Haplotype analysis of two recurrent CDKN2A mutations in 10 melanoma families : evidence for common founders and independent mutations

Germ-line mutations in CDKN2A have been shown to predispose to cutaneous malignant melanoma. We have identified 2 new melanoma kindreds which carry a duplication of a 24bp repeat present in the 5' region of CDKN2A previously identified in melanoma families from Australia and the United States. This mutation has now been reported in 5 melanoma families from 3 continents: Europe, North America, and Australasia. The M53I mutation in exon 2 of CDKN2A has also been documented in 5 melanoma families from Australia and North America. The aim of this study was to determine whether the occurrence of the mutations in these families from geographically diverse populations represented mutation hotspots within CDKN2A or were due to common ancestors. Haplotypes of 11 microsatellite markers flanking CDKN2A were constructed in 5 families carrying the M53I mutation and 5 families carrying the 24bp duplication. There were some differences in the segregating haplotypes due primarily to recombinations and mutations within the short tandem-repeat markers; however, the data provide evidence to indicate that there were at least 3 independent 24bp duplication events and possibly only 1 original M53I mutation. This is the first study to date which indicates common founders in melanoma families from different continents.

Microarray expression profiling in melanoma reveals a BRAF mutation signature

We have used microarray gene expression profiling and machine learning to predict the presence of BRAF mutations in a panel of 61 melanoma cell lines. The BRAF gene was found to be mutated in 42 samples (69%) and intragenic mutations of the NRAS gene were detected in seven samples (11%). No cell line carried mutations of both genes. Using support vector machines, we have built a classifier that differentiates between melanoma cell lines based on BRAF mutation status. As few as 83 genes are able to discriminate between BRAF mutant and BRAF wild-type samples with clear separation observed using hierarchical clustering. Multidimensional scaling was used to visualize the relationship between a BRAF mutation signature and that of a generalized mitogen-activated protein kinase (MAPK) activation (either BRAF or NRAS mutation) in the context of the discriminating gene list. We observed that samples carrying NRAS mutations lie somewhere between those with or without BRAF mutations. These observations suggest that there are gene-specific mutation signals in addition to a common MAPK activation that result from the pleiotropic effects of either BRAF or NRAS on other signaling pathways, leading to measurably different transcriptional changes.

Quantifying in-plane deformation of plate elements using vibration characteristics

Plate elements are used in many engineering applications. In-plane loads and deformations have significant influence on the vibration characteristics of plate elements. Numerous methods have been developed to quantify the effects of in-plane loads and deformations of individual plate elements with different boundary conditions based on their natural frequencies. However, these developments cannot be applied to the plate elements in a structural system as the natural frequency is a global parameter for the entire structure. This highlights the need for a method to quantify in-plane deformations of plate elements in structural framing systems. Motivated by this gap in knowledge, this research has developed a comprehensive vibration based procedure to quantify in-plane deformation of plate elements in a structural framing system. This procedure with its unique capabilities to capture the influence of load migration, boundary conditions and different tributary areas is presented herein and illustrated through examples.

Vibration characteristics of concrete-steel composite floor structures

This paper discusses the vibration characteristics of a concrete-steel composite multi-panel floor structure; the use of these structures is becoming more common. These structures have many desirable properties but are prone to excessive and complex vibration, which is not currently well understood. Existing design codes and practice guides provide generic advice or simple techniques that cannot address the complex vibration in these types of low-frequency structures. The results of this study show the potential for an adverse dynamic response from higher and multi-modal excitation influenced by human-induced pattern loading, structural geometry, and activity frequency. Higher harmonics of the load frequency are able to excite higher modes in the composite floor structure in addition to its fundamental mode. The analytical techniques used in this paper can supplement the current limited code and practice guide provisions for mitigating the impact of human-induced vibrations in these floor structures.

Screening, isolation, and decolonisation strategies in the control of meticillin resistant Staphylococcus aureus in intensive care units : cost effectiveness evaluation

Objective: To assess the cost-effectiveness of screening, isolation and decolonisation strategies in the control of methicillin-resistant Staphylococcus aureus (MRSA) in intensive care units (ICUs). Design: Economic evaluation. Setting: England and Wales. Population: ICU patients. Main outcome measures: Infections, deaths, costs, quality adjusted life years (QALYs), incremental cost-effectiveness ratios for alternative strategies, net monetary benefits (NMBs). Results: All strategies using isolation but not decolonisation improved health outcomes but increased costs. When MRSA prevalence on admission to the ICU was 5% and the willingness to pay per QALY gained was between £20,000 and £30,000, the best such strategy was to isolate only those patients at high risk of carrying MRSA (either pre-emptively or following identification by admission and weekly MRSA screening using chromogenic agar). Universal admission and weekly screening using polymerase chain reaction (PCR)-based MRSA detection coupled with isolation was unlikely to be cost-effective unless prevalence was high (10% colonised with MRSA on admission to the ICU). All decolonisation strategies improved health outcomes and reduced costs. While universal decolonisation (regardless of MRSA status) was the most cost-effective in the short-term, strategies using screening to target MRSA carriers may be preferred due to reduced risk of selecting for resistance. Amongst such targeted strategies, universal admission and weekly PCR screening coupled with decolonisation with nasal mupirocin was the most cost-effective. This finding was robust to ICU size, MRSA admission prevalence, the proportion of patients classified as high-risk, and the precise value of willingness to pay for health benefits. Conclusions: MRSA control strategies that use decolonisation are likely to be cost-saving in an ICU setting provided resistance is lacking, and combining universal PCR-based screening with decolonisation is likely to represent good value for money if untargeted decolonisation is considered unacceptable. In ICUs where decolonisation is not implemented there is insufficient evidence to support universal MRSA screening outside high prevalence settings.

3D ellipsoid fitting for multi-view gait recognition

Gait recognition approaches continue to struggle with challenges including view-invariance, low-resolution data, robustness to unconstrained environments, and fluctuating gait patterns due to subjects carrying goods or wearing different clothes. Although computationally expensive, model based techniques offer promise over appearance based techniques for these challenges as they gather gait features and interpret gait dynamics in skeleton form. In this paper, we propose a fast 3D ellipsoidal-based gait recognition algorithm using a 3D voxel model derived from multi-view silhouette images. This approach directly solves the limitations of view dependency and self-occlusion in existing ellipse fitting model-based approaches. Voxel models are segmented into four components (left and right legs, above and below the knee), and ellipsoids are fitted to each region using eigenvalue decomposition. Features derived from the ellipsoid parameters are modeled using a Fourier representation to retain the temporal dynamic pattern for classification. We demonstrate the proposed approach using the CMU MoBo database and show that an improvement of 15-20% can be achieved over a 2D ellipse fitting baseline.

Planning of distribution networks for medium voltage and low voltage

Determination of the placement and rating of transformers and feeders are the main objective of the basic distribution network planning. The bus voltage and the feeder current are two constraints which should be maintained within their standard range. The distribution network planning is hardened when the planning area is located far from the sources of power generation and the infrastructure. This is mainly as a consequence of the voltage drop, line loss and system reliability. Long distance to supply loads causes a significant amount of voltage drop across the distribution lines. Capacitors and Voltage Regulators (VRs) can be installed to decrease the voltage drop. This long distance also increases the probability of occurrence of a failure. This high probability leads the network reliability to be low. Cross-Connections (CC) and Distributed Generators (DGs) are devices which can be employed for improving system reliability. Another main factor which should be considered in planning of distribution networks (in both rural and urban areas) is load growth. For supporting this factor, transformers and feeders are conventionally upgraded which applies a large cost. Installation of DGs and capacitors in a distribution network can alleviate this issue while the other benefits are gained. In this research, a comprehensive planning is presented for the distribution networks. Since the distribution network is composed of low and medium voltage networks, both are included in this procedure. However, the main focus of this research is on the medium voltage network planning. The main objective is to minimize the investment cost, the line loss, and the reliability indices for a study timeframe and to support load growth. The investment cost is related to the distribution network elements such as the transformers, feeders, capacitors, VRs, CCs, and DGs. The voltage drop and the feeder current as the constraints are maintained within their standard range. In addition to minimizing the reliability and line loss costs, the planned network should support a continual growth of loads, which is an essential concern in planning distribution networks. In this thesis, a novel segmentation-based strategy is proposed for including this factor. Using this strategy, the computation time is significantly reduced compared with the exhaustive search method as the accuracy is still acceptable. In addition to being applicable for considering the load growth, this strategy is appropriate for inclusion of practical load characteristic (dynamic), as demonstrated in this thesis. The allocation and sizing problem has a discrete nature with several local minima. This highlights the importance of selecting a proper optimization method. Modified discrete particle swarm optimization as a heuristic method is introduced in this research to solve this complex planning problem. Discrete nonlinear programming and genetic algorithm as an analytical and a heuristic method respectively are also applied to this problem to evaluate the proposed optimization method.

