HAL-Pasteur
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Division of labor in trypanosome RNA processing and export through expanded Mex67 paralogs
No full textInternational audienceIn animals and fungi, bulk messenger RNA (mRNA) export to the cytoplasm is mediated by the Mex67/Mtr2 (NXF1/NXT1) heterodimer and driven by an ATP-dependent remodeling machinery on the cytoplasmic side of nuclear pore complexes, the exclusive gateways of nucleocytoplasmic transport. Uniquely, we show that trypanosomes have three distinct Mex67 paralogs (TbMex67, TbMex67b, and TbMex67L); each having a different non-redundant role in ribosomal RNA (rRNA) processing and mRNA export. Specifically, TbMex67 and TbMex67b retain canonical roles in mRNA export, albeit associating with specific mRNA cohorts and differing protein and mRNA interactomes in the vertebrate host and insect vector forms of the parasite. Further, TbMex67 and TbMex67b paralogs associate with the GTPase Ran export machinery, rather than ATP-dependent helicases, demonstrating significant departure in RNA export mechanisms in trypanosomes. In contrast, TbMex67L is not involved in mRNA export but primarily associates with ribosome biogenesis factors. Thus, in trypanosomes Mex67 paralogs have diverse functionalities with implications for evolutionary origins and diversity of the control of gene expression
Process evaluation of a school-based vaccination intervention to improve HPV vaccine coverage: A mixed-method study embedded in the French PrevHPV cluster randomized controlled trial
No full textInternational audienceBackgroundHuman papillomavirus vaccine coverage (HPV VC) remains suboptimal in many countries. French authorities launched the PrevHPV research program, which included a cluster randomized controlled trial (cRCT) to evaluate the effectiveness of an ‘at-school vaccination’ intervention. Within this trial, we conducted a process evaluation of this intervention, specifically analyzing (i) its implementation, (ii) its mechanisms of impact, and (iii) the contextual factors influencing implementation (facilitators/barriers).MethodWe conducted a mixed-method study embedded in the PrevHPV cRCT (April 2021–April 2022). ‘At-school vaccination’ consisted of vaccination day(s) on school premises where mobile vaccination teams (MVTs) initiated HPV vaccination free of charge for eligible adolescents (i.e., non-vaccinated adolescents aged 11+). Quantitative data were collected through activity reports and self-administered questionnaires of adolescents and school staff. Qualitative data collected through six focus groups with school staff and MVTs were analyzed using thematic analysis.ResultsOf the 31 schools (14,772 adolescents) randomized to implement ‘at-school vaccination’, 12 (39 %) dropped out. Among the participating schools, analysis of implementation showed that 17 % of adolescents returned valid consent forms, of whom 89 % initiated vaccination. MVTs played a central role in implementing vaccination day(s), supported by several school staff (e.g., school nurses, education assistants). Regarding mechanisms of impacts, satisfaction with the vaccination days was high among adolescents and school staff. The intervention generated both positive and negative group effects among adolescents. Contextual factors that facilitated implementation included the preparation of a list of adolescents to be vaccinated and the availability and motivation of school staff. The main barriers related to the management of consent forms and missing health records.ConclusionWe formulated recommendations for implementing at-school vaccination, which may be particularly helpful for the French school HPV vaccination campaigns that were scaled up nationally in 2023. We also discussed potential macro-level improvement strategies, involving modifications to the legislative framework
The genetic driver of Acute Necrotizing Encephalopathy, RANBP2, regulates the inflammatory response to Influenza A virus infection
No full textInternational audienceInfluenza virus infections can cause severe complications such as Acute Necrotizing Encephalopathy (ANE), which is characterised by a rapid onset of pathological inflammation following febrile infection. Heterozygous dominant mutations in the nucleoporin RANBP2/Nup358 predispose to influenza-triggered ANE1. The aim of our study was to determine whether RANBP2 plays a role in IAV-triggered inflammatory responses. We found that the depletion of RANBP2 in a human airway epithelial cell line increases IAV genomic replication by favouring the import of the viral polymerase subunits, PB1, PB2, and PA, following viral transcription and translation. Additionally, RANBP2 knockdown enhances the cytoplasmic export of viral genomic RNA (vRNA) and disrupts segment stoichiometry, which is associated with elevated production of the pro-inflammatory chemokines CXCL8, CXCL10, CCL2, CCL3, and CCL4 in human primary macrophages. Using CRISPR-Cas9 knock-in for the ANE1 disease variant RANBP2-T585M, we further demonstrate that this point mutation causes a loss-of-localisation phenotype that excludes RANBP2 from the nuclear envelope, which phenocopies RANBP2 knockdown by increasing IAV replication and driving pro-inflammatory cytokine expression following infection. Together, our results reveal that RANBP2 regulates influenza RNA replication and nuclear export, thereby restraining virus-induced hyperinflammation, and further suggest that ANE1 pathogenesis results from the impaired localisation of RANBP2 at the nuclear envelope
A Standards-Based Knowledge Graph that Bridges Scientific Workflows, Run-Time Provenance, and Tool Registries
