A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons

The mesencephalic dopaminergic (mesDA) system regulates behavior and movement control and has been implicated in psychiatric and affective disorders. We have identified a bicoid-related homeobox gene, Ptx3, a member of the Ptx-subfamily, that is uniquely expressed in these neurons. Its expression starting at E11.5 in the developing mouse midbrain correlates with the appearance of mesDA neurons. The number of Ptx3-expressing neurons is reduced in Parkinson patients, and these neurons are absent from 6-hydroxy-dopamine-lesioned rats, an animal model for this disease. Thus, Ptx3 is a unique transcription factor marking the mesDA neurons at the exclusion of other dopaminergic neurons, and it may be involved in developmental determination of this neuronal lineage.

Binding site of brefeldin A at the interface between the small G protein ADP-ribosylation factor 1 (ARF1) and the nucleotide-exchange factor Sec7 domain

Sec7 domains (Sec7d) catalyze the exchange of guanine nucleotide on ARFs. Recent studies indicated that brefeldin A (BFA) inhibits Sec7d-catalyzed nucleotide exchange on ARF1 in an uncompetitive manner by trapping an early intermediate of the reaction: a complex between GDP-bound ARF1 and Sec7d. Using 3H-labeled BFA, we show that BFA binds to neither isolated Sec7d nor isolated ARF1–GDP, but binds to the transitory Sec7d–ARF1–GDP complex and stabilizes it. Two pairs of residues at positions 190–191 and 198–208 (Arno numbering) in Sec7d contribute equally to the stability of BFA binding, which is also sensitive to mutation of H80 in ARF1. The catalytic glutamic (E156) residue of Sec7d is not necessary for BFA binding. In contrast, BFA does not bind to the intermediate catalytic complex between nucleotide-free ARF1 and Sec7d. These results suggest that, on initial docking steps between ARF1–GDP and Sec7d, BFA inserts like a wedge between the switch II region of ARF1–GDP and a surface encompassing residues 190–208, at the border of the characteristic hydrophobic groove of Sec7d. Bound BFA would prevent the switch regions of ARF1–GDP from reorganizing and forming tighter contacts with Sec7d and thereby would maintain the bound GDP of ARF1 at a distance from the catalytic glutamic finger of Sec7d.

Juglone, an inhibitor of the peptidyl-prolyl isomerase Pin1, also directly blocks transcription

The C-terminal domain (CTD) of the large subunit of RNA polymerase II plays a role in transcription and RNA processing. Yeast ESS1, a peptidyl-prolyl cis/trans isomerase, is involved in RNA processing and can associate with the CTD. Using several types of assays we could not find any evidence of an effect of Pin1, the human homolog of ESS1, on transcription by RNA polymerase II in vitro or on the expression of a reporter gene in vivo. However, an inhibitor of Pin1, 5-hydroxy-1,4-naphthoquinone (juglone), blocked transcription by RNA polymerase II. Unlike N-ethylmaleimide, which inhibited all phases of transcription by RNA polymerase II, juglone disrupted the formation of functional preinitiation complexes by modifying sulfhydryl groups but did not have any significant effect on either initiation or elongation. Both RNA polymerases I and III, but not T7 RNA polymerase, were inhibited by juglone. The primary target of juglone has not been unambiguously identified, although a site on the polymerase itself is suggested by inhibition of RNA polymerase II during factor-independent transcription of single-stranded DNA. Because of its unique inhibitory properties juglone should prove useful in studying transcription in vitro.

Controlling small guanine–nucleotide-exchange factor function through cytoplasmic RNA intramers

ADP-ribosylation factor (ARF) GTPases and their regulatory proteins have been implicated in the control of diverse biological functions. Two main classes of positive regulatory elements for ARF have been discovered so far: the large Sec7/Gea and the small cytohesin/ARNO families, respectively. These proteins harbor guanine–nucleotide-exchange factor (GEF) activity exerted by the common Sec7 domain. The availability of a specific inhibitor, the fungal metabolite brefeldin A, has enabled documentation of the involvement of the large GEFs in vesicle transport. However, because of the lack of such tools, the biological roles of the small GEFs have remained controversial. Here, we have selected a series of RNA aptamers that specifically recognize the Sec7 domain of cytohesin 1. Some aptamers inhibit guanine–nucleotide exchange on ARF1, thereby preventing ARF activation in vitro. Among them, aptamer M69 exhibited unexpected specificity for the small GEFs, because it does not interact with or inhibit the GEF activity of the related Gea2-Sec7 domain, a member of the class of large GEFs. The inhibitory effect demonstrated in vitro clearly is observed as well in vivo, based on the finding that M69 produces similar results as a dominant-negative, GEF-deficient mutant of cytohesin 1: when expressed in the cytoplasm of T-cells, M69 reduces stimulated adhesion to intercellular adhesion molecule-1 and results in a dramatic reorganization of F-actin distribution. These highly specific cellular effects suggest that the ARF-GEF activity of cytohesin 1 plays an important role in cytoskeletal remodeling events of lymphoid cells.

