Biology subjects

Schindler, S.

Publications and source records attributed to Schindler, S..

10 recordsLinked to original sources

bioRxiv2025

Early neural responses to nonconscious fearful and neutral faces - an ERP study

Prioritized processing of fearful compared to neutral faces is reflected in differential event-related potentials (ERPs). There is an ongoing debate about the extent to which faces in general and fearful faces in particular enhance specific ERPs if they are not consciously perceived. Specifically, the N170 has been suggested as the most likely candidate for enhanced processing of nonconscious fearful faces. In this pre-registered study, we tested in a large sample based on sequential Bayesian sampling (N = 64) whether early components of the ERP (P1, N170, and early posterior negativity; EPN) discriminate between fearful faces, neutral faces, and non-facial control stimuli. Consciousness was manipulated by presenting stimuli for 17 ms in a backward masking design, with the mask following immediately or after a delay of 200 ms. Participants rated their subjective perception on a perceptual awareness scale in each trial. Importantly, only trials in which nothing but the mask was perceived were considered for the analysis of nonconscious effects. The results showed strong evidence for an increased N170 in response to nonconscious fearful compared to neutral faces; however, this difference was significantly smaller than in the conscious condition. Furthermore, we obtained strong evidence for N170 differences between nonconscious faces and no-faces. For P1 and EPN amplitudes, no significant effects were observed in the nonconscious conditions, although exploratory analyses of the P1 peak interval suggest nonconscious face-no-face differentiation. These results support the notion that nonconscious emotion and face processing are detectable in early neural responses and show that these nonconscious effects are considerably weaker than the corresponding conscious effects.

neuroscience↗

bioRxiv2024

Retinoic acid signaling suppresses chondrocyte identity during cartilage development and regeneration

Cartilage is a dynamic tissue during development, repair, and disease. Within developing endochondral bones, chondrocytes at growth plate edges transition to osteoblasts, adipocytes, and other connective tissue in the marrow cavity, and in diseases such as Multiple Osteochondromas (MO) chondrocytes form abnormally around growth plates and contribute to ectopic bone. On the other hand, the inability to form new chondrocytes to maintain damaged joints contributes to the high incidence of osteoarthritis. In order to assess the ability of zebrafish to regenerate cartilage, we developed a nitroreductase-based cartilage ablation model. Following ablation at larval to adult stages, we observed new chondrocytes forming around the dead cartilage matrix, with cartilage outgrowths in ablated endochondral bones resembling the exostoses of MO. By generating a perichondrium-restricted hyal4:GFP transgenic line, we show that new chondrocytes arise from the perichondrium surrounding the ablated cartilage. In addition, we observe enriched expression of the retinoic acid (RA) synthesis gene aldh1a2 in the perichondrium following ablation, and the RA degrading enzyme gene cyp26b1 in newly forming chondrocytes. Consistent with RA signaling suppressing chondrogenesis, treatment with the RA receptor gamma agonist palovarotene, which has been used to treat MO, prevented ablation-induced chondrogenesis. Although we find that BMP signaling is also required for ablation-induced chondrogenesis, we show a distinct role for RA signaling in suppressing sox9a expression and chondrogenesis. Moreover, palovarotene resulted in a near complete loss of growth plates in uninjured zebrafish, which was due to the precocious dedifferentiation and exit of chondrocytes from the growth plate. Our findings suggest a common chondrocyte suppressive role of RA signaling within the developing growth plates and regenerating perichondrium, which may explain the growth plate defects observed when using RA agonists to treat MO.

developmental biology↗

bioRxiv2024

Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST

Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models in mice. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From this data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

molecular biology↗

bioRxiv2023

High-resolution spatial multi-omics reveals cell-type specific nuclear compartments

