Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk

Validatie van de Depressie lijst (DL) en de Geriatric Depression Scale (GDS-30) bij Verpleeghuisbewoners van Somatische en Psychogeriatrische Afdelingen

Een validatie studie teneinde inzicht te geven in 1) de inhoudsvaliditeit, de concurrente validiteit en de interne consistentie van de Geriatric Depression Scale (GDS-30) en de Depressielijst (DL) voor het meten van depressie bij verpleeghuisbewoners en 2) de invloed van cognitief functioneren op het aantal missing items op de DL en de GDS-30. Een cross-sectionele studie met data afkomstig uit de effectstudie ‘Act in Case of Depression’. De steekproefomvang bestond uit verpleeghuisbewoners (N=432) van PG en somatische afdelingen. Meetinstrumenten: DL, GDS-30 en de Mini Mental State Examination (MMSE) voor cognitief functioneren. Experts beoordeelden de DL en de GDS-30 als geschikt voor afname bij verpleeghuisbewoners zonder cognitieve problemen. Echter ongeschikt voor afname bij verpleeghuisbewoners met ernstige cognitieve problemen. Experts vonden de items relevant voor de somatische cliënten, echter was er minder consensus over de itemrelevantie voor PG cliënten. De DL en de GDS-30 vertoonden een sterke interne consistentie en een sterke onderlinge correlatie. Er was geen associatie tussen de stemmingssymptomen van de DL en de GDS-30 en motivatie symptomen van de DL aan de ene kant en de MMSE aan de andere kant. De motivatiesymptomen gemeten met de GDS-30 vertoonden een middelmatige associatie met cognitief functioneren. Cliënten van PG afdelingen hadden meer missing items op de DL en op de GDS-30 dan cliënten van somatische afdelingen. Cognitief functioneren vertoonde een zwakke associatie met het aantal missing items op de DL en de GDS-30.

Multivariate analysis of regional-scale geochemical data for environmental monitoring

A compositional multivariate approach is used to analyse regional scale soil geochemical data obtained as part of the Tellus Project generated by the Geological Survey Northern Ireland (GSNI). The multi-element total concentration data presented comprise XRF analyses of 6862 rural soil samples collected at 20cm depths on a non-aligned grid at one site per 2 km2. Censored data were imputed using published detection limits. Using these imputed values for 46 elements (including LOI), each soil sample site was assigned to the regional geology map provided by GSNI initially using the dominant lithology for the map polygon. Northern Ireland includes a diversity of geology representing a stratigraphic record from the Mesoproterozoic, up to and including the Palaeogene. However, the advance of ice sheets and their meltwaters over the last 100,000 years has left at least 80% of the bedrock covered by superficial deposits, including glacial till and post-glacial alluvium and peat. The question is to what extent the soil geochemistry reflects the underlying geology or superficial deposits. To address this, the geochemical data were transformed using centered log ratios (clr) to observe the requirements of compositional data analysis and avoid closure issues. Following this, compositional multivariate techniques including compositional Principal Component Analysis (PCA) and minimum/maximum autocorrelation factor (MAF) analysis method were used to determine the influence of underlying geology on the soil geochemistry signature. PCA showed that 72% of the variation was determined by the first four principal components (PC’s) implying “significant” structure in the data. Analysis of variance showed that only 10 PC’s were necessary to classify the soil geochemical data. To consider an improvement over PCA that uses the spatial relationships of the data, a classification based on MAF analysis was undertaken using the first 6 dominant factors. Understanding the relationship between soil geochemistry and superficial deposits is important for environmental monitoring of fragile ecosystems such as peat. To explore whether peat cover could be predicted from the classification, the lithology designation was adapted to include the presence of peat, based on GSNI superficial deposit polygons and linear discriminant analysis (LDA) undertaken. Prediction accuracy for LDA classification improved from 60.98% based on PCA using 10 principal components to 64.73% using MAF based on the 6 most dominant factors. The misclassification of peat may reflect degradation of peat covered areas since the creation of superficial deposit classification. Further work will examine the influence of underlying lithologies on elemental concentrations in peat composition and the effect of this in classification analysis.

