Neurons are MHC Class I-Dependent Targets for CD8 T Cells upon Neurotropic Viral Infection

Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage

rec. a Registrum Petri Diaconi (Montecassino, Archivio dell’Abbazia, Reg. 3), edizione a cura di J.-M. Martin, P. Chastang, E. Cuozzo, L. Feller, G. Orofino, A. Thomas, M. Villani, 4 volumi, Istituto Storico italiano per il Medioevo (Fonti per la storia dell’Italia medievale, Antiquitates 45) 978-88-98079-24-7, Roma 2015

Studies on the relative contribution of inter- and intra-population trait variations in broad-niched species along edaphic gradients are still scarce. Here, we explore the variation of eight traits in five populations of Cyanotis longifolia, a broad-niched metallophyte thriving on very broad gradients of soil copper concentration in Central Africa. Variation at species level was decomposed into covariation with copper, variation among sites, and residual variation. The proportion of the variance explained by the site and by the local copper gradient in each site ranged from 10 to 32% and between 5 and 51% respectively, depending on trait. At the species level, specific leaf area decreased and leaf Cu and Co concentrations increased with increasing soil Cu concentration. Surprisingly, traits related to plant size show a quadratic response with higher values on both high and low soil Cu concentrations. This could be accounted for by population-specific patterns of covariation with soil copper. Population specific traits responses were found, with some populations exhibiting no significant response while the others sometimes show opposing variation patterns. The reasons for such idiosyncratic patterns are discussed in terms of interactions with other soil factors influencing Cu availability and toxicity. In further studies on trait variation along toxicity gradients, we recommend to investigate the small scale edaphic variability and to measure traits at the population level to capture the diversity of functional responses.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Changing provenance of the early Cretaceous rift and sag-related sediments of the Congo basin: Combining detrital zircon and apatite U-Th-Pb geochronology approach

International audienceThis study provides the first detrital zircon and apatite U-Th-Pb geochronology on the Berriasian prerift, Barremian synrift, and Aptian sag strata of the Congo basin, with the goal to reconstruct sediment provenance and relief evolution of the central South-Atlantic rifted- margin during the Early Cretaceous. Detrital zircons from 6 samples and detrital apatites from 3 samples collected from exploration wells and outcrops were analyzed for U-Th-Pb dating (LA-ICPMS). Six populations have been obtained: (1) Carboniferous- Permian, (2) Late Neoproterozoic-Ordovician, (3) early Neoproterozoic, (4) Mesoproterozoic, (5) Paleoproterozoic and (6) Archean.The Berriasian prerift strata contain six populations of zircon (1 to 6) and five populations of apatite (1 to 5), interpreted as derived from various source terranes (e.g. Gondwanide, Brasiliano and Transamazonian orogenic belts) in South-America plate. This result implies a mixing of sediments from several distinct source regions and a long-distance transport, that is consistent with the deposition in a gentle proto-rift sag basin with a low relief.Detrital zircon and apatite suites of Barremian synrift strata clearly contrast with those from prerift strata. These synrift strata contains three populations of zircons (4 to 6) and three populations of apatites (2, 3 and 5), which are consistent with local sediment sourcing from the marginal West-Congo belt, which was uplifted and exhumed along the rift flank. This imply a major change in provenance and a reorganization of the drainage pattern in response to fault bloc-tilting and rift-shoulder development during the Barremian main phase of the South- Atlantic rifting, resulting in the formation of significant topography relief.Four samples from the Aptian sag strata yielded different age distributions, reflecting spatial and temporal changes in sediment provenance within the same stratigraphy unit. However, these populations also indicate local sediment sourcing from the West-Congo belts, implying no significant change in sediment provenance between the main rift phase and rift-drift transition phase. The different age distributions obtained for the Sag strata can be ascribed to the heterogeneity of the source terranes and to the occurrence of multiple catchment systems with small drainage areas.This work emphasizes the importance of combining detrital zircon and apatite U-Th-Pb geochronology data for sediment provenance analyzing

Substrate area confinement is a key determinant of cell velocity in collective migration

