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International audience; Scientific examination of the heart of Blessed Pauline Jaricot—a French missionary figure—was carried out in 2022. As tandem mass spectrometry proteotyping has proven to be valuable to obtain the broad taxonomic repertoire of a given sample without any a priori information, we aimed at exploring the conditions of preservation of the relics and possible conditions of death. Metaproteomics and high-resolution microtomography imaging approaches were combined. A dataset comprising 6731 high-resolution MS/MS spectra was acquired and 968 of these spectra could be assigned to specific peptidic biomolecules. Based on the taxonomical information encompassed by the identified peptide sequences, 5 phyla were identified amongst eukaryota (94% of the biomass): Ascomycota (55%), with the species Aspergillus versicolor, Trichophyton mentagrophytes and Aspergillus glaucus, corresponding to expected cadaverous fungal flora; Chordata (42%), represented by a unique species, Homo sapiens; Streptophyta (3%); and Arthropoda (traces). Bacteria (6% of the biomass) were poorly represented. No trace of embalming substance could be retrieved, nor any pathogens. Imaging evidenced no heart defect nor embalming traces. No evidence that was inconsistent with natural and spontaneous conservation could be retrieved. This study prefigures the power of modern molecular techniques such as paleoproteotyping coupled to microtomography to gain insight into historical relics.

We consider a spatially extended mean-field model of a FitzHugh–Nagumo neural network, with a rescaled interaction kernel. Our main purpose is to prove that its asymptotic limit in the regime of strong local interactions converges toward a system of reaction–diffusion equations taking account for the average quantities of the network. Our approach is based on a modulated energy argument, to compare the macroscopic quantities computed from the solution of the transport equation, and the solution of the limit system. The main difficulty, compared to the literature, lies in the need of regularity in space of the solutions of the limit system and a careful control of an internal nonlocal dissipation.

We consider a reaction-diffusion-reproduction equation, modeling a population which is spatially heterogeneous. The dispersion of each individuals is influenced by its phenotype. In the literature, the asymptotic propagation speed of an asexual population has already been rigorously determined. In this paper we focus on the difference between the asexual reproduction case, and the sexual reproduction case, involving a non-local term modeling the reproduction. This comparison leads to a different invasion speed according to the reproduction. After a formal analysis of both cases, leading to a heuristic of the asymptotic behaviour of the invasion fronts, we give some numerical evidence that the acceleration rate of the spatial spreading of a sexual population is slower than the acceleration rate of an asexual one. The main difficulty to get sharper results on a transient comes from the non-local sexual reproduction term.

