Synthesis, screening and use of parasitic O-glycans and mimetics for improved C-type lectin receptor targeting

184 p.O-glycans from the helminth Schistosoma mansoni represent promising leads in the development of immunomodulatory compounds via the interaction with C-type lectin receptors (CLRs), as reported for DC-SIGN, L-SIGN, Langerin and MGL. We undertook the chemoenzymatic synthesis of an O-glycan library inspired from structures previously isolated from the helminth. We described the synthesis of parasitic O-glycan cores mucin core 2 and the S.mansoni specific core. Enzymatic elongations towards a library of O-glycans were limited to the Galß-1,6GalNAc arm of the cores owing to an unanticipated acceptor specificity of the recombinant glycosyltransferase LgtA_X. Synthesized as aminopentyl glycosides, eight O-glycans were obtained and were printed on-chip alongside N-glycans available from our laboratory. The array was enzymatically modified using a FucT from H.pylori in conjunction with either a fucose or 6-azido-fucose donor and arrayed against a selection of CLRs, revealing interesting features in the CLR specificity and suggesting the existence of exploitable chemical space for CLR targeting.CIC BiomaGUN

Parental perceptions of their child\u27s weight and health

Childhood obesity is a major health problem facing children in the United States. How parents view their children\u27s weight is an important consideration for health care professionals. The purpose of this study was to explore parental perceptions of their children\u27s weight and health

Synthesis, screening and use of parasitic O-glycans and mimetics for improved C-type lectin receptor targeting

184 p.O-glycans from the helminth Schistosoma mansoni represent promising leads in the development of immunomodulatory compounds via the interaction with C-type lectin receptors (CLRs), as reported for DC-SIGN, L-SIGN, Langerin and MGL. We undertook the chemoenzymatic synthesis of an O-glycan library inspired from structures previously isolated from the helminth. We described the synthesis of parasitic O-glycan cores mucin core 2 and the S.mansoni specific core. Enzymatic elongations towards a library of O-glycans were limited to the Galß-1,6GalNAc arm of the cores owing to an unanticipated acceptor specificity of the recombinant glycosyltransferase LgtA_X. Synthesized as aminopentyl glycosides, eight O-glycans were obtained and were printed on-chip alongside N-glycans available from our laboratory. The array was enzymatically modified using a FucT from H.pylori in conjunction with either a fucose or 6-azido-fucose donor and arrayed against a selection of CLRs, revealing interesting features in the CLR specificity and suggesting the existence of exploitable chemical space for CLR targeting.CIC BiomaGUN

The human kindness curriculum: An innovative preclinical initiative to highlight kindness and empathy in medicine.

BackgroundPrior studies have shown a marked drop in empathy among students during their third (clinical) year of medical school. Curricula developed to address this problem have varied greatly in content and have not always been subjected to validated measures of impact.MethodsIn 2015, we initiated a Human Kindness (HK) curriculum for the initial 2 years of medical school. This mandatory 12-h curriculum (6 h/year) included an innovative series of lectures and patient interactions with regard to compassion and empathy in the clinical setting. Both quantitative (Jefferson Scale of Empathy [JSE]) and qualitative data were collected prospectively to evaluate the impact of the HK curriculum.ResultsIn the initial Pilot Year, neither 1st (Group 1) nor 2nd (Group 2) year medical students showed pre-post changes in JSE scores. Substantial changes were made to the curriculum based on faculty and student evaluations. In the following Implementation Year, both the new 1st (Group 3) and the now 2nd year (Group 4) students, who previously experienced the Pilot Year, showed significant improvements in post-course JSE scores; this improvement remained valid across subanalyses of gender, age, and student career focus (e.g., internal medicine, surgery, etc.). Despite the disappointingly flat initial Pilot Year JSE scores, the 3rd year students (Group 2) who experienced only the Pilot Year of the curriculum (i.e., 2nd year students at the time of the Pilot Year) had subsequent JSE scores that did not show the typical decline associated with the clinical years. Students generally evaluated the HK curriculum positively and rated it as being important to their medical education and development as a physician.DiscussionA required preclinical curriculum focused on HK resulted in significant improvements in medical student empathy; this improvement was maintained during the 1st clinical year of training

Capreomycin is active against non-replicating M. tuberculosis

BACKGROUND: Latent tuberculosis infection (LTBI) is affecting one-third of the world population, and activation of LTBI is a substantial source of new cases of tuberculosis. LTBI is caused by tubercle bacilli in a state of non-replicating persistence (NRP), and the goal of this study was to evaluate the activity in vitro of various antimicrobial agents against non-replicating M. tuberculosis. METHODS: To achieve a state of NRP we placed broth cultures of M. tuberculosis (three strains) in anaerobic conditions, and in this model tested all known anti-TB drugs and some other antimicrobial agents (a total of 32 drugs). The potential effect was evaluated by plating samples from broth cultures for determining the number of viable bacteria (CFU/ml) during a prolonged period of cultivation. Besides drug-free controls we used metronidazole for positive controls, the only drug known so far to be effective against tubercle bacilli in anaerobic setting. RESULTS: On a background of non-replicating conditions in drug-free cultures and clear bactericidal effect of metronidazole none of the antimicrobial agents tested produced effect similar to that of metronidazole except capreomycin, which was as bactericidal at the same level as metronidazole. CONCLUSION: The unique ability of capreomycin to be bactericidal in vitro among the anti-TB drugs against non-replicating tubercle bacilli may justify the search for other drugs among peptide antibiotics with similar activity. This phenomenon requires further studies on the mechanism of action of capreomycin, and evaluation of its activity in appropriate animal models

