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.     

Induction of Oxidative Stress and Antioxidative Mechanisms in Arabidopsis thaliana after Uranium Exposure at pH 7.5

To evaluate the environmental impact of uranium (U) contamination, it is important to investigate the effects of U at ecologically relevant conditions. Since U speciation, and hence its toxicity, strongly depends on environmental pH, the present study aimed to investigate dose-dependent effects of U at pH 7.5. Arabidopsis thaliana plants (Mouse-ear Cress) were exposed for three days to different U concentrations at pH 7.5. In the roots, the increased capacities of ascorbate peroxidase and glutathione reductase indicate an important role for the ascorbate-glutathione cycle during U-induced stress. However, a significant decrease in the ascorbate redox state was observed after exposure to 75 and 100 µM U, indicating that those roots are severely stressed. In accordance with the roots, the ascorbate-glutathione cycle plays an important role in the antioxidative defence systems in A. thaliana leaves exposed to U at pH 7.5 as the ascorbate and glutathione biosynthesis were upregulated. In addition, small inductions of enzymes of the antioxidative defence system were observed at lower U concentrations to counteract the U-induced stress. However, at higher U concentrations it seems that the antioxidative defence system of the leaves collapses as reductions in enzyme activities and gene expression levels were observed.     

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.     

On information and communication technology and production cost in construction industry: evidence from the Netherlands

The interplay between information and communication technology (ICT) and the competitiveness of construction firms is considered. More specifically, the question is whether firms that invest in information and communication technology have a production cost advantage. The economics literature hypothesizes that ICT brings about a production cost advantage, as ICT brings flexibility and improves the planning, organization and control of work. To test this proposition for the construction industry, a production cost function allowing for the inclusion of ICT is formulated. Using statistical nearest-neighbour matching methods it is possible to identify the effect of ICT on production costs thereby controlling for economic moderators. Data from a sample of Dutch construction firms reveal that those firms that installed ICT capital do have a production cost advantage. The results indicate further that firms need a minimum level of ICT capital to fully benefit from its production cost advantage.     

Immune and Anticancer Responses Elicited by Fully Synthetic Aberrantly Glycosylated MUC1 Tripartite Vaccines Modified by a TLR2 or TLR9 Agonist

The mucin MUC1 is overexpressed and aberrantly glycosylated by many epithelial cancer cells manifested by truncated O‐linked saccharides. Although tumor‐associated MUC1 has generated considerable attention because of its potential for the development of a therapeutic cancer vaccine, it has been difficult to design constructs that consistently induce cytotoxic T‐lymphocytes (CTLs) and ADCC‐mediating antibodies specific for the tumor form of MUC1. We have designed, chemically synthesized, and immunologically examined vaccine candidates each composed of a glycopeptide derived from MUC1, a promiscuous T_helper peptide, and a TLR2 (Pam₃CysSK₄) or TLR9 (CpG‐ODN 1826) agonist. It was found that the Pam₃CysSK₄‐containing compound elicits more potent antigenic and cellular immune responses, resulting in a therapeutic effect in a mouse model of mammary cancer. It is thus shown, for the first time, that the nature of an inbuilt adjuvant of a tripartite vaccine can significantly impact the quality of immune responses elicited against a tumor‐associated glycopeptide. The unique adjuvant properties of Pam₃CysSK₄, which can reduce the suppressive function of regulatory T cells and enhance the cytotoxicity of tumor‐specific CTLs, are likely responsible for the superior properties of the vaccine candidate 1 .     

Does attention capacity moderate the effect of driver distraction in older drivers?