Implementing a structural continuity constraint and a halting method for the topology optimization of energy absorbers

This study investigates topology optimization of energy absorbing structures in which material damage is accounted for in the optimization process. The optimization objective is to design the lightest structures that are able to absorb the required mechanical energy. A structural continuity constraint check is introduced that is able to detect when no feasible load path remains in the finite element model, usually as a result of large scale fracture. This assures that designs do not fail when loaded under the conditions prescribed in the design requirements. This continuity constraint check is automated and requires no intervention from the analyst once the optimization process is initiated. Consequently, the optimization algorithm proceeds towards evolving an energy absorbing structure with the minimum structural mass that is not susceptible to global structural failure. A method is also introduced to determine when the optimization process should halt. The method identifies when the optimization method has plateaued and is no longer likely to provide improved designs if continued for further iterations. This provides the designer with a rational method to determine the necessary time to run the optimization and avoid wasting computational resources on unnecessary iterations. A case study is presented to demonstrate the use of this method.

Multi-scale colorectal tumour segmentation using a novel coarse to fine strategy

This paper addresses the problem of colorectal tumour segmentation in complex real world imagery. For efficient segmentation, a multi-scale strategy is developed for extracting the potentially cancerous region of interest (ROI) based on colour histograms while searching for the best texture resolution. To achieve better segmentation accuracy, we apply a novel bag-of-visual-words method based on rotation invariant raw statistical features and random projection based l2-norm sparse representation to classify tumour areas in histopathology images. Experimental results on 20 real world digital slides demonstrate that the proposed algorithm results in better recognition accuracy than several state of the art segmentation techniques.

Analyzing Gene Centres with the Help of the Checklist Method – the Case of Syria

The present survey of species diversity of cultivated plants is the first for Syria. Some cultivated species will be added in the future, because due to the civil war in Syria, it was not possible to visit the country in the frame of the present work, as initially planned. Checklists proved to be a useful tool for overviewing the cultivated plants of selected areas and allow a characterization of the state of plant genetic resources of Syria. Syria has experienced several civilizations. Man settled in this productive land since ancient times and used its resources. However, such use has led to changes in vegetation and decline of wildlife through the country, in seashore areas, interior, mountains, and grassland. Plant domestication and growing started more than 10,000 years ago in West Asia. Since then, plentiful of economic plant species were present and used by man and his domesticated animals. Forming a part of the Fertile Crescent, where many of the world’s agricultural plants have evolved, Syria is extremely rich in agrobiodiversity. Wild progenitors of wheat and barley and wild relatives of many fruit trees such as almonds and pistachio as well as forage species are still found in marginal lands and less disturbed areas. These are threatened by a wide range of human activities, notably modern, extensive agriculture, overgrazing, overcutting and urban expansion. Syria is also considered as part of one of the main centres of origin, according to Vavilov, who had collected in Syria in 1926. The first expeditions to crop fields showed the exclusive nature of cultivated plants in Syria with a high number of endemic forms. Furthermore, Syria is a part of a biodiversity hotspot. Several studies have been performed to study agrobiodiversity in different parts of Syria, but usually on wild species. Many collections have been carried out; however, they focussed preferably on cereals and pulses, and particularly on wheat, like Vavilov’s expedition. Only 30 crops make up the major part of the conserved Syrian crop plant material in the genebank, indicating that most of the remaining 7,000 species of cultivated plants and many other valuable genetic resources species have only been included on a limited scale in the genebank collections. Although a small country (185,180 km2), Syria accommodates numerous ecosystems that allow for a large diversity of plant genetic resources for agriculture ranging from cold-requiring to subtropical crops to live and thrive. Only few references are available in this respect. The aim of the present study was to complete a checklist of Syria’s cultivated plants of agriculture and horticulture excluding plants only grown as ornamental or for forestry. Furthermore, plants taken for reforestation have not been included, if they do not have also agricultural or horticultural uses. Therefore, the inclusion of plants into the checklist follows the same principles as “Mansfeld’s Encyclopedia”. Main sources of information were published literature, floras of Syria, Lebanon and the Mediterranean, as well as Syrian printed sources in Arabic and/or English, reports from FAO on agricultural statistics in Syria, and data from ICARDA and Bioversity International. In addition, personal observations gathered during professional work in the General Commission for Scientific Agricultural Research (GCSAR) in Syria (since 1989) and participation in projects were taken into account. These were: (1) A project on “Conservation and Sustainable Use of Dry Land Agrobiodiversity in the Near East” with participation of Jordan, Lebanon, Syria, and the Palestinian Authority, focussing on landraces and wild relatives of barley, wheat, lentil, alliums, feed legumes, and fruit trees (1999–2005). (2) A project for vegetable landraces (1993–1995) in collaboration with the former International Plant Genetic Resources Institute and the UN Development Programme, in which 380 local vegetable accessions were evaluated. For medicinal plants and fruit trees I was in personal contact with departments of GCSAR and the Ministry of Agriculture and Agrarian Reform, as well as with private organizations. The resulting checklist was compared with the catalogues of crop plants of Italy and a checklist of cultivated plants of Iraq. The cultivated plant species are presented in alphabetical order according to their accepted scientific names. Each entry consists of a nomenclatural part, folk names, details of plant uses, the distribution in Syria (by provinces), a textual description, and references to literature. In total, 262 species belonging to 146 genera and 57 families were identified. Within-species (intraspecific) diversity is a significant measure of the biodiversity. Intraspecific diversity for wild plants has been and remains to be well studied, but for crop plants there are only few results. Mansfeld’s method is an actual logical contribution to such studies. Among the families, the following have the highest number of crop species: Leguminosae (34 spp.), Rosaceae (24), Gramineae (18), Labiatae (18), Compositae (14), Cruciferae (14), Cucurbitaceae (11), Rutaceae (10), Malvaceae (9), Alliaceae (7), and Anacardiaceae (7). The establishment of an effective programme for the maintenance of plant genetic resources in Syria started in the mid-1970s. This programme considered ex situ and in situ collection of the genetic resources of various field crops, fruit trees and vegetables. From a plant genetic resources viewpoint, it is clear that the homegarden is an important location for the cultivation of so-called neglected and underutilized species (neglected from a research side and underutilized from a larger economic side). Such species have so far not received much care from ecologists, botanists and agronomists, and they are considerably under-represented in genebanks.

