Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury

Funding Information: This article is based upon work from COST Action EU‐CARDIOPROTECTION CA16225 supported by COST ( European Cooperation in Science and Technology ). C.J.Z. was supported by a grant from European Foundation of the Study of Diabetes and from Boehringer –Ingelheim to investigate the cardiac working mechanism of empagliflozin. V.B. received funding from the European Social Fund (project No 09.3.3-LMT-K-712-01-0131) under grant agreement with the Research Council of Lithuania . E.L. research is supported by funding from the Latvian Council of Science , project TRILYSOX, grant No. LZP-2018/1–0082. Publisher Copyright: © 2021 The Author(s)The heart is the most metabolically flexible organ with respect to the use of substrates available in different states of energy metabolism. Cardiac mitochondria sense substrate availability and ensure the efficiency of oxidative phosphorylation and heart function. Mitochondria also play a critical role in cardiac ischemia/reperfusion injury, during which they are directly involved in ROS-producing pathophysiological mechanisms. This review explores the mechanisms of ROS production within the energy metabolism pathways and focuses on the impact of different substrates. We describe the main metabolites accumulating during ischemia in the glucose, fatty acid, and Krebs cycle pathways. Hyperglycemia, often present in the acute stress condition of ischemia/reperfusion, increases cytosolic ROS concentrations through the activation of NADPH oxidase 2 and increases mitochondrial ROS through the metabolic overloading and decreased binding of hexokinase II to mitochondria. Fatty acid-linked ROS production is related to the increased fatty acid flux and corresponding accumulation of long-chain acylcarnitines. Succinate that accumulates during anoxia/ischemia is suggested to be the main source of ROS, and the role of itaconate as an inhibitor of succinate dehydrogenase is emerging. We discuss the strategies to modulate and counteract the accumulation of substrates that yield ROS and the therapeutic implications of this concept.publishersversionPeer reviewe

A study on wear evaluation of railway wheels based on multibody dynamics and wear computation

The wear evolution of railway wheels is a very important issue in railway engineering. In the past, the reprofiling intervals of railway vehicle steel wheels have been scheduled according to designers' experience. Today, more reliable and accurate tools in predicting wheel wear evolution and wheelset lifetime can be used in order to achieve economical and safety benefits. In this work, a computational tool that is able to predict the evolution of the wheel profiles for a given railway system, as a function of the distance run, is presented. The strategy adopted consists of using a commercial multibody software to study the railway dynamic problem and a purpose-built code for managing its pre- and post-processing data in order to compute the wear. The tool is applied here to realistic operation scenarios in order to assess the effect of some service conditions on the wheel wear progression

Altered mitochondrial metabolism in the insulin-resistant heart.

Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA-induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.COST Action MitoEAGL

KEYLINK: towards a more integrative soil representation for inclusion in ecosystem scale models. I. review and model concept

The relatively poor simulation of the below-ground processes is a severe drawback for many ecosystem models, especially when predicting responses to climate change and management. For a meaningful estimation of ecosystem production and the cycling of water, energy, nutrients and carbon, the integration of soil processes and the exchanges at the surface is crucial. It is increasingly recognized that soil biota play an important role in soil organic carbon and nutrient cycling, shaping soil structure and hydrological properties through their activity, and in water and nutrient uptake by plants through mycorrhizal processes. In this article, we review the main soil biological actors (microbiota, fauna and roots) and their effects on soil functioning. We review to what extent they have been included in soil models and propose which of them could be included in ecosystem models. We show that the model representation of the soil food web, the impact of soil ecosystem engineers on soil structure and the related effects on hydrology and soil organic matter (SOM) stabilization are key issues in improving ecosystem-scale soil representation in models. Finally, we describe a new core model concept (KEYLINK) that integrates insights from SOM models, structural models and food web models to simulate the living soil at an ecosystem scale

CXCR3 identifies human naive CD8+ T cells with enhanced effector differentiation potential

In mice, the ability of naive T (TN) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8+ TN cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3+ TN cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide-HLA class I Ags.Moreover, CXCR3+ TN cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3+ TN cells were transcriptionally equivalent to murine CXCR3+ TN cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8+ T cells

STC1 and PTHrP modify carbohydrate and lipid metabolism in liver of a teleost fish

Stanniocalcin 1 (STC1) and parathyroid hormone-related protein (PTHrP) are calciotropic hormones in vertebrates. Here, a recently hypothesized metabolic role for these hormones is tested on European sea bass treated with: (i) teleost PTHrP(1-34), (ii) PTHrP(1-34) and anti-STC1 serum (pro-PTHrP groups), (iii) a PTHrP antagonist PTHrP(7-34) or (iv) PTHrP(7-34) and STC1 (pro-STC1 groups). Livers were analysed using untargeted metabolic profiling based on proton nuclear magnetic resonance (1H-NMR) spectroscopy. Concentrations of branched-chain amino acid (BCAA), alanine, glutamine and glutamate increased in pro-STC1 groups suggesting their mobilization from the muscle to the liver for degradation and gluconeogenesis from alanine and glutamine. In addition, only STC1 treatment decreased the concentrations of succinate, fumarate and acetate, indicating slowing of the citric acid cycle. In the pro-PTHrP groups the concentrations of glucose, erythritol and lactate decreased, indicative of gluconeogenesis from lactate. Taurine, trimethylamine, trimethylamine N-oxide and carnitine changed in opposite directions in the pro-STC1 versus the pro-PTHrP groups, suggesting opposite effects, with STC1 stimulating lipogenesis and PTHrP activating lipolysis/β-oxidation of fatty acids. These findings suggest a role for STC1 and PTHrP related to strategic energy mechanisms that involve the production of glucose and safeguard of liver glycogen reserves for stressful situations.Portuguese Foundation for Science and Technology (FCT) SFRH/BD/103185/2014info:eu-repo/semantics/publishedVersio

