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61.
Dr. Alexander Fries Dr. Laura S. Mazzaferro Dr. Björn Grüning Dr. Philippe Bisel Karin Stibal Patrick C. F. Buchholz Prof. Dr. Jürgen Pleiss Prof. Dr. Georg A. Sprenger Prof. Dr. Michael Müller 《Chembiochem : a European journal of chemical biology》2019,20(13):1672-1677
Chorismate and isochorismate constitute branch-point intermediates in the biosynthesis of many aromatic metabolites in microorganisms and plants. To obtain unnatural compounds, we modified the route to menaquinone in Escherichia coli. We propose a model for the binding of isochorismate to the active site of MenD ((1R,2S, 5S,6S)-2-succinyl-5-enolpyruvyl-6-hydroxycyclohex-3-ene-1-carboxylate (SEPHCHC) synthase) that explains the outcome of the native reaction with α-ketoglutarate. We have rationally designed variants of MenD for the conversion of several isochorismate analogues. The double-variant Asn117Arg–Leu478Thr preferentially converts (5S,6S)-5,6-dihydroxycyclohexa-1,3-diene-1-carboxylate (2,3-trans-CHD), the hydrolysis product of isochorismate, with a >70-fold higher ratio than that for the wild type. The single-variant Arg107Ile uses (5S,6S)-6-amino-5-hydroxycyclohexa-1,3-diene-1-carboxylate (2,3-trans-CHA) as substrate with >6-fold conversion compared to wild-type MenD. The novel compounds have been made accessible in vivo (up to 5.3 g L−1). Unexpectedly, as the identified residues such as Arg107 are highly conserved (>94 %), some of the designed variations can be found in wild-type SEPHCHC synthases from other bacteria (Arg107Lys, 0.3 %). This raises the question for the possible natural occurrence of as yet unexplored branches of the shikimate pathway. 相似文献
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ABSTRACTGiven that online platforms disrupt established industries and challenge existing institutions, they can only be successful if their innovation becomes both legal and legitimate. This requires ‘institutional work’ that changes perceptions and regulations within society. Rather than only focussing on the online platform as the sole agent engaging in institutional work, our study analyses institutional work as a collective process. We investigate the case of home-sharing platform Airbnb and the process of institutional change its introduction prompted regarding short-term rental in Amsterdam, London and New York. We find, contrary to the popular view of online platforms as disruptive entrepreneurs, that the platform mainly focusses on creating new institutions rather than disrupting existing ones, and that users and non-users undertake most of the institutional work activities. We also show that different types of actors carry out different types of institutional work suggesting that the process of institutional work is highly distributed. 相似文献
64.
D.R. Santos‐Peñate C.M. Campos‐Rodríguez J.A. Moreno‐Pérez 《International Transactions in Operational Research》2019,26(1):340-363
The ‐centroid problem or leader–follower problem is generalized considering different customer choice rules where a customer may use facilities belonging to different firms, if the difference in travel distance (or time) is small enough. Assuming essential goods, some particular customer choice rules are analyzed. Linear programming formulations for the generalized ‐medianoid and ‐centroid problems are presented and an exact solution approach is applied. Some computational examples are included. 相似文献
65.
Bram H. Frohock Jessica M. Gilbertie Dr. Jennifer C. Daiker Dr. Lauren V. Schnabel Dr. Joshua G. Pierce 《Chembiochem : a European journal of chemical biology》2020,21(7):933-937
The failure of frontline antibiotics in the clinic is one of the most serious threats to human health and requires a multitude of novel therapeutics and innovative approaches to treatment so as to curtail the growing crisis. In addition to traditional resistance mechanisms resulting in the lack of efficacy of many antibiotics, most chronic and recurring infections are further made tolerant to antibiotic action by the presence of biofilms. Herein, we report an expanded set of 5-benzylidene-4-oxazolidinones that are able to inhibit the formation of Staphylococcus aureus biofilms, disperse preformed biofilms, and, in combination with common antibiotics, are able to significantly reduce the bacterial load in a robust collagen-matrix model of biofilm infection. 相似文献
66.
ABSTRACT Design and implementation of an effective dissemination programme for decentralised renewable energy system necessitate an accurate estimate of its utilisation potential. Hence, in this study, an attempt has been made to develop frameworks to estimate the utilisation potential of decentralised renewable energy systems in the state of Uttarakhand in India. Estimations imply large resource, technical and economic potentials of the domestic solar water heater, solar home system, solar lantern, family size biogas plant and improved biomass cookstove in Uttarakhand. With higher impact on the purchasing power of households, prevailing soft loan scheme has been found to be more appropriate than a capital subsidy for promoting the usage of decentralised renewable energy systems. 相似文献
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68.
Mobile software applications have to cope with a particular environment that involves small size, limited resources, high autonomy requirements, competitive business models and many other challenges. To provide development guidelines that respond to these needs, several practices have been introduced; however, it is not clear how these guidelines may contribute to solve the issues present in the mobile domain. Furthermore, the rapid evolution of the mobile ecosystem challenges many of the premises upon which the proposed practices were designed. In this paper, we present a survey of the literature on software assurance practices for mobile applications, with the objective of describing them and assessing their contribution and success. We identified, organized and reviewed a body of research that spans in three levels: software development processes, software product assurance practices, and software implementation practices. By carrying out this literature survey, we reviewed the different approaches that researchers on Software Engineering have provided to address the needs that raise in the mobile software development arena. Moreover, we review the evolution of these practices, identifying how the constant changes and modernization of the mobile execution environment has impacted the methods proposed in the literature. Finally, we introduced discussion on the application of these practices in a real productive setting, opening an area for further research that may determine if practitioners have followed the proposed assurance paradigms. 相似文献
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70.
Valence M. K. Ndesendo Yahya E. Choonara Leith C. R. Meyer Pradeep Kumar Lomas K. Tomar Charu Tyagi 《Drug development and industrial pharmacy》2015,41(8):1274-1287
Context and objective: The aim of this study was to develop, characterize and evaluate a mucoadhesive caplet resulting from a polymeric blend (polymeric caplet) for intravaginal anti-HIV-1 delivery.Materials and methods: Poly(lactic-co-glycolic) acid, ethylcellulose, poly(vinylalcohol), polyacrylic acid and modified polyamide 6, 10 polymers were blended and compressed to a caplet-shaped device, with and without two model drugs 3′-azido-3′-deoxythymidine (AZT) and polystyrene sulfonate (PSS). Thermal analysis, infrared spectroscopy and microscopic analysis were carried out on the caplets employing temperature-modulated DSC (TMDSC), Fourier transform infra-red (FTIR) spectrometer and scanning electron microscope, respectively. In vitro and in vivo drug release analyses as well as the histopathological toxicity studies were carried out on the drug-loaded caplets. Furthermore, molecular mechanics (MM) simulations were carried out on the drug-loaded caplets to corroborate the experimental findings.Results and discussion: There was a big deviation between the Tg of the polymeric caplet from the Tg's of the constituent polymers indicating a strong interaction between constituent polymers. FTIR spectroscopy confirmed the presence of specific ionic and non-ionic interactions within the caplet. A controlled near zero-order drug release was obtained for AZT (20 d) and PSS (28 d). In vivo results, i.e. the drug concentration in plasma ranged between 0.012–0.332?mg/mL and 0.009–0.256?mg/mL for AZT and PSS over 1–28 d.Conclusion: The obtained results, which were corroborated by MM simulations, attested that the developed system has the potential for effective delivery of anti-HIV-agents. 相似文献