Tetraspanin 6: A novel regulator of hippocampal synaptic transmission and long term plasticity

Tetraspanins (Tspan) are transmembrane proteins with important scaffold and signalling functions. Deletions of Tetraspanin 6 (Tspan6) gene, a member of the tetraspanin family, have been reported in patients with Epilepsy Female-restricted with Mental Retardation (EFMR). Interestingly, mutations in Tspan7, highly homologous to Tspan6, are associated with X-linked intellectual disability, suggesting that these two proteins are important for cognition. Considering recent evidences showing that Tspan7 plays a key role in synapse development and AMPAR trafficking, we initiated the study of Tspan6 in synaptic function using a Tspan6 knock out mouse model. Here we report that hippocampal field recordings from Tspan6 knock out mice show an enhanced basal synaptic transmission and impaired long term potentiation (LTP). A normal paired-pulse facilitation response suggests that Tspan6 affects the properties of the postsynaptic rather than the presynaptic terminal. However, no changes in spine morphology or postsynaptic markers could be detected in Tspan6 KO mice compared with wild types. In addition, Tspan6 KO mice show normal locomotor behaviour and no defects in hippocampus-dependent memory tests

Kidney segmentation in 3D CT images using B-Spline Explicit Active Surfaces

In this manuscript, we propose to adapt the B-Spline Explicit Active Surfaces (BEAS) framework for semi-automatic kidney segmentation in computed tomography (CT) images. To study the best energy functional for kidney CT extraction, three different localized region-based energies were implemented within the BEAS framework, namely localized Chan-Vese, localized Yezzi, and signed localized Yezzi energies. Moreover, a novel gradient-based regularization term is proposed. The method was applied on 18 kidneys from 9 CT datasets, with different image properties. Several energy combinations were contrasted using surface-based comparison against ground truth meshes, assessing their accuracy and robustness against surface initialization. Overall, the hybrid energy functional combining the localized signed Yezzi energy with gradient-based regularization simultaneously showed the highest accuracy and the lowest sensitivity to the initialization. Volumetric analysis demonstrated the feasibility of the method from a clinical point of view, with similar reproducibility to manual observers.The authors acknowledge FCT - Fundação para a Ciência e a Tecnologia, Portugal, and the European Social Found, European Union, for funding support through the Programa Operacional Capital Humano (POCH) in the scope of the PhD grants SFRH/BD/93443/2013 (S. Queirós) and SFRH/BD/95438/2013 (P. Morais).info:eu-repo/semantics/publishedVersio

Spatial reversal learning defect coincides with hypersynchronous telencephalic BOLD functional connectivity in APP(NL-F/NL-F) knock-in mice

Amyloid pathology occurs early in Alzheimer’s disease (AD), and has therefore been the focus of numerous studies. Transgenic mouse models have been instrumental to study amyloidosis, but observations might have been confounded by APP-overexpression artifacts. The current study investigated early functional defects in an APP knock-in mouse model, which allows assessing the effects of pathological amyloid-beta (Aβ) without interference of APP-artifacts. Female APPNL/NL knock-in mice of 3 and 7 months old were compared to age-matched APPNL-F/NL-F mice with increased Aβ42/40 ratio and initial Aβ-plaque deposition around 6 months of age. Spatial learning was examined using a Morris water maze protocol consisting of acquisition and reversal trials interleaved with reference memory tests. Functional connectivity (FC) of brain networks was assessed using resting-state functional MRI (rsfMRI). The Morris water maze data revealed that 3 months old APPNL-F/NL-F mice were unable to reach the same reference memory proficiency as APPNL/NL mice after reversal training. This cognitive defect in 3-month-old APPNL-F/NL-F mice coincided with hypersynchronous FC of the hippocampal, cingulate, caudate-putamen, and default-mode-like networks. The occurrence of these defects in APPNL-F/NL-F mice demonstrates that cognitive flexibility and synchronicity of telencephalic activity are specifically altered by early Aβ pathology without changes in APP neurochemistry

Copper(0)-mediated radical polymerisation in a self-generating biphasic system

Herein, we demonstrate the synthesis of well-defined poly(n-alkyl acrylate)s via copper(0)-mediated radical polymerisation in a self-generating biphasic system. During the polymerisation of n-butyl acrylate in DMSO, the polymer phase separates to yield a polymer-rich layer with very low copper content (ICP-MS analysis: 0.016 wt%). The poly(n-butyl acrylate) has been characterized by a range of techniques, including GPC, NMR and MALDI-TOF, to confirm both the controlled character of the polymerisation and the end group fidelity. Moreover, we have successfully chain extended poly(n-butyl acrylate) in this biphasic system several times with n-butyl acrylate to high conversion without intermediate purification steps. A range of other alkyl acrylates have been investigated and the control over the polymerisation is lost as the hydrophobicity of the polymer increases due to the increase in alkyl chain length indicating that it is important for the monomer to be soluble in the polar solvent

Long-term miR-669a therapy alleviates chronic dilated cardiomyopathy in dystrophic mice.

BACKGROUND: Dilated cardiomyopathy (DCM) is a leading cause of chronic morbidity and mortality in muscular dystrophy (MD) patients. Current pharmacological treatments are not yet able to counteract chronic myocardial wastage, thus novel therapies are being intensely explored. MicroRNAs have been implicated as fine regulators of cardiomyopathic progression. Previously, miR-669a downregulation has been linked to the severe DCM progression displayed by Sgcb-null dystrophic mice. However, the impact of long-term overexpression of miR-669a on muscle structure and functionality of the dystrophic heart is yet unknown. METHODS AND RESULTS: Here, we demonstrate that intraventricular delivery of adeno-associated viral (AAV) vectors induces long-term (18 months) miR-669a overexpression and improves survival of Sgcb-null mice. Treated hearts display significant decrease in hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Moreover, miR-669a treatment increases sarcomere organization, reduces ventricular atrial natriuretic peptide (ANP) levels, and ameliorates gene/miRNA profile of DCM markers. Furthermore, long-term miR-669a overexpression significantly reduces adverse remodeling and enhances systolic fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage. CONCLUSIONS: Our findings provide the first evidence of long-term beneficial impact of AAV-mediated miRNA therapy in a transgenic model of severe, chronic MD-associated DCM

Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice

Slc17a5−/− mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10–p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5−/− mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5−/− mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders