全文获取类型
收费全文 | 270篇 |
免费 | 26篇 |
出版年
2023年 | 4篇 |
2022年 | 6篇 |
2021年 | 11篇 |
2020年 | 3篇 |
2019年 | 8篇 |
2018年 | 5篇 |
2017年 | 6篇 |
2016年 | 5篇 |
2015年 | 20篇 |
2014年 | 13篇 |
2013年 | 14篇 |
2012年 | 19篇 |
2011年 | 10篇 |
2010年 | 6篇 |
2009年 | 16篇 |
2008年 | 12篇 |
2007年 | 9篇 |
2006年 | 13篇 |
2005年 | 16篇 |
2004年 | 14篇 |
2003年 | 8篇 |
2002年 | 8篇 |
1998年 | 3篇 |
1997年 | 3篇 |
1996年 | 2篇 |
1995年 | 2篇 |
1993年 | 2篇 |
1992年 | 2篇 |
1986年 | 2篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1981年 | 4篇 |
1976年 | 3篇 |
1973年 | 2篇 |
1971年 | 3篇 |
1967年 | 6篇 |
1966年 | 2篇 |
1965年 | 3篇 |
1964年 | 1篇 |
1963年 | 3篇 |
1962年 | 1篇 |
1961年 | 1篇 |
1960年 | 1篇 |
1959年 | 3篇 |
1958年 | 1篇 |
1957年 | 1篇 |
1954年 | 1篇 |
1950年 | 1篇 |
1938年 | 1篇 |
1936年 | 1篇 |
排序方式: 共有296条查询结果,搜索用时 15 毫秒
141.
142.
M. Cervera-Tison L. E. Tailford C. Fuell L. Bruel G. Sulzenbacher B. Henrissat J. G. Berrin M. Fons T. Giardina N. Juge 《Applied and environmental microbiology》2012,78(21):7720-7732
Ruminococcus gnavus belongs to the 57 most common species present in 90% of individuals. Previously, we identified an α-galactosidase (Aga1) belonging to glycoside hydrolase (GH) family 36 from R. gnavus E1 (M. Aguilera, H. Rakotoarivonina, A. Brutus, T. Giardina, G. Simon, and M. Fons, Res. Microbiol. 163:14–21, 2012). Here, we identified a novel GH36-encoding gene from the same strain and termed it aga2. Although aga1 showed a very simple genetic organization, aga2 is part of an operon of unique structure, including genes putatively encoding a regulator, a GH13, two phosphotransferase system (PTS) sequences, and a GH32, probably involved in extracellular and intracellular sucrose assimilation. The 727-amino-acid (aa) deduced Aga2 protein shares approximately 45% identity with Aga1. Both Aga1 and Aga2 expressed in Escherichia coli showed strict specificity for α-linked galactose. Both enzymes were active on natural substrates such as melibiose, raffinose, and stachyose. Aga1 and Aga2 occurred as homotetramers in solution, as shown by analytical ultracentrifugation. Modeling of Aga1 and Aga2 identified key amino acids which may be involved in substrate specificity and stabilization of the α-linked galactoside substrates within the active site. Furthermore, Aga1 and Aga2 were both able to perform transglycosylation reactions with α-(1,6) regioselectivity, leading to the formation of product structures up to [Hex]12 and [Hex]8, respectively. We suggest that Aga1 and Aga2 play essential roles in the metabolism of dietary oligosaccharides and could be used for the design of galacto-oligosaccharide (GOS) prebiotics, known to selectively modulate the beneficial gut microbiota. 相似文献
143.
Krista B. Goodman Michael J. Bury Mui Cheung Maria A. Cichy-Knight Sarah E. Dowdell Allison K. Dunn Dennis Lee Jeffrey A. Lieby Michael L. Moore Daryl A. Scherzer Deyou Sha Dominic P. Suarez Dennis J. Murphy Mark R. Harpel Eric S. Manas Dean E. McNulty Roland S. Annan Rosalie E. Matico Benjamin K. Schwartz John J. Trill Michael C. Jaye 《Bioorganic & medicinal chemistry letters》2009,19(1):27-30
Endothelial lipase (EL) activity has been implicated in HDL catabolism, vascular inflammation, and atherogenesis, and inhibitors are therefore expected to be useful for the treatment of cardiovascular disease. Sulfonylfuran urea 1 was identified in a high-throughput screening campaign as a potent and non-selective EL inhibitor. A lead optimization effort was undertaken to improve potency and selectivity, and modifications leading to improved LPL selectivity were identified. Radiolabeling studies were undertaken to establish the mechanism of action for these inhibitors, which were ultimately demonstrated to be irreversible inhibitors. 相似文献
144.
Nicolas Charrier Brian Clarke Leanne Cutler Emmanuel Demont Colin Dingwall Rachel Dunsdon Julie Hawkins Colin Howes Julia Hubbard Ishrut Hussain Graham Maile Rosalie Matico Julie Mosley Alan Naylor Alistair O’Brien Sally Redshaw Paul Rowland Virginie Soleil Kathrine J. Smith Sharon Sweitzer Gareth Wayne 《Bioorganic & medicinal chemistry letters》2009,19(13):3674-3678
Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration. 相似文献
145.
146.
