Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

Telomere length in circulating leukocytes is associated with lung function and disease

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (β= −0.0452, p=0.024) as well as COPD (β= −0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10−7), FVC (p=2.07×10−5), and FEV1/FVC (p=5.27×10−3). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

Antidepressants, but not antipsychotics, modulate GR function in human whole blood: An insight into molecular mechanisms

Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Recently, we showed that this impairment is indeed due to a dysfunction of GR in depressed patients (Carvalho et al., 2009), and that the ability of the antidepressant clomipramine to decrease GR function in peripheral blood cells is impaired in patients with major depression who are clinically resistant to treatment (Carvalho et al. 2008). To further investigate the effect of antidepressants on GR function in humans, we have compared the effect of the antidepressants clomipramine, amytriptiline, sertraline, paroxetine and venlafaxine, and of the antipsychotics, haloperidol and risperidone, on GR function in peripheral blood cells from healthy volunteers (n=33). GR function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. Compared to vehicle-treated cells, all antidepressants inhibited dexamethasone (DEX, 10-100nM) inhibition of LPS-stimulated IL-6 levels (p values ranging from 0.007 to 0.1). This effect was specific to antidepressants, as antipsychotics had no effect on DEX-inhibition of LPS-stimulated IL-6 levels. The phosphodiesterase (PDE) type 4 inhibitor, rolipram, potentiated the effect of antidepressants on GR function, while the GR antagonist, RU-486, inhibited the effect of antidepressants on GR function. These findings indicate that the effect of antidepressants on GR function are specific for this class of psychotropic drugs, and involve second messenger pathways relevant to GR function and inflammation. Furthermore, it also points towards a possible mechanism by which one maybe able to overcome treatment-resistant depression. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders.

GPU accelerated algorithms for computing matrix function vector products with applications to exponential integrators and fractional diffusion

The efficient computation of matrix function vector products has become an important area of research in recent times, driven in particular by two important applications: the numerical solution of fractional partial differential equations and the integration of large systems of ordinary differential equations. In this work we consider a problem that combines these two applications, in the form of a numerical solution algorithm for fractional reaction diffusion equations that after spatial discretisation, is advanced in time using the exponential Euler method. We focus on the efficient implementation of the algorithm on Graphics Processing Units (GPU), as we wish to make use of the increased computational power available with this hardware. We compute the matrix function vector products using the contour integration method in [N. Hale, N. Higham, and L. Trefethen. Computing Aα, log(A), and related matrix functions by contour integrals. SIAM J. Numer. Anal., 46(5):2505–2523, 2008]. Multiple levels of preconditioning are applied to reduce the GPU memory footprint and to further accelerate convergence. We also derive an error bound for the convergence of the contour integral method that allows us to pre-determine the appropriate number of quadrature points. Results are presented that demonstrate the effectiveness of the method for large two-dimensional problems, showing a speedup of more than an order of magnitude compared to a CPU-only implementation.

WT1 interacts with MAD2 and regulates mitotic checkpoint function

Tumour suppressors safeguard the fidelity of the mitotic checkpoint by transcriptional regulation of genes that encode components of the mitotic checkpoint complex (MCC). Here we report a new role for the tumour suppressor and transcription factor, WT1, in the mitotic checkpoint. We show that WT1 regulates the MCC by directly interacting with the spindle assembly checkpoint protein, MAD2. WT1 colocalizes with MAD2 during mitosis and preferentially binds to the functionally active, closed-conformer, C-MAD2. Furthermore, WT1 associates with the MCC containing MAD2, BUBR1 and CDC20, resulting in prolonged inhibition of the anaphase-promoting complex/cyclosome (APC/C) and delayed degradation of its substrates SECURIN and CYCLIN B1. Strikingly, RNA interference-mediated depletion of WT1 leads to enhanced turnover of SECURIN, decreased lag time to anaphase and defects in chromosome segregation. Our findings identify WT1 as a regulator of the mitotic checkpoint and chromosomal stability.

