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Design of Fast Redox-Controlled Self-Immolative Selenium-Based Cysteine Surrogates
No full textInternational audienceThe self-immolation of N-selenoethyl cysteine derivatives into cysteine exhibits a strong Thorpe–Ingold effect. Notably, the gem-dimethyl substitution α to the selenium atom achieved rate accelerations up to 252-fold, enabling Cys unmasking through C–N bond cleavage within minutes. These investigations offer valuable insights into the mechanism of selenoethyl arm breakdown and new redox-sensitive Cys surrogates
Oncogenic mutations convert MET from a pro-apoptotic tumor suppressor to an oncogenic driver
No full textSUMMARY Dependence receptors can exert both oncogenic and tumor-suppressive activities. In cancers, downregulation of dependence receptors or overexpression of their ligands are well-established mechanisms that drive tumor progression. However, direct genetic alterations abolishing the pro-apoptotic function of dependence receptors have not been documented so far. MET, a receptor tyrosine kinase classically viewed as an oncogene, has also been proposed to act as a dependence receptor through its caspase-mediated cleavage, but whether this property impacts tumorigenesis remained unknown. In ∼3% of lung adenocarcinomas, MET mutations leading to exon 14 skipping (METex14Del) remove both the caspase site and the adjacent CBL-binding motif, thereby preventing generation of the pro-apoptotic p40MET fragment. METex14Del promotes sustained signaling, enhanced invasion, apoptosis resistance, and tumor growth in HGF-humanized mice. Genome editing revealed that combined —but not individual— mutations of the caspase and CBL sites phenocopy METex14Del. Moreover, inducible re-expression of p40MET in METex14Del-expressing cells restored apoptosis and suppressed tumor formation. Altogether, our findings identify MET exon 14 skipping as the first oncogenic mutation that drives tumorigenesis by abolishing the tumor-suppressive pro-apoptotic function of a dependence receptor, thereby redefining the oncogenic potential of MET
Life-threatening immune-related adverse events in the intensive care unit: a narrative review
No full textInternational audienceBackgroundImmune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by significantly improving survival across various malignancies. However, they are associated with immune-related adverse events (irAEs), resulting from excessive immune activation. Some irAEs can be life-threatening and require intensive care unit (ICU) management. These toxicities involve cardiovascular, pulmonary, hepatic, gastrointestinal, neurologic, endocrine, and hematologic systems and often occur early in the ICI course. As ICI become increasingly integrated into earlier phases of cancer care, intensivists must be prepared to manage irAEs.DesignNarrative review objectives: To summarize the evolving evidence on the epidemiology, diagnosis, and management of severe irAEs requiring intensive care by looking for the most relevant articles up to August 2025. The review emphasizes (1) the rationale and timing for immunosuppression beyond corticosteroids, (2) the integration of hemodynamic and organ support strategies, and (3) the importance of multidisciplinary coordination between oncology and critical care teams.ResultsEarly recognition, structured diagnostic evaluation, and multidisciplinary management are key to optimizing outcomes. Although overall mortality remains high-particularly in myocarditis and multisystem involvement-timely diagnosis and individualized immunosuppressive therapy can improve survival. Rechallenge with ICIs may be cautiously considered in selected patients after full clinical recovery and comprehensive risk assessment. This review aims to support intensivists facing this emerging clinical scenario by synthesizing current evidence and practical strategies for balancing immune modulation with oncologic efficacy in the ICU setting
Spatial modeling of the population dynamics of Anopheles mosquitoes in Madagascar
