p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation

p53 is the central member of a critical tumor suppressor pathway in virtually all tumor types, where it is silenced mainly by missense mutations. In melanoma, p53 predominantly remains wild type, thus its role has been neglected. To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the 'high-p53'Mdm4+/- mouse to the well-established TP-ras0/+ murine melanoma progression model. After treatment with the carcinogen dimethylbenzanthracene (DMBA), TP-ras0/+ mice on the Mdm4+/- background developed fewer tumors with a delay in the age of onset of melanomas compared to TP-ras0/+ mice. Furthermore, we observed a dramatic decrease in tumor growth, lack of metastasis with increased survival of TP-ras0/+: Mdm4+/- mice. Thus, p53 effectively prevented the conversion of small benign tumors to malignant and metastatic melanoma. p53 activation in cultured primary melanocyte and melanoma cell lines using Nutlin-3, a specific Mdm2 antagonist, supported these findings. Moreover, global gene expression and network analysis of Nutlin-3-treated primary human melanocytes indicated that cell cycle regulation through the p21WAF1/CIP1 signaling network may be the key anti-melanomagenic activity of p53.

The life-cycle of the fashion garment and the role of Australian mass market designers

This paper uses the lens of life-cycle thinking to discuss recent developments in the Australian mass market fashion industry, and to explore the opportunities and barriers to implementing lifecycle thinking within mass market design processes. Life-cycle analysis is a quantitative tool used to assess the environmental impact of a material or product. However the underlying thinking of life-cycle analysis can also be employed more generally, enabling a designer to assess their processes and design decisions for sustainability. A fashion designer employing life cycle thinking would consider every stage in the life of a garment from fibre and textiles through to consumer use, to eventual disposal and beyond disposal to reuse and later disassembly for fibre recycling. Although life-cycle thinking is rarely considered in the design processes of the fast-paced, price-driven mass market, this paper explores its potential and suggests ways in which it could be implemented.

Microbial colonisation of human follicular fluid and adverse in vitro fertilisation outcomes

