Increased phospho-mTOR expression in megakaryocytic cells derived from CD34+ progenitors of essential thrombocythaemia and myelofibrosis patients

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Anti-DFS70 antibodies detected by specific methods in patients with thrombosis or recurrent pregnancy loss: no evidence of an association

A dense fine speckled pattern (DFS) caused by antibodies to the DFS70 kDa nuclear protein is a relatively common finding while testing for anti-nuclear antibodies (ANA) by indirect immunofluorescence (IIF) on HEp-2 cells. However, despite many efforts and numerous studies, the clinical significance of anti-DFS70 antibodies is still unknown as they can be found in patients with various disorders and even in healthy subjects. In this study we aimed at verifying whether these antibodies are associated with thrombotic events or with unexplained recurrent pregnancy loss (RPL). We studied 443 patients with venous or arterial thrombosis or RPL and 244 controls by IIF on HEp-2 cells and by a DFS70-specific chemiluminescent immunoassay (CIA). The DFS pattern was observed in IIF in 31/443 (7.0%) patients and in 6/244 (2.5%) controls (p\u2009=\u20090.01) while anti-DFS70 specific antibodies were detected by CIA in 11 (2.5%) patients and in one (0.4%) control (p\u2009=\u20090.06). Positive samples, either by IIF or by CIA, were then assayed by a second DFS70-specific line-immunoassay (LIA) method: 83.3% of the CIA positive samples were confirmed DFS70 positive versus only 29.7% of the IIF positive samples. These findings show that IIF overestimates anti-DFS70 antibody frequency and that results obtained by specific CIA and LIA assays do not indicate that venous or arterial thrombosis or RPL are linked to a higher prevalence of anti-DFS70 antibodies

Intégration de données multi-omiques et exploration visuelle interactive des données pour explorer la dynamique du système mitochondrial

Les mitochondries sont des organites subcellulaires qui jouent un rôle central dans de nombreux processus cellulaires. Différents tissus, ainsi que différentes conditions de santé et d'âge se caractérisent par une différence dans la morphologie et la composition des mitochondries qui sont adaptées aux besoins de l'environnement cellulaire. Dans ce travail, j'ai appliqué une approche de biologie systémique pour modéliser les mitochondries, car ces organites sont largement distribués et ont un interactome relativement petit. Pour mieux comprendre la dynamique mitochondriale, nous avons développé la plate-forme mitoXplorer, qui intègre un interactome mitochondrial avec des données omiques. J'ai étendu les fonctionnalités de mitoXplorer, en creant une nouvelle version, mitoXplorer 2.0, qui permet de mieux comprendre l'interaction entre les mitochondries et leur environnement cellulaire. Dans cette mise à jour, j'ai ajouté plusieurs fonctionnalités d'analyse intégrative en aval qui permettent à mitoXplorer d'aller au-delà de la simple visualisation des données. L'une des nouveautés de mitoXplorer 2.0 permet d'identifier les régulateurs transcriptionnels des processus mitochondriaux. Cela a été rendu possible en combinant mitoXplorer avec AnnoMiner, un deuxieme outil que j'ai co-développé pendant ma thèse. AnnoMiner permet d'intégrer différentes données omiques, telles que l'épigénétique et l'occupation des facteurs de transcription avec des données transcriptomiques aidant à démêler la régulation des gènes. Avec mitoXplorer 2.0, les scientifiques disposent de la plateforme web la plus complète dédiée aux mitochondries à ce jour.Mitochondria are subcellular organelles that have a central role in many cellular processes, including cellular energy production, calcium signalling and apoptosis. Different tissues, as well as different health and age conditions are characterised by a difference in mitochondrial morphology and composition which are tailored to suit the needs of the cellular environment.With this work I applied a systems biology approach to model mitochondria, as these organelles are widely studied and possess a relatively small interactome. To better understand mitochondrial dynamics, we developed the visual data mining (VDM) platform mitoXplorer, which integrates a manually curated mitochondrial interactome with user supplied, as well as publicly available, omics data. I extended the functionality of mitoXplorer, implementing a novel version, mitoXplorer 2.0 which allows better understanding of the interaction between mitochondria and their cellular environment. In this updated version, I added multiple downstream integrative analyses functions which allows mitoXplorer to go beyond simple data visualization. One of the novel functions of mitoXplorer 2.0 helps in identifying transcriptional regulators of mitochondrial processes. This has been made possible by combining mitoXplorer with AnnoMiner, another tool I co-developed during my PhD. AnnoMiner allows to integrate different omics data, such as epigenetic and transcription factor occupancy with transcriptomics data helping unravel gene regulation. With mitoXplorer 2.0, scientists interested in deciphering mitochondrial dynamics are provided with the most complete web-based platform dedicated to mitochondria available at date

