Showing papers by "University of Western Australia published in 2012"

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Abstract: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Biomass allocation to leaves, stems and roots: meta-analyses of interspecific variation and environmental control

Abstract: Contents Summary 30 I. Allocation in perspective 31 II. Topics of this review 32 III. Methodology 32 IV. Environmental effects 33 V. Ontogeny 36 VI. Differences between species 40 VII. Physiology and molecular regulation 41 VIII. Ecological aspects 42 IX. Perspectives 45 Acknowledgements 45 References 45 Appendices A1–A4 49 Summary We quantified the biomass allocation patterns to leaves, stems and roots in vegetative plants, and how this is influenced by the growth environment, plant size, evolutionary history and competition. Dose–response curves of allocation were constructed by means of a meta-analysis from a wide array of experimental data. They show that the fraction of whole-plant mass represented by leaves (LMF) increases most strongly with nutrients and decreases most strongly with light. Correction for size-induced allocation patterns diminishes the LMF-response to light, but makes the effect of temperature on LMF more apparent. There is a clear phylogenetic effect on allocation, as eudicots invest relatively more than monocots in leaves, as do gymnosperms compared with woody angiosperms. Plants grown at high densities show a clear increase in the stem fraction. However, in most comparisons across species groups or environmental factors, the variation in LMF is smaller than the variation in one of the other components of the growth analysis equation: the leaf area : leaf mass ratio (SLA). In competitive situations, the stem mass fraction increases to a smaller extent than the specific stem length (stem length : stem mass). Thus, we conclude that plants generally are less able to adjust allocation than to alter organ morphology.

Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Abstract: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Abstract: Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Misinformation and Its Correction: Continued Influence and Successful Debiasing

Abstract: The widespread prevalence and persistence of misinformation in contemporary societies, such as the false belief that there is a link between childhood vaccinations and autism, is a matter of public concern. For example, the myths surrounding vaccinations, which prompted some parents to withhold immunization from their children, have led to a marked increase in vaccine-preventable disease, as well as unnecessary public expenditure on research and public-information campaigns aimed at rectifying the situation.We first examine the mechanisms by which such misinformation is disseminated in society, both inadvertently and purposely. Misinformation can originate from rumors but also from works of fiction, governments and politicians, and vested interests. Moreover, changes in the media landscape, including the arrival of the Internet, have fundamentally influenced the ways in which information is communicated and misinformation is spread.We next move to misinformation at the level of the individual, and review ...

Landscape moderation of biodiversity patterns and processes - eight hypotheses

Abstract: Understanding how landscape characteristics affect biodiversity patterns and ecological processes at local and landscape scales is critical for mitigating effects of global environmental change. In this review, we use knowledge gained from human-modified landscapes to suggest eight hypotheses, which we hope will encourage more systematic research on

Seagrass ecosystems as a globally significant carbon stock

Abstract: Seagrass meadows are some of the most productive ecosystems on Earth. An analysis of organic carbon data from just under one thousand seagrass meadows indicates that, globally, these systems could store between 4.2 and 8.4 Pg carbon.

Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen

Abstract: Purpose Treatment for metastatic colorectal cancer (mCRC) commonly involves a fluoropyrimidine-based chemotherapy regimen such as infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) or fluorouracil, leucovorin, and oxaliplatin, often combined with bevacizumab or an epidermal growth factor receptor monoclonal antibody. We studied the effect of adding the novel antiangiogenic agent aflibercept (also known as ziv-aflibercept in the United States) to FOLFIRI in patients with mCRC previously treated with oxaliplatin, including patients who received prior bevacizumab. Patients and Methods Patients were randomly assigned to receive aflibercept (4 mg/kg intravenously; 612 patients) or placebo (614 patients) every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary end point was overall survival. Results Adding aflibercept to FOLFIRI significantly improved overall survival relative to placebo plus FOLFIRI (hazard ratio [HR], 0.817; 95.34% CI, 0.713 to 0.937; P .0032) with median survival times of 13.50 versus 12.06 months, respectively. Aflibercept also significantly improved progression-free survival (PFS; HR, 0.758; 95% CI, 0.661 to 0.869; P .0001), with median PFS times of 6.90 versus 4.67 months, respectively. The effects on overall survival and PFS exhibited a consistent trend across prespecified subgroup analyses, including bevacizumab pretreated patients. Response rate was 19.8% (95% CI, 16.4% to 23.2%) with aflibercept plus FOLFIRI compared with 11.1% (95% CI, 8.5% to 13.8%) with placebo plus FOLFIRI (P .0001). Adverse effects reported with aflibercept combined with FOLFIRI included the characteristic anti–vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Abstract: Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Biological applications of magnetic nanoparticles

