Veterinary Biosciences - Research Publications
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ItemSynthesis, Characterization, and Biological Activity of Ferrocenyl Analogues of the Anthelmintic Drug Monepantel(AMER CHEMICAL SOC, 2016-10-10)There is major demand for the development of structurally new anti-infectives using innovative approaches to circumvent multidrug resistance in parasites. Herein, we describe the synthesis and characterization of ferrocenyl precursors and derivatives (2-8) of an anthelmintic drug, monepantel. All compounds were isolated as their racemates and characterized by 1H, 13C, and 19F NMR spectroscopy, mass spectrometry, and IR spectroscopy. The purity of individual compounds was confirmed by elemental microanalysis. The molecular structures of three of the organometallic compounds (5-7) were also established by X-ray crystallography. The biological activities of these compounds were then evaluated in vitro on various important eukaryotic parasites, including H. contortus, T. colubriformis, and D. immitis. The potencies against D. immitis (canine heartworm) of two compounds, a ferrocene-containing precursor (4) and the final ferrocene-based monepantel derivative (8), were shown to be moderate (EC50 = 3.70 μg/mL for 4 and 5.60 μg/mL for 8) and were comparable with those of the controls AAD85 (EC50 = 2.20 μg/mL) and a commercial drug, ivermectin (EC50 = 1.00-3.00 μg/mL). The assessment of the cytotoxicity using cancerous HeLa and noncancerous MRC-5 cell lines revealed that these compounds have moderate to low toxicities in mammalian cells, thereby showing selective activity on parasites.
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ItemCan New Digital Technologies Support Parasitolocy Teaching and Learning?(ELSEVIER SCI LTD, 2016-07)Traditionally, parasitology courses have mostly been taught face-to-face on campus, but now digital technologies offer opportunities for teaching and learning. Here, we give a perspective on how new technologies might be used through student-centred teaching approaches. First, a snapshot of recent trends in the higher education is provided; then, a brief account is given of how digital technologies [e.g., massive open online courses (MOOCs), flipped classroom (FC), games, quizzes, dedicated Facebook, and digital badges] might promote parasitology teaching and learning in digital learning environments. In our opinion, some of these digital technologies might be useful for competency-based, self-regulated, learner-centred teaching and learning in an online or blended teaching environment.
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ItemInvestigating the Role of RIO Protein Kinases in Caenorhabditis elegans (vol 10, e0117444, 2015)(PUBLIC LIBRARY SCIENCE, 2016-05-18)[This corrects the article DOI: 10.1371/journal.pone.0117444.].
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ItemPipeline for the identification and classification of ion channels in parasitic flatworms(BMC, 2016-03-16)BACKGROUND: Ion channels are well characterised in model organisms, principally because of the availability of functional genomic tools and datasets for these species. This contrasts the situation, for example, for parasites of humans and animals, whose genomic and biological uniqueness means that many genes and their products cannot be annotated. As ion channels are recognised as important drug targets in mammals, the accurate identification and classification of parasite channels could provide major prospects for defining unique targets for designing novel and specific anti-parasite therapies. Here, we established a reliable bioinformatic pipeline for the identification and classification of ion channels encoded in the genome of the cancer-causing liver fluke Opisthorchis viverrini, and extended its application to related flatworms affecting humans. METHODS: We built an ion channel identification + classification pipeline (called MuSICC), employing an optimised support vector machine (SVM) model and using the Kyoto Encyclopaedia of Genes and Genomes (KEGG) classification system. Ion channel proteins were first identified and grouped according to amino acid sequence similarity to classified ion channels and the presence and number of ion channel-like conserved and transmembrane domains. Predicted ion channels were then classified to sub-family using a SVM model, trained using ion channel features. RESULTS: Following an evaluation of this pipeline (MuSICC), which demonstrated a classification sensitivity of 95.2 % and accuracy of 70.5 % for known ion channels, we applied it to effectively identify and classify ion channels in selected parasitic flatworms. CONCLUSIONS: MuSICC provides a practical and effective tool for the identification and classification of ion channels of parasitic flatworms, and should be applicable to a broad range of organisms that are evolutionarily distant from taxa whose ion channels are functionally characterised.
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ItemMaking sense of genomes of parasitic worms: Tackling bioinformatic challenges(PERGAMON-ELSEVIER SCIENCE LTD, 2016)Billions of people and animals are infected with parasitic worms (helminths). Many of these worms cause diseases that have a major socioeconomic impact worldwide, and are challenging to control because existing treatment methods are often inadequate. There is, therefore, a need to work toward developing new intervention methods, built on a sound understanding of parasitic worms at molecular level, the relationships that they have with their animal hosts and/or the diseases that they cause. Decoding the genomes and transcriptomes of these parasites brings us a step closer to this goal. The key focus of this article is to critically review and discuss bioinformatic tools used for the assembly and annotation of these genomes and transcriptomes, as well as various post-genomic analyses of transcription profiles, biological pathways, synteny, phylogeny, biogeography and the prediction and prioritisation of drug target candidates. Bioinformatic pipelines implemented and established recently provide practical and efficient tools for the assembly and annotation of genomes of parasitic worms, and will be applicable to a wide range of other parasites and eukaryotic organisms. Future research will need to assess the utility of long-read sequence data sets for enhanced genomic assemblies, and develop improved algorithms for gene prediction and post-genomic analyses, to enable comprehensive systems biology explorations of parasitic organisms.
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ItemIs Cryptosporidium from the common wombat (Vombatus ursinus) a new species and distinct from Cryptosporidium ubiquitum?(ELSEVIER SCIENCE BV, 2016-10)The emerging zoonotic pathogen Cryptosporidium ubiquitum has been found in a variety of mammalian hosts, including humans, throughout the world. Advances in the molecular characterization of this parasite using the sequence of the 60kDa glycoprotein (gp60) gene have allowed the classification of "subtypes". Sequences derived from faecal samples from the common wombat (Vombatus ursinus) have identified a novel gp60 subtype designated here as C. ubiquitum XIIg. Phylogenetic analysis suggests that subtypes of C. ubiquitum can be divided into generalist and specialist groups, which is important when considering the zoonotic potential of C. ubiquitum in the context of drinking water safety.
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ItemOrganometallic Derivatization of the Nematocidal Drug Monepantel Leads to Promising Antiparasitic Drug Candidates(WILEY-V C H VERLAG GMBH, 2016-11)The discovery of novel drugs against animal parasites is in high demand due to drug-resistance problems encountered around the world. Herein, the synthesis and characterization of 27 organic and organometallic derivatives of the recently launched nematocidal drug monepantel (Zolvix® ) are described. The compounds were isolated as racemates and were characterized by 1 H, 13 C, and 19 F NMR spectroscopy, mass spectrometry, and IR spectroscopy, and their purity was verified by microanalysis. The molecular structures of nine compounds were confirmed by X-ray crystallography. The anthelmintic activity of the newly designed analogues was evaluated in vitro against the economically important parasites Haemonchus contortus and Trichostrongylus colubriformis. Moderate nematocidal activity was observed for nine of the 27 compounds. Three compounds were confirmed as potentiators of a known monepantel target, the ACR-23 ion channel. Production of reactive oxygen species may confer secondary activity to the organometallic analogues. Two compounds, namely, an organic precursor (3 a) and a cymantrene analogue (9 a), showed activities against microfilariae of Dirofilaria immitis in the low microgram per milliliter range.
