Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.

A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.

Large-scale temperature response to external forcing in simulations and reconstructions of the last millennium

Understanding natural climate variability and its driving factors is crucial to assessing future climate change. Therefore, comparing proxy-based climate reconstructions with forcing factors as well as comparing these with paleoclimate model simulations is key to gaining insights into the relative roles of internal versus forced variability. A review of the state of modelling of the climate of the last millennium prior to the CMIP5–PMIP3 (Coupled Model Intercomparison Project Phase 5–Paleoclimate Modelling Intercomparison Project Phase 3) coordinated effort is presented and compared to the available temperature reconstructions. Simulations and reconstructions broadly agree on reproducing the major temperature changes and suggest an overall linear response to external forcing on multidecadal or longer timescales. Internal variability is found to have an important influence at hemispheric and global scales. The spatial distribution of simulated temperature changes during the transition from the Medieval Climate Anomaly to the Little Ice Age disagrees with that found in the reconstructions. Thus, either internal variability is a possible major player in shaping temperature changes through the millennium or the model simulations have problems realistically representing the response pattern to external forcing. A last millennium transient climate response (LMTCR) is defined to provide a quantitative framework for analysing the consistency between simulated and reconstructed climate. Beyond an overall agreement between simulated and reconstructed LMTCR ranges, this analysis is able to single out specific discrepancies between some reconstructions and the ensemble of simulations. The disagreement is found in the cases where the reconstructions show reduced covariability with external forcings or when they present high rates of temperature change.

Greenland accumulation and its connection to the large-scale atmospheric circulation in ERA-Interim and paleoclimate simulations

Changes in Greenland accumulation and the stability in the relationship between accumulation variability and large-scale circulation are assessed by performing time-slice simulations for the present day, the preindustrial era, the early Holocene, and the Last Glacial Maximum (LGM) with a comprehensive climate model. The stability issue is an important prerequisite for reconstructions of Northern Hemisphere atmospheric circulation variability based on accumulation or precipitation proxy records from Greenland ice cores. The analysis reveals that the relationship between accumulation variability and large-scale circulation undergoes a significant seasonal cycle. As the contributions of the individual seasons to the annual signal change, annual mean accumulation variability is not necessarily related to the same atmospheric circulation patterns during the different climate states. Interestingly, within a season, local Greenland accumulation variability is indeed linked to a consistent circulation pattern, which is observed for all studied climate periods, even for the LGM. Hence, it would be possible to deduce a reliable reconstruction of seasonal atmospheric variability (e.g., for North Atlantic winters) if an accumulation or precipitation proxy were available that resolves single seasons. We further show that the simulated impacts of orbital forcing and changes in the ice sheet topography on Greenland accumulation exhibit strong spatial differences, emphasizing that accumulation records from different ice core sites regarding both interannual and long-term (centennial to millennial) variability cannot be expected to look alike since they include a distinct local signature. The only uniform signal to external forcing is the strong decrease in Greenland accumulation during glacial (LGM) conditions and an increase associated with the recent rise in greenhouse gas concentrations.

Large scale variation in Enterococcus faecalis illustrated by the genome analysis of strain OG1RF.

BACKGROUND: Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OG1RF, which is commonly used for molecular manipulation and virulence studies. RESULTS: The 2,739,625 base pair chromosome of OG1RF was found to contain approximately 232 kilobases unique to this strain compared to V583, the only publicly available sequenced strain. Almost no mobile genetic elements were found in OG1RF. The 64 areas of divergence were classified into three categories. First, OG1RF carries 39 unique regions, including 2 CRISPR loci and a new WxL locus. Second, we found nine replacements where a sequence specific to V583 was substituted by a sequence specific to OG1RF. For example, the iol operon of OG1RF replaces a possible prophage and the vanB transposon in V583. Finally, we found 16 regions that were present in V583 but missing from OG1RF, including the proposed pathogenicity island, several probable prophages, and the cpsCDEFGHIJK capsular polysaccharide operon. OG1RF was more rapidly but less frequently lethal than V583 in the mouse peritonitis model and considerably outcompeted V583 in a murine model of urinary tract infections. CONCLUSION: E. faecalis OG1RF carries a number of unique loci compared to V583, but the almost complete lack of mobile genetic elements demonstrates that this is not a defining feature of the species. Additionally, OG1RF's effects in experimental models suggest that mediators of virulence may be diverse between different E. faecalis strains and that virulence is not dependent on the presence of mobile genetic elements.

High-density large-scale field emitter arrays for x-ray free electron laser cathodes

High brightness electron sources are of great importance for the operation of the hard X-ray free electron lasers. Field emission cathodes based on the double-gate metallic field emitter arrays (FEAs) can potentially offer higher brightness than the currently used ones. We report on the successful application of electron beam lithography for fabrication of the large-scale single-gate as well as double-gate FEAs. We demonstrate operational high-density single-gate FEAs with sub-micron pitch and total number of tips up to 106 as well as large-scale double-gate FEAs with large collimation gate apertures. The details of design, fabrication procedure and successful measurements of the emission current from the single- and double-gate cathodes are presented.

