Notch and NOXA-related pathways in melanoma cells

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

Objectifying early-number : a visual nomenclature to express mathematical domain knowledge

To address issues of divisive ideologies in the Mathematics Education community and to subsequently advance educational practice, an alternative theoretical framework and operational model is proposed which represents a consilience of constructivist learning theories whilst acknowledging the objective but improvable nature of domain knowledge. Based upon Popper’s three-world model of knowledge, the proposed theory supports the differentiation and explicit modelling of both shared domain knowledge and idiosyncratic personal understanding using a visual nomenclature. The visual nomenclature embodies Piaget’s notion of reflective abstraction and so may support an individual’s experience-based transformation of personal understanding with regards to shared domain knowledge. Using the operational model and visual nomenclature, seminal literature regarding early-number counting and addition was analysed and described. Exemplars of the resultant visual artefacts demonstrate the proposed theory’s viability as a tool with which to characterise the reflective abstraction-based organisation of a domain’s shared knowledge. Utilising such a description of knowledge, future research needs to consider the refinement of the operational model and visual nomenclature to include the analysis, description and scaffolded transformation of personal understanding. A detailed model of knowledge and understanding may then underpin the future development of educational software tools such as computer-mediated teaching and learning environments.

Cost efficiency v quality service : using CHAT as a tool for understanding change and transformation in work practices

This chapter provides an analysis of feedback from key stakeholders, collected as part of a research project, on the problems and tensions evident in the collective work practices of learning advisers employed in learning assistance services at an Australian metropolitan university (Peach, 2003). The term 'learning assistance' is used in the Australian higher education sector generally to refer to student support services that include assistance with academic writing and other study skills. The aim of the study was to help learning advisers and other key stakeholders develop a better understanding of the work activity with a view to using this understanding to generate improvements in service provision. Over twenty problems and associated tensions were identified through stakeholder feedback however the focus of this chapter is the analysis of tensions related to a cluster of problems referred to as cost-efficiency versus quality service. Theoretical modelling derived from the tools made available through cultural historical activity theory and expansive visibilsation (Engestrom and Miettinen, 1999) and excerpts from data are used to illustrate how different understandings of the purpose of learning assistance services impacts on the work practices of learning advisers and creates problems and tensions in relation to the type of service available (including use of technology),level of service available, and learning adviser workload.

Social Procurement: Promoting the sustainability of NPOs through the transformation of economic, social and cultural capital

Social procurement provides a key source of income for the Third Sector, and is vital for the sustainability of many nonprofit organisations. Social procurement involves the exchange of economic capital from one organisation, typically government (although for-profit and non-profit organisations can also purchase), with a nonprofit organisations in order to deliver other forms of. It is this transformation of economic capital into other forms of capital (cultural, human, social) in the social procurement process, which is the focus of this paper. Four case studies, which are representative of the four main types of social procurement, will be examined in order to trace how economic capital is transformed into other types of capital in each of these cases. In so doing, the paper will advance our understanding of social procurement theoretically, and lead to a wider discussion about the role of social procurement in ensuring the sustainability of nonprofit organisations, and the civil societies in which they operate.

Pharmacological consequence of the A118G μ opioid receptor polymorphism on morphine-and fentanyl-mediated modulation of Ca2+ channels in humanized mouse sensory neurons

Background: The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele. Methods: The coupling of wild-type and mutant μ opioid receptors to voltage-gated Ca channels after exposure to either ligand was examined by employing the whole cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele. RESULTS:: The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately fivefold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared with the 118AA mice. Conclusions: This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor's pharmacology in sensory neurons. In addition, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids. © 2011 the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology.

Towards an orchestration theory in business transformation management (research in progress)

Business transformations are large-scale organisational change projects that, evidence suggests, are often unsuccessful. This study aims to develop a conceptual model that explains how management services that are required for a business transformation are orchestrated during such a initiative. We classify management services such as (but not limited to) change management, risk management, IT management, financial management, program management and so forth as bearing transformational and/or transactional capabilities in a transformation initiative. We then draw upon three principles of musical composition, namely melody, harmony and rhythm, and illustrate how they apply to the orchestration of management services in the management of business transformations. In order to illustrate our emerging model, we examine the case of Malaysia Airlines, who have managed to successfully turnaround the near-bankrupt organisation beyond survival. We demonstrate how the notions of melody, harmony and rhythm can be used to describe their endeavour. We conclude by discussing next steps of our research.

