Deciphering an isolated lung phenotype of NKX2-1 frameshift pathogenic variant

Backgroundto perform a functional analysis of a new NK2 homeobox 1 (NKX2-1) variant (c.85_86del denominated NKX2-1DEL) identified in a family presenting with isolated respiratory disease, in comparison to another frameshift variant (c.254dup denominated NKX2-1DUP) identified in a subject with classical brain-lung-thyroid syndrome.Methodspathogenic variants were introduced into the pcDNA3-1(+)-wt-TTF1 plasmid. The proteins obtained were analyzed by western blot assay. Subcellular localization was assessed by confocal microscopy in A549 and Nthy cells. Transactivation of SFTPA, SFTPB, SFTPC, and ABCA3 promoters was assessed in A549 cells. Thyroglobulin promoter activity was measured with the paired box gene 8 (PAX8) cofactor in Nthy cells.ResultsThe two sequence variants were predicted to produce aberrant proteins identical from the 86th amino acid, with deletion of their functional homeodomain, including the nuclear localization signal. However, 3D conformation prediction of the conformation prediction of the mutant protein assumed the presence of a nuclear localization signal, a bipartite sequence, confirmed by confocal microscopy showing both mutant proteins localized in the nucleus and cytoplasm. Transcriptional activity with SFTPA, SFTPB, SFTPC, ABCA3 and thyroglobulin promoters was significantly decreased with both variants. However, with NKX2-1DEL, thyroglobulin transcriptional activity was maintained with the addition of PAX8.ConclusionThese results provide novel insights into understanding the molecular mechanism of phenotypes associated with NKX2-1 pathogenic variants

Multidisciplinary investigation on cold seeps with vigorous gas emissions in the Sea of Marmara (MarsiteCruise): Strategy for site detection and sampling and first scientific outcome

MarsiteCruise was undertaken in October/November 2014 in the Sea of Marmara to gain detailed insight into the fate of fluids migrating within the sedimentary column and partially released into the water column. The overall objective of the project was to achieve a more global understanding of cold-seep dynamics in the context of a major active strike-slip fault. Five remotely operated vehicle (ROV) dives were performed at selected areas along the North Anatolian Fault and inherited faults. To efficiently detect, select and sample the gas seeps, we applied an original procedure. It combines sequentially (1) the acquisition of ship-borne multibeam acoustic data from the water column prior to each dive to detect gas emission sites and to design the tracks of the ROV dives, (2) in situ and real-time Raman spectroscopy analysis of the gas stream, and (3) onboard determination of molecular and isotopic compositions of the collected gas bubbles. The in situ Raman spectroscopy was used as a decision-making tool to evaluate the need for continuing with the sampling of gases from the discovered seep, or to move to another one. Push cores were gathered to study buried carbonates and pore waters at the surficial sediment, while CTD-Rosette allowed collecting samples to measure dissolved-methane concentration within the water column followed by a comparison with measurements from samples collected with the submersible Nautile during the Marnaut cruise in 2007. Overall, the visited sites were characterized by a wide diversity of seeps. CO2- and oil-rich seeps were found at the westernmost part of the sea in the Tekirdag Basin, while amphipods, anemones and coral populated the sites visited at the easternmost part in the Cinarcik Basin. Methane-derived authigenic carbonates and bacterial mats were widespread on the seafloor at all sites with variable size and distributions. The measured methane concentrations in the water column were up to 377 μmol, and the dissolved pore-water profiles indicated the occurrence of sulfate depleting processes accompanied with carbonate precipitation. The pore-water profiles display evidence of biogeochemical transformations leading to the fast depletion of seawater sulfate within the first 25-cm depth of the sediment. These results show that the North Anatolian Fault and inherited faults are important migration paths for fluids for which a significant part is discharged into the water column, contributing to the increase of methane concentration at the bottom seawater and favoring the development of specific ecosystems

