FRAXE-associated mental retardation protein (FMR2) is an RNA-binding protein with high affinity for G-quartet RNA forming structure

FRAXE is a form of mild to moderate mental retardation due to the silencing of the FMR2 gene. The cellular function of FMR2 protein is presently unknown. By analogy with its homologue AF4, FMR2 was supposed to have a role in transcriptional regulation, but robust evidences supporting this hypothesis are lacking. We observed that FMR2 co-localizes with the splicing factor SC35 in nuclear speckles, the nuclear regions where splicing factors are concentrated, assembled and modified. Similarly to what was reported for splicing factors, blocking splicing or transcription leads to the accumulation of FMR2 in enlarged, rounded speckles. FMR2 is also localized in the nucleolus when splicing is blocked. We show here that FMR2 is able to specifically bind the G-quartet-forming RNA structure with high affinity. Remarkably, in vivo, in the presence of FMR2, the ESE action of the G-quartet situated in mRNA of an alternatively spliced exon of a minigene or of the putative target FMR1 appears reduced. Interestingly, FMR1 is silenced in the fragile X syndrome, another form of mental retardation. All together, our findings strongly suggest that FMR2 is an RNA-binding protein, which might be involved in alternative splicing regulation through an interaction with G-quartet RNA structure

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

The experimental analysis of problematic video gaming and cognitive skills: a systematic review

There is now a growing literature demonstrating the excessive gaming can have negative detrimental effects on a small minority of gamers. This has led to much debate in the psychological literature on both the positive and negative effects of gaming. One specific area that has been investigated is the effect of gaming on different types of cognitive skills. The present study carried a systematic review examining the studies that have examined the impact of problematic gaming on cognitive skills. Following a number of inclusion and exclusion criteria, a total of 18 studies were identified that had investigated three specific cognitive skills: (i) multi-second time perception (4 studies), inhibition (7 studies), and decision-making (7 studies). Based on the studies reviewed, the findings demonstrate that the pathological and/or excessive use of videogames leads to more negative consequences on cognitive processes. Contexte et objectifs: Jouer aux jeux vidéo est devenu l’une des activités mondiales majeures avec des millions de personnes y jouant tous les jours. Suivant ce succès, les jeux vidéo ont grandement évolué, multipliant les genres (p.ex., MMORPG, MOBA, FPS); certains de ces jeux demandant un grand investissement de la part des joueurs. Cet investissement peut devenir excessif, voire pathologique, et de nombreuses études ont exploré ce risque, menant à l’inclusion de l’« Usage pathologique des jeux sur Internet » dans l’appendice du DSM-5 (American Psychiatric Association, 2013). Cependant, malgré les risques sous-jacents d’une addiction (p.e.x., pertes de relations, difficultés scolaires), il a également été démontré que le jeu vidéo pouvait significativement améliorer les performances des joueurs (p.ex., performances sur un simulateur de chirurgie, Fanning, Fenton, Johnson, Johnson, & Rehman, 2011; meilleure recherche visuelle, Sims & Mayer, 2002). De plus, il a été démontré que le fait de jouer à ces jeux pouvait impacter les capacités cognitives des joueurs (p.ex., Durlach, Kring, & Bowens, 2009). Une revue systématique sur l’impact d’une utilisation pathologique/excessive sur ces capacités a donc été menée. Méthode: La recherche d’articles a été menée sur quatre bases de données (p.ex., Google Scholar, PubMed, Science Direct, PsychINFO). Afin d’être inclus dans cette revue, les articles revus par les pairs devaient: (i) dater d’au moins 2000 (les jeux vidéo ayant grandement évolué depuis), (ii) inclure au moins une étude expérimentale sur les processus cognitifs des joueurs, (iii) inclure des joueurs excessifs/pathologiques, (iv) être publiés en anglais, et (v) Ne pas avoir été utilisés dans une revue de littérature auparavant (p.ex., études en fMRI). Après sélection des articles et tri des doublons, la recherche a mené à 18 résultats dans 3 sections différentes (c.-à-d., Perception du temps supérieur à la seconde, Inhibition, et Prise de décision). Résultats: Les expériences sur la perception du temps montrent des résultats hétérogènes, certaines études ne montrant aucun résultat (p.ex.., Rivero, Covre, Reyes, & Bueno, 2012), d’autres des résultats partiels (Rau, Peng, & Yang, 2006), voire des résultats significatifs (Tobin & Grondin, 2009). Cependant, les études démontrant des résultats (potentiellement) significatifs incluaient des utilisateurs pathologiques, contrairement aux études sans résultats significatifs. Cette différence de population pouvant potentiellement expliquer cette différence. Les études sur l’inhibition montrent le même type de résultats hétérogènes, cependant, une fois ces études classées par type d’inhibition, il apparaîtrait que les joueurs montrent une inhibition de la réponse prépotente réduite (p.ex., au travers de tâches Go/Nogo, Littel et al., 2012), celle-ci étant aggravée lorsque des stimuli liés aux jeux étaient inclus dans la tâche (p.ex., Liu et al., 2014). Cependant, la seule étude ayant exploré l’annulation d’une réponse prépotente n’a pas démontré d’inhibition réduite, les joueurs de jeux-vidéos d’action présentant des temps de réactions réduits (Colzato, van den Wildenberg, Zmigrod, & Hommel, 2013). Finalement, Les études sur la prise de décision montrent des résultats similaires au travers des études, c’est-à-dire des lacunes à prendre des décisions dans des contextes de risque (p.ex., Pawlikowski & Brand, 2011), une prise de décision intacte dans les tâches à contextes ambigus (p.ex., Nuyens et al., 2016), et une tendance à préférer une récompense moindre immédiate à une récompense plus importante après un délai variable (Weinstein, Abu, Timor, & Mama, 2016). Discussion: Malgré les divers résultats contraires, et le peu d’étude sur certains processus, il est clair qu’une utilisation pathologique des jeux vidéo peut mener à des difficultés cognitives. Cependant, sachant que les études sur les performances susmentionnées ne recrutaient que des participants sains, il est supposable qu’une utilisation normale mènerait à des performances améliorées, sans aucune contrepartie négative. Plus d’études seraient donc nécessaires afin de déterminer l’impact différent des jeux vidéo sur les processus cognitifs en fonction du degré et type d’utilisation de ceux-ci (c.-à-d., utilisation occasionnelle, fréquente, ou pathologique)

