A population-specific HTR2B stop codon predisposes to severe impulsivity

Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency > 1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity.

Conceptualising business models : definitions, frameworks and classifications

The business model concept is gaining traction in different disciplines but is still criticized for being fuzzy and vague and lacking consensus on its definition and compositional elements. In this paper we set out to advance our understanding of the business model concept by addressing three areas of foundational research: business model definitions, business model elements, and business model archetypes. We define a business model as a representation of the value logic of an organization in terms of how it creates and captures customer value. This abstract and generic definition is made more specific and operational by the compositional elements that need to address the customer, value proposition, organizational architecture (firm and network level) and economics dimensions. Business model archetypes complement the definition and elements by providing a more concrete and empirical understanding of the business model concept. The main contributions of this paper are (1) explicitly including the customer value concept in the business model definition and focussing on value creation, (2) presenting four core dimensions that business model elements need to cover, (3) arguing for flexibility by adapting and extending business model elements to cater for different purposes and contexts (e.g. technology, innovation, strategy),(4) stressing a more systematic approach to business model archetypes by using business model elements for their description, and (5) suggesting to use business model archetype research for the empirical exploration and testing of business model elements and their relationships.

China's "Responsible Protection" concept : re-interpreting the Responsibility to Protect (R2P) and military intervention for humanitarian purposes

This article assesses the extent to which the recently formulated Chinese concept of “Responsible Protection” (RP) offers a valuable contribution to the normative debate over R2P’s third pillar following the controversy over military intervention in Libya. While RP draws heavily on previous proposals such as the original 2001 ICISS report and Brazil’s “Responsibility while Protecting” (RwP), by amalgamating and re-packaging these earlier ideas in a more restrictive form the initiative represents a new and distinctive interpretation of R2P. However, some aspects of RP are framed too narrowly to provide workable guidelines for determining the permissibility of military intervention for civilian protection purposes, and should therefore be clarified and refined. Nevertheless, the Chinese proposal remains significant because it offers important insights into Beijing’s current stance on R2P. More broadly, China’s RP and Brazil’s RwP initiatives illustrate the growing willingness of rising, non-Western powers to assert their own normative preferences on sovereignty, intervention and global governance.

The effect of hip muscle strengthening on pain and disability for individuals with non-specific low back pain : a randomized controlled trial

Introduction Clinical guidelines for the treatment of chronic low back pain suggest the use of supervised exercise. Motor control (MC) based exercise is widely used within clinical practice but its efficacy is equivalent to general exercise therapy. MC exercise targets the trunk musculature. Considering the mechanical links between the hip, pelvis, and lumbar spine, surprisingly little focus has been on investigating the contribution of the hip musculature to lumbopelvic support. The purpose of this study is to compare the efficacy of two exercise programs for the treatment of non-specific low back pain (NSLBP). Methods Eighty individuals aged 18-65 years of age were randomized into two groups to participate in this trial. The primary outcome measures included self-reported pain intensity (0-100mm VAS) and percent disability (Oswestry Disability Index V2). Bilateral measures of hip strength (N/kg) and two dimensional frontal plane mechanics (º) were the secondary outcomes. Outcomes were measured at baseline and following a six-week home based exercise program including weekly sessions of real-time ultrasound imaging. Results Within group comparisons revealed clinically meaningful reductions in pain for both groups. The MC exercise only (N= 40, xˉ =-20.9mm, 95%CI -25.7, -16.1) and the combined MC and hip exercise (N= 40, xˉ = -24.9mm, 95%CI -30.8, -19.0). There was no statistical difference in the change of pain (xˉ =-4.0mm, t= -1.07, p=0.29, 95%CI -11.5, 3.5) or disability (xˉ =-0.3%, t=-0.19, p=0.85, 95%CI -11.5, 3.5) between groups. Conclusion Both exercise programs had similar and positive effects on NSLBP which support the use of the home based exercise programs with weekly supervised visits. However, the addition of specific hip strengthening exercises to a MC based exercise program did not result in significantly greater reductions in pain or disability. Trial Registration NCTO1567566 Funding: Worker’s Compensation Board Alberta Research Grant.