A conceptual model to link deep customer insights to both growth opportunities and organisational strategy in SME’s as part of a design led transformation journey

Although Design Led Innovation activities aim to raise the value of design within the business, knowledge about which tools are available to support companies and how to apply them to make the connection between design for new product development and design as a strategic driver of growth is needed. This paper presents a conceptual method to supplement existing process and tools to assist companies to grow through design. The model extends the authors’ previous work to explore how through storytelling, customer observation can be captured and translated into new meaning, then creating new design propositions shaped into product needs, which can drive internal business activities, brand and the strategic vision. The paper contributes to a gap in the theoretical frameworks and literature by highlighting the need to align and scale design processes which match the needs of SME’s as they transition along a trajectory to become design led businesses.

Influencing the experience of people in urban public places through mobile mediated interactions

This paper introduces our research on influencing the experience of people in urban public places through mobile mediated interactions. Information and communication technology (ICT) devices are sometimes used to create personal space while in public. ICT devices could also be utilised to digitally augment the urban space with non-privacy sensitive data enabling mobile mediated interactions in an anonymous way between collocated strangers. We present what motivates the research on digital augmentations and mobile mediated interactions between unknown urban dwellers, define the research problem that drives this study and why it is significant research in the field of pervasive social networking. The paper illustrates three design interventions enabling social pervasive content sharing and employing pervasive presence, awareness and anonymous social user interaction in urban public places. The paper concludes with an outlook and summarises the research effort.

Can transfer of learning be enriched by valuing knowledge transformation and co-creation? Exploring new ways to improve training design

This paper argues that a possible cause of issues with management education outcomes is the fact that most training models operate from a limited ‘transfer’ metaphor. This theoretical paper contends that by reconceptualising existing models, specifically Holton’s transfer of learning model, to incorporate multiple processes and acknowledge the importance of educator- or trainer-student interaction in co-creating knowledge, there is potential to improve training design and ultimately achieve more satisfactory training outcomes.

Cyclin-dependent kinase-mediated phosphorylation of RBP1 and pRb promotes their dissociation to mediate release of the SAP30·mSin3·HDAC transcriptional repressor complex

Eukaryotic cell cycle progression is mediated by phosphorylation of protein substrates by cyclin-dependent kinases (CDKs). A critical substrate of CDKs is the product of the retinoblastoma tumor suppressor gene, pRb, which inhibits G1-S phase cell cycle progression by binding and repressing E2F transcription factors. CDK-mediated phosphorylation of pRb alleviates this inhibitory effect to promote G1-S phase cell cycle progression. pRb represses transcription by binding to the E2F transactivation domain and recruiting the mSin3·histone deacetylase (HDAC) transcriptional repressor complex via the retinoblastoma-binding protein 1 (RBP1). RBP1 binds to the pocket region of pRb via an LXCXE motif and to the SAP30 subunit of the mSin3·HDAC complex and, thus, acts as a bridging protein in this multisubunit complex. In the present study we identified RBP1 as a novel CDK substrate. RBP1 is phosphorylated by CDK2 on serines 864 and 1007, which are N- and C-terminal to the LXCXE motif, respectively. CDK2-mediated phosphorylation of RBP1 or pRb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation. Consistent with these findings, RBP1 phosphorylation is increased during progression from G 1 into S-phase, with a concurrent decrease in its association with pRb in MCF-7 breast cancer cells. These studies provide new mechanistic insights into CDK-mediated regulation of the pRb tumor suppressor during cell cycle progression, demonstrating that CDK-mediated phosphorylation of both RBP1 and pRb induces their dissociation to mediate release of the mSin3·HDAC transcriptional repressor complex from pRb to alleviate transcriptional repression of E2F.

Leading the transformation of learning and praxis in science classrooms

Individual science teachers who have inspired colleagues to transform their classroom praxis have been labelled transformational leaders. As the notion of distributed leadership became more accepted in the educational literature, the focus on the individual teacher-leader shifted to the study of leadership praxis both by individuals (whoever they might be) and by collectives within schools and science classrooms. This review traces the trajectory of leadership research, in the context of learning and teaching science, from an individual focus to a dialectical relationship between individual and collective praxis. The implications of applying an individual-collective perspective to praxis for teachers, students and their designated leaders are discussed.