Performance load testing and structural adequacy evaluation of road bridge decks

Many ageing road bridges, particularly timber bridges, require urgent improvement due to the demand imposed by the recent version of the Australian bridge loading code, AS 5100. As traffic volume plays a key role in the decision of budget allocations for bridge refurbishment/ replacement, many bridges in low volume traffic network remain in poor condition with axle load and/ or speed restrictions, thus disadvantaging many rural communities. This thesis examines an economical and environmentally sensible option of incorporating disused flat rail wagons (FRW) in the construction of bridges in low volume, high axle load road network. The constructability, economy and structural adequacy of the FRW road bridge is reported in the thesis with particular focus of a demonstration bridge commissioned in regional Queensland. The demonstration bridge comprises of a reinforced concrete slab (RCS) pavement resting on two FRWs with custom designed connection brackets at regular intervals along the span of the bridge. The FRW-RC bridge deck assembly is supported on elastomeric rubber pads resting on the abutment. As this type of bridge replacement technology is new and its structural design is not covered in the design standards, the in-service structural performance of the FRW bridge subjected to the high axle loadings prescribed in AS 5100 is examined through performance load testing. Both the static and the moving load tests are carried out using a fully laden commonly available three-axle tandem truck. The bridge deck is extensively strain gauged and displacement at several key locations is measured using linear variable displacement transducers (LVDTs). A high speed camera is used in the performance test and the digital image data are analysed using proprietary software to capture the locations of the wheel positions on the bridge span accurately. The wheel location is thus synchronised with the displacement and strain time series to infer the structural response of the FRW bridge. Field test data are used to calibrate a grillage model, developed for further analysis of the FRW bridge to various sets of high axle loads stipulated in the bridge design standard. Bridge behaviour predicted by the grillage model has exemplified that the live load stresses of the FRW bridge is significantly lower than the yield strength of steel and the deflections are well below the serviceability limit state set out in AS 5100. Based on the results reported in this thesis, it is concluded that the disused FRWs are competent to resist high axle loading prescribed in AS 5100 and are a viable alternative structural solution of bridge deck in the context of the low volume road networks.

Continuum of police crime : an empirical study of court cases

The great majority of police officers are committed to honourable and competent public service and consistently demonstrate integrity and accountability in carrying out the often difficult, complex and sometimes dangerous, activities involved in policing by consent. However, in every police agency there exists an element of dishonesty, lack of professionalism and criminal behaviour. This article is based on archival research of criminal behaviour in the Norwegian police force. A total of 60 police employees were prosecuted in court because of misconduct and crime from 2005 to 2010. Court cases were coded as two potential predictors of court sentence in terms of imprisonment days, ie, type of deviance and level of deviance. Categories of police crime and levels were organised according to a conceptual framework developed for assessing and managing police deviance. Empirical findings support the hypothesis that as the seriousness of police crime increases in breadth and depth so also does the severity of the court sentence as measured by time in prison.

Exploratory investigation of atmospheric total suspended particulate matter and heavy metals in urban air

Atmospheric concentration of total suspended particulate matter (TSP) and associated heavy metals are a great concern due to their adverse health impacts and contribution to stormwater pollution. This paper discusses the outcomes of a study which investigated the variation of atmospheric TSP and heavy metal concentrations with traffic and land use characteristics during weekdays and weekends. Data for this study was gathered from fifteen sites at the Gold Coast, Australia using a high volume air sampler. The study detected consistently high TSP concentrations during weekdays compared to weekends. This confirms the significant influence of traffic related sources on TSP loads during weekdays. Both traffic and land use related sources equally contribute to TSP during weekends. Almost all the measured heavy metals showed high concentration on weekdays compared to weekends indicating significant contributions from traffic related emissions. Among the heavy metals, Zn concentration was the highest followed by Pb. It is postulated that re-suspension of previously deposited reserves was the main Pb source. Soil related sources were the main contributors of Mn.

Comparing the medium-term effects of exercise or dietary restriction on appetite regulation and compensatory responses

