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

Study of Effect on Teeth of Intermittent Fluoridation of a Community Water Supply

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67913/2/10.1177_00220345530320011601.pd

Nematic phases and the breaking of double symmetries

In this paper we present a phase classification of (effectively) two-dimensional non-Abelian nematics, obtained using the Hopf symmetry breaking formalism. In this formalism one exploits the underlying double symmetry which treats both ordinary and topological modes on equal footing, i.e. as representations of a single (non-Abelian) Hopf symmetry. The method that exists in the literature (and is developed in a paper published in parallel) allows for a full classification of defect mediated as well as ordinary symmetry breaking patterns and a description of the resulting confinement and/or liberation phenomena. After a summary of the formalism, we determine the double symmetries for tetrahedral, octahedral and icosahedral nematics and their representations. Subsequently the breaking patterns which follow from the formation of admissible defect condensates are analyzed systematically. This leads to a host of new (quantum and classical) nematic phases. Our result consists of a listing of condensates, with the corresponding intermediate residual symmetry algebra and the symmetry algebra characterizing the effective ``low energy'' theory of surviving unconfined and liberated degrees of freedom in the broken phase. The results suggest that the formalism is applicable to a wide variety of two dimensional quantum fluids, crystals and liquid crystals.Comment: 17 pages, 2 figures, correction to table VII, updated reference

The breaking of quantum double symmetries by defect condensation

In this paper, we study the phenomenon of Hopf or more specifically quantum double symmetry breaking. We devise a criterion for this type of symmetry breaking which is more general than the one existing in the literature, and therefore extends the number of possible breaking patterns that can be described consistently. We start by recalling why the extended symmetry notion of quantum double algebras is an optimal tool when analyzing a wide variety of two dimensional physical systems including quantum fluids, crystals and liquid crystals. The power of this approach stems from the fact that one may characterize both ordinary and topological modes as representations of a single (generally non-Abelian) Hopf symmetry. In principle a full classification of defect mediated as well as ordinary symmetry breaking patterns and subsequent confinement phenomena can be given. The formalism applies equally well to systems exhibiting global, local, internal and/or external (i.e. spatial) symmetries. The subtle differences in interpretation for the various situations are pointed out. We show that the Hopf symmetry breaking formalism reproduces the known results for ordinary (electric) condensates, and we derive formulae for defect (magnetic) condensates which also involve the phenomenon of symmetry restoration. These results are applied in two papers which will be published in parallel.Comment: 65 pages, 7 figures, correction in table 3, updated reference

Sugar prevalence in Aedes albopictus differs by habitat, sex and time of day on Masig Island, Torres Strait, Australia

Background: Sugar feeding is a fundamental behaviour of many mosquito species. For Aedes albopictus, an important vector of dengue virus and chikungunya virus, little is known about its sugar-feeding behaviour, and no studies have been conducted on this in the southern hemisphere. This knowledge is pivotal for determining the potential of attractive targeted sugar baits (ATSBs) to control this important vector. Methods: The prevalence of sugar was assessed in 1808 Ae. albopictus from Masig Island, Torres Strait, Australia collected between 13 and 25 March 2020. Fructose presence and content in field-collected Ae. albopictus were quantified using the cold anthrone assay. Results: Significantly more male (35.8%) than female (28.4%) Ae. albopictus were sugar fed. There was a significant interaction between sex and time of day on the probability of capturing sugar-fed Ae. albopictus. For both sexes, fructose prevalence and content were higher in mosquitoes caught in the morning than in the afternoon. Female Ae. albopictus collected in the residential habitat were significantly more likely to be sugar fed than those collected in the woodland habitat. Conclusions: These findings provide baseline information about the sugar-feeding patterns of Ae. albopictus and provide essential information to enable an assessment of the potential of ATSBs for vector suppression and control on Masig Island, with relevance to other locations where this species occurs

Mapping adaptation of barley to droughted environments

Identifying barley genomic regions influencing the response of yield and its components to water deficits will aid in our understanding of the genetics of drought tolerance and the development of more drought tolerant cultivars. We assembled a population of 192 genotypes that represented landraces, old, and contemporary cultivars sampling key regions around the Mediterranean basin and the rest of Europe. The population was genotyped with a stratified set of 50 genomic and EST derived molecular markers, 49 of which were Simple Sequence Repeats (SSRs), which revealed an underlying population sub-structure that corresponded closely to the geographic regions in which the genotypes were grown. A more dense whole genome scan was generated by using Diversity Array Technology (DArT®) to generate 1130 biallelic markers for the population. The population was grown at two contrasting sites in each of seven Mediterranean countries for harvest 2004 and 2005 and grain yield data collected. Mean yield levels ranged from 0.3 to 6.2 t/ha, with highly significant genetic variation in low-yielding environments. Associations of yield with barley genomic regions were then detected by combining the DArT marker data with the yield data in mixed model analyses for the individual trials, followed by multiple regression of yield on markers to identify a multi-locus subset of significant markers/QTLs. QTLs exhibiting a pre-defined consistency across environments were detected in bins 4, 6, 6 and 7 on barley chromosomes 3H, 4H, 5H and 7H respectivel

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

Survey of Farmers Market Managers in California: Food Safety Perspectives

We conducted a survey to characterize certified California farmers markets (FMs) regarding location, seasonality, size, product, product labeling, advertising methods, postharvest practices, regulations governing vendors, training offered, and training interests. Data obtained from the survey highlight the need for improvement regarding food safety and can serve as a basis for development of collaborative education by Extension educators, regulatory agencies, and FMs. Extension professionals can play a proactive role in such training opportunities, focusing outreach efforts for training according to applicable findings and including online training venues to maximize reach to stakeholders

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