Régulation post-transcriptionnelle de l'expression du facteur de transcription ATF4 lors de stress induits par des agents chimiothérapeutiques

Lors d'un stress, les cellules eucaryotes activent des mécanismes de défense afin de s'adapter aux conditions extrêmes et de survivre. Ces mêmes mécanismes peuvent être exploités par les cellules cancéreuses pour survivre au stress thérapeutique. La réponse intégrée au stress (ISR) est une réaction cellulaire qui joue un rôle crucial dans l'adaptation des cellules face à différents stress notamment en régulant la transcription et la traduction de nombreux gènes cibles spécifiques. Durant cette réponse, les cellules stressées réduisent aussi leur métabolisme général, entre autres en inhibant la traduction des ARNm, et économisent ainsi l'énergie nécessaire pour réparer les dommages causés par le stress. En conditions de stress, la traduction générale des ARNm est inhibée principalement au niveau de son étape d'initiation. Un des mécanismes clés induisant l'inhibition de l'initiation de la traduction est la phosphorylation du facteur d'initiation de la traduction eIF2a (eukaryotic translation initiation factor 2a). Bien que cette phosphorylation d'eIF2a, induite par le stress, entraine une inhibition globale de la synthèse protéique, elle induit d'une part la formation d'entités cytoplasmiques à ARN appelées granules de stress mais elle favorise également la traduction spécifique des ARNm spécifiques codant pour des facteurs de réponse au stress, dont le facteur de transcription ATF4. Ce facteurjoue un rôle clé lors de la réponse au stress soit en activant les voies de survie ou au contraire en favorisant celles de mort cellulaire. Ces fonctions opposées d'ATF4 dans la réponse cellulaire au stress dépendent largement de son niveau d'expression. Ainsi, nous avons cherché à caractériser le(s) mécanismes(s) de régulation de l'expression d'ATF4 lors de stress thérapeutiques au sein de cellules cancéreuses. Nous avons montré l'implication des granules de stress (GS) dans la régulation de l'expression de l'ARNm d'ATF4 lors d'un stress thérapeutique engendré par le traitement avec l'agent chimiothérapeutique sorafenib au sein de cellules d'hépatocarcinomes. Cette régulation implique la séquestration d'une fraction de l'ARNm d'ATF4 dans les GS induites par le traitement avec la sorafenib, prévenant sa surexpression létale ; ceci permet de maintenir un niveau d'expression d'ATF4 basal mais nécessaire à la survie des cellules cancéreuses. Afin de caractériser le(s) mécanisme(s) responsable(s) de l'expression basale d'ATF4, permettant la résistance des cellules cancéreuses aux traitements thérapeutiques, un RNA pull-down utilisant des fragments d'ARN biotinylés d'ATF4 a l'aide d'extraits de cellules cancéreuses soumises à un stress thérapeutique a été réalisé. L'analyse par ii spectrométrie de masse des complexes protéiques associés aux fragments d'ARN d'ATF4 biotinylés a permis l'identification d'une dizaine de protéines qui pourraient interagir avec l'ARNm d'ATF4, dont l'ARN hélicase DDX3. Nous avons observé que DDX3 promeut au niveau traductionnel l'expression d'AFT4. Des tests d'interaction protéine-protéine montrent que DDX3 est un composant du complexe d'initiation de la traduction eIF4F. L'interaction entre DDX3 et le complexe eIF4F est potentiellement médiée par le facteur eIF4G, qui est également nécessaire à la traduction d'ATF4 induite en condition de stress. Enfin, la diminution de l'expression d'ATF4 au sein de cellules issues d'hépatocarcinomes résistants via la déplétion de DDX3 sensibilise les cellules cancéreuses à la mort induite par le traitement avec la sorafenib. Cette étude caractérise de nouveaux mécanismes de régulation de l'expression du facteur ATF4 qui se produit lors de stress et qui pourraient être ciblés afin de prévenir la chimiorésistance.During physiological or environmental stress, cells activate defense mechanisms to survive. These same mechanisms may be exploited by cancer cells to survive therapeutic stresses. The integrated stressresponse (ISR) is one of the cell responses that play a crucial role in the adaptation of cells to various stresses such as the transcriptional and translational régulation of many specific target genes. During this cell response, stressed cells reduce their general metabolism in part by inhibiting mRNA translation, thereby saving energy needed to repair stress-induced damages. Under stress conditions, the regulation oftranslation occurs mainly at its initiation step through the phosphorylation of the translation initiation factor eIF2a. While this phosphorylation, induced by stress, causes a global inhibition ofprotein synthesis, it induces on the one hand the formation of cytoplasmic RNA entities called stress granules (GS) but it also promotes the preferential translation of specific mRNAs coding for stress response factors. Among those, ATF4 is a master transcription factor that orchestrates gene expression during various stresses including those involved in cancer, by either activating survival pathways or on the contrary promoting those of cell death. These opposite ATF4 functions in the cellular stress response depend largely on its expression level linked to its translational regulation by the phosphorylation of eIF2a. Thereby, we sought to characterize the mechanisms(s) that regulate the expression ofATF4 during therapeutic stresses in cancer cells. We described the implication of stress granules in the regulation of ATF4 expression during stress induced by the treatment with sorafenib, a chemotherapeutic agent used to treat hepatocellular carcinoma (HCC). This novel mechanism involves the formation of stress granules that sequester a fraction of ATF4 mRNA in its repressed form, thus preventing its lethal overexpression. This resulted in a basal level of ATF4 expression which is necessary for the survival of cancer cells. Then, in order to characterize the mechanism(s) (e.g. RNAbinding proteins and translation initiation factors such as eIF4G) responsible for the basal translation of ATF4 mRNA allowing the resistance of cancer cells to therapeutic treatments, we performed a biotinylated RNA-pulldown assay with cancer cells extracts subjected to sorafenib. Mass spectrometry analyses of the protein complexes associated with ATF4 biotinylated-RNA fragments led to the identification ofthe DEAD-boxRNA helicase DDX3, as potential interactor with ATF4 mRNA. By combining depletion experiments with various biochemical assays (e.g. luciferase assays), we showed that DDX3 drives sorafenib-induced iv ATF4 mRNA expression at the translational level. Protein-interaction assays identified DDX3 as a component of the translation initiation complex eIF4F. The interaction between DDX3 and the eIF4F complex is potentially mediated by eIF4GI, which we found to be required forsorafenib-induced ATF4 expression. Furthermore, reducing ATF4 expression in resistant HCC cellsthrough DDX3 depletion sensitizes cancer cellsto Sorafenib-induced cell death. Thus, this study identified new regulatory pathways of ATF4 factor that could be targeted to prevent drug resistance in cancer cells and improve the conventional therapies

