Showing papers by "Monash University published in 2009"

Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43

Abstract: The immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recent evidence indicates that normal intestinal microbiota might also positively influence immune responses, and protect against the development of inflammatory diseases. One of these elements may be short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis and other colitic diseases is a change in 'healthy' microbiota such as Bifidobacterium and Bacteriodes, and a concurrent reduction in SCFAs. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis. SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2), and here we show that SCFA-GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFAs was necessary for the normal resolution of certain inflammatory responses, because GPR43-deficient (Gpr43(-/-)) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This seemed to relate to increased production of inflammatory mediators by Gpr43(-/-) immune cells, and increased immune cell recruitment. Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed a similar dysregulation of certain inflammatory responses. GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.

Fire in the Earth System

Abstract: Fire is a worldwide phenomenon that appears in the geological record soon after the appearance of terrestrial plants. Fire influences global ecosystem patterns and processes, including vegetation distribution and structure, the carbon cycle, and climate. Although humans and fire have always coexisted, our capacity to manage fire remains imperfect and may become more difficult in the future as climate change alters fire regimes. This risk is difficult to assess, however, because fires are still poorly represented in global models. Here, we discuss some of the most important issues involved in developing a better understanding of the role of fire in the Earth system.

Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers

Abstract: Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .

A Randomized Trial of Vertebroplasty for Painful Osteoporotic Vertebral Fractures

Abstract: Background Vertebroplasty has become a common treatment for painful osteoporotic vertebral fractures, but there is limited evidence to support its use. Methods We performed a multicenter, randomized, double-blind, placebo-controlled trial in which participants with one or two painful osteoporotic vertebral fractures that were of less than 12 months' duration and unhealed, as confirmed by magnetic resonance imaging, were randomly assigned to undergo vertebroplasty or a sham procedure. Participants were stratified according to treatment center, sex, and duration of symptoms (<6 weeks or ≥6 weeks). Outcomes were assessed at 1 week and at 1, 3, and 6 months. The primary outcome was overall pain (on a scale of 0 to 10, with 10 being the maximum imaginable pain) at 3 months. Results A total of 78 participants were enrolled, and 71 (35 of 38 in the vertebroplasty group and 36 of 40 in the placebo group) completed the 6-month follow-up (91%). Vertebroplasty did not result in a significant advantage in any measure...

The PEDro scale is a valid measure of the methodological quality of clinical trials: a demographic study.

Abstract: Questions: Does the PEDro scale measure only one construct ie, the methodological quality of clinical trials? What is the hierarchy of items of the PEDro scale from least to most adhered to? Is there any effect of year of publication of trials on item adherence? Are PEDro scale ordinal scores equivalent to interval data? Design: Rasch analysis of two independent samples of 100 clinical trials from the PEDro database scored using the PEDro scale. Results: Both samples of PEDro data showed fit to the Rasch model with no item misfit. The PEDro scale item hierarchy was the same in both samples, ranging from the most adhered to item random allocation, to the least adhered to item therapist blinding. There was no differential item functioning by year of publication. Original PEDro ordinal scores were highly correlated with transformed PEDro interval scores (r = 0.99). Conclusion: The PEDro scale is a valid measure of the methodological quality of clinical trials. It is valid to sum PEDro scale item scores to obtain a total score that can be treated as interval level measurement and subjected to parametric statistical analysis. [de Morton NA (2009) The PEDro scale is a valid measure of the methodological quality of clinical trials: a demographic study. Australian Journal of Physiotherapy 55: 129–133]

Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders

Abstract: Despite G-protein-coupled receptors (GPCRs) being among the most fruitful targets for marketed drugs, intense discovery efforts for several GPCR subtypes have failed to deliver selective drug candidates. Historically, drug discovery programmes for GPCR ligands have been dominated by efforts to develop agonists and antagonists that act at orthosteric sites for endogenous ligands. However, in recent years, there have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function. These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.

Framework Analysis: A Qualitative Methodology for Applied Policy Research

Abstract: Policies and procedures govern organizations whether they are private or public, for-profit or not-for profit. Review of such policies and procedures are done periodically to ensure optimum efficiency within the organization. Framework analysis is a qualitative method that is aptly suited for applied policy research. Framework analysis is better adapted to research that has specific questions, a limited time frame, a pre-designed sample and a priori issues. In the analysis, data is sifted, charted and sorted in accordance with key issues and themes using five steps: familiarization; identifying a thematic framework; indexing; charting; and mapping and interpretation. Framework analysis provides an excellent tool to assess policies and procedures from the very people that they affect.

