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Drivers of plant-associated invertebrate community structure in West-European coastal dunes
No full textInternational audienceThe organisation of species assemblages is affected by environmental factors acting at different spatial scales. To understand the drivers behind the community structure of invertebrates associated with marram grass -a dune-building ecosystem engineer -, we set up a stratified sampling scheme in six biogeographic sectors along the North Sea. We tested to which degree invertebrate species composition is affected by the spatial organisation of marram grass tussocks. Using distance-based RDA and a joint species distribution modelling approach, we show biogeography to be the most important driver, followed by species-specific responses to marram grass cover and vitality. Traits and phylogeny had a minor influence on the species distribution patterns. The residual species covariation suggests negative interactions between groups of specialist and generalist species. Our research indicates that the biological value of nature-based solutions for coastal protection can be optimized by the design of a heterogeneous marram grass planting scheme and/or development
Cardiovascular risk associated with glucagon-like peptide-1 receptor agonists versus other conventional glucose-lowering drugs in patients with type-2 diabetes: protocol for a nationwide observational comparative study in routine care.
No full textInternational audienceIntroduction: Several cardiovascular outcome trials have been conducted to assess the cardiovascular safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP1-RAs) on cardiorenal outcomes in patients with type-2 diabetes (T2D). However, the strict requirements of randomised controlled trials to avoid most confounding factors are at the expense of external validity. Using national real-world data, we aimed to evaluate the effectiveness of GLP-1RAs in association with metformin especially on cardiovascular events, hospitalisation for heart failure and all-cause death in comparison with other diabetes treatment schemes using dipeptidyl peptidase IV inhibitors, sulfonylureas/glinides or insulin also associated with metformin. Sodium-glucose transport protein 2 inhibitors (SGLT-2i) will be excluded as comparators, as this class of oral hypoglycaemic agents just started in 2020 to be marketed in France.Methods and analysis: The Système National des Données de Santé is a comprehensive nationwide administrative healthcare database in France that covers approximately 67 million people.Several cohorts of adult patients with T2D initiating any GLP1-RA in dual or triple therapies, as recommended by the French Health authorities, will be identified in this database over the period 2016–2021. These cohorts will be defined by the combination of glucose-lowering drugs prescribed simultaneously with GLP1-RA and diabetes treatment received over a 6-month period before GLP1-RA initiation. They will be first matched with T2D controls (1:3 ratio) based on the year of drug initiation and treatment regimens before and simultaneously with GLP1-RA in the different selected cohorts. Comparative analyses will be conducted versus these control groups, adjusting for cardiovascular event history and a propensity score considering age, sex, area of residence, deprivation index, comorbidities, duration of diabetes, use of lipid-lowering drugs, anticoagulants, antiplatelet therapies and blood pressure-lowering therapies. Comparative analyses will be conducted versus these control groups, using a high-dimensional propensity scores method and fixed baseline characteristics. Treatment effects on the different outcomes measured will be estimated for each GLP1-RA group, through HR and their corresponding CIs (95% CI) using Cox regressions and/or competitive risk regressions when necessary.Ethics and dissemination The study has been approved by an independent ethics committee (Comité éthique et scientifique pour les recherches, les études et les évaluations dans le domaine de la santé, Paris, France; reference: 8699786, dated 2 June 2022) and has been registered with the French National Data Protection Commission (Commission Nationale de l'Informatique et des Libertés, Paris, France; reference: 922161, dated 26 June 2022). The findings of this study will be published in peer-reviewed scientific journals and presented at international conferences.Trial registration number F20220803152803
Optimizing Enantiomeric Resolution of Chiral Triazoles in Supercritical Fluid Chromatography
