Engineering of Three-Finger Fold Toxins Creates Ligands with Original Pharmacological Profiles for Muscarinic and Adrenergic Receptors

Protein engineering approaches are often a combination of rational design and directed evolution using display technologies. Here, we test “loop grafting,” a rational design method, on three-finger fold proteins. These small reticulated proteins have exceptional affinity and specificity for their diverse molecular targets, display protease-resistance, and are highly stable and poorly immunogenic. The wealth of structural knowledge makes them good candidates for protein engineering of new functionality. Our goal is to enhance the efficacy of these mini-proteins by modifying their pharmacological properties in order to extend their use in imaging, diagnostics and therapeutic applications. Using the interaction of three-finger fold toxins with muscarinic and adrenergic receptors as a model, chimeric toxins have been engineered by substituting loops on toxin MT7 by those from toxin MT1. The pharmacological impact of these grafts was examined using binding experiments on muscarinic receptors M1 and M4 and on the α1A-adrenoceptor. Some of the designed chimeric proteins have impressive gain of function on certain receptor subtypes achieving an original selectivity profile with high affinity for muscarinic receptor M1 and α1A-adrenoceptor. Structure-function analysis supported by crystallographic data for MT1 and two chimeras permits a molecular based interpretation of these gains and details the merits of this protein engineering technique. The results obtained shed light on how loop permutation can be used to design new three-finger proteins with original pharmacological profiles

Magnetic properties of variably serpentinized peridotites and their implication for the evolution of oceanic core complexes

Serpentinization of ultramafic rocks during hydrothermal alteration at mid-ocean ridges profoundly changes the physical, chemical, rheological, and magnetic properties of the oceanic lithosphere. There is renewed interest in this process following the discovery of widespread exposures of serpentinized mantle on the seafloor in slow spreading oceans. Unroofing of mantle rocks in these settings is achieved by displacement along oceanic detachment faults, which eventually results in structures known as oceanic core complexes (OCCs). However, we have limited understanding of the mechanisms of serpentinization at the seafloor and in particular their relationship with the evolution of OCCs. Since magnetite is a direct product of serpentinization, the magnetic properties of variably serpentinized peridotites can provide unique insights into these mechanisms and their evolution in the oceanic lithosphere. Here we present new results from an integrated, rock magnetic, paleomagnetic, and petrological study of variably serpentinized peridotites from the first fossil OCC recognized in an ophiolite. Integration with existing data from mid-ocean ridge-related abyssal peridotites recovered from several scientific ocean drilling sites yields the first magnetic database from peridotites extending across the complete range (0–100%) of degrees of serpentinization. Variations in a range of magnetic parameters with serpentinization, and associated paleomagnetic data, provide: (i) key constraints on the mechanism(s) of serpentinization at mid-ocean ridges; (ii) insights on the potential for serpentinized peridotites to contribute to marine magnetic anomalies; and (iii) evidence that leads to a new conceptual model for the evolution of serpentinization and related remanence acquisition at OCCs

Magmatism, serpentinization and life: Insights through drilling the Atlantis Massif (IODP Expedition 357)

IODP Expedition 357 used two seabed drills to core 17 shallow holes at 9 sites across Atlantis Massif ocean core complex (Mid-Atlantic Ridge 30°N). The goals of this expedition were to investigate serpentinization processes and microbial activity in the shallow subsurface of highly altered ultramafic and mafic sequences that have been uplifted to the seafloor along a major detachment fault zone. More than 57 m of core were recovered, with borehole penetration ranging from 1.3 to 16.4 meters below seafloor, and core recovery as high as 75% of total penetration in one borehole. The cores show highly heterogeneous rock types and alteration associated with changes in bulk rock chemistry that reflect multiple phases of magmatism, fluid-rock interaction and mass transfer within the detachment fault zone. Recovered ultramafic rocks are dominated by pervasively serpentinized harzburgite with intervals of serpentinized dunite and minor pyroxenite veins; gabbroic rocks occur as melt impregnations and veins. Dolerite intrusions and basaltic rocks represent the latest magmatic activity. The proportion of mafic rocks is volumetrically less than the amount of mafic rocks recovered previously by drilling the central dome of Atlantis Massif at IODP Site U1309. This suggests a different mode of melt accumulation in the mantle peridotites at the ridge-transform intersection and/or a tectonic transposition of rock types within a complex detachment fault zone. The cores revealed a high degree of serpentinization and metasomatic alteration dominated by talc-amphibole-chlorite overprinting. Metasomatism is most prevalent at contacts between ultramafic and mafic domains (gabbroic and/or doleritic intrusions) and points to channeled fluid flow and silica mobility during exhumation along the detachment fault. The presence of the mafic lenses within the serpentinites and their alteration to mechanically weak talc, serpentine and chlorite may also be critical in the development of the detachment fault zone and may aid in continued unroofing of the upper mantle peridotite/gabbro sequences. New technologies were also developed for the seabed drills to enable biogeochemical and microbiological characterization of the environment. An in situ sensor package and water sampling system recorded real-time variations in dissolved methane, oxygen, pH, oxidation reduction potential (Eh), and temperature and during drilling and sampled bottom water after drilling. Systematic excursions in these parameters together with elevated hydrogen and methane concentrations in post-drilling fluids provide evidence for active serpentinization at all sites. In addition, chemical tracers were delivered into the drilling fluids for contamination testing, and a borehole plug system was successfully deployed at some sites for future fluid sampling. A major achievement of IODP Expedition 357 was to obtain microbiological samples along a west–east profile, which will provide a better understanding of how microbial communities evolve as ultramafic and mafic rocks are altered and emplaced on the seafloor. Strict sampling handling protocols allowed for very low limits of microbial cell detection, and our results show that the Atlantis Massif subsurface contains a relatively low density of microbial life

