全文获取类型
收费全文 | 939篇 |
免费 | 85篇 |
国内免费 | 9篇 |
出版年
2023年 | 7篇 |
2022年 | 13篇 |
2021年 | 13篇 |
2020年 | 17篇 |
2019年 | 23篇 |
2018年 | 38篇 |
2017年 | 23篇 |
2016年 | 26篇 |
2015年 | 28篇 |
2014年 | 66篇 |
2013年 | 64篇 |
2012年 | 39篇 |
2011年 | 42篇 |
2010年 | 46篇 |
2009年 | 38篇 |
2008年 | 65篇 |
2007年 | 59篇 |
2006年 | 38篇 |
2005年 | 36篇 |
2004年 | 27篇 |
2003年 | 22篇 |
2002年 | 20篇 |
2001年 | 18篇 |
2000年 | 9篇 |
1999年 | 11篇 |
1998年 | 8篇 |
1997年 | 11篇 |
1996年 | 11篇 |
1995年 | 12篇 |
1994年 | 15篇 |
1993年 | 8篇 |
1992年 | 9篇 |
1991年 | 13篇 |
1990年 | 11篇 |
1989年 | 5篇 |
1988年 | 8篇 |
1987年 | 9篇 |
1986年 | 6篇 |
1985年 | 14篇 |
1984年 | 16篇 |
1983年 | 7篇 |
1982年 | 12篇 |
1981年 | 10篇 |
1980年 | 7篇 |
1979年 | 11篇 |
1978年 | 6篇 |
1977年 | 12篇 |
1976年 | 6篇 |
1975年 | 7篇 |
1974年 | 6篇 |
排序方式: 共有1033条查询结果,搜索用时 689 毫秒
121.
Valérie Guillet Ségolène Galandrin Laurent Maveyraud Simon Ladevèze Vincent Mariaule Cécile Bon Nathalie Eynard Mamadou Daffé Hedia Marrakchi Lionel Mourey 《The Journal of biological chemistry》2016,291(15):7973-7989
Mycolic acids are essential components of the mycobacterial cell envelope, and their biosynthetic pathway is one of the targets of first-line antituberculous drugs. This pathway contains a number of potential targets, including some that have been identified only recently and have yet to be explored. One such target, FadD32, is required for activation of the long meromycolic chain and is essential for mycobacterial growth. We report here an in-depth biochemical, biophysical, and structural characterization of four FadD32 orthologs, including the very homologous enzymes from Mycobacterium tuberculosis and Mycobacterium marinum. Determination of the structures of two complexes with alkyl adenylate inhibitors has provided direct information, with unprecedented detail, about the active site of the enzyme and the associated hydrophobic tunnel, shedding new light on structure-function relationships and inhibition mechanisms by alkyl adenylates and diarylated coumarins. This work should pave the way for the rational design of inhibitors of FadD32, a highly promising drug target. 相似文献
122.
The aim of this work was to discover if there is enough ATP citrate lyase (EC 4.1.3.8) in the cytosol of the leaves of Pisum sativum L. to catalyse the synthesis of the acetyl CoA needed for terpenoid synthesis. Estimates of the maximum catalytic activity of the enzyme in leaves of 7-d-old peas gave values of 113 nmol min-1 g-1 fresh weight. The rate of carotenoid accumulation in these leaves corresponded to a requirement for acetyl CoA of 0.7 nmol min-1 g-1 fresh weight. The distribution of marker enzymes during fractionation of homogenates of leaves from 7 to 10-d-old peas showed that differential centrifugation led to the isolation in reasonable yields of chloroplasts, mitochondria, peroxisomes and the endomembrane system. None of the above components of the leaf contained appreciable detectable activity of ATP citrate lyase, the distribution of which closely paralleled that of the cytosolic marker. It was concluded that in young leaves of pea most of the ATP citrate lyase is in the cytosol. 相似文献
123.
Carolina Elejalde-Palmett Ignacio Martinez San Segundo Imène Garroum Laurence Charrier Damien De Bellis Antonio Mucciolo Aurore Guerault Jie Liu Viktoria Zeisler-Diehl Asaph Aharoni Lukas Schreiber Bénédicte Bakan Mads H. Clausen Markus Geisler Christiane Nawrath 《Current biology : CB》2021,31(10):2111-2123.e9
- Download : Download high-res image (193KB)
- Download : Download full-size image
124.
High titer 1-butanol production in Escherichia coli has previously been achieved by overexpression of a modified clostridial 1-butanol production pathway and subsequent deletion of native fermentation pathways. This strategy couples growth with production as 1-butanol pathway offers the only available terminal electron acceptors required for growth in anaerobic conditions. With further inclusion of other well-established metabolic engineering principles, a titer of 15 g/L has been obtained. In achieving this titer, many currently existing strategies have been exhausted, and 1-butanol toxicity level has been surpassed. Therefore, continued engineering of the host strain for increased production requires implementation of alternative strategies that seek to identify non-obvious targets for improvement. In this study, a metabolomics-driven approach was used to reveal a CoA imbalance resulting from a pta deletion that caused undesirable accumulation of pyruvate, butanoate, and other CoA-derived compounds. Using metabolomics, the reduction of butanoyl-CoA to butanal catalyzed by alcohol dehydrogenase AdhE2 was determined as a rate-limiting step. Fine-tuning of this activity and subsequent release of free CoA restored the CoA balance that resulted in a titer of 18.3 g/L upon improvement of total free CoA levels using cysteine supplementation. By enhancing AdhE2 activity, carbon flux was directed towards 1-butanol production and undesirable accumulation of pyruvate and butanoate was diminished. This study represents the initial report describing the improvement of 1-butanol production in E. coli by resolving CoA imbalance, which was based on metabolome analysis and rational metabolic engineering strategies. 相似文献
125.
