Angiopoietin-like 4 based therapeutics for proteinuria and kidney disease

Current drugs used to treat proteinuric disorders of the kidney have been borrowed from other branches of medicine, and are only partially effective. The discovery of a central, mechanistic role played by two different forms of the secreted glycoprotein angiopoietin-like 4 (Angptl4) in human and experimental glomerular disease has opened new treatment avenues. Localized upregulation of a hyposialylated form (lacks sialic acid residues) of Angptl4 secreted by podocytes induces the cardinal morphological and clinical manifestations of human minimal change disease, and is also being increasingly recognized as a significant contributor toward proteinuria in experimental diabetic nephropathy. Oral treatment with low doses of N-acetyl-D-mannosamine, a naturally occurring precursor of sialic acid, improves sialylation of Angptl4 in vivo, and reduces proteinuria by over 40%. By contrast, a sialylated circulating form of Angptl4, mostly secreted from skeletal muscle, heart and adipose tissue in all major primary glomerular diseases, reduces proteinuria while also causing hypertriglyceridemia. Intravenous administration of recombinant human Angptl4 mutated to avoid hypertriglyceridemia and cleavage has remarkable efficacy in reducing proteinuria by as much as 65% for 2 weeks after a single low dose. Both interventions are mechanistically relevant, utilize naturally occurring pathways, and represent new generation therapeutic agents for chronic kidney disease related to glomerular disorders

Radiation Characterization of Optical Frequency Domain Reflectometry Fiber-Based Distributed Sensors

We studied the responses of fiber-based temperature and strain sensors related to Optical Frequency Domain Reflectometry (OFDR) and exposed to high γ-ray doses up to 10 MGy. Three different commercial fiber classes are used to investigate the evolution of OFDR parameters with dose, thermal treatment and fiber core/cladding composition. We find that the fiber coating is affected by both thermal and radiation treatments and this modification results in an evolution of the internal stress distribution inside the fiber that influences its temperature and strain Rayleigh coefficients. These two environmental parameters introduce a relative error up to 5% on temperature and strain measures. This uncertainty can be reduced down to 0.5% if a pre-thermal treatment at 80°C and/or a pre-irradiation up to 3 MGy are performed before insertion of the fiber in the harsh environment of interest. These preliminary results demonstrate that OFDR fiber-based distributed sensors look as promising devices to be integrated in radiation environments with associated large ionizing doses

Etude du déséquilibre de liaison dans des lignées de poules de types génétiques "ponte" et "chair"

International audienceLa structure du déséquilibre de liaison (DL) au sein des populations en sélection impacte fortement la précision obtenue lors des études de cartographie de QTL ou lors de l'évaluation génomique des reproducteurs. Chez les oiseaux, la structure hétérogène du génome nécessite de décrire précisément le DL pour optimiser la sélection. L'utilisation des puces SNP haute densité pour le génotypage des populations de volailles est une opportunité pour approfondir notre connaissance de la structure du DL de ces populations. L'objectif de cette étude est d'acquérir une connaissance haute résolution de la structure du DL au sein de populations de poules de types ponte et chair. Nous avons analysé les génotypes (puce 600 K Affymetrix® Axiom® HD SNP) de 1541 animaux issus de 3 populations. L'étendue et le niveau du DL ont été estimés par le r 2 moyen à distance physique donnée entre SNP. Cette étude met en évidence des différences importantes de structure du DL entre lignées et entre chromosomes. L'étendue et le niveau du DL sont plus importants dans les lignées de type ponte ou pour les macro-chromosomes et le chromosome Z. Ce niveau important de DL peut faciliter la détection de QTL sur ces chromosomes, mais peut également compliquer la localisation fine de polymorphismes causaux. A l'inverse, le faible niveau de DL observé sur les micro-chromosomes nécessite l'utilisation d'une forte densité de SNP pour détecter une association avec un phénotype, mais devrait permettre la cartographie fine d'un polymorphisme causal. Ces différences sont à prendre en considération pour définir une stratégie de génotypage économique et efficace pour la cartographie fine de QTL ou l'évaluation génomique. ABSTRACT A Linkage disequilibrium study in layers and broiler commercial chicken populations. Knowledge of the linkage disequilibrium (LD) pattern is useful in animal genetic studies as it underlies mapping studies and genomic selection. This is all the more important in birds given the heterogeneous structure of the avian karyotype. Recently, the availability of the high density 600 K Affymetrix® Axiom® HD SNP genotyping array allowed to assess an in-depth knowledge of the LD pattern in chicken genome. The aim of the present study was to assess a higher resolution of the LD pattern in chicken genome in layer and broiler lines. In this study, we analyzed genotypes of 1541 animals from layers and broiler commercial populations to characterize their LD pattern. LD was measured by the average r 2 value at a given physical distance between SNP. LD extended over a larger region for layer lines than for broiler line. Most differences between lines appeared at small interval distances (< 0.5Mb). LD extent and decay differed considerably between chromosomes categories. Average r 2 values were higher for Z chromosome than for macro, intermediates and micro-chromosomes. The extent of useful LD observed for autosomal chromosomes was at least tenfold longer for layer lines than for broiler. Finally, this study shed light on high LD for Z chromosome. The differences in LD pattern observed between chromosomes and chicken lines should be taken into account to define an economically efficient genotyping strategy

