Involvement of Exo1b in DNA damage-induced apoptosis

Apoptosis is essential for the maintenance of inherited genomic integrity. During DNA damage-induced apoptosis, mechanisms of cell survival, such as DNA repair are inactivated to allow cell death to proceed. Here, we describe a role for the mammalian DNA repair enzyme Exonuclease 1 (Exo1) in DNA damage-induced apoptosis. Depletion of Exo1 in human fibroblasts, or mouse embryonic fibroblasts led to a delay in DNA damage-induced apoptosis. Furthermore, we show that Exo1 acts upstream of caspase-3, DNA fragmentation and cytochrome c release. In addition, induction of apoptosis with DNA-damaging agents led to cleavage of both isoforms of Exo1. The cleavage of Exo1 was mapped to Asp514, and shown to be mediated by caspase-3. Expression of a caspase-3 cleavage site mutant form of Exo1, Asp514Ala, prevented formation of the previously observed fragment without any affect on the onset of apoptosis. We conclude that Exo1 has a role in the timely induction of apoptosis and that it is subsequently cleaved and degraded during apoptosis, potentially inhibiting DNA damage repair.

Conformational flexibility revealed by the crystal structure of a crenarchaeal RadA

Homologous recombinational repair is an essential mechanism for repair of double-strand breaks in DNA. Recombinases of the RecA-fold family play a crucial role in this process, forming filaments that utilize ATP to mediate their interactions with singleand double-stranded DNA. The recombinase molecules present in the archaea (RadA) and eukaryota (Rad51) are more closely related to each other than to their bacterial counterpart (RecA) and, as a result, RadA makes a suitable model for the eukaryotic system. The crystal structure of Sulfolobus solfataricus RadA has been solved to a resolution of 3.2 A° in the absence of nucleotide analogues or DNA, revealing a narrow filamentous assembly with three molecules per helical turn. As observed in other RecA-family recombinases, each RadA molecule in the filament is linked to its neighbour via interactions of a short b-strand with the neighbouring ATPase domain. However, despite apparent flexibility between domains, comparison with other structures indicates conservation of a number of key interactions that introduce rigidity to the system, allowing allosteric control of the filament by interaction with ATP. Additional analysis reveals that the interaction specificity of the five human Rad51 paralogues can be predicted using a simple model based on the RadA structure.

Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks

DNA double-strand break (DSB) repair via the homologous recombination pathway is a multi-stage process, which results in repair of the DSB without loss of genetic information or fidelity. One essential step in this process is the generation of extended single-stranded DNA (ssDNA) regions at the break site. This ssDNA serves to induce cell cycle checkpoints and is required for Rad51 mediated strand invasion of the sister chromatid. Here, we show that human Exonuclease 1 (Exo1) is required for the normal repair of DSBs by HR. Cells depleted of Exo1 show chromosomal instability and hypersensitivity to ionising radiation (IR) exposure. We find that Exo1 accumulates rapidly at DSBs and is required for the recruitment of RPA and Rad51 to sites of DSBs, suggesting a role for Exo1 in ssDNA generation. Interestingly, the phosphorylation of Exo1 by ATM appears to regulate the activity of Exo1 following resection, allowing optimal Rad51 loading and the completion of HR repair. These data establish a role for Exo1 in resection of DSBs in human cells, highlighting the critical requirement of Exo1 for DSB repair via HR and thus the maintenance of genomic stability.

Alternative dispute resolution : are apology and forgiveness simply two sides of the one coin?

Alternative dispute resolution (a.d.r.) processes are entrenched in western style legal systems. Forms of dispute resolution are utilised within schools and health systems; built in to commercial contracts; found in workplaces, clubs and organisations; and accepted in general day-to-day community disputes. The a.d.r. literature includes references to ‘apology’, but is largely silent on ‘forgiveness’. Where an apology is offered as part of a dispute resolution process, practice suggests that formalised ‘forgiveness’ rarely follows. Mediators may agree there is a meaningful place for apology in dispute resolution processes, but are most unlikely to support a view that forgiveness, as a conscious act, has an equivalent place. Yet, if forgiveness is not limited to the ‘pardoning of an offence’, but includes a ‘giving up of resentment’, or the relinquishing of a grudge, then forgiveness may play an underestimated role in dispute management. In the context of some day-to-day dispute management practice, this paper questions whether forgiveness should follow an apology; and concludes that meaningful resolutions can be reached without any formal element of ‘forgiveness’ or absolution. However, dispute management practitioners need to be aware of the latent role other aspects of forgiveness may play for the disputing parties.

