Developing an acoustic-phonetic characterization of dysarthric speech in French

- ISBN: 2-9517408-6-7 - Domaines: Phonetic Databases, Phonology, Person IdentificationInternational audienceThis paper presents the rationale, objectives and advances of an on-going project (the DesPho-APaDy project funded by the French National Agency of Research) which aims to provide a systematic and quantified description of French dysarthric speech, over a large population of patients and three dysarthria types (related to the parkinson's disease, the Amyotrophic Lateral Sclerosis disease, and a pure cerebellar alteration). The two French corpora of dysarthric patients, from which the speech data have been selected for analysis purposes, are firstly described. Secondly, this paper discusses and outlines the requirement of a structured and organized computerized platform in order to store, organize and make accessible (for selected and protected usage) dysarthric speech corpora and associated patients' clinical information (mostly disseminated in different locations: labs, hospitals, ...). The design of both a computer database and a multi-field query interface is proposed for the clinical context. Finally, advances of the project related to the selection of the population used for the dysarthria analysis, the preprocessing of the speech files, their orthographic transcription and their automatic alignment are also presented

N-truncated Abeta starting with position four : early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody

Abstract Background The amyloid hypothesis in Alzheimer disease (AD) considers amyloid β peptide (Aβ) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated Aβ peptides especially N-truncated pyroglutamate AβpE3-42 have been extensively studied. Together with full-length Aβ1–42 and Aβ1–40, N-truncated AβpE3-42 and Aβ4–42 are major variants in AD brain. Although Aβ4–42 has been known for a much longer time, there is a lack of studies addressing the question whether AβpE3-42 or Aβ4–42 may precede the other in Alzheimer’s disease pathology. Results Using different Aβ antibodies specific for the different N-termini of N-truncated Aβ, we discovered that Aβ4-x preceded AβpE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel Aβ4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated Aβ species. While NT4X-167 significantly rescued Aβ4–42 toxicity in vitro no beneficial effect was observed against Aβ1–42 or AβpE3-42 toxicity. Phenylalanine at position four of Aβ was imperative for antibody binding, because its replacement with alanine or proline completely prevented binding. Although amyloid plaques were observed using NT4X-167 in 5XFAD transgenic mice, it barely reacted with plaques in the brain of sporadic AD patients and familial cases with the Arctic, Swedish and the presenilin-1 PS1Δ9 mutation. A consistent staining was observed in blood vessels in all AD cases with cerebral amyloid angiopathy. There was no cross-reactivity with other aggregates typical for other common neurodegenerative diseases showing that NT4X-167 staining is specific for AD. Conclusions Aβ4-x precedes AβpE3-x in the well accepted 5XFAD AD mouse model underlining the significance of N-truncated species in AD pathology. NT4X-167 therefore is the first antibody reacting with Aβ4-x and represents a novel tool in Alzheimer research

A Plant-Specific Transcription Factor IIB-Related Protein, pBRP2, Is Involved in Endosperm Growth Control

General transcription factor IIB (TFIIB) and TFIIB-related factor (BRF), are conserved RNA polymerase II/III (RNAPII/III) selectivity factors that are involved in polymerase recruitment and transcription initiation in eukaryotes. Recent findings have shown that plants have evolved a third type of B-factor, plant-specific TFIIB-related protein 1 (pBRP1), which seems to be involved in RNAPI transcription. Here, we extend the repertoire of B-factors in plants by reporting the characterization of a novel TFIIB-related protein, plant-specific TFIIB-related protein 2 (pBRP2), which is found to date only in the Brassicacea family. Unlike other B-factors that are ubiquitously expressed, PBRP2 expression is restricted to reproductive organs and seeds as shown by RT-PCR, immunofluorescence labelling and GUS staining experiments. Interestingly, pbrp2 loss-of-function specifically affects the development of the syncytial endosperm, with both parental contributions required for wild-type development. pBRP2, is the first B-factor to exhibit cell-specific expression and regulation in eukaryotes, and might play a role in enforcing bi-parental reproduction in angiosperms

Is leadership a reliable concept in animals? An empirical study in the horse

International audienceLeadership is commonly invoked when accounting for the coordination of group movements in animals, yet it remains loosely defined. In parallel, there is increased evidence of the sharing of group decisions by animals on the move. How leadership integrates within this recent framework on collective decision-making is unclear. Here, we question the occurrence of leadership in horses, a species in which this concept is of prevalent use. The relevance of the three main definitions of leadership - departing first, walking in front travel position, and eliciting the joining of mates - was tested on the collective movements of two semi-free ranging groups of Przewalski horses (Equus ferus przewalskii). We did not find any leader capable of driving most group movements or recruiting mates more quickly than others. Several group members often displayed pre-departure behaviours at the same time, and the simultaneous departure of several individuals was common. We conclude that the decision-making process was shared by several group members a group movement (i.e., partially shared consensus) and that the leadership concept did not help to depict individual departure and leading behaviour across movements in both study groups. Rather, the different proxies of leadership produced conflicting information about individual contributions to group coordination. This study discusses the implications of these findings for the field of coordination and decision-making research

