A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Intérêt de la contention lombaire dans la prise en charge thérapeutique des lombalgies communes. Conseils du pharmacien orthopédiste

REIMS-BU Santé (514542104) / SudocSudocFranceF

Patients in permanent vegetative or minimally conscious states: A literature review of the psychological and health impacts on healthcare personnel

International audienceBACKGROUND: To address the quality of life of patients in Permanent Vegetative or Minimally Conscious States, the occupational health of those around them must also be taken into account. OBJECTIVE: By analyzing how the available scientific literature has addressed this issue, this study seeks to better understand how caring for these patients affects healthcare professionals’ psychological and health status. METHODS: We identified and selected 15 publications from both Anglophone and Francophone databases, i.e., Cairn, Francis, HAL, PsycINFO, PubMed, ResearchGate and ScienceDirect. RESULTS: The reviewed publications and studies highlight the difficulties healthcare professionals face with regard to the relationship with patients and their families. Two studies in particular suggest that the difficulties these professionals experience daily can lead to burnout. Other potential burnout factors include the healthcare profession category, the work environment, lack of training and the time spent working with this specific group of patients. CONCLUSIONS: Our literature review highlights the institutional and personal resources that may prevent these occupational risks. It also provides avenues for future research

The RNA-Binding Protein Unr Prevents Mouse Embryonic Stem Cells Differentiation Toward the Primitive Endoderm Lineage

International audienceThe maintenance of embryonic stem cells (ESCs) pluripotency depends on key transcription factors, chromatin remodeling proteins, and microRNAs. The roles of RNA-binding proteins are however poorly understood. We report that the cytoplasmic RNA-binding protein Unr prevents the differentiation of ESCs into primitive endoderm (PrE). We show that unr knockout (unr(-/-) ) ESCs spontaneously differentiate into PrE, and that Unr re-expression in unr(-/-) ESCs reverses this phenotype. Nevertheless, unr(-/-) ESCs retain pluripotency, producing differentiated teratomas, and the differentiated unr(-/-) ESCs coexpress the PrE inducer Gata6 and the pluripotency factors Oct4, Nanog, and Sox2. Interestingly, in the differentiated unr(-/-) ESCs, Nanog and Sox2 exhibit a dual nuclear and cytoplasmic localization. This situation, that has never been reported, likely reflects an early differentiation state toward PrE. Finally, we show that Unr destabilizes Gata6 mRNAs and we propose that the post-transcriptional repression of Gata6 expression by Unr contributes to the stabilization of the ESCs pluripotent state

Widely-Tunable Quantum Cascade-Based Sources for the Development of Optical Gas Sensors

Spectroscopic techniques based on Distributed FeedBack (DFB) Quantum Cascade Lasers (QCL) provide good results for gas detection in the mid-infrared region in terms of sensibility and selectivity. The main limitation is the QCL relatively low tuning range (~10 cm−1) that prevents from monitoring complex species with broad absorption spectra in the infrared region or performing multi-gas sensing. To obtain a wider tuning range, the first solution presented in this paper consists of the use of a DFB QCL array. Tuning ranges from 1335 to 1387 cm−1 and from 2190 to 2220 cm−1 have been demonstrated. A more common technique that will be presented in a second part is to implement a Fabry–Perot QCL chip in an external-cavity (EC) system so that the laser could be tuned on its whole gain curve. The use of an EC system also allows to perform Intra-Cavity Laser Absorption Spectroscopy, where the gas sample is placed within the laser resonator. Moreover, a technique only using the QCL compliance voltage technique can be used to retrieve the spectrum of the gas inside the cavity, thus no detector outside the cavity is needed. Finally, a specific scheme using an EC coherent QCL array can be developed. All these widely-tunable Quantum Cascade-based sources can be used to demonstrate the development of optical gas sensors

Replicative aging down-regulates the myogenic regulatory factors in human myoblasts

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Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin’s lymphoma B cells

International audienceBACKGROUND: Non-Hodgkin's B-cell lymphomas account for approximately 70% of B-cell lymphomas. While its incidence is dramatically increasing worldwide, the disease is still associated with high morbidity due to ineffectiveness of conventional therapies, creating an urgent need for novel therapeutic approaches. Unconventional compounds, including polyphenols and the cytokine TRAIL, are being extensively studied for their capacity to restore apoptosis in a large number of tumors, including lymphomas. DESIGN AND METHODS: Molecular mechanisms of TRAIL-resistance and reactivation of the apoptotic machinery by quercetin in non-Hodgkin's lymphoma cell lines were determined by Hoescht, flow cytometry, Western blot, qPCR, by use of siRNA or pharmacological inhibitors of the mitochondrial pathway and by immunoprecipitation followed by post-translational modification analysis. RESULTS: Results demonstrate that quercetin, a natural flavonoid, restores TRAIL-induced cell death in resistant transformed follicular lymphoma B-cell lines, despite high Bcl-2 expression levels due to the chromosomal translocation t(14;18). Quercetin rescues mitochondrial activation by inducing the proteasomal degradation of Mcl-1 and by inhibiting survivin expression at the mRNA level, irrespective of p53. Restoration of the TRAIL pathway requires Bax and Bak but is independent of enhanced TRAIL DISC formation. CONCLUSIONS: We demonstrate that inactivation of survivin and Mcl-1 expression by quercetin is sufficient to restore TRAIL sensitivity in resistant non-Hodgkin's lymphoma B cells. Our results suggest, therefore, that combining quercetin with TRAIL treatments may be useful in the treatment of non-Hodgkin's lymphoma

Longitudinal high-resolution imaging through a flexible intravital imaging window

International audienceIntravital microscopy (IVM) is a powerful technique that enables imaging of internal tissues at (sub)cellular resolutions in living animals. Here, we present a silicone-based imaging window consisting of a fully flexible, sutureless design that is ideally suited for long-term, longitudinal IVM of growing tissues and tumors. Crucially, we show that this window, without any customization, is suitable for numerous anatomical locations in mice using a rapid and standardized implantation procedure. This low-cost device represents a substantial technological and performance advance that facilitates intravital imaging in diverse contexts in higher organisms, opening previously unattainable avenues for in vivo imaging of soft and fragile tissues