Role of Human Topoisomerase I in DNA Repair and Apoptosis

Human topoisomerase I (htopoI) is an enzyme that up to now was believed to function mainly in the removal of torsional stress generated during transcription and replication. In 1998, it was found that htopoI might play another important role in the cellular response to DNA damage -- the so-called htopoI damage response. Since this initial discovery, many studies have suggested that the htopoI damage response is involved in DNA repair as well as in apoptosis. Here we discuss the earliest as well as the latest results in this field. Combining all of the published and as yet unpublished results, we suggest and discuss a model of how htopoI may function during DNA repair and apoptosis. Furthermore, numerous results show that the htopoI damage response is not a spontaneous event, but is strictly regulated by cellular signalling pathways. We discuss which pathways may be involved and how the htopoI damage response is activated. Although the htopoI damage response was discovered several years ago, research in this area is just beginning. The future will surely bring more clarity regarding the precise mechanism behind the involvement of htopoI in DNA repair and apoptosis, as well as its implications for a broader understanding of how the human organism ensures genomic stability.

Improving short utterance i-vector speaker verification using utterance variance modelling and compensation techniques

This paper proposes techniques to improve the performance of i-vector based speaker verification systems when only short utterances are available. Short-length utterance i-vectors vary with speaker, session variations, and the phonetic content of the utterance. Well established methods such as linear discriminant analysis (LDA), source-normalized LDA (SN-LDA) and within-class covariance normalisation (WCCN) exist for compensating the session variation but we have identified the variability introduced by phonetic content due to utterance variation as an additional source of degradation when short-duration utterances are used. To compensate for utterance variations in short i-vector speaker verification systems using cosine similarity scoring (CSS), we have introduced a short utterance variance normalization (SUVN) technique and a short utterance variance (SUV) modelling approach at the i-vector feature level. A combination of SUVN with LDA and SN-LDA is proposed to compensate the session and utterance variations and is shown to provide improvement in performance over the traditional approach of using LDA and/or SN-LDA followed by WCCN. An alternative approach is also introduced using probabilistic linear discriminant analysis (PLDA) approach to directly model the SUV. The combination of SUVN, LDA and SN-LDA followed by SUV PLDA modelling provides an improvement over the baseline PLDA approach. We also show that for this combination of techniques, the utterance variation information needs to be artificially added to full-length i-vectors for PLDA modelling.

Cellular stress triggers the human topoisomerase I damage response independently of DNA damage in a p53 controlled manner

The 'human topoisomerase I (htopoI) damage response' was reported to be triggered by various kinds of DNA lesions. Also, a high and persistent level of htopoI cleavage complexes correlated with apoptosis. In the present study, we demonstrate that DNA damage-independent induction of cell death using colcemid and tumor necrosis factor is also accompanied by a strong htopoI response that correlates with the onset of apoptotic hallmarks. Consequently, these results suggest that htopoI cleavage complex formation may be caused by signaling pathways independent of the kind of cellular stress. Thus, protein interactions or signaling cascades induced by DNA damage or cellular stress might lead to the formation of stabilized cleavage complexes rather than the DNA lesion itself. Finally, we show that p53 not only plays a key role in the regulation of the htopoI response to UV-C irradiation but also to treatment with colcemid.

Higher-order non-linear analysis of steel structures. Part I : elastic second-order formulation

This paper presents a higher-order beam-column formulation that can capture the geometrically non-linear behaviour of steel framed structures which contain a multiplicity of slender members. Despite advances in computational frame software, analyses of large frames can still be problematic from a numerical standpoint and so the intent of the paper is to fulfil a need for versatile, reliable and efficient non-linear analysis of general steel framed structures with very many members. Following a comprehensive review of numerical frame analysis techniques, a fourth-order element is derived and implemented in an updated Lagrangian formulation, and it is able to predict flexural buckling, snap-through buckling and large displacement post-buckling behaviour of typical structures whose responses have been reported by independent researchers. The solutions are shown to be efficacious in terms of a balance of accuracy and computational expediency. The higher-order element forms a basis for augmenting the geometrically non-linear approach with material non-linearity through the refined plastic hinge methodology described in the companion paper.