Les réseaux de la réforme sociale à Genève autour des années 1900

À travers le cas de la philanthropie genevoise au début du xxe siècle, cet article revient sur le lien entre action bienfaisante et cohésion sociale. Fondée sur une source publiée en 1903, l’Annuaire philanthropique genevois, qui recense les œuvres charitables et leurs membres, l’analyse de réseau permet d’identifier de manière systématique les liens qui existent entre les institutions et les acteurs qui constituent le champ de la philanthropie et, partant, de restituer une vision globale du milieu réformateur genevois. Nous montrons que ce réseau s’articule autour d’une partie centrale et cohésive, qui lie entre elles des œuvres qui poursuivent des ambitions de réforme sociale similaires, caractérisées par une prise en charge individuelle. À l’inverse, la majorité des œuvres qui permettent aux individus de faire face collectivement aux risques sont isolées dans le réseau.This article examines the relationship between philanthropic action and social cohesion by examining the case of Geneva at the beginning of the 20th century. Our research is based on a philanthropic directory published in 1903 which lists Geneva’s charitable organizations and their members. Network analysis of this source allowed us to systematically identify the ties that existed between the different institutions and actors of the philanthropic sphere, thus making it possible to get a complete picture of Geneva’s reformist circles. We show that this network was based around a central, cohesive core which tied together different organizations with similar ambitions for social reform based on individual advocacy. Conversely, most of the charities that allowed individuals to respond collectively to risks were isolated in the network

Allaitement maternel et xénobiotiques de l'environnement

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

BCGite généralisée (à propos d'un cas clinique)

Le cancer de vessie est au onzième rang des cancers chez l'homme. Le principal facteur de risque est le tabagisme. Les tumeurs superficielles de vessie représentent 70 à 80% des cancers vésicaux. Elles se caractérisent par leur potentiel de récidive et de progression. La BCGthérapie intravésicale est le traitement de référence des carcinomes urothéliaux à haut risque de récidive et de progression depuis les années 70. Cette thérapie est entachée par des complications souvent peu sévères et locales, mais aussi graves réalisant une réaction d'hypersensibilité retardée ou une dissémination bactérienne pouvant mettre en jeu le pronostic vital et appelée " BCGite généralisée ". Il n'existe pas à l'heure actuelle de consensus sur les doses de BCG et les schémas instillatoires. L'avenir de la BCGthérapie est à la biologie moléculaire et à une approche thérapeutique individualisée afin d'optimiser son activité anti-tumorale tout en diminuant les effets indésirables.The bladder cancer is in the ninth row of cancers in the world. The main risk factor is tobacco. Superficial bladder tumours represent 70 at 80% of bladder cancers. They are distinguished by their potential of recurrence and progression. The BCGtherapy is the reference treatment of transitional cell carcinoma of the bladder with high risk of recurrence and progression disease since the seventies. This treatment is soiled by some complications mainly not very severe and local but also serious realizing a delayed hypersensitivity reaction or a sepsis which can impaired vital prognosis, and called "Generalized BCGitis". There is not at the present time a consensus as regards doses of BCG and therapeutic schedules. The BCGtherapy's future belong to molecular biology and to an individualized therapeutic approach in order to optimize the antitumoural activity while decreasing the adverse effects.PARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Improving transcriptome de novo assembly by using a reference genome of a related species: Translational genomics from oil palm to coconut.

The palms are a family of tropical origin and one of the main constituents of the ecosystems of these regions around the world. The two main species of palm represent different challenges: coconut (Cocos nucifera L.) is a source of multiple goods and services in tropical communities, while oil palm (Elaeis guineensis Jacq) is the main protagonist of the oil market. In this study, we present a workflow that exploits the comparative genomics between a target species (coconut) and a reference species (oil palm) to improve the transcriptomic data, providing a proteome useful to answer functional or evolutionary questions. This workflow reduces redundancy and fragmentation, two inherent problems of transcriptomic data, while preserving the functional representation of the target species. Our approach was validated in Arabidopsis thaliana using Arabidopsis lyrata and Capsella rubella as references species. This analysis showed the high sensitivity and specificity of our strategy, relatively independent of the reference proteome. The workflow increased the length of proteins products in A. thaliana by 13%, allowing, often, to recover 100% of the protein sequence length. In addition redundancy was reduced by a factor greater than 3. In coconut, the approach generated 29,366 proteins, 1,246 of these proteins deriving from new contigs obtained with the BRANCH software. The coconut proteome presented a functional profile similar to that observed in rice and an important number of metabolic pathways related to secondary metabolism. The new sequences found with BRANCH software were enriched in functions related to biotic stress. Our strategy can be used as a complementary step to de novo transcriptome assembly to get a representative proteome of a target species. The results of the current analysis are available on the website PalmComparomics (http://palm-comparomics.southgreen.fr/)