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A multi-modal and temporal antibiotic resistance knowledge graph
No full textInternational audienceUnderstanding how antibiotic resistance genes spread is essential for protecting human, animal, and environmental health. It requires collaboration across multiple fields and expertise under One Health initiatives, emphasizing the pressing need to consolidate diverse antibiotic data from human, animal, and environmental samples. In this paper, we propose a domain-specific Knowledge Graph leveraging the SOSA ontology to uniformly represent multi-modal data and their analysis while allowing the description of provenance metadata covering both time and geographical locations. This work is driven by a national consortium of antibiotic resistance experts (ABRomics). As experimental results,we show how this domain knowledge can be used to answer a specific expert question as well as increasing the FAIRness of antibiotic resistance data
Questionner les technologies avec Andrew Feenberg. Perspectives critiques et socio-philosophiques
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A Deep Learning Approach for Predicting the Response to Anti-VEGF Treatment in Diabetic Macular Edema Patients Using Optical Coherence Tomography Images
No full textInternational audienceDiabetic macular edema (DME) is a serious complication of diabetes that can lead to vision loss, making the prediction of patient response to anti-vascular endothelial growth factor (anti-VEGF) treatment crucial for optimizing therapeutic strategies. This study introduces ESSDP (Extended Siam Saves Diabetes Patients), a novel deep learning approach leveraging a Siamese network architecture with EfficientNetB2 to predict therapeutic response in DME patients through optical coherence tomography (OCT) image analysis. By classifying patients into good or poor responder groups based on central macular thickness reduction after injection, the proposed framework achieved a predictive performance with an accuracy of 0.80, sensitivity of 0.71, precision of 0.89, and an F1-Score of 0.74. These findings highlight the potential of Siamese network-based deep learning architectures as effective tools for predicting treatment outcomes in DME patients, even when working with limited datasets, and pave the way for enhancing personalized treatment strategies in ophthalmology
In vitro CRISPR/CASX 4q35 D4Z4 ablation as a potential therapeutic strategy for facioscapulohumeral muscular dystrophy type 1
No full textLysosomal damage is a therapeutic target in Duchenne muscular dystrophy.
No full textInternational audienceDuchenne muscular dystrophy (DMD), a muscle degenerative disease affecting young boys, arises from the loss of dystrophin. Current gene therapy approaches aim to restore a shortened form of dystrophin (microdystrophin) via adeno-associated vector delivery. While recent clinical studies show promise, therapeutic efficacy remains incomplete, emphasizing the need for improved approaches. Here, we identified lysosomal perturbations in myofibers of patients with DMD and animal models, an overlooked mechanism of cellular damage in muscular dystrophies. These were notably marked by the up-regulation and recruitment of Galectin-3, a biomarker of lysosomal membrane permeabilization, to lysosomes, alongside alterations in lysosome number, morphology, and function. Microdystrophin therapy in Dmd mdx mice fails to fully correct these damages. However, combining it with trehalose, a lysosome-protective disaccharide, substantially improves the outcome, enhancing muscle function, myopathology, and transcriptome. These findings highlight lysosomal damage as an important pathomechanism in DMD and suggest that combining trehalose with gene therapy could enhance therapeutic efficacy
Identification de mécanismes de compensation impliqués dans la physiopathologie de la myopathie des ceintures de type R2
No full textLimb girdle muscular dystrophies are a heterogeneous group of genetic diseases leading to progressive loss of the limb girdle muscles. Caused by mutations in the gene encoding dysferlin, limb girdle myopathy type R2 (or LGMDR2, formerly known as LGMD2B) is a rare disease affecting less than 1 in 100,000 people for which there is no treatment. A recent study has highlighted the high variability in the clinic and the age of onset of symptoms between patients (Fernandez-Eulate G et al., 2021). Because this difference is not correlated to patient's genotypes, recent in vitro findings suggest that the overexpression of some genes probably participate in a compensatory mechanism against increased proteolysisIn order to identify these compensatory mechanisms, we compared the gene expression profiles of muscle biopsies obtained from patients with early- and late-onset symptoms. Several pathways were identified, including autophagy, which appears to play an important role in the disease, especially in the ability to preserve fibers from stress and damage.The protective role of autophagy