Veterinary Biosciences - Research Publications
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ItemNo correlation between microbiota composition and blood parameters in nesting flatback turtles (Natator depressus).(Springer Science and Business Media LLC, 2020-05-20)The microbiota is considered critical for normal vertebrate homeostasis and it may exert its effects at a local level within the gastrointestinal tract, or systemically through the production of bacterial metabolites. To date, investigations into the role that the microbiota plays in reptile physiology are rare. To address this knowledge gap, we explored the relationship between differences in microbial communities to see if they accounted for differences in haematology and biochemistry values, in different populations of nesting flatback turtles (Natator depressus). We found that microbiota composition was not correlated to any of the blood analytes we measured in flatbacks. This study is the first of its kind in reptiles and highlights the need for further investigations to determine mechanisms by which the microbiota influences the physiology and health of reptiles.
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ItemMicrobial symbiosis and coevolution of an entire clade of ancient vertebrates: the gut microbiota of sea turtles and its relationship to their phylogenetic history.(Springer Science and Business Media LLC, 2020-05-07)BACKGROUND: The microbiota plays a critical role in host homeostasis and has been shown to be a major driving force in host evolution. However, our understanding of these important relationships is hampered by a lack of data for many species, and by significant gaps in sampling of the evolutionary tree. In this investigation we improve our understanding of the host-microbiome relationship by obtaining samples from all seven extant species of sea turtle, and correlate microbial compositions with host evolutionary history. RESULTS: Our analysis shows that the predominate phyla in the microbiota of nesting sea turtles was Proteobacteria. We also demonstrate a strong relationship between the bacterial phyla SR1 and sea turtle phylogeny, and that sea turtle microbiotas have changed very slowly over time in accordance with their similarly slow phenotypic changes. CONCLUSIONS: This is one of the most comprehensive microbiota studies to have been performed in a single clade of animals and further improves our knowledge of how microbial populations have influenced vertebrate evolution.
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ItemGeneration of a safe and efficacious llama single-domain antibody fragment (vHH) targeting the membrane-proximal region of 4-1BB for engineering therapeutic bispecific antibodies for cancer.(BMJ, 2021-06)BACKGROUND: The discovery of checkpoint inhibitors towards cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has been revolutionary for the treatment of cancers. These therapies have only offered an average of 20%-30% response rates across the tumor spectrum and the combination of agonists towards the tumor-necrosis superfamily members, such as 4-1BB and CD40, has shown potent efficacy in preclinical studies; however, these agonists have exhibited high degrees of toxicity with limited efficacy in human trials. In this study, we have generated a single-domain antibody towards a unique epitope of 4-1BB that limits its potential on-target toxicity while maintaining sufficient potency. This 4-1BB binder is ideal for use in the engineering of multispecific antibodies to localize 4-1BB activation within the tumor microenvironment, as shown here by a anti-PD-L1/4-1BB bispecific candidate (PM1003). METHODS: To determine the functional activity of the 4-1BB- and PD-L1-binding elements of PM1003, in vitro luciferase reporter and primary cell assays were used to test the potency of programmed cell death 1 ligand 1 (PD-L1) blockade and PD-L1-mediated 4-1BB activation via cross-bridging. X-ray crystallography was conducted to resolve the binding epitopes of the respective binding arms, and accurate binding kinetics were determined using standard affinity measurement techniques. Human 4-1BB and/or PD-L1 knock-in mice were used in cancer models for testing the in vivo antitumor efficacy of PM1003, and safety was evaluated further. RESULTS: PM1003 shows potent activation of 4-1BB and blockade of PD-L1 in cell-based assays. 4-1BB activation was exerted through the bridging of PD-L1 on target cells and 4-1BB on effector cells. No PD-L1-independent activation of 4-1BB was observed. Through X-ray crystallography, a unique binding epitope in the cysteine-rich domain 4 (CRD4) region was resolved that provides high potency and potentially low on-target toxicity as determined by primary immune cell assays and toxicity evaluation in vivo. CONCLUSIONS: A unique single-domain antibody was discovered that binds to the CRD4 domain of 4-1BB. When incorporated into a 4-1BB/PD-L1 bispecific (PM1003), we have shown the potent inhibition of PD-L1 activity with 4-1BB agonism upon cross-bridging with PD-L1 in vitro. Antitumor activity with minimal toxicity was found in vivo. Thus, PM1003 is a uniquely differentiating and next generation therapeutic agent for cancer therapy.