Studies on betanin natural dye incorporated ZnO composites at nano and micro scale for photonic device applications

Green energy and Green technology are the most of the quoted terms in the context of modern science and technology. Technology which is close to nature is the necessity of the modern world which is haunted by global warming and climatic alterations. Proper utilization of solar energy is one of the goals of Green Energy Movement. The present thesis deals with the work carried out in the eld of nanotechnology and its possible use in various applications (employing natural dyes) like solar cells. Unlike arti cial dyes, the natural dyes are available, easy to prepare, low in cost, non-toxic, environmentally friendly and fully biodegradable. Looking to the 21st century, the nano/micro sciences will be a chief contributor to scienti c and technological developments. As nanotechnology progresses and complex nanosystems are fabricated, a growing impetus is being given to the development of multi-functional and size-dependent materials. The control of the morphology, from the nano to the micrometer scales, associated with the incorporation of several functionalities can yield entirely new smart hybrid materials. They are special class of materials which provide a new method for the improvement of the environmental stability of the material with interesting optical properties and opening a land of opportunities for applications in the eld of photonics. Zinc oxide (ZnO) is one such multipurpose material that has been explored for applications in sensing, environmental monitoring, and bio-medical systems and communications technology. Understanding the growth mechanism and tailoring their morphology is essential for the use of ZnO crystals as nano/micro electromechanical systems and also as building blocks of other nanosystems.

Development of a Rational Characterization Method for Iowa Fly Ash, HR-286, Annual Progress Report 2, 1987

The following report summarizes research activities on the project for the period December 1, 1986 to November 30, 1987. Research efforts for the second year deviated slightly from those described in the project proposal. By the end of the second year of testing, it was possible to begin evaluating how power plant operating conditions influenced the chemical and physical properties of fly ash obtained from one of the monitored power plants (Ottumwa Generating Station, OGS). Hence, several of the tasks initially assigned to the third year of the project (specifically tasks D, E, and F) were initiated during the second year of the project. Manpower constraints were balanced by delaying full scale implementation of the quantitative X-ray diffraction and differential thermal analysis tasks until the beginning of the third year of the project. Such changes should have little bearing on the outcome of the overall project.

A method for assessing ecological values to reconcile multiple land use needs

We present a new method for ecologically sustainable land use planning within multiple land use schemes. Our aims were (1) to develop a method that can be used to locate important areas based on their ecological values; (2) to evaluate the quality, quantity, availability, and usability of existing ecological data sets; and (3) to demonstrate the use of the method in Eastern Finland, where there are requirements for the simultaneous development of nature conservation, tourism, and recreation. We compiled all available ecological data sets from the study area, complemented the missing data using habitat suitability modeling, calculated the total ecological score (TES) for each 1 ha grid cell in the study area, and finally, demonstrated the use of TES in assessing the success of nature conservation in covering ecologically valuable areas and locating ecologically sustainable areas for tourism and recreational infrastructure. The method operated quite well at the level required for regional and local scale planning. The quality, quantity, availability, and usability of existing data sets were generally high, and they could be further complemented by modeling. There are still constraints that limit the use of the method in practical land use planning. However, as increasing data become available and open access, and modeling tools improve, the usability and applicability of the method will increase.