This study, investigating 263 women undergoing trans-vaginal oocyte retrieval for in vitro fertilisation (IVF) found that microorganisms colonising follicular fluid contributed to adverse IVF (pre-implantation) and pregnancy (post-implantation) outcomes including poor quality embryos, failed pregnancy and early pregnancy loss (< 37 weeks gestation). Some microorganisms also showed in vitro growth patterns in liquid media that appeared to be enhanced by the hormonal stimulation protocol used for oocyte retrieval. Elaborated cytokines within follicular fluid were also associated with adverse IVF outcomes. This study is imperative because infertility affects 16% of the human population and the numbers of couples needing assistance continues to increase. Despite significant improvements in the technical aspects of assisted reproductive technologies (ART), the live birth rate has not increased proportionally. Overt genital tract infection has been associated with both infertility and adverse pregnancy outcomes (including miscarriage and preterm birth) as a direct result of the infection or the host response to it. Importantly, once inflammation had become established, medical treatment often failed to prevent these significant adverse outcomes. Current evaluations of fertility focus on the ovary as a site of steroid hormone production and ovulation. However, infertility as a result of subclinical colonisation of the ovary has not been reported. Furthermore, identification of the microorganisms present in follicular fluid and the local cytokine profile may provide clinicians with an early indication of the prognosis for IVF treatment in infertile couples, thus allowing antimicrobial treatment and/or counselling about possible IVF failure. During an IVF cycle, multiple oocytes undergo maturation in vivo in response to hormonal hyperstimulation. Oocytes for in vitro insemination are collected trans-vaginally. The follicular fluid that bathes the maturing oocyte in vivo, usually is discarded as part of the IVF procedure, but provides a unique opportunity to investigate microbial causes of adverse IVF outcomes. Some previous studies have identified follicular fluid markers that predict IVF pregnancy outcomes. However, there have not been any detailed microbiological studies of follicular fluid. For this current study, paired follicular fluid and vaginal secretion samples were collected from women undergoing IVF cycles to determine whether microorganisms in follicular fluid were associated with adverse IVF outcomes. Microorganisms in follicular fluid were regarded as either "colonisers" or "contaminants"; colonisers, if they were unique to the follicular fluid sample, and contaminants if the same microorganisms were detected in the vaginal and follicular fluid samples indicating that the follicular fluid was merely contaminated during the oocyte retrieval process. Quite unexpectedly, by these criteria, we found that follicular fluid from approximately 30% of all subjects was colonised with bacteria. Fertile and infertile women with colonised follicular fluid had decreased embryo transfer rates and decreased pregnancy rates compared to women with contaminated follicular fluids. The observation that follicular fluid was not always sterile, but contained a diverse range of microorganisms, is novel. Many of the microorganisms we detected in follicular fluid are known opportunistic pathogens that have been detected in upper genital tract infections and are associated with adverse pregnancy outcomes. Bacteria were able to survive for at least 28 weeks in vitro, in cultures of follicular fluid. Within 10 days of establishing these in vitro cultures, several species (Lactobacillus spp., Bifidobacterium spp., Propionibacterium spp., Streptococcus spp. and Salmonella entericus) had formed biofilms. Biofilms play a major role in microbial pathogenicity and persistence. The propensity of microbial species to form biofilms in follicular fluid suggests that successful treatment of these infections with antimicrobials may be difficult. Bifidobacterium spp. grew, in liquid media, only if concentrations of oestradiol and progesterone were similar to those achieved in vivo during an IVF cycle. In contrast, the growth of Streptococcus agalactiae and Escherichia coli was inhibited or abolished by the addition of these hormones to culture medium. These data suggest that the likelihood of microorganisms colonising follicular fluid and the species of bacteria involved is influenced by the stage of the menstrual cycle and, in the case of IVF, the nature and dose of steroid hormones administered for the maturation of multiple oocytes in vivo. Our findings indicate that the elevated levels of steroid hormones during an IVF cycle may influence the microbial growth within follicular fluid, suggesting that the treatment itself will impact on the microflora present in the female upper genital tract during pre-conception and early post-conception phases of the cycle. The effect of the host immune response on colonising bacteria and on the outcomes of IVF also was investigated. White blood cells reportedly compose between 5% and 15% of the cell population in follicular fluid. The follicular membrane is semi-permeable and cells are actively recruited as part of the normal menstrual cycle and in response to microorganisms. A previous study investigated follicular fluid cytokines from infertile women and fertile oocyte donors undergoing IVF, and concluded that there were no significant differences in the cytokine concentrations between the two groups. However, other studies have reported differences in the follicular fluid cytokine levels associated with infertile women with endometriosis or polycystic ovary syndrome. In this study, elevated levels of interleukin (IL)-1 á, IL-1 â and vascular endothelial growth factor (VEGF) in vaginal fluid were associated with successful fertilisation, which may be useful marker for successful fertilisation outcomes for women trying to conceive naturally or prior to oocyte retrieval for IVF. Elevated levels of IL-6, IL-12p40, granulocyte colony stimulating factor (GCSF) and interferon-gamma (IFN ã) in follicular fluid were associated with successful embryo transfer. Elevated levels of pro-inflammatory IL-18 and decreased levels of anti-inflammatory IL-10 were identified in follicular fluid from women with idiopathic infertility. Successful fertilisation and implantation is dependent on a controlled pro-inflammatory environment, involving active recruitment of pro-inflammatory mediators to the genital tract as part of the menstrual cycle and early pregnancy. However, ongoing pregnancy requires an enhanced anti-inflammatory environment to ensure that the maternal immune system does not reject the semi-allergenic foetus. The pro-inflammatory skew in the follicular fluid of women with idiopathic infertility, correlates with normal rates of fertilisation, embryo discard and embryo transfer, observed for this cohort, which were similar to the outcomes observed for fertile women. However, their pregnancy rate was reduced compared to fertile women. An altered local immune response in follicular fluid may provide a means of explaining infertility in this cohort, previously defined as 'idiopathic'. This study has found that microorganisms colonising follicular fluid may have contributed to adverse IVF and pregnancy outcomes. Follicular fluid bathes the cumulus oocyte complex during the in vivo maturation process, and microorganisms in the fluid, their metabolic products or the local immune response to these microorganisms may result in damage to the oocytes, degradation of the cumulus or contamination of the IVF culture system. Previous studies that have discounted bacterial contamination of follicular fluid as a cause of adverse IVF outcomes failed to distinguish between bacteria that were introduced into the follicular fluid at the time of trans-vaginal oocyte retrieval and those that colonised the follicular fluid. Those bacteria that had colonised the fluid may have had time to form biofilms and to elicit a local immune response. Failure to draw this distinction has previously prevented consideration of bacterial colonisation of follicular fluid as a cause of adverse IVF outcomes. Several observations arising from this study are of significance to IVF programs. Follicular fluid is not always sterile and colonisation of follicular fluid is a cause of adverse IVF and pregnancy outcomes. Hormonal stimulation associated with IVF may influence whether follicular fluid is colonised and enhance the growth of specific species of bacteria within follicular fluid. Bacteria in follicular fluid may form biofilms and literature has reported that this may influence their susceptibility to antibiotics. Monitoring the levels of selected cytokines within vaginal secretions may inform fertilisation outcomes. This study has identified novel factors contributing to adverse IVF outcomes and that are most likely to affect also natural conception outcomes. Early intervention, possibly using antimicrobial or immunological therapies may reduce the need for ART and improve reproductive health outcomes for all women.

