Gut Microbiota, Probiotics and Diabetes

Diabetes is a condition of multifactorial origin, involving several molecular mechanisms related to the intestinal microbiota for its development. In type 2 diabetes, receptor activation and recognition by microorganisms from the intestinal lumen may trigger inflammatory responses, inducing the phosphorylation of serine residues in insulin receptor substrate-1, reducing insulin sensitivity. In type 1 diabetes, the lowered expression of adhesion proteins within the intestinal epithelium favours a greater immune response that may result in destruction of pancreatic β cells by CD8+ T-lymphocytes, and increased expression of interleukin-17, related to autoimmunity. Research in animal models and humans has hypothesized whether the administration of probiotics may improve the prognosis of diabetes through modulation of gut microbiota. We have shown in this review that a large body of evidence suggests probiotics reduce the inflammatory response and oxidative stress, as well as increase the expression of adhesion proteins within the intestinal epithelium, reducing intestinal permeability. Such effects increase insulin sensitivity and reduce autoimmune response. However, further investigations are required to clarify whether the administration of probiotics can be efficiently used for the prevention and management of diabetes

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Alloimmunization and variants of the RH system : new bioinformatics approaches

Les antigènes du système de groupe sanguin RH ou « Rhésus », ont une importance majeure en transfusion, de par l’immunogénicité de ses antigènes et les conséquences hémolytiques potentiellement graves d’une allo-immunisation. L’antigène D (RH1) est particulièrement important, avec des centaines d’allèles du gène RHD codant pour des antigènes D plus ou moins altérés (« variants »).Le premier volet de ce travail propose une approche bioinformatique par modélisation comparative. L’analyse statique d’un modèle RhD monomérique, puis d’un modèle trimérique avec son partenaire indispensable RhAG, est confrontée aux techniques sérologiques classiques et aux cas d’alloimmunisation publiés. Les domaines extracellulaires de RhD sont définis le plus précisément possible grâce à l’étude de l’accessibilité des différentes parties de la protéine. Des simulations de dynamique moléculaire de modèles trimériques de composition différente (RhD et/ou RhAG) permettent d’étudier le comportement structural des protéines sauvages. Ces études démontrent une corrélation et une complémentarité entre les approches bioinformatiques et sérologiques.Le deuxième volet de ce travail concerne la mise en place d’une base de données moderne pour les variants RhD appelée « RHeference ». Elle recense l’ensemble des données disponibles sur l’antigène D et ses variants (articles et résumés présentés en congrès), actuellement disséminées dans la littérature, et pallie les limitations des ressources actuelles.In transfusion medicine, blood group antigens from the RH or « Rhesus » system, especially the D (RH1) antigen, with hundreds of RHD alleles coding for more or less altered D antigens (« variants »), play a major role, due to their immunogenicity and the potential severe consequences of an alloimmunization.In the first part of this work, a comparative modelling approach is proposed. The static analysis of a model for the RhD monomer, and for the trimer that RhD forms with RhAG, is compared to classical serologic methods, and published anti-D cases. The extracellular parts of RhD are precisely defined through the study of the accessibility of the residues. Molecular dynamics simulations of trimer models with different compositions (RhD and/or RhAG) allow the description of the structural behaviour of wild type proteins. These studies demonstrate the correlation and complementarity of bioinformatics and serologic approaches.The second part of this work implements a modern, online database named « RHeference ». It gathers all available data regarding the D antigen and its variants (published articles and conference abstracts), currently scattered in the literature, without the limitations of currently available resources

A Review of the Literature Organized Into a New Database: RHeference

International audienceHundreds of articles containing heterogeneous data describe D variants or add to the knowledge of known alleles. Data can be difficult to find despite existing online blood group resources and genetic and literature databases. We have developed a modern, elaborate database for D variants, thanks to an extensive literature search with meticulous curation of 387 peer-reviewed articles and 80 abstracts from major conferences and other sources. RHeference contains entries for 710 RHD alleles, 11 RHCE alleles, 30 phenotype descriptions (preventing data loss from historical sources), 35 partly characterized alleles, 3 haplotypes, and 16 miscellaneous entries. The entries include molecular, phenotypic, serological, alloimmunization, haplotype, geographical, and other data, detailed for each source. The main characteristics are summarized for each entry. The sources for all information are included and easily accessible through doi and PMID links. Overall, the database contains more than 10,000 individual pieces of data. We have set up the database architecture based on our previous expertise on database setup and biocuration for other topics, using modern technologies such as the Django framework, BioPython, Bootstrap, and Jquery. This architecture allows an easy access to data and enables simple and complex queries: combining multiple mutations, keywords, or any of the characteristics included in the database. RHeference provides a complement to existing resources and will continue to grow as our knowledge expands and new articles are published. The database url is http://www.rheference.org/

RHCE*01 48G>C, 366del allele with silencedRHCE*ce expression

International audienceNo abstract availabl

Insights into anti‐D formation in carriers of RhD variants through studies of 3D intraprotein interactions

