A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each ). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls () and were highly significant in the combined dataset (). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set , replication set , combined ). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine

We have identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of which we genotyped 24 in a Caucasian population comprising 827 unrelated cases and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor gene showed significant association with migraine. This association was independently replicated in a case-control population collected separately. We used experiments with insulin receptor RNA and protein to investigate functionality for the migraine-associated single-nucleotide polymorphisms. We suggest possible functions for the insulin receptor in migraine pathogenesis.

The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer

Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective synthases differ considerably with respect to the pathways described. While prostacyclin synthase is generally believed to be anti-tumor, a pro-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of thromboxane synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer. © 2010 Elsevier B.V. All rights reserved.

Communication Interception Technology (CIT) and its use in the fight against Transnational Organised Crime (TOC) in Australia : a review of the literature

In recent times, technology has advanced in such a manner that the world can now communicate in means previously never thought possible. Transnational organised crime groups, who have exploited these new technologies as basis for their criminal success, however, have not overlooked this development, growth and globalisation. Law enforcement agencies have been confronted with an unremitting challenge as they endeavour to intercept, monitor and analyse these communications as a means of disrupting the activities of criminal enterprises. The challenge lies in the ability to recognise and change tactics to match an increasingly sophisticated adversary. The use of communication interception technology, such as phone taps or email interception, is a tactic that when used appropriately has the potential to cause serious disruption to criminal enterprises. Despite the research that exists on CIT and TOC, these two bodies of knowledge rarely intersect. This paper builds on current literature, drawing them together to provide a clearer picture of the use of CIT in an enforcement and intelligence capacity. It provides a review of the literature pertaining to TOC, the structure of criminal enterprises and the vulnerability of communication used by these crime groups. Identifying the current contemporary models of policing it reviews intelligence-led policing as the emerging framework for modern policing. Finally, it assesses the literature concerning CIT, its uses within Australia and the limitations and arguments that exist. In doing so, this paper provides practitioners with a clearer picture of the use, barriers and benefits of using CIT in the fight against TOC. It helps to bridge the current gaps in modern policing theory and offers a perspective that can help drive future research.

Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer : potential targets for chemoprevention and systemic therapy

The epidermal growth factor receptor (EGFR) is part of a family of plasma membrane receptor tyrosine kinases that control many important cellular functions, from growth and proliferation to cell death. Cyclooxygenase (COX)-2 is an enzyme which catalyses the conversion of arachidonic acid to prostagladins and thromboxane. It is induced by various inflammatory stimuli, including the pro-inflammatory cytokines, Interleukin (IL)-1β, Tumour Necrosis Factor (TNF)-α and IL-2. Both EGFR and COX-2 are over-expressed in non-small cell lung cancer (NSCLC) and have been implicated in the early stages of tumourigenesis. This paper considers their roles in the development and progression of lung cancer, their potential interactions, and reviews the recent progress in cancer therapies that are directed toward these targets. An increasing body of evidence suggests that selective inhibitors of both EGFR and COX-2 are potential therapeutic agents for the treatment of NSCLC, in the adjuvant, metastatic and chemopreventative settings. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Playing with Grammar in the Early Years : Learning about Language in the Australian Curriculum : English

