Prion protein expression and functional importance in developmental angiogenesis: role in oxidative stress and copper homeostasis.

International audienceAIM: It has been convincingly shown that oxidative stress and toxicity by deregulated metals, such as copper (Cu), are tightly linked to the development of pre-eclampsia and intrauterine growth retardation (IUGR), the most threatening pathologies of human pregnancy. However, mechanisms implemented to control these effects are far from being understood. Among proteins that bind Cu and insure cellular protection against oxidative stress is the cellular prion protein (PrP(C)), a glycosyl phosphatidyl inositol-anchored glycoprotein, which we reported to be highly expressed in human placenta. Herein, we investigated the pathophysiological role of PrP(C) in Cu and oxidative stress homeostasis in vitro using human placenta and trophoblast cells, and in vivo using three strains of mice (C57Bl6, PrP(C) knockout mice [PrP(-/-)], and PrP(C) overexpressing mice [Tga20]). RESULTS: At the cellular level, PrP(C) protection against oxidative stress was established in multiple angiogenic processes: proliferation, migration, and tube-like organization. For the animal models, lack (PrP(-/-)) or overexpression (Tga20) of PrP(C) in gravid mice caused severe IUGR that was correlated with a decrease in litter size, changes in Cu homeostasis, increase in oxidative stress response, development of hypoxic environment, failure in placental function, and maintenance of growth defects of the offspring even 7.5 months after delivery. INNOVATION: PrP(C) could serve as a marker for the idiopathic IUGR disease. CONCLUSION: These findings demonstrate the stress-protective role of PrP(C) during development, and propose PrP(C) dysregulation as a novel causative element of IUGR

Bacteria isolated from lung modulate asthma susceptibility in mice

Asthma is a chronic, non-curable, multifactorial disease with increasing incidence in industrial countries. This study evaluates the direct contribution of lung microbial components in allergic asthma in mice. Germ-Free and Specific-Pathogen-Free mice display similar susceptibilities to House Dust Mice-induced allergic asthma, indicating that the absence of bacteria confers no protection or increased risk to aeroallergens. In early life, allergic asthma changes the pattern of lung microbiota, and lung bacteria reciprocally modulate aeroallergen responsiveness. Primo-colonizing cultivable strains were screened for their immunoregulatory properties following their isolation from neonatal lungs. Intranasal inoculation of lung bacteria influenced the outcome of allergic asthma development: the strain CNCM I 4970 exacerbated some asthma features whereas the pro-Th1 strain CNCM I 4969 had protective effects. Thus, we confirm that appropriate bacterial lung stimuli during early life are critical for susceptibility to allergic asthma in young adults

A Neuron-Glial Perspective for Computational Neuroscience

International audienceThere is growing excitement around glial cells, as compelling evidence point to new, previously unimaginable roles for these cells in information processing of the brain, with the potential to affect behavior and higher cognitive functions. Among their many possible functions, glial cells could be involved in practically every aspect of the brain physiology in health and disease. As a result, many investigators in the field welcome the notion of a Neuron-Glial paradigm of brain function, as opposed to Ramon y Cayal's more classical neuronal doctrine which identifies neurons as the prominent, if not the only, cells capable of a signaling role in the brain. The demonstration of a brain-wide Neuron-Glial paradigm however remains elusive and so does the notion of what neuron-glial interactions could be functionally relevant for the brain computational tasks. In this perspective, we present a selection of arguments inspired by available experimental and modeling studies with the aim to provide a biophysical and conceptual platform to computational neuroscience no longer as a mere prerogative of neuronal signaling but rather as the outcome of a complex interaction between neurons and glial cells

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Action Selection and Mental Transformation Based on a Chain of Forward Models

Hoffmann H, Möller R. Action Selection and Mental Transformation Based on a Chain of Forward Models. In: Schaal S, Ijspeert A, Billard A, Vijayakumar S, Hallam J, Meyer J-A, eds. From Animals to Animats 8 (Proc. 8th Intl. Conf. on the Simulation of Adaptive Behavior). MIT Press; 2004: 213-222

Orientation-dependent work function of in situ annealed strontium titanate

International audienceWe have used energy-filtered x-ray photoelectron emission microscopy (XPEEM) and synchrotron radiation to measure the grain orientation dependence of the work function of a sintered niobium-doped strontium titanate ceramic. A significant spread in work function values is found. Grain orientation and surface reducing/oxidizing conditions are the main factors in determining the work function. Energy-filtered XPEEM looks ideally suited for analysis of other technologically interesting polycrystalline samples