Infrastructure, investment and development evaluation: A Complex Stakeholder Perception Mapping approach for improving local and regional economic development outcomes

Partial evaluation of infrastructure investments have resulted in expensive mistakes, unsatisfactory outcomes and increased uncertainties for too many stakeholders, communities and economies in both developing and developed nations. "Complex Stakeholder Perception Mapping" (CSPM), is a novel approach that can address existing limitations by inclusively framing, capturing and mapping the spectrum of insights and perceptions using extended Geographic Information Systems. Maps generated in CSPM offer presentations of flexibly combined, complex perceptions of stakeholders on multiple aspects of development. CSPM extends the applications of GIS software in non-spatial mapping and of Multi-Criteria Analysis with a multidimensional evaluation platform and augments decision science capabilities in addressing complexities. Application of CSPM can improve local and regional economic gains from infrastructure projects and aid any multi-objective and multi-stakeholder decision situations.

Eruption centres of the Hamilton area of the Newer Volcanics Province, Victoria, Australia: Pinpointing volcanoes from a multifaceted approach to landform mapping

Volcanic eruption centres of the mostly 4.5 Ma-5000 BP Newer Volcanics Province in the Hamilton area of southeastern Australia were examined in detail using a multifaceted approach, including ground truthing and analysis of ArcGIS Total Magnetic Intensity and seamless geology data, NASA Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) digital elevation models and Google Earth satellite image interpretation. Sixteen eruption centres were recognised in the Hamilton area, including three previously unrecorded volcanoes-one of which, the Cas Maar, constitutes the northernmost maar-cone volcanic complex in the Western Plains subprovince. Seven previously allocated eruption centres were placed into question based on field and laboratory observations. Three phases of volcanic activity have been suggested by other authors and are interpreted to correlate with ages of >4 Ma, ca 2 Ma and <0.5 Ma, which may be further subdivided based on preservation of outcrop. Geochemical compositions of the dominantly basaltic products become increasingly alkaline and enriched in incompatible elements from Phases 1 to 2, with Phase 3 eruptions both covering the entire geochemical range and extending into increasingly enriched compositions. This research highlights the importance of a multifaceted approach to landform mapping and demonstrates that additional volcanic centres may yet be discovered in the Newer Volcanics Province

IT consumerization and its effects on IT business value, IT capabilities, and the IT function

IT consumerization is both a major opportunity and significant challenge for organizations. However, IS research has hardly discussed the implications for IT management so far. In this paper we address this topic by empirically identifying organizational themes for IT consumerization and conceptually exploring the direct and indirect effects on the business value of IT, IT capabilities, and the IT function. More specifically, based on two case studies, we identify eight organizational themes: consumer IT strategy, policy development and responsibilities, consideration of private life of employees, user involvement into IT-related processes, individualization, updated IT infrastructure, end user support, and data and system security. The contributions of this paper are: (1) the identification of organizational themes for IT consumerization; (2) the proposed effects on the business value of IT, IT capabilities and the IT function, and; (3) combining empirical insights into IT consumerization with managerial theories in the IS discipline.

