Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing

Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment

Designer Gene Delivery Vectors: Molecular Engineering and Evolution of Adeno-Associated Viral Vectors for Enhanced Gene Transfer

Gene delivery vectors based on adeno-associated virus (AAV) are highly promising due to several desirable features of this parent virus, including a lack of pathogenicity, efficient infection of dividing and non-dividing cells, and sustained maintenance of the viral genome. However, several problems should be addressed to enhance the utility of AAV vectors, particularly those based on AAV2, the best characterized AAV serotype. First, altering viral tropism would be advantageous for broadening its utility in various tissue or cell types. In response to this need, vector pseudotyping, mosaic capsids, and targeting ligand insertion into the capsid have shown promise for altering AAV specificity. In addition, library selection and directed evolution have recently emerged as promising approaches to modulate AAV tropism despite limited knowledge of viral structure–function relationships. Second, pre-existing immunity to AAV must be addressed for successful clinical application of AAV vectors. “Shielding” polymers, site-directed mutagenesis, and alternative AAV serotypes have shown success in avoiding immune neutralization. Furthermore, directed evolution of the AAV capsid is a high throughput approach that has yielded vectors with substantial resistance to neutralizing antibodies. Molecular engineering and directed evolution of AAV vectors therefore offer promise for generating ‘designer’ gene delivery vectors with enhanced properties

Effect of inhibition of dynein function and microtubule-altering drugs on AAV2 transduction.

AbstractOver the past decade, adeno-associated (AAV) virus has emerged as an important vector for gene therapy. As a result, understanding its basic biology, including intracellular trafficking, has become increasingly important. Here, we describe the effect of inhibiting dynein function or altering the state of microtubule polymerization on rAAV2 transduction. Overexpression of dynamitin, resulting in a functional inhibition of the minus-end-directed microtubule motor protein dynein, did not inhibit transduction. Equally, treatment of cells with nocodazole, or concentrations of vinblastine that result in the disruption of microtubules, had no significant effect on transduction. In contrast, high concentrations of Taxol and vinblastine, resulting in microtubule stabilization and the formation of tubulin paracrystals respectively, reduced rAAV2 transduction in a vector-dose-dependent manner. These results demonstrate that AAV2 can infect HeLa cells independently of dynein function or an intact microtubule network

20 pièces modernes pour orgue.

Offertoire sur des noëls ; Prière à Notre-Dame / Boëllmann -- Prélude ; Alleluia (Final) / Bossi -- Andante / Boulay -- Marche de fête / Büsser -- Marche nuptiale / Catherine -- Pastorale ; Cantabile ; Pièce héroïque ; Choral (no. 3) / Franck -- Communion ; Marche religieuse / Gigout -- Canzone / Handel-Thorley -- Prélude et Petit canon / d'Indy - Prélude et fugue ; Bénédiction nuptiale ; Fantaisie ; Marche religieuse / Saint-Saëns