Megalithic building techniques in the Languedoc region of southern France: recent excavations at two dolmens in Hérault

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Tumorigenèse, progression tumorale et zonation fonctionnelle du cortex surrénalien

Adrenocortical carcinoma (ACC) is a rare tumour associated with poor prognosis and for which, efficient therapeutic approaches are not available. It is therefore essential to understand the molecular mechanisms involved in CCS development in order to improve their clinical management. The two most frequent alterations in ACC are overexpression of IGF2 and constitutive activation of β-catenin. Our lab has previously demonstrated the oncogenic activity of β-catenin in the adrenal cortex by developing a mouse model of constitutive β-catenin activation (ΔCat mice). However, the low malignant progression in ΔCat mice suggests that other alterations are necessary for acquisition of malignancy. The initial aim of my thesis was to test the oncogenic potential of IGF2 alone or associated with constitutive β-catenin activation. We showed that overexpression of Igf2 in the adrenal cortex does not trigger adrenal cortex tumourigenesis. In a context of constitutive β-catenin activation, overexpression of Igf2 promotes tumour development at later stages. However the formation of malignant tumours remains a rare event. These data suggest that the overexpression of Igf2 and constitutive activation of β-catenin are not sufficient to trigger malignant tumour progression. Retrospective analysis of available ACC transcriptome data highlighted overexpression of the putative oncogene and histone methyltransferase EZH2 in ACC, which was associated with poor prognosis. My in vitro studies suggest that EZH2 is overexpressed in response to overexpression of E2F transcription factors and that it could be involved in control of proliferation, apoptosis and oncogenic capacities of adrenocortical carcinoma cells H295R. Interestingly, the availability of pharmacologic inhibitors suggests that EZH2 could be a novel therapeutic target for the treatment of ACC. In parallel, we sought to identify the mechanisms involved in zonation of the adrenal cortex. During adrenal cortex renewal, cells first differentiate as glomerulosa before switching to fasciculata as they move within the cortex. Establishment of glomerulosa identity relies on the Wnt/β-catenin pathway, which induces expression of genes involved in glomerulosa differentiation and inhibits fasciculata identity. These data suggest that β-catenin has to be inhibited in order to allow the lineage conversion from glomerulosa to fasciculata. We thus postulated that PKA signalling pathway, which is triggered by ACTH binding to its receptor MC2R in zona fasciculata, played a role in repressing Wnt/β-catenin signalling to allow fasciculata differentiation. Using pharmacologic and genetic models, we have shown that PKA inhibits β-catenin signalling, which leads to loss of zona glomerulosa and expansion of zona fasciculata. The inhibitor effect of PKA on β-catenin pathway could be the result of decreased expression of Wnt4. Indee, a decrease of Wnt4 expression is observed in response to PKA activation and inactivation of Wnt4 in the adrenal cortex phenocopies PKA activation. We have also shown that PKA inhibits oncogenic effects of β-catenin in the adrenal cortex. The observation of decreased ACTH/PKA signalling in ACC suggests that this inhibition could be relevant to human adrenal tumour development.Les carcinomes cortico-surrénaliens (CCS) sont des tumeurs malignes rares de mauvais pronostic et pour lesquelles les options thérapeutiques efficaces sont inexistantes. Il est donc indispensable de comprendre les mécanismes moléculaires impliqués dans le développement des CCS, afin d’améliorer leur prise en charge. Les deux altérations les plus fréquentes dans les CCS sont une surexpression du facteur de croissance IGF2 et l'activation constitutive de la voie Wnt/β-caténine. Le laboratoire a mis en évidence le rôle oncogénique de la β-caténine à l'aide d'un modèle murin (souris ΔCat) présentant une activation constitutive de la β-caténine dans la cortico-surrénale. Toutefois, la faible pénétrance du phénotype malin suggère la nécessité d'autres altérations pour la progression tumorale. L’objectif initial de ma thèse était de tester le pouvoir oncogénique de IGF2, seul ou en association avec l’activation constitutive de la β-caténine. Les modèles de surexpression de Igf2 dans la cortico-surrénale nous ont permis de montrer que Igf2 n'initie pas le développement de tumeurs cortico-surrénaliennes. Dans un contexte d'activation de la β-caténine, la surexpression de Igf2 favorise le développement tumoral à des stades tardifs. Toutefois la formation de tumeurs malignes reste un évènement rare. Ces résultats suggèrent donc que la surexpression de Igf2 et l'activation de la β-caténine ne sont pas suffisantes dans notre modèle pour induire le développement de CCS. Une analyse rétrospective des données de transcriptome nous a permis de mettre en évidence une surexpression de l’oncogène putatif et histone méthyl-transférase EZH2, qui est associée à un mauvais pronostic. Mes travaux in vitro suggèrent que EZH2 est surexprimé en réponse à une surexpression des facteurs E2F et qu’il pourrait être impliqué dans le contrôle de la prolifération, de l'apoptose et de certaines caractéristiques tumorales des cellules cortico-surrénaliennes humaines H295R. Des inhibiteurs pharmacologiques étant disponibles, EZH2 pourrait constituer une cible thérapeutique intéressante pour le traitement des CCS. En parallèle de ces travaux, nous avons cherché à identifier les mécanismes impliqués dans la zonation du cortex surrénalien. Au cours du renouvellement tissulaire, les cellules acquièrent d’abord une identité glomérulée puis fasciculée. L'identité de la zone glomérulée repose en partie sur l'activité de la voie Wnt/β-caténine. Cette voie de signalisation induit l'expression de gènes essentiels à l'identité de cette zone et inhibe l'identité fasciculée. La différenciation fasciculée des cellules doit donc reposer en partie, sur l'inhibition de cette voie de signalisation. Nous avons donc émis l'hypothèse que la signalisation PKA, activée dans la zone fasciculée par la liaison de l'ACTH à son récepteur MC2R, s'oppose à l'activité de la β-caténine pour permettre la différenciation fasciculée. A l'aide d'approches pharmacologiques et génétiques, nous avons pu mettre en évidence que l'activation de la PKA inhibe la voie Wnt/β-caténine dans le cortex surrénalien et que ceci est à l'origine d'une perte de la zone glomérulée au profit d'une expansion de la fasciculée. L'effet de la PKA sur la voie Wnt résulte au moins en partie de l'inhibition de l'expression de Wnt4 en réponse à l'activation de la PKA. En effet une diminution d'expression de Wnt4 est observée en réponse à l'activation de la PKA dans la cortico-surrénale et l'invalidation de Wnt4 spécifiquement dans le cortex induit un phénotype proche de celui observé lors de l'activation de la PKA. Au delà des mécanismes moléculaires de la zonation, nous avons également montré que l’effet inhibiteur de la PKA sur la signalisation Wnt était capable de s’opposer aux effets oncogéniques de la β- caténine dans la cortico-surrénale. Ces observations pourraient s’avérer pertinentes, la voie de signalisation ACTH/PKA étant inhibée dans les CCS