The human topoisomerase I damage response plays a role in apoptosis

Previous studies have shown that human topoisomerase I cleavage complexes form as a response to various DNA damages in vivo, the so called human topoisomerase I “damage response”. It was suggested that this damage response may play a role in DNA repair as well as in apoptosis, but only very few investigations have been done and the significance of the damage response still remains unclear. Here we demonstrate that human topoisomerase I cleavage complexes induced by high doses of UV irradiation are highly stable for up to 48 h. Furthermore, we show that human topoisomerase I cleavage complexes correlate with apoptosis. However, at low UV doses the cleavage complex level was very low and the complexes were repaired. Surprisingly, we found that high levels of stable cleavage complexes were not only found in UV-irradiated cells but also in untreated cells that underwent apoptosis. A possible role of human topoisomerase I in apoptosis is discussed.

People living in hilly residential areas in metropolitan Perth have less diabetes : spurious association or important environmental determinant?

BACKGROUND: Variations in 'slope' (how steep or flat the ground is) may be good for health. As walking up hills is a physiologically vigorous physical activity and can contribute to weight control, greater neighbourhood slopes may provide a protective barrier to weight gain, and help prevent Type 2 diabetes onset. We explored whether living in 'hilly' neighbourhoods was associated with diabetes prevalence among the Australian adult population. METHODS: Participants ([greater than or equal to]25years; n=11,406) who completed the Western Australian Health and Wellbeing Surveillance System Survey (2003-2009) were asked whether or not they had medically-diagnosed diabetes. Geographic Information Systems (GIS) software was used to calculate a neighbourhood mean slope score, and other built environment measures at 1600m around each participant's home. Logistic regression models were used to predict the odds of self-reported diabetes after progressive adjustment for individual measures (i.e., age, sex), socioeconomic status (i.e., education, income), built environment, destinations, nutrition, and amount of walking. RESULTS: After full adjustment, the odds of self-reported diabetes was 0.72 (95% CI 0.55-0.95) and 0.52 (95% CI 0.39-0.69) for adults living in neighbourhoods with moderate and higher levels of slope, respectively, compared with adults living in neighbourhoods with the lowest levels of slope. The odds of having diabetes was 13% lower (odds ratio 0.87; 95% CI 0.80-0.94) for each increase of one percent in mean slope. CONCLUSIONS: Living in a hilly neighbourhood may be protective of diabetes onset or this finding is spurious. Nevertheless, the results are promising and have implications for future research and the practice of flattening land in new housing developments.

Fasting increases serum bilirubin levels in clinically normal, healthy males but not females : a retrospective study from phase I clinical trial participants

Aim: To examine if fasting affects serum bilirubin levels in clinical healthy males and females. Methods: We utilised retrospective data from phase 1 clinical trials where blood was collected in either a fed or fasting state at screening and pre-dosing time points and analysed for total bilirubin levels as per standard clinical procedures. Participants were clinically healthy males (n = 105) or females (n = 30) aged 18 to 48 inclusive who participated in a phase 1 clinical trial in 2012 or 2013. Results: We found a statistically significant increase in total serum bilirubin levels in fasting males as compared to non-fasting males. The fasting time correlated positively with increased bilirubin levels. The age of the healthy males did not correlate with their fasting bilirubin level. We found no correlation between fasting and bilirubin levels in clinically normal females. Conclusions: The recruitment and screening of volunteers for a clinical trial is a time-consuming and expensive process. This study clearly demonstrates that testing for serum bilirubin should be conducted on non-fasting male subjects. If fasting is required, then participants should not be excluded from a trial based on an elevated serum bilirubin that is deemed non-clinically significant.

