ORCID Profile
0000-0001-5618-0555
Current Organisations
Murdoch University
,
Edith Cowan University
,
University of Western Australia
,
Curtin University
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Publisher: MDPI AG
Date: 05-11-2021
DOI: 10.3390/SCI3040040
Abstract: Type 2 diabetes mellitus (T2DM) has been strongly associated with single nucleotide polymorphisms (SNPs) in the TCF7L2 gene. This study investigated the association between rs12255372, rs7903146 in the TCF7L2 gene and T2DM in a Ghanaian population. A case-control study design was used for this study. A total of 106 T2DM patients and 110 control participants were selected. Basic data collected included body mass index, blood pressure and socio-demographics. Fasting blood s les were collected and processed for: serum lipid analysis, plasma glucose estimation and plasma HbA1c estimation. Parts of the whole blood s les were used for DNA extraction using a modified salting-out method. Common and allele-specific primers were designed for genotyping using the Modified Tetra-Primer Amplification assay. Associations were evaluated using logistic regression models. The rs7903146 risk variant was significantly associated with 2.16 vs. 4.06 increased odds for T2DM in patients years vs. ≥60 years. Both rs7903146 and rs12255372 were significantly associated with increased odds of T2DM in women, overweight/obese, T2DM negative family history (T2DM-NFH) and low-HDL-C. In a multivariate model, rs7903146 but not rs12255372 was significantly associated with 2.18, 5.01 and 2.25 increased odds of T2DM, under the codominant, recessive and additive model, respectively (p 0.05). The association between rs7903146 and rs12255372 with T2DM is more highly associated in a subgroup—women and those with T2DM-NFH, yet who have cardiometabolic risk.
Publisher: Informa UK Limited
Date: 1997
Publisher: Bioscientifica
Date: 22-10-2016
DOI: 10.1530/JOE-15-0290
Abstract: Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with β-cell dysfunction. A genome-wide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 ( SUR1 ) and Kcnj11 ( Kir6.2 ). The NZO Abcc8 allele was associated with a ∼211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8 / Kcnj11 genes and displayed significant improvements in early-phase glucose-mediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving β-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to β-cell dysfunction in T2D.
Publisher: Springer Science and Business Media LLC
Date: 06-1998
DOI: 10.1007/PL00006355
Abstract: One of the most important factors affecting the increase of clients' satisfaction is how health care providers (HCP) communicate with clients. On the other hand, different factors can hinder proper communication and thus education, which is one of the main tasks of HCP. Therefore, the purpose of this study was to investigate communication barriers to education to referrals from the perspective of referrals to health centers (RHC) and HCP. This descriptive-analytical study was conducted on RHC and HCP in Kerman in 2021. Using a multi-stage s ling method, 162 HCP and 414 RHC were included in the study. The data collection tool was two researcher-made questionnaires. Data were analyzed using SPSS 16. From the perspective of RHC and HCP, most communication barriers were related to environmental and then socio-cultural factors. Among the demographic variables of HCP, level of education showed a significant relationship with the physical-psychological, verbal-non-verbal, and informational domains. And in relation to RHC, a significant relationship was found between education and job in the socio-cultural field and environmental barriers ( HCP face a variety of barriers in educating people, most of which are related to environmental factors. Given the cost-effectiveness of education to the public, it is essential that planners and policymakers use strategies to eliminate environmental factors as well as the placement of indigenous HCP in health facilities to reduce communication barriers.
Publisher: eLife Sciences Publications, Ltd
Date: 25-01-2019
DOI: 10.7554/ELIFE.42424
Abstract: Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this idea to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset to Prkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit gene Rrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure. Mechanistically, variation in the ‘usual suspects’ by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.
Publisher: Springer Science and Business Media LLC
Date: 06-2008
DOI: 10.1007/S00335-008-9134-9
Abstract: Identification of genes underlying complex traits presents a challenge to which geneticists have responded with many erse approaches. A common feature of these approaches is that different research groups must, on a case-by-case basis, replicate similar efforts in recruitment, genetic characterization, and analyses. To avoid this expensive "churning," an alternative approach has been proposed: production of an experimental genetic reference population, the Collaborative Cross, in which both genetic ersity and mapping power are maximized. Since this population consists of inbred mouse strains, further advantages are that it is essentially infinitely reproducible genetic characterization needs to be performed only once and the founder strains' genomes have been or will be sequenced, allowing imputation of allele sequences of all members of the reference population. Here we describe the establishment of such a genetic reference population, which we dub "The Gene Mine." Over 1000 genetically distinct lines have been established, descended from eight erse founder strains. Preliminary phenotypic ascertainment of these strains indicates unexpected variability arising from independent assortment of genetic variants. The Gene Mine will be a powerful resource for characterization of essentially any mouse phenotype that has a genetic basis.