Central role of nodal farmers in seed exchanges for biodiversity dynamics: example of "curadoras" for the quinoa conservation in Mapuche communities in south Chile

Ce document présente une partie des résultats d'une étude concernant le quinoa (Chenopodium quinoa willd.) effectuée auprès des communautés Mapuche de la région Araucanía au sud du Chili. L'objectif était d'évaluer les éléments de l'histoire du quinoa de cette région et le rôle des différents acteurs (agriculteurs et intitutions) impliqués dans la dynamique de biodiversité de cette plante. Tout d'abord, après que la conquête espagnole sa culture a quasi disparu, pour être remplacée par le riz et le blé dans le régime alimentaire des Mapuche. Néanmoins, quelques familles n'ont jamais cessé de cultiver le quinoa et ont conservé leurs variétés de famille. En 1996, une O.N.G. locale a commencé à développer des projets sur le quinoa, avec la constitution d'une première collection " landraces ", accompagné d'une récupération des savoirs locaux sur sa culture et ses usages, puis la réalisation d'ateliers sur les pratiques et des utilisations agricoles. Afin de recueillir toutes les informations concernant le quinoa, les systèmes de culture, la gestion des semences et les échanges, nous avons réalisé des enquêtes semi-structurées et qualitatives avec des paysans et des institutions de 4 villages représentant les deux zones agro-écologiques principales de la région. Le premier résultat est le fait que quoique plusieurs projets se soient développés il est clair que les paysans eux-mêmes sont les acteurs principaux de la conservation de biodiversité. Le deuxième résultat démontre qu'il y a deux types d'échanges dans les communautés et ils représentent l'accès principal aux semences. Le premier type est un échange " individuel " (entre personnes ou familles) à l'intérieur de la communauté. Le deuxième type est une sorte de marché traditionnel qui est organisé comme grand événement avec une cérémonie d'ouverture et la présentation de chaque participant. Dans chaque type d'échanges, nous pouvons noter les mêmes noms des participants principaux, appelés " Curadoras ". Ces agriculteurs semblent être particuliers et peuvent être comme " noeud de réseaux " parce qu'ils jouent un rôle essentiel dans des échanges et la circulation des semences (en cultivant un niveau élevé de la diversité, par la connaissance concernant les variétés et leur adaptation et les modes de gestion). En conclusion, ces fermiers nodaux participent à quasi tous les Trafkintüs (échanges) organisés dans la région, donnant une dynamique aux échanges et la confiance aux divers fermiers auxquels ils fournissent les semences. Le dernier et troisième résultat de cette étude est le fait que la même O.N.G. s'appuie sur la connaissance des systèmes semenciers locaux pour la conservation de diversité en organisant des ateliers entre les agriculteurs en mobilisant les " Curadoras ", qui participent activement comme formateurs. (Résumé d'auteur

NRG1 functions downstream of EDS1 to regulate TIR-NLR-mediated plant immunity in Nicotiana benthamiana.

Effector-triggered immunity (ETI) in plants involves a large family of nucleotide-binding leucine-rich repeat (NLR) immune receptors, including Toll/IL-1 receptor-NLRs (TNLs) and coiled-coil NLRs (CNLs). Although various NLR immune receptors are known, a mechanistic understanding of NLR function in ETI remains unclear. The TNL Recognition of XopQ 1 (Roq1) recognizes the effectors XopQ and HopQ1 from Xanthomonas and Pseudomonas, respectively, which activates resistance to Xanthomonas euvesicatoria and Xanthomonas gardneri in an Enhanced Disease Susceptibility 1 (EDS1)-dependent way in Nicotiana benthamiana In this study, we found that the N. benthamiana N requirement gene 1 (NRG1), a CNL protein required for the tobacco TNL protein N-mediated resistance to tobacco mosaic virus, is also essential for immune signaling [including hypersensitive response (HR)] triggered by the TNLs Roq1 and Recognition of Peronospora parasitica 1 (RPP1), but not by the CNLs Bs2 and Rps2, suggesting that NRG1 may be a conserved key component in TNL signaling pathways. Besides EDS1, Roq1 and NRG1 are necessary for resistance to Xanthomonas and Pseudomonas in N. benthamiana NRG1 functions downstream of Roq1 and EDS1 and physically associates with EDS1 in mediating XopQ-Roq1-triggered immunity. Moreover, RNA sequencing analysis showed that XopQ-triggered gene-expression profile changes in N. benthamiana were almost entirely mediated by Roq1 and EDS1 and were largely regulated by NRG1. Overall, our study demonstrates that NRG1 is a key component that acts downstream of EDS1 to mediate various TNL signaling pathways, including Roq1 and RPP1-mediated HR, resistance to Xanthomonas and Pseudomonas, and XopQ-regulated transcriptional changes in N. benthamiana

A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry.

Psychoactive compounds such as chloroquine and amphetamine act by dissipating the pH gradient across intracellular membranes, but the physiological mechanisms that normally regulate organelle pH remain poorly understood. Interestingly, recent human genetic studies have implicated the endosomal Na+/H+ exchanger NHE9 in both autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). Plasma membrane NHEs regulate cytosolic pH, but the role of intracellular isoforms has remained unclear. We now find that inactivation of NHE9 in mice reproduces behavioral features of ASD including impaired social interaction, repetitive behaviors, and altered sensory processing. Physiological characterization reveals hyperacidic endosomes, a cell-autonomous defect in glutamate receptor expression and impaired neurotransmitter release due to a defect in presynaptic Ca2+ entry. Acute inhibition of synaptic vesicle acidification rescues release but without affecting the primary defect due to loss of NHE9