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Transcriptomic and Functional Comparison of Cells Isolated From Healthy and Degenerated Ovine Intervertebral Discs
No full textInternational audienceIntervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain, yet its cellular and molecular mechanisms remain incompletely understood. Sheep represent a valuable in vivo and ex vivo model for IVDD due to their anatomical and biomechanical similarities with humans and the possibility to access disc samples at early stages of degeneration. In vitro, isolated annulus fibrosus (AF) and nucleus pulposus (NP) cells may provide insights into age-associated degenerative processes; this work investigates how well they capture senescence and metabolic alterations observed in vivo. Transcriptomic profiling of AF and NP cells from healthy young lambs and mildly degenerated aged sheep revealed distinct age-and tissuespecific signatures, with upregulation of inflammatory mediators, ECM-remodelling enzymes, and senescence-associated genes in aged cells. Cross-species deconvolution using a human single-cell RNA-sequencing reference confirmed conserved transcriptional modules between aged sheep and human degenerated discs, underscoring the model's translational relevance. However, functional assays demonstrated comparable responses of young and aged cells under basal conditions and after exposure to pro-degenerative stressors (IL-1β, senescence induction). Altogether, these findings validate sheep cells as a suitable in vitro model for studying disc degeneration mechanisms and for preclinical testing, although aged donors offer no clear additional functional benefits
Spatiotemporal cellular dynamics of the notochord shape intervertebral disc morphogenesis in the mouse embryo through apoptosis and proliferation
No full textInternational audienceBackground: The notochord is a midline structure essential for vertebrate embryogenesis, contributing to the development of the nervous system, digestive tract, and vertebral column. In particular, notochord signaling is indispensable for proper patterning and coordinated development of alternating vertebrae and intervertebral discs (IVDs). Later, notochordal cells (NCs) mature and adopt a characteristic vacuolated morphology before giving rise to the core of the forming IVD, the nucleus pulposus (NP). Postnatally, NCs play a pivotal role in maintaining disc integrity through the secretion of specific factors and extracellular matrix (ECM). Despite its importance in disc formation and homeostasis, the morphogenetic mechanisms underlying the notochord's transformation into the NP are insufficiently characterized.Results: We conducted a comprehensive histological and immunohistochemical analysis to investigate the cellular events governing NP formation in the mouse developing spine. Temporal analysis of intracytoplasmic vacuole formation using Lamp-1 marker revealed that vacuolation contributed to NP growth, while cell density progressively decreased. In addition, quantitative analyses demonstrated a notable proliferative capacity within notochordal cells coupled with region-specific apoptotic activity in sclerotome, at future disc sites.Conclusions: This study highlights the intricate balance of cellular proliferation, programmed cell death, matrix remodeling, and vacuolation dynamics as key determinants in shaping the NP along the rostro-caudal axis
An innovative analytical approach for a comprehensive overview of internal exposure to pesticides
No full textPlant protection products used in agriculture contain molecules specifically designed to be toxic to target organisms. However, their use can also have unintended effects, posing potential risks to ecosystems and non-target organisms, including humans. Research has deepened our understanding of the links between exposure to these substances and the effects observed in the environment. In particular, studies have highlighted how even low levels of exposure can cause chronic effects on non-target organisms and disrupt ecosystems. These findings underscore the importance of quantifying and characterising these exposures in order to better assess their potential impacts on human health and the environment.International audienceHuman exposure to contaminants, including pesticides, is generally estimated using indirect methods. Conventional biomonitoring methods remain focused on a limited number of known substances, leaving the risks associated with multiple exposures currently underexplored.We propose an innovative approach to detect as many pesticide exposure markers as possible in an untargeted manner by combining three complementary mass spectrometry platforms coupled with chromatography. This approach, based on the exposome concept (Wild, David), allows us to produce exposure data on a wide range of pesticides and metabolites by screening a broad panel of exposure markers. The results demonstrate the added value of this approach, applied to two epidemiological studies (PELAGIE and Nutrinet-Santé), to test for associations with health parameters.</p
De nouveaux alliés du bien-être des animaux confrontés aux défis des transitions agroécologiques et climatiques
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Essai de mise au point d'un nouveau milieu de réfrigération du sperme de cheval
