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An easy and reproducible method for a large-zone deep partial-thickness burn model in the mini-pig
No full textInternational audienceNo abstract availabl
On the potential benefits of entropic regularization for smoothing Wasserstein estimators
No full text54 pages, 12 figuresInternational audienceThis paper is focused on the study of entropic regularization in optimal transport as a smoothing method for Wasserstein estimators, through the prism of the classical tradeoff between approximation and estimation errors in statistics. Wasserstein estimators are defined as solutions of variational problems whose objective function involves the use of an optimal transport cost between probability measures. Such estimators can be regularized by replacing the optimal transport cost by its regularized version using an entropy penalty on the transport plan. The use of such a regularization has a potentially significant smoothing effect on the resulting estimators. In this work, we investigate its potential benefits on the approximation and estimation properties of regularized Wasserstein estimators. Our main contribution is to discuss how entropic regularization may reach, at a lowest computational cost, statistical performances that are comparable to those of un-regularized Wasserstein estimators in statistical learning problems involving distributional data analysis. To this end, we present new theoretical results on the convergence of regularized Wasserstein estimators. We also study their numerical performances using simulated and real data in the supervised learning problem of proportions estimation in mixture models using optimal transport
Hierarchical folding-upon-binding of an intrinsically disordered protein
No full textInternational audienceIntrinsically disordered proteins (IDPs) often undergo folding-upon-binding to their partners via short linear motifs, typically 5-15 amino acids in length. However, a significant proportion of IDPs do not adhere to this paradigm but fold upon binding through extended regions comprising multiple molecular recognition elements. For these IDPs, the binding mechanisms and the structural characteristics of their folding intermediates remain poorly understood. Here we unveil hierarchical folding of an IDP as it binds to its partner, exemplified by the disordered signaling effector POSH and the small GTPase Rac1. By combining nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography, we resolve at atomic resolution how POSH transitions from a fully disordered state to a highly ordered, Rac1-bound conformation through two structurally distinct folding intermediates. The folding of each element is contingent on the successful structuring of the preceding element, highlighting a hierarchical folding-upon-binding mechanism. Our work highlights the potential of targeting folding intermediates and conformational transitions to unlock therapeutic opportunities for IDPs
Traveling Waves in a Hybrid Reaction‐Diffusion‐Difference SEIR Epidemic Model With Nonlocal Transmission and Protection Phase With Delay
No full textInternational audienceIn this paper, we study the existence and non‐existence of traveling waves for a SEIR epidemic model with diffusion. This system is coupled to an age‐structured protection equation that takes into account a proportion of susceptible individuals who protect themselves from the disease through medical treatment or vaccination with temporary immunity, for example. The model includes a compartment of exposed individuals to represent diseases with an incubation period. In addition, the model contains a nonlinear saturated incidence rate to describe the interaction between susceptible and infected individuals. By solving the equation associated with the exposed compartment, we obtain a nonlocal integral representation of the exposed population as a function of the nonlinear incidence rate. This reformulation reduces the model to an hybrid system of reaction‐diffusion equations coupled to a continuous difference equation that includes a delay and a nonlocal term, reflecting the movement of individuals during the protection and exposure phases. For wave speeds above a certain threshold, we construct lower and upper solutions for the resulting hybrid system. Finally, we apply Schauder's fixed point theorem in an appropriate function space to establish the existence of progressive wave solutions
Prenatal and prepubertal exposures to organochlorine compounds and perfluoroalkyl substances and pubertal development at age 12: The PELAGIE cohort study
No full textInternational audienceBackground: Emerging evidence suggests that prenatal and prepubertal exposure to organochlorine compounds (OCs) and perfluoroalkyl substances (PFASs) is associated with children's reproductive health. This study examines the potential impact of these exposures on pubertal development in 12-year-old children.Methods: Based on the French PELAGIE mother-child cohort, concentrations of OCs and PFASs were measured in cord blood (from 2003 to 2006) and in blood at age 12 (from 2016 to 2018). Medical staff assessed pubertal development (Tanner stages) at age 12, and girls self-reported age at menarche annually (ages 9-16). Associations between exposures and delayed or earlier pubertal development were analyzed using multinomial logistic and Cox regression models, adjusting for confounders, and using quantile g-computation for compound