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Targeting ATF6α Attenuates UVB ‐Induced Senescence and Improves Skin Homeostasis by Regulating IL8 Expression
No full textInternational audienceABSTRACT Skin aging is influenced by both intrinsic and extrinsic factors, particularly UV radiation, and is characterized by an accumulation of senescent cells. Remarkably, exposure to UV can trigger senescence in different skin cell types, including dermal fibroblasts. However, the molecular mechanisms underlying UV‐induced senescence and the impact of the related senescence‐associated secretory phenotype (SASP) on the homeostasis of the overlying epidermis remain poorly understood. Here, we identified that both chronological aging and photoaging induce the unfolded protein response (UPR) in human dermal samples. We demonstrated that silencing ATF6α disrupts the establishment of the UVB‐induced senescent phenotype by preventing the onset of several senescent biomarkers and alters the composition of the SASP, consequently affecting its impact on the increased proliferation of keratinocytes embedded in reconstructed human epidermis. Moreover, we found that ATF6α partially mediates IL8 expression involved in the hyperproliferation of cultured keratinocytes. Together, our findings highlight the importance of the ATF6α/IL8 axis in regulating the homeostasis of neighboring cells during skin photoaging, thus suggesting ATF6α as a potentially promising target for senotherapeutic interventions
Mathematical modelling of the contribution of senescent fibroblasts to basement membrane digestion during carcinoma invasion
No full textSenescent cells have been recognized to play major roles in tumor progression and are nowadays included in the hallmarks of cancer.Our work aims to develop a mathematical model capable of capturing a pro-invasion effect of senescent fibroblasts located in the conjunctive tissue. We focus in the present article on the first moments of the invasion cascade. Considering a localized epithelial tumor, we model the digestion of the collagen fibers of the basement membrane by the proteolytic enzyme MMP-2. The activation of MMP-2 is modelled in detail, as MT1-MMPs bound to the surface of tumor cells interact with proMMPs and TIMPs, proteins enriched in the secretome of senescent Cancer-Associated Fibroblasts, along with its inhibition by TIMPs. Using numerical simulations of the model, calibrated via an extensive literature search, reproducing biologically relevant scenarios, we test the model’s suitability to investigate the effect on basement membrane digestion of fibroblasts presenting a senescence-associated secretory phenotype. Via model reduction, steady state and global sensitivity analyses, we identify the most influential parameters in view of their calibration with empirical data. We conclude the paper discussing mathematical and interdisciplinary perspectives
Letter to the editors : Diagnosing Kearns-Sayre syndrome requires documentation of the underlying genetic defect
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Prise en charge du paludisme en Guyane : quels enjeux dans ce dernier territoire endémique français en 2024 ?
No full textInternational audienceFrench Guiana, the last malaria-endemic region of France, is facing an epidemic resurgence of malaria since the end of 2023. This epidemic, primarily caused by Plasmodium vivax, mainly affects populations that are far from the healthcare system. It has highlighted the difficulties of providing a full course of treatment. This includes both curative treatment with artemisinin derivatives (following the withdrawal of chloroquine from the market) and eradicative treatment with primaquine, with the challenge of excluding G6PD deficiency.The aim of this paper is to describe the problems of malaria diagnosis and management in this unique territory, to highlight the adaptations made and to propose diagnostic, therapeutic and follow-up schemes adapted to the possibilities of access to the health system, with a view to homogenizing practices. This article also highlights the innovative strategies implemented in French Guiana to deal with this new epidemic: health mediation, mobile malaria team, rapid diagnostic tests and immediate out-of-hospital treatment Test and Treat, devel-opment of self-diagnosis and self-treatment. These proposals are part of a campaign to eliminate malaria in France in the short term.Malaria control in French Guiana: What are the challenges in this last endemic French territory in 2024? French Guiana, the last malaria-endemic region of France, is facing an epidemic resurgence of malaria since the end of 2023. This epidemic, primarily caused by Plasmodium vivax, mainly affects populations that are far from the healthcare system. It has highlighted the difficulties of providing a full course of treatment. This includes both curative treatment with artemisinin derivatives (following the withdrawal of chloroquine from the mar-ket) and eradicative treatment with primaquine, with the challenge of excluding G6PD deficiency. The aim of this paper is to describe the problems of malaria diagnosis and management in this unique territory, to highlight the adaptations made and to propose diagnostic, therapeutic and follow-up