Réflexions sur l’implantation et l’architecture des dolmens à couloir et à antichambre du Causse de l’Hortus (Hérault, France)

Parmi les dolmens les plus imposants du mégalithisme héraultais, ceux du Lamalou, du Capucin et de Feuilles sont situés sur le Causse de l’Hortus, dans la région des garrigues languedociennes. Leur architecture massive se démarque par la présence systématique d’une antichambre, délimitée par des piliers d’entrée, dont la fonction reste difficile à percevoir. Néanmoins, elle contribue incontestablement à la monumentalisation de ces dolmens au même titre que les importants tumulus qui les enserrent. Les sépultures étudiées forment un groupe homogène tant par leur implantation géographique au sein d’un territoire spécifique que par leur architecture. La succession et la délimitation des espaces sont sensiblement identiques même si les matériaux sont utilisés différemment. Une approche plus globale des dolmens à antichambre du Languedoc montre des différences de gestion de l’espace interne des monuments mégalithiques par rapport à leur contexte géoculturel.Among the most imposing dolmens of Hérault’s megalithism, those of Lamalou, Capucin and Feuilles are situated on Hortus limestone plateau, in the Languedoc’s scrubland area. Their massive architecture distances itself by the systematic presence of an anteroom, bounded by pillars of entrance, whose function is difficult to define. However, the anteroom contributes unmistakably to the monumentalisation of these dolmens in the same way as important tumulus which encloses them. The studied graves form a homogeneous group both by their geographical situation within a specific territory and by their architecture. The succession and the demarcation of spaces are appreciably identical even if materials are differently used. A more global approach of dolmens with anteroom of Languedoc shows differences of management of the internal space with regard to their geocultural context