induction in LGMDR2 myoblasts was then studied by identifying gene signatures expressed in specific subsets of affected or preserved muscle cells by single-cell mRNA sequencing.Finally, to translate these findings into therapeutic applications, we conducted a multiparametric screening of seventeen autophagy inducers in immortalized myoblasts derived from LGMDR2 patients, with the aim of identifying novel pharmacological compounds capable of enhancing membrane repair through autophagy induction.Among the drugs tested, six were found to effectively stimulate autophagy and improve membrane repair.Our findings demonstrate that inhibition of the mTOR pathway improves the cellular phenotype and underscore the potential of autophagy activators as a promising therapeutic target for LGMDR2.Les dystrophies musculaires des ceintures sont un groupe hétérogène de maladies génétiques entraînant une perte progressive des muscles des ceintures. Causée par des mutations du gène codant pour la dysferline, la myopathie des ceintures de type R2 (ou LGMDR2, anciennement appelée LGMD2B) est une maladie rare qui touche moins d'une personne sur 100 000 et pour laquelle il n'existe pas de traitement. Une étude récente a mis en évidence la grande variabilité de la clinique et de l'âge d'apparition des symptômes entre les patients (Fernandez-Eulate G et al., 2021). Cette différence n'étant pas corrélée aux génotypes des patients, de récentes découvertes in vitro suggèrent que la surexpression de certains gènes participe probablement à un mécanisme compensatoire contre l'augmentation de la protéolyse.Afin d'identifier ces mécanismes compensatoires, nous avons comparé les profils d'expression génique de biopsies musculaires obtenues chez des patients présentant des symptômes précoces et tardifs. Plusieurs voies ont été identifiées, dont l'autophagie, qui semble jouer un rôle important dans la maladie, notamment dans la capacité à préserver les fibres du stress et des dommages.Le rôle protecteur de l'induction de l'autophagie dans les myoblastes LGMDR2 a ensuite été étudié en identifiant les signatures génétiques exprimées dans des sous-ensembles spécifiques de cellules musculaires affectées ou préservées par séquençage de l'ARNm d'une seule cellule.Enfin, pour traduire ces résultats en applications thérapeutiques, nous avons effectué un criblage multiparamétrique de dix-sept inducteurs de l'autophagie dans des myoblastes immortalisés dérivés de patients LGMDR2, dans le but d'identifier de nouveaux composés pharmacologiques capables d'améliorer la réparation membranaire par l'induction de l'autophagie. Parmi les médicaments testés, six se sont révélés capables de stimuler efficacement l'autophagie et d'améliorer la réparation des membranes.Nos résultats démontrent que l'inhibition de la voie mTOR améliore le phénotype cellulaire et soulignent le potentiel des activateurs de l'autophagie en tant que cible thérapeutique prometteuse pour la LGMDR2
Origin and evolutionary trajectories of brown algal sex chromosomes
No full textThe raw sequence reads for the Oxford Nanopore data, Hi-C libraries and RNA-seq libraries are available in the Sequence Read Archive under BioProject accession number PRJNA1059008. All genome assemblies and annotations are also accessible through the Phaeoexplorer database (https://phaeoexplorer.sb-roscoff.fr/) for comparative genomics analyses.International audienceResearch on the biology and evolution of sex chromosomes has primarily focused on diploid XX/XY and ZW/ZZ systems. In contrast, the rise, evolution and demise of U/V systems has remained an enigma. Here we analyse genomes of nine brown algal species with different sexual systems to determine the history of their sex determination. U/V sex chromosomes emerged between 450 and 224 million years ago, when a region containing the pivotal male-determinant MIN ceased recombining. Seven ancestral genes within the sex-determining region show remarkable conservation over this vast evolutionary time, although nested inversions caused expansions of the sex locus, independently in each lineage. We evaluate whether these expansions are associated with increased morphological complexity and sexual differentiation, and show that taxonomically restricted genes evolve unexpectedly often in U and V chromosomes. We also investigate two situations in which U/V-linked regions have changed. First, we demonstrate that convergent evolution of two monoicous species occurred by ancestral males acquiring U-specific genes. Second, the Fucus dioecious system involves new sex-determining gene(s), acting upstream of formerly V-specific genes during development. Both situations have led to the demise of U and V chromosomes and erosion of their specific genomic characteristics
Closest relatives of poxviruses are spread in the gut of humans and animals worldwide: the egoviruses
