Toxines et Transferts ioniques

Collection Rencontres en Toxinologie, ISSN 1760-6004 ; http://sfet.asso.fr/international/images/stories/SFET/pdf/Ebook-RT19-2011-signets.pdfInternational audienc

Identification of a stable complex between a [NiFe]‐hydrogenase catalytic subunit and its maturation protease

Salmonella enterica serovar Typhimurium has the ability to use molecular hydrogen as a respiratory electron donor. This is facilitated by three [NiFe]‐hydrogenases termed Hyd‐1, Hyd‐2, and Hyd‐5. Hyd‐1 and Hyd‐5 are homologous oxygen‐tolerant [NiFe]‐hydrogenases. A critical step in the biosynthesis of a [NiFe]‐hydrogenase is the proteolytic processing of the catalytic subunit. In this work, the role of the maturation protease encoded within the Hyd‐5 operon, HydD, was found to be partially complemented by the maturation protease encoded in the Hyd‐1 operon, HyaD. In addition, both maturation proteases were shown to form stable complexes, in vivo and in vitro, with the catalytic subunit of Hyd‐5. The protein–protein interactions were not detectable in a strain that could not make the enzyme metallocofactor

Interactions climat-calotte durant la greenhouse Crétacé-Paléogène (120-34 Ma) : influence de la paléogéographie et du CO2 atmosphérique

On geological timescales, global climate proxies indicate that variations of large magnitude occur between the Cretaceous and the Cenozoic. On the long term, these variations are mostly determined by the equilibrium between the greenhouse gases composition of the atmosphere, primarily the CO2, and continental weathering set up by the spatial location of Earth’s landmasses. Here, the links between paleogeography and CO2 are looked upon in a climate-ice sheet interactions framework during a greenhouse period of Earth history (120 – 34 Ma). A suite of models involving both coupled and ice sheet models have been used to demonstrate that paleogeographic reorganizations have regulated the presence of ice over Antarctica during the Cretaceous. In a second time and using a similar setup, a new method for climate-ice sheet coupling have been developed and applied to the Eocene-Oligocene (EO) glaciation to yield a new scenario of ice evolution, in good agreement with data. Two feedbacks related to this glaciation and the coeval atmospheric CO2 fall are investigated. First, it is shown that the EO glaciation generates an intensification of the Antarctic Circumpolar Current. Second, within a data-model study demonstrating active Asian monsoons as old as the mid-Eocene, it is shown that the climatic change at the end of the Eocene is responsible for a reduction in the intensity of the Asian monsoon. Finally, with the aim of analysing the effect of paleogeographic changes on marine biogeochemistry during the Cenozoic, sensitivity tests to Drake Passage and Panama Seaway have been carried out.Les enregistrements climatiques globaux à l’échelle géologique entre le Crétacé et le début du Cénozoïque indiquent des variations de grande amplitude. Sur le long terme, celles-ci sont déterminées par l’équilibre entre la composition atmosphérique en gaz à effet de serre, principalement le CO2, issus du dégazage volcanique et l’altération continentale, modulée par les mouvements tectoniques des continents. Dans cette thèse, les liens entre paléogéographie et CO2 ont été étudiés dans le contexte des interactions entre climat et calottes de glace au cours d’un intervalle de temps dit de « greenhouse », entre 120 et 34 Ma. L’utilisation d’une suite de modèles impliquant un modèle couplé moyenne résolution, un modèle atmosphérique haute résolution et un modèle de calotte de glace, a permis de montrer que les changements paléogéographiques survenant au Crétacé ont régulé la présence de glace en Antarctique. Dans un second temps, une nouvelle méthode de couplage climat-calotte a été développée pour étudier la glaciation Eocène-Oligocène. Ces développements ont permis de reconstruire une évolution fidèle de celle-ci, en bon accord avec les données. Deux rétroactions liées à cette glaciation et à la chute concomitante du CO2 atmosphérique sont étudiées. En premier lieu, l’impact de la glaciation sur le Courant Circumpolaire Antarctique est abordé, montrant que celle-ci génère une intensification de ce courant. Ensuite, au sein d’une étude mêlant données et modèles pour documenter la présence de moussons en Asie dès l’Eocène moyen, il est montré que le changement climatique de la fin de l’Eocène induit une baisse d’intensité de la mousson asiatique. Enfin, dans la perspective d’analyser les conséquences des changements paléogéographiques du Cénozoïque sur la biogéochimie marine, des tests de sensibilité aux passages océaniques de Panama et de Drake ont été réalisés

Rather First in a Village than Second in Rome? The Effect of Students' Class Rank in Primary School on Subsequent Academic Achievements

Using panel data on Italian students from 2013 to 2019, we compare the effect of a student's class rank to the effect of class quality in primary school on subsequent academic outcomes. We propose a new strategy to identify the impact of rank while controlling for peer effects, by leveraging grades on class exams to construct the rank, and grades on national standardized tests to control for students' ability. Ranking first in primary school compared to last results in an improvement of 8.1 percentiles in the national standardized test grade distribution in middle school and 7.6 percentiles in high school. Despite the sizable impact of rank, our analysis highlights that a one standard deviation increase in class quality is five-fold greater than a similar increase in rank. Finally, using an extensive student survey, we establish that the rank effect is channeled through sorting into better high schools and psychological mechanisms

Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis

This document is the Accepted Manuscript version of the following article: Riessland et al., 'Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis', The American Journal of Human Genetics, Vol. 100 (2): 297-315, first published online 26 January 2017. The final, published version is available online at doi: http://dx.doi.org/10.1016/j.ajhg.2017.01.005 © 2017 American Society of Human Genetics.Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss. However, rarely individuals with homozygous absence of SMN1 and only three to four SMN2 copies are fully asymptomatic, suggesting protection through genetic modifier(s). Previously, we identified plastin 3 (PLS3) overexpression as an SMA protective modifier in humans and showed that SMN deficit impairs endocytosis, which is rescued by elevated PLS3 levels. Here, we identify reduction of the neuronal calcium sensor Neurocalcin delta (NCALD) as a protective SMA modifier in five asymptomatic SMN1-deleted individuals carrying only four SMN2 copies. We demonstrate that NCALD is a Ca(2+)-dependent negative regulator of endocytosis, as NCALD knockdown improves endocytosis in SMA models and ameliorates pharmacologically induced endocytosis defects in zebrafish. Importantly, NCALD knockdown effectively ameliorates SMA-associated pathological defects across species, including worm, zebrafish, and mouse. In conclusion, our study identifies a previously unknown protective SMA modifier in humans, demonstrates modifier impact in three different SMA animal models, and suggests a potential combinatorial therapeutic strategy to efficiently treat SMA. Since both protective modifiers restore endocytosis, our results confirm that endocytosis is a major cellular mechanism perturbed in SMA and emphasize the power of protective modifiers for understanding disease mechanism and developing therapies.Peer reviewedFinal Accepted Versio

A Tethered Bilayer Assembled on Top of Immobilized Calmodulin to Mimic Cellular Compartmentalization

International audienceBACKGROUND: Biomimetic membrane models tethered on solid supports are important tools for membrane protein biochemistry and biotechnology. The supported membrane systems described up to now are composed of a lipid bilayer tethered or not to a surface separating two compartments: a "trans" side, one to a few nanometer thick, located between the supporting surface and the membrane; and a "cis" side, above the synthetic membrane, exposed to the bulk medium. We describe here a novel biomimetic design composed of a tethered bilayer membrane that is assembled over a surface derivatized with a specific intracellular protein marker. This multilayered biomimetic assembly exhibits the fundamental characteristics of an authentic biological membrane in creating a continuous yet fluid phospholipidic barrier between two distinct compartments: a "cis" side corresponding to the extracellular milieu and a "trans" side marked by a key cytosolic signaling protein, calmodulin. METHODOLOGY/PRINCIPAL FINDINGS: We established and validated the experimental conditions to construct a multilayered structure consisting in a planar tethered bilayer assembled over a surface derivatized with calmodulin. We demonstrated the following: (i) the grafted calmodulin molecules (in trans side) were fully functional in binding and activating a calmodulin-dependent enzyme, the adenylate cyclase from Bordetella pertussis; and (ii) the assembled bilayer formed a continuous, protein-impermeable boundary that fully separated the underlying calmodulin (trans side) from the above medium (cis side). CONCLUSIONS: The simplicity and robustness of the tethered bilayer structure described here should facilitate the elaboration of biomimetic membrane models incorporating membrane embedded proteins and key cytoplasmic constituents. Such biomimetic structures will also be an attractive tool to study translocation across biological membranes of proteins or other macromolecules

Changes in the high latitude Southern Hemisphere through the Eocene-Oligocene Transition:a model-data comparison

International audienceAbstract. The global and regional climate changed dramatically with the expansion of the Antarctic Ice Sheet at the Eocene–Oligocene transition (EOT). These large-scale changes are generally linked to declining atmospheric pCO2 levels and/or changes in Southern Ocean gateways such as the Drake Passage around this time. To better understand the Southern Hemisphere regional climatic changes and the impact of glaciation on the Earth's oceans and atmosphere at the EOT, we compiled a database of 10 ocean and 4 land-surface temperature reconstructions from a range of proxy records and compared this with a series of fully coupled, low-resolution climate model simulations from two models (HadCM3BL and FOAM). Regional patterns in the proxy records of temperature show that cooling across the EOT was less at high latitudes and greater at mid-latitudes. While certain climate model simulations show moderate–good performance at recreating the temperature patterns shown in the data before and after the EOT, in general the model simulations do not capture the absolute latitudinal temperature gradient shown by the data, being too cold, particularly at high latitudes. When taking into account the absolute temperature before and after the EOT, as well as the change in temperature across it, simulations with a closed Drake Passage before and after the EOT or with an opening of the Drake Passage across the EOT perform poorly, whereas simulations with a drop in atmospheric pCO2 in combination with ice growth generally perform better. This provides further support for previous research that changes in atmospheric pCO2 are more likely to have been the driver of the EOT climatic changes, as opposed to the opening of the Drake Passage