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Heavy Metal and Bacteria: Deciphering how Zinc is deployed as an antimicrobial response
No full textInternational audienceIntroduction and ObjectivesAntimicrobial resistance is a growing challenge that is expected to result in an estimated 1.9 million deaths per year by 2050[1]. Thus, it is paramount to discover new ways to strengthen our immune system against bacterial infections. Our approach is to enhance macrophages, which play a key role in our innate immune system and are at the forefront of fighting bacterial infections. Throughout evolution, macrophages have developed a large arsenal of antimicrobial pathways to rapidly eliminate pathogens[2]. One of these involves using heavy metals, such as zinc, to poison pathogens[3]. Here, we reveal the possible mechanisms by which macrophages modulate intracellular zinc concentration during bacterial infection and how pathogens can evade this response.Materials and MethodsMacrophages are a highly heterogeneous population, making it difficult to assess the role of specific genes in the zinc toxicity response. To gain a clearer understanding, we developed a High-Through Bacterial-paired scRNAseq of human monocyte-derived macrophages (HMDM) infected with an E. coli zinc-stress reporter strain. We then confirmed our results through a doxycycline-inducible system in THP-1 cells and by using specific E. coli mutants for zinc importer or exporter genes. Finally, to support our hypothesis, we pre-sensitised the bacteria to zinc toxicityand observed their survival in different conditions.Results, Discussion and ConclusionWe identified different HMDM sub-populations harbouring zinc-stressed E. coli and found that the expression of the zinc exporter SLC30A1 was enriched in one of these clusters, which supports our previous observations[4]. We also found that metallothioneins MT1H and MT1G, as well as the zinc exporter SLC30A4, were strongly expressed in HMDM containing zinc-stressed bacteria. Using a doxycycline-inducible system in a monocyte/macrophage human cell line, we discovered that inducing zinc starvation on intracellular E. coli renders the bacteria more susceptible to subsequent zinc toxicity. Our finding was confirmed in vitro, where E. coli was found to be more sensitive to zinc stress when starved beforehand. Overall, our results provide insight into the mechanism behind zinc toxicity in macrophages and offer a potential new target for enhancing our antibacterial responses
Le management désenchanté: Erreurs, échecs et bullshit en management.
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The PTCHD1 protein: A prominent actor in brain function and in neurodevelopmental disorders
No full textInternational audienceNeurodevelopmental disorders (NDDs) encompass a broad spectrum of conditions, including intellectual disability (ID), Attention Deficit Hyperactivity Disorders (ADHD) and autism spectrum disorders (ASD), often linked to disrupted synaptic functionality. Among the major NDD genes, PTCHD1 (Patched Domain Containing 1) encodes a transmembrane protein which acts as a crucial regulator of synaptic function. Mutations and microdeletions in PTCHD1 have been associated with global developmental delays such as ID, ASD, and behavioral abnormalities. This review explores the neurodevelopmental functions of PTCHD1, particularly its position within the synaptic environment, from the association with the postsynaptic proteome to the regulation of several major neuronal signaling pathways, cholesterol homeostasis and receptor trafficking. In a pathophysiological context, studies in Ptchd1 knockout mouse models revealed abnormal behavioral phenotypes, linked to synaptic impairments, including reduced excitatory postsynaptic currents and altered dendritic morphology similarly to recent results on human-derived neuronal models. By synthesizing findings from genetic, molecular, and behavioral studies, this review underscores the multifaceted roles of PTCHD1 in neurodevelopment and synaptic regulation. Understanding its function in synaptic pathways may provide crucial insights into the pathophysiology of NDDs, emphasizing the need for further research to clarify its role as a potential synaptic, orphan receptor.</div
Sciences archéologiques et statistiques: Questions, données, méthodes
