Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity

Zircon age of vaugnerite intrusives from the Central and Southern Vosges crystalline massif (E France): contribution to the geodynamics of the European Variscan belt

To provide a better picture of the active geodynamics along the Variscan suture zones during the late collisional stage (particularly regarding the evolution of the orogenic system towards HT conditions), we focused here on vaugnerites, which consist of mafic ultra-potassic magmatic rocks, intrusive into the granite-gneiss sequences of the Variscan Vosges crystalline massif. Those rocks, though subordinate in volume, are frequently associated with late-collisional granites. In the Central-Southern Vosges, they appear either as (1) pluton margin of the Southern Vosges Ballons granite complex or (2) composite dykes intrusive into migmatite and metamorphic sequences classically referred to as granite-gneiss unit (Central Vosges). Both types correspond to melanocratic rocks with prominent, Mg-rich, biotite and hornblende (20–40% vol., 64 < mg# < 78), two-feldspar and quartz. Those Vosges vaugnerites display geochemical signatures characteristic of ultra-potassic mafic to intermediate, metaluminous to slightly peraluminous rocks. Zircon U-Pb ages were obtained by Laser Ablation Inductively Coupled Plasma Mass Spectrometry. Zircon grains were extracted from a sillimanite-bearing gneiss from the granite-gneiss unit hosting the Central Vosges vaugnerites. They yielded an age at 451 ± 9 Ma, indicating a pre-Variscan Upper Ordovician protolith for the host sequence. Zircon from the four vaugnerite intrusives display U-Pb ages (± 2σ) of 340 ± 2.5 Ma (Ballons), 340 ± 25 Ma, 340 ± 7 Ma and 336 ± 10 Ma (Central Vosges). Synchronous within uncertainty, vaugnerite age data suggest a relatively early emplacement during the Late Variscan collisional history (i.e. Middle Visean times). These results are in line with previously published ages from the Southern Vosges volcano-sedimentary sequences (Oderen-Markstein) and the nearby ultra-potassic granite complexes from the Central and Southern Vosges (Ballons, Crêtes) thereby arguing for a magmatic event of regional significance. Recent petrological studies on vaugnerites suggest that they derive from partial melting of a metasomatized mantle contaminated to some different degrees by elements of continental crust. We propose here that the major ultra-potassic magmatic pulse at 340–335 Ma is a consequence of a significant change into the dynamics of the Rhenohercynian subduction system below the Central-Southern Vosges. In the light of recent thermo-mechanical modelling experiments on mature continental collision, magmatism could result from a syn-collisional lithospheric delamination mechanism involving (1) first, continental subduction evolving towards (2) the underthrusting of the Avalonian continental margin lower crust and (3) the initiation of lithospheric delamination within the supra-subduction retro-wedge (Saxothuringian-Moldanubian continental block). This delamination would drive the emplacement of an asthenospheric upwelling, initially localized along the Variscan suture zones, and gradually propagating towards the southern front of the belt during the Late Carboniferous, as the delamination front migrated at the base of the crust

The Sarro-Lorraine Basin (SLB) in the frame of the Variscan orogeny: structure and tecto-sedimentary schedule

International audienceThe Sarro-Lorraine Basin (SLB) is only known in subsurface in the eastern part of the Paris Basin beneath the Mesozoic sedimentary cover. It is the western extension of the Saar-Nahe basin outcropping in Germany. The nature of its sedimentary filling, of Pennsylvanian (Westphalian-Stephanian) to Permian age, is known through numerous coal and oil exploration wells, most of which drilled before the 1990s. The sedimentary deposits consist of clayey to conglomerate silicoclastic sediments rich in coal (mainly Westphalian), typical of fluviolacustrine environments. Significant uncertainties remain regarding the structure of the SLB, mainly due to the limited number of seismic profiles available to the scientific community. The commonly accepted hypothesis (based among other things on rare seismic profiles dating from the 1960s) proposes that the subsidence initiated in the Namuro-Westphalian and continued at least until the beginning of Permian times. The sedimentation would have been controlled by a network of normal faults (e. g. the Metz fault) located in the north of the future basin, potentially with a strike-slip component. In order to remove the uncertainties mentioned above and to question the established interpretation, the BRGM (French Geological Survey) and the University of Lille (France), in addition to 175 km reprocessed by BRGM, have recently reprocessed more than 180 km of industrial seismic lines acquired in the 1980s. The interpretation of these seismic profiles reprocessed with modern methods gives a new image of the geometry and cartographic extension of the SLB (e.g. the clear unconformity between the Westphalian and Stephano-Permian sedimentary series, Permian post-rift deposits, possible extension of the SLB to the north beyond the Metz fault). We interpret the observed sedimentary and structural geometries in terms of negative tectonic inversion at the end of the Variscan orogenic process: the normal faults controlling the stephano-permian sedimentation ("rifting") are thus rooted in the thrusts coeval with the Westphalian molasse-like sedimentation. In order to place the SLB in the Variscan geodynamic context, these new observations are confronted with Variscan deformations known further east in Germany, where they are described in details; the SLB would then record the syn-to post-orogenic evolution (according to the tectonic inversion process) of a segment of the Saxo-Thuringian zone directly south of the Rheno-Hercynian suture

Perturbations des environnements marins, à la limite Frasnien-Famennien (Devonien Terminal) (apport de la géochimie inorganique et du magnétisme des roches)

Le Dévonien supérieur est une période marquée par des variations climatiques importantes et de nombreuses perturbations environnementales, tant dans le domaine continental (surrection de chaînes de montagnes, développement des plantes vasculaires) que dans le domaine marin (fluctuations du niveau marin, crise biologique, stockage de matière organique). La mise en place de façon quasi-globale de niveaux riches en matière organique au Frasnien terminal, les horizons Kellwasser, et leur impact sur le cycle du carbone ont retenu plus particulièrement notre attention au cours de ce travail. L'étude pluridisciplinaire menée sur des séries sédimentaires situées de part et d'autre de la chaîne éovarisque nous permet de reconstituer les variations des environnements marins à la limite Frasnien-Famennien, dans les régions du Massif Schisteux Rhénan, des Montagnes du Harz (Allemagne), de la Meseta occidentale et de l'Anti-Atlas (Maroc). La démarche adoptée repose principalement sur l'analyse géochimique et l'étude du magnétisme des roches. A partir des résultats obtenus, un modèle de formation des horizons Kellwasser au cours du Frasnien terminal est proposé. Durant l'épisode de dépôt de l'horizon Kellwasser inférieur, l'appauvrissement en oxygène serait le résultat d'une hausse importante de la productivité primaire. Cette hausse de productivité et la consommation d'oxygène auraient été induites par l'eutrophisation des milieux marins peu profonds. La libération accrue de nutriment proviendrait d'une intensification de l'altération chimique, faisant suite au développement des plantes vasculaires et à la mise en place de la chaîne éovarisque à partir du Dévonien supérieur.Ce phénomène d'altération a vraisemblablement été favorisé par un climat particulièrement chaud et humide. Durant l'épisode de dépôt de l'horizon Kellwasser supérieur, l'appauvrissement en oxygène résulterait de la stratification des eaux dans les environnements profonds, due à une diminution de la circulation océanique, causée par un confinement plus important des bassins. Cette stratification a été accrue durant la période de haut niveau marin associée à l'horizon Kelhvasser supérieur. Les eaux anoxiques ont pu se répandre dans les environnements de plates-formes à la faveur de la montée eustatique. La mise en place de conditions anoxiques, voire localement euxiniques, a favorisé la diffusion des nutriments libérés par la reminéralisation de la matière organique. Ces nutriments ont pu rejoindre épisodiquement les eaux de surface, à la faveur d'interruptions temporaires de la stratification des eaux, et ainsi intensifier la productivité primaire. Il est proposé que cette période de stockage accrue de carbone organique dans les sédiments ait fortement perturbé le cycle du carbone à long terme, conduisant, au final, à une chute notable de la pression de CO2 atmosphérique et au refroidissement du climat à la base du Famennien. Ainsi, ces travaux suggèrent que la formation des horizons Kellwasser résulte de la conjonction de divers' phénomènes, comprenant la tectonique s.l. ,l'évolution des végétaux, la physiographie des océans, la productivité marine, le tout en interactions directes et indirectes avec le climat.LILLE1-BU (590092102) / SudocSudocFranceF

The Sarro-Lorraine Basin (SLB) in the frame of the Variscan orogeny: structure and tecto-sedimentary schedule