No full textSource Agritrop Cirad (https://agritrop.cirad.fr/615830/) * Autres projets (id;sigle;titre): 72068719CA00001;RISE;(MDG) Recherche, Innovation, Surveillance et Evaluation//International audienceBackground: Malaria, whose parasites are transmitted by Anopheles mosquitoes, remains a major public health burden in Madagascar despite the control measures led by the National Malaria Control Program. Understanding the population dynamics of Anopheles mosquitoes is therefore essential to optimize malaria surveillance and control. This study aimed to develop a model incorporating environmental, climatic and agricultural determinants of Anopheles abundance to predict their spatiotemporal distribution.Methods: We developed a model of spatiotemporal dynamics for four Anopheles species, vectors of malaria parasite in Madagascar: Anopheles arabiensis, Anopheles coustani, Anopheles funestus and Anopheles gambiae. This model was based on the life cycle of Anopheles and accounted for both the aquatic and aerial phases of their development. It used a system of differential equations to estimate the number of Anopheles mosquitoes at each stage of development. The Ocelet language, dedicated to the modeling of spatial dynamics, was used to produce simulations based on climate and environmental data. The model explicitly integrates the agricultural calendar to adjust the environmental carrying capacity of larval habitats. Model outputs were validated with entomological data collected in Vohimasy (Farafangana districts, 2014–2017).Results: 24 simulation outputs, from three Anopheles species and eight sites, were obtained and the validation revealed a significant correlation between field observations and model predictions: the correlation coefficients obtained ranged from 0.70 to 0.76. The predicted abundance of host-seeking Anopheles varied seasonally influenced by precipitation, temperature and environmental carrying capacity. The model exhibited robustness across sites with diverse climates and accurately reproduced interannual dynamics. The integration of the agricultural calendar significantly reduced the overestimation of the density of host-seeking adult females.Conclusion: The developed Anopheles dynamics model provides a valuable tool for predicting mosquito abundance and distribution over time and space. It correctly predicted the abundance at villages with contrasting climates and reproduced interannual dynamics well. A distinctive aspect of this work lies in the explicit integration of seasonal agricultural practices into the estimation of larval habitat availability. This allows for a more accurate and transferable modeling of Anopheles population dynamics
Isolation and structure elucidation of cell surface polysaccharides from Oenococcus oeni
No full textInternational audienceThe Gram-positive bacterium Oenococcus oeni is a major player in wine malolactic fermentation. In O. oeni, cell wall polysaccharides are considered putative receptors for bacteriophages, virus predators that lead to fermentation failures. In this study, we have developed an efficient stepwise extraction protocol to extract polysaccharides from the cell wall of O. oeni IOEBS277, which were analyzed by methylation, 1D, 2D-NMR spectroscopy, and MALDI-QIT-TOF mass spectrometry. The chemical structures of the two major purified polysaccharides were elucidated. The first one is a heteropolysaccharide with repeating units consisting of a branched hexasaccharide and one glycerol residue, linked by phosphodiester bonds. The second one consists of a →6)-β-Galf-(1→ galactofuranan chain partially substituted on the C-2 hydroxyl with β-Glcp. HR-MAS NMR analysis of intact O. oeni cells indicated that both polysaccharides are exposed to the bacterial surface
Advancing High-Throughput Cellular Atomic Force Microscopy with Automation and Artificial Intelligence
No full textInternational audienceAtomic force microscopy (AFM) has reached a significant level of maturity in biology, demonstrated by the diversity of modes for obtaining not only topographical images but also insightful mechanical and adhesion data by performing force measurements on delicate samples with a controlled environment (e.g., liquid, temperature, pH). Numerous studies have applied AFM to describe biological phenomena at the molecular and cellular scales, and even on tissues. Despite these advances, AFM is not established as a diagnostic tool in the biomedical field. This article describes the reasons for this gap, focusing on one of the main weaknesses of bio-AFM: its low data throughput. We review current efforts to improve the automation of AFM measurements in particular on living cells, as well as the developments in automating data analysis. For the latter, artificial intelligence (AI) is progressively employed to classify data to distinguish healthy and diseased cells or tissues. Finally, we propose a roadmap to foster the application of bio-AFM into medical diagnostics
Evolution of Blood Innate Immune Cell Phenotypes Following SARS-CoV-2 Infection in Hospitalized Patients with COVID-19
