Influence of Receptor Polymorphisms on the Response to alpha-Adrenergic Receptor Blockers in Pheochromocytoma Patients

Background: Presurgical treatment with an α-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced α-adrenergic receptor mediated vasoconstriction in patients with pheochromocytoma or sympathetic paraganglioma (PPGL). There is, however, a considerable interindividual variation in the dose-response relationship regarding the magnitude of blood pressure reduction or the occurrence of side effects. We hypothesized that genetically determined differences in α-adrenergic receptor activity contribute to this variability in dose-response relationship. Methods: Thirty-one single-nucleotide polymorphisms (SNPs) of the α1A, α1B, α1D adrenoreceptor (ADRA1A, ADRA1B, ADRA1D) and α2A, α2B adrenoreceptor (ADRA2A, ADRA2B) genes were genotyped in a group of 116 participants of the PRESCRIPT study. Haplotypes were constructed after determining linkage disequilibrium blocks. Results: The ADRA1B SNP rs10515807 and the ADRA2A SNPs rs553668/rs521674 were associated with higher dosages of α-adrenergic receptor blocker (p < 0.05) and with a higher occurrence of side effects (rs10515807) (p = 0.005). Similar associations were found for haplotype block 6, which is predominantly defined by rs10515807. Conclusions: This study suggests that genetic variability of α-adrenergic receptor genes might be associated with the clinically observed variation in beneficial and adverse therapeutic drug responses to α-adrenergic receptor blockers. Further studies in larger cohorts are needed to confirm our observations

3D Imaging on heterogeneous surfaces on laterite drill core materials

The SOLSA project aims to construct an analytical expert system for on-line-on-mine-real-time mineralogical and geochemical analyses on sonic drilled cores. A profilometer is indispensable to obtain reliable and quantitative data from RGB and hyperspectral cameras, and to get 3D definition of close-to-surface objects such as rheology (grain shape, grain size, fractures and vein systems), material hardness and porosities. Optical properties of minerals can be analyzed by focusing on the reflectance. Preliminary analyses were performed with the commercial scan control profilometer MI-CRO-EPSILON equipped with a blue 405 nm laser on a conveyor belt (depth resolution: 10 μm; surface resolution: 30x30 μm2 (maximum resolution; 1m drill core/4 min). Drill core parts and rocks with 4 different surface roughness states: (1) sonic drilled, (2) diamond saw-cut, polished at (3) 6 mm and (4) 0.25 μm were measured (see also abstract Duée et al. this volume). The ΜICRO- EPSILON scanning does not detect such small differences of surface roughness states. Profilometer data can also be used to access rough mineralogical identification of some mineral groups like Fe-Mg silicates, quartz and feldspars). Drill core parts from a siliceous mineralized breccia and laterite with high and deep porosity and fractures were analyzed. The determination of holes’ convexity and fractures) is limited by the surface/depth ratio. Depending on end-user’s needs, parameters such as fracture densities and mineral content should be combined, and depth and surface resolutions should be optimized, to speed up “on-line-on-mine-real- time” mineral and chemical analyses in order to reach the target of about 80 m/day of drilled core

Efficient long-term open-access data archiving in mining industries

Efficient data collection, analysis and preservation are needed to accomplish adequate business decision making. Long-lasting and sustainable business operations, such as mining, add extra requirements to this process: data must be reliably preserved over periods that are longer than that of a typical software life-cycle. These concerns are of special importance for the combined on-line-on-mine-real-time expert system SOLSA (http://www.solsa-mining.eu/) that will produce data not only for immediate industrial utilization, but also for the possible scientific reuse. We thus applied the experience of scientific data publishing to provide efficient, reliable, long term archival data storage. Crystallography, a field covering one of the methods used in the SOLSA expert system, has long traditions of archiving and disseminating crystallographic data. To that end, the Crystallographic Interchange Framework (CIF, [1]) was developed and is maintained by the International Union of Crystallography (IUCr). This framework provides rich means for describing crystal structures and crystallographic experiments in an unambiguous, human- and machine- readable way, in a standard that is independent of the underlying data storage technology. The Crystallography Open Database (COD, [2]) has been successfully using the CIF framework to maintain its open-access crystallographic data collection for over a decade [3,4]. Since the CIF framework is extensible it is possible to use it for other branches of knowledge. The SOLSA system will generate data using different methods of material identification: XRF, XRD, Raman, IR and DRIFT spectroscopy. For XRD, the CIF is usable out-of-the-box, since we can rely on extensive data definition dictionaries (ontologies) developed by the IUCr and the crystallographic community. For spectroscopic techniques such dictionaries, to our best knowledge, do not exist; thus, the SOLSA team is developing CIF dictionaries for spectroscopic techniques to be used in the SOLSA expert system. All dictionaries will be published under liberal license and communities are encourage to join the development, reuse and extend the dictionaries where necessary. These dictionaries will enable access to open data generated by SOLSA by all interested parties. The use of the common CIF framework will ensure smooth data exchange among SOLSA partners and seamless data publication from the SOLSA project