Symptoms of Poststroke Depression among Stroke Survivors: An Appraisal of Psychiatry Needs and Care during Physiotherapy Rehabilitation

Purpose. To identify stroke survivors with symptoms of poststroke depression and the extent of psychiatry needs and care they have received while on physiotherapy rehabilitation. Participants. Fifty stroke survivors (22 females and 28 males) at the outpatient unit of Physiotherapy Department, University of Nigeria Teaching Hospital, Enugu, who gave their informed consent, were randomly selected. Their age range and mean age were 26–66 years and 54.76 ± 8.79 years, respectively. Method. A multiple case study of 50 stroke survivors for symptoms of poststroke depression was done with Beck’s Depression Inventory, mini mental status examination tool, and Modified Motor Assessment Scale. The tests were performed independently by the participants except otherwise stated and scored on a scale of 0–6. Data were analyzed using -test for proportional significance and chi-square test for determining relationship between variables, at p < 0.05. Results. Twenty-one (42.0%) stroke survivors had symptoms of PSD, which was significantly dependent on duration of stroke ( = 21.680, df = 6, and p = 0.001), yet none of the participants had a psychiatry review. Conclusions. Symptoms of PSD may be common in cold compared to new cases of stroke and may need psychiatry care while on physiotherapy rehabilitation.

Simplified design method for energy dissipating devices in retrofitting of seismically isolated bridges

Abstract: Highway bridges have great values in a country because in case of any natural disaster they may serve as lines to save people’s lives. Being vulnerable under significant seismic loads, different methods can be considered to design resistant highway bridges and rehabilitate the existing ones. In this study, base isolation has been considered as one efficient method in this regards which in some cases reduces significantly the seismic load effects on the structure. By reducing the ductility demand on the structure without a notable increase of strength, the structure is designed to remain elastic under seismic loads. The problem associated with the isolated bridges, especially with elastomeric bearings, can be their excessive displacements under service and seismic loads. This can defy the purpose of using elastomeric bearings for small to medium span typical bridges where expansion joints and clearances may result in significant increase of initial and maintenance cost. Thus, supplementing the structure with dampers with some stiffness can serve as a solution which in turn, however, may increase the structure base shear. The main objective of this thesis is to provide a simplified method for the evaluation of optimal parameters for dampers in isolated bridges. Firstly, performing a parametric study, some directions are given for the use of simple isolation devices such as elastomeric bearings to rehabilitate existing bridges with high importance. Parameters like geometry of the bridge, code provisions and the type of soil on which the structure is constructed have been introduced to a typical two span bridge. It is concluded that the stiffness of the substructure, soil type and special provisions in the code can determine the employment of base isolation for retrofitting of bridges. Secondly, based on the elastic response coefficient of isolated bridges, a simplified design method of dampers for seismically isolated regular highway bridges has been presented in this study. By setting objectives for reduction of displacement and base shear variation, the required stiffness and damping of a hysteretic damper can be determined. By modelling a typical two span bridge, numerical analyses have followed to verify the effectiveness of the method. The method has been used to identify equivalent linear parameters and subsequently, nonlinear parameters of hysteretic damper for various designated scenarios of displacement and base shear requirements. Comparison of the results of the nonlinear numerical model without damper and with damper has shown that the method is sufficiently accurate. Finally, an innovative and simple hysteretic steel damper was designed. Five specimens were fabricated from two steel grades and were tested accompanying a real scale elastomeric isolator in the structural laboratory of the Université de Sherbrooke. The test procedure was to characterize the specimens by cyclic displacement controlled tests and subsequently to test them by real-time dynamic substructuring (RTDS) method. The test results were then used to establish a numerical model of the system which went through nonlinear time history analyses under several earthquakes. The outcome of the experimental and numerical showed an acceptable conformity with the simplified method.

Mixing performance evaluation of additive manufactured milli-scale reactors

The mixing performance of three passive milli-scale reactors with different geometries was investigated at different Reynolds numbers. The effects of design and operating characteristics such as mixing channel shape and volume flow rate were investigated. The main objective of this work was to demonstrate a process design method that uses on Computational Fluid Dynamics (CFD) for modeling and Additive Manufacturing (AM) technology for manufacture. The reactors were designed and simulated using SolidWorks and Fluent 15.0 software, respectively. Manufacturing of the devices was performed with an EOS M-series AM system. Step response experiments with distilled Millipore water and sodium hydroxide solution provided time-dependent concentration profiles. Villermaux-Dushman reaction experiments were also conducted for additional verification of CFD results and for mixing efficiency evaluation of the different geometries. Time-dependent concentration data and reaction evaluation showed that the performance of the AM-manufactured reactors matched the CFD results reasonably well. The proposed design method allows the implementation of new and innovative solutions, especially in the process design phase, for industrial scale reactor technologies. In addition, rapid implementation is another advantage due to the virtual flow design and due to the fast manufacturing which uses the same geometric file formats.