First steps toward harmonized human biomonitoring in Europe : demonstration project to perform human biomonitoring on a European scale

'Reproduced with permission from Environmental Health Perspectives'

Pathways to Low Carbon Transport in the EU – From Possibility to Reality. Report of the CEPS Task Force on transport and climate change. CEPS Task Force Report, June 2013

A new CEPS Task Force Report has identified possible pathways for achieving the EU’s ambitious climate change targets. It concludes that a GHG emissions reduction in line with EU climate change policy is possible, but it requires immediate action. This report argues that most of the reductions required of the transport sector in the EU could come from more energy-efficient vehicles, combined with the gradual introduction of low-carbon fuels and new engine technologies. The key policy for reducing GHG emissions in road transport is the steady tightening of emissions standards in line with technological progress. The report also identifies strategies for the transport system to become more energy and/or carbon efficient, arguing that leverage can be further enhanced by local and city governments’ incentives for efficient and low-carbon vehicles in line with local circumstances and choices. The Task Force on Low Carbon Transport brought together a diverse set of stakeholders from the car and oil industries, business associations, international organisations, member states, academic experts and NGOs. This authoritative report is the result of that unique collaboration.

Impact of the Decarbonisation of the Energy System on Employment in Europe. CEPS Special Report No. 82, February 2014

This paper presents a methodology for calculating the potential impact of the new socio-ecological transition away from fossil fuels on employment in EU energy supply. The methodology is based on “employment factors” (i.e. labour intensities) of different energy technologies. These employment factors are applied to changing energy mixes as projected by the decarbonisation scenarios of the European Commission’s Energy Roadmap 2050. In particular, we analyse quantitative (number of jobs) and qualitative (qualification levels) impacts on employment in extraction and processing of primary (fossil) fuels and in the power sector for the years 2020, 2030 and 2050. The results show that the energy sector will provide not only more jobs as the new socio-ecological transition unfolds, but also jobs requiring higher-level qualifications when compared with the current energy sector.

On Ukrainian Gas Transit and South Stream. There may be more than meets the eye. CEPS Commentaries, 21 March 2014

The EU relies to a considerable degree on imports to meet its demand for natural gas. Whereas Norwegian export pipelines are directly connected to the EU gas system, a major share of Russian gas flows through the Ukrainian territory before reaching consumers located other consumers located down in the supply chain (e.g. Slovakia, Hungary or Italy). But is the Ukrainian gas transit route still a risk? Will the construction of the South Stream pipeline further reduce the importance of Ukraine as a transit country? Or is there more at stake here than meets the eye?

Is Europe vulnerable to Russian gas cuts? CEPS Commentaries, 12 March 2014

The EU relies heavily on imports to meet its demand for natural gas. Nearly 23% of the gas burned by the EU member states is produced in Russian gas fields. Ukraine remains one of the main supply routes for Russian gas flowing into Europe. Consequently, mounting tensions between Russia and Ukraine concerning the Crimean Peninsula brought back memories of past gas supply disruptions, most notably of 2009. The question today is whether the EU in 2014 is equally vulnerable to potential (forced or voluntary) cuts in Russian gas supplies as it was five years ago. In this commentary, Arno Behrens and Julian Wieczorkiewicz look into two different scenarios. First, could Europe sustain longer cuts in gas supplies from Russia? And second, what impact would disruptions of Russian gas deliveries to Ukraine have on the EU? Essentially the authors argue that Russia is highly dependent on gas exports to Europe, while Europe could resort to alternatives to Russian gas. In addition, Europe is much better prepared for potential short-term supply disruptions than it was five years ago.

The Potential Evolution of the European Energy System to 2020 and 2050. CEPS Working Document No. 392, 26 March 2014

This paper assesses the impact of decarbonisation of the energy sector on employment in Europe. Setting the stage for such an assessment, the paper provides an analysis of possible pathways to decarbonise Europe’s energy system, taking into account EU greenhouse gas emissions reduction targets for 2020 and 2050. It pays particular attention to various low-carbon technologies that could be deployed in different regions of the EU. It concludes that efficiency and renewables play a major role in any decarbonisation scenario and that the power sector is the main enabler for the transition to a low-carbon economy in Europe, despite rising electricity demand. The extent of the decline in the share of fossil fuels will largely depend on the existence of carbon capture and storage (CCS), which remains a major source of uncertainty.