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Steerable Thin-Film Electrode Array for Cochlear Implantation: Design and Development for Future Atraumatic Insertion
No full textInternational audienceDuring cochlear implant surgery, standard electrode arrays are inserted into the scala tympani to stimulate the spiral ganglion cells and rehabilitate hearing in deaf patients. However, conventional electrode arrays' stiffness and passive nature lead to potential trauma or incomplete insertion during the procedure. To overcome these limitations, an original steerable thin film electrode array (TFEA) has been developed. First, the twenty gold electrodes, distributed over a 25 mm length, with an average surface area of 0.16 mm2, are significantly larger than those of existing TFEAs. These larger electrode surface areas enable safe neural stimulation within charge density limits below the Shannon threshold. By adjusting the material thicknesses, the proposed TFEA offers tunable stiffness, enabling safer and more flexible insertion. The microfabrication process, using SU-8 negative photoresist thin films, is both cost-effective and straightforward. In addition, the ability to dynamically adjust the curvature of the TFEA during insertion into a 3D printed cochlea model using low voltage conducting polymer based micro-actuator has been demonstrated. This marks the first instance of electrode array insertion with adaptive curvature, minimizing contact with cochlear walls. Successful insertion was achieved, with a curvature angle close to 360°. This active TFEA has the potential to improve insertion control and reduce the risk of trauma during cochlear implantation
An ancient DNA perspective on the Russian conquest of Yakutia
No full textInternational audienceYakut communities from northeastern Siberia inhabit some of the coldest environments on Earth, preserving an extraordinary archaeological record. Their history was profoundly reshaped by the Russian conquest, which introduced cereals, pathogens and Christianity beginning in 1632 (refs. 1,2,3,4,5). However, the biological impact of these transformations remains unknown. Here we generated extensive ancient DNA data to elucidate contemporary changes in Yakut genomic diversity and oral microbiomes. We found Yakut origins tracing back to local populations that admixed with Trans-Baikal groups migrating as the Great Mongol Empire spread. Despite the Russian conquest, the Yakut gene pool and oral microbiomes appeared largely stable, although smallpox strains distinct from those documented in Europe by approximately 1650 circulated. Marital practices generally maintained low consanguinity, with the exception of one female bearing the latest markers of traditional shamanism, who was the daughter of second-degree relatives
An integrated quantitative single-objective light-sheet microscope for subcellular dynamics in embryos and cultured multicellular systems
No full textQuantitative imaging of subcellular processes in living embryos, stem-cell systems, and organoid models requires microscopy platforms that combine high spatial resolution, fast volumetric acquisition, long-term stability, and minimal phototoxicity. Single-objective light-sheet approaches based on oblique plane microscopy (OPM) are well suited for live imaging in standard sample geometries, but most existing implementations lack the optical calibration, timing precision, and end-to-end integration required for reproducible quantitative measurements.Here we present a fully integrated and quantitatively characterized OPM platform engineered for dynamic studies of transcription and nuclear organization in embryos, embryonic stem cells, and threedimensional culture systems. The system combines high-numerical-aperture remote refocusing with tilt-invariant light-sheet scanning and hardware-timed synchronization of laser excitation, galvo scanning, and camera readout. We provide a comprehensive characterization of the optical performance, including point-spread function, sampling geometry, usable field of view, and system stability, establishing a well-defined framework for quantitative volumetric imaging.To support high-throughput operation, we developed a unified acquisition and reconstruction pipeline that enables real-time volumetric imaging at hardware-limited rates while preserving deterministic timing and reproducible geometry. Using this platform, we demonstrate quantitative threedimensional imaging of MS2-labeled transcription sites in living Drosophila embryos, cultured mouse embryonic stem cells, and mESC-derived gastruloids, enabling extraction of transcriptional intensity traces across diverse biological contexts.Together, this work establishes OPM as a robust and quantitatively calibrated single-objective light-sheet platform for transcription imaging in complex living systems, providing a foundation for future studies of gene regulation and nuclear dynamics across developmental and stem-cell model
Evolutionary Advantage of Diversity-Generating Retroelements in Switching Environments
No full textInternational audienceDiversity-Generating Retroelements (DGRs) create rapid, targeted variation within specific genomic regions in phages and bacteria. They operate through stochastic retro-transcription of a template region (TR) into a variable region (VR), which typically encodes ligand-binding proteins. Despite their prevalence, the evolutionary conditions that maintain such hypermutating systems remain unclear. Here we introduce a two-timescale framework separating fast VR diversification from slow TR evolution, allowing the dynamics of DGR-controlled loci to be analytically understood from the TR design point of view. We quantity the fitness gain provided by the diversification mechanism of DGR in the presence of environmental switching with respect to standard mutagenesis. Our framework accounts for observed patterns of DGR activity in human-gut Bacteroides and clarifies when constitutive DGR activation is evolutionarily favored
