Cloning and characterization of a novel human gene related to vascular endothelial growth factor

This paper describes the cloning and characterization of a new member of the vascular endothelial growth factor (VEGF) gene family, which we have designated VRF for VEGF-related-factor. Sequencing of cDNAs from a human fetal brain library and RT-PCR products from normal and tumor tissue cDNA pools indicate two alternatively spliced messages with open reading frames of 621 and 564 bp, respectively. The predicted proteins differ at their carboxyl ends resulting from a shift in the open reading frame. Both isoforms show strong homology to VEGF at their amino termini, but only the shorter isoform maintains homology to VEGF at its carboxyl terminus and conserves all 16 cysteine residues of VEGF165. Similarity comparisons of this isoform revealed overall protein identity of 48% and conservative substitution of 69% with VEGF189. VRF is predicted to contain a signal peptide, suggesting that it may be a secreted factor. The VRF gene maps to the D11S750 locus at chromosome band 11q13, and the protein coding region, spanning approximately 5 kb, is comprised of 8 exons that range in size from 36 to 431 bp. Exons 6 and 7 are contiguous and the two isoforms of VRF arise through alternate splicing of exon 6. VRF appears to be ubiquitously expressed as two transcripts of 2.0 and 5.5 kb; the level of expression is similar among normal and malignant tissues.

A genome-based strategy uncovers frequent BRAF mutations in melanoma

Using a genome-scanning approach to search for oncogenes, a recent report identifies somatic mutations in the signaling gene BRAF that are particularly prevalent in melanoma.

Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia

To gain insight into melanoma pathogenesis, we characterized an insertional mouse mutant, TG3, that is predisposed to develop multiple melanomas. Physical mapping identified multiple tandem insertions of the transgene into intron 3 of Grm1 (encoding metabotropic glutamate receptor 1) with concomitant deletion of 70 kb of intronic sequence. To assess whether this insertional mutagenesis event results in alteration of transcriptional regulation, we analyzed Grm1 and two flanking genes for aberrant expression in melanomas from TG3 mice. We observed aberrant expression of only Grm1. Although we did not detect its expression in normal mouse melanocytes, Grm1 was ectopically expressed in the melanomas from TG3 mice. To confirm the involvement of Grm1 in melanocytic neoplasia, we created an additional transgenic line with Grm1 expression driven by the dopachrome tautomerase promoter. Similar to the original TG3, the Tg(Grm1)EPv line was susceptible to melanoma. In contrast to human melanoma, these transgenic mice had a generalized hyperproliferation of melanocytes with limited transformation to fully malignant metastasis. We detected expression of GRM1 in a number of human melanoma biopsies and cell lines but not in benign nevi and melanocytes. This study provides compelling evidence for the importance of metabotropic glutamate signaling in melanocytic neoplasia.

High frequency of BRAF mutations in nevi

To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.

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.

Notch and NOXA-related pathways in melanoma cells

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

Teachers’ and parents’ perspectives of digital technology in the lives of young children

The pervasiveness of technology in the 21st Century has meant that adults and children live in a society where digital devices are integral to their everyday lives and participation in society. How we communicate, learn, work, entertain ourselves, and even shop is influenced by technology. Therefore, before children begin school they are potentially exposed to a range of learning opportunities mediated by digital devices. These devices include microwaves, mobile phones, computers, and console games such as Playstations® and iPods®. In Queensland preparatory classrooms and in the homes of these children, teachers and parents support and scaffold young children’s experiences, providing them with access to a range of tools that promote learning and provide entertainment. This paper examines teachers’ and parents’ perspectives and considers whether they are techno-optimists who advocate for and promote the inclusion of digital technology, or whether they are they techno-pessimists, who prefer to exclude digital devices from young children’s everyday experiences. An exploratory, single case study design was utilised to gather data from three teachers and ten parents of children in the preparatory year. Teacher data was collected through interviews and email correspondence. Parent data was collected from questionnaires and focus groups. All parents who responded to the research invitation were mothers. The results of data analysis identified a misalignment among adults’ perspectives. Teachers were identified as techno-optimists and parents were identified as techno-pessimists with further emergent themes particular to each category being established. This is concerning because both teachers and mothers influence young children’s experiences and numeracy knowledge, thus, a shared understanding and a common commitment to supporting young children’s use of technology would be beneficial. Further research must investigate fathers’ perspectives of digital devices and the beneficial and detrimental roles that a range of digital devices, tools, and entertainment gadgets play in 21st Century children’s lives.

Determining operational measures from multi-camera surveillance systems using soft biometrics

CCTV and surveillance networks are increasingly being used for operational as well as security tasks. One emerging area of technology that lends itself to operational analytics is soft biometrics. Soft biometrics can be used to describe a person and detect them throughout a sparse multi-camera network. This enables them to be used to perform tasks such as determining the time taken to get from point to point, and the paths taken through an environment by detecting and matching people across disjoint views. However, in a busy environment where there are 100's if not 1000's of people such as an airport, attempting to monitor everyone is highly unrealistic. In this paper we propose an average soft biometric, that can be used to identity people who look distinct, and are thus suitable for monitoring through a large, sparse camera network. We demonstrate how an average soft biometric can be used to identify unique people to calculate operational measures such as the time taken to travel from point to point.

Experimentally induced diesel engine injector faults and some preliminary acoustic emission signal observations

Diesel engine fuel injector faults can lead to reduced power, increased fuel consumption and greater exhaust emission levels and if left unchecked, can eventually lead to premature engine failure. This paper provides an overview of the Diesel, or compression ignition combustion process, and of the two basic fuel injector nozzle designs used in Diesel engines, namely, the pintle-type and hole-type nozzles. Also described are some common faults associated with these two types of fuel injector nozzles and the techniques previously used to experimentally simulate these faults. This paper also presents a recent experimental campaign undertaken using two different diesel engines whereby various fuel injector nozzle faults were induced into the engines. The first series of tests was undertaken using a turbo-charged 5.9 litre; Cummins Diesel engine whist the second series of tests was undertaken using a naturally aspirated 4 cylinder, 2.216 litre, Perkins Diesel engine. Data corresponding to different injector fault conditions was captured using in-cylinder pressure, and acoustic emission transducers along with both crank-angle encoder and top-dead centre reference signals. Using averaged in-cylinder pressure signals, it was possible to qualify the severity of the faults whilst averaged acoustic emission signals were in turn, used as the basis for wavelets decomposition. Initial observations from this signal decomposition are also presented and discussed.

A study on acoustic emission signal propagation of a small size multi-cylinder diesel engine

Acoustic emission has been found effective in offering earlier fault detection and improving identification capabilities of faults. However, the sensors are inherently uncalibrated. This paper presents a source to sensor paths calibration technique which can lead to diagnosis of faults in a small size multi-cylinder diesel engine. Preliminary analysis of the acoustic emission (AE) signals is outlined, including time domain, time-frequency domain, and the root mean square (RMS) energy. The results reveal how the RMS energy of a source propagates to the adjacent sensors. The findings lead to allocate the source and estimate its inferences to the adjacent sensor, and finally help to diagnose the small size diesel engines by minimising the crosstalk from multiple cylinders.

New variational Bayesian approaches for statistical data mining : with applications to profiling and differentiating habitual consumption behaviour of customers in the wireless telecommunication industry