In this thesis, we study a spatially organised neuronal network, that is the interactions between two neurons only depend on their positions. If we only consider a relatively small number of cells, the electric activity of each neuron can be modeled with the FitzHugh-Nagumo system. Yet, if we attempt to study the collective behaviour of a more sizeable assembly of neurons, we must find other models, corresponding to a larger scale of observation. Thus, the purpose of this thesis is to establish a rigourous mathematical link between the microscopic FitzHugh-Nagumo model, and macroscopic models which account for the evolution of average electrical quantities at any position in the network.The first step of our strategy consists in deriving a rigourous link between the microscopic model and an intermediary model as the number of neurons tends to infinity. We obtain a partial differential equation, which gives the evolution of the probability density of finding neurons at any time depending on their position and membrane potential. Therefore, it describes a mesoscopic scale of observation of the network.Then, we study the average electrical quantities computed from the mesoscopic model. In order to find a system of equations satisfied by these macroscopic quantities, we consider the regime of strong local interactions. To do so, we provide two different ways of rescaling. Using a relative entropy method, we find a mathematical link between the intermediary model and a reaction-diffusion system. Depending on the rescaling we choose, the diffusion term can be local or non local in space.Finally, we tackle the study of this last change of scale from a numerical analysis viewpoint. In particular, we introduce a discretization of the mesoscopic model which is asymptotic preserving in the regime of strong local interactions. Hence, we can numerically estimate rates of convergence, and we observe some dynamics of the intermediary model.; Dans cette thèse, nous étudions un réseau neuronal spatialement organisé, c’est-à-dire que les interactions entre deux neurones ne dépendent que de leurs positions. Si nous ne considérons qu’un nombre relativement restreint de cellules, l’activité électrique de chaque neurone peutêtre modélisée grâce au système de FitzHugh-Nagumo. Toutefois, si nous cherchons à étudier le comportement collectif d’un groupe de neurones plus nombreux, il devient essentiel de trouver d’autres modèles, correspondant à une échelle d’observation plus grande. L’objectif decette thèse est donc d’établir un lien mathématique rigoureux entre le modèle microscopique de FitzHugh-Nagumo, et des modèles macroscopiques qui donnent l’évolution des quantités électriques moyennes à chaque position dans le réseau.La première étape de notre stratégie consiste à établir un lien rigoureux entre le modèle microscopique et un modèle intermédiaire, en faisant tendre le nombre de neurones vers l’infini. Nous obtenons une équation à dérivées partielles qui donne l’évolution de la densité de probabilité de trouver des neurones à chaque instant en fonction de leur position et de leur potentiel de membrane. Elle décrit alors une échelle mésoscopique d’observation du réseau.Ensuite, nous étudions les valeurs électriques moyennes calculées à partir du modèle mésoscopique. Afin de trouver un système d’équations satisfait par ces quantités macroscopiques, nous considérons le cas où les interactions locales entre neurones sont fortes. Pour cela, nous pro-posons deux redimensionnements possibles. En utilisant une méthode d’entropie relative, nous établissons un lien mathématique entre le modèle intermédiaire et un système de réaction-diffusion. Le terme de diffusion sera local ou non local en espace, selon le redimensionnement que nous aurons choisi.Enfin, nous attaquons l’étude de ce dernier changement d’échelle du point de vue de l’analyse numérique. En particulier, nous présentons une discrétisation du modèle mésoscopique qui préserve l’asymptotique dans le régime des interactions locales fortes. Ainsi, nous sommes capa-bles d’estimer des vitesses de convergence et d’observer des dynamiques du modèle intermédiaire.

In this thesis, we study a spatially organised neuronal network, that is the interactions between two neurons only depend on their positions. If we only consider a relatively small number of cells, the electric activity of each neuron can be modeled with the FitzHugh-Nagumo system. Yet, if we attempt to study the collective behaviour of a more sizeable assembly of neurons, we must find other models, corresponding to a larger scale of observation. Thus, the purpose of this thesis is to establish a rigourous mathematical link between the microscopic FitzHugh-Nagumo model, and macroscopic models which account for the evolution of average electrical quantities at any position in the network.The first step of our strategy consists in deriving a rigourous link between the microscopic model and an intermediary model as the number of neurons tends to infinity. We obtain a partial differential equation, which gives the evolution of the probability density of finding neurons at any time depending on their position and membrane potential. Therefore, it describes a mesoscopic scale of observation of the network.Then, we study the average electrical quantities computed from the mesoscopic model. In order to find a system of equations satisfied by these macroscopic quantities, we consider the regime of strong local interactions. To do so, we provide two different ways of rescaling. Using a relative entropy method, we find a mathematical link between the intermediary model and a reaction-diffusion system. Depending on the rescaling we choose, the diffusion term can be local or non local in space.Finally, we tackle the study of this last change of scale from a numerical analysis viewpoint. In particular, we introduce a discretization of the mesoscopic model which is asymptotic preserving in the regime of strong local interactions. Hence, we can numerically estimate rates of convergence, and we observe some dynamics of the intermediary model.; Dans cette thèse, nous étudions un réseau neuronal spatialement organisé, c’est-à-dire que les interactions entre deux neurones ne dépendent que de leurs positions. Si nous ne considérons qu’un nombre relativement restreint de cellules, l’activité électrique de chaque neurone peutêtre modélisée grâce au système de FitzHugh-Nagumo. Toutefois, si nous cherchons à étudier le comportement collectif d’un groupe de neurones plus nombreux, il devient essentiel de trouver d’autres modèles, correspondant à une échelle d’observation plus grande. L’objectif decette thèse est donc d’établir un lien mathématique rigoureux entre le modèle microscopique de FitzHugh-Nagumo, et des modèles macroscopiques qui donnent l’évolution des quantités électriques moyennes à chaque position dans le réseau.La première étape de notre stratégie consiste à établir un lien rigoureux entre le modèle microscopique et un modèle intermédiaire, en faisant tendre le nombre de neurones vers l’infini. Nous obtenons une équation à dérivées partielles qui donne l’évolution de la densité de probabilité de trouver des neurones à chaque instant en fonction de leur position et de leur potentiel de membrane. Elle décrit alors une échelle mésoscopique d’observation du réseau.Ensuite, nous étudions les valeurs électriques moyennes calculées à partir du modèle mésoscopique. Afin de trouver un système d’équations satisfait par ces quantités macroscopiques, nous considérons le cas où les interactions locales entre neurones sont fortes. Pour cela, nous pro-posons deux redimensionnements possibles. En utilisant une méthode d’entropie relative, nous établissons un lien mathématique entre le modèle intermédiaire et un système de réaction-diffusion. Le terme de diffusion sera local ou non local en espace, selon le redimensionnement que nous aurons choisi.Enfin, nous attaquons l’étude de ce dernier changement d’échelle du point de vue de l’analyse numérique. En particulier, nous présentons une discrétisation du modèle mésoscopique qui préserve l’asymptotique dans le régime des interactions locales fortes. Ainsi, nous sommes capa-bles d’estimer des vitesses de convergence et d’observer des dynamiques du modèle intermédiaire.

