11 Interfakultäre Einrichtungen
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Item Open Access Association between vitamin D status and eryptosis : results from the German National Cohort study(2023) Ewendt, Franz; Schmitt, Marvin; Kluttig, Alexander; Kühn, Julia; Hirche, Frank; Kraus, Frank B.; Ludwig-Kraus, Beatrice; Mikolajczyk, Rafael; Wätjen, Wim; Bürkner, Paul-Christian; Föller, Michael; Stangl, Gabriele I.Vitamin D, besides its classical effect on mineral homeostasis and bone remodeling, can also modulate apoptosis. A special form of apoptosis termed eryptosis appears in erythrocytes. Eryptosis is characterized by cell shrinkage, membrane blebbing, and cell membrane phospholipid disorganization and associated with diseases such as sepsis, malaria or iron deficiency, and impaired microcirculation. To our knowledge, this is the first study that linked vitamin D with eryptosis in humans. This exploratory cross-sectional trial investigated the association between the vitamin D status assessed by the concentration of plasma 25-hydroxyvitamin D (25(OH)D) and eryptosis. Plasma 25(OH)D was analyzed by LC-MS/MS, and eryptosis was estimated from annexin V-FITC-binding erythrocytes by FACS analysis in 2074 blood samples from participants of the German National Cohort Study. We observed a weak but clear correlation between low vitamin D status and increased eryptosis ( r = − 0.15; 95% CI [− 0.19, − 0.10]). There were no differences in plasma concentrations of 25(OH)D and eryptosis between male and female subjects. This finding raises questions of the importance of vitamin D status for eryptosis in terms of increased risk for anemia or cardiovascular events.Item Open Access Not sorcery after all : roles of multiple charged residues in membrane insertion of gasdermin-A3(2022) Korn, Viktoria; Pluhackova, KristynaGasdermins execute programmatory cell death, known as pyroptosis, by forming medium-sized membrane pores. Recently, the molecular structure of those pores as well as the diversity in their shape and size have been revealed by cryoTEM and atomic force microscopy, respectively. Even though a growth of smaller to larger oligomers and reshaping from slits to rings could be documented, the initiation of the gasdermin pore formation remains a mystery. In one hypothesis, gasdermin monomers insert into membranes before associating into oligomeric pores. In the other hypothesis, gasdermin oligomers preassemble on the membrane surface prior to membrane insertion. Here, by studying the behavior of monomeric membrane-inserted gasdermin-A3 (GSDMA3), we unveil that a monomeric gasdermin prefers the membrane-adsorbed over the membrane-inserted state. Our results thus support the hypothesis of oligomers preassembling on the membrane surface before membrane penetration. At the same time, our simulations of small membrane-inserted arcs of GSDMA3 suggest that the inserting oligomer can be small and does not have to comprise a full ring of approximately 26-30 subunits. Moreover, our simulations have revealed an astonishingly large impact of salt-bridge formation and protein surroundings on the transmembrane passage of charged residues, reducing the energetic cost by up to 53% as compared to their free forms. The here observed free energy barrier of mere 5.6 kcal/mol for the membrane insertion of monomeric GSDMA3 explains the surprising ability of gasdermins to spontaneously self-insert into cellular membranes.Item Open Access WildLab : a naturalistic free viewing experiment reveals previously unknown electroencephalography signatures of face processing(2022) Gert, Anna L.; Ehinger, Benedikt V.; Timm, Silja; Kietzmann, Tim C.; König, PeterNeural mechanisms of face perception are predominantly studied in well‐controlled experimental settings that involve random stimulus sequences and fixed eye positions. Although powerful, the employed paradigms are far from what constitutes natural vision. Here, we demonstrate the feasibility of ecologically more valid experimental paradigms using natural viewing behaviour, by combining a free viewing paradigm on natural scenes, free of photographer bias, with advanced data processing techniques that correct for overlap effects and co‐varying non‐linear dependencies of multiple eye movement parameters. We validate this approach by replicating classic N170 effects in neural responses, triggered by fixation onsets (fixation event‐related potentials [fERPs]). Importantly, besides finding a strong correlation between both experiments, our more natural stimulus paradigm yielded smaller variability between subjects than the classic setup. Moving beyond classic temporal and spatial effect locations, our experiment furthermore revealed previously unknown signatures of face processing: This includes category‐specific modulation of the event‐related potential (ERP)'s amplitude even before fixation onset, as well as adaptation effects across subsequent fixations depending on their history.Item Open Access Position-dependent effects of RNA-binding proteins in the context of co-transcriptional splicing(2023) Horn, Timur; Gosliga, Alison; Li, Congxin; Enculescu, Mihaela; Legewie, StefanAlternative