Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents

Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC₅₀ value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC₅₀ value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.     

Automated conceptual model clustering: a relator-centric approach

Software and Systems Modeling - In recent years, there has been a growing interest in the use of reference conceptual models to capture information about complex and sensitive business domains...     

A field survey of metal binding to metallothionein and other cytosolic ligands in liver of eels using an on-line isotope dilution method in combination with size exclusion (SE) high pressure liquid chromatography (HPLC) coupled to Inductively Coupled Plasma time-of-flight Mass Spectrometry (ICP-TOFMS)

The effect of metal exposure on the accumulation and cytosolic speciation of metals in livers of wild populations of European eel with special emphasis on metallothioneins (MT) was studied. Four sampling sites in Flanders showing different degrees of heavy metal contamination were selected for this purpose. An on-line isotope dilution method in combination with size exclusion (SE) high pressure liquid chromatography (HPLC) coupled to Inductively Coupled Plasma time-of-flight Mass Spectrometry (ICP-TOFMS) was used to study the cytosolic speciation of the metals. The distribution of the metals Cd, Cu, Ni, Pb and Zn among cytosolic fractions displayed strong differences. The cytosolic concentration of Cd, Ni and Pb increased proportionally with the total liver levels. However, the cytosolic concentrations of Cu and Zn only increased above a certain liver tissue threshold level. Cd, Cu and Zn, but not Pb and Ni, were largely associated with the MT pool in correspondence with the environmental exposure and liver tissue concentrations. Most of the Pb and Ni and a considerable fraction of Cu and Zn, but not Cd, were associated to High Molecular Weight (HMW) fractions. The relative importance of the Cu and Zn in the HMW fraction decreased with increasing contamination levels while the MT pool became progressively more important. The close relationship between the cytosolic metal load and the total MT levels or the metals bound on the MT pool indicates that the metals, rather than other stress factors, are the major factor determining MT induction.     

Using an eye tracker for accurate eye movement artifact correction

We present a new method to correct eye movement artifacts in electroencephalogram (EEG) data. By using an eye tracker, whose data cannot be corrupted by any electrophysiological signals, an accurate method for correction is developed. The eye-tracker data is used in a Kalman filter to estimate which part of the EEG is of ocular origin. The main assumptions for optimal correction are summed and their validity is proven. The eye-tracker-based correction method is objectively evaluated on simulated data of four different types of eye movements and visually evaluated on experimental data. Results are compared to three established correction methods: Regression, Principal Component Analysis, and Second-Order Blind Identification. A comparison of signal to noise ratio after correction by these methods is given in Table II and shows that our method is consistently superior to the other three methods, often by a large margin. The use of a reference signal without electrophysiological influences, as provided by an eye tracker, is essential to achieve optimal eye movement artifact removal.     

A Design-Based Structural Test Method for a Switched-Resistor DAC

In this paper, a design-based structural testing method is presented to enable a fast, low cost test for a switched-resistor digital-to-analogue converter (DAC). A 24-bit stereo DAC is used to demonstrate this. After schematic-level simulations and experimental verification, it is found that the dynamic parameter THD can be predicted by the static test. Practical production wafer test and final test results evaluate this structural test method by comparing it with the traditional THD test method. In this paper the simulation results, the relevant measurement results, and the testing results are discussed. Finally, the application recommendations are given.

Road safety risk evaluation and target setting using data envelopment analysis and its extensions