Potentialités de l’acarien prédateur Amblyseius swirskii (Athias-Henriot) (Acari: Phytoséiidae) dans la lutte biologique contre la mouche blanche Bemisia tabaci (Genn.), vecteur de la mosaïque du manioc en Afrique

La mosaïque africaine du manioc est une maladie redoutable qui ravage les champs de manioc en Afrique. Elle est causée par un virus dont le vecteur principal est la mouche blanche Bemisia tabaci. Un des moyens de lutte contre cette maladie passe par la lutte contre le vecteur B. tabaci, réputé très résistant aux insecticides chimiques. L’acarien prédateur phytoséiide Amblyseius swirskii a été identifié en Europe comme un potentiel prédateur de B. tabaci. Dans une série d’études au laboratoire nous avons déterminé la capacité de deux populations (israélienne et béninoise) de A. swirskii à contrôler les populations de B. tabaci, réduisantainsi l’incidence de la mosaïque sur les plants de manioc. Pour chacune des deux populations du prédateur, les taux de prédation, d’oviposition et de survie des femelles adultes nourries aux larves de premier stade de B.tabaci, en présence ou en absence de pollen de maïs, étaient très faibles par rapport à ceux obtenus dans des études précédentes avec du pollen de la massette, Typha australis ou du maïs. Aussi, les paramètresbiologiques démographiques montrent que sur les larves de B. tabaci le niveau de population de A. swirskii a décru très rapidement pour s’annuler, attestant que B. tabaci n’est pas une proie idéale pour le prédateur. Autotal, ces résultats indiquent que A. swirskii ne serait pas un bon agent de lutte biologique contre B. tabaci sur les plants de manioc en Afrique.Mots clés : Manihot esculenta, aleurode, Aleyrodidae, paramètres démographiques, supplément nutritif