No full textNational audienceLes statistiques sont partie intégrante du raisonnement archéologique, pour structurer des ensembles d’information archéologique, pour établir des ordres de grandeur ou encore mettre en relation différents processus afin de proposer des interprétations de phénomènes passés. Dans la pratique, l’approche statistique engage, de manière sous-jacente, des concepts archéologiques liés au questionnement, repose sur l’identification d’éléments empiriques correspondants, utilise des méthodes statistiques pour l’analyse. C’est donc un dialogue entre archéologie et statistiques auquel nous sommes conviés, qui ne peut pas être réduit à sa simple expression technique.Face à un enjeu de sensibilisation et de transmission des connaissances des pratiques statistiques pour l’archéologie, cet ouvrage offre une approche didactique interdisciplinaire accessible aux non-spécialistes. Réciproquement, il permettra aux statisticiens d’appréhender la manière dont les archéologues transcrivent une problématique plus ou moins complexe en un schéma d’analyse statistique. Dans une première partie, nous partons des questions que se posent les archéologues lorsqu’il s’agit de reconstituer des chronologies, de comprendre les dynamiques spatiales, de lire des informations anthropologiques. Des exemples d’études sont présentés sous l’angle de trois dimensions articulées autour des questions « Quand ? », « Où ? », « Qui/Quoi ? ». Dans une deuxième partie, nous invitons le lecteur à approcher les méthodes statistiques, des plus simples aux plus élaborées. En réunissant les contributions de spécialistes de la chronologie, de la culture matérielle, de la géographie du passé, de l’anthropologie biologique, de la paléontologie et de la statistique, cet ouvrage propose un panorama non exhaustif d’études de cas qui, à travers la diversité des objets empiriques et des approches statistiques mobilisés, éprouvent les méthodes et les conditions d’application des outils non sans aborder apports et limites interprétatifs.Cet ouvrage s’adresse aux apprenants comme aux praticiens, étudiants et scientifiques intéressés par la mobilisation de méthodes statistiques pour répondre à des problématiques archéologiques. Il a pour ambition de décloisonner les approches en offrant à chacun des pistes de réflexion quel que soit le niveau de lecture
Transgenerational transmission of an environmental modification in quails: changes in phenotypic variance components across three generations
No full textWhile epigenetic variations can contribute to shaping phenotypic diversity, it can be challenging to isolate and quantify the portion of trait variability under epigenetic influence. The present study compares the phenotypic response for different phenotypes of two epilines of Japanese quails ( Coturnix japonica ), with similar genetic structure across three generations following an initial genistein ingestion in the ancestors’ diet. Linear and linear mixed models were fitted to extract the fraction of variance allocated to multiple factors such as dam, family, sex, reproductive status and epiline. The latter was found to be significantly associated with body weight and with heart, abdominal fat and testicle weight adjusted by body weight. The proportion of phenotypic variance explained by the epiline progressively increased from the first generation (G0) to the last (G2), leading - for example in body weight at slaughter - to an average difference for adult males and females in G2 of 9 grams and 14 grams respectively, between genistein treated offspring (epi+) and controls (epi-). These findings suggest a possible transgenerational effect of the initial diet disruption. In tissue weights, production and behavioural traits, the effect of the epiline accounted for smaller fractions of phenotypic variability and overall large residual variances were observed, underlining the complex nature of the analysed traits. This innovative experimental design allowed for a characterization of the impact of transgenerational effects on a variety of phenotypic traits, which will be useful for prioritizing traits for future genetic and epigenetic association studies. Implications Nowadays, changes in the environment occur more frequently and livestock species can struggle to adapt to these rapid shifts. It is therefore important to understand the impact of the environment on animals. In this study, we evaluate how an initial modification in prior generations can also affect subsequent ones. By collecting different traits of interest (growth, tissues, production, and behaviour), we compare the response to a change in the ancestors diet across three successive generations. Our findings highlight the importance of considering the potential multi-generational effects of changes to the environment. This could provide guidelines for better poultry management in order to ensure animal welfare while maintaining sustainable production yields
The modulation of the immune response and gut microbiota through the inoculation of commensal bacteria effectively reduces Salmonella colonization
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Uno, nessuno, molti autori. Anonimato, autorialità collettiva e controversie religiose nell’Italia del Cinquecento
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Positron emission tomography-based comparison of methods for exposing macaques to respiratory pathogens
