Peptidyl Vinyl Ketone Irreversible Inhibitors of Rhodesain: Modifications of the P2 Fragment

In this paper, we report the design, synthesis and biological investigation of a series of peptidyl vinyl ketones obtained by modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense. Investigation of the structure–activity relationship led us to identify new rhodesain inhibitors endowed with an improved selectivity profile (a selectivity index of up to 22 000 towards the target enzyme), and/or an improved antitrypanosomal activity in the sub-micromolar range.     

Optimized protocol for the biocompatibility testing of compression stockings and similar products with close skin contact in vitro

Biocompatibility of six different compression stockings and cytotoxic effects were determined using HaCaT keratinocytes, L929 mouse fibroblasts, primary adult and juvenile keratinocytes Cells were quantified using a luminometric ATP assay and the photometric BCA test. Cytotoxic effects were determined by LDH release. An area-based extraction ratio of 1.25 cm²:mL could be shown to be superior to the weight-based extraction of test material. Extraction medium should be an acidic sweat solution as this helps to recreate in vivo conditions. Monolayer cultures of HaCaT keratinocytes or L929 mouse fibroblasts should be used for testing. Primary adult keratinocytes or primary juvenile keratinocytes can also be used. For the latter, testing under DMEM with FCS is recommended to achieve comparable results. It was found that the compression stockings tested exhibited no negative influence on cell viability in vitro and no direct cytotoxic effects measured as release of LDH. Hence, good biocompatibility could be asserted.     

Feature-based Groundwater Hydrograph Clustering Using Unsupervised Self-Organizing Map-Ensembles

Hydrograph clustering helps to identify dynamic patterns within aquifers systems, an important foundation of characterizing groundwater systems and their influences, which is necessary to effectively manage groundwater resources. We develope an unsupervised modeling approach to characterize and cluster hydrographs on regional scale according to their dynamics. We apply feature-based clustering to improve the exploitation of heterogeneous datasets, explore the usefulness of existing features and propose new features specifically useful to describe groundwater hydrographs. The clustering itself is based on a powerful combination of Self-Organizing Maps with a modified DS2L-Algorithm, which automatically derives the cluster number but also allows to influence the level of detail of the clustering. We further develop a framework that combines these methods with ensemble modeling, internal cluster validation indices, resampling and consensus voting to finally obtain a robust clustering result and remove arbitrariness from the feature selection process. Further we propose a measure to sort hydrographs within clusters, useful for both interpretability and visualization. We test the framework with weekly data from the Upper Rhine Graben System, using more than 1800 hydrographs from a period of 30 years (1986-2016). The results show that our approach is adaptively capable of identifying homogeneous groups of hydrograph dynamics. The resulting clusters show both spatially known and unknown patterns, some of which correspond clearly to external controlling factors, such as intensive groundwater management in the northern part of the test area. This framework is easily transferable to other regions and, by adapting the describing features, also to other time series-clustering applications.

     

Comparison of chlorine and chloramine in the release of mercury from dental amalgam

The purpose of this project was to compare the ability of chlorine (HOCl/OCl⁻) and monochloramine (NH₂Cl) to mobilize mercury from dental amalgam. Two types of amalgam were used in this investigation: laboratory-prepared amalgam and samples obtained from dental-unit wastewater. For disinfectant exposure simulations, 0.5 g of either the laboratory-generated or clinically obtained amalgam waste was added to 250 mL amber bottles. The amalgam samples were agitated by end-over-end rotation at 30 rpm in the presence of 1 mg/L chlorine, 10 mg/L chlorine, 1 mg/L monochloramine, 10 mg/L monochloramine, or deionized water for intervals of 0 h, 2 h, 4 h, 8 h, and 24 h for the clinically obtained amalgam waste samples and 4 h and 24 h for the laboratory-prepared samples. Chlorine and monochloramine concentrations were measured with a spectrophotometer. Samples were filtered through a 0.45 µm membrane filter and analyzed for mercury with USEPA standard method 245.7. When the two sample types were combined, the mean mercury level in the 1 mg/L chlorine group was 0.020 mg/L (n = 25, SD = 0.008). The 10 mg/L chlorine group had a mean mercury concentration of 0.59 mg/L (n = 25, SD = 1.06). The 1 mg/L chloramine group had a mean mercury level of 0.023 mg/L (n = 25, SD = 0.010). The 10 mg/L chloramine group had a mean mercury level of 0.024 mg/L (n = 25, SD = 0.011). Independent samples t-tests showed that there was a significant difference between the natural log mercury measurements of 10 mg/L chlorine compared to those of 1 mg/L and 10 mg/L chloramine. Changing from chlorine to chloramine disinfection at water treatment plants would not be expected to produce substantial increases in dissolved mercury levels in dental-unit wastewater.     

