Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids

Studies of human T cell development require robust model systems that recapitulate the full span of thymopoiesis, from hematopoietic stem and progenitor cells (HSPCs) through to mature T cells. Existing in vitro models induce T cell commitment from human HSPCs; however, differentiation into mature CD3^+TCR-αβ^+ single-positive CD8^+ or CD4^+ cells is limited. We describe here a serum-free, artificial thymic organoid (ATO) system that supports efficient and reproducible in vitro differentiation and positive selection of conventional human T cells from all sources of HSPCs. ATO-derived T cells exhibited mature naive phenotypes, a diverse T cell receptor (TCR) repertoire and TCR-dependent function. ATOs initiated with TCR-engineered HSPCs produced T cells with antigen-specific cytotoxicity and near-complete lack of endogenous TCR Vβ expression, consistent with allelic exclusion of Vβ-encoding loci. ATOs provide a robust tool for studying human T cell differentiation and for the future development of stem-cell-based engineered T cell therapies

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Avantages et inconvénients de placer une fratrie ensemble dans la même institution: le point de vue des éducateurs et des fratries

L’objectif de ce travail est de comprendre dans quelle mesure le placement commun des fratries en institution est bénéfique ou non pour les éducateurs ainsi que pour les frères et soeurs. Il s’agit également de définir une prise en charge éducative qui soit adaptée aux besoins de chacun. Nous avons voulu répondre à plusieurs hypothèses portant sur l’accueil des fratries en institution. Dans ce but, deux catégories d’hypothèses ont été formulées. D’une part, celles qui soutiennent le placement commun des germains et qui valorisent les liens fraternels, en disant que ceux-ci permettent de mieux vivre des expériences familiales difficiles, et de faciliter l’intégration dans l’institution. D’autre part, celles qui avancent qu’il existe plusieurs facteurs pouvant freiner le placement commun tels les loyautés familiales ou des difficultés à s’intégrer dans l’institution. Pour répondre à ces hypothèses, nous avons d’abord défini et développé les concepts théoriques utiles à la compréhension de nos questionnements. Ensuite, afin de pouvoir mieux saisir les enjeux d’une telle situation, nous avons interrogé six éducateurs sociaux travaillant avec des fratries, et cinq germains ayant été placés avec leur fratrie en foyer. Ce double regard nous a permis d’identifier les difficultés liées au placement commun, mais aussi les bénéfices de celui-ci qui semblent primer. En effet, le placement semble avantageux, autant pour les professionnels que pour les frères et soeurs. Professionnellement et personnellement, nous sommes arrivées à la conclusion que dans de nombreux cas, les liens fraternels nourrissent le placement commun. Pourtant, il semble utile de préciser qu’il existe des situations dans lesquelles la présence de l’ensemble de la fratrie en institution peut être remise en question. Ces deux approches divergentes sont approfondies et argumentées dans ce travail de recherche

Autonomous object modeling and exploiting: a new approach based on affordances from continual interaction with environment

International audienceWe present an architecture for self-motivated agents to generate behaviors in an environment that is continuous, both in space and time, through a continual interaction process. The long-term goal is to design agents that construct their own knowledge of objects and space through experience of the environment , rather than exploiting pre-coded knowledge. The agent exploits this constructed knowledge to exhibit behaviors satisfying its self-motivated principles, based on valences attributed to interactions, that specify inborn behavioral preferences. Over time, the agent learns the relation between its perception of objects and the interactions that they afford, in the form of data structures, called signatures of interaction. The agent keeps track of enacted interactions in a spatial memory in which it can use signatures to recognize and localize distant possibilities of interactions, and exhibits behaviors that satisfy its motivation principles, accordingly to this approach. In this paper, we propose a continual decision cycle between an agent and its environment to cope with the constraints that an artificial agent would meet in a physical environment

Autonomous object modeling and exploiting: a new approach based on affordances from continual interaction with environment