Identification of Biofilm-Associated Cluster (bac) in Pseudomonas aeruginosa Involved in Biofilm Formation and Virulence

Biofilms are prevalent in diseases caused by Pseudomonas aeruginosa, an opportunistic and nosocomial pathogen. By a proteomic approach, we previously identified a hypothetical protein of P. aeruginosa (coded by the gene pA3731) that was accumulated by biofilm cells. We report here that a ΔpA3731 mutant is highly biofilm-defective as compared with the wild-type strain. Using a mouse model of lung infection, we show that the mutation also induces a defect in bacterial growth during the acute phase of infection and an attenuation of the virulence. The pA3731 gene is found to control positively the ability to swarm and to produce extracellular rhamnolipids, and belongs to a cluster of 4 genes (pA3729–pA3732) not previously described in P. aeruginosa. Though the protein PA3731 has a predicted secondary structure similar to that of the Phage Shock Protein, some obvious differences are observed compared to already described psp systems, e.g., this unknown cluster is monocistronic and no homology is found between the other proteins constituting this locus and psp proteins. As E. coli PspA, the amount of the protein PA3731 is enlarged by an osmotic shock, however, not affected by a heat shock. We consequently named this locus bac for biofilm-associated cluster

Le ManNAc, une nouvelle thérapie dans la néphropathie à lésions glomérulaires minimes

Les thérapies actuellement utilisées dans la néphropathie à lésions glomérulaires minimes (LGM) ne sont que partiellement efficaces et comportent des effets secondaires importants. Un nouveau modèle animal présentant plusieurs caractéristiques de la LGM humaine a été développé. Il a permis de montrer qu’un défaut de sialylation de la protéine Angptl4 était impliqué dans le développement de la protéinurie. Dans ce modèle, Angptl4 est surexprimée au niveau du podocyte qui sécrète majoritairement la protéine sous une forme hyposialylée. La supplémentation de ces animaux en ManNac, un précurseur d’acide sialique, restaure partiellement la sialylation d’Angptl4 et réduit significativement leur protéinurie. La thérapie par le ManNAc semble donc prometteuse et pourrait être utilisée en complément des glucocorticoïdes chez les patients atteints de LGM

Effect of antibiotic co-administration on young and mature biofilms of cystic fibrosis clinical isolates: the importance of the biofilm model.