Previous studies have shown that exercise (Ex) interventions create a stronger coupling between energy intake (EI) and energy expenditure (EE) leading to increased homeostasis of the energy-balance (EB) regulatory system compared to a diet intervention where an un-coupling between EI and EE occurs. The benefits of weight loss from Ex and diet interventions greatly depend on compensatory responses. The present study investigated an 8-week medium-term Ex and diet intervention program (Ex intervention comprised of 500kcal EE five days per week over four weeks at 65-75% maximal heart rate, whereas the diet intervention comprised of a 500kcal decrease in EI five days per week over four weeks) and its effects on compensatory responses and appetite regulation among healthy individuals using a between- and within-subjects design. Effects of an acute dietary manipulation on appetite and compensatory behaviours and whether a diet and/or Ex intervention pre-disposes individuals to disturbances in EB homeostasis were tested. Energy intake at an ad libitum lunch test meal after a breakfast high- and low-energy pre-load (the high energy pre-load contained 556kcal and the low energy pre-load contained 239kcal) were measured at the Baseline (Weeks -4 to 0) and Intervention (Weeks 0 to 4) phases in 13 healthy volunteers (three males and ten females; mean age 35 years [sd + 9] and mean BMI 25 kg/m2 [sd + 3.8]) [participants in each group included Ex=7, diet=5 (one female in the diet group dropped out midway), thus, 12 participants completed the study]. At Weeks -4, 0 and 4, visual analogue scales (VAS) were used to assess hunger and satiety and liking and wanting (L&W) for nutrient and taste preferences using a computer-based system (E-Prime v1.1.4). Ad libitum test meal EI was consistently lower after the HE pre-load compared to the LE pre-load. However, this was not consistent during the diet intervention however. A pre-load x group interaction on ad libitum test meal EI revealed that during the intervention phase the Ex group showed an improved sensitivity to detect the energy content between the two pre-loads and improved compensation for the ad libitum test meal whereas the diet group’s ability to differentiate between the two pre-loads decreased and showed poorer compensation (F[1,10]=2.88, p-value not significant). This study supports previous findings of the effect Ex and diet interventions have on appetite and compensatory responses; Ex increases and diet decreases energy balance sensitivity.

Protection of microgrids using differential relays

A microgrid provides economical and reliable power to customers by integrating distributed resources more effectively. Islanded operation enables a continuous power supply for loads during a major grid disturbance. Reliability of a microgrid can be further increased by forming a mesh configuration. However, the protection of mesh microgrids is a challenging task. In this paper, protection schemes are discussed using current differential protection of a microgrid. The protection challenges associated with bi-directional power flow, meshed configuration, changing fault current level due to intermittent nature of DGs and reduced fault current level in an islanded mode are considered in proposing the protection solutions. Relay setting criterion and current transformer (CT) selection guidelines are also discussed. The results are verified using MATLAB calculations and PSCAD simulations.

Pharmacological consequence of the A118G μ opioid receptor polymorphism on morphine-and fentanyl-mediated modulation of Ca2+ channels in humanized mouse sensory neurons

Background: The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele. Methods: The coupling of wild-type and mutant μ opioid receptors to voltage-gated Ca channels after exposure to either ligand was examined by employing the whole cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele. RESULTS:: The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately fivefold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared with the 118AA mice. Conclusions: This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor's pharmacology in sensory neurons. In addition, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids. © 2011 the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology.

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

Mapping intermedia news flows : topical discussions in the Australian and French political blogospheres

The growth of technologies and tools branded as =new media‘ or =Web 2.0‘ has sparked much discussion about the internet and its place in all facets of social life. Such debate includes the potential for blogs and citizen journalism projects to replace or alter journalism and mainstream media practices. However, while the journalism-blog dynamic has attracted the most attention, the actual work of political bloggers, the roles they play in the mediasphere and the resources they use, has been comparatively ignored. This project will look at political blogging in Australia and France - sites commenting on or promoting political events and ideas, and run by citizens, politicians, and journalists alike. In doing so, the structure of networks formed by bloggers and the nature of communication within political blogospheres will be examined. Previous studies of political blogging around the world have focussed on individual nations, finding that in some cases the networks are divided between different political ideologies. By comparing two countries with different political representation (two-party dominated system vs. a wider political spectrum), this study will determine the structure of these political blogospheres, and correlate these structures with the political environment in which they are situated. The thesis adapts concepts from communication and media theories, including framing, agenda setting, and opinion leaders, to examine the work of political bloggers and their place within the mediasphere. As well as developing a hybrid theoretical base for research into blogs and other online communication, the project outlines new methodologies for carrying out studies of online activity through the analysis of several topical networks within the wider activity collected for this project. The project draws on hyperlink and textual data collected from a sample of Australian and French blogs between January and August 2009. From this data, the thesis provides an overview of =everyday‘ political blogging, showing posting patterns over several months of activity, away from national elections and their associated campaigns. However, while other work in this field has looked solely at cumulative networks, treating collected data as a static network, this project will also look at specific cases to see how the blogospheres change with time and topics of discussion. Three case studies are used within the thesis to examine how blogs cover politics, featuring an international political event (the Obama inauguration), and local political topics (the opposition to the =Création et Internet‘, or HADOPI, law in France, the =Utegate‘ scandal in Australia). By using a mixture of qualitative and quantitative methods, the study analyses data collected from a population of sites from both countries, looking at their linking patterns, relationship with mainstream media, and topics of interest. This project will subsequently help to further develop methodologies in this field and provide new and detailed information on both online networks and internet-based political communication in Australia and France.