International audience; We consider a spatially-extended model for a network of interacting FitzHugh-Nagumo neurons without noise, and rigorously establish its mean-field limit towards a nonlocal kinetic equation as the number of neurons goes to infinity. Our approach is based on deterministic methods, and namely on the stability of the solutions of the kinetic equation with respect to their initial data. The main difficulty lies in the adaptation in a deterministic framework of arguments previously introduced for the mean-field limit of stochastic systems of interacting particles with a certain class of locally Lipschitz continuous interaction kernels. This result establishes a rigorous link between the microscopic and mesoscopic scales of observation of the network, which can be further used as an intermediary step to derive macroscopic models. We also propose a numerical scheme for the discretization of the solutions of the kinetic model, based on a particle method, in order to study the dynamics of its solutions, and to compare it with the microscopic model.

International audience; We introduce a spatially extended transport kinetic FitzHugh-Nagumo model with forced local interactions and prove that its hydrodynamic limit converges towards the classical nonlocal reaction-diffusion FitzHugh-Nagumo system. Our approach is based on a relative entropy method, where the macroscopic quantities of the kinetic model are compared with the solution to the nonlocal reaction-diffusion system. This approach allows to make the rigorous link between kinetic and reaction-diffusion models.

Background Dengue is a major public health concern in pediatric populations in endemic regions. A recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) is under development for the control of dengue with a 3-dose (0-6-12 month) vaccination schedule. Methods In this controlled phase II trial conducted in the Philippines, 210 toddlers aged 12-15 months were randomized to 4 groups: 3 groups received the CYD-TDV vaccination schedule and a measles, mumps and rubella (MMR) vaccine given either concomitantly with the first CYD-TDV dose or 1 month earlier; 1 group received 3 active control vaccines. Safety and reactogenicity were assessed after each dose. Immunogenicity was assessed 30 days after vaccinations using the plaque reduction neutralization test against dengue and enzyme-linked immunosorbent assay methods against MMR antigens. Results Injection site and systemic reactions occurred at similar rates across CYD-TDV groups, except for fever, which was more frequent after CYD-TDV and MMR coadministration (28.8%) compared with other groups (12-20%). Reactogenicity did not increase with subsequent CYD-TDV injections. There were no safety issues with the study vaccine. CYD-TDV achieved a balanced antibody response to all 4 dengue serotypes across the study groups, with geometric mean titers in the range of 105-124, 147-213, 311-387 and 127-160 for serotypes 1, 2, 3 and 4, respectively. CYD-TDV coadministration did not affect MMR immunogenicity (≥95% seroprotection against MMR) and vice versa. Conclusions The CYD-TDV has an acceptable safety and immunogenicity profile in toddlers and when coadministered with MMR.