Currently, comparison between countries in terms of their road safety performance is widely conducted in order to better understand one's own safety situation and to learn from those best-performing countries by indicating practical targets and formulating action programmes. In this respect, crash data such as the number of road fatalities and casualties are mostly investigated. However, the absolute numbers are not directly comparable between countries. Therefore, the concept of risk, which is defined as the ratio of road safety outcomes and some measure of exposure (e.g., the population size, the number of registered vehicles, or distance travelled), is often used in the context of benchmarking. Nevertheless, these risk indicators are not consistent in most cases. In other words, countries may have different evaluation results or ranking positions using different exposure information. In this study, data envelopment analysis (DEA) as a performance measurement technique is investigated to provide an overall perspective on a country's road safety situation, and further assess whether the road safety outcomes registered in a country correspond to the numbers that can be expected based on the level of exposure. In doing so, three model extensions are considered, which are the DEA based road safety model (DEA-RS), the cross-efficiency method, and the categorical DEA model. Using the measures of exposure to risk as the model's input and the number of road fatalities as output, an overall road safety efficiency score is computed for the 27 European Union (EU) countries based on the DEA-RS model, and the ranking of countries in accordance with their cross-efficiency scores is evaluated. Furthermore, after applying clustering analysis to group countries with inherent similarity in their practices, the categorical DEA-RS model is adopted to identify best-performing and underperforming countries in each cluster, as well as the reference sets or benchmarks for those underperforming ones. More importantly, the extent to which each reference set could be learned from is specified, and practical yet challenging targets are given for each underperforming country, which enables policymakers to recognize the gap with those best-performing countries and further develop their own road safety policy.     

Athermal arrayed waveguide gratings in silicon-on-insulator by overlaying a polymer cladding on narrowed arrayed waveguides

Athermal arrayed waveguide gratings (AWGs) in silicon-on-insulator (SOI) are experimentally demonstrated for the first time to our knowledge. By using narrowed arrayed waveguides, and then overlaying a polymer layer, the wavelength temperature dependence of the AWGs is successfully reduced to -1.5 pm/°C, which is more than 1 order of magnitude less than that of normal SOI AWGs. The athermal behavior of the AWGs is obtained with little degradation of their performance. For the central channel, the cross talk is less than -15 dB and the insertion loss is around 2.6 dB. Good characteristics can be maintained with temperatures up to 75 °C. The total size of the device is 350 μm × 250 μm.     

Adoption and Use of Interorganizational ICT in a Construction Project

The objective of this research is to explain why actors are not using interorganizational information and communication technology (ICT) in construction projects in the intended way, by determining the mechanisms that influence the way actors use this ICT over time during a construction project. This explorative research results in a theoretical model that contains four key categories that explains the way actors use ICT in construction projects: (1) personal motivation; (2) external motivation; (3) knowledge and skills; and (4) acting opportunities. The model is compared with three existing influential models about the adoption and use of ICT: the unified theory of acceptance and use of technology, the theory of planned behavior, and the technology acceptance model. In these models missing elements are found. In addition, it is found that fundamental characteristics of construction projects, such as the fragmented and temporarily nature of construction projects, and the different working practices, resources, and objectives of the organizations involved cause most of the barriers to the intended use of interorganizational ICT.     

Occurrence,prevention and remediation of toxigenic fungi and mycotoxins in silage: a review

Ruminants are considered to be less sensitive towards mycotoxins than monogastric animals because rumen microbiota have mycotoxin‐detoxifying capacities. Therefore the effect of mycotoxins towards ruminants has been studied to a lesser extent compared with monogastric animals. Worldwide, a high proportion of the ruminant diet consists of silages made of forage crops (i.e. all parts of the crop above the stubble are harvested). In practice, silages are often contaminated with multiple mycotoxins. Exposure to a cocktail of mycotoxins can hamper animal production and have severe health consequences. In this article the different aspects associated with mycotoxin contamination of silage are reviewed ‘from seed to feed’. An overview is given on the occurrence of toxigenic fungal species and their concomitant mycotoxins in forage crops before and after ensiling. The mycotoxin load of visually non‐mouldy samples and mouldy hot spots within the same silo is also compared. Subsequently, this review delves into different problem‐solving strategies. A logical first step is prevention of mould growth and mycotoxin production in the field, during harvest and during ensiling. If prevention should fail, several remediation strategies are available. These are listed, mainly focusing on the possibilities of microbial degradation of mycotoxins in vivo in silage. © 2015 Society of Chemical Industry