Food habits, ecomorphological patterns and niche breadth of the squeaker, Synodontis schall (Pisces: Siluriformes: Mochokidae) from Niger River in Northern Benin

 The squeaker, Synodontis schall dominates the Mochokid fish sub-community in Niger River in Northern Benin and shows a great economic and commercial importance. The diet of S. schall has been analysed to evaluate the food habit and resource utilization in this regional River. Fish samplings were made monthly from February 2015 to July 2016 using unbaited longlines and traps, seines and experimental gillnets. The results indicated that S. schall is an omnivore foraging in benthic and pelagic habitats with diet dominated by aquatic insects (34.32%), sand particles (18.768%), macrophytes (13.415%), seeds (8.549%), roots (8.319%), detritus (5.344%), mollusks (1.204%) and phytoplankton (0.6255%). The omnivore food habit depicted was also shown by the ecomorphological analysis mainly the relative gut length (GL/SL) varying between 0.8 and 5. The species showed high diet flexibility with high niche breadth ranging between 1.86 and 5.74. Synodontis schall exhibited an ontogenetic diet shift that was also confirmed by Pianka’s diet overlap indexes ranging between Øjk=0.54-0.93. The conservation and the sustainable fisheries exploitation of S. schall require the reinforcement of fishing regulation, habitat protection and ecosystem follow-up. 

Demographic parameters and exploitation rate of five key fishes of Okpara Stream, Oueme River, Benin, West Africa

The current study was carried out on Okpara Stream in Northern Benin to evaluate the demographic factors with inferences on fisheries status of five dominant fish species, which were sampled monthly intervals for 18 months. Asymptotic length (L∞) ranged from 36.23 cm (Brycinus macrolepidotus) to 18.8 cm (Hemichromis fasciatus). Growth rates (K) varied between 1.6 yr-1 and 0.66 yr-1 with growth performance index (Φ’) ranging from 2.4 to 3.1. Theoretical age at length zero (t0) varied -0.95 year for Marcusenius senegalensis to -0.59 year for Shilbe intermedius. Except for B. macolepidotus, total mortalities were higher than 2 year-1 and length at first capture (L50) ranged 7.72-12.09 cm. Marcusenius senegalensis and S. intermedius showed one annual peak of recruitment, whereas H. fasciatus, Oreochromis niloticus and B. macrolepidotus displayed two peaks. The results indicated that the stocks of these five species were underexploited. However, the low length at first capture (L50) recorded for some species, requires the implementation of early fisheries management scheme to assure a sustainable exploitation of these fishes

Transfer RNA-derived small RNAs in the cancer transcriptome

The cellular lifetime includes stages such as differentiation, proliferation, division, senescence and apoptosis.These stages are driven by a strictly ordered process of transcription dynamics. Molecular disruption to RNA polymerase assembly, chromatin remodelling and transcription factor binding through to RNA editing, splicing, post-transcriptional regulation and ribosome scanning can result in significant costs arising from genome instability. Cancer development is one example of when such disruption takes place. RNA silencing is a term used to describe the effects of post-transcriptional gene silencing mediated by a diverse set of small RNA molecules. Small RNAs are crucial for regulating gene expression and microguarding genome integrity.RNA silencing studies predominantly focus on small RNAs such as microRNAs, short-interfering RNAs and piwi-interacting RNAs. We describe an emerging renewal of inter-est in a‘larger’small RNA, the transfer RNA (tRNA).Precisely generated tRNA-derived small RNAs, named tRNA halves (tiRNAs) and tRNA fragments (tRFs), have been reported to be abundant with dysregulation associated with cancer. Transfection of tiRNAs inhibits protein translation by displacing eukaryotic initiation factors from messenger RNA (mRNA) and inaugurating stress granule formation.Knockdown of an overexpressed tRF inhibits cancer cell proliferation. Recovery of lacking tRFs prevents cancer metastasis. The dual oncogenic and tumour-suppressive role is typical of functional small RNAs. We review recent reports on tiRNA and tRF discovery and biogenesis, identification and analysis from next-generation sequencing data and a mechanistic animal study to demonstrate their physiological role in cancer biology. We propose tRNA-derived small RNA-mediated RNA silencing is an innate defence mechanism to prevent oncogenic translation. We expect that cancer cells are percipient to their ablated control of transcription and attempt to prevent loss of genome control through RNA silencing

