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Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disorder. FMF is caused by mutations in the MEFV gene, encoding pyrin, an inflammasome sensor. The best characterized pathogenic mutations associated with FMF cluster in exon 10. Yet, mutations have been described along the whole MEFV coding sequence. Exon 10 encodes the B30.2 domain of the pyrin protein, but the function of this human-specific domain remains unclear. Pyrin is an inflammasome sensor detecting RhoA GTPase inhibition following exposure to bacterial toxins such as TcdA. Here, we demonstrate that the B30.2 domain is dispensable for pyrin inflammasome activation in response to this toxin. Deletion of the B30.2 domain mimics the most typical FMF-associated mutation and confers spontaneous inflammasome activation in response to pyrin dephosphorylation. Our results indicate that the B30.2 domain is a negative regulator of the pyrin inflammasome that acts independently from and downstream of pyrin dephosphorylation. Additionally, we identify the central helical scaffold (CHS) domain of pyrin, which lies immediately upstream of the B30.2 domain as a second regulatory domain. Mutations affecting the CHS domain mimic pathogenic mutations in the B30.2 domain and render the pyrin inflammasome activation under the sole control of the dephosphorylation. In addition, specific mutations in the CHS domain strongly increase the cell susceptibility to steroid catabolites, recently described to activate pyrin, in both a cell line model and in monocytes from genotype-selected FMF patients. Taken together, our work reveals the existence of two distinct regulatory regions at the C-terminus of the pyrin protein, that act in a distinct manner to regulate positively or negatively inflammasome activation. Furthermore, our results indicate that different mutations in pyrin regulatory domains have different functional impacts on the pyrin inflammasome which could contribute to the diversity of pyrin-associated autoinflammatory diseases.

The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defenses against RhoA-manipulating pathogens. Pyrin activation proceeds in two steps. Yet, the second step is still poorly understood. Using cells constitutively activated for the pyrin step 1, a chemical screen identifies etiocholanolone and pregnanolone, two catabolites of testosterone and progesterone, acting at low concentrations as specific step 2 activators. High concentrations of these metabolites fully and rapidly activate pyrin, in a human specific, B30.2 domain-dependent manner and without inhibiting RhoA. Mutations in MEFV, encoding pyrin, cause two distinct autoinflammatory diseases pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) and familial Mediterranean fever (FMF). Monocytes from PAAND patients, and to a lower extent from FMF patients, display increased responses to these metabolites. This study identifies an unconventional pyrin activation mechanism, indicates that endogenous steroid catabolites can drive autoinflammation, through the pyrin inflammasome, and explains the "steroid fever" described in the late 1950s upon steroid injection in humans. ispartof: CELL REPORTS vol:41 issue:2 ispartof: location:United States status: published

Clostridium neonatale is a potential opportunistic pathogen recovered from faecal samples in cases of necrotizing enterocolitis (NEC), a gastrointestinal disease affecting preterm neonates. Although the C. neonatale species description and name validation were published in 2018, comparative genomics are lacking. In the present study, we provide the closed genome assembly of the C. neonatale ATCC BAA-265T (=250.09) reference strain with a manually curated functional annotation of the coding sequences. Pan-, core- and accessory genome analyses were performed using the complete 250.09 genome (4.7 Mb), three new assemblies (4.6–5.6 Mb), and five publicly available draft genome assemblies (4.6–4.7 Mb). The C. neonatale pan-genome contains 6840 genes, while the core-genome has 3387 genes. Pan-genome analysis revealed an ‘open’ state and genomic diversity. The strain-specific gene families ranged from five to 742 genes. Multiple mobile genetic elements were predicted, including a total of 201 genomic islands, 13 insertion sequence families, one CRISPR-Cas type I-B system and 15 predicted intact prophage signatures. Primary virulence classes including offensive, defensive, regulation of virulence-associated genes and non-specific virulence factors were identified. The presence of a tet(W/N/W) gene encoding a tetracycline resistance ribosomal protection protein and a 23S rRNA methyltransferase ermQ gene were identified in two different strains. Together, our results revealed a genetic diversity and plasticity of C. neonatale genomes and provide a comprehensive view of this species genomic features, paving the way for the characterization of its biological capabilities.

International audience

Popoff Michel. Héraldique et emblématique chez les Gonzague de Man toue jusqu'au XVIe siècle. In: Bulletin de la Société Nationale des Antiquaires de France, 2000, 2004. pp. 280-288.