No full textInternational audienceInnate immune cells appear to have an important implication in the resolution and/or the aggravation of the COVID-19 pathogenesis after infection with SARS-CoV-2. To better appreciate the role of these cells during COVID-19, changes in blood eosinophil, the neutrophil and monocyte count, and levels of surface protein markers have been reported. However, analyses at several timepoints of multiple surface markers on granulocytes and monocytes over a period of one month after a SARS-CoV-2 infection are missing. Therefore, in this study, we performed blood eosinophil, neutrophil, and monocyte phenotyping using a list of surface proteins and flow cytometry during a period of 30 days after the hospitalization of patients with severe SARS-CoV-2 infections. Blood cell counts were reported at seven different timepoints over the 30-day period as well as measures of multiple mediators in serum using a targeted multiplex assay approach. Our results indicate a 95% drop in the blood eosinophil count by D1, with eosinophils displaying a phenotype defined as CD69/CD63/CD125 high and CCR3/CD44 low during the early phases of hospitalization. Conversely, by D7 the neutrophil count increased significantly and displayed an immature, activated, and immunosuppressive phenotype (i.e., 3% of CD10/CD16 low and CD10 low CD177 high , 6.7% of CD11b high CD62L low , and 1.6% of CD16 high CD62L low ), corroborated by enhanced serum proteins that are markers of neutrophil activation. Finally, our results suggest a rapid recruitment of non-classical monocytes leaving CD163/CD64 high and CD32 low monocytes in circulation during the very early phase. In conclusion, our study reveals potential very early roles for eosinophils and monocytes in the pathogenesis of COVID-19 with a likely reprogramming of eosinophils in the bone marrow. The exact roles of the pro-inflammatory neutrophils and the functions of the eosinophils and</div
Impact of aging on gut-lung-adipose tissue interactions and lipid metabolism during influenza infection in mice
No full textInternational audienceInfluenza remains a major threat to human health, especially for the elderly. Aging leads to substantial changes to lung function, gut microbiota, and white adipose tissue (WAT)-a key endocrine organ regulating energy balance and lipid metabolism. In the current study, we performed a multi-omics analysis to investigate how influenza impacts the gut-lung-adipose tissue axis differently with age at days 2, 4, 7, 14, and 28 post-infection (dpi). Compared to young-adult mice, aged mice experienced worse disease outcomes following infection, along with distinct WAT alterations, including impaired browning, heightened inflammation, and reduced innate immune cell recruitment. Age-related differences were also evidenced in infection-driven shifts in gut microbiota. Akkermansia levels rose only in young mice from 4 dpi, while Faecalibaculum and Muribaculum expanded exclusively in aged mice at 7 dpi, the only timepoint at which their abundance correlated with lung pathology. Serum metabolomics at 7 dpi also revealed age-dependent metabolic responses to infection. Compared to their non-infected counterparts, young mice had lower levels of p-Cresol-sulfate and Indoxyl-sulfate alongside higher triglycerides, whereas aged mice showed disrupted glycerophospholipid metabolism. By pinpointing specific gut bacteria as potential probiotics and identifying lipid pathways associated with disease progression, these findings could lead to the development of targeted, age-specific strategies to mitigate influenza severity in the elderly.Influenza A virus (IAV) infections remain a major global public health challenge, driving recurrent seasonal outbreaks and occasional pandemics, and significantly contributing to severe respiratory diseases 1 . Worldwide, IAV infections are estimated to cause 3 to 5 million cases of severe illness and approximately 290,000 to 650,000 respiratory deaths each year 2 . Influenza-related morbidity and mortality disproportionately affect several at-risk populations, including individuals with obesity and those aged 65 and over 3,4 . Notably, more than 90% of annual influenza-related deaths occur among the elderly 5 .Chronological aging is associated with a marked decline in both innate and adaptive immunity, a process known as immunosenescence 6 . This age-related immune dysfunction weakens the host's ability to defend against respiratory intruders and to generate an effective response following vaccination 4 . Additionally, inflammaging, a state of chronic low-grade inflammation, is a hallmark of the aging immune system 7 . Advanced age also leads to progressive impairment of pulmonary functions, including reduced lung elasticity, weakened respiratory muscles, diminished lung capacity, and impaired mucociliary clearance of inhaled pathogens 8,9 . Other factors, such as comorbidities and nutritional deficiencies, further compromise the ability of older adults to respond to</div