The prognosis of patients with cystic fibrosis (CF) has improved dramatically over the last three decades although the majority of patients still die in early adulthood. Infection with Pseudomonas aeruginosa has generally been associated with declining lung function and increased mortality in patients. This study aimed to investigate the in vitro activity of tobramycin/clarithromycin combination on biofilms of clinical isolates of P. aeruginosa, meticillin-susceptible and -resistant Staphylococcus aureus, and Burkholderia cepacia. First, the impact of antibiotic co-administration on biofilms at different stages of maturation, i.e. during early formation and on 24-h-old and 12-day-old biofilms, was compared. The 24-h-old biofilms were found to behave differently compared with those aged 12 days, which were more resistant to antibiotics. A kinetic study of antibiotic co-administration twice a day for 9 days on 12-day-old P. aeruginosa biofilms was then performed to simulate the effect of treatment of CF patients by inhaled tobramycin through aerosolisation (TOBI). The results obtained support a synergistic activity of tobramycin/clarithromycin combination on biofilms of P. aeruginosa PY02 and PA01, with a logarithmic bacterial decrease of 3.37 and 3.96, respectively. On the other hand, increased resistance to each of the antibacterial agents used alone was observed. This study highlights the importance of the biofilm stage for in vitro investigations and enabled the development of an in vitro model of mature biofilm that is more appropriate to mimic in vivo conditions in CF patients.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

L’Astrée. Première partie (1607)

International audienceÉdition critique établie sous la direction de Delphine Denis. Un siècle après l'Arcadia de Sannazar (1504), L'Astrée marque l'achèvement de la conquête de l'antique fable pastorale par les littératures européennes en langues vulgaires : paru entre 1607 et 1628, le roman d'Honoré d'Urfé est le dernier des grands chefs-d'oeuvre nourris de la veine des histoires de bergers. Mais la narration des amours de Céladon et Astrée dans la Gaule du Ve siècle inaugure aussi une nouvelle époque de la littérature française. Premier des grands récits publiés à l'époque où la France répare les plaies nées des guerres de Religion, l'oeuvre est très vite apparue comme une étape décisive dans l'art du roman, en même temps que, par sa philosophie de " l'honnête amitié ", elle s'est imposée à ses lecteurs comme une référence commune, offrant ainsi la mémoire littéraire des manières de sentir et d'aimer de l'âge classique. Le présent volume d'un ensemble appelé à compter cinq tomes constitue la première édition critique intégrale de L'Astrée : fondée sur un établissement scrupuleux du texte, elle est pour la première fois accompagnée d'un important appareil d'annotation

Influence of the implementation of strengths-based nursing and healthcare on early childhood nurses’ competencies ::a mixed-method study

Background : The scope of practice for nurses caring for families has evolved to meet the challenges presented by societal changes and increasing needs. In 2015, early childhood nurses from a Swiss region decided to implement a new model of care to guide their practice. The aim of this study was to explore the changes to early childhood nurses’ practices following the implementation of the strengths-based nursing and healthcare (SBNH) approach to care. Methods : This study of early childhood nurses’ (N = 61) practices used a pre-post intervention design and a mixed-method approach. Nurses’ competencies and changes in practice were measured using the Nurse Competence Scale (NCS). The quantitative data were analysed using descriptive statistics, Kruskal Wallis tests and logistic regression. Thematic analysis was used to derive themes from the qualitative data. Results : After the intervention, frequency of competency use increased in all domains of the NCS except the “teaching-coaching” domain; perceived levels of competencies also increased in all areas except “helping role” and “diagnostic functions”. Age and length of employment at the current post hindered improvement in the “teaching-coaching” competency. Interviews revealed themes related to the implementation process: “adaptability”, “implementation process”, “ambivalence” and “engagement to change”. Other themes were related to practice changes: “developing a disciplinary identity”, “path with families” and “strengths”. Conclusion : This study showed that the use of perceived competencies changed over time after the introduction of SBNH into practice. Nurses questioned and adapted their routines based on SBNH. Nurse’s vision of care also changed; they felt that their care was congruent with their values. For families, this approach allowed a change of vision with a resource-centred approach. Implementation of models of care such as the SBNH in the early childhood context is innovative, as little research in the literature addresses the early childhood community home-visiting context is still modest. This research underlines the added value of this approach on early childhood nurses’ competencies