No full textInternational audienceNon-human primates (NHPs) are relevant models for studies of human respiratory infections due to their similar anatomy and susceptibility to human pathogens, resulting in comparable disease manifestations following exposure via aerosols or liquid instillation. An understanding of pathogen deposition in the respiratory tract (RT) of NHPs according to the method of exposure is essential for infectious disease modeling. Here, we evaluated and compared three conventional exposure systems commonly used to replicate human RT infections: liquid endotracheal instillation (IT), facemask (FM) aerosol inhalation, and head-only exposure (HOE) aerosol inhalation. Using PET/CT imaging with [18F] fluorodeoxyglucose ([18F]FDG) as the radiotracer, we quantified deposition across the upper respiratory tract (URT), lower respiratory tract (LRT), and digestive tract in anesthetized, spontaneously breathing cynomolgus macaques. A 98.0 ± 1.4 % deposited dose in the LRT was obtained with IT, whereas FM gave only 28.2 ± 6.4 % (MMAD: 3.1 μm GSD 2.2) and HOE gave 40.4 ± 19.0 % (MMAD: 1.9 μm GSD 2.0). This variability of deposition rates highlights the need for precise metrology tools. The homogeneity of lung deposition was improved and ratio between peripheral deposition/central deposition (P/C ratio) were higher with FM, and particularly with the HOE device, than with IT. An in vivo study of macaques inhaling Bacillus atrophaeus spore suspensions tracked with [18F]FDG revealed a correlation between radioactivity and spore concentration in respiratory samples (nasal/tracheal swabs, bronchoalveolar lavage) after inhalation. In conclusion, exposure systems significantly affect pathogen dose deposition and distribution within NHP airways. Methods should thus mimic inhalation scenarios to improve vaccine or countermeasure efficacy trials against natural or intentional biological threats exposure. Finally, PET/CT imaging provides a robust tool for monitoring and controlling exposure, decreasing the number of animals required for studies through precise dose control and tissue targeting
Tegument Protein pUL47 Is Important but Not Essential for Horizontal Transmission of Vaccinal Strain SB-1 of Gallid Alphaherpesvirus 3
No full textInternational audienceThe gallid alphaherpesvirus 3 (GaAHV3) SB-1, a Mardivirus used as a vaccine against Marek’s disease, has been proposed as an interesting viral vector for poultry vaccination. However, SB-1 is highly transmissible between chickens, a feature that may be a limitation for the use of live recombinant vaccines. We have previously shown that UL47 is essential for horizontal transmission of the pathogenic Marek’s disease virus between chickens, but it is completely dispensable for replication and pathogenesis. In contrast, the role of UL47 in the biology of SB-1 remains unknown. To study that, we generated an SB-1 mutant lacking UL47 (∆47) from a commercial SB-1 isolate. This mutant replicated and spread like the WT in primary fibroblasts, indicating no growth defects in cell culture. In vivo, chickens inoculated with ∆47 had significantly reduced viral loads in the blood and the spleen, and transport to the skin was delayed compared to WT inoculated chickens. Strikingly, the ∆47 mutant was present in 66% of contact birds. As expected, 100% of contact birds were positive for the WT. In conclusion, our findings reveal that UL47 facilitates GaAHV3 SB-1 replication in vivo, which is important for latency establishment but is not essential for horizontal transmission, unlike for MDV
La enseñanza de la gramática del español en la educación secundaria francesa : de las directrices ministeriales a la percepción del alumnado
No full textInternational audienceEl objetivo de este trabajo es ofrecer un panorama de cómo se ha orientado la enseñanza de la gramática del español en las aulas de los institutos franceses desde el pasado siglo, para proporcionar en segundo término un contexto adecuado en el que poder poner en relación las actuales directrices del ministerio respecto a su enseñanza con las considera-ciones de los alumnos. Con este propósito, se ha realizado un estudio de campo en el que se ha aplicado un cuestionario a estudiantes (N=404) de diferentes universidades públi-cas francesas en el que se indaga sobre tres aspectos fundamentales: el lugar que ocupa la gramática en la clase de español lengua extranjera, la manera como se practica y se ejer-cita la gramática y su opinión acerca de la importancia de la gramática en el aprendizaje de una lengua y su nivel de satisfacción con el lugar que efectivamente se le da en el aula. El análisis de los textos oficiales y de la bibliografía sobre el tema, así como los resultados obtenidos gracias al cuestionario, permiten concluir que la prioridad en la clase de espa-ñol de secundaria es la expresión oral espontánea del alumno en torno a temas culturales seleccionados de acuerdo con los ejes del programa vigente, lo que relega la gramática a un claro segundo plano. Este lugar secundario en el que se encuentra no satisface a los es-tudiantes, quienes no solo piden gramática, sino que demandan además una práctica ra-zonada de la lengua, a la que se le dedique el tiempo necesario