DMP pour le projet "Subversion immunitaire épigénétique dans les macrophages infectés par Leishmania"
No full text2025 3. Overview of the data 3.1. What is the purpose of the data collection/generation?Objective 1: Mapping infection-and LSD1-dependent changes of the macrophage epigenome. ATACseq, CUT&RUN, ChemSeq and RNA seq data plus gene promoters list Objective 2: Characterization of the role of macrophage LSD1 in intracellular Leishmania infection. siRNA sequences, compounds/protacs... structures, viability assays , anti-leishmanial assays, biochemical assays Objective 3: Identification of LSD1-dependent, regulatory mechanisms required for parasite survival. Proteomic data, system level analyses, anti-leishmanial readouts 3.2. How many dataset(s) will you generate during this project? 73.3. What is the nature and format of generated/collected data?Sequencing paired-end data in fastaq.gz format stored at the Biomics Institut Pasteur platform and in the NCBI public functional genomics data repository GEO (Gene Expression Omnibus) when available online for publication. Microscopy images from confocal and classical fluorescence microscopes in proprietary, tiff and PNG formats are stored in internal servers and backcopied in external hard disksThe following data are stored on hard disks and internal servers : *Real-time PCR data in .ixo format *Excel, Word, Access and PDF documents *Gel electrophoresis and WB images in jpeg, tiff and PNG formats *Liquid chromatography-tandem mass spectrometry (LC-MS/MS) data processed using myProMS v3.10.0 (https://github.com/bioinfo-pf-curie/myproms) * cytoscape data in PNG or JPEG 3.4. Give the expected volume of generated data for this project -FASTQ, a text-based format for storing both a biological sequence (usually nucleotide sequence) and its corresponding quality scores. Describe in more detail the data in this datasetThe dataset consists of Bulk RNA-Seq data derived from Mus musculus primary macrophages. The experimental design is a 2x2 factorial setup comprising: *Biological Material: Primary macrophages (uninfected vs. infected). *Treatment: Treated with an epigenetic inhibitor vs. untreated (vehicle control). *Data Type: The dataset includes raw raw sequencing reads (FASTQ format) and processed aligned data/count matrices (BAM/TXT format). 8.1.5. Describe the method of data collection and/or generation The dataset is generated and processed via the following pipeline: *Acquisition: Illumina Hiseq2500 platform; single-end 65 bp reads with strand specificity. *Pre-processing: Reads cleaned with cutadapt (v1.11); sequences <25 nt removed. *Alignment: Mapped to Reference Genome GRCm38 (Ensembl 94) using STAR (v2.5.0a). *Quantification: Gene counting via featureCounts (v1.4.6-p3) using parameters -t gene -s 0. *Availability: Publicly accessible via the NCBI Gene Expression Omnibus (GEO) repository (ongoing Superseries submission)." 8.1.6. Describe your dataset with keywords RNA-seq, Transcriptomics, Mus musculus, Primary macrophages, Epigenetics,</div
The m6A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages
No full textMacrophages are the major host cells of the protozoan parasite Leishmania in mammalian infection. These key innate immune cells display remarkable phenotypic plasticity ranging from pro-inflammatory M1 to anti-inflammatory M2 macrophages that can control infection and tissue homeostasis, respectively. It has been recognized that Leishmania exploits macrophage phenotypic plasticity to establish chronic infection. However, the current notion that these parasites simply trigger an M2-like phenotype seems over-simplified considering the immunopathology observed during leishmaniasis -in particular in response to Leishmania amazonensis -which is often characterized by a mixed Th1/Th2 immune response. Here we combined a series of systems-level analyses to shed new light on the phenotype of Leishmania-infected macrophages (LIMs) during short-and long-term infection, in vitro and in vivo. Immuno-metabolic profiling by RNA-seq, RT-qPCR, cytokine immunoassays, and real-time bioenergetic flux analysis of L. amazonensis-infected bone marrow-derived macrophages (BMDMs) revealed a highly complex and unique phenotypic and bioenergetic signature. In vitro LIMs were characterized by co-expression of both M1 and M2 markers at RNA and protein levels and increased expression of glycolytic genes that matched a progressive metabolic switch from a M2-like respiratory to a M1-like glycolytic energy production observed for both long-term in vitro and in vivo infected macrophages. Unlike in M1 macrophages, glycolytic gene expression did not correlate with increased expression of its key regulatory HIF-1α. In contrast, siRNA knock down experiments in primary BMDMs uncovered an essential role of the m 6 A reader protein IGF2BP2 in stabilizing m 6 A modified transcripts of the glycolytic pathway, contributing to HIF-1α-independent induction of glycolysis. In conclusion, L. amazonensis establishes a complex and unique phenotypic shift in infected macrophages in vitro and in vivo that combines M1-like and M2-like immunometabolomic characteristics and implicates differential mRNA stability in induction of aerobic glycolysis. Our data thus uncover epi-transcriptomic regulation as a novel target for Leishmania immune subversion to establish a host cell phenotype beneficial for intracellular parasite development and chronic infection
Ridge-penalised spectral least-squares estimation for point processes