Inventing life: Intellectual property and the new biology

In 2009, the National Research Council of the National Academies released a report on A New Biology for the 21st Century. The council preferred the term ‘New Biology’ to capture the convergence and integration of the various disciplines of biology. The National Research Council stressed: ‘The essence of the New Biology, as defined by the committee, is integration—re-integration of the many sub-disciplines of biology, and the integration into biology of physicists, chemists, computer scientists, engineers, and mathematicians to create a research community with the capacity to tackle a broad range of scientific and societal problems.’ They define the ‘New Biology’ as ‘integrating life science research with physical science, engineering, computational science, and mathematics’. The National Research Council reflected: 'Biology is at a point of inflection. Years of research have generated detailed information about the components of the complex systems that characterize life––genes, cells, organisms, ecosystems––and this knowledge has begun to fuse into greater understanding of how all those components work together as systems. Powerful tools are allowing biologists to probe complex systems in ever greater detail, from molecular events in individual cells to global biogeochemical cycles. Integration within biology and increasingly fruitful collaboration with physical, earth, and computational scientists, mathematicians, and engineers are making it possible to predict and control the activities of biological systems in ever greater detail.' The National Research Council contended that the New Biology could address a number of pressing challenges. First, it stressed that the New Biology could ‘generate food plants to adapt and grow sustainably in changing environments’. Second, the New Biology could ‘understand and sustain ecosystem function and biodiversity in the face of rapid change’. Third, the New Biology could ‘expand sustainable alternatives to fossil fuels’. Moreover, it was hoped that the New Biology could lead to a better understanding of individual health: ‘The New Biology can accelerate fundamental understanding of the systems that underlie health and the development of the tools and technologies that will in turn lead to more efficient approaches to developing therapeutics and enabling individualized, predictive medicine.’ Biological research has certainly been changing direction in response to changing societal problems. Over the last decade, increasing awareness of the impacts of climate change and dwindling supplies of fossil fuels can be seen to have generated investment in fields such as biofuels, climate-ready crops and storage of agricultural genetic resources. In considering biotechnology’s role in the twenty-first century, biological future-predictor Carlson’s firm Biodesic states: ‘The problems the world faces today – ecosystem responses to global warming, geriatric care in the developed world or infectious diseases in the developing world, the efficient production of more goods using less energy and fewer raw materials – all depend on understanding and then applying biology as a technology.’ This collection considers the roles of intellectual property law in regulating emerging technologies in the biological sciences. Stephen Hilgartner comments that patent law plays a significant part in social negotiations about the shape of emerging technological systems or artefacts: 'Emerging technology – especially in such hotbeds of change as the life sciences, information technology, biomedicine, and nanotechnology – became a site of contention where competing groups pursued incompatible normative visions. Indeed, as people recognized that questions about the shape of technological systems were nothing less than questions about the future shape of societies, science and technology achieved central significance in contemporary democracies. In this context, states face ongoing difficulties trying to mediate these tensions and establish mechanisms for addressing problems of representation and participation in the sociopolitical process that shapes emerging technology.' The introduction to the collection will provide a thumbnail, comparative overview of recent developments in intellectual property and biotechnology – as a foundation to the collection. Section I of this introduction considers recent developments in United States patent law, policy and practice with respect to biotechnology – in particular, highlighting the Myriad Genetics dispute and the decision of the Supreme Court of the United States in Bilski v. Kappos. Section II considers the cross-currents in Canadian jurisprudence in intellectual property and biotechnology. Section III surveys developments in the European Union – and the interpretation of the European Biotechnology Directive. Section IV focuses upon Australia and New Zealand, and considers the policy responses to the controversy of Genetic Technologies Limited’s patents in respect of non-coding DNA and genomic mapping. Section V outlines the parts of the collection and the contents of the chapters.

The links between public tendencies and the urban design framework of Brisbane’s public squares: Mapping urban design frameworks present in Brisbane public squares and the correlating activities of the Australian public

This research seeks to demonstrate the ways in which urban design factors, individually and in various well-considered arrangements, stimulate and encourage social activities in Brisbane’s public squares through the mapping and analysis of user behaviour. No design factors contribute to public space in isolation, so the combinations of different design factors, contextual and social impacts as well as local climate are considered to be highly influential to the way in which Brisbane’s public engages with public space. It is this local distinctiveness that this research seeks to ascertain. The research firstly pinpoints and consolidates the design factors identified and recommended in existing literature and then maps the identified factors as they are observed at case study sites in Brisbane. This is then set against observational mappings of the site’s corresponding user activities and engagement. These mappings identify a number of patterns of behaviour; pertinently that “activated” areas of social gathering actively draw people in, and the busier a space is, both the frequency and duration of people lingering in the space increases. The study finds that simply providing respite from the urban environment (and/or weather conditions) does not adequately encourage social interaction and that people friendly design factors can instigate social activities which, if coexisting in a public space, can themselves draw in further users of the space. One of the primary conclusions drawn from these observations is that members of the public in Brisbane are both actively and passively social and often seek out locations where “people-watching” and being around other members of the public (both categorised as passive social activities) are facilitated and encouraged. Spaces that provide respite from the urban environment but that do not sufficiently accommodate social connections and activities are less favourable and are often left abandoned despite their comparable tranquillity and available space.

