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

The mediating effect of task presentation on collaboration and children's acquisition of scientific reasoning

There has been considerable research concerning peer interaction and the acquisition of children's scientific reasoning. This study investigated differences in collaborative activity between pairs of children working around a computer with pairs of children working with physical apparatus and related any differences to the development of children's scientific reasoning. Children aged between 9 and 10 years old (48 boys and 48 girls) were placed into either same ability or mixed ability pairs according to their individual, pre-test performance on a scientific reasoning task. These pairs then worked on either a computer version or a physical version of Inhelder and Piaget's (1958) chemical combination task. Type of presentation was found to mediate the nature and type of collaborative activity. The mixed-ability pairs working around the computer talked proportionally more about the task and management of the task; had proportionally more transactive discussions and used the record more productively than children working with the physical apparatus. Type of presentation was also found to mediated children's learning. Children in same ability pairs who worked with the physical apparatus improved significantly more than same ability pairs who worked around the computer. These findings were partially predicted from a socio-cultural theory and show the importance of tools for mediating collaborative activity and collaborative learning

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

Popular attitudes to memory, the body, and social identity : the rise of external commemoration in Britain, Ireland, and New England

A comparative analysis of samples of external memorials from burial grounds in Britain, Ireland and New England reveals a widespread pattern of change in monument style and content, and exponential growth in the number of permanent memorials from the 18th century onwards. Although manifested in regionally distinctive styles on which most academic attention has so far been directed, the expansion reflects global changes in social relationships and concepts of memory and the body. An archaeological perspective reveals the importance of external memorials in articulating these changing attitudes in a world of increasing material consumption

Indirect search for dark matter: prospects for GLAST

Possible indirect detection of neutralino, through its gamma-ray annihilation product, by the forthcoming GLAST satellite from our galactic halo, M31, M87 and the dwarf galaxies Draco and Sagittarius is studied. Gamma-ray fluxes are evaluated for the two representative energy thresholds, 0.1 GeV and 1.0 GeV, at which the spatial resolution of GLAST varies considerably. Apart from dwarfs which are described either by a modified Plummer profile or by a tidally-truncated King profiles, fluxes are compared for halos with central cusps and cores. It is demonstrated that substructures, irrespective of their profiles, enhance the gamma-ray emission only marginally. The expected gamma-ray intensity above 1 GeV at high galactic latitudes is consistent with the residual emission derived from EGRET data if the density profile has a central core and the neutralino mass is less than 50 GeV, whereas for a central cusp only a substantial enhancement would explain the observations. From M31, the flux can be detected above 0.1 GeV and 1.0 GeV by GLAST only if the neutralino mass is below 300 GeV and if the density profile has a central cusp, case in which a significant boost in the gamma-ray emission is produced by the central black hole. For Sagittarius, the flux above 0.1 GeV is detectable by GLAST provided the neutralino mass is below 50 GeV. From M87 and Draco the fluxes are always below the sensitivity limit of GLAST.Comment: 14 Pages, 7 Figures, 3 Tables, version to appear on Physical Review

A sociocultural analysis of the development of pre-service and beginning teachers’ pedagogical identities as users of technology

This paper reports on a study that investigated the pedagogical practices and beliefs of pre-service and beginning teachers in integrating technology into the teaching of secondary school mathematics. A case study documents how one teachers modes of working with technology changed over time and across different school contexts, and identifies relationships between a range of personal and contextual factors that influenced the development of his identity as a teacher. This analysis views teachers learning as increasing participation in sociocultural practices, and uses Valsiners concepts of the Zone of Proximal Development, Zone of Free Movement, and Zone of Promoted Action to offer a dynamic way of theorising teacher learning as identity formation