Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10-5), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10-4) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10-9). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

Growth patterns in preterm infants born appropriate for gestational age

Aim: This study aimed to document the growth patterns of a contemporary cohort of preterm infants born appropriate for gestational age (AGA). It was hypothesised that preterm AGA (PT-AGA) infants would display poorer growth than full-term AGA (FT-AGA) infants. Methods: Sixty-four PT-AGA infants and 64 FT-AGA infants were assessed at 0, 4, 8 and 12 months of corrected age (CA). Measurements of weight and length were recorded at each of the specified ages. Centers for Disease Control and Prevention growth data were used to calculate Z-scores for weight and length based on CA. Results: The mean length and weight Z-scores of PT-AGA infants were found to be significantly less than those of FT-AGA infants at term, 4, 8 and 12 months of CA (P < 0.001). The mean weight Z-score of PT-AGA infants was found to be less than their mean length Z-score at each time point, though the differences were not significant. Conclusions: The results of this study suggest that PT-AGA infants are likely to display poorer growth than FT-AGA infants until at least 1 year of CA. Long-term growth monitoring in this population is recommended. © 2008 The Authors.

BPMN process views construction

Process view technology is catching more attentions in modern business process management, as it enables the customisation of business process representation. This capability helps improve the privacy protection, authority control, flexible display, etc., in business process modelling. One of approaches to generate process views is to allow users to construct an aggregate on their underlying processes. However, most aggregation approaches stick to a strong assumption that business processes are always well-structured, which is over strict to BPMN. Aiming to build process views for non-well-structured BPMN processes, this paper investigates the characteristics of BPMN structures, tasks, events, gateways, etc., and proposes a formal process view aggregation approach to facilitate BPMN process view creation. A set of consistency rules and construction rules are defined to regulate the aggregation and guarantee the order preservation, structural and behaviour correctness and a novel aggregation technique, called EP-Fragment, is developed to tackle non-well-structured BPMN processes.

Metal-free graphitic carbon nitride as mechano-catalyst for hydrogen evolution reaction

Graphitic carbon nitride (g-C3N4), as a promising metal-free catalyst for photo-catalytic and electrochemical water splitting, has recently attracted tremendous research interest. However, the underlying catalytic mechanism for the hydrogen evolution reaction (HER) is not fully understood. By using density functional theory calculations, here we have established that the binding free energy of hydrogen atom (ΔGH∗0) on g-C3N4 is very sensitive to mechanical strain, leading to substantial tuning of the HER performance of g-C3N4 at different coverages. The experimentally-observed high HER activity in N-doped graphene supported g-C3N4 (Zheng et al., 2014) is actually attributed to electron-transfer induced strain. A more practical strategy to induce mechanical strain in g-C3N4 is also proposed by doping a bridge carbon atom in g-C3N4 with an isoelectronic silicon atom. The calculated ΔGH∗0 on the Si-doped g-C3N4 is ideal for HER. Our results indicate that g-C3N4 would be an excellent metal-free mechano-catalyst for HER and this finding is expected to guide future experiments to efficiently split water into hydrogen based on the g-C3N4 materials.

A follow up MRI-based geometry and computational fluid dynamics study of carotid bifurcation

Cardiovascular disease is the leading causes of death in the developed world. Wall shear stress (WSS) is associated with the initiation and progression of atherogenesis. This study combined the recent advances in MR imaging and computational fluid dynamics (CFD) and evaluated the patient-specific carotid bifurcation. The patient was followed up for 3 years. The geometry changes (tortuosity, curvature, ICA/CCA area ratios, central to the cross-sectional curvature, maximum stenosis) and the CFD factors (Velocity distribute, Wall Shear Stress (WSS) and Oscillatory Shear Index (OSI)) were compared at different time points.The carotid stenosis was a slight increase in the central to the cross-sectional curvature, and it was minor and variable curvature changes for carotid centerline. The OSI distribution presents ahigh-values in the same region where carotid stenosis and normal border, indicating complex flow and recirculation.The significant geometric changes observed during the follow-up may also cause significant changes in bifurcation hemodynamics.

