Collaboration entre recherche académique et industrie dans l'étude d'un nouveau médicament anti-ostéoporotique

L'activité de l'ostéoclaste, cellule en charge de la résorption osseuse, est soumise à différents facteurs de régulation. Parmi eux, ceux issus de la matrice, en particulier les minéraux qui en sont libérés, comme le calcium, sont déterminants. Nous avons montré que la variation de concentration en calcium dans le milieu régulait l'activité de résorption et la durée de vie des ostéoclastes. Le développement d'une nouvelle thérapeutique, le ranélate de strontium, a montré des effets cliniques très intéressants reposant sur une stimulation des activités de formation de l'os par les ostéoblastes et une modulation des activités de résorption osseuse. Sur la base de nos connaissances de la physiologie de l'ostéoclaste, en particulier des voies de signalisation calcique, et de la maîtrise de différents modèles cellulaires ostéoclastiques, une collaboration logique s'est créée entre notre laboratoire et Servier afin d'approfondir les mécanismes à l'origine des effets du ranélate de strontium sur les ostéoclastes. En quelques années, cette collaboration s'est progressivement enrichie d'autres intervenants scientifiques afin de mieux éclairer ces mécanismes. Il a ainsi été montré que le strontium interagissait probablement avec le récepteur sensible au calcium et que les voies de signalisation intracellulaires activées par le calcium et le ranélate de strontium via ce récepteur étaient différentes. Dans le cadre de cette coopération avec Servier, des échanges avec d'autres laboratoires universitaires ont été initiés, telles que la mise en commun de techniques et de connaissances. Ainsi, il a été possible de confirmer la présence du récepteur sensible au calcium sur les ostéoclastes et de montrer son rôle dans les effets du ranélate de strontium sur l'ostéoclaste.The activity of the osteoclast, the cell responsible for bone resorption, is subjected to different regulation factors. Amongst these, those issued from the matrix, particularly released minerals such as calcium, are determinants. We have shown that variations in calcium concentration in the medium regulates resorption activity and duration of the osteoclast lifespan. The development of a new therapeutic agent, strontium ranelate, has shown very interesting clinical effects reliant on the stimulation of bone formation activity by osteoblasts and modulation of bone resorption activity. From our knowledge regarding osteoclast physiology, in particular calcium signaling pathways, and the control of different osteoclast cellular models, a consequent collaboration was formed between our laboratory and Servier in order to elaborate on the effects of strontium ranelate on the osteoclast. In several years, this collaboration has been further enriched by other collaborators in order to better understand this mechanism. It has also been shown that strontium likely interacts with the calcium-sensing receptor and that the pathways of intracellular signaling pathways activated by calcium and strontium ranelate via this receptor are different. In fact, within the scope of this collaboration with Servier, exchanges with other academic laboratories were initiated and collaboration on numerous techniques became possible. Then, it has been possible to confirm the presence of the calcium-sensing receptor on the osteoclasts and to demonstrate its role in the molecular events associated with strontium ranelate's effects on the osteoclast

Belgium

The stability of rock slopes is often guided significantly by the structural geology of the rocks composing the slope. In this work, we analyse the influence of structural characteristics, and of their seismic response, on large and deep-seated rock slope failure development. The study is focused on the Tamins and Fernpass rockslides in the European Alps and on the Balta and Eagle’s Lake rockslides in the southeastern Carpathians. These case studies are compared with catastrophic rock slope failures with ascertained or very likely seismic origin in the Tien Shan Mountains. The main goal is to identify indicators for seismically induced rock slope failures based on the source zone rock structures and failure scar geometry. We present examples of failures in anti-dip slopes and along-strike rock structures that were potentially (or partially) caused by seismic triggering, and we also consider a series of mixed structural types, which are more difficult to interpret conclusively. This morpho-structural study is supported by 2D and 3D distinct element numerical models of the Balta site (with reconstructed initial mountain morphology) showing that seismic shaking typically induces deeper-seated deformation in initially ‘stable’ rock slopes. In addition, for failures partially triggered by seismic shaking, these studies can help identify the contribution of the seismic factor to slope instability. The identification of the partial seismic origin on the basis of the dynamic response of rock structures can be particularly interesting for case histories in less seismically active mountain regions (in comparison with the Andes, Tien Shan, Pamirs), such as in the European Alps and the Carpathian Mountains. 3D models were also run to simulate the full rock avalanche process, including the formation of a dam on the valley floor