To characterize the cell mediated immunity (CMI) induced by the investigational CYD tetravalent dengue vaccine (TDV), we developed a whole-blood, intracellular cytokine staining (ICS) assay and a multiplex assay, each requiring 3 mL of blood. We assessed CMI before and 28 d after a first and third injection of CYD-TDV and one year after the third injection in a subset of 80 adolescents and adults enrolled in a phase II trial in Singapore (ClinicalTrial.gov NCT NCT00880893). CD4/IFNγ/TNFα responses specific to dengue NS3 were detected before vaccination. Vaccination induced YF-17D-NS3-specific CD8/IFNγ responses, without significant TNFα, and a CYD-specific Th1/Tc1 cellular response in all participants, which was characterized by predominant IFNγ secretion compared with TNFα, associated with low level IL-13 secretion in multiplex analysis of peripheral blood mononuclear cells (PBMC) supernatants after restimulation with each the CYD vaccine viruses. Responses were directed mainly against CYD-4 after the first vaccination, and were more balanced against all four serotypes after the third vaccination. The same qualitative profile was observed one year after the third vaccination, with approximately 2-fold lower NS3-specific responses, and 3-fold lower serotype-specific cellular responses. These findings confirm previous observations regarding both the nature and specificity of cellular responses induced by CYD-TDV, and for the first time demonstrate the persistence of cellular responses after one year. We also established the feasibility of analyzing CMI with small blood samples, allowing such analysis to be considered for pediatric trials.

Dengue and yellow fever (YF) viruses are closely related members of the Flaviviridae family. Given the inherent similarities between the YF vaccine and dengue vaccine (CYD-TDV) candidate, it is possible that the latter could interfere with the response to the licensed YF vaccine when coadministered.In this randomized, observer-blind, controlled, phase III trial, conducted in Colombia and Peru, 787 toddlers were administered YF vaccine concomitantly with CYD-TDV (group 1) or placebo (group 2), followed by CYD-TDV after 6 and 12 months. YF and dengue neutralizing antibody titers were determined using a 50% plaque reduction neutralization test. Noninferiority was demonstrated if the lower limit of the 2-sided 95% confidence interval of the difference in seroconversion rates [(YF + CYD-TDV) - YF alone] was greater than -10%. The safety of both vaccines was also assessed.Concomitant administration of YF with either CYD-TDV or placebo yielded YF seroconversion rates of 100.0% and 99.7%, respectively. The difference in YF seroconversion rates between the 2 groups was 0.33% (95% confidence interval:0.98; 1.87), demonstrating that the immune response against YF administered concomitantly with CYD-TDV was noninferior to YF administered with placebo. After 2 injections of CYD-TDV, the percentage of participants with dengue titres ≥10 (1/dil) for the 4 dengue serotypes were 91.2%-100% for group 1 and 97.2%-100% in group 2. There were no safety concerns during the study period.Concomitant administration of YF vaccine with CYD-TDV has no relevant impact on the immunogenicity or safety profile of the YF vaccine.

Control/eradication plans of bovine herpesvirus 1 (BHV1) and suid herpesvirus 1 (SHV1) infections involve vaccination with inactivated or attenuated gE-deleted marker vaccines and associated companion serological tests to discriminate naturally infected from vaccinated animals. Blocking or competitive enzyme-linked immunosorbent assays (ELISAs) have been designed for the detection of specific antibodies against BHV1 or SHV1 gE glycoprotein. The antigen source usually consists of a crude viral preparation in which gE is associated with other envelope glycoproteins. Such assays suffer from a lack of specificity which is not due to serological cross-reactions with other pathogens. Interestingly, false-positive results occur with sera collected from multivaccinated cattle or pigs. After multivaccination with a marker vaccine, the binding of the conjugated monoclonal antibody used as a tracer, could be hampered by antibodies directed against the other viral glycoproteins. In order to validate the steric hindrance hypothesis, a simple preadsorption of such samples was carried out with a preparation of antigen devoid of gE, prior to the blocking ELISA itself. The decrease in antibody concentrations against the major glycoproteins, clearly leads to a better discrimination between positive and negative samples; that is between infected and multivaccinated animals, without significant loss of sensitivity. This experiment confirms the steric hindrance hypothesis, therefore serum preadsorption could be an easy way to improve the specificity of currently available diagnostic tests.

