Evidence for u.v. induction of CDKN2 mutations in melanoma cell lines

The CDKN2 gene, encoding the cyclin dependent kinase inhibitor p16, is a tumour suppressor gene involved in melanoma and maps to chromosome band 9p22. Mutations or interstitial deletions of this gene have been found both in the germline of familial melanoma cases and somatically in melanoma cell lines. Previous mutation analyses of melanoma cell lines have indicated a high frequency of C:G to T:A transitions, with all of these mutations occurring at dipyrimidine sites. Including three melanoma cell lines carrying tandem CC to TT mutations, the spectrum of mutations so far reported indicates a possible role for u.v. radiation in the mutagenesis of this gene in some tumours. To further examine this hypothesis we have characterised mutations of the CDKN2 gene in 30 melanoma cell lines. Nineteen lines carried complete or partial homozygous deletions of the gene. Of the remaining cell lines, eight were shown by direct sequencing of PCR products from exon 1 and exon 2 to carry a total of nine different mutations of CDKN2. Two cell lines carried tandem CC to TT mutations and a high rate of C:G to T:A transitions was observed. This study provides further evidence for the role of u.v. light in the genesis of melanoma, with one target being the CDKN2 tumour suppressor gene.

p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a gamma-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.

Load modelling : induction motors

Modelling the power systems load is a challenge since the load level and composition varies with time. An accurate load model is important because there is a substantial component of load dynamics in the frequency range relevant to system stability. The composition of loads need to be charaterised because the time constants of composite loads affect the damping contributions of the loads to power system oscillations, and their effects vary with the time of the day, depending on the mix of motors loads. This chapter has two main objectives: 1) describe the load modelling in small signal using on-line measurements; and 2) present a new approach to develop models that reflect the load response to large disturbances. Small signal load characterisation based on on-line measurements allows predicting the composition of load with improved accuracy compared with post-mortem or classical load models. Rather than a generic dynamic model for small signal modelling of the load, an explicit induction motor is used so the performance for larger disturbances can be more reliably inferred. The relation between power and frequency/voltage can be explicitly formulated and the contribution of induction motors extracted. One of the main features of this work is the induction motor component can be associated to nominal powers or equivalent motors

Topological map induction using neighbourhood information of places

In topological mapping, perceptual aliasing can cause different places to appear indistinguishable to the robot. In case of severely corrupted or non-available odometry information, topological mapping is difficult as the robot is challenged with the loop-closing problem; that is to determine whether it has visited a particular place before. In this article we propose to use neighbourhood information to disambiguate otherwise indistinguishable places. Using neighbourhood information for place disambiguation is an approach that neither depends on a specific choice of sensors nor requires geometric information such as odometry. Local neighbourhood information is extracted from a sequence of observations of visited places. In experiments using either sonar or visual observations from an indoor environment the benefits of using neighbourhood clues for the disambiguation of otherwise identical vertices are demonstrated. Over 90% of the maps we obtain are isomorphic with the ground truth. The choice of the robot’s sensors does not impact the results of the experiments much.

Induction motor load impact on power system eigenvalue sensitivity analysis

Load modelling plays an important role in power system dynamic stability assessment. One of the widely used methods in assessing load model impact on system dynamic response is parametric sensitivity analysis. A composite load model-based load sensitivity analysis framework is proposed. It enables comprehensive investigation into load modelling impacts on system stability considering the dynamic interactions between load and system dynamics. The effect of the location of individual as well as patches of composite loads in the vicinity on the sensitivity of the oscillatory modes is investigated. The impact of load composition on the overall sensitivity of the load is also investigated.

A ‘service logic’ rationale for business model innovation

Successful firms use business model innovation to rethink the way they do business and transform industries. However, current research on business model innovation is lacking theoretical underpinnings and is in need of new insights. This objective of this paper is to advance our understanding of both the business model concept and business model innovation based on service logic as foundation for customer value and value creation. We present and discuss a rationale for business models based on ‘service logic’ with service as a value-supporting process and compared it with a business model based on ‘goods logic’ with goods as value-supporting resources. The implications for each of the business model dimensions: customer, value proposition, organizational architecture and revenue model, are described and discussed in detail.

Agreement between self-reported use of in vitro fertilization or ovulation induction, and medical insurance claims in Australian women aged 28–36 years

STUDY QUESTION: What is the self-reported use of in vitro fertilization (IVF) and ovulation induction (OI) in comparison with insurance claims by Australian women aged 28–36 years? SUMMARY ANSWER: The self-reported use of IVF is quite likely to be valid; however, the use of OI is less well reported. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Population-based research often relies on the self-reported use of IVF and OI because access to medical records can be difficult and the data need to include sufficient personal identifying information for linkage to other data sources. There have been few attempts to explore the reliability of the self-reported use of IVF and OI using the linkage to medical insurance claims for either treatment. STUDY DESIGN: This prospective, population-based, longitudinal study included the cohort of women born during 1973–1978 and participating in the Australian Longitudinal Study on Women's Health (ALSWH) (n = 14247). From 1996 to 2009, participants were surveyed up to five times. PARTICIPANTS AND SETTING: Participants self-reported their use of IVF or OI in two mailed surveys when aged 28–33 and 31–36 years (n = 7280), respectively. This study links self-report survey responses and claims for treatment or medication from the universal national health insurance scheme (i.e. Medicare Australia). MAIN RESULTS AND THE ROLE OF CHANCE: Comparisons between self-reports and claims data were undertaken for all women consenting to the linkage (n = 3375). The self-reported use of IVF was compared with claims for OI for IVF (Kappa, K = 0.83), oocyte collection (K = 0.82), sperm preparation (K = 0.83), intracytoplasmic sperm injection (K = 0.40), fresh embryo transfers (K = 0.82), frozen embryo transfers (K = 0.64) and OI for IVF medication (K = 0.17). The self-reported use of OI was compared with ovulation monitoring (K = 0.52) and OI medication (K = 0.71). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: There is a possibility of selection bias due to the inclusion criteria for participants in this study: (1) completion of the last two surveys in a series of five and (2) consent to the linkage of their responses with Medicare data. GENERALIZABILITY TO OTHER POPULATIONS: The results are relevant to questionnaire-based research studies with infertile women in developed countries. STUDY FUNDING/COMPETING INTEREST(S): ALSWH is funded by the Australian Government Department of Health and Ageing. This research is funded by a National Health and Medical Research Council Centre of Research Excellence grant.

Frame-rate stereopsis using non-parametric transforms and programmable logic

A frame-rate stereo vision system, based on non-parametric matching metrics, is described. Traditional metrics, such as normalized cross-correlation, are expensive in terms of logic. Non-parametric measures require only simple, parallelizable, functions such as comparators, counters and exclusive-or, and are thus very well suited to implementation in reprogrammable logic.