2D and 3D dynamic numerical modelling of seismically induced rock slope failure

peer reviewedThe stability of rock slopes is often guided by the structural geology of the rocks composing the slope. Especially, discontinuities can significantly influence slope stability according to their orientation with respect to the one of general slope. Here, we will focus on the triggering of giant rockslides. The final goal is to identify failure characteristics allowing us to distinguish seismic trigger modes from climatic ones, notably on the basis of the source zone rock structures. This study is supported by dynamic numerical modelling. More specifically, we will present results based on a parametric numerical study, using distinct element codes designed for 2D and 3D dynamic analysis. This study was applied to the Balta rockslide in the SE Carpathian Mountains (Romania) that has been extensively studied by Mreyen et al. (2019) during the last years

Grecs et indigènes de la Catalogne à la mer Noire

Le programme de travail qui aboutit à ce livre s’inscrit dans le cadre du réseau d’excellence européen Ramses2, initié par la Maison méditerranéenne des sciences de l’homme. Une demi-douzaine de tables rondes ont réuni entre 2006 et 2008, d’un bout à l’autre de la Méditerranée (à Empúries, Aix-en-Provence, Palerme, Naples, Athènes), quelque soixante-dix chercheurs essentiellement français, italiens et espagnols, mais aussi anglais, grecs, bulgares, roumains, canadiens et russes. Il s’agissait d’étudier les rapports d’acculturation entre colons grecs et populations indigènes, en tenant compte des différences géographiques et chronologiques mais aussi de l’historiographie et des habitudes de recherche des diverses institutions. Les nombreuses communications qui ont jalonné les six tables rondes sont ici la plupart du temps précédées de textes introductifs. Une première partie, consacrée aux approches régionales, permet d’illustrer l’état de la recherche dans quelques régions choisies (autour d’Empuries, d’Himère, de Marseille, de Vélia, en Thrace et en mer Noire). La seconde partie, thématique, aborde un certain nombre de thèmes de recherche dans les régions précédentes, mais aussi dans d’autres régions du monde de la colonisation grecque. Le point de vue adopté dans ce livre est d’abord celui de la culture matérielle ; l’approche en est essentiellement archéologique. On se demandera par exemple quels sont les indices archéologiques qui permettent de dire si un site est habité par des Grecs, par des indigènes ou par une population “mixte”, et comment ces indices ont été appréciés selon les périodes et selon les régions. Beaucoup de communications présentent des synthèses régionales ou thématiques, mais une large place est faite également à des sites inédits, pour lesquels on n’a pas hésité à livrer une abondante documentation (plans, matériel de fouille). C’est en effet par le renouvellement de la documentation archéologique que nous pouvons espérer avancer dans la compréhension des rapports d’acculturation entre les colons grecs et les populations locales

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

L’audience par vidéoconférence Pli juridique – 20 avril 2023

Analyse de l'avant projet de loi portant organisation des audiences par vidéoconférence dans le cadre des procédures judiciaires (inédit

On ℓ1-symmetric distributions : a mixture approach

International audienceWe consider a class of distributions (and measures) on Mp which are symmetric with respect to the ^j-norm (i.e., V x = (xi,..., xp) g Mp, = Y)p=1 |x,-|). In our approach, we are primarily concerned with the construction of the uniform measure on the unit ^i-sphere S-{x 6 itiflSMli = !}• We can view it as a surface measure, or defined by linear functional or using geometric aspects. An ^i-symmetric distribution is a mixture of uniform distributions on the ^i-spheres of radius r centered at the origin. We give some characterizations such as the stochastic representation, the factorization of the density and the survival function. Furthermore the marginals and conditional distributions are given