Pivotal Role of Toll-Like Receptors 2 and 4, Its Adaptor Molecule MyD88, and Inflammasome Complex in Experimental Tubule-Interstitial Nephritis

Tubule-interstitial nephritis (TIN) results in decreased renal function and interstitial inflammation, which ultimately leads to fibrosis. Excessive adenine intake can cause TIN because xanthine dehydrogenase (XDH) can convert this purine into an insoluble compound, which precipitates in the tubuli. Innate immune sensors, such as Toll-like receptors (TLR) and inflammasome complex, play a crucial role in the initiation of inflammation. The aim of this study was to evaluate the roles of TLR-2 and -4, Myd88 and inflammasome complex in an experimental model of TIN. Here, we show that wild-type (WT) mice fed adenine-enriched food exhibited significant renal dysfunction and enhanced cellular infiltration accompanied by collagen deposition. They also presented higher gene and protein expression of pro-inflammatory cytokines. In contrast, TLR-2, -4, MyD88, ASC and Caspase-1 KO mice showed renoprotection associated with expression of inflammatory molecules at levels comparable to controls. Furthermore, treatment of WT animals with allopurinol, an XDH inhibitor, led to reduced levels of uric acid, oxidative stress, collagen deposition and a downregulation of the NF-kB signaling pathway. We concluded that MyD88 signaling and inflammasome participate in the development of TIN. Furthermore, inhibition of XDH seems to be a promising way to therapeutically target the developing inflammatory process

Nutrition for the ageing brain: towards evidence for an optimal diet

As people age they become increasingly susceptible to chronic and extremely debilitating brain diseases. The precise cause of the neuronal degeneration underlying these disorders, and indeed normal brain ageing remains however elusive. Considering the limits of existing preventive methods, there is a desire to develop effective and safe strategies. Growing preclinical and clinical research in healthy individuals or at the early stage of cognitive decline has demonstrated the beneficial impact of nutrition on cognitive functions. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). The latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive ageing are presented. Furthermore, several key points related to mechanisms contributing to brain ageing, pathological conditions affecting brain function, and brain biomarkers are also discussed. Overall, findings are inconsistent and fragmented and more research is warranted to determine the underlying mechanisms and to establish dose-response relationships for optimal brain maintenance in different population subgroups. Such approaches are likely to provide the necessary evidence to develop research portfolios that will inform about new dietary recommendations on how to prevent cognitive decline

Bases moléculaires du syndrome de l'X Fragile :<br />Identification d'un nouvel ARNm cible de FMRP et établissement d'un nouveau mécanisme d'action

