Affecting the macrophage response to infection by integrating signaling and gene-regulatory networks

Obesity has reached epidemic proportions in recent years. The World Health Organization estimated in 2008 that 1.4 billion people were overweight of whom 500 million were obese. Obesity associates with a wide range of conditions, such as cardiovascular diseases, cancer, diabetes, and neurological disorders, and causes approximately 2.8 million deaths each year. Many studies have established that obesity strongly impacts the normal function of the immune system: it dysregulates production of inflammatory and anti–inflammatory cytokines, alters numbers of immune cells, and causes an overall weaker immune response. Developing therapies that aim to improve the immune response is crucial in order to increase the quality of life of obese subjects and to reduce their ever–increasing healthcare-related costs. The long-term objective of this work is to contribute to the development of therapies that can increase the immune response in obese macrophages. In particular, gene modifications adjusting the response to infection in obese macrophages closer to that of lean macrophages are desired. To this end, the present work focused on the Toll-like Receptors (TLRs), which play an essential role in the detection of pathogens and the initiation of both innate and acquired immune responses. Genes essential to the transmission of the infection signal were first identified using a model of the TLR signaling pathways. These genes provided the basis for reconstructing a gene regulatory network that not only accounts for information coming from the TLRs, but also regulates key reactions within the pathways. The topology and regulatory functions of this network were identified by applying novel computational techniques to time-series gene-expression datasets. The TLR signaling and gene-regulatory networks were then integrated to develop a modeling framework for macrophage that predicts the time behavior of several markers for infection. Finally, formal verification techniques were used to demonstrate that the model satisfies several properties characteristic of the response to infection in macrophage. The work detailed in this dissertation offers a suitable platform for developing and testing biological hypotheses that aim to improve responses to infection

The national security key indicators as a part of economic development in the conditions of digitization

International audienceMethylglyoxal is a faulty metabolite. It is a ubiquitous by-product of glucose and amino acid metabolism that spontaneously reacts with proximal amino groups in proteins and nucleic acids, leading to impairment of their function. The glyoxalase pathway evolved early in phylogeny to bring about rapid catabolism of methylglyoxal, and an understanding of the role of methylglyoxal and the glyoxalases in many diseases is beginning to emerge. Metabolic processing of methylglyoxal is very rapid in vivo and thus notoriously difficult to detect and quantify. Here we show that C-13 nuclei in labeled methylglyoxal can be hyperpolarized using dynamic nuclear polarization, providing C-13 nuclear magnetic resonance signal enhancements in the solution state close to 5,000-fold. We demonstrate the applications of this probe of metabolism for kinetic characterization of the glyoxalase system in isolated cells as well as mouse brain, liver and lymphoma in vivo

Glyoxalase activity in human erythrocytes and mouse lymphoma, liver and brain probed with hyperpolarized C-13-methylglyoxal

Methylglyoxal is a faulty metabolite. It is a ubiquitous by-product of glucose and amino acid metabolism that spontaneously reacts with proximal amino groups in proteins and nucleic acids, leading to impairment of their function. The glyoxalase pathway evolved early in phylogeny to bring about rapid catabolism of methylglyoxal, and an understanding of the role of methylglyoxal and the glyoxalases in many diseases is beginning to emerge. Metabolic processing of methylglyoxal is very rapid in vivo and thus notoriously difficult to detect and quantify. Here we show that 13C nuclei in labeled methylglyoxal can be hyperpolarized using dynamic nuclear polarization, providing 13C nuclear magnetic resonance signal enhancements in the solution state close to 5,000-fold. We demonstrate the applications of this probe of metabolism for kinetic characterization of the glyoxalase system in isolated cells as well as mouse brain, liver and lymphoma in vivo

Therapeutic administration of Tregitope-Human Albumin Fusion with Insulin Peptides to promote Antigen-Specific Adaptive Tolerance Induction.

Type 1 Diabetes (T1D) is an autoimmune disease that is associated with effector T cell (Teff) destruction of insulin-producing pancreatic beta-islet cells. Among the therapies being evaluated for T1D is the restoration of regulatory T cell (Treg) activity, specifically directed toward down-modulation of beta-islet antigen-specific T effector cells. This is also known as antigen-specific adaptive tolerance induction for T1D (T1D ASATI). Tregitopes (T regulatory cell epitopes) are natural T cell epitopes derived from immunoglobulin G (IgG) that were identified in 2008 and have been evaluated in several autoimmune disease models. In the T1D ASATI studies presented here, Tregitope peptides were administered to non-obese diabetic (NOD) mice at the onset of diabetes within two clinically-relevant delivery systems (liposomes and in human serum albumin [HSA]-fusion products) in combination with preproinsulin (PPI) target antigen peptides. The combination of Tregitope-albumin fusions and PPI peptides reduced the incidence of severe diabetes and reversed mild diabetes, over 49 days of treatment and observation. Combining HSA-Tregitope fusions with PPI peptides is a promising ASATI approach for therapy of T1D