An efficient approach for the direct synthesis of lithium niobate powders

Lithium niobate powders from the raw powders of Li2 O5 are directly synthesized by a combustion method with urea fuel. The synthesis parameters (e.g. the calcination temperature, calcination time, and urea-to-(Li2 CO3 + Nb2 O5) quantity ratio) are studied to reveal the optimized synthesis conditions for preparing high-quality lithium niobate powders. In our present work, it is found that a urea-to-(Li2 CO3 + Nb2 O5) ratio close to 3, calcination temperature at 550-600 degrees and reaction time around 2.5h may lead to high-quality lithium niobate powsers. The microstructure of synthesized powders is further studied; a possible mechanism of the involved reactions is also proposed.

Sustaining the next generation of teacher-researchers to work for social justice

This chapter explores a research project involving teachers working with some of the most disadvantaged young people in South Australia, children growing up in poverty, in families struggling with homelessness and ill-health, in the outer southern suburbs. Additionally, there were particular children were struggling with intellectual, emotional and social difficulties which were extreme enough for them not be included in a mainstream class. The research project made two crucial interrelated moves to support teachers to tackle this tough work. First, the project had an explicit social justice agenda. We were not simply researching literacy outcomes, but literacy pedagogies for the students teachers were most worried about. And we wanted to understand how the material conditions of students’ everyday lifeworlds impacted on the working conditions of teachers’ schoolworlds. We sought to open up a discursive space where teachers could talk about poverty, violence, racism and classism in ways that would take them beyond despair and into new imaginings and positive action. Second, the project was designed to start from the urgent questions of early career teachers and to draw on the accumulated practice wisdom of their chosen mentors. Hence we designed not only a teacher-researcher community, but cross-generational networks. Our aim was to build the capacities of both generations to address long-standing educational problems in new ways that drew overtly on their different and complementary resources.

Periodontal regeneration and mesenchymal stem cells

The ultimate goal of periodontal therapy is to regenerate periodontal supporting tissues, but this is hard to achieve as the results of periodontal techniques for regeneration are clinically unpredictable. Stem cells owing to their plasticity and proliferation potential provides a new paradigm for periodontal regeneration. Stem cells from mesenchyme can self renew and generate new dental tissues (including dentin and cementum), alveolar bone and periodontal ligament, and thus they have great potential in periodontal regeneration. This chapter presents an insight into mesenchymal stem cells and their potential use in periodontal regeneration. In this chapter the cellular and molecular biology in periodontal regeneration will be introduced, followed by a range of conventional surgical procedures for periodontal regeneration will be discussed. Mesenchymal stem cells applied in regenerated periodontal tissue and their biological characterizations in vitro will be also introduced. Lastly, the use of mesenchymal stem cell to repair periodontal tissues in large animal models will be also reviewed.

Changes in resting and walking energy expenditure and walking speed during pregnancy in obese women

Background Energy conserving processes reported in undernourished women during pregnancy are a recognised strategy to provide energy required to support fetal development. Women who are obese before conceiving arguably have sufficient fat stores to support the energy demands of pregnancy without the need to provoke energy conserving mechanisms. Objective We tested the hypothesis that obese women would demonstrate behavioural adaptation (i.e. decrease in self-selected walking (SSW) speed) but not metabolic compensation (i.e. decrease in resting metabolic rate (RMR) or metabolic cost of walking) during gestation. Design RMR, SSW speed, metabolic cost of walking, and anthropometry were measured in 23 women (BMI: 33.6 ± 2.5 kg/m2; 31 ± 4 years) at approximately weeks 15 (wk 15) and 30 (wk 30) of gestation. RMR was also measured in two cohorts of non-pregnant controls matched for age, weight and height of the pregnant cohort at wk 15 (N=23) and wk 30 (N=23). Results GWG varied widely (11.3 ± 5.4 kg) and 52% of women gained more weight than is recommended. RMR increased significantly by an average 177 ± 176 kcal/d (11±12%; P<0.0001); however the within-group variability was large. Both the metabolic cost of walking and SSW speed decreased significantly (P<0.01). While RMR increased in >80% of the cohort, the net oxygen cost of walking decreased in the same proportion of women. Conclusions While the increase in RMR was greater than was explained by weight gain, there was evidence of both behavioural and biological compensation in the metabolic cost of walking in obese women during gestation.

