Estimating the parameters in mixtures of circular and spherical distributions

In this thesis we compare various methods for estimating the unknown parameters in mixtures of circular and spherical distributions. We study the von Mises distribution on the circle and the Fisher distribution on the sphere. We propose a new method of estimation based on the characteristic function and compare it with the classical methods based on maximum likelihood and moments. Thus far these methods have only been successfully applied to distributions on the line. Here we show that the extension to circular and spherical distributions is reasonably straightforward and convergence to the final estimates is fairly rapid. We apply these methods to various simulated and real data sets and show that the results obtained for the mixture of two von Mises distributions are satisfactory but generally depend on the sample size and method of estimation used. However, results obtained for the mixture of two Fisher distributions show that maximum likelihood performs best overall

RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease

[EN]Objective Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD. Design RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3(-/-)) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks. Results RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3(-/-) mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3(-/-) mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor. (PPAR.) was increased in Ripk3(-/-) mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPAR. in controlling fat deposition and fibrosis. Conclusion Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.Main funding is provided by FEDER funds through the COMPETE programme and by national funds through Fundacao para a Ciencia e a Tecnologia to CMPR (grants SAICTPAC/0019/2015-LISBOA-01-0145--FEDER-016405 and PTDC/MED-FAR/29097/2017 -LISBOA-01-0145-FEDER-029097). Additional funding comes from research grant APEF (Portuguese Association for the Study of Liver)/BAYER 2020 to MBA. JG is funded by the Fondation pour la Recherche Medicale (ARF20170938613), the Institute of Cardiometabolism and Nutrition (PAP17NECJG), the Societe Francophone du Diabete (R19114DD) and the Mairie de Paris (Emergences -R18139DD). MBA, PMR, MMP and ALS were investigators or students funded by Fundacao para a Ciencia e a Tecnologia

Multi-Institutional Evaluation of Pathologists' Assessment Compared to Immunoscore.

BACKGROUND The Immunoscore (IS) is a quantitative digital pathology assay that evaluates the immune response in cancer patients. This study reports on the reproducibility of pathologists' visual assessment of CD3+- and CD8+-stained colon tumors, compared to IS quantification. METHODS An international group of expert pathologists evaluated 540 images from 270 randomly selected colon cancer (CC) cases. Concordance between pathologists' T-score, corresponding hematoxylin-eosin (H&E) slides, and the digital IS was evaluated for two- and three-category IS. RESULTS Non-concordant T-scores were reported in more than 92% of cases. Disagreement between semi-quantitative visual assessment of T-score and the reference IS was observed in 91% and 96% of cases before and after training, respectively. Statistical analyses showed that the concordance index between pathologists and the digital IS was weak in two- and three-category IS, respectively. After training, 42% of cases had a change in T-score, but no improvement was observed with a Kappa of 0.465 and 0.374. For the 20% of patients around the cut points, no concordance was observed between pathologists and digital pathology analysis in both two- and three-category IS, before or after training (all Kappa < 0.12). CONCLUSIONS The standardized IS assay outperformed expert pathologists' T-score evaluation in the clinical setting. This study demonstrates that digital pathology, in particular digital IS, represents a novel generation of immune pathology tools for reproducible and quantitative assessment of tumor-infiltrated immune cell subtypes

Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort

Necroptosis : a new therapeutic target in Non-Alcoholic Steatohepatitis

La progression de la NAFLD vers le stade de la NASH est positivement corrélée à la mort des hépatocytes. La nécroptose, une voie de mort programmée, a récemment été identifiée comme un acteur de cette progression. Cette thèse dresse le potentiel des médiateurs de la nécroptose RIPK1, RIPK3 et MLKL comme cibles thérapeutiques de la NAFLD. Méthodes : L’expression hépatique et les concentrations plasmatiques de RIPK1, RIPK3 et MLKL ont été évaluées chez les patients atteints de la NAFLD. Des souris C57/BL6J développant une NAFLD ont été traitées par RIPA-56, un inhibiteur de RIPK1, pendant 12 semaines (PRO) ou 4 semaines (CUR). Des souris Ripk3-/- sous régime CDAA ont été euthanasiées à 32 ou 66 semaines afin de clarifier l’impact de RIPK3 dans le développement de la NAFLD. De plus, des cultures primaires d’hépatocytes humains stéatosiques ont été traités par RIPA-56 ou NSA, un inhibiteur de MLKL. L’invalidation de MLKL dans une lignée hépatocytaire murine AML-12-MLKL-KO a permis d’élucider son implication dans le métabolisme des lipides. Résultats : L’inhibition de RIPK1 entraîne une régulation négative des médiateurs RIPK3 et MLKL dans le foie. La stéatose, la cytolyse hépatique, l’inflammation et la fibrose sont drastiquement diminués (CUR), voire normalisés (PRO). Les expériences in vitro sont en accord avec ces résultats. La lignée AML-12-MLKL-KO et les souris RIPK3-/- ont une respiration mitochondriale et une β-oxydation améliorées. Chez l'humain, l’expression de RIPK3 corrèle positivement avec les scores d’inflammation et de fibrose. Conclusion : Inhiber la voie de la nécroptose empêche le développement de la NASH.In NAFLD, hepatocytes can undergo necroptosis: a regulated form of necrotic cell death mediated by RIPK1. Herein, we assessed the potential of RIPK1, RIPK3 & MLKL to act as therapeutic targets in NAFLD. Methods: The effect of RIPA-56, a specific inhibitor of RIPK1, was evaluated in HFD-fed mice and in primary human steatotic hepatocytes (PHH). Wild-type or Ripk3-/- mice were fed a CDAA diet or an isocaloric control diet for 32 and 66 weeks. RIPK1, RIPK3 & MLKL concentrations were measured in the serum of patients with NAFLD. RIPK1, RIPK3 and MLKL mRNA levels were measured in patients with variable NAFLD severity. Results: When used as either a prophylactic or curative treatment, RIPA-56 caused a downregulation of MLKL and a reduction of liver injury, inflammation and fibrosis, characteristic of NASH, as well as of steatosis. This effect was reproduced by treating PHH with RIPA-56 or NSA (an inhibitor of MLKL), and by knockout of MLKL in fat-loaded AML-12 mouse hepatocytes. MLKL-KO led to activation of mitochondrial respiration and an increase in β-oxidation in steatotic hepatocytes. Along with decreased MLKL activation, RIPK3-/- mice exhibited increased activities of the liver mitochondrial respiratory chain complexes in experimental NASH. In patients with NAFLD, serum concentrations of RIPK1, RIPK3 & MLKL increased in correlation with activity. RIPK3 expression gradually increased with histological severity and correlated with inflammation grade and fibrosis stage. Conclusion: RIPK1 inhibition improves NASH features and reverses steatosis via an MLKL-dependent mechanism that partly involves an increase in mitochondrial respiration

