Centronuclear myopathy in labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide

Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ~70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previously identified an autosomal recessive form of CNM in French Labrador retrievers from an experimental pedigree, and showed that a loss-of-function mutation in the protein tyrosine phosphatase-like A (PTPLA) gene segregated with CNM. Around the world, client-owned Labrador retrievers with a similar clinical presentation and histopathological changes in muscle biopsies have been described. We hypothesized that these Labradors share the same PTPLA<sup>cnm</sup> mutation. Genotyping of an international panel of 7,426 Labradors led to the identification of PTPLA<sup>cnm</sup> carriers in 13 countries. Haplotype analysis demonstrated that the PTPLA<sup>cnm</sup> allele resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires. PTPLA-deficient Labradors will help define the integrated role of PTPLA in the existing CNM gene network. They will be valuable complementary large animal models to test innovative therapies in CNM

Can Monkeys Make Investments Based on Maximized Pay-off?

Animals can maximize benefits but it is not known if they adjust their investment according to expected pay-offs. We investigated whether monkeys can use different investment strategies in an exchange task. We tested eight capuchin monkeys (Cebus apella) and thirteen macaques (Macaca fascicularis, Macaca tonkeana) in an experiment where they could adapt their investment to the food amounts proposed by two different experimenters. One, the doubling partner, returned a reward that was twice the amount given by the subject, whereas the other, the fixed partner, always returned a constant amount regardless of the amount given. To maximize pay-offs, subjects should invest a maximal amount with the first partner and a minimal amount with the second. When tested with the fixed partner only, one third of monkeys learned to remove a maximal amount of food for immediate consumption before investing a minimal one. With both partners, most subjects failed to maximize pay-offs by using different decision rules with each partner' quality. A single Tonkean macaque succeeded in investing a maximal amount to one experimenter and a minimal amount to the other. The fact that only one of over 21 subjects learned to maximize benefits in adapting investment according to experimenters' quality indicates that such a task is difficult for monkeys, albeit not impossible

The mismeasure of ape social cognition

In his classic analysis, The Mismeasure of Man, Gould (1981) demolished the idea that intelligence was an inherent, genetic trait of different human groups by emphasizing, among other things, (a) its sensitivity to environmental input, (b) the incommensurate pre-test preparation of different human groups, and (c) the inadequacy of the testing contexts, in many cases. According to Gould, the root cause of these oversights was confirmation bias by psychometricians, an unwarranted commitment to the idea that intelligence was a fixed, immutable quality of people. By virtue of a similar, systemic interpretive bias, in the last two decades, numerous contemporary researchers in comparative psychology have claimed human superiority over apes in social intelligence, based on two-group comparisons between postindustrial, Western Europeans and captive apes, where the apes have been isolated from European styles of social interaction, and tested with radically different procedures. Moreover, direct comparisons of humans with apes suffer from pervasive lapses in argumentation: Research designs in wide contemporary use are inherently mute about the underlying psychological causes of overt behavior. Here we analyze these problems and offer a more fruitful approach to the comparative study of social intelligence, which focuses on specific individual learning histories in specific ecological circumstances

Study of the Role of the Tyrosine Kinase Receptor MerTK in the Development of Kidney Ischemia-Reperfusion Injury in RCS Rats

Renal ischaemia reperfusion (I/R) triggers a cascade of events including oxidative stress, apoptotic body and microparticle (MP) formation as well as an acute inflammatory process that may contribute to organ failure. Macrophages are recruited to phagocytose cell debris and MPs. The tyrosine kinase receptor MerTK is a major player in the phagocytosis process. Experimental models of renal I/R events are of major importance for identifying I/R key players and for elaborating novel therapeutical approaches. A major aim of our study was to investigate possible involvement of MerTK in renal I/R. We performed our study on both natural mutant rats for MerTK (referred to as RCS) and on wild type rats referred to as WT. I/R was established by of bilateral clamping of the renal pedicles for 30′ followed by three days of reperfusion. Plasma samples were analysed for creatinine, aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), kidney injury molecule -1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels and for MPs. Kidney tissue damage and CD68-positive cell requirement were analysed by histochemistry. monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), and histone 3A (H3A) levels in kidney tissue lysates were analysed by western blotting. The phagocytic activity of blood-isolated monocytes collected from RCS or WT towards annexin-V positive bodies derived from cultured renal cell was assessed by fluorescence-activated single cell sorting (FACS) and confocal microscopy analyses. The renal I/R model for RCS rat described for the first time here paves the way for further investigations of MerTK-dependent events in renal tissue injury and repair mechanisms

