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Cross-sectional evaluation of exposure to ozone, nitrogen dioxide, and particulate mass levels on circulating immune markers in women in the California Teachers Study
No full textInternational audienceAbstract Exposure to ambient air pollutants, specifically ozone (O 3 ), nitrogen dioxide (NO 2 ), ultrafine, fine or coarse particulate matter (PM 0.1 , PM 2.5 , and PM 10 ), has been linked to a number of adverse health outcomes, including cardiovascular disease. Changes in immune response may be a key mechanism underlying these effects. Within the California Teachers Study cohort, we conducted a cross-sectional analysis of 1,898 women to assess the associations between exposure to O 3 , NO 2 , PM 0.1 , PM 2.5 , and PM 10 and 15 immune markers measured from serum samples collected in 2015. Daily residential exposures to O 3 , NO 2 , PM 0.1 , PM 2.5 , and PM 10 were estimated by a validated chemical transport model and averaged over 12-, 3-, and 1-month periods prior to blood draw. Fifteen immune markers (categorized as quartiles) were estimated per interquartile range (IQR) of air pollutant exposures using multivariable ordinal logistic regressions adjusted for age, body mass index, and respective pollutants. Immune markers were also grouped into immune pathways (pro-inflammatory/macrophage activation, B-cell activation, and T-cell activation). After applying Bonferroni correction, elevated exposure to O 3 levels at all three exposure windows were associated with elevated circulating levels of IL-1β (interleukin-1 beta), IL-8 (interleukin 8), sTNFR2 (soluble tumor necrosis factor receptor 2), and sgp130 (soluble glycoprotein 130). Elevated O 3 at 3- and 1-month periods were associated with increased levels of sCD27 (soluble cluster of differentiation 27) and BAFF (B-cell activating factor). In pathway analyses, O 3 was consistently and significantly associated with the pro-inflammatory/macrophage activation pathway (12-month OR = 1.49, 3-month OR = 1.57, 1-month OR = 1.54) and with B-cell activation at all three exposure windows (12-month OR = 1.24, 3-month OR = 1.53, 1-month OR = 1.41). NO 2 was positively associated with TNFα at the 3- and 1-month exposure windows. For the PM size fractions, sporadic, mainly inverse, associations with immune markers were observed. Elevated O 3 exposure up to one year prior to blood draw was associated with elevated immune markers related to pro-inflammatory response, macrophage activation, and B cell activation. These findings suggest potential immunologic pathways linking air pollution to adverse health outcomes in women
Bright Circularly Polarized Electrochemiluminescence from Heterobinuclear Ir III –Au I Enantiomers
No full textInternational audienceThe development of efficient circularly polarized electrochemiluminescence (CP‐ECL) probes is still at its infancy and examples are still very limited. Yet, their achievement would enable gathering a readout that carries privileged information on the probe's chiral environment by monitoring luminescence polarization bias with high signal‐to‐noise ratio. Notwithstanding, this is a highly challenging task and requires judicious chemical engineering of chiral ECL‐active emitters. Herein, we aim at expanding the palette of CP‐ECL luminophores by presenting a novel class of enantiopure heterobinuclear Ir(III)–Au(I) complexes, which are investigated thoroughly by means of chemical, structural, and (chiro‐)optical techniques. The ground and excited state properties are also elucidated by using density functional theory (DFT) approaches including spin‐orbital coupling (SOC) perturbation. The chiral‐at‐metal complexes display luminescence with a polarization bias of the emitted light that is function of the helical arrangement of the coordination sphere around the Ir(III) center. Overall, the photo‐ and electro‐active complexes unraveled in this work combine unparallelly high photoluminescence quantum yield in the orange region, excellent circularly polarized luminescence (CPL) brightness up to 4.5 M −1 cm −1 with a notable ECL activity. Finally, these features provide emitters with CP‐ECL efficiency that encompass remarkably by a factor 3.5 that of the well‐known benchmark tris ‐(2,2′‐bipyridyl)ruthenium(II)
Animal models of attention-deficit/hyperactivity disorder: Diversity and validity
