Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and reexpression of cohesin

Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterize the transcriptional profile of cortical neurons from CdLS patients and find deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupts 3D genome organization and transcriptional control in post-mitotic cortical mouse neurons, demonstrating that cohesin is continuously required for neuronal gene expression. The genes affected by acute depletion of cohesin belong to similar gene ontology classes and show significant numerical overlap with genes deregulated in CdLS. Interestingly, reconstitution of cohesin function largely rescues altered gene expression, including the expression of genes deregulated in CdLS

Competition Soft Law in National Courts: Quo Vadis?

This paper is based on an empirical data-set of 103 national competition cases of EU Member States, which contain judicial reasoning on supranational, Commission-issued competition soft law. The paper enquires into the possible reasons for detected national judicial attitudes to supranational soft competition instruments – namely – endorsement, rejection, persuasion, and neglect. In particular, the empirical data suggests that the overwhelming majority of judicial endorsement of soft law happens with regard to the so-called Guidelines on Vertical Restraints, which are also the most cited supranational competition soft instrument in the courts of the jurisdictions under observation (Germany, France, the Netherlands and the United Kingdom). A staggering 62 per cent of all judicial soft law references are references to the said guidelines. By contrast, the so-called Article 82 Guidance Paper receives the lowest amount of references – a mere 8 per cent – and is also more often than not either rejected or neglected by the national judiciaries. The other two soft instruments under observation in this study – the Guidelines on Horizontal Cooperation Agreements and the Article 81(3) Guidelines – are engaged with sparingly (they comprise 13 and 16 per cent of the total cases, respectively) and with varying success. The thus summarised results offer fruitful ground for analysis, which this paper performs in its Section 4. Several factors that could explain the above observations are therefore discussed in detail

The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors

CXCR3 plays important roles in angiogenesis, inflammation, and cancer. However, the precise mechanism of regulation and activity in tumors is not well known. We focused on CXCR3-A conformation and on the mechanisms controlling its activity and trafficking and investigated the role of CXCR3/LRP1 cross talk in tumor cell invasion. Here we report that agonist stimulation induces an anisotropic response with conformational changes of CXCR3-A along its longitudinal axis. CXCR3-A is internalized via clathrin-coated vesicles and recycled by retrograde trafficking. We demonstrate that CXCR3-A interacts with LRP1. Silencing of LRP1 leads to an increase in the magnitude of ligand-induced conformational change with CXCR3A focalized at the cell membrane, leading to a sustained receptor activity and an increase in tumor cell migration. This was validated in patient-derived glioma cells and patient samples. Our study defines LRP1 as a regulator of CXCR3, which may have important consequences for tumor biology