Étude des effets potentiels du récepteur MerTK sur le développement des lésions liées à une ischémie/reperfusion rénale chez le rat

Ischemia reperfusion is characterized by two distinct phases: a cessation then a return of blood supply and may occur in some pathological situations as well as during organ transplantation. This sequence of events can induce cell death, formation of cell debris and microparticles. Apoptotic bodies and microparticles are characterized by the exposure of phosphatidylserine on the outer membrane bilayer. Ischemia reperfusion-induced cell damage lead to the activation of inflammation and to leukocyte recruitment through the release of cytokines/chemokines. Recruited macrophages may phagocyte cellular debris and microparticles. It has previously been established that the MerTK tyrosine kinase receptor, expressed by several cell types including macrophages, plays a major role in the phagocytosis process. The vitamin K-dependent anticoagulant factor Protein S is the MerTK receptor ligand. It binds by its C-terminus to MerTK receptor on the surface of macrophages and by its N-terminus to phosphatidylserins exposed by apoptotic bodies and microparticles bridging thereby the phagocytes (macrophages) to the substrate (phosphatidylserine exposing bodies). The objective of our study is to characterize the role of MerTK in both the development of lesions induced by renal ischemia reperfusion and in post-ischemic repair. We used a model of RCS (Royal College of Surgeons) rats characterized by a defective MerTK due to a natural mutation in the MerTK gene. Simulation of renal ischemia reperfusion is performed by clamping the artery and renal vein. The blood and kidneys are collected and, using ELISA, Western Blot and biochemical assays, markers of kidney function and lesions, inflammation and leukocyte recruitment are determined. Histological lesions on renal sections are monitored by HES-PAS staining, and the location and quantification of leukocyte recruitment were assessed by immunohistochemistry technique. We also used flow cytometry to quantify microparticles of platelet, endothelial and leukocyte origin in plasma. Finally, we studied the possible role of MerTK in phagocytosis in vitro, by co-incubation of apoptotic bodies with monocytes/macrophages, derived from the blood of MerTK-deficient RCS rats or control rats normally expressing this receptor.Our work has made it possible to develop a technique for detecting microparticles by double labelling, with an antibody specific to cell origin and annexin V, a molecule that marks all microparticles by binding to phosphatidylserine. The quantification of these microparticles shows an increase, post-surgery, of platelet, endothelial and leukocyte origin. The measurements of creatinine, a marker of renal function, as well as those of inflammatory markers and histological lesions did not show significant differences between any of the renal ischemia reperfusion groups. Nevertheless, macrophage infiltration 3 days after ischemia reperfusion seems more important in RCS rats than in control rats. In addition, in vitro phagocytosis did not show any significant difference between RCS rats and their control. Our study suggests minimal involvement of the MerTK receptor in the development and repair of lesions during a sequence of renal ischemia reperfusion. Nevertheless, this work has enabled us to characterize and quantify the microparticles generated following renal ischemia reperfusion by techniques that could subsequently be used in the evaluation of biomarkers of renal lesions.L'ischémie reperfusion se caractérise par deux phases distinctes : une cessation puis un retour de l’apport sanguin et peut se produire dans certaines situations pathologiques et lors de la transplantation d’organes. Cette séquence d’évènements peut induire la mort cellulaire, la formation de débris cellulaires et de microparticules. Les corps apoptotiques et les microparticules se caractérisent par l’exposition de la phosphatidylsérine sur le feuillet externe de leur membrane. Les cellules lésées suite à l’ischémie reperfusion entraînent, par le relargage de cytokines/chimiokines, l’activation de l’inflammation et le recrutement de leucocytes, tel que les macrophages. Les macrophages permettent l’élimination par phagocytose des débris cellulaires et des microparticules. Il a été établi précédemment que le récepteur tyrosine kinase MerTK, exprimé par plusieurs types cellulaires dont les macrophages, joue un rôle majeur dans la phagocytose. En effet, l’interaction du récepteur MerTK avec son ligand, la protéine S, permet la formation d’un pont entre le macrophage et les phosphatidylsérines exposées par les corps apoptotiques et les microparticules. MerTK contribue aussi à une régulation négative de l’expression de certaines molécules pro-inflammatoires impliquées dans le recrutement leucocytaire. L’objectif de notre étude est de caractériser le rôle de MerTK dans le développement des lésions induites par une ischémie reperfusion rénale mais aussi dans la réparation post-ischémique. Nous avons utilisé un modèle de rats RCS (Royal College of Surgeons) caractérisés par un MerTK défectueux en raison d’une mutation naturelle dans le gène MerTK. La simulation de l’ischémie reperfusion rénale s’effectue par le clampage de l’artère et de la veine rénale. Le sang et les reins prélevés permettent d’évaluer, via des techniques d’ELISA, de Western Blot et de dosages biochimiques, des marqueurs de la fonction et de lésions rénales, d’inflammation et de recrutement leucocytaire. Les lésions histologiques sur des coupes rénales sont mises en évidence par les colorations HES-PAS, et la localisation ainsi que la quantification du recrutement leucocytaire ont été évaluées par la technique d’immunohistochimie. Nous avons par ailleurs utilisé la technique de cytométrie en flux pour quantifier les microparticules d’origine plaquettaires, endothéliales et leucocytaires dans le plasma. Enfin, nous avons étudié le rôle possible de MerTK dans la phagocytose in vitro, par co-incubation de corps apoptotiques avec des monocytes/macrophages, provenant de sang de rats RCS déficients en MerTK ou de rats contrôles exprimant normalement ce récepteur

