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.     

Spray Drying of Lactobacillus plantarum WCFS1 Guided by Predictive Modeling

Shelf life of probiotic microorganisms can be retained by drying. Spray drying is an economically interesting alternative to freeze drying with that respect. However, the viability can decrease due to the drying process and testing it is laborious and expensive. This research shows that the viability of Lactobacillus plantarum WCFS1 during pilot scale drying can be predicted with kinetics gathered at a single droplet level. Using this approach, it could be demonstrated that the viability of L. plantarum WCFS1 during spray drying is mainly determined by the combination of temperature and moisture content during the first 0.5 seconds after atomization. The combination of a high moisture content and a high temperature appeared most detrimental to the residual viability. Moreover, it was found to be important to take into account the particle size distribution during atomization when predicting viability, since this has a large effect on the moisture content during this first 0.5 seconds. Finally, it was observed that shelf life during storage was mainly determined by the moisture content of the powder. A lower moisture content resulted in a higher viability. Above a moisture content of 6%, shelf life stability rapidly decreased in the applied maltodextrin (DE = 16) matrix.     

Learning in a changing environment.

Multiple cue probability learning studies have typically focused on stationary environments. We present 3 experiments investigating learning in changing environments. A fine-grained analysis of the learning dynamics shows that participants were responsive to both abrupt and gradual changes in cue–outcome relations. We found no evidence that participants adapted to these types of change in qualitatively different ways. Also, in contrast to earlier claims that these tasks are learned implicitly, participants showed good insight into what they learned. By fitting formal learning models, we investigated whether participants learned global functional relationships or made localized predictions from similar experienced exemplars. Both a local (the associative learning model) and a global learning model (the Bayesian linear filter) fitted the data of the first 2 experiments. However, the results of Experiment 3, which was specifically designed to discriminate between local and global learning models, provided more support for global learning models. Finally, we present a novel model to account for the cue competition effects found in previous research and displayed by some of our participants. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

‘Disruptive technologies’, ‘pedagogical innovation’: What’s new? Findings from an in-depth study of students’ use and perception of technology

The paper describes the findings from a study of students’ use and experience of technologies. A series of in-depth case studies were carried out across four subject disciplines, with data collected via survey, audio logs and interviews. The findings suggest that students are immersed in a rich, technology-enhanced learning environment and that they select and appropriate technologies to their own personal learning needs. The findings have profound implications for the way in which educational institutions design and support learning activities.     

The effect of silicide on ESD performance of transistors

In this paper a new model for localized breakdown in NMOSTs under ESD stress is developed, which accounts for the reduced ESD strength in silicided devices. The model explains the impact of a stabilizing drain resistance on second breakdown current for both silicided and unsilicided protections.     

Appropriation of a shared workspace: Organizing principles and their application

The use and effects of a CSCL-tool are not always predictable from the properties of the tool alone, but depend on how that tool is appropriated. This paper presents the findings from a case study about the appropriation of a graphical shared workspace. When students are presented with a new tool they may encounter competing constraints and multiple possibilities for interacting with it. We argue that during critical events the students make choices, and in order to collaborate, coordinate these choices as a group. We study appropriation by looking into the ways in which small groups organize their contributions during a computer-mediated argumentative discussion. The results of our study illustrate how certain principles for organization emerge from an implicit negotiation of conventions, with mutual influence between the students and the tool.     

Metal Nanocatalyst Sintering Interrogated at Complementary Length Scales

Metal nanoparticle (NP) sintering is a prime cause of catalyst degradation, limiting its economic lifetime and viability. To date, sintering phenomena are interrogated either at the bulk scale to probe averaged NP properties or at the level of individual NPs to visualize atomic motion. Yet, “mesoscale” strategies which bridge these worlds can chart NP populations at intermediate length scales but remain elusive due to characterization challenges. Here, a multi-pronged approach is developed to provide complementary information on Pt NP sintering covering multiple length scales. High-resolution scanning electron microscopy (HRSEM) and Monte Carlo simulation show that the size evolution of individual NPs depends on the number of coalescence events they undergo during their lifetime. In its turn, the probability of coalescence is strongly dependent on the NP's mesoscale environment, where local population heterogeneities generate NP-rich “hotspots” and NP-free zones during sintering. Surprisingly, advanced in situ synchrotron X-ray diffraction shows that not all NPs within the small NP sub-population are equally prone to sintering, depending on their crystallographic orientation on the support surface. The demonstrated approach shows that mesoscale heterogeneities in the NP population drive sintering and mitigation strategies demand their maximal elimination via advanced catalyst synthesis strategies.