As teacher/researchers interested in the pursuit of socially-just outcomes in early childhood education, the form and function of language occupies a special position in our work. We believe that mastering a range of literacy competences includes not only the technical skills for learning, but also the resources for viewing and constructing the world (Freire and Macdeo, 1987). Rather than seeing knowledge about language as the accumulation of technical skills alone, the viewpoint to which we subscribe treats knowledge about language as a dialectic that evolves from, is situated in, and contributes to a social arena (Halliday, 1978). We do not shy away from this position just because children are in the early years of schooling. In ‘Playing with Grammar’, we focus on the Foundation to Year 2 grouping, in line with the Australian Curriculum, Assessment and Reporting Authority’s (hereafter ACARA) advice on the ‘nature of learners’ (ACARA, 2013). With our focus on the early years of schooling comes our acknowledgement of the importance and complexity of play. At a time where accountability in education has moved many teachers to a sense of urgency to prove language and literacy achievement (Genishi and Dyson, 2009), we encourage space to revisit what we know about literature choices and learning experiences and bring these together to facilitate language learning. We can neither ignore, nor overemphasise, the importance of play for the development of language through: the opportunities presented for creative use and practice; social interactions for real purposes; and, identifying and solving problems in the lives of young children (Marsh and Hallet, 2008). We argue that by engaging young children in opportunities to play with language we are ultimately empowering them to be active in their language learning and in the process fostering a love of language and the intricacies it holds. Our goal in this publication is to provide a range of highly practical strategies for scaffolding young children through some of the Content Descriptions from the Australian Curriculum English Version 5.0, hereafter AC:E V5.0 (ACARA, 2013). This recently released curriculum offers a new theoretical approach to building children’s knowledge about language. The AC:E V5.0 uses selected traditional terms through an approach developed in systemic functional linguistics (see Halliday and Matthiessen, 2004) to highlight the dynamic forms and functions of multimodal language in texts. For example, the following statement, taken from the ‘Language: Knowing about the English language’ strand states: English uses standard grammatical terminology within a contextual framework, in which language choices are seen to vary according to the topics at hand, the nature and proximity of the relationships between the language users, and the modalities or channels of communication available (ACARA, 2013). Put simply, traditional grammar terms are used within a functional framework made up of field, tenor, and mode. An understanding of genre is noted with the reference to a ‘contextual framework’. The ‘topics at hand’ concern the field or subject matter of the text. The ‘relationships between the language users’ is a description of tenor. There is reference to ‘modalities’, such as spoken, written or visual text. We posit that this innovative approach is necessary for working with contemporary multimodal and cross-cultural texts (see Exley and Mills, 2012). We believe there is enormous power in using literature to expose children to the richness of language and in turn develop language and literacy skills. Taking time to look at language patterns within actual literature is a pathway to ‘…capture interest, stir the imagination and absorb the [child]’ into the world of language and literacy (Saxby, 1993, p. 55). In the following three sections, we have tried to remain faithful to our interpretation of the AC:E V5.0 Content Descriptions without giving an exhaustive explanation of the grammatical terms. Other excellent tomes, such as Derewianka (2011), Humphrey, Droga and Feez (2012), and Rossbridge and Rushton (2011) provide these more comprehensive explanations as does the AC:E V5.0 Glossary. We’ve reproduced some of the AC:E V5.0 glossary at the end of this publication. Our focus is on the structure and unfolding of the learning experiences. We outline strategies for working with children in Foundation, Year 1 and Year 2 by providing some demonstration learning experiences based on texts we’ve selected, but maintain that the affordances of these strategies will only be realised when teaching and learning is purposively tied to authentic projects in local contexts. We strongly encourage you not to use only the resource texts we’ve selected, but to capitalise upon your skill for identifying the language features in the texts you and the children are studying and adapt some of the strategies we have outlined. Each learning experience is connected to one of the Content Descriptions from the AC:E V5.0 and contains an experience specific purpose, a suggested resource text and a sequence for the experience that always commences with an orientation to text followed by an examination of a particular grammatical resource. We expect that each of these learning experiences will take a couple if not a few teaching episodes to work through, especially if children are meeting a concept for the first time. We hope you use as much, or as little, of each experience as is needed. Our plans allow for focused discussion, shared exploration and opportunities to revisit the same text for the purpose of enhancing meaning making. We do not want the teaching of grammar to slip into a crisis of irrelevance or to be seen as a series of worksheet drills with finite answers. Strategies for effective practice, however, have much portability. We are both very keen to hear from teachers who are adopting and adapting these learning experiences in their classrooms. Please email us on b.exley@qut.edu.au or lkervin@uow.edu.au. We’d love to continue the conversation with you over time.

