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SOX10-Mediated Regulation of Enteric Glial Phenotype in vitro and its Relevance for Neuroinflammatory Disorders
No full textInternational audienceThe transcription factor SOX10 is a key regulator of myelinated glial cell phenotype and function, with a known role in multiple sclerosis (MS). SOX10 is also expressed in enteric glial cells (EGC) within the gut, yet its regulatory functions in EGC remain poorly understood. This study aimed to identify SOX10 target genes that influence EGC phenotype and may have implications for MS. An EGC cell line was established for doxycycline-inducible SOX10 overexpression. Impact of SOX10 overexpression on EGC phenotype was assessed by genome-wide expression analysis and results were validated via RT-qPCR and western blot. Data were compared with SOX10 ChIP-seq and transcriptomic datasets from MS patients to identify pan-glial SOX10 target genes potentially linked to neuroinflammatory disorders. SOX10 overexpression was associated with ectopic upregulation of genes related to myelin regulation and glial differentiation, as evidenced by increased PLP1 expression at mRNA and protein levels. Comparison to ChIP-seq and MS datasets highlight SOX10 target genes, including PLP1, RNF130, NES and APOD potentially involved in central and peripheral manifestations of MS pathology. Our findings support a cell-specific regulation of EGC phenotype through SOX10 expression level and identify SOX10-regulated genes relevant to EGC function. This research advances the understanding of EGC diversity and provide information about glial cells targeting in neuroinflammatory disorders
Inteligência Artificial, Saúde, Segurança e Riscos Psicossociais no Trabalho: Oportunidades e Desafios
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Mutation of Brain Aromatase Impairs Behavior and Neuroplasticity in Adult Zebrafish
No full textInternational audienceBrain aromatase, an enzyme responsible for the local synthesis of estrogens, plays a key role in regulating behavior and neuroplasticity in mammals. In teleost fish, brain aromatase is encoded by the cyp19a1b gene, which is strongly expressed in radial glial cells; however, the specific functions of this enzyme are currently unknown. To investigate its role, a cyp19a1b‐mutant zebrafish line was generated using gene‐editing techniques. Behavioral, neurogenic, and neurotransmission‐related parameters were assessed in adult male and female zebrafish. Behavioral analysis highlighted significant alterations in mutant zebrafish, including changes in swimming activity, boldness, sociability, and aggression, with a stronger effect in males compared to females. Beyond these behavioral modifications, mutant zebrafish exhibited disrupted cell proliferation patterns, as assessed by PCNA immunofluorescence in key forebrain regions. Specifically, proliferation decreased in the telencephalon and in the caudal hypothalamus of mutant zebrafish while increasing in the olfactory bulbs. The number of dopaminergic and serotonergic neurons, visualized by immunofluorescence, remained unchanged. Similarly, HPLC‐ED quantification of monoamines and their metabolites showed no significant differences between mutant and wild‐type zebrafish. To further explore the impact of the cyp19a1b mutation on gene expression, transcriptomic analysis was performed using BRB‐Seq technology. Gene expression analyses identified several processes affected by the mutation, including cell proliferation, apoptosis, estrogen signaling, neuroplasticity, and behavioral regulation, in a sex‐ and region‐dependent manner. In conclusion, our results demonstrate that several behaviors, including locomotor activity, sociability, aggressiveness, and anxiety, exhibit marked sexual dimorphism. They show that the cyp19a1b mutation affects locomotor activity in a context‐dependent manner, increases boldness, and reduces aggressiveness. In addition, transcriptomic analyses revealed widespread dysregulation of gene expression, which likely contributes to the observed behavioral alterations. Taken together, these findings underscore the crucial role of brain aromatase in the neurobiological regulation of diverse behaviors.imag
Levofloxacin in Bone and Joint Infections: Development of an Application for Model‐Informed Precision Dosing
