Preface to the special issue on selected papers from the Second International Conference on Semiconductor Photochemistry SP-2

This article gives an overview of the Second International Conference on Semiconductor Photochemistry, SP-2

Screening the Medicines for Malaria Venture (MMV) Pandemic Response Box chemical library on Caenorhabditis elegans identifies re-profiled candidate anthelmintic drug leads

The 3 major classes of soil transmitted helminths (whipworm, hookworm and Ascaris) affect 1.5 billion people worldwide mostly in poor countries, where they have adverse effects on child development, nutrition, and the work capacity of adults. Although there are drugs effective on Ascaris, notably the benzimidazoles, those same drugs show poor efficacy particularly against whipworm (Trichuris trichiura) and to a certain extent hookworm. Parasitic nematodes also infect farm livestock and companion animals. Resistance to currently deployed human and veterinary anthelmintic drugs is a growing problem. Therefore, new chemical anthelmintic lead compounds are urgently needed. One of the fastest routes to a novel therapeutic lead is to screen libraries of drugs which are either already approved for human use or have already been part of clinical trials. We have pursued this approach to anthelmintic lead discovery using an invertebrate automated phenotyping platform (INVAPP) for screening chemicals and the well-established nematode genetic model organism Caenorhabditis elegans. The 400 compound Medicines for Malaria Venture (MMV) Pandemic Response Box library was screened with each compound tested initially at 1.0x10-4 M. We identified 6 compounds (MMV1593515 (vorapaxar), MMV102270 (diphyllin), MMV1581032 (ABX464), MMV1580796 (rubitecan), MMV1580505 and MMV1593531) active in both an L1-L4 growth/motility assay and in an L4 motility assay. For vorapaxar, an EC50 of 5.7x10-7 M was observed, a value comparable to those of some commercial anthelmintics. Although not a parasite, the ease with which high-throughput screens can be pursued on the free-living nematode C. elegans makes this a useful approach to identify chemical leads and complements the often lower-throughput experiments on parasitic nematode models

Anthelmintic drug discovery: target identification, screening methods and the role of open science

Helminths, including cestodes, nematodes and trematodes, are a huge global health burden, infecting hundreds of millions of people. In many cases, existing drugs such as benzimidazoles, diethylcarbamazine, ivermectin and praziquantel are insufficiently efficacious, contraindicated in some populations, or at risk of the development of resistance, thereby impeding progress towards World Health Organization goals to control or eliminate these neglected tropical diseases. However, there has been limited recent progress in developing new drugs for these diseases due to lack of commercial attractiveness, leading to the introduction of novel, more efficient models for drug innovation that attempt to reduce the cost of research and development. Open science aims to achieve this by encouraging collaboration and the sharing of data and resources between organisations. In this review we discuss how open science has been applied to anthelmintic drug discovery. Open resources, including genomic information from many parasites, are enabling the identification of targets for new antiparasitic agents. Phenotypic screening remains important, and there has been much progress in open-source systems for compound screening with parasites, including motility assays but also high content assays with more detailed investigation of helminth physiology. Distributed open science compound screening programs, such as the Medicines for Malaria Venture Pathogen Box, have been successful at facilitating screening in diverse assays against many different parasite pathogens and models. Of the compounds identified so far in these screens, tolfenpyrad, a repurposed insecticide, shows significant promise and there has been much progress in creating more potent and selective derivatives. This work exemplifies how open science approaches can catalyse drug discovery against neglected diseases

An automated high-throughput system for phenotypic screening of chemical libraries on C. elegans and parasitic nematodes

Parasitic nematodes infect hundreds of millions of people and farmed livestock. Further, plant parasitic nematodes result in major crop damage. The pipeline of therapeutic compounds is limited and parasite resistance to the existing anthelmintic compounds is a global threat. We have developed an INVertebrate Automated Phenotyping Platform (INVAPP) for high-throughput, plate-based chemical screening, and an algorithm (Paragon) which allows screening for compounds that have an effect on motility and development of parasitic worms. We have validated its utility by determining the efficacy of a panel of known anthelmintics against model and parasitic nematodes: Caenorhabditis elegans, Haemonchus contortus, Teladorsagia circumcincta, and Trichuris muris. We then applied the system to screen the Pathogen Box chemical library in a blinded fashion and identified compounds already known to have anthelmintic or anti-parasitic activity, including tolfenpyrad, auranofin, and mebendazole; and 14 compounds previously undescribed as anthelmintics, including benzoxaborole and isoxazole chemotypes. This system offers an effective, high-throughput system for the discovery of novel anthelmintics

Dihydrobenz[e][1,4]oxazepin-2(3H)-ones, a new anthelmintic chemotype immobilising whipworm and reducing infectivity in vivo.