No full textInternational audienceChirality plays a crucial role in the pharmacological activity of triazoles, a key scaffold in antifungal agents and various therapeutic applications. This study focuses on optimizing the enantiomeric resolution of chiral triazoles using supercritical fluid chromatography (SFC) and 10 different columns, either immobilized or coated, chlorinated or nonchlorinated, cellulose or amylose‐based chiral stationary phases (CSPs). Four novel triazoles and two marketed ones (tebuconazole and hexaconazole) were separated to determine optimal resolution conditions. The best resolution was achieved using chlorinated amylose‐based CSPs across the tested compounds. Optical rotation and X‐ray crystallography were employed to determine the absolute configurations of the purified enantiomers
The kinase domain of TRPM7 interacts with PAK1 and regulates pancreatic cancer cell epithelial-to-mesenchymal transition
No full textPancreatic ductal adenocarcinoma (PDAC) is the main and the deadliest form of pancreatic cancer. This is a major problem of public health since it will become the second leading cause of death by cancer in the next few years, mainly due to the lack of efficient therapies. Transient Receptor Potential Cation Channel Subfamily M Member 7 (TRPM7) protein, a cation channel fused with a serine/threonine kinase domain is overexpressed in PDAC and associated with a low survival. In this work, we aim to study the role of kinase domain on pancreatic cell fates by using a model of kinase domain deletion by CRISPR-Cas9. PANC-1 and MIA PaCa-2 PDAC cell lines were used and kinase domain was deleted by CRISPR-Cas9 strategy. Kinase domain deletion (ΔK) was validated by RT-qPCR and western-blots. The effect of kinase domain deletion on channel function was studied by patch-clamp and Mn 2+ -quenching. The cell phenotype was studied by MTT and cell migration/invasion assays. Finally, the role of kinase domain was studied in vivo in xenografted mice. Here we show that TRPM7 kinase domain is required to maintain a mesenchymal phenotype in PDAC cells. We also demonstrated that TRPM7 and PAK1 interact in the same protein complexes. Moreover, TRPM7 kinase domain is required for carcinogenesis and cancer cell dissemination in vivo . Intriguingly, the role of TRPM7 kinase is cell specific and may depend on the KRAS oncogene mutation status. In conclusion, TRPM7 kinase domain is required to maintain a mesenchymal and aggressive phenotype in PDAC cells, and it could be a promising target against PDAC
PARP ‐1 Inhibition Increases Oxidative Stress in Ets‐1‐Expressing MDA ‐ MB ‐231 Breast Cancer Cells
No full textInternational audienceBackground The Ets‐1 transcription factor plays a primordial role in regulating the expression of numerous genes implicated in cancer progression. In a previous study, we revealed that poly(ADP‐ribose) polymerase‐1 (PARP‐1) inhibition by PJ‐34 results in Ets‐1 level increase in cells, which is related with cell death of Ets‐1‐expressing cancer cells. Aims The mechanism of the antitumor effect of PARP‐1 inhibition was investigated in the Ets‐1‐expressing MDA‐MB‐231 breast cancer cells. Methods and Results We tested the effects of four PARP inhibitors (PARPi) (PJ‐34, Veliparib, Olaparib, and Rucaparib). We first demonstrated that PARPi reduced cells growth through G2/M cell cycle arrest. Next, we evaluated PARP‐1 inhibition effect on oxidative DNA damage in Ets‐1‐overexpressing and Ets‐1‐non‐expressing breast cancer cells and we showed that PARPi led only Ets‐1‐overexpressing cells to accumulate it, which triggers the DNA damage response as revealed by the increase in the level of a panel of DNA damage‐related proteins. Importantly, we demonstrated that PARPi increased reactive oxygen species (ROS), only in Ets‐1‐overexpressing cells and this is accompanied by upregulation of p47 phox expression, a subunit of the NAPDH oxidase (NOX). Conclusion These preliminary findings correlate PARPi‐induced oxidative DNA damage/oxidative stress to Ets‐1 expression in breast cancer cells
Site-Specific Incorporation of Fluorinated Prolines into Proteins and their Impact on Neighbouring Residues