This thesis investigates profiling and differentiating customers through the use of statistical data mining techniques. The business application of our work centres on examining individuals’ seldomly studied yet critical consumption behaviour over an extensive time period within the context of the wireless telecommunication industry; consumption behaviour (as oppose to purchasing behaviour) is behaviour that has been performed so frequently that it become habitual and involves minimal intentions or decision making. Key variables investigated are the activity initialised timestamp and cell tower location as well as the activity type and usage quantity (e.g., voice call with duration in seconds); and the research focuses are on customers’ spatial and temporal usage behaviour. The main methodological emphasis is on the development of clustering models based on Gaussian mixture models (GMMs) which are fitted with the use of the recently developed variational Bayesian (VB) method. VB is an efficient deterministic alternative to the popular but computationally demandingMarkov chainMonte Carlo (MCMC) methods. The standard VBGMMalgorithm is extended by allowing component splitting such that it is robust to initial parameter choices and can automatically and efficiently determine the number of components. The new algorithm we propose allows more effective modelling of individuals’ highly heterogeneous and spiky spatial usage behaviour, or more generally human mobility patterns; the term spiky describes data patterns with large areas of low probability mixed with small areas of high probability. Customers are then characterised and segmented based on the fitted GMM which corresponds to how each of them uses the products/services spatially in their daily lives; this is essentially their likely lifestyle and occupational traits. Other significant research contributions include fitting GMMs using VB to circular data i.e., the temporal usage behaviour, and developing clustering algorithms suitable for high dimensional data based on the use of VB-GMM.

Perceptions of online learning in an Australian university : Malaysian students' perspectives

Several researchers have reported that cultural and language differences can affect online interactions and communications between students from different cultural backgrounds. Other researchers have asserted that online learning is a tool that can improve teaching and learning skills, but, its effectiveness depends on how the tool is used. Therefore, this study aims to investigate the kinds of challenges encountered by the international students and how they actually cope with online learning. To date little research exists on the perceptions of online learning environments by international Asian students, in particular Malaysian students who study in Australian Universities; hence this study aims to fill this gap. A mixed-method approach was used to collect quantitative and qualitative data using a modified Online Learning Environment Survey (OLES) instrument and focus group interviews. The sample comprised 76 international students from a university in Brisbane. Thirty-five domestic Australian students were included for comparison. Contrary to assumptions from previous research, the findings revealed that there were few differences between the international Asian students from Malaysia and Australian students with regard to their perceptions of online learning. Another cogent finding that emerged was that online learning was most effective when included within blended learning environments. The students clearly indicated that when learning in a blended environment, it was imperative that appropriate features are blended in and customised to suit the particular needs of international students. The study results indicated that the university could improve the quality of the blended online learning environment by: 1) establishing and maintaining a sense of learning community; 2) enhancing the self motivation of students; and 3) professional development of lecturers/tutors, unit coordinators and learning support personnel. Feedback from focus group interviews, highlighted the students‘ frustration with a lack of cooperative learning, strategies and skills which were expected of them by their lecturers/tutors in order to work productively in groups. They indicated a strong desire for lecturers/tutors to provide them prior training in these strategies and skills. The students identified four ways to optimise learning opportunities in cross-cultural spaces. These were: 1) providing preparatory and ongoing workshops focusing on the dispositions and roles of students within student-centred online learning environments; 2) providing preparatory and ongoing workshops on collaborative group learning strategies and skills; 3) providing workshops familiarising students with Australian culture and language; and 4) providing workshops on strategies for addressing technical problems. Students also indicated a strong desire for professional development of lecturers/tutors focused on: 1) teacher attributes, 2) ways to culturally sensitive curricula, and 3) collaborative learning and cooperative working strategies and skills, and 4) designing flexible program structures. Recommendations from this study will be useful to Australian universities where Asian international students from Malaysia study in blended learning environments. An induction program (online skills, collaborative and teamwork skills, study expectations plus familiarisation with Australian culture) for overseas students at the commencement of their studies; a cultural awareness program for lecturers (cultural sensitivity, ways to communicate and a better understanding of Asian educational systems), upskilling of lecturers‘ ability to structure their teaching online and to apply strong theoretical underpinnings when designing learning activities such as discussion forums, and consistency with regards to how content is located and displayed in a learning management system like Blackboard. Through addressing the research questions in this study, the researcher hopes to contribute to and advance the domain of knowledge related to online learning, and to better understand how international Malaysian students‘ perceive online learning environments. These findings have theoretical and pragmatic significance.