Les quais n^os 1, 12 et 13 du port romain de Saint-Lupien à Rezé/<i>Ratiatum</i> (Loire-Atlantique)

International audienceIn the final years of the 1st c. AD that the riverbank of the Saint-Lupien district in Rezé/Ratiatum (Loire-Atlantique) was the object of an ambitious urban planning program that transformed it, subsequently emerging as a structured and monumental constructed space. The bank of the Loire was thus punctuated, and then divided into several construction modules built according to box construction guidelines. Initially, and in the most northernly cases, these boxes were constituted of a robust oak timber framework blended with a solid stone infill. They reflect an artificial terracing and underwent a mutual architectural evolution, traversing multiple transformations, gradually giving rise to an exclusive use of dry stone style toward the middle of the 2nd c. AD. before their early abandonment in the first years of the 3rd c. AD. Excavated simultaneously with the box no 9, boxes nos 1, 12 and 13, were only partially observed through the excavation of small test trenches within each box. Though limited in scope, these trenches were sufficient to underscore the singularity of their morphology, their architectural characteristics and the unique evolutionary processes influencing them.C’est dans les toutes dernières années du Ier s. apr. J.-C. que le trait de rive du quartier de Saint-Lupien à Rezé/Ratiatum (Loire-Atlantique), soumis à un ample programme d’urbanisme, apparaît sous une forme bâtie structurée et monumentale. La berge de la Loire est ainsi jalonnée et fractionnée en plusieurs modules de construction bâtis selon le principe du caisson et servant de quais. Initialement tous constitués d’une charpente en chêne robuste mêlée à un remplissage en pierre massif, pour les plus septentrionaux, ces caissons traduisent une mise en terrasse artificielle et connaissent une évolution architecturale commune, passant par de nombreuses transformations et aboutissant progressivement à un usage exclusif de la pierre sèche vers le milieu du IIe s., avant leur abandon précoce dans la première moitié du IIIe s. Fouillés en parallèle du caisson no 9, le plus complet, les caissons nos 1, 12 et 13 n’ont été observés que partiellement et dans des fenêtres de fouille réduites, mais néanmoins suffisantes pour mettre en évidence quelques spécificités en matière de construction. Cet article entend donc souligner leur originalité à travers leur morphologie, leurs caractéristiques architecturales et leur évolution

Actualisation des données sur la trame viaire de Corseul. Un premier bilan des opérations archéologiques effectuées depuis 2002

Ferrette Romuald, Ménez Nicolas, Chevet Pierre. Actualisation des données sur la trame viaire de Corseul. Un premier bilan des opérations archéologiques effectuées depuis 2002. In: Aremorica. Études sur l'ouest de la Gaule romaine, n°8, 2017. pp. 27-56

Une ceinture gauloise découverte à Corseul (Côtes-d'Armor, FR) ?

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Actualisation des données sur la trame viaire de Corseul. Un premier bilan des opérations archéologiques effectuées depuis 2002.

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Un atelier de tisserand devenu poubelle d’une auberge. La vie d’un quartier aux abords de la ville de Corseul (Côtes-d’Armor) au Ier s. de notre ère.

International audienceI1 arrive que les fouilles livrent suffisamment de vestiges pour que l'on soit en mesure deproposer une interprétation qui dépasse le stade de l'analyse archéologique proprement dite,c'est-à-dire qui nous plonge dans la vie quotidienne de ceux qui vécurent en un lieu donné.Rarement un tel panorama repose sur de véritables preuves, mais plutôt sur des faisceaux d'indicesconvergents, pertinents, remis en situation, qui rendent possible une histoire, celle qui estpermise par les découvertes et notre compréhension de celles-ci.Dans le cas présent, c'est une séquence de quelques décennies sur un espace restreint dequelques centaines de mètres carrés que nous désirons présenter, une séquence qui peut se résumerpar la phrase suivante: « un atelier de tisserand devenu la poubelle d'une auberge». Unesituation suffisamment extraordinaire pour qu'elle suscite la curiosité et surtout donne l'envied'en savoir plus sur les indices qui sont à l'origine de cette proposition

Un atelier de tisserand devenu poubelle d’une auberge. La vie d’un quartier aux abords de la ville de Corseul (Côtes-d’Armor) au Ier s. de notre ère.

International audienceI1 arrive que les fouilles livrent suffisamment de vestiges pour que l'on soit en mesure deproposer une interprétation qui dépasse le stade de l'analyse archéologique proprement dite,c'est-à-dire qui nous plonge dans la vie quotidienne de ceux qui vécurent en un lieu donné.Rarement un tel panorama repose sur de véritables preuves, mais plutôt sur des faisceaux d'indicesconvergents, pertinents, remis en situation, qui rendent possible une histoire, celle qui estpermise par les découvertes et notre compréhension de celles-ci.Dans le cas présent, c'est une séquence de quelques décennies sur un espace restreint dequelques centaines de mètres carrés que nous désirons présenter, une séquence qui peut se résumerpar la phrase suivante: « un atelier de tisserand devenu la poubelle d'une auberge». Unesituation suffisamment extraordinaire pour qu'elle suscite la curiosité et surtout donne l'envied'en savoir plus sur les indices qui sont à l'origine de cette proposition

Un territoire de tradition potière à Bais (Ille-et-Vilaine) : de La Tène D2 au Haut-Empire

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