Psychotropic medication use in adolescents with intellectual disability living in the community

Purpose Information on the use of psychotropic medications in adolescents with intellectual disability is scant. Such information can guide interventions to improve psychotropic medication use in this population. We investigated the prevalence of, and factors associated with, psychotropic medication use in adolescents with intellectual disability in Australia who live in the community. Methods Cross-sectional data were obtained from adolescents with intellectual disability living in the community in South East Queensland, Australia, between February 2007 and September 2010. Self-reported information on medication use was extracted from a health screening tool. Demographic and medical data were collected through parent/caregiver surveys. Medications were classified according to the Anatomical Therapeutic Chemical classification system. Psychopathology was assessed using the Developmental Behaviour Checklist Short Form. Logistic regression analysis was used to assess the association of demographic and medical characteristics with psychotropic medication use. Results There were 176 participants (median age = 16 years, range = 11–19 years; 55% male). Psychotropics were used by 20% of participants. Psychostimulants were the commonest psychotropic class, used by 9% of participants. Multipsychotropic prescribing was not common with only seven participants using more than one psychotropic agent. After adjusting for potentially confounding variables, use of psychotropic medications was significantly associated with male gender (adjusted odds ratio = 3.6; 95% confidence interval = 1.3–9.5) and having major behaviour problems (3.1; 1.1–8.9). Conclusions Adolescents with intellectual disability use a wide range of psychotropic medications. Being male and having major behaviour problems are associated with the use of psychotropic medications. Research examining the rationale for psychotropic prescribing in this population is needed. Copyright © 2013 John Wiley & Sons, Ltd.

Posttranscriptional gene silencing is not compromised in the Arabidopsis CARPEL FACTORY (DICER-LIKE1) mutant, a homolog of dicer-1 from Drosophila

Posttranscriptional silencing (PTGS) in plants, nematodes, Drosophila, and perhaps all eukaryotes operates by sequence-specific degradation or translational inhibition of the target mRNA. These processes are mediated by duplexed RNA. In Drosophila and nematodes, double-stranded (ds)RNA or self-complementary RNA is processed into fragments of approximately 21 nt by Dicer-1 [1, 2]. These small interfering RNAs (siRNAs) serve as guides to target degradation of homologous single-stranded (ss)RNA [1, 3]. In some cases, the approximately 21 nt guide fragments derived from endogenous, imperfectly self-complementary RNAs cause translational inhibition of their target mRNAs, with which they have substantial, but not perfect sequence complementarity [4-6]. These small temporal RNAs (stRNAs) belong to a class of noncoding microRNAs (miRNAs), 20-24 nt in length, that are found in flies, plants, nematodes, and mammals [4, 6-12]. In nematodes, the Dicer-1 enzyme catalyzes the production of both siRNA and stRNA [2, 13-15]. Mutation of the Arabidopsis Dicer-1 homolog, CARPEL FACTORY (CAF), blocks miRNA production [1, 4, 16-18]. Here, we report that the same caf mutant does not block either PTGS or siRNA production induced by self-complementary hairpin RNA. This suggests either that this mutation only impairs miRNA formation or, more interestingly, that plants have two distinct dicer-like enzymes, one for miRNA and another for siRNAi production.

Soybean dwarf luteovirus contains the third variant genome type in the luteovirus group

Complementary DNAs covering the entire RNA genome of soybean dwarf luteovirus (SDV) were cloned and sequenced. Computer analysis of the 5861 nucleotide sequence revealed five major open reading frames (ORFs) possessing conservation of sequence and organisation with known luteovirus sequences. Comparative analyses of the genome structure show that SDV shares sequence homology and features of gene organisation with barley yellow dwarf virus (PAV isolate) in the 5' half of the genome, yet is more closely related to potato leafroll virus in its 3' coding regions. In addition, SDV differs from other known luteoviruses in possessing an exceptionally long 3' terminal sequence with no apparent coding capacity. We conclude from these data that the SDV genome represents a third variant genome type in the luteovirus group.