The mitoXplorer 2.0 update: integrating and interpreting mitochondrial expression dynamics within a cellular context

International audienceAbstract Mitochondria are subcellular organelles present in almost all eukaryotic cells, which play a central role in cellular metabolism. Different tissues, health and age conditions are characterized by a difference in mitochondrial structure and composition. The visual data mining platform mitoXplorer 1.0 was developed to explore the expression dynamics of genes associated with mitochondrial functions that could help explain these differences. It, however, lacked functions aimed at integrating mitochondria in the cellular context and thus identifying regulators that help mitochondria adapt to cellular needs. To fill this gap, we upgraded the mitoXplorer platform to version 2.0 (mitoXplorer 2.0). In this upgrade, we implemented two novel integrative functions, network analysis and transcription factor enrichment, to specifically help identify signalling or transcriptional regulators of mitochondrial processes. In addition, we implemented several other novel functions to allow the platform to go beyond simple data visualization, such as an enrichment function for mitochondrial processes, a function to explore time-series data, the possibility to compare datasets across species and an IDconverter to help facilitate data upload. We demonstrate the usefulness of these functions in three specific use cases. mitoXplorer 2.0 is freely available without login at http://mitoxplorer2.ibdm.univ-mrs.fr

AnnoMiner is a new web-tool to integrate epigenetics, transcription factor occupancy and transcriptomics data to predict transcriptional regulators

International audienceGene expression regulation requires precise transcriptional programs, led by transcription factors in combination with epigenetic events. Recent advances in epigenomic and transcriptomic techniques provided insight into different gene regulation mechanisms. However, to date it remains challenging to understand how combinations of transcription factors together with epigenetic events control cell-type specific gene expression. We have developed the AnnoMiner web-server, an innovative and flexible tool to annotate and integrate epigenetic, and transcription factor occupancy data. First, AnnoMiner annotates user-provided peaks with gene features. Second, AnnoMiner can integrate genome binding data from two different transcriptional regulators together with gene features. Third, AnnoMiner offers to explore the transcriptional deregulation of genes nearby, or within a specified genomic region surrounding a user-provided peak. AnnoMiner’s fourth function performs transcription factor or histone modification enrichment analysis for user-provided gene lists by utilizing hundreds of public, high-quality datasets from ENCODE for the model organisms human, mouse, Drosophila and C. elegans . Thus, AnnoMiner can predict transcriptional regulators for a studied process without the strict need for chromatin data from the same process. We compared AnnoMiner to existing tools and experimentally validated several transcriptional regulators predicted by AnnoMiner to indeed contribute to muscle morphogenesis in Drosophila . AnnoMiner is freely available at http://chimborazo.ibdm.univ-mrs.fr/AnnoMiner/

Alleanza Contro il Cancro: The accreditation system of the Excellence Network of Italian Cancer Centers in the precision medicine era