No full textAbstract Large and giant double-stranded DNA viruses within the phylum Nucleocytoviricota are diverse and prevalent in the environment where they substantially affect the ecology and evolution of eukaryotes 1–4 . Until now, these viruses were only sporadically found in the digestive system of vertebrates 5–7 . Here, we present the discovery of a diversified group of Nucleocytoviricota viruses dubbed egoviruses that almost exclusively occur in the digestive system of vertebrates worldwide. Egoviruses are most closely related to poxviruses and represent a third order within the class Pokkesviricetes 8 . They contain large linear genomes that include genes linked to multilayered icosahedral capsids only observed in asfuviruses. The widespread occurrence of egovirus genes in genomes of metamonads (with signal particularly enriched among Trichomonas and Tritrichomonas ), and their co-existence in human fecal samples as demonstrated by our metagenomic survey point towards a preferential infection of unicellular eukaryotes known to prevail, often as symbionts or pathogens, in the gut of vertebrates worldwide 9 . Notably, the numerous Egovirales genes found throughout Trichomonas vaginalis genomes (>3% of their gene pools) designate this prominent sexually transmitted human pathogen as a likely vector to the spread of egoviruses. Notably, one egovirus clade is human-specific, evolutionarily constrained, and spread across continents, demonstrating a long-term association with the human population at a global scale. Egoviruses represent the only diverse, widespread, and abundant group of double-stranded DNA viruses infecting eukaryotes in the digestive system of vertebrates, with implications for human health, capsid evolution and the origin of poxviruses
Tara Polaris: Shedding light on microbial and climate feedback processes in the Arctic atmosphere
No full textInternational audienceThe central Arctic is experiencing warming up to four times faster than the global average. This Arctic amplification is accompanied by large deviations in climate projections, making anticipation of high-impact, near-term regional biodiversity and climate change difficult. Several atmospheric processes contribute simultaneously to Arctic amplification and biodiversity change yet remain largely unstudied, not least because of the difficulty to access the central Arctic Ocean and conduct year-round studies. This article introduces the near- to mid-term objectives of the Tara Polar Station scoping group on “atmosphere-biosphere interactions,” with a focus on identifying and quantifying the origin and genetic composition of local and long-range transported biogenic particles that can impact biodiversity and cloud formation, the role of the stratified boundary layer on vertical fluxes of cloud seeds, bioaerosols and nutrients, and the impact of clouds on atmospheric light transmission. The Tara Polar Station is a fortified research vessel built to drift in the Arctic sea ice throughout the next 20 years in ten Tara Polaris expeditions, each lasting one and a half years. The platform allows for year-round interdisciplinary studies targeted at understanding the central Arctic Ocean ecosystem functioning, biodiversity, and climate change at the ocean-ice-atmosphere nexus. This scoping group will deploy novel and automated instruments for in situ, real-time vertical and remote sensing observations of aerosols, clouds, and radiation. The link between the biosphere and atmosphere will be investigated specifically through bio- and chemo-molecular sampling of air, clouds, ice, and water. We expect the early Tara Polaris expeditions to deliver insights that can be implemented into models for improved scenarios of Arctic change, in particular for the next few decades when we expect a regime shift in summer sea-ice presence
Tissular chromatin-state cartography based on double-barcoded DNA arrays that capture unloaded PA-Tn5 transposase
No full textInternational audienceRecent developments in spatial omics are revolutionizing our understanding of tissue structure organization and their deregulation in disease. Here, we present a strategy for capturing chromatin histone modification signatures across tissue sections by taking advantage of a double-barcoded DNA arrays design compatible with in situ Protein A–transposase Tn5 tagmentation. This approach has been validated in presence of fresh-frozen mouse brain tissues but also in decalcified formalin-fixed paraffin-embedded (FFPE) mouse paw samples, in which either the histone modification H3K4 trimethylation or H3K27 acetylation has been used as proxy for interrogating active promoter signatures. Furthermore, because combinatorial enrichment of multiple histone modifications was shown to code for various states of gene transcriptional status (active, bivalent, repressed), we have integrated several histone modifications generated from consecutive mouse embryo sections to reveal changes in chromatin states across the tissue. Overall, this spatial epigenomic technology combined with the use of a spatial chromatin-state analytical strategy paves the way for future epigenetics studies for addressing tissue architecture complexity