The Fragile X Syndrome, the most common form of inherited mental retardation, is due to the absence of FMRP (Fragile X Mental Retardation Protein). FMRP is a quasi ubiquitous protein with high expression levels in neurones and spermatogonia. It is endowed of a nuclear localisation signal (NLS), a nuclear export signal (NES), RNA binding motives (KH domains and RGG box). FMRP is thought to shuttle between the nucleus and the cytoplasm where it is associated with active translating polyribosomes. FMRP is also a part of a ribonucleoprotein complex where it interacts with its two homologs FXR1P and FXR2P and is supposed to play several roles in mRNA metabolism.Two RNA structures were found to be bound by FMRP, the G-quartet and the kissing complex structures. Several RNAs were described to be putative targets for FMRP but neither their specific interaction with the latter nor the functional significance of this interaction were investigated.The principal aim of my thesis was to better understand the molecular functions of FMRP and its involvement in the posttranscriptional regulation of its mRNA targets. The project was achieved by two majors questions :- Understanding the Influence of FMRP intercators on its affinity for mRNAs- Searching for novel FMRP RNA structure targets and analysis of the FMRP/RNA interactions.We were able to show that only the muscular isoform of FXR1P is able to bind specifically the G-quartet structure leading us to conclude that FXR1P acts in a aynergic rather than a compensatory way with FMRP.In another hand, we demonstrated the specific interaction between FMRP and a novel structure harboured by the Sod1 mRNA that we named SSLIP (Sod1 Stem Loops Interacting with FMRP). SSLIP distribution on polyribosomes is altered in the absence of FMRP leading to a decrease in the Sod1 protein level. Using a reporter system we have shown that FMRP/SSLIP interaction will enhance the translation of the Sod1. These observations lead us to establish a novel mechanism by which FMRP may regulate the translation of its target mRNAs.Le syndrome de l'X fragile est la cause la plus fréquente de retard mental héréditaire. Ce syndrome est du à l'absence de la protéine FMRP (Fragile X Mental Retardation Protein). FMRPest exprimée dans de nombreux tissus, et surtout dans les neurones et dans les spermatogonies. Elle possède un signal de localisation nucléaire (NLS), et un signal d'export nucléaire (NES), des motifs de liaison à l'ARN (deux domaines KH et une boîte RGG). La présence d'un NLS et d'un NES suggère que FMRP fasse la navette entre le noyau et le cytoplasme pour le transport de l'ARNm. Bien que la sublocalisation et le rôle de FMRP dans le noyau ne soient pas encore connus, dans le cytoplasme FMRP est associée aux polyribosomes faisant partie d'un complexe ribonucléoprotéique où elle interagit avec ses deux homologues FXR1P et FXR2P. Deux structures de liaison pour FMRP ont été identifiées et caractérisées: le "purine-quartet" et le « kissing complex». Plusieurs ARN ont été identifiés comme cibles potentielles de FMRP. Ces ARN sont derégulés chez les souris Fmr1 nulles, mais la signification fonctionnelle de l'interaction FMRP/ARN reste toujours partiellement connue. L'objectif principal de ma thèse étant la compréhension du mécanisme d'action de FMRP sur ces ARN cibles, ce projet a été abordé en deux points principaux :-Recherche de l'influence des protéines qui interagissent avec FMRP sur sa capacité (affinité) à se lier à l'ARN-Recherche de nouvelles séquences/structures cibles de FMRP et analyse du rôle de l'interaction FMRP/ARN.Nous avons pu montrer une interaction spécifique uniquement entre l'isoforme musculaire de FXR1P avec la structure de G-quartet. Cela nous a permis d'établir un rôle synergique et non compensatoire de FXR1P sur FMRP. D'un autre côté, nous avons démontré l'interaction spécifique de FMRP avec une nouvelle structure présente dans l'ARNm de la Sod1 que nous avons appelé SSLIP (Sod1 Stem Loops Interacting with FMRP). La distribution de SSLIP sur les polyribosomes est altérée en absence de FMRP ce qui conduit à une faible expression de la protéine Sod1. En utilisant un système de gène rapporteur, nous avons montré que l'interaction FMRP/SSLIP favorise la traduction de la Sod1 ce qui nous a permis d'établir un nouveau mécanisme d'action de la protéine FMRP sur ces cibles ARN

Estudo comparativo de combustíveis para fumigador apícula

Procurou-se detectar possíveis diferenças na eficácia com que a fumaça oriunda de diferentes materiais induz a reação de ingurgitamento e a redução transitória da reação agressiva das abelhas quando manipulada. Os combustíveis ensaiados foram: maravalha, estopa embebida em lubrificantes minerais, aparas de làe madeira podre. O delineamento experimental em blocos casualizados abrangeu quatro tratamentos e nove repetições. A análise de variância revelou diferenças significativas a 1% entre os tratamentos. O teste de Tukey mostrou ser significativa a diferença entre a là(pior) e os demais

Estudo comparativo de combustíveis para fumigador apícula

Procurou-se detectar possíveis diferenças na eficácia com que a fumaça oriunda de diferentes materiais induz a reação de ingurgitamento e a redução transitória da reação agressiva das abelhas quando manipulada. Os combustíveis ensaiados foram: maravalha, estopa embebida em lubrificantes minerais, aparas de lã e madeira podre. O delineamento experimental em blocos casualizados abrangeu quatro tratamentos e nove repetições. A análise de variância revelou diferenças significativas a 1% entre os tratamentos. O teste de Tukey mostrou ser significativa a diferença entre a lã (pior) e os demais

RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation

RBM5, a regulator of alternative splicing of apoptotic genes, and its highly homologous RBM6 and RBM10 are RNA-binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation, and its modulation recapitulates or antagonizes the effects of RBM5, 6, and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation.E.B. was supported by a Marie Curie postdoctoral fellowship (FP7-PEOPLE-2009-IEF). Work in E.E.’s group is supported by Consolider RNAREG, BIO2011-23920, and FSI2011-035 from Sandra Ibarra/nFoundation. Work in J.V.’s lab is supported by Fundación Botín, AICR, Fundación Alicia Koplowitz, Consolider RNAREG, and Ministerio de Economía y Competitividad