The Systems Biology Graphical Notation

Abstract: Circuit diagrams and Unified Modeling Language diagrams are just two examples of standard visual languages that help accelerate work by promoting regularity, removing ambiguity and enabling software tool support for communication of complex information. Ironically, despite having one of the highest ratios of graphical to textual information, biology still lacks standard graphical notations. The recent deluge of biological knowledge makes addressing this deficit a pressing concern. Toward this goal, we present the Systems Biology Graphical Notation (SBGN), a visual language developed by a community of biochemists, modelers and computer scientists. SBGN consists of three complementary languages: process diagram, entity relationship diagram and activity flow diagram. Together they enable scientists to represent networks of biochemical interactions in a standard, unambiguous way. We believe that SBGN will foster efficient and accurate representation, visualization, storage, exchange and reuse of information on all kinds of biological knowledge, from gene regulation, to metabolism, to cellular signaling.

Cracking the BAFF code

Abstract: The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting.

A cross-level perspective on employee creativity: goal orientation, team learning behavior, and individual creativity

Abstract: We developed and tested a cross-level model of individual creativity, integrating goal orientation theory and team learning research. Using hierarchical linear modeling, we found cross-level interactions between individuals’ goal orientation and team learning behavior in a cross-national sample of 25 R&D teams comprising 198 employees. We hypothesized and found a nonlinear interaction between individual learning orientation and team learning behavior: in teams higher in team learning behavior, the positive relationship between learning orientation and creativity was attenuated at higher levels of learning orientation. An individual approach orientation was positively related to creativity only when team learning behavior was high.

A shear gradient–dependent platelet aggregation mechanism drives thrombus formation

Abstract: Platelet aggregation at sites of vascular injury is essential for hemostasis and arterial thrombosis. It has long been assumed that platelet aggregation and thrombus growth are initiated by soluble agonists generated at sites of vascular injury. By using high-resolution intravital imaging techniques and hydrodynamic analyses, we show that platelet aggregation is primarily driven by changes in blood flow parameters (rheology), with soluble agonists having a secondary role, stabilizing formed aggregates. We find that in response to vascular injury, thrombi initially develop through the progressive stabilization of discoid platelet aggregates. Analysis of blood flow dynamics revealed that discoid platelets preferentially adhere in low-shear zones at the downstream face of forming thrombi, with stabilization of aggregates dependent on the dynamic restructuring of membrane tethers. These findings provide insight into the prothrombotic effects of disturbed blood flow parameters and suggest a fundamental reinterpretation of the mechanisms driving platelet aggregation and thrombus growth.

Ownership Concentration, Foreign Shareholding, Audit Quality, and Stock Price Synchronicity: Evidence from China

Abstract: This paper investigates the effects of largest-shareholder ownership concentration, foreign ownership, and audit quality on the amount of firm-specific information incorporated into share prices, as measured by stock price synchronicity, of Chinese-listed firms over the 1996-2003 period. We show that synchronicity is a concave function of ownership by the largest shareholder with its maximum at an approximately 50% level. Further, we find that synchronicity is higher when the largest shareholder is government related. We also find that foreign ownership and auditor quality are inversely associated with synchronicity. Finally, we show that the amount of earnings information reflected in stock returns is lower for firms with high synchronicity.

Toxin B is essential for virulence of Clostridium difficile

Abstract: Clostridium difficile is the leading cause of infectious diarrhoea in hospitals worldwide, because of its virulence, spore-forming ability and persistence. C. difficile-associated diseases are induced by antibiotic treatment or disruption of the normal gastrointestinal flora. Recently, morbidity and mortality resulting from C. difficile-associated diseases have increased significantly due to changes in the virulence of the causative strains and antibiotic usage patterns. Since 2002, epidemic toxinotype III NAP1/027 strains, which produce high levels of the major virulence factors, toxin A and toxin B, have emerged. These toxins have 63% amino acid sequence similarity and are members of the large clostridial glucosylating toxin family, which are monoglucosyltransferases that are pro-inflammatory, cytotoxic and enterotoxic in the human colon. Inside host cells, both toxins catalyse the transfer of glucose onto the Rho family of GTPases, leading to cell death. However, the role of these toxins in the context of a C. difficile infection is unknown. Here we describe the construction of isogenic tcdA and tcdB (encoding toxin A and B, respectively) mutants of a virulent C. difficile strain and their use in the hamster disease model to show that toxin B is a key virulence determinant. Previous studies showed that purified toxin A alone can induce most of the pathology observed after infection of hamsters with C. difficile and that toxin B is not toxic in animals unless it is co-administered with toxin A, suggesting that the toxins act synergistically. Our work provides evidence that toxin B, not toxin A, is essential for virulence. Furthermore, it is clear that the importance of these toxins in the context of infection cannot be predicted exclusively from studies using purified toxins, reinforcing the importance of using the natural infection process to dissect the role of toxins in disease.

