Functional consequences of sphingomyelinase-induced changes in erythrocyte membrane structure.

Inflammation enhances the secretion of sphingomyelinases (SMases). SMases catalyze the hydrolysis of sphingomyelin into phosphocholine and ceramide. In erythrocytes, ceramide formation leads to exposure of the removal signal phosphatidylserine (PS), creating a potential link between SMase activity and anemia of inflammation. Therefore, we studied the effects of SMase on various pathophysiologically relevant parameters of erythrocyte homeostasis. Time-lapse confocal microscopy revealed a SMase-induced transition from the discoid to a spherical shape, followed by PS exposure, and finally loss of cytoplasmic content. Also, SMase treatment resulted in ceramide-associated alterations in membrane-cytoskeleton interactions and membrane organization, including microdomain formation. Furthermore, we observed increases in membrane fragility, vesiculation and invagination, and large protein clusters. These changes were associated with enhanced erythrocyte retention in a spleen-mimicking model. Erythrocyte storage under blood bank conditions and during physiological aging increased the sensitivity to SMase. A low SMase activity already induced morphological and structural changes, demonstrating the potential of SMase to disturb erythrocyte homeostasis. Our analyses provide a comprehensive picture in which ceramide-induced changes in membrane microdomain organization disrupt the membrane-cytoskeleton interaction and membrane integrity, leading to vesiculation, reduced deformability, and finally loss of erythrocyte content. Understanding these processes is highly relevant for understanding anemia during chronic inflammation, especially in critically ill patients receiving blood transfusions

Red Blood Cell Homeostasis: Pharmacological Interventions to Explore Biochemical, Morphological and Mechanical Properties.

Duringtheirpassagethroughthecirculation,redbloodcells(RBCs)encounterseverephysiologicalconditionsconsistingofmechanicalstress,oxidativedamageandfastchangesinionicandosmoticconditions.Inordertosurvivefor120days,RBCsadapttotheirsurroundingsbysubtleregulationofmembraneorganizationandmetabolism.RBChomeostasisdependsoninteractionsbetweentheintegralmembraneproteinband3withothermembraneandcytoskeletalproteins,andwithkeyenzymesofvariousmetabolicpathways.Theseinteractionsareregulatedbythebindingofdeoxyhemoglobintoband3,andbyasignalingnetworkrevolvingaroundLynkinaseandSrcfamilykinase-mediatedphosphorylationofband3.Hereweshowthatmanipulationoftheinteractionbetweenthelipidbilayerandthecytoskeleton,usingvariouspharmacologicalagentsthatinterferewithprotein-proteininteractionsandmembranelipidorganization,hasvariouseffectson:(1)morphology,asshownbyhighresolutionmicroscopyandquantitativeimageanalysis;(2)organizationofmembraneproteins,asindicatedbyimmunofluorescenceconfocalmicroscopyandquantitativeaswellasqualitativeanalysisofvesiclegeneration;(3)membranelipidorganization,asindicatedbyflowcytometricanalysisofphosphatidylserineexposure;(4)deformability,asassessedincapillary-mimickingcircumstancesusingamicrofluidicssystem;(5)deformabilityasdeterminedusingaspleen-mimickingdevice;(6)metabolicactivityasindicatedbymetabolomics.Ourdatashowthatthereisacomplexrelationshipbetweenredcellmorphology,membraneorganizationanddeformability.Also,ourdatashowthatredbloodcellshavearelativelyhighresistancetodisturbanceofmembraneorganizationinvitro,whichmayreflecttheircapacitytowithstandmechanical,oxidativeandosmoticstressinvivo

An investigation of the phase locking index for measuring of interdependency of cortical source signals recorded in the EEG

The phase locking index (PLI) was introduced to quantify in a statistical sense the phase synchronization of two signals. It has been commonly used to process biosignals. In this article, we investigate the PLI for measuring the interdependency of cortical source signals (CSSs) recorded in the Electroencephalogram (EEG). To this end, we consider simple analytical models for the mapping of simulated CSSs into the EEG. For these models, the PLI is investigated analytically and through numerical simulations. An evaluation is made of the sensitivity of the PLI to the amount of crosstalk between the sources through biological tissues of the head. It is found that the PLI is a useful interdependency measure for CSSs, especially when the amount of crosstalk is small. Another common interdependency measure is the coherence. A direct comparison of both measures has not been made in the literature so far. We assess the performance of the PLI and coherence for estimation and detection purposes based on, respectively, a normalized variance and a novel statistical measure termed contrast. Based on these performance measures, it is found that the PLI is similar or better than the CM in most cases. This result is also confirmed through analysis of EEGs recorded from epileptic patients

From novel discovery tools and biomarkers to precision medicine—basic cardiovascular science highlights of 2021/22

\ua9 2022 Oxford University Press. All rights reserved.Here, we review the highlights of cardiovascular basic science published in 2021 and early 2022 on behalf of the European Society of Cardiology Council for Basic Cardiovascular Science. We begin with non-coding RNAs which have emerged as central regulators cardiovascular biology, and then discuss how technological developments in single-cell ‘omics are providing new insights into cardiovascular development, inflammation, and disease. We also review recent discoveries on the biology of extracellular vesicles in driving either protective or pathogenic responses. The Nobel Prize in Physiology or Medicine 2021 recognized the importance of the molecular basis of mechanosensing and here we review breakthroughs in cardiovascular sensing of mechanical force. We also summarize discoveries in the field of atherosclerosis including the role of clonal haematopoiesis of indeterminate potential, and new mechanisms of crosstalk between hyperglycaemia, lipid mediators, and inflammation. The past 12 months also witnessed major advances in the field of cardiac arrhythmia including new mechanisms of fibrillation. We also focus on inducible pluripotent stem cell technology which has demonstrated disease causality for several genetic polymorphisms in long-QT syndrome and aortic valve disease, paving the way for personalized medicine approaches. Finally, the cardiovascular community has continued to better understand COVID-19 with significant advancement in our knowledge of cardiovascular tropism, molecular markers, the mechanism of vaccine-induced thrombotic complications and new anti-viral therapies that protect the cardiovascular system