Trichuris trichiura is a human parasitic whipworm infecting around 500 million people globally, damaging the physical growth and educational performance of those infected. Current drug treatment options are limited and lack efficacy against the worm, preventing an eradication programme. It is therefore important to develop new treatments for trichuriasis. Using Trichuris muris, an established model for T. trichiura, we screened a library of 480 novel drug-like small molecules for compounds causing paralysis of the ex vivo adult parasite. We identified a class of dihydrobenz[e][1,4]oxazepin-2(3H)-one compounds with anthelmintic activity against T. muris. Further screening of structurally related compounds and resynthesis of the most potent molecules led to the identification of 20 active dihydrobenzoxazepinones, a class of molecule not previously implicated in nematode control. The most active immobilise adult T. muris with EC50 values around 25–50μM, comparable to the existing anthelmintic levamisole. The best compounds from this chemotype show low cytotoxicity against murine gut epithelial cells, demonstrating selectivity for the parasite. Developing a novel oral pharmaceutical treatment for a neglected disease and deploying it via mass drug administration is challenging. Interestingly, the dihydrobenzoxazepinone OX02983 reduces the ability of embryonated T. muris eggs to establish infection in the mouse host in vivo. Complementing the potential development of dihydrobenzoxazepinones as an oral anthelmintic, this supports an alternative strategy of developing a therapeutic that acts in the environment, perhaps via a spray, to interrupt the parasite lifecycle. Together these results show that the dihydrobenzoxazepinones are a new class of anthelmintic, active against both egg and adult stages of Trichuris parasites. They demonstrate encouraging selectivity for the parasite, and importantly show considerable scope for further optimisation to improve potency and pharmacokinetic properties with the aim of developing a clinical agent

L-band synthetic aperture radar imagery performs better than optical datasets at retrieving woody fractional cover in deciduous, dry savannahs

Woody canopy cover (CC) is the simplesttwo dimensional metric for assessing the presence ofthe woody component in savannahs, but detailed validated maps are not currently available in southern African savannahs. A number of international EO programs (including in savannah landscapes) advocate and use optical LandSAT imagery for regional to country-wide mapping of woody canopy cover. However, previous research has shown that L-band Synthetic Aperture Radar (SAR) provides good performance at retrieving woody canopy cover in southern African savannahs. This study’s objective was to evaluate, compare and use in combination L-band ALOS PALSAR and LandSAT-5 TM, in a Random Forest environment, to assess the benefits of using LandSAT compared to ALOS PALSAR. Additional objectives saw the testing of LandSAT-5 image seasonality, spectral vegetation indices and image textures for improved CC modelling. Results showed that LandSAT-5 imagery acquired in the summer and autumn seasons yielded the highest single season modelling accuracies (R2 between 0.47 and 0.65), depending on the year but the combination of multi-seasonal images yielded higher accuracies (R2 between 0.57 and 0.72). The derivation of spectral vegetation indices and image textures and their combinations with optical reflectance bands provided minimal improvement with no optical-only result exceeding the winter SAR L-band backscatter alone results (R2 of ∼0.8). The integration of seasonally appropriate LandSAT-5 image reflectance and L-band HH and HV backscatter data does provide a significant improvement for CC modelling at the higher end of the model performance (R2 between 0.83 and 0.88), but we conclude that L-band only based CC modelling be recommended for South African regionshttp://www.elsevier.com/locate/jag2017-10-31hb2016Geography, Geoinformatics and Meteorolog

2,4-Diaminothieno[3,2-d]pyrimidines, a new class of anthelmintic with activity against adult and egg stages of whipworm

The human whipworm Trichuris trichiura is a parasite that infects around 500 million people globally, with consequences including damage to physical growth and educational performance. Current drugs such as mebendazole have a notable lack of efficacy against whipworm, compared to other soil-transmitted helminths. Mass drug administration programs are therefore unlikely to achieve eradication and new treatments for trichuriasis are desperately needed. All current drug control strategies focus on post-infection eradication, targeting the parasite in vivo. Here we propose developing novel anthelmintics which target the egg stage of the parasite in the soil as an adjunct environmental strategy. As evidence in support of such an approach we describe the actions of a new class of anthelmintic compounds, the 2,4-diaminothieno[3,2-d]pyrimidines (DATPs). This compound class has found broad utility in medicinal chemistry, but has not previously been described as having anthelmintic activity. Importantly, these compounds show efficacy against not only the adult parasite, but also both the embryonated and unembryonated egg stages and thereby may enable a break in the parasite lifecycle

From ideal reactor concepts to reality: the novel drum reactor for photocatalytic wastewater treatment.

This article reports the development of a novel drum photocatalytic reactor for treating dye effluent streams. The parameters for operation including drum rotation speed, light source distance, catalyst loading and H2O2 doping have been investigated using methylene blue as a model pollutant. Effluent can be generated by a number of domestic and industrial sources, including pharmaceutical, oil and gas, agricultural, food and chemical sectors. The work reported here proposes the application of semiconductor photocatalysis as a final polishing step for the removal of hydrocarbons from effluents sources, initial studies have proved effective in removing residual hydrocarbons from the effluent

Hyper-temporal C-band SAR for baseline woody structural assessments in deciduous savannas