Collective cell migration is fundamental throughout development, during wound healing and in many diseases. Although much effort has focused on cell–cell junctions, a role for physical confinement in collective cell migration remains unclear. Here, we used adhesive microstripes of varying widths to mimic the spatial confinement experienced by follower cells within epithelial tissues. Our results reveal that the substrate area confinement is sufficient to modulate the three-dimensional cellular morphology without the need for intercellular adhesive cues. Our findings show a direct correlation between the migration velocity of confined cells and their cell–substrate adhesive area. Closer examination revealed that adhesive area confinement reduces lamellipodial protrusive forces, decreases the number of focal complexes at the leading edge and prevents the maturation of focal adhesions at the trailing edge, together leading to less effective forward propelling forces. The release of follower confinement required for the emergence of leader cells is associated with a threefold increase in contractile stress and a tenfold increase in protrusive forces, together providing a sufficient stress to generate highly motile mesenchymal cells. These findings demonstrate that epithelial confinement alone can induce follower-like behaviours and identify substrate adhesive area confinement as a key determinant of cell velocity in collective migration

Timed use of digoxin prevents heart ischemia-reperfusion injury through a REV-ERBα-UPS signaling pathway

International audienceMyocardial ischemia–reperfusion injury (MIRI) induces life-threatening damages to the cardiac tissue, and pharmacological means to achieve cardioprotection are sorely needed. MIRI severity varies along the day–night cycle and is molecularly linked to components of the cellular clock, including the nuclear receptor REV-ERBα, a transcriptional repressor. Here we show that digoxin administration in mice is cardioprotective when timed to trigger REV-ERBα protein degradation. In cardiomyocytes, digoxin increases REV-ERBα ubiquitinylation and proteasomal degradation, which depend on REV-ERBα’s ability to bind its natural ligand, heme. Inhibition of the membrane-bound Src tyrosine-kinase partially alleviated digoxin-induced REV-ERBα degradation. In untreated cardiomyocytes, REV-ERBα proteolysis is controlled by several E3 ubiquitin ligases and the proteasome subunit PSMB5. Among these, only SIAH2 and PSMB5 contributed to digoxin-induced degradation of REV-ERBα. Thus, controlling REV-ERBα proteostasis through the ubiquitin–proteasome system is an appealing cardioprotective strategy. Our data support the timed use of clinically approved cardiotonic steroids in prophylactic cardioprotection

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Comparison of Immediate With Delayed Stenting Using the Minimalist Immediate Mechanical Intervention Approach in Acute ST-Segment-Elevation Myocardial Infarction: The MIMI Study.

International audienceDelayed stent implantation after restoration of normal epicardial flow by a minimalist immediate mechanical intervention aims to decrease the rate of distal embolization and impaired myocardial reperfusion after percutaneous coronary intervention. We sought to confirm whether a delayed stenting (DS) approach (24-48 hours) improves myocardial reperfusion, versus immediate stenting, in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention.In the prospective, randomized, open-label minimalist immediate mechanical intervention (MIMI) trial, patients (n=140) with ST-segment-elevation myocardial infarction ≤12 hours were randomized to immediate stenting (n=73) or DS (n=67) after Thrombolysis In Myocardial Infarction 3 flow restoration by thrombus aspiration. Patients in the DS group underwent a second coronary arteriography for stent implantation a median of 36 hours (interquartile range 29-46) after randomization. The primary end point was microvascular obstruction (% left ventricular mass) on cardiac magnetic resonance imaging performed 5 days (interquartile range 4-6) after the first procedure. There was a nonsignificant trend toward lower microvascular obstruction in the immediate stenting group compared with DS group (1.88% versus 3.96%; P=0.051), which became significant after adjustment for the area at risk (P=0.049). Median infarct weight, left ventricular ejection fraction, and infarct size did not differ between groups. No difference in 6-month outcomes was apparent for the rate of major cardiovascular and cerebral events.The present findings do not support a strategy of DS versus immediate stenting in patients with ST-segment-elevation infarction undergoing primary percutaneous coronary intervention and even suggested a deleterious effect of DS on microvascular obstruction size.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01360242