MSGP: the first database of the protein components of the mammalian stress granules

In response to different stress stimuli, cells transiently form stress granules (SGs) in order to protect themselves and re-establish homeostasis. Besides these important cellular functions, SGs are now being implicated in different human diseases, such as neurodegenerative disorders and cancer. SGs are ribonucleoprotein granules, constituted by a variety of different types of proteins, RNAs, factors involved in translation and signaling molecules, being capable of regulating mRNA translation to facilitate stress response. However, until now a complete list of the SG components has not been available. Therefore, we aimer at identifying and linting in an open access database all the proteins described so far as components of SGs. The identification was made through an exhaustive search of studies listed in PubMed and double checked. Moreover, for each identified protein several details were also gathered from public databases, such as the molecular function, the cell types in which they were detected, the type of stress stimuli used to induce SG formation and the reference of the study describing the recruitment of the component to SGs. Expression levels in the context of different neurodegenerative diseases were also obtained and are also described in the database. The Mammalian Stress Granules Proteome is available at https://msgp.pt/, being a new and unique open access online database, the first to list all the protein components of the SGs identified so far. The database constitutes an important and valuable tool for researchers in this research area of growing interest.Portuguese Science and Technology Foundation (FCT) project ALG-01-0145-FEDER-29480 Algarve Biomedical Center (ABC) Município de Loulé French Muscular Dystrophy Association Ataxia UK FCT SFRH/BD/133192/2017info:eu-repo/semantics/publishedVersio

Healthy dietary indices and risk of depressive outcomes : a systematic review and meta-analysis of observational studies

With depression being the psychiatric disorder incurring the largest societal costs in developed countries, there is a need to gather evidence on the role of nutrition in depression, to help develop recommendations and guide future psychiatric health care. The aim of this systematic review was to synthesize the link between diet quality, measured using a range of predefined indices, and depressive outcomes. Medline, Embase and PsychInfo were searched up to 31st May 2018 for studies that examined adherence to a healthy diet in relation to depressive symptoms or clinical depression. Where possible, estimates were pooled using random effect meta-analysis with stratification by observational study design and dietary score. A total of 20 longitudinal and 21 cross-sectional studies were included. These studies utilized an array of dietary measures, including: different measures of adherence to the Mediterranean diet, the Healthy Eating Index (HEI) and Alternative HEI (AHEI), the Dietary Approaches to Stop Hypertension, and the Dietary Inflammatory Index. The most compelling evidence was found for the Mediterranean diet and incident depression, with a combined relative risk estimate of highest vs. lowest adherence category from four longitudinal studies of 0.67 (95% CI 0.55-0.82). A lower Dietary Inflammatory Index was also associated with lower depression incidence in four longitudinal studies (relative risk 0.76; 95% CI: 0.63-0.92). There were fewer longitudinal studies using other indices, but they and cross-sectional evidence also suggest an inverse association between healthy diet and depression (e.g., relative risk 0.65; 95% CI 0.50-0.84 for HEI/AHEI). To conclude, adhering to a healthy diet, in particular a traditional Mediterranean diet, or avoiding a pro-inflammatory diet appears to confer some protection against depression in observational studies. This provides a reasonable evidence base to assess the role of dietary interventions to prevent depression.Peer reviewe

An anti-inflammatory diet as a potential intervention for depressive disorders: A systematic review and meta-analysis

© 2018 The Authors Background & aims: There is a large body of evidence which supports the role of inflammation in the pathophysiology of mental health disorders, including depression. Dietary patterns have been shown to modulate the inflammatory state, thus highlighting their potential as a therapeutic tool in disorders with an inflammatory basis. Here we conduct a systematic review and meta-analysis of current literature addressing whether there is a link between the inflammatory potential of a diet and risk of depression or depressive symptoms. Methods: A systematic literature search was performed to identify studies that reported an association between the inflammatory potential of the diet and risk of depressive symptoms or diagnosis of depression. Random effect models were used to meta-analyse effect sizes. Quality assessment, publication bias, sensitivity and subgroup analyses were also performed. Results: Eleven studies, with a total of 101,950 participants at baseline (age range: 16–72 years old), were eligible for review. A significant association between a pro-inflammatory diet and increased risk of depression diagnosis or symptoms was evident, relative to those on an anti-inflammatory diet (OR: 1.40, 95% confidence intervals: 1.21–1.62, P < 0.001). No publication bias was detected; however, some study heterogeneity was evident (I2 = 63%, P < 0.001). Subgroup analyses suggested the main source of study heterogeneity was the study design (cross-sectional or longitudinal) and the effect measure used (odds ratio, hazard ratio or relative risk). Conclusion: These results provide an association between pro-inflammatory diet and risk of depression. Thus, adopting an anti-inflammatory diet may be an effective intervention or preventative means of reducing depression risk and symptoms

Nutritional determinants of mental health in two French cohorts : SU.VI.MAX and NutriNet-Santé

La dépression est un trouble mental courant et la première cause d’incapacité dans le monde. Elle a été associée à une mauvaise qualité de vie, un déclin physique, et un risque accru de décès prématuré. De plus, la dépression entraîne un poids économique considérable, faisant d’elle une préoccupation majeure de santé publique. Les facteurs prédisposant ou protecteurs sont divers et inclus des indicateurs de mode de vie modifiables. De nombreuses études ont en effet suggéré que l’alimentation pourrait jouer un rôle important dans la survenue d’une dépression, toutefois peu de ces études se sont intéressées aux scores ou indices nutritionnels définis « a priori ». Ainsi, cette thèse avait pour objectif général d’étudier le lien entre la qualité globale du régime alimentaire (évaluée à l’aide de divers scores et indices nutritionnels « a priori ») et la dépression (plus précisément une symptomatologie dépressive), à partir des données issues des cohortes SU.VI.MAX et NutriNet-Santé. Les résultats de nos travaux ont mis en évidence une association inverse entre l’adéquation à l’alimentation méditerranéenne ou aux recommandations nutritionnelles (françaises et internationales) et le risque de symptômes dépressifs incidents.Toutefois, l’étude portant sur l’adéquation à l’alimentation méditerranéenne ne montrait des résultats significatifs que chez les hommes. Par ailleurs, l’alimentation « pro-inflammatoire » était positivement associée au risque de symptômes dépressifs incidents, mais dans la cohorte SU.VI.MAX, les associations n’étaient significatives que dans des sous-groupes de la population à savoir : les hommes, les fumeurs et les personnes pratiquant peu d’activité physique. Nos travaux ont également permis de mettre en évidence que l’adéquation à un nombre croissant d’indicateurs de mode de vie « sain » était inversement associée au risque de symptômes dépressifs incidents.L’ensemble de ces résultats suggèrent que la promotion des modes de vie « sains » (incluant une alimentation « saine ») serait importante dans une stratégie de prévention primaire des symptômes dépressifs.Depression is a common mental disorder and the leading cause of disability worldwide. It has been associated with poor quality of life, physical decline, and increased risk of premature death. In addition, depression leads to a considerable economic burden, making it a major global public health. Protective and risk factors are diverse and include modifiable lifestyle indicators. Several studies have suggested that diet may play an important role in the risk of depression, but few of these studies have investigated the relationship between « a priori » dietary scores and depression. This thesis thus aims to investigate the relationship between overall diet quality evaluated using various nutritional « a priori » scores and incident depressive symptoms, using the data from SU.VI.MAX and NutriNet-Santé cohorts.Our findings showed an inverse association between adherence to the Mediterranean diet or nutritional recommendations (French and international) and the risk of incident depressive symptoms. However, the study on adherence to the Mediterranean diet showed significant results in men only. Moreover, « pro-inflammatory » diet was positively associated with the risk of incident depressive symptoms, but in the SU.VI.MAX cohort, the associations were significant only in some subgroups of the population: men, smokers and participants with low physical activity. We also showed that an increasing number of « healthy » lifestyle indicators was inversely associated with incident depressive symptoms.All of these findings suggest that promoting « healthy » lifestyles (including « healthy » diet) could be an important strategy in primary prevention of depressive symptoms