Alleanza Contro il Cancro (Alliance Against Cancer (ACC)) is a network of excellence comprising cancer centers with high standard patient care and research supervised by the Italian Ministry of Health. Founded in 2002, ACC has recently entered a renovation process in order to further increase quality procedures and international standing of the network. The Organization of European Cancer Institutes (OECI) accreditation system contributes significantly to this renovation process, which is generally directed towards all the main activities of cancer care and research, but has a particular attention to the treatment of advanced cancers that cannot be cured by standard procedures in conventional hospitals

mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations

International audienceMitochondria participate in metabolism and signal-ing. They adapt to the requirements of various cell types. Publicly available expression data permit to study expression dynamics of genes with mitochon-drial function (mito-genes) in various cell types, conditions and organisms. Yet, we lack an easy way of extracting these data for mito-genes. Here, we introduce the visual data mining platform mitoXplorer, which integrates expression and mutation data of mito-genes with a manually curated mitochondrial interactome containing ∼1200 genes grouped in 38 mitochondrial processes. User-friendly analysis and visualization tools allow to mine mitochondrial expression dynamics and mutations across various datasets from four model species including human. To test the predictive power of mitoXplorer, we quantify mito-gene expression dynamics in trisomy 21 cells, as mitochondrial defects are frequent in tri-somy 21. We uncover remarkable differences in the regulation of the mitochondrial transcriptome and proteome in one of the trisomy 21 cell lines, caused by dysregulation of the mitochondrial ribosome and resulting in severe defects in oxidative phosphory-lation. With the newly developed Fiji plugin mito-Morph, we identify mild changes in mitochondrial morphology in trisomy 21. Taken together, mitoX-plorer (http://mitoxplorer.ibdm.univ-mrs.fr) is a user-friendly, web-based and freely accessible software, aiding experimental scientists to quantify mitochon-drial expression dynamics

Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers

Human muscle is a hierarchically organised tissue with its contractile cells called myofibers packed into large myofiber bundles. Each myofiber contains periodic myofibrils built by hundreds of contractile sarcomeres that generate large mechanical forces. To better understand the mechanisms that coordinate human muscle morphogenesis from tissue to molecular scales, we adopted a simple in vitro system using induced pluripotent stem cell-derived human myogenic precursors. When grown on an unrestricted two-dimensional substrate, developing myofibers spontaneously align and self-organise into higher-order myofiber bundles, which grow and consolidate to stable sizes. Following a transcriptional boost of sarcomeric components, myofibrils assemble into chains of periodic sarcomeres that emerge across the entire myofiber. More efficient myofiber bundling accelerates the speed of sarcomerogenesis suggesting that tension generated by bundling promotes sarcomerogenesis. We tested this hypothesis by directly probing tension and found that tension build-up precedes sarcomere assembly and increases within each assembling myofibril. Furthermore, we found that myofiber ends stably attach to other myofibers using integrin-based attachments and thus myofiber bundling coincides with stable myofiber bundle attachment in vitro. A failure in stable myofiber attachment results in a collapse of the myofibrils. Overall, our results strongly suggest that mechanical tension across sarcomeric components as well as between differentiating myofibers is key to coordinate the multi-scale self-organisation of muscle morphogenesis

Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers

Human muscle is a hierarchically organised tissue with its contractile cells called myofibers packed into large myofiber bundles. Each myofiber contains periodic myofibrils built by hundreds of contractile sarcomeres that generate large mechanical forces. To better understand the mechanisms that coordinate human muscle morphogenesis from tissue to molecular scales, we adopted a simple in vitro system using induced pluripotent stem cell-derived human myogenic precursors. When grown on an unrestricted two-dimensional substrate, developing myofibers spontaneously align and self-organise into higher-order myofiber bundles, which grow and consolidate to stable sizes. Following a transcriptional boost of sarcomeric components, myofibrils assemble into chains of periodic sarcomeres that emerge across the entire myofiber. More efficient myofiber bundling accelerates the speed of sarcomerogenesis suggesting that tension generated by bundling promotes sarcomerogenesis. We tested this hypothesis by directly probing tension and found that tension build-up precedes sarcomere assembly and increases within each assembling myofibril. Furthermore, we found that myofiber ends stably attach to other myofibers using integrin-based attachments and thus myofiber bundling coincides with stable myofiber bundle attachment in vitro. A failure in stable myofiber attachment results in a collapse of the myofibrils. Overall, our results strongly suggest that mechanical tension across sarcomeric components as well as between differentiating myofibers is key to coordinate the multi-scale self-organisation of muscle morphogenesis