Validation of a sequential data assimilation method applied to cardiac electrophysiology

International audienceImproved electroanatomical recordings and imaging capabilities prompts for trying to personalize cardiac electrical models. Though it is challenging, data assimilation is a family of methods relevant to this problem. It consists in estimating the state of the system thanks to observations. Among the two main approaches, variationnal and sequential, we choose to investigate the possibilities of a sequential method based on an atrial model and atrial electroanatomical maps. The method combines a state observer and a Kalman filter to estimate some parameters in the model

Extensive NEUROG3 occupancy in the human pancreatic endocrine gene regulatory network.

OBJECTIVE: Mice lacking the bHLH transcription factor (TF) Neurog3 do not form pancreatic islet cells, including insulin-secreting beta cells, the absence of which leads to diabetes. In humans, homozygous mutations of NEUROG3 manifest with neonatal or childhood diabetes. Despite this critical role in islet cell development, the precise function of and downstream genetic programs regulated directly by NEUROG3 remain elusive. Therefore, we mapped genome-wide NEUROG3 occupancy in human induced pluripotent stem cell (hiPSC)-derived endocrine progenitors and determined NEUROG3 dependency of associated genes to uncover direct targets. METHODS: We generated a novel hiPSC line (NEUROG3-HA-P2A-Venus) where NEUROG3 is HA-tagged and fused to a self-cleaving fluorescent VENUS reporter. We used the CUT&RUN technique to map NEUROG3 occupancy and epigenetic marks in pancreatic endocrine progenitors (PEP) that were differentiated from this hiPSC line. We integrated NEUROG3 occupancy data with chromatin status and gene expression in PEPs as well as their NEUROG3-dependence. In addition, we investigated whether NEUROG3 binds type 2 diabetes mellitus (T2DM)-associated variants at the PEP stage. RESULTS: CUT&RUN revealed a total of 863 NEUROG3 binding sites assigned to 1263 unique genes. NEUROG3 occupancy was found at promoters as well as at distant cis-regulatory elements that frequently overlapped within PEP active enhancers. De novo motif analyses defined a NEUROG3 consensus binding motif and suggested potential co-regulation of NEUROG3 target genes by FOXA or RFX transcription factors. We found that 22% of the genes downregulated in NEUROG3-/- PEPs, and 10% of genes enriched in NEUROG3-Venus positive endocrine cells were bound by NEUROG3 and thus likely to be directly regulated. NEUROG3 binds to 138 transcription factor genes, some with important roles in islet cell development or function, such as NEUROD1, PAX4, NKX2-2, SOX4, MLXIPL, LMX1B, RFX3, and NEUROG3 itself, and many others with unknown islet function. Unexpectedly, we uncovered that NEUROG3 targets genes critical for insulin secretion in beta cells (e.g., GCK, ABCC8/KCNJ11, CACNA1A, CHGA, SCG2, SLC30A8, and PCSK1). Thus, analysis of NEUROG3 occupancy suggests that the transient expression of NEUROG3 not only promotes islet destiny in uncommitted pancreatic progenitors, but could also initiate endocrine programs essential for beta cell function. Lastly, we identified eight T2DM risk SNPs within NEUROG3-bound regions. CONCLUSION: Mapping NEUROG3 genome occupancy in PEPs uncovered unexpectedly broad, direct control of the endocrine genes, raising novel hypotheses on how this master regulator controls islet and beta cell differentiation

The ARIA-MASK-air® approach

Funding Information: The authors thank Ms Véronique Pretschner for submitting the paper. MASK‐air has been supported by Charité Universitätsmedizin Berlin, EU grants (EU Structural and Development Funds Languedoc Roussillon and Region PACA; POLLAR: EIT Health; Twinning: EIP on AHA; Twinning DHE: H2020; Catalyse: Horizon Europe) and educational grants from Mylan‐Viatris, ALK, GSK, Novartis, Stallergènes‐Greer and Uriach. None for the study. ® Publisher Copyright: © 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.MASK-air®, a validated mHealth app (Medical Device regulation Class IIa) has enabled large observational implementation studies in over 58,000 people with allergic rhinitis and/or asthma. It can help to address unmet patient needs in rhinitis and asthma care. MASK-air® is a Good Practice of DG Santé on digitally-enabled, patient-centred care. It is also a candidate Good Practice of OECD (Organisation for Economic Co-operation and Development). MASK-air® data has enabled novel phenotype discovery and characterisation, as well as novel insights into the management of allergic rhinitis. MASK-air® data show that most rhinitis patients (i) are not adherent and do not follow guidelines, (ii) use as-needed treatment, (iii) do not take medication when they are well, (iv) increase their treatment based on symptoms and (v) do not use the recommended treatment. The data also show that control (symptoms, work productivity, educational performance) is not always improved by medications. A combined symptom-medication score (ARIA-EAACI-CSMS) has been validated for clinical practice and trials. The implications of the novel MASK-air® results should lead to change management in rhinitis and asthma.publishersversionpublishe

Validation of a sequential data assimilation method applied to cardiac electrophysiology

