Le temps du débat législatif

La réforme constitutionnelle de 2008, la loi organique du 15 avril 2009 et les modifications des règlements de l’Assemblée nationale et du Sénat ont instauré de nouveaux instruments de gestion du temps législatif, pour une meilleure efficacité du travail parlementaire. Mais la tentative d’un partage plus équitable du temps (entre le Gouvernement et le Parlement) s’agissant de la maîtrise de l’ordre du jour et (entre la majorité parlementaire et les autres groupes) s’agissant de la prise de parole, a partiellement échoué. En outre, les débats en séance publique sont soumis à des tempi accélérés susceptibles de nuire à la qualité de la discussion. Enfin, l’encadrement du droit d’amendement en vue de lutter contre l’obstruction reste fortement controversé.The time of legislative debate: a shared, punctuated and framed time. The 2008 constitutional reform, the 15 April 2009 law and the amendments to the procedural rules of the National Assembly and the Senate established new instruments for managing legislative time in order to produce more efficient parliamentary work. However, the attempt to create a fairer distribution of time (between Government and Parliament) in terms of control over the agenda and (between the parliamentary majority and the other groups) regarding each group’s interventions to voice opinions was only partially successful. Besides, the accelerated time frames imposed on debates in public sessions are likely to harm the quality of discussions. Finally, the regulation of the right to amendment with a view to combating obstructions remains extremely controversial

Le traité de l’Élysée et les différents domaines de la coopération franco-allemande

Le traité de l’Élysée, conclu le 22 janvier 1963 par le Général de Gaulle et le Chancelier Adenauer, a eu pour objectif politique de sceller la « réconciliation » franco-allemande/germano-française. Il ne constitue certes qu’un renforcement de la coopération, donc une étape dans la coopération progressive qui s’est instaurée entre l’Allemagne et la France depuis l’après-guerre, mais une étape décisive, au moins sur le plan symbolique. Il marque en outre l’essor d’un partenariat institutionnel au sein du « couple » franco-allemand, considéré depuis comme le moteur de la construction européenne.The purpose of the Élysée Treaty, which was signed on 22nd January 1963 by General de Gaulle and Chancellor Adenauer, was to set the seal on reconciliation between France and Germany. Although it represents, admittedly, merely a strengthening of the cooperation, and therefore a step forward in the progressive cooperation established between Germany and France in the post-war period, it is a decisive step, at least symbolically. It also signals the development of an institutional partnership between the French and German “couple”, which has been regarded as the driving force of European construction ever since

Diverse and potentially manipulative signalling with ascarosides in the model nematode C. elegans

BACKGROUND: Animals use environmental information to make developmental decisions to maximise their fitness. The nematode Caenorhabditis elegans measures its environment to decide between arresting development as dauer larvae or continuing to grow and reproduce. Worms are thought to use ascarosides as signals of population density and this signalling is thought to be a species-wide honest signal. We compared recently wild C. elegans lines’ dauer larva arrest when presented with the same ascaroside signals and in different food environments. RESULTS: We find that the hitherto canonical dauer larva response does not hold among these lines. Ascaroside molecules can, depending on the food environment, both promote and repress dauer larva formation. Further, these recently wild C. elegans lines also produce ascaroside mixtures that induce a wide diversity of dauer larva formation responses. We further find that the lines differ in the quantity and ratios of ascaroside molecules that they release. Some of the dauer larva formation responses are consistent with dishonest signalling. CONCLUSIONS: Together, the results suggest that the idea that dauer larva formation is an honestly-signalled C. elegans-wide effect does not hold. Rather, the results suggest that ascaroside-based signalling is a public broadcast information system, but where the correct interpretation of that information depends on the worms’ context, and is a system open to dishonest signalling

