The Insulator Protein SU(HW) Fine-Tunes Nuclear Lamina Interactions of the Drosophila Genome

Specific interactions of the genome with the nuclear lamina (NL) are thought to assist chromosome folding inside the nucleus and to contribute to the regulation of gene expression. High-resolution mapping has recently identified hundreds of large, sharply defined lamina-associated domains (LADs) in the human genome, and suggested that the insulator protein CTCF may help to demarcate these domains. Here, we report the detailed structure of LADs in Drosophila cells, and investigate the putative roles of five insulator proteins in LAD organization. We found that the Drosophila genome is also organized in discrete LADs, which are about five times smaller than human LADs but contain on average a similar number of genes. Systematic comparison to new and published insulator binding maps shows that only SU(HW) binds preferentially at LAD borders and at specific positions inside LADs, while GAF, CTCF, BEAF-32 and DWG are mostly absent from these regions. By knockdown and overexpression studies we demonstrate that SU(HW) weakens genome – NL interactions through a local antagonistic effect, but we did not obtain evidence that it is essential for border formation. Our results provide insights into the evolution of LAD organization and identify SU(HW) as a fine-tuner of genome – NL interactions

SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Bayesian network analysis of targeting interactions in chromatin

In eukaryotes, many chromatin proteins together regulate gene expression. Chromatin proteins often direct the genomic binding pattern of other chromatin proteins, for example, by recruitment or competition mechanisms. The network of such targeting interactions in chromatin is complex and still poorly understood. Based on genome-wide binding maps, we constructed a Bayesian network model of the targeting interactions among a broad set of 43 chromatin components in Drosophila cells. This model predicts many novel functional relationships. For example, we found that the homologous proteins HP1 and HP1C each target the heterochromatin protein HP3 to distinct sets of genes in a competitive manner. We also discovered a central role for the remodeling factor Brahma in the targeting of several DNA-binding factors, including GAGA factor, JRA, and SU(VAR)3-7. Our network model provides a global view of the targeting interplay among dozens of chromatin components

Potential for Various Riverine Flood DRR Measures at the Global Scale

Flooding events that occur on the Earth’s rivers annually cause large amounts of monetary and human impacts. These impacts are expected to increase through the end of the 21st century for various reasons. Decision makers must take action now and implement disaster risk reduction measures to avoid large increases to damages in the future. On the global scale, we model three disaster risk reduction measures – namely dykes and levees, dry-proofing, and zoning restrictions – and evaluate them in terms of their economic performance (via benefit-cost analysis) as well as their ability to achieve a predefined risk reduction target based on current relative levels of risk, referred here to as efficacy. We show that large decreases to future expected annual damages can be obtained if certain measures are implemented throughout various sub-national regions of the world, most notably in regions with high levels of projected population growth. We see that the two aforementioned evaluation metrics, when used to select a disaster risk reduction measure for implementation, result in different outcomes for three-fourths of the world’s sub-national regions, most often in East Asia and the Pacific as well as South Asia. In these instances, decision makers must choose what is more important – achieving a risk reduction target, or having investments pay-off in the long run, even if it requires a large amount of up-front capital. This opens the dialogue for incorporating other non-monetary values into the decision making process for disaster risk management, and also points to the potential of hybridising riverine adaptation measures to achieve multiple risk and societal objectives at once

LOFAR and APERTIF Surveys of the Radio Sky : Probing Shocks and Magnetic Fields in Galaxy Clusters

At very low frequencies, the new pan-European radio telescope LOFAR is opening the last unexplored window of the electromagnetic spectrum for astrophysical studies. The revolutionary APERTIF-phased arrays that are about to be installed on the Westerbork radio telescope (WSRT) will dramatically increase the survey speed for the WSRT. Combined surveys with these two facilities will deeply chart the northern sky over almost two decades in radio frequency from similar to 15 up to 1400 MHz. Here we briefly describe some of the capabilities of these new facilities and what radio surveys are planned to study fun-damental issues related to the formation and evolution of galaxies and clusters of galaxies. In the second part we briefly review some recent observational results directly showing that diffuse radio emission in clusters traces shocks due to cluster mergers. As these diffuse radio sources are relatively bright at low frequencies, LOFAR should be able to detect thousands of such sources up to the epoch of cluster formation. This will allow addressing many question about the origin and evolution of shocks and magnetic fields in clusters. At the end we briefly review some of the first and very preliminary LOFAR results on clusters.Peer reviewe

Localising global urban development; simulating local exposure to natural hazards in the global 2UP model

Future population growth is expected to concentrate in urban agglomerations that are already exposed to numerous natural hazards. It is difficult, however, to assess this increase in risk as natural hazards are often concentrated in space and population growth scenarios tend to be defined at much coarser scales. By combining recently released high-resolution spatial data on land use, population density and natural hazards with a novel, computationally effective simulation approach we analyse global increases in local exposure to two important natural hazards: flood risk and landslides. We develop global spatially explicitp rojections of population change and urban expansion using a land-use and population allocation model. The model is developed in the Geo Data and Model Server (GeoDMS) modelling framework, that also underlies Land Use Scanner and several other operational models of land-use change developed for individual countries, larger river catchment areas and the territory of the European Union. The model disaggregates scenario-based national-level population estimates to a high resolution spatial grid (30 arc seconds). It simulates local population development and urban growth on a global scale. The main steps include: 1) compiling current global population and urban land use data layers; 2) developing projections of future population and urban area growth; 3) defining suitable locations for future development following a logistic regression analysis explaining urban patterns around the globe; 4) allocating future urban area development and population change; 5) assessing exposure to natural hazards. We conclude that on global scale urban development is likely to strongly increase exposure to both floods and landslides. In almost all world regions urban growth during the coming decades is larger in hazard-prone areas than in non-exposed areas. This is especially prevalent for countries in Sub-Saharan Africa and South Asia. In developed countries growth rates are much lower and show far less variation between exposed and non-exposed areas. In our presentation we will discuss the functioning of the model, its calibration and validation and the most interesting outcomes. We will briefly reflect on its usefulness for policymakers, suggesting that the model is best applied in fast developing regions where model-based risk assessments were hitherto impossible because of a lack of data

The potential of global coastal flood risk reduction using various DRR measures

Coastal flood risk is a serious global challenge facing current and future generations. Several disaster risk reduction (DRR) measures have been posited as ways to reduce the deleterious impacts of coastal flooding. On a global scale, however, efforts to model the future effects of DRR measures (beyond structural) are limited. In this paper, we use a global-scale flood risk model to estimate the risk of coastal flooding and to assess and compare the efficacy and economic performance of various DRR measures, namely dykes and coastal levees, dry-proofing of urban assets, zoning restrictions in flood-prone areas, and management of foreshore vegetation. To assess the efficacy of each DRR measure, we determine the extent to which it can limit future flood risk as a percentage of regional GDP to the same proportional value as today (a "relative risk constant"objective). To assess their economic performance, we estimate the economic benefits and costs of implementing each measure. If no DRR measures are implemented to mitigate future coastal flood risk, we estimate expected annual damages to exceed USD 1.3 trillion by 2080, directly affecting an estimated 11.5 million people on an annual basis. Low- and high-end scenarios reveal large ranges of impact uncertainty, especially in lower-income regions. On a global scale, we find the efficacy of dykes and coastal levees in achieving the relative risk constant objective to be 98 %, of dry-proofing to be 49 %, of zoning restrictions to be 11 %, and of foreshore vegetation to be 6 %. In terms of direct costs, the overall figure is largest for dry-proofing (USD 151 billion) and dykes and coastal levees (USD 86 billion), much more than those of zoning restrictions (USD 27 million) and foreshore vegetation (USD 366 million). These two more expensive DRR measures also exhibit the largest potential range of direct costs. While zoning restrictions and foreshore vegetation achieve the highest global benefit-cost ratios (BCRs), they also provide the smallest magnitude of overall benefit. We show that there are large regional patterns in both the efficacy and economic performance of modelled DRR measures that display much potential for flood risk reduction, especially in regions of the world that are projected to experience large amounts of population growth. Over 90 % of sub-national regions in the world can achieve their relative risk constant targets if at least one of the investigated DRR measures is employed. While future research could assess the indirect costs and benefits of these four and other DRR measures, as well as their subsequent hybridization, here we demonstrate to global and regional decision makers the case for investing in DRR now to mitigate future coastal flood risk.</p