Understanding the function and mechanisms of intestinal cell kinase in the growth and survival of prostate cancer cells

This project was a step forward in discovering the potential role of intestinal cell kinase in prostate cancer development. Intestinal cell kinase was shown to be upregulated in prostate cancer cells and altered expression led to changes in key cell survival proteins. This study used in vitro experiments to monitor changes in cell growth, protein and RNA expression.

Cross-cultural adaptation and validation of the Foot Function Index to Spanish

Background The purpose of this study was to adapt and validate the Foot Function Index to the Spanish (FFI-Sp) following the guidelines of the American Academy of Orthopaedic Surgeons. Methods A cross-sectional study 80 participants with some foot pathology. A statistical analysis was made, including a correlation study with other questionnaires (the Foot Health Status Questionnaire, EuroQol 5-D, Visual Analogue Pain Scale, and the Short Form SF-12 Health Survey). Data analysis included reliability, construct and criterion-related validity and factor analyses. Results The principal components analysis with varimax rotation produced 3 principal factors that explained 80% of the variance. The confirmatory factor analysis showed an acceptable fit with a comparative fit index of 0.78. The FFI-Sp demonstrated excellent internal consistency on the three subscales: pain 0.95; disability 0.96; and activity limitation 0.69, the subscale that scored lowest. The correlation between the FFI-Sp and the other questionnaires was high to moderate. Conclusions The Spanish version of the Foot Function Index (FFI-Sp) is a tool that is a valid and reliable tool with a very good internal consistency for use in the assessment of pain, disability and limitation of the function of the foot, for use both in clinic and research.

A kinematic analysis of the hand function

Background The evaluation of the hand function is an essential element within the clinical practice. The usual assessments are focus on the ability to perform activities of daily life. The inclusion of instruments to measure kinematic variables provides a new approach to the assessment. Inertial sensors adapted to the hand could be used as a complementary instrument to the traditional assessment. Material: clinimetric assessment (Upper Limb Functional Index, Quick Dash), antrophometric variables (eight and weight), dynamometry (palm preasure) was taken. Functional analysis was made with Acceleglove system for the right hand and computer system. The glove has six acceleration sensor, one on each finger and another one on the reverse palm. Method Analytic, transversal approach. Ten healthy subject made six task on evaluation table (tripod pinch, lateral pinch and tip pinch, extension grip, spherical grip and power grip). Each task was made and measure three times, the second one was analyze for the results section. A Matlab script was created for the analysis of each movement and detection phase based on module vector. Results The module acceleration vector offers useful information of the hand function. The data analysis obtained during the performance of functional gestures allows to identify five different phases within the movement, three static phase and tow dynamic, each module vector was allied to one task. Conclusion Module vector variables could be used for the analysis of the different task made by the hand. Inertial sensor could be use as a complement for the traditional assessment system.

Mapping genetic influences on brain fiber architecture with high angular resolution diffusion imaging (HARDI)

We report the first 3D maps of genetic effects on brain fiber complexity. We analyzed HARDI brain imaging data from 90 young adult twins using an information-theoretic measure, the Jensen-Shannon divergence (JSD), to gauge the regional complexity of the white matter fiber orientation distribution functions (ODF). HARDI data were fluidly registered using Karcher means and ODF square-roots for interpol ation; each subject's JSD map was computed from the spatial coherence of the ODFs in each voxel's neighborhood. We evaluated the genetic influences on generalized fiber anisotropy (GFA) and complexity (JSD) using structural equation models (SEM). At each voxel, genetic and environmental components of data variation were estimated, and their goodness of fit tested by permutation. Color-coded maps revealed that the optimal models varied for different brain regions. Fiber complexity was predominantly under genetic control, and was higher in more highly anisotropic regions. These methods show promise for discovering factors affecting fiber connectivity in the brain.