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.

The Queensland study of melanoma : Environmental and genetic associations (Q-MEGA); Study design, baseline characteristics, and repeatability of phenotype and sun exposure measures

Cutaneous malignant melanoma (CMM) is a major health issue in Queensland, Australia, which has the world’s highest incidence. Recent molecular and epidemiologic studies suggest that CMM arises through multiple etiological pathways involving gene-environment interactions. Understanding the potential mechanisms leading to CMM requires larger studies than those previously conducted. This article describes the design and baseline characteristics of Q-MEGA, the Queensland Study of Melanoma: Environmental and Genetic Associations, which followed up 4 population-based samples of CMM patients in Queensland, including children, adolescents, men aged over 50, and a large sample of adult cases and their families, including twins. Q-MEGA aims to investigate the roles of genetic and environmental factors, and their interaction, in the etiology of melanoma. Three thousand, four hundred and seventy-one participants took part in the follow-up study and were administered a computer-assisted telephone interview in 2002-2005. Updated data on environmental and phenotypic risk factors, and 2777 blood samples were collected from interviewed participants as well as a subset of relatives. This study provides a large and well-described population-based sample of CMM cases with follow-up data. Characteristics of the cases and repeatability of sun exposure and phenotype measures between the baseline and the follow-up surveys, from 6 to 17 years later, are also described.

Exercise for health : a breast cancer recovery program - quality of life benefits [Conference Abstract]

Introduction: Five-year survival from breast cancer in Australia is 87%. Hence, ensuring a good quality of life (QOL) has become a focal point of cancer research and clinical interest. Exercise during and after treatment has been identified as a potential strategy to optimise QOL of women diagnosed with breast cancer.----- Methods: Exercise for Health is a randomised controlled trial of an eight-month, exercise intervention delivered by Exercise Physiologists. An objective of this study was to assess the impact of the exercise program during and following treatment on QOL. Queensland women diagnosed with unilateral breast cancer in 2006/07 were eligible to participate. Those living in urban-Brisbane (n=194) were allocated to either the face-to-face exercise group, the telephone exercise group, or the usual-care group, and those living in rural Queensland (n=143) were allocated to the telephone exercise group or the usual-care group. QOL, as assessed by the Functional Assessment of Cancer Therapy-Breast (FACT-B+4) questionnaire, was measured at 4-6 weeks (pre-intervention), 6 months (mid-intervention) and 12 months (three months post-intervention) post-surgery.----- Results: Significant (P<0.01) increases in QOL were observed between pre-intervention and three months post-intervention 12 months post-surgery for all women. Women in the exercise groups experienced greater mean positive changes in QOL during this time (+10 points) compared with the usual-care groups (+5 to +7 points) after adjusting for baseline QOL. Although all groups experienced an overall increase in QOL, approximately 20% of urban and rural women in the usual-care groups reported a decline in QOL, compared with 10% of women in the exercise groups.----- Conclusions: This work highlights the potential importance of participating in physical activity to optimise QOL following a diagnosis of breast cancer. Results suggest that the telephone may be an effective medium for delivering exercise counselling to newly diagnosed breast cancer patients.

QoS-Based Web Service Scheduling Accommodating Inter-Service Dependencies Using Minimal-Conflict Hill-Climbing Repair Genetic Algorithm

In the filed of semantic grid, QoS-based Web service scheduling for workflow optimization is an important problem.However, in semantic and service rich environment like semantic grid, the emergence of context constraints on Web services is very common making the scheduling consider not only quality properties of Web services, but also inter service dependencies which are formed due to the context constraints imposed on Web services. In this paper, we present a repair genetic algorithm, namely minimal-conflict hill-climbing repair genetic algorithm, to address scheduling optimization problems in workflow applications in the presence of domain constraints and inter service dependencies. Experimental results demonstrate the scalability and effectiveness of the genetic algorithm.

A Penalty-based Genetic Algorithm for QoS-AwareWeb Service Composition with Inter-Service Dependencies and Conflicts

In Web service based systems, new value-added Web services can be constructed by integrating existing Web services. A Web service may have many implementations, which are functionally identical, but have different Quality of Service (QoS) attributes, such as response time, price, reputation, reliability, availability and so on. Thus, a significant research problem in Web service composition is how to select an implementation for each of the component Web services so that the overall QoS of the composite Web service is optimal. This is so called QoS-aware Web service composition problem. In some composite Web services there are some dependencies and conflicts between the Web service implementations. However, existing approaches cannot handle the constraints. This paper tackles the QoS-aware Web service composition problem with inter service dependencies and conflicts using a penalty-based genetic algorithm (GA). Experimental results demonstrate the effectiveness and the scalability of the penalty-based GA.

Towards Humane Technologies: Biotechnologies, New Media and Ethics

What are the ethical and political implications when the very foundations of life —things of awe and spiritual significance — are translated into products accessible to few people? This book critically analyses this historic recontextualisation. Through mediation — when meaning moves ‘from one text to another, from one discourse to another’ — biotechnology is transformed into analysable data and into public discourses. The unique book links biotechnology with media and citizenship. As with any ‘commodity’, biological products have been commodified. Because enormous speculative investment rests on this, risk will be understated and benefit will be overstated. Benefits will be unfairly distributed. Already, the bioprospecting of Southern megadiverse nations, legally sanctioned by U.S. property rights conventions, has led to wealth and health benefits in the North. Crucial to this development are biotechnological discourses that shift meanings from a “language of life” into technocratic discourses, infused with neo-liberal economic assumptions that promise progress and benefits for all. Crucial in this is the mass media’s representation of biotechnology for an audience with poor scientific literacy. Yet, even apparently benign biotechnology spawned by the Human Genome Project such as prenatal screening has eugenic possibilities, and genetic codes for illness are eagerly sought by insurance companies seeking to exclude certain people. These issues raise important questions about a citizenship that is founded on moral responsibility for the wellbeing of society now and into the future. After all, biotechnology is very much concerned with the essence of life itself. This book provides a space for alternative and dissident voices beyond the hype that surrounds biotechnology.

