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Analyse transcriptomique des réseaux de régulation génique et des facteurs de transcription clés des tumeurs neuroendocrines pancréatiques
No full textInternational audienc
Ingestion of environmentally sourced polyvinyl chloride microplastic fragments increases colon inflammation and fibrosis in mice
No full textInternational audiencePlastics released into the environment inevitably degrade into microplastics, which subsequently enter the food web. As a result, humans are chronically exposed to microplastics through ingestion. However, studies evaluating the effects of environmentally derived microplastics are limited. This study aimed to elucidate the impact of subchronic exposure to environmentally sourced polyvinyl chloride (PVC) microplastics on mammalian intestinal tissue and gut microbiota. Microplastics were generated from cryoground environmental debris and consisted of irregularly shaped PVC fragments (45-100 μm), containing 16 additives, including 7 known endocrine disruptors. Mice were exposed to PVC-contaminated food (50 μg/g) for 26 days. Under steady-state conditions, PVC exposure increased molecular markers of inflammation and oxidative stress without inducing overt histomorphological alterations in the colon. In a model of chronic colitis, PVC exposure exacerbated clinical symptoms, histological damage, and molecular markers of inflammation and fibrosis. These effects were associated with increased recruitment of neutrophils to the colon. Correlation analyses revealed significant associations between colitis exacerbation and increased relative abundances of Gastranaerophilales, Parasutterella, Clostridium sensu stricto 1, Colidextribacter, and Dubosiella, alongside a reduction in Lactobacillus and an enrichment of the isopropanol biosynthesis pathway. These findings add to growing evidence that real-world microplastics, including non-spherical PVC fragments, can induce intestinal toxicity.</div
A comprehensive phylogenomic view of the living xenarthran radiation
No full textInternational audienceXenarthrans (armadillos, anteaters, and sloths) represent one of the four main clades of placental mammals but remain underrepresented in genomic studies. Recent molecular evidence revealed hidden species diversity which suggests that additional species remain to be discovered. To address this knowledge gap, we generated 72 new xenarthran genomes constituting the most comprehensivegenomic dataset for the group to date. By first analyzing 261 mitochondrial genomes, including several new museum specimens of three-toed sloths (Bradypus spp.) and pygmy anteaters (Cyclopes spp.), we confirmed divergent lineages and revealed potentially overlooked species diversity. Genome-widecomparisons of 92 individuals largely validated these mitogenomic findings, uncovering distinct species within the broadly distributed brown-throated three-toed sloth (B. variegatus), now restricted to the Amazon Basin, with B. ephippiger west of the Andes and B. griseus in Central America. Similarly, we corroborated recently described pygmy anteater species and suggested two distinct lineages within C.didactylus. In armadillos, genome-scale data affirmed the four recently described Dasypus species and supported reclassifying all Euphractinae members under the genus Euphractus. Our phylogenomic analyses detected signals of incomplete lineage sorting and gene flow pointing to a few remaining phylogenetic uncertainties. Demographic reconstructions revealed a general decline in effectivepopulation sizes, with four species showing critically low genomic diversity, raising potential conservation concerns. Our study provides the first exhaustive assessment of the evolutionary history of xenarthrans at the genome level and identifies directions for future taxonomic investigations andconservation status assessments in this major placental clade
Palladium-Catalyzed C–H Arylation of Quinoidal Scaffolds Through Homogeneous and Heterogeneous Pathways: Advancing Toward Trypanocidal Prototypes
No full textInternational audienceA Pd-mediated C-H activation methodology was developed for the direct arylation of quinoidal skeletons, both by means of homogeneous catalysis and heterogeneous catalysis using metal-decorated carbon nanotubes, enabling the direct functionalization of quinones in moderate to excellent yields. The derivatives obtained were tested against trypomastigote forms of Trypanosoma cruzi, showing promising biological activity
Evaluating the impact of the Malakit intervention on malaria transmission in the Guiana Shield: a mathematical modelling study
No full textInternational audienceBackground: Malaria elimination in mobile and hard-to-reach populations calls for novel, tailored interventions. In French Guiana, the malaria burden is high among the population working in illegal gold mining. Between April 2018 and March 2020, we implemented Malakit, a new intervention targeting gold miners, and relying on the distribution of kits for the self-diagnosis and self-treatment of malaria. In this study, we evaluate the impact of Malakit on malaria transmission.Methods: We fitted mathematical models of the transmission of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) to surveillance data from Brazil and Suriname and to prevalence data from cross-sectional surveys to estimate the change in treatment coverages and reproduction numbers between the pre-intervention (2014-2018) and