Veterinary Biosciences - Research Publications

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    Maternal contact and positive human interactions during lactation impacts piglet performance and behaviour during lactation
    Tomas, K ; Savaglia, J ; Plush, KJ ; D’Souza, DN ; Butler, KL ; Hemsworth, PH ; Tilbrook, AJ (Frontiers Media SA, 2023-01-01)
    Introduction Early life interactions with the sow or humans can have lifelong consequences on welfare and performance in pigs. It was hypothesised that piglets that received increased maternal contact and positive human contact would display improved responses to stressful events and improved performance. Methods Ninety-eight litters were allocated to a 2 x 2 factorial design for maternal contact (MC+)/restricted maternal contact (MC-); and positive human contact (HC+)/no additional human contact (HC-). Modified farrowing crates were used to restrict maternal contact (MC-) and litters in the HC+ treatment received five minutes of daily positive human interaction (stroking). Behavioural and physiological responses were assessed during processing at three days of age and during a behaviour test in which piglets were introduced to an empty arena, novel object, human hand and human standing in the arena at 18 days of age. Observations of behaviour in the home pen and growth and survival of piglets to weaning were also assessed. Results At processing, MC- piglets had more squeals (P = 0.015), tended to have more grunts (P = 0.063) and struggle attempts (P = 0.079), and had increased plasma cortisol concentrations (P = 0.009) after processing than MC+ piglets. During the behaviour test, HC+ piglets were more active (P = 0.014) and had more vocalisations (P < 0.05) in the empty arena than HC piglets. Furthermore, HC+ piglets were more likely to approach a human standing in the arena (P = 0.006) than HC- piglets. MC- piglets were less active (P = 0.008) and were less likely to approach the novel object (P = 0.049) than MC+ piglets. MC+ piglets tended to have higher weaning weights (P = 0.055) and more MC+ piglets were successfully weaned (P = 0.022) than MC- piglets. There was no significant effect of HC on piglet performance. Discussion While positive handling did not affect behavioural and physiological stress response to processing, HC+ reduced fear of novelty and humans. These findings highlight the importance of early life experiences has on stress resilience early in life.
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    Free drug percentage of moxidectin declines with increasing concentrations in the serum of marsupials
    Stott, EK ; Nie, S ; Williamson, NA ; Skerratt, LF (ELSEVIER, 2024-04)
    Moxidectin (MOX) is a macrocyclic lactone used to eliminate endo and ectoparasites in many mammalian species. It is notably the active ingredient of the anti-parasitic drug Cydectin®, manufactured by Virbac, and is frequently used to treat sarcoptic mange in Australian wildlife. Protein binding plays a significant role in the efficacy of a drug, as the unbound/free drug in plasma ultimately reflects the pharmacologically relevant concentration. This study aimed to investigate the free drug percentage of Moxidectin after in vitro spiking into the sera of four sarcoptic mange-susceptible Australian wildlife species; the koala (Phascolarctos cinereus), the bare-nosed wombat (Vombatus ursinus), the eastern grey kangaroo (Macropus giganteus), and the mountain brushtail possum (Trichosurus cunninghami). Three concentration points of MOX were tested for each individual: 20 pg/μL, 100 pg/μL and 500 pg/μL. Serum from five individuals of each species underwent an equilibrium dialysis followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results showed an atypical concentration dependent binding across all species, where free drug percentage decreased as MOX concentration increased. In addition, wombats showed significantly lower free drug levels. These findings call for further research into the mechanisms of moxidectin protein binding to help understand MOX pharmacokinetics in marsupials.
