Biology subjects

Glaser, M.

Publications and source records attributed to Glaser, M..

7 recordsLinked to original sources

bioRxiv2026

Electrical Stunning does not affect Brain Tissue Integrity and Stress Response in Larval Zebrafish

Electrical stunning is a humane euthanasia method for larval zebrafish, and a suitable euthanasia protocol has recently been established. Here, we assess the associated stress response and tissue integrity. When compared to MS-222 overdose and hypothermia, electrical stunning caused no significant Hsp70 increase. Brain tissue was preserved and muscle tissue affected only slightly. Our results support the suitability of electrical stunning for humane euthanasia and artifact-free post-mortem analyses.

systems biology↗

bioRxiv2026

Lysosome-Related Organelles Orchestrate Guanine Crystal