Public participation in infrastructure and construction projects in China: From an EIA-based to a whole-cycle process

Many governments world-wide are increasingly encouraging the involvement of interested individuals, groups and organisations in their publicinfrastructure and construction (PIC) projects as a means of improving the openness, transparency and accountability of the decision-making process and help improve the projects’ long-term viability and benefits to the community. In China, however, the current participatory mechanism at the project level exists only as part of the environmental impact assessment (EIA) process. With an increasing demand for PIC projects and social equality in China, this suggests a need to bring the participatory process into line with international practice. The aim of this paper, therefore, is to identify the weaknesses of EIA-basedpublicparticipation in China and the means by which it may be improved for the whole lifecycle of PIC schemes. To do this, the results of a series of interviews with a diverse group of experts is reported which analyse the nature and extent of existing problems of publicparticipation in EIA and suggestions for improvement. These indicate that the current level of participation in PIC projects is quite limited, particularly in the crucial earlier stages, primarily due to traditional culture and values, uneven progress in the adoption of participatory mechanisms, the risk of not meeting targets and lack of confidence in public competence. Finally, aprocess flowchart is proposed to guide construction practitioners and the community in general.

Regulating assisted reproductive technologies in Victoria : the impact of changing policy concerning the accessibility of in vitro fertilisation for preimplantation tissue-typing

On 1 January 2010, the Assisted Reproductive Treatment Act 2008 (Vic) came into force. The legislation was the outcome of a detailed review and consultation process undertaken by the Victorian Law Reform Commission. Arguably, the change to the regulatory framework represents a significant shift in policy compared to previous regulatory approaches on this topic in Victoria. This article considers the impact of the new legislation on eligibility for reproductive treatments, focusing on the accessibility of such services for the purpose of creating a “saviour sibling”. It also highlights the impact of the Victorian regulatory body’s decision to abolish its regulatory policies on preimplantation genetic diagnosis and preimplantation tissue-typing, concluding that the regulatory approach in relation to these latter issues is similar to other Australian jurisdictions where such practices are not addressed by a statutory framework.

Spectrum sensing using two-stage detection to compensate for reduced primary user duty cycle

Spectrum sensing is considered to be one of the most important tasks in cognitive radio. One of the common assumption among current spectrum sensing detectors is the full presence or complete absence of the primary user within the sensing period. In reality, there are many situations where the primary user signal only occupies a portion of the observed signal and the assumption of primary user duty cycle not necessarily fulfilled. In this paper we show that the true detection performance can degrade from the assumed achievable values when the observed primary user exhibits a certain duty cycle. Therefore, a two-stage detection method incorporating primary user duty cycle that enhances the detection performance is proposed. The proposed detector can improve the probability of detection under low duty cycle at the expense of a small decrease in performance at high duty cycle.

