Science Collected Works - Research Publications
Now showing items 1-12 of 93
Impaired glucose metabolism and exercise capacity with muscle-specific glycogen synthase 1 (gys1) deletion in adult mice
(ELSEVIER SCIENCE BV, 2016-03-01)
OBJECTIVE: Muscle glucose storage and muscle glycogen synthase (gys1) defects have been associated with insulin resistance. As there are multiple mechanisms for insulin resistance, the specific role of glucose storage defects is not clear. The aim of this study was to examine the effects of muscle-specific gys1 deletion on glucose metabolism and exercise capacity. METHODS: Tamoxifen inducible and muscle specific gys-1 KO mice were generated using the Cre/loxP system. Mice were subjected to glucose tolerance tests, euglycemic/hyperinsulinemic clamps and exercise tests. RESULTS: gys1-KO mice showed ≥85% reduction in muscle gys1 mRNA and protein concentrations, 70% reduction in muscle glycogen levels, postprandial hyperglycaemia and hyperinsulinaemia and impaired glucose tolerance. Under insulin-stimulated conditions, gys1-KO mice displayed reduced glucose turnover and muscle glucose uptake, indicative of peripheral insulin resistance, as well as increased plasma and muscle lactate levels and reductions in muscle hexokinase II levels. gys1-KO mice also exhibited markedly reduced exercise and endurance capacity. CONCLUSIONS: Thus, muscle-specific gys1 deletion in adult mice results in glucose intolerance due to insulin resistance and reduced muscle glucose uptake as well as impaired exercise and endurance capacity. IN BRIEF: This study demonstrates why the body prioritises muscle glycogen storage over liver glycogen storage despite the critical role of the liver in supplying glucose to the brain in the fasting state and shows that glycogen deficiency results in impaired glucose metabolism and reduced exercise capacity.
Tumour-associated neutrophils and loss of epithelial PTEN can promote corticosteroid-insensitive MMP-9 expression in the chronically inflamed lung microenvironment
(BMJ PUBLISHING GROUP, 2017-12-01)
Matrix metalloproteinase-9 (MMP-9) is increased in a number of pathological lung conditions, where the proteinase contributes to deleterious remodelling of the airways. While both lung cancer and COPD are associated with increased MMP-9 expression, the cellular and molecular drivers of MMP-9 remain unresolved. In this study, MMP-9 transcript measured within the tumour region from patients with non-small-cell lung cancer (NSCLC) and coexisting COPD was found to be uniformly increased relative to adjacent tumour-free tissue. MMP-9 gene expression and immunohistochemistry identified tumour-associated neutrophils, but not macrophages, as a predominant source of this proteinase. In addition, PTEN gene expression was significantly reduced in tumour and there was evidence of epithelial MMP-9 expression. To explore whether PTEN can regulate epithelial MMP-9 expression, a small interfering (si)RNA knockdown strategy was used in Beas-2B bronchial epithelial cells. PTEN knockdown by siRNA selectively increased MMP-9 expression in response to lipopolysaccharide in a corticosteroid-insensitive manner. In summary, tumour-associated neutrophils represent an important source of MMP-9 in NSCLC, and loss of epithelial PTEN may further augment steroid-insensitive expression.
Phylodynamic Reconstruction Reveals Norovirus GII. 4 Epidemic Expansions and their Molecular Determinants
(PUBLIC LIBRARY SCIENCE, 2010-05-01)
Noroviruses are the most common cause of viral gastroenteritis. An increase in the number of globally reported norovirus outbreaks was seen the past decade, especially for outbreaks caused by successive genogroup II genotype 4 (GII.4) variants. Whether this observed increase was due to an upswing in the number of infections, or to a surveillance artifact caused by heightened awareness and concomitant improved reporting, remained unclear. Therefore, we set out to study the population structure and changes thereof of GII.4 strains detected through systematic outbreak surveillance since the early 1990s. We collected 1383 partial polymerase and 194 full capsid GII.4 sequences. A Bayesian MCMC coalescent analysis revealed an increase in the number of GII.4 infections during the last decade. The GII.4 strains included in our analyses evolved at a rate of 4.3-9.0x10(-3) mutations per site per year, and share a most recent common ancestor in the early 1980s. Determinants of adaptation in the capsid protein were studied using different maximum likelihood approaches to identify sites subject to diversifying or directional selection and sites that co-evolved. While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication. We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant. While norovirus infections are generally mild and self-limiting, more severe outcomes of infection frequently occur in elderly and immunocompromized people, and no treatment is available. The observed pattern of continually emerging novel variants of GII.4, causing elevated numbers of infections, is therefore a cause for concern.
Benefits and challenges of incorporating citizen science into university education.