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ItemA descriptive retrospective study on mortality and involuntary culling in beef and dairy cattle production systems of Western Australia (1981-2018)(WILEY, 2021-09)Identifying and quantifying the relative frequency of involuntary losses is an essential first step in developing fit-for-purpose herd health programmes. The objective of this study was to provide an estimate of the relative frequency of reasons for mortality among south-west Western Australian beef and dairy cattle, based on necropsy findings from a university-based veterinary pathology referral centre over 38 years. A total of 904 cattle were submitted for postmortem examination throughout the study period. Gastrointestinal, cardiopulmonary and reproductive conditions were the most common causes of mortality in cattle submitted for necropsy at Murdoch University for the period 1981-2018. In dairy cattle, the common problems were gastrointestinal (bloat, abomasal displacements) 18% (59/320), cardiovascular (traumatic reticulo-pericarditis) 9% (30/320) and respiratory conditions (pneumonia) 8% (27/320). In beef cattle, the most common conditions were gastrointestinal (bloat, rumen acidosis) 11% (39/358), reproductive (metritis) 11% (38/358), cardiovascular (traumatic reticulo-pericarditis) 7% (25/358), respiratory (pneumonia) 7% (24/358), lameness (fractures) 6%, (21/358) and hepatobiliary conditions (blue-green algae poisoning, hepatotoxicity) 6% (21/358). Selection bias and missing data were potential confounders in this study. Although necropsy investigations provide useful information on animal mortalities and avenues for future herd health programmes, there is a need to standardise data capture methods and disease definition criteria, and conduct more detailed recording of data both at the farm level and at necropsy diagnostic centres.
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ItemCrystal structure of a GDP-6-OMe-4-keto-L-xylo-heptose reductase from Campylobacter jejuni(WILEY, 2021-08)Carbohydrates play a major role in infection strategies of various enteric pathogens. In Campylobacter jejuni, the most common cause of gastroenteritis, uniquely modified heptoses found in surface carbohydrates are synthesized by specific pathways. Owing to the importance of such pathways for the infectious potential of pathogens and/or their virulence, these biosynthesis pathways present potential targets for therapeutic intervention. Here, we determined the crystal structure of GDP-6-OMe-4-keto-L-xylo-heptose reductase (MlghC), an enzyme within the L-gluco-heptose synthesis pathway of C. jejuni strain NCTC 11168. This enzyme lacks the canonical tyrosine residue of the conserved catalytic Ser-Lys-Tyr triad commonly found among functionally related reductases. Despite adopting the overall two-domain fold shared with other short-chain dehydrogenase/reductase family members, subtle structural differences in the interface between the cofactor- and substrate-binding domains explain the absence of epimerase activity and different substrate specificity of this reductase. Modeling of the product-bound complex based on the crystal structure presented here suggests that a tyrosine residue unique to MlghC replaces the missing canonical residue of the catalytic triad.
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ItemNo Preview AvailableKathmandu Declaration on Cysticercosis : Towards Eradication(Annapurna Neurological Institute & Allied Sciences, 2021-02-10)In December 2018, an international conference on cysticercosis was held in Kathmandu,Nepal with the theme, “Towards Eradication”. With the collaboration and participation of human-health and animal-health related organizations, the culmination of this event was the Kathmandu Declaration on cysticercosisrealizing an urgency to take action for its prevention and management.Of the 10 points mentioned in the declaration, all of the keynote speakers and participants on the conference endorsed the activities on commitment for eliminating cysticercosis, urgedthe government to internalize its primary responsibility and role in controlling cysticercosis, and called for the stakeholders for multisectoral collaboration. The authors believe that this declaration and further action definitely strive towards meeting the theme of the conference to eradicate cysticercosis with
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ItemNo Preview Available'It's our job': Constraints to investigation of a typical disease events-Opinions of Australian veterinarians(WILEY, 2021-08)Frontline health practitioners need to be adequately prepared to recognize and respond to atypical disease presentations, some of which may have zoonotic potential. Data from previous research have suggested that veterinarians may face challenges in investigation of disease events due to time and money constraints. As part of an Australia-wide survey project, veterinarians were asked to answer an open-ended question regarding potential constraints in investigation of atypical disease events where there may be concern about a zoonosis or emerging infectious disease. Qualitative data were analysed using thematic content analysis with the consideration of the respondent's area of practice and level of experience. Five main themes were identified which encapsulated constraints to disease investigation described by participants, namely: (a) financing of disease investigations, including client willingness/ability to pay in absence of alternative government schemes; (b) client-related factors, including willingness to consent to investigation and comply with instructions; (c) professional preparedness to act, related to practitioner knowledge and technical competency; (d) workplace environment, impacted by physical, logistical and managerial aspects of workplaces; and (e) access to external technical support, primarily from government veterinary services. Successful investigation and management of atypical diseases, including potential zoonoses, requires preparedness of all veterinarians. Continuing professional education for veterinarians in infection prevention and control and biosecurity, alongside adequate government funding and support will help facilitate optimal health and biosecurity outcomes. Both state and federal governments need to review existing animal health structures to ensure cohesive responses for future disease events.