The effect of varying diagnostic terminology within patient discharge information on expected mild traumatic brain injury outcome

This study aimed to determine if systematic variation of the diagnostic terminology embedded within written discharge information (i.e., concussion or mild traumatic brain injury, mTBI) would produce different expected symptoms and illness perceptions. We hypothesized that compared to concussion advice, mTBI advice would be associated with worse outcomes. Sixty-two volunteers with no history of brain injury or neurological disease were randomly allocated to one of two conditions in which they read a mTBI vignette followed by information that varied only by use of the embedded terms concussion (n = 28) or mTBI (n = 34). Both groups reported illness perceptions (timeline and consequences subscale of the Illness Perception Questionnaire-Revised) and expected Postconcussion Syndrome (PCS) symptoms 6 months post injury (Neurobehavioral Symptom Inventory, NSI). Statistically significant group differences due to terminology were found on selected NSI scores (i.e., total, cognitive and sensory symptom cluster scores (concussion > mTBI)), but there was no effect of terminology on illness perception. When embedded in discharge advice, diagnostic terminology affects some but not all expected outcomes. Given that such expectations are a known contributor to poor mTBI outcome, clinicians should consider the potential impact of varied terminology on their patients.

Boken, berättelsen, pengarna I den digitala tidsåldern [The book, the story and the money in the digital age]

År 2012 är distribution av litteratur via internet inte längre en framtidsvision, utan ett etablerat format vid sidan av traditionella format som exempelvis pocketboken, den inbundna boken och ljudboken (AAP 2011; Amazon 2011; PaidContent 2011). Men den digitala tekniken etablerar inte enbart ett nytt format, utan förändrar också grundförutsättningarna för litterära konstformer och marknader. Detta kapitel behandlar en betydelsefull aspekt av denna förändring, nämligen hur den digitala tekniken påverkar relationen mellan läsare och författare och ökar läsarens inflytande över den kreativa processen. I den digitala tidsåldern är det möjligt att skapa berättelser online i en interaktiv process som involverar både läsare och författare. Kapitlet presenterar modeller för hur sådan “samproducerad e-litteratur” förändrar marknaden för litteratur och hur den påverkar den traditionella litteraturen.

Mobility and out-of-home activities of older people living in suburban environments : ‘Because I'm a driver, I don't have a problem'

Governments are challenged by the need to ensure that ageing populations stay active and engaged as they age. Therefore, it is critical to investigate the role of mobility in older people's engagement in out-of-home activities, and to identify the experiences they have within their communities. This research investigates the use of transportation by older people and its implications for their out-of-home activities within suburban environments. The qualitative, mixed-method approach employs data collection methods which include a daily travel diary (including a questionnaire), Global Positioning System (GPS) tracking and semi-structured interviews with older people living in suburban environments in Brisbane, Australia. Results show that older people are mobile throughout the city, and their car provides them with that opportunity to access desired destinations. This ability to drive allows older people to live independently and to assist others who do not drive, particularly where transport alternatives are not as accessible. The ability to transport goods and other people is a significant advantage of the private car over other transport options. People with no access to private transportation who live in low-density environments are disadvantaged when it comes to participation within the community. Further research is needed to better understand the relationship between transportation and participation within the community environment, to assist policy makers and city and transportation planners to develop strategies for age-friendly environments within the community.

‘I came to this country for a better life��� : factors mediating employment trajectories among young people who migrated to Australia as refugees during adolescence

Located at the intersection of two vulnerable groups in the contemporary labour market, young people who migrate as refugees during adolescence face a unique constellation of opportunities and challenges that shape their employment trajectories. Yet the tendency for research to focus on the early years of refugee settlement means that we have an inadequate understanding the factors that mediate their employment decisions, experiences and outcomes. Based on interviews with 51 young people, this article explores how aspirations, responsibilities, family, education and networks are understood to influence the employment trajectories of adolescent refugee migrants. While this article draws attention to the complex and dynamic range of challenges and constraints that these young people negotiate in the pursuit of satisfying and sustainable employment, what also emerges is an optimistic and determined cohort who, even as they at times unsuccessfully prepare for and navigate the labour market, maintain high hopes for a better life.

Older driver safety and mobility : where to from here?

