72 research outputs found
A metabolic interplay coordinated by HLX balances haematopoietic stem cell maintenance and differentiation
No full textUpregulation of the non-clustered homeobox transcription factor HLX (H2.0-like Homeobox) is frequently observed in patients with acute myeloid leukemia. Since developmental pathways are often reactivated in cancer, we asked whether hlx1 plays a role during haematopoietic development and blood cell differentiation in zebrafish. During the transient wave of haematopoiesis, hlx1 knock-down leads to diminished numbers of erythrocytes and increased numbers of myeloid cells. From RNA-seq analysis of sorted control or hlx1 morphant endothelial cells we could see that many erythroid genes were downregulated upon hlx1 knock-down. Indeed, ChIP-seq analysis of human blood cell lines confirmed that HLX binds to the regulatory region of one of the main regulators of erythropoiesis, namely SCL, suggesting that Hlx1 genetically participates in maintaining a balance between erythroid and myeloid cells during the transient wave of haematopoiesis in zebrafish.As for the definitive wave of haematopoiesis, tissue specific overexpression of human HLX leads to aberrant production of hematopoietic stem and progenitor cells (HSPCs) and increased numbers of immature myeloid cells at 48 hours post fertilization. On the other hand, hlx1 morphants have diminished numbers of definitive HSPCs, which can be rescued by means if overexpression of the human ortholog. Edu-labelling of endothelial cells, the precursors of HSPCs, from overexpressing or morphant fish showed hyper- or hypo-proliferation of these cells, respectively. To delve into the molecular mechanism of HLX, we used to the expression analysis of sorted endothelial cells from zebrafish that overexpress HLX in endothelial cells and hlx1 morphants. We found that overexpression of HLX leads to mitochondrial dysfunction and downregulation of oxidative phosphorylation. On the other hand, down-regulation of hlx1 nicely corroborated the overexpression data showing the opposite results. ATAC-seq performed on hlx1 morphant endothelial cells confirmed chromatin accessibility changes of mitochondrial electron transport chain genes and ppard genes, which are important for lipid metabolism and fatty acid oxidation.Firstly, we verified our zebrafish HSPC phenotype in human cells, by performing a Colony Forming Unit assays (CFU) in primary CD34+ progenitor hematopoietic cells. Indeed, overexpression of HLX results in an increased number of colonies, whereas down regulation greatly compromises the ability of CD34+ cells to form colonies. To further verify our results, we assesed metabolism both in zebrafish and in CD34+ cells. Seahorse metabolic assays revealed that overexpression of HLX reduces the oxidative phosphorylation capacity in both systems. Moreover, HLX overexpression leads to decreased mitochondrial potential, as detected by TMRM staining, which suggests that HLX can regulate the HSPC metabolic state. From ChIP-seq in HLX overexpressing blood cell lines, we figured that HLX directly regulates metabolic genes by binding to regulatory regions of mitochondrial genes (e.g., NDUFS4, OPA1, and SDHC), as well as PPARδ.Finally, experiments showed that zebrafish hlx1 morphant treatment with a PPARδ agonist can rescue the HSPC phenotype, while treatment with an antagonist can rescue the immature myeloid phenotype in HLX overexpressing fish. These results were recapitulated in CD34+ cells. In summary, our findings establish HLX as a novel regulator of metabolism in haematopoietic stem cells
COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences
No full textSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first identified in December 2019 as a novel respiratory pathogen and is the causative agent of Corona Virus disease 2019 (COVID-19). Early on during this pandemic, it became apparent that SARS-CoV-2 was not only restricted to infecting the respiratory tract, but the virus was also found in other tissues, including the vasculature. Individuals with underlying pre-existing co-morbidities like diabetes and hypertension have been more prone to develop severe illness and fatal outcomes during COVID-19. In addition, critical clinical observations made in COVID-19 patients include hypercoagulation, cardiomyopathy, heart arrythmia, and endothelial dysfunction, which are indicative for an involvement of the vasculature in COVID-19 pathology. Hence, this review summarizes the impact of SARS-CoV-2 infection on the vasculature and details how the virus promotes (chronic) vascular inflammation. We provide a general overview of SARS-CoV-2, its entry determinant Angiotensin-Converting Enzyme II (ACE2) and the detection of the SARS-CoV-2 in extrapulmonary tissue. Further, we describe the relation between COVID-19 and cardiovascular diseases (CVD) and their impact on the heart and vasculature. Clinical findings on endothelial changes during COVID-19 are reviewed in detail and recent evidence from in vitro studies on the susceptibility of endothelial cells to SARS-CoV-2 infection is discussed. We conclude with current notions on the contribution of cardiovascular events to long term consequences of COVID-19, also known as “Long-COVID-syndrome”. Altogether, our review provides a detailed overview of the current perspectives of COVID-19 and its influence on the vasculature
Etangs anciens et plans d'eau contemporains en Indre-et-Loire
No full textAfter propounding a renewed characterisation, the author gives a census and a cartographical analysis of all impoundments of water in the department of Indre-et-Loire, from artificial lakes to farm ponds, distinguishing between ancient, recent and present creations. The inquest bears on all hydrological, biotic and socio-economic aspects. The impacts of reservoir multiplication are more precisely studied through intensive observation of a small drainage basin. Some consequences are drawn bearing upon water transit, sediment transport, humid ecosystems and associated human activities (fishing, irrigation, leisure).Après établissement d'une typologie actualisée, l'auteur recense et cartographie les ouvrages stockant l'eau en Indre-et-Loire (étangs, plans d'eau, retenues col- linaires, mares, pièces d'eau...). Il distingue trois périodes d'établissement (ancien, récent, contemporain). Des relevés de terrain détaillés permettent de décrire les caractéristiques des ouvrages (installations hydrauliques, formes, environnement et végétation, ressources hydrologiques et qualité des eaux, données socio-économiques afférentes) L'analyse des mécanismes est approfondie par l'étude d'un petit bassin densément équipé, selon la méthode de l'hydrolimnigramme. Compte tenu du doublement des volumes stockés depuis 1960, l'auteur tente de dégager les conséquences de cette multiplication des plans d'eau sur les fonctionnement des milieux naturels et sur les activités humaines correspondantes (pêche, irrigation, loisir).Busnel Laurent. Etangs anciens et plans d'eau contemporains en Indre-et-Loire. In: Norois, n°138, Avril-Juin 1988. pp. 159-172
Refugee depots for Polish emigrants in Châteauroux and Indre department in the years 1831-1833
No full textIn the article the author presents the setting up and operation of refugee depots (Fr. dépôts) in the Indre department for Polish emigrants who arrived in France after the fall of the November Uprising. The refugee depot in Châteauroux was one of the several depots founded by the French government. It was intended for civil exiles. The other camps for military refugees were set up in Avignon, Lunel, Besançon, Bourges, Lons-le-Saunier, Salins and Dijon. From the beginning of August 1832 till August 1833, the French authorities directed civilians to cities of Indre: Châteauroux – the capital of the department, as well as Issoudun, Levroux, La Chatre, Argenton, Buzançais, Chatillon, Saint Benoit, and La Blanc. The author establishes that in that period of time, 634 Polish refugees went through the camps of the Indre department. Most of them were students (from the Vilnius University), young officials and members of free professions. They came from the pre-partition areas of the former Polish-Lithuanian Commonwealth (Lithuania, Volhynia and Podolia). Despite the restrictive policy of the administration and the fact that they stayed in the French province, the Poles engaged in the social and political life of emigration. They participated actively in democratic and educational organizations of the Great Emigration. In many cases, by their own determination, they went to study and obtained aducation at French universities and technical universities. The article is based on sources from the Indre Department Archives in Châteauroux, archives of the Defense Historical Service in Vincennes, the National Archives in Paris, the Polish Library in Paris, the Princes Czartoryski Library in Krakow, and academic studies
Etangs anciens et plans d'eau contemporains en Indre-et-Loire
No full textAfter propounding a renewed characterisation, the author gives a census and a cartographical analysis of all impoundments of water in the department of Indre-et-Loire, from artificial lakes to farm ponds, distinguishing between ancient, recent and present creations. The inquest bears on all hydrological, biotic and socio-economic aspects. The impacts of reservoir multiplication are more precisely studied through intensive observation of a small drainage basin. Some consequences are drawn bearing upon water transit, sediment transport, humid ecosystems and associated human activities (fishing, irrigation, leisure).</jats:p
Le transport par voie navigable. L'exemple du site de Tendu (Indre)
No full textDuring a rescue excavation at Tendu (Indre) in 1994, a canal has been discovered. It was dug during the 1st century AD to link a quarry to a near river. This discovery testifies that a waterway was chosen for stone transport. From its dimensions, we can deduce those of the boats being used. This canal is the first attested from archaeological investigations, at least in Gaul. For the author, this innovation gives indication of a scientific quest still not competed more than an actual scarcity of this kind of hydrographic amenagement.Fouillé en 1994 lors d'une opération préventive, le site de Tendu (Indre) a permis la découverte d'un canal, établi au Ier s. de notre ère, reliant une carrière à une rivière proche. Cette découverte atteste le choix de la voie navigable pour le transport de la pierre. Les dimensions du canal permettent d'envisager celles des bateaux utilisés. Ce canal gallo-romain est le premier révélé par l'archéologie, au moins en Gaule. L'auteur propose de voir dans cette nouveauté le signe d'une démarche archéologique incomplète plutôt que celui d'une réelle rareté de ce type d'aménagement hydrographique.Pichon Michel. Le transport par voie navigable. L'exemple du site de Tendu (Indre) . In: Gallia, tome 59, 2002. pp. 83-88