Impact of socioeconomic status on cancer incidence and stage at diagnosis: selected findings from the surveillance, epidemiology, and end results: National Longitudinal Mortality Study

Abstract: Background Population-based cancer registry data from the Surveillance, Epidemiology, and End Results (SEER) Program at the National Cancer Institute (NCI) are mainly based on medical records and administrative information. Individual-level socioeconomic data are not routinely reported by cancer registries in the United States because they are not available in patient hospital records. The U.S. representative National Longitudinal Mortality Study (NLMS) data provide self-reported, detailed demographic and socioeconomic data from the Social and Economic Supplement to the Census Bureau’s Current Population Survey (CPS). In 1999, the NCI initiated the SEER-NLMS study, linking the population-based SEER cancer registry data to NLMS data. The SEER-NLMS data provide a new unique research resource that is valuable for health disparity research on cancer burden. We describe the design, methods, and limitations of this data set. We also present findings on cancer-related health disparities according to individual-level socioeconomic status (SES) and demographic characteristics for all cancers combined and for cancers of the lung, breast, prostate, cervix, and melanoma.

Polymorphism of human cytochrome P450 enzymes and its clinical impact

Abstract: Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.

Optimized Design of Stationary Frame Three Phase AC Current Regulators

Abstract: Current regulation plays an important role in modern power electronic AC conversion systems The most direct strategy to regulate such currents is to use a simple closed loop proportional-integral (PI) regulator, which has no theoretical stability limits as the proportional and integral gains are increased, since it is only a second order system However, pulsewidth modulation (PWM) transport and controller sampling delays limit the gain values that can be achieved in practical systems Taking these limitations into account, this paper presents an analytical method to determine the best possible gains that can be achieved for any class of practical linear AC current controller The analysis shows that the maximum possible proportional gain is determined by the plant series inductance, the DC bus voltage and the transport and sampling delays, while the maximum possible integral gain is determined primarily by the transport and sampling delays The work is applicable to stationary frame PI regulators, stationary frame controllers with back electromotive force compensation, stationary frame P+ resonant (PR) controllers, and synchronous d- q frame controllers, since they all have identical proportional and integral gains that must be optimized for any particular application

On the concept of ionicity in ionic liquids

Abstract: Ionic liquids are liquids comprised totally of ions However, not all of the ions present appear to be available to participate in conduction processes, to a degree that is dependent on the nature of the ionic liquid and its structure There is much interest in quantifying and understanding this ‘degree of ionicity’ phenomenon In this paper we present transport data for a range of ionic liquids and evaluate the data firstly in terms of the Walden plot as an approximate and readily accessible approach to estimating ionicity An adjusted Walden plot that makes explicit allowance for differences in ion sizes is shown to be an improvement to this approach for the series of ionic liquids described In some cases, where diffusion measurements are possible, it is feasible to directly quantify ionicity via the Nernst–Einstein equation, confirming the validity of the adjusted Walden plot approach Some of the ionic liquids studied exhibit ionicity values very close to ideal; this is discussed in terms of a model of a highly associated liquid in which the ion correlations have similar impact on both the diffusive and conductive motions Ionicity, as defined, is thus a useful measure of adherence to the Nernst–Einstein equation, but is not necessarily a measure of ion availability in the chemical sense

Framework Analysis: A Qualitative Methodology for Applied Policy Research

Abstract: Policies and procedures govern organizations whether they are private or public, for-profit or not-forprofit. Review of such policies and procedures are done periodically to ensure optimum efficiency within the organization. Framework analysis is a qualitative method that is aptly suited for applied policy research. Framework analysis is better adapted to research that has specific questions, a limited time frame, a pre-designed sample and a priori issues. In the analysis, data is sifted, charted and sorted in accordance with key issues and themes using five steps: familiarization; identifying a thematic framework; indexing; charting; and mapping and interpretation. Framework analysis provides an excellent tool to assess policies and procedures from the very people that they affect.

Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges

Abstract: Progressive supranuclear palsy (PSP) is a clinical syndrome comprising supranuclear palsy, postural instability, and mild dementia. Neuropathologically, PSP is defined by the accumulation of neurofibrillary tangles. Since the first description of PSP in 1963, several distinct clinical syndromes have been described that are associated with PSP; this discovery challenges the traditional clinicopathological definition and complicates diagnosis in the absence of a reliable, disease-specific biomarker. We review the emerging nosology in this field and contrast the clinical and pathological characteristics of the different disease subgroups. These new insights emphasise that the pathological events and processes that lead to the accumulation of phosphorylated tau protein in the brain are best considered as dynamic processes that can develop at different rates, leading to different clinical phenomena. Moreover, for patients for whom the diagnosis is unclear, clinicians must continue to describe accurately the clinical picture of each individual, rather than label them with inaccurate diagnostic categories, such as atypical parkinsonism or PSP mimics. In this way, the development of the clinical features can be informative in assigning less common nosological categories that give clues to the underlying pathology and an understanding of the expected clinical course.

Formal definition and dating of the GSSP (Global Stratotype Section and Point) for the base of the Holocene using the Greenland NGRIP ice core, and selected auxiliary records

Abstract: The Greenland ice core from NorthGRIP (NGRIP) contains a proxy climate record across the Pleistocene-Holocene boundary of unprecedented clarity and resolution. Analysis of an array of physical and chemical parameters within the ice enables the base of the Holocene, as reflected in the first signs of climatic warming at the end of the Younger Dryas/Greenland Stadial 1 cold phase, to be located with a high degree of precision. This climatic event is most clearly reflected in an abrupt shift in deuterium excess values, accompanied by more gradual changes in d 18 O, dust concentration, a range of chemical species, and annual layer thickness. A timescale based on multi-parameter annual layer counting provides an age of 11 700 calendar yr b2 k (before AD 2000) for the base of the Holocene, with a maximum counting error of 99 yr. A proposal that an archived core from this unique sequence should constitute the Global Stratotype Section and Point (GSSP) for the base of the Holocene Series/Epoch (Quaternary System/Period) has been ratified by the International Union of Geological Sciences. Five auxiliary stratotypes for the Pleistocene-Holocene boundary have also been recognised. Copyright # 2008 John Wiley & Sons, Ltd.

Cross-disciplinary perspectives on meta-learning for algorithm selection

Abstract: The algorithm selection problem [Rice 1976] seeks to answer the question: Which algorithm is likely to perform best for my problemq Recognizing the problem as a learning task in the early 1990's, the machine learning community has developed the field of meta-learning, focused on learning about learning algorithm performance on classification problems. But there has been only limited generalization of these ideas beyond classification, and many related attempts have been made in other disciplines (such as AI and operations research) to tackle the algorithm selection problem in different ways, introducing different terminology, and overlooking the similarities of approaches. In this sense, there is much to be gained from a greater awareness of developments in meta-learning, and how these ideas can be generalized to learn about the behaviors of other (nonlearning) algorithms. In this article we present a unified framework for considering the algorithm selection problem as a learning problem, and use this framework to tie together the crossdisciplinary developments in tackling the algorithm selection problem. We discuss the generalization of meta-learning concepts to algorithms focused on tasks including sorting, forecasting, constraint satisfaction, and optimization, and the extension of these ideas to bioinformatics, cryptography, and other fields.

Microalgal biomass as a fermentation feedstock for bioethanol production

Abstract: BACKGROUND: The increasing cost of fossil fuels as well as the escalating social and industrial awareness of the environmental impacts associated with the use of fossil fuels has created the need for more sustainable fuel options. Bioethanol, produced from renewable biomass such as sugar and starch materials, is believed to be one of these options, and it is currently being harnessed extensively. However, the utilization of sugar and starch materials as feedstocks for bioethanol production creates a major competition with the food market in terms of land for cultivation, and this makes bioethanol from these sources economically less attractive. RESULT: This study explores the suitability of microalgae (Chlorococum sp.) as a substrate for bioethanol production via yeast (Saccharomyces bayanus) under different fermentation conditions. Results show a maximum ethanol concentration of 3.83 g L−1 obtained from 10 g L−1 of lipid-extracted microalgae debris. CONCLUSION: This productivity level (∼38% w/w), which is in keeping with that of current production systems endorses microalgae as a promising substrate for bioethanol production. Copyright © 2009 Society of Chemical Industry