Improved electroanatomical recordings and imaging capabilities prompts for trying to personalize cardiac electrical models. Though it is challenging, data assimilation is a family of methods relevant to this problem. It consists in estimating the state of the system thanks to observations. Among the two main approaches, variationnal and sequential, we choose to investigate the possibilities of a sequential method based on an atrial model and atrial electroanatomical maps. The method combines a state observer and a Kalman filter to estimate some parameters in the model

Variations sur le thème du « code histone »

Les histones sont les pièces maîtresses de la compaction de l’ADN en chromatine et jouent un rôle majeur dans la régulation des fonctions du génome. Elles sont les cibles de multiples modifications post-traductionnelles qui apportent une information épigénétique. L’ensemble de ces modifications constituerait un « code histone », permettant d’associer à chaque combinaison de modifications un état particulier de la chromatine. De surcroît, les histones se déclinent sous forme de variants dont on sait qu’ils diffèrent par leur séquence, leur fonction et leur mécanisme d’incorporation dans la chromatine. Ce répertoire élargi d’informations permet d’envisager de nouvelles possibilités de régulation épigénétique.Histones are the fundamental structural proteins intimately associated with eukaryotic DNA to form a highly ordered and condensed nucleoproteic complex termed chromatin. They are the targets of various posttranslational modifications including acetylation, methylation, phosphorylation and ubiquitination that modulate the structure/function of chromatin. The combinatorial nature of histone modifications is hypothesized to define a « histone code » that considerably extends the information potential of the genetic code, giving rise to epigenetic information. Moreover, most core histones consist of several nonallelic variants that can mark specific loci and could play an important role in establishment and maintenance of epigenetic memory. Here we will briefly present our current knowledge about histone posttranslational modifications and their implications in the regulation of epigenetic information. We will next describe core histone variants, insisting on their mode of incorporation into chromatin to discuss their epigenetic function and inheritance

Identification of low molecular weight nuclear complexes containing integrase during the early stages of HIV-1 infection.

International audienceABSTRACT: BACKGROUND: HIV-1 replication requires integration of its reverse transcribed viral cDNA into a host cell chromosomes. The DNA cutting and joining reactions associated to this key step are catalyzed by the viral protein integrase (IN). In infected cells, IN binds the viral cDNA, together with viral and cellular proteins, to form large nucleoprotein complexes. However, the dynamics of IN complexes formation is still poorly understood. RESULTS: Here, we characterized IN complexes during the early stages of T-lymphocyte infection. We found that following viral entry into the host cell, IN was rapidly targeted to proteasome-mediated degradation. Interactions between IN and cellular cofactors LEDGF/p75 and TNPO3 were detected as early as 6 h post-infection. Size exclusion chromatography of infected cell extracts revealed distinct IN complexes in vivo. While at 2 h post-infection the majority of IN eluted within a high molecular weight complex competent for integration (IN complex I), IN was also detected in a low molecular weight complex devoid of full-length viral cDNA (IN complex II, ~440 KDa). At 6 h post-infection the relative proportion of IN complex II increased. Inhibition of reverse transcription or integration did not alter the elution profile of IN complex II in infected cells. However, in cells depleted for LEDGF/p75 IN complex II shifted to a lower molecular weight complex (IN complex III, ~150 KDa) containing multimers of IN. Notably, cell fractionation experiments indicated that both IN complex II and III were exclusively nuclear. Finally, IN complex II was not detected in cells infected with a virus harboring a mutated IN defective for LEDGF/p75 interaction and tetramerization. CONCLUSIONS: Our findings indicate that, shortly after viral entry, a significant portion of DNA--free IN that is distinct from active pre-integration complexes accumulates in the nucleus

Front observer for data assimilation of electroanatomical mapping data for a numerical atrial model

The purpose of our work is to personalize an atrial model of the propagation of the action potential, based on electrical catheter data with the help of the data assimilation approach introduced in [Collin & Al, Journal of Computational Physics 2015]. The originality of the approach is to indroduce a Luenberger observer of a surface atrial model of the propagation which can pursue - like in classical Kalman filtering approach - the actual activation front reconstructed from catheter data. Moreover, this approach may account for the breakthrough of new activation fronts at anytime with an additional topological gradient term. In the present work, we adapt this approach to the bilayer surface atrial model of th propagation of action potentials [Labarthe & Al, Europace 2014], and evaluated for the first time on a real patient's dataset. First, the model was geometrically fit to the patient's data. A fiber architecture was added to the geometry. Then an initial electrophysiological state was guessed, and the model was run with the Luenberger filter for some catheter data acquired during a CARTO procedure. All along the simulation, the filter corrects the action potential so as to track CARTO local activation times, while preserving a biophysical behavior. With this technique, we are able to reconstruct smooth activation maps over the whole atrial surfaces. This promising technique may also allow to reconstruct velocity fields and directions, phase map and possibly give information on repolarization. This work results from a collaborative project carried out during a training session at CEMRACS 2016 in Marseille, Luminy

PEAMUST : Adaptation Multi-Stress et Régulations biologiques pour l’amélioration du rendement et de la stabilité du pois protéagineux

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