No full textInternational audienceAttention-deficit/hyperactivity disorder (ADHD) is one of the most widespread neurodevelopmental disorders globally, marked by chronic symptoms of inattention and/or hyperactivity-impulsivity. Its multifactorial origin and phenotypic heterogeneity make it a complex condition, and despite substantial research, the precise causes of ADHD remain poorly understood. A significant challenge in advancing ADHD research is the lack of a unified resource that consolidates animal models across different species and considers the diversity of ADHD subtypes and associated coexisting conditions. This lack of standardization of the models delays progress in developing a deeper understanding of the neuronal and molecular mechanisms behind the disorder, which is essential to advance its treatment. This review aims to bridge this gap by offering a comprehensive compilation of available animal models used in ADHD research, accompanied by an evaluation of their validity. It is essential for researchers to have access to a range of models, each selected based on the specific scientific objectives and hypotheses of their studies. The review highlights that an extensive approach to studying ADHD, including its various dimensions and associated conditions, requires the use of multiple animal models. Moreover, it emphasizes the importance of assessing the mechanisms and broader effects of current pharmacological treatments while also exploring novel therapeutic possibilities. By providing a clearer and more structured resource, this work pursues to assist researchers in selecting the most appropriate models for their investigations. Additionally, it aims to contribute to the broader understanding of ADHD neurobiology, offering new perspectives for new models and the potential for more targeted therapeutic strategies. SIGNIFICANT STATEMENT: Attention-deficit/hyperactivity disorder (ADHD), one of the most prevalent neurodevelopmental disorders globally, is marked by inattention and/or hyperactivity-impulsivity. This review evaluates animal models for ADHD and its coexisting conditions, emphasizing the need for diverse models to reflect its complexity. It underscores the importance of selecting appropriate models to address specific research goals and investigates current and potential pharmacological treatments, providing a vital resource for advancing ADHD research and improving therapeutic approaches
MobiCT: a UMI-based circulating tumor DNA analysis pipeline
No full textInternational audienceMobiCT is a bioinformatics pipeline designed to detect ultra-low-frequency variants present in cell-free DNA samples using unique molecular identifier (UMI). The pipeline is composed of three main stages: (i) UMI deduplication, (ii) alignment to reference genome, and (iii) variant calling. It has been validated using a range of cancer patients and control samples, demonstrating sensitivity, precision, and F1-score around 90%. Implemented in Nextflow, following the nf-core guidelines, MobiCT ensures reliability and reproducibility, making it suitable for both research and clinical applications
Self-assemblies from prodrugs composed of antimicrobial peptides: a revolution in local lung cancer treatment, with microbiota as a main actor
No full textInternational audienceHuman microbiota is now recognized as a fundamental organ of the body. In its healthy state, it fulfills essential local and systemic functions, whereas dysbiosis disrupts these roles and can contribute to disease. Although numerous studies have examined the relationship between microbiota and cancer, often revealing conflicting mechanisms and outcomes, this work has focused almost exclusively on the gut, leaving the lung microbiota largely unexplored. In this project, a ferrocifen compound was selected as an anticancer agent for lung cancer therapy. We found that lung microbiota actively degraded the ferrocifen. To prevent this degradation, the antibacterial peptide buforin II was synthesized, purified, and characterized. After confirming its antimicrobial activity, it was covalently conjugated to the ferrocifen, yielding an amphiphilic bioconjugate. This prodrug was subsequently formulated into self-assembled structures to enhance ferrocifen solubility and bioavailability. The resulting self-assemblies were evaluated in an orthotopic murine model of lung cancer and administered via nebulization to assess their therapeutic efficacy. A significant reduction in tumor progression and an improved predicted survival in mice were obtained. Together, these findings highlight the capacity of the lung microbiota to interfere with anticancer therapies and underscore the importance of considering this flora when designing treatment strategies for lung cancer
Physiopathology of fibrinolysis in sepsis-induced disseminated intravascular coagulation: Emerging mechanisms and pharmacological targets
