Cyclin A/CDK2 regulates multiple G2 phase pathways

The cell cycle is a carefully choreographed series of phases that when executed successfully will allow the complete replication of the genome and the equal division of the genome and other cellular content into two independent daughter cells. The inability of the cell to execute cell division successfully can result in either checkpoint activation to allow repair and/or apoptosis and/or mutations/errors that may or may not lead to tumourgenesis. Cyclin A/CDK2 is the primary cyclin/CDK regulating G2 phase progression of the cell cycle. Cyclin A/CDK2 activity peaks in G2 phase and its inhibition causes a G2 phase delay that we have termed 'the cyclin A/CDK2 dependent G2 delay'. Understanding the key pathways that are involved in the cyclin A/CDK2 dependent G2 delay has been the primary focus of this study. Characterising the cyclin A/CDK2 dependent G2 delay revealed accumulated levels of the inactive form of the mitotic regulator, cyclin B/CDK1. Surprisingly, there was also increased microtubule nucleation at the centrosomes, and the centrosomes stained for markers of cyclin B/CDK1 activity. Both microtubule nucleation at the centrosomes and phosphoprotein markers were lost with short-term treatment of CDK1/2 inhibition. Cyclin A/CDK2 localised at the centrosomes in late G2 phase after separation of the centrosomes but before the start of prophase. Thus G2 phase cyclin A/CDK2 controls the timing of entry into mitosis by controlling the subsequent activation of cyclin B/CDK1, but also has an unexpected role in coordinating the activation of cyclin B/CDK1 at the centrosome and in the nucleus. In addition to regulating the timing of cyclin B/CDK1 activation and entry into mitosis in the unperturbed cell cycle, cyclin A/CDK2 also was shown to have a role in G2 phase checkpoint recovery. Known G2 phase regulators were investigated to determine whether they had a role in imposing the cyclin A/ CDK2 dependent G2 delay. Examination of the critical G2 checkpoint arrest protein, Chk1, which also has a role during unperturbed G2/M phases revealed the presence of activated Chk1 in G2 phase, in a range of cell lines. Activated Chk1 levels were shown to accumulate in cyclin A/CDK2 depleted/inhibited cells. Further investigations revealed that Chk1, but not Chk2, depletion could reverse the cyclin A/CDK2 dependent G2 delay. It was confirmed that the accumulative activation of Chk1 was not a consequence of DNA damage induced by cyclin A depletion. The potential of cyclin A/CDK2 to regulate Chk1 revealed that the inhibitory phosphorylations, Ser286 and Ser301, were not directly catalysed by cyclin A/CDK2 in G2 phase to regulate mitotic entry. It appeared that the ability of cyclin A/CDK2 to regulate cyclin B/CDK1 activation impacted cyclin B/CDK1s phosphorylation of Chk1 on Ser286 and Ser301, thereby contributing to the delay in G2/M phase progression. Chk1 inhibition/depletion partially abrogated the cyclin A/CDK2 dependent G2 delay, and was less effective in abrogating G2 phase checkpoint suggesting that other cyclin A/CDK2 dependent mechanisms contributed to these roles of cyclin A/CDK2. In an attempt to identify these other contributing factors another G2/M phase regulator known to be regulated by cyclin A/CDK2, Cdh1 and its substrates Plk1 and Claspin were examined. Cdh1 levels were reduced in cyclin A/CDK2 depleted/inhibited cells although this had little effect on Plk1, a known Cdh1 substrate. However, the level of another substrate, Claspin, was increased. Cdh1 depletion mimicked the effect of cyclin A depletion but to a weaker extent and was sufficient at increasing Claspin levels similar to the increase caused by cyclin A depletion. Co-depletion of cyclin A and Claspin blocked the accumulation of activated Chk1 normally seen with cyclin A depletion alone. However Claspin depletion alone did not reduce the cyclin A/CDK2 dependent G2 delay but this is likely to be a result of inhibition of S phase roles of Claspin. Together, these data suggest that cyclin A/CDK2 regulates a number of different mechanisms that contribute to G2/M phase progression. Here it has been demonstrated that in normal G2/M progression and possibly to a lesser extent in G2 phase checkpoint recovery, cyclin A/CDK2 regulates the level of Cdh1 which in turn affects at least one of its substrates, Claspin, and consequently results in the increased level of activated Chk1 observed. However, the involvement of Cdh1 and Claspin alone does not explain the G2 phase delay observed with cyclin A/CDK2 depletion/inhibition. It is likely that other mechanisms, possibly including cyclin A/CDK2 regulation of Wee1 and FoxM1, as reported by others, combine with the mechanism described here to regulate normal G2/M phase progression and G2 phase checkpoint recovery. These findings support the critical role for cyclin A/CDK2 in regulating progression into mitosis and suggest that upstream regulators of cyclin A/CDK2 activation will also be critical controllers of this cell cycle transition. The pathways that work to co-ordinate cell cycle progression are very intricate and deciphering these pathways, required for normal cell cycle progression, is key to understanding tumour development. By understanding cell cycle regulatory pathways it will allow the identification of the pathway/s and their mechanism/s that become affected in tumourgenesis. This will lead to the development of better targeted therapies, inferring better efficacy with fewer side effects than commonly seen with the use of traditional therapies, such as chemotherapy. Furthermore, this has the potential to positively impact the development of personalised medicines and the customisation of healthcare.