No full textInternational audienceThe incorporation of fluorinated amino acids into proteins provides new opportunities to study biomolecular structure-function relationships in an elegant manner. The available strategies to incorporate the majority of fluorinated amino acids are not site-specific or imply important structural modifications. Here, we present a chemical biology approach for the site-specific incorporation of three commercially available Cγ-modified fluoroprolines that has been validated using a non-pathogenic version of huntingtin exon-1 (HttExon-1). 19F, 1H and 15N NMR chemical shifts measured for multiple variants of HttExon-1 indicated that the trans/cis ratio was strongly dependent on the fluoroproline variant and the sequence context. By isotopically labelling the rest of the protein, we have shown that the extent of spectroscopic perturbations to the neighbouring residues depends on the number of fluorine atoms and the stereochemistry at Cγ, as well as the isomeric form of the fluoroproline. We have rationalized these observations by means of extensive molecular dynamics simulations, indicating that the observed atomic chemical shift perturbations correlate with the distance to fluorine atoms and that the effect remains very local. These results validate the site-specific incorporation of fluoroprolines as an excellent strategy to monitor intra- and intermolecular interactions in disordered proline-rich proteins
Inflammation aiguë pulmonaire : aspects mécanistiques, diagnostiques, phénotypiques et environnementaux chez le patient de réanimation
No full textMy research investigates the inflammatory respiratory failure in critically ill patients, focusing on three main areas: 1. The study of endocan as a biomarker and regulator of acute pulmonary inflammation and Acute Respiratory Distress Syndrome (ARDS). My research in humans, mice, and in vitro has shown the anti-inflammatory role of endocan, notably by inhibiting immune cell recruitment. I have also explored the clinical utility of endocan as a prognostic and phenotypic marker in ARDS and sepsis, as well as its role in predicting thromboembolic events and delayed intubation in COVID-19. Future work aims to explore the prognostic value of endocan kinetics in the initial phase of ARDS. 2. Characterizing the diagnosis of Ventilator-Associated Pneumonia (VAP) and the role of fungal etiologies. My research has evaluated the performance of various diagnostic methods for VAP. I also coordinate the European multicenter prospective study ASPIC, which aims to assess the frequency of invasive pulmonary aspergillosis as an etiology of VAP. A second interventional study is subsequently planned to evaluate the impact of systematic aspergillosis screening on patient prognosis. 3. Evaluating the effects of air pollution on critically illness patients. Ongoing studies in mice are exploring the long-term effects of exposure to diesel particles on ARDS, suggesting an increase in pulmonary fibrosis and an alteration in the immune response. I am also supervising a project aimed at quantifying particulate pollutants in airway macrophages of ICU patients. I co-supervise a PhD project examining the impact of fine particles on IL-20 cytokine expression and their role in controlling Streptococcus pneumoniae infection. I also coordinate the GAÏA (Group for Assessment of ICU-related Impacts of Air pollution), through which we have established a retrospective cohort of over 4,000 patients at the Lille University Hospital, studying the association between air pollution and various characteristics of critically ill patients: prognosis, risk of VAP and multi-drug resistant bacterial infections, anti-IFN I autoimmunity in severe COVID-19, and particulate matter burden in macrophages. Finally, a prospective study will explore the particulate matter burden in macrophages in severe pneumoniaMes travaux de recherche étudient la défaillance respiratoire inflammatoire en réanimation, en se concentrant sur trois axes principaux : 1. L'étude d'endocan comme biomarqueur et régulateur de l'inflammation pulmonaire aiguë et du Syndrome de Détresse Respiratoire Aiguë (SDRA). Mes travaux chez l'homme, la souris et in vitro ont mis en évidence le rôle anti-inflammatoire d'endocan, notamment eninhibant le recrutement des cellules immunitaires. J’ai en outre exploré l'intérêt clinique d'endocan comme marqueur pronostique et phénotypique dans le SDRA et le sepsis, ainsi que son rôle dans la prédiction d'événements thrombo-emboliques et de l'intubation tardive dans la COVID-19. Les travaux futurs visent à explorer l'intérêt pronostique de la cinétique d'endocan en phase initiale du SDRA. 2. La caractérisation du diagnostic des Pneumonies Acquises sous Ventilation Mécanique (PAVM) et la place des étiologies fongiques. Mes recherches ont évalué les performances de différentes méthodes diagnostiques pour les PAVM. Je coordonne également l'étude prospective multicentrique européenne ASPIC, qui vise à évaluer la fréquence de l'aspergillose pulmonaire invasive comme étiologie de la PAVM. Une seconde étude interventionnelle est par la suite envisagée afin d’évaluer l'impact d'une recherche systématique d'aspergillose sur le pronostic des patients. 3. L'évaluation des effets de la pollution de l'air sur le patient de réanimation. Des études en cours chez la souris explorent les effets tardifs de l'exposition aux particules Diesel sur le SDRA, suggérant une augmentation de la fibrose pulmonaire et une altération de la réponse immunitaire. J’encadre en outre un projet visant à quantifier les polluants particulaires dans les macrophages des voies aériennes des patients de réanimation. Un travail de Thèse que je co-encadre examine l'impact des particules fines sur l'expression des cytokines IL-20 et leur rôle dans le contrôle de l'infection à Streptococcus pneumoniae. Je coordonne par ailleurs le GAÏA (Group for Assesment of ICU-related Impacts of Air pollution) grâce auquel nous avons mis en place au CHU de Lille une cohorte rétrospective de plus de 4000 patients, étudiant l'association entre la pollution de l'air et diverses caractéristiques du patient de réanimation : pronostic, risque de PAVM et d'infections à bactéries multi-résistantes, auto-immunité anti-IFN I dans le COVID grave et empreinte particulaire dans les macrophages. Enfin, une étude prospective explorera l'empreinte particulaire dans les macrophages lors des pneumonies grave
Analyse épidémiologique des Entérobactéries Résistantes aux Carbapénèmes (ERC) dans le Sud-Ouest de l'océan Indien
No full textInternational audienc
Genetic relatedness of Staphylococcus aureus isolates within food outbreaks by single nucleotide polymorphisms
No full textInternational audienceInvestigation of bacterial food outbreaks by whole genome sequencing can rely on the inspection of the genetic relatedness between isolates through the application of single nucleotide polymorphism (SNP) thresholds. However, there is no consensus for Staphylococcus aureus in the context of food outbreaks. In this study, we propose a SNP cut-off by taking into account the mutation rate and the evolution time of this pathogen in food. Through in vitro microevolution, we determined the mutation rate of three S. aureus strains grown under mimicked food stressing conditions. From the mutation rate, we set a cut-off of 28 SNPs considering 30 days as evolution time based on the average shelf-life of foods contaminated by S. aureus and the timeline for identifying this pathogen in outbreaks. The SNP threshold was applied to retrospectively study ten staphylococcal food outbreaks to assess whether isolates from food and/or of human origin from the same outbreak were epidemiologically related. To interpret SNP distances, phylogenetic tree topologies and bootstraps were integrated and showed that isolates differing by up to 28 SNPs were monophyletic. Our suggested cut-off can be used in outbreak management to identify closely related S. aureus strains
Beyond 2025: Projections of cardiothoracic surgeon demographics in France
No full textInternational audienceBackgroundCardiothoracic surgeons are essential healthcare practitioners but there are demographic challenges and training complexities. Understanding workforce trends is critical to ensure future capacity and adaptability in France.AimsThis study assessed the current state of the cardiothoracic surgery workforce in France and projected demographic trends through 2040.MethodsData from the French Society of Thoracic and Cardiovascular Surgery (2023) were used to analyse all active cardiothoracic surgeons and residents. The study included statistical analysis with an Opportunity Index to forecast surgeon inflow and outflow over 15 years.ResultsThe cardiothoracic workforce comprised 958 individuals, marking a 15% increase since 2012. Among senior surgeons, 52% practiced cardiac and 48% thoracic surgery. Public institutions employed 60%, while the private sector accounted for 40%. The median age of residents was 29 years, with females representing 55% of the 2022 surgical training cohort. Regional disparities were noted, with Limoges and Caen presenting the best future opportunities. Growth in surgeon numbers is expected to continue steadily until 2040, but challenges in securing permanent positions for trainees, especially in cardiac surgery, may arise after 2035.ConclusionThe outlook for cardiothoracic surgery in France is balanced, with significant demographic shifts such as increased female representation. To sustain growth and align with patient and practitioner needs, workforce adaptation and inclusivity should be prioritized