Determinants and consequences of information sharing with key suppliers

The economic environment of today can be characterized as highly dynamic and competitive if not being in a constant flux. Globalization and the Information Technology (IT) revolution are perhaps the main contributing factors to this observation. While companies have to some extent adapted to the current business environment, new pressures such as the recent increase in environmental awareness and its likely effects on regulations are underway. Hence, in the light of market and competitive pressures, companies must constantly evaluate and if necessary update their strategies to sustain and increase the value they create for shareholders (Hunt and Morgan, 1995; Christopher and Towill, 2002). One way to create greater value is to become more efficient in producing and delivering goods and services to customers, which can lead to a strategy known as cost leadership (Porter, 1980). Even though Porter (1996) notes that in the long run cost leadership may not be a sufficient strategy for competitive advantage, operational efficiency is certainly necessary and should therefore be on the agenda of every company. ----- ----- ----- Better workflow management, technology, and resource utilization can lead to greater internal operational efficiency, which explains why, for example, many companies have recently adopted Enterprise Resource Planning (ERP) Systems: integrated softwares that streamline business processes. However, as today more and more companies are approaching internal operational excellence, the focus for finding inefficiencies and cost saving opportunities is moving beyond the boundaries of the firm. Today many firms in the supply chain are engaging in collaborative relationships with customers, suppliers, and third parties (services) in an attempt to cut down on costs related to for example, inventory, production, as well as to facilitate synergies. Thus, recent years have witnessed fluidity and blurring regarding organizational boundaries (Coad and Cullen, 2006). ----- ----- ----- The Information Technology (IT) revolution of the late 1990’s has played an important role in bringing organizations closer together. In their efforts to become more efficient, companies first integrated their information systems to speed up transactions such as ordering and billing. Later collaboration on a multidimensional scale including logistics, production, and Research & Development became evident as companies expected substantial benefits from collaboration. However, one could also argue that the recent popularity of the concepts falling under Supply Chain Management (SCM) such as Vendor Managed Inventory, Collaborative Planning, Replenishment, and Forecasting owe to the marketing efforts of software vendors and consultants who provide these solutions. Nevertheless, reports from professional organizations as well as academia indicate that the trend towards interorganizational collaboration is gaining wider ground. For example, the ARC Advisory Group, a research organization on supply chain solutions, estimated that the market for SCM, which includes various kinds of collaboration tools and related services, is going to grow at an annual rate of 7.4% during the years 2004-2008, reaching to $7.4 billion in 2008 (Engineeringtalk 2004).

Time course of temperature effects on cardiovascular mortality in Brisbane, Australia

Objective To quantify the lagged effects of mean temperature on deaths from cardiovascular diseases in Brisbane, Australia. Design Polynomial distributed lag models were used to assess the percentage increase in mortality up to 30 days associated with an increase (or decrease) of 1°C above (or below) the threshold temperature. Setting Brisbane, Australia. Patients 22 805 cardiovascular deaths registered between 1996 and 2004. Main outcome measures Deaths from cardiovascular diseases. Results The results show a longer lagged effect in cold days and a shorter lagged effect in hot days. For the hot effect, a statistically significant association was observed only for lag 0–1 days. The percentage increase in mortality was found to be 3.7% (95% CI 0.4% to 7.1%) for people aged ≥65 years and 3.5% (95% CI 0.4% to 6.7%) for all ages associated with an increase of 1°C above the threshold temperature of 24°C. For the cold effect, a significant effect of temperature was found for 10–15 lag days. The percentage estimates for older people and all ages were 3.1% (95% CI 0.7% to 5.7%) and 2.8% (95% CI 0.5% to 5.1%), respectively, with a decrease of 1°C below the threshold temperature of 24°C. Conclusions The lagged effects lasted longer for cold temperatures but were apparently shorter for hot temperatures. There was no substantial difference in the lag effect of temperature on mortality between all ages and those aged ≥65 years in Brisbane, Australia.

Researching the 'reception' of indigenous affairs in Australia

The Reporting and Reception of Indigenous Issues in the Australian Media was a three year project financed by the Australian government through its Australian Research Council Large Grants Scheme and run by Professor John Hartley (of Murdoch and then Edith Cowan University, Western Australia). The purpose of the research was to map the ways in which indigeneity was constructed and circulated in Australia's mediasphere. The analysis of the 'reporting' element of the project was almost straightforward: a mixture of content analysis of a large number of items in the media, and detailed textual analysis of a smaller number of key texts. The discoveries were interesting - that when analysis approaches the media as a whole, rather than focussing exclusively on news or serious drama genres, then representation of indigeneity is not nearly as homogenous as has previously been assumed. And if researchers do not explicitly set out to uncover racism in every text, it is by no means guaranteed they will find it1. The question of how to approach the 'reception' of these issues - and particularly reception by indigenous Australians - proved to be a far more challenging one. In attempting to research this area, Hartley and I (working as a research assistant on the project) often found ourselves hampered by the axioms that underlie much media research. Traditionally, the 'reception' of media by indigenous people in Australia has been researched in ethnographic ways. This research repeatedly discovers that indigenous people in Australia are powerless in the face of new forms of media. Indigenous populations are represented as victims of aggressive and powerful intrusions: ‘What happens when a remote community is suddenly inundated by broadcast TV?’; ‘Overnight they will go from having no radio and television to being bombarded by three TV channels’; ‘The influence of film in an isolated, traditionally oriented Aboriginal community’2. This language of ‘influence’, ‘bombarded’, and ‘inundated’, presents metaphors not just of war but of a war being lost. It tells of an unequal struggle, of a more powerful force impinging upon a weaker one. What else could be the relationship of an Aboriginal audience to something which is ‘bombarding’ them? Or by which they are ‘inundated’? This attitude might best be summed up by the title of an article by Elihu Katz: ‘Can authentic cultures survive new media?’3. In such writing, there is little sense that what is being addressed might be seen as a series of discursive encounters, negotiations and acts of meaning-making in which indigenous people — communities and audiences —might be productive. Certainly, the points of concern in this type of writing are important. The question of what happens when a new communication medium is summarily introduced to a culture is certainly an important one. But the language used to describe this interaction is a misleading one. And it is noticeable that such writing is fascinated with the relationship of only traditionally-oriented Aboriginal communities to the media of mass communication.

Maternal exposure to ambient temperature and the risk of preterm birth and stillbirth in Brisbane, Australia

Almost 10% of all births are preterm and 2.2% are stillbirths globally. Recent research has suggested that environmental factors may be a contributory cause to these adverse birth outcomes. The authors examined the relationship between ambient temperature and preterm birth and stillbirth in Brisbane, Australia between 2005 and 2009 (n = 101,870). They used a Cox proportional hazard model with live birth and stillbirth as competing risks. They also examined if there were periods of the pregnancy where exposure to high temperatures had a greater effect. Exposure to higher ambient temperatures during pregnancy increased the risk of stillbirth. The hazard ratio for stillbirth was 0.3 at 12 °C relative to the reference temperature at 21 °C. The temperature effect was greatest for fetuses of less than 36 weeks of gestation. There was an association between higher temperature and shorter gestation, as the hazard ratio for live birth was 0.96 at 15 °C and 1.02 at 25 °C. This effect was greatest at later gestational ages. The results provide strong evidence of an association between increased temperature and increased risk of stillbirth and shorter gestations.

Bringing protection home : healing the schism between international obligations and national safeguards created by extraterritorial processing

Extraterritorial processing schemes are designed to prevent and deter access to statutory and judicial safeguards in the country responsible for the interception and transfer of asylum seekers to a third country. In line with this objective, they incorporate interdiction, transfer and processing practices and standards that are deliberately isolated from the national legal and institutional protections within either the intercepting state or the third country where processing occurs. Australia's recent disbandment of its extraterritorial processing centres in third countries highlights the fact that extraterritorial processing schemes have proven unworkable as a matter of international law, as they negate the national safeguards fundamental to the satisfaction of a state's protection obligations.

Multiple evolutionary rate classes in animal genome evolution

The proportion of functional sequence in the human genome is currently a subject of debate. The most widely accepted figure is that approximately 5% is under purifying selection. In Drosophila, estimates are an order of magnitude higher, though this corresponds to a similar quantity of sequence. These estimates depend on the difference between the distribution of genomewide evolutionary rates and that observed in a subset of sequences presumed to be neutrally evolving. Motivated by the widening gap between these estimates and experimental evidence of genome function, especially in mammals, we developed a sensitive technique for evaluating such distributions and found that they are much more complex than previously apparent. We found strong evidence for at least nine well-resolved evolutionary rate classes in an alignment of four Drosophila species and at least seven classes in an alignment of four mammals, including human. We also identified at least three rate classes in human ancestral repeats. By positing that the largest of these ancestral repeat classes is neutrally evolving, we estimate that the proportion of nonneutrally evolving sequence is 30% of human ancestral repeats and 45% of the aligned portion of the genome. However, we also question whether any of the classes represent neutrally evolving sequences and argue that a plausible alternative is that they reflect variable structure-function constraints operating throughout the genomes of complex organisms.