Institute of Comparative Medicine

Glasgow, United Kingdom

Institute of Comparative Medicine

Glasgow, United Kingdom
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Kraase M.,Institute of Comparative Medicine | Sloan R.,Institute of Comparative Medicine | Klein D.,University of Veterinary Medicine Vienna | Logan N.,Institute of Comparative Medicine | And 4 more authors.
Veterinary Immunology and Immunopathology | Year: 2010

Feline immunodeficiency virus (FIV), an immunosuppressive lentivirus found in cats worldwide, is studied to illuminate mechanisms of lentiviral pathogenesis and to identify key components of protective immunity. During replication, lentiviruses accumulate errors of nucleotide mis-incorporation due to the low-fidelity of reverse transcriptase and recombination between viral variants, resulting in the emergence of a complex viral "quasispecies". In patients infected with HIV-1, env sequences may vary by up to 10% and the detection of quasispecies with greater heterogeneity is associated with higher viral loads and reduced CD4+ T cell numbers [1], indicating that transmission of more complex quasispecies may lead to disease progression. However, little is known about how FIV evolves as disease progresses, or why some cats develop AIDS rapidly while disease progression is slow in others. The aim of this study was to determine whether disease progression may be governed by viral evolution and to examine the diversity of viral variants emerging following infection with an infectious molecular clone. The FIV env gene encoding the envelope glycoprotein (Env) was examined at early (12 weeks) and late (322 weeks) stages of FIV infection in two groups of cats infected experimentally with the FIV-GL8 molecular clone. Viral variants were detected within quasispecies in cats in the late stages of FIV infection that contained differing amino acid compositions in several variable loops of Env, some of which were identified as determinants of receptor usage and resistance to neutralization. Therefore these results indicate that the FIV env gene evolves during the course of infection, giving rise to variants that resist neutralization and likely lead to disease progression. © 2009 Elsevier B.V. All rights reserved.


Simuunza M.,University of Glasgow | Simuunza M.,University of Zambia | Weir W.,University of Glasgow | Courcier E.,Institute of Comparative Medicine | And 2 more authors.
Veterinary Parasitology | Year: 2011

Tick-borne diseases are a constraint to livestock production in many developing countries as they cause high morbidity and mortality, which results in decreased production of meat, milk and other livestock by-products. The most important tick-borne diseases of livestock in sub-Saharan Africa are East Coast fever (caused by Theileria parva), babesiosis (caused by Babesia bigemina and B. bovis), anaplasmosis (caused by Anaplasma marginale) and heartwater (caused by Ehrlichia ruminantium). Despite their economic importance, information on the epidemiology of these diseases in many countries, including Zambia, is often inadequate, making rational disease control strategies difficult to implement. In this study 18S and 16S rRNA gene PCR assays were used for a comprehensive epidemiological analysis of tick-borne disease of cattle in three provinces of Zambia (Lusaka, Central and Eastern). All the disease pathogens under study (T. parva, T. mutans, T. taurotragi, B. bovis, B. bigemina, Anaplasma spp and E. ruminantium) were prevalent in each of the provinces surveyed. However, variation was observed in prevalence between regions and seasons. There was no association between live vaccination against East Coast fever and being PCR positive for T. parva. A number of risk factors were shown to be associated with (a) the occurrence of tick-borne pathogens in cattle and (b) cattle tick burdens in the wet season. A negative association was observed between the number of co-infecting pathogens and the erythrocyte packed cell volume (PCV) of carrier cattle. © 2010.


Chamba A.,Center for Immune Regulation | Holder M.J.,Center for Immune Regulation | Jarrett R.F.,Institute of Comparative Medicine | Shield L.,Institute of Comparative Medicine | And 3 more authors.
Leukemia Research | Year: 2010

B-cell lines of diverse neoplastic origin express the serotonin transporter (SERT/SLC6A4) and growth arrest in response to SERT-ligands, including the antidepressants chlomipramine and fluoxetine. Here we detail SLC6A4 transcript (Q-PCR) and protein (FACS) expression in primary cells from patients with: chronic lymphocytic leukaemia; mantle cell lymphoma; follicular lymphoma; Burkitt's lymphoma; and diffuse large B-cell lymphoma. The ability of the SERT-binding antidepressants to impact the growth of these cells when sustained on CD154-transfected fibroblasts was also determined. The results reveal a broad spectrum of primary B-cell malignancies expressing SLC6A4 with a proportion additionally displaying growth arrest on SERT-ligand exposure. © 2010 Elsevier Ltd.


Krapf G.,Childrens Cancer Research Institute | Kaindl U.,Childrens Cancer Research Institute | Kilbey A.,Institute of Comparative Medicine | Fuka G.,Childrens Cancer Research Institute | And 6 more authors.
Oncogene | Year: 2010

Approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia have an ETV6/RUNX1 (E/R) gene fusion that results from a t(12;21). This genetic subgroup of leukemia is associated with near-triploidy, near-tetraploidy, and trisomy 21 as rather specific types of secondary changes. Here, we show that, unlike various controls, E/R-expressing Ba/F3 clones acquire a tetraploid karyotype on prolonged culture, corroborating the assumption that E/R may attenuate the mitotic checkpoint (MC). Consistent with this notion, E/R-expressing diploid murine and human cell lines have decreased proportions of cells with 4N DNA content and a lower mitotic index when treated with spindle toxins. Moreover, both RUNX1 and E/R regulate mitotic arrest-deficient 2 L1 (MAD2L1), an essential MC component, by binding to promoter-inherent RUNX1 sites, which results in down-regulation of MAD2L1 mRNA and protein in E/R-expressing cells. Forced expression of E/R also abolishes RUNX1-induced reporter activation, whereas E/R with a mutant DNA-binding site leads to only minor effects. Our data link for the first time E/R, MC, and MAD2L1 and provide new insights into the function of the E/R fusion gene product. Although tetraploidy is an almost exclusive feature of E/R-positive leukemias, its rarity within this particular subgroup implies that further yet unknown factors are required for its manifestation. © 2010 Macmillan Publishers Limited All rights reserved.


Denwood M.J.,Institute of Comparative Medicine | Reid S.W.J.,Institute of Comparative Medicine | Love S.,Institute of Comparative Medicine | Nielsen M.K.,Copenhagen University | And 3 more authors.
Preventive Veterinary Medicine | Year: 2010

The Faecal Egg Count Reduction Test (FECRT) is the most widely used method of assessing the efficacy of anthelmintics, and is the only in vivo technique currently approved for use with horses. Equine Faecal Egg Count (FEC) data are frequently characterised by a low mean, high variability, small sample size and frequent zero count observations. Accurate analysis of the data therefore depends on the use of an appropriate statistical technique. Analyses of simulated FECRT data by methods based on calculation of the empirical mean and variance, non-parametric bootstrapping, and Markov chain Monte Carlo (MCMC) are compared. The MCMC method consistently outperformed the other methods, independently of the distribution from which the data were generated. Bootstrapping produced notional 95% confidence intervals containing the true parameter as little as 40% of the time with sample sizes of less than 50. Analysis of equine FECRT data yielded inconclusive results in 53 of 63 (84%) datasets, suggesting that the routine use of prior sample size calculations should be adopted to ensure sufficient data are collected. The authors conclude that computationally intensive parametric methods such as MCMC be used for analysis of FECRT data with sample sizes of less than 50, in order to avoid erroneous inference about the true efficacy of anthelmintics in the field. © 2009 Elsevier B.V. All rights reserved.


Stepek G.,Institute of Comparative Medicine | McCormack G.,Institute of Comparative Medicine | Page A.P.,Institute of Comparative Medicine
Molecular and Biochemical Parasitology | Year: 2010

The cuticle of parasitic nematodes performs many critical functions and is essential for proper development and for protection from the host immune response. The biosynthesis, assembly, modification and turnover of this exoskeleton have been most extensively studied in the free-living nematode, Caenorhabditis elegans, where it represents a complex multi-step process involving a whole suite of enzymes. The biosynthesis of the cuticle has an additional level of complexity, as many of the enzymes also require additional proteins to aid their activation and selective inhibition. Blister-5 (BLI-5) represents a protein with a kunitz-type serine protease interacting domain and is involved in cuticle collagen biosynthesis in C. elegans, through its interaction with subtilisin-like processing enzymes (such as BLI-4). Mutation of the bli-5 gene causes blistering of the collagenous adult cuticle. Homologues of BLI-5 have been identified in several parasitic species that span different nematode clades. In this study, we molecularly and biochemically characterize BLI-5 homologues from the clade V nematodes C. elegans and Haemonchus contortus and from the clade III filarial nematode Brugia malayi. The nematode BLI-5 orthologues possess a shared domain structure and perform similar in vitro and in vivo functions, performing important proteolytic enzyme functions. The results demonstrate that the bli-5 genes from these diverse parasitic nematodes are able to complement a C. elegans bli-5 mutant and thereby support the use of the C. elegans model system to examine gene function in the experimentally less-amenable parasitic species. © 2009 Elsevier B.V. All rights reserved.


Yuan Z.Q.,Institute of Comparative Medicine | Bennett L.,Institute of Comparative Medicine | Campo M.S.,Institute of Comparative Medicine | Nasir L.,Institute of Comparative Medicine
Virus Research | Year: 2010

BPV-1 and less commonly BPV-2 are associated with the pathogenesis of equine skin tumours termed sarcoids. We recently documented the transcriptional changes that are induced by BPV-1 in equine fibroblasts using microarray analyses. TLR4 expression was found to be significantly down-regulated by BPV-1. In the present study, we show that TLR4 expression is significantly decreased following the exogenous expression of BPV-1 E2 and E7 in primary equine fibroblasts. The results were confirmed by the demonstration of increased TLR4 expression following siRNA suppression of BPV-1 E2 and E7 viral gene expression. These data imply that BPV-1 is able to subvert the innate immune response by downregulation of TLR4. © 2010 Elsevier B.V. All rights reserved.

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