Second generation of Fucose-based DC-SIGN ligands : affinity improvement and specificity versus Langerin

DC-SIGN and Langerin are two C-type lectins involved in the initial steps of HIV infections: the former acts as a viral attachment factor and facilitates viral invasion of the immune system, the latter has a protective effect. Potential antiviral compounds targeted against DC-SIGN were synthesized using a common fucosylamide anchor. Their DC-SIGN affinity was tested by SPR and found to be similar to that of the natural ligand Lewis-X (Le X). The compounds were also found to be selective for DC-SIGN and to interact only weakly with Langerin. These molecules are potentially useful therapeutic tools against sexually transmitted HIV infection

Targeting of the C-Type Lectin Receptor Langerin Using Bifunctional Mannosylated Antigens

Langerhans cells (LCs) are antigen-presenting cells that reside in the skin. They uniquely express high levels of the C-type lectin receptor Langerin (CD207), which is an attractive target for antigen delivery in immunotherapeutic vaccination strategies against cancer. We here assess a library of 20 synthetic, well-defined mannoside clusters, built up from one, two, and three of six monomannosides, dimannosides, or trimannosides, appended to an oligopeptide backbone, for binding with Langerin using surface plasmon resonance and flow cytometric quantification. It is found that Langerin binding affinity increases with increasing number of mannosides. Hexavalent presentation of the mannosides resulted in binding affinities ranging from 3 to 12 mu M. Trivalent presentation of the dimannosides and trimannosides led to Langerin affinity in the same range. The model melanoma gp100 antigenic peptide was subsequently equipped with a hexavalent cluster of the dimannosides and trimannosides as targeting moieties. Surprisingly, although the bifunctional conjugates were taken up in LCs in a Langerin-dependent manner, limited antigen presentation to cytotoxic T cells was observed. These results indicate that targeting glycan moieties on immunotherapeutic vaccines should not only be validated for target binding, but also on the continued effects on biology, such as antigen presentation to both CD8(+)and CD4(+)T cells.Bio-organic Synthesi

Early EMDR defusing in a COVID-19 testing center

National audienc

DC-SIGN neck domain is a pH-sensor controlling oligomerization: SAXS and hydrodynamic studies of extracellular domain

DC-SIGN is a C-type lectin receptor of dendritic cells and is involved in the early stages of numerous infectious diseases. DC-SIGN is organized into a tetramer enabling multivalent interaction with pathogens. Once formed, the DC-SIGN-pathogen complex can be internalized into compartments of increasing acidity. We have studied the pH dependence of the oligomerization state and conformation of the entire extracellular domain and neck region. We present evidence for equilibrium between the monomeric and tetrameric states of the extracellular domain, which exhibits a marked dependence with respect to both pH and ionic strength. Using solution x-ray scattering we have obtained a molecular envelope of the extracellular domain in which a model has been built. Our results highlight the central role of the neck domain in the pH-sensitive control of the oligomerization state, in the extended conformation of the protein, and in carbohydrate recognition domain organization and presentation. This work opens new insight into the molecular mechanism of ligand release and points to new avenues to block the first step of this important infection pathway

The human NAIP-NLRC4-inflammasome senses the Pseudomonas aeruginosa T3SS inner-rod protein.

While NLRC4-dependent sensing of intracellular Gram-negative pathogens such as Salmonella enterica serovar typhimurium is a beneficial host response, NLRC4-dependent sensing of the Pseudomonas aeruginosa type 3 secretion system (T3SS) has been shown to be involved in pathogenicity. In mice, different pathogen-associated microbial patterns are sensed by the combination of the NLRC4-inflammasome with different neuronal apoptosis inhibitory proteins (NAIPs). NAIP2 is involved in sensing PscI, an inner-rod protein of the P. aeruginosa T3SS. Surprisingly, only a single human NAIP (hNAIP) has been found. Moreover, there is no description of hNAIP-NLRC4 inflammasome recognition of T3SS inner-rod proteins in humans. Here, we show that the P. aeruginosa T3SS inner-rod protein PscI and needle protein PscF are both sensed by the hNAIP-NLRC4 inflammasome in human macrophages and PBMCs from healthy donors, allowing caspase-1 and IL-1β maturation and resulting in a robust inflammatory response. TLR4 and TLR2 are involved in redundantly sensing these two T3SS components

L'hydrologie tropicale : géosciences et outil pour le développement : mélanges à la mémoire de Jean Rodier

Le logiciel Cheiamaz a été développé pour prévoir l'évolution de la crue à Manaus, sur la base d'une modélisation de type statistique des séries chronologiques de cotes observées aux principales stations brésiliennes du bassin de l'Amazone. Des équations de prévision ont été établies pour des échéances variant de 10 à 60 jours, par une méthode de régression progressive ascendante, couplée à une procédure d'élimination graduelle descendante des variables à envisager compte-tenu des lacunes que comportent les séries de données. Les écarts quadratiques moyens, en calage et en validation, varient de moins de 10 cm pour le délai de 10 jours, à environ 40 cm pour celui de 60 jours. Une méthode neuronale a d'autre part été testée pour prévoir la cote maximale de la crue. Le logiciel Cheiamaz permet enfin de comparer a posteriori les prévisions émises antérieurement avec les données effectivement observées. (Résumé d'auteur

Validation de la version française de l’échelle abrégée d’appréciation psychiatrique étendue avec ancrage, BPRS-E(A) [Validation of the French version of the expanded Brief Psychiatric Rating Scale with anchor BPRS-E(A)].