An isolated MOSFET gate driver

Traditional methods of isolated MOSFET/IGBT gate drive are presented, and their pros and cons assessed. The best options are chosen to meet our objective— a small, high speed, low cost, low power isolated gate drive module. Two small ferrite bead transformers are used for isolation, one transmits power at 2.5MHz, the other sends narrow set reset pulses. On the secondary these pulses drive a transistor totem pole to ensure high current drive, and the value is held by CMOS buffers with positive feedback. An alternative design for driving logic level devices uses only an HC buffer on the secondary. Double sided SMDconstruction (primary one side, secondary on the other) yields an upright module 40x18x5mm. Propagation delaywas 20ns, and rise/fall time 15ns with a 1nF load. The design places no limits on frequency of operation or duty cycle. Power supply requirementswere 5V@20mA for operation below 100kHz, dominated by magnetising current.

The effects of standardised assessment (NAPLAN) on teacher pedagogy at two Queensland schools

The purpose of this qualitative interpretative case study was to explore how the National Assessment Program – Literacy and Numeracy (NAPLAN) requirements may be affecting pedagogies of two Year 3, Year 5 and Year 7 teachers at two Queensland schools. The perceived problem was that standardised assessment NAPLAN practices and its growing status as a key measure of education quality throughout Australia has the potential to limit the everyday literacy and numeracy practices of teachers to instructional methods primarily focused on teaching to the test. The findings demonstrate how increased explicit teaching of NAPLAN content and procedural knowledge prior to testing has the potential to negatively impact on the teaching of everyday literacy and numeracy skills and knowledge that extend beyond those concerned with NAPLAN. Such teaching limited opportunity for what teachers reported as valued collaborative learning contexts aiming for long-term literacy and numeracy results.

The effects of hot and cold temperatures on emergency hospital admissions in Brisbane, Australia

As Earth's climate is rapidly changing, the impact of ambient temperature on health outcomes has attracted increasing attention in the recent time. Considerable number of excess deaths has been reported because of exposure to ambient hot and cold temperatures. However, relatively little research has been conducted on the relation between temperature and morbidity. The aim of this study was to characterize the relationship between both hot and cold temperatures and emergency hospital admissions in Brisbane, Australia, and to examine whether the relation varied by age and socioeconomic factors. It aimed to explore lag structures of temperature–morbidity association for respiratory causes, and to estimate the magnitude of emergency hospital admissions for cardiovascular diseases attributable to hot and cold temperatures for the large contribution of both diseases to the total emergency hospital admissions. A time series study design was applied using routinely collected data of daily emergency hospital admissions, weather and air pollution variables in Brisbane during 1996–2005. Poisson regression model with a distributed lag non-linear structure was adopted to assess the impact of temperature on emergency hospital admissions after adjustment for confounding factors. Both hot and cold effects were found, with higher risk of hot temperatures than that of cold temperatures. Increases in mean temperature above 24.2oC were associated with increased morbidity, especially for the elderly ≥ 75 years old with the largest effect. The magnitude of the risk estimates of hot temperature varied by age and socioeconomic factors. High population density, low household income, and unemployment appeared to modify the temperature–morbidity relation. There were different lag structures for hot and cold temperatures, with the acute hot effect within 3 days after hot exposure and about 2-week lagged cold effect on respiratory diseases. A strong harvesting effect after 3 days was evident for respiratory diseases. People suffering from cardiovascular diseases were found to be more vulnerable to hot temperatures than cold temperatures. However, more patients admitted for cardiovascular diseases were attributable to cold temperatures in Brisbane compared with hot temperatures. This study contributes to the knowledge base about the association between temperature and morbidity. It is vitally important in the context of ongoing climate change. The findings of this study may provide useful information for the development and implementation of public health policy and strategic initiatives designed to reduce and prevent the burden of disease due to the impact of climate change.

