Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm (TAA). To date, no effective pharmacological therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. Methods: Combining transcriptomics and metabolic analysis of aortas from a Marfan mouse model ( Fbn1 c1039g/+ ) and MFS-patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMCs) by conditional depleting mitochondrial transcription factor A (Tfam) ( Myh11-Cre ERT2 Tfam flox/flox mice). We have used a mouse model of Marfan syndrome to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration Results: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1 c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial-DNA content, were reduced in aortas from young Fbn1 c1039g/+ mice. In vitro experiments in Fbn1 -silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS-patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient-VSMCs mice, lose their contractile capacity, showed aortic aneurysms and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside (NR) rapidly reverses aortic aneurysm in Fbn1 c1039g/+ mice. Conclusions: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan Syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.

Iris López-de-Solís y Carlos Martín-López ResumenLa digitalización y el desarrollo de las posibilidades que ofrece internet están favoreciendo que los archivos audiovisuales incorporen parte de sus fondos a la Web, con fines comerciales, no lucrativos o educativos. Se describen los diferentes servicios de las páginas web de los archivos según su naturaleza y los usuarios finales, el desarrollo de nuevas estrategias de negocio, la presencia en las redes sociales, la creación de canales de distribución, programas educativos y proyectos de cooperación. Además el acceso abierto a los fondos de muchos archivos en la Web favorece el trabajo de las producciones cinematográficas, que encuentran en ellos una nueva fuente de inspiración. Palabras claveArchivos audiovisuales, Documentación audiovisual, Fuentes de información, Internet, Estrategias de negocio, Programas educativos, Web 2.0, Redes sociales, Digitalización. Title: New business strategies and valorization of online audiovisual archives AbstractDigitization and the rapid development of Internet capabilities are encouraging audiovisual archives to add parts of their collections to the web, both for commercial and for nonprofit or education purposes. This article describes the different services offered by online archives, befitting the nature of the archive and of the end users in each case, their development of new business strategies, presence in social networks, creation of distribution channels, educational programs and collaboration projects. Moreover, the open access that the Internet allows also helps film production companies, who find in these archives a new source of inspiration.

Previous studies using conventional echocardiographic measurements have reported subclinical left ventricular (LV) diastolic abnormalities in patients with Marfan syndrome (MFS). Left atrial (LA) strain allows an accurate categorization of LV diastolic dysfunction. We aimed to characterize LV myocardial performance in a cohort of MFS patients using STE-derived measurements (LV and LA strain) along with conventional echocardiographic parameters. We studied 127 adult patients with MFS (no prior cardiac surgery or signi cant valvular regurgitation) and 38 healthy controls. We performed detailed echocardiograms and selected left atrial reservoir strain (LASr) as a surrogate of impaired relaxation. Additionally, we searched for possible determinants of LASr in patients with MFS, with a special focus on the elastic properties of the aorta. In spite of lower E-wave, septal and lateral e' velocities and average E/e' ratio in MFS patients, all participants had normal diastolic function according to current guidelines. MFS patients exhibited reduced LV global longitudinal strain (19.3 ± 2.6 vs 21.6 ± 2.1%, p < 0,001) and reduced LASr (32.9 ± 8.5 vs 43.3 ± 7.8%, p < 0.001) compared to controls. In the MFS cohort, we found weak signi cant (p < 0.05

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