International audienceThe Sarro-Lorraine Basin (SLB) is only known in subsurface in the eastern part of the Paris Basin beneath the Mesozoic sedimentary cover. It is the western extension of the Saar-Nahe basin outcropping in Germany. The nature of its sedimentary filling, of Pennsylvanian (Westphalian-Stephanian) to Permian age, is known through numerous coal and oil exploration wells, most of which drilled before the 1990s. The sedimentary deposits consist of clayey to conglomerate silicoclastic sediments rich in coal (mainly Westphalian), typical of fluviolacustrine environments. Significant uncertainties remain regarding the structure of the SLB, mainly due to the limited number of seismic profiles available to the scientific community. The commonly accepted hypothesis (based among other things on rare seismic profiles dating from the 1960s) proposes that the subsidence initiated in the Namuro-Westphalian and continued at least until the beginning of Permian times. The sedimentation would have been controlled by a network of normal faults (e. g. the Metz fault) located in the north of the future basin, potentially with a strike-slip component. In order to remove the uncertainties mentioned above and to question the established interpretation, the BRGM (French Geological Survey) and the University of Lille (France), in addition to 175 km reprocessed by BRGM, have recently reprocessed more than 180 km of industrial seismic lines acquired in the 1980s. The interpretation of these seismic profiles reprocessed with modern methods gives a new image of the geometry and cartographic extension of the SLB (e.g. the clear unconformity between the Westphalian and Stephano-Permian sedimentary series, Permian post-rift deposits, possible extension of the SLB to the north beyond the Metz fault). We interpret the observed sedimentary and structural geometries in terms of negative tectonic inversion at the end of the Variscan orogenic process: the normal faults controlling the stephano-permian sedimentation ("rifting") are thus rooted in the thrusts coeval with the Westphalian molasse-like sedimentation. In order to place the SLB in the Variscan geodynamic context, these new observations are confronted with Variscan deformations known further east in Germany, where they are described in details; the SLB would then record the syn-to post-orogenic evolution (according to the tectonic inversion process) of a segment of the Saxo-Thuringian zone directly south of the Rheno-Hercynian suture

Modélisation 3-D de la structure du bassin minier du Nord-Pas-de-Calais : analyse critique des anciennes interprétations de 1905 et 1963

International audienc

Projet de modélisation en 4-D du bassin houiller du Nord – Pas-de-Calais : des tables de verre du musée de Lille à une modélisation géométrique et tectonique par ordinateur

International audienceThe dynamics of mountain belt front results from interaction between deformation processes (tectonics) that create relief, and surface processes (erosion, sedimentation and climate) that destroy them. In the field, it has been studied on recent examples, but also on ancient ones. In this paper, we investigate the Nord-Pas de Calais coal basin, a portion of the northern foreland basin of the Palaeozoic variscan belt, which developed about 300 Myr ago. It represents a field case whose coal mining transformed it into an industrial and societal object that greatly influences the local history. Today, it is located in a reconverting territory whose development is planned for being economically, industrially and ecologically sustainable. To support this approach, it is necessary to improve the scientific knowledge and the understanding of the subsurface, in particular the geometry of the various sedimentary bodies and the faults that affect them. In this paper, we present the first steps of a larger project aimed at synthesizing the numerous geological data available on the basin (drilling, gallery surveys, geophysical imagery) and proposing a modern three-dimensional geological interpretation. The fourth dimension (time) will be implemented through geological cross-section restoration and physical modelling. The challenge is important because this new subsurface model can serve as a scientific support for environmental and energetic discussions that interest the Region (geological and environmental risks, geothermal potential). This will provide a valuable and unprecedented educational tool for regional actors and teachers, enabling them to better communicate about this area where 1.2 million people live.La dynamique d’un front de chaîne de montagnes résulte d’interactions entre les processus de déformation (la tectonique) qui initient les reliefs et les processus de surface (l’érosion, la sédimentation, le climat) qui les détruisent. Souvent étudiée à partir d’exemples naturels récents, cette thématique est peu abordée sur des chaînes de montagnes anciennes. Dans le cadre de cet article, nous nous intéressons au Bassin Houiller du Nord-Pas-de-Calais, bassin d’avant-chaîne localisé au front Nord de la grande chaîne varisque, développée il y a environ 300 Ma. Il s’agit d’un objet géologique dont l’exploitation du charbon en a fait un objet industriel et sociétal singulier qui a façonné l’histoire régionale. Aujourd'hui, il s’agit d’un territoire en reconversion dont le développement s’inscrit dans la durabilité tant industrielle, économique, qu’écologique. Pour soutenir cette démarche, il est nécessaire d’améliorer les connaissances scientifiques et notre compréhension du soussol, notamment la géométrie des différents ensembles sédimentaires et des discontinuités qui les affectent. Dans cet article, nous exposons les premières étapes d’un projet plus vaste visant à reprendre les nombreuses données géologiques disponibles sur le bassin (forages, levés de galerie, imagerie géophysique) et d’en proposer une interprétation géologique intégrée dans un environnement en trois dimensions. La quatrième dimension (le temps) sera abordée par la restauration de coupes géologiques et la construction de modèles expérimentaux. L’enjeu est important car ce nouveau modèle du sous-sol pourra servir de support scientifique de base aux problématiques environnementales et énergétiques discutées en région (risques géologiques et environnementaux « après-mine », potentiel géothermique). Il fournira également un outil pédagogique précieux et inédit aux acteurs du développement régional et aux enseignants, leur permettant de mieux faire connaître ce bassin sur lequel vivent aujourd'hui 1,2 million d’habitants