International audienceThe Brief Psychiatric Rating Scale was initially developed as a rapid method to assess symptom change in psychiatric inpatients of various diagnoses. The original version was expanded to an 18-item version and thereafter to a 24-item version to increase sensitivity to a broader range of psychotic and affective symptoms. The latest version of the expanded 24- item BPRS provides probe questions and detailed anchor points for the ratings for each item. Studies have shown the expanded and anchored 24-item BPRS to be a sensitive and effective measure of psychiatric symptoms with good interrater reliability that can be maintained over time. To our knowledge, there are eight published papers including factor analyses of the BPRS-E(A). While many similarities are evident between these studies, inconsistencies are apparent that may have been due to sample size, characteristics and / or methodological differences in the factor analysis computation. Among these studies, six provided a four-factor solution. There was no French version of this scale available. After its translation into French and back translation, we investigated the validity of the French BPRS-E(A) version. We carried out a component analysis on the data of 111 participants of various diagnoses, mostly hospitalised for a first psychotic episode, yielding to a three-factor solution (positive symptoms--disorganisation; depression-anxiety and negative symptoms). A good internal consistency and interrater reliability were found. These results confirm the psychometric value of the BPRS-E(A) in its French version. We compared those findings to earlier reports; similarities and differences are discussed

Projet NEUROPHYTO : Evaluation des effets sur le neurodéveloppement de l’exposition prénatale et postnatale aux produits phytopharmaceutiques

National audienceLes périodes prénatale et néonatale constituent des fenêtres de sensibilité particulières vis-à-vis des contaminants chimiques de l’environnement. Un nombre croissant d’études épidémiologiques et toxicologiques suggère que l’exposition aux pesticides pendant ces périodes pourrait impacter la santé des enfants à la naissance ainsi que leur développement, avec des retentissements possibles tout au long de la vie. Le projet NEUROPHYTO a comme premier objectif de décrire l’exposition de 200 enfants de la cohorte nationale Elfe à une large gamme de produits phytosanitaires, allant de la période in utero aux 3 ans et demi grâce aux dosages de biomarqueurs d’exposition dans les urines et dans les cheveux.Une évaluation de l’exposition interne notamment au niveau de tissus cibles tels que le cerveau sera réalisée grâce à des modèles toxicocinétiques à fondement physiologique pour la petite enfance. Une fois ces profils de doses internes établis pour les enfants, deux grands volets seront mis en œuvre afin de développer les connaissances sur les liens entre expositions et effets sur le neurodéveloppement. Un premier volet sera consacré à la mise en œuvre d’une approche épidémiologique basée sur l’étude des données sur le développement neuropsychologique et moteur des enfants de la cohorte Elfe. Le second volet sera dédié à l’amélioration des connaissances mécanistiques sur les liens entre l’exposition aux produits phytosanitaires et l’apparition de troubles neurodéveloppementaux, via des méthodologies innovantes. Des modèles computationnels seront développés et de nouveaux ‘adverse outcome pathways’ (AOPs) seront proposés.Ce projet permettra d’appuyer les politiques publiques en apportant des éléments ciblés sur les fenêtres de sensibilité pré- et post-natales ainsi qu’une analyse des valeurs toxicologiques de référence existantes incluant la proposition de valeurs dédiées à l’évaluation des risques d’effets neurodéveloppementaux chez les enfants

Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor

The C-type lectin receptor DC-SIGN has been highlighted as the coreceptor for the spike protein of the SARS-CoV-2 virus. A multivalent glycomimetic ligand, Polyman26, has been found to inhibit DC-SIGN-dependent trans-infection of SARS-CoV-2. The molecular details underlying avidity generation in such systems remain poorly characterized. In an effort to dissect the contribution of the known multivalent effects ─ chelation, clustering, and statistical rebinding ─ we studied a series of dendrimer constructs related to Polyman26 with a rod core rationally designed to engage simultaneously two binding sites of the tetrameric DC-SIGN. Binding properties of these compounds have been studied with a range of biophysical techniques, including recently developed surface plasmon resonance oriented-surface methodology. Using molecular modeling we addressed, for the first time, the impact of the carbohydrate recognition domains’ flexibility of the DC-SIGN tetramer on the compounds’ avidity. We were able to gain deeper insight into the role of different binding modes, which in combination produce a construct with a nanomolar affinity despite a limited valency. This multifaceted experimental-theoretical approach provides detailed understanding of multivalent ligand/multimeric protein interactions which can lead to future predictions. This work opens the way to the development of new virus attachment blockers adapted to different C-type lectin receptors of viruses