The Notch Delta-4 ligand helps to maintain the quiescence and the short-term reconstitutive potential of Haematopoietic Progenitor Cells through activation of a key gene network: Delta-4/Notch pathway retains the HPCs potential

International audienceUnderstanding the role of Notch and its ligands within the different bone marrow niches could shed light on the mechanisms regulating haematopoietic progenitor cells (HPCs) maintenance and self renewal. Here, we report that murine bone marrow HPCs activation by the vascular Notch Delta4 ligand maintains a significant proportion of cells specifically in the G0 state. Furthermore, Delta4/Notch pathway limits significantly the loss of the in vivo short-term reconstitutive potential upon transplantation of Delta-4 activated HPCs into lethally irradiated recipient mice. Both effects are directly correlated with the decrease of cell cycle genes transcription such as CYCLIN-D1, − D2, and -D3, and the upregulation of stemness related genes transcription such as BMI1, GATA2, HOXB4 and C-MYC. In addition, the transcriptional screening also highlights new downstream post-transcriptional factors, named PUMILIO1 and − 2, as part of the stem signature associated with the Delta4/Notch signalling pathway

The actin-based motor protein myosin II regulates MHC class II trafficking and BCR-driven antigen presentation

Antigen (Ag) capture and presentation onto major histocompatibility complex (MHC) class II molecules by B lymphocytes is mediated by their surface Ag receptor (B cell receptor [BCR]). Therefore, the transport of vesicles that carry MHC class II and BCR–Ag complexes must be coordinated for them to converge for processing. In this study, we identify the actin-associated motor protein myosin II as being essential for this process. Myosin II is activated upon BCR engagement and associates with MHC class II–invariant chain complexes. Myosin II inhibition or depletion compromises the convergence and concentration of MHC class II and BCR–Ag complexes into lysosomes devoted to Ag processing. Accordingly, the formation of MHC class II–peptides and subsequent CD4 T cell activation are impaired in cells lacking myosin II activity. Therefore, myosin II emerges as a key motor protein in BCR-driven Ag processing and presentation

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Épidémiologie et physiopathologie de la mucoviscidose

Depuis la découverte du gène en 1989, il a été montré que les mutations du gène CFTR sont à I'origine d'une cascade d'événements cellulaires aboutissant à I'expression des symptômes de la maladie. Les scientifiques identifient progressivement ces événements afin de développer des stratégies thérapeutiques pour traiter I'origine de la maladie : thérapie génique et thérapie de la protéine et celles pour traiter les symptômes. L'amélioration des soins et I'organisation de la recherche clinique reposent en partie sur la connaissance des caractéristiques de la population atteinte de mucoviscidose. Le Registre français de la mucoviscidose (RFM) existe depuis 1992 et a identifié en 2005 plus de 4600 patients. Les analyses annuelles montrent une augmentation de I'espérance de vie à la naissance (46 ans), en parallèle avec une augmentation de la proportion d'adultes (40 %). Sur le plan microbiologique, si le taux de colonisation bronchique baisse pour le Burkholderia cepacia et les streptocoques (autres que S. pneumoniae), il est en hausse pour I'Aspergillus, le staphylocoque doré résistant à la méticilline et le Stenotrophomonas maltophilia. Cependant I'augmentation de I'espérance de vie s'accompagne de complications multiples liées à la maladie et les traitements mis en place dès le diagnostic restent Iourds et contraignants

Long-term noninvasive ventilation in patients with cystic fibrosis

Background: The benefits of long-termnoninvasive positive pressure ventilation (NPPV) have not yet been evaluated in patients with cystic fibrosis (CF). Objectives: To evaluate the effect of 1 year of NPPV on lung function in patients with advanced CF. Methods: Data were obtained from the French CF Registry. Patients who started NPPV (ventilated group, n = 41) were compared to matched controls (control group, n = 41). Each ventilated patient was matched to a control 1 year before the start of NPPV (year –1) for gender, CFTR genotype, age ± 5 years and forced expiratory volume in 1 s (FEV1) ± 10%. The ventilated group was compared to the control group at year –1, during the year of NPPV initiation (year 0) and 1 year after NPPV (year +1). Results: At year –1, the two groups were comparable with regard to forced vital capacity (FVC; 43.7 vs. 49.1% in the ventilated group and the control group, respectively) and FEV1 (28.2 vs. 28.5%). At year 0, the ventilated group had significantly greater declines in FVC (–3.6 ± 9.2 vs. +0.8 ± 8.9%, p = 0.03) and in FEV1 (–3.0 ± 6.7 vs. +2.6 ± 4.4, p < 0.0001). At year +1, the decreases in FVC (–2.1 ± 10.0 vs. –2.2 ± 9.9%) and in FEV1 (–2.2 ± 6.7 vs. –2.3 ± 6.2%) were similar in both groups. Conclusions: These data show that NPPV is associated with stabilization of the decrease in lung function in patients with advanced CF

Comprehensive Functional Analysis of the 18 Vibrio cholerae N16961 Toxin-Antitoxin Systems Substantiates Their Role in Stabilizing the Superintegron.

International audienceThe role of chromosomal toxin-antitoxin (TA) systems, which are ubiquitous within the genomes of free-living bacteria, is still debated. We have scanned the Vibrio cholerae N16961 genome for class 2 TA genes and identified 18 gene pair candidates. Interestingly, all but one are located in the chromosome 2 superintegron (SI). The single TA found outside the SI is located on chromosome 1 and is related to the well-characterized HipAB family, which is known to play a role in antibiotic persistence. We investigated this clustering within the SI and its possible biological consequences by performing a comprehensive functional analysis on all of the putative TA systems. We demonstrate that the 18 TAs identified encode functional toxins and that their cognate antitoxins are able to neutralize their deleterious effects when expressed in Escherichia coli. In addition, we reveal that the 17 predicted TA systems of the SI are transcribed and expressed in their native context from their own promoters, a situation rarely found in integron cassettes. We tested the possibility of interactions between noncognate pairs of all toxins and antitoxins and found no cross-interaction between any of the different TAs. Although these observations do not exclude other roles, they clearly strengthen the role of TA systems in stabilizing the massive SI cassette array of V. cholerae. The chromosomal toxin-antitoxin systems have been shown to play various, sometimes contradictory roles, ranging from genomic stabilization to bacterial survival via persistence. Determining the interactions between TA systems hosted within the same bacteria is essential to understand the hierarchy between these different roles. We identify here the full set of class 2 TAs carried in the Vibrio cholerae N16961 genome and found they are all, with a single exception, located in the chromosome 2 superintegron. Their characterization, in terms of functionality, expression, and possible cross-interactions, supports their main role as being the stabilization of the 176-cassette-long array of the superintegron but does not exclude dual roles, such as stress response elements, persistence, and bacteriophage defense through abortive infection mechanisms