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    Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity
    Shanley, HT ; Taki, AC ; Nguyen, N ; Wang, T ; Byrne, JJ ; Ang, C-S ; Leeming, MG ; Nie, S ; Williamson, N ; Zheng, Y ; Young, ND ; Korhonen, PK ; Hofmann, A ; Chang, BCH ; Wells, TNC ; Haberli, C ; Keiser, J ; Jabbar, A ; Sleebs, BE ; Gasser, RB (ELSEVIER SCI LTD, 2024-04)
    Within the context of our anthelmintic discovery program, we recently identified and evaluated a quinoline derivative, called ABX464 or obefazimod, as a nematocidal candidate; synthesised a series of analogues which were assessed for activity against the free-living nematode Caenorhabditis elegans; and predicted compound-target relationships by thermal proteome profiling (TPP) and in silico docking. Here, we logically extended this work and critically evaluated the anthelmintic activity of ABX464 analogues on Haemonchus contortus (barber's pole worm) - a highly pathogenic nematode of ruminant livestock. First, we tested a series of 44 analogues on H. contortus (larvae and adults) to investigate the nematocidal pharmacophore of ABX464, and identified one compound with greater potency than the parent compound and showed moderate activity against a select number of other parasitic nematodes (including Ancylostoma, Heligmosomoides and Strongyloides species). Using TPP and in silico modelling studies, we predicted protein HCON_00074590 (a predicted aldo-keto reductase) as a target candidate for ABX464 in H. contortus. Future work aims to optimise this compound as a nematocidal candidate and investigate its pharmacokinetic properties. Overall, this study presents a first step toward the development of a new nematocide.
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    Marked genetic diversity within Blastocystis in Australian wildlife revealed using a next generation sequencing-phylogenetic approach
    Koehler, A ; Herath, HMPD ; Hall, RS ; Wilcox, S ; Gasser, RB (ELSEVIER, 2024-04)
    Blastocystis is a genus of intestinal stramenopiles that infect vertebrates, and may cause disease of the alimentary tract. Currently, at least 40 genotypes ("subtypes") of Blastocystis are recognised worldwide based on sequence data for the small subunit of the nuclear ribosomal RNA (SSU-rRNA) gene. Despite the numerous studies of Blastocystis worldwide, very few studies have explored Blastocystis in wild animals, particularly in Australia. Here, we used a PCR-based next generation sequencing (NGS)-phylogenetic approach to genetically characterise and classify Blastocystis variants from selected wildlife in the Australian state of Victoria. In total, 1658 faecal samples were collected from nine host species, including eastern grey kangaroo, swamp wallaby, common wombat, deer, European rabbit, canines and emu. Genomic DNA was extracted from these samples, a 500 bp region of the SSU-rRNA gene amplified by polymerase chain reaction (PCR) and, then, a subset of samples sequenced using Illumina technology. Primary PCR detected Blastocystis in 482 of the 1658 samples (29%), with the highest percentage in fallow deer (63%). Subsequent, Illumina-based sequencing of a subset of 356 samples revealed 55 distinct amplicon sequence variants (ASVs) representing seven currently-recognised subtypes (STs) [ST13 (prominent in marsupials), ST10, ST14, ST21, ST23, ST24 and ST25 (prominent in deer)] and two novel STs (ST45 and ST46) in marsupials. Mixed infections of different STs were observed in macropods, deer, emu and canids (fox, feral dog or dingo), but no infection was detected in rabbits or wombats. This study reveals marked genetic diversity within Blastocystis in a small number of species of wild animals in Australia, suggesting complexity in the genetic composition and transmission patterns of members of the genus Blastocystis in this country.