Abstract: In this review an overview about biological applications of magnetic colloidal nanoparticles will be given, which comprises their synthesis, characterization, and in vitro and in vivo applications. The potential future role of magnetic nanoparticles compared to other functional nanoparticles will be discussed by highlighting the possibility of integration with other nanostructures and with existing biotechnology as well as by pointing out the specific properties of magnetic colloids. Current limitations in the fabrication process and issues related with the outcome of the particles in the body will be also pointed out in order to address the remaining challenges for an extended application of magnetic nanoparticles in medicine.

Detrital zircon record and tectonic setting

Abstract: Detrital zircon spectra refl ect the tectonic setting of the basin in which they are deposited. Convergent plate margins are charac-terized by a large proportion of zircon ages close to the depositional age of the sediment, whereas sediments in collisional, extensional and intracratonic settings contain greater proportions with older ages that refl ect the history of the underlying basement. These differences can be resolved by plotting the distribution of the difference between the measured crystallization ages (CA) of individual zircon grains present in the sediment and the depositional age (DA) of the sedi-ment. Application of this approach to successions where the original nature of the basin and/or the link to source are no longer preserved constrains the tectonic setting in which the sediment was deposited.INTRODUCTION Detrital zircons are a minor constituent of clastic sedimentary rocks, yet their physiochemical resilience and high concentrations of certain key trace elements means that they have become an important phase in sedimentary provenance analysis and in crustal evolution studies (e.g., Cawood et al., 2007b; Hawkesworth et al., 2010). Large numbers of in situ, high precision analyses of both igneous and detrital zircons are now available, and a striking feature of the zircon record is that it clusters into peaks of crystallization ages (Condie et al., 2009). Compilations of crys-tallization ages for detrital and igneous zircons show remarkably similar patterns of peaks and troughs, although with some variation in the rela-tive amplitude of the peaks (Condie et al., 2009). This coincidence sug-gests that the sedimentary record is a valid representation of the magmatic record (Hawkesworth et al., 2010).We establish that detrital zircon spectra have distinctive age distribu-tion patterns that refl ect the tectonic setting of the basin in which they are deposited. These patterns are principally controlled by (i) the volumes of magma generated in each tectonic setting and their preservation poten-tial, (ii) the ease with which magmatic and detrital zircons of various ages and origins become incorporated into the sedimentary record, and (iii) the record of old zircons incorporated into the sediment. These in turn provide a framework that can be used to constrain the tectonic setting of sedimen-tary packages. This approach distinguishes between three tectonic settings (i.e., convergent, collisional, and extensional), and it is most sensitive when the depositional age of the sediment investigated is well constrained. Basin setting will evolve with tectonic regime; for example, arc-continent or continent-continent collision will result in the evolution of convergent and extensional basins into collisional foreland basins. Hence the three settings distinguished herein are end-members, and the zircon age patterns associ-ated with each show a spectrum of distributions that merge and overlap rather than defi ne discrete fi elds. Discriminant plots developed for igneous rock geochemistry (e.g., Pearce and Cann, 1973) or sediment framework modes (e.g., Dickinson and Suczek, 1979) often have diffuse boundaries or overlap between fi elds, but remain important approaches in understanding and constraining tectonic setting. Equally important, exceptions to simple end-member classifi cations can provide insight into subtleties of tectonic process, such as outlined below for Avalonia in eastern North America.

Health Care Customer Value Cocreation Practice Styles

Abstract: This article explores in-depth what health care customers actually do when they cocreate value. Combining previously published research with data collected from depth interviews, field observation,...