No full textCette thèse est une étude comparative de mobilités totale et progressive de spermatozoïdes d’étalon après réfrigération dans 8 milieux : Hippex, Hippex RH, TH, plus, Prime, INRA96 (témoin), Beyond® et Equiplus. Les analyses sont faites dans les mêmes conditions de préparation et stockage, sur 22 éjaculats issus de 7 sujets de 3 à 16 ans et de races différentes. Après prélèvement, la mobilité moyenne est de 64,8% à T0. La semence était centrifugée, puis diluée dans les milieux respectifs à une concentration de 100 millions de spermatozoïdes/mL et les tubes stockés à +4°C. Toutes les 24h, 100µl de chaque tube est extrait et placé dans un tube Eppendorf à l’étuve à +37°C avant analyse de la mobilité avec l’analyseur CASA. A T48h, la mobilité des spermatozoïdes obtenue est 44,5+/-17,1% dans l’INRA96, 24,1+/-15% dans le Beyond®, 32,7+/-16,7% dans l’Equiplus, 26,5+/-23,1% dans l’Hippex, 24,5+/-19% dans l’HippexPlus, 19,5+/-20,1% dans l’HippexPrime, 28,9+/-21,3% dans l’HippexTH, 28,9+/-19% dans l’HippexRH. L’INRA96 était plus performant, la comparaison par paire révélant des différences significatives avec les milieux Beyond®, Hippex, Plus, Prime et RH. Sur la mobilité progressive, les moyennes obtenues sont 17,8+/-13,1% dans l’INRA96, 6,4+/-4,7% dans le Beyond®, 14,7+/-12,6% dans l’Equiplus, 13,3+/-12,6% dans l’Hippex, 12,3+/-11,3% dans l’HippexPlus, 7,6+/-9,9% dans l’HippexPrime, 15,5+/-12,7% dans l’HippexTH et 15,1+/-11,9% dans l’HippexRH. Chez certains sujets, l’essai a montré une meilleure mobilité dans l’INRA96, dès 48 heures et de plus de 30% après 96 heures. L’Hippex, l’Hippex Plus, RH et TH sont compatibles avec une réfrigération de 48 heures pour deux chevaux de l’essai
An Exploration of the Breast Milk Nutriome, Exposome and Microbiome and their Links to Early Growth in Preterm Infants
No full textInternational audienceBackground: Breastfeeding promotes improved growth and development in preterm infants, yet the mechanisms underlying these benefits remain unclear.Objective: This study explored the interplay of breast-milk nutritional, microbiological, and environmental chemical exposure on early preterm infant growth.Methods: In the prospective LACTACOL-cohort, growth was assessed in 137 exclusively breastfed preterm infants (including 40 twins) using Z-scores of discharge weight and fat-free mass (FFM, by air-displacement plethysmography). Breast-milk samples were analyzed for their nutriome (targeted and untargeted metabolomic and lipidomic profiling), exposome (targeting persistent organic pollutants, POPs), and microbiome (16s rRNA-sequencing). Correlation analysis and sequential random forest modelling were applied to integrate multi-omics datasets and identify determinants of discharge weight Z-score (36 observations) and FFM (21 observations).Results: The nutriome emerged as the primary contributor to the postnatal growth in preterm infants. Choline-containing lipids (sphingolipids, phosphatidylcholines and their plasmalogen forms), positively contributed to weight Z-score. Sphingomyelin enriched in nervonic acid supported positively FFM Z-score, whereas oxylipins had a negative effect. The exposome exhibited complex effects: the dioxin-like compound 1,2,3,7,8-PeCDD negatively impacted weight, while the polychlorinated biphenyl 123 positively influenced both weight and lean mass gains. Brominated flame retardants were associated with a lower FFM Z-score. Although the microbiome showed an overall minor impact, it varied with POPs and postnatal growth terciles, highlighting the co-dependencies between milk components.Conclusions: This integrative hypothesis-generating pilot study provides novel evidence on the richness of breast-milk composition and the interplay of nutriome, exposome, microbiome in breast-milk and their joint influence on postnatal growth in preterm infants.Clinical trial registry: LACTACOL, ClinicalTrials.gov ID NCT NCT01493063 https://clinicaltrials.gov/study/NCT01493063
High throughput sequencing in the diagnosis and surveillance of tick-borne diseases: A narrative review
No full textInternational audienceTicks are blood-feeding arthropods that can transmit a wide variety of microorganisms (bacteria, viruses, protozoa, and filarial nematodes) when they feed on various vertebrate hosts. In the recent years, high-throughput sequencing (HTS), also called next-generation sequencing, has become a key tool for detecting and characterizing microorganisms, whether they are pathogens or part of the tick's own microbiota. This narrative review summarizes current applications of HTS for the surveillance and diagnosis of tick-borne diseases within a One Health framework.From nucleic acids extracted from a tick sample, HTS enables the possibility of simultaneous detection of multiple microorganisms, and provides valuable information on potential reservoir hosts through blood meal analysis. It has revealed a vast diversity of bacterial, viral, protozoan agents and filarial nematodes in various tick species worldwide, including unexpected or novel pathogens. HTS has also improved our understanding of the tick microbiota and how it interacts with pathogens, which could have an impact on vector competence.In the field of microbiological diagnosis, HTS provides a complementary or alternative approach to traditional diagnostic tests, particularly in cases with non-specific symptoms or when the etiology is unknown. HTS has proven to be effective in detecting rare or novel pathogens, including some transmitted by ticks. It has also enabled the reconstruction of whole genomes of microorganisms from clinical samples or ticks, thereby improving our understanding of the molecular epidemiology of these agents.By bridging the vector, its pathogens, the reservoir host, and human or animal clinical outcomes, HTS represents a cornerstone technology for future integrated surveillance systems of TBDs within a One Health perspective
