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Lateral movement of lithospheric fragments along strike-slip faults in response to collision (escape tectonics) has characterized convergent settings since the onset of plate tectonics and is a mechanism for the formation of new plates. The Anatolian plate was created by the sequential connection of strike-slip faults following ≥10 m.y. of distributed deformation that ultimately localized into plate-bounding faults. Thermochronology data and seismic images of lithosphere structure near the East Anatolian fault zone (EAFZ) provide insights into the development of the new plate and escape system. Low-temperature thermochronology ages of rocks in and near the EAFZ are significantly younger than in other fault zones in the region, e.g., apatite (U-Th)/He: 11–1 Ma versus 27–13 Ma. Young apatite (U-Th)/He ages and thermal history modeling record thermal resetting along the EAFZ over the past ~5 m.y. and are interpreted to indicate thermal activity triggered by strike-slip faulting in the EAFZ as it formed as a through-going, lithosphere-scale structure. The mechanism for EAFZ formation may be discerned from S-wave velocity images from the Continental Dynamics–Central Anatolian Tectonics (CD-CAT) seismic experiment. These images indicate that thin but strong Arabian lithospheric mantle extends ~50–150 km north beneath Anatolian crust and would have been located near the present surficial location of the Bitlis-Zagros suture zone (co-located with the EAFZ in our study area) at ca. 5 Ma. Underthrusting of strong Arabian lithosphere facilitated localization of the EAFZ and thus was a fundamental control on the formation of the Anatolian plate and escape system. more...

Technical improvements at the end of the Bronze Age led to the rise of a 1rst generation of major sea powers around the Mediterranean Sea, such as Etruria in modern Italy. The Etruscan coast was the fringed by a series of large lagoons. Only one survives today: the lagoon of Orbetello. The lagoon is preserved by two subparallel sand spits that connect former Argentario island to mainland Italy, as situation that today protects it from rapid infilling. A third sand spit, in the middle of the lagoon, hosts the Etruscan city of Orbetello. Today, three canals connect the lagoon to the sea. A massive phase of eutrophication driven by the ingress of fertilizers has plagued the lagoon in late 20th Century. Eutrophication at times has spurred fish and bird kills, and the release of mercury in the water column. Major contingency plans have been implemented to fight off eutrophication, with various success. However little is known of the lagoon management and the evolution of Orbetello before the 17th century CE. Nonetheless, the wealth of the city and the health of its lagoon have been tightly related during the past three millennia. To track this coevolution, a large team of researcher has been assembled to conduct an analysis of the lagoon sediments using XRF scanning of cored sediments, SMIR, Rock Eval, hyperspectral imaging of chromatic pigments, analysis of mercury and phosphorus content, ostracods and pollen assemblages, to document the links between sediment facies, eutrophication and salinity crises, as a result of successive phases of rise and demise of lagoon management over the past three millennia. Here, we focus on the sub-bottom imaging conducted in the very shallow (< 1.5m) waters of this extensive (30 km2) lagoon. The Exail Echoes 10 000 sub-bottom profiler reveals individual layers that can be traced across the lagoon, allowing stratigraphic correlations between cores, and highlighting the environmental significance of the sedimentary facies. Acoustic imaging using a 3.5 kHz Chirp systems from Exail (Haliotis R/V) was conducted offshore to document the architecture of the sand spits protecting the lagoon. The architecture of the deposits, 14C, OSL, and U-Th dating reveal that the lagoon results from the drowning of strandplains that started forming on both side of the older, central sand spit, at the end of the postglacial transgression. Drowning accompanied the final rise in sea level over the past 6.5 ka, forming two lagoons on both sides of the central spit. These initial lagoons eventually coalesced after drowning the central sand spit. Continuation of the lagoon level rise since Antiquity led to the flooding of Bronze Age, Etruscan and Roman settlements. Sub-bottom imaging in the lagoon reveals buried structures possibly used for navigation and salinity control. Sedimentation is marked by an alternation of black, shelly organic silty clays and decimeter-thick layers of broken shells. Radiocarbon dating indicates that the cores capture up to five millennia of sedimentation, with a sharp decrease in sedimentation rates four millennia ago. more...

The expression of the Huntingtin protein, well known for its involvement in the neurodegenerative Huntington’s disease, has been confirmed in skeletal muscle. The impact of HTT deficiency was studied in human skeletal muscle cell lines and in a mouse model with inducible and muscle-specific HTT deletion. Characterization of calcium fluxes in the knock-out cell lines demonstrated a reduction in excitation–contraction (EC) coupling, related to an alteration in the coupling between the dihydropyridine receptor and the ryanodine receptor, and an increase in the amount of calcium stored within the sarcoplasmic reticulum, linked to the hyperactivity of store-operated calcium entry (SOCE). Immunoprecipitation experiments demonstrated an association of HTT with junctophilin 1 (JPH1) and stromal interaction molecule 1 (STIM1), both providing clues on the functional effects of HTT deletion on calcium fluxes. Characterization of muscle strength and muscle anatomy of the muscle-specific HTT-KO mice demonstrated that HTT deletion induced moderate muscle weakness and mild muscle atrophy associated with histological abnormalities, similar to the phenotype observed in tubular aggregate myopathy. Altogether, this study points toward the hypotheses of the involvement of HTT in EC coupling via its interaction with JPH1, and on SOCE via its interaction with JPH1 and/or STIM1. more...

International audience; BackgroundMicrobeam radiation therapy (MRT) is a treatment modality based on spatial fractionation of synchrotron generated x-rays into parallel, high dose, microbeams of a few microns width. MRT is still an under-development radiosurgery technique for which, promising preclinical results on brain tumors and epilepsy encourages its clinical transfer.PurposeA safe clinical transfer of MRT needs a specific treatment planning system (TPS) that provides accurate dose calculations in human patients, taking into account the MRT beams properties (high dose gradients, spatial fractionation, polarization effects). So far, the most advanced MRT treatment planning system, based on a hybrid dose calculation algorithm, is limited to a macroscopic rendering of the dose and does not account for the complex dose distribution inherent to MRT if delivered as conformal irradiations with multiple incidences. For overcoming these limitations, a multi-scale full Monte-Carlo calculation engine called penMRT has been developed and benchmarked against two general purpose Monte Carlo codes: penmain based on PENELOPE and Gate based on Geant4.MethodsPenMRT, is based on the PENELOPE (2018) Monte Carlo (MC) code, modified to take into account the voxelized geometry of the patients (CT-scans) and offering an adaptive micrometric dose calculation grid independent to the CT size, location and orientation. The implementation of the dynamic memory allocation in penMRT, makes the simulations feasible within a huge number of dose scoring bins. The possibility of using a source replication approach to simulate arrays of microbeams, and the parallelization using OpenMPI have been added to penMRT in order to increase the calculation speed for clinical usages. This engine can be implemented in a TPS as a dose calculation core.ResultsThe performance tests highlight the reliability of penMRT to be used for complex irradiation conditions in MRT. The benchmarking against a standard PENELOPE code did not show any significant difference for calculations in centimetric beams, for a single microbeam and for a microbeam array. The comparisons between penMRT and Gate as an independent MC code did not show any difference in the beam paths, whereas in valley regions, relative differences between the two codes rank from 1 to 7.5% which are probably due to the differences in physics lists that are used in these two codes. The reliability of the source replication approach has also been tested and validated with an underestimation of no more than 0.6% in low dose areas.ConclusionsGood agreements (a relative difference between 0 to 8%) were found when comparing calculated peak to valley dose ratio (PVDR) values using penMRT, for irradiations with a full microbeam array, with calculated values in the literature. The high-resolution calculated dose maps obtained with penMRT are used to extract differential and cumulative dose-volume histograms (DVHs) and analyze treatment plans with much finer metrics regarding the irradiation complexity. To our knowledge, these are the first high-resolution dose maps and associated DVHs ever obtained for cross-fired microbeams irradiation, which is bringing a significant added value to the field of treatment planning in spatially fractionated radiation therapy. more...

