21 research outputs found
Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload
Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent the major genetic risk for Parkinson’s disease (PD), while homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disorder, which may involve severe neurodegeneration. We have previously demonstrated impaired autophagy and proteasomal degradation pathways and mitochondrial dysfunction in neurons from GBA1 knockout (gba1^{-/-}) mice. We now show that stimulation with physiological glutamate concentrations causes pathological [Ca^{2+}]_{c} esponses and delayed calcium deregulation, collapse of mitochondrial membrane potential and an irreversible fall in the ATP/ADP ratio. Mitochondrial Ca^{2+} uptake was reduced in gba1^{−/−} cells as was expression of the mitochondrial calcium uniporter. The rate of free radical generation was increased in gba1^{−/−} neurons. Behavior of gba1^{+/−} neurons was similar to gba1^{−/−} in terms of all variables, consistent with a contribution of these mechanisms to the pathogenesis of PD. These data signpost reduced bioenergetic capacity and [Ca^{2+}]_{c} dysregulation as mechanisms driving neurodegeneration
mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria
The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [18F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria. </p
Hot deformation microstructures of Al-1 %Mn single crystals
To determine the basic mechanisms of substructure development within the grains of hot rolled A1 alloys, the influence of processing conditions on the hot channel-die compression structures of Al-l%Mn single crystals has been systematically characterised by automatic EBSD orientation maps. Analysis of the microstructures gives the subgrain sizes and misorien- tation angle distributions, which can be described by physically based mathematical functions. The average subgrain size decreases, as expected, with increasing Zener-Hollomon parameter Z (or increasing flow stress). Most crystals have similar subgrain sizes and distributions. In contrast, the Cube oriented crystals are composed of bands of fine and coarse subgrains. The average adjacent disorientations are also quite similar and are shown to increase with flow stress (or Z). However, the spatially heterogeneous structures of the cube grains are associated with significantly higher average disorientations
Ion irradiation induced solute clustering in steel: a 3D nanoanalysis with the tomographic atom-probe
Ion irradiation induced solute clustering in steel: a 3D nanoanalysis with the tomographic atom-probe
Micro-mechanism of fatigue crack growth: comparison between carbon black filled natural and styrene butadiene rubbers
International audienc
TNF Receptor 2 Signaling Prevents DNA Methylation at the Foxp3 Promoter and Prevents Pathogenic Conversion of Regulatory T Cells
Regulatory T (Treg) cells expressing the transcription factor Foxp3 play an important role in maintaining immune homeostasis. Chronic inflammation is associated with reduced Foxp3 expression, function, and loss of phenotypic stability. Previous studies have established the importance of TNF receptor 2 (TNFR2) in the generation and/or activation of Treg cells. In this study, we assess the importance of TNFR2 in healthy mice and under inflammatory conditions. Our findings reveal that, in health, TNFR2 is important not only for the generation of Treg cells, but also for regulating their functional activity. We also show that TNFR2 maintains Foxp3 expression in Treg cells by restricting DNA methylation at the Foxp3 promoter. In inflammation, loss of TNFR2 results in increased severity and chronicity of experimental arthritis, reduced total numbers of Treg cells, reduced accumulation of Treg cells in inflamed joints, and loss of inhibitory activity. In addition, we demonstrate that, under inflammatory conditions, loss of TNFR2 causes Treg cells to adopt a proinflammatory Th17-like phenotype. It was concluded that TNFR2 signaling is required to enable Treg cells to promote resolution of inflammation and prevent them from undergoing dedifferentiation. Consequently, TNFR2-specific agonists or TNF1-specific antagonists may be useful in the treatment of autoimmune disease
Modelling of full-scale industrial rolling and recrystallisation of strips of alloy 3103
Models for thermo-mechanical processing of metals have recently been developed in a European collaborative project. The scope has been work-hardening, deformation texture evolution and recrystallisation. In the present work these models have been combined with finite element modelling in order to predict microstructural properties of rolled strips of alloy 3103 subjected to full-scale industrial rolling and subsequent recrystallisation annealing. All sub-models demonstrated good prediction power. Integration and combination of the sub-models with finite element modelling represents a powerful tool for virtual processing and optimisation of industrial products and processing conditions
TNF receptor 2 signaling prevents DNA methylation at the Foxp3 promoter and prevents pathogenic conversion of regulatory T cells.
Regulatory T (Treg) cells expressing the transcription factor Foxp3 play an important role in maintaining immune homeostasis. Chronic inflammation is associated with reduced Foxp3 expression, function, and loss of phenotypic stability. Previous studies have established the importance of TNF receptor 2 (TNFR2) in the generation and/or activation of Treg cells. In this study, we assess the importance of TNFR2 in healthy mice and under inflammatory conditions. Our findings reveal that, in health, TNFR2 is important not only for the generation of Treg cells, but also for regulating their functional activity. We also show that TNFR2 maintains Foxp3 expression in Treg cells by restricting DNA methylation at the Foxp3 promoter. In inflammation, loss of TNFR2 results in increased severity and chronicity of experimental arthritis, reduced total numbers of Treg cells, reduced accumulation of Treg cells in inflamed joints, and loss of inhibitory activity. In addition, we demonstrate that, under inflammatory conditions, loss of TNFR2 causes Treg cells to adopt a proinflammatory Th17-like phenotype. It was concluded that TNFR2 signaling is required to enable Treg cells to promote resolution of inflammation and prevent them from undergoing dedifferentiation. Consequently, TNFR2-specific agonists or TNF1-specific antagonists may be useful in the treatment of autoimmune disease