Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d -mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar KD values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as 1H,15N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability. 相似文献
Plasmonic Ag@ZnO core@shell nanoparticles are formed by synthesis inside helium droplets with subsequent deposition and controlled oxidation. The particle size and shape can be controlled from spherical sub-10 nm particles to larger elongated structures. An advantage of the method is the complete absence of solvents, precursors, and other chemical agents. The obtained particle morphology and elemental composition have been analyzed by scanning transmission electron microscopy (STEM) and energy dispersive X-ray spectroscopy (EDS). The results reveal that the produced particles form a closed and homogeneous ZnO layer around a 2–3 nm Ag core with a uniform thickness of (1.33 ± 0.15) nm and (1.63 ± 0.31) nm for spherical and wire-like particles, respectively. The results are supported by ultraviolet photoelectron spectroscopy (UPS), which indicates a fully oxidized shell layer for the particles studied by STEM. The plasmonic properties of the produced spherical Ag@ZnO core@shell particles are investigated by two-photon photoelectron (2PPE) spectroscopy. Upon excitation of the localized surface plasmon resonance in Ag at around 3 eV, plasmonic enhancement leads to the liberation of electrons with high kinetic energy. This is observed for both Ag and Ag@ZnO particles, showing that even if a Ag cluster is covered by the ZnO layer, a plasmonic enhancement can be observed by photoelectron spectroscopy.
Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewisx has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewisx and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved. 相似文献
Membrane fouling by macromolecular dissolved organic compounds is still a fundamental drawback in low-pressure membrane filtration of secondary effluent. In this study, pre-treatment of secondary effluent by coagulation and/or adsorption was investigated in terms of removal of different dissolved organic carbon (DOC) fractions, especially macromolecular substances. DOC fractionation has been characterised by size exclusion chromatography. Adsorption tests using four commercially available activated carbons yielded a removal of small as well as larger organic compounds, revealing differences in the affinity towards macromolecules depending on the type of applied activated carbon. By contrast, coagulation removed predominantly larger molecules, i.e., biopolymers and humic substances. In terms of DOC reduction, the coagulant ferric chloride was superior to aluminium chloride. A combination of coagulation and adsorption resulted in the addition of individual removal efficiencies, suggesting that different fractions of organic compounds were involved in each of the processes. After removal of macromolecular organic compounds either by coagulation or by adsorption, a significant reduction of membrane fouling was observed in tests using two different types of ultrafiltration flat-sheet membranes in 20-h cross-flow filtration tests. 相似文献
In order to account for complex interactions between humans climate and the water cycle, the research consortium GLOWA-Danube (www.glowa-danube.de) has developed the simulation system DANUBIA which consists of 17 coupled models. DANUBIA was applied to investigate various impacts of global-change between 2011 and 2060 in the Upper Danube Catchment. This article describes part 2 of an article series with investigations of socio-economic aspects, while part 1 (Barthel et al. in Grundwasser 16(4), doi:10.1007/s007-011-01794, 2011) deals with natural-spatial aspects. The principles of socio-economic actor-modeling and interactions between socio-economic and natural science model components are described here. We present selected simulations that show impacts on groundwater from changes in agriculture, tourism, economy, domestic water users and water supply. Despite decreases in water consumption, the scenario simulations show significant decreases in groundwater quantity. On the other hand, groundwater quality will likely be influenced more severely by land use changes compared to direct climatic causes. However, overall changes will not be dramatic. 相似文献
To minimize the risk posed by runoff from row crops, Prince Edward Island introduced buffer legislation in 2000. The legislation mandates 10-m and 20-m buffers, respectively, for moderate sloped (i.e. < 5%) and steep sloped (i.e. > 5%) agricultural fields that border streams. Since 2001, Environment Canada has been evaluating the effectiveness of various buffer widths on operational farms in reducing toxicity and contaminant concentrations in runoff. Sample collectors, placed in 44 fields at the field edge (0 m), 10 m and at distances out to 30 m, collected overland flow following rainfall-induced runoff events. Samples were collected within 24 hours of an event and analysed for seven pesticides (endosulfan, chlorothalonil, carbofuran, linuron, metribuzin, metalaxyl, mancozeb), water quality parameters and Daphnia magna toxicity. The 10-m buffer required for moderate sloped fields was effective at reducing contaminant concentrations but not always to less than lethal concentrations to Daphnia magna. Limited data beyond 10 m for fields of both slope types precluded making recommendations on a suitable buffer width for shallow sloped fields and evaluating the effectiveness of 20-m buffers for steep sloped fields. When paired data were combined and statistically tested for all fields, the studied pesticides underwent a 52-98% and 68-100% reduction in aqueous and particulate concentrations within 10 m and 30 m, respectively. In addition, by 10 m, soluble phosphorus, nitrate-nitrogen and total suspended solids were reduced by 34%, 38% and 64%, respectively. Results suggest buffer zones on operational farms are capable of achieving contaminant reductions comparable to those reported for controlled experiments. Inconsistent siting of sample collectors beyond 10 m limited the evaluation of the effects of field slope and buffer width on buffer effectiveness on working farms. Future studies on buffer efficiency on operational farms should focus on building the data set beyond 10 m and evaluating load reductions. 相似文献
This paper explores how programme management (as opposed to project management) can contribute to the effective design and delivery of megaprojects. Traditionally, project management is considered to be performance focused and task oriented, whilst programme management entails a more strategic focus. The programme management literature suggests that this can result in tensions between the management of the projects and the programme as a whole. This paper uses the findings of the €2.4 billion Room for the River flood protection programme in the Netherlands as a case study, because indicators about its budget, time, quality and stakeholder satisfaction suggest high programme management performance upon completion of the planning and design stage of its 39 river widening projects. Based on a literature review, document analysis and 55 face-to-face interviews, we have analysed how the programme management of the programme contributed to this result. Six attributes for effective programme management that are identified from the project and programme management literature are used to structure the research data. Consecutively, the interactions between project and programme management are analysed. The analysis of Room for the River reveals a combined strategic/performance focus at the level of both programme and project management that enables a collaborative approach between programme and project management. This particularly enables effective stakeholder collaboration, coordination and adaptation of the programme to contextual changes, newly acquired insights and the changing needs of consecutive planning stages, which positively contributes to the performance of the programme as a whole. 相似文献
We solve systems of boolean implicit equations and relations with union and complementation. If the languages are regular, we determine whether a system of implicit boolean equations or relations has solutions. If there is a solution, we provide an effective construction of a (regular) solution. We give representations for maximal and minimal solutions. Moreover, we also solve the problem of uniqueness of solutions as well as whether infinitely many solutions exist. 相似文献