MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs

Multi-walled carbon nanotubes (MWCNTs) are extensively produced and used in composite materials and electronic applications, thus increasing risk of worker and consumer exposure. MWCNTs are an inhomogeneous group of nanomaterials that come in various lengths, shapes and with different metal contaminations, which makes hazard evaluation difficult. However, several studies suggest that length plays an important role in the toxicity induced by MWCNTs. How the length influences toxicity at the molecular level is yet to be characterized. Female C57BL/6 mice were exposed by single intratracheal instillation to 18, 54 or 162 µg/mouse of a short MWCNT (NRCWE-026, 847±102 nm in length) or long MWCNT (NM-401, 4048±366 nm in length). The two MWCNTs were extensively characterized. Lung tissues were harvested 24 h, 3 d and 28 d after exposure. We employed DNA microarrays, bronchoalveolar lavage fluid analysis, comet assay and dichlorodihydrofluorescein assay in order to profile the pulmonary responses. Bioinformatics tools were then applied to compare and contrast the expression profiles and to build a length dependent property-response matrix for gene-by-gene comparison. The toxicogenomic analysis of the global mRNA changes after exposure to the short, entangled NRCWE-026 or the longer, stiffer NM-401 showed high degree of similarities. The toxicity of both MWCNTs was driven by strong inflammatory and acute phase responses, which peaked at day 3 and was observed both in bronchoalveolar lavage cell influx and in gene expression profiles. The inflammatory response was sustained at post-exposure day 28. Also, at the sub-chronic level, we identified a sub-set of 14 fibrosis related genes that were uniquely differentially regulated after exposure to NM-401. Acellular ROS production occurred almost exclusively with NRCWE-026, however the longer NM-401 induced in vivo DNA strand breaks and differential regulation of genes involved in free radical scavenging more readily than NRCWE-026. Our results indicate that the global mRNA response after exposure to MWCNTs is length independent at the acute time points, but that fibrosis may be length dependent sub-chronic end point.JRC.H.6-Digital Earth and Reference Dat

The Perfect Finance Minister: Whom to Appoint as Finance Minister to Balance the Budget?

The role and influence of the finance minister within the cabinet are discussed with increasing prominence in the recent theoretical literature on the political economy of budget deficits. It is generally assumed that the spending ministers can raise their reputation purely with new or more extensive expenditure programs, whereas solely the finance minister is interested to balance the budget. Using a dynamic panel model to study the development of public deficits in the German states between 1960 and 2009, we identify several personal characteristics of the finance ministers that significantly influence budgetary performance. Namely her professional background seems to affect budget deficits. During times of fiscal stress, our results can guide prime ministers in the nominating of finance ministers in order to assure sound budgeting

The Little Ice Age climate of New Zealand reconstructed from Southern Alps cirque glaciers : a synoptic type approach

Little Ice Age (LIA) austral summer temperature anomalies were derived from palaeoequilibrium line altitudes at 22 cirque glacier sites across the Southern Alps of New Zealand. Modern analog seasons with temperature anomalies akin to the LIA reconstructions were selected, and then applied in a sampling of high-resolution gridded New Zealand climate data and global reanalysis data to generate LIA climate composites at local, regional and hemispheric scales. The composite anomaly patterns assist in improving our understanding of atmospheric circulation contributions to the LIA climate state, allow an interrogation of synoptic type frequency changes for the LIA relative to present, and provide a hemispheric context of the past conditions in New Zealand. An LIA summer temperature anomaly of -0.56 °C (±0.29°C) for the Southern Alps based on palaeo-equilibrium lines compares well with local tree-ring reconstructions of austral summer temperature. Reconstructed geopotential height at 1,000 hPa (z1000) suggests enhanced southwesterly flow across New Zealand occurred during the LIA to generate the terrestrial temperature anomalies. The mean atmospheric circulation pattern for summer resulted from a crucial reduction of the 'HSE'-blocking synoptic type (highs over and to the west of NZ; largely settled conditions) and increases in both the 'T'- and 'SW'-trough synoptic types (lows passing over NZ; enhanced southerly and southwesterly flow) relative to normal. Associated land-based temperature and precipitation anomalies suggest both colder- and wetter-than-normal conditions were a pervasive component of the base climate state across New Zealand during the LIA, as were colder-than-normal Tasman Sea surface temperatures. Proxy temperature and circulation evidence were used to corroborate the spatially heterogeneous Southern Hemisphere composite z1000 and sea surface temperature patterns generated in this study. A comparison of the composites to climate mode archetypes suggests LIA summer climate and atmospheric circulation over New Zealand was driven by increased frequency of weak El Niño-Modoki in the tropical Pacific and negative Southern Annular Mode activity.22 page(s

Picking the Brains of MPC Members

This paper reports and analyzes the results from a questionnaire sent to all present and former members of the Riksbank's Executive Board, the monetary policy committee (MPC) of the Swedish central bank. The questions cover a number of issues discussed in the growing literature on monetary policy making by committees. The paper thus relates research to the views of practitioners in a way that has not been done before. We find, among other things, that many members consider the six-person strong Riksbank MPC to be slightly too large, that it is very common that members have decided before the policy meeting how they will vote, and that members, when forming their opinions, consider input from the staff more important than input from their colleagues

Phenotypically Silent Bone Morphogenetic Protein Receptor 2 Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing the Risk for Neointimal Transformation

Background: Bmpr2 (bone morphogenetic protein receptor 2) mutations are critical risk factors for hereditary pulmonary arterial hypertension (PAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-LO (5-lipoxygenase) provokes lung inflammation and transient PAH in Bmpr2+/- mice. Accordingly, 5-LO and its metabolite, leukotriene B4, are candidates for the second hit. The purpose of this study was to determine how 5-LO-mediated pulmonary inflammation synergized with phenotypically silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats. Methods: Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to 1 year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus, monocrotaline, SU5416, SU5416 with chronic hypoxia, or chronic hypoxia alone. Bmpr2-mutant hereditary PAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells with impaired BMPR2 signaling were exposed to increased 5-LO-mediated inflammation and were assessed for phenotypic and transcriptomic changes. Results: Lung inflammation, induced by intratracheal delivery of 5-LO-expressing adenovirus, elicited severe PAH with intimal remodeling in Bmpr2+/- rats but not in their wild-type littermates. Neointimal lesions in the diseased Bmpr2+/- rats gained endogenous 5-LO expression associated with elevated leukotriene B4 biosynthesis. Bmpr2-mutant hereditary PAH patients similarly expressed 5-LO in the neointimal cells. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant and proliferative pulmonary artery endothelial cells with mesenchymal characteristics. These transformed cells expressed nuclear envelope-localized 5-LO consistent with induced leukotriene B4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated nuclear factor Kappa B subunit (NF-κB), interleukin-6, and transforming growth factor beta (TGF-β) signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-β antagonism suggests that TGF-β is critical for neointimal transformation. Conclusions: In a new 2-hit model of disease, lung inflammation induced severe PAH pathology in Bmpr2+/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-β signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced leukotriene B4 production. This study offers an explanation of how an environmental injury unleashes the destructive potential of an otherwise silent genetic mutation