Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Direct bone marrow HSC transplantation enhances local engraftment at the expense of systemic engraftment in NSG mice

Direct bone marrow (BM) injection has been proposed as a strategy to bypass homing inefficiencies associated with intravenous (IV) hematopoietic stem cell (HSC) transplantation. Despite physical delivery into the BM cavity, many donor cells are rapidly redistributed by vascular perfusion, perhaps compromising efficacy. Anchoring donor cells to 3-dimensional (3D) multicellular spheroids, formed from mesenchymal stem/stromal cells (MSC) might improve direct BM transplantation. To test this hypothesis, relevant combinations of human umbilical cord blood-derived CD34(+) cells and BM-derived MSC were transplanted into NOD/SCID gamma (NSG) mice using either IV or intrafemoral (IF) routes. IF transplantation resulted in higher human CD45(+) and CD34(+) cell engraftment within injected femurs relative to distal femurs regardless of cell combination, but did not improve overall CD45(+) engraftment at 8 weeks. Analysis within individual mice revealed that despite engraftment reaching near saturation within the injected femur, engraftment at distal hematopoietic sites including peripheral blood, spleen and non-injected femur, could be poor. Our data suggest that the retention of human HSC within the BM following direct BM injection enhances local chimerism at the expense of systemic chimerism in this xenogeneic model.

Moderation as judgement practice: Reconciling system level accountability and local level practice

Internationally, recognition of the role of assessment to inform the learning process has received much attention in recent years. Assessment for learning, not just of learning is being supported by an increasing body of literature providing strategies that teachers and their students can incorporate to support the learning process (Assessment Reform Group, 2002; Broadfoot & Black, 2004; James, 2006). Concurrently there has been an increase internationally in systemic accountability requirements of schools in terms of student results. The convergence of these two movements has resulted in some education systems promoting standards-driven reform involving authentic assessment and a re-examination of the relationship between the teacher and the student in the learning process. In this context standards are intended to be used as the basis for judgements of student achievement; while the results from assessment tasks are meant to both inform the teaching/learning process, and to report and track student progress. In such system, the role and reliability of teacher judgement takes centre stage.

A framework for analyzing system intelligence of the building control system : a study of the integrated building management system

The lack of satisfactory consensus for characterizing the system intelligence and structured analytical decision models has inhibited the developers and practitioners to understand and configure optimum intelligent building systems in a fully informed manner. So far, little research has been conducted in this aspect. This research is designed to identify the key intelligent indicators, and develop analytical models for computing the system intelligence score of smart building system in the intelligent building. The integrated building management system (IBMS) was used as an illustrative example to present a framework. The models presented in this study applied the system intelligence theory, and the conceptual analytical framework. A total of 16 key intelligent indicators were first identified from a general survey. Then, two multi-criteria decision making (MCDM) approaches, the analytic hierarchy process (AHP) and analytic network process (ANP), were employed to develop the system intelligence analytical models. Top intelligence indicators of IBMS include: self-diagnostic of operation deviations; adaptive limiting control algorithm; and, year-round time schedule performance. The developed conceptual framework was then transformed to the practical model. The effectiveness of the practical model was evaluated by means of expert validation. The main contribution of this research is to promote understanding of the intelligent indicators, and to set the foundation for a systemic framework that provide developers and building stakeholders a consolidated inclusive tool for the system intelligence evaluation of the proposed components design configurations.

Predication and propagation : a method for analyzing evaluative meanings in technology policy

In this article I outline and demonstrate a synthesis of the methods developed by Lemke (1998) and Martin (2000) for analyzing evaluations in English. I demonstrate the synthesis using examples from a 1.3-million-word technology policy corpus drawn from institutions at the local, state, national, and supranational levels. Lemke's (1998) critical model is organized around the broad 'evaluative dimensions' that are deployed to evaluate propositions and proposals in English. Martin's (2000) model is organized with a more overtly systemic-functional orientation around the concept of 'encoded feeling'. In applying both these models at different times, whilst recognizing their individual usefulness and complementarity, I found specific limitations that led me to work towards a synthesis of the two approaches. I also argue for the need to consider genre, media, and institutional aspects more explicitly when claiming intertextual and heteroglossic relations as the basis for inferred evaluations. A basic assertion made in this article is that the perceived Desirability of a process, person, circumstance, or thing is identical to its 'value'. But the Desirability of anything is a socially and thus historically conditioned attribution that requires significant amounts of institutional inculcation of other 'types' of value-appropriateness, importance, beauty, power, and so on. I therefore propose a method informed by critical discourse analysis (CDA) that sees evaluation as happening on at least four interdependent levels of abstraction.