Dermatophytes are causing superficial mycosis in animals and humans. Depending on the geophilic, zoophilic or anthropophilic origin of the fungus but also on the immunological status of the patient, symptomatology can widely differ. Nevertheless, each species is currently associated with typical clinical manifestations, even if atypical localizations and/or clinical pictures are sometimes also reported. Diagnostic tools applied to species identification have been changing since the last two decades with the more frequent use of molecular methods currently considered nowadays as reference methods for species identification. It becomes obvious that the algorithm used for the distinction of closely related species needs to combine phenotypic and genomic methods. All these different points are discussed, and the most recent novel species causing or involved in human dermatophytosis are reported. 相似文献
147.
Mark A. J. Huijbregts Zoran J. N. Steinmann Pieter M. F. Elshout Gea Stam Francesca Verones Marisa Vieira Michiel Zijp Anne Hollander Rosalie van Zelm 《The International Journal of Life Cycle Assessment》2017,22(2):138-147
Purpose
Life cycle impact assessment (LCIA) translates emissions and resource extractions into a limited number of environmental impact scores by means of so-called characterisation factors. There are two mainstream ways to derive characterisation factors, i.e. at midpoint level and at endpoint level. To further progress LCIA method development, we updated the ReCiPe2008 method to its version of 2016. This paper provides an overview of the key elements of the ReCiPe2016 method.Methods
We implemented human health, ecosystem quality and resource scarcity as three areas of protection. Endpoint characterisation factors, directly related to the areas of protection, were derived from midpoint characterisation factors with a constant mid-to-endpoint factor per impact category. We included 17 midpoint impact categories.Results and discussion
The update of ReCiPe provides characterisation factors that are representative for the global scale instead of the European scale, while maintaining the possibility for a number of impact categories to implement characterisation factors at a country and continental scale. We also expanded the number of environmental interventions and added impacts of water use on human health, impacts of water use and climate change on freshwater ecosystems and impacts of water use and tropospheric ozone formation on terrestrial ecosystems as novel damage pathways. Although significant effort has been put into the update of ReCiPe, there is still major improvement potential in the way impact pathways are modelled. Further improvements relate to a regionalisation of more impact categories, moving from local to global species extinction and adding more impact pathways.Conclusions
Life cycle impact assessment is a fast evolving field of research. ReCiPe2016 provides a state-of-the-art method to convert life cycle inventories to a limited number of life cycle impact scores on midpoint and endpoint level.148.
Keller PM Rust T Murphy DJ Matico R Trill JJ Krawiec JA Jurewicz A Jaye M Harpel M Thrall S Schwartz B 《Journal of biomolecular screening》2008,13(6):468-475
Endothelial lipase (EL) is a 482-amino-acid protein from the triglyceride lipase gene family that uses a Ser-His-Asp triad for catalysis. Its expression in endothelial cells and preference for phospholipids rather than triglycerides are unique. Animal models in which it is overexpressed or knocked out indicate EL levels are inversely correlated with high-density lipoprotein cholesterol (HDL-C). HDL-C is commonly referred to as the good form of cholesterol because it is involved in the reverse cholesterol transport pathway, in which excess cholesterol is effluxed from peripheral tissues for excretion or reabsorption. Thus, EL inhibition in humans is expected to lead to increases in HDL levels and possibly a decrease in cardiovascular disease. To discover inhibitors of EL, a coupled assay for EL has been developed, using its native substrate, HDL. Hydrolysis of HDL by EL yields free fatty acids, which are coupled through acyl-CoA synthetase, acyl-CoA oxidase, and horseradish peroxidase to produce the fluorescent species resorufin. This assay was developed into a 5-microL, 1536-well assay format, and a high-throughput screen was executed against the GSK collection. In addition to describing the screening results, novel post-HTS mechanism-of-action studies were developed for EL and applied to 1 of the screening hits as an example. 相似文献
149.
Gomes RC Soares RM Nakamura CV Souto-Padrón T de Souza RF de Azevedo Soares Semêdo LT Alviano CS Rodrigues Coelho RR 《FEMS microbiology letters》2008,286(1):118-123
Chitin from Streptomyces lunalinharesii spores, detected on its outermost surface layer, was isolated and characterized by chemical and spectroscopic methods, transmission electron microscopy and flow cytometry analysis. Gold–chitinase- and gold–lectin ( Lycopersicum esculentum agglutinin, LEA)-conjugated labels were used in microscopy experiments, whereas a fluorescence–lectin (LEA) conjugate was used in flow cytometry analysis. Chitin isolation consisted of several steps of hot alkali and nitrous acid treatment, and the final material was obtained in the colloidal form. The infrared and the 13 C CP/MAS NMR spectra of Streptomyces sp. colloidal chitin and colloidal chitin obtained from commercial crab shell chitin were very similar. Incubation of the spores with gold-labeled lectin, or gold-labeled recombinant chitinase, showed the presence of gold particles around the spore surface, indicating the specific binding of the lectin or the recombinant chitinase with the chitin present on the outermost surface. Flow cytometry analysis, using the fluorescence–lectin conjugate, confirmed these results. According to scanning electron microscopy, S. lunalinharesii presented spore surface ornamentation belonging to the spiny group. This is the first detailed characterization of chitin on the spore's outermost layer from a Streptomyces species. 相似文献
150.
Clarke B Demont E Dingwall C Dunsdon R Faller A Hawkins J Hussain I MacPherson D Maile G Matico R Milner P Mosley J Naylor A O'Brien A Redshaw S Riddell D Rowland P Soleil V Smith KJ Stanway S Stemp G Sweitzer S Theobald P Vesey D Walter DS Ward J Wayne G 《Bioorganic & medicinal chemistry letters》2008,18(3):1011-1016
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay. 相似文献