Queensland Institute for Medical Research

Brisbane, Australia

Queensland Institute for Medical Research

Brisbane, Australia
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Fornito A.,Monash University | Fornito A.,University of Melbourne | Zalesky A.,University of Melbourne | Breakspear M.,Queensland Institute for Medical Research | And 2 more authors.
NeuroImage | Year: 2013

The human brain is a complex, interconnected network par excellence. Accurate and informative mapping of this human connectome has become a central goal of neuroscience. At the heart of this endeavor is the notion that brain connectivity can be abstracted to a graph of nodes, representing neural elements (e.g., neurons, brain regions), linked by edges, representing some measure of structural, functional or causal interaction between nodes. Such a representation brings connectomic data into the realm of graph theory, affording a rich repertoire of mathematical tools and concepts that can be used to characterize diverse anatomical and dynamical properties of brain networks. Although this approach has tremendous potential - and has seen rapid uptake in the neuroimaging community - it also has a number of pitfalls and unresolved challenges which can, if not approached with due caution, undermine the explanatory potential of the endeavor. We review these pitfalls, the prevailing solutions to overcome them, and the challenges at the forefront of the field. © 2013 Elsevier Inc.

Barnes E.C.,Griffith University | Choomuenwai V.,Griffith University | Andrews K.T.,Griffith University | Andrews K.T.,Queensland Institute for Medical Research | And 2 more authors.
Organic and Biomolecular Chemistry | Year: 2012

The plant-derived natural product 14-hydroxy-6,12-muuroloadien-15-oic acid (1) was identified as a unique scaffold that could be chemically elaborated to generate novel lead- or drug-like screening libraries. Prior to synthesis a virtual library was generated and prioritised based on drug-like physicochemical parameters such as log P, log D5.5, hydrogen bond donors/acceptors, and molecular weight. The natural product scaffold (1) was isolated from the endemic Australian plant Eremophila mitchellii and then utilised in the parallel solution-phase generation of two series of analogues. The first library consisted of six semi-synthetic amide derivatives, whilst the second contained six carbamate analogues. These libraries have been evaluated for antimalarial activity using a chloroquine-sensitive Plasmodium falciparum line (3D7) and several compounds displayed low to moderate activity with IC50 values ranging from 14 to 33 μM. © 2012 The Royal Society of Chemistry.

Keller M.C.,University of Colorado at Boulder | Garver-Apgar C.E.,University of Colorado at Denver | Wright M.J.,Queensland Institute for Medical Research | Martin N.G.,Queensland Institute for Medical Research | And 5 more authors.
PLoS Genetics | Year: 2013

Traits that are attractive to the opposite sex are often positively correlated when scaled such that scores increase with attractiveness, and this correlation typically has a genetic component. Such traits can be genetically correlated due to genes that affect both traits ("pleiotropy") and/or because assortative mating causes statistical correlations to develop between selected alleles across the traits ("gametic phase disequilibrium"). In this study, we modeled the covariation between monozygotic and dizygotic twins, their siblings, and their parents (total N = 7,905) to elucidate the nature of the correlation between two potentially sexually selected traits in humans: height and IQ. Unlike previous designs used to investigate the nature of the height-IQ correlation, the present design accounts for the effects of assortative mating and provides much less biased estimates of additive genetic, non-additive genetic, and shared environmental influences. Both traits were highly heritable, although there was greater evidence for non-additive genetic effects in males. After accounting for assortative mating, the correlation between height and IQ was found to be almost entirely genetic in nature. Model fits indicate that both pleiotropy and assortative mating contribute significantly and about equally to this genetic correlation. © 2013 Keller et al.

Shanks G.D.,Australian Army Malaria Institute | Shanks G.D.,University of Queensland | Shanks G.D.,Queensland Institute for Medical Research | Lee S.-E.,Armed Forces Health Surveillance Center | And 2 more authors.
American Journal of Epidemiology | Year: 2011

Rotuma is an isolated Polynesian island. In January 1911, most residents of Rotuma (population approximately 2,600) were exposed to measles virus for the first time. The official mortality register documented 491 deaths due to all causes among Rotumans during 1911 (cumulative measles-related mortality: 12.8%); most deaths occurred in April-May and were attributed to measles and its sequelae. Measles-related mortality rates were higher among young children (23.4 per 100 person-years) and young adults (17.1 per 100 person-years) than among adolescents (11.0 per 100 person-years) and older adults (5.6 per 100 person-years); females (16.2 per 100 person-years) died at a higher rate than males (13.2 per 100 person-years). Gastrointestinal complications (75%), not respiratory complications, were the predominant clinical manifestations of fatal measles cases; tuberculosis mortality was unusually high during the year of the epidemic. In 1911, measles-related mortality varied by nearly 3-fold across geographic districts (range, 7.4%-21.6%). The extreme mortality due to measles on Rotuma typifies the experiences of isolated populations after first encounters with measles; it suggests that prior exposures to a narrow range of microbes and genetic homogeneity predispose isolated populations to lethal outcomes when they are first exposed to highly contagious and pathogenic viruses (e.g., measles, influenza). © The Author 2011. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