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/)

Lipides et maladie d'Alzheimer (influence du statut et de la signalisation lipidiques sur la neurodégénérescence induite par le peptide AB soluble)

La maladie d Alzheimer (MA) est une démence progressive caractérisée dans ses stades précoces par une perte synaptique et une dégénérescence neuronale. Aucun traitement efficace n est disponible à ce jour et les mécanismes moléculaires impliqués sont encore mal connus. Des études récentes, menées notamment par notre équipe, indiquent que les oligomères de peptide amyloïde-ß (Aß) interagissent avec la membrane plasmique et y induisent un stress cellulaire impliquant des cascades apoptotiques. Ce travail a été consacré à l étude de l influence du statut lipidique sur la sensibilité des neurones au peptide Aß soluble et sur la signalisation pro-apoptotique. Nous avons montré que ce peptide induit un remodelage membranaire conduisant à la mort neuronale en activant des voies pro-apoptotiques et en inhibant des voies de survie. Par contre, la supplémentation du milieu en acide docosahexaénoïque (DHA), acide gras polyinsaturé de type ?3, protège les neurones de la mort induite par le peptide Aß. Cet effet préventif semble dépendre d une incorporation du DHA pouvant localement induire un remodelage membranaire discret capable de préserver des voies de croissance et de survie cellulaire. Le DHA n agit toutefois pas en inhibant l activation de la phospholipase A2 cytosolique (cPLA2) et le stress oxydant induits par le peptide Aß, mécanismes que nous avons observés être impliqués dans la voie pro-apoptotique menant à la production de céramides suite à l activation des sphingomyélinases. Ces enzymes occupent une position essentielle dans la toxicité du peptide Aß, puisqu un prétraitement par le DHA ou par la sphingosine-1-phosphate, connue pour son potentiel antiapoptotique, protège les neurones en inhibant la sphingomyélinase acide. Les travaux de cette thèse ont donc montré que les lipides, molécules structurales mais aussi médiateurs de signalisation, sont des acteurs essentiels à considérer pour le développement de stratégies préventives ou thérapeutiques contre la MAAlzheimer s disease (AD) is a progressive dementia characterised in the early stages by synaptic loss and neurodegeneration. Currently, no effective treatments are available and the molecular mechanisms implicated are still unknown. Recent studies, including ours, indicate that the direct interaction between soluble amyloid-ß (Aß) oligomers and the plasma membrane initiates a cellular stress involving apoptotic cascades. The present work focuses on the impact of lipid status on neuronal susceptibility to the toxicity of soluble Aß peptide and on the pro-apoptotic signalling pathways. We showed that this peptide induces membrane remodelling, thereby activating pro-apoptotic pathways and inhibiting survival signalling, which leads to neuronal cell death. This was however prevented in neurons cultured in a medium supplemented with docosahexaenoic acid (DHA), an ?3 polyunsaturated fatty acid. This protective effect seems to rely on subtle local membrane remodelling due to DHA incorporation, which maintains active survival and growth pathways. DHA did not prevent either cytosolic phospholipase A2 (cPLA2) or oxidative stress upon soluble Aß peptide exposure. These two events have already been reported by our team to be implicated in a pro-apoptotic cascade leading to ceramide production due to the activation of sphingomyelinases. These enzymes very likely play a central role in Aß peptide toxicity, as pretreatments with DHA or sphingosine-1-phosphate, a well-known anti-apoptotic compound, lead to neuronal protection through the inhibition of acid sphingomyelinase. This PhD thesis demonstrates that lipids, as structural molecules as well as signalling mediators, are essential players that could be used to develop strategies for the prevention or treatment of ADNANCY/VANDOEUVRE-INPL (545472102) / SudocSudocFranceF

Neuroprotective effects of DHA in Alzheimer’s disease models

Alzheimer’s disease (AD) is a major public health concern in all developped countries. Although the precise cause of AD is still unknown, a growing body of evidence supports the notion that soluble oligomers of amyloid b-peptide (Aβ) may be the proximate effectors of synaptic injuries and neuronal death in the early stages of AD. AD patients display lower levels of docosahexaenoic acid (DHA, C22:6; n-3) in plasma and brain tissues as compared to control subjects of same age. Furthermore, epidemiological studies suggest that high DHA intake might have protective properties against neurodegenerative diseases. These observations are supported by in vivo studies showing that DHA-rich diets limit the synaptic loss and cognitive defects induced by Aβ peptide. Although the molecular basis underlying these neuroprotective effects remains unknown, several mechanisms have been proposed such as (i) regulation of the expression of potentially protective genes, (ii) activation of antiinflammatory pathways, (iii) modulation of functional properties of the synaptic membranes along with changes in their physicochemical and structural features. We recently demonstrated that DHA protects neurons from soluble Aβ oligomer-induced apoptosis. Indeed, DHA pretreatment was observed to significantly increase neuronal survival upon Aβ treatment by preventing cytoskeleton perturbations, caspase activation and apoptosis, as well as by promoting ERK-related survival pathways. These data suggest that DHA enrichment most likely induces changes in neuronal membrane properties with functional outcomes, thereby increasing protection from soluble Aβ oligomers. Such neuroprotective effects could be of major interest in the prevention of AD and other neurodegenerative diseases