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ItemNo Preview AvailableGlobal health security must embrace a One Health approach: Contributions and experiences of veterinarians during the COVID-19 response in Australia(ELSEVIER, 2021-12)SARS-CoV-2, a betacoronavirus of likely zoonotic origin, was first reported in December 2019. Its rapid worldwide spread precipitated a range of interventions, including by veterinarians, due to impacts on human health and well-being as well as animal health and welfare. We conducted 36 key informant interviews to explore the responses of Australian veterinarians, their engagement in One Health collaboration and cooperation, and their existing and developed insights to the COVID-19 pandemic. Responses were analysed using thematic analysis. Australian veterinarians provided valuable contributions to the national COVID-19 response by protecting animal welfare, maintaining local food security, providing essential veterinary services while mitigating human health risks in clinical settings and providing both key skills and surge capacity to the human health response. This was all guided by skills in scientific literacy and evidence-based communication. Informants identified a clear and urgent need for greater One Health coordination during pandemic prevention, preparedness, and response, even in the case of a disease which largely only affects humans.
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ItemNo Preview AvailableWhole-genome based strain identification of fowlpox virus directly from cutaneous tissue and propagated virus(Public Library of Science (PLoS), 2021)Fowlpox (FP) is an economically important viral disease of commercial poultry. The fowlpox virus (FPV) is primarily characterised by immunoblotting, restriction enzyme analysis in combination with PCR, and/or nucleotide sequencing of amplicons. Whole-genome sequencing (WGS) of FPV directly from clinical specimens prevents the risk of potential genome modifications associated with in vitro culturing of the virus. Only one study has sequenced FPV genomes directly from clinical samples using Nanopore sequencing, however, the study didn’t compare the sequences against Illumina sequencing or laboratory propagated sequences. Here, the suitability of WGS for strain identification of FPV directly from cutaneous tissue was evaluated, using a combination of Illumina and Nanopore sequencing technologies. Sequencing results were compared with the sequence obtained from FPV grown in chorioallantoic membranes (CAMs) of chicken embryos.
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ItemNo Preview AvailablePhytochemical Profiling and Biological Testing of the Constituents of the Australian Plant Haemodorum brevisepalum(AMER CHEMICAL SOC, 2021-11-26)Phytochemical profiling was undertaken on the crude extracts of the bulbs, stems, and the fruits of Haemodorum brevisepalum, to determine the nature of the chemical constituents present. This represents the first study to investigate the fruits of a species of Haemodorum. In total, 13 new and 17 previously reported compounds were isolated and identified. The new compounds were of the phenylphenalenone-type class, with a representative of a novel structural form, named tentatively "oxabenzochromenone" (1), a compound akin to an intermediate in a recently proposed phenylphenalenone metabolic network (2), seven new phenylphenalenones (4-10), four new phenylbenzoisochromenones (11-14), and a new phenylbenzoisochromenone derivative (18). The previously reported compounds identified were of the following structure classes: oxabenzochrysenone (3, 23-26), flavonol (15, 16), phenylbenzoisochromenone (17, 21, 22, 27-30), and phenylphenalenone (19, 20). Compounds 2-4, 6-9, 15-18, 21, 22, and 26 were subjected to antimicrobial evaluation with moderate activity observed against Staphylococcus aureus MRSA and slight activity against Pseudomonas aeruginosa and Candida albicans. Compounds 4, 6-9, 17, and 21 were also evaluated for anthelminthic activity against larvae of the blood-feeding parasitic nematode Haemonchus contortus.