First data on the protohistoric funerary practices in the region of Khaybar (Saudi Arabia)

The landscape of the Arabian Peninsula is spotted by hundreds of thousands of dry-stone megalithic funerary structures. Our study region in northwestern Saudi Arabia, near the modern city of Khaybar, and covering 56 sq. km, has yielded more than 14,000 of them. Despite there huge number and density, the lack of excavations in the region refrains from understanding their refined chronology and funerary practices. Through our research started with the Khaybar Longue Durée Archaeological Projec..

Belvédère-Campomoro – Capu di Lugu

Le plateau de Capu di Lugu est situé sur la rive sud du golfe de Valinco à environ 11 km à l’ouest de Sartène, sur la commune de Belvédère-Campomoro. Cette entité géographique d’environ 60 ha, cultivée jusqu’à époque récente, était en déshérence et se couvrait progressivement de maquis jusqu’à la réouverture de la piste et la mise en œuvre de travaux agricoles. Ces travaux sont à l’origine de notre intervention durant l’été 2013 puisque les deux monuments de « Stantare de Capo di Lugo », clas..

Measuring Happiness: From Fluctuating Happiness to Authentic–Durable Happiness

On the basis of the theoretical distinction between self-centeredness and selflessness (Dambrun and Ricard, 2011), the main goal of this research was to develop two new scales assessing distinct dimensions of happiness. By trying to maximize pleasures and to avoid displeasures, we propose that a self-centered functioning induces a fluctuating happiness in which phases of pleasure and displeasure alternate repeatedly (i.e., Fluctuating Happiness). In contrast, a selfless psychological functioning postulates the existence of a state of durable plenitude that is less dependent upon circumstances but rather is related to a person’s inner resources and abilities to deal with whatever comes his way in life (i.e., Authentic–Durable Happiness). Using various samples (n = 735), we developed a 10-item Scale measuring Subjective Fluctuating Happiness (SFHS) and a 13-item scale assessing Subjective Authentic–Durable Happiness (SA–DHS). Results indicated high internal consistencies, satisfactory test–retest validities, and adequate convergent and discriminant validities with various constructs including a biological marker of stress (salivary cortisol). Consistent with our theoretical framework, while self-enhancement values were related only to fluctuating happiness, self-transcendence values were related only to authentic–durable happiness. Support for the distinction between contentment and inner-peace, two related markers of authentic happiness, also was found

GLI1(+) progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue

As certain strains of mice age, hyperplastic lesions resembling gonadal tissue accumulate beneath the adrenal capsule. Gonadectomy (GDX) accelerates this heterotopic differentiation, resulting in the formation of wedge-shaped adrenocortical neoplasms that produce sex steroids. Stem/progenitor cells that reside in the adrenal capsule and retain properties of the adrenogonadal primordium are thought to be the source of this heterotopic tissue. Here, we demonstrate that GLI1(+) progenitors in the adrenal capsule give rise to gonadal-like cells that accumulate in the subcapsular region. A tamoxifen-inducible Cre driver (Glil-creER(T2)) and two reporters (R26R-lacZ, R26R-confetti) were used to track the fate of GLI1(+) cells in the adrenal glands of B6D2F2 mice, a strain that develops both GDX-induced adrenocortical neoplasms and age-dependent subcapsular cell hyperplasia. In gonadectomized B6D2F2 mice GLI1(+) progenitors contributed to long-lived adrenal capsule cells and to adrenocortical neoplasms that expressed Gata4 and Foxl2, two prototypical gonadal markers. Pdgfra, a gene expressed in adrenocortical stromal cells, was upregulated in the GDX-induced neoplasms. In aged non-gonadectomized B6D2F2 mice GLI1(+) progenitors gave rise to patches of subcapsular cell hyperplasia. Treatment with GANT61, a small-molecule GLI antagonist, attenuated the upregulation of gonadal-like markers (Gata4, Foxl2) in response to GDX. These findings support the premise that GLI1(+) progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic tissue. (C) 2016 Elsevier Ireland Ltd. All rights reserved.Peer reviewe