Sleepiness : how a biological drive can influence other risky road user behaviours

The Safe System approach to road safety utilises a holistic view of the interactions among vehicles, roads and road users. Yet, the contribution of each of these factors to crashes is vastly different. The role of road users is widely acknowledged as an overwhelming contributor to road crashes. Substantial gains have been made with improvements to vehicle and roads over a number of years. However, improvements of the road user’s behaviour has been (in some cases) less substantial. A road user behaviour that is relatively unregulated is driver sleepiness, which is part of the ‘fatal five’ of risky road user behaviours. The effect of sleepiness is ubiquitous – sleepiness is a state that most, if not all drivers on our roads has experienced, and is habitually exposed to. The quality and quantity of daily sleep is integral to our level of neurobehavioural performance during wakefulness and as such can have a compounding effect on a number of other risky driving behaviours. This paper will discuss the potential influence of sleepiness as an interceding factor for a number of risky driving behaviours. Little effort has been given to increasing awareness of the deleterious and wide ranging effects that sleepiness has on road safety. Given the wide ranging influence of sleepiness, improvements of ‘sleep health’ as a protective factor at the community or individual level could lead to significant reductions in road trauma and increases of general well being. A discussion of potential actions to reduce sleepiness is required if reductions of road trauma are to continue.

Searching for value : the influence of policy and reform on nurses’ sense of value in long-term aged care in Australia.

Contemporary literature on long-term aged care focuses heavily on issues associated with the recruitment and retention of nursing staff, such as job satisfaction and attitudes towards caring for older people. This paper aims to highlight one aspect of a larger study of registered nurses' experiences in long-term aged care in Australia and the influence that government policy and reform has in shaping that experience. This insight into aspects of nurses' everyday experience also contributes to a broader understanding of job satisfaction in long-term care. Findings from this study suggest that registered nurses experience tension in their search for value in their practice, which incorporates professional, political and social mediators of value and worth. These issues are discussed in relation to the impact of policy and reform on nurses' sense of value in long-term aged care and highlight the need for sensitive policy initiatives that support issues of value in nursing practice.

Restorative justice and “Empowerment” : producing and governing active subjects through “Empowering” practices

During the last quarter-century, restorative justice has emerged as a widely utilised response to crime in Western nations. This article, which stems from a Foucauldian genealogy of restorative justice, argues that its embeddedness within the discourse of ‘‘empowerment’’ renders restorative justice a politically acceptable response to crime. ‘‘Empowerment’’, it is argued, is one of many conditions of emergence of restorative justice. The discourse of ‘‘empowerment’’ underpins restorative justice in tangible ways, and has informed legislation and policy in Western jurisdictions. This article seeks to problematise the taken-for-granted nature of this discourse. It argues that the discourse of ‘‘empowerment’’ produces restorative justice subjects who are increasingly governed and governable. As ‘‘empowering’’ restorative practices are targeted towards ‘‘disempowered’’ individuals and communities, concerns are raised about the potential of restorative justice to disproportionately impact upon socially marginalised populations and to increase social exclusion.

A review of sedation scales for the cardiac catheterization laboratory

Sedation scales have the potential to facilitate effective procedural sedation and analgesia in the cardiac catheterization laboratory (CCL). For this potential to become realised, a scale that is suitable for use in the CCL either needs to be identified or developed. To identify sedation scales, a review of Medline and CINHAL was conducted. One sedation scale for the CCL, the NASPE SED, and 15 Intensive Care Unit (ICU) scales met the inclusion and exclusion criteria. Analysis of the scale’s item structures and psychometric properties was then performed. None of these scales were deemed suitable for use in the CCL. As such, further research is required to develop a new scale. The new scale should consist of more than one item because it will be the most effective for tracking the patient’s response to medications. Specific tests required to conduct a rigorous evaluation of the new scale’s psychometric properties are outlined in this paper.

