Current therapies for human African trypanosomiasis (HAT) are unsatisfactory and under threat from emerging drug resistance linked to the loss of transporters, e.g., the P2 aminopurine transporter (TbAT1). Here we compare the uptake and trypanocidal properties of furamidine (DB75), recently evaluated in clinical trials against stage 1 (haemolymphatic) HAT, and two aza analogues, DB820 and CPD0801 (DB829), which are candidate compounds for treatment of stage 2 (neurological) disease. Values of 50% inhibitory concentrations (IC 50 s) determined in vitro against both wild-type and transporter mutant parasites were submicromolar, with DB75 trypanotoxicity shown to be better than and DB820 trypanotoxicity similar to that of the widely used veterinary trypanocide diminazene, while CPD0801 was less active. Activity correlated with uptake and with the minimum drug exposure time necessary to kill trypanosomes: DB75 accumulated at double and 10-fold the rates of DB820 and CPD0801, respectively. All three compounds inhibited P2-mediated adenosine transport with similar K i values, indicating affinity values for this permease in the low to submicromolar range. Uptake of DB75, DB820, and CPD0801 was significantly reduced in tbat1 ؊/؊ parasites and was sensitive to inhibition by adenine, showing that all three compounds are substrates for the P2 transporter. Uptake in vitro was significantly less than that seen with parasites freshly isolated from infected rats, correlating with a downregulation of P2 activity in vitro. We conclude that DB75, DB820, and CPD0801 are actively accumulated by Trypanosoma brucei brucei, with P2 as the main transport route. The aza analogues of DB75 accumulate more slowly than furamidine itself and reveal less trypanocidal activity in standard in vitro drug sensitivity assays.

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African trypanosomiasis is a disease of humans and livestock in many areas south of the Sahara. Resistance to the few existing drugs is a major impediment to the control of these diseases, and we investigated how resistance to the main veterinary drug diminazene aceturate correlates with changes in drug transport in resistant strains. The strain tbat1(Ϫ/Ϫ), lacking the TbAT1/P2 aminopurine transporter implicated previously in diminazene transport, was adapted to higher levels of diminazene resistance. The resulting cell line was designated ABR and was highly cross-resistant to other diamidines and moderately resistant to cymelarsan. Procyclic trypanosomes were shown to be a convenient model to study diamidine uptake in Trypanosoma brucei brucei given the lack of TbAT1/P2 and a 10-fold higher activity of the high-affinity pentamidine transporter (HAPT1). Diminazene could be transported by HAPT1 in procyclic trypanosomes. This drug transport activity was lacking in the ABR line, as reported previously for the pentamidineadapted line B48. The K m for diminazene transport in bloodstream tbat1(Ϫ/Ϫ) trypanosomes was consistent with uptake by HAPT1. Diminazene transport in ABR and B48 cells was reduced compared with tbat1(Ϫ/Ϫ), but their resistance phenotype was different: B48 displayed higher levels of resistance to pentamidine and the melaminophenyl arsenicals, whereas ABR displayed higher resistance to diminazene. These results establish a loss of HAPT1 function as a contributing factor to diminazene resistance but equally demonstrate for the first time that adaptations other than those determining the initial rates of drug uptake contribute to diamidine and arsenical resistance in African trypanosomes.

The development, validation and control of a bi-mode train model is presented. A detailed modular model of a United Kingdom Class 800 train, which included carbon dioxide emissions data, was developed in MATLAB/Simulink. This model was validated against data obtained from a full day of rail journeys in the south-west of England. The validated model was used to develop control measures to reduce the carbon dioxide emissions of the train. Combining adaptive speed limit control with selective engine shutdown reduced the carbon dioxide emissions by 19.1% over a representative route without affecting the train’s on-time performance. The model was used to develop a tool for investigating the emissions benefits of (intermittent/discontinuous) route electrification. This tool shows that electrification of a route can reduce the carbon dioxide emissions by 66%.

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Background Despite their important role in railway operations, switches and crossings (S&C) have changed little since their conception over a century ago. It stands now that the existing designs for S&C are reaching their maximum point of incremental performance improvement, and only a radical redesign can overcome the constraints that current designs are imposing on railway network capacity. This paper describes the process of producing novel designs for next generation switches and crossings, as part of the S-CODE project. Methods Given the many aspects that govern a successful S&C design, it is critical to adopt multi criteria decision making (MCDM) processes to identify a specific solution for the next generation of switches and crossings. However, a common shortcoming of these methods is that their results can be heavily influenced by external factors, such as uncertainty in criterium weighting or bias of the evaluators, for example. This paper therefore proposes a process based on the Pugh Matrix method to reduce such biases by using sensitivity analysis to investigate them and improve the reliability of decision making. Results In this paper, we analysed the influences of three different external factors, measuring the sensitivity of ranking due to (a) weightings, (b) organisational and (c) discipline bias. The order of preference of the results was disturbed only to a minimum while small influences of bias were detected. Conclusions Through this case study, we believe that the paper demonstrates an effective case study for a quantitative process that can improve the reliability of decision making.

This paper focuses on modelling, control, realisation and performance analysis of a full-scale demonstrator for a novel railway track switch. For over a century, railway track switches (or points) have been allowing trains to safely change between routes. As they are safety-critical elements of the rail network, when they fail, the signalling system will prevent trains from using that route. This means poor reliability (or lack of availability) leads to significant delays and costs; hence there is huge interest from researchers and engineers in improving the overall reliability of track switches. This paper presents new results, which represent a meaningful first step toward a revolution in the way track switches are actuated. A “REPOINT-Light” railway track switch demonstrator is introduced which uses a new concept of locking to allow redundant actuation with three actuator bearers operating under closed-loop feedback control. The new concept, its control system and its mechanical viability are tested in experiments at the Great Central Railway in the UK. To support the design of the actuators and the control system, a dynamic simulation model is developed by co-simulation involving Simulink and Simpack. The experimental results presented are used to validate the models and the paper discusses how the models themselves are used as the vehicle for the design of feedback controllers. Virtual testing of the controllers in simulation is a vital step prior to the implementation and deployment of the controllers in the demonstrator switch. The major contribution of this work is demonstrating, for the first time at full scale on a real-world track switch, that it is possible to use one-out-of-three actuator redundancy to provide fault-tolerant operation of railway track switch.

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