splicing is an important step in eukaryotic mRNA pre-processing which increases the complexity of gene expression programs, but is frequently altered in disease. Previous work on the regulation of alternative splicing has demonstrated that splicing is controlled by RNA-binding proteins (RBPs) and by epigenetic DNA/histone modifications which affect splicing by changing the speed of polymerase-mediated pre-mRNA transcription. The interplay of these different layers of splicing regulation is poorly understood. In this paper, we derived mathematical models describing how splicing decisions in a three-exon gene are made by combinatorial spliceosome binding to splice sites during ongoing transcription. We additionally take into account the effect of a regulatory RBP and find that the RBP binding position within the sequence is a key determinant of how RNA polymerase velocity affects splicing. Based on these results, we explain paradoxical observations in the experimental literature and further derive rules explaining why the same RBP can act as inhibitor or activator of cassette exon inclusion depending on its binding position. Finally, we derive a stochastic description of co-transcriptional splicing regulation at the single-cell level and show that splicing outcomes show little noise and follow a binomial distribution despite complex regulation by a multitude of factors. Taken together, our simulations demonstrate the robustness of splicing outcomes and reveal that quantitative insights into kinetic competition of co-transcriptional events are required to fully understand this important mechanism of gene expression diversity.Item Open Access Integrating a dynamic central metabolism model of cancer cells with a hybrid 3D multiscale model for vascular hepatocellular carcinoma growth(2022) Lapin, Alexey; Perfahl, Holger; Jain, Harsh Vardhan; Reuss, MatthiasWe develop here a novel modelling approach with the aim of closing the conceptual gap between tumour-level metabolic processes and the metabolic processes occurring in individual cancer cells. In particular, the metabolism in hepatocellular carcinoma derived cell lines (HEPG2 cells) has been well characterized but implementations of multiscale models integrating this known metabolism have not been previously reported. We therefore extend a previously published multiscale model of vascular tumour growth, and integrate it with an experimentally verified network of central metabolism in HEPG2 cells. This resultant combined model links spatially heterogeneous vascular tumour growth with known metabolic networks within tumour cells and accounts for blood flow, angiogenesis, vascular remodelling and nutrient/growth factor transport within a growing tumour, as well as the movement of, and interactions between normal and cancer cells. Model simulations report for the first time, predictions of spatially resolved time courses of core metabolites in HEPG2 cells. These simulations can be performed at a sufficient scale to incorporate clinically relevant features of different tumour systems using reasonable computational resources. Our results predict larger than expected temporal and spatial heterogeneity in the intracellular concentrations of glucose, oxygen, lactate pyruvate, f16bp and Acetyl-CoA. The integrated multiscale model developed here provides an ideal quantitative framework in which to study the relationship between dosage, timing, and scheduling of anti-neoplastic agents and the physiological effects of tumour metabolism at the cellular level. Such models, therefore, have the potential to inform treatment decisions when drug response is dependent on the metabolic state of individual cancer cells.Item Open Access Salivary cortisol and alpha-amylase as stress markers to evaluate an individualized music intervention for people with dementia : feasibility and pilot analyses(2024) Hillebrand, Mareike Christina; Sindermann, Cornelia; Montag, Christian; Wuttke, Alexandra; Heinzelmann, Rebecca; Haas, Heidrun; Wilz, GabrieleObjectives: We investigated salivary biomarkers of stress, more specifically, cortisol and alpha-amylase, to evaluate effects of individualized music listening (IML) in people with dementia.MethodParticipants were N = 64 nursing home residents with dementia (meanage = 83.53 ± 7.71 years, 68.8% female). Participants were randomly assigned to either listening to their favorite music every other day for a period of six weeks (intervention), or standard care (control). Using the Saliva Children`s Swab (SCS), saliva was collected before, after, and 20 min after IML sessions at the beginning and end of the intervention period for the analysis of salivary alpha-amylase and cortisol.
Results: Using the SCS was feasible in people with dementia. Nevertheless, there was no effect of IML on salivary stress markers.
Discussion: Although using SCS was feasible, active patient engagement is required. Future studies need to corroborate findings in larger samples.
Trial registration: German Clinical Trials Register: DRKS00015641, ISRCTN registry: ISRCTN59052178.