Progress and challenges of disaster health management in China : a scoping review

Background Despite the importance of an effective health system response to various disasters, relevant research is still in its infancy, especially in middle- and low-income countries. Objective This paper provides an overview of the status of disaster health management in China, with its aim to promote the effectiveness of the health response for reducing disaster-related mortality and morbidity. Design A scoping review method was used to address the recent progress of and challenges to disaster health management in China. Major health electronic databases were searched to identify English and Chinese literature that were relevant to the research aims. Results The review found that since 2003 considerable progress has been achieved in the health disaster response system in China. However, there remain challenges that hinder effective health disaster responses, including low standards of disaster-resistant infrastructure safety, the lack of specific disaster plans, poor emergency coordination between hospitals, lack of portable diagnostic equipment and underdeveloped triage skills, surge capacity, and psychological interventions. Additional challenges include the fragmentation of the emergency health service system, a lack of specific legislation for emergencies, disparities in the distribution of funding, and inadequate cost-effective considerations for disaster rescue. Conclusions One solution identified to address these challenges appears to be through corresponding policy strategies at multiple levels (e.g. community, hospital, and healthcare system level).

Reflexive writers : re-thinking writing development and assessment in schools

Writing is a complex and highly individual activity, which is approached in different ways by different writers. Writers reflexively mediate subjective and objective conditions in specific and nuanced ways to produce a product in time and place. This paper uses a critical realist theory of reflexivity to argue that the teaching and assessment of writing must account for the different ways that students manage and make decisions in their writing. Data from linguistically and culturally diverse primary students in Australia are used to illustrate how four distinct reflexive modalities constitute the ways in which students approach writing. The paper offers a new approach to assessing writing for and of learning that considers writers as reflexive and agentic in different ways. It posits the importance of making visible and explicit the context and reflexive decision-making as writers shape a product for a purpose and audience.

Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A

We show that in melanoma cells oncogenic BRAF, acting through MEK and the transcription factor BRN2, downregulates the cGMP-specific phosphodiesterase PDE5A. Although PDE5A downregulation causes a small decrease in proliferation, its major impact is to stimulate a dramatic increase in melanoma cell invasion. This is because PDE5A downregulation leads to an increase in cGMP, which induces an increase in cytosolic Ca2+, stimulating increased contractility and inducing invasion. PDE5A downregulation also this leads to an increase in short-term and long-term colonization of the lungs by melanoma cells. We do not observe this pathway in NRAS mutant melanoma or BRAF mutant colorectal cells. Thus, we show that in melanoma cells oncogenic BRAF induces invasion through downregulation of PDE5A.

Multiliteracies pedagogy : creating claymations with adolescent, post-beginner English language learners

In addressing literacy in high school education, it is important to foreground the particular issues faced by growing numbers of English Language Learners (ELLs). In our increasingly culturally and linguistically diverse classrooms, this is a matter for all literacy teachers, as well as ELL specialists. In Australia, teachers of ELLs are experimenting with Multiliteracies pedagogy which provides rich opportunities to explore language learning experiences and outcomes that stretch beyond exercises in reproduction in written and oral modes only. This paper documents the practice of a high school teacher who uses a claymation project, producing a movie by stop-motion filming of clay figures, with a class of low-level English literacy learners. Drawing on observations of three particular students, the paper outlines a number of possibilities of this approach for English language learners. These include increased individual agency; enhanced engagement through collaboration; and the opportunity to explore various elements of multimodal text design.

Psycho-educational assessment of specific learning disabilities: Views and practices of Australian psychologists and guidance counsellors

This paper reports an investigation of the views and practices of 203 Australian psychologists and guidance counsellors with respect to psycho-educational assessment of students with Specific Learning Disabilities (SLDs). Results from an online survey indicated that practitioners draw upon a wide-range of theoretical perspectives when conceptualising and identifying SLDs, including both response to intervention and IQ – achievement discrepancy models. Intelligence tests (particularly the Wechsler scales) are commonly employed, with the main stated reasons for their use being ‘traditional’ perspectives (including IQ-achievement discrepancy-based definitions of SLDs), to exclude a diagnosis of intellectual disability, and to guide further assessment and intervention. In contrast participants reported using measures of academic achievement and tests of specific cognitive deficits known to predict SLDs (e.g., phonological awareness) relatively infrequently.

Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol

The coffee components kahweol and cafestol (K/C) have been reported to protect the colon and other organs of the rat against the formation of DNA adducts by 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) and aflatoxin B1. PhIP is a cooked-food mutagen to which significant human exposure and a role in colon cancer etiology are attributed, and, interestingly, such cancers appear to develop at a lower rate in consumers of coffees with high amounts of K/C. Earlier studies in rodent liver have shown that a key role in the chemopreventive effect of K/C is likely to be due to the potential of these compounds to induce the detoxification of xenobiotics by glutathione transferase (GST) and to enhance the synthesis of the corresponding co-factor glutathione. However, mutagens like PhIP may also be detoxified by UDP-glucuronosyl transferase (UDPGT) for which data are lacking regarding a potential effect of K/C. Therefore, in the present study, we investigated the effect of K/C on UDPGT and, concomitantly, we studied overall GST and the pattern of individual GST classes, particularly GST-θ, which was not included in earlier experiments. In addition, we analyzed the organ-dependence of these potentially chemopreventive effects. K/C was fed to male F344 rats at 0.122% in the chow for 10 days. Enzyme activities in liver, kidney, lung, colon, salivary gland, pancreas, testis, heart and spleen were quantified using five characteristic substrates and the hepatic protein pattern of GST classes α, μ, and π was studied with affnity chromatography/HPLC. Our study showed that K/C is not only capable of increasing overall GST and GST classes α, μ, and π but also of enhancing UDGPT and GST-θ. All investigated K/C effects were strongest in liver and kidney, and some response was seen in lung and colon but none in the other organs. In summary, our results show that K/C treatment leads to a wide spectrum of increases in phase II detoxification enzymes. Notably, these effects occurred preferentially in the well perfused organs liver and kidney, which may thus not only contribute to local protection but also to anti-carcinogenesis in distant, less stimulated organs such as the colon.

Sector-specific regimes

This Chapter considers a number of sector-specific access regimes that apply to infrastructure that exhibits natural monopoly characteristics. With the exception of Pt XIC of the CCA which regulates access to telecommunications infrastructure, they adopt the same form of negotiate-arbitrate model found in Pt IIIA of the CCA. In the event of a failure to negotiate commercial terms and conditions of access they allow the regulator to impose cost based (building block)tariffs. The regulator's decisions are subject to merits review and/or judicial review. The Chapter is divided into four Parts: • Part I considers access regulation in the electricity sector; • Part II considers access regulation in the gas sector; • Part III considers access regulation in the telecommunications sector; and • Part N considers access regulation in relation to port and rail bulk supply chains.

Characterization of the tail-specific protease (Tsp) from Legionella

Bacterial tail-specific proteases (Tsps) have been attributed a wide variety of functions including intracellular virulence, cell wall morphology, proteolytic signal cascades and stress response. This study tested the hypothesis that Tsp has a key function for the transmissive form of Legionella pneumophila. A tsp mutant was generated in Legionella pneumophila 130b and the characteristics of this strain and the isogenic wild-type were examined using a range of growth and proteomic analyses. Recombinant Tsp protein was also produced and analyzed. The L. pneumophila tsp mutant showed no defect in growth on rich media or during thermo-osmotic stress conditions. In addition, no defects in cellular morphology were observed when the cells were examined using transmission electron microscopy. Purified recombinant Tsp was found to be an active protease with a narrow substrate range. Proteome analysis using iTRAQ (5% coverage of the proteome) found that, of those proteins detected, only 5 had different levels in the tsp mutant compared to the wild type. ACP (Acyl Carrier Protein), which has a key role for Legionella differentiation to the infectious form, was reduced in the tsp mutant; however, tsp(-) was able to infect and replicate inside macrophages to the same extent as the wild type. Combined, these data demonstrate that Tsp is a protease but is not essential for Legionella growth or cell infection. Thus, Tsp may have functional redundancy in Legionella.

Tumor-suppressor gene promoter hypermethylation in saliva of head and neck cancer patients

Head and neck squamous cell carcinoma (HNSCC) accounts for a bulk of the oral and laryngeal cancers, the majority (70%) of which are associated with smoking and excessive drinking, major known risk factors for the development of HNSCC. In contrast to reports that suggest an inverse relationship between smoking and global DNA CpG methylation, hypermethylation of promoters of a number of genes was detected in saliva collected from patients with HNSCC. Using a sensitive methylation-specific polymerase chain reaction (MSP) assay to determine specific methylation events in the promoters of RASSF1A, DAPK1, and p16 genes, we demonstrate that we can detect tumor presence with an overall accuracy of 81% in the DNA isolated from saliva of patients with HNSCC (n = 143) when compared with the DNA isolated from the saliva of healthy nonsmoker controls (n = 31). The specificity for this MSP panel was 87% and the sensitivity was 80%(with a Fisher exact test P < .0001). In addition, the test panel performed extremely well in the detection of the early stages of HNSCCs, with a sensitivity of 94% and a specificity of 87%, and a high. concordance value of 0.8, indicating an excellent overall agreement between the presence of HNSCC and a positive MSP panel result. In conclusion, we demonstrate that the promoter methylation of RASSF1A, DAPK1, and p16 MSP panel is useful in detecting hypermethylation events in a noninvasive manner in patients with HNSCC.