Development of the sustainable building and construction products industry in Australia

This paper draws on a major study the authors conducted for the Australian Government in 2009. It focuses on the diffusion issues surrounding the uptake of sustainable building and construction products in Australia. Innovative sustainable products can minimise the environmental impact during construction, while maximising asset performance, durability and re-use. However, there are significant challenges faced by designers and clients in the selection of appropriate sustainable products in consideration of the integrated design solution, including overall energy efficiency, water conservation, maintenance and durability, low-impact use and consumption. The paper is a review of the current state of sustainable energy and material product innovations in Australia. It examines the system dynamics surrounding these innovations as well as the drivers and obstacles to their diffusion throughout the Australian construction industry. The case product types reviewed comprise: solar energy technology, small wind turbines, advanced concrete technology, and warm-mixed asphalt. The conclusions highlight the important role played by Australian governments in facilitating improved adoption rates. This applies to governments in their various roles, but particularly as clients/owners, regulators, and investors in education, training, research and development. In their role as clients/owners, the paper suggests that government can better facilitate innovation within the construction industry by adjusting specification policies to encourage the uptake of sustainable products. In the role as regulators, findings suggest governments should be encouraging the application of innovative finance options and positive end-user incentives to promote sustainable product uptake. Also, further education for project-based firms and the client/end users about the long-term financial and environmental benefits of innovative sustainable products is required. As more of the economy’s resources are diverted away from business-as-usual and into the use of sustainable products, some project-based firms may face short-term financial pain in re-shaping their businesses. Government policy initiatives can encourage firms make the necessary adjustments to improve innovative sustainable product diffusion throughout the industry.

Technology : new horizons in teaching law

17.1 Up until the 1990s the methods used to teach the law had evolved little since the first law schools were established in Australia. As Keyes and Johnstone observed: In the traditional model, most teachers uncritically replicate the learning experiences that they had when students, which usually means that the dominant mode of instruction is reading lecture notes to large classes in which students are largely passive. Traditional legal education has been described in the following terms: Traditionally law is taught through a series of lectures, with little or no student involvement, and a tutorial programme. Sometimes tutorials are referred to as seminars but the terminology used is often insignificant: both terms refer to probably the only form of student participation that takes place throughout these students‘ academic legal education. The tutorial consists of analysing the answers, prepared in advanced (sic), to artificial Janet and John Doe problems or esoteric essay questions. The primary focus of traditional legal education is the transmission of content knowledge, more particularly the teaching of legal rules, especially those drawn from case law. This approach has a long pedigree. Writing in 1883, Dicey proposed that nothing can be taught to students of greater value, either intellectually or for the purposes of legal practice, than the habit of looking on the law as a series of rules‘.

Cerclage, evolution and potential of a Cinderella Technology : an overview with reference to periprosthetic fractures

Periprosthetic fractures are increasingly frequent. The fracture may be located over the shaft of the prosthesis, at its tip or below (21). The treatment of explosion fractures is difficult because the shaft blocks the application of implants, like screws, which need to penetrate the medullary cavity. The cerclage, as a simple periosteal loop, made of wire or more recently cable, does not only avoid the medullary cavity. Its centripetal mode of action is well suited for reducing and maintaining radially displaced fractures. Furthermore, the cerclage lends itself well for minimally invasive internal fixation. New insight challenges the disrepute of which the cerclage technology suffered for decades. The outcome of cerclage fixation benefits from an improved understanding of its technology, mechano-biology and periosteal blood supply. Preconceived and generally accepted opinions like "strangulation of blood supply" need to be re-examined. Recent mechanical evaluations (22) demonstrate that the wire application may be improved but cable is superior in hand- ling, maintenance of tension and strength. Beside the classical concepts of absolute and relative stability a defined stability condition needs consideration. It is typical for cerclage. Called "loose-lock stability" it specifies the situation where a loosened implant allows first unimpeded displacement changing abruptly into a locked fixation preventing further dislocation.