Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma

We report that 10% of melanoma tumors and cell lines harbor mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. These novel mutations include three truncating mutations and 20 missense mutations occurring at evolutionary conserved residues in FGFR2 as well as among all four FGFRs. The mutation spectrum is characteristic of those induced by UV radiation. Mapping of these mutations onto the known crystal structures of FGFR2 followed by in vitro and in vivo studies show that these mutations result in receptor loss of function through several distinct mechanisms, including loss of ligand binding affinity, impaired receptor dimerization, destabilization of the extracellular domains, and reduced kinase activity. To our knowledge, this is the first demonstration of loss-of-function mutations in a class IV receptor tyrosine kinase in cancer. Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer.

Vertical growth and resonator properties of hexagonally shaped zinc oxide nanonails

We synthesized vertically aligned nail-shaped ZnO nanocrystal arrays on silicon substrates via a combination of a carbothermal reduction method and textured ZnO seeding layers that were precoated on silicon substrates by thermally decomposing zinc acetate, and studied their optical properties using cathodoluminescence (CL) and photoluminescence techniques. The ZnO nanonails show a sharp band-gap edge UV emission and a defect-related broad green emission. Monochromatic CL images of an individual ZnO nanonail show variations in spatial distributions of respective CL bands that had different origins. We attribute the spatial variation of CL images to an uneven distribution of luminescent defects and/or a structure-related light out-coupling from hexagonal ZnO nanostructures. The most distinct CL feature from the hexagonal head of an individual ZnO nanonail was the occurrence of a series of distinct resonant peaks within the visible wavelength range. It appeared that the head of a nanonail played the role of a hexagonal cavity so that polarizationdependent whispering gallery modes were stimulated by electron beam excitation.

Assessment of retinal structure and visual function in association with diabetic peripheral neuropathy

Diabetes is an increasingly prevalent disease worldwide. Providing early management of the complications can prevent morbidity and mortality in this population. Peripheral neuropathy, a significant complication of diabetes, is the major cause of foot ulceration and amputation in diabetes. Delay in attending to complication of the disease contributes to significant medical expenses for diabetic patients and the community. Early structural changes to the neural components of the retina have been demonstrated to occur prior to the clinically visible retinal vasculature complication of diabetic retinopathy. Additionally visual functionloss has been shown to exist before the ophthalmoscopic manifestations of vasculature damage. The purpose of this thesis was to evaluate the relationship between diabetic peripheral neuropathy and both retinal structure and visual function. The key question was whether diabetic peripheral neuropathy is the potential underlying factor responsible for retinal anatomical change and visual functional loss in people with diabetes. This study was conducted on a cohort with type 2 diabetes. Retinal nerve fibre layer thickness was assessed by means of Optical Coherence Tomography (OCT). Visual function was assessed using two different methods; Standard Automated Perimetry (SAP) and flicker perimetry were performed within the central 30 degrees of fixation. The level of diabetic peripheral neuropathy (DPN) was assessed using two techniques - Quantitative Sensory Testing and Neuropathy Disability Score (NDS). These techniques are known to be capable of detecting DPN at very early stages. NDS has also been shown as a gold standard for detecting 'risk of foot ulceration'. Findings reported in this thesis showed that RNFL thickness, particularly in the inferior quadrant, has a significant association with severity of DPN when the condition has been assessed using NDS. More specifically it was observed that inferior RNFL thickness has the ability to differentiate individuals who are at higher risk of foot ulceration from those who are at lower risk, indicating that RNFL thickness can predict late-staged DPN. Investigating the association between RNFL and QST did not show any meaningful interaction, which indicates that RNFL thickness for this cohort was not as predictive of neuropathy status as NDS. In both of these studies, control participants did not have different results from the type 2 cohort who did not DPN suggesting that RNFL thickness is not a marker for diagnosing DPN at early stages. The latter finding also indicated that diabetes per se, is unlikely to affect the RNFL thickness. Visual function as measured by SAP and flicker perimetry was found to be associated with severity of peripheral neuropathy as measured by NDS. These findings were also capable of differentiating individuals at higher risk of foot ulceration; however, visual function also proved not to be a maker for early diagnosis of DPN. It was found that neither SAP, nor flicker sensitivity have meaningful associations with DPN when neuropathy status was measured using QST. Importantly diabetic retinopathy did not explain any of the findings in these experiments. The work described here is valuable as no other research to date has investigated the association between diabetic peripheral neuropathy and either retinal structure or visual function.

