Evidence that alpha7 nicotinic receptor modulates glutamate release from mouse neocortical gliosomes

The presence of nicotinic receptors on astrocytes in human and rat brain has been previously demonstrated however their possible functional role is still poorly understood. In this study we investigated on the presence of nicotinic receptors on gliosomes, purified from mouse cortex, and on their role in eliciting glutamate release. Epibatidine significantly increased basal release of [3H]D-aspartate and of endogenous glutamate from mouse gliosomes but not from synaptosomes. This effect was prevented by methyllycaconitine, alpha-bungarotoxin and mecamylamine but not by dihydro-beta-erythroidine. Epibatidine provoked also a significant increase of calcium concentration in gliosomes but not in synaptosomes; the increase in [Ca2+]i induced by epibatidine and KCl in gliosomes was very similar to each other. The present results indicate that alpha7 nicotinic receptors exist on mouse cortical glial particles and stimulate glutamate release.     

Clinical and radiologic rebound after discontinuation of natalizumab therapy in a highly active multiple sclerosis patient was not halted by dimethyl-fumarate: a case report

Background

The evidence on the use of the oral dimethyl-fumarate after the discontinuation of treatment with natalizumab in people with Multiple Sclerosis is still little. Natalizumab discontinuation may induce the recurrence or rebound of the clinical and neuroradiological disease activity. Currently no therapeutic approach has been established to abolish disease reactivation and rebound after natalizumab interruption.

Case Presentation

We describe a case of a 21-year-old woman affected from a highly active relapsing-remitting Multiple Sclerosis who developed a clinical and radiological rebound 5 months after the last infusion of natalizumab, while she was being treated with dimethyl-fumarate 240 mg twice daily. She had received a bridge “therapy” with Cyclophosphamide before staring dimethyl-fumarate.

Conclusion

We report on this case to stimulate further research to establish whether new current and future drugs available for multiple sclerosis are able to halt the disease rebound after the natalizumab interruption.

     

Will krill fare well under Southern Ocean acidification?

Antarctic krill embryos and larvae were experimentally exposed to 380 (control), 1000 and 2000 µatm pCO₂ in order to assess the possible impact of ocean acidification on early development of krill. No significant effects were detected on embryonic development or larval behaviour at 1000 µatm pCO₂; however, at 2000 µatm pCO₂ development was disrupted before gastrulation in 90 per cent of embryos, and no larvae hatched successfully. Our model projections demonstrated that Southern Ocean sea water pCO₂ could rise up to 1400 µatm in krill''s depth range under the IPCC IS92a scenario by the year 2100 (atmospheric pCO₂ 788 µatm). These results point out the urgent need for understanding the pCO₂-response relationship for krill developmental and later stages, in order to predict the possible fate of this key species in the Southern Ocean.     

Chromatin assembly factor CAF-1 is required for cellular differentiation during plant development

Chromatin assembly factor CAF-1 facilitates the formation of nucleosomes on newly replicated DNA in vitro. However, the role of CAF-1 in development is poorly understood because mutants are not available in most multicellular model organisms. Biochemical evidence suggests that FASCIATA1, FASCIATA2 and MSI1 form CAF-1 in Arabidopsis thaliana. Because fasciata mutants are viable, CAF-1 is not essential for cell division in plants. Arabidopsis CAF-1 mutants have defects in shoot apical meristems; in addition, CAF-1 is required to establish seedling architecture, leaf size and trichome differentiation. CAF-1 is needed to restrict branching of trichomes on rosette leaves. Increased trichome branching in CAF-1 mutants is not strictly correlated with increased nuclear DNA content. In addition, fas2 glabra3 double mutants show an additive genetic interaction, demonstrating that CAF-1 acts genetically parallel to the GLABRA3-containing, endoreduplication-coupled trichome branching pathway. However, CAF-1 is often needed to restrict endoreduplication, because seedlings of most CAF-1 mutants have increased ploidy. Notably, in the Landsberg erecta background, loss of CAF-1 does not affect ploidy, demonstrating that loss of CAF-1 can be compensated in some Arabidopsis accessions. These results reveal that the functions of FAS1, FAS2 and MSI1 are not restricted to meristems, but are also needed to control genome replication at multiple steps of development.     

Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes

Genome-wide experimental methods to identify disease genes, such as linkage analysis and association studies, generate increasingly large candidate gene sets for which comprehensive empirical analysis is impractical. Computational methods employ data from a variety of sources to identify the most likely candidate disease genes from these gene sets. Here, we review seven independent computational disease gene prioritization methods, and then apply them in concert to the analysis of 9556 positional candidate genes for type 2 diabetes (T2D) and the related trait obesity. We generate and analyse a list of nine primary candidate genes for T2D genes and five for obesity. Two genes, LPL and BCKDHA, are common to these two sets. We also present a set of secondary candidates for T2D (94 genes) and for obesity (116 genes) with 58 genes in common to both diseases.     

Constitutive NADPH oxidase 4 activity resides in the composition of the B-loop and the penultimate C terminus

Redox regulation of signaling molecules contributes critically to propagation of intracellular signals. The main source providing reactive oxygen species (ROS) for these physiological processes are activated NADPH oxidases (Nox/Duox family). In a pathophysiological context, some NADPH oxidase complexes produce large amounts of ROS either as part of the antimicrobial immune defense or as pathologic oxidative stress in many chronic diseases. Thus, understanding the switch from a dormant, inactive conformation to the active state of these enzymes will aid the development of inhibitors. As exogenously expressed Nox4 represents the only constitutively active enzyme in this family, analysis of structural determinants that permit this active conformation was undertaken. Our focus was directed toward a cell-based analysis of the first intracellular loop, the B-loop, and the C-terminus, two regions of Nox family enzymes that are essential for electron transfer. Mutagenesis of the B-loop identified several unique residues and a polybasic motif that contribute to the catalytic activity of Nox4. By using a multifaceted approach, including Nox4-Nox2 chimeras, mutagenesis, and insertion of Nox2 domains, we show here that the penultimate 22 amino acids of Nox4 are involved in constitutive ROS generation. The appropriate spacing of the C-terminal Nox4 sequence may cooperate with a discrete arginine-based interaction site in the B-loop, providing an intrinsically active interface that could not be disrupted by peptides derived from the Nox4 C-terminus. These results indicate that accessibility for a Nox4-specific peptide inhibitor might be difficult to achieve in vivo.