No full textInternational audienceSeptic shock represents the most severe form of an infection, marked by a dysregulated host response that can lead to multiple organ failure and death. Among these patients, 30-40% develop disseminated intravascular coagulation (DIC), a life-threatening complication associated with a 60% increase in mortality. DIC is characterized by widespread activation of the coagulation cascade, resulting in disseminated microthrombi and a hypercoagulable state. This prothrombotic profile arises from the upregulated expression of tissue factor by endothelial cells, monocytes, and neutrophils, combined with insufficient regulation by endogenous anticoagulant pathways. In addition, a profound impairment of fibrinolysis further contributes to this imbalance. Initially, this fibrinolytic insufficiency was attributed to elevated plasma levels of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor. More recently, it has been shown that DIC-associated fibrinolytic insufficiency during septic shock involves plasminogen degradation driven by neutrophil elastase carried by neutrophil extracellular traps circulating in patients' plasma.The failure to resolve this hypercoagulable state and restore hemostatic balance has emerged as a key determinant of poor outcomes in DIC. Therefore, elucidating the mechanisms underlying fibrinolytic insufficiency is very important both to identify at-risk patients and to treat DIC.This review provides an overview of the most recent advances in our understanding of fibrinolytic dysregulation in sepsis-induced DIC, with a particular focus on emerging molecular mechanisms and their implications for the identification of novel pharmacological targets
Evolution of the sentinel lymph node procedure following the approval of adjuvant anti-PD-1 therapy for stage IIB and IIC melanoma: A multicenter study from RICMEL database
No full textInternational audienceIntroduction: Programmed cell death protein (PD)-1 inhibitors can be initiated for stage IIB-IIC melanomas after complete surgical resection following marketing authorization, to reduce the risk of recurrence later in the disease course. A year after this significant change to our therapeutic arsenal in France, we reflect on how this earlier initiation of immunotherapy may influence the practice of the sentinel lymph node biopsy (SLNB) and the overall staging of melanomas, particularly in an era where SLNB is increasingly considered outdated. The aim of this study is to compare the incidence of de novo IIB-IIC-III melanoma between 2021/2022 and 2023, and to examine the relationship between the stage III incidence and the number of SLN procedures to determine whether this therapeutic change has impacted melanoma staging practices.Materials and methods: We conducted a retrospective cohort study of 1158 de novo melanomas stage IIB-IIC and III diagnosed between 2021 and 2023. Data were extracted from the RICMEL database, a French, multicenter melanoma registry.Results: The incidence of SLNB dropped significantly following the marketing authorization of adjuvant anti-PD-1 therapy, decreasing from 59.1 % in 2021/2022 to 38.1 % in 2023 (p < 0.0001). This decline was accompanied by a significant shift in the staging of IIB-IIC-III melanomas.Conclusion: Although prognostic scores or new marketing authorization could suggest performing fewer SLNBs, the reduced use of SLNB due to earlier access to immunotherapy may result in inaccurate melanoma staging, potentially affecting prognosis and treatment decisions
Oral indomethacin modifies small intestine biofilms and host-microbe interaction mediators
No full textInternational audienceBackground and aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause small intestinal injury and dysbiosis. Although NSAID-induced dysbiosis is well-characterized and contributes to enteropathy, the changes in host-bacterial interactions during enteropathy remain largely unexplored. Here we assessed the expression pattern of six toll-like receptors (TLRs) and three antimicrobial peptides (AMPs) over the course of indomethacin (IND)-induced enteropathy in rats, and evaluated their correlations with inflammation and dysbiosis. In addition, we assessed for the first time the effect of IND on small intestinal mucosal biofilm structure.Materials and methods: Mucosal injury, inflammation and expression of TLR and AMP genes were evaluated at five time points following IND administration. Gut microbiota composition was determined by 16S rRNA gene sequencing. Small intestinal mucosal biofilms were visualized using fluorescent in situ hybridisation.Key findings: We found that TLR1, TLR2 and cathelicidin were upregulated, TLR5 was downregulated, whereas TLR6 and TLR9 were not altered in enteropathy. TLR4 expression showed only subtle differences, but correlated with α-defensin 5 and β-defensin 2 levels. We found several correlations between TLRs, AMPs, inflammation and gut bacteria in severe enteropathy, but in early disease stage TLR1, TLR2, TLR5 and cathelicidin expression were more strongly associated with inflammation, whereas TLR4 and defensins were more dependent on gut dysbiosis. IND treatment also caused mild damage to the mucosal microbiota biofilm.Significance: This is the first comprehensive characterization of the time-dependent changes in TLRs, AMPs and mucosal biofilm in NSAID-treated rats, which may help to identify new strategies for the treatment of enteropathy
