66 research outputs found
Mussel as a Tool to Define Continental Watershed Quality
Bivalves appear as relevant sentinel species in aquatic ecotoxicology and water quality assessment. This is particularly true in marine ecosystems. In fact, several biomonitoring frameworks in the world used mollusks since several decades on the base of contaminant accumulation (Mussel Watch, ROCCH) and/or biological responses called biomarker (OSPAR) measurements. In freshwater systems, zebra and quagga mussels could represent alternative sentinels, which could be seen as the counterparts of mussel marine species. This chapter presents original studies and projects underlying the interest of these freshwater mussels for water quality monitoring based on contaminant accumulation and biomarker development measurements. These sentinel species could be used as a tool for chemical/biological monitoring of biota under the European water framework directive and for the development of effect-based monitoring tools
Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patientsâ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p
Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patientsâ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy
Long-term results of middle fossa plugging of superior semicircular canal dehiscences: clinically and instrumentally demonstrated efficiency in a retrospective series of 16 ears
KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.
Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-KuÄinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site
The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity
La sensibilité auditive à l'harmonicité, en présence ou en l'absence de déficit cochléaire
The auditory system fuses into one percept simultaneous pure tones whose frequenciesare harmonically related, even if these pure tones are perfectly resolved by the cochlea.This harmonic fusion contributes to auditory scene analysis requiring segregation ofsimultaneous harmonic complex tones. Two studies reported here aimed to clarify itsmechanism in normal-hearing listeners. The first study measured the discrimination offrequency ratios close to the octave (2:1) for simultaneous or consecutive pure tones. Theresults show that the simultaneous octave is recognized by a mechanism which isinsensitive to the direction of deviations from the octave, whereas this is not the case forthe sequential octave. A second study explored this difference between the simultaneousand sequential octaves by means of subjective judgments on the degree of fusion or theperceptual affinity between pure tones presented simultaneously or sequentially. Theresults indicate that harmonic fusion and pitch affinity are not directly related phenomena.The third study measured the detection of a change in frequency ratio for simultaneouspure tones in listeners with normal hearing or mild to moderate cochlear hearing loss.The results indicate that sensitivity to harmonicity is a robust phenomenon, sometimesaltered by cochlear lesions but resistant to severe deficits in frequency discrimination.However, while inharmonicity detection is asymmetric in normal-hearing listeners, itbecomes symmetric in the presence of cochlear hearing loss, suggesting that theunderlying mechanism is different in the latter case.Le systĂšme auditif fusionne en un seul percept des sons purs simultanĂ©s dont lesfrĂ©quences sont harmoniquement liĂ©es, mĂȘme si ces sons purs sont parfaitement rĂ©soluspar la cochlĂ©e. Cette fusion harmonique contribue Ă lâanalyse des scĂšnes auditives nĂ©cessitantla sĂ©grĂ©gation de sons complexes harmoniques simultanĂ©s. Deux des Ă©tudes dĂ©crites iciont eu pour but d'en prĂ©ciser le mĂ©canisme chez les auditeurs sains. La premiĂšre a mesurĂ©la discrimination de rapports de frĂ©quences voisins de lâoctave (2:1) pour des sons purssimultanĂ©s ou consĂ©cutifs. Les rĂ©sultats montrent que lâoctave simultanĂ©e est reconnuepar un mĂ©canisme insensible Ă la direction des Ă©carts par rapport Ă lâoctave, alors que teln'est pas le cas pour l'octave sĂ©quentielle. Une deuxiĂšme Ă©tude a explorĂ© cette diffĂ©renceentre octave simultanĂ©e et octave sĂ©quentielle par des jugements subjectifs du degrĂ© defusion ou de lâaffinitĂ© perceptive entre sons purs prĂ©sentĂ©s simultanĂ©ment ousĂ©quentiellement. Les rĂ©sultats indiquent que fusion harmonique et affinitĂ© de hauteurtonale ne sont pas des phĂ©nomĂšnes directement liĂ©s. La troisiĂšme Ă©tude a portĂ© sur ladĂ©tection dâun changement de rapport de frĂ©quences entre sons purs simultanĂ©s chez desauditeurs sains ou porteurs dâune surditĂ© cochlĂ©aire lĂ©gĂšre Ă moyenne. Cette Ă©tude rĂ©vĂšleque la sensibilitĂ© Ă lâharmonicitĂ© est un phĂ©nomĂšne robuste, parfois altĂ©rĂ© chez les sujetssourds mais rĂ©sistant Ă une forte dĂ©gradation de la discrimination frĂ©quentielle. Il apparaĂźtcependant que la dĂ©tection dâinharmonicitĂ©, asymĂ©trique chez les auditeurs sains, devientsymĂ©trique en prĂ©sence de lĂ©sions cochlĂ©aires, ce qui semble indiquer que le mĂ©canismeutilisĂ© est diffĂ©rent dans ce cas
Auditory sensitivity to harmonicity, in the presence or absence of cochlear deficit
Le systĂšme auditif fusionne en un seul percept des sons purs simultanĂ©s dont lesfrĂ©quences sont harmoniquement liĂ©es, mĂȘme si ces sons purs sont parfaitement rĂ©soluspar la cochlĂ©e. Cette fusion harmonique contribue Ă lâanalyse des scĂšnes auditives nĂ©cessitantla sĂ©grĂ©gation de sons complexes harmoniques simultanĂ©s. Deux des Ă©tudes dĂ©crites iciont eu pour but d'en prĂ©ciser le mĂ©canisme chez les auditeurs sains. La premiĂšre a mesurĂ©la discrimination de rapports de frĂ©quences voisins de lâoctave (2:1) pour des sons purssimultanĂ©s ou consĂ©cutifs. Les rĂ©sultats montrent que lâoctave simultanĂ©e est reconnuepar un mĂ©canisme insensible Ă la direction des Ă©carts par rapport Ă lâoctave, alors que teln'est pas le cas pour l'octave sĂ©quentielle. Une deuxiĂšme Ă©tude a explorĂ© cette diffĂ©renceentre octave simultanĂ©e et octave sĂ©quentielle par des jugements subjectifs du degrĂ© defusion ou de lâaffinitĂ© perceptive entre sons purs prĂ©sentĂ©s simultanĂ©ment ousĂ©quentiellement. Les rĂ©sultats indiquent que fusion harmonique et affinitĂ© de hauteurtonale ne sont pas des phĂ©nomĂšnes directement liĂ©s. La troisiĂšme Ă©tude a portĂ© sur ladĂ©tection dâun changement de rapport de frĂ©quences entre sons purs simultanĂ©s chez desauditeurs sains ou porteurs dâune surditĂ© cochlĂ©aire lĂ©gĂšre Ă moyenne. Cette Ă©tude rĂ©vĂšleque la sensibilitĂ© Ă lâharmonicitĂ© est un phĂ©nomĂšne robuste, parfois altĂ©rĂ© chez les sujetssourds mais rĂ©sistant Ă une forte dĂ©gradation de la discrimination frĂ©quentielle. Il apparaĂźtcependant que la dĂ©tection dâinharmonicitĂ©, asymĂ©trique chez les auditeurs sains, devientsymĂ©trique en prĂ©sence de lĂ©sions cochlĂ©aires, ce qui semble indiquer que le mĂ©canismeutilisĂ© est diffĂ©rent dans ce cas.The auditory system fuses into one percept simultaneous pure tones whose frequenciesare harmonically related, even if these pure tones are perfectly resolved by the cochlea.This harmonic fusion contributes to auditory scene analysis requiring segregation ofsimultaneous harmonic complex tones. Two studies reported here aimed to clarify itsmechanism in normal-hearing listeners. The first study measured the discrimination offrequency ratios close to the octave (2:1) for simultaneous or consecutive pure tones. Theresults show that the simultaneous octave is recognized by a mechanism which isinsensitive to the direction of deviations from the octave, whereas this is not the case forthe sequential octave. A second study explored this difference between the simultaneousand sequential octaves by means of subjective judgments on the degree of fusion or theperceptual affinity between pure tones presented simultaneously or sequentially. Theresults indicate that harmonic fusion and