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.     

Testing the validity of the spherical DEM model in simulating real granular screening processes

We investigate the flow of a granular material over a vibrated horizontal screen. We perform a direct quantitative comparison, across a range of operating conditions, between laboratory scale experiments and simulations using the discrete element method (DEM). We test the extent to which the commonly employed DEM approximation of particles being spherical affects the ability of the model to realistically reproduce the behaviour of industrial screening systems where the particles are generally non-spherical in shape.The simulation geometry and input particle size distribution are set up to exactly match the experimental system, which consists of a horizontal screen with a wire mesh cloth onto which quarry rock is fed at a series of input flow rates. The screen is vibrated, causing the granular bed to flow over the deck and vertically stratify with finer material passing through the screen, where it is collected in a series of bins located along the length of the screen. The size distribution of the material flowing through each section of the screen is found by analyzing the contents of each collection bin.The best agreement is found for very low flow rates, where the vast majority of the below aperture size material is rapidly captured just after it enters the screen in both the simulation and experiment. At higher flow rates, significant quantitative errors are found with the over-prediction of the flow rate through the screen for near grate sized particles. This is attributed to the higher rate of percolation through the bed and the easier capture by the screen surface of the spherical shaped material. The near aperture sized spherical particles also show a very strong tendency to peg the screen, becoming trapped in the screen openings and limiting further flow through those parts the screen. The use of spherical particles in the DEM simulation of vibrating screens is therefore found to be inadequate for modelling realistic flow and separation of particles that are not actually spherical.     

Re-purposing existing generic games and simulations for e-learning

There is a growing interest among teachers in using games as a part of their lesson plans. A standardised, interoperable approach to the sharing of such game-based lesson plans would allow teachers and educational technologists to compare and contrast Digital Game Based Learning scenarios, allowing best practices and lessons learned to emerge. Although games can be used as ‘add-ons’ in educational contexts, greater benefits can be attained by integrating games more fully into the educational process, i.e. by repurposing existing games to target the specific learning objectives. In this article we analyse this problem. We developed two possible solutions based on the integration and the interaction of games and learning scenarios. The first solution is based on ‘pedagogical wrappers’, where games are linked to e-learning flows but without interaction and communication. The second solution sees a tighter integration which supports ongoing interaction and communication between game and e-learning flow. We applied both solutions to a generic game. This game was firstly programmed in Action Script and later re-used for learning purposes and represented in IMS Learning Design. We analysed the pros and cons of each solution and identify research topics for further research.     

Online bin stretching with three bins

Online bin stretching is a semi-online variant of bin packing in which the algorithm has to use the same number of bins as an optimal packing, but is allowed to slightly overpack the bins. The goal is to minimize the amount of overpacking, i.e., the maximum size packed into any bin. We give an algorithm for online bin stretching with a stretching factor of \(11/8 = 1.375\) for three bins. Additionally, we present a lower bound of \(45/33 = 1.\overline{36}\) for online bin stretching on three bins and a lower bound of 19/14 for four and five bins that were discovered using a computer search.     

Robust forecasting of mortality and fertility rates: A functional data approach

A new method is proposed for forecasting age-specific mortality and fertility rates observed over time. This approach allows for smooth functions of age, is robust for outlying years due to wars and epidemics, and provides a modelling framework that is easily adapted to allow for constraints and other information. Ideas from functional data analysis, nonparametric smoothing and robust statistics are combined to form a methodology that is widely applicable to any functional time series data observed discretely and possibly with error. The model is a generalization of the Lee-Carter (LC) model commonly used in mortality and fertility forecasting. The methodology is applied to French mortality data and Australian fertility data, and the forecasts obtained are shown to be superior to those from the LC method and several of its variants.     