Ensuring colloidal stability of cisplatin-loaded mesoporous silica nanoparticles: from synthesis to cytotoxicity assays
No full textInternational audienceMesoporous silica nanoparticles (MSNs) have attracted significant attention as a promising drug delivery platform for cancer treatment. However, their colloidal stability often remains overlooked, despite the numerous drawbacks associated with its absence. In this study, the enhancement of the colloidal stability of thoroughly characterised (TEM, DLS, zeta potential, TGA, XRD, N 2 physisorption) monodisperse MCM-41 MSNs in physiological conditions through the grafting a comb-like copolymer was successfully accomplished (preservation of the hydrodynamic diameter and the polydispersity index for at least 3 days). The loading of a therapeutic agent, cisplatin, was then achieved (12 wt%) without compromising their colloidal stability, and drug release kinetics were evaluated in cell culture medium, observing a complete release of the cargo after 48 h. Cytotoxicity studies conducted before and after drug loading confirmed the innocuousness of unloaded MSNs and demonstrated cytotoxic effects comparable to those of free cisplatin for the loaded nanoparticles (IC 50 = 23 and 13 μM CDDP for loaded MSNs versus 24 and 11 μM CDDP for free cisplatin in, respectively, SW480 and A549 cell lines).Particular emphasis was placed on ensuring the reproducibility of the results (e.g., hydrodynamic diameter and polydispersity index were measured across 49 independent synthesis) and on thoroughly evaluating the colloidal stability of the nanoparticles throughout the study, from synthesis to cytotoxicity assays. To the best of our knowledge, this work represents the first systematic study of the conditions required to develop stable colloidal suspensions of monodispersed mesoporous silica nanoparticles loaded with cisplatin, achieving high reproducibility, which constitutes a novel and robust contribution to the field.</p
Organic geochemical investigations of an MIS 5 fire in the Palaeolithic deposits of Ormesson (Seine-et-Marne, France): Anthropic or natural?
No full textInternational audienceDespite the central role of fire in Pleistocene and Palaeolithic lifeways, the relationship among hominins, fire, and their environment remains unclear. Ancient combustion residues hold a wealth of molecular data that may help to resolve some of these questions, yet standardised guidelines for reconstructing past fire traces are notably lacking. In this study, we examine extensive combustion residues overlying Middle Palaeolithic deposits from the open-air site of Ormesson (France). To determine whether the combustion residues are of natural or human origin, multiproxy approaches including anthracology, lipid biomarker, and benzene polycarboxylic acid (BPCA) analyses are applied. These techniques are used to characterise organic matter and pyrogenic carbon compositions in the deposits, providing insights into surrounding vegetation, palaeoenvironmental shifts, and the production parameters involved in the formation of the char assemblage. Lipid biomarker evidence suggests that the pre-fire local environment featured abundant coniferous vegetation (e.g., Pinaceae taxa), which is supported by anthracological evidence for a predominance of Pinus cf. sylvestris/nigra complemented by Betula sp. taxa. The post-fire environment saw a contraction of coniferous vegetation, concurrent with an expansion of deciduous taxa, grasses and herbaceous material. The combustion event, which resulted in 67 % of the charcoal assemblage exhibiting vitrification, produced PyC contents of up to 362 g/kg OC in soil samples and 443 g/kg OC in charcoal samples, with aromatic condensation values of up to 34 %. BPCA-derived predictions of heat treatment temperatures yielded values of approximately 300–400 °C for charcoal samples and 400–550 °C for soil samples in the burned layer, constituting the first instance in which quantitative temperature estimations are obtained from BPCA results. Based on the integrated evidence, we accept the null hypothesis that the studied combustion residues are natural in origin. However, the similarity of archaeometric and geochemical signatures from natural and human-controlled fires underscores the need for interdisciplinary, multiproxy efforts to improve the identification of past fire regimes