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peer reviewedConférence Permanente du Développement Territoria

Evaluation of therapeutic properties of fermented vegetables extract (OM-X®) in the model of colitis induced by Citrobacter rodentium in mice

AbstractInfection of mice with Citrobacter rodentium serves as a model to study human intestinal infections. C. rodentium infection leads to increased production of inflammatory cytokines, immune cell infiltration and damage to the gut barrier. We used this model of colitis to evaluate the therapeutic properties of OM-X®, an extract prepared by fermentation of vegetables, seaweeds, fruits and mushrooms. Administration of OM-X® to C. rodentium-infected mice reduced damage to the intestinal epithelium, lowered inflammation scores, increased IL-10 expression and maintained FoxP3 gene expression. OM-X® also partially prevented bacterial translocation, increased expression of tight junction genes and increased proliferation of epithelial cells. PCR analysis of stool samples showed that OM-X® significantly reduced the populations of bacteria harboring buk gene (mostly Clostridium species). It is suggested that alterations of microbiota composition, following OM-X® consumption, contribute to protection against infection and epithelial damage, and lead to an increased expression of anti-inflammatory cytokines

Waterfilling in MIMO Systems with Power Constraints on Each Transmitter

In this paper we investigate power allocation in MIMO-OFDM systems. We describe the optimal power allocations under two different constraints: a constraint on the total power of all transmitters (TXs) which is applicable in wireless applications, and a constraint on the power of each TX which is more relevant in wireline applications. We describe the optimal TX/RX structure which in combination with the optimal power allocation achieves the MIMO-OFDM channel capacity (under the chosen constraints), with low complexity. Simulations show the benefits of using a total power constraint in place of a per-TX power constraint are largest when the TXs see channels with significantly different attenuations

Molecular MRI of apoptosis in atherosclerotic plaque by using a peptide-vectorized paramagnetic imaging probe

Introduction. Molecular and cellular imaging of atherosclerosis has garnered more interest at the beginning of the 21st century, with aims to image in vivo biological properties of plaque lesions. Apoptosis seems an attractive target for the diagnosis of vulnerable atherosclerotic plaques prone to a thrombotic event [1]. In this context, phosphatidylserine exposure on the outer leaflet of the cell membrane is one of the earliest detectable molecular events in apoptosis. The aim of the present work was to screen for apoptosis peptide binders by phage display with the final purpose to detect apoptotic cells in atherosclerotic plaques by MRI. A phosphatidylserine-specific peptide identified by phage display was thus used to design an MRI contrast agent (CA) that was evaluated as a potential in vivo reporter of apoptotic cells. Methods. A library of linear 6-mer random peptides (fused to the pIII protein of M13 bacteriophage) was screened in vitro against immobilized phosphatidylserine. Phage DNA was isolated and sequenced by Sanger method. The affinity of peptides for phosphatidylserine was evaluated by ELISA, using the Kd and IC50 as criteria of peptide selection. The phosphatidylserine-specific peptide and its scrambled homologous were attached to a linker (8-amino-3,6-dioxaoctanoyl) and conjugated to DTPA-isothiocyanate. The products were purified by dialysis and by column chromatography, and complexed with gadolinium chloride. After its evaluation using apoptotic cells and a mouse model of liver apoptosis, the phosphatidylserine-targeted CA was used to image atherosclerotic lesions on ApoE-/- transgenic mice. Apoptotic cells were detected on liver and aorta specimens by the immunostaining of phosphatidylserine and of active caspase-3. Results. Sequencing of the phage genome highlighted nine different peptides. Their alignment with amino acid sequences of relevant proteins revealed a frequent homology with Ca2+ channels, which reminds the function of annexins. Alignment with molecules involved in apoptosis, i.e. Fas antigen ligand and apoptosis associated tyrosine-kinase, provides a direct correlation between peptide selection and utility. The in vivo MRI studies performed at 4.7T suggest that the majority of the increased liver or aorta localization of the new phosphatidylserine-targeted CA is the result of a specific interaction with apoptotic cells, providing proof of concept that apoptosis-related pathologies could be diagnosed by MRI with a low-molecular weight paramagnetic agent. Conclusion. The new CA could have a real potential in the diagnosis and therapy monitoring of atherosclerotic disease and of other apoptosis-associated pathologies, such as cancer, ischemia, chronic inflammation, autoimmune disorders, transplant rejection, neurodegenerative disorders, and diabetes mellitus. The phage display-derived peptide could also play a potential therapeutic role through anticoagulant activity by mimicking the role of annexin V, the endogenous ligand of phosphatidylserine. References 1. Tabas I. Apoptosis and plaque destabilization in atherosclerosis: the role of macrophage apoptosis induced by cholesterol. Cell Death Differ. 2004, 11, S12-S16