Predicting Eucalyptus spp. stand volume in Zululand,South Africa: an analysis using a stochastic gradient boosting regression ensemble with multi-source data sets

Accurate, reliable, and up-to-date forest stand volume information is a prerequisite for a detailed evaluation of commercial forest resources and their sustainable management. Commercial forest responses to global climate change remain uncertain, and hence the mapping of stand volume as carbon sinks is fundamentally important in understanding the role of forests in stabilizing climate change effects. The aim of this study was to examine the utility of stochastic gradient boosting (SGB) and multi-source data to predict stand volume of a Eucalyptus plantation in South Africa. The SGB ensemble, random forest (RF), and stepwise multiple-linear regression (SMLR) were used to predict Eucalyptus stand volume and other related tree-structural attributes such as mean tree height and mean diameter at breast height (DBH). Multi-source data consisted of SPOT-5 raw spectral features (four bands), 14 spectral vegetation indices, rainfall data, and stand age. When all variables were used, the SGB algorithm showed that stand volume can be accurately estimated (R² = 0.78 and RMSE = 33.16 m³ ha^?1 (23.01% of the mean)). The competing RF ensemble produced an R² value of 0.76 and a RMSE value of 37.28 m³ ha^?1 (38.28% of the mean). SMLR on the other hand, produced an R² value of 0.65 and an RMSE value of 42.50 m³ ha^?1 (42.50% of the mean). Our study further showed that Eucalyptus mean tree height (R² = 0.83 and RMSE = 1.63 m (9.08% of the mean)) and mean diameter at breast height (R² = 0.74 and RMSE = 1.06 (7.89% of the mean)) can also be reasonably predicted using SGB and multi-source data. Furthermore, when the most important SGB model-selected variables were used for prediction, the predictive accuracies improved significantly for mean DBH (R² = 0.81 and RMSE = 1.21 cm (6.12% of the mean)), mean tree height (R² = 0.86 and RMSE = 1.39 m (7.02% of the mean)), and stand volume (R² = 0.83 and RMSE = 29.58 m³ ha^?1 (17.63% of the mean)). These results underscore the importance of integrating multi-source data with remotely sensed data for predicting Eucalyptus stand volume and related tree-structural attributes.     

User Preference for a Control-Based Reduced Processing Decision Support Interface

This study examined trainee crime-scene investigators' preference for, and accuracy in using, four different computer-based decision support interface designs, each of which incorporated a different reduced processing information acquisition strategy. The interfaces differed on the basis of the number of options that could be considered simultaneously and the level of control that could be exercised over the number and sequence in which feature values were accessed. Forty trainee investigators completed six decision scenarios in which they were asked to acquire information and formulate a decision by selecting one of three options. The study comprised two phases, the first of which involved familiarizing participants with each of the four interface designs and collecting performance and subjective data. The second phase involved trainees selecting one of the four interfaces to engage in a fifth and sixth decision scenario involving high or low levels of time-pressure. The results indicated that the “all options, full control” interface was the preferred option in the low time-pressure condition. Although the strategy remained the most frequently selected in the high time-pressure condition, this preference was not significant. It was concluded that the perceptions of difficulty and the degree of user control over information acquisition were more important than perceived efficiency in the selection of computer-based interface designs. The outcomes have implications for the design of decision support systems.     

The Doomsday distributed termination detection protocol

Distributed termination detection (DTD) algorithms are important since they detect globally stable states in distributed computations. Here we introduce a new DTD mechanism, the Doomsday protocol together with its proof of correctness. Doomsday is generic since it forms the basis for a number of new and existing DTD algorithms for which the correctness proof may be reused. The paper describes the Doomsday protocol, provides its formal proof, derives one new DTD algorithm and shows how other hitherto unrelated algorithms, Dijkstra–Scholten, Task Balancing and Credit Recovery, can be derived from the protocol. The paper concludes by examining various properties of the protocol in the context of existing DTD algorithms. This work was supported in part by Visiting Fellowship grant EPSRC GR/R84481/01 “The Doomsday Protocol” and by Australian Research Council ARC Linkage International Grant LX0349049 “Extending a Family of Garbage Collectors”.