pitch affinity are not directly related phenomena.The third study measured the detection of a change in frequency ratio for simultaneouspure tones in listeners with normal hearing or mild to moderate cochlear hearing loss.The results indicate that sensitivity to harmonicity is a robust phenomenon, sometimesaltered by cochlear lesions but resistant to severe deficits in frequency discrimination.However, while inharmonicity detection is asymmetric in normal-hearing listeners, itbecomes symmetric in the presence of cochlear hearing loss, suggesting that theunderlying mechanism is different in the latter case
Multiple activities of allosteric inhibitors of the interaction between HIV-1 Integrase and its cofactor LEDGF/p75
VIH-1, lâagent Ă©tiologique du Syndrome de lâImmunodĂ©ficience Acquise, est un rĂ©trovirus qui infecte les cellules immunitaires et dĂ©tourne leur machinerie cellulaire pour se rĂ©pliquer rapidement. Lors de lâinfection, le gĂ©nome ARN est rĂ©trotranscrit en ADN par la transcriptase inverse virale (RT), puis lâinsertion du gĂ©nome proviral dans lâADN de la cellule hĂŽte est une Ă©tape obligatoire du cycle viral catalysĂ©e par lâenzyme virale IntĂ©grase (IN). Lâinteraction de lâIN avec son cofacteur essentiel, la protĂ©ine nuclĂ©aire LEDGF/p75, dirige lâintĂ©gration Ă lâintĂ©rieur de gĂšnes dans des rĂ©gions fortement exprimĂ©es de la chromatine, ce qui permet la production efficace de nouveaux virions. Les Inhibiteurs AllostĂ©riques IntĂ©grase-LEDGF (INLAIs) sont une nouvelle classe de molĂ©cules antirĂ©trovirales se liant Ă lâIN au site de liaison de LEDGF/p75. Conçus pour inhiber compĂ©titivement lâinteraction protĂ©ine-protĂ©ine IN-LEDGF/p75, ils inhibent Ă©galement les activitĂ©s enzymatiques de lâIntĂ©grase et augmentent son niveau de multimĂ©risation.Nous avons Ă©tudiĂ© plusieurs nouvelles sĂ©ries dâINLAIs de la sociĂ©tĂ© Mutabilis, et avons pu dĂ©montrer que ces molĂ©cules inhibent lâintĂ©gration, mais ont aussi un effet antirĂ©troviral plus puissant et indĂ©pendant de LEDGF/p75 post-intĂ©gration au cours de la maturation des virions, qui conduit Ă la production de virus non infectieux, ayant une morphologie excentrique caractĂ©risĂ©e par un dĂ©faut dâencapsidation du gĂ©nome viral. Lors de lâinfection de cellules par ces virus, le cycle viral sâarrĂȘte Ă lâĂ©tape de rĂ©trotranscription du gĂ©nome viral. Nous avons montrĂ© que ces virions contiennent pourtant un gĂ©nome viral stable et fonctionnel, une RT active et lâARNtLys3 qui sert dâamorce Ă la rĂ©trotranscription, et ont Ă©galement conservĂ© leur immunorĂ©activitĂ© pour les lymphocytes B et T. En Ă©valuant lâimpact du polymorphisme de lâIN au voisinage du site de liaison, nous avons identifiĂ© le variant polymorphe Ala125, pour lequel lâINLAI MUT-A perd concomitamment son effet sur la maturation des virions et sur la multimĂ©risation de lâIN, tandis quâil inhibe aussi bien lâintĂ©gration et lâinteraction IN-LEDGF, prouvant que lâeffet tardif des INLAIs est associĂ© Ă lâinduction de la multimĂ©risation de lâIN. Nous avons pu associer la multimĂ©risation de lâIN Ă une dĂ©stabilisation du dimĂšre par les INLAIs en analysant les co-structures de MUT-A avec les intĂ©grases polymorphes. Les INLAIs, outre leur intĂ©rĂȘt thĂ©rapeutique sont de remarquables rĂ©actifs qui ont permis de dĂ©montrer le rĂŽle essentiel de lâintĂ©grase Ă trois Ă©tapes clĂ©s du cycle viral du VIH-1 : la rĂ©trotranscription, lâintĂ©gration et la maturation des virions.HIV-1, the causative agent of AIDS, is a retrovirus that infects immune cells and hijacks their cell machinery to achieve rapid replication. In the course of infection, the RNA genome is reverse transcribed into DNA by the viral Reverse Transcriptase (RT) before the obligatory insertion of the proviral genome into the host cell DNA catalyzed by the viral enzyme Integrase (IN). The interaction of IN with its essential cofactor, the nuclear protein LEDGF/p75, targets integration within gene