Detection of mesoscale thermal fronts from 4km data using smoothing techniques: Gradient-based fronts classification and basin scale application

In order to optimize frontal detection in sea surface temperature fields at 4 km resolution, a combined statistical and expert-based approach is applied to test different spatial smoothing of the data prior to the detection process. Fronts are usually detected at 1 km resolution using the histogram-based, single image edge detection (SIED) algorithm developed by Cayula and Cornillon in 1992, with a standard preliminary smoothing using a median filter and a 3 × 3 pixel kernel. Here, detections are performed in three study regions (off Morocco, the Mozambique Channel, and north-western Australia) and across the Indian Ocean basin using the combination of multiple windows (CMW) method developed by Nieto, Demarcq and McClatchie in 2012 which improves on the original Cayula and Cornillon algorithm. Detections at 4 km and 1 km of resolution are compared. Fronts are divided in two intensity classes (“weak” and “strong”) according to their thermal gradient. A preliminary smoothing is applied prior to the detection using different convolutions: three type of filters (median, average and Gaussian) combined with four kernel sizes (3 × 3, 5 × 5, 7 × 7, and 9 × 9 pixels) and three detection window sizes (16 × 16, 24 × 24 and 32 × 32 pixels) to test the effect of these smoothing combinations on reducing the background noise of the data and therefore on improving the frontal detection. The performance of the combinations on 4 km data are evaluated using two criteria: detection efficiency and front length. We find that the optimal combination of preliminary smoothing parameters in enhancing detection efficiency and preserving front length includes a median filter, a 16 × 16 pixel window size, and a 5 × 5 pixel kernel for strong fronts and a 7 × 7 pixel kernel for weak fronts. Results show an improvement in detection performance (from largest to smallest window size) of 71% for strong fronts and 120% for weak fronts. Despite the small window used (16 × 16 pixels), the length of the fronts has been preserved relative to that found with 1 km data. This optimal preliminary smoothing and the CMW detection algorithm on 4 km sea surface temperature data are then used to describe the spatial distribution of the monthly frequencies of occurrence for both strong and weak fronts across the Indian Ocean basin. In general strong fronts are observed in coastal areas whereas weak fronts, with some seasonal exceptions, are mainly located in the open ocean. This study shows that adequate noise reduction done by a preliminary smoothing of the data considerably improves the frontal detection efficiency as well as the global quality of the results. Consequently, the use of 4 km data enables frontal detections similar to 1 km data (using a standard median 3 × 3 convolution) in terms of detectability, length and location. This method, using 4 km data is easily applicable to large regions or at the global scale with far less constraints of data manipulation and processing time relative to 1 km data.

Large-scale dynamic hydrofracturing, healing and fracture network characterization

Permeability of a rock is a dynamic property that varies spatially and temporally. Fractures provide the most efficient channels for fluid flow and thus directly contribute to the permeability of the system. Fractures usually form as a result of a combination of tectonic stresses, gravity (i.e. lithostatic pressure) and fluid pressures. High pressure gradients alone can cause fracturing, the process which is termed as hydrofracturing that can determine caprock (seal) stability or reservoir integrity. Fluids also transport mass and heat, and are responsible for the formation of veins by precipitating minerals within open fractures. Veining (healing) thus directly influences the rock’s permeability. Upon deformation these closed factures (veins) can refracture and the cycle starts again. This fracturing-healing-refacturing cycle is a fundamental part in studying the deformation dynamics and permeability evolution of rock systems. This is generally accompanied by fracture network characterization focusing on network topology that determines network connectivity. Fracture characterization allows to acquire quantitative and qualitative data on fractures and forms an important part of reservoir modeling. This thesis highlights the importance of fracture-healing and veins’ mechanical properties on the deformation dynamics. It shows that permeability varies spatially and temporally, and that healed systems (veined rocks) should not be treated as fractured systems (rocks without veins). Field observations also demonstrate the influence of contrasting mechanical properties, in addition to the complexities of vein microstructures that can form in low-porosity and permeability layered sequences. The thesis also presents graph theory as a characterization method to obtain statistical measures on evolving network connectivity. It also proposes what measures a good reservoir should have to exhibit potentially large permeability and robustness against healing. The results presented in the thesis can have applications for hydrocarbon and geothermal reservoir exploration, mining industry, underground waste disposal, CO2 injection or groundwater modeling.