Takeshi Sassa Katsuhiro Suzuki Emi Haruki 《Bioscience, biotechnology, and biochemistry》2013,77(1):303-304
Quinolactacide isolated from Penicillium citrinum F 1539 was synthesized and evaluated for its insecticidal activities. The key steps of the total synthesis were an acyl migration reaction of the enol ester intermediate and dehydrogenation of tetrahydroquinolactacide with manganese dioxide. The synthesized quinolactacide showed 100% and 42% mortality against the green peach aphid (Myzus persicae) and diamondback moth (Plutella xylostella) at 500 ppm, respectively. 相似文献
126.
Dandan Liang Hongjin Chen Leping Zhao Wenxin Zhang Jie Hu Zhiguo Liu Peng Zhong Wei Wang Jingying Wang Guang Liang 《生物化学与生物物理学报:疾病的分子基础》2018,1864(1):133-142
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD begins with steatosis and advances to nonalcoholic steatohepatitis (NASH) and cirrhosis. The molecular mechanisms involved in NAFLD progression are not understood. Based on recent studies showing dysregulation of epidermal growth factor receptor (EGFR) in animal models of liver injury, we sought to determine if inhibition of EGFR mitigates liver fibrosis and HSC activation in NAFLD. We utilized the high fat diet (HFD)-induced murine model of liver injury to study the role of EGFR in NAFLD. The lipid accumulation, oxidative stress, hepatic stellate cell (HSC) activation and matrix deposition were examined in the liver tissues. We also evaluated the EGFR signaling pathway, ROS activation and pro-fibrogenic phenotype in oxidized low density lipoproteins (ox-LDL) challenged cultured HSCs. We demonstrate that EGFR was phosphorylated in liver tissues of HFD murine model of NAFLD. Inhibition of EGFR prevented diet-induced lipid accumulation, oxidative stress, and HSC activation and matrix deposition. In cultured HSCs, we show that ox-LDL caused rapid activation of the EGFR signaling pathway and induce the production of reactive oxygen species. EGFR also mediated HSC activation and promoted a pro-fibrogenic phenotype. In conclusion, our data demonstrate that EGFR plays an important role in NAFLD and is an attractive target for NAFLD therapy. 相似文献
127.
Verena Hiebl Angela Ladurner Simone Latkolik Verena M. Dirsch 《Biotechnology advances》2018,36(6):1657-1698
Nuclear receptors (NRs) represent attractive targets for the treatment of metabolic syndrome-related diseases. In addition, natural products are an interesting pool of potential ligands since they have been refined under evolutionary pressure to interact with proteins or other biological targets.This review aims to briefly summarize current basic knowledge regarding the liver X (LXR) and farnesoid X receptors (FXR) that form permissive heterodimers with retinoid X receptors (RXR). Natural product-based ligands for these receptors are summarized and the potential of LXR, FXR and RXR as targets in precision medicine is discussed. 相似文献
128.
Christelle David Laurent Bischoff Hervé Meudal Catherine Llorens-Cortes Bernard Pierre Roques Marie-Claude Fournié-Zaluski 《International journal of peptide research and therapeutics》1997,4(4-6):411-414
Summary In order to study the physiological role of aminopeptidase A(APA), several α-mercapto-β-amino acyl dipeptides were synthesized
to obtain compounds having a high affinity for APA and a high selectivity versus aminopeptidase N (APN). Sulfornamide and
carboxylate moieties which have been shown to be recognized by the S1 subsite of the enzyme were introduced on the side chain of the α-mercapto-β-amino acyl sub-unit, the latter being coupled
to dipeptides optimized to interact with the S'1 and S'2 subsites by means of combinatorial chemistry. Good affinities (16nM) were obtained, the selectivity factors being up to 160-fold
versus APN. 相似文献
129.
L.M Stonell M.H Cake G.W Power I.C Potter 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》1997,118(4):845-850
The Vmax of rat muscle mitochondrial CPT I toward the coenzyme A derivatives of 16:0, 16:1n-7, 18:1n-9, and 22:6n-3 were far lower than those recorded previously for this enzyme in rat liver at the same temperature (37°C). However, the Vmax of 7.0 nmol · min−1 · mg mitochondrial protein−1 for linoleoyl CoA (18:2n-6), which was the greatest recorded for the five acyl CoAs examined in muscle, was similar to that in liver. These comparisons presumably reflect a difference in the essential fatty acid requirements of these two rat tissues. Although the Vmax values for CPT I in the musculature of a lower vertebrate (larval lamprey) at 20°C were similar to those exhibited toward the coenzyme A derivatives of 16:0, 16:1n-7, 18:1n-9, and 22:6n-3 by the CPT I of rat musculature at 37°C, the corresponding Vmax toward 18:2n-6 (3.2 nmol · min−1 · mg mitochondrial protein−1) was lower. The latter relatively low activity may spare from oxidation this essential fatty acid, which is in low abundance in the diet of larval lampreys. Although the Vmax values toward the four nonessential fatty acids in larval lamprey muscle were similar to those in rat muscle, the corresponding K0.5 values were lower, thus indicating that the musculature of larval lampreys has a high capacity for energy generation through β-oxidation. 相似文献
130.
Eckhard Wollenweber 《Phytochemistry》1985,24(7):1493-1494
The known acylated flavonoid aglycones are reviewed. Their substitution patterns and their distribution in plants are discussed briefly. A new pair of flavonol esters is reported in Notholaena candida var. candida, the acetate and butyrate of isognaphalin. 相似文献