International audienceBackground: Many RhD variants associated with anti-D formation (partial D) in carriers exposed to the conventional D antigen carry mutations affecting extracellular loop residues. Surprisingly, some carry mutations affecting transmembrane or intracellular domains, positions not thought likely to have a major impact on D epitopes.Study design and methods: A wild-type Rh trimer (RhD1 RhAG2 ) was modeled by comparative modeling with the human RhCG structure. Taking trimer conformation, residue accessibility, and position relative to the lipid bilayer into account, we redefine the domains of the RhD protein. We generated models for RhD variants carrying one or two amino acid substitutions associated with anti-D formation in published articles (25 variants) or abstracts (12 variants) and for RHD*weak D type 38. We determined the extracellular substitutions and compared the interactions of the variants with those of the standard RhD.Results: The findings of the three-dimensional (3D) analysis were correlated with anti-D formation for 76% of RhD variants: 15 substitutions associated with anti-D formation concerned extracellular residues, and structural differences in intraprotein interactions relative to standard RhD were observed in the others. We discuss the mechanisms by which D epitopes may be modified in variants in which the extracellular residues are identical to those of standard RhD and provide arguments for the benignity of p.T379M (RHD*DAU0) and p.G278D (RHD*weak D type 38) in transfusion medicine.Conclusion: The study of RhD intraprotein interactions and the precise redefinition of residue accessibility provide insight into the mechanisms through which RhD point mutations may lead to anti-D formation in carriers

Molecular characterization of 13 new RHD alleles

International audienceThis report describes 13 novel RHD alleles predicted by serological elements and confirmed by exon genotyping

Participation locale et appropriation citoyenne

La mise en oeuvre d'actions publiques à l'échelle de la région et des territoires locaux, pour répondre au défi du changement climatique, implique que les populations concernées par ces projets s'en approprient les finalités et modalités. La question de la participation du public aux décisions d'aménagement et de développement durable a fait l'objet d'une abondante littérature qui souligne les ambiguïtés de l'exercice et les limites des outils utilisés. Jusqu'à présent, les expérimentations menées autour du changement climatique, à l'échelle territoriale, ne dérogent guère à ce constat. Si la production d'un savoir adapté est cruciale, l'éducation à l'environnement joue également un rôle central. Les exemples de l'implantation de projets d'énergie renouvelable, celui des écoquartiers urbains ou des TEPOS (Territoires à Énergie POSitive, devenus récemment TEPCV) attestent qu'il faut changer de modèle décisionnel et sortir de la recherche d'une "acceptabilité sociale" à moindre coût

Participation locale et appropriation citoyenne

La mise en oeuvre d'actions publiques à l'échelle de la région et des territoires locaux, pour répondre au défi du changement climatique, implique que les populations concernées par ces projets s'en approprient les finalités et modalités. La question de la participation du public aux décisions d'aménagement et de développement durable a fait l'objet d'une abondante littérature qui souligne les ambiguïtés de l'exercice et les limites des outils utilisés. Jusqu'à présent, les expérimentations menées autour du changement climatique, à l'échelle territoriale, ne dérogent guère à ce constat. Si la production d'un savoir adapté est cruciale, l'éducation à l'environnement joue également un rôle central. Les exemples de l'implantation de projets d'énergie renouvelable, celui des écoquartiers urbains ou des TEPOS (Territoires à Énergie POSitive, devenus récemment TEPCV) attestent qu'il faut changer de modèle décisionnel et sortir de la recherche d'une "acceptabilité sociale" à moindre coût

High immunogenicity of red blood cell antigens restricted to the population of African descent in a cohort of sickle cell disease patients

International audienceBACKGROUND : Sickle cell disease (SCD) patients undergo multiple red blood cell (RBC) transfusions and are regularly exposed to low‐prevalence (LP) antigens specific to individuals of African descent. This study evaluated the prevalence of antibodies against LP antigens in SCD patients and the need to identify these antibodies in everyday practice.STUDY DESIGN AND METHODS : Plasma from 211 SCD patients was tested with RBCs expressing the following LP antigens: RH10 (V), RH20 (VS), RH23 (DW), RH30 (Goa), KEL6 (Jsa), and MNS6 (He).RESULTS : Nine LP antibodies were found in eight patients (3.8%): five anti‐RH23, two anti‐RH30, and two anti‐MNS6. The exposure risk, calculated for each LP antigen, was below 3% per RBC unit, for all antigens tested. Thus, in this cohort of transfused SCD patients, the prevalence of LP antibodies was similar to that of antibodies against antigens of the FY, JK, and MNS blood group systems. These findings also reveal the occurrence of anti‐RH23 in SCD patients. No anti‐RH20 or anti‐KEL6 were found, despite the high frequency of mismatch situations.CONCLUSION : These results highlight the immunogenicity of these LP antigens, and the evanescence of antibodies against LP antigens. They also highlight the importance of appropriate pretransfusion testing for patients frequently transfused, who are likely to be exposed to multiple types of blood group antigens