Measuring CRM and SCM benefits : a preliminary measurement model

Organizations invest heavily in Customer Relationship Management (CRM) and Supply Chain Management (SCM) systems, and their related infrastructure, presumably expecting positive benefits to the organization. Assessing the benefits of such applications is an important aspect of managing such systems. Considering the salient differences between CRM and SCM applications with other intra-organizational applications, existing Information Systems benefits measurement models and frameworks are ill-suited to gauge benefits of inter-organizational systems. This paper reports the preliminary findings of a measurement model developed to assess benefits of CRM and SCM applications. The preliminary model, which reflects the characteristics of the Analytic Theory, is derived using a review of 55 academic studies and 44 papers from the practice. Six hundred and six identified benefits were then synthesized in to 74 non-overlapping benefits, arranged under six dimensions.

The managerial benefits of tax compliance: perception by small business taxpayers

Research undertaken in 2006 – 2007 investigated the perception of managerial benefits of tax compliance by small business taxpayers. Survey data from a sample of 300 small business taxpayers and responses to semi-structured interviews of owner managers were examined. The study found that a majority of small business taxpayers recognised that tax compliance activities led to better record keeping and to an improved knowledge of their financial affairs. However, there seemed to be a general reluctance by respondents to accept the idea that benefits could be derived as a result of complying with tax. The findings of this study are important as it is the first research that systematically investigated managerial benefits and their perception by small business taxpayers in Australia.

QoS-based web service composition accommodating inter-service dependencies using minimal-conflict , hill-climbing repair genetic algorithm

In the field of semantic grid, QoS-based Web service composition is an important problem. In semantic and service rich environment like semantic grid, the emergence of context constraints on Web services is very common making the composition consider not only QoS properties of Web services, but also inter service dependencies and conflicts which are formed due to the context constraints imposed on Web services. In this paper, we present a repair genetic algorithm, namely minimal-conflict hill-climbing repair genetic algorithm, to address the Web service composition optimization problem in the presence of domain constraints and inter service dependencies and conflicts. Experimental results demonstrate the scalability and effectiveness of the genetic algorithm.

Sustainable housing implementation through mutual benefits to stakeholders : a decision making approach

Improved public awareness and strong sentiments towards environmental issues will continue to create increasing demand for sustainable housing (SH) in the coming years. Despite this potential, the up-take rate of sustainable housing in new build and through home renovation is not as high as expected within the housing industry. This is in contrast to the influx of emerging building technologies, new materials and innovative designs seen in exemplar homes built worldwide. How we should use the increasing awareness of SH and emerging technologies as an impetus to change the un-sustainable designs and practices of the building industry is high on the agenda of the government and majority of the stakeholders involved. This warrants the study of multifaceted strategies that meet the needs of multiple stakeholders and integrated seamlessly into housing development processes. Specifically, the different perceptions, roles and incentives of stakeholders, who inevitably need to ensure their benefits and commercial returns, should be highlighted and acted upon. ----- This paper discusses the preliminary findings of a research project that aims to promote SH implementation by identifying and materializing the mutual benefits among key stakeholders. The aim is to be achieved through questionnaire surveys, structural equation modelling, interviews and case studies with seven major stakeholders within the Australian housing industry. This research identifies the influence and relationship of relevant factors, investigates preferences, similarities and differences between stakeholders on perceived benefits and in turn explores the mutual-benefit strategy package that facilitates decision making towards sustainable housing development.

Regulatory approaches to genetic testing in insurance

Rapid advancements in the field of genetic science have engendered considerable debate, speculation, misinformation and legislative action worldwide. While programs such as the Human Genome Project bring the prospect of seemingly miraculous medical advancements within imminent reach, they also create the potential for significant invasions of traditional areas of privacy and human dignity through laying the potential foundation for new forms of discrimination in insurance, employment and immigration regulation. The insurance industry, which has of course, traditionally been premised on discrimination as part of its underwriting process, is proving to be the frontline of this regulatory battle with extensive legislation, guidelines and debate marking its progress.

Benefits of collaborative ICT adoption for building project management

Purpose : Effective flow of data and communication at every stage of a construction project is essential for achieving required coordination and collaboration between the project participants, leading to successful management of the projects. In present scenario, when project participants are geographically separated, adoption of information communication technology (ICT) enables such effective communication. Thus, the purpose of this paper is to focus on ICT adoption for building project management.---------- Design/methodology/approach : It is difficult to quantitatively evaluate the benefits of ICT adoption in the multiple enterprise scenario of building project management. It requires qualitative analysis based on the perceptions of the construction professionals. The paper utilizes interpretive structural modeling (ISM) technique to assess importance of perceived benefits and their driving power and dependence on other benefits.---------- Findings : The developed ISM model shows that all the categories of benefits, i.e. benefits related to projects, team management, technology, and organization are inter-related and cannot be achieved in isolation. But, organization- and technology-related benefits have high-driving power and these are “strategic benefits” for the project team organizations. Thus, organizations are required to give more attention on strategically increasing these benefits from application of ICT. Originality/value – This analysis provides a road map to managers or project management organizations to decide that if they are planning ICT adoption for achieving certain benefits then which are the other driving benefits that should be achieved prior to that and also which are the dependent benefits that would be achieved by default.