Refugia: identifying and understanding safe havens for biodiversity under climate change

Abstract: Aim Identifying and protecting refugia is a priority for conservation under projected anthropogenic climate change, because of their demonstrated ability to facilitate the survival of biota under adverse conditions. Refugia are habitats that components of biodiversity retreat to, persist in and can potentially expand from under changing environmental conditions. However, the study and discussion of refugia has often been ad hoc and descriptive in nature. We therefore: (1) provide a habitat-based concept of refugia, and (2) evaluate methods for the identification of refugia. Location Global. Methods We present a simple conceptual framework for refugia and examine the factors that describe them. We then demonstrate how different disciplines are contributing to our understanding of refugia, and the tools that they provide for identifying and quantifying refugia. Results Current understanding of refugia is largely based on Quaternary phylogeographic studies on organisms in North America and Europe during significant temperature fluctuations. This has resulted in gaps in our understanding of refugia, particularly when attempting to apply current theory to forecast anthropogenic climate change. Refugia are environmental habitats with space and time dimensions that operate on evolutionary time-scales and have facilitated the survival of biota under changing environmental conditions for millennia. Therefore, they offer the best chances for survival under climate change for many taxa, making their identification important for conservation under anthropogenic climate change. Several methods from various disciplines provide viable options for achieving this goal. Main conclusions The framework developed for refugia allows the identification and description of refugia in any environment. Various methods provide important contributions but each is limited in scope; urging a more integrated approach to identify, define and conserve refugia. Such an approach will facilitate better understanding of refugia and their capacity to act as safe havens under projected anthropogenic climate change.

Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery

Abstract: CONTEXT Of the 200 million adults worldwide who undergo noncardiac surgery each year, more than 1 million will die within 30 days. OBJECTIVE To determine the relationship between the peak fourth-generation troponin T (TnT) measurement in the first 3 days after noncardiac surgery and 30-day mortality. DESIGN, SETTING, AND PARTICIPANTS A prospective, international cohort study that enrolled patients from August 6, 2007, to January 11, 2011. Eligible patients were aged 45 years and older and required at least an overnight hospital admission after having noncardiac surgery. MAIN OUTCOME MEASURES Patients' TnT levels were measured 6 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We undertook Cox regression analysis in which the dependent variable was mortality until 30 days after surgery, and the independent variables included 24 preoperative variables. We repeated this analysis, adding the peak TnT measurement during the first 3 postoperative days as an independent variable and used a minimum P value approach to determine if there were TnT thresholds that independently altered patients' risk of death. RESULTS A total of 15,133 patients were included in this study. The 30-day mortality rate was 1.9% (95% CI, 1.7%-2.1%). Multivariable analysis demonstrated that peak TnT values of at least 0.02 ng/mL, occurring in 11.6% of patients, were associated with higher 30-day mortality compared with the reference group (peak TnT ≤ 0.01 ng/mL): peak TnT of 0.02 ng/mL (adjusted hazard ratio [aHR], 2.41; 95% CI, 1.33-3.77); 0.03 to 0.29 ng/mL (aHR, 5.00; 95% CI, 3.72-6.76); and 0.30 ng/mL or greater (aHR, 10.48; 95% CI, 6.25-16.62). Patients with a peak TnT value of 0.01 ng/mL or less, 0.02, 0.03-0.29, and 0.30 or greater had 30-day mortality rates of 1.0%, 4.0%, 9.3%, and 16.9%, respectively. Peak TnT measurement added incremental prognostic value to discriminate those likely to die within 30 days for the model with peak TnT measurement vs without (C index = 0.85 vs 0.81; difference, 0.4; 95% CI, 0.2-0.5; P < .001 for difference between C index values). The net reclassification improvement with TnT was 25.0% (P < .001). CONCLUSION Among patients undergoing noncardiac surgery, the peak postoperative TnT measurement during the first 3 days after surgery was significantly associated with 30-day mortality.

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

Abstract: Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Reducing the Risks of Herbicide Resistance: Best Management Practices and Recommendations

Abstract: Herbicides are the foundation of weed control in commercial crop-production systems. However, herbicide-resistant (HR) weed populations are evolving rapidly as a natural response to selection pressure imposed by modern agricultural management activities. Mitigating the evolution of herbicide resistance depends on reducing selection through diversification of weed control techniques, minimizing the spread of resistance genes and genotypes via pollen or propagule dispersal, and eliminating additions of weed seed to the soil seedbank. Effective deployment of such a multifaceted approach will require shifting from the current concept of basing weed management on single-year economic thresholds.