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ItemThe complement of family M1 aminopeptidases of Haemonchus contortus - Biotechnological implications(PERGAMON-ELSEVIER SCIENCE LTD, 2016)Although substantial research has been focused on the 'hidden antigen' H11 of Haemonchus contortus as a vaccine against haemonchosis in small ruminants, little is know about this and related aminopeptidases. In the present article, we reviewed genomic and transcriptomic data sets to define, for the first time, the complement of aminopeptidases (designated Hc-AP-1 to Hc-AP-13) of the family M1 with homologues in Caenorhabditis elegans, characterised by zinc-binding (HEXXH) and exo-peptidase (GAMEN) motifs. The three previously published H11 isoforms (accession nos. X94187, FJ481146 and AJ249941) had most sequence similarity to Hc-AP-2 and Hc-AP-8, whereas unpublished isoforms (accession nos. AJ249942 and AJ311316) were both most similar to Hc-AP-3. The aminopeptidases characterised here had homologues in C. elegans. Hc-AP-1 to Hc-AP-8 were most similar in amino acid sequence (28-41%) to C. elegans T07F10.1; Hc-AP-9 and Hc-AP-10 to C. elegans PAM-1 (isoform b) (53-54% similar); Hc-AP-11 and Hc-AP-12 to C. elegans AC3.5 and Y67D8C.9 (26% and 50% similar, respectively); and Hc-AP-13 to C. elegans C42C1.11 and ZC416.6 (50-58% similar). Comparative analysis suggested that Hc-AP-1 to Hc-AP-8 play roles in digestion, metabolite excretion, neuropeptide processing and/or osmotic regulation, with Hc-AP-4 and Hc-AP-7 having male-specific functional roles. The analysis also indicated that Hc-AP-9 and Hc-AP-10 might be involved in the degradation of cyclin (B3) and required to complete meiosis. Hc-AP-11 represents a leucyl/cystinyl aminopeptidase, predicted to have metallopeptidase and zinc ion binding activity, whereas Hc-AP-12 likely encodes an aminopeptidase Q homologue also with these activities and a possible role in gonad function. Finally, Hc-AP-13 is predicted to encode an aminopeptidase AP-1 homologue of C. elegans with hydrolase activity, suggested to operate, possibly synergistically with a PEPT-1 ortholog, as an oligopeptide transporter in the gut for protein uptake and normal development and/or reproduction of the worm. An appraisal of structure-based amino acid sequence alignments revealed that all conceptually translated Hc-AP proteins, with the exception of Hc-AP-12, adopt a topology similar to those observed for the two subgroups of mammalian M1 aminopeptidases, which possess either three (I, II and IV) or four (I-IV) domains. In contrast, Hc-AP-12 lacks the N-terminal domain (I), but possesses a substantially expanded domain III. Although further work needs to be done to assess amino acid sequence conservation of the different aminopeptidases among individual worms within and among H. contortus populations, we hope that these insights will support future localisation, structural and functional studies of these molecules in H. contortus as well as facilitate future assessments of a recombinant subunit or cocktail vaccine against haemonchosis.
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ItemUnderstanding Haemonchus contortus Better Through Genomics and Transcriptomics(ELSEVIER ACADEMIC PRESS INC, 2016)Parasitic roundworms (nematodes) cause substantial mortality and morbidity in animals globally. The barber's pole worm, Haemonchus contortus, is one of the most economically significant parasitic nematodes of small ruminants worldwide. Although this and related nematodes can be controlled relatively well using anthelmintics, resistance against most drugs in common use has become a major problem. Until recently, almost nothing was known about the molecular biology of H. contortus on a global scale. This chapter gives a brief background on H. contortus and haemonchosis, immune responses, vaccine research, chemotherapeutics and current problems associated with drug resistance. It also describes progress in transcriptomics before the availability of H. contortus genomes and the challenges associated with such work. It then reviews major progress on the two draft genomes and developmental transcriptomes of H. contortus, and summarizes their implications for the molecular biology of this worm in both the free-living and the parasitic stages of its life cycle. The chapter concludes by considering how genomics and transcriptomics can accelerate research on Haemonchus and related parasites, and can enable the development of new interventions against haemonchosis.
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ItemToxocara malaysiensis infection in domestic cats in Vietnam - An emerging zoonotic issue?(ELSEVIER, 2016-01)Toxocara canis of canids is a parasitic nematode (ascaridoid) that infects humans and other hosts, causing different forms of toxocariasis. This species of Toxocara appears to be the most important cause of human disease, likely followed by Toxocara cati from felids. Although some studies from Malaysia and China have shown that cats can harbor another congener, T. malaysiensis, no information is available about this parasite for other countries. Moreover, the zoonotic potential of this parasite is unknown at this point. In the present study, we conducted the first investigation of domestic dogs and cats for Toxocara in Vietnam using molecular tools. Toxocara malaysiensis was identified as a common ascaridoid of domestic cats (in the absence of T. cati), and T. canis was commonly found in dogs. Together with findings from previous studies, the present results emphasize the need to explore the significance and zoonotic potential of T. malaysiensis in Vietnam and other countries where this parasite is endemic and prevalent in cats.
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