ECOSBot: a multicenter validation pilot study of a generative AI tool for OSCE-based nephrology training
No full textInternational audienceBackgroundDeveloping diagnostic reasoning in nephrology is particularly challenging due to its pathophysiological complexity and reliance on abstract clinical data. Objective Structured Clinical Examinations (OSCEs) are pivotal for nephrology training but remain resource-intensive and difficult to scale. Generative artificial intelligence (AI) offers a promising alternative, yet its capacity to emulate nephrology-specific OSCEs has not been formally assessed.MethodsWe developed ECOSBot, a web-based tool powered by GPT-4o, to simulate both standardized patients and examiners for nephrology-focused OSCEs. In this multicenter prospective study, undergraduate medical students from five French medical schools interacted with ECOSBot across four clinical stations. All interactions were double-rated by nephrology faculty members to establish a gold standard. ECOSBot’s performance was evaluated against this standard using four criteria (script coverage, authenticity, correctness and relevance) for patient simulation, and via checklists and competency-based ratings for examiner scoring. Usability was assessed using the Chatbot Usability Questionnaire (CUQ), adapted to include six items on feedback quality.ResultsNinety-one students generated 2939 prompts across 184 OSCE sessions. ECOSBot demonstrated high fidelity in patient simulation: authenticity 98.6% [95% confidence interval (CI) 98.2–99.0], correctness 98.3% (95% CI 97.9–98.7) and relevance 99.2% (95% CI 98.9–99.5), including during exchanges not explicitly covered by the pre-specified scenario. As an examiner, ECOSBot showed strong agreement with human raters on global scores [intraclass correlation coefficient (ICC) = 0.94, 95% CI 0.91–0.96], consistent across case formats, training levels and institutions. However, scoring of attitude and communication skills was less reliable (ICC = 0.44, 95% CI 0.28–0.58). Median CUQ score was 69.7/100, with 91.7% of students finding the tool highly useful for OSCE preparation in nephrology.ConclusionsECOSBot reliably simulated both roles in nephrology OSCEs with high fidelity and strong alignment with expert rating. While challenges remain for subjective skill assessment, this tool offers a scalable and autonomous solution to enhance nephrology education
Anti-tau VHH therapy against PHF6: a safe approach to slowing the phenotype of tau pathology
No full textInternational audienceBackgroundTauopathies share common features, including tau aggregation, which plays a central role in neurodegeneration. However, these disorders are highly heterogeneous, particularly in the spread of pathological tau species between cells. In Alzheimer’s disease, intracellular tau aggregation is followed by a propagation between cells leading to a hierarchical pathway of neurodegeneration, whereas in other tauopathies, such as progressive supranuclear palsy (PSP), pathological tau remains largely confined within neurons and exhibits more limited spread. This variability raises the question of whether tailored treatments for each tauopathy might offer more therapeutic benefit. Hence, we designed two different immunological approaches using single domain antibody fragments, also called VHHs, to target intracellular and extracellular tau. This study aims to first evaluate the safety of these immunological tools on physiological tau and then their potential to slow disease progression.MethodsWe selected the pro-aggregative tau hexapeptide PHF6 as a common target for the VHHs. These VHHs were cloned in viral vectors allowing to compare two different expression systems: 1) intracytosolic expression to prevent tau accumulation (intraVHH) and 2) secretion into the interstitial fluid, to prevent tau spreading (extraVHH). By stereotactic injection of viral vectors, these VHHs were expressed in the brain of transgenic or wild-type mice and three readouts were studied: behavior, brain imaging and tau lesions.ResultsWe validated the correct addressing of intra- and extraVHHs. These two constructs were not associated with adverse effects, even in the absence of tau overexpression, in wild-type mice. Their efficacy was demonstrated in transgenic mouse tau models, either chronic long-term or in acute seeding with injections of human brain homogenates from Alzheimer's disease patients. They both can slow down several pathological effects (i.e. cognitive deficits, cerebral atrophy and neuronal hyperphosphorylation of tau).ConclusionsThis study is a proof of concept demonstrating that VHHs can be engineered to reduce both intra- and extracellular tau pathologies without major adverse effects, making them of interest for therapeutic applications