Identifying contemporary and historic sources of soil polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in an industrial urban setting

A study of soil polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) concentrations was undertaken in the vicinity of a municipal solid waste incinerator (MSWI) in Newcastle upon Tyne as a result of concerns raised by local residents about potential contamination from fugitive and stack emissions. The study area was divided into four sectors (north-east (NE), south-east (SE), north-west (NW) and south-west (SW)) around the MSWI, and sampling sites were located up to a distance of 2.25 km. Based on air dispersion modelling, the sampling density was four times greater in the NE (downwind) sector compared to the SW (upwind) direction, and twice as great in the NW and SE sectors. PCDD/F concentrations found in soil samples ranged from 6 to 1911 ng I-TEQ/kg DW with a median of 32 ng I-TEQ/kg DW. There was no evidence of elevated concentrations downwind of the MSWI compared to other directions, nor of any trend in concentration at increasing distance from the MSWI. We concluded, therefore, that the MSWI fugitive and stack emissions were not a major source of PCDD/F contamination. Analysis of PCDD/F homologue profiles showed that samples exhibiting furan-dominated and OCDD-dominated profiles and a profile characteristic of the MSWI ash occurred in distinct clusters. Those samples showing the furan-dominated profile had the largest PCDD/F concentrations measured as I-TEQ, followed by samples with the incinerator profile, the deposition profile, and the OCDD-dominated profile. We identified some contamination hotspots located in the SW and SE sampling sectors (upwind of the MSWI), and potential sources for these hotspots were sought by using historic land use data from maps of the locality dating back to 1856. We concluded that the cluster of very high concentrations of PCDD/F in soils showing the furan homologue profile were most likely to have resulted from the disposal of graphite electrode sludges from brine electrolysis carried out at a chemical works between the 1890s and the 1930s.     

Metal contamination of urban soils in the vicinity of a municipal waste incinerator: one source among many

Concern from local residents about possible contamination with metals and PCDD/F (dioxins and furans) from fugitive and stack emissions from the Byker municipal solid waste incinerator in Newcastle upon Tyne led the City Council to initiate a study of the concentration of these pollutants in soils. We report here the results for the metals and arsenic. Soils were sampled at distances up to 2.25 km from the incinerator stack. The intensity of sampling in concentric zones was four times greater in the northeast (down-wind) direction, and twice as great in the northwest and southeast directions, compared to the southwest (up-wind) direction. In total 163 samples were collected and analyzed for total As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn. Concentrations were generally elevated above background levels, but were typical of those found in other urban areas. For As, Cd, Cu, Hg, Pb, and Zn, contamination hotspots were identified. These were spread throughout the sampling area, and there was no evidence of greater concentrations down-wind of the incinerator compared to other directions, nor of any trend in concentration at increasing distance from the incinerator. We concluded that metal contamination resulting from the incinerator could not be detected in an environment with generally elevated concentrations. Potential sources for many of the hotspots of contamination were identified in a survey of historic land use based on maps of the locality dating back to 1856. Detailed investigations of particular areas with serious contamination will now be undertaken by the local authorities using the CLEA (Contaminated Land Exposure Assessment) model.     

Changing places: New Zealand Houses by Winkler & Eisenhofer 1958 to 1969

The Austrian-born architects Erwin Winkler and Fritz Eisenhofer immigrated to New Zealand during the 1950s. After working at the Housing Division of the Ministry of Works, they established a joint architectural practice in 1958 when the growing New Zealand economy and governmental efforts, such as the Group Housing Scheme, increased the building of homes. At the same time the repetitive appearance of English Cottage Style state houses, that had been built in reaction to a severe housing shortage after the Second World War, led to a demand for architecturally designed homes. In reaction to this,Winkler & Eisenhofer established a reputation as a non-conformist practice in creating homes that not only offered modern open-plan living, but also featured unusual features, murals or sculptures. After New Zealand had overcome the housing shortage by the early 1960s, and during an economic upsurge, the practice received commissions from wealthy clients and was no longer competing with builders who offered standardised homes. Winkler & Eisenhofer now oriented their houses towards contemporary American precedents created for a clientele who wished their homes to reflect individuality, internationality and modernity. A number of architectural practices sought at the same time to develop a distinct New Zealand architectural idiom. This paper investigates how the careers of Winkler & Eisenhofer developed at a time when the demand for homes that were designed to overcome a housing shortage, shifted to a demand for modern houses that reflected a newly developing life-style. Within the complex discourse on architectural modernism in New Zealand, Winkler & Eisenhofer's houses were created outside of the ongoing search for a distinct New Zealand style.