schemes adapted to the possibilities of access to the health system, with a view to homogenizing practices. This article also highlights the innovative strategies implemented in French Guiana to deal with this new epidemic: health mediation, mobile malaria team, rapid diagnostic tests and immediate out-of-hospital treatment Test and Treat, develop-ment of self-diagnosis and self-treatment. These proposals are part of a campaign to eliminate malaria in France in the short term. Prise en charge du paludisme en Guyane?: quels enjeux dans ce dernier territoire endémique français en 2024?? La Guyane, dernier territoire endémique du paludisme en France, fait face à une recrudescence épidémique de paludisme depuis fin 2023. Cette épidémie, majoritairement causée par Plasmodium vivax, touche principalement des populations éloignées du système de soins. Elle a permis de mettre en lumière les difficultés de délivrance du traitement complet. Celui-ci comprend à la fois un traitement curatif de l’accès par dérivés de l’artémisinine (suite au retrait de la chloroquine du marché) et un traitement éradicateur par primaquine, avec les enjeux d’écarter un déficit en G6PD. Ce travail a pour objectifs de décrire les problématiques de diagnostic et de prise en charge du paludisme sur ce territoire singulier, de mettre en avant les adaptations réalisées et de proposer des schémas diagnostiques, thérapeutiques et de suivi adaptés aux possibilités d’accès au système de soins dans un but d’homogénéisation des pratiques. Cet article a aussi pour dessein de souligner les stratégies innovantes mises en place en Guyane pour faire face à cette nouvelle épidémie : médiation en santé, équipe mobile « paludisme », tests diagnostiques rapides et traitement immédiat hors les murs Test and Treat, développement d’auto-diagnostic et d’auto-traitement. Ces propositions s’intègrent dans une volonté d’élimination du paludisme à court terme sur le territoire français
Reevaluating the presence of Rhipicephalus australis (Acari: Ixodidae) in Southeast Asia: A phylogenetic approach based on Cambodian tick samples
No full textInternational audienceMorphological variability between Rhipicephalus australis and R. microplus has led to taxonomic ambiguity, leading to species misidentification. Rhipicephalus australis is reported to have a distribution range in Pacific Ocean region extending to several Southeast Asian countries, including Cambodia, although its presence in continental Southeast Asia has not been supported by molecular data. With growing evidence of conflicting morphological characters, this study aimed to evaluate the presence of R. australis in Cambodia using both morphological and molecular identification. Tick specimens were collected from cattle across 21 provinces of Cambodia, and a subset of 95 R. microplus complex (37 morphologically identified as R. australis, 39 R. microplus, and 19 nymphs) was selected for molecular analysis. DNA barcoding of the cox1 gene was performed, and a maximum likelihood phylogenetic tree revealed that all specimens clustered within R. microplus clade A. These findings, along with previous observations from other regions, suggest that, in the absence of molecular data, there is no definitive evidence to support the presence of R. australis in continental Southeast Asia, particularly in Cambodia
sST2 is a key outcome biomarker in COVID-19: insights from discovery randomized trial
No full textInternational audienceWe investigated whether baseline levels of biomarkers related to endotheliopathy, thromboinflammation, and fibrosis were associated with clinical outcomes in hospitalized COVID-19 patients. We analyzed the associations between baseline levels of 21 biomarkers and time to hospital discharge and change in NEWS-2 score in patients from DisCoVeRy trial. We fitted multivariate models adjusted for baseline ISARIC 4C score, disease severity, D-dimer values, and treatment regimen. Between March 22 and June 29, 2020, 603 participants were randomized; 454 had a sample collected at baseline and analyzed. The backward selection of multivariate models showed that higher baseline levels of soluble suppressor of tumorigenicity 2 (sST2) and nucleosomes were statistically associated with a lower chance of hospital discharge before day 29 (sST2: aHR 0.24, 95% CI [0.15-0.38], p < 10-9; nucleosomes: aHR 0.62, 95% CI [0.48-0.81], p < 10-3). Likewise, higher levels of baseline sST2 were statistically associated with lower changes in the NEWS-2 score between baseline and day 15 (adjusted beta 4.47, 95% CI [2.65-6.28], p < 10-5). Moreover, we evaluated sST2 involvement in a confirmation cohort (SARCODO study, 103 patients) and found that elevated baseline sST2 levels were significantly associated with lower rates of hospital discharge before day 29 and a higher model performance (AUC at day 29 of 92%) compared to models without sST2. sST2 emerged as an independent predictor of clinical outcomes in two large cohort of hospitalized COVID-19 patients, warranting further investigation to elucidate its role in disease progression and potential as a therapeutic target
Physicochemical stability of a polysorbate-80-containing solvent compounded in the hospital pharmacy and used to reconstitute a biologic for nebulisation.
