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SourceAvailable from: Dimitrios I Fotiadis[Show abstract] [Hide abstract]
ABSTRACT: Atherosclerosis is a progressive disease characterized by inflammation, monocyte-macrophage migration, and lipid accumulation in the vascular wall. Atherosclerosis is initially characterized by endothelial dysfunction, which favors lipid and cell elements crossing inside blood vessel wall. In this study we investigated our three-dimensional computer model of plaque formation and development which we tested on experimental results obtained from rabbits and clinical study on human carotid and coronary arteries. Firstly, a model of plaque formation in the rabbit animal LDL transport model within simple experimental design is simulated numerically using animal data and histological recordings. Then some human patient data from carotid and coronary artery were used. The 3D blood flow is described by the Navier-Stokes equations, together with the continuity equation. Mass transfer within the blood lumen and through the arterial wall is coupled with the blood flow, and is modeled by a convection-diffusion equation. The LDL transports in lumen of the vessel and through the vessel tissue (which has a mass consumption term) are coupled by Kedem-Katchalsky equations. The inflammatory process is modeled using three additional reaction-diffusion partial differential equations. A full three-dimensional model was created. It includes blood flow and LDL concentration, as well as plaque formation and progression. From patient human carotid artery data we matched plaque volume progression using two and three time points for baseline, three and twelve months follow up. Also a group of patients with coronary artery disease (CAD) and intermediate lesions was evaluated by Computed Tomography Angiography (CTA), together with an innovative approach to simulate the WSS-related low density lipoprotein (LDL) transport across the endothelium and to identify LDL accumulation sites. The novelty of this work lies in the systematic verification of prediction of plaque progression by repeated CTA, six months after the baseline evaluation, and by patient-specific determinations of boundary conditions, including coronary vasodilating capability, known to affect local flow conditions. Our results for plaque localization correspond to low shear stress zone and we fitted parameters from our model using nonlinear least square method. Understanding and prediction of the evolution of N. Filipovic et al.: ARTREAT project: computer, experimental and clinical analysis of three-dimensional plaque… 130 atherosclerotic plaques either into vulnerable or stable plaques are major tasks for the medical community.
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ABSTRACT: Francisella tularensis is a highly virulent facultative intracellular pathogen causing the severe disease tularemia in mammals. As for other bacteria, iron is essential for its growth but very few mechanisms for iron acquisition have been identified. Here, we analyzed if and how F. tularensis can utilize heme, a major source of iron in vivo. This is by no means obvious since the bacterium lacks components of traditional heme-uptake systems. We show that SCHU S4, the prototypic strain of subspecies tularensis, grew in vitro with heme as the sole iron source. By screening a SCHU S4 transposon insertion library, 16 genes were identified as important to efficiently utilize heme, two of which were required to avoid heme toxicity. None of the identified genes appeared to encode components of a potential heme-uptake apparatus. Analysis of SCHU S4 deletion mutants revealed that each of the components FeoB, the siderophore system, and FupA, contributed to the heme-dependent growth. In the case of the former two systems, iron acquisition was impaired, whereas the absence of FupA did not affect iron uptake but led to abnormally high binding of iron to macromolecules. Overall, the present study demonstrates that heme supports growth of F. tularensis and that the requirements for the utilization are highly complex and to some extent novel.PLoS ONE 03/2015; 10(3):e0119143. DOI:10.1371/journal.pone.0119143
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ABSTRACT: Dendritic cells (DC) interact with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this study, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1). Increased biosynthesis of the immunosuppressive enzyme was detected in DCs inoculated with the CTB-INS fusion protein but not in DCs inoculated with proinsulin, CTB, or an unlinked combination of the two proteins. Immunoblot and PCR analyses of vaccine treated DCs detected IDO1mRNA by 3 hours and IDO1 protein synthesis by 6 hours after vaccine inoculation. Determination of IDO1 activity in vaccinated DCs by measurement of tryptophan degradation products (kynurenines) showed increased tryptophan cleavage into N-formyl kynurenine. Vaccination did not interfere with monocytes differentiation into DC, suggesting the vaccine can function safely in the human immune system. Treatment of vaccinated DCs with pharmacological NF-κB inhibitors ACHP or DHMEQ significantly inhibited IDO1 biosynthesis, suggesting a role for NF-κB signaling in vaccine up-regulation of dendritic cell IDO1. Heat map analysis of the proteomic data revealed an overall down-regulation of vaccinated DC functions, suggesting vaccine suppression of DC maturation. Together, our experimental data indicate that CTB-INS vaccine induction of IDO1 biosynthesis in human DCs may result in the inhibition of DC maturation generating a durable state of immunological tolerance. Understanding how CTB-INS modulates IDO1 activity in human DCs will facilitate vaccine efficacy and safety, moving this immunosuppressive strategy closer to clinical applications for prevention of type 1 diabetes autoimmunity.PLoS ONE 02/2015; 10(2):e0118562. DOI:10.1371/journal.pone.0118562
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