Effect of inflow and outflow angles on the computational hemodynamics in abdominal aortic aneurysm

To help with the clinical screening and diagnosis of abdominal aortic aneurysm (AAA), we evaluated the effect of inflow angle (IA) and outflow bifurcation angle (BA) on the distribution of blood flow and wall shear stress (WSS) in an idealized AAA model. A 2D incompressible Newtonian flow is assumed and the computational simulation is performed using finite volume method. The results showed that the largest WSS often located at the proximal and the distal end of the AAA. An increase in IA resulted in an increase in maximum WSS. We also found that WSS was maximal when BA was 90°. IA and BA are two important geometrical factors, they may help with AAA risk assessment along with the commonly used AAA diameter.

Mechanical analysis of foot plantar fascia during normal walking condition

Foot plantar fascia is an important foot tissue in stabilizing the longitudinal arch of human foot. Direct measurement to monitor the mechanical situation of plantar fascia at human locomotion is difficult. The purpose of this study was to construct a three-dimensional finite element model of the foot to calculate the internal stress/strain value of plantar fascia during different stage of gait. The simulated stress distribution of plantar fascia was the lowest at heel-strike, which concentrated on the medial side of calcaneal tubercle. The peak stress of plantar fascia was appeared at push-off, and the value is more than 5 times of the heel-strike position. Current FE model was able to explore the plantar fascia tension trend at the main sub-phases of foot. More detailed fascia model and intrinsic muscle forces could be developed in the further study.

Stress analysis of carotid plaque based on in vivo MRI of acute symptomatic and asymptomatic patients

Stress analysis within carotid plaques based on in vivo MR imaging has shown to be useful for the identification of vulnerable atheroma. This study is to investigate whether magnetic resonance imaging (MRI) based-biomechanical stress analysis of carotid plaques can differentiate acute symptomatic and asymptomatic patients. 54 asymptomatic and 45 acute symptomatic patients underwent in vivo multi-contrast MRI of the carotid arteries. Plaque geometry used for finite element analysis was derived from in vivo MR images at the site of maximum and minimum plaque burden. In total 198 slices were used for the computational simulations. A pre shrink technique was used to refine the simulation. Maximum principle stress at the vulnerable plaque sites (i.e. critical stress) was extracted for the selected slices and a comparison was performed between the two groups. Critical stress at the site of maximum plaque burden is significantly higher in acute symptomatic patients as compared to asymptomatic patients [median: 198.0kPa (inter quartile range (IQR) = (119.8 - 359.0) vs. 138.4kPa (83.8, 242.6), p=0.04]. No significant difference was found at the minimum plaque burden site between the two groups [196.7kPa (133.3- 282.7) vs. 182.4kPa (117.2 - 310. 6), p=0.82). Stress analysis at the site of maximal plaque burden can be effectively used for differentiating acute symptomatic carotid plaques from asymptomatic plaques. This maybe potentially used for development of biomechanical risk stratification criteria based on plaque burden in future studies.

Curvedness study on atherosclerosis plaques and its implications to plaque stress

Atherosclerosis plaque rupture has been considered to be a mechanical failure of the thin fibrous cap, resulted from extreme plaque stress. Plaque stress was affected by many factors from morphological features to biological abnormalities. In this study, geometrical factors (curvedness, fibrous cap thickness) were studied on assessing plaque vulnerability in comparison with stress analysis results obtained by fluid structure interaction from 20 human carotid atherosclerosis plaques. The results show that plaque surface curvedness could contribute to extreme stress level, especially in plaque shoulder region. General plaque stress distribution could be predicted by fibrous cap thickness and curvedness with multi-regression model. With more features included in the regression model, plaque stress could be easily calculated and used to assess plaque vulnerability.