No full textInternational audienceObjectives To assess the long-term physicochemical stability of a solvent (10 mM phosphate buffer pH 6.5 containing sodium chloride (145 mM) and polysorbate 80 (PS80) 0.02%) used to reconstitute a biologic for nebulisation. The solvent was compounded in the hospital pharmacy and stored in amber glass vials at −20°C for 1 year.Methods Samples were analysed immediately on compounding and then 1, 3, 6, 9 and 12 months after storage at −20°C (immediately after thawing, and also 1 month later keeping the vials at 2–8°C). The assays included a visual examination, measurement of the pH, osmolality, sub-visible particulate contamination, the concentration of PS80, and the concentration of oleic acid and peroxides (both major markers of PS80 degradation). Quantification of PS80 was challenging due to the substance’s molecular heterogeneity and the lack of a good chromophore. The strategy adopted consisted of hydrolysis in a strong base and then liquid-liquid extraction of the oleic acid (PS80’s hydrolysis product). The oleic acid content was determined using reversed phase high performance liquid chromatography with ultraviolet detection. The peroxide content was determined spectrophotometrically using a ferrous oxidation with xylenol orange assay.Results Over 12 months, there was no significant change in the samples’ visual appearance, pH and osmolality. The PS80 concentration remained above 90% of the initial value. The subvisible particle counts remained far below the European Pharmacopoeia thresholds. The oleic acid content of the non-hydrolysed samples remained constant, and no peroxide was detected.Conclusions A PS80-containing solvent is stable for 1 year when stored at −20°C (±5°C) in amber glass vials. Moreover, the solvent is stable for up to 1 month after thawing if stored at 2–8°C
New Record of Rhipicephalus fulvus (Neumann, 1913) from Goats and Sheep in Northeastern Algeria After more than a Century
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Toward a deeper understanding of dengue: novel method for quantification and isolation of envelope protein epitope-specific antibodies
No full textInternational audienceThe dengue viruses (DENV) envelope (E) protein is the main target of the antibody (Ab) response. Abs target different epitopes on the E-protein, including sE-dimer, E domain III (EDIII), and fusion loop (FL). Anti-EDIII Abs are mainly serotype-specific, whereas anti-FL Abs can induce antibody-dependent enhancement (ADE) in vitro . Abs targeting sE-dimer epitopes can cross-neutralize different DENV serotypes. However, the involvement of each Ab subset in disease pathogenicity and/or protection remains unclear. We aimed to optimize the quantification and purification of DENV E-protein epitope-specific Abs from human samples. C-terminal biotinylated DENV2 E recombinant proteins (EDIII, soluble E [sE], and sE-dimer) were coupled to color-coded magnetic microspheres for a multiplex immunoassay (MIA), testing different antigen concentrations. Assay performance was evaluated using well-characterized anti-DENV monoclonal antibodies (mAbs) and total IgG from DENV seronegative and seropositive human plasma. Specific FL epitopes were blocked with mouse mAb clone 4G2 to quantify anti-FL- and sE-dimer-specific Abs, measuring antigen-antibody reactions as median fluorescence intensity (MFI). For isolation of E-protein epitope-specific antibodies, sE-proteins were conjugated to streptavidin resin beads. Total IgG from human plasma was incubated with immobilized EDIII to elute anti-EDIII Abs. The flow-through was incubated with sE-dimer resin beads to elute sE-dimer specific Ab enriched fraction, and the flow-through was applied to immobilized sE to elute anti-FL Abs. In conclusion, we have developed a serological assay to detect E-protein epitope-specific Abs in DENV-infected humans. Additionally, we successfully isolated anti-EDIII, anti-FL, and an enriched fraction of sE-dimer specific Abs from human samples. IMPORTANCE The development of effective dengue virus (DENV) vaccines has been hampered by limited insights into the immunological mechanisms of protection. Our study addresses this gap by introducing a refined multiplex microsphere-based immunoassay (MIA) to quantify and isolate antibodies (Abs) targeting specific E-protein epitopes, such as E domain III (EDIII), the fusion loop (FL), and the sE-dimer specific Abs. This method provides detailed epitope-specific Ab profiling with high sensitivity and requires minimal sample volumes. The ability to isolate specific Ab subsets from human plasma also enables detailed investigations into their roles in protection or pathogenesis, paving the way for more effective dengue interventions
Rev-erb-α antagonism in alveolar macrophages protects against pneumococcal infection in elderly mice
No full textInternational audienceCircadian rhythms control the diurnal nature of many physiological, metabolic, and immune processes. We hypothesized that age-related impairments in circadian rhythms are associated with high susceptibility to bacterial respiratory tract infections. Our data show that the time-of-day difference in the control of Streptococcus pneumoniae infection is altered in elderly mice. A lung circadian transcriptome analysis revealed that aging alters the daily oscillations in the expression of a specific set of genes and that some pathways that are rhythmic in young-adult mice are non-rhythmic or time shifted in elderly mice. In particular, the circadian expression of the clock component Rev-erb-α and apelin/apelin receptor was altered in elderly mice. In young-adult mice, we discovered an interaction between Rev-erb-α and the apelinergic axis that controls host defenses against S. pneumoniae via alveolar macrophages. Pharmacological repression of Rev-erb-α in elderly mice resulted in greater resistance to pneumococcal infection. These data suggest the causative role of age-associated impairments in circadian rhythms on respiratory infections and have clinical relevance