Biology subjects

Laufs, U.

Publications and source records attributed to Laufs, U..

4 recordsLinked to original sources

bioRxiv2026

Canonical Correlation Analysis and Multi-Channel Cardiography Improve Artefact Cleaning in Heartbeat-Locked Analyses

Cardiac artefacts are problematic for neurophysiological analyses, especially for heartbeat-locked brain responses where neural activity and artefacts co-occur in time. Traditional approaches using single-channel electrocardiography for artefact removal do not fully capture the multidimensional spread of cardiac fields. Moreover, even if several channels are recorded, no established methods exists for integrating them for artefact removal. Here, we propose a multivariate approach based on Canonical Correlation for cardiac artefact removal and report its effectiveness in electroencephalography recorded simultaneously with a custom 15-channel electrocardiography in 14 participants. We quantify cleaning quality via residual R-peak artefact and neural signal preservation via alpha power. Canonical Correlation systematically outperforms the traditional Independent Component Analysis in both reducing R-peak artefacts and preserving alpha power. By analysing all possible channel combinations, we found that neck or supraclavicular electrodes improve cleaning when only a few channels are available. With four or five channels, precordial electrodes in combination with limb or supraclavicular locations provide a performance comparable to the 15-channel setup. While these findings require validation in other datasets, we outline clear decision criteria for cleaning efficiency and show that canonical correlation is a reliable approach for multi-channel cardiac artefact removal.

neuroscience↗

bioRxiv2024

Mitochondrial reactive oxygen species cause arrhythmias in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and caused by genetic variants that often increase sarcomeric Ca2+ sensitivity. While Ca2+ sensitization explains diastolic dysfunction, the genesis of ventricular arrhythmias is unresolved. Here, we show that HCM mutations or pharmacological interventions that increase myofilament Ca2+ sensitivity generate bioenergetic mismatch and oxidative stress during {beta}-adrenergic stimulation which provide a trigger and a substrate for arrhythmias. For any given sarcomere shortening that produces work and consumes ATP, less Ca2+ stimulates the Krebs cycle to maintain mitochondrial NADH. This reverses the mitochondrial transhydrogenase to regenerate NADH from NADPH, supporting ATP production at the cost of NADPH-dependent antioxidative capacity. The ensuing overflow of reactive oxygen species (ROS) from mitochondria and glutathione oxidation induce spontaneous Ca2+ release from the sarcoplasmic reticulum and Ca2+ waves, well-defined triggers of arrhythmias. Furthermore, transhydrogenase-dependent ROS formation slows electrical conduction during {beta}-adrenergic stimulation in vivo, providing a substrate for arrhythmias. Chronic treatment with a mitochondrially-targeted ROS scavenger abolishes the arrhythmic burden during {beta}-adrenergic stimulation in HCM mice in vivo, while inducing mitochondrial ROS with a redox cycler is sufficient to induce arrhythmias in wild-type animals. These findings may lead to new strategies to prevent sudden cardiac death in patients with HCM.

physiology↗

bioRxiv2023

Membrane-bound Interleukin-1α mediates leukocyte adhesion during atherogenesis

BackgroundThe interleukin-1 (IL-1) family and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome contribute to atherogenesis but the underlying mechanism are incompletely understood. Unlike IL-1{beta}, IL-1 is not dependent on the NLRP3 inflammasome to exert its pro-inflammatory effects. Here, a non-genetic model was applied to characterize the role of IL-1, IL-1{beta} and NLRP3 for the pathogenesis of atherosclerosis. MethodsAtherogenesis was induced by gain-of-function PCSK9-AAV8 mutant viruses and feeding of a high-fat western diet (WTD) for 12 weeks in C57Bl6/J wildtype mice (control) and in Il1a-/-, Nlrp3-/-, and Il1b-/- mice. ResultsIl1a-/- mice showed reduced atherosclerotic plaque area in the aortic root with lower lipid accumulation, while no difference was observed between wildtype, Nlrp3-/- and Il1b-/- mice. Serum proteomic analysis showed a reduction of pro-inflammatory cytokines (e.g. IL-1{beta}, IL-6) in Il1a-/- as well as in Nlrp3-/- and Il1b-/- mice. Bone marrow dendritic cells (BMDC) of WT, Nlrp3-/- and Il1b-/- mice and primary human monocytes showed translocation of IL-1 to the plasma membrane (csIL-1) upon stimulation with LPS. The translocation of IL-1 to the cell surface was regulated by myristoylation and increased in mice with hypercholesterolemia. CsIL-1 and IL1R1 protein-protein interaction on endothelial cells induced VCAM1 expression and monocyte adhesion, which was abrogated by the administration of neutralizing antibodies against IL-1 and IL1R1. ConclusionsIl1a-/- mice, but not Nlrp3-/- or Il1b-/- mice, are protected from atherosclerosis after induction of hypercholesterolemia independent of circulating cytokines. Myristoylation and translocation of IL-1 to the cell surface in myeloid cells facilitates leukocyte adhesion and contributes to the development of atherosclerosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/543077v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@c54814org.highwire.dtl.DTLVardef@1ff1971org.highwire.dtl.DTLVardef@df5605org.highwire.dtl.DTLVardef@889a1a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO The role of cell-surface (cs) IL-1a in the initiation of atherosclerosis. C_FIG

immunology↗

bioRxiv2021

A novel non-genetic murine model of hyperglycemia and hyperlipidemia-associated accelerated atherosclerosis

ObjectiveAtherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s). Methods and ResultsWild-type mice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less -SMA-positive area) and had more inflammation (increased plasma IL-1{beta} level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemic mice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks. ConclusionWe established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice.

pharmacology and toxicology↗