The pomegranate cycle : reconfiguring opera through performance, technology & composition

The Pomegranate Cycle is a practice-led enquiry consisting of a creative work and an exegesis. This project investigates the potential of self-directed, technologically mediated composition as a means of reconfiguring gender stereotypes within the operatic tradition. This practice confronts two primary stereotypes: the positioning of female performing bodies within narratives of violence and the absence of women from authorial roles that construct and regulate the operatic tradition. The Pomegranate Cycle redresses these stereotypes by presenting a new narrative trajectory of healing for its central character, and by placing the singer inside the role of composer and producer. During the twentieth and early twenty-first century, operatic and classical music institutions have resisted incorporating works of living composers into their repertory. Consequently, the canon’s historic representations of gender remain unchallenged. Historically and contemporarily, men have almost exclusively occupied the roles of composer, conductor, director and critic, and therefore men have regulated the pedagogy, performance practices, repertoire and organisations that sustain classical music. In this landscape, women are singers, and few have the means to challenge the constructions of gender they are asked to reproduce. The Pomegranate Cycle uses recording technologies as the means of driving change because these technologies have already challenged the regulation of the classical tradition by changing people’s modes of accessing, creating and interacting with music. Building on the work of artists including Phillips and van Veen, Robert Ashley and Diamanda Galas, The Pomegranate Cycle seeks to broaden the definition of what opera can be. This work examines the ways in which the operatic tradition can be hybridised with contemporary musical forms such as ambient electronica, glitch, spoken word and concrete sounds as a way of bringing the form into dialogue with contemporary music cultures. The ultilisation of other sound cultures within the context of opera enables women’s voices and stories to be presented in new ways, while also providing a point of friction with opera’s traditional storytelling devices. The Pomegranate Cycle simulates aesthetics associated with Western art music genres by drawing on contemporary recording techniques, virtual instruments and sound-processing plug-ins. Through such simulations, the work disrupts the way virtuosic human craft has been used to generate authenticity and regulate access to the institutions that protect and produce Western art music. The DIY approach to production, recording, composition and performance of The Pomegranate Cycle demonstrates that an opera can be realised by a single person. Access to the broader institutions which regulate the tradition are not necessary. In short, The Pomegranate Cycle establishes that a singer can be more than a voice and a performing body. She can be her own multimedia storyteller. Her audience can be anywhere.

Sustainability in road transport : an integrated life cycle analysis for estimating emissions

Despite of a significant contribution of transport sector in the global economy and society, it is one of the largest sources of global energy consumption, green house gas emissions and environmental pollutions. A complete look onto the whole life cycle environmental inventory of this sector will be helpful to generate a holistic understanding of contributory factors causing emissions. Previous studies were mainly based on segmental views which mostly compare environmental impacts of different modes of transport, but very few consider impacts other than the operational phase. Ignoring the impacts of non-operational phases, e.g., manufacture, construction, maintenance, may not accurately reflect total contributions on emissions. Moreover an integrated study for all motorized modes of road transport is also needed to achieve a holistic estimation. The objective of this study is to develop a component based life cycle inventory model which considers impacts of both operational and non-operational phases of the whole life as well as different transport modes. In particular, the whole life cycle of road transport has been segmented into vehicle, infrastructure, fuel and operational components and inventories have been conducted on each component. The inventory model has been demonstrated using the road transport of Singapore. Results show that total life cycle green house gas emissions from the road transport sector of Singapore is 7.8 million tons per year, among which operational phase and non-operational phases contribute about 55% and about 45%, respectively. Total amount of criteria air pollutants are 46, 8.5, 33.6, 13.6 and 2.6 thousand tons per year for CO, SO2, NOx, VOC and PM10, respectively. From the findings, it can be deduced that stringent government policies on emission control measures have a significant impact on reducing environmental pollutions. In combating global warming and environmental pollutions the promotion of public transport over private modes is an effective sustainable policy.