introns in highly transcribed chromatine regions, which allows efficient production of new virions. IN-LEDGF Allosteric Inhibitors (INLAIs) are a novel class of antiretroviral molecules binding IN at the LEDGF/p75-binding site. Designed to competitively inhibit IN-LEDGF/p75 protein-protein interaction, they are also capable of inhibiting IN enzymatic activities and raising the IN multimerization level.We studied several new INLAI series from the company Mutabilis. We could demonstrate that these molecules inhibit integration, but also have a more potent, LEDGF-independent, antiretroviral effect during virion maturation, resulting in the production of non-infectious virions. Virions produced upon INLAI treatment have an eccentric morphology characterized by an encapsidation defect of the viral genome, and lead to an infection block at reverse transcription. Yet, we showed that these virions package a stable and functional viral genome, an active RT and the tRNALys3 primer for reverse transcription, and also keep their immunoreactivity towards B- and T-cell lymphocytes. When evaluating the influence of polymorphism at the edge of the binding site, we identified the IN Ala125 polymorphic variant which causes the concomitant loss of MUT-A effect on virion maturation and IN multimerization, whereas inhibition of integration and IN-LEDGF interaction are maintained. This proves that INLAIs exert their late stage effect through induction of IN multimerization. We could associate IN multimerization to INLAI-induced dimer destabilization by analyzing MUT-A co-structures with polymorphic integrases. Beside their therapeutic interest INLAIs are highly valuable reagents that allowed to demonstrate the essential role of integrase at three key steps of the HIV-1 replication cycle, reverse transcription, integration and virus maturation
La perception de l'harmonicité des sons en présence ou en l'absence de surdité neurosensorielle
Le systĂšme auditif central d'un sujet normo-entendant fusionne perceptivement les composantes spectrales des sons complexes harmoniques, bien que ces composantes soient initialement sĂ©parĂ©es par la cochlĂ©e. Cette fusion harmonique joue un rĂŽle important dans l'analyse des scĂšnes acoustiques multi-sources, situations dans lesquelles la gĂȘne auditive des patients atteints de surditĂ© neurosensorielle est gĂ©nĂ©ralement exacerbĂ©e. L'objectif de cette thĂšse Ă©tait d'une part de clarifier les mĂ©canismes de la fusion harmonique chez les auditeurs sains, et d'autre part d'Ă©tudier l'impact des surditĂ©s neurosensorielles sur la sensibilitĂ© Ă l'harmonicitĂ©. Une premiĂšre expĂ©rience, menĂ©e sur des auditeurs sains, a portĂ© sur la reconnaissance auditive de l'octave harmonique, formĂ©e par des sons purs simultanĂ©s dont le rapport frĂ©quentiel est Ă©gal Ă 2. L'expĂ©rience montre que le mĂ©canisme permettant cette reconnaissance est insensible Ă la direction d'un Ă©cart par rapport Ă l'octave. Il apparaĂźt par contre que, pour des sons purs prĂ©sentĂ©s consĂ©cutivement, l'octave ne reprĂ©sente plus une singularitĂ© du point de vue de la discrimination perceptive. Une seconde expĂ©rience, incluant des sujets atteints de surditĂ© neurosensorielle lĂ©gĂšre Ă moyenne, montre que l'effet de ces surditĂ©s sur la sensibilitĂ© absolue Ă l'harmonicitĂ© est trĂšs variable d'un individu Ă l'autre, et semble reflĂ©ter avant tout le niveau d'altĂ©ration de la discrimination frĂ©quentielle. Cependant, l'expĂ©rience fait apparaĂźtre chez tous les sujets testĂ©s la conservation d'une sensibilitĂ© relative Ă l'harmonicitĂ© : le seuil de dĂ©tection d'une inharmonicitĂ© par rapport Ă l'octave s'avĂšre toujours meilleur que le seuil de dĂ©tection d'une diffĂ©rence entre des rapports de frĂ©quences inharmoniques, mĂȘme en prĂ©sence de pertes tonales moyennes supĂ©rieures Ă 45 dB entre 500 et 4000 Hz.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF
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