Episignature analysis of moderate effects and mosaics

DNA methylation classifiers (episignatures) help to determine the pathogenicity of variants of uncertain significance (VUS). However, their sensitivity is limited due to their training on unambiguous cases with strong-effect variants so that the classification of variants with reduced effect size or in mosaic state may fail. Moreover, episignature evaluation of mosaics as a function of their degree of mosaicism has not been developed so far. We improved episignatures with respect to three categories. Applying (i) minimum-redundancy-maximum-relevance feature selection we reduced their length by up to one order of magnitude without loss of accuracy. Performing (ii) repeated re-training of a support vector machine classifier by step-wise inclusion of cases in the training set that reached probability scores larger than 0.5, we increased the sensitivity of the episignature-classifiers by 30%. In the newly diagnosed patients we confirmed the association between DNA methylation aberration and age at onset of KMT2B-deficient dystonia. Moreover, we found evidence for allelic series, including KMT2B-variants with moderate effects and comparatively mild phenotypes such as late-onset focal dystonia. Retrained classifiers also can detect mosaics that previously remained below the 0.5-threshold, as we showed for KMT2D-associated Kabuki syndrome. Conversely, episignature-classifiers are able to revoke erroneous exome calls of mosaicism, as we demonstrated by (iii) comparing presumed mosaic cases with a distribution of artificial in silico-mosaics that represented all the possible variation in degree of mosaicism, variant read sampling and methylation analysis

p38 MAPK Regulates Expression of Immune Response Genes and Contributes to Longevity in C. elegans

The PMK-1 p38 mitogen-activated protein kinase pathway and the DAF-2–DAF-16 insulin signaling pathway control Caenorhabditis elegans intestinal innate immunity. pmk-1 loss-of-function mutants have enhanced sensitivity to pathogens, while daf-2 loss-of-function mutants have enhanced resistance to pathogens that requires upregulation of the DAF-16 transcription factor. We used genetic analysis to show that the pathogen resistance of daf-2 mutants also requires PMK-1. However, genome-wide microarray analysis indicated that there was essentially no overlap between genes positively regulated by PMK-1 and DAF-16, suggesting that they form parallel pathways to promote immunity. We found that PMK-1 controls expression of candidate secreted antimicrobials, including C-type lectins, ShK toxins, and CUB-like genes. Microarray analysis demonstrated that 25% of PMK-1 positively regulated genes are induced by Pseudomonas aeruginosa infection. Using quantitative PCR, we showed that PMK-1 regulates both basal and infection-induced expression of pathogen response genes, while DAF-16 does not. Finally, we used genetic analysis to show that PMK-1 contributes to the enhanced longevity of daf-2 mutants. We propose that the PMK-1 pathway is a specific, indispensable immunity pathway that mediates expression of secreted immune response genes, while the DAF-2–DAF-16 pathway appears to regulate immunity as part of a more general stress response. The contribution of the PMK-1 pathway to the enhanced lifespan of daf-2 mutants suggests that innate immunity is an important determinant of longevity

Caenorhabditis elegans HCF-1 Functions in Longevity Maintenance as a DAF-16 Regulator

The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals

Monogenic variants in dystonia: an exome-wide sequencing study

Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222;excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations

GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.</p

<scp>ReSurveyEurope</scp>: A database of resurveyed vegetation plots in Europe

AbstractAimsWe introduce ReSurveyEurope — a new data source of resurveyed vegetation plots in Europe, compiled by a collaborative network of vegetation scientists. We describe the scope of this initiative, provide an overview of currently available data, governance, data contribution rules, and accessibility. In addition, we outline further steps, including potential research questions.ResultsReSurveyEurope includes resurveyed vegetation plots from all habitats. Version 1.0 of ReSurveyEurope contains 283,135 observations (i.e., individual surveys of each plot) from 79,190 plots sampled in 449 independent resurvey projects. Of these, 62,139 (78%) are permanent plots, that is, marked in situ, or located with GPS, which allow for high spatial accuracy in resurvey. The remaining 17,051 (22%) plots are from studies in which plots from the initial survey could not be exactly relocated. Four data sets, which together account for 28,470 (36%) plots, provide only presence/absence information on plant species, while the remaining 50,720 (64%) plots contain abundance information (e.g., percentage cover or cover–abundance classes such as variants of the Braun‐Blanquet scale). The oldest plots were sampled in 1911 in the Swiss Alps, while most plots were sampled between 1950 and 2020.ConclusionsReSurveyEurope is a new resource to address a wide range of research questions on fine‐scale changes in European vegetation. The initiative is devoted to an inclusive and transparent governance and data usage approach, based on slightly adapted rules of the well‐established European Vegetation Archive (EVA). ReSurveyEurope data are ready for use, and proposals for analyses of the data set can be submitted at any time to the coordinators. Still, further data contributions are highly welcome.</jats:sec

Faire l'Europe au quotidien

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