The International DORIS Service (IDS) - Recent Developments in Preparation for ITRF2013

The International DORIS Service (IDS) was created in 2003 under the umbrella of the International Association of Geodesy (IAG) to foster scientific research related to the French DORIS tracking system and to deliver scientific products, mostly related to the International Earth rotation and Reference systems Service (IERS). We first present some general background related to the DORIS system (current and planned satellites, current tracking network and expected evolution) and to the general IDS organization (from Data Centers, Analysis Centers and Combination Center). Then, we discuss some of the steps recently taken to prepare the IDS submission to ITRF2013 (combined weekly time series based on individual solutions from several Analysis Centers). In particular, recent results obtained from the Analysis Centers and the Combination Center show that improvements can still be made when updating physical models of some DORIS satellites, such as Envisat, Cryosat-2 or Jason-2. The DORIS contribution to ITRF2013 should also benefit from the larger number of ground observations collected by the last generation of DGXX receivers (first instrument being onboard Jason-2 satellite). In particular for polar motion, sub-millarcsecond accuracy seems now to be achievable. Weekly station positioning internal consistency also seems to be improved with a larger DORIS constellation

Promiscuous \u3cem\u3eCoxiella burnetii\u3c/em\u3e CD4 Epitope Clusters Associated With Human Recall Responses Are Candidates for a Novel T-Cell Targeted Multi-Epitope Q Fever Vaccine

Coxiella burnetii, the causative agent of Q fever, is a Gram-negative intracellular bacterium transmitted via aerosol. Regulatory approval of the Australian whole-cell vaccine Q-VAX® in the US and Europe is hindered by reactogenicity in previously exposed individuals. The aim of this study was to identify and rationally select C. burnetii epitopes for design of a safe, effective, and less reactogenic T-cell targeted human Q fever vaccine. Immunoinformatic methods were used to predict 65 HLA class I epitopes and 50 promiscuous HLA class II C. burnetii epitope clusters, which are conserved across strains of C. burnetii. HLA binding assays confirmed 89% of class I and 75% of class II predictions, and 11 HLA class II epitopes elicited IFNγ responses following heterologous DNA/DNA/peptide/peptide prime-boost immunizations of HLA-DR3 transgenic mice. Human immune responses to the predicted epitopes were characterized in individuals naturally exposed to C. burnetii during the 2007–2010 Dutch Q fever outbreak. Subjects were divided into three groups: controls with no immunological evidence of previous infection and individuals with responses to heat-killed C. burnetii in a whole blood IFNγ release assay (IGRA) who remained asymptomatic or who experienced clinical Q fever during the outbreak. Recall responses to C. burnetii epitopes were assessed by cultured IFNγ ELISpot. While HLA class I epitope responses were sparse in this cohort, we identified 21 HLA class II epitopes that recalled T-cell IFNγ responses in 10–28% of IGRA+ subjects. IGRA+ individuals with past asymptomatic and symptomatic C. burnetii infection showed a comparable response pattern and cumulative peptide response which correlated with IGRA responses. None of the peptides elicited reactogenicity in a C. burnetii exposure-primed guinea pig model. These data demonstrate that a substantial proportion of immunoinformatically identified HLA class II epitopes show long-lived immunoreactivity in naturally infected individuals, making them desirable candidates for a novel human multi-epitope Q fever vaccine

Glyoxalase activity in human erythrocytes and mouse lymphoma, liver and brain probed with hyperpolarized 13C-methylglyoxal.

Methylglyoxal is a faulty metabolite. It is a ubiquitous by-product of glucose and amino acid metabolism that spontaneously reacts with proximal amino groups in proteins and nucleic acids, leading to impairment of their function. The glyoxalase pathway evolved early in phylogeny to bring about rapid catabolism of methylglyoxal, and an understanding of the role of methylglyoxal and the glyoxalases in many diseases is beginning to emerge. Metabolic processing of methylglyoxal is very rapid in vivo and thus notoriously difficult to detect and quantify. Here we show that 13C nuclei in labeled methylglyoxal can be hyperpolarized using dynamic nuclear polarization, providing 13C nuclear magnetic resonance signal enhancements in the solution state close to 5,000-fold. We demonstrate the applications of this probe of metabolism for kinetic characterization of the glyoxalase system in isolated cells as well as mouse brain, liver and lymphoma in vivo

Snow accumulation and ablation measurements in a midlatitude mountain coniferous forest (Col de Porte, France, 1325 m altitude): the Snow Under Forest (SnoUF) field campaign data set