Simple rules to contain an invasive species with a complex life cycle and high dispersal capacity

Designing practical rules for controlling invasive species is a challenging task for managers, particularly when species are long-lived, have complex life cycles and high dispersal capacities. Previous findings derived from plant matrix population analyses suggest that effective control of long-lived invaders may be achieved by focusing on killing adult plants. However, the cost-effectiveness of managing different life stages has not been evaluated. We illustrate the benefits of integrating matrix population models with decision theory to undertake this evaluation, using empirical data from the largest infestation of mesquite (Leguminosae: Prosopis spp) within Australia. We include in our model the mesquite life cycle, different dispersal rates and control actions that target individuals at different life stages with varying costs, depending on the intensity of control effort. We then use stochastic dynamic programming to derive cost-effective control strategies that minimize the cost of controlling the core infestation locally below a density threshold and the future cost of control arising from infestation of adjacent areas via seed dispersal. Through sensitivity analysis, we show that four robust management rules guide the allocation of resources between mesquite life stages for this infestation: (i) When there is no seed dispersal, no action is required until density of adults exceeds the control threshold and then only control of adults is needed; (ii) when there is seed dispersal, control strategy is dependent on knowledge of the density of adults and large juveniles (LJ) and broad categories of dispersal rates only; (iii) if density of adults is higher than density of LJ, controlling adults is most cost-effective; (iv) alternatively, if density of LJ is equal or higher than density of adults, management efforts should be spread between adults, large and to a lesser extent small juveniles, but never saplings. Synthesis and applications.In this study, we show that simple rules can be found for managing invasive plants with complex life cycles and high dispersal rates when population models are combined with decision theory. In the case of our mesquite population, focussing effort on controlling adults is not always the most cost-effective way to meet our management objective.

Anticipating the use of life extension technologies : possible pointers from the adoption of assisted reproductive technologies

The first effective life extension technologies might well become available within the next few years. Experts from the University of Queensland, Australia, explore the possible public reaction to these therapies and the ethical and social concerns they raise, drawing on the experience of assisted reproduction technologies

Contraceptive changes after reproductive events among Australian women born in 1973 to 1978: A longitudinal study from 1996 to 2009

Background Women change contraception as they try to conceive, space births, and limit family size. This longitudinal analysis examines contraception changes after reproductive events such as birth, miscarriage or termination among Australian women born from 1973 to 1978 to identify potential opportunities to increase the effectiveness of contraceptive information and service provision. Methods Between 1996 and 2009, 5,631 Australian women randomly sampled from the Australian universal health insurance (Medicare) database completed five self-report postal surveys. Three longitudinal logistic regression models were used to assess the associations between reproductive events (birth only, birth and miscarriage, miscarriage only, termination only, other multiple events, and no new event) and subsequent changes in contraceptive use (start using, stop using, switch method) compared with women who continued to use the same method. Results After women experienced only a birth, or a birth and a miscarriage, they were more likely to start using contraception. Women who experienced miscarriages were more likely to stop using contraception. Women who experienced terminations were more likely to switch methods. There was a significant interaction between reproductive events and time indicating more changes in contraceptive use as women reach their mid-30s. Conclusion Contraceptive use increases after the birth of a child, but decreases after miscarriage indicating the intention for family formation and spacing between children. Switching contraceptive methods after termination suggests these pregnancies were unintended and possibly due to contraceptive failure. Women’s contact with health professionals around the time of reproductive events provides an opportunity to provide contraceptive services.

A framework for life cycle cost estimation of a product family at the early stage of product development

A cost estimation method is required to estimate the life cycle cost of a product family at the early stage of product development in order to evaluate the product family design. There are difficulties with existing cost estimation techniques in estimating the life cycle cost for a product family at the early stage of product development. This paper proposes a framework that combines a knowledge based system and an activity based costing techniques in estimating the life cycle cost of a product family at the early stage of product development. The inputs of the framework are the product family structure and its sub function. The output of the framework is the life cycle cost of a product family that consists of all costs at each product family level and the costs of each product life cycle stage. The proposed framework provides a life cycle cost estimation tool for a product family at the early stage of product development using high level information as its input. The framework makes it possible to estimate the life cycle cost of various product family that use any types of product structure. It provides detailed information related to the activity and resource costs of both parts and products that can assist the designer in analyzing the cost of the product family design. In addition, it can reduce the required amount of information and time to construct the cost estimation system.