The association between socioeconomic status and depression in Vietnamese adults : pilot study

This study examined the prevalence of depressive symptoms and elucidated the causal pathway between socioeconomic status and depression in a community in the central region of Vietnam. The study used a combination of qualitative and quantitative research methods. Indepth interviews were applied with two local psychiatric experts and ten residents for qualitative research. A cross sectional survey with structured interview technique was implemented with 100 residents in the pilot quantitative survey. The Center for Epidemiological Studies-Depression Scale (CES-D) was applied to valuate depressive symptoms ( CES-D score over 21) and depression ( CESD core over 25). Ordinary Least Squares Regression following the three steps of Baron and Kenny’s framework was employed for testing mediation models. There was a strong social gradient with respect to depressive symptoms. People with higher education levels reported fewer depressive symptoms (lower CES-D scores). Incomes were also inversely associated with depressive symptoms, but only the ones at the bottom of the quartile income. Low level and unstable individuals in terms of occupation were associated with higher depressive symptoms compared with the highest occupation group. Employment status showed the strongest gradient with respect to its impact on the burden of depressive symptoms compared with other indicators of SES. Findings from this pilot study suggest a pattern on the negative association between socioeconomic status and depression in Vietnamese adults.

Exploring postnatal depression in Thua Thien Hue Province, Central Vietnam

Introduction Postnatal depression (PND) is an important public health issue due to its impact on maternal wellbeing, infant development, and family cohesion. The estimated prevalence of PND during the first 12 months post-partum ranges between10-20% worldwide. Whilst PND used to be considered a syndrome only occurring in western countries, there is now evidence that it occurs throughout the world, and often at higher rates in low and middleincome countries. To date, there has been little research into PND in South East Asia and only two community-based surveys in Vietnam, one in Ho Chi Minh City in 1999 and one in Hanoi and Ha Nam in 2009. This study will investigate health worker attitudes about risk and protective factors for PND among women in Thua Thien Hue province in central Vietnam. Methodology In 2009, 23 health professionals participated in qualitative exploratory research of postnatal depression in Hue. This included two focus groups with 12 health professionals who completed a concept mapping process, and in-depth interviews with another 11 health professionals. Results Many factors relating to postnatal depression were identified including socio-economic status, son preference, mother’s health, infant health, social support from family and the community, and health promoting behaviours. In-depth interviews highlighted community knowledge and attitudes surrounding PND such as traditional confinement practices and fear of experiencing stigma. Conclusion The findings of this research will be used to plan a substantial community-based quantitative survey in order to establish prevalence of PND and surrounding social determinants in central Vietnam.

Levels of social trust among men from refugee backgrounds after the 2011 Queensland floods

Purpose This paper examines the relationship between flood exposure and levels of social trust among a cohort of adult men from refugee backgrounds who were affected by the 2011 Queensland floods in Australia. Design/methodology/approach A quantitative questionnaire was administered to 141 men from refugee backgrounds almost two years after the 2011 Queensland floods. The survey was administered in person by trained peer in-terviewers, and included a number of standardised instruments assessing respondents’ so-cio-demographic characteristics, levels of social trust towards and from neighbours, the police, the wider Australian community, and the media, and exposure to and impact of the floods. Multiple logistic regression analyses were used to assess the relationship between flood exposure and social trust adjusting for pre-disaster levels of trust and other potentially confounding variables. Findings Participants with higher levels of flood exposure were significantly more likely to report greater levels of trust both towards and from their neighbours, the wider Australian community, and the media, and they were also more likely to believe that most people can be trusted. Research limitations/implications Although the study reports on data collected two years after the floods, the analysis has adjusted for pre-disaster measures of social trust and other socio-demographic variables. Originality/value Our paper has highlighted the important place of social trust and social capital for refugee communities in a post-disaster setting. Disaster responses that support social capital among marginalised populations are critical to increasing community resilience and supporting recovery.

Leadership in problem-oriented policing

Purpose – The purpose of this paper is to explore the role of leadership in problem-oriented policing (POP). Design/methodology/approach – This paper uses interrupted time series models to isolate the impact on crime trends of a transformational leader's efforts to spearhead the implementation of a program of POP, called the problem solving model (PSM), in a southern state in Australia. Findings – This paper finds that the PSM led directly to an impact on overall crime, with a significant reduction in crimes per 100,000 persons per year after the introduction of the PSM. The majority of the overall crime drop attributable to implementation of POP was driven by reductions in property crime. It was noted that the leadership influence of the PSM was not effective in reducing all types of crime. Crimes against the person where not affected by the introduction of the PSM and public nuisance crimes largely followed the forecasted, upward trajectory. Practical implications – The driver behind the PSM was Commissioner Hyde and the success of the PSM is largely attributable to his strong commitment to transformational leadership and a top-down approach to implementation. These qualities encapsulate the original ideas behind POP that Goldstein (1979, 2003), back in 1979, highlighted as critical for the success of future POP programs. Social implications – Reducing crime is an important part of creating safe communities and improving quality of life for all citizens. This research shows that successful implementation of the PSM within South Australia under the strong leadership of Commissioner Hyde was a major factor in reducing property crime and overall crime rates. Originality/value – This paper is valuable because it demonstrates the link between strong leadership in policing, the commissioner's vision for POP and how his vision then translated into widespread adoption of POP. The study empirically shows that the statewide adoption of POP led to significant reductions in crime, particularly property crime.

Vertical dynamic interaction of trains and rail steel bridges

Rail steel bridges are vulnerable to high impact forces due to the passage of trains; unfortunately the determination of these transient impact forces is not straightforward as these are affected by a large number of parameters, including the wagon design, the wheel-rail contact and the design parameters of the bridge deck and track, as well as the operational parameters – wheel load and speed. To determine these impact forces, a detailed rail train-track/bridge dynamic interaction model has been developed, which includes a comprehensive train model using multi-body dynamics approach and a flexible track/bridge model using Euler– Bernoulli beam theory. Single and multi-span bridges have been modelled to examine their dynamic characteristics. From the single span bridge, the train critical speed is determined; the minimum distance of two peak loadings is found to affect the train critical speed. The impact factor and the dynamic characteristics are discussed.

Characteristics of spatial variation, size distribution, formation and growth of particles in urban environments

This thesis is the first comprehensive study of important parameters relating to aerosols' impact on climate and human health, namely spatial variation, particle size distribution and new particle formation. We determined the importance of spatial variation of particle number concentration in microscale environments, developed a method for particle size parameterisation and provided knowledge about the chemistry of new particle formation. This is a significant contribution to our understanding of processes behind the transformation and dynamics of urban aerosols. This PhD project included extensive measurements of air quality parameters using state of the art instrumentation at each of the 25 sites within the Brisbane metropolitan area and advanced statistical analysis.

Design of an integrated platform for V2X wireless communications and positioning supporting C-ITS safety applications

In this paper, an integrated inter-vehicles wireless communications and positioning system supporting alternate positioning techniques is proposed to meet the requirements of safety applications of Cooperative Intelligent Transportation Systems (C-ITS). Recent advances have repeatedly demonstrated that road safety problems can be to a large extent addressed via a range of technologies including wireless communications and positioning in vehicular environments. The novel communication stack utilizing a dedicated frequency spectrum (e.g. at 5.9 GHz band), known as Dedicated Short-Range Communications (DSRC), has been particularly designed for Wireless Access in Vehicular Environments (WAVE) to support safety applications in highly dynamic environments. Global Navigation Satellite Systems (GNSS) is another essential enabler to support safety on rail and roads. Although current vehicle navigation systems such as single frequency Global Positioning System (GPS) receivers can provide route guidance with 5-10 meters (road-level) position accuracy, positioning systems utilized in C-ITS must provide position solutions with lane-level and even in-lane-level accuracies based on the requirements of safety applications. This article reviews the issues and technical approaches that are involved in designing a vehicular safety communications and positioning architecture; it also provides technological solutions to further improve vehicular safety by integrating the DSRC and GNSS-based positioning technologies.