International audienceWe present an architecture for self-motivated agents to generate behaviors in an environment that is continuous, both in space and time, through a continual interaction process. The long-term goal is to design agents that construct their own knowledge of objects and space through experience of the environment , rather than exploiting pre-coded knowledge. The agent exploits this constructed knowledge to exhibit behaviors satisfying its self-motivated principles, based on valences attributed to interactions, that specify inborn behavioral preferences. Over time, the agent learns the relation between its perception of objects and the interactions that they afford, in the form of data structures, called signatures of interaction. The agent keeps track of enacted interactions in a spatial memory in which it can use signatures to recognize and localize distant possibilities of interactions, and exhibits behaviors that satisfy its motivation principles, accordingly to this approach. In this paper, we propose a continual decision cycle between an agent and its environment to cope with the constraints that an artificial agent would meet in a physical environment

Autonomous object modeling and exploiting: a new approach based on affordances from continual interaction with environment

International audienceWe present an architecture for self-motivated agents to generate behaviors in an environment that is continuous, both in space and time, through a continual interaction process. The long-term goal is to design agents that construct their own knowledge of objects and space through experience of the environment , rather than exploiting pre-coded knowledge. The agent exploits this constructed knowledge to exhibit behaviors satisfying its self-motivated principles, based on valences attributed to interactions, that specify inborn behavioral preferences. Over time, the agent learns the relation between its perception of objects and the interactions that they afford, in the form of data structures, called signatures of interaction. The agent keeps track of enacted interactions in a spatial memory in which it can use signatures to recognize and localize distant possibilities of interactions, and exhibits behaviors that satisfy its motivation principles, accordingly to this approach. In this paper, we propose a continual decision cycle between an agent and its environment to cope with the constraints that an artificial agent would meet in a physical environment

Autonomous affordance construction without planning for environment-agnostic agents

International audienceWe present an architecture for self-motivated agents to organize their behaviors according to possibilities of interactions proposed by the environment, and to modify the environment to construct new possibilities of interactions. The long-term goal is to design agents that construct their own knowledge of objects through experience, rather than exploiting pre-coded knowledge, and exploit this knowledge to generate complex behaviors that satisfy their intrinsic motivation principles. Self-motivation is defined here as a tendency, based on inborn behavioral preferences, to experiment and to respond to behavioral opportunities afforded by the environment. Over time, the agent integrates, through its experience, relations between interactions and object affording them in the form of data structures, called signatures of interaction, which encode the minimal spatial configurations affording an interaction. The agent then exploits these signatures to recognize distant possibilities of interactions (or affordances), but also incomplete affordances. These structures help the agent defining behaviors that can construct affordances from separated elements. Experiments with a simulated agent show that they learn to navigate in their environment, reaching, avoiding and constructing objects according to the valence of the interactions that they afford

Working Memory Training for Adults with ADHD

International audience[No abstract

Inhomogeneity and Lagrangian unsteadiness in turbulent thermal convection

International audienceWe present an experimental study of non-homogeneous turbulence using a Rayleigh-Bénard convection cell. The fluid motion is forced by a temperature difference between two horizontal plates. Using Lagrangian tracking on a large volume we can capture part of the Large Scale Circulation. The velocity statistics are strongly affected by the inhomogeneous mean flow but we recover the typical Homogeneous Isotropic Turbulence statistics by removing the local average. We discuss and explain a Lagrangian unsteadiness which persists because of the Large Scale Circulation oscillations. Our Lagrangian approach is a new way to study specificities of the convective roll motions in turbulent thermal convection. We propose a model based on the convolution between the Large Scale Circulation oscillations and the turbulent fluctuations to explain the shape of the velocity PDFs. However, the acceleration statistics are not affected by the mean flow

L'entraînement de la mémoire de travail par le programme Cogmed et le TDAH - EMtextbarconsulte

International audience[No abstract