Expression of CD11c Is Associated with Unconventional Activated T Cell Subsets with High Migratory Potential

Ajudes rebudes: Marie Curie Career Integration Grant; Dexeus Foundation for Women's Health Research; i Contratos Ramón y CajalCD11c is an α integrin classically employed to define myeloid dendritic cells. Although there is little information about CD11c expression on human T cells, mouse models have shown an association of CD11c expression with functionally relevant T cell subsets. In the context of genital tract infection, we have previously observed increased expression of CD11c in circulating T cells from mice and women. Microarray analyses of activated effector T cells expressing CD11c derived from naïve mice demonstrated enrichment for natural killer (NK) associated genes. Here we find that murine CD11c+ T cells analyzed by flow cytometry display markers associated with non-conventional T cell subsets, including γδ T cells and invariant natural killer T (iNKT) cells. However, in women, only γδ T cells and CD8+ T cells were enriched within the CD11c fraction of blood and cervical tissue. These CD11c+ cells were highly activated and had greater interferon (IFN)-γ secretory capacity than CD11c- T cells. Furthermore, circulating CD11c+ T cells were associated with the expression of multiple adhesion molecules in women, suggesting that these cells have high tissue homing potential. These data suggest that CD11c expression distinguishes a population of circulating T cells during bacterial infection with innate capacity and mucosal homing potential

Src Kinases Are Required for a Balanced Production of IL-12/IL-23 in Human Dendritic Cells Activated by Toll-Like Receptor Agonists

BACKGROUND: Pathogen recognition by dendritic cells (DC) is crucial for the initiation of both innate and adaptive immune responses. Activation of Toll-like Receptors (TLRs) by microbial molecular patterns leads to the maturation of DC, which present the antigen and activate T cells in secondary lymphoid tissues. Cytokine production by DC is critical for shaping the adaptive immune response by regulating T helper cell differentiation. It was previously shown by our group that Src kinases play a key role in cytokines production during TLR4 activation in human DC. PRINCIPAL FINDINGS: In this work we investigated the role of Src kinases during different TLRs triggering in human monocyte-derived DC (MoDC). We found that Src family kinases are important for a balanced production of inflammatory cytokines by human MoDC upon stimulation of TLR3 and 8 with their respective agonists. Disruption of this equilibrium through pharmacological inhibition of Src kinases alters the DC maturation pattern. In particular, while expression of IL-12 and other inflammatory cytokines depend on Src kinases, the induction of IL-23 and co-stimulatory molecules do not. Accordingly, DC treated with Src inhibitors are not compromised in their ability to induce CD4 T cell proliferation and to promote the Th17 subset survival but are less efficient in inducing Th1 differentiation. CONCLUSIONS: We suggest that the pharmacological modulation of DC maturation has the potential to shape the quality of the adaptive immune response and could be exploited for the treatment of inflammation-related diseases

Ensemble modelling, uncertainty and robust predictions of organic carbon in long-term bare-fallow soils

ACKNOWLEDGEMENTS This study was supported by the project “C and N models inter-comparison and improvement to assess management options for GHG mitigation in agro-systems worldwide” (CN-MIP, 2014- 2017), which received funding by a multi-partner call on agricultural greenhouse gas research of the Joint Programming Initiative ‘FACCE’ through national financing bodies. S. Recous, R. Farina, L. Brilli, G. Bellocchi and L. Bechini received mobility funding by way of the French Italian GALILEO programme (CLIMSOC project). The authors acknowledge particularly the data holders for the Long Term Bare-Fallows, who made their data available and provided additional information on the sites: V. Romanenkov, B.T. Christensen, T. Kätterer, S. Houot, F. van Oort, A. Mc Donald, as well as P. Barré. The input of B. Guenet and C. Chenu contributes to the ANR “Investissements d’avenir” programme with the reference CLAND ANR-16-CONV-0003. The input of P. Smith and C. Chenu contributes to the CIRCASA project, which received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no 774378 and the projects: DEVIL (NE/M021327/1) and Soils‐R‐GRREAT (NE/P019455/1). The input of B. Grant and W. Smith was funded by Science and Technology Branch, Agriculture and Agri-Food Canada, under the scope of project J-001793. The input of A. Taghizadeh-Toosi was funded by Ministry of Environment and Food of Denmark as part of the SINKS2 project. The input of M. Abdalla contributes to the SUPER-G project, which received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no 774124.Peer reviewedPostprin