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 .     

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.     

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.     

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.     

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.     

Generating short‐term probabilistic wind power scenarios via nonparametric forecast error density estimators

Forecasts of available wind power are critical in key electric power systems operations planning problems, including economic dispatch and unit commitment. Such forecasts are necessarily uncertain, limiting the reliability and cost‐effectiveness of operations planning models based on a single deterministic or “point” forecast. A common approach to address this limitation involves the use of a number of probabilistic scenarios, each specifying a possible trajectory of wind power production, with associated probability. We present and analyze a novel method for generating probabilistic wind power scenarios, leveraging available historical information in the form of forecasted and corresponding observed wind power time series. We estimate nonparametric forecast error densities, specifically using epi‐spline basis functions, allowing us to capture the skewed and nonparametric nature of error densities observed in real‐world data. We then describe a method to generate probabilistic scenarios from these basis functions that allows users to control for the degree to which extreme errors are captured. We compare the performance of our approach to the current state‐of‐the‐art considering publicly available data associated with the Bonneville Power Administration, analyzing aggregate production of a number of wind farms over a large geographic region. Finally, we discuss the advantages of our approach in the context of specific power systems operations planning problems: stochastic unit commitment and economic dispatch. Our methodology is embodied in the joint Sandia–University of California Davis Prescient software package for assessing and analyzing stochastic operations strategies.     

Evaluating the effectiveness of a post-license education program for young novice drivers in Belgium

The disproportionately large number of traffic accidents of young novice drivers highlights the need for an effective driver education program. The Goals for Driving Education (GDE) matrix shows that driver education must target both lower and higher levels of driver competences. Research has indicated that current education programs do not emphasize enough the higher levels, for example awareness and insight. This has raised the importance of insight programs. On the Road (OtR), a Flemish post-license driver education program, is such an insight program that aims to target these higher levels. The program focus is on risky driving behavior like speeding and drink driving. In addition, the program addresses risk detection and risk-related knowledge. The goal of the study was to do an effect evaluation of this insight program at immediate post-test and 2 months follow-up. In addition, the study aimed to generalize the results of this program to comparable programs in order to make usable policy recommendations. A questionnaire based on the Theory of Planned Behavior (TPB) was used in order to measure participants’ safety consciousness of speeding and drink driving. Moreover, we focused on risk detection and risk-related knowledge. Participants (N = 366) were randomly assigned to a baseline—follow-up group or a post-test—follow-up group.     

The use of interorganisational ICT in United States construction projects

In recent research, the use of ICT applications in real time construction projects have been documented and analysed extensively. However, there is a need for identifying and analysing in-depth the mechanisms influencing the use of interorganisational ICT applications and for solutions to eliminate potential barriers to the successful use of ICT. A model is developed providing insights in these mechanisms. Based on this model and expert interviews in the United States construction industry directions for solutions to barriers to the successful use of interorganisational ICT — document management applications, workflow management applications, and product modelling applications — in construction projects are formulated. These solutions focus on stimulating the personal motivation to use ICT, the external motivation to use this technology, and facilitating conditions in terms of knowledge and skills and acting opportunities to use ICT.