Identification of an Intracellular Site of Prion Conversion

Prion diseases are fatal, neurodegenerative disorders in humans and animals and are characterized by the accumulation of an abnormally folded isoform of the cellular prion protein (PrPC), denoted PrPSc, which represents the major component of infectious scrapie prions. Characterization of the mechanism of conversion of PrPC into PrPSc and identification of the intracellular site where it occurs are among the most important questions in prion biology. Despite numerous efforts, both of these questions remain unsolved. We have quantitatively analyzed the distribution of PrPC and PrPSc and measured PrPSc levels in different infected neuronal cell lines in which protein trafficking has been selectively impaired. Our data exclude roles for both early and late endosomes and identify the endosomal recycling compartment as the likely site of prion conversion. These findings represent a fundamental step towards understanding the cellular mechanism of prion conversion and will allow the development of new therapeutic approaches for prion diseases

Overview of Current Drugs and Molecules in Development for Spinal Muscular Atrophy Therapy

The full text of this article can be found here: https://link.springer.com/article/10.1007/s40265-018-0868-

Protease-Resistant Prions Selectively Decrease Shadoo Protein

The central event in prion diseases is the conformational conversion of the cellular prion protein (PrPC) into PrPSc, a partially protease-resistant and infectious conformer. However, the mechanism by which PrPSc causes neuronal dysfunction remains poorly understood. Levels of Shadoo (Sho), a protein that resembles the flexibly disordered N-terminal domain of PrPC, were found to be reduced in the brains of mice infected with the RML strain of prions [1], implying that Sho levels may reflect the presence of PrPSc in the brain. To test this hypothesis, we examined levels of Sho during prion infection using a variety of experimental systems. Sho protein levels were decreased in the brains of mice, hamsters, voles, and sheep infected with different natural and experimental prion strains. Furthermore, Sho levels were decreased in the brains of prion-infected, transgenic mice overexpressing Sho and in infected neuroblastoma cells. Time-course experiments revealed that Sho levels were inversely proportional to levels of protease-resistant PrPSc. Membrane anchoring and the N-terminal domain of PrP both influenced the inverse relationship between Sho and PrPSc. Although increased Sho levels had no discernible effect on prion replication in mice, we conclude that Sho is the first non-PrP marker specific for prion disease. Additional studies using this paradigm may provide insight into the cellular pathways and systems subverted by PrPSc during prion disease

Development of randomized trials in adults with medulloblastoma - the example of EORTC 1634-BTG/NOA-23

Simple Summary Medulloblastoma is rare after puberty. Among several molecular subgroups that have been described, the sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal population and can be targeted with smoothened (SMO) inhibitors. However, no practice-changing prospective clinical trials have been published in adults to date. Tumors often recur, and treatment toxicity is relevant. Thus, the EORTC 1634-BTG/NOA-23 trial for post-pubertal patients with standard risk medulloblastoma will aim to increase treatment efficacy and to decrease treatment toxicity. Patients will be randomized between standard-dose vs. reduced-dosed radiotherapy, and SHH-subgroup patients will also be randomized between the SMO inhibitor sonidegib (Odomzo(TM,), Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone. In ancillary studies, we will investigate tumor tissue, blood and cerebrospinal fluid samples, magnetic resonance images, and radiotherapy plans to gain information that may improve future treatment. Patients will also be monitored long-term for late side effects of therapy, health-related quality of life, cognitive function, social and professional live outcomes, and reproduction and fertility. In summary, EORTC 1634-BTG/NOA-23 is a unique multi-national effort that will help to council patients and clinical scientists for the appropriate design of treatments and future clinical trials for post-pubertal patients with medulloblastoma. Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (Odomzo(TM), Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.Neurolog

Optimised and Rapid Pre-clinical Screening in the SOD1G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis (ALS)

The human SOD1G93A transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS). In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3–4 months) is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6) SOD1G93A transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved

Lift improvement usign piezoelectric actuator

This paper deals with the determination of the lift improvement of plane winy using pulsed jets generated by piezoelectric actuators. This actuator is constituted by a large bimorph constituted by piezoelectric patches cemented on a brass plate. The bimorph is inserted into a rigid case and one of the long edge plate is clamped the other is free. An alternating voltage is applied to the piezoelectric patches inducing the bending of the brass plate which opens and closes a 100 x 1 mm2 slit. Due to the internal static pressure pulsated jets arc formed and escape the slit. This actuator is inserted into a particular wing profile in order to measure the pressure modifications induced by the jets and the corresponding lift improvements are deduced. The best functioning conditions of the actuator and the lift improvement are determined and discusse

Focus sur le système endocannabinoïde et la reprotoxicité du cannabis chez la femme à l’heure du débat sur sa dépénalisation en France

International audienceAmong recreative compounds, marijuana is the most used worldwide. Delta9THC binding on brain endocannabinoid receptors drives its psychotropic effects. The endocannabinoid system (ECS) is an endogenous neurohormonal system essential for homeostasis composed of ligands, metabolic enzymes and at least 2 receptors discovered to date. In female reproduction, the ECS regulates the hypothalamic-pituitary axis and many steps of the reproduction process, such as ovulation, tubal transportation and trophoblast implantation. Delta9THC can cross the placental barrier and bind to the fetal endocannabinoid system. In humans, fetal and obstetrical consequences of marijuana use during pregnancy are intrauterine growth restriction and preterm delivery. In the light of legalization projects currently reviewed in several western countries, further research should be conducted to improve knowledge on maternal, fetal and reprotoxic consequences of marijuana use during reproductive age and pregnancy.Le cannabis est le psychotrope récréatif le plus utilisé dans le monde. Les effets recherchés sont obtenus par l’action du delta9THC sur les récepteurs cérébraux du système endocannabinoïde. Le système endocannabinoïde est indispensable à l’homéostasie de l’organisme. Il est composé d’un ensemble de récepteurs, ligands endogènes et d’enzymes de son métabolisme distribués de manière ubiquitaire dans l’organisme. Chez la femme, il participe à la régulation de nombreuses étapes du processus de reproduction : régulation de l’axe hypothalamohypophysaire, ovulation, transport tubaire, implantation trophoblastique. Le delta9THC, lipophile, traverse la barrière placentaire et peut se fixer sur le système endocannabinoïde fœtal qui apparaît précocement au cours du développement. Chez l’humain, les conséquences fœtales et obstétricales connues de la consommation de cannabis au cours de la grossesse sont principalement le retard de croissance et l’accouchement prématuré. Au vu des discussions actuellement menées dans plusieurs pays concernant la légalisation de la consommation de cannabis, de nouvelles recherches sont nécessaires pour en préciser les conséquences maternelles, fœtales et reprotoxiques