H008 Le blocage des récepteurs AT1 de L′angiotensine II inhibe L′hypertrophie ventriculaire gauche et L′activation de FHL1 chez la souris hétérozygote déficiente en cMyBP-C

Les mutations de la protéine C cardiaque (cMyBP-C) sont une cause de cardiomyopathies hypertrophiques (CMH). Les souris transgéniques hétérozygotes défi cientes en cMyBP-C (HET) présentent une CMH d′apparition tardive à fonction systolique conservée. Le système rénine angiotensine (SRA) cardiaque joue un rôle important dans l′hypertrophie, mais son rôle dans le développement d′une CMH génétiquement déterminée a été peu étudié.Cette étude évaluait le rôle du SRA dans l′induction de la CMH chez la souris HET. Des souris HET et sauvages (WT), âgées de 5 mois, ont été traitées par irbésartan (50mg/kg/jour) ou placebo pendant 8 semaines. L′expression dans le ventricule gauche (VG) des gènes de l′enzyme de conversion de l′angiotensine I (ACE), du récepteur AT1 de l′angiotensine II (AGTR1), de la calcineurine A (PPP3CB) de la calcipressin 1 (RCAN1), et de FHL1 (four and a half LIM domains 1, une protéine associée à cMyBP-C au sein du sarcomère) a été analysée par RT-qPCR.Après 8 semaines de traitement, la pression artérielle est normale dans tous les groupes. Le poids du VG/poids du corps des souris HET est augmenté par rapport aux WT (3,9±0,3 vs. 3,3±0,4mg/g; p<0.01) dans le groupe placebo. Dans les groupes traités par irbésartan, ce rapport est comparable pour les souris HET (3,4±0,5mg/g) et WT (3,2±0,4mg/g; p=ns). L′expression des gènes de l′ACE, PPP3CB et RCAN1 est comparable entre les souris HET et WT et n′est pas affectée par le traitement par irbésartan. L′expression d′AGTR1 est similaire chez les souris HET et WT traitées par placebo mais augmente après traitement par irbésartan uniquement chez les souris HET. A l′inverse, l′expression de FHL1 est activée chez les souris HET par rapport aux souris WT mais cette augmentation est prévenue par le traitement par irbésartan.En conclusion, chez la souris cMyBP-C, le développement de l′hypertrophie est accompagné par une augmentation de l′expression du gène FHL1 dans le VG. Le traitement par irbésartan inhibe l′hypertrophie et l′activation de l′expression de FHL1 don′t le mécanisme reste à déterminer

Implicating Calpain in Tau-Mediated Toxicity In Vivo

Alzheimer's disease and other related neurodegenerative disorders known as tauopathies are characterized by the accumulation of abnormally phosphorylated and aggregated forms of the microtubule-associated protein tau. Several laboratories have identified a 17 kD proteolytic fragment of tau in degenerating neurons and in numerous cell culture models that is generated by calpain cleavage and speculated to contribute to tau toxicity. In the current study, we employed a Drosophila tauopathy model to investigate the importance of calpain-mediated tau proteolysis in contributing to tau neurotoxicity in an animal model of human neurodegenerative disease. We found that mutations that disrupted endogenous calpainA or calpainB activity in transgenic flies suppressed tau toxicity. Expression of a calpain-resistant form of tau in Drosophila revealed that mutating the putative calpain cleavage sites that produce the 17 kD fragment was sufficient to abrogate tau toxicity in vivo. Furthermore, we found significant toxicity in the fly retina associated with expression of only the 17 kD tau fragment. Collectively, our data implicate calpain-mediated proteolysis of tau as an important pathway mediating tau neurotoxicity in vivo

Late local glacial maximum in the Central Altiplano triggered by cold and locally-wet conditions during the paleolake Tauca episode (17–15 ka, Heinrich 1)

The timing and causes of the last deglaciation in the southern tropical Andes is poorly known. In the Central Altiplano, recent studies have focused on whether this tropical highland was deglaciated before, synchronously or after the global last glacial maximum (~ 21 ka BP). In this study we present a new chronology based on cosmogenic ^3He (^3He_c) dating of moraines on Cerro Tunupa, a volcano that is located in the centre of the now vanished Lake Tauca (19.9°S, 67.6°W). These new ^3He_c ages suggest that the Tunupa glaciers remained close to their maximum extent until 15 ka BP, synchronous with the Lake Tauca highstand (17–15 ka BP). Glacial retreat and the demise of Lake Tauca seem to have occurred rapidly and synchronously, within dating uncertainties, at ~15 ka BP. We took advantage of the synchronism of these events to combine a glacier model with a lake model in order to reconstruct precipitation and temperature during the Lake Tauca highstand. This new approach indicates that, during the Tauca highstand (17–15 ka BP), the centre of the Altiplano was characterized by temperature ~ 6.5 °C cooler and average precipitation higher by a factor ranging between ×1.6 and ×3 compared to the present. Cold and wet conditions thus persisted in a significant part of the southern tropical Andes during the Heinrich 1 event (17–15 ka BP). This study also demonstrates the extent to which the snowline of glaciers can be affected by local climatic conditions and emphasizes that efforts to draw global climate inferences from glacial extents must also consider local moisture conditions