Analyse de l’efficacité des mécanismes de contrôle des banques au Bénin

This article deals with banking governance and aims to analyze the effectiveness of the control mechanisms of banks in Benin, with regard to theories of corporate governance which offer a framework for analyzing the control mechanisms of managers. To this end, we have mobilized, on the one hand, the theories of agency and transaction costs which propose mechanisms to discipline the behavior of managers and, on the other hand, the theory of entrenchments which makes it possible to analyze the effectiveness of these mechanisms. To achieve our objective, we adopted the following methodological choices: our work undertakes verification and explanation process. We therefore find it relevant to adopt a hypothetico-deductive approach. To implement this approach, we chose a quantitative approach. The analysis of the literature allowed us to define and propose an appropriate measurement of the different variables retained as part of this research. We then developed a simultaneous equation model based on the Shrieves and Dahl (1992) model which constitutes the anchor point of numerous empirical works. We chose to use simultaneous equations in order to highlight the simultaneity of effects between the endogenous variables of our model. At the end of our analyzes which made it possible to understand the behavior of banks in Benin, we find that the banking control mechanisms are effective and contribute in a complementary manner to disciplining the behavior of banks in Benin, which results in an improvement in the level of capital and the performance of banks then the reduction of their level of risk. However, our results argue in favor of actions to improve internal governance within Beninese banks in accordance with international prudential recommendations. Furthermore, the chosen analytical framework is based solely on the explanatory power of the shareholder-disciplinary approach to governance, this can be seen as a limitation of this research. &nbsp;Keywords&nbsp;: Banking governance, prudential regulation, banking supervision Classification JEL&nbsp;: G28, G38 Paper type&nbsp;: Empirical ResearchCet article traite de la gouvernance bancaire et a pour objectif d’analyser l’efficacité des mécanismes de contrôle des banques au Bénin, au regard des théories de gouvernance d‘entreprise qui offrent un cadre d’analyse des mécanismes de contrôle des dirigeants. À cet effet, nous avons mobilisé d’une part les théories de l’agence et des coûts de transaction qui proposent des mécanismes pour discipliner le comportement des dirigeants et d’autre part la théorie de l’enracinement qui permet d’analyser l’efficacité de ces mécanismes. Pour atteindre notre objectif, nous avons adopté les choix méthodologiques suivants&nbsp;: notre travail entreprend une démarche de vérification et d’explication. Nous trouvons donc pertinent d’adopter une démarche hypothético-déductive. Pour mettre en œuvre cette démarche, nous avons choisi une approche quantitative. L’analyse de la littérature nous a permis de définir et de proposer une mesure appropriée des différentes variables retenues dans le cadre de cette recherche. Nous avons ensuite développé un modèle à équations simultanées basé sur le modèle de Shrieves et Dahl (1992) qui constitue le point d’ancrage de nombreux travaux empiriques. Nous avons choisi d’utiliser les équations simultanées afin de mettre en lumière la simultanéité des effets entre les variables endogènes de notre modèle. À l’issue de nos analyses qui ont permis de comprendre le comportement des banques au Bénin, nous trouvons que les mécanismes de contrôle bancaire sont efficaces et contribuent de manière complémentaire à discipliner le comportement des banques au Bénin, ce qui se traduit par une amélioration du niveau de capital et de la performance des banques puis la réduction de leur niveau de risque. Cependant nos résultats plaident en faveur des actions pour améliorer la gouvernance interne au sein des banques béninoises conformément aux recommandations prudentielles internationales. Par ailleurs, le cadre d’analyse choisi est basé uniquement sur le pouvoir explicatif de l’approche disciplinaire actionnariale de la gouvernance, ce qui peut être vu comme une limite de cette recherche. Mots clés&nbsp;: Gouvernance bancaire, réglementation prudentielle, contrôle bancaire. JEL Classification&nbsp;: G28, G38 Type du papier&nbsp;: Recherche empiriqu