Modélisation numérique du cycle du carbone et des cycles biogéochimiques (application aux perturbations climatiques de l'Ordovicien terminal, du Dévonien terminal et du Miocène moyen)

Le CO2 est un gaz à effet de serre reconnu comme un forçage important du climat à l échelle des temps géologiques. Sa variation au cours du Phanérozoïque détermine les périodes froides dites "icehouse" et chaudes dites "greenhouse". Au cours de ces grandes tendances climatiques ont eu lieu des perturbations courtes à l échelle du Phanérozoïque au cours desquelles le cycle du carbone et donc la concentration en CO2 dans l atmosphère ont été perturbés. A l aide d un modèle numérique du cycle du carbone construit au cours de la thèse et basé sur une version déjà existante et publié par Grard et al. (2005). Les simulations effectuées ont permis de tester différents processus. Au cours du Miocène Moyen, nous mettons en avant la possibilité d une intensification du stockage de carbone d origine continentale en déposant 1,5.10*18 moles de carbone en 3 millions d années. Cette intensification est l hypothèse la plus plausible pour permettre d expliquer l excursion isotopique du ?*13C observée à cette période. Les travaux sur l Ordovicien terminal ont permis de proposer une nouvelle théorie quant à la mise en place de la glaciation hirnantienne. Cette hypothèse est la mise en place d un trapp basaltique. Finalement, les travaux concernant le Dévonien terminal ont permis de vérifier l hypothèse selon laquelle une orogenèse, processus géodynamique s étalant sur plusieurs dizaines de millions d années, peut entraîner une perturbation transitoire du cycle du carbone, de quelques millions d années, associée à la phase de surrection initiale. Nous montrons ainsi que l orogenèse Eovarisque peut être la cause principale des événements Kellwasser au niveau de la limite Frasnien-Famennien.Carbon dioxide is a greenhouse gas known to be a primary driver of the Earth climate at a geological time scale. Its variation during the Phanerozoic determines icehouse and greenhouse periods. Brief perturbations, marked by carbon cycle and consequently atmospheric carbon dioxide concentration changes, occur during the Phanerozoic. During the PhD a numerical carbon cycle box model has been updated based on a previous version published by Grard et al. (2005). The modelisations realized during the PhD alowed to test different processes leading to a carbon cycle destabilization over several million of years. During the middle Miocene, we propose an intensification of the burial of continental organic carbon by burying 1.5x10*18 mol C in 3 millions of years. This process constitutes the more acceptable scenario that could explain the positive ?*13C excursion of the middle Miocene. Modeling on the Late Ordovician has led to the suggestion of a new hypothesis explaining the Hirnantian cooling : the installation of a continental basaltic province. Finally, the modeling on the Late Devonian has tested the hypothesis that a long-term (more than 10 Myr) geodynamical process such as a major orogeny could lead to a short-term (less than 2 Myr) carbon cycle perturbation associated to the initial mountain uplift. We show that the Eovariscan orogeny can be at the origin of the two Kellwasser events at the Frasnian-Famennian boundary.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Diagenetic versus detrital origin of the magnetic susceptibility variations in some carbonate Frasnian-Famennian boundary sections from Northern Africa and Western Europe: implications for paleoenvironmental reconstructions.

17 pagesInternational audienceTo provide a new insight into the diagenetic versus detrital origin of the magnetic susceptibility variations in ancient carbonate sequences, a study was conducted within four Frasnian–Famennian platform carbonate sections from Germany, France and Morocco. The study includes along-section magnetic susceptibility and carbonate content measurements complemented by analyses of magnetic hysteresis parameters, inorganic geochemistry and clay mineralogy. Our results show that the magnetic susceptibility evolution is dominantly controlled by the variations in the concentration of low-coercivity ferromagnetic magnetite grains and, to a lesser extent, of paramagnetic clays. In more detail, hysteresis ratios suggest the coexistence of two magnetite populations with significantly different grain size: (1) a dominantly coarsegrained detrital fraction including a mixture of multidomain and single-domain particles (2) an authigenic finegrained fraction composed of a mixture of single-domain and superparamagnetic particles. Despite a diagenetic imprint on the clay assemblages, no relationship is established between magnetic susceptibility and illite crystallinity, therefore discarding a noticeable distortion of primary within-section magnetic susceptibility evolution. The overall inherited character of the magnetic susceptibility fluctuations is corroborated by a significant correlation of magnetic susceptibility with terrigenous proxies (Zr, Th). The poorer correlation of magnetic susceptibility with the Fe content is consistent with the existence of a very fine-grained authigenic magnetite component that possibly induces a global magnetic susceptibility increase at the section scale, but no distortion of the within-section evolution. The magnetic susceptibility curves presented here provide a general record of climate-driven detrital influx and carbonate productivity through Frasnian–Lower Famennian times