Recommender systems meet species distribution modelling
No full textRecommender systems techniques can naturally lend themselves to species distribution modelling if biological species are treated as items and places where they occur are treated as users. In this setting recommendation scores can reflect which habitats are suited for which species. Recommendation scores can also be used for reconstructing relative abundances of species, and analysing their rises and declines over millions of years in the past. Analysis of such predictions can shed light on the effects of changing environments on the biosphere now and in the past, as well as help to make predictions for the future. The major potential advantage of the recommender systems treatment over many existing solutions is the large spatial and temporal scale at which such analysis can be done within a single model. A single model makes predictions easier to compare globally in space and over time. While algorithmic application of recommender systems techniques to species distribution modelling is relatively straightforward, model selection and evaluation is particularly challenging, as there is no possibility for online tests or on-demand sampling, since the past worlds are long gone. Explainability is paramount in these tasks. Here we highlight the main challenges and promising directions of evaluation of such modelling, which is still in early stages of development. We show how aggregated prediction statistics and constraints may help for reliable model selection and evaluation. We illustrate the approaches on a case study of the mammalian fossil record from Europe around 8-17 millions of years ago.Peer reviewe
TAGLN2 regulates T cell activation by stabilizing the actin cytoskeleton at the immunological synapse
No full textThe formation of an immunological synapse (IS) requires tight regulation of actin dynamics by many actin polymerizing/depolymerizing proteins. However, the significance of actin stabilization at the IS remains largely unknown. In this paper, we identify a novel function of TAGLN2-an actin-binding protein predominantly expressed in T cells-in stabilizing cortical F-actin, thereby maintaining F-actin contents at the IS and acquiring LFA-1 (leukocyte function-associated antigen-1) activation after T cell receptor stimulation. TAGLN2 blocks actin depolymerization and competes with cofilin both in vitro and in vivo. Knockout of TAGLN2 (TAGLN2-/-) reduced F-actin content and destabilized F-actin ring formation, resulting in decreased cell adhesion and spreading. TAGLN2-/-T cells displayed weakened cytokine production and cytotoxic effector function. These findings reveal a novel function of TAGLN2 in enhancing T cell responses by controlling actin stability at the IS.open
Identification of side effects of COVID-19 drug candidates on embryogenesis using an integrated zebrafish screening platform
No full textDrug repurposing is an important strategy in COVID-19 treatment, but many clinically approved compounds have not been extensively studied in the context of embryogenesis, thus limiting their administration during pregnancy. Here we used the zebrafish embryo model organism to test the effects of 162 marketed drugs on cardiovascular development. Among the compounds used in the clinic for COVD-19 treatment, we found that Remdesivir led to reduced body size and heart functionality at clinically relevant doses. Ritonavir and Baricitinib showed reduced heart functionality and Molnupiravir and Baricitinib showed effects on embryo activity. Sabizabulin was highly toxic at concentrations only 5 times higher than Cmax and led to a mean mortality of 20% at Cmax. Furthermore, we tested if zebrafish could be used as a model to study inflammatory response in response to spike protein treatment and found that Remdesivir, Ritonavir, Molnupiravir, Baricitinib as well as Sabizabulin counteracted the inflammatory response related gene expression upon SARS-CoV-2 spike protein treatment. Our results show that the zebrafish allows to study immune-modulating properties of COVID-19 compounds and highlights the need to rule out secondary defects of compound treatment on embryogenesis. All results are available on a user friendly web-interface https://share.streamlit.io/alernst/covasc_dataapp/main/CoVasc_DataApp.py that provides a comprehensive overview of all observed phenotypic effects and allows personalized search on specific compounds or group of compounds. Furthermore, the presented platform can be expanded for rapid detection of developmental side effects of new compounds for treatment of COVID-19 and further viral infectious diseases.This work was funded by the Swiss National Science Foundation NRP78 4078P0_198297 to Nadia Mercader and
Grant 310030_189136 to Stephen Leib.S
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