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Fasciola hepatica infection is responsible for substantial economic losses in livestock worldwide and poses a threat to human health in endemic areas. The mainstay of control in livestock and the only drug licenced for use in humans is triclabendazole (TCBZ). TCBZ resistance has been reported on every continent and threatens effective control of fasciolosis in many parts of the world. To date, understanding the genetic mechanisms underlying TCBZ resistance has been limited to studies of candidate genes, based on assumptions of their role in drug action. Taking an alternative approach, we combined a genetic cross with whole-genome sequencing to localise a ~3.2Mbp locus within the 1.2Gbp F . hepatica genome that confers TCBZ resistance. We validated this locus independently using bulk segregant analysis of F . hepatica populations and showed that it is the target of drug selection in the field. We genotyped individual parasites and tracked segregation and reassortment of SNPs to show that TCBZ resistance exhibits Mendelian inheritance and is conferred by a dominant allele. We defined gene content within this locus to pinpoint genes involved in membrane transport, (e.g. ATP-binding cassette family B, ABCB1), transmembrane signalling and signal transduction (e.g. GTP-Ras-adenylyl cyclase and EGF-like protein), DNA/RNA binding and transcriptional regulation (e.g. SANT/Myb-like DNA-binding domain protein) and drug storage and sequestration (e.g. fatty acid binding protein, FABP) as prime candidates for conferring TCBZ resistance. This study constitutes the first experimental cross and genome-wide approach for any heritable trait in F . hepatica and is key to understanding the evolution of drug resistance in Fasciola spp. to inform deployment of efficacious anthelmintic treatments in the field.

The trematode Fasciola hepatica is responsible for chronic zoonotic infection globally. Despite causing a potent T-helper 2 response, it is believed that potent immunomodulation is responsible for rendering this host reactive non-protective host response thereby allowing the parasite to remain long-lived. We have previously identified a growth factor, FhTLM, belonging to the TGF superfamily can have developmental effects on the parasite. Herein we demonstrate that FhTLM can exert influence over host immune functions in a host receptor specific fashion. FhTLM can bind to receptor members of the Transforming Growth Factor (TGF) superfamily, with a greater affinity for TGF-β RII. Upon ligation FhTLM initiates the Smad2/3 pathway resulting in phenotypic changes in both fibroblasts and macrophages. The formation of fibroblast CFUs is reduced when cells are cultured with FhTLM, as a result of TGF-β RI kinase activity. In parallel the wound closure response of fibroblasts is also delayed in the presence of FhTLM. When stimulated with FhTLM blood monocyte derived macrophages adopt an alternative or regulatory phenotype. They express high levels interleukin (IL)-10 and arginase-1 while displaying low levels of IL-12 and nitric oxide. Moreover they also undergo significant upregulation of the inhibitory receptor PD-L1 and the mannose receptor. Use of RNAi demonstrates that this effect is dependent on TGF-β RII and mRNA knock-down leads to a loss of IL-10 and PD-L1. Finally, we demonstrate that FhTLM aids newly excysted juveniles (NEJs) in their evasion of antibody-dependent cell cytotoxicity (ADCC) by reducing the NO response of macrophages-again dependent on TGF-β RI kinase. FhTLM displays restricted expression to the F. hepatica gut resident NEJ stages. The altered fibroblast responses would suggest a role for dampened tissue repair responses in facilitating parasite migration. Furthermore, the adoption of a regulatory macrophage phenotype would allow for a reduced effector response targeting juvenile parasites which we demonstrate extends to an abrogation of the ADCC response. Thus suggesting that FhTLM is a stage specific evasion molecule that utilises host cytokine receptors. These findings are the first to clearly demonstrate the interaction of a helminth cytokine with a host receptor complex resulting in immune modifications that facilitate the non-protective chronic immune response which is characteristic of F. hepatica infection.