52 Genetic Loci Influencing Myocardial Mass.

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.</p

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape:A Large-Scale Genome-Wide Interaction Study (vol 11, e1005378, 2015)

The arcOGEN Consortium should be listed as an author of this article. They contributed to the genome-wide association study results presented in this work. They should be listed in the author byline at position 292 and affiliated with The Arthritis Research UK Osteoarthritis Genetics Consortium. They should also be included in the footnote designating consortia which is underneath the author affiliation list in the PDF version of the article, and in the S2 Text. Please view the correct S2 Text below, containing correct consortia members

TRIM4Post-Mining: Transition Information Modelling for Attractive Post-Mining Landscapes—A Conceptual Framework

TRIM4Post-Mining is a H2020/RFCS-funded project that brings together a consortium of European experts from industry and academia to develop an integrated information modelling system. This is designed to support decision making and planning during the transition from coal exploitation to a revitalized post-mining landscape, enabling infrastructure development for agricultural and industrial utilization, and contributing to the recovery of energy and materials from coal mining dumps. The smart system will be founded upon a high-resolution spatiotemporal database, utilizing state-of-the-art multi-scale and multi-sensor monitoring technologies that characterize dynamic processes in coal waste dumps related to timely, dependent deformation and geochemical processes. It will integrate efficient methods for operational and post-mining monitoring, comprehensive spatiotemporal data analytics, feature extraction, and predictive modelling; this will allow for the identification of potential contamination areas and the forecasting of geotechnical risks and ground conditions. For the interactive exploration of alternative land-use planning scenarios—in terms of residual risks, technical feasibility, environmental and social impact, and affordability—up-to-date data and models will be embedded in an interactive planning system based on Virtual Reality and Augmented Reality technology, forming a TRIM—a Transition Information Modelling System. This contribution presents the conceptual approach and main constituents, and describes the state-of-the-art and detailed anticipated methodological approach for each of the constituents. This is supported by the presentation of the first results and a discussion of future work. An anticipated second contribution will focus on the main findings, technology readiness and a discussion of future work.Resource Engineerin

TRIM4Post-Mining: Transition Information Modelling for Attractive Post-Mining Landscapes&mdash;A Conceptual Framework

TRIM4Post-Mining is a H2020/RFCS-funded project that brings together a consortium of European experts from industry and academia to develop an integrated information modelling system. This is designed to support decision making and planning during the transition from coal exploitation to a revitalized post-mining landscape, enabling infrastructure development for agricultural and industrial utilization, and contributing to the recovery of energy and materials from coal mining dumps. The smart system will be founded upon a high-resolution spatiotemporal database, utilizing state-of-the-art multi-scale and multi-sensor monitoring technologies that characterize dynamic processes in coal waste dumps related to timely, dependent deformation and geochemical processes. It will integrate efficient methods for operational and post-mining monitoring, comprehensive spatiotemporal data analytics, feature extraction, and predictive modelling; this will allow for the identification of potential contamination areas and the forecasting of geotechnical risks and ground conditions. For the interactive exploration of alternative land-use planning scenarios&mdash;in terms of residual risks, technical feasibility, environmental and social impact, and affordability&mdash;up-to-date data and models will be embedded in an interactive planning system based on Virtual Reality and Augmented Reality technology, forming a TRIM&mdash;a Transition Information Modelling System. This contribution presents the conceptual approach and main constituents, and describes the state-of-the-art and detailed anticipated methodological approach for each of the constituents. This is supported by the presentation of the first results and a discussion of future work. An anticipated second contribution will focus on the main findings, technology readiness and a discussion of future work