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    Structure activity relationship and target prediction for ABX464 analogues in Caenorhabditis elegans
    Shanley, HT ; Taki, AC ; Nguyen, N ; Wang, T ; Byrne, JJ ; Ang, C-S ; Leeming, MG ; Nie, S ; Williamson, N ; Zheng, Y ; Young, ND ; Korhonen, PK ; Hofmann, A ; Wells, TNC ; Jabbar, A ; Sleebs, BE ; Gasser, RB (PERGAMON-ELSEVIER SCIENCE LTD, 2024-01-15)
    Global challenges with treatment failures and/or widespread resistance in parasitic worms against commercially available anthelmintics lend impetus to the development of new anthelmintics with novel mechanism(s) of action. The free-living nematode Caenorhabditis elegans is an important model organism used for drug discovery, including the screening and structure-activity investigation of new compounds, and target deconvolution. Previously, we conducted a whole-organism phenotypic screen of the 'Pandemic Response Box' (from Medicines for Malaria Venture, MMV) and identified a hit compound, called ABX464, with activity against C. elegans and a related, parasitic nematode, Haemonchus contortus. Here, we tested a series of 44 synthesized analogues to explore the pharmacophore of activity on C. elegans and revealed five compounds whose potency was similar or greater than that of ABX464, but which were not toxic to human hepatoma (HepG2) cells. Subsequently, we employed thermal proteome profiling (TPP), protein structure prediction and an in silico-docking algorithm to predict ABX464-target candidates. Taken together, the findings from this study contribute significantly to the early-stage drug discovery of a new nematocide based on ABX464. Future work is aimed at validating the ABX464-protein interactions identified here, and at assessing ABX464 and associated analogues against a panel of parasitic nematodes, towards developing a new anthelmintic with a mechanism of action that is distinct from any of the compounds currently-available commercially.
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    Advances in Managing Chytridiomycosis for Australian Frogs: Gradarius Firmus Victoria.
    Berger, L ; Skerratt, LF ; Kosch, TA ; Brannelly, LA ; Webb, RJ ; Waddle, AW (Annual Reviews, 2024-02-15)
    Extensive knowledge gains from research worldwide over the 25 years since the discovery of chytridiomycosis can be used for improved management. Strategies that have saved populations in the short term and/or enabled recovery include captive breeding, translocation into disease refugia, translocation from resistant populations, disease-free exclosures, and preservation of disease refuges with connectivity to previous habitat, while antifungal treatments have reduced mortality rates in the wild. Increasing host resistance is the goal of many strategies under development, including vaccination and targeted genetic interventions. Pathogen-directed strategies may be more challenging but would have broad applicability. While the search for the silver bullet solution continues, we should value targeted local interventions that stop extinction and buy time for evolution of resistance or development of novel solutions. As for most invasive species and infectious diseases, we need to accept that ongoing management is necessary. For species continuing to decline, proactive deployment and assessment of promising interventions are more valid than a hands-off, do-no-harm approach that will likely allow further extinctions.
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    4. Early life maternal contact has long-term impacts on pig growth
    Tomas, K ; Savaglia, J ; Plush, KJ ; D'Souza, DN ; Butler, KL ; Hemsworth, PH ; Tilbrook, AJ (Elsevier BV, 2023-11)
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    Analysis of Haemonchus embryos at single cell resolution identifies two eukaryotic elongation factors as intervention target candidates.
    Korhonen, PK ; Wang, T ; Young, ND ; Byrne, JJ ; Campos, TL ; Chang, BCH ; Taki, AC ; Gasser, RB (Elsevier BV, 2024-12)
    Advances in single cell technologies are allowing investigations of a wide range of biological processes and pathways in animals, such as the multicellular model organism Caenorhabditis elegans - a free-living nematode. However, there has been limited application of such technology to related parasitic nematodes which cause major diseases of humans and animals worldwide. With no vaccines against the vast majority of parasitic nematodes and treatment failures due to drug resistance or inefficacy, new intervention targets are urgently needed, preferably informed by a deep understanding of these nematodes' cellular and molecular biology - which is presently lacking for most worms. Here, we created the first single cell atlas for an early developmental stage of Haemonchus contortus - a highly pathogenic, C. elegans-related parasitic nematode. We obtained and curated RNA sequence (snRNA-seq) data from single nuclei from embryonating eggs of H. contortus (150,000 droplets), and selected high-quality transcriptomic data for > 14,000 single nuclei for analysis, and identified 19 distinct clusters of cells. Guided by comparative analyses with C. elegans, we were able to reproducibly assign seven cell clusters to body wall muscle, hypodermis, neuronal, intestinal or seam cells, and identified eight genes that were transcribed in all cell clusters/types, three of which were inferred to be essential in H. contortus. Two of these genes (i.e. Hc-eef-1A and Hc-eef1G), coding for eukaryotic elongation factors (called Hc-eEF1A and Hc-eEF1G), were also demonstrated to be transcribed and expressed in all key developmental stages of H. contortus. Together with these findings, sequence- and structure-based comparative analyses indicated the potential of Hc-eEF1A and/or Hc-eEF1G as intervention targets within the protein biosynthesis machinery of H. contortus. Future work will focus on single cell studies of all key developmental stages and tissues of H. contortus, and on evaluating the suitability of the two elongation factor proteins as drug targets in H. contortus and related nematodes, with a view to finding new nematocidal drug candidates.