The CREp program and the ICE-D production rate calibration database: A fully parameterizable and updated online tool to compute cosmic- ray exposure ages

International audienc

Be-10-derived Himalayan denudation rates and sediment budgets in the Ganga basin

The Himalayas represent the archetype of mountain building due to active continental collision and are considered in many studies as the locus of intense interactions between climate, denudation and tectonics. Estimates of modern denudation rates across the entire range remain, however, relatively sparse. In this study, in situ-produced cosmogenic Be-10 concentrations were measured in detritic quartz in order to determine basin-scale denudation rates for the central part of the Himalayan range. River sand was sampled over several years in the main trans-Himalayan rivers, from the Himalayan front to the Ganga outlet in Bangladesh. The calculated Be-10 denudation rates of the trans-Himalayan river basins range from 0.5 to 2.4 mm yr(-1) (average 1.3 mm yr(-1)) and vary by up to a factor of 3 between sampling years. These denudation rates strongly contrast with the 0.007 mm yr(-1) denudation rate of southern tributary basins draining the Indian craton. This work also shows that in the Ganga basin, no systematic evolution of average Be-10 concentrations is observed during floodplain transfer, implying that distal samples can be used to estimate the integrated denudation rate of the whole central Himalayan range. Samples from the Ganga in Bangladesh display remarkably low variability in Be-10 concentration, implying an average Himalayan denudation rate of 1.0-1.1 mm yr(-1). However, within the floodplain, several samples suggest a recent perturbation of sediment transport dynamics with a recent increase in the relative sediment contribution from southern tributaries. The Himalayan sediment flux, deduced from the Be-10 denudation rate of the range, is 610 +/- 230 Mt yr(-1). This flux is consistent, within uncertainty, with sediment fluxes derived from sediment gauging. The similarity of the two flux estimates suggests that Himalayan erosion fluxes have remained stable over the last centuries, even if the large uncertainties associated with each method hamper more precise assessments

Progressive glacial retreat in the Southern Altiplano (Uturuncu volcano, 22 degrees S) between 65 and 14 ka constrained by cosmogenic He-3 dating

This work presents the first reconstruction of late Pleistocene glacier fluctuations on Uturuncu volcano, in the Southern Tropical Andes. Cosmogenic(3)He dating of glacial landforms provides constraints on ancient glacier position between 65 and 14 ka. Despite important scatter in the exposure ages on the oldest moraines, probably resulting from pre-exposure, these He-3 data constrain the timing of the moraine deposits and subsequent glacier recessions: the Uturuncu glacier may have reached its maximum extent much before the global LGM, maybe as early as 65 ka, with an equilibrium line altitude (ELA) at 5280 m. Then, the glacier remained close to its maximum position, with a main stillstand identified around 40 ka, and another one between 35 and 17 ka, followed by a limited recession at 17 ka. Then, another glacial stillstand is identified upstream during the late glacial period, probably between 16 and 14 ka, with an ELA standing at 5350 m. This stillstand is synchronous with the paleolake Tauca highstand. This result indicates that this regionally wet and cold episode, during the Heinrich 1 event, also impacted the Southern Altiplano. The ELA rose above 5450 m after 14 La, synchronously with the Bolling-Allerod

Paleo-erosion rates in Central Asia since 9 Ma: A transient increase at the onset of Quaternary glaciations?

Erosion is a fundamental player of the interactions existing between internal geodynamics and climate, in particular through its influence on the carbon dioxide budget. However, long term (> Ma) erosion rates, estimated indirectly from sediment budget, remain poorly constrained. While some studies suggest that worldwide erosion rates increased at the Plio-Pleistocene climatic transition (~4–2 Ma), the validity of this observation and its significance is a matter of debate due to potential biases of the sedimentary record and to the influence of sea level fall on the global sedimentary flux to marginal basins. In the present study, we estimate erosion rates over the last ~9 Ma using in situ produced cosmogenic ^(10)Be concentrations measured in magnetostratigraphically dated continental sediments. We focus on an intracontinental endorheic watershed draining the northern Tianshan in Central Asia, a key region regarding the ongoing debate. While erosion rates between 0.1 and 1 mm·yr^(−1) are derived from most of our record, they reach values as high as ~2.5 mm·yr^(−1) from 2.5 to 1.7 Ma. Then, after 1.7 Ma, recent andmodern erosion rates fell below 1 mm·yr^(−1). This temporary increase is correlated with the onset of Quaternary ice ages and suggests that global climate had a significant and transient impact on erosion