Publisher: Oxford University Press (OUP)
Date: 09-2014
DOI: 10.1534/GENETICS.114.163014
Abstract: The Collaborative Cross (CC) was designed to facilitate rapid gene mapping and consists of hundreds of recombinant inbred lines descended from eight erse inbred founder strains. A decade in production, it can now be applied to mapping projects. Here, we provide a proof of principle for rapid identification of major-effect genes using the CC. To do so, we chose coat color traits since the location and identity of many relevant genes are known. We ascertained in 110 CC lines six different coat phenotypes: albino, agouti, black, cinnamon, and chocolate coat colors and the white-belly trait. We developed a pipeline employing modifications of existing mapping tools suitable for analyzing the complex genetic architecture of the CC. Together with analysis of the founders’ genome sequences, mapping was successfully achieved with sufficient resolution to identify the causative genes for five traits. Anticipating the application of the CC to complex traits, we also developed strategies to detect interacting genes, testing joint effects of three loci. Our results illustrate the power of the CC and provide confidence that this resource can be applied to complex traits for detection of both qualitative and quantitative trait loci.
Publisher: Springer Science and Business Media LLC
Date: 12-1997
DOI: 10.1007/PL00006264
Abstract: Sequence analysis of a 237 kb genomic fragment from the central region of the MHC has revealed that the HLA-B and HLA-C genes are contained within duplicated segments peri-B (53 kb) and peri-C (48 kb), respectively, and separated by an intervening sequence (IF) of 30 kb. The peri-B and peri-C segments share at least 90% sequence homology except when interrupted by insertions/deletions including Alu, L1, an endogenous retrovirus, and pseudogenes. The sequences of peri-B, IF, and peri-C were searched for the presence of Alu elements to use as markers of evolution, chromosomal rearrangements, and polymorphism. Of 29 Alu elements, 14 were identified in peri-B, 11 in peri-C, and 4 in IF. The Alu elements in peri-B and peri-C clustered phylogenetically into two clades which were classified as "preduplication" and "postduplication" clades. Four Alu J elements that are shared by peri-B and peri-C and are flanked by homologous sequences in their paralogous locations, respectively, clustered into a "preduplication" clade. By contrast, the majority of Alu elements, which are unique to either peri-B or peri-C, clustered into a postduplication clade together with the Alu consensus subfamily members ranging from platyrrhine-specific (Spqxcg) to catarrhine-specific Alu sequences (Y). The insertion of platyrrhine-specific Alu elements in postduplication locations of peri-B and peri-C implies that these two segments are the products of a duplication which occurred in primates prior to the ergence of the New World primate from the human lineage (35-44 mya). Examination of the paralogous Alu integration sites revealed that 9 of 14 postduplication Alu sequences have produced microsatellites of different length and sequence within the Alu 3'-poly A tail. The present analysis supports the hypothesis that HLA-B and HLA-C genes are products of an extended segmental duplication between 44 and 81 million years ago (mya), and that subsequent ersification of both genomic segments occurred because of the mobility and mutation of retroelements such as Alu repeats.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.BBAGRM.2017.08.004
Abstract: Different genes encode the α-actin isoforms that are predominantly expressed in heart and skeletal muscle. Mutations in the skeletal muscle α-actin gene (ACTA1) cause muscle diseases that are mostly lethal in the early postnatal period. We previously demonstrated that the disease phenotype of ACTA1 mouse models could be rescued by transgenic over-expression of cardiac α-actin (ACTC1). ACTC1 is the predominant striated α-actin isoform in the heart but is also expressed in developing skeletal muscle. To develop a translatable therapy, we investigated the genetic regulation of Actc1 expression. Using strains from The Collaborative Cross (CC) genetic resource, we found that Actc1 varies in expression by up to 24-fold in skeletal muscle. We defined significant expression quantitative trait loci (eQTL) associated with early adult Actc1 expression in soleus and heart. eQTL in both heart and soleus mapped to the Actc1 locus and replicate an eQTL mapped for Actc1 in BXD heart and quadriceps. We built on this previous work by analysing genes within the eQTL peak regions to prioritise likely candidates for modifying Actc1 expression. Additionally we interrogated the CC founder haplotype contributions to enable prioritisation of genetic variants for functional analyses. Methylation around the Actc1 transcriptional start site in early adult skeletal muscle negatively correlated with Actc1 expression in a strain-dependent manner, while other marks of regulatory potential (histone modification and chromatin accessibility) were unaltered. This study provides novel insights into the complex genetic regulation of Actc1 expression in early adult skeletal muscles.
