Inhibitory Killer Immunoglobulin-like receptors to self HLA-B and HLA-C ligands contribute differentially to Natural Killer cell functional potential in HIV infected Slow Progressors

Ce manuscrit est une pré-publication d'un article paru dans Clinical Immunology 2012; 143(3): 246-255 url: http://www.journals.elsevier.com/clinical-immunology/IRSC et FRSQ - Réseau SIDA et maladies infectieuse

Rightward hemispheric asymmetries in auditory language cortex in children with autistic disorder: an MRI investigation

Purpose: determine if language disorder in children with autistic disorder (AD) corresponds to abnormalities in hemispheric asymmetries in auditory language cortex. Methods: MRI morphometric study in children with AD (n = 50) to assess hemispheric asymmetries in auditory language cortex. A key region of interest was the planum temporale (PT), which is larger in the left hemisphere in most healthy individuals. Results: (i) Heschl’s gyrus and planum polare showed typical hemisphere asymmetry patterns; (ii) posterior Superior Temporal Gyrus (pSTG) showed significant rightward asymmetry; and (iii) PT showed a trend for rightward asymmetry that was significant when constrained to right-handed boys (n = 30). For right-handed boys, symmetry indices for pSTG were significantly positively correlated with those for PT. PT asymmetry was age dependent, with greater rightward asymmetry with age. Conclusions: results provide evidence for rightward asymmetry in auditory association areas (pSTG and PT) known to subserve language processing. Cumulatively, our data provide evidence for a differing maturational path for PT for lower functioning children with AD, with both pre- and post-natal experience likely playing a role in PT asymmetry

The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage

Background: We describe the genome of the western painted turtle, Chrysemys picta bellii, one of the most widespread, abundant, and well-studied turtles. We place the genome into a comparative evolutionary context, and focus on genomic features associated with tooth loss, immune function, longevity, sex differentiation and determination, and the species' physiological capacities to withstand extreme anoxia and tissue freezing.Results: Our phylogenetic analyses confirm that turtles are the sister group to living archosaurs, and demonstrate an extraordinarily slow rate of sequence evolution in the painted turtle. The ability of the painted turtle to withstand complete anoxia and partial freezing appears to be associated with common vertebrate gene networks, and we identify candidate genes for future functional analyses. Tooth loss shares a common pattern of pseudogenization and degradation of tooth-specific genes with birds, although the rate of accumulation of mutations is much slower in the painted turtle. Genes associated with sex differentiation generally reflect phylogeny rather than convergence in sex determination functionality. Among gene families that demonstrate exceptional expansions or show signatures of strong natural selection, immune function and musculoskeletal patterning genes are consistently over-represented.Conclusions: Our comparative genomic analyses indicate that common vertebrate regulatory networks, some of which have analogs in human diseases, are often involved in the western painted turtle's extraordinary physiological capacities. As these regulatory pathways are analyzed at the functional level, the painted turtle may offer important insights into the management of a number of human health disorders

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/)

Etude neurophysiologique des interactions auditivo-visuelles au cours du développement normal et dans l'autisme infantile

L hypothèse de ce travail est que l incapacité des enfants atteints d autisme à avoir une perception globale et unifiée du monde qui les entoure serait liée à un dysfonctionnement cérébral de l intégration multisensorielle. Les interactions auditivo-visuelles ont été étudiées au cours du développement normal et dans l autisme infantile par les méthodes de cartographie des potentiels évoqués. Des modulations précoces et tardives des réponses auditive et visuelle sont observées chez l adulte et l enfant sain. Chez l enfant autiste, bien que les réponses sensorielles soient relativement préservées, les effets d interactions sur ces réponses visuelle et auditive ne sont pas retrouvés. De plus, une activité frontale est enregistrée sur l hémisphère droit chez les sujets sains alors qu elle est localisée à gauche chez les enfants autistes. Ces anomalies électrophysiologiques sont discutées en fonction des particularités sensorielles et cognitives observées dans l autisme.The hypothesis of this study was that the inability of children with autism to have a global and unified perception of the surrounding world would be due to a brain dysfunction affecting multisensory integration. Auditory-visual interactions were studied throughout normal development and in infantile autism using event-related potentials mapping. Early and late modulations of auditory and visual responses were observed in both healthy adults and children. In children with autism, although the sensory responses were overall preserved, interaction effects on these auditory and visual responses were not found. In addition, a frontal activity was recorded on the right hemisphere in healthy subjects whereas it was localized on the left side in children with autism. These electrophysiological abnormalities are discussed according to the sensory and cognitive particularities observed in autism.TOURS-BU Médecine (372612103) / SudocSudocFranceF

