Genome-wide association studies and musculoskeletal diseases

Bone and joint diseases are major causes of morbidity and mortality worldwide, and their prevalence is increasing as the average population age increases. Most common musculoskeletal diseases show significant heritability, and few have treatments that prevent disease or can induce true treatment-free, disease-free remission. Furthermore, despite valiant efforts of hypothesis-driven research, our understanding of the etiopathogenesis of these conditions is, with few exceptions, at best moderate. Therefore, there has been a long-standing interest in genetics research in musculoskeletal disease as a hypothesis-free method for investigating disease etiopathogenesis. Important contributions have been made through the identification of monogenic causes of disease, but the holy grail of human genetics research has been the identification of the genes responsible for common diseases. The development of genome-wide association (GWA) studies has revolutionized this field, and led to an explosion in the number of genes identified that are definitely involved in musculoskeletal disease pathogenesis. However, this approach will not identify all common disease genes, and although the current progress is exciting and proves the potential of this research discipline, other approaches will be required to identify many of the types of genetic variation likely to be involved.

Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function

Memory T cells develop early during the preclinical stages of autoimmune diseases and have traditionally been considered resistant to tolerance induction. As such, they may represent a potent barrier to the successful immunotherapy of established autoimmune diseases. It was recently shown that memory CD8+ T cell responses are terminated when Ag is genetically targeted to steady-state dendritic cells. However, under these conditions, inactivation of memory CD8+ T cells is slow, allowing transiently expanded memory CD8+ T cells to exert tissue-destructive effector function. In this study, we compared different Ag-targeting strategies and show, using an MHC class II promoter to drive Ag expression in a diverse range of APCs, that CD8+ memory T cells can be rapidly inactivated by MHC class II+ hematopoietic APCs through a mechanism that involves a rapid and sustained downregulation of TCR, in which the effector response of CD8+ memory cells is rapidly truncated and Ag-expressing target tissue destruction is prevented. Our data provide the first demonstration that genetically targeting Ag to a broad range of MHC class II+ APC types is a highly efficient way to terminate memory CD8+ T cell responses to prevent tissue-destructive effector function and potentially established autoimmune diseases. Copyright © 2010 by The American Association of Immunologists, Inc.

ERAP2 functional knockout in humans does not alter surface heavy chains or HLA-B27, inflammatory cytokines or endoplasmic reticulum stress markers

Introduction Single nucleotide polymorphisms in ERAP2 are strongly associated with ankylosing spondylitis (AS). One AS-associated single nucleotide polymorphism, rs2248374, causes a truncated ERAP2 protein that is degraded by nonsense-mediated decay. Approximately 25% of the populations of European ancestry are therefore natural ERAP2 knockouts. We investigated the effect of this associated variant on HLA class I allele presentation, surface heavy chains, endoplasmic reticulum (ER) stress markers and cytokine gene transcription in AS. Methods Patients with AS and healthy controls with either AA or GG homozygous status for rs2248374 were studied. Antibodies to CD14, CD19-ECD, HLA-A-B-C, Valpha7.2, CD161, anti-HC10 and anti-HLA-B27 were used to analyse peripheral blood mononuclear cells. Expression levels of ER stress markers (GRP78 and CHOP) and proinflammatory genes (tumour necrosis factor (TNF), IL6, IL17 and IL22) were assessed by qPCR. Results There was no significant difference in HLAclass I allele presentation or major histocompatibility class I heavy chains or ER stress markers GRP78 and CHOP or proinflammatory gene expression between genotypes for rs2248374 either between cases, between cases and controls, and between controls. Discussion Large differences were not seen in HLAB27 expression or cytokine levels between subjects with and without ERAP2 in AS cases and controls. This suggests that ERAP2 is more likely to influence AS risk through other mechanisms.

Managing infrastructure transitions : a complex adaptive systems perspective

Engineering assets such as roads, rail, bridges and other forms of public works are vital to the effective functioning of societies {Herder, 2006 #128}. Proficient provision of this physical infrastructure is therefore one of the key activities of government {Lædre, 2006 #123}. In order to ensure engineering assets are procured and maintained on behalf of citizens, government needs to devise the appropriate policy and institutional architecture for this purpose. The changing institutional arrangements around the procurement of engineering assets are the focus of this paper. The paper describes and analyses the transition to new, more collaborative forms of procurement arrangements which are becoming increasingly prevalent in Australia and other OECD countries. Such fundamental shifts from competitive to more collaborative approaches to project governance can be viewed as a major transition in procurement system arrangements. In many ways such changes mirror the shift from New Public Management, with its emphasis on the use of market mechanisms to achieve efficiencies {Hood, 1991 #166}, towards more collaborative approaches to service delivery, such as those under network governance arrangements {Keast, 2007 #925}. However, just as traditional forms of procurement in a market context resulted in unexpected outcomes for industry, such as a fragmented industry afflicted by chronic litigation {Dubois, 2002 #9}, the change to more collaborative forms of procurement is unlikely to be a panacea to the problems of procurement, and may well also have unintended consequences. This paper argues that perspectives from complex adaptive systems (CAS) theory can contribute to the theory and practice of managing system transitions. In particular the concept of emergence provides a key theoretical construct to understand the aggregate effect that individual project governance arrangements can have upon the structure of specific industries, which in turn impact individual projects. Emergence is understood here as the macro structure that emerges out of the interaction of agents in the system {Holland, 1998 #100; Tang, 2006 #51}.

Organisational challenges in understanding and implementing effective buiness continuity management strategies in a complex and critical organisation : an airport case study

With the increasing complexity of modern day threats and the growing sophistication of interlinked and interdependent operating environments, Business Continuity Management (BCM) has emerged as a new discipline, offering a strategic approach to safeguarding organisational functions. Of significant interest is the application of BCM frameworks and strategies within critical infrastructure, and in particular the aviation industry. Given the increased focus on security and safety for critical infrastructures, research into the adoption of BCM principles within an airport environment provides valuable management outcomes and research into a previously neglected area of inquisition. This research has used a single case study methodology to identify possible impediments to BCM adoption and implementation by the Brisbane Airport Corporation (BAC). It has identified a number of misalignments between the required breadth of focus for a BCM program, identified differing views on specific roles and responsibilities required during a major disruptive event and illustrated the complexities of the Brisbane Airport which impede the understanding and implementation of effective Business Continuity Management Strategies.

Wavelet based approaches and high resolution methods for complex process models

Many industrial processes and systems can be modelled mathematically by a set of Partial Differential Equations (PDEs). Finding a solution to such a PDF model is essential for system design, simulation, and process control purpose. However, major difficulties appear when solving PDEs with singularity. Traditional numerical methods, such as finite difference, finite element, and polynomial based orthogonal collocation, not only have limitations to fully capture the process dynamics but also demand enormous computation power due to the large number of elements or mesh points for accommodation of sharp variations. To tackle this challenging problem, wavelet based approaches and high resolution methods have been recently developed with successful applications to a fixedbed adsorption column model. Our investigation has shown that recent advances in wavelet based approaches and high resolution methods have the potential to be adopted for solving more complicated dynamic system models. This chapter will highlight the successful applications of these new methods in solving complex models of simulated-moving-bed (SMB) chromatographic processes. A SMB process is a distributed parameter system and can be mathematically described by a set of partial/ordinary differential equations and algebraic equations. These equations are highly coupled; experience wave propagations with steep front, and require significant numerical effort to solve. To demonstrate the numerical computing power of the wavelet based approaches and high resolution methods, a single column chromatographic process modelled by a Transport-Dispersive-Equilibrium linear model is investigated first. Numerical solutions from the upwind-1 finite difference, wavelet-collocation, and high resolution methods are evaluated by quantitative comparisons with the analytical solution for a range of Peclet numbers. After that, the advantages of the wavelet based approaches and high resolution methods are further demonstrated through applications to a dynamic SMB model for an enantiomers separation process. This research has revealed that for a PDE system with a low Peclet number, all existing numerical methods work well, but the upwind finite difference method consumes the most time for the same degree of accuracy of the numerical solution. The high resolution method provides an accurate numerical solution for a PDE system with a medium Peclet number. The wavelet collocation method is capable of catching up steep changes in the solution, and thus can be used for solving PDE models with high singularity. For the complex SMB system models under consideration, both the wavelet based approaches and high resolution methods are good candidates in terms of computation demand and prediction accuracy on the steep front. The high resolution methods have shown better stability in achieving steady state in the specific case studied in this Chapter.

United we stand, divided we fall: the failure of an accounting information system in a major radiology provider

This article explores the way in which a major Australian radiology organization implemented a complex accounting information system and how workers in the 72 radiology practises that had to use it resisted the change. The study reports on the issues that led to the circumvention of the system by individuals and, after only three years, complete withdrawal of the accounting information system by the parent organization. This article has implications for firms in the health care and other sectors considering implementing new accounting information systems. Organizations need to incorporate change management techniques and provide open communication to all stakeholders to minimize disruption and potential problems.

Give and take in major gift relationships

This article investigates the complex phenomenon of major gift giving to charitable institutions. Drawing on empirical evidence from interviews with 16 Australian major donors (who gave a single gift of at least AU$10,000 in 2008 or 2009), we seek to better understand donor expectations and (dis)satisfaction. Given growing need for social services, and the competition among nonprofit organisations (NPOs) to secure sustainable funding, this research is particularly timely. Currently, little is known about major donors’ expectations, wants and needs. Equity theory, with the concept of reciprocity at its core, was found to provide a useful framework for understanding these phenomena. A model of equitable major gift relationships was developed from the data, which portrays balanced relationships and identifies potential areas of dissatisfaction for major donors. We conclude by offering suggestions for NPOs seeking to understand the complexities of major gift relationships, with practical implications for meeting donors’ needs.

