The localisation of the apical Par/Cdc42 polarity module is specifically affected in microvillus inclusion disease

corrigéInternational audienceBACKGROUND INFORMATION: . Microvillus inclusion disease (MVID) is a genetic disorder affecting intestinal absorption. It is caused by mutations in MYO5B or syntaxin 3 (STX3) affecting apical membrane trafficking. Morphologically MVID is characterised by a depletion of apical microvilli and the formation of microvillus inclusions inside the cells, suggesting a loss of polarity. To investigate this hypothesis we examined the location of essential apical polarity determinants in five MVID patients. RESULTS: We found that the polarity determinants Cdc42, Par6B, PKCζ/ι and the structural proteins ezrin and phospho-ezrin were lost from the apical membrane and accumulated either in the cytoplasm or on the basal side of enterocytes in patients which suggests an inversion of cell polarity. Moreover microvilli-like structures were observed at the basal side in electron microscopy. We next performed Myo5B depletion in 3D-grown human Caco2 cells forming cysts and we found a direct link between the loss of Myo5B and the mislocalisation of the same apical proteins; furthermore we observed that a majority of cyst displayed an inverted polarity phenotype as seen in some patients. Finally we found that this loss of polarity was specific for MVID: tissue samples of patients with Myo5B independent absorption disorders showed normal polarity but we identified Cdc42 as a potentially essential biomarker for tricho-hepato-enteric syndrome. CONCLUSION: Our findings indicate that the loss of Myo5B induces a strong loss of enterocyte polarity, potentially leading to polarity inversion. SIGNIFICANCE: Our results show that polarity determinants could be useful markers to help establishing a diagnosis in patients. Furthermore they could be used to characterise other rare intestinal absorption diseases

Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of pancreatic β-cells by the immune system that involves innate and adaptive immune cells. Mucosal-associated invariant T cells (MAIT cells) are innate-like T-cells that recognize derivatives of precursors of bacterial riboflavin presented by the major histocompatibility complex (MHC) class I–related molecule MR1. Since T1D is associated with modification of the gut microbiota, we investigated MAIT cells in this pathology. In patients with T1D and mice of the non-obese diabetic (NOD) strain, we detected alterations in MAIT cells, including increased production of granzyme B, which occurred before the onset of diabetes. Analysis of NOD mice that were deficient in MR1, and therefore lacked MAIT cells, revealed a loss of gut integrity and increased anti-islet responses associated with exacerbated diabetes. Together our data highlight the role of MAIT cells in the maintenance of gut integrity and the control of anti-islet autoimmune responses. Monitoring of MAIT cells might represent a new biomarker of T1D, while manipulation of these cells might open new therapeutic strategies

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Parcours de paroles, Frédéric Moser & Philippe Schwinger

International audienceDepuis 2009, le duo d'artistes Frédéric Moser et Philippe Schwinger parcourt le pays pour réaliser la série de vidéos intitulée France, détours. Dans cette enquête, ils partent à la rencontre de jeunes français, donnent la parole à des adolescents de milieux et de territoires urbains divers, les interrogeant sur leur situation et conditions de vie dans la société. Après plusieurs années de pratique théâtrale, à laquelle ils ne cessent d'emprunter diverses stratégies de représentation, les deux artistes suisses s'engagent dans une démarche qui allie approche théorique, enquêtes sur le terrain et mises en forme plastiques de dispositifs. Ils élaborent des propositions artistiques oscillant entre authenticité apparente et processus de construction complexes, dans une attention critique aux constructions de la réalité. Pour chaque film de la série France, détours, les artistes choisissent de travailler sur un réel discursif avec de jeunes adultes dont le point commun est d'expérimenter cette vive période de questionnement qu'est l'adolescence, moment carrefour d'un devenir citoyen. Cette série s’inspire de douze émissions réalisées par Jean -Luc Godard et Anne-Marie Miéville à partir de 1979 : France, Tour, Détour, deux enfants, série elle-même librement inspirée du livre de lecture scolaire Le Tour de la France par deux enfants

Innovative Lehr- und Lernmethoden zur Entwicklung von ethischen Kompetenzen in der Pflegeausbildung: eine Literaturübersicht

