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 Combining all of the published and as yet unpublished results, we suggest and discuss a model of how htopoI may function during DNA repair and apoptosis.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.

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.

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.

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.

Crypto Topics and Applications I

In this chapter, we discuss four related areas of cryptology, namely, authentication, hashing, message authentication codes (MACs), and digital signatures. These topics represent active and growing research topics in cryptology. Space limitations allow us to concentrate only on the essential aspects of each topic. The bibliography is intended to supplement our survey. We have selected those items which providean overview of the current state of knowledge in the above areas. Authentication deals with the problem of providing assurance to a receiver that a communicated message originates from a particular transmitter, and that the received message has the same content as the transmitted message. A typical authentication scenario occurs in computer networks, where the identity of two communicating entities is established by means of authentication. Hashing is concerned with the problem of providing a relatively short digest–fingerprint of a much longer message or electronic document. A hashing function must satisfy (at least) the critical requirement that the fingerprints of two distinct messages are distinct. Hashing functions have numerous applications in cryptology. They are often used as primitives to construct other cryptographic functions. MACs are symmetric key primitives that provide message integrity against active spoofing by appending a cryptographic checksum to a message that is verifiable only by the intended recipient of the message. Message authentication is one of the most important ways of ensuring the integrity of information that is transferred by electronic means. Digital signatures provide electronic equivalents of handwritten signatures. They preserve the essential features of handwritten signatures and can be used to sign electronic documents. Digital signatures can potentially be used in legal contexts.

“I drove after drinking alcohol” and other risky driving behaviours reported by young novice drivers in Queensland, Australia

Background. Volitional risky driving behaviours such as drink- and drug-driving (i.e. substance-impaired driving) and speeding contribute to the overrepresentation of young novice drivers in road crash fatalities, and crash risk is greatest during the first year of independent driving in particular. Aims. To explore the: 1) self-reported compliance of drivers with road rules regarding substance-impaired driving and other risky driving behaviours (e.g., speeding, driving while tired), one year after progression from a Learner to a Provisional (intermediate) licence; and 2) interrelationships between substance-impaired driving and other risky driving behaviours (e.g., crashes, offences, and Police avoidance). Methods. Drivers (n = 1,076; 319 males) aged 18-20 years were surveyed regarding their sociodemographics (age, gender) and self-reported driving behaviours including crashes, offences, Police avoidance, and driving intentions. Results. A relatively small proportion of participants reported driving after taking drugs (6.3% of males, 1.3% of females) and drinking alcohol (18.5% of males, 11.8% of females). In comparison, a considerable proportion of participants reported at least occasionally exceeding speed limits (86.7% of novices), and risky behaviours like driving when tired (83.6% of novices). Substance-impaired driving was associated with avoiding Police, speeding, risky driving intentions, and self-reported crashes and offences. Forty-three percent of respondents who drove after taking drugs also reported alcohol-impaired driving. Discussion and Conclusions. Behaviours of concern include drink driving, speeding, novice driving errors such as misjudging the speed of oncoming vehicles, violations of graduated driver licensing passenger restrictions, driving tired, driving faster if in a bad mood, and active punishment avoidance. Given the interrelationships between the risky driving behaviours, a deeper understanding of influential factors is required to inform targeted and general countermeasure implementation and evaluation during this critical driving period. Notwithstanding this, a combination of enforcement, education, and engineering efforts appear necessary to improve the road safety of the young novice driver, and for the drink-driving young novice driver in particular.

The SCRAMSPACE I scramjet flight design and construction

The design activities of the development of the SCRAMSPACE I scramjet-powered free-flight experiment are described in this paper. The objectives of this flight are first described together with the definition of the primary, secondary and tertiary experiments. The Scramjet configuration studied is first discussed together with the rocket motor system selected for this flight. The different flight sequences are then explained, highlighting the SCRAMSPACE I free-flyer separation and re-orientation procedures. A design trade-off study is then described considering vehicle stability, packaging, thermo-structural analysis and trajectory, discussing the alignment of the predicted performance with the mission scientific requirements. The global system architecture and instrumentation of the vehicle are then explained. The conclusions of this design phase are that a vehicle design has been produced which is able to meet the mission scientific goals and the procurement & construction of the vehicle are ongoing.