p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a gamma-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.

Professional capabilities for twenty-first century creative careers : lessons from outstandingly successful Australian artists and designers

Artists and designers are positioned at the centre of the 21st century creative economy. In order to recognise and make the most of the opportunities afforded by this new era, artists and designers still require the creativity, disciplinary depth of knowledge, and technical skills traditionally possessed by professionals in these fields – skills which are a core strength of higher and further art and design education. However, they may also require a range of other, ‘21st century’ creative capabilities which are harder to define, teach for and assess, and are not the focus of traditional art and design pedagogies. This article draws upon the findings of nine in-depth interviews with award-winning Australian artists and designers about their careers and working practices, along with recent international research about the characteristics of the 21st century creative career, in order to highlight the importance of certain professional capabilities for art and design. It discusses the implications of these findings for art and design educators in universities, and curricular and pedagogic considerations associated with embedding these capabilities into undergraduate courses.

Taking a leap of faith : are investors left short changed?

This dissertation examines the compliance and performance of a large sample of faith based (religious) ethical funds - the Shari'ah-compliant equity funds (SEFs), which may be viewed as a form of ethical investing. SEFs screen their investment for compliance with Islamic law, where riba (conventional interest expense), maysir (gambling), gharar (excessive uncertainty), and non-halal (non-ethical) products are prohibited. Using a set of stringent Shari'ah screens similar to those of MSCI Islamic, we first examine the extent to which SEFs comply with the Shari'ah law. Results show that only about 27% of the equities held by SEFs are Shari'ah-compliant. While most of the fund holdings pass the business screens, only about 42% pass the total debt to total assets ratio screen. This finding suggests that, in order to overcome a significant reduction in the investment opportunity, Shari'ah principles are compromised, with SEFs adopting lax screening rules so as to achieve a financial performance. While younger funds and funds that charge higher fees and are domiciled in more Muslim countries are more Shari'ah-compliant, we find little evidence of a positive relationship between fund disclosure of the Shari'ah compliance framework and Shari'ah-compliance. Clearly, Shari'ah compliance remains a major challenge for fund managers and SEF investors should be aware of Shari'ah-compliance risk since the fund managers do not always fulfill their fiduciary obligation, as promised in their prospectus. Employing a matched firm approach for a survivorship free sample of 387 SEFs, we then examine an issue that has been heavily debated in the literature: Does ethical screening reduce investment performance? Results show that it does but only by an average of 0.04% per month if benchmarked against matched conventional funds - this is a relatively small price to pay for religious faith. Cross-sectional regressions show an inverse relationship between Shari'ah compliance and fund performance: every one percentage increase in total compliance decreases fund performance by 0.01% per month. However, compliance fails to explain differences in the performance between SEFs and matched funds. Although SEFs do not generally perform better during crisis periods, further analysis shows evidence of better performance relative to conventional funds only during the recent Global Financial Crisis; the latter is consistent with popular media claims.

Who drives E&P innovation?

Few would argue that the upstream oil and gas industry has become more technology- intensive over the years. At the same time, the increasing costs and complexity of today’s exploration and production (E&P) technologies are making it increasingly difficult for any one company to support an aggressive research and development (R&D) agenda single handedly. The coming together of these two evolutionary forces gives rise to important questions. How does innovation happen in the E&P industry? Specifically, what ideas and inputs flow from which parts of the industry’s value network, and where do these inputs go? And how do firms and organizations from different countries contribute differently to this process? This survey was designed to shed light on these issues.

The Music Industry : Music in the Cloud, 2nd edition

The music industry is going through a period of immense change brought about in part by the digital revolution. What is the role of music in the age of computers and the Internet? How has the music industry been transformed by the economic and technological upheavals of recent years, and how is it likely to change in the future? This thoroughly revised and updated new edition provides an international overview of the music industry and its future prospects in the world of global entertainment. Patrik Wikström illuminates the workings of the music industry, and captures the dynamics at work in the production of musical culture between the transnational media conglomerates, the independent music companies and the public. New to this second edition are expanded sections on the structure of the music industry, online business models and the links between social media and music. Engaging and comprehensive, The Music Industry will be a must-read for students and scholars of media and communication studies, cultural studies, popular music, sociology and economics.