No full textInternational audienceLevofloxacin is a valuable antibiotic in the treatment of bone and joint infections. Due to the known risk of treatment failure and bacterial resistance, the development of tools facilitating pharmacokinetic/pharmacodynamic parameter monitoring to inform precision dosing is needed. Therefore, we assessed the use of Bayesian estimation to predict AUC0–24 and Cmax of levofloxacin under various sampling scenarios realistic in clinical routine. Furthermore, we developed a free web‐based application allowing model‐informed precision dosing. All published population pharmacokinetic models of ofloxacin and levofloxacin in bone and joint infections were researched and their predictive performance was compared using a real‐life data cohort. We used simulated data to validate the robustness of various scenarios for Bayesian estimation of AUC0–24 and Cmax with up to three samples, including the potential impact of an incorrectly reported sampling time at peak concentration. Relative bias and relative root mean square error were estimated to assess accuracy and precision, respectively. One of the three published levofloxacin models showed negligible mean relative prediction error (0.02 ± 0.09). We modified it to a closed form approximation to facilitate the implementation in the application. The 2‐sample scenario (T0h‐T3h) allowed accurate and precise AUC0–24 estimations for 500 mg q12h and 750 mg q24h dosing regimens. None of the tested scenarios allowed a satisfactory estimation of Cmax. We finally developed and validated a free web‐based application (https://levoshiny.iame‐research.center/) using the selected model. The Shiny application will be useful in clinical practice to individualize dose regimens based on the AUC0–24 obtained using the proposed limited sampling strategy
Bovine ampullary and isthmic epithelial spheroids: proteomic profile and physiological features for in vitro studies of gamete-oviduct interactions.
No full textInternational audienceAfter mating or insemination, spermatozoa reach the first part of the oviduct, known as the isthmus, where a subpopulation binds to the epithelial cilia, forming a reservoir. Then, spermatozoa migrate toward the ampulla, where additional interactions with cilia occur and fertilization takes place. Exploring sperm-oviduct interactions requires physiologically relevant in vitro models. Our goal was to characterize isthmic and ampullary epithelial spheroids in terms of cellular, proteomic and sperm binding properties. Spheroids measuring 100-150 µm in diameter, formed after a 3-day culture of pre-ovulatory oviduct mucosa fragments, were selected and analyzed for (i) epithelial, fibroblast and cilia markers by immunostaining, (ii) proteomic content by dia-PASEF nanoLC-MS/MS, and (iii) ability to interact with bull spermatozoa during a 6-h co-culture, assessed by confocal and scanning electron microscopy. Cells within both isthmic and ampullary spheroids showed positive immunostaining for cytokeratin and no staining for vimentin. Ampullary spheroids consistently exhibited a higher proportion of ciliated cells compared to isthmic spheroids (24.5 % vs 20 %; p < 0.05; variation coefficients among replicates of 15 and 11 %, respectively). A total of 6914 proteins were quantified, of which 1010 (14 %) were differentially abundant between isthmic and ampullary spheroids. Following co-culture, 95-97 % of bound spermatozoa were attached by their head to cilia of both spheroid groups. The density of bound spermatozoa was on average 33-45 % higher on ampullary compared to isthmic spheroids (p < 0.001). This study provides a well-differentiated oviduct epithelium model for in vitro investigations of gamete and embryo interactions with the oviduct
Comparing randomized trial designs to estimate treatment effect in rare diseases with longitudinal models: a simulation study showcased by Autosomal Recessive Cerebellar Ataxias using the SARA score
No full textInternational audienceParallel designs with an end-of-treatment analysis are commonly used for randomised trials, but they remain challenging to conduct in rare diseases due to small sample size and heterogeneity. A more powerful alternative could be to use model-based approaches. We investigated the performance of longitudinal modelling to evaluate disease-modifying treatments in rare diseases using simulations. Our setting was based on a model describing the progression of the standard clinician-reported outcome SARA score in patients with ARCA (Autosomal Recessive Cerebellar Ataxia), a group of ultra-rare, genetically defined, neurodegenerative diseases. We performed a simulation study to evaluate the influence of trials settings on their ability to detect a treatment effect slowing disease progression, using a previously published non-linear mixed effect logistic model. We compared the power of