Extensive magnetic fabric investigations have been conducted on the Late Jurassic sedimentary black shales (37 sites, 362 samples), the so-called Terres Noires Formation, from the Southern Subalpine Chains (western Alps). This study completes a previous study done in the Northern Subalpine Chains which demonstrated that the Terres Noires Formation preserves a subtle magnetic lineation related to tectonic transport direction. In the Southern Subalpine Chains (Diois, Devoluy, Embrunais, Digne nappe), similar magnetic fabrics have been found. The shape of the magnetic fabric is oblate and locally mirrors the gradient of deformation in the Embrunais footwall. The magnetic foliation is parallel to the bedding or to the slaty cleavage. About 50% of the magnetic lineations have down-dip magnetic directions while the other magnetic lineations are sub-horizontal or parallel to the intersection bedding/cleavage. The tectonic magnetic fabrics recorded in the Embrunais confirm the ability of the Terres Noires to record tectonic transport direction. The magnetic fabric geometry suggests SW-directed tectonic transport in the Southern Subalpine Chains. The Diois appears as a tip zone where transport directions are abruptly clockwise rotated from NW-directed in the Northern Subsalpine Chains to SW-directed. The magnetic fabric from the Digne nappe exhibits a fan pattern of transport directions in close agreement with the arcuate shape of the thrust.

The Ivory Coast-Ghana (ICG) marginal ridge is a prominent feature of the ICG transform margin and includes a fossil ridge partially buried by a thick, undeformed sedimentary cover. The fossil ICG ridge is 130 km long and 25 km wide, and towers over the adjacent rifted basin (deep Ivorian basin, DIB) and the oceanic crust by 1.3 km and more than 4 km, respectively. It formed in three successive stages. 1. (1) During the rifting of the DIB, both vertical and horizontal motions between the DIB and the South American plate varied along the plate boundary. This relative motion occurred in an accommodation zone that tilted the northern slope of the ICG ridge along en-echelon, mainly strike-slip, faults. 2. (2) After the rifting of the DIB, the relative motion remained constant along the transform plate boundary. At this time strike-slip deformation was localized into a narrow and highly deformed belt that truncated the accommodation zone. 3. (3) Finally, the transform motion occurred between the DIB and an occanic plate. Thermal exchanges between the two adjacent plates induced thermal uplift of the ICG ridge that amplified previous tectonic tilting.

En 1757 paraissait à Paris, « aux dépens de l’Auteur », sous le nom de Pierre-Paul Dubuisson, un Armorial des principales maisons et familles du royaume, particulièrement de celles de Paris et de l’Isle de France, contenant les armes des princes, seigneurs, grands officiers de la couronne & de la Maison du Roi, celles des cours souveraines, &c. avec l’explication de tous les blasons, en deux petits volumes in-12° à pagination multiple. Ce véritable « Bottin mondain » de la seconde moitié du x...

Detailed study of microfaults and associated striated fault planes affecting the Early Cretaceous infilling of Rio do Peixe basins (northeast Brazil) allows us to determine a regional stress field with a NNW-SSE oriented extensional component. In the basement, reactivated E-W and NE-SW ductile shear zones of Pan-African age both controlled the architecture and elongation of the basins. These en-echelon half-grabens illustrate the first stages of intracontinental rifting of a pre-fractured crust. During the Early Cretaceous, the northeast Brazilian province was subjected to NW-SE extension related to the eastward opening of the South Atlantic ocean.

International audience; We surveyed the junction between the central and southern Philippine Trench and the Sangihe Trench near 6øN using swath bathymetry, gravity, and magnetics. These data, along with seismicity, allow us to discuss the genetic relations between these trenches and the forces acting on converging plates. Our final model favors the northern extension of the Halmahera Arc up to 8øN, with three segments offset left-laterally along NW-SE transform faults. Accretion of the northern segment to Mindanao Island 4 to 5 m.y. ago resulted in the failure within the Philippine Sea Plate east of the arc. Initiation of the Philippine Trench between 7øN and 10øN agrees with the maximum recorded depth of the Philippine Trench floor (10,000 m below sea-level) and Philippine Sea slab (200 km). South of 6øN (trench junction), another segment of the arc is being subducted beneath the Sangihe margin, while south of 3øN, the southern segment of the Halmahera Arc is still active. The rapid southward shallowing of the trench floor along the southern Philippine Trench, the type of faulting affecting both sides of the trench, the lack of significant interplate seismicity, and the concentration of the seismicity beneath the Miangas-Talaud Ridge are interpreted as a slowing down of the subduction along this branch of the Philippine Trench compared with the rest of the subduction zone. The Sangihe deformation front has been recognized up to 7øN but seems active only south of 6øN.

Popoff Michel. Un armorial de la Cour des monnoyes 1641-1787. In: Revue numismatique, 6e série - Tome 152, année 1997 pp. 291-332.

L'arc de Castellane est un arc satellite de l'arc des Alpes occidentales. Il s'étend entre Digne, au nord et les Baous de Saint-Jeannet, au sud-est. Il se compose d'une branche occidentale de direction méridienne et d'une branche orientale orientée est-ouest. Notre travail concerne essentiellement la branche occidentale qui borde, à l'ouest, le bassin sédimentaire mio-pliocene de Digne-Valensole. Cette branche se caractérise en outre par la présence d'accidents sub-méridiens dont les principaux ont servi de guide a la progression vers le S-SW de la nappe de Digne qui représente l'élément majeur de cet arc. Ainsi nous montrons tout au long de notre travail combien l'héritage est important dans la structuration de l'arc de Castellane et précisons les modalités et les ages de cette structuration sur la branche occidentale; pas de résumé