Hintergrund: Die Entwicklung der technologischen sowie innovativen Methoden erreicht zunehmend die Pflegeschulen. Bereits jede Schweizer Universität sowie Fachhochschule hat das E-Learning integriert. Im Bereich der Pflege ist ein konstanter Wandel präsent, die Fähigkeiten der und die Erwartungen an die künftigen Pflegefachpersonen werden zunehmend anspruchsvoller. Daher wird es immer bedeutender, innovative Methoden für das Erlernen von ethischen Kompetenzen zu integrieren, um eine effektive Qualität der Lerntätigkeit zu erreichen. In der Praxis werden die Pflegefachpersonen jeden Tag mit neuen zu behandelnden Menschen, unbekannten Situationen und auch mit verschiedenen ethischen Dilemmata konfrontiert. Aufgrund dessen und wegen der Lernmöglichkeiten, welche die Digitalisierung mit sich bringt, wurde der Fokus dieser Arbeit auf die Entwicklung von ethischen Kompetenzen der Pflegestudierenden durch innovative Lernmethoden gelegt. Methode: Die Literaturrecherche wurde anhand von Suchbegriffen in den Datenbanken PubMed und CINAHL durchgeführt. In Bezug auf die Forschungsfrage wurden Suchbegriffe definiert und Einschluss- sowie Ausschlusskriterien festgelegt. Mithilfe der Beurteilungsinstrumente wurden die verwendeten Studien kritisch beurteilt, die Ergebnisse tabellarisch zusammengefasst, analysiert und diskutiert. Ergebnisse: Es wurden sechs Studien in der Literaturübersicht berücksichtigt, davon fünf quasiexperimentelle und eine Pilotstudie. Die Ergebnisse zeigen, dass die innovativen Lehr- und Lernmethoden, wie onlineorientiertes, fragenorientiertes, simulationsorientiertes, visuell-, auditiv- und kinästhetikorientiertes Lernen (VAK), die Entwicklung von ethischen Kompetenzen im Studium fördern und verbessern. Schlussfolgerung: Innovative Lehr- und Lernmethoden lassen sich gut in die Praxis implementieren. Es wird jedoch empfohlen, die innovativen Lehr- und Lernmethoden mit einer traditionellen Lernmethode zu ergänzen, um eine bessere Kompetenzentwicklung zu sichern. Hilfreich ist hierbei, wenn die Studierenden eine aktive Rolle beim Lernen einnehmen, denn dadurch wird das Erlernen der Kompetenzen verbessert

Enquête autour des émotions ressenties par les étudiants lors de la réalisation d’un geste courant en odontologie chez les patients enfants et adultes

Contexte : Les émotions ressenties par les étudiants en chirurgie dentaire pendant les stages cliniques peuvent influencer leur motivation, leur engagement au travail, leur santé mentale et physique et leurs apprentissages, dans le bon comme dans le mauvais sens. But : L’objectif principal de cette étude était d’évaluer la charge émotionnelle des étudiants pendant la réalisation d’un soin courant chez un enfant et chez un adulte. Méthode : Une étude prospective descriptive a été menée auprès d’étudiants de 5e année volontaires (n = 143). Un questionnaire portant sur les émotions ressenties était complété immédiatement après chaque avulsion dentaire réalisée par un étudiant. Nous les avons interrogés sur la confiance en soi, la satisfaction au travail ou encore l’anxiété à différentes étapes de la consultation. Résultats : Soigner des enfants est une source d’anxiété pour les étudiants. Ils se sentent moins confiants et éprouvent des difficultés pour communiquer avec les jeunes enfants qu’on retrouve nettement moins face à des patients adultes. La disponibilité des superviseurs et le travail en binôme sont quant à eux des facteurs rassurants. Conclusion : La dentisterie pédiatrique est une discipline stressante pour les étudiants, avec un panel d’émotions spécifiques qui pourrait expliquer le peu d’attrait de la discipline

Les systèmes d'information en appui à la connaissance et la diffusion des systèmes de culture économes en pesticides : l'exemple du système d'information Agrosyst du réseau de fermes et d'expérimentations du plan Ecophyto

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Effects of parity on metabolism, redox status and cytokines in early lactating dairy cows

International audienceIn dairy cows during early lactation, inflammation and oxidative stress can occur and lead to a risk of cell damages and may be related to the metabolic status. Our objective was to investigate the influence of parity on the metabolic, redox status and immunity of dairy cows. Fifteen Holstein cows were classified into four groups according to calving date with 7 primiparous and 8 multiparous cows. Blood samples were collected 3 weeks before calving and 4, 8 and 12 weeks postpartum and after calving milk was sampled at the same times. Plasma metabolic and redox status markers were analysed by spectrophotometry. In leucocytes collected from milk, the expression of genes coding for antioxidant enzymes were analysed by RTqPCR. Plasma cytokines were analysed after an ex vivo challenge of whole-blood cells with or without heat-killed Escherichia coli. Data were analysed with a mixed model including parity, week, and their interaction as fixed effects, and cow as a random effect. As expected, milk production was higher in multiparous than in primiparous cows. Plasma non-esterified fatty acids and β-hydroxybutyrate were higher in multiparous than in primiparous respectively at the 2nd and the 4th weeks of lactation, whereas glucose was lower. Multiparous cows have higher d-ROM at 8 weeks in plasma, higher GPX activity in erythrocytes at 4 weeks, and higher Sod1 expression levels at 4 weeks in milk leucocytes. Associated with these results, multiparous cows had a higher level of vitamin E but lower plasma concentrations of cytokines CXCL10, CCL2, IL1Rα and IFNγ. After E. coli challenge, at the 3rd week before and the 8th week after calving, the immunity of multiparous cows would be less effective with lower IL1α and TNFα. The increased energy metabolism is accompanied by an increase in the antioxidant response to resolve redox balance, and by a probably less effective immunity in multiparous compared with primiparous cows