Using protein design algorithms to understand the molecular basis of disease caused by protein–DNA interactions: the Pax6 example

Quite often a single or a combination of protein mutations is linked to specific diseases. However, distinguishing from sequence information which mutations have real effects in the protein’s function is not trivial. Protein design tools are commonly used to explain mutations that affect protein stability, or protein–protein interaction, but not for mutations that could affect protein–DNA binding. Here, we used the protein design algorithm FoldX to model all known missense mutations in the paired box domain of Pax6, a highly conserved transcription factor involved in eye development and in several diseases such as aniridia. The validity of FoldX to deal with protein–DNA interactions was demonstrated by showing that high levels of accuracy can be achieved for mutations affecting these interactions. Also we showed that protein-design algorithms can accurately reproduce experimental DNA-binding logos. We conclude that 88% of the Pax6 mutations can be linked to changes in intrinsic stability (77%) and/or to its capabilities to bind DNA (30%). Our study emphasizes the importance of structure-based analysis to understand the molecular basis of diseases and shows that protein–DNA interactions can be analyzed to the same level of accuracy as protein stability, or protein–protein interactions

La question philosophique de la peine de mort

En prenant pour objet d'étude les discours les plus emblématiques qu'ait produit la philosophie moderne au sujet de la peine de mort, notre intention n'est nullement de peser le pour et le contre en vue de déterminer quelle position s'avère la plus raisonnable. Il s'agit plus précisément d'examiner la possibilité de fonder en raison le refus catégorique de la peine capitale. A cet égard, l'examen des différents discours philosophiques nous montre à quel point cette raison est avant tout divisée contre elle-même. En effet, au terme d'un travail visant à sonder la cohérence interne des partisans de la peine de mort (Locke, Kant, Stuart Mill) ainsi que de ses adversaires (Beccaria, Bentham), il nous est apparu impossible de conclure à un défaut de rationalité de la part de ceux-ci ou de ceux-là. Ce que l'on constate au contraire, c'est que chaque démonstration se déploie à partir d'un certain nombre de principes éthiques indémontrables. Bien plus, chaque théorie pénale est susceptible de donner lieu à des prises de position radicalement différentes. Mais pour peu que l'on se refuse à concevoir un abîme insurmontable entre la raison d'une part, et ce que Pascal et Rousseau nomment le cœur d'autre part, la philosophie morale peut bénéficier d'une approche dans laquelle le raisonnement et la sensibilité se complètent au lieu de constituer une alternative. C'est dans l'œuvre de Jean-Jacques Rousseau qu'il convient selon nous de repérer les éléments permettant d'éviter le double écueil du rationalisme dogmatique et de l'émotivisme relativiste.This thesis is a study about the most significant philosophical writings on death penalty under the Enlightment period. Our main purpose is not to present the pros and cons on such a matter but to examine the possibility to give a rational foundation to a categorical condemnation of death penalty. Our aim is to determine wether one should understand the distance between opponents and supporters of such a punishment as a gap between rationality and passion or sensitivity. It is striking to notice that both sides tend to qualify their opponent's position as irrational. On one hand, those in favour of capital punishment are usually considered as blinded by a strong desire of revenge; on the other hand, abolitionists are accused of betraying justice because of their compassion toward criminals. But is the answer to the question of death penalty a matter of pure rationality? By studying the writings of those who opposed it (Beccaria, Bentham, Fichte) and those who supported it (Kant and John Stuart Mill), we came to the conclusion that it is totally hopeless to expect our reason alone to put an end to this debate. In reality, human reason is able to produce different conclusions depending on the premises we choose to consider as right. Our second conclusion is that it is even impossible to say that retributivism and utilitarianism in themselves support or oppose death penalty. Different versions and interpretations of these two theories lead their defenders to different positions. Finally we found in Jean-Jacques Rousseau's works some decisive elements in order to argue against death penalty without ending into dogmatic rationalism nor pure emotivism.NANTERRE-BU PARIS10 (920502102) / SudocSudocFranceF

Analysis of the Genetic Diversity and Population Structure of Four Senegalese Sheep Breeds Using Medium-Density Single-Nucleotide Polymorphisms

International audienceIn Senegal, sheep breeds have adapted to their environment and play a key socio-economic role. This study aimed to explore the genetic diversity and structure of four Senegalese sheep breeds (Peul-peul, Djallonke, Touabire, and Ladoum) and their relationships with global sheep breeds. To that end, forty-seven sheep were genotyped using the OvineSNP50 BeadChip, and these genotypic data were analysed with those of 73 sheep breeds representative of worldwide ovine diversity (2729 animals). The average observed heterozygosity (Ho) ranged from 0.293 in Djallonke sheep to 0.339 in Touabire sheep. The estimated Fis values were low, ranging from 0.019 for Ladoum to 0.034 for Peul-peul sheep. The estimated Fst values were low (0.003–0.044) among the trypanosusceptible breeds (Peul-peul, Touabire, and Ladoum) but high between the previous breeds and the trypanotolerant Djallonke breed (0.075–0.116), indicating better genetic conservation of the Djallonke sheep. A principal component analysis revealed clustering of the Senegalese sheep breeds according to their geographic distribution. However, owing to genetic improvement practices, the introgression of Touabire sheep blood seems to have reshaped the genetic landscape of the trypanosusceptible sheep breeds in Senegal. The Senegalese sheep breeds showed lower genetic diversity than their presumed ancestral sheep breeds of the Middle East. They also presented some relatedness with Caribbean sheep breeds, which reveals their contribution to the global genetic diversity and to the development of Caribbean sheep breeds

Can empathy be taught? A cross-sectional survey assessing training to deliver the diagnosis of end stage renal disease

International audienceBackground: Receiving the diagnosis of kidney failure has a major impact on patients. Yet, the way in which this diagnosis should be delivered is not formally taught within our medical curriculum. To fill this gap we set up a training course of kidney failure diagnosis delivery for nephrology trainees since 2016. This study assessed the effectiveness of this educational intervention.Methods: The primary outcome was change in the empathy score immediately after the training session and several months afterward, based on the Jefferson Scale of Physician Empathy (JSPE). Self-reported change in clinical practice was also evaluated. As control groups, we assessed empathy levels in untrained nephrology trainees (n = 26) and senior nephrologists (n = 71). Later on (>6 months) we evaluated participants’ perception of changes in their clinical practice due to the training.Results: Six training sessions permitted to train 46 trainees. Most respondents (76%) considered the training to have a durable effect on their clinical practice. Average empathy scores were not significantly different in pre-trained trainees (average JSPE: 103.7 ± 11.4), untrained trainees (102.8 ± 16.4; P = 0.81) and senior nephrologists (107.2 ± 13.6; P = 0.15). Participants’ empathy score significantly improved after the training session (112.8 ± 13.9; P = 0.003). This improvement was sustained several months afterwards (average JSPE 110.5 ± 10.8; P = 0.04).Conclusion: A single 4-hour training session can have long lasting impact on empathy and clinical practice of participants. Willingness to listen, empathy and kindness are thought to be innate and instinctive skills, but they can be acquired and should be taught