Publisher: Informa UK Limited
Date: 11-10-2023
Publisher: The Company of Biologists
Date: 05-2008
DOI: 10.1242/JEB.012047
Abstract: The correlation between ontogenetic changes in the spectral absorption characteristics of retinal photoreceptors and expression of visual pigment opsins was investigated in the black bream, Acanthopagrus butcheri. To establish whether the spectral qualities of environmental light affected the complement of visual pigments during ontogeny, comparisons were made between fishes reared in: (1) broad spectrum aquarium conditions (2) short wavelength-reduced conditions similar to the natural environment or (3) the natural environment (wild-caught). Microspectrophotometry was used to determine the wavelengths of spectral sensitivity of the photoreceptors at four developmental stages: larval, post-settlement, juvenile and adult. The molecular sequences of the rod (Rh1) and six cone (SWS1, SWS2A and B, Rh2Aα and β, and LWS) opsins were obtained and their expression levels in larval and adult stages examined using quantitative RT-PCR. The changes in spectral sensitivity of the cones were related to the differing levels of opsin expression during ontogeny. During the larval stage the predominantly expressed opsin classes were SWS1, SWS2B and Rh2Aα, contrasting with SWS2A, Rh2Aβ and LWS in the adult. An increased proportion of long wavelength-sensitive double cones was found in fishes reared in the short wavelength-reduced conditions and in wild-caught animals, indicating that the expression of cone opsin genes is also regulated by environmental light.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 05-06-2015
Abstract: Diabetic retinopathy (DR) is a major cause of blindness globally. Investigating the underlying mechanisms of DR would be aided by a suitable mouse model that developed key features seen in the human disease, and did so without carrying genetic modifications. This study was undertaken to produce such a model. Our panel of Collaborative Cross strains was screened for DR-like features after induction of diabetes by intravenous injection with alloxan or streptozotocin. Both flat-mounted whole-retina and histologic sections were studied for the presence of retinal lesions. Progression of DR was also studied by histologic examination of the retinal vascular and neural structure at various time points after diabetes onset. In addition, microarray investigations were conducted on retinas from control and diabetic mice. Features of DR such as degenerated pericytes, acellular capillaries, minor vascular proliferation, gliosis of Müller cells, and loss of ganglion cells were noted as early as day 7 in some mice. These lesions became more evident with time. After 21 days of diabetes, severe vascular proliferation, microaneurysms, preretinal damage, increased Müller cell gliosis, and damage to the outer retina were all obvious. Microarray studies found significant differential expression of multiple genes known to be involved in DR. The FOT_FB strain provides a useful model to investigate the pathogenesis of DR and to develop treatments for this vision-threatening disease.
Publisher: The American Association of Immunologists
Date: 02-2019
Abstract: Variations in the proportion and number of specific immune cell types among healthy in iduals are influenced by both heritable and nonheritable factors. Mouse models, subjected to fewer nonheritable factors than humans, allow the identification of genetic factors that shape the immune system. We characterized immunological trait variability in the Collaborative Cross (CC), a powerful genetic resource of recombinant inbred mouse strains derived from eight erse founder strains. Of the 18 immunological traits studied in more than 60 CC strains, eight showed genome-wide significant linkage, revealing new genetic loci linked to specific immune traits. We also found that these traits were highly subject to heritable influences. As for humans, mouse immunological traits varied as a continuum rather than as discrete immunophenotypes. The CC thus represents a useful resource to identify factors that determine immunological variations, as well as defining other immune traits likely to be heritable in humans.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2020
Publisher: Oxford University Press (OUP)
Date: 02-2012
DOI: 10.1534/GENETICS.111.132639
Abstract: The Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU), and at Geniad in Western Australia (GND). These institutions aim to make publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 SNPs designed to be maximally informative in the CC and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On chromosome 2, there is significant overrepresentation of WSB/EiJ alleles, and on chromosome X, there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of in idual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.