No full textPenalised estimation methods for point processes usually rely on a large amount of independent repetitions for cross-validation purposes. However, in the case of a single realisation of the process, existing cross-validation methods may be impractical depending on the chosen model. To overcome this issue, this paper presents a Ridge-penalised spectral least-squares estimation method for second-order stationary point processes. This is achieved through two novel approaches: a p-thinning-based cross-validation method to tune the penalisation parameter, relying on the spectral representation of the process; and the introduction of a spectral least-squares contrast based around the asymptotic properties of the periodogram of the sample. The proposed method is then illustrated by a simulation study on linear Hawkes processes in the context of parametric estimation, highlighting its performances against more traditional approaches, specifically when working with short observation windows
Compassionate Use of Olorofim for Invasive Mold Infections: A Nationwide Observational Study in France
No full textInternational audienceBackground: The increasing incidence of resistant invasive mold infections (IMIs) has highlighted the need for novel antifungal agents. Olorofim, a first-in-class orotomide, has shown promising efficacy in a recent phase II study, but clinical data remain limited.Methods: We conducted a retrospective multicenter cohort study in France, including all patients who received olorofim under compassionate use for proven or probable non-Mucorales IMIs. Eligible patients had IMIs refractory to or intolerance to standard antifungals or no effective treatment options. Efficacy was defined as mycological and clinical control of infection; safety was also assessed.Results: Between January 2020 and December 2023, 17 patients (median age, 39 years) received olorofim. Underlying conditions included primary immunodeficiency (n = 4) and lung transplantation (n = 5). Sites of infection included the lung (88.2%) and the central nervous system (23.5%), with 5 cases of disseminated disease. In total, 23 strains were identified, mostly Aspergillus fumigatus (34.8%) and Microascus spp (13%). The median duration of prior antifungal therapy was 9.1 months. Olorofim was used primarily for refractory IMIs (70.6%) and in combination with other antifungals in 82.4% of cases. Olorofim minimum inhibitory concentrations were ≤0.5 mg/L in the 8 available isolates. Among 15 evaluable patients, 5 (33.3%) achieved clinical and mycological success, 7 (46.7%) had partial responses, and 3 (20%) experienced treatment failure. The 3-month mortality rate was 29.4% (5 of 17). No severe adverse events were reported.Conclusions: Olorofim exhibited potential efficacy and good tolerability in patients with refractory IMIs. Further data from ongoing clinical trials are needed to confirm these findings
Immersive Rehabilitation Therapy (MoveR) Improves Postural and Visuo-Attentional Skills in Children with ADHD: A Clinical Study
No full textInternational audienceBackground: Motor as well as attentional skills are deficient in children with attention deficit hyperactivity disorder (ADHD). The aim of the present study was to explore whether a short immersive rehabilitation therapy could improve motor and visuo-attentional capabilities in children with ADHD. Methods: Forty children with ADHD participated in this study; IQ-, sex-and age-matched children were splitted in two groups (G1 and G2) of twenty. An unpredictable random sequence was used to allocate a child to group G1 (trained group) or G2 (control group). Oculomotor and postural performance for both groups of children were objectively assessed twice (before and after 16 min) by using an eye tracker and platform. Group G1 only underwent 16 min of immersive rehabilitation therapy, while the control group (G2) had 16 min of resting. The immersive therapy consisted of performing physical movement while training visual discrimination, attention and spatial orientation skills. Results: After 16 min, significant improvements in the fixation area (p = 0.008) and in the number of catch-up saccades during pursuit eye movements (p < 0.001), as well as a smaller postural instability index (PII) (p < 0.001), were observed for the trained group (G1) only. Conclusions: These findings suggest that children with ADHD could benefit from a short immersive therapy to improve both visualattention and motor performances. This new immersive therapy is a useful tool allowing a better integration of both visual and motor sensory inputs via the cortico/cerebellar network. Follow-up studies on a larger number of children with ADHD will be necessary to explore the eventual possible persistence of such a training effect and imaging works will help to understand where such adaptive mechanisms take place
Discovery and mechanism of negative allosteric modulation of the α7 nicotinic acetylcholine receptor by nanobodies
No full textInternational audienceα7 nicotinic receptors are neurotransmitter-gated ion channels involved in neurological and inflammatory diseases. Ligands acting on its neurotransmitter binding site and on the channel domain of α7 have been extensively developed, yielding a wide range of orthosteric effectors and allosteric positive modulators. Here, we present the functional and structural characterization of two camelid antibody fragments, or nanobodies, F1 and E6, that inhibit α7 activity by acting as negative allosteric modulators, an underrepresented class of ligands. Cryo-EM structures of the nanobodies in complex with α7 show that both nanobodies form a pentameric bundle at the apex of the receptor, each nanobody interacting through a conserved set of residues at α7 subunit interfaces. Electrophysiological experiments suggest that E6 inhibits the activity of α7 by stabilizing its resting conformation, and that internanobodies interactions are key to its activity. Those two nanobodies expand the toolbox for human α7 modulation, opening new possibilities for its pharmacological control with far reaching potentialities in clinics