Hume D.A.,Roslin Institute | MacDonald K.P.A.,Queensland Institute for Medical Research
Blood | Year: 2012

Macrophage-colony stimulating factor (CSF-1) signaling through its receptor (CSF-1R) promotes the differentiation of myeloid progenitors into heterogeneous populations of monocytes, macrophages, dendritic cells, and bone-resorbing osteoclasts. In the periphery, CSF-1 regulates the migration, proliferation, function, and survival of macrophages, which function at multiple levels within the innate and adaptive immune systems. Macrophage populations elicited by CSF-1 are associated with, and exacerbate, a broad spectrum of pathologies, including cancer, inflammation, and bone disease. Conversely, macrophages can also contribute to immunosuppression, disease resolution, and tissue repair. Recombinant CSF-1, antibodies against the ligand and the receptor, and specific inhibitors of CSF-1R kinase activity have been each been tested in a range of animal models and in some cases, in patients. This review examines the potential clinical uses of modulators of the CSF-1/CSF-1R system. We conclude that CSF-1 promotes a resident-type macrophage phenotype. As a treatment, CSF-1 has therapeutic potential in tissue repair. Conversely, inhibition of CSF-1R is unlikely to be effective in inflammatory disease but may have utility in cancer. © 2012 by The American Society of Hematology.

Phipps A.I.,Fred Hutchinson Cancer Research Center | Buchanan D.D.,Queensland Institute for Medical Research | Makar K.W.,Fred Hutchinson Cancer Research Center | Win A.K.,University of Melbourne | And 5 more authors.
British Journal of Cancer | Year: 2013

Background: Mutations in the Kirsten Ras (KRAS) oncogene are common in colorectal cancer (CRC). The role of KRAS-mutation status as a prognostic factor, however, is unclear. We evaluated the relationship between KRAS-mutation status and CRC survival, considering heterogeneity in this association by tumour and patient characteristics.Methods:The population-based study included individuals diagnosed with CRC between 1998-2007 in Western Washington State. Tumour specimens were tested for KRAS exon 2 mutations, the BRAF p.V600E mutation, and microsatellite instability (MSI). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between KRAS-mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumour site, stage, and MSI. We conducted additional analyses combining KRAS-mutation, BRAF-mutation, and MSI status.Results:Among 1989 cases, 31% had KRAS-mutated CRC. Kirsten Ras (KRAS)-mutated CRC was associated with poorer disease-specific survival (HR=1.37, 95% CI: 1.13-1.66). This association was not evident in cases who presented with distant-stage CRC. Cases with KRAS-wild-type/BRAF-wild-type/ MSI-high CRC had the most favourable prognosis; those with CRC exhibiting a KRAS-or BRAF-mutation and no MSI had the poorest prognosis. Patterns were similar for overall survival.Conclusion:Kirsten Ras (KRAS)-mutated CRC was associated with statistically significantly poorer survival after diagnosis than KRAS-wild-type CRC. © 2013 Cancer Research UK. All rights reserved.

Neilsen P.M.,University of Adelaide | Noll J.E.,University of Adelaide | Suetani R.J.,University of Adelaide | Schulz R.B.,University of Adelaide | And 4 more authors.
Oncotarget | Year: 2011

Mutations in the TP53 gene commonly result in the expression of a full-length protein that drives cancer cell invasion and metastasis. Herein, we have deciphered the global landscape of transcriptional regulation by mutant p53 through the application of a panel of isogenic H1299 derivatives with inducible expression of several common cancer-associated p53 mutants. We found that the ability of mutant p53 to alter the transcriptional profile of cancer cells is remarkably conserved across different p53 mutants. The mutant p53 transcriptional landscape was nested within a small subset of wild-type p53 responsive genes, suggesting that the oncogenic properties of mutant p53 are conferred by retaining its ability to regulate a defined set of p53 target genes. These mutant p53 target genes were shown to converge upon a p63 signalling axis. Both mutant p53 and wild-type p63 were co-recruited to the promoters of these target genes, thus providing a molecular basis for their selective regulation by mutant p53. We demonstrate that mutant p53 manipulates the gene expression pattern of cancer cells to facilitate invasion through the release of a pro-invasive secretome into the tumor microenvironment. Collectively, this study provides mechanistic insight into the complex nature of transcriptional regulation by mutant p53 and implicates a role for tumor-derived p53 mutations in the manipulation of the cancer cell secretome. © Neilsen et al.

