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

A humanised anti-IGF-1R monoclonal antibody (AVE1642) enhances Bortezomib-induced apoptosis in myeloma cells lacking CD45

The humanised form of an antagonistic anti-IGF-1R mAb (AVE1642) selectively inhibits the growth of CD45neg myeloma cells. AVE1642 strongly increased bortezomib-induced apoptosis, correlated with an increase of Noxa expression. These results support the therapeutic use of anti-IGF-1R/bortezomib in CD45neg Myeloma patients, particularly those with the most aggressive form, t(4,14)

New Technologies’ Promise to the Self and the Becoming of the Sacred: Insights from Georges Bataille’s Concept of Transgression

This article draws on Georges Bataille’s concept of transgression, a key element in Bataille’s theory of the sacred, to highlight structural implications of the way the self-empowerment ethos of new technologies suffuses the digital tracking culture. Pointing to the original conceptual stance of transgression, worked out against prohibition, I first argue that, beyond a critique of new technologies’ promise of self-empowerment as coming at the expense of an acknowledgement of the ultimate taboo—death—is the problem of the sanitizing of the tension between the crossing of the line of the symbolic taboo and prohibition; this undermines a “libidinal investment” towards the sacred, which is central in Bataille’s theory. Second, focussing on “eroticism”, since this embodies the emancipative potential of the Bataillean sacred, I argue that while a fear of eroticism marks out the digital technological realm, this is covered up by the blurring of boundaries between pleasure, fun and sex(iness) that currently governs our experience with technological devices

Optimization and evaluation of a non-invasive tool for peste des petits ruminants surveillance and control

Peste des petits ruminants (PPR) is a highly contagious and devastating viral disease affecting mainly sheep and goats, but also a large number of wild species within the order Artiodactyla. A better understanding of PPR transmission dynamics in multi-host systems is necessary to efficiently control the disease, in particular where wildlife and livestock co-occur. Notably, the role of wildlife in PPR epidemiology is still not clearly understood. Non-invasive strategies to detect PPR infection without the need for animal handling could greatly facilitate research on PPR epidemiology and management of the disease in atypical hosts and in complex field situations. Here, we describe optimized methods for the direct detection of PPR virus genetic material and antigen in fecal samples. We use these methods to determine the detection window of PPR in fecal samples, and compare the sensitivity of these methods to standard invasive sampling and PPR diagnostic methods using field samples collected at a wildlife-livestock interface in Africa. Our results show that quantitative reverse transcription PCR (RT-QPCR) amplification of PPRV from fecal swabs has good sensitivity in comparison to ocular swabs. Animals infected by PPRV could be identified relatively early on and during the whole course of infection based on fecal samples using RT-QPCR. Partial gene sequences could also be retrieved in some cases, from both fecal and ocular samples, providing important information about virus origin and relatedness to other PPRV strains. Non-invasive strategies for PPRV surveillance could provide important data to fill major gaps in our knowledge of the multi-host PPR epidemiology

A flavoprotein supports cell wall properties in the necrotrophic fungus Alternaria brassicicola

Background Flavin-dependent monooxygenases are involved in key biological processes as they catalyze a wide variety of chemo-, regio- and enantioselective oxygenation reactions. Flavoprotein monooxygenases are frequently encountered in micro-organisms, most of which require further functional and biocatalytic assessment. Here we investigated the function of the AbMak1 gene, which encodes a group A flavin monooxygenase in the plant pathogenic fungus Alternaria brassicicola, by generating a deficient mutant and examining its phenotype. Results Functional analysis indicates that the AbMak1 protein is involved in cell wall biogenesis and influences the melanization process. We documented a significant decrease in melanin content in the Δabmak1 strain compared to the wild-type and complemented strains. We investigated the cell wall morphology and physical properties in the wild-type and transformants using electron and atomic force microscopy. These approaches confirmed the aberrant morphology of the conidial wall structure in the Δabmak1 strain which had an impact on hydrophilic adhesion and conidial surface stiffness. However, there was no significant impairment in growth, conidia formation, pathogenicity or susceptibility to various environmental stresses in the Δabmak1 strain. Conclusion This study sheds new light on the function of a fungal flavin-dependent monooxygenase, which plays an important role in melanization

Care in the time of catastrophe: citizenship, community and the ecological imagination

Published without an abstract

The Saffman-Taylor problem on a sphere

The Saffman-Taylor problem addresses the morphological instability of an interface separating two immiscible, viscous fluids when they move in a narrow gap between two flat parallel plates (Hele-Shaw cell). In this work, we extend the classic Saffman-Taylor situation, by considering the flow between two curved, closely spaced, concentric spheres (spherical Hele-Shaw cell). We derive the mode-coupling differential equation for the interface perturbation amplitudes and study both linear and nonlinear flow regimes. The effect of the spherical cell (positive) spatial curvature on the shape of the interfacial patterns is investigated. We show that stability properties of the fluid-fluid interface are sensitive to the curvature of the surface. In particular, it is found that positive spatial curvature inhibits finger tip-splitting. Hele-Shaw flow on weakly negative, curved surfaces is briefly discussed.Comment: 26 pages, 4 figures, RevTex, accepted for publication in Phys. Rev.

Modelling net-zero emissions energy systems requires a change in approach

Energy modelling can assist national decision makers in determining strategies that achieve net-zero greenhouse gas (GHG) emissions. However, three key challenges for the modelling community are emerging under this radical climate target that needs to be recognized and addressed. A first challenge is the need to represent new mitigation options not currently represented in many energy models. We emphasize here the under representation of end-use sector demand-side options due to the traditional supply side focus of many energy models, along with issues surrounding robustness in deploying carbon dioxide removal (CDR) options. A second challenge concerns the types of models used. We highlight doubts about whether current models provide sufficient relevant insights on system feasibility, actor behaviour, and policy effectiveness. A third challenge concerns how models are applied for policy analyses. Priorities include the need for expanding scenario thinking to incorporate a wider range of uncertainty factors, providing insights on target setting, alignment with broader policy objectives, and improving engagement and transparency of approaches. There is a significant risk that without reconsidering energy modelling approaches, the role that the modelling community can play in providing effective decision support may be reduced. Such support is critical, as countries seek to develop new Nationally Determined Contributions and longer-term strategies over the next few years

Modelling net-zero emissions energy systems requires a change in approach

Energy modelling can assist national decision makers in determining strategies that achieve net-zero greenhouse gas (GHG) emissions. However, three key challenges for the modelling community are emerging under this radical climate target that needs to be recognized and addressed. A first challenge is the need to represent new mitigation options not currently represented in many energy models. We emphasize here the under representation of end-use sector demand-side options due to the traditional supply side focus of many energy models, along with issues surrounding robustness in deploying carbon dioxide removal (CDR) options. A second challenge concerns the types of models used. We highlight doubts about whether current models provide sufficient relevant insights on system feasibility, actor behaviour, and policy effectiveness. A third challenge concerns how models are applied for policy analyses. Priorities include the need for expanding scenario thinking to incorporate a wider range of uncertainty factors, providing insights on target setting, alignment with broader policy objectives, and improving engagement and transparency of approaches. There is a significant risk that without reconsidering energy modelling approaches, the role that the modelling community can play in providing effective decision support may be reduced. Such support is critical, as countries seek to develop new Nationally Determined Contributions and longer-term strategies over the next few years