A non ouabain-like inhibitor of the sodium pump was separated from uremic plasma ultrafiltrates and normal urine. Under the same chromatographic conditions (C18 column and a gradient of acetonitrile as eluant), ouabain was eluted in a fraction different from the inhibitor. Affinity chromatography based on the formation of a complex between Na,K-ATPase and the inhibitor achieved the differentiation ouabain. Without magnesium and sodium phosphate, ouabain could not bind to enzyme whereas the inhibitor did. A study of Na,K-ATPase enzyme kinetics showed the inhibitor was not competitive for K+, which further differentiates it from ouabain. It was uncompetitive for ATP and seemed competitive for Na+. These results indicate that the inhibitor acts inside the cell, unlike ouabain, and thus its action mechanism appears to be original.

1. Trimetazidine is an anti-ischaemic drug effective in different experimental models but its mechanism of action is not fully understood. Data indicate that mitochondria could be the main target of this drug. The aim of this work was to investigate the binding of [3H]-trimetazidine on a purified preparation of rat liver mitochondria. 2. [3H]-trimetazidine binds to two populations of mitochondrial binding sites with Kd values of 0.96 and 84 microM. The total concentration of binding sites is 113 pmol mg(-1) protein. Trimetazidine binding sites are differently distributed. The high-affinity ones are located on the outer membranes and represent only a small part (4%) of total binding sites, whereas the low-affinity ones are located on the inner membranes and are more abundant (96%) with a Bmax=108 pmol mg(-1) protein. 3. Drug displacement studies with pharmacological markers for different mitochondrial targets showed that [3H]-trimetazidine binding sites are different from previously described mitochondrial sites. 4. The possible involvement of [3H]-trimetazidine binding sites in the regulation of the mitochondrial permeability transition pore (MTP), a voltage-dependent channel sensitive to cyclosporin A, was investigated with mitochondrial swelling experiments. Trimetazidine inhibited the mitochondrial swelling induced by Ca2+ plus tert-butylhydroperoxide (t-BH). This effect was concentration-dependent with an IC50 value of 200 microM. 5. Assuming that trimetazidine effectiveness may be related to its structure as an amphiphilic cation, we compared it with other compounds exhibiting the same chemical characteristic both for their ability to inhibit MTP opening and to displace [3H]-trimetazidine bound to mitochondria. Selected compounds were drugs known to interact with various biological membranes. 6. A strong correlation between swelling inhibition potency and low-affinity [3H]-trimetazidine binding sites was observed: r=0.907 (n=24; P

1. The effects of zidovudine (ZDV) and zidovudine triphosphate (ZDV-3P) on Ca2+-induced mitochondrial permeability transition (MPT), respiratory control ratio (RCR) and ATP synthesis have been investigated on isolated rat liver mitochondria. 2. ZDV slightly but significantly decreased RCR and ATP synthesis but was ineffective in inhibiting MPT. In contrast, ZDV-3P did not alter RCR and ATP synthesis but strongly inhibited MPT (IC50 = 3.0 +/- 0.9 microM). 3. The effect of ZDV-3P on mitochondrial swelling required a preincubation time. When incubated 10 min with mitochondria, ZDV-3P (8 microM) totally inhibited the rate of swelling. 4. ADP, ATP and atractyloside, which are agents known to interact with the mitochondrial adenine nucleotide carrier (ANC), antagonized the effect of ZDV-3P on mitochondrial swelling. Indeed, the IC50 value of ZDV-3P increased from 3.0 to 17.4, 93.6 and 66.5 microM, in the presence of 20 microM, ADP, ATP or atractyloside, respectively. 5. ZDV-3P did not displace [3H]-ATP from its mitochondrial binding site(s) whereas ADP and atractyloside did, suggesting that ZDV-3P and [3H]-ATP do not share the same binding sites. 6. ZDV-3P did not affect either mitochondrial respiration or ATP synthesis but inhibited Ca2+-dependent mitochondrial swelling. It was concluded that mitochondrial toxic effects observed during the chronic administration of ZDV cannot be related to its active metabolite (ZDV-3P).