Study of potential effects of the tyrosine kinase receptor MerTK on the development of ischemia/renal perfusion-related lesions in rats

L'ischémie reperfusion se caractérise par deux phases distinctes : une cessation puis un retour de l’apport sanguin et peut se produire dans certaines situations pathologiques et lors de la transplantation d’organes. Cette séquence d’évènements peut induire la mort cellulaire, la formation de débris cellulaires et de microparticules. Les corps apoptotiques et les microparticules se caractérisent par l’exposition de la phosphatidylsérine sur le feuillet externe de leur membrane. Les cellules lésées suite à l’ischémie reperfusion entraînent, par le relargage de cytokines/chimiokines, l’activation de l’inflammation et le recrutement de leucocytes, tel que les macrophages. Les macrophages permettent l’élimination par phagocytose des débris cellulaires et des microparticules. Il a été établi précédemment que le récepteur tyrosine kinase MerTK, exprimé par plusieurs types cellulaires dont les macrophages, joue un rôle majeur dans la phagocytose. En effet, l’interaction du récepteur MerTK avec son ligand, la protéine S, permet la formation d’un pont entre le macrophage et les phosphatidylsérines exposées par les corps apoptotiques et les microparticules. MerTK contribue aussi à une régulation négative de l’expression de certaines molécules pro-inflammatoires impliquées dans le recrutement leucocytaire. L’objectif de notre étude est de caractériser le rôle de MerTK dans le développement des lésions induites par une ischémie reperfusion rénale mais aussi dans la réparation post-ischémique. Nous avons utilisé un modèle de rats RCS (Royal College of Surgeons) caractérisés par un MerTK défectueux en raison d’une mutation naturelle dans le gène MerTK. La simulation de l’ischémie reperfusion rénale s’effectue par le clampage de l’artère et de la veine rénale. Le sang et les reins prélevés permettent d’évaluer, via des techniques d’ELISA, de Western Blot et de dosages biochimiques, des marqueurs de la fonction et de lésions rénales, d’inflammation et de recrutement leucocytaire. Les lésions histologiques sur des coupes rénales sont mises en évidence par les colorations HES-PAS, et la localisation ainsi que la quantification du recrutement leucocytaire ont été évaluées par la technique d’immunohistochimie. Nous avons par ailleurs utilisé la technique de cytométrie en flux pour quantifier les microparticules d’origine plaquettaires, endothéliales et leucocytaires dans le plasma. Enfin, nous avons étudié le rôle possible de MerTK dans la phagocytose in vitro, par co-incubation de corps apoptotiques avec des monocytes/macrophages, provenant de sang de rats RCS déficients en MerTK ou de rats contrôles exprimant normalement ce récepteur.Ischemia reperfusion is characterized by two distinct phases: a cessation then a return of blood supply and may occur in some pathological situations as well as during organ transplantation. This sequence of events can induce cell death, formation of cell debris and microparticles. Apoptotic bodies and microparticles are characterized by the exposure of phosphatidylserine on the outer membrane bilayer. Ischemia reperfusion-induced cell damage lead to the activation of inflammation and to leukocyte recruitment through the release of cytokines/chemokines. Recruited macrophages may phagocyte cellular debris and microparticles. It has previously been established that the MerTK tyrosine kinase receptor, expressed by several cell types including macrophages, plays a major role in the phagocytosis process. The vitamin K-dependent anticoagulant factor Protein S is the MerTK receptor ligand. It binds by its C-terminus to MerTK receptor on the surface of macrophages and by its N-terminus to phosphatidylserins exposed by apoptotic bodies and microparticles bridging thereby the phagocytes (macrophages) to the substrate (phosphatidylserine exposing bodies). The objective of our study is to characterize the role of MerTK in both the development of lesions induced by renal ischemia reperfusion and in post-ischemic repair. We used a model of RCS (Royal College of Surgeons) rats characterized by a defective MerTK due to a natural mutation in the MerTK gene. Simulation of renal ischemia reperfusion is performed by clamping the artery and renal vein. The blood and kidneys are collected and, using ELISA, Western Blot and biochemical assays, markers of kidney function and lesions, inflammation and leukocyte recruitment are determined. Histological lesions on renal sections are monitored by HES-PAS staining, and the location and quantification of leukocyte recruitment were assessed by immunohistochemistry technique. We also used flow cytometry to quantify microparticles of platelet, endothelial and leukocyte origin in plasma. Finally, we studied the possible role of MerTK in phagocytosis in vitro, by co-incubation of apoptotic bodies with monocytes/macrophages, derived from the blood of MerTK-deficient RCS rats or control rats normally expressing this receptor. Our work has made it possible to develop a technique for detecting microparticles by double labelling, with an antibody specific to cell origin and annexin V, a molecule that marks all microparticles by binding to phosphatidylserine. The quantification of these microparticles shows an increase, post-surgery, of platelet, endothelial and leukocyte origin. The measurements of creatinine, a marker of renal function, as well as those of inflammatory markers and histological lesions did not show significant differences between any of the renal ischemia reperfusion groups. Nevertheless, macrophage infiltration 3 days after ischemia reperfusion seems more important in RCS rats than in control rats. In addition, in vitro phagocytosis did not show any significant difference between RCS rats and their control. Our study suggests minimal involvement of the MerTK receptor in the development and repair of lesions during a sequence of renal ischemia reperfusion. Nevertheless, this work has enabled us to characterize and quantify the microparticles generated following renal ischemia reperfusion by techniques that could subsequently be used in the evaluation of biomarkers of renal lesions