Qualitative inquiry as transformation and agency : the black sheep and workplace mobbing

This chapter discusses an action research project into the lived experience of the workplace mobbing phenomenon. The action research methodology is based on the exemplarian model (Coenen & Khonraad, 2003) from the Netherlands Group. This model requires positive outcomes for those immersed in the problem to reduce the adversity of their circumstances. The findings challenge the psychological perspective of the existing bullying literature that tends to focus on individual behaviour. This research, undertaken over a three year period with 212 participants, identified the dysfunctional nature of public sector bureaucracies and the power gained through gossip and rumour as some of the key emergent themes to explain the workplace mobbing problem. In addition, resistance, conscientisation, and agency were identified as the key to transformation for those targeted. The discussion focuses on the crystallisation phase of the exemplarian model where the participants identified themselves as the Black Sheep and adopted the motto that “a black sheep is a biting beast” (Bastard, 1565 or 6-1618, p. 90), reflecting a sense of empowerment, individual agency, and a sense of humour in dealing with the serious yet seemingly absurd reality of their situations. The identity of the Black Sheep was consolidated when the group organised a 2 day conference with over 200 attendees to discuss how best to prevent workplace mobbing. This self-affirming action was a proactive step towards metaphorically “biting back” at the problem. A number of positive outcomes were achieved including the conference with over 200 attending leading to national media coverage across Australia and additional interviews with magazines, newspapers, and radio.

Bacterially mediated iron cycling and associated biogeochemical processes in a subtropical shallow coastal aquifer: implications for groundwater quality

Bacterially mediated iron redox cycling exerts a strong influence on groundwater geochemistry, but few studies have investigated iron biogeochemical processes in coastal alluvial aquifers from a microbiological viewpoint. The shallow alluvial aquifer located adjacent to Poona estuary on the subtropical Southeast Queensland coast represents a redox-stratified system where iron biogeochemical cycling potentially affects water quality. Using a 300 m transect of monitoring wells perpendicular to the estuary, we examined groundwater physico-chemical conditions and the occurrence of cultivable bacterial populations involved in iron (and manganese, sulfur) redox reactions in this aquifer. Results showed slightly acidic and near-neutral pH, suboxic conditions and an abundance of dissolved iron consisting primarily of iron(II) in the majority of wells. The highest level of dissolved iron(III) was found in a well proximal to the estuary most likely a result of iron curtain effects due to tidal intrusion. A number of cultivable, (an)aerobic bacterial populations capable of diverse carbon, iron, or sulfur metabolism coexisted in groundwater redox transition zones. Our findings indicated aerobic, heterotrophic respiration and bacterially mediated iron/sulfur redox reactions were integral to carbon cycling in the aquifer. High abundances of dissolved iron and cultivable iron and sulfur bacterial populations in estuary-adjacent aquifers have implications for iron transport to marine waters. This study demonstrated bacterially mediated iron redox cycling and associated biogeochemical processes in subtropical coastal groundwaters using culture-based methods.

Biomimetic tubular nanofiber mesh and platelet rich plasma-mediated delivery of BMP-7 for large bone defect regeneration.

There is a growing need for successful bone tissue engineering strategies and advanced biomaterials that mimic the structure and function of native tissues carry great promise. Successful bone repair approaches may include an osteoconductive scaffold, osteoinductive growth factors, cells with an osteogenic potential and capacity for graft vascularisation. To increase osteoinductivity of biomaterials, the local combination and delivery of growth factors has been developed. In the present study we investigated the osteogenic effects of calcium phosphate (CaP)-coated nanofiber mesh tube-mediated delivery of BMP-7 from a PRP matrix for the regeneration of critical sized segmental bone defects in a small animal model. Bilateral full-thickness diaphyseal segmental defects were created in twelve male Lewis rats and nanofiber mesh tubes were placed around the defect. Defects received either treatment with a CaP-coated nanofiber mesh tube (n = 6), an un-coated nanofiber mesh tube (n=6) a CaP-coated nanofiber mesh tube with PRP (n=6) or a CaP-coated nanofiber mesh tube in combination with 5 μg BMP-7 and PRP (n = 6). After 12 weeks, bone volume and biomechanical properties were evaluated using radiography, microCT, biomechanical testing and histology. The results demonstrated significantly higher biomechanical properties and bone volume for the BMP group compared to the control groups. These results were supported by the histological evaluations, where BMP group showed the highest rate of bone regeneration within the defect. In conclusion, BMP-7 delivery via PRP enhanced functional bone defect regeneration, and together these data support the use of BMP-7 in the treatment of critical sized defects.