Description: Precipitation downscaling improves the coarse resolution and poor representation of precipitation in global climate models and helps end users to assess the likely hydrological impacts of climate change. This paper integrates perspectives from meteorologists, climatologists, statisticians, and hydrologists to identify generic end user (in particular, impact modeler) needs and to discuss downscaling capabilities and gaps. End users need a reliable representation of precipitation intensities and temporal and spatial variability, as well as physical consistency, independent of region and season. In addition to presenting dynamical downscaling, we review perfect prognosis statistical downscaling, model output statistics, and weather generators, focusing on recent developments to improve the representation of space-time variability. Furthermore, evaluation techniques to assess downscaling skill are presented. Downscaling adds considerable value to projections from global climate models. Remaining gaps are uncertainties arising from sparse data; representation of extreme summer precipitation, subdaily precipitation, and full precipitation fields on fine scales; capturing changes in small-scale processes and their feedback on large scales; and errors inherited from the driving global climate model.

Description: Reading out the temperature-memory of polymers, which is their ability to remember the temperature where they were deformed recently, is thus far unavoidably linked to erasing this memory effect. Here temperature-memory polymer actuators (TMPAs) based on cross-linked copolymer networks exhibiting a broad melting temperature range (ΔTm) are presented, which are...

Description: Introduction Emergency rooms (ERs) generally assign a preliminary diagnosis to patients, who are then hospitalised and may subsequently experience a change in their lead diagnosis (cDx). In ERs, the cDx rate varies from around 15% to more than 50%. Among the most frequent reasons for diagnostic errors are cognitive slips, which mostly result from faulty data synthesis. Furthermore, physicians have been repeatedly found to be poor self-assessors and to be overconfident in the quality of their diagnosis, which limits their ability to improve. Therefore, some of the clinically most relevant research questions concern how diagnostic decisions are made, what determines their quality and what can be done to improve them. Research that addresses these questions is, however, still rare. In particular, field studies that allow for generalising findings from controlled experimental settings are lacking. The ER, with its high throughput and its many simultaneous visits, is perfectly suited for the study of factors contributing to diagnostic error. With this study, we aim to identify factors that allow prediction of an ER's diagnostic performance. Knowledge of these factors as well as of their relative importance allows for the development of organisational, medical and educational strategies to improve the diagnostic performance of ERs. Methods and analysis We will conduct a field study by collecting diagnostic decision data, physician confidence and a number of influencing factors in a real-world setting to model real-world diagnostic decisions and investigate the adequacy, validity and informativeness of physician confidence in these decisions. We will specifically collect data on patient, physician and encounter factors as predictors of the dependent variables. Statistical methods will include analysis of variance and a linear mixed-effects model. Ethics and dissemination The Bern ethics committee approved the study under KEK Number 197/15. Results will be published in peer-reviewed scientific medical journals. Authorship will be determined according to ICMJE guidelines. Trial registration number The study protocol Version 1.0 from 17 May 2015 is registered in the Inselspital Research Database Information System (IRDIS) and with the IRB (‘Kantonale Ethikkomission’) Bern under KEK Number 197/15.

Description: Dry aerosol size distributions and scattering coefficients were measured on 10 flights in 32 clear air regions adjacent to tropical storm anvils over the eastern Atlantic Ocean. Aerosol properties in these regions were compared with those from background air in the upper troposphere at least 40 km from clouds. Median values for aerosol scattering coefficient and particle number concentration 〉0.3 μm diameter were higher at the anvil edges than in background air, showing that convective clouds loft particles from the lower troposphere to the upper troposphere. These differences are statistically significant. The aerosol enhancement zones extended ~10-15 km horizontally and ~ 0.25 km vertically below anvil cloud edges, but were not due to hygroscopic growth since particles were measured under dry conditions. Number concentrations of particles 〉0.3 μm diameter were enhanced more for the cases where Saharan dust layers were identified below the clouds with airborne lidar. Median number concentrations in this size range increased from ~100 l -1 in background air to ~400 l -1 adjacent to cloud edges with dust below, with larger enhancements for stronger storm systems. Integration with satellite cloud frequency data indicates that this transfer of large particles from low to high altitudes by convection has little impact on dust concentrations within the Saharan Air Layer itself. However, it can lead to substantial enhancement in large dust particles and, therefore, heterogeneous ice nuclei in the upper troposphere over the Atlantic. This may induce a cloud/aerosol feedback effect that could impact cloud properties in the region and downwind.