The liver fluke Fasciola hepatica is a major pathogen of livestock worldwide, causing huge economic losses to agriculture, as well as 2.4 million human infections annually. Here we provide a draft genome for F. hepatica, which we find to be among the largest known pathogen genomes at 1.3 Gb. This size cannot be explained by genome duplication or expansion of a single repeat element, and remains a paradox given the burden it may impose on egg production necessary to transmit infection. Despite the potential for inbreeding by facultative self-fertilisation, substantial levels of polymorphism were found, which highlights the evolutionary potential for rapid adaptation to changes in host availability, climate change or to drug or vaccine interventions. Non-synonymous polymorphisms were elevated in genes shared with parasitic taxa, which may be particularly relevant for the ability of the parasite to adapt to a broad range of definitive mammalian and intermediate molluscan hosts. Large-scale transcriptional changes, particularly within expanded protease and tubulin families, were found as the parasite migrated from the gut, across the peritoneum and through the liver to mature in the bile ducts. We identify novel members of anti-oxidant and detoxification pathways and defined their differential expression through infection, which may explain the stage-specific efficacy of different anthelmintic drugs. The genome analysis described here provides new insights into the evolution of this important pathogen, its adaptation to the host environment and external selection pressures. This analysis also provides a platform for research into novel drugs and vaccines.

The development and experimental performance of instrumentation to measure ageing-related spectroscopic changes in bitumen is described. Oxidation of bitumen at the surface increases the number of carbonyl (C=O) bonds, and this can be measured in the 6 μm region (1700 cm −1 ) of the mid-infrared. Standoff measurements of surface reflectivity were performed using 4 discrete wavelengths, 3 for the carbonyl absorption and the fourth as a spectral reference. The standoff height of 20 cm caused problems resulting from the presence of numerous strong absorption lines of atmospheric water in the optical path, which was solved by use of wavelengths centred within available “water windows” and a pathlength-matched reference channel. The instrument was tested using bitumen samples aged artificially using UV exposure. Results illustrating the instrument’s response to bitumen age, along with tolerance to changes in height and tilt, are shown. Measurements made during preliminary field trials on outdoor asphalt are also demonstrated. Part 1 of this paper describes the scientific challenges involved in designing this instrument.

A strategy is described to make in-situ measurements of a spectroscopic marker of ageing in bitumen binders used on asphalt-paved roads. Oxidation of bitumen at the surface increases the number of carbonyl (C=O) bonds, and this can be measured in the 6 μm region (1700 cm −1 ) of the mid-infrared. A measurement strategy is proposed to make standoff measurements of surface reflectivity in this region, despite the challenge presented by numerous strong absorption lines from atmospheric water vapour within the optical path. An instrument design is described to make measurements at 4 discrete laser wavelengths, namely 1593.0, 1641.4 and 1731.3 cm −1 (around 6 µm) and at 2633.6 cm −1 (3.8 µm), the first 3 responding to carbonyl absorption and the fourth acting as a spectral reference that is substantially unaffected by ageing. Part 2 of this paper describes the implementation of such an instrument and its experimental performance.

The importance of the gut microbiome for host health has been the subject of intense research over the last decade. In particular, there is overwhelming evidence for the influence of resident microbiota on gut mucosal and systemic immunity; with significant implications for the outcome of gastrointestinal (GI) infections, such as parasitic helminths. The horse is a species that relies heavily on its gut microbiota for GI and overall health, and disturbances in this complex ecosystem are often associated with life-threatening disease. In turn, nearly all horses harbour parasitic helminths from a young age, the most prevalent of which are the small strongyles, or cyathostomins. Research describing the relationship between gut microbiota and cyathostomin infection is in its infancy, however, to date there is evidence of meaningful interactions between these two groups of organisms which not only influence the outcome of cyathostomin infection but have long term consequences for equine host health. Here, we describe these interactions alongside supportive evidence from other species and suggest novel theories and avenues for research which have the potential to revolutionize our approach to cyathostomin prevention and control in the future.

Australian resource-extraction industries—mining, fisheries and forestry—operate year-round in the natural environment with all three exposed to climate extremes and to long-term climatic change. However, the industries differ in terms of size, ownership and mobility. Although mining companies are ‘mobile,’ a commitment to a mine site makes them immobile at a location dictated by the presence of a mineral; forestry of natural and managed trees takes place in a specifically selected location that can be changed given a reasonably long time-frame and high financial investment; fishing is the last of the major hunting industries, and despite operating from fixed ports, fishers chase fish across the ocean. All three industries as employers and product providers seek a sustainable future under a changing climate but are subject to environmental variability that impacts on their activities. As each industry has historically dealt with and survived major climate impacts, they typically consider themselves to be resilient, although we illustrate in several case studies that recent climate variability significantly impacts productivity and current resilience is limited. Projected climate change and variability are likely to exacerbate impacts on these industries through new or intensified hazards. Although each industry performs risk management controls to minimize climate-related impacts, a new approach incorporating future climate projections in addition to historical experiences would better prepare each to reduce vulnerability to changing climate. We find that wholesale transformation may not be appropriate or necessary at this time for these industries, and in most cases anticipatory, incremental adaptation should be encouraged, while larger-scale changes are considered in the longer term. Additionally, to overcome some of the barriers and promote the drivers of adaptation, we suggest that a model of adaptive governance coupled with greater use of climate champions may be the most effective method for improving adaptation uptake in these industries.