Frequency response function based structural damage detection using artificial neural networks

Damage detection in structures has become increasingly important in recent years. While a number of damage detection and localization methods have been proposed, few attempts have been made to explore the structure damage with frequency response functions (FRFs). This paper illustrates the damage identification and condition assessment of a beam structure using a new frequency response functions (FRFs) based damage index and Artificial Neural Networks (ANNs). In practice, usage of all available FRF data as an input to artificial neural networks makes the training and convergence impossible. Therefore one of the data reduction techniques Principal Component Analysis (PCA) is introduced in the algorithm. In the proposed procedure, a large set of FRFs are divided into sub-sets in order to find the damage indices for different frequency points of different damage scenarios. The basic idea of this method is to establish features of damaged structure using FRFs from different measurement points of different sub-sets of intact structure. Then using these features, damage indices of different damage cases of the structure are identified after reconstructing of available FRF data using PCA. The obtained damage indices corresponding to different damage locations and severities are introduced as input variable to developed artificial neural networks. Finally, the effectiveness of the proposed method is illustrated and validated by using the finite element modal of a beam structure. The illustrated results show that the PCA based damage index is suitable and effective for structural damage detection and condition assessment of building structures.

Periodically forced natural convection through the roof of an attic-shaped building

In this study, numerical simulations of natural convection in an attic space subject to diurnal temperature condition on the sloping wall have been carried out. An explanation of choosing the period of periodic thermal effect has been given with help of the scaling analysis which is available in the literature. Moreover, the effects of the aspect ratio and Rayleigh number on the fluid flow and heat transfer have been discussed in details as well as the formation of a pitchfork bifurcation of the flow at the symmetric line of the enclosure.

Re-thinking how we plan to address technically complex problems : drawing on planning theory to guide practice in revision of land use plans in coastal high hazard zones

Queensland's new State Planning Policy for Coastal Protection, released in March and approved in April 2011 as part of the Queensland Coastal Plan, stipulates that local governments prepare and implement adaptation strategies for built up areas projected to be subject to coastal hazards between present day and 2100. Urban localities within the delineated coastal high hazard zone (as determined by models incorporating a 0.8 meter rise in sea level and a 10% increase in the maximum cyclone activity) will be required to re-evaluate their plans to accommodate growth, revising land use plans to minimise impacts of anticipated erosion and flooding on developed areas and infrastructure. While implementation of such strategies would aid in avoidance or minimisation of risk exposure, communities are likely to face significant challenges in such implementation, especially as development in Queensland is so intensely focussed upon its coasts with these new policies directing development away from highly desirable waterfront land. This paper examines models of planning theory to understand how we plan when faced with technically complex problems towards formulation of a framework for evaluating and improving practice.

An exploration of young students' ability to generalise function tasks

The Early Years Generalising Project involves Australian students, Years 1-4 (age 5-9), and explores how the students grasp and express generalisations. This paper focuses on the data collected from clinical interviews with Year 3 and 4 cohorts in an investigative study focusing on the identifications, prediction and justification of function rules. It reports on students' attempts to generalise from function machine contexts, describing the various ways students express generalisation and highlighting the different levels of justification given by students. Finally, we conjecture that there are a set of stages in the expression and justification of generalisations that assist students to reach generality within tasks.

Older drivers’ insight into their hazard perception ability

Even though the driving ability of older adults may decline with age, there is evidence that some individuals attempt to compensate for these declines using strategies such as restricting their driving exposure. Such compensatory mechanisms rely on drivers’ ability to evaluate their own driving performance. This paper focuses on one key aspect of driver ability that is associated with crash risk and has been found to decline with age: hazard perception. Three hundred and seven drivers, aged 65 to 96, completed a validated video-based hazard perception test. There was no significant relationship between hazard perception test response latencies and drivers’ ratings of their hazard perception test performance, suggesting that their ability to assess their own test performance was poor. Also, age related declines in hazard perception latency were not reflected in drivers’ self-ratings. Nonetheless, ratings of test performance were associated with self-reported regulation of driving, as was self-rated driving ability. These findings are consistent with the proposal that, while self-assessments of driving ability may be used by drivers to determine the degree to which they restrict their driving, the problem is that drivers have little insight into their own driving ability. This may impact on the potential road safety benefits of self-restriction of driving because drivers may not have the information needed to optimally self-restrict. Strategies for addressing this problem are discussed.

The role of cognitive and visual abilities as predictors in the Multifactorial Model of Driving Safety

Objective The current study evaluated part of the Multifactorial Model of Driving Safety to elucidate the relative importance of cognitive function and a limited range of standard measures of visual function in relation to the Capacity to Drive Safely. Capacity to Drive Safely was operationalized using three validated screening measures for older drivers. These included an adaptation of the well validated Useful Field of View (UFOV) and two newer measures, namely a Hazard Perception Test (HPT), and a Hazard Change Detection Task (HCDT). Method Community dwelling drivers (n = 297) aged 65–96 were assessed using a battery of measures of cognitive and visual function. Results Factor analysis of these predictor variables yielded factors including Executive/Speed, Vision (measured by visual acuity and contrast sensitivity), Spatial, Visual Closure, and Working Memory. Cognitive and Vision factors explained 83–95% of age-related variance in the Capacity to Drive Safely. Spatial and Working Memory were associated with UFOV, HPT and HCDT, Executive/Speed was associated with UFOV and HCDT and Vision was associated with HPT. Conclusion The Capacity to Drive Safely declines with chronological age, and this decline is associated with age-related declines in several higher order cognitive abilities involving manipulation and storage of visuospatial information under speeded conditions. There are also age-independent effects of cognitive function and vision that determine driving safety.

Acoustic hazard detection for pedestrians with obscured hearing

Pedestrians’ use of mp3 players or mobile phones can pose the risk of being hit by motor vehicles. We present an approach for detecting a crash risk level using the computing power and the microphone of mobile devices that can be used to alert the user in advance of an approaching vehicle so as to avoid a crash. A single feature extractor classifier is not usually able to deal with the diversity of risky acoustic scenarios. In this paper, we address the problem of detection of vehicles approaching a pedestrian by a novel, simple, non resource intensive acoustic method. The method uses a set of existing statistical tools to mine signal features. Audio features are adaptively thresholded for relevance and classified with a three component heuristic. The resulting Acoustic Hazard Detection (AHD) system has a very low false positive detection rate. The results of this study could help mobile device manufacturers to embed the presented features into future potable devices and contribute to road safety.

Variational Bayes and the reduced dependence approximation for the autologistic model on an irregular grid with applications

Discrete Markov random field models provide a natural framework for representing images or spatial datasets. They model the spatial association present while providing a convenient Markovian dependency structure and strong edge-preservation properties. However, parameter estimation for discrete Markov random field models is difficult due to the complex form of the associated normalizing constant for the likelihood function. For large lattices, the reduced dependence approximation to the normalizing constant is based on the concept of performing computationally efficient and feasible forward recursions on smaller sublattices which are then suitably combined to estimate the constant for the whole lattice. We present an efficient computational extension of the forward recursion approach for the autologistic model to lattices that have an irregularly shaped boundary and which may contain regions with no data; these lattices are typical in applications. Consequently, we also extend the reduced dependence approximation to these scenarios enabling us to implement a practical and efficient non-simulation based approach for spatial data analysis within the variational Bayesian framework. The methodology is illustrated through application to simulated data and example images. The supplemental materials include our C++ source code for computing the approximate normalizing constant and simulation studies.

Genetic evidence for the vital function of osterix in cementogenesis

To date, attempts to regenerate a complete tooth, including the critical periodontal tissues associated with the tooth root, have not been successful. Controversy still exists regarding the origin of the cell source for cellular cementum (epithelial or mesenchymal). This disagreement may be partially due to a lack of understanding of the events leading to the initiation and development of the tooth roots and supportive tissues, such as the cementum. Osterix (OSX) is a transcriptional factor essential for osteogenesis, but its role in cementogenesis has not been addressed. In the present study, we first documented a close relationship between the temporal- and spatial-expression pattern of OSX and the formation of cellular cementum. We then generated 3.6 Col 1-OSX transgenic mice, which displayed accelerated cementum formation vs. WT controls. Importantly, the conditional deletion of OSX in the mesenchymal cells with two different Cre systems (the 2.3 kb Col 1 and an inducible CAG-CreER) led to a sharp reduction in cellular cementum formation (including the cementum mass and mineral deposition rate) and gene expression of dentin matrix protein 1 (DMP1) by cementocytes. However, the deletion of the OSX gene after cellular cementum formed did not alter the properties of the mature cementum as evaluated by backscattered SEM and resin-cast SEM. Transient transfection of Osx in the cementoblasts in vitro significantly inhibited cell proliferation and increased cell differentiation and mineralization. Taken together, these data support 1) the mesenchymal origin of cellular cementum (from PDL progenitor cells); 2) the vital role of OSX in controlling the formation of cellular cementum; and 3) the limited remodeling of cellular cementum in adult mice.