No full textInternational audienceLife science workflows are now prevalent for implementing, executing, and sharing complex data analyses, increasing their scalability and reproducibility. Adhering to the FAIR principles for software further reinforces their reproducibility and the reliability of their results. To maximize their FAIRness, consistent and standardised annotations are critical across several levels: workflows, individual steps, software tools, and input/output data. Such comprehensive metadata make workflows easier to understand, reuse and reproduce, while keeping track of the provenance of their results. However, a unified, queryable knowledge framework that integrates workflows with enriched metadata is lacking. To address this, we developed an integrated workflow knowledge base, that consolidates FAIR metadata from diverse sources and workflow languages into a standardised graph-based representation. It leverages established ontologies and standards (e.g. EDAM, schema.org) to enrich metadata, and link the workflow structure with its execution traces. Our approach provides FAIR-compliant metadata of publicly available pipelines, enabling queries at every granularity level, while accounting for the quality of source data annotation
Selection for function in complex distributed pathological systems
No full textInternational audiencePathological processes are often conceptualized as localized phenomena anchored in a primary tumor, a focal lesion, or a single organ. However, growing evidence indicates that many diseases persist and progress as complex distributed systems, maintained by interactions among multiple sites. Building on the emerging framework of selection for function, which can be applied to understand the evolutionary persistence of both replicating and non‐replicating entities, we propose that metastases, amyloidoses, fibroses, autoimmune syndromes, granulomatous diseases, and multifocal reproductive disorders can all be understood as complex evolving pathological systems within individuals. In these contexts, local units such as metastatic nodules, amyloid plaques, or fibrotic foci act as semi‐autonomous entities, yet achieve collective persistence through systemic flows, feedback loops, and network‐level interactions, where local structuration gives rise to systemic effects. At certain points, lesions that produce mediators can trigger systemic alterations that, in turn, favor the emergence and persistence of additional lesions. This creates a vicious cycle in which local and systemic dynamics reinforce one another, helping these specific pathological networks to overcome host defense mechanisms and persist (i.e., be ‘selected’ via differential persistence). This perspective unifies seemingly disparate conditions under the principle of system persistence, reframing pathology as an emergent organizational property of a pathological system rather than as isolated local breakdowns of organismal components. It also carries important implications for evolutionary medicine, suggesting a taxonomy of diseases that distinguishes localized from distributed functional pathologies. Clinically, it underscores the need to go beyond focal interventions, advocating instead for therapies that disrupt pathological connectivity, destabilize network coherence, and monitor systemic biomarkers of disease persistence. Recognizing the role of selection for function in the emergence and persistence of complex pathological systems opens new avenues for both theoretical integration and therapeutic innovation in evolutionary medicine
Mobility-driven synthetic contact matrices as a scalable solution for real-time pandemic response modeling
No full textInternational audienceAccurately capturing time-varying human behavior remains a major challenge for real-time epidemic modeling and response. During the COVID-19 pandemic, synthetic contact matrices derived from mobility and behavioral data emerged as a scalable alternative to empirical contact surveys, yet their comparative performance remained unclear. Here, we systematically evaluate synthetic and empirical age-stratified contact matrices in France from March 2020 to May 2022, comparing contact patterns and their ability to reproduce observed epidemic dynamics. While both sources captured similar temporal trends in contacts, empirical matrices recorded 3.4 times more contacts for individuals under 19 than synthetic matrices during school-open periods. The model parameterized with synthetic matrices provided the best fit to hospital admissions and best captured hospitalization patterns for adolescents, adults, and seniors, whereas deviations remained for children across both models. Neither matrix allowed models to fully reproduce serological trends in children, highlighting the challenges both approaches face in capturing their disease-relevant contacts. The weekly update of synthetic matrices enabled smoother reconstructions of hospitalization trends during transitional phases, while empirical matrices required strong assumptions between survey waves. These findings support synthetic matrices as a reliable, flexible, cost-effective operational tool for real-time epidemic modeling, and highlight the need for routine collection of age-stratified mobility data to improve pandemic response
Socioeconomic and nutritional determinants outweigh gut microbiota influence on neurodevelopment in young children from Antananarivo, Madagascar
No full textInternational audienceIn 2024, stunted child growth affected 150 million children under the age of five years, underscoring its critical impact on global health. Stunting has also been associated with neurodevelopmental delays. This study explores the relationship between stunting, the fecal microbiota, and neurodevelopment in 2–5-year-old children from the Afribiota cross-sectional study in Madagascar. Children were assessed using the Ages and Stages Questionnaire (ASQ-3), covering five developmental domains (communication, personal-social, problem-solving, fine and gross motor). Fecal samples were analyzed via 16S rRNA gene amplicon sequencing. Classical bi- and multivariate analysis was combined with Structural Equation Modelling to evaluate direct and indirect associations between different clinical factors, the microbiota and neurodevelopment. Our study shows that stunting and low socioeconomic status are consistently linked to poorer neurodevelopmental outcomes, while low branched-chain amino acids and hemoglobin levels are associated with stunting. Furthermore, a higher microbial diversity within individuals (α-diversity—specifically the Shannon index-) was directly linked to improved neurodevelopment scores in one of the tested models, while gut microbiota variation between individuals (β-diversity) was not associated with neurodevelopment. These findings support the hypothesis of neurodevelopment being primarily influenced by nutritional and social factors, with a more limited role for microbiota diversity