Neuroprotective effects of DHA in Alzheimer’s disease models

Alzheimer’s disease (AD) is a major public health concern in all developped countries. Although the precise cause of AD is still unknown, a growing body of evidence supports the notion that soluble oligomers of amyloid b-peptide (Aβ) may be the proximate effectors of synaptic injuries and neuronal death in the early stages of AD. AD patients display lower levels of docosahexaenoic acid (DHA, C22:6; n-3) in plasma and brain tissues as compared to control subjects of same age. Furthermore, epidemiological studies suggest that high DHA intake might have protective properties against neurodegenerative diseases. These observations are supported by in vivo studies showing that DHA-rich diets limit the synaptic loss and cognitive defects induced by Aβ peptide. Although the molecular basis underlying these neuroprotective effects remains unknown, several mechanisms have been proposed such as (i) regulation of the expression of potentially protective genes, (ii) activation of antiinflammatory pathways, (iii) modulation of functional properties of the synaptic membranes along with changes in their physicochemical and structural features. We recently demonstrated that DHA protects neurons from soluble Aβ oligomer-induced apoptosis. Indeed, DHA pretreatment was observed to significantly increase neuronal survival upon Aβ treatment by preventing cytoskeleton perturbations, caspase activation and apoptosis, as well as by promoting ERK-related survival pathways. These data suggest that DHA enrichment most likely induces changes in neuronal membrane properties with functional outcomes, thereby increasing protection from soluble Aβ oligomers. Such neuroprotective effects could be of major interest in the prevention of AD and other neurodegenerative diseases

Neuroprotective effects of DHA in Alzheimer’s disease models

Alzheimer’s disease (AD) is a major public health concern in all developped countries. Although the precise cause of AD is still unknown, a growing body of evidence supports the notion that soluble oligomers of amyloid b-peptide (Aβ) may be the proximate effectors of synaptic injuries and neuronal death in the early stages of AD. AD patients display lower levels of docosahexaenoic acid (DHA, C22:6; n-3) in plasma and brain tissues as compared to control subjects of same age. Furthermore, epidemiological studies suggest that high DHA intake might have protective properties against neurodegenerative diseases. These observations are supported by in vivo studies showing that DHA-rich diets limit the synaptic loss and cognitive defects induced by Aβ peptide. Although the molecular basis underlying these neuroprotective effects remains unknown, several mechanisms have been proposed such as (i) regulation of the expression of potentially protective genes, (ii) activation of antiinflammatory pathways, (iii) modulation of functional properties of the synaptic membranes along with changes in their physicochemical and structural features. We recently demonstrated that DHA protects neurons from soluble Aβ oligomer-induced apoptosis. Indeed, DHA pretreatment was observed to significantly increase neuronal survival upon Aβ treatment by preventing cytoskeleton perturbations, caspase activation and apoptosis, as well as by promoting ERK-related survival pathways. These data suggest that DHA enrichment most likely induces changes in neuronal membrane properties with functional outcomes, thereby increasing protection from soluble Aβ oligomers. Such neuroprotective effects could be of major interest in the prevention of AD and other neurodegenerative diseases

Acide docosahexaénoïque et maladie d’Alzheimer : des raisons d’espérer ?

Alzheimer’s disease is a major public health concern in all developped countries. Although the precise cause of Alzheimer’s disease is still unknown, soluble oligomers of the neurotoxic hydrophobic amyloid-β (Aβ) peptide are known to play a critical role. Aging is associated with a loss of docosahexaenoic acid (DHA) in brain tissues in which it is the main polyunsaturated fatty acid. Epidemiological studies on human populations suggested that diets enriched in ω3 fatty acids are associated with reduced risk of Alzheimer’s disease. Furthermore, patients affected by Alzheimer’s disease display lower levels of DHA in plasma and brain tissues as compared to control subjects of same age. Studies on animals showed that diets enriched with DHA limit the synaptic loss and cognitive defects induced by the Aβ peptide. Several mechanisms have been proposed for this protective effects. DHA can induce the expression of potentially protective genes. Conversion of DHA into neuroprotectins has been shown to be alternatively involved in the protection against the Aβ peptide. Eventually, results have been provided suggesting that particular membrane microdomains could be remodelled and subsequently be involved in the neuroprotective process induced by DHA