mixtures.Results: Among 502 children (250 girls, 252 boys; median age: 12.8 years), prenatal PFUdA exposure in girls was associated with delayed breast development [OR (95 %CI): 2.05 (1.03,4.06)]. In boys, prenatal PFHxS exposure was associated with reduced risk of earlier gonadal development [0.47 (0.26,0.83)], and β-HCH with reduced risks of both delayed [0.66 (0.43,0.99)] and earlier [0.69 (0.48,0.97)] pubic hair development. Prepubertal exposure in girls to HCB, PCBs, and PFASs was associated with increased risk of delayed breast development [e.g., pfoa: 2.53 (1.04,6.12)] and later age at menarche [e.g., ΣPCBs: HR 0.77 (0.61,0.97)]. In boys, prepubertal p,p'-DDE was associated with increased risk of earlier puberty [gonadal development: 1.77 (1.09,2.88); pubic hair growth: 1.56 (1.01,2.44)], while PCB-118 was associated with delayed development. Prepubertal PFASs were associated with reduced risk of earlier puberty [e.g., PFHxS-gonadal stages: 0.39 (0.20,0.75)]. In mixture analyses, no associations were observed with regards to prenatal exposure, but prepubertal exposure was associated with delayed pubertal development in girls.Conclusion: Prenatal and prepubertal exposure to OCs and PFASs may alter pubertal development at age 12 in girls and boys, underscoring the need for further research
Cushing syndrome
No full textInternational audienceCushing syndrome (CS) is a constellation of signs and symptoms caused by excessive exposure to exogenous or endogenous glucocorticoid hormones. Endogenous CS is caused by increased cortisol production by one or both adrenal glands (adrenal CS) or by elevated adrenocorticotropic hormone (ACTH) secretion from a pituitary tumour (Cushing disease (CD)) or non-pituitary tumour (ectopic ACTH secretion), which stimulates excessive cortisol production. CS is associated with severe multisystem morbidity, including impaired cardiovascular and metabolic function, infections and neuropsychiatric disorders, which notably reduce quality of life. Mortality is increased owing to pulmonary emboli, infection, myocardial infarction and cerebrovascular accidents. The clinical presentation is variable and because some CS signs and symptoms are common in the general population, the diagnosis might not be considered until many features have accumulated. Guidelines recommend screening patients with suspected CS with 24-h urine cortisol, bedtime salivary cortisol and/or 1 mg dexamethasone suppression test. Subsequently, determining the aetiology of CS is important as it affects management. The first-line therapy for all aetiologies of endogenous CS is surgical resection of the causal tissue, including corticotroph adenoma or ectopic tumour for ACTH-dependent CS or unilateral or bilateral adrenalectomy for adrenal CS. Second-line therapies include steroidogenesis inhibitors for any cause of CS, pituitary radiation (with or without steroidogenesis inhibitors) for CD, and bilateral adrenalectomy for ACTH-dependent causes of CS
Combination of Orai1 inhibitor CM5480 with specific therapy mitigates pulmonary hypertension and its cardiac dysfunction
No full textInternational audiencePulmonary arterial hypertension (PAH) is a rare and incurable disease characterized by progressive narrowing of pulmonary arteries (PA), resulting in right ventricular (RV) hypertrophy, RV failure, and eventually death. Orai1 inhibition has emerged as promising therapeutic approach to mitigate PAH. In this study, we investigated the efficacy of a clinically applicable selective Orai1 inhibitor, CM5480, and its effects when combined with standard PAH therapies in a preclinical PAH model. In male and female monocrotaline PAH-rats, CM5480 monotherapy improved hemodynamics, PA, and RV remodeling, as confirmed by RV catheterization, echocardiography, histology, and unbiased RNA-Seq. Standard PAH therapies, ambrisentan or sildenafil, achieved modest improvements in experimental PAH. In contrast, combination therapies with CM5480 yielded significantly greater benefits in reducing PA remodeling and improving cardiac function compared with monotherapies. Furthermore, in vitro experiments showed that Orai1 knockdown reduced pulmonary endothelial cell dysfunction in PAH and that the Orai1 pathway is independent of standard PAH-targeted pathways in PA smooth muscle cells (PASMCs). Finally, we found enhanced Orai1 expression/function in PASMCs and pulmonary vein SMCs from patients with pulmonary veno-occlusive disease. These findings suggest that Orai1 inhibition represents a potentially novel and complementary therapeutic strategy for PAH by acting at pulmonary vascular and RV levels
Distinct molecular profiles characterize the spontaneous growth rate of IDHmt low-grade astrocytomas and oligodendrogliomas