The mammalian nucleus is compartmentalized by diverse subnuclear structures. These subnuclear structures, marked by nuclear bodies and histone modifications, are often cell-type specific and affect gene regulation and 3D genome organization1-3. Understanding nuclear organization requires identifying the molecular constituents of subnuclear structures and mapping their associations with specific genomic loci in individual cells, within complex tissues. Here, we introduce two-layer DNA seqFISH+, which allows simultaneous mapping of 100,049 genomic loci, together with nascent transcriptome for 17,856 genes and a diverse set of immunofluorescently labeled subnuclear structures all in single cells in cell lines and adult mouse cerebellum. Using these multi-omics datasets, we showed that repressive chromatin compartments are more variable by cell type than active compartments. We also discovered a single exception to this rule: an RNA polymerase II (RNAPII)-enriched compartment was associated with long, cell-type specific genes (> 200kb), in a manner distinct from nuclear speckles. Further, our analysis revealed that cell-type specific facultative and constitutive heterochromatin compartments marked by H3K27me3 and H4K20me3 are enriched at specific genes and gene clusters, respectively, and shape radial chromosomal positioning and inter-chromosomal interactions in neurons and glial cells. Together, our results provide a single-cell high-resolution multi-omics view of subnuclear compartments, associated genomic loci, and their impacts on gene regulation, directly within complex tissues.

genomics↗

bioRxiv2022

Fitness benefits from co-display favour subdominant male-male partnerships between phenotypes

Male-male competition over matings is a key driving force in the evolution of courtship. Typically, competition is an individual affair selecting for dominance and aggression. Yet, some males forgo direct confrontation and improve their reproductive success through cooperation. Occasionally, this leads to specialized alternative reproductive tactics that operate at the intersection of cooperation and conflict. We used a community game model, informed with empirical data derived from previous studies, to examine cooperation dynamics between lekking male ruffs (Calidris pugnax) using two different tactics: resident and satellite. Residents defend display courts against other residents on leks. In contrast, satellites forgo court defence and engage in cooperative co-display with selected residents. Co-displaying appears to alter female mate choice, yet the exact mechanism and consequences remain unclear. We modelled individual male mating success as a function of lek size, resident rank, and satellite competitiveness. Our most realistic model assumed that co-display draws copulations from residents proportional to the existing mating skew among them. Under this assumption, all residents benefit from co-display over single display when a satellite is on the lek, except for -residents co-displaying with the most competitive satellites on large leks. Thus, satellites could nearly always choose their preferred co-display partner, but achieved the highest copulation rates with lower ranking (subdominant) residents on intermediate sized leks. Co-display between the satellite and lower ranking residents reduced the mating skew among residents. However, since copulations for satellites were similar over a range of potential co-display partners, a variety of co-displaying dyads is to be expected, which is consistent with observations in nature. We conclude that, given our model assumptions, co-displaying reduces the impact of male dominance on reproductive success and ultimately alters the course of sexual selection.

evolutionary biology↗

bioRxiv2021

Integrated spatial genomics in tissues reveals invariant and cell type dependent nuclear architecture

Nuclear architecture in tissues can arise from cell-type specific organization of nuclear bodies, chromatin states and chromosome structures. However, the lack of genome-wide measurements to interrelate such modalities within single cells limits our overall understanding of nuclear architecture. Here, we demonstrate integrated spatial genomics in the mouse brain cortex, imaging thousands of genomic loci along with RNAs and subnuclear markers simultaneously in individual cells. We revealed chromatin fixed points, combined with cell-type specific organization of nuclear bodies, arrange the interchromosomal organization and radial positioning of chromosomes in diverse cell types. At the sub-megabase level, we uncovered a collection of single-cell chromosome domain structures, including those for the active and inactive X chromosomes. These results advance our understanding of single-cell nuclear architecture in complex tissues.

systems biology↗

bioRxiv2020

The molecular basis for a temperature-sensitive Mycobacterium smegmatis glgE mutant

BackgroundThe bacterial GlgE pathway is the third known route to glycogen and is the only one present in mycobacteria. It contributes to the virulence of Mycobacterium tuberculosis. The involvement of GlgE in glycogen biosynthesis was discovered twenty years ago when the phenotype of a temperature-sensitive Mycobacterium smegmatis mutation was rescued by the glgE gene. The evidence at the time suggested glgE coded for a glucanase responsible for the hydrolysis of glycogen, in stark contrast with recent evidence showing GlgE to be a polymerase responsible for its biosynthesis. MethodsWe reconstructed and examined the temperature-sensitive mutant and characterised the mutated GlgE enzyme. ResultsThe mutant strain accumulated the substrate for GlgE, -maltose-1-phosphate, at the non-permissive temperature. The glycogen assay used in the original study was shown to give a false positive result with -maltose-1-phosphate. The accumulation of -maltose-1-phosphate was due to the lowering of the kcat of GlgE as well as a loss of stability 42 {o}C. The reported rescue of the phenotype by GarA could potentially involve an interaction with GlgE, but none was detected. ConclusionsWe have been able to reconcile apparently contradictory observations and shed light on the basis for the phenotype of the temperature-sensitive mutation. General SignificanceThis study highlights how the lowering of flux through the GlgE pathway can slow the growth mycobacteria.