Description: Due to the duality in terms of (1) the groundwater flow field and (2) the discharge conditions, flow patterns of karst aquifer systems are complex. Estimated aquifer parameters may differ by several orders of magnitude from local (borehole) to regional (catchment) scale because of the large contrast in hydraulic parameters between matrix and conduit, their heterogeneity and anisotropy. One approach to deal with the scale effect problem in the estimation of hydraulic parameters of karst aquifers is the application of large-scale experiments such as long-term high-abstraction conduit pumping tests, stimulating measurable groundwater drawdown in both, the karst conduit system as well as the fractured matrix. The numerical discrete conduit-continuum modeling approach MODFLOW-2005 Conduit Flow Process Mode1 (CFPM1) is employed to simulate laminar and non-laminar conduit flow, induced by large-scale experiments, in combination with Darcian matrix flow. Effects of large-scale experiments were simulated for idealized settings. Subsequently, diagnostic plots and analyses of different fluxes are applied to interpret differences in the simulated conduit drawdown and general flow patterns. The main focus is set on the question to which extent different conduit flow regimes will affect the drawdown in conduit and matrix depending on the hydraulic properties of the conduit system, i.e. conduit diameter and relative roughness. In this context, CFPM1 is applied to investigate the importance of considering turbulent conditions for the simulation of karst conduit flow. This work quantifies the relative error that results from assuming laminar conduit flow for the interpretation of a synthetic large-scale pumping test in karst.

Description: Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied through experimental and computational analysis. Integrating gene regulation data with a human metabolic network prompted the establishment of an open-sourced web portal, IDARE (Integrated Data Nodes of Regulation), for visualizing various gene-related data in context of metabolic pathways. Motivated by increasing availability of deep sequencing studies, we obtained ChIP-seq data from widely studied human umbilical vein endothelial cells. Interestingly, we found that association of metabolic genes with multiple transcription factors (TFs) enriched disease-associated genes. To demonstrate further extensions enabled by examining these networks together, constraint-based modeling was applied to data from human preadipocyte differentiation. In parallel, data on gene expression, genome-wide ChIP-seq profiles for peroxisome proliferator-activated receptor (PPAR) , CCAAT/enhancer binding protein (CEBP) α, liver X receptor (LXR) and H3K4me3 and microRNA target identification for miR-27a, miR-29a and miR-222 were collected. Disease-relevant key nodes, including mitochondrial glycerol-3-phosphate acyltransferase (GPAM), were exposed from metabolic pathways predicted to change activity by focusing on association with multiple regulators. In both cell types, our analysis reveals the convergence of microRNAs and TFs within the branched chain amino acid (BCAA) metabolic pathway, possibly providing an explanation for its downregulation in obese and diabetic conditions.

Description: Deregulated cell migration and invasion are hallmarks of metastatic cancer cells. Phosphorylation on residue Ser5 of the actin-bundling protein L-plastin activates L-plastin and has been reported to be crucial for invasion and metastasis. Here, we investigate signal transduction leading to L-plastin Ser5 phosphorylation using 4 human breast cancer cell lines. Whole-genome microarray analysis comparing cell lines with different invasive capacities and corresponding variations in L-plastin Ser5 phosphorylation level revealed that genes of the ERK/MAPK pathway are differentially expressed. It is noteworthy that in vitro kinase assays showed that ERK/MAPK pathway downstream ribosomal protein S6 kinases α-1 (RSK1) and α-3 (RSK2) are able to directly phosphorylate L-plastin on Ser5. Small interfering RNA- or short hairpin RNA-mediated knockdown and activation/inhibition studies followed by immunoblot analysis and computational modeling confirmed that ribosomal S6 kinase (RSK) is an essential activator of L-plastin. Migration and invasion assays showed that RSK knockdown led to a decrease of up to 30% of migration and invasion of MDA-MB-435S cells. Although the presence of L-plastin was not necessary for migration/invasion of these cells, immunofluorescence assays illustrated RSK-dependent recruitment of Ser5-phosphorylated L-plastin to migratory structures. Altogether, we provide evidence that the ERK/MAPK pathway is involved in L-plastin Ser5 phosphorylation in breast cancer cells with RSK1 and RSK2 kinases able to directly phosphorylate L-plastin residue Ser5.—Lommel, M. J., Trairatphisan, P., Gäbler, K., Laurini, C., Muller, A., Kaoma, T., Vallar, L., Sauter, T., Schaffner-Reckinger, E. L-plastin Ser5 phosphorylation in breast cancer cells and in vitro is mediated by RSK downstream of the ERK/MAPK pathway.

Description: We previously showed that disease-linked metabolic genes are often under combinatorial regulation. Using the genome-wide ChIP-Seq binding profiles for 93 transcription factors in nine different cell lines, we show that genes under high regulatory load are significantly enriched for disease-association across cell types. We find that transcription factor load correlates with the enhancer load of the genes and thereby allows the identification of genes under high regulatory load by epigenomic mapping of active enhancers. Identification of the high enhancer load genes across 139 samples from 96 different cell and tissue types reveals a consistent enrichment for disease-associated genes in a cell type-selective manner. The underlying genes are not limited to super-enhancer genes and show several types of disease-association evidence beyond genetic variation (such as biomarkers). Interestingly, the high regulatory load genes are involved in more KEGG pathways than expected by chance, exhibit increased betweenness centrality in the interaction network of liver disease genes, and carry longer 3' UTRs with more microRNA (miRNA) binding sites than genes on average, suggesting a role as hubs integrating signals within regulatory networks. In summary, epigenetic mapping of active enhancers presents a promising and unbiased approach for identification of novel disease genes in a cell type-selective manner.