Forests strongly modify the accumulation, metamorphism and melting of snow in midlatitude and high-latitude regions. Recently, snow routines in hydrological and land surface models were improved to incorporate more accurate representations of forest snow processes, but model intercomparison projects have identified deficiencies, partly due to incomplete knowledge of the processes controlling snow cover in forests. The Snow Under Forest (SnoUF) project was initiated to enhance knowledge of the complex interactions between snow and vegetation. Two field campaigns, during the winters 2016–2017 and 2017–2018, were conducted in a coniferous forest bordering the snow study at Col de Porte (1325 m a.s.l., French Alps) to document the snow accumulation and ablation processes. This paper presents the field site, the instrumentation and the collection and postprocessing methods. The observations include distributed forest characteristics (tree inventory, lidar measurements of forest structure, subcanopy hemispherical photographs), meteorology (automatic weather station and an array of radiometers), snow cover and depth (snow pole transect and laser scan) and snow interception by the canopy during precipitation events. The weather station installed under dense canopy during the first campaign has been maintained since then and has provided continuous measurements throughout the year since 2018. Data are publicly available from the repository of the Observatoire des Sciences de l'Univers de Grenoble (OSUG) data center at https://doi.org/10.17178/SNOUF.2022 (Sicart et al., 2022).</p

Multi-antigen Vaccination With Simultaneous Engagement of the OX40 Receptor Delays Malignant Mesothelioma Growth and Increases Survival in Animal Models

Malignant Mesothelioma (MM) is a rare and highly aggressive cancer that develops from mesothelial cells lining the pleura and other internal cavities, and is often associated with asbestos exposure. To date, no effective treatments have been made available for this pathology. Herein, we propose a novel immunotherapeutic approach based on a unique vaccine targeting a series of antigens that we found expressed in different MM tumors, but largely undetectable in normal tissues. This vaccine, that we term p-Tvax, is comprised of a series of immunogenic peptides presented by both MHC-I and -II to generate robust immune responses. The peptides were designed using in silico algorithms that discriminate between highly immunogenic T cell epitopes and other harmful epitopes, such as suppressive regulatory T cell epitopes and autoimmune epitopes. Vaccination of mice with p-Tvax led to antigen-specific immune responses that involved both CD8+ and CD4+ T cells, which exhibited cytolytic activity against MM cells in vitro. In mice carrying MM tumors, p-Tvax increased tumor infiltration of CD4+ T cells. Moreover, combining p-Tvax with an OX40 agonist led to decreased tumor growth and increased survival. Mice treated with this combination immunotherapy displayed higher numbers of tumor-infiltrating CD8+ and CD4+ T cells and reduced T regulatory cells in tumors. Collectively, these data suggest that the combination of p-Tvax with an OX40 agonist could be an effective strategy for MM treatment

Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis

Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization and dynamics of the inter-organellar contact established by sheets of curved rough endoplasmic reticulum closely wrapped around the mitochondria (wrappER). To elucidate the in vivo function of this contact, mouse liver fractions enriched in wrappER-associated mitochondria are analyzed by transcriptomics, proteomics, and lipidomics. The biochemical signature of the wrappER points to a role in the biogenesis of very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion and increases hepatic fatty acids, lipid droplets, and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, recapitulates this hepatic dyslipidemia phenotype and promotes remodeling of the wrappER-mitochondria contact. The discovery that liver wrappER-mitochondria contacts participate in VLDL biology suggests an involvement of inter-organelle contacts in systemic lipid homeostasis.Fil: Anastasia, Irene. Laval University; Canadá. Brain Research Center; CanadáFil: Ilacqua, Nicolò. Laval University; Canadá. Brain Research Center; CanadáFil: Raimondi, Andrea. San Raffaele Scientific Institute; ItaliaFil: Lemieux, Philippe. Brain Research Center; CanadáFil: Ghandehari-Alavijeh, Rana. Brain Research Center; CanadáFil: Faure, Guilhem. Broad Institute of MIT and Harvard; Estados Unidos. National Center For Biotechnology Information; Estados UnidosFil: Mekhedov, Sergei L.. National Center For Biotechnology Information ; Estados UnidosFil: Williams, Kevin J.. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Caicci, Federico. Università di Padova; ItaliaFil: Valle, Giorgio. Università di Padova; ItaliaFil: Giacomello, Marta. Università di Padova; ItaliaFil: Quiroga, Ariel Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina. University of Alberta; CanadáFil: Lehner, Richard. University of Alberta; CanadáFil: Miksis, Michael J.. Northwestern University; Estados UnidosFil: Toth, Katalin. University of Ottawa; CanadáFil: de Aguiar Vallim, Thomas Q.. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Koonin, Eugene V.. National Center For Biotechnology Information ; Estados UnidosFil: Scorrano, Luca. Università di Padova; ItaliaFil: Pellegrini, Luca. Laval University; Canad