intervention (2018-2020) periods. Using counterfactual scenario analysis, we estimated the impact of the intervention on malaria incidence.Findings: Treatment coverage increased in the intervention compared to the pre-intervention period, the effect being stronger for Pf malaria (from 20.6% [95% CrI 17.0, 25.7] to 81.7% [95% CrI 67.9, 96.4]) than Pv malaria (from 22.3% [95% CrI 19.3, 25.7] to 47.3% [95% CrI 42.6, 52.3]). Concomitantly, the mean reproduction number decreased from 0.96 (95% CrI 0.93, 1.00) to 0.34 (95% CrI 0.22, 0.46), for Pf, and from 1.13 (95% CrI 1.10, 1.16) to 0.86 (95% CrI 0.82, 0.90) for Pv. We estimated that between 2018 and 2020 Malakit helped avert a total of 1231 (95% CrI 589, 1870) and 2406 (95% CrI 1191, 3621) symptomatic infections by Pf and Pv, respectively, corresponding to a 44.2% reduction of the overall malaria incidence (95% CrI -52.5, -34.5).Interpretation: Malakit had a significant impact on malaria transmission by improving the access to treatment for the population working in illegal gold mining in French Guiana. Building on the regional efforts of the past fifteen years, Malakit contributed to another step towards malaria elimination in the Guiana Shield.Funding: European Union, Global Fund, MoH of Brazil, Cayenne Hospital, Health Regional Agency of French Guiana
Fetal hemoglobin enables malaria parasite growth in sickle cells but augments production of transmission stage parasites
No full textInternational audienceSickle cell trait is the quintessential example of the human evolutionary response to malaria, providing protection against severe disease, but leading to sickle cell disease (SCD) in the homozygous state. Fetal Hemoglobin (HbF) reduces the pathology of SCD and several mutations lead to the prolonged production of HbF into childhood and adult life. HbF has been suggested to contribute to protection against malaria. Two long-term cohorts were genotyped for three quantitative trait loci associated with HbF production and analyzed for HbF titers, malaria clinical episodes and the production of parasite stages infectious to mosquitoes, gametocytes, in asymptomatic infections. Plasmodium falciparum parasites were also grown in vitro in HbSS cells with measured levels of HbF. The genetic determinants of prolonged HbF production were associated with increased HbF titers and that increased HbF afforded protection from malaria disease but increased the production of gametocytes. The presence of HbF in sickled red cells was also shown in in vitro culture to enable parasite persistence in conditions otherwise deleterious for the parasite and enabled complete maturation of gametocytes. The beneficial personal effect of HbF, whether through protection against malaria or alleviating effects of SCD, is seemingly offset by increased parasite transmissibility and potential disease burden for the community. These individuals represent a potentially important reservoir of infection and could be targeted in elimination strategies
Efficacy of non-pyrethroid indoor residual spraying or intensive behaviour change communication in combination with long-lasting insecticidal nets for malaria control in west Africa: a pragmatic, cluster-randomised, controlled trial
No full textInternational audienceBackground: Since 2015, progress in the control of malaria has stalled owing to multiple factors, including the probable reduced efficacy of long-lasting insecticidal nets (LLINs) caused by insecticide resistance and plateauing LLIN use rates. This study aimed to assess the additional effect of non-pyrethroid indoor residual spraying (IRS) and intensive behaviour change communication (BCC) when combined with LLINs on malaria in rural west Africa.Methods: This pragmatic, parallel-group, cluster-randomised, controlled trial took place in community settings in Burkina Faso and Côte d'Ivoire. Villages (clusters) with an average population of 300 inhabitants, a minimum distance between villages of 2 km, and year-round accessibility by a four-wheel drive vehicle were eligible for inclusion. A simple randomisation approach with a computer-generated random number sequence was used to assign 39 villages with a total population of 10 750 inhabitants to three groups: LLIN alone (16 villages; the control group), LLIN plus IRS (11 villages), and LLIN plus BCC (12 villages). Field teams that collected epidemiological data and laboratory staff were masked to intervention allocation; it was not possible to mask participants, field teams that implemented the interventions, or study investigators to intervention allocation. The IRS intervention consisted of pirimiphos-methyl treatment of the dwellings and the BCC intervention focused on promoting LLIN use, environmental sanitation, and early health-seeking behaviour through home visits, interpersonal talks, and group talks. The primary outcome was malaria incidence rate in the whole population as measured by passive case detection at health centres. Data were collected for 10 months before (the pre-intervention period) and 10 months after (the post-intervention period) randomisation. All outcome data were analysed by intention to treat and using constrained baseline analyses. The trial is registered with ClinicalTrials.gov, NCT03074435, and is completed.Findings: Between November, 2016, and August, 2018, 215 000 theoretical person-months of follow-up resulted in 3612 malaria cases recorded by passive case detection during both pre-intervention and post-intervention periods. During the post-intervention period, passive case detection showed a 23% reduction in malaria incidence rate (rate ratio 0.77 [95% CI 0.64-0.93], p=0.0073) in the LLIN plus IRS group and a 22% reduction (0.78 [0.63-0.96], p=0.020) in the LLIN plus BCC group compared with the LLIN-alone (control) group. No IRS-related adverse effects were recorded. Interpretation Results show that the addition of non-pyrethroid IRS or intensive BCC to LLINs can effectively reduce the number of malaria cases. The effect of IRS observed in our trial was intermediate compared with that reported in previous trials conducted in Africa. Notably, this study provides the first trial-based evidence supporting the effectiveness of an intensive BCC intervention, which is a promising result but requires confirmation through additional studies.Contexte: Depuis 2015, les progrès dans la lutte contre le paludisme ont stagné en raison de multiples facteurs, notamment l'efficacité probablement réduite des moustiquaires imprégnées d'insecticide à longue durée (MILDA) causée par la résistance des moustiques aux insecticides, ainsi que la stagnation des taux d'utilisation des MILDA. Cette étude visait à évaluer l'effet additionnel de la pulvérisation intra-domiciliaire (PID) utilisant un insecticide non pyréthrinoïde et de la communication intensive pour le changement de comportement (CCC), lorsqu'elles sont combinées aux MILDA, sur le paludisme en Afrique de l'Ouest rurale.Méthodes: Cet essai contrôlé randomisé en grappes, pragmatique et en groupes parallèles, s’est déroulé dans des communautés rurales du Burkina Faso et de la Côte d’Ivoire. Les villages (unités de randomisation) admissibles devaient compter en moyenne 300 habitants, être séparés d’au moins 2 km les uns des autres, et rester accessibles toute l’année en véhicule tout-terrain. Une randomisation simple, basée sur une séquence de nombres aléatoires générée par ordinateur, a permis d’attribuer 39 villages (10 750 habitants au total) à trois groupes : MILDA seule (16 villages ; groupe témoin), MILDA + PID (11 villages), et MILDA + CCC (12 villages). Les équipes de terrain chargées de la collecte des données épidémiologiques et le personnel de laboratoire étaient masqués quant à l'allocation des interventions ; il n'était cependant pas possible de masquer les participants, les équipes responsables de la mise en œuvre ou les investigateurs. L’intervention de PID consistait à traiter les habitations avec du pirimiphos-méthyl. L’intervention de CCC visait à promouvoir l’utilisation des MILDA, l’assainissement de l’environnement, et le recours précoce aux soins par des visites à domicile, des entretiens interpersonnels et des discussions de groupe. Le critère principal était l’incidence du paludisme dans la population générale, mesurée par la détection passive des cas dans les centres de santé. Les données ont été collectées pendant 10 mois avant (période pré-intervention) et 10 mois après (période post-intervention) la randomisation. Toutes les données de résultat ont été analysées selon le principe de l’intention de traiter, en utilisant des analyses des longitudinales avec données de base contraintes. Cet essai est enregistré sur ClinicalTrials.gov (NCT03074435) et est terminé.Résultats: Entre novembre 2016 et août 2018, 215 000 personnes-mois théoriques de suivi ont permis de recenser 3 612 cas de paludisme par détection passive, pendant les périodes pré- et post-intervention. Durant la période post-intervention, la détection passive a montré une réduction de 23 % du taux d’incidence du paludisme dans le groupe MILDA + PID (rapport de taux 0,77 [IC 95 % 0,64–0,93], p=0,0073), et une réduction de 22 % dans le groupe MILDA + CCC (0,78 [0,63–0,96], p=0,020), comparé au groupe MILDA seule. Aucun effet indésirable lié à la PID n’a été signalé.Interprétation: Ces résultats montrent que l’ajout de la PID non pyréthrinoïde ou d’une CCC intensive aux MILDA peut réduire efficacement le nombre de cas de paludisme. L’effet observé de la PID dans cet essai est intermédiaire par rapport à ceux rapportés dans d’autres essais menés en Afrique. Notamment, cette étude fournit la première preuve issue d’un essai randomisé de l’efficacité d’une intervention de CCC intensive, un résultat prometteur qui nécessite toutefois d’être confirmé par des études supplémentaires
Insight into tick and flea species infesting the North African Hedgehog Atelerix algirus in Tunisia
No full textInternational audienceHedgehogs are small wild mammals known to host various ectoparasites, including hard ticks and fleas, which can transmit vector-borne pathogens to humans and animals. We investigated the ectoparasites infesting 10 hedgehogs (Atelerix algirus) captured in northern Tunisia and found both ticks and fleas. Ectoparasite species were identified based on their morphological characteristics as well as using molecular methods via the partial amplification of the 16 S rRNA, the mitochondrial Cytochrome C Oxidase subunit I, and the 18 S rRNA genes. Four tick species were identified: Haemaphysalis erinacei, followed by Rhipicephalus sanguineus, Ixodes ventalloi, and Hyalomma aegyptium. Molecular analysis confirmed the presence of the subspecies Haemaphysalis erinacei turanica, with phylogenetic clustering suggesting a genetic relationship with tick populations in Algeria, Turkey, and China. Two additional flea species were identified: Archaeopsylla erinacei, the hedgehog flea, and Ctenocephalides felis, the cat flea, both known to be vectors of pathogens. We confirmed that hedgehogs were infested with Archaeopsylla erinacei maura, with the obtained sequences clustering closely with those previously reported in Spain. This genetic similarity may suggest a shared origin and indicate a wider geographic distribution for this subspecies. Our study underscores the importance of understanding the interactions between hedgehogs, ectoparasites, and their environments. Our findings may inform public health strategies and wildlife management, aiming to control ectoparasite populations and reduce the risk of the emergence of zoonotic diseases
