The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse

Dominant optic atrophy is a rare inherited optic nerve degeneration caused by mutations in the mitochondrial fusion gene OPA1. Recently, the clinical spectrum of dominant optic atrophy has been extended to frequent syndromic forms, exhibiting various degrees of neurological and muscle impairments frequently found in mitochondrial diseases. Although characterized by a specific loss of retinal ganglion cells, the pathophysiology of dominant optic atrophy is still poorly understood. We generated an Opa1 mouse model carrying the recurrent Opa1(delTTAG) mutation, which is found in 30% of all patients with dominant optic atrophy. We show that this mouse displays a multi-systemic poly-degenerative phenotype, with a presentation associating signs of visual failure, deafness, encephalomyopathy, peripheral neuropathy, ataxia and cardiomyopathy. Moreover, we found premature age-related axonal and myelin degenerations, increased autophagy and mitophagy and mitochondrial supercomplex instability preceding degeneration and cell death. Thus, these results support the concept that Opa1 protects against neuronal degeneration and opens new perspectives for the exploration and the treatment of mitochondrial diseases

Global sourcing of low-inorganic arsenic rice grain

Arsenic in rice grain is dominated by two species: the carcinogen inorganic arsenic (the sum of arsenate and arsenite) and dimethylarsinic acid (DMA). Rice is the dominant source of inorganic arsenic into the human diet. As such, there is a need to identify sources of low-inorganic arsenic rice globally. Here we surveyed polished (white) rice across representative regions of rice production globally for arsenic speciation. In total 1180 samples were analysed from 29 distinct sampling zones, across 6 continents. For inorganic arsenic the global x ~ x~ was 66 μg/kg, and for DMA this figure was 21 μg/kg. DMA was more variable, ranging from < 2 to 690 μg/kg, while inorganic arsenic ranged from < 2 to 399 μg/kg. It was found that inorganic arsenic dominated when grain sum of species was < 100 μg/kg, with DMA dominating at higher concentrations. There was considerable regional variance in grain arsenic speciation, particularly in DMA where temperate production regions had higher concentrations. Inorganic arsenic concentrations were relatively consistent across temperate, subtropical and northern hemisphere tropical regions. It was only in southern hemisphere tropical regions, in the eastern hemisphere that low-grain inorganic arsenic is found, namely East Africa (x ~ x~  < 10 μg/kg) and the Southern Indonesian islands (x ~ x~  < 20 μg/kg). Southern hemisphere South American rice was universally high in inorganic arsenic, the reason for which needs further exploration

Rice grain cadmium concentrations in the global supply-chain

One of cadmium’s major exposure routes to humans is through rice consumption. The concentrations of cadmium in the global polished (white), market rice supply-chain were assessed in 2270 samples, purchased from retailers across 32 countries, encompassing 6 continents. It was found on a global basis that East Africa had the lowest cadmium with a median for both Malawi and Tanzania at 4.9 μg/kg, an order of magnitude lower than the highest country, China with a median at 69.3 μg/kg. The Americas were typically low in cadmium, but the Indian sub-continent was universally elevated. In particular certain regions of Bangladesh had high cadmium, that when combined with the high daily consumption rate of rice of that country, leads to high cadmium exposures. Concentrations of cadmium were compared to the European Standard for polished rice of 200 μg/kg and 5% of the global supply-chain exceeded this threshold. For the stricter standard of 40 μg/kg for processed infant foods, for which rice can comprise up to 100% by composition (such as rice porridges, puffed rice cereal and cakes), 25% of rice would not be suitable for making pure rice baby foods. Given that rice is also elevated in inorganic arsenic, the only region of the world where both inorganic arsenic and cadmium were low in grain was East Africa