Keller M.C.,University of Colorado at Boulder | Medland S.E.,Queensland Institute for Medical Research | Duncan L.E.,University of Colorado at Boulder
Behavior Genetics | Year: 2010

The classical twin design (CTD) uses observed covariances from monozygotic and dizygotic twin pairs to infer the relative magnitudes of genetic and environmental causes of phenotypic variation. Despite its wide use, it is well known that the CTD can produce biased estimates if its stringent assumptions are not met. By modeling observed covariances of twins' relatives in addition to twins themselves, extended twin family designs (ETFDs) require less stringent assumptions, can estimate many more parameters of interest, and should produce less biased estimates than the CTD. However, ETFDs are more complicated to use and interpret, and by attempting to estimate a large number of parameters, the precision of parameter estimates may suffer. This paper is a formal investigation into a simple question: Is it worthwhile to use more complex models such as ETFDs in behavioral genetics? In particular, we compare the bias, precision, and accuracy of estimates from the CTD and three increasingly complex ETFDs. We find the CTD does a decent job of estimating broad sense heritability, but CTD estimates of shared environmental effects and the relative importance of additive versus non-additive genetic variance can be biased, sometimes wildly so. Increasingly complex ETFDs, on the other hand, are more accurate and less sensitive to assumptions than simpler models. We conclude that researchers interested in characterizing the environment or the makeup of genetic variation should use ETFDs when possible. © 2009 Springer Science+Business Media, LLC.

Choomuenwai V.,Griffith University | Choomuenwai V.,Queensland Institute for Medical Research | Andrews K.T.,Griffith University | Andrews K.T.,Queensland Institute for Medical Research | Davis R.A.,Griffith University
Bioorganic and Medicinal Chemistry | Year: 2012

As part of a research program aimed at discovering new antimalarial leads from Australian macrofungi a unique fungi-derived prefractionated library was screened against a chloroquine-sensitive Plasmodium falciparum line (3D7) using a radiometric growth inhibition assay. A library fraction derived from a Cortinarius species displayed promising antimalarial activity. UV-guided fractionation on the CH2Cl2/MeOH extract from this fungus resulted in the isolation of four known compounds: (1S,3R)-austrocortirubin (1), (1S,3S)-austrocortirubin (2), 1-deoxyaustrocortirubin (3), and austrocortinin (4). Compound 2 was used as a natural product scaffold in the parallel solution-phase synthesis of a small library of N-substituted tetrahydroanthraquinones (5-15). All compounds (1-15) were tested in vitro against P. falciparum 3D7 parasites and (1S,3S)-austrocortirubin (2), the major fungal constituent, was shown to be the most active compound with an IC 50 of 1.9 μM. This compound displayed moderate cytotoxicity against neonatal foreskin fibroblast (NFF) cells with an IC50 of 15.6 μM. © 2012 Elsevier Ltd. All rights reserved.

Keller M.C.,University of Colorado at Boulder | Visscher P.M.,Queensland Institute for Medical Research | Goddard M.E.,University of Melbourne | Goddard M.E.,Australian Department of Primary Industries and Fisheries
Genetics | Year: 2011

Inbreeding depression, which refers to reduced fitness among offspring of related parents, has traditionally been studied using pedigrees. In practice, pedigree information is difficult to obtain, potentially unreliable, and rarely assessed for inbreeding arising from common ancestors who lived more than a few generations ago. Recently, there has been excitement about using SNP data to estimate inbreeding (F) arising from distant common ancestors in apparently "outbred" populations. Statistical power to detect inbreeding depression using SNP data depends on the actual variation in inbreeding in a population, the accuracy of detecting that with marker data, the effect size, and the sample size. No one has yet investigated what variation in F is expected in SNP data as a function of population size, and it is unclear which estimate of F is optimal for detecting inbreeding depression. In the present study, we use theory, simulated genetic data, and real genetic data to find the optimal estimate of F, to quantify the likely variation in F in populations of various sizes, and to estimate the power to detect inbreeding depression. We find that F estimated from runs of homozygosity (F roh), which reflects shared ancestry of genetic haplotypes, retains variation in even large populations (e.g., SD = 0.5% when N e = 10,000) and is likely to be the most powerful method of detecting inbreeding effects from among several alternative estimates of F. However, large samples (e.g., 12,000-65,000) will be required to detect inbreeding depression for likely effect sizes, and so studies using Froh to date have probably been underpowered. © 2011 by the Genetics Society of America.

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