Vascular smooth muscle cells in Marfan syndrome aneurysm: the broken bricks in the aortic wall

Marfan syndrome (MFS) is a connective tissue disorder with multiple organ manifestations. The genetic cause of this syndrome is the mutation of the FBN1 gene, encoding the extracellular matrix (ECM) protein fibrillin-1. This genetic alteration leads to the degeneration of microfibril structures and ECM integrity in the tunica media of the aorta. Indeed, thoracic aortic aneurysm and dissection represent the leading cause of death in MFS patients. To date, the most effective treatment option for this pathology is the surgical substitution of the damaged aorta. To highlight novel therapeutic targets, we review the molecular mechanisms related to MFS etiology in vascular smooth muscle cells, the foremost cellular type involved in MFS pathogenesis.     

Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase

Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses.     

Real‐Time Forecasts of Inflation: The Role of Financial Variables

We present a mixed‐frequency model for daily forecasts of euro area inflation. The model combines a monthly index of core inflation with daily data from financial markets; estimates are carried out with the MIDAS regression approach. The forecasting ability of the model in real time is compared with that of standard VARs and of daily quotes of economic derivatives on euro area inflation. We find that the inclusion of daily variables helps to reduce forecast errors with respect to models that consider only monthly variables. The mixed‐frequency model also displays superior predictive performance with respect to forecasts solely based on economic derivatives. Copyright © 2012 John Wiley & Sons, Ltd.     

Biotin as a regulator of some haematic parameters and of DNA-content of the liver of old rats

Summary Biotin administration to old rats (28 months) causes in the blood an increase of ATP, glucose, triglycerides, alkaline phosphatase and a decrease of cholesterol and acid phosphatase; in the liver DNA and electrostatic interactions between DNA and histones are increased. Such parameters come within the values shown by adult rats.     

Studies on the relationships between biotin and the behaviour of B and T lymphocytes in the guinea-pig

Summary In biotin-deficient guinea-pigs the number of circulating neutrophils is increased; lymphocytes carrying B and T markers are decreased. Incubation with biotin increases significantly the number of lymphocytes carrying B and T markers, from biotin-deficient guinea-pigs; no increase was observed when the lymphocytes from normal guinea-pigs were incubated.     

A short gamma-ray burst apparently associated with an elliptical galaxy at redshift z = 0.225

Gamma-ray bursts (GRBs) come in two classes: long (> 2 s), soft-spectrum bursts and short, hard events. Most progress has been made on understanding the long GRBs, which are typically observed at high redshift (z approximately 1) and found in subluminous star-forming host galaxies. They are likely to be produced in core-collapse explosions of massive stars. In contrast, no short GRB had been accurately (< 10') and rapidly (minutes) located. Here we report the detection of the X-ray afterglow from--and the localization of--the short burst GRB 050509B. Its position on the sky is near a luminous, non-star-forming elliptical galaxy at a redshift of 0.225, which is the location one would expect if the origin of this GRB is through the merger of neutron-star or black-hole binaries. The X-ray afterglow was weak and faded below the detection limit within a few hours; no optical afterglow was detected to stringent limits, explaining the past difficulty in localizing short GRBs.     

Analysis of the coding genome of diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. Although a number of structural alterations have been associated with the pathogenesis of this malignancy, the full spectrum of genetic lesions that are present in the DLBCL genome, and therefore the identity of dysregulated cellular pathways, remains unknown. By combining next-generation sequencing and copy number analysis, we show that the DLBCL coding genome contains, on average, more than 30 clonally represented gene alterations per case. This analysis also revealed mutations in genes not previously implicated in DLBCL pathogenesis, including those regulating chromatin methylation (MLL2; 24% of samples) and immune recognition by T cells. These results provide initial data on the complexity of the DLBCL coding genome and identify novel dysregulated pathways underlying its pathogenesis.     

Effects of biotin deficiency on serum proteins and plasma amino acids

Summary In biotin-deficient rats, a decrease of total proteins, attributable to a decrease of albumin anda ₁-globulin fractions, a decrease of the pre--lipoproteins and an increase of the -lipoproteins, was observed, together with a rise of total amino acids. Such a situation may be related to the influence of biotin on the synthesis of RNA and proteins.