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showing 10 items of 10255 documents
Enzyme replacement therapy with recombinant pro-CTSD (cathepsin D) corrects defective proteolysis and autophagy in neuronal ceroid lipofuscinosis
2019
CTSD (cathepsin D) is one of the major lysosomal proteases indispensable for the maintenance of cellular proteostasis by turning over substrates of endocytosis, phagocytosis and autophagy. Consequently, CTSD deficiency leads to a strong impairment of the lysosomal-autophagy machinery. In mice and humans CTSD dysfunction underlies the congenital variant (CLN10) of neuronal ceroid lipofuscinosis (NCL). NCLs are distinct lysosomal storage disorders (LSDs) sharing various hallmarks, namely accumulation of protein aggregates and ceroid lipofuscin leading to neurodegeneration and blindness. The most established and clinically approved approach to treat LSDs is enzyme replacement therapy (ERT) aim…
The growing role of precision medicine for the treatment of autoimmune diseases; results of a systematic review of literature and Experts’ Consensus
2021
International audience; Autoimmune diseases (AIDs) share similar serological, clinical, and radiological findings, but, behind these common features, there are different pathogenic mechanisms, immune cells dysfunctions, and targeted organs. In this context, multiple lines of evidence suggest the application of precision medicine principles to AIDs to reduce the treatment failure. Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient, thus it could be a new approach for management of AIDS which considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in ch…
Interleukin-9 and T helper type 9 cells in rheumatic diseases
2016
Summary Interleukin (IL)-9 is a 28-30 kDa monomeric glycosylated polypeptide belonging to the IL-7/IL-9 family of proteins that bind to a composite receptor consisting of the private receptor IL-9R and the IL-2 receptor, gamma (IL-2RG), a common gamma subunit shared by the receptors of many different cytokines. The IL-9R is expressed widely and IL-9 impacts a number of effector cells, such as effector T cells, B cells, innate lymphoid cells, mast cells, polymorphonuclear cells, epithelial cells and smooth muscle cells, playing an important role in regulating inflammatory immunity. The critical role of IL-9 in promoting cellular and humoral immune responses makes it an important focus of pot…
The best way to assess visually induced motion sickness in a fixed-base driving simulator
2017
Abstract Objective Driving simulator usage is becoming more widespread, yet many users still experience substantial motion sickness-like symptoms induced by optical flow, called visually induced motion sickness (VIMS). The Fast Motion sickness Scale (FMS) allows for continuous on-line assessment of VIMS. Using mixed models for ordinal data, this study investigated how to optimally analyze FMS data, and then used the resulting models to examine the development of symptoms over time in detail. Additionally, the study explored the impact of specific VIMS-inducing road elements. Methods Twenty-eight healthy young adults without prior simulator experience completed six courses on two days in a f…
A solution of the minimum-time velocity planning problem based on lattice theory
2018
For a vehicle on an assigned path, we find the minimum-time speed law that satisfies kinematic and dynamic constraints, related to maximum speed and maximum tangential and transversal acceleration. We present a necessary and sufficient condition for the feasibility of the problem and a simple operator, based on the solution of two ordinary differential equations, which computes the optimal solution. Theoretically, we show that the problem feasible set, if not empty, is a lattice, whose supremum element corresponds to the optimal solution.
Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth
2012
International audience; Chemotherapeutic agents are widely used for cancer treatment. In addition to their direct cytotoxic effects, these agents harness the host's immune system, which contributes to their antitumor activity. Here we show that two clinically used chemotherapeutic agents, gemcitabine (Gem) and 5-fluorouracil (5FU), activate the NOD-like receptor family, pyrin domain containing-3 protein (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. Chemotherapy-triggered IL-1β secretion relied on lysosomal permeabilization and the relea…
Imaging Noncanonical Autophagy and LC3-Associated Phagocytosis in Cultured Cells
2019
International audience; Monitoring of ATG8 proteins by western blotting and immunofluorescence microscopy are the most common methods to monitor the autophagy pathway. However, it has recently been shown that ATG8 proteins can be lipidated to non-autophagosome, single-membrane compartments through a noncanonical autophagy pathway. This is commonly found to occur during macro-endocytic processes such as phagocytosis, where it has been termed LC3-associated phagocytosis, and upon lysosomotropic drug treatment. Therefore, care is required when interpreting data based on ATG8 in order to conclude whether a signal relates to the canonical or noncanonical pathway. Here we provide methods to monit…
Application of high-content screening for the study of hepatotoxicity: Focus on food toxicology
2020
Safety evaluation of thousands of chemicals that are directly added to or come in contact with food is needed. Due to the central role of the liver in intermediary and energy metabolism and in the biotransformation of foreign compounds, the hepatotoxicity assessment is essential. New approach methodologies have been proposed for the safety evaluation of compounds with the idea of rapidly gaining insight into effects on biochemical mechanisms and cellular processes and screening large number of compounds. In this sense, high-content screening (HCS) is the application of automated microscopy and image analysis for better understanding of complex biological functions and mechanisms of toxicity…
Identité narrative, déprise et vécu du vieillissement
2018
Cet article se propose d’envisager le rapport entre deprise et recit de soi comme source de continuite identitaire dans une perspective philosophique, en reference a la notion d’identite narrative de Paul Ricœur. Si le recit de soi permet de mettre en forme le temps que l’on vit sans supposer un noyau non changeant de l’identite, ce recit devrait favoriser le processus de deprise. Mais cette mise en forme du temps par le recit se heurte a plusieurs obstacles : l’invisibilite de notre propre vieillissement qui ne nous laisse pas l’elaborer, sauf a souscrire aux regards exterieurs qui nous objectivent ; la difficulte d’articuler ce recit avec nos valeurs fondamentales dans la duree du temps d…
Structural and Functional Characterization of Autophosphorylation in Bacterial Histidine Kinases
2019
Autophosphorylation of histidine kinases (HK) is the first step for signal transduction in bacterial two-component signalling systems. As HKs dimerize, the His residue is phosphorylated in cis or trans depending on whether the ATP molecule used in the reaction is bound to the same or the neighboring subunit, respectively. The cis or trans autophosphorylation results from an alternative directionality in the connection between helices α1 and α2 in the HK DHp domain, in such a way that α2 could be oriented almost 90° counterclockwise or clockwise with respect to α1. Sequence and length variability of this connection appears to lie behind the different directionality and is implicated in partn…