G protein-coupled receptor-mediated calcium signaling in astrocytes

Astrocytes express a large variety of G~protein-coupled receptors (GPCRs) which mediate the transduction of extracellular signals into intracellular calcium responses. This transduction is provided by a complex network of biochemical reactions which mobilizes a wealth of possible calcium-mobilizing second messenger molecules. Inositol 1,4,5-trisphosphate is probably the best known of these molecules whose enzymes for its production and degradation are nonetheless calcium-dependent. We present a biophysical modeling approach based on the assumption of Michaelis-Menten enzyme kinetics, to effectively describe GPCR-mediated astrocytic calcium signals. Our model is then used to study different mechanisms at play in stimulus encoding by shape and frequency of calcium oscillations in astrocytes.Comment: 35 pages, 6 figures, 1 table, 3 appendices (book chapter

Gi/o-protein coupled receptors in the aging brain

Cells translate extracellular signals to regulate processes such as differentiation, metabolism and proliferation, via transmembranar receptors. G protein-coupled receptors (GPCRs) belong to the largest family of transmembrane receptors, with over 800 members in the human species. Given the variety of key physiological functions regulated by GPCRs, these are main targets of existing drugs. During normal aging, alterations in the expression and activity of GPCRs have been observed. The central nervous system (CNS) is particularly affected by these alterations, which results in decreased brain functions, impaired neuroregeneration, and increased vulnerability to neuropathologies, such as Alzheimer's and Parkinson diseases. GPCRs signal via heterotrimeric G proteins, such as Go, the most abundant heterotrimeric G protein in CNS. We here review age-induced effects of GPCR signaling via the Gi/o subfamily at the CNS. During the aging process, a reduction in protein density is observed for almost half of the Gi/o-coupled GPCRs, particularly in age-vulnerable regions such as the frontal cortex, hippocampus, substantia nigra and striatum. Gi/o levels also tend to decrease with aging, particularly in regions such as the frontal cortex. Alterations in the expression and activity of GPCRs and coupled G proteins result from altered proteostasis, peroxidation of membranar lipids and age-associated neuronal degeneration and death, and have impact on aging hallmarks and age-related neuropathologies. Further, due to oligomerization of GPCRs at the membrane and their cooperative signaling, down-regulation of a specific Gi/o-coupled GPCR may affect signaling and drug targeting of other types/subtypes of GPCRs with which it dimerizes. Gi/o-coupled GPCRs receptorsomes are thus the focus of more effective therapeutic drugs aiming to prevent or revert the decline in brain functions and increased risk of neuropathologies at advanced ages.This work was supported by Fundação para a Ciência e Tecnologia, Centro 2020 and Portugal 2020, the COMPETE program, QREN, and the European Union (FEDER program) via the GoBack project (PTDC/CVT-CVT/32261/2017), the pAGE program (Centro-01-0145-FEDER-000003), and Institute for Biomedicine iBiMED (UID/BIM/04501/2013; UID/BIM/04501/2019).publishe

Faut-il encore parler d'approche qualitative et d'approche quantitative?

International audienceLa distinction classique dans les manuels de sciences humaines entre approche qualitative et approche quantitative a-t-elle toujours un sens? Cet article cherche à préciser ce que sous-entend cette distinction sur un certain nombre de dimensions: le type de recherches (exploratoire ou non, intensive ou extensive, integrative ou parcellisante, objective ou interprétative), la méthode de collecte de données, le type de variables et le traitement statistique adopté. L'article tend à montrer que la transformation très profonde des traitements statistiques remet fondamentalement en cause cette distinction et exige un effort d'adaptation de la part des chercheurs

Faut-il encore parler d'approche qualitative et d'approche quantitative?

International audienceLa distinction classique dans les manuels de sciences humaines entre approche qualitative et approche quantitative a-t-elle toujours un sens? Cet article cherche à préciser ce que sous-entend cette distinction sur un certain nombre de dimensions: le type de recherches (exploratoire ou non, intensive ou extensive, integrative ou parcellisante, objective ou interprétative), la méthode de collecte de données, le type de variables et le traitement statistique adopté. L'article tend à montrer que la transformation très profonde des traitements statistiques remet fondamentalement en cause cette distinction et exige un effort d'adaptation de la part des chercheurs