Unraveling an enhancer-silencer regulatory element showing epistatic interaction with a variant that escaped genome-wide association studies
No full textInternational audienceRegulation of gene expression has recently been complicated by identifying Epromoters, a subset of promoters with enhancer function. Here, we uncovered a dual cis-regulatory element, “ESpromoter,” exhibiting both enhancer and silencer function as a regulator of the nearby genes ATP2B4 and LAX1 in single human T cells. Through an integrative approach, we pinpointed functional rs11240391, a severe malaria-risk variant that escapes detection in genome-wide association studies, challenging conventional strategies for identifying causal variants. CRISPR-modified cells demonstrated the regulatory effect of ESpromoter and rs11240391 on LAX1 expression and T cell activation. Furthermore, our findings revealed an epistatic interaction between ESpromoter SNPs and rs11240391, impacting severe malaria susceptibility by further reducing LAX1 expression. This groundbreaking discovery challenges the conventional enhancer-silencer dichotomy. It highlights the sophistication of transcriptional regulation and argues for an integrated approach combining genetics, epigenetics, and genomics to identify new therapeutic targets for complex diseases
Impacts sur la santé publique de la dynamique des populations de renards
No full textOpinion and report approved by the Expert Committee Socio-economic analysis in its plenary session on 11 May 2023 and the Expert Committee Animal health and welfare (CES SABA) in its plenary session on 06 June 2023. The French Agency for Food, Environmental and Occupational Health & Safety provides independent scientific opinions and reports. The original version of the ANSES opinion and report in French is available on the website of ANSES at https://www.anses.fr/fr/system/files/SABA2022SA0049Ra.pdf.Suggested citation: ANSES. (2023). Avis et rapport de l'Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail relatif à l'évaluation des impacts sur la santé publique de la dynamique des populations de renards (Saisine 2022-SA-0049). Maisons-Alfort: ANSES, 200 p.International audienceThe Red Fox (Vulpes vulpes) can be hunted as a game species. It may also be listed as a “species likely to cause damage” (ESOD – the acronym in French), for public health reasons among others. Conversely, benefits linked to the presence of foxes are also put forward, such as the predation of rodents carrying zoonotic agents. In this context, ANSES was asked to: (1) list the zoonoses present in France for which foxes play an epidemiological role, (2) identify other public health impacts associated with changes in fox populations, (3) explain the relative importance of the effects of changes in fox populations for humans and/or the environment, (4) analyse the feasibility of a cost‐benefit analysis (CBA) of the prevention and impacts associated with these zoonoses. In France, the fox is a source of zoonotic pathogens, with a major role for Echinococcus multilocularis, a parasite for which the fox is the main source of environmental contamination. However, reducing fox populations does not reduce the risk of transmission of E. multilocularis to humans or domestic animals, and may even have the opposite effect to the one intended. The main levers for action are those relating to exposure to environmental contamination. The fox is part of complex trophic networks, in which its specific role in regulating prey populations is impossible to determine because (i) several predators share the same prey, with a variable role for the fox among the predators, (ii) the dynamics of prey populations is also conditioned by factors other than predation. The relationship between the abundance of rodents and the risk of disease for humans has not been demonstrated either, due to the complexity of the trophic and epidemiological networks, their highly probable variability from one ecosystem to another, and the multiplicity of hosts. As a result, the data currently available does not allow any conclusions to be drawn about the epidemiological role of the fox as a predator of rodents hosting zoonotic agents. Finally, there is no public health justification for culling foxes, particularly for ESOD classification, except in the very specific and localised context of the fight against bovine tuberculosis, for which the selective culling of foxes in and around the livestock buildings of a domestic outbreak has been proposed. In addition, the expertise concluded to the feasibility of a CBA targeted at assessing the burden of alveolar echinococcosis and measures to prevent its transmission. The feasibility study shows the partial nature of a CBA targeting zoonoses, without taking into account other roles played by the fox in the ecosystem