Difficulties with clinical practice guidelines for congenital syphilis prevention in Colombia: a qualitative study
No full textInternational audienceBackgroundCongenital syphilis (CS) is considered a preventable disease. However, it remains a major public-health concern in Colombia, where healthcare authorities have suggested that the main issue is the incorrect implementation of the clinical practice guidelines (CPG). This study aimed to understand why this preventable disease cannot be prevented in Chocó and Caldas, two regions of Colombia.MethodsA qualitative online study, using a multi-method approach following interpretative and ethnographic online research principles, was conducted in two regions of Colombia (Chocó and Caldas) during the COVID-19 pandemic.ResultsBesides the difficulties of, and barriers to, implementing the CPG identified in other studies in Colombia and elsewhere, three main gaps are highlighted as results of the study. (1) The CPG is usually implemented in a fragmented system. It specifies timelines and trajectories to be met in dynamic, inter-connected and under-resourced systems. (2) The CPG’s implementation requires measures and activities that go before and beyond prenatal care and involve more than pregnant women and healthcare workers. (3) The CPG are for preventing the specific disease, but the implementation is enacted in relation to other diseases (HIV, COVID-19, hepatitis B, hypertension, diabetes) and their protocols and clinical guidelines.ConclusionsThe implementation of the CPG is important but insufficient for CS prevention. The CPG does not operate in isolation. In addition to the knowledge of the CPG and the provision of the necessary resources, it is crucial to consider the activities and processes before and after prenatal care to address the fragmentation of the healthcare system and healthcare services provision. Moreover, it is essential to coordinate the activities and practices for other diseases (HIV, COVID-19, hypertension, hepatitis B, diabetes) with those of the CPG
Genetic Diversity and Excretion Kinetics of Enteroviruses Excreted by Patients with Primary Immunodeficiency in Tunisia over a Five-Year Period (2020-2024)
No full textInternational audienceEnteroviruses (EVs) are small, non-enveloped RNA viruses that can cause diverse clinical outcomes, particularly severe in patients with primary immunodeficiency (PID) due to their impaired ability to clear infections. This study aimed to characterize EV excretion among 138 Tunisian PID patients over a five-year period, to identify circulating EV serotypes and assess their genetic diversity. A total of 558 stool samples were collected and analyzed by virus isolation and intratypic differentiation using RT-qPCR. Molecular typing was performed through Sanger sequencing of the VP1 region and whole genome sequencing using Next-Generation Sequencing (NGS) technologies. Phylogenetic analysis was conducted using the Maximum Likelihood (ML) method. EVs were detected in 55 stool samples from 23 patients. The excretion kinetics of EVs ranged between 30 and 946 days. Thirteen serotypes were identified, including one Poliovirus (PV) and twelve Non-Polio Enteroviruses (NPEVs), predominantly belonging to species B. Two previously unreported serotypes in Tunisia were detected: Coxsackievirus A5 (CVA5) and Echovirus type 19 (E19). In addition, five patients presented enhanced susceptibility to the excretion of successive EV serotypes, and one patient exhibited a co-infection. A possible recombination event was identified in one patient involving Coxsackievirus B5 (CVB5), Coxsackievirus A9 (CVA9) and Coxsackievirus B1 (CVB1) sequences. Phylogenetic analysis showed close genetic relationships with European, American and Asian strains. These findings underscore the dynamic nature of EV circulation and the importance of ongoing molecular surveillance to detect emerging serotypes and guide public health strategies
Bass amplification impacts emotional, neural and physiological responses to music
No full textInternational audienceLive music is highly appreciated for its emotional impact, often enhanced by louder sound levels to boost audience arousal and engagement. As high sound levels cause hearing damage and disturb nearby residents, focusing on audio quality offers a safer way to enhance emotional responses to music. However, how quality parameters, such as the balance between low and high frequencies, impact and link emotional, neural and physiological responses is unclear.This study examines how low-frequency amplification affects listeners' arousal and its connection to neural and physiological responses during music listening. Two experiments were conducted: (i) in controlled laboratory conditions and (ii) in more ecological, live settings.Subjective reports indicate that amplified bass significantly increases arousal, with a lesser but noticeable effect on valence. Electroencephalography (EEG) recordings show that early auditory components are unaffected by bass amplification, but the arousing effect is linked to enhanced oscillatory features in the low delta (2-5 Hz) frequency range, suggesting active, predictive tracking of music.In natural music-listening settings, portable electrodermal activity (EDA) sensors were used to measure emotional and physiological responses. Results confirm that bass amplification increases arousal and that EDA better captures emotional integration in response to bass amplification than EEG. This suggests that low frequencies engage additional sensory or emotional circuits beyond traditional auditory pathways, and that EDA provides a more objective and practical measure of emotional responses in naturalistic environments.Overall, bass amplification effectively enhances the emotional music experience, and EDA is a valuable tool for objectively capturing emotional responses in live settings