Fertility and infertility : studies in reproductive epidemiology in Australia

Worldwide, there are few large-scale epidemiological studies on infertility. In Australia, population-based research on infertility is limited to a few small-scale studies. Therefore, the prevalence of infertility and unmet need for specialist medical advice and treatment cannot be estimated reliably. Women who have used assisted reproductive technologies (ART) are recorded in treatment registries. However, there are many infertile women who are excluded from these clinical populations because they neither seek advice nor use treatment. The thesis was based on a biopsychosocial model of health and used the methods of reproductive epidemiology to address the lack of national data on the prevalence of infertility in Australia. Firstly, numbers of births and pregnancy losses were investigated in two generations of women participating in the Australian Longitudinal Study on Women’s Health (ALSWH). The ALSWH is a broad-ranging, longitudinal examination of biological, psychological and social factors that impact on women’s health and wellbeing. Women from three age cohorts were randomly sampled from the population using the universal public health insurance (i.e., Medicare) database and ALSWH participants were representative of the female population. However, the studies in the thesis only involved data from two cohorts. The younger cohort were born in 1973-78 and completed up to four mailed surveys between 1996 (when they were aged 18-23 years, n=14247) and 2006 (28-33 years, n=9145). The mid-aged cohort were born in 1946-51 and completed four mailed surveys between 1996 (when they were aged 45-50 years n=13715) and 2004 (53-58 years, n=10905). Compared to other studies that focus on outcomes of single pregnancies, these studies included all pregnancy outcomes by developing comprehensive reproductive histories for each woman. Pregnancy outcomes included birth, miscarriage, stillbirth, termination and ectopic pregnancy. Women in the youngest cohort (born in 1973-78) were only just reaching their peak childbearing years and many (44%) had yet to report their first pregnancy outcome. Women from the mid-aged cohort (born 1946-51) had completed their reproductive lives and 92% were able to report on their lifetime pregnancy outcomes. Pregnancy losses, especially miscarriage, were common for both generations of women. Secondly, the prevalence of infertility, seeking medical advice and using treatment was identified for these two generations of women. For the older generation, the lifetime prevalence of infertility and demand for treatment was investigated in the context of the specialist medical services which became available circa 1980. By this time, however, most of these older women had already been pregnant and completed their families. For women who experienced infertility (11%), their options for advice and treatment were limited and less than half (42%) had used any treatment. More recently for the younger generation of women, who were aged 28-33 years in 2006, specialist advice and treatment were extensively available. Among women who had tried to conceive or had been pregnant (n=5936), 17% had experienced infertility and the majority (72%) were able to access medical advice. However, after seeking advice only half of these infertile women had used treatment with fertility hormones or in vitro fertilisation (IVF). Overall for infertile women aged up to 33 years, only one-third had used these treatments. Thirdly, the barriers to accessing medical advice and using treatment for infertility were identified for women aged less than 34 years. Among a community sample of infertile women aged 28-33 years (ALSWH participants), self-reported depression was found to be a barrier to accessing medical advice. The characteristics of these infertile women in the community who had (n=121) or had not (n=110) used treatment were compared to infertile women aged 27-33 years (n=59) attending four fertility clinics. Compared to infertile women in the community, living in major cities and having private health insurance were associated with early use of treatment for infertility at specialist clinics by women aged <34 years. In contrast to most clinical studies of IVF, the final study reported in the thesis took into account repeated IVF cycles and the impact of women’s individual histories on IVF outcomes. Among 121 infertile women (aged 27-46 years) who had 286 IVF cycles, older age and prolonged use of the oral contraceptive pill were associated with fewer eggs collected. Further, women in particular occupations had lower proportions of eggs fertilised normally than women in other occupational groups. These studies form the first large-scale epidemiological examination of infertility in Australia. The finding that two-thirds of women with infertility had not used treatment indicates that there is an unmet need for specialist treatment in women aged less than 34 years. However, barriers to accessing treatment prevent women using ART at a younger age when there is a higher chance of pregnancy.