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

Cabinet-Makers' Awareness and Usage of Rainforest Cabinet Timbers in Queensland

This paper reports findings of surveys into the usage of, and attitudes to, rainforest cabinet timbers by cabinet-makers in Queensland, Australia. In determining policies to promote growing of native rainforest trees on private land, it is necessary to know the market requirements for various cabinet species. The species most in demand by cabinet-makers are identified in this paper. Suitability and availability are found to be important determinants of cabinet-maker demand for timber. The species being planted in north Queensland are not a close match with those predicted by cabinet-makers to be in greatest demand in the future

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

Novae Ejecta as Colliding Shells

Following on our initial absorption-line analysis of fifteen novae spectra we present additional evidence for the existence of two distinct components of novae ejecta having different origins. As argued in Paper I one component is the rapidly expanding gas ejected from the outer layers of the white dwarf by the outburst. The second component is pre-existing outer, more slowly expanding circumbinary gas that represents ejecta from the secondary star or accretion disk. We present measurements of the emission-line widths that show them to be significantly narrower than the broad P Cygni profiles that immediately precede them. The emission profiles of novae in the nebular phase are distinctly rectangular, i.e., strongly suggestive of emission from a relatively thin, roughly spherical shell. We thus interpret novae spectral evolution in terms of the collision between the two components of ejecta, which converts the early absorption spectrum to an emission-line spectrum within weeks of the outburst. The narrow emission widths require the outer circumbinary gas to be much more massive than the white dwarf ejecta, thereby slowing the latter's expansion upon collision. The presence of a large reservoir of circumbinary gas at the time of outburst is suggestive that novae outbursts may sometime be triggered by collapse of gas onto the white dwarf, as occurs for dwarf novae, rather than steady mass transfer through the inner Lagrangian point.Comment: 12 pages, 3 figures; Revised manuscript; Accepted for publication in Astrophysics & Space Scienc

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

Electric current circuits in astrophysics

Cosmic magnetic structures have in common that they are anchored in a dynamo, that an external driver converts kinetic energy into internal magnetic energy, that this magnetic energy is transported as Poynting fl ux across the magnetically dominated structure, and that the magnetic energy is released in the form of particle acceleration, heating, bulk motion, MHD waves, and radiation. The investigation of the electric current system is particularly illuminating as to the course of events and the physics involved. We demonstrate this for the radio pulsar wind, the solar flare, and terrestrial magnetic storms

The Inert Doublet Model and Inelastic Dark Matter

The annual modulation observed by DAMA/NaI and DAMA/Libra may be interpreted in terms of elastic or inelastic scattering of dark matter particles. In this paper we confront these two scenarios within the framework of a very simple extension of the Standard Model, the Inert Doublet Model (IDM). In this model the dark matter candidate is a scalar, the lightest component of an extra Higgs doublet. We first revisit the case for the elastic scattering of a light scalar WIMP, M_DM~10 GeV, a scenario which requires that a fraction of events in DAMA are channelled. Second we consider the possibility of inelastic Dark Matter (iDM). This option is technically natural in the IDM, in the sense that the mass splitting between the lightest and next-to-lightest neutral scalars may be protected by a Peccei-Quinn (PQ) symmetry. We show that candidates with a mass M_DM between ~535 GeV and ~50 TeV may reproduce the DAMA data and have a cosmic abundance in agreement with WMAP. This range may be extended to candidates as light as ~50 GeV if we exploit the possibility that the approximate PQ symmetry is effectively conserved and that a primordial asymmetry in the dark sector may survive until freeze-out.Comment: 16 pages, 7 figures. v2: minor changes and discussion on the embedding in SO(10) added. v3: matches the published version in JCA

Dark Matter Direct Detection with Non-Maxwellian Velocity Structure

The velocity distribution function of dark matter particles is expected to show significant departures from a Maxwell-Boltzmann distribution. This can have profound effects on the predicted dark matter - nucleon scattering rates in direct detection experiments, especially for dark matter models in which the scattering is sensitive to the high velocity tail of the distribution, such as inelastic dark matter (iDM) or light (few GeV) dark matter (LDM), and for experiments that require high energy recoil events, such as many directionally sensitive experiments. Here we determine the velocity distribution functions from two of the highest resolution numerical simulations of Galactic dark matter structure (Via Lactea II and GHALO), and study the effects for these scenarios. For directional detection, we find that the observed departures from Maxwell-Boltzmann increase the contrast of the signal and change the typical direction of incoming DM particles. For iDM, the expected signals at direct detection experiments are changed dramatically: the annual modulation can be enhanced by more than a factor two, and the relative rates of DAMA compared to CDMS can change by an order of magnitude, while those compared to CRESST can change by a factor of two. The spectrum of the signal can also change dramatically, with many features arising due to substructure. For LDM the spectral effects are smaller, but changes do arise that improve the compatibility with existing experiments. We find that the phase of the modulation can depend upon energy, which would help discriminate against background should it be found.Comment: 34 pages, 16 figures, submitted to JCAP. Tables of g(v_min), the integral of f(v)/v from v_min to infinity, derived from our simulations, are available for download at http://astro.berkeley.edu/~mqk/dmdd