(Public Library of Science (PLoS), 2017)
A common feature of many citizen science projects is the collection of data by unpaid contributors with the expectation that the data will be used in research. Here we report a teaching strategy that combined citizen science with inquiry-based learning to offer first year university students an authentic research experience. A six-year partnership with the Australian phenology citizen science program ClimateWatch has enabled biology students from the University of Western Australia to contribute phenological data on plants and animals, and to conduct the first research on unvalidated species datasets contributed by public and university participants. Students wrote scientific articles on their findings, peer-reviewed each other's work and the best articles were published online in a student journal. Surveys of more than 1500 students showed that their environmental engagement increased significantly after participating in data collection and data analysis. However, only 31% of students agreed with the statement that "data collected by citizen scientists are reliable" at the end of the project, whereas the rate of agreement was initially 79%. This change in perception was likely due to students discovering erroneous records when they mapped data points and analysed submitted photographs. A positive consequence was that students subsequently reported being more careful to avoid errors in their own data collection, and making greater efforts to contribute records that were useful for future scientific research. Evaluation of our project has shown that by embedding a research process within citizen science participation, university students are given cause to improve their contributions to environmental datasets. If true for citizen scientists in general, enabling participants as well as scientists to analyse data could enhance data quality, and so address a key constraint of broad-scale citizen science programs.
Optoelectronic characteristics of rr-P3HT:PC61BM-based organic solar cells
(MYU K.K., 2020-07-20)
It is well known that organic solar cells (OSCs) are made using organic materials because of their mechanical flexibility and low manufacturing cost. Their efficiency, however, remains low for several reasons, including limited light absorption and poor charge mobility. Although OSCs are a fascinating supplement to silicon-based solar cells, they have yet to provide good efficiency for a prolonged period. Combining a narrowband donor and an electron acceptor [regioregular poly 3-hexylthiohene-2,5-diyl (rr-P3HT) and 6,6-phenyl-C61-butyric acid methyl ester (PC61BM), respectively] is a prevalent approach towards efficient organic cells. In our work, a device of configuration indium tin oxide (ITO)/poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)/rr-P3HT:PC61BM/Al was fabricated and characterized both electrically and optically. Various solar cell constraints were optimized to maximize the performance of OSCs. Ultimately, a device with a maximum power conversion efficiency (PCE) of approximately 1.4% was achieved under the optimum fabrication conditions.
High CD26 and Low CD94 Expression Identifies an IL-23 Responsive V delta 2(+) T Cell Subset with a MAIT Cell-like Transcriptional Profile
(CELL PRESS, 2020-06-16)
Vδ2+ T cells play a critical role in immunity to micro-organisms and cancer but exhibit substantial heterogeneity in humans. Here, we demonstrate that CD26 and CD94 define transcriptionally, phenotypically, and functionally distinct Vδ2+ T cell subsets. Despite distinct antigen specificities, CD26hiCD94lo Vδ2+ cells exhibit substantial similarities to CD26hi mucosal-associated invariant T (MAIT) cells, although CD26- Vδ2+ cells exhibit cytotoxic, effector-like profiles. At birth, the Vδ2+Vγ9+ population is dominated by CD26hiCD94lo cells; during adolescence and adulthood, Vδ2+ cells acquire CD94/NKG2A expression and the relative frequency of the CD26hiCD94lo subset declines. Critically, exposure of the CD26hiCD94lo subset to phosphoantigen in the context of interleukin-23 (IL-23) and CD26 engagement drives the acquisition of a cytotoxic program and concurrent loss of the MAIT cell-like phenotype. The ability to modulate the cytotoxic potential of CD26hiCD94lo Vδ2+ cells, combined with their adenosine-binding capacity, may make them ideal targets for immunotherapeutic expansion and adoptive transfer.
Responses of grasses to experimental submergence in summer: implications for the management of unseasonal flows in regulated rivers
<jats:title>Abstract</jats:title> <jats:p>River regulation has altered the seasonal timing of flows in many rivers worldwide, impacting the survival and growth of riparian plants. In south-eastern Australia, demand for irrigation water in summer often results in high river flows during a season that would naturally experience low flows. Although unseasonal high summer flows are thought to significantly impact waterways, their effects on vegetation are poorly quantified. We investigated the responses of five grass species commonly occurring in riparian zones to different durations of submergence in summer. We experimentally tested the response of three exotic and two native grasses to four submergence treatments (4 weeks, 8 weeks, 2-week pulses and no submergence), and two levels of shading (no shading and 80% light reduction), over 8 weeks in summer and early autumn. All submergence treatments, including the 2-week pulse, resulted in the death of all plants of three species (<jats:italic>Bromus catharticus</jats:italic>, <jats:italic>Dactylis glomerata</jats:italic> and <jats:italic>Rytidosperma caespitosum</jats:italic>). <jats:italic>Lolium perenne</jats:italic> exhibited moderate survival rates in the shorter-duration unshaded submergence treatments, while <jats:italic>Poa labillardierei</jats:italic> largely survived all treatments. Similar responses across species were observed for plant height and biomass, although height generally increased while biomass growth was reduced by shading. These results show that even 2-week periods of summer submergence can reduce growth and cause the death of some riparian grasses. Although some species may survive longer submergence durations, impacts on other aspects of fitness, and ongoing effects of repeated unseasonal submergence, remain uncertain. Our study highlights that the impacts of unseasonal flows require further investigation and careful management.</jats:p>
The Australian Science Communicators conference 2020
(SCUOLA INT SUPERIORE STUDI AVANZATI-S I S S A-INT SCH ADVANCED STUDIES, 2020-01-01)
<jats:p>This special issue of JCOM features six commentary articles from the research stream of the Australian Science Communicators conference, held in February 2020. These opportunistic assessments and deliberate analyses explore important themes of trust, engagement, and communication strategy across a diverse range of scientific contexts. Together, they demonstrate the importance of opportunities to come together and share the research that underpins our practice. The conference and these commentaries enable us to engage in professional development during these exceptional times when successful evidence-based science communication is of critical significance.</jats:p>
Pediatric Anthracycline-Induced Cardiotoxicity: Mechanisms, Pharmacogenomics, and Pluripotent Stem-Cell Modeling.
Anthracycline-induced cardiotoxicity (ACT) is a severe adverse drug reaction for a subset of children treated with anthracyclines as part of chemotherapy protocols. The identification of genetic markers associated with increased ACT susceptibility has clinical significance toward improving patient care and our understanding of the molecular mechanisms involved in ACT. Human-induced pluripotent stem cell-derived cardiomyocytes represent a novel approach to determine the pharmacogenomics of ACT and guide the development of genetic screening tests.
Single sample scoring of molecular phenotypes
BACKGROUND: Gene set scoring provides a useful approach for quantifying concordance between sample transcriptomes and selected molecular signatures. Most methods use information from all samples to score an individual sample, leading to unstable scores in small data sets and introducing biases from sample composition (e.g. varying numbers of samples for different cancer subtypes). To address these issues, we have developed a truly single sample scoring method, and associated R/Bioconductor package singscore ( https://bioconductor.org/packages/singscore ). RESULTS: We use multiple cancer data sets to compare singscore against widely-used methods, including GSVA, z-score, PLAGE, and ssGSEA. Our approach does not depend upon background samples and scores are thus stable regardless of the composition and number of samples being scored. In contrast, scores obtained by GSVA, z-score, PLAGE and ssGSEA can be unstable when less data are available (NS < 25). The singscore method performs as well as the best performing methods in terms of power, recall, false positive rate and computational time, and provides consistently high and balanced performance across all these criteria. To enhance the impact and utility of our method, we have also included a set of functions implementing visual analysis and diagnostics to support the exploration of molecular phenotypes in single samples and across populations of data. CONCLUSIONS: The singscore method described here functions independent of sample composition in gene expression data and thus it provides stable scores, which are particularly useful for small data sets or data integration. Singscore performs well across all performance criteria, and includes a suite of powerful visualization functions to assist in the interpretation of results. This method performs as well as or better than other scoring approaches in terms of its power to distinguish samples with distinct biology and its ability to call true differential gene sets between two conditions. These scores can be used for dimensional reduction of transcriptomic data and the phenotypic landscapes obtained by scoring samples against multiple molecular signatures may provide insights for sample stratification.
Naphthoquinone Metabolites Produced by Monacrosporium ambrosium, the Ectosymbiotic Fungus of Tea Shot-Hole Borer, Euwallacea fornicatus, in Stems of Tea, Camellia sinensis
(Springer Science and Business Media LLC, 2018-01)
The tea shot-hole borer beetle (TSHB, Euwallacea fornicatus) causes serious damage in plantations of tea, Camellia sinensis var. assamica, in Sri Lanka and South India. TSHB is found in symbiotic association with the ambrosia fungus, Monacrosporium ambrosium (syn. Fusarium ambrosium), in galleries located within stems of tea bushes. M. ambrosium is known to be the sole food source of TSHB. Six naphthoquinones produced during spore germination in a laboratory culture broth of M. ambrosium were isolated and identified as dihydroanhydrojavanicin, anhydrojavanicin, javanicin, 5,8-dihydroxy-2-methyl-3-(2-oxopropyl)naphthalene-1,4-dione, anhydrofusarubin and solaniol. Chloroform extracts of tea stems with red-colored galleries occupied by TSHB contained UV active compounds similar to the above naphthoquinones. Laboratory assays demonstrated that the combined ethyl acetate extracts of the fungal culture broth and mycelium inhibited the growth of endophytic fungi Pestalotiopsis camelliae and Phoma multirostrata, which were also isolated from tea stems. Thus, pigmented naphthoquinones secreted by M. ambrosium during spore germination may prevent other fungi from invading TSHB galleries in tea stems. The antifungal nature of the naphthoquinone extract suggests that it protects the habitat of TSHB. We propose that the TSHB fungal ectosymbiont M. ambrosium provides not only the food and sterol skeleton necessary for the development of the beetle during its larval stages, but also serves as a producer of fungal inhibitors that help to preserve the purity of the fungal garden of TSHB.