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    Bayesian Validation of the Indirect Immunofluorescence Assay and Its Superiority to the Enzyme-Linked Immunosorbent Assay and the Complement Fixation Test for Detecting Antibodies against Coxiella burnetii in Goat Serum
    Muleme, M ; Stenos, J ; Vincent, G ; Campbell, A ; Graves, S ; Warner, S ; Devlin, JM ; Nguyen, C ; Stevenson, MA ; Wilks, CR ; Firestone, SM ; Pasetti, MF (AMER SOC MICROBIOLOGY, 2016-06)
    Although many studies have reported the indirect immunofluorescence assay (IFA) to be more sensitive in detection of antibodies to Coxiella burnetii than the complement fixation test (CFT), the diagnostic sensitivity (DSe) and diagnostic specificity (DSp) of the assay have not been previously established for use in ruminants. This study aimed to validate the IFA by describing the optimization, selection of cutoff titers, repeatability, and reliability as well as the DSe and DSp of the assay. Bayesian latent class analysis was used to estimate diagnostic specifications in comparison with the CFT and the enzyme-linked immunosorbent assay (ELISA). The optimal cutoff dilution for screening for IgG and IgM antibodies in goat serum using the IFA was estimated to be 1:160. The IFA had good repeatability (>96.9% for IgG, >78.0% for IgM), and there was almost perfect agreement (Cohen's kappa > 0.80 for IgG) between the readings reported by two technicians for samples tested for IgG antibodies. The IFA had a higher DSe (94.8%; 95% confidence interval [CI], 80.3, 99.6) for the detection of IgG antibodies against C. burnetii than the ELISA (70.1%; 95% CI, 52.7, 91.0) and the CFT (29.8%; 95% CI, 17.0, 44.8). All three tests were highly specific for goat IgG antibodies. The IFA also had a higher DSe (88.8%; 95% CI, 58.2, 99.5) for detection of IgM antibodies than the ELISA (71.7%; 95% CI, 46.3, 92.8). These results underscore the better suitability of the IFA than of the CFT and ELISA for detection of IgG and IgM antibodies in goat serum and possibly in serum from other ruminants.
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    The role of animal welfare in improving the future of farming
    Doyle, RE ; Campbell, AJD ; Dione, M ; Woodruff, M ; Munoz, C ; Alemayehu, G ; Berhe, T ; Knight-Jones, T ; Wilson, C (CSIRO Publishing, 2022)
    Context: Animal production plays a critical role in many global challenges around sustainability, including climate change and resilience, One Health and food security. With this role comes pressures on livestock welfare. Aims: This paper demonstrates key contributions animal welfare makes to global sustainability challenges. Methods: This paper highlights ‘win–win’ improvements for both animal welfare and other aspects of sustainability by using the following four case studies: tail docking Australian sheep, agroforestry systems in Ethiopia, the Australian dairy-beef industry, and strategic feeding of goats in Pakistan. Key results: These case studies show how animal welfare can be improved alongside livelihoods. However, even in these win–win situations, the adoption of improved practices is not guaranteed. Conclusions: Long-term, sustained change in animal welfare can simultaneously make in roads to other challenges around sustainability. To do this, we must have a broader understanding of the system in which the animals are raised, so that barriers to change can be identified. Implications: Lessons from these case studies can be applied to other production contexts and challenges, highlighting the universal value of understanding and addressing animal welfare.