Infrastructure transitions toward sustainability : a complex adaptive systems perspective

To ensure infrastructure assets are procured and maintained by government on behalf of citizens, appropriate policy and institutional architecture is needed, particularly if a fundamental shift to more sustainable infrastructure is the goal. The shift in recent years from competitive and resource-intensive procurement to more collaborative and sustainable approaches to infrastructure governance is considered a major transition in infrastructure procurement systems. In order to better understand this transition in infrastructure procurement arrangements, the concept of emergence from Complex Adaptive Systems (CAS) theory is offered as a key construct. Emergence holds that micro interactions can result in emergent macro order. Applying the concept of emergence to infrastructure procurement, this research examines how interaction of agents in individual projects can result in different industry structural characteristics. The paper concludes that CAS theory, and particularly the concept of ‘emergence’, provides a useful construct to understand infrastructure procurement dynamics and progress towards sustainability.

Shifting meanings : The role of metaphors in collective meaning–making in complex project leadership

This paper examines the use of metaphors in collective meaning-making in the work of managers and leaders of megaprojects, drawing on interviews with thirty-three leaders of complex projects in a case study organisation responsible for the delivery of major acquisitions. Recognising the notion of both contextualised and decontextualised approaches to either seeking to elicit or project metaphors, the paper describes the various ways in practising project leaders describe their work and the synergies these metaphors have with the broader social discourse and theorisation around complexity and the language of complex adaptive systems. The paper presents our case study findings where we outline our typology of meta-metaphors describing project leaders’ multiple roles and our interpretation of the significance of these choices.

Critical factors for successful housing reconstruction projects following a major disaster

Post–disaster reconstruction projects are often considered ineffectual or unproductive because on many occasions in the past they have performed extremely poorly during post-contract occupation, or have failed altogether to deliver acceptable outcomes. In some cases, these projects have already failed even before their completion, leading many sponsor aid organisations to hold these projects up as examples of how not to deliver housing reconstruction. Research into some previous unsuccessful projects has revealed that often the lack of adequate knowledge regarding the context and complexity involved in the implementation of these projects is generally responsible for their failure. Post-disaster reconstruction projects are certainly very complex in nature, often very context-specific and they can vary widely in magnitude. Despite such complexity, reconstruction projects can still have a high likelihood of success if adequate consideration is given to the importance of factors which are known to positively influence reconstruction efforts. Good outcomes can be achieved when planners and practitioners ensure best practices are embedded in the design of reconstruction projects at the time reconstruction projects they are first instigated. This paper outlines and discusses factors that significantly contribute to the successful delivery of post-disaster housing reconstruction projects.

Guanxi as complex adaptive system : definition, description and underlying principles

Guanxi has become a common term in the wider business community and has attracted an increasing attention of researchers. However, a consistent understanding of the concept continues to be elusive. We critically review the extant guanxi literature to identify the major inconsistencies in the way guanxi is currently conceptualized and develop a conceptualization of guanxi which views guanxi as a complex adaptive system formed by the strategic establishing, evolving, utilizing, and maintaining of personal relationships based upon social norms of trust and reciprocal obligation unique to the Chinese culture. This study contributes to research of guanxi and to the field of Chinese management in several ways. First, we identify four levels of inconsistency surrounding the conceptualization of guanxi in the literature, thus clarifying the current common sources of confusion. Second, this study deconstructs the level and core values of guanxi to provide a more transparent picture, enabling researchers to develop more robust measures of guanxi. Finally, we made progress towards a more comprehensive understanding of guanxi by introducing the complex adaptive system perspective into the guanxi research.

Defence industry projects : investigating the impact of major project manager attributes on stakeholder relationships and project success

This thesis identifies attributes, skills and behaviours that major project managers require for stakeholder relationships competence and project success within a major project environment. It develops valid and reliable measures of internal and external stakeholder relationships competence, tests a complex conceptual model and explores the effectiveness of the QUT Executive Masters of Complex Project Management and Strategic Procurement in developing major project managers' stakeholder relationships competence. Implications of this thesis are for government and industry in identifying factors associated with major project success, as this will lead to better major project outcomes potentially resulting in time and monetary savings of years and billions of dollars.

Dynamic self-organization phenomena in complex ionized gas systems : new paradigms and technological aspects

An overview of dynamic self-organization phenomena in complex ionized gas systems, associated physical phenomena, and industrial applications is presented. The most recent experimental, theoretical, and modeling efforts to understand the growth mechanisms and dynamics of nano- and micron-sized particles, as well as the unique properties of the plasma-particle systems (colloidal, or complex plasmas) and the associated physical phenomena are reviewed and the major technological applications of micro- and nanoparticles are discussed. Until recently, such particles were considered mostly as a potential hazard for the microelectronic manufacturing and significant efforts were applied to remove them from the processing volume or suppress the gas-phase coagulation. Nowadays, fine clusters and particulates find numerous challenging applications in fundamental science as well as in nanotechnology and other leading high-tech industries.