Publisher: MDPI AG
Date: 19-11-2020
Abstract: Genetic variants that are associated with susceptibility to type 2 diabetes (T2D) are important for identification of in iduals at risk and can provide insights into the molecular basis of disease. Analysis of T2D in domestic animals provides both the opportunity to improve veterinary management and breeding programs as well as to identify novel T2D risk genes. Australian-bred Burmese (ABB) cats have a 4-fold increased incidence of type 2 diabetes (T2D) compared to Burmese cats bred in the United States. This is likely attributable to a genetic founder effect. We investigated this by performing a genome-wide association scan on ABB cats. Four SNPs were associated with the ABB T2D phenotype with p values .005. All exons and splice junctions of candidate genes near significant single-nucleotide polymorphisms (SNPs) were sequenced, including the genes DGKG, IFG2BP2, SLC8A1, E2F6, ETV5, TRA2B and LIPH. Six candidate polymorphisms were followed up in a larger cohort of ABB cats with or without T2D and also in Burmese cats bred in America, which exhibit low T2D incidence. The original SNPs were confirmed in this cohort as associated with the T2D phenotype, although no novel coding SNPs in any of the seven candidate genes showed association with T2D. The identification of genetic markers associated with T2D susceptibility in ABB cats will enable preventative health strategies and guide breeding programs to reduce the prevalence of T2D in these cats.
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.TOXICON.2011.07.008
Abstract: To assess histopathological changes in clinically envenomed tiger snake patients and identify tissue specific localisation of venom toxins using immunohistochemistry. One feline and one canine patient admitted to the Murdoch Pet Emergency Centre (MPEC), Murdoch University with tiger snake (Notechis sp.) envenoming. Both patients died as a result of envenomation. Non-envenomed tissue was also collected and used for comparison. Biopsy s les (heart, lung, kidney andskeletal muscle tissue) were retrieved 1-2 h post death and processed for histopathological examination using Haemotoxylin and Eosin, Martius Scarlet Blue and Periodic Acid Schiff staining. Tissues were examined by light microscopy and tissue sections subjected to immunohistochemical staining using in-house generated monoclonal and polyclonal antibodies against Notechis venoms. Venom-induced pathological changes were observed in the lungs, kidneys and muscle tissue of both patients. Evidence, not previously noted, of procoagulant venom effects were apparent, with formed thrombi in the heart, lungs (small fibrillar aggregates and larger, discrete thrombi) and kidneys. Immunohistochemical assays revealed venom present in the pulmonary tissue, in and around the glomerular capsule and surrounding tubules in renal tissue and scattered throughout the Gastrocnemius muscle tissue. This work has shown pathological evidence of procoagulant venom activity supporting previous suggestions that an initial thrombotic state occurs in envenomed patients. We have shown that venom toxins are able to be localised to specific tissues, in this case, venom was detected in the lung, kidney and muscle tissues of clinically envenomed animals. Future work will examine specific toxin localisation using monoclonal antibodies and identify if antivenom molecules are able to reach their target tissues.
Publisher: Elsevier BV
Date: 2022
Publisher: MDPI AG
Date: 26-04-2021
DOI: 10.20944/PREPRINTS202104.0650.V1
Abstract: Type-2 diabetes mellitus (T2DM) have been strongly associated with single nucleotide polymorphisms (SNPs) in the TCF7L2 gene. This study investigated the association between rs12255372, rs7903146 and T2DM in a Ghanaian population. A case-control study design was used for this study. A total of 106 T2DM patients and 110 control participants were selected. Basic data collected included body mass index, blood pressure and socio-demographics. Fasting blood s les were collected and used for serum lipid analysis, HbA1c, plasma glucose estimation and DNA extraction. Common and allele-specific primers were designed for genotyping using the Modified Tetra-Primer Amplification assay. Associations were evaluated using logistic regression models. The rs7903146 risk variant was significantly associated with 2.16 vs 4.06 increased odds for T2DM in patients
Start Date: 2016
End Date: 2016
Funder: Edith Cowan University
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