Phosphatidic Acid: From Pleiotropic Functions to Neuronal Pathology

Among the cellular lipids, phosphatidic acid (PA) is a peculiar one as it is at the same time a key building block of phospholipid synthesis and a major lipid second messenger conveying signaling information. The latter is thought to largely occur through the ability of PA to recruit and/or activate specific proteins in restricted compartments and within those only at defined submembrane areas. Furthermore, with its cone-shaped geometry PA locally changes membrane topology and may thus be a key player in membrane trafficking events, especially in membrane fusion and fission steps, where lipid remodeling is believed to be crucial. These pleiotropic cellular functions of PA, including phospholipid synthesis and homeostasis together with important signaling activity, imply that perturbations of PA metabolism could lead to serious pathological conditions. In this mini-review article, after outlining the main cellular functions of PA, we highlight the different neurological diseases that could, at least in part, be attributed to an alteration in PA synthesis and/or catabolism

Spatial control of nucleoporin condensation by fragile X-related proteins

Nucleoporins (Nups) build highly organized nuclear pore complexes (NPCs) at the nuclear envelope (NE). Several Nups assemble into a sieve-like hydrogel within the central channel of the NPCs. In the cytoplasm, the soluble Nups exist, but how their assembly is restricted to the NE is currently unknown. Here, we show that fragile X-related protein 1 (FXR1) can interact with several Nups and facilitate their localization to the NE during interphase through a microtubule-dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup condensates. Likewise, models of fragile X syndrome (FXS), characterized by a loss of FMRP, accumulate Nup granules. The Nup granule-containing cells show defects in protein export, nuclear morphology and cell cycle progression. Our results reveal an unexpected role for the FXR protein family in the spatial regulation of nucleoporin condensation

Large-scale neuroanatomical study uncovers 198 gene associations in mouse brain morphogenesis.

Brain morphogenesis is an important process contributing to higher-order cognition, however our knowledge about its biological basis is largely incomplete. Here we analyze 118 neuroanatomical parameters in 1,566 mutant mouse lines and identify 198 genes whose disruptions yield NeuroAnatomical Phenotypes (NAPs), mostly affecting structures implicated in brain connectivity. Groups of functionally similar NAP genes participate in pathways involving the cytoskeleton, the cell cycle and the synapse, display distinct fetal and postnatal brain expression dynamics and importantly, their disruption can yield convergent phenotypic patterns. 17% of human unique orthologues of mouse NAP genes are known loci for cognitive dysfunction. The remaining 83% constitute a vast pool of genes newly implicated in brain architecture, providing the largest study of mouse NAP genes and pathways. This offers a complementary resource to human genetic studies and predict that many more genes could be involved in mammalian brain morphogenesis

The G-quartet containing FMRP binding site in FMR1 mRNA is a potent exonic splicing enhancer

The fragile X mental retardation protein (FMRP) is a RNA-binding protein proposed to post-transcriptionally regulate the expression of genes important for neuronal development and synaptic plasticity. We previously demonstrated that FMRP binds to its own FMR1 mRNA via a guanine-quartet (G-quartet) RNA motif. However, the functional effect of this binding on FMR1 expression was not established. In this work, we characterized the FMRP binding site (FBS) within the FMR1 mRNA by a site directed mutagenesis approach and we investigated its importance for FMR1 expression. We show that the FBS in the FMR1 mRNA adopts two alternative G-quartet structures to which FMRP can equally bind. While FMRP binding to mRNAs is generally proposed to induce translational regulation, we found that mutations in the FMR1 mRNA suppressing binding to FMRP do not affect its translation in cellular models. We show instead that the FBS is a potent exonic splicing enhancer in a minigene system. Furthermore, FMR1 alternative splicing is affected by the intracellular level of FMRP. These data suggest that the G-quartet motif present in the FMR1 mRNA can act as a control element of its alternative splicing in a negative autoregulatory loop

A Novel Function for Fragile X Mental Retardation Protein in Translational Activation

Fragile X syndrome, the most frequent form of inherited mental retardation, is due to the absence of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in several steps of RNA metabolism. To date, two RNA motifs have been found to mediate FMRP/RNA interaction, the G-quartet and the “kissing complex,” which both induce translational repression in the presence of FMRP. We show here a new role for FMRP as a positive modulator of translation. FMRP specifically binds Superoxide Dismutase 1 (Sod1) mRNA with high affinity through a novel RNA motif, SoSLIP (Sod1 mRNA Stem Loops Interacting with FMRP), which is folded as three independent stem-loop structures. FMRP induces a structural modification of the SoSLIP motif upon its interaction with it. SoSLIP also behaves as a translational activator whose action is potentiated by the interaction with FMRP. The absence of FMRP results in decreased expression of Sod1. Because it has been observed that brain metabolism of FMR1 null mice is more sensitive to oxidative stress, we propose that the deregulation of Sod1 expression may be at the basis of several traits of the physiopathology of the Fragile X syndrome, such as anxiety, sleep troubles, and autism

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Intelligence économique territoriale de l'aire d'influence du Port de Marseille Fos

PARIS-EST Marne-la-Vallee-BU (774682101) / SudocSudocFranceF

Utilisation de l'écologie industrielle et de l'intelligence économique territoriale pour le développement durable d'une zone industrialo-portuaire

This paper presents the issue and the methodology of an ongoing competitive and territorial intelligence approach of the industrial and harbour area of Fos-sur-Mer (Bouches-du-Rhône, France). It aims knowing this territory, to make it more competitive, while respecting the populations and the environment.The originality of the method is to use the industrial ecology approach as a tool for the competitive intelligence. The first results show that industrial ecology and competitive intelligence are complementary tools to support the sustainable development of an industrial area.Une approche d'intelligence économique territoriale a été mise en place au sein de la zone industrialo-portuaire (ZIP) de Fos-sur-Mer, à l'initiative du Port autonome de Marseille (PAM), en 2004. Elle vise à mieux connaitre ce territoire pour le rendre plus compétitif et diversifier ses activités, dans le respect des populations et de l'environnement. L'originalité de la méthode est d'utiliser l'écologie industrielle comme outil d'intelligence économique territoriale.L'objectif de cette étude est d'assurer un développement durable de la ZIP et son insertion dans le tissu urbain, industriel et naturel existant. Les premiers résultats y sont présentés et montrent que l'écologie industrielle et l'intelligence économique et territoriale sont des outils complémentaires pour soutenir le développement durable d'une zone d'activité

Bases moléculaires du syndrome de l X fragile (Etude de l'implication de la protéine FMRP dans le métabolisme des ARN messagers)

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF