Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus

Introduction ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs) based around its active PC-moiety. To provide proof of concept that ES-62-based SMAs exhibit therapeutic potential in SLE, we have investigated the capacity of two SMAs to protect against nephritis when administered to MRL/Lpr mice after onset of kidney damage. Methods SMAs 11a and 12b were evaluated for their ability to suppress antinuclear antibody (ANA) generation and consequent kidney pathology in MRL/Lpr mice when administered after the onset of proteinuria. Results SMAs 11a and 12b suppressed development of ANA and proteinuria. Protection reflected downregulation of MyD88 expression by kidney cells and this was associated with reduced production of IL-6, a cytokine that exhibits promise as a therapeutic target for this condition. Conclusions SMAs 11a and 12b provide proof of principle that synthetic compounds based on the safe immunomodulatory mechanisms of parasitic worms can exhibit therapeutic potential as a novel class of drugs for SLE, a disease for which current therapies remain inadequate

The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma

Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma

Endosulfan Resistance in Hypothenemus hampei (Coleoptera: Scolytidae) in New Caledonia

ABSTRACT The Potter tower direct spray technique was used to determine the susceptibility to endosulfan of 16 strains of Hypothenemus hampei (Ferrari) from the East and West Coasts of New Caledonia. Strains from the drier West Coast were susceptible, whereas susceptible and resistant strains were recorded from the wetter East Coast. This is the first record of resistance in H . hampei and Scolytidae. High levels of up to 1,000-fold endosulfan resistance were detected from five locations. These were associated with poor field control since 1986 and highly significant increases in berry infestation from 1985 to 1987. Detection of resistance follows 6 yr of lindane use and 10 yr of biannual endosulfan application

Engaging stakeholders in research to address water-energy-food (WEF) nexus challenges

The water–energy–food (WEF) nexus has become a popular, and potentially powerful, frame through which to analyse interactions and interdependencies between these three systems. Though the case for transdisciplinary research in this space has been made, the extent of stakeholder engagement in research remains limited with stakeholders most commonly incorporated in research as end-users. Yet, stakeholders interact with nexus issues in a variety of ways, consequently there is much that collaboration might offer to develop nexus research and enhance its application. This paper outlines four aspects of nexus research and considers the value and potential challenges for transdisciplinary research in each. We focus on assessing and visualising nexus systems; understanding governance and capacity building; the importance of scale; and the implications of future change. The paper then proceeds to describe a novel mixed-method study that deeply integrates stakeholder knowledge with insights from multiple disciplines. We argue that mixed-method research designs—in this case orientated around a number of cases studies—are best suited to understanding and addressing real-world nexus challenges, with their inevitable complex, non-linear system characteristics. Moreover, integrating multiple forms of knowledge in the manner described in this paper enables research to assess the potential for, and processes of, scaling-up innovations in the nexus space, to contribute insights to policy and decision making

The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma

Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma

Aerosol delivery of trail pheromone disrupts the foraging of the red imported fire ant, \u3ci\u3eSolenopsis invicta\u3c/i\u3e

BACKGROUND: The fire ant, Solenopsis invicta, is one of the most aggressive and invasive species in the world. The trail pheromone Z,E-α-farnesene (91% purity)was prepared, and disruption of worker trail orientation was tested using an ethanol based aerosol formulation presenting a single puff of this compound by airbrush and compressed air. Trail-following behavior was recorded by overhead webcam and ants digitized before and after presentation of the aerosol treatment at four rates (1.6, 16, 160 and 1600 ng cm−2). RESULTS: Ants preferred 110 ng cm−1 over 11, 1.1 and 0.11 ng cm−1 for trail following. Within seconds of presentation of 1600 ng cm−2, the highest dose tested, trail disruption was observed. Disruption was evident as reduced arrival success and reduction in the trail integrity statistic (r2), as well as increased deviation from the trail (deg). The distribution of walking track angles was also flattened. CONCLUSIONS: The feasibility of using aerosol for delivery of trail pheromone was demonstrated, but the need for high purity combined with the difficulty of commercial supply makes this technique impractical. However, the commercial production of Z,E-α-farnesene of high purity by industrial biotechnology or from (E)-nerolidol may be possible in future, which would facilitate further development of trail pheromone disruption of S. invicta