The older adult population (65 years and over) represents a rapid growing segment of the population in many developed countries. Unlike earlier cohorts of older drivers that included many who were familiar with public transportation, the present cohort of older drivers historically has a greater reliance on the private automobile as their main form of transportation. Recent studies of older adults’ travel patterns reported automobile to be responsible for over 80% of the total number of hours spent on all trips. While older drivers, as a group, does not demonstrate a particular road risk, the evident demographic change and the increased physical fragility and severity of crash-related injuries makes older driver safety a prevalent public health issue. This study systematically reviewed the safety and mobility outcomes of existing strategies used internationally to manage older driver safety, with a specific focus on age-based testing (ABT), license restriction and self-regulation (i.e. voluntary limiting driving in potentially hazardous situations). ABT remains the most commonly adopted strategy by licensing authorities both within Australia and internationally. Heterogeneity in the development of functional declines, and in driving behaviours within the older driver population, makes age an unreliable index of driving capacity. Given the counter-productive safety and mobility outcomes of ABT strategies, their continued popularity within both the legislative and public domains remains problematic. Self-regulation may provide greater potential for reducing older drivers’ crash risk while maintaining their mobility and independence. The current body of literature on older drivers’ self-regulation is systematically reviewed. Despite being promoted by researchers and licensing authorities as a strategy to maintain older driver safety and mobility, the proportion of older drivers who self-regulate, and exactly how they do so, remains unclear. Future research on older drivers’ adoption of self-regulation, particularly the underlying psychological factors that underlies this process, is needed in order to promote its use within the older driver community.

Global story-telling in a socially-networked world

Journalists work in an intensively time-pressured environment, researching and writing to daily, often 24 hour, deadlines and always aware of the competition with other news outlets to be first with the news. This results, as Karen Sanders has observed, in journalists having very little time for reflection. “If they do reflect, it’s usually after a decision has been made” (Sanders 2003, 168). Yet time for reflection upon professional practice is important, especially in an era of extremely rapid and seismic technological change in the global media. This paper will reflect upon how freelance journalists can use advances in social media and web-based connectedness to tell global stories via mainstream media outlets. In exploring this question, I will examine the techniques and communications technologies used by three reporters working in the UK and Australia to find, investigate and break a series of articles, published simultaneously on the front pages of The Australian and The Times (London) newspapers, was a result of a six month investigation. The series exposed a 50-year cover-up of the serial abuse of children by one of the Church of England's most senior clergy, Robert Waddington, in Australia and the UK. It unearthed the existence of a culture of physical and sexual abuse at St Barnabas boarding school in Queensland, the sudden closure of the school and disappearance of student files - as well as Waddington's subsequent offences against children while Dean of Manchester Cathedral. We produced more than 20 articles. The coverage sparked church-ordered investigations in both countries, and also prompted the Archbishop of Canterbury to order a commission of inquiry – headed by a sitting UK judge - as well as a nationwide child safety audit of dioceses in Britain. In Australia, the church referred the case and handed its files to the Royal Commission into Child Sexual Abuse. The coverage marked the first publishing collaboration between The Australian and The Times to break an exclusive story in Australia and Britain simultaneously, on May 10, 2013.

Should I stay or should I go? The challenges and opportunities of moving between university systems

The scientific job market has evolved to a truly globalized market. This is epitomized not only by the English language being the de facto scientific language but also by the increasing share of native language journals that are being offered in multiple languages or have or will fully converted to English (such as, for example, the BISE journal in 2015). Similarly, a plethora of exchange programs exists that allow students and academic staff to visit other institutions and exchange knowledge, ideas, and learning opportunities. While student migration across scientific institutions is an established phenomenon (Gribble, 2008) with ample structures, policies, and schemes such as ERASMUS1 in place, academic staff migration between countries is still a challenge, even if exchange programs exist (Enders, 1998). One reason may be that different career paths, varying teaching loads and different evaluation schemes for what constitutes scientific excellence are notable. This also influences the decision of where to start and continue an academic career. While the university systems themselves have been examined previously (Galliers and Whitley, 2007; Lyytinen et al., 2007) and while there is knowledge about career requirements in different university systems (Dennis et al., 2006; Dean et al., 2011; Loos et al., 2013; Recker, 2013), we still do not know much about individual and contextual decisions of academics that either consider or execute a migration between university systems.