Réponse électrophysiologique à la voix humaine au cours du développement normal et dans l'autisme

L autisme est caractérisé par des difficultés majeures de la socialisation. Ces perturbations ont été mises en lien avec des déficits de perception des stimuli sociaux (voix, visages) chez des adultes avec autisme. L objectif de ce travail est d étudier la réponse électrophysiologique de la voix humaine au cours du développement dans l autisme en comparaison au développement normal. Une réponse positive, spécifique à la voix, localisée au niveau fronto-temporal (Fronto-Temporal Positivity to Voice : FTPV) et latéralisée à droite a été mise en évidence chez les adultes et enfants sains. Bien que retardée d environ 20 ms, cette réponse est également enregistrée chez les enfants avec autisme. En revanche, elle n est pas observée chez les adultes avec autisme. Cette perte de fonctionnalité des réseaux neuronaux impliqués dans le traitement de la voix est discutée selon une perspective développementale et en lien avec les déficits d interactions sociales qui caractérisent l autisme.Autism is characterized by major social disorders with difficulties that have been linked to disorders of perception of social stimuli (voices, faces) in adults with autism. The aim of this study was to investigate the electrophysiological response to human voice in normal development and in adults and children with autism. A specific positive response to voice located over the fronto-temporal region (Fronto-Temporal Positivity to Voice: FTPV) with right lateralization was identified in normal adults and children. Although delayed by about 20 ms, this specific response was also recorded in children with autism. In contrast, the FTPV was not present in adults with autism. This loss of function in neural networks involved in voice processing is discussed from a developmental perspective and in relation with the disorders of social interaction found in autism.TOURS-Bibl.électronique (372610011) / SudocSudocFranceF

Candidate Electrophysiological Endophenotypes of Hyper-Reactivity to Change in Autism.

International audienceAlthough resistance to change is a main feature of autism, the brain processes underlying this aspect of the disorder remain poorly understood. The aims of this study were to examine neural basis of auditory change-detection in children with autism spectrum disorders (ASD; N = 27) through electrophysiological patterns (MMN, P3a) and to test whether these are quantitatively related to intolerance of change (using the BSE-R scale). ASD displayed significantly shorter MMN latency and larger P3a than controls, indicating a greater tendency to switch attention to deviant events. These electrophysiological abnormalities were significantly more marked in children who displayed greater difficulties in tolerating change. The atypical neurophysiological mechanism of change perception identified might thus be associated with one of the hallmark behavioural manifestations of autism

The Education of NK Cells Determines Their Responsiveness to Autologous HIV-Infected CD4 T Cells

International audienceSeveral studies support a role for specific killer immunoglobulin-like receptor (KIR)-HLA combinations in protection from HIV infection and slower progression to AIDS. Natural killer (NK) cells acquire effector functions through education, a process that requires the interaction of inhibitory NK cell receptors with their major histocompatibility complex (MHC) class I (or HLA class I [HLA-I]) ligands. HLA-C allo-types are ligands for the inhibitory KIRs (iKIRs) KIR2DL1, KIR2DL2, and KIR2DL3, whereas the ligand for KIR3DL1 is HLA-Bw4. HIV infection reduces the expression of HLA-A,-B, and-C on the surfaces of infected CD4 (iCD4) T cells. Here we investigated whether education through iKIR-HLA interactions influenced NK cell responses to autologous iCD4 cells. Enriched NK cells were stimulated with autologous iCD4 cells or with uninfected CD4 cells as controls. The capacities of single-positive (sp) KIR2DL1, KIR2DL2, KIR2DL3, and KIR3DL1 NK cells to produce CCL4, gamma inter-feron (IFN-␥), and/or CD107a were assessed by flow cytometry. Overall, we observed that the potency of NK cell education was directly related to the frequency of each spiKIR ϩ NK cell's ability to respond to the reduction of its cognate HLA ligand on autologous iCD4 cells, as measured by the frequency of production by spiKIR ϩ NK cells of CCL4, IFN-␥, and/or CD107a. Both NK cell education and HIV-mediated changes in HLA expression influenced NK cell responses to iCD4 cells