MLKL in liver parenchymal cells promotes liver cancer in murine metabolic dysfunction-associated steatotic liver disease
No full textInternational audienceThe rising prevalence of hepatocellular carcinoma (HCC) in the last decade is mostly attributable to the growing epidemic of metabolic dysfunction-associated steatotic liver diseases (MASLD). However, the transition from steatosis to steatohepatitis (MASH) and ultimately to HCC is not fully understood. As an executioner protein of necroptosis, the mixed-lineage kinase domain-like protein (MLKL) has been proposed to contribute to MASH and HCC development. To investigate its role in disease progression, mice whose liver parenchymal cells (LPCs) no longer expressed MLKL (MlklLPC-KO) were compared to their control counterparts (Mlklfl/fl) using an experimental model combining diabetes induction and a high-fat high-sugar diet (HFHSD) for 4, 8, or 12 weeks. Notably, HFHSD failed to induce detectable hepatic necroptosis in Mlklfl/fl mice, with no phosphorylated MLKL observed by Western blot. Both genotypes displayed similar steatosis and mild fibrosis, consistent with comparable MASH severity, and this condition progressed to HCC. Interestingly, the incidence of liver tumors in MlklLPC-KO mice was significantly reduced, which was associated with a delay in the onset of systemic and hepatic inflammation. At the early stage of the disease (4th week), the absence of MLKL in LPCs appeared to confer a protective effect on the liver, reducing metabolic stress, as reflected by a lower ceramide-to- sphingomyelin ratio, along with oxidative stress and DNA damage. Altogether, our data suggest that MLKL in LPCs contributes to HCC initiation in the context of MASH, potentially involving its described non-canonical role within mitochondria, promoting oxidative stress, a cancer hallmark. This study provides new insights into evaluating the therapeutic potential of targeting MLKL, as its inhibition in LPCs may represent an effective strategy for treating MASH-related HCC
Assessing patients’ knowledge and skills after pharmaceutical consultations in interventional cardiology: A competency framework-based approach
No full textInternational audienceBackground: Percutaneous closure of patent foramen ovale or atrial septal defect is associated with procedural risks and requires optimal care management. Providing tailored educational support to patients may help to improve their safety and engagement in the care.Aim: To observe the effect of pharmaceutical consultations on the knowledge and skills of patients undergoing percutaneous closure of patent foramen ovale or atrial septal defect.Methods: Multicentre meetings with healthcare professionals from university hospitals, as well as an expert patient, were organized to develop a patient-centred competency framework. Based on this framework, a consultation guide and information sheet were produced to support patients in acquiring key skills for managing their disease. A total of 31 patients were included in the study, 21 of whom attended both the preoperative and 6-month follow-up pharmaceutical consultations to assess changes in knowledge and skills. Patient satisfaction with the consultation and information sheet was evaluated.Results: The competency framework includes 89 skills for patients with patent foramen ovale and 92 for patients with atrial septal defect. This observational study showed an improvement in knowledge and skills between consultations. For example, knowledge regarding cardiac follow-up improved between the preoperative consultation and the 6-month follow-up, increasing from 3 to 9 (P<0.05). Most patients (90%) preferred to have the consultation before the procedure, as it reassured them and enhanced their engagement with care management. All patients expressed satisfaction with the educational tools provided.Conclusions: Pharmaceutical consultations may support patients to acquire the knowledge and skills necessary for safe and autonomous management of their medical devices after returning home
Real-life use of bone-targeting agents for bone metastases in France between 2009 and 2018: Results of the OPTIMOS study
No full textInternational audienceAim: To determine the use of bone-targeting agents (BTAs) in clinical practice in France and the occurrence of skeletal-related events (SREs) in cancer patients with bone metastases.Methods: This study analysed data, recorded prospectively in a French National Health Insurance database, for patients who had a first diagnosis of bone metastases between 2009 and 2018.Results: A total of 6,663 patients were analysed (mean age 69.7 ± 13.2 years, 53.2 % male) corresponding to 2,363 bone metastases only patients and 4,300 patients with SREs at inclusion. The most frequent primary cancers were breast (15.8 %), prostate (13.4 %), lung (12.6 %) and digestive cancer (10.6 %). Six-hundred and twenty-one patients (9.3 %) were treated with BTAs (52.7 % with denosumab). Median [IQR] time between inclusion and BTA initiation was similar with denosumab (3.3 months [1.2-7.9]) and bisphosphonates (3.3 months [1.2-8.7]). Patients with a SRE at inclusion and early BTA initiation (≤3 months) had a significative lower incidence of a second SRE at 12 months than those with late initiation (13.6 % [95 %CI: 8.1-20.4] vs. 21.6 % [14.8-29.2] respectively; p < 0.001).Conclusion: BTAs are underused in bone metastases patients in France. There is an urgent need to optimise bone metastases management in accordance with ESMO 2020 guidelines