats, lactate dehydrogenase (LDH) activity in cerebral cortex, striatum, olfactory bulb, hippocampus, hypothalamus, pons and medulla, and cerebellum was significantly increased (by 100%–370%) compared to those in P10 normoxic rats. In P10 hypoxic rats, hexokinase (HK) activity in hypothalamus, hippocampus, olfactory bulb, midbrain, and cerebral cortex was significantly decreased (by 15%–30%). Neither -ketoglutarate dehydrogenase complex (KGDHC, which is believed to have an important role in the regulation of the tricarboxylic acid [TCA] cycle flux) nor citrate synthase (CS) activity was significantly decreased in the eight regions of P10 hypoxic rats compared to those in P10 normoxic rats. In P30 hypoxic rats, LDH activity was only increased in striatum (by 19%), whereas HK activity was only significantly decreased (by 30%) in this region. However, KGDHC activity was significantly decreased in olfactory bulb, hippocampus, hypothalamus, cerebral cortex, and cerebellum (by 20%–40%) in P30 hypoxic rats compared to those in P30 normoxic rats. Similarly, CS activity was decreased, but only in olfactory bulb, hypothalamus, and midbrain (by 9%–21%) in P30 hypoxic rats. Our results suggest that at least some of the mechanisms underlying the hypoxia-induced changes in activities of glycolytic enzymes implicate the upregulation of HIF-1. Moreover, our observation that chronic postnatal hypoxia induces differential effects on brain glycolytic and TCA cycle enzymes may have pathophysiological implications (e.g., decreased in energy metabolism) in childhood diseases (e.g., sudden infant death syndrome) in which hypoxia plays a role. 相似文献