Expression Profiles of Ligands for Activating Natural Killer Cell Receptors on HIV Infected and Uninfected CD4+ T Cells

Natural Killer (NK) cell responses to HIV-infected CD4 T cells (iCD4) depend on the integration of signals received through inhibitory (iNKR) and activating NK receptors (aNKR). iCD4 activate NK cells to inhibit HIV replication. HIV infection-dependent changes in the human leukocyte antigen (HLA) ligands for iNKR on iCD4 are well documented. By contrast, less is known regarding the HIV infection related changes in ligands for aNKR on iCD4. We examined the aNKR ligand profiles HIV p24+ HIV iCD4s that maintained cell surface CD4 (iCD4+), did not maintain CD4 (iCD4−) and uninfected CD4 (unCD4) T cells for expression of unique long (UL)-16 binding proteins-1 (ULBP-1), ULBP-2/5/6, ULBP-3, major histocompatibility complex (MHC) class 1-related (MIC)-A, MIC-B, CD48, CD80, CD86, CD112, CD155, Intercellular adhesion molecule (ICAM)-1, ICAM-2, HLA-E, HLA-F, HLA-A2, HLA-C, and the ligands to NKp30, NKp44, NKp46, and killer immunoglobulin-like receptor 3DS1 (KIR3DS1) by flow cytometry on CD4 T cells from 17 HIV-1 seronegative donors activated and infected with HIV. iCD4+ cells had higher expression of aNKR ligands than did unCD4. However, the expression of aNKR ligands on iCD4 where CD4 was downregulated (iCD4−) was similar to (ULBP-1, ULBP-2/5/6, ULBP-3, MIC-A, CD48, CD80, CD86 and CD155) or significantly lower than (MIC-B, CD112 and ICAM-2) what was observed on unCD4. Thus, HIV infection can be associated with increased expression of aNKR ligands or either baseline or lower than baseline levels of aNKR ligands, concomitantly with the HIV-mediated downregulation of cell surface CD4 on infected cells

Follicle-stimulating hormone promotes nerve growth factor and vascular endothelial growth factor expression in epithelial ovarian cells

Ovarian cancer is the first cause of death for gynecological malignances in developed countries and around 80% correspond to Epithelial Ovarian Cancer (EOC). Overexpression of Nerve Growth Factor (NGF) and its high affinity receptor TRKA are involved in EOC progression, modulating several oncogenic processes such as angiogenesis by the increase of Vascular Endothelial Growth Factor (VEGF). FSH receptors (FSH-R) are present in EOC, but their changes and contribution during EOC progression are still not thoroughly known. The aims of this study were to evaluate the abundance of FSH receptors during EOC differentiation and to determine whether FSH modulates oncoproteins such as NGF and VEGF in ovarian cells. FSH-R expression in EOC tissues and cell lines (A2780, poorly differentiated EOC cells and HOSE, non-tumoral ovarian surface epithelial cells) were measured by RT- PCR and laser capture of epithelial cells from EOC samples by qPCR. FSH-R protein levels were evaluated by immunohisto/cytochemistry. Additionally, ovarian explants and ovarian cell lines were stimulated with FSH and/or FSH-R inhibitor to assess NGF and VEGF mRNA and protein levels. The results showed that FSH-R levels decreased during loss of EOC cell differentiation, nevertheless these receptors are still present in poorly differentiated EOC. FSH increased NGF expression in ovarian cells, which was prevented using a FSH-R inhibitor. Similarly, in ovarian cancer explants, FSH increased NGF and VEGF mRNA, as well as NGF protein levels. These results suggest that FSH would display a key role not only in initial stages of EOC, but also in late stages of this disease, by modulation of NGF and VEGF levels in EOC cell