Signaling interactions in the adrenal cortex

The major physiological stimuli of aldosterone secretion are angiotensin II (AII) and extracellular K+ whereas cortisol production is primarily regulated by corticotrophin (ACTH) in fasciculata cells. AII triggers Ca2+ release from internal stores that is followed by store-operated and voltage-dependent Ca2+ entry whereas K+-evoked depolarisation activates voltage-dependent Ca2+ channels. ACTH acts primarily through the formation of cAMP and subsequent protein phosphorylation by protein kinase A. Both Ca2+ and cAMP facilitate the transfer of cholesterol to mitochondrial inner membrane. The cytosolic Ca2+ signal is transferred into the mitochondrial matrix and enhances pyridine nucleotide reduction. Increased formation of NADH results in increased ATP production whereas that of NADPH supports steroid production. In reality, the control of adrenocortical function is a lot more sophisticated with second messengers crosstalking and mutually modifying each other’s pathways. Cytosolic Ca2+ and cGMP are both capable of modifying cAMP metabolism whilst cAMP may enhance Ca2+ release and voltage-activated Ca2+ channel activity. Besides, mitochondrial Ca2+ signal brings about cAMP formation within the organelle and this further enhances aldosterone production. Maintained aldosterone and cortisol secretion are optimized by the concurrent actions of Ca2+ and cAMP, as exemplified by the apparent synergism of Ca2+ influx (inducing cAMP formation) and Ca2+ release during response to AII. Thus, cross-actions of parallel signal transducing pathways are not mere intracellular curiosities but rather substantial phenomena which fine-tune the biological response. Our review focuses on these functionally relevant interactions between the Ca2+ and the cyclic nucleotide signal transducing pathways hitherto described in the adrenal cortex

Emulsified lipids: formulation and control of end-use properties

In many practical applications including foods, cosmetics, pharmaceuticals, etc., lipids are emulsified in an aqueous phase in the presence of surface-active molecules and other additives like thickening/gelling agents. Once fabricated, the emulsions may exhibit all kinds of rheological behaviors from viscous fluid to elastic pastes, and transitions: reversible phase transitions as a result of droplet interactions that may be modified to a large extent, and irreversible transitions that generally involve their destruction. Besides the predominance of empiricism in controlling most of the end-use properties, the scientific background of emulsions is progressing. In this paper we aim to review some advances concerning the control of the structure, the texture (rheological properties) and the ageing of emulsions

Stem Cells, Self-Renewal, and Lineage Commitment in the Endocrine System

The endocrine system coordinates a wide array of body functions mainly through secretion of hormones and their actions on target tissues. Over the last decades, a collective effort between developmental biologists, geneticists, and stem cell biologists has generated a wealth of knowledge related to the contribution of stem/progenitor cells to both organogenesis and self-renewal of endocrine organs. This review provides an up-to-date and comprehensive overview of the role of tissue stem cells in the development and self-renewal of endocrine organs. Pathways governing crucial steps in both development and stemness maintenance, and that are known to be frequently altered in a wide array of endocrine disorders, including cancer, are also described. Crucially, this plethora of information is being channeled into the development of potential new cell-based treatment modalities for endocrine-related illnesses, some of which have made it through clinical trials