Alphavirus Entry and Membrane Fusion

The study of enveloped animal viruses has greatly advanced our understanding of the general properties of membrane fusion and of the specific pathways that viruses use to infect the host cell. The membrane fusion proteins of the alphaviruses and flaviviruses have many similarities in structure and function. As reviewed here, alphaviruses use receptor-mediated endocytic uptake and low pH-triggered membrane fusion to deliver their RNA genomes into the cytoplasm. Recent advances in understanding the biochemistry and structure of the alphavirus membrane fusion protein provide a clearer picture of this fusion reaction, including the protein’s conformational changes during fusion and the identification of key domains. These insights into the alphavirus fusion mechanism suggest new areas for experimental investigation and potential inhibitor strategies for anti-viral therapy

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15–90. The effects of dementia, mild cognitive impairment, Parkinson’s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p \u3c 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p \u3e 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders

Virus genomes reveal factors that spread and sustained the Ebola epidemic.

The 2013-2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic 'gravity' model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics

Immunothérapie du diabète auto-immun (de la prévention au traitement de la maladie établie)

Le but de notre travail a été de mettre en place des stratégies innovantes d'immuno-intervention permettant d'agir de manière efficace sur la progression du diabète auto-immun. Nous nous sommes focalisés sur deux stratégies : l'utilisation d'anticorps monoclonaux anti-CD3 et celle de produits bactériens. Les anticorps anti-CD3 possèdent la capacité remarquable d'induire une tolérance durable et spécifique vis-à-vis les antigènes du soi chez la souris NOD, spontanément diabétique. Nous avons établi et caractérisé des souris NOD transgéniques exprimant la molécule CD3s humaine (NOD-huCD3e). Cette souris développe un diabète auto-immun spontané identique à la souris NOD conventionnelle, est sensible au traitement par les anticorps anti-CD3 murins et humains et représente donc un modèle préclinique idéal. Dans un deuxième effort, nous avons étudié le rôle protecteur de certains composants bactériens, prioritairement des agonistes du récepteur Toll-like 4 (TLR4), sur la survenue du diabète.Our aim was the development of innovative strategies of immune-intervention allowing efficient interfering with progression of autoimmune diabetes, even at a late stage. We focussed on two strategies: usage of monoclonal anti-CD3 antibodies and of bacterial products. Anti-CD3 antibodies have the remarkable capacity to induce long-lasting and antigen-specific tolerance in NOD mice, which spontaneously develop diabetes. We generated and characterised transgenic NOD mice expressing the human CD3s chain (NOD-huCD3s). These mice spontaneously develop autoimmune diabetes, identical to conventional NOD mice, respond to treatment with murine- or human-specific anti-CD3 antibodies and thus present an ideal preclinical model. In a second effort, we studied the protective effect of certain bacterial products, primary of Toll-like receptor 4 (TLR4) agonists, on the development of diabetes. These molecules are interesting candidates for a transfer into the clinics.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF