BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell cycle arrest and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here we report that estrogen and estrogen metabolites can cause DNA double strand breaks (DSB) in estrogen receptor-α negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolising enzymes, such as CYP1A1, in breast cells. Lastly, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumours in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.

The Times They Are A Changin': The Effect of Institutional Change on Cooperative Behaviour at 26,000ft over Sixty Years

In 2006, Sir Edmund Hillary lambasted the modern climbing fraternity for abandoning other climbers to a slow frozen death on Everest, claiming that in his day they would never leave someone to die. This followed the controversial death of David Sharp, passed by an estimated 40 climbers who were more interested in the summit than the life of a fellow human being. But was this stinging criticism true or just the faded recollections of a former climbing giant? This book investigates that claim through a narrative analysis, which combines the empirical analysis of Hawley and Salisbury's Himalayan Expedition Database with the anecdotal evidence provided by a plethora of newspaper articles and books. While there is evidence supporting the claim that commercialization is to blame for the breakdown of pro-social behaviour, the results cannot conclude if it is the commercial climber or the operator driving the problem and that the Sherpa are the saving grace.

The role of institutional pressures and top management support in the intention to adopt cloud computing solutions

Purpose – While many studies have predominantly looked at the benefits and risks of cloud computing, little is known whether and to what extent institutional forces play a role in cloud computing adoption. The purpose of this paper is to explore the role of institutional factors in top management team’s (TMT’s) decision to adopt cloud computing services. Design/methodology/approach – A model is developed and tested with data from an Australian survey using the partial least squares modeling technique. Findings – The results suggest that mimetic and coercive pressures influence TMT’s beliefs in the benefits of cloud computing. The results also show that TMT’s beliefs drive TMT’s participation, which in turn affects the intention to increase the adoption of cloud computing solutions. Research limitations/implications – Future studies could incorporate the influences of local actors who might also press for innovation. Practical implications – Given the influence of institutional forces and the plethora of cloud-based solutions on the market, it is recommended that TMTs exercise a high degree of caution when deciding for the types of applications to be outsourced as organizational requirements in terms of performance and security will differ. Originality/value – The paper contributes to the growing empirical literature on cloud computing adoption and offers the institutional framework as an alternative lens with which to interpret cloud-based information technology outsourcing.

Acquaintance or partner? Social economy organisations, institutional logics and regional development in Australia

The social economy as a regional development actor is gaining greater attention given its purported ability to address social and environmental problems. This growth in interest is occurring within a global environment that is calling for a more holistic understanding of development compared to traditionally economic-centric conceptions. While regional development policies and practices have long considered for-profit businesses as agents for regional growth, there is a relatively limited understanding of the role of the social economy as a development actor. The institutional environment is a large determinant of all kinds of entrepreneurial activity, and therefore understanding the relationships between the social economy and broader regional development processes is warranted. This paper moves beyond suggestions of an economic-centric focus of regional development by utilising institutional logics as a theoretical framework for understanding the role of social enterprise in regional development. A multiple case study of ten social enterprises in two regional locations in Australia suggests that social enterprise can represent competing logics to economic-centric institutional values and systems. The paper argues that dominant institutional logics can constrain or promote the inter-play between the social and the economic aspects of development, in the context of social enterprise.

A germline polymorphism of thymine DNA glycosylase induces genomic instability and cellular transformation

Thymine DNA glycosylase (TDG) functions in base excision repair, a DNA repair pathway that acts in a lesion-specific manner to correct individual damaged or altered bases. TDG preferentially catalyzes the removal of thymine and uracil paired with guanine, and is also active on 5-fluorouracil (5-FU) paired with adenine or guanine. The rs4135113 single nucleotide polymorphism (SNP) of TDG is found in 10% of the global population. This coding SNP results in the alteration of Gly199 to Ser. Gly199 is part of a loop responsible for stabilizing the flipped abasic nucleotide in the active site pocket. Biochemical analyses indicate that G199S exhibits tighter binding to both its substrate and abasic product. The persistent accumulation of abasic sites in cells expressing G199S leads to the induction of double-strand breaks (DSBs). Cells expressing the G199S variant also activate a DNA damage response. When expressed in cells, G199S induces genomic instability and cellular transformation. Together, these results suggest that individuals harboring the G199S variant may have increased risk for developing cancer.

Pushing the boundaries' versus identifying the boundaries: An institutional perspective of NPM Principles

This paper considers the boundaries of new public management (NPM) principles in the context of the mandate for a commercial approach within in a New Zealand state-owned enterprise (SOE). Investigating a commercial approach to NPM through an institutional theory lens, the case study highlights complexities and potential conflict between structured NPM principles and the more complex reality. Analysis reveals blurred lines and boundaries have implications for public sector organisations such as SOEs, government and other stakeholders, where managers push the boundaries beyond the point where stakeholders are comfortable. Thus, a key challenge involves developing clearer institutional boundaries to balance freedoms with stakeholder acceptability.

Institutional constraints on altruism in the formation of a venture idea

This thesis is about the social orientation of new venture ideas and how the degree of social orientation is influenced by the entrepreneur's level of altruism, by industry norms, and by nonprofit work experience. Potential entrepreneurs were asked to generate new venture ideas based on 3D-printing and their ideas were rated for degree of social orientation. It was found that while greater altruism leads to more socially-oriented venture ideas, the influence of altruism on the venture idea is constrained by the profit-maximization norm that is prevalent in most industries.

Capacity building of early career researchers through cross-institutional mentoring

Most early career researchers in the first five years following doctoral qualification are faced with research challenges and opportunities, which necessitate the ability to navigate and overcome barriers, and to identify and benefit from possibilities. In this chapter, the authors outline an intentional mentoring initiative aimed at building the capacity of early career researchers within the Excellence in Research in Early Years Education Collaborative Research Network (CRN) in Australia. The initiative involved partnering early career researchers with experienced researchers and the inclusion of an early career representative on the network planning committee. The chapter discusses the many benefits for the mentee arising from the initiative including increased publication, momentum and confidence, as well as exposure to new methodologies, theoretical frameworks, and productive collaborative partnerships. It is hoped, however, that the findings will be of relevance to similar and diverse (funded/unfunded) research programs and collaborative networks wherever mentoring is applied as a capacity building strategy to assist researchers.

A cyclostationary multi-domain analysis of fluid instability in Kaplan turbines

Hydraulic instabilities represent a critical problem for Francis and Kaplan turbines, reducing their useful life due to increase of fatigue on the components and cavitation phenomena. Whereas an exhaustive list of publications on computational fluid-dynamic models of hydraulic instability is available, the possibility of applying diagnostic techniques based on vibration measurements has not been investigated sufficiently, also because the appropriate sensors seldom equip hydro turbine units. The aim of this study is to fill this knowledge gap and to exploit fully, for this purpose, the potentiality of combining cyclostationary analysis tools, able to describe complex dynamics such as those of fluid-structure interactions, with order tracking procedures, allowing domain transformations and consequently the separation of synchronous and non-synchronous components. This paper will focus on experimental data obtained on a full-scale Kaplan turbine unit, operating in a real power plant, tackling the issues of adapting such diagnostic tools for the analysis of hydraulic instabilities and proposing techniques and methodologies for a highly automated condition monitoring system. © 2015 Elsevier Ltd.