Evaluation des besoins et des activités. Problématique de leur localisation. Critères, méthodes et applications pour la révision des plans de secteur. Problématique pour la mise en oeuvre des zones d'aménagement différé

Rapport final de la subvention 2001, Cinquième Volum

In vitro biomedical applications of functionalized iron oxide nanoparticles, including those not related to magnetic properties.

peer reviewedSuperparamagnetic iron oxide nanoparticles (SPION) are very promising contrast media, especially for molecular imaging, due to their superior NMR efficacy. They even have wider biomedical applications such as in drug and gene delivery, tissue engineering and bioseparation, or as sensitive biological nanosensors. By coupling them to affinity ligands, SPION can bind to drugs, proteins, enzymes, antibodies or nucleotides. For in vitro biomedical applications, the detection of molecular interaction is possible by using a diversity of systems capable of sensing the magnetic properties of these materials. The goal of the present work was to develop and validate various in vitro biomedical applications of ultrasmall superparamagnetic particles of iron oxide (USPIO), including some that are not related to their magnetic properties. USPIO coated with dextran, starch or bisphosphonate exposing carboxylate groups were synthesized and some of them were functionalized by conjugating various biomolecules, such as biotin, streptavidin and apoptosis, or VCAM-1 specific peptides. The in vitro biomedical applications assessed in the present work included: (1) the relaxometric measurement of antibody concentration, cell receptor expression, molecular interaction, and enzymatic activity in aqueous suspensions; (2) MRI visualization of cells and detection of molecular interaction in an ELISA system; (3) ELISA applications of USPIO derivatives; and (4) detection of specific biomolecules by histochemistry. Our results confirm that rapid and simple in vitro detection of a diversity of functionalized SPION with relevance in medicine is possible by the existing NMR techniques and by chemical staining reactions. The protocols can be applied to minimally prepared biological samples (e.g. whole blood, blood plasma or serum, cell suspensions, biopsies, histological preparations, etc.), and often do not need complicated systems of signal amplification. The use of SPION labeled compounds could furthermore contribute to cost reductions in the diagnosis and in patient care

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Conception, mise en oeuvre et modélisation de réacteurs pour la précipitation de particules à propriétés contrôlées : application à la pseudo-boehmite

Non disponible / Not availableL'objectif de ce travail est de développer des nouveaux réacteurs permettant une bonne maîtrise des réactions de précipitation, processus chimique rapide donnant naissance à une phase solide. Ces nouveaux réacteurs doivent être des mélangeurs rapides capables d'influencer, voire de contrôler les propriétés des particules fabriquées. Deux approches expérimentales ont été adoptées : (1) l'étude des phénomènes de mélange des réactifs et (2) l'étude de l'influence des conditions opératoires sur la précipitation d'un produit modèle. Le produit modèle choisi pour cette étude est la pseudo-boehmite. La pseudo-boehmite, catalyseur industriel, doit satisfaire de nombreuses propriétés : surface spécifique, volume poreux, taille des pores, cristallinité, distribution de taille des particules et morphologie des agglomérats. Ces propriétés sont très sensibles aux conditions opératoires et hydrodynamiques des réacteurs de précipitation. D'où l'intérêt d'utiliser la pseudo-boehmite comme produit modèle pour la précipitation. Quatre réacteurs originaux sont étudiés : le Réacteur à Disque Tournant, le Réacteur à Effet Vortex, le Réacteur avec Alimentation par le Fond et le Réacteur à Jets Lamellaires. L'étude du micromélange, réalisée à l'aide de la réaction chimique test mise au point par l'équipe du Professeur Villermaux et du macromélange, réalisée à l'aide de réacteurs de visualisation et de réactions de décoloration acide-base, ont permis de développer et de modéliser ces nouveaux réacteurs. Les réactions de précipitation de la pseudo-boehmite ont permis de dégager les grandes tendances de l'évolution des propriétés des particules en fonction des conditions opératoires. En vue de comprendre l'effet du mûrissement sur les particules de pseudo-boehmite, forme d'alumine mal cristallisée, l'influence des conditions de mûrissement (température, pH, puissance moyenne d'agitation et concentration de la suspension de particules) sur l'évolution des propriétés des particules est étudiée. Les caractéristiques des particules étudiées sont: la distribution de taille des particules, la taille des cristallites, la cristallinité, la surface spécifique, le volume poreux total et la teneur en eau. Le mécanisme de mûrissement des particules de pseudo-boehmite initialement amorphes a ainsi été mis en évidence et modélisé. Le Réacteur à Disque Tournant a été sélectionné pour réaliser des simulations à l'aide du code commercial FLUENT. L'hydrodynamique et le mélange des réactifs ont été simulés à l'aide du modèle k-e. Les effets de l'influence de la concentration des réactifs, de la vitesse d'agitation et de la position des tubes d'alimentation ont été simulés et comparés aux résultats expérimentaux