Examining the impact of climate change on dengue transmission in the Asia-Pacific region

Dengue fever (DF) is a serious public health concern in many parts of the world. An increase in DF incidence has been observed globally over the past decades. Multiple factors including urbanisation, increased international travels and global climate change are thought to be responsible for increased DF. However, little research has been conducted in the Asia-Pacific region about the impact of these changes on dengue transmission. The overarching aim of this thesis is to explore the spatiotemporal pattern of DF transmission in the Asia-Pacific region and project the future risk of DF attributable to climate change. Annual data of DF outbreaks for sixteen countries in the Asia-Pacific region over the last fifty years were used in this study. The results show that the geographic range of DF in this region increased significantly over the study period. Thailand, Vietnam and Laos were identified as the highest risk areas and there was a southward expansion observed in the transmission pattern of DF which might have originated from Philippines or Thailand. Additionally, the detailed DF data were obtained and the space-time clustering of DF transmission was examined in Bangladesh. Monthly DF data were used for the entire country at the district level during 2000-2009. Dhaka district was identified as the most likely DF cluster in Bangladesh and several districts of the southern part of Bangladesh were identified as secondary clusters in the years 2000-2002. In order to examine the association between meteorological factors and DF transmission and to project the future risk of DF using different climate change scenarios, the climate-DF relationship was examined in Dhaka, Bangladesh. The results show that climate variability (particularly maximum temperature and relative humidity) was positively associated with DF transmission in Dhaka. The effects of climate variability were observed at a lag of four months which might help to potentially control and prevent DF outbreaks through effective vector management and community education. Based on the quantitative assessment of the climate-DF relationship, projected climate change will likely increase mosquito abundance and activity and DF in this area. Assuming a temperature increase of 3.3oC without any adaptation measures and significant changes in socio-economic conditions, the consequence will be devastating, with a projected annual increase of 16,030 cases in Dhaka, Bangladesh by the end of this century. Therefore, public health authorities need to be prepared for likely increase of DF transmission in this region. This study adds to the literature on the recent trends of DF and impacts of climate change on DF transmission. These findings may have significant public health implications for the control and prevention of DF, particularly in the Asia- Pacific region.

The Internet of Things : new digital capital in the hands of customers

The Internet of Things facilitates the identification, digitization, and control of physical objects. However, it is the availability of cost effective sensors, mobile smart devices, scalable cloud infrastructure, and advanced analytics that have consumerized the Internet of Things. The accessibility of digital representations of things has transformative potential and provides entire new affordances for organizations and their ecosystems across most industries.

Traffic state estimation from partial Bluetooth and volume observations : case study in the Brisbane metropolitan area

The application of the Bluetooth (BT) technology to transportation has been enabling researchers to make accurate travel time observations, in freeway and arterial roads. The Bluetooth traffic data are generally incomplete, for they only relate to those vehicles that are equipped with Bluetooth devices, and that are detected by the Bluetooth sensors of the road network. The fraction of detected vehicles versus the total number of transiting vehicles is often referred to as Bluetooth Penetration Rate (BTPR). The aim of this study is to precisely define the spatio-temporal relationship between the quantities that become available through the partial, noisy BT observations; and the hidden variables that describe the actual dynamics of vehicular traffic. To do so, we propose to incorporate a multi- class traffic model into a Sequential Montecarlo Estimation algorithm. Our framework has been applied for the empirical travel time investigations into the Brisbane Metropolitan region.

In vivo and in vitro models demonstrate a role for caveolin-1 in the pathogenesis of ischaemic acute renal failure

Caveolae and their proteins, the caveolins, transport macromolecules; compartmentalize signalling molecules; and are involved in various repair processes. There is little information regarding their role in the pathogenesis of significant renal syndromes such as acute renal failure (ARF). In this study, an in vivo rat model of 30 min bilateral renal ischaemia followed by reperfusion times from 4 h to 1 week was used to map the temporal and spatial association between caveolin-1 and tubular epithelial damage (desquamation, apoptosis, necrosis). An in vitro model of ischaemic ARF was also studied, where cultured renal tubular epithelial cells or arterial endothelial cells were subjected to injury initiators modelled on ischaemia-reperfusion (hypoxia, serum deprivation, free radical damage or hypoxia-hyperoxia). Expression of caveolin proteins was investigated using immunohistochemistry, immunoelectron microscopy, and immunoblots of whole cell, membrane or cytosol protein extracts. In vivo, healthy kidney had abundant caveolin-1 in vascular endothelial cells and also some expression in membrane surfaces of distal tubular epithelium. In the kidneys of ARF animals, punctate cytoplasmic localization of caveolin-1 was identified, with high intensity expression in injured proximal tubules that were losing basement membrane adhesion or were apoptotic, 24 h to 4 days after ischaemia-reperfusion. Western immunoblots indicated a marked increase in caveolin-1 expression in the cortex where some proximal tubular injury was located. In vitro, the main treatment-induced change in both cell types was translocation of caveolin-1 from the original plasma membrane site into membrane-associated sites in the cytoplasm. Overall, expression levels did not alter for whole cell extracts and the protein remained membrane-bound, as indicated by cell fractionation analyses. Caveolin-1 was also found to localize intensely within apoptotic cells. The results are indicative of a role for caveolin-1 in ARF-induced renal injury. Whether it functions for cell repair or death remains to be elucidated.

Time as the critical factor in the investigation of the relationship between pollutant wash-off and rainfall characteristics

The approach adopted for investigating the relationship between rainfall characteristics and pollutant wash-off process is commonly based on the use of parameters which represent the entire rainfall event. This does not permit the investigation of the influence of rainfall characteristics on different sectors of the wash-off process such as first flush where there is a high pollutant wash-off load at the initial stage of the runoff event. This research study analysed the influence of rainfall characteristics on the pollutant wash-off process using two sets of innovative parameters by partitioning wash-off and rainfall characteristics. It was found that the initial 10% of the wash-off process is closely linked to runoff volume related rainfall parameters including rainfall depth and rainfall duration while the remaining part of the wash-off process is primarily influenced by kinetic energy related rainfall parameters, namely, rainfall intensity. These outcomes prove that different sectors of the wash-off process are influenced by different segments of a rainfall event.

Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart

G protein-coupled receptors (GPCRs) are critical for cardiovascular physiology. Cardiac cells express >100 nonchemosensory GPCRs, indicating that important physiological and potential therapeutic targets remain to be discovered. Moreover, there is a growing appreciation that members of the large, distinct taste and odorant GPCR families have specific functions in tissues beyond the oronasal cavity, including in the brain, gastrointestinal tract and respiratory system. To date, these chemosensory GPCRs have not been systematically studied in the heart. We performed RT-qPCR taste receptor screens in rodent and human heart tissues that revealed discrete subsets of type 2 taste receptors (TAS2/Tas2) as well as Tas1r1 and Tas1r3 (comprising the umami receptor) are expressed. These taste GPCRs are present in cultured cardiac myocytes and fibroblasts, and are enriched in myocytes, which we corroborated using in situ hybridization. Tas1r1 gene-targeted mice (Tas1r1Cre/Rosa26tdRFP) strikingly recapitulated these data. In vivo taste receptor expression levels were developmentally regulated in the postnatal period. Intriguingly, several Tas2rs were upregulated in cultured rat myocytes and in mouse heart in vivo following starvation. The discovery of taste GPCRs in the heart opens an exciting new field of cardiac research. We predict that these taste receptors may function as nutrient sensors in the heart.