I wanna draw like you: Inter-and intra-individual differences in orang-utan drawings

Recently discovered, the oldest human abstract drawing is around 73,000 years. Although the origins of drawing behaviour have remained an enigma to this day, light may be shone on the subject through its study among our closest neighbours, the great apes. This study analyses 749 drawings of five female Bornean orang-utans (Pongo pygmaeus) at Tama Zoological Park in Japan. We searched for differences between individuals but also tried to identify possible temporal changes among the drawings of one individual, Molly, who drew almost 1,300 drawings from 2006 to 2016. A classical analysis of the drawings was carried out after collecting quantitative and qualitative variables. Our findings reveal evidence of differences in the drawing style of the five individuals as well as creative changes in Molly's drawing style throughout her lifetime. Individuals differed in terms of the colours used, the space they filled but also the shapes (fan patterns, circles or loops) they drew. Molly drew less and less as she grew older, and we found a significant difference between drawings produced in winter, when orang-utans were kept inside and had less activity, and those produced during other seasons. Our results suggest that the drawing behaviour of these five orangutans is not random and that differences among individuals might reflect differences of styles, states of mind but also motivation to draw. These novel results are a significant contribution to our understanding of how drawing behaviour evolved in hominids

An overview of tools to decipher O-GlcNAcylation from historical approaches to new insights

International audienceO-GlcNAcylation is a post-translational modification which affects approximately 5000 human proteins. Its involvement has been shown in many if not all biological processes. Variations in O-GlcNAcylation levels can be associated with the development of diseases. Deciphering the role of O-GlcNAcylation is an important issue to (i) understand its involvement in pathophysiological development and (ii) develop new therapeutic strategies to modulate O-GlcNAc levels. Over the past 30 years, despite the development of several approaches, knowledge of its role and regulation have remained limited. This review proposes an overview of the currently available tools to study O-GlcNAcylation and identify O-GlcNAcylated proteins. Briefly, we discuss pharmacological modulators, methods to study O-GlcNAcylation levels and approaches for O-GlcNAcylomic profiling. This review aims to contribute to a better understanding of the methods used to study O-GlcNAcylation and to promote efforts in the development of new strategies to explore this promising modification

Nomination des commissaires au dépouillement du scrutin pour le complément du comité des Transports, postes et messageries, lors de la séance du 29 fructidor an II (15 septembre 1794)

Barailon Jean-François, Pelé Bon Thomas, Bernard de Saint Affrique Louis, Béraud Marcellin. Nomination des commissaires au dépouillement du scrutin pour le complément du comité des Transports, postes et messageries, lors de la séance du 29 fructidor an II (15 septembre 1794). In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XCVII - Du 23 fructidor an II au 2 vendémiaire an III (9 au 23 septembre 1794) Paris : CNRS éditions, 1993. p. 200