No full textInternational audienceBackground: The life expectancy of patients with diffuse IDH-mutant low-grade gliomas (IDHmt LGG) ranges from 5 to over 20 years. Tumor behavior, including spontaneous growth rate, varies even within homogeneously classified subtypes of oligodendroglioma and astrocytoma. Risk-adjusted treatment strategies are needed to avoid therapy-related toxicities, without compromising outcome. The spontaneous tumor volume growth rate (TVGR) serves as a prognostic marker and predicts response to therapy. Accurate prediction of TVGR through biomarkers would enable an improved evidence-based risk management.Patients & methods: A cohort of 77 patients treated in Montpellier, France, for IDHmt LGG grade II (WHO 2016) (29 oligodendrogliomas, 48 astrocytomas) was constituted (age >18 years; MRI scans, frozen tumor tissue). The DNA methylome (Illumina, EPIC array) and transcriptome (RNAseq) were established. TVGR was determined based on serial MRIs collected over the "watch & wait" period before first treatment beyond surgery. Transcriptomic and methylome data were analyzed for signatures associated with TVGR using rank-rank regression followed by preranked gene set enrichment analysis.Results: : The median TVGR was lower in IDHmt codeleted compared to non-codeleted LGG, (0.241 year-1 range 0.082-0.366 vs 0.424 year-1 range 0.264-0.609, p < 0.001). In codeleted IDHmt LGG, TVGR was associated with upregulated gene signatures for neuronal systems, synaptic activity, and activation of repressed or poised signatures of neural progenitor cells; while the TVGR in non-codeleted IDHmt LGG was dominanted by upregulated proliferation-related signatures, including DNA replication and repair.Conclusion: Spontaneous TVGR of codeleted and non-codeleted IDHmt LGG involve distinct biological processes, suggesting possible differences in response to therapies
Virtual reality-based cognitive rehabilitation programme to support employment in patients with breast cancer: protocol for the Cog-RV pilot study
No full textInternational audienceIntroduction Cancer-related cognitive impairment is frequently reported by patients with breast cancer after chemotherapy. These difficulties can hinder return to work. It is therefore particularly important to assess and manage these impairments, especially to facilitate employment. We propose the Cog-VR pilot study to assess patient adherence to a virtual reality (VR)-based cognitive rehabilitation programme to support employment. Methods and analysis This prospective interventional pilot study aims to assess adherence to a VR-based cognitive rehabilitation programme in patients with breast cancer (n=23) treated by chemotherapy reporting cognitive complaints following cancer and its treatments. The programme consists of six weekly individual sessions (1 hour/week), including cognitive training, psychoeducation and VR immersion (10–15 min). VR tasks train executive functions, attention, memory and processing speed. The primary endpoint is the programme adherence, defined as completing at least five out of six VR sessions, each lasting a minimum of 5 min. The main secondary endpoints are objective cognitive tests and patient-reported outcomes (subjective cognitive functioning (Functional Assessment of Cancer Therapy—Cognitive Scale), anxiety/depression (Hospital Anxiety and Depression Scale) and fatigue (Functional Assessment of Chronic Illness Therapy—Fatigue)) assessed before and after the programme. Furthermore, cyber sickness (Simulator Sickness Questionnaire) at each session, VR usability (System Usability Scale—third session) and patient satisfaction to the programme will also be assessed. Ethics and dissemination The study was approved by the local ethics committee (French Ouest II personal protection committee no. ID RCB: 2023-A02163-42) on January 2024. It was validated by the review board of the participating center. An individual participant data-sharing statement is not planned. Written informed consent will be obtained from all patients before any study procedure. The results of this pilot study will be disseminated through peer-reviewed journals and conference presentations. Trial registration number NCT06267014
Combined pharmacological targeting of CD9+ progenitors alleviates obesity-induced adipose tissue fibrosis and metabolic impairment
No full textInternational audienceAbstract Chronic kidney disease (CKD) is a complex and progressive condition ultimately leading to premature death. Diabetes is the leading cause of end-stage kidney disease worldwide. Up till 2024, international clinical guidelines have established three therapeutic pillars to delay CKD progression in people with type 2 diabetes (T2D): renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors, and the non-steroidal mineralocorticoid receptor antagonist finerenone. With the recent results from the Evaluate Renal Function with Semaglutide Once Weekly study, the glucagon-like peptide-l receptor agonist (GLP-1 RA) class is now considered a new therapeutic pillar in reducing CKD complications in this patient population. In this expert opinion, we identify patient populations at risk of developing new onset or worsening pre-existing CKD to explore optimal therapeutic strategies, introducing GLP-1 RAs. We highlight the important challenges that remain in optimising, sequencing, and combining these four therapeutic pillars. Even though the conventional approach of combining the pillars has been based on the historical emergence of evidence, we discuss the factors that would influence physicians’ decision for preferring one pillar over another, and for selecting a certain combination, whether performed simultaneously or sequentially. These factors include the grade of CKD and the level of albuminuria; diabetic control (glycaemia); comorbidities: atherosclerotic cardiovascular disease, heart failure, obesity; concomitant medications; biological variables: potassium serum levels. The efficacy and safety profiles of each pillar, as demonstrated in landmark trials that have clearly shown the nephroprotective effects, along with real-world data, should also be carefully considered when selecting the most appropriate therapeutic option