Background Fasciola hepatica is of worldwide significance, impacting on the health, welfare and productivity of livestock and regarded by WHO as a re-emerging zoonosis. Triclabendazole (TCBZ), the drug of choice for controlling acute fasciolosis in livestock, is also the drug used to treat human infections. However TCBZ-resistance is now considered a major threat to the effective control of F. hepatica . It has yet to be demonstrated whether F. hepatica undergoes a genetic clonal expansion in the snail intermediate host, Galba truncatula , and to what extent amplification of genotypes within the snail facilitates accumulation of drug resistant parasites. Little is known about genotypic and phenotypic variation within and between F. hepatica isolates. Results Six clonal isolates of F. hepatica (3× triclabendazole-resistant, TCBZ-R and 3× triclabendazole-susceptible, TCBZ-S) were generated. Snails infected with one miracidium started to shed cercariae 42–56 days post-infection and shed repeatedly up to a maximum of 11 times. A maximum of 884 cercariae were shed by one clonally-infected snail ( Fh LivS1) at a single time point, with > 3000 clonal metacercariae shed over its lifetime. Following experimental infection all 12 sheep were FEC positive at the time of TCBZ treatment. Sheep infected with one of three putative TCBZ-S clones and treated with TCBZ had no parasites in the liver at post-mortem , whilst sheep each infected with putative TCBZ-R isolates had 35–165 adult fluke at post-mortem , despite TCBZ treatment. All six untreated control animals had between 15–127 parasites. A single multi-locus genotype was reported for every fluke from each of the six clonal isolates. Adult F. hepatica showed considerable variation in weight, ranging from 20–280 mg, with variation in weight evident within and amongst clonal isolates. Conclusions A genetic clonal expansion occurs within G. truncatula , highlighting the potential for amplification of drug resistant genotypes of F. hepatica . Variation in the weight of parasites within and between clonal isolates and when comparing isolates that are either susceptible or resistant to TCBZ represent inherent variation in liver fluke and cannot be attributed to their resistance or susceptibility traits.

Geotechnical complexity in mining often leads to geotechnical uncertainty which impacts both safety and productivity. However, as mining progresses, particularly for strip mining operations, a body of knowledge is acquired which reduces this uncertainty and can potentially be used by mining engineers to improve the prediction of future mining conditions. In this paper, we describe a new method to support this approach based on modelling and neural networks. A high-level causal model of the mining operations based on historical data for a number of parameters was constructed which accounted for parameter interactions, including hydrogeological conditions, weather, and prior operations. An artificial neural network was then trained on this historical data, including production data. The network can then be used to predict future production based on presently observed mining conditions as mining proceeds and compared with the model predictions. Agreement with the predictions indicates confidence that the neural network predictions are properly supported by the newly available data. The efficacy of this approach is demonstrated using semi-synthetic data based on an actual mine.

The helminth Fasciola hepatica causes fasciolosis throughout the world, a major disease of livestock and an emerging zoonotic disease in humans. Sustainable control mechanisms such as vaccination are urgently required. To discover potential vaccine targets we undertook a genome screen to identify members of the transforming growth factor (TGF) family of proteins. Herein we describe the discovery of three ligands belonging to this superfamily and the cloning and characterisation of an activin/TGF like molecule we term FhTLM. FhTLM has a limited expression pattern both temporally across the parasite stages but also spatially within the worm. Furthermore, a recombinant form of this protein is able to enhance the rate (or magnitude) of multiple developmental processes of the parasite indicating a conserved role for this protein superfamily in the developmental biology of a major trematode parasite. Our study demonstrates for the first time the existence of this protein superfamily within F. hepatica and assigns a function to one of the three identified ligands. Moreover further exploration of this superfamily may yield future targets for diagnostic or vaccination purposes due to its stage restricted expression and functional role.