Look before you leap : the epistemic violence that sometimes hides behind the word "inclusion"

This paper demonstrates how Indigenous Studies is controlled in some Australian universities in ways that continue the marginalisation, denigration and exploitation of Indigenous peoples. Moreover, it shows how the engagement of white notions of “inclusion” can result in the maintenance of racism, systemic marginalisation, white race privilege and radicalised subjectivity. A case study will be utilised which draws from the experience of two Indigenous scholars who were invited to be part of a panel to review one Australian university’s plan and courses in Indigenous studies. The case study offers the opportunity to destabilise the relationships between oppression and privilege and the epistemology that maintains them. The paper argues for the need to examine exactly what is being offered when universities provide opportunities for “inclusion”.

The epistemology that maintains white race privilege, power and control of Indigenous Studies and Indigenous peoples' participation in universities

This paper represents my attempt to turn the gaze and demonstrate how Indigenous Studies is controlled in some Australian universities in ways that witness Indigenous peoples being further marginalised, denigrated and exploited. I have endeavoured to do this through sharing an experience as a case study. I have opted to write about it as a way of exposing the problematic nature of racism, systemic marginalisation, white race privilege and radicalised subjectivity played out within an Australian higher education institution and because I am dissatisfied with the on-going status quo. In bringing forth analysis to this case study, I reveal the relationships between oppression, white race privilege and institutional privilege and the epistemology that maintains them. In moving from the position of being silent on this experience to speaking about it, I am able to move from the position of object to subject and to gain a form of liberated voice (hooks 1989:9). Furthermore, I am hopeful that it will encourage others to examine their own practices within universities and to challenge the domination that continues to subjugate Indigenous peoples.

The critical competences needed for innovative organizational inter-firm and intra-firm integration

In today's highly challenging business environment, an innovative and systemic approach is imperative to survival and growth. Organisational integration and technological integration, are often seen as a catalyst of change that could lead to significant improvements in organisations. The levels of improvement in inter and intra firm integration should arise from a detailed understanding and development of competences within and between organisations. Preliminary findings suggest that lack of trust across organisational cultures within the firms has a negative influence on the development of the capabilities to integrate and align technological innovations and hinders implementation and the effectiveness of the operations. Additionally, poor communication and conflict effects customer satisfaction. Firms need to transfer the competences that support cooperative integration, developed through interaction with supply chain partners, to their relationship arrangements with other supply chain partners, as these are key to ensuring low operational costs.

Termination of a minor’s pregnancy : critical issues for consent and the criminal law

The recent Supreme Court decision of Queensland v B [2008] 2 Qd R 562 has significant implications for the law that governs consent and abortions. The judgment purports to extend the ratio of Secretary, Department of Health and Community Services (NT) v JWB and SMB (1991) 175 CLR 218 (Marion’s Case) and impose a requirement of court approval for terminations of pregnancy for minors who are not Gillick-competent. This article argues against the imposition of this requirement on the ground that such an approach is an unjustifiable extension of the reasoning in Marion’s Case. The decision, which is the first judicial consideration in Queensland of the position of medical terminations, also reveals systemic problems with the criminal law in that State. In concluding that the traditional legal excuse for abortions will not apply to those which are performed medically, Queensland v B provides further support for calls to reform this area of law.

Changing assessment practices : the case for online moderation

Online moderation meetings have the potential to support the collaborative professional development of teachers, and the formation of a common understanding of what denotes quality in student work in a standards based assessment system. In doing so systemic calls for consistency across education systems are also being met. In this paper a case for employing online moderation meetings is developed through recourse to the demands of learning in the twenty-first century and the place of assessment within those discourses. It is argued that empirical data is needed on the efficacy of online moderation meetings to guide future practice as the use of information and communication technologies increases in education systems. Online moderation is one way of gathering teachers across vast distances to share their understandings and develop common meanings of assessment. While it is suggested that online moderation is one possible procedure to meet systemic requirements and support teachers’ professional collaboration, the implementation of such a system also introduces new challenges for schools and teachers. Meeting online to discuss professional understandings is a new way of operating for teachers and involves technology that has not yet been fully utilised within education departments. Issues such as the types of interactions that are afforded within such an environment, as well as technical operating problems that occur when using technology impact on the employment of online meetings. Online moderation meetings while potentially solving the issue of developing common understandings across an entire department also pose new issues to be resolved. There is a need for research into the efficacy of online moderation meetings so that future policy decisions may be based on sound empirical data. It is imperative that as new ways of knowing and acting are incorporated into school curriculum and pedagogy, assessment practices are also aligned. Online moderation meetings can support such practices by enabling teachers to communicate with a wider and more diverse group of teachers to establish common understandings.

The genetic basis of human height : the role of estrogen

Height is a complex physical trait that displays strong heritability. Adult height is related to length of the long bones, which is determined by growth at the epiphyseal growth plate. Longitudinal bone growth occurs via the process of endochondral ossification, where bone forms over the differentiating cartilage template at the growth plate. Estrogen plays a major role in regulating longitudinal bone growth and is responsible for inducing the pubertal growth spurt and fusion of the epiphyseal growth plate. However, the mechanism by which estrogen promotes epiphyseal fusion is poorly understood. It has been hypothesised that estrogen functions to regulate growth plate fusion by stimulating chondrocyte apoptosis, angiogenesis and bone cell invasion in the growth plate. Another theory has suggested that estrogen exposure exhausts the proliferative capacity of growth plate chondrocytes, which accelerates the process of chondrocyte senescence, leading to growth plate fusion. The overall objective of this study was to gain a greater understanding of the molecular mechanisms behind estrogen-mediated growth and height attainment by examining gene regulation in chondrocytes and the role of some of these genes in normal height inheritance. With the heritability of height so well established, the initial hypothesis was that genetic variation in candidate genes associated with longitudinal bone growth would be involved in normal adult height variation. The height-related genes FGFR3, CBFA1, ER and CBFA1 were screened for novel polymorphisms using denaturing HPLC and RFLP analysis. In total, 24 polymorphisms were identified. Two SNPs in ER (rs3757323 C>T and rs1801132 G>C) were strongly associated with adult male height and displayed an 8 cm and 9 cm height difference between homozygous genotypes, respectively. The TC haplotype of these SNPs was associated with a 6 cm decrease in height and remarkably, no homozygous carriers of the TC haplotype were identified in tall subjects. No significant associations with height were found for polymorphisms in the FGFR3, CBFA1 or VDR genes. In the epiphyseal growth plate, chondrocyte proliferation, matrix synthesis and chondrocyte hypertrophy are all major contributors to long bone growth. As estrogen plays such a significant role in both growth and final height attainment, another hypothesis of this study was that estrogen exerted its effects in the growth plate by influencing chondrocyte proliferation and mediating the expression of chondrocyte marker genes. The examination of genes regulated by estrogen in chondrocyte-like cells aimed to identify potential regulators of growth plate fusion, which may further elucidate mechanisms involved in the cessation of linear growth. While estrogen did not dramatically alter the proliferation of the SW1353 cell line, gene expression experiments identified several estrogen regulated genes. Sixteen chondrocyte marker genes were examined in response to estrogen concentrations ranging from 10-12 M to 10-8 M over varying time points. Of the genes analysed, IHH, FGFR3, collagen II and collagen X were not readily detectable and PTHrP, GHR, ER, BMP6, SOX9 and TGF1 mRNAs showed no significant response to estrogen treatments. However, the expression of MMP13, CBFA1, BCL-2 and BAX genes were significantly decreased. Interestingly, the majority of estrogen regulated genes in SW1353 cells are expressed in the hypertrophic zone of the growth plate. Estrogen is also known to regulate systemic GH secretion and local GH action. At the molecular level, estrogen functions to inhibit GH action by negatively regulating GH signalling. GH treated SW1353 cells displayed increases in MMP9 mRNA expression (4.4-fold) and MMP13 mRNA expression (64-fold) in SW1353 cells. Increases were also detected in their respective proteins. Treatment with AG490, an established JAK2 inhibitor, blocked the GH mediated stimulation of both MMP9 and MMP13 mRNA expression. The application of estrogen and GH to SW1353 cells attenuated GH-stimulated MMP13 levels, but did not affect MMP9 levels. Investigation of GH signalling revealed that SW1353 cells have high levels of activated JAK2 and exposure to GH, estrogen, AG490 and other signalling inhibitors did not affect JAK2 phosphorylation. Interestingly, AG490 treatment dramatically decreased ERK2 signalling, although GH did stimulate ERK2 phosphorylation above control levels. AG490 also decreased CBFA1 expression, a transcription factor known to activate MMP9 and MMP13. Finally, GH and estrogen treatment increased expression of SOCS3 mRNA, suggesting that SOCS3 may regulate JAK/STAT signalling in SW1353 cells. The modulation of GH-mediated MMP expression by estrogen in SW1353 cells represents a potentially novel mechanism by which estrogen may regulate longitudinal bone growth. However, further investigation is required in order to elucidate the precise mechanisms behind estrogen and GH regulation of MMP13 expression in SW1353 cells. This study has provided additional evidence that estrogen and the ER gene are major factors in the regulation of growth and the determination of adult height. Newly identified polymorphisms in the ER gene not only contribute to our understanding of the genetic basis of human height, but may also be useful in association studies examining other complex traits. This study also identified several estrogen regulated genes and indicated that estrogen modifies the expression of genes which are primarily expressed in the hypertrophic region of the epiphyseal growth plate. Furthermore, synergistic studies incorporating GH and estrogen have revealed the ability of estrogen to attenuate the effects of GH on MMP13 expression, revealing potential pathways by which estrogen may modulate growth plate fusion, longitudinal bone growth and even arthritis.