Models for studying cellular invasion of basement membranes

Invasion of extracellular matrices is crucial to a number of physiological and pathophysiological states, including tumor cell metastasis, arthritis, embryo implantation, wound healing, and early development. To isolate invasion from the additional complexities of these scenarios a number of in vitro invasion assays have been developed over the years. Early studies employed intact tissues, like denuded amniotic membrane (1) or embryonic chick heart fragments (2), however recently, purified matrix components or complex matrix extracts have been used to provide more uniform and often more rapid analyses (for examples, see the following integrin studies). Of course, the more holistic view of invasion offered in the earlier assays is valuable and cannot be fully reproduced in these more rapid assays, but advantages of reproducibility among replicates, ease of preparation and analysis, and overall high throughput favor the newer assays. In this chapter, we will focus on providing detailed protocols for Matrigel-based assays (Matrigel=reconstituted basement membrane; reviewed in ref. (3)). Matrigel is an extract from the transplantable Engelbreth-Holm-Swarm murine sarcoma that deposits a multilammelar basement membrane. Matrigel is available commercially (Becton Dickinson, Bedford, MA), and can be manipulated as a liquid at 4°C into a variety of different formats. Alternatively, cell culture inserts precoated with Matrigel can be purchased for even greater simplicity.

Global Politics of Health

International responses to the outbreak of SARS, the spread of HIV/AIDS, and the promotion of health as a human right all demonstrate how global politics have a profound effect on the way we think about and respond to major health challenges. Despite a growing interest in the relationship between health and international relations there has yet to be a systematic study of the links between them. Global Health Issues aims to fill this gap – ultimately showing how world politics can be good, or bad, for your health. This book calls for a more nuanced understanding of the nature of the current global health crisis and the political dilemmas faced by those responsible for the development and implementation of responses to it. By charting these debates and showing how they shape the way actors think about key issues relating to health, such as people movement; infectious disease; the business of health; and the consequences of war; this volume provides an innovative and comprehensive introduction to health and international relations for students of global politics, health studies and related disciplines.

Can measures of limb loading and dynamic stability during the squat maneuver provide an index of early functional recovery following unilateral total hip arthroplasty?

Objective: To investigate limb loading and dynamic stability during squatting in the early functional recovery of total hip arthroplasty (THA) patients. Design: Cohort study Setting: Inpatient rehabilitation clinic. Participants: A random sample of 61 THA patients (34♂/27♀; 62±9 yrs, 77±14 kg, 174±9 cm) was assessed twice, 13.2±3.8 days (PRE) and 26.6±3.3 days post-surgery (POST), and compared with a healthy reference group (REF) (22♂/16♀; 47±12yrs; 78±20kg; 175±10cm). Interventions: THA patients received two weeks of standard in-patient rehabilitation. Main Outcome Measure(s): Inter-limb vertical force distribution and dynamic stability during the squat maneuver, as defined by the root mean square (RMS) of the center of pressure in antero-posterior and medio-lateral directions, of operated (OP) and non-operated (NON)limbs. Self-reported function was assessed via FFb-H-OA 2.0 questionnaire. Results: At PRE, unloading of the OP limb was 15.8% greater (P<.001, d=1.070) and antero-posterior and medio-lateral center of pressure RMS were 30-34% higher in THA than REF P<.05). Unloading was reduced by 12.8% towards a more equal distribution from PRE to POST (P<.001, d=0.874). Although medio-lateral stability improved between PRE and POST (OP: 14.8%, P=.024, d=0.397; NON: 13.1%, P=.015, d=0.321), antero-posterior stability was not significantly different. Self-reported physical function improved by 15.8% (P<.001, d=0.965). Conclusion(s): THA patients unload the OP limb and are dynamically more unstable during squatting in the early rehabilitation phase following total hip replacement than healthy adults. Although loading symmetry and medio-lateral stability improved to the level of healthy adults with rehabilitation, antero-posterior stability remained impaired. Measures of dynamic stability and load symmetry during squatting provide quantitative information that can be used to clinically monitor early functional recovery from THA.

Social Media and Everyday Politics

From selfies and memes to hashtags and parodies, social media are used for mundane and personal expressions of political commentary, engagement, and participation. The coverage of politics reflects the social mediation of everyday life, where individual experiences and thoughts are documented and shared online. In Social Media and Everyday Politics, Tim Highfield examines political talk as everyday occurrences on Twitter, Facebook, blogs, Tumblr, Instagram, and more. He considers the personal and the political, the serious and the silly, and the everyday within the extraordinary, as politics arises from seemingly banal and irreverent topics. The analysis features international examples and evolving practices, from French blogs to Vines from Australia, via the Arab Spring, Occupy, #jesuischarlie, Eurovision, #blacklivesmatter, Everyday Sexism, and #illridewithyou. This timely book will be a valuable resource for students and scholars in media and communications, internet studies, and political science, as well as general readers keen to understand our contemporary media and political contexts.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.