Late-onset adverse events (AEs) of anti-programmed cell death 1 (anti-PD1) antibodies have not been systematically described.The purpose was to evaluate late-onset AEs in melanoma patients treated with anti-PD1 administered for at least 2 years in a real-life setting.Patients were screened from MelBase, a French multicentric biobank dedicated to the prospective follow up of unresectable stage III or IV melanoma. The study included 119 patients who received anti-PD1 during at least 2 years from January 2013 to November 2019. Median follow up was 41.7 months (range, 25.2-57.5 months). Fifty-three patients received nivolumab and 66 patients received pembrolizumab.AEs occurred in 99 patients (83%) with a median time of 13.3 months (range, 0-53.9 months), including severe AEs (grade 3 or 4) in 30 patients (30%). Late-onset AEs, mostly grades 1 or 2, occurred in 51 (43%) patients and led to 5 (4%) hospitalizations, of which 4 were severe. Factors associated with late-onset AEs in multivariate analysis were early-onset AEs (within the first 2 years of treatment) and treatment duration (P = .02 and P = .03, respectively).Our data demonstrate the possibility of late-onset AEs occurring after 2 years of anti-PD1 therapy. Late-onset AEs appear frequently and were mostly mild or moderate. Early-onset AEs and prolonged anti-PD1 treatment may increase the risk of late-onset AEs. more...

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The immediate social context at the time of drug consumption is critical at modulating it. The neurobiological substrate of such an influence is however poorly documented. The presence of a stranger peer, naïve to the drug, has been shown to reduce recreational cocaine intake in rats with similar results in human cocaine users. Here we assessed its influence in rats having previously lost their control over drug consumption. The subthalamic nucleus (STN) has been shown to play a critical role in cocaine motivation, escalation and re-escalation, as well as compulsive drug seeking. We show here that after escalation of cocaine intake, the presence of a stranger peer drastically reduced cocaine intake. The same effect was observed after both optogenetic inhibition and high-frequency stimulation of the STN in absence of a peer. We further show that the beneficial influence of social presence is mediated via the STN.One Sentence SummaryThe presence of a stranger peer drastically decreases cocaine intake after drug escalation, as does a subthalamic optogenetic modulation. more...

This research program, involving French and Italian institutions, aims at understanding how the settling and development of the Etruscan city of Orbetello affected the environmental evolution of its lagoon, and how the evolution of the lagoon affected in turn the economics of Orbetello. In other words, to define how the life of the city has been influenced by its own impact on the lagoon. To achieve this we have followed two lines of research. One is historical, based on the analysis of iconographic, textual and archaeological archives from antiquity to the present day. The other, paleoenvironmental, is based on the analysis of sedimentary archives. The idea is to combine several investigation methods to map the dynamics of sedimentation, by means of geophysical prospecting (imaging of the sedimentary architecture using acoustic profiles) and the study of sedimentary cores. The latter allow the dating of sediments, the analysis of their biological components to reconstitute lagoon palaeoenvironments (ostracods, pollen, dinoflagellate cysts, malacofauna, composition of organic matter), and the analysis of metallic contaminants, highlighting the changes induced by lagoon management and the development of the city. more...

International audience; This research program, involving French and Italian institutions, aims at understanding how the settling and development of the Etruscan city of Orbetello affected the environmental evolution of its lagoon, and how the evolution of the lagoon affected in turn the economics of Orbetello. In other words, to define how the life of the city has been influenced by its own impact on the lagoon. To achieve this we have followed two lines of research. One is historical, based on the analysis of iconographic, textual and archaeological archives from antiquity to the present day. The other, paleoenvironmental, is based on the analysis of sedimentary archives. The idea is to combine several investigation methods to map the dynamics of sedimentation, by means of geophysical prospecting (imaging of the sedimentary architecture using acoustic profiles) and the study of sedimentary cores. The latter allow the dating of sediments, the analysis of their biological components to reconstitute lagoon palaeoenvironments (ostracods, pollen, dinoflagellate cysts, malacofauna, composition of organic matter), and the analysis of metallic contaminants, highlighting the changes induced by lagoon management and the development of the city. more...