Introduction: Because of the increased use of im plantable access systems, the incidence of blood stream and catheter infections associated with these systems has concomitantly increased. Classically, he parin-lock flush solutions were used to prevent thrombosis; more recently, vancomycin was added to the solution to prevent infections caused by Gram- positive bacteria, particularly coagulase-negative Staphylococci. Disorders due to Gram-negative organ isms have now appeared in oncologic patients. We therefore tested the addition of colistin to heparin- vancomycin solutions. Colistin was chosen for its good activity against Gram-negative bacteria (98% susceptibility in our hospital), its good tolerance due to low systemic passage, and its low cost. Methods: We developed formulations contain ing heparin (100 IU/mL) and various concentrations of vancomycin (10-500 μg/mL) and colistin (10-100 μg/mL) in 0.9% NaCl. Each sterile solution was tested for physical and chemical compatibility (spectropho tometry, nuclear magnetic resonance, and pH mea surements) and its antibacterial activity (against ox acillin-resistant Staphylococcus aureus, Enterococcus faecium, Klebsiella pneumoniae exhibiting broad- spectrum betalactamase (BSBL), imipenem-resistant Pseudomonas aeruginosa) for 2 months at 4°C and at room temperature. Results: The most suitable combination of drugs is heparin (100 IU/mL), vancomycin (100 μg/mL), and colistin (100 μg/mL). This flush solution main tains activity when stored at 4°C for up to 1 month. Conclusions: We feel that the combination of heparin, vancomycin, and colistin can be used as a flush solution for indwelling catheters.

The sodium pump and Na+/H+ antiport activities in red blood cells from uremic hemodialyzed patients were measured concomitantly. The patients selected (n = 35) were normotensive and free of intercurrent illness known to affect Na transport. The Na pump activity of intact red blood cells in suspension in their own plasma was measured by flow microcalorimetry. The Na+/H+ antiport activity of the erythrocytes from the same patients was determined by a titrimetric technique. The mean global value of the sodium pump was lower in uremics than in controls (13.3 +/- 0.6 vs. 11.3 +/- 0.8 mW/l cells, P0.05). The Na+/H+ antiport maximal activity was decreased in uremics (2.9 +/- 0.3 vs. 4.6 +/- 0.5 mmol H+/l cells/h, P0.05). Our results thus confirm that uremia per se can affect sodium transport. Moreover it has been shown that a decrease in Na+/H+ antiport activity is able to counteract an impairment of sodium pump. The decrease found in this study could thus explain, at least in part, the absence of hypertension in the patients studied despite their decreased sodium pump activity.

The hypothesis of an interaction between trimetazidine and the immunosuppressive effect of cyclosporin A was investigated in two models: a) ex vivo, the lymphoproliferative response of normal human lymphocytes to phytohemagglutinin and a murine monoclonal antibody against the CD3 T-lymphocyte membrane complex; b) in vivo, the delayed hypersensitivity response model in mouse. The uptake of methyl-3H-thymidine was measured in both models. For the lymphoproliferative response, statistical analysis showed that there was a significant inhibitory effect of cyclosporin A on cell proliferation (P < 0.001) and confidence intervals obtained by ANOVA showed the equivalence of the results when trimetazidine was combined with cyclosporin A (all CI95% < or = 10). In the delayed hypersensitivity model, cyclosporin A was also found to be very effective in inhibiting the immune response (P < 0.001), while trimetazidine did not interfere with cyclosporin A's effect. It was concluded that trimetazidine exerted neither an immunostimulatory nor an immunosuppressive effect in the two models, suggesting of the absence of interaction between trimetazidine and cyclosporin A's effectiveness when both drugs are given in combination.