parallel, crossover and delayed start designs, investigating several trial settings: trial duration (2 or 5 years); disease progression rate (slower or faster); magnitude of residual error (σ=2 or σ=0.5); number of patients (100 or 40); method of statistical analysis (longitudinal analysis with non-linear or linear models; standard statistical analysis), and we investigated their influence on the type 1 error and corrected power of randomised trials. In all settings, using non-linear mixed effect models resulted in controlled type 1 error and higher power (88% for a parallel design) than a rich (75% for a parallel design) or sparse (49% for a parallel design) linear mixed effect model or standard statistical analysis (36% for a parallel design). Parallel and delayed start designs performed better than crossover designs. With slow disease progression and high residual error, longer durations are needed for power to be greater than 80%, 5 years for slower progression and 2 years for faster progression ataxias. In our settings, using non-linear mixed effect modelling allowed all three designs to have more power than a standard end-of-treatment analysis. Our analysis also showed that delayed start designs are promising as, in this context, they are as powerful as parallel designs, but with the advantage that all patients are treated within this design
Current use of donor lymphocyte infusions after allogenic stem cell transplantation in Europe: a survey on behalf of the cellular therapy and immunobiology working party of the EBMT
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Comprendre et définir le savoir expérientiel
No full textInternational audienceExperiential knowledge is the contemporary major argument justifying the solicitation of a new type of actor - the peer - in the fields of disability, mental health, chronic illness, but also addiction, extreme poverty and neurodevelopmental disorders. This article aims to understand and define the concept of experiential knowledge. In order to do so, the methodology used consists of two steps. First, a short review of the literature makes it possible to situate the concept in the context of its emergence. This will clarify the debates about its scientific validity or its legitimacy in the name of the democratization of our societies. Then, a critical analysis of Thomasina Borkman's theoretical proposals highlights the issue of intersubjectivity and leads to the characterization of the different dimensions of experiential knowledge and its definition.Le savoir expérientiel est l’argument phare contemporain justifiant le recours à un nouveau type d’acteur – le pair – dans les champs du handicap, de la santé mentale, de la maladie chronique, mais aussi des addictions, de la grande pauvreté ou encore des troubles neurodéveloppementaux. Cet article vise à comprendre et à définir le concept de savoir expérientiel. La méthode employée pour ce faire est constituée en deux temps. Tout d’abord, une courte recension de la littérature permet de situer ce concept dans son contexte d’émergence. Les débats autour de sa validité scientifique ou encore de sa légitimité au nom de la démocratisation de nos sociétés sont ainsi éclairés. Ensuite, une analyse des propositions théoriques de Thomasina Borkman - auteure à l’origine de ce concept - et leur critique partielle permettent de fonder un argumentaire rationnel mettant en avant la question de l’intersubjectivité, menant à la caractérisation des différentes dimensions du savoir expérientiel et à sa définition
Identifying signatures of past and present cryovolcanism on Europa
No full textInternational audienceEuropa, the most visibly active icy moon of Jupiter, is a prime target for the search for life in the outer solar system. Two spacecraft missions, Europa Clipper from the National Aeronautics and Space Administration (NASA) and the Jupiter Icy Moon Explorer (JUICE) from the European Space Agency (ESA), will observe its surface, probe its interior structure, and characterize the space environment starting in 2030. Occasional eruptions of water sourced from Europa’s interior may provide a window on the interior conditions and habitability of the moon. Here, we investigate the storage and evolution of briny water in Europa’s ice shell and propose a framework to interpret spectral, thermal, radar and gravity data collected by future missions. We show that it is possible to discriminate between water erupting from the deep ocean or from shallow liquid reservoirs using combined measurements of the material’s salinity, surface temperature and ice shell thickness