Biochar-mediated changes in soil quality and plant growth in a three year field trial

Abstract: While many laboratory studies have focused on the short term effects of biochar addition to soil), there have been comparatively few tracing its longer term effects in the field. This study investigated the multiyear impact of biochar on crop performance and soil quality with specific emphasis on carbon (C) and nitrogen (N) cycling over a 3 y period. Biochar was added to an agricultural field at 0, 25 and 50 t ha(-1) and planted with maize (year 1) and grass (years 2 and 3). Biochar addition affected plant performance in the grass crop with significant increases in foliar N (year 2) and above-ground biomass (year 3). Below-ground, biochar increased soil respiration, fungal and bacterial growth rate and turnover in year 2. This change coincided with a shift toward a bacterial dominated decomposer community, suggesting a decrease in the potential for microbially mediated C sequestration. Biochar did not affect dissolved organic C (DOC) and N (DON), NO3- or NH4+ pool sizes. Similarly, biochar addition had limited effects on the turnover of C-14-labelled SOC (plant litter), DOC (sugars and organic acids) and DON (amino acids) and no long term effect on N mineralization, NH3 volatilization, denitrification and NH4+ sorption. After 3 years in the field, the alkalinity associated with the biochar had been fully neutralized and biochar lost most of its cations (K, Na, Ca) but had built up an associated microbial community. We conclude that biochar addition to soil causes small and potentially transient changes in a temperate agroecosystem functioning. Importantly, many of the short-term effects of biochar on plant growth and soil behavior reported from laboratory studies were not observed in the field emphasizing the need for long term field trials to help inform agronomic management decisions involving biochar. (C) 2011 Elsevier Ltd. All rights reserved. (Less)

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Abstract: Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Functions of Macronutrients

Abstract: Publisher Summary This chapter focuses on the role played by various macronutrients such as nitrogen (N), sulfur (S), phosphorus (P), magnesium (Mg), calcium (Ca), and potassium (K) in plant metabolism and growth and describes the symptoms of deficiency and toxicity of these macronutrients. N is the most essential element required after carbon, and it plays a central role in plant metabolism as a constituent of proteins, nucleic acids, chlorophyll, coenzymes, phytohormones, and secondary metabolites. When it is taken as ammonium or nitrate, it is assimilated into amino acids either in the roots or shoots and within the plant, it is translocated as nitrate or amino acids. Sulfur is taken up as sulphate and assimilated into S-containing amino acids such as cysteine that are used to synthesize S-containing enzymes and coenzymes as well as secondary compounds such as phytochelatins (detoxification of metals) or aliins and glucosinolates (feeding deterrents). Phosphorus is a structural element in nucleic acids, and as a component of adenosine phosphates, it plays an important role in energy transfer, and it is also essential for transfer of carbohydrates in leaf cells. Magnesium is a component of chlorophyll, and it is required for photosynthesis and protein synthesis. Calcium is important for cell wall and membrane stabilization, osmoregulation, and as second messenger, thereby allowing plants to regulate developmental processes in response to environmental stimuli. The main role of K is osmoregulation, which is important for cell extension and stomata movement, and it affects loading of sucrose and the rate of mass flow-driven solute movement within the plant.

Opportunities for improving phosphorus-use efficiency in crop plants.

Abstract: Limitation of grain crop productivity by phosphorus (P) is widespread and will probably increase in the future. Enhanced P efficiency can be achieved by improved uptake of phosphate from soil (P-acquisition efficiency) and by improved productivity per unit P taken up (P-use efficiency). This review focuses on improved P-use efficiency, which can be achieved by plants that have overall lower P concentrations, and by optimal distribution and redistribution of P in the plant allowing maximum growth and biomass allocation to harvestable plant parts. Significant decreases in plant P pools may be possible, for example, through reductions of superfluous ribosomal RNA and replacement of phospholipids by sulfolipids and galactolipids. Improvements in P distribution within the plant may be possible by increased remobilization from tissues that no longer need it (e.g. senescing leaves) and reduced partitioning of P to developing grains. Such changes would prolong and enhance the productive use of P in photosynthesis and have nutritional and environmental benefits. Research considering physiological, metabolic, molecular biological, genetic and phylogenetic aspects of P-use efficiency is urgently needed to allow significant progress to be made in our understanding of this complex trait.