Savanna ecosystems and their woody vegetation provide valuable resources and ecosystem services. Locally calibrated and cost effective estimates of these resources are required in order to satisfy commitments to monitor and manage change within them. Baseline maps of woody resources are important for analyzing change over time. Freely available, and highly repetitive, C-band data has the potential to be a viable alternative to high-resolution commercial SAR imagery (e.g., RADARSAT-2, ALOS2) in generating large-scale woody resources maps. Using airborne LiDAR as calibration, we investigated the relationships between hyper-temporal C-band ASAR data and woody structural parameters, namely total canopy cover (TCC) and total canopy volume (TCV), in a deciduous savanna environment. Results showed that: the temporal filter reduced image variance; the random forest model out-performed the linear model; while the TCV metric consistently showed marginally higher accuracies than the TCC metric. Combinations of between 6 and 10 images could produce results comparable to high resolution commercial (C- & L-band) SAR imagery. The approach showed promise for producing a regional scale, locally calibrated, baseline maps for the management of deciduous savanna resources, and lay a foundation for monitoring using time series of data from newer C-band SAR sensors (e.g., Sentinel1).Greg Asner, through the CAO campaign and acknowledged partners, provided funding for the LiDAR acquisition and LiDAR processing, as well as interpretation and review of the results.http://www.mdpi.com/journal/remotesensingam2016Electrical, Electronic and Computer EngineeringGeography, Geoinformatics and Meteorolog

Savannah woody structure modelling and mapping using multi-frequency (X-, C- and L-band) synthetic aperture radar data

Structural parameters of the woody component in African savannahs provide estimates of carbon stocks that are vital to the understanding of fuelwood reserves, which is the primary source of energy for 90% of households in South Africa (80% in Sub-Saharan Africa) and are at risk of over utilisation. The woody component can be characterised by various quantifiable woody structural parameters, such as tree cover, tree height, above ground biomass (AGB) or canopy volume, each been useful for different purposes. In contrast to the limited spatial coverage of ground-based approaches, remote sensing has the ability to sense the high spatio-temporal variability of e.g. woody canopy height, cover and biomass, as well as species diversity and phenological status – a defining but challenging set of characteristics typical of African savannahs. Active remote sensing systems (e.g. Light Detection and Ranging – LiDAR; Synthetic Aperture Radar – SAR), on the other hand, may be more effective in quantifying the savannah woody component because of their ability to sense within-canopy properties of the vegetation and its insensitivity to atmosphere and clouds and shadows. Additionally, the various components of a particular target’s structure can be sensed differently with SAR depending on the frequency or wavelength of the sensor being utilised. This study sought to test and compare the accuracy of modelling, in a Random Forest machine learning environment, woody above ground biomass (AGB), canopy cover (CC) and total canopy volume (TCV) in South African savannahs using a combination of X-band (TerraSAR-X), C-band (RADARSAT-2) and L-band (ALOS PALSAR) radar datasets. Training and validation data were derived from airborne LiDAR data to evaluate the SAR modelling accuracies. It was concluded that the L-band SAR frequency was more effective in the modelling of the CC (coefficient of determination or R2 of 0.77), TCV (R2 of 0.79) and AGB (R2 of 0.78) metrics in Southern African savannahs than the shorter wavelengths (X- and C-band) both as individual and combined (X + C-band) datasets. The addition of the shortest wavelengths also did not assist in the overall reduction of prediction error across different vegetation conditions (e.g. dense forested conditions, the dense shrubby layer and sparsely vegetated conditions). Although the integration of all three frequencies (X + C + L-band) yielded the best overall results for all three metrics (R2 = 0.83 for CC and AGB and R2 = 0.85 for TCV), the improvements were noticeable but marginal in comparison to the L-band alone. The results, thus, do not warrant the acquisition of all three SAR frequency datasets for tree structure monitoring in this environment.Council for Scientific and Industrial Research (CSIR) – South Africa, the Department of Science and Technology, South Africa (Grant Agreement DST/CON 0119/2010, Earth Observation Application Development in Support of SAEOS) and the European Union’s Seventh Framework Programme (FP7/2007-2013, Grant Agreement No. 282621, AGRICAB) for funding this study. The Xband StripMap TerraSAR-X scenes were acquired under a proposal submitted to the TerraSAR-X Science Service of the German Aerospace Center (DLR). The C-band Quad-Pol RADARSAT-2 scenes were provided by MacDonald Dettwiler and Associates Ltd. – Geospatial Services Inc. (MDA GSI), the Canadian Space Agency (CSA), and the Natural Resources Canada’s Centre for Remote Sensing (CCRS) through the Science and Operational Applications Research (SOAR) programme. The L-band ALOS PALSAR FBD scenes were acquired under a K&C Phase 3 agreement with the Japanese Aerospace Exploration Agency (JAXA). The Carnegie Airborne Observatory is supported by the Avatar Alliance Foundation, John D. and Catherine T. MacArthur Foundation, Gordon and Betty Moore Foundation, W.M. Keck Foundation, the Margaret A. Cargill Foundation, Mary Anne Nyburg Baker and G. Leonard Baker Jr., and William R. Hearst III. The application of the CAO data in South Africa is made possible by the Andrew Mellon Foundation, Grantham Foundation for the Protection of the Environment, and the endowment of the Carnegie Institution for Science.http://www.elsevier.com/locate/isprsjprs2016-07-31hb201