A hybrid method for large-scale short-term scheduling of make-and-pack production processes

Due to the ongoing trend towards increased product variety, fast-moving consumer goods such as food and beverages, pharmaceuticals, and chemicals are typically manufactured through so-called make-and-pack processes. These processes consist of a make stage, a pack stage, and intermediate storage facilities that decouple these two stages. In operations scheduling, complex technological constraints must be considered, e.g., non-identical parallel processing units, sequence-dependent changeovers, batch splitting, no-wait restrictions, material transfer times, minimum storage times, and finite storage capacity. The short-term scheduling problem is to compute a production schedule such that a given demand for products is fulfilled, all technological constraints are met, and the production makespan is minimised. A production schedule typically comprises 500–1500 operations. Due to the problem size and complexity of the technological constraints, the performance of known mixed-integer linear programming (MILP) formulations and heuristic approaches is often insufficient. We present a hybrid method consisting of three phases. First, the set of operations is divided into several subsets. Second, these subsets are iteratively scheduled using a generic and flexible MILP formulation. Third, a novel critical path-based improvement procedure is applied to the resulting schedule. We develop several strategies for the integration of the MILP model into this heuristic framework. Using these strategies, high-quality feasible solutions to large-scale instances can be obtained within reasonable CPU times using standard optimisation software. We have applied the proposed hybrid method to a set of industrial problem instances and found that the method outperforms state-of-the-art methods.

Sparse computation for large-scale binary classification

Well-known data mining algorithms rely on inputs in the form of pairwise similarities between objects. For large datasets it is computationally impossible to perform all pairwise comparisons. We therefore propose a novel approach that uses approximate Principal Component Analysis to efficiently identify groups of similar objects. The effectiveness of the approach is demonstrated in the context of binary classification using the supervised normalized cut as a classifier. For large datasets from the UCI repository, the approach significantly improves run times with minimal loss in accuracy.

A climatological analysis of high-precipitation events in Dronning Maud Land, Antarctica, and associated large-scale atmospheric conditions

The link between high precipitation in Dronning Maud Land (DML), Antarctica, and the large-scale atmospheric circulation is investigated using ERA-Interim data for 1979–2009. High-precipitation events are analyzed at Halvfarryggen situated in the coastal region of DML and at Kohnen Station located in its interior. This study further includes a comprehensive comparison of high precipitation in ERA-Interim with precipitation data from the Antarctic Mesoscale Prediction System (AMPS) and snow accumulation measurements from automatic weather stations (AWSs), with the limitations of such a comparison being discussed. The ERA-Interim and AMPS precipitation data agree very well. However, the correspondence between high precipitation in ERA-Interim and high snow accumulation at the AWSs is relatively weak. High-precipitation events at both Halvfarryggen and Kohnen are typically associated with amplified upper level waves. This large-scale atmospheric flow pattern is preceded by the downstream development of a Rossby wave train from the eastern South Pacific several days before the precipitation event. At the surface, a cyclone located over the Weddell Sea is the main synoptic ingredient for high precipitation both at Halvfarryggen and at Kohnen. A blocking anticyclone downstream is not a requirement for high precipitation per se, but a larger share of blocking occurrences during the highest-precipitation days in DML suggests that these blocks strengthen the vertically integrated water vapor transport (IVT) into DML. A strong link between high precipitation and the IVT perpendicular to the local orography suggests that IVT could be used as a “proxy” for high precipitation, in particular over DML's interior.

The geography of large-scale land acquisitions: Analysing socio-ecological patterns of target contexts in the global South

This paper analyses local geographical contexts targeted by transnational large-scale land acquisitions (>200 ha per deal) in order to understand how emerging patterns of socio-ecological characteristics can be related to processes of large-scale foreign investment in land. Using a sample of 139 land deals georeferenced with high spatial accuracy, we first analyse their target contexts in terms of land cover, population density, accessibility, and indicators for agricultural potential. Three distinct patterns emerge from the analysis: densely populated and easily accessible croplands (35% of land deals); remote forestlands with lower population densities (34% of land deals); and moderately populated and moderately accessible shrub- or grasslands (26% of land deals). These patterns are consistent with processes described in the relevant case study literature, and they each involve distinct types of stakeholders and associated competition over land. We then repeat the often-cited analysis that postulates a link between land investments and target countries with abundant so-called “idle” or “marginal” lands as measured by yield gap and available suitable but uncultivated land; our methods differ from the earlier approach, however, in that we examine local context (10-km radius) rather than countries as a whole. The results show that earlier findings are disputable in terms of concepts, methods, and contents. Further, we reflect on methodologies for exploring linkages between socioecological patterns and land investment processes. Improving and enhancing large datasets of georeferenced land deals is an important next step; at the same time, careful choice of the spatial scale of analysis is crucial for ensuring compatibility between the spatial accuracy of land deal locations and the resolution of available geospatial data layers. Finally, we argue that new approaches and methods must be developed to empirically link socio-ecological patterns in target contexts to key determinants of land investment processes. This would help to improve the validity and the reach of our findings as an input for evidence-informed policy debates.