Working-correlation-structure identification in generalized estimating equations

Selecting an appropriate working correlation structure is pertinent to clustered data analysis using generalized estimating equations (GEE) because an inappropriate choice will lead to inefficient parameter estimation. We investigate the well-known criterion of QIC for selecting a working correlation Structure. and have found that performance of the QIC is deteriorated by a term that is theoretically independent of the correlation structures but has to be estimated with an error. This leads LIS to propose a correlation information criterion (CIC) that substantially improves the QIC performance. Extensive simulation studies indicate that the CIC has remarkable improvement in selecting the correct correlation structures. We also illustrate our findings using a data set from the Madras Longitudinal Schizophrenia Study.

From challenges to activities: Categories of play in videogames

Creating better gameplay experiences is dependent upon understand the act of gameplay. An expert focus group of games researchers, designers and players refined 16 activity categories from an existing list of 30 commonly used videogame challenges. Identifying categories of play activities has future potential to facilitate better research design and game design.

Transcending disciplinary, cultural and national boundaries: Emergent technologies, new education landscape and the cloud workshop project

As technology continues to become more accessible, miniaturised and diffused into the environment, the potential of wearable technology to impact our lives in significant ways becomes increasingly viable. Wearables afford unique interaction, communication and functional capabilities between users, their environment as well as access to information and digital data. Wearables also demand an inter-disciplinary approach and, depending on the purpose, can be fashioned to transcend cultural, national and spatial boundaries. This paper presents the Cloud Workshop project based on the theme of ‘Wearables and Wellbeing; Enriching connections between citizens in the Asia-Pacific region’, initiated through a cooperative partnership between Queensland University of Technology (QUT), Hong Kong Baptist University (HKBU) and Griffith University (GU). The project was unique due to its inter-disciplinary, inter-cultural and inter-national scope that occurred simultaneously between Australia and Hong Kong.

Multiple roles of transfer prices: One vs. two books

This paper investigates multiple roles of transfer prices for shipments of goods and services between entities of a multinational enterprise. At the center is the role of transfer pricing (TP) in tax manipulation, but other roles having to do with internal operations or strategic delegation, etc. are also considered. The interesting question is to what extent and how the different roles of TPs interfere with each other. The answer depends on whether companies use one or two books, i.e. whether they (can) apply different TPs for different purposes. We illustrate, in a stylized model, the competing aims of tax manipulation and strategic delegation. Finally, we briefly look at selected reform proposals, concluding that either TP problems are not addressed, or else new distortions will be introduced instead.

Governing child care in neoliberal times: Discursive constructions of children as economic units and early childhood educators as investment brokers

At any given time in the field of early childhood, there are discourses at play, producing images of children, and these ways of seeing children might be competing, colliding and/or complementing each other. It is fairly widely accepted that in many countries there are versions of dominant discourses that shape and are shaped by current practices in the field of early childhood. These include (1) romantic notions of children running free and connecting with nature and (2) the ‘Bart Simpson’ version of the naughty, cute or savage child, untamed and in need of civilising. These are far from being the only two discursive constructions of children present in current policies and practices. If early childhood professionals are to be active in shaping and implementing policies that affect their work and workforce, it is important that they are aware of the forces at play. In this article, we point to another powerful discourse at play in the Australian context of early childhood education, the image of children as economic units: investments in the future. We show how a ‘moment of arising’ in contemporary policy contexts, dominated by neoliberal principles of reform and competition, has charged early childhood educators in Australia with the duties of a ‘broker’, ensuring that young children are worth the investment. In this article, we begin with (1) a key policy document in early childhood education in Australia and examine the discursive affordances which shape the document. Next, (2) we pinpoint the shifts in how the work of child care is perceived by interrogating this key policy document through a methodology of discursive analysis. We then turn attention (3) to the work of this policy document along with other discourses which directly affect images of children and the shaping role these have on the work of educators. We conclude with (4) a consideration of how the work of early childhood professionals has come to be shaped by this economic discourse, and how they are being required to both work within the policy imperatives and likely to resist this new demand of them.