Les mécanismes de mort cellulaire dans la stéatohépatite non alcoolique

La mort hépatocellulaire chronique et l’inflammation qui en résulte sont des évènements clés dans la progression de la stéatose hépatique non alcoolique (NAFL) vers la stéatohépatite non alcoolique (NASH). La NASH est un état sévère de la maladie qui est associé au développement de la fibrose et qui peut à terme évoluer vers la cirrhose et le cancer du foie. L’apoptose a initialement été étudiée comme cible potentielle pour réduire la mort des hépatocytes dans la NASH. Cependant, des études récentes suggèrent que l’inhibition des caspases est inefficace pour traiter les patients atteints de NASH et pourrait même aggraver la maladie en redirigeant les hépatocytes vers d’autres voies de mort cellulaire. De nouvelles formes de mort cellulaire dites lytiques ont récemment été identifiées et induisent de fortes réponses inflammatoires causées par la perméabilisation des membranes cellulaires. Le contrôle de ces voies de mort lytiques offre par conséquent de nouvelles opportunités thérapeutiques pour traiter la NASH. Cette revue résume les mécanismes moléculaires déclenchant l’apoptose et les voies de mort lytiques, parmi lesquelles la nécroptose, la pyroptose et la ferroptose, et discute de leur pertinence dans la NASH

Review on Recent Applications of Cold Plasma for Safe and Sustainable Food Production: Principles, Implementation, and Application Limits

International audienceThe food and agricultural industries have numerous practical advantages to be gained from the use of cold plasma technology. This paper attempts to showcase the possible uses of cold plasma in the food sector, while also highlighting the most recent developments and market trends. The efficiency of cold plasma in enhancing food products' quality and shelf life has been demonstrated in several investigations. This review has concentrated on current research into how this technology affects various food chain production stages. Cold plasma has become a cutting-edge non-thermal technique that can be used to ensure food safety. The precise mechanism underlying the effectiveness of cold plasma is still unclear. Understanding these mechanisms and potential elements that can restrict or increase their effectiveness and results is crucial to further enhancing and implementing cold plasma treatment in food processing. The main objective of this review is to investigate the use of plasma, its exceptional characteristics, and its advantages in safe, sustainable food production. In particular, this review summarizes recent studies on the use of cold plasma for microorganisms and pesticides treatment, compiling them and discussing their content. As reported in the literature, a critical point has also been reviewed about some diverse plasma configurations. A comparative study of the efficacy of cold plasma in environmental applications (microorganisms/pesticides) has also been reviewed from the literature

Culture-negative necrotizing otitis externa: diagnosis and management

Abstract Objective We aim to describe the clinical features and therapeutic management of necrotizing otitis externa (NOE) with negative culture. Patients and methods We included all patients with NOE, who were treated in the period between 2008 and 2020 in our department. Results A total of 25 cases of NOE were included. The result of the culture was negative in 13 cases (52%). All patients received a local treatment prior to hospitalization, and eight patients (61.5%) received oral antibiotic. A sampling of the otorrhea was done for all patients. Fungal serology was performed for six patients; it was positive in two cases. The prescribed first-line was ciprofloxacin in combination with ceftazidime for 10 patients, while it was based on the use of imipenem with ciprofloxacin for 2 patients and one patient only received ciprofloxacin. An improvement was noted in 10 cases (77%). The second-line treatment in the three cases of resistance was imipenem with ciprofloxacin in one case. For the two patients with a positive aspergillus serology, one patient received teicoplanin, fusidic acid, imipenem, and voriconazole and the other patient received voriconazole. The total duration of the treatment was a minimum of 6 weeks. An improvement was noted in all cases, and recurrence was noted in 3 cases. Conclusion In our study, there were no clinical or radiological specificities noted in NEO with negative culture. Sampling must be repeated. Fungal origin should be suspected in refractory forms and empiric antifungal treatment may be useful