biochemistry↗

bioRxiv2019

Altered hypothalamic microstructure in human obesity

Obesity is a multifactorial disorder driven by sustained energy imbalance. The hypothalamus is an important regulator of energy homeostasis and therefore likely involved in obesity pathophysiology. Animal studies suggest that obesity-related diets induce structural changes in the hypothalamus through inflammation-like processes. Whether this translates to humans is however largely unknown. Therefore, we aimed to assess obesity-related differences in hypothalamic macro- and microstructure based on a multimodal approach using T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) acquired at 3 Tesla in a large well-characterized sample of the Leipzig Research Center for Civilization Diseases (LIFE) cohort (n1 = 338, 48% females, age 21-78 years, BMI 18-43 kg/m2). We found that higher body mass index (BMI) selectively predicted higher mean proton diffusivity (MD) within the hypothalamus, indicative of compromised microstructure in the underlying tissue. Results were independent from confounders and confirmed in another independent sample (n2 = 236). In addition, while hypothalamic volume was not associated with obesity, we identified a sexual dimorphism and larger hypothalamic volumes in the left compared to the right hemisphere. Using two large samples of the general population, we showed that a higher BMI specifically relates to altered microstructure in the hypothalamus, independent from confounders such as age, sex and obesity-associated co-morbidities. This points to persisting microstructural changes in a key regulatory area of energy homeostasis occurring with excessive weight. These findings may help to better understand the pathomechanisms of obesity and other eating-related disorders.

neuroscience↗

bioRxiv2017

Predicting The Evolutionary Consequences Of Trophy Hunting On A Quantitative Trait

Some ecologists suggest that trophy hunting (e.g. harvesting males with a desirable trait above a certain size) can lead to rapid phenotypic change, which has led to an ongoing discussion about evolutionary consequences of trophy hunting. Claims of rapid evolution come from the statistical analyses of data, with no examination of whether these results are theoretically plausible. We constructed simple quantitative genetic models to explore how a range of hunting scenarios affects the evolution of a trophy such as horn length. We show that trophy hunting does lead to trophy evolution defined as change in the mean breeding value of the trait. However, the fastest rates of phenotypic change attributable to trophy hunting via evolution that are theoretically possible under standard assumptions of quantitative genetics are 1 to 2 orders of magnitude slower than the fastest rates reported from statistical analyses. Our work suggests a re-evaluation of the likely evolutionary consequences of trophy hunting would be appropriate when setting policy. Our work does not consider the ethical or ecological consequences of trophy hunting.

evolutionary biology↗

bioRxiv2016

Adaptive and Non-adaptive Responses of Populations to Environmental Change

Understanding how the natural world will be impacted by environmental change over the coming decades is one of the most pressing challenges facing humanity. Addressing this challenge is difficult because environmental change can generate both population level plastic and evolutionary responses, with plastic responses being either adaptive or non-adaptive. We develop an approach that links quantitative genetic theory with data-driven structured models to allow prediction of population responses to environmental change via plasticity and adaptive evolution. After introducing general new theory, we construct a number of example models to demonstrate that evolutionary responses to environmental change over the short-term will be considerably slower than plastic responses, and that the rate of adaptive evolution to a new environment depends upon whether plastic responses are adaptive or non-adaptive. Parameterization of the models we develop requires information on genetic and phenotypic variation and demography that will not always be available, meaning that simpler models will often be required to predict responses to environmental change. We consequently develop a method to examine whether the full machinery of the evolutionarily explicit models we develop will be needed to predict responses to environmental change, or whether simpler non-evolutionary models that are now widely constructed may be sufficient.

evolutionary biology↗