With age, a decline in attention capacity may occur and this may impact driving performance especially while distracted. Although the effect of distraction on driving performance of older drivers has been investigated, the moderating effect of attention capacity on driving performance during distraction has not been investigated yet. Therefore, the aim was to investigate whether attention capacity has a moderating effect on older drivers’ driving performance during visual distraction (experiment 1) and cognitive distraction (experiment 2). In a fixed-based driving simulator, older drivers completed a driving task without and with visual distraction (experiment 1, N = 17, mean age 78 years) or cognitive distraction (experiment 2, N = 35, mean age 76 years). Several specific driving measures of varying complexity (i.e., speed, lane keeping, following distance, braking behavior, and crashes) were investigated. In addition to these objective driving measures, subjective measures of workload and driving performance were also included. In experiment 1, crash occurrence increased with visual distraction and was negatively related to attention capacity. In experiment 2, complete stops at stop signs decreased, initiation of braking at pedestrian crossings was later, and crash occurrence increased with cognitive distraction. Interestingly, for a measure of lane keeping (i.e., standard deviation of lateral lane position (SDLP)), effects of both types of distraction were moderated by attention capacity. Despite the decrease of driving performance with distraction, participants estimated their driving performance during distraction as good. These results imply that attention capacity is important for driving. Driver assessment and training programs might therefore focus on attention capacity. Nonetheless, it is crucial to eliminate driver distraction as much as possible given the deterioration of performance on several driving measures in those with low and high attention capacity.     

Connect & Drive: design and evaluation of cooperative adaptive cruise control for congestion reduction

Road throughput can be increased by driving at small inter-vehicle time gaps. The amplification of velocity disturbances in upstream direction, however, poses limitations to the minimum feasible time gap. This effect is covered by the notion of string stability. String-stable behavior is thus considered an essential requirement for the design of automatic distance control systems, which are needed to allow for safe driving at time gaps well below 1 s. Using wireless inter-vehicle communications to provide real-time information of the preceding vehicle, in addition to the information obtained by common Adaptive Cruise Control (ACC) sensors, appears to significantly decrease the feasible time gap, which is shown by practical experiments with a test fleet consisting of six passenger vehicles. The large-scale deployment of this system, known as Cooperative ACC (CACC), however, poses challenges with respect to the reliability of the wireless communication system. A solution for this scalability problem can be found in decreasing the transmission power and/or beaconing rate, or adapting the communications protocol. Although the main CACC objective is to increase road throughput, the first commercial application of CACC is foreseen to be in truck platooning, since short distance following is expected to yield significant fuel savings in this case.

     

Chloride binding isotherm from migration and diffusion tests

Chloride binding is often described by chloride binding isotherm, which is closely related to the service life of concrete structures in chloride environments. Many methods have been proposed to determine chloride binding isotherm. Compared to other methods, chloride binding isotherms obtained directly from nonsteady-state diffusion tests seem closer to the reality. We studied the chloride binding isotherm from both nonsteady-state electrical-accelerated migration and diffusion tests at different temperatures. Twelve concrete mixes with different supplementary cementing materials and water-to-binder ratios of 0.35, 0.48 and 0.6 were cast for study. The specimens after diffusion (or migration) tests were sliced layer by layer, and acid-soluble and free chloride contents of each layer were measured. A chloride binding isotherm was obtained from one specimen. Experimental results indicated that electrical voltage had a slight effect on the chloride binding isotherm of concrete. Temperature had a positive effect on chloride binding. The higher the water-to-binder ratio was, the higher the chloride binding was.     

Evaluative conditioning in humans: A meta-analysis.

This article presents a meta-analysis of research on evaluative conditioning (EC), defined as a change in the liking of a stimulus (conditioned stimulus; CS) that results from pairing that stimulus with other positive or negative stimuli (unconditioned stimulus; US). Across a total of 214 studies included in the main sample, the mean EC effect was d = .52, with a 95% confidence interval of .466–.582. As estimated from a random-effects model, about 70% of the variance in effect sizes were attributable to true systematic variation rather than sampling error. Moderator analyses were conducted to partially explain this variation, both as a function of concrete aspects of the procedural implementation and as a function of the abstract aspects of the relation between CS and US. Among a range of other findings, EC effects were stronger for high than for low contingency awareness, for supraliminal than for subliminal US presentation, for postacquisition than for postextinction effects, and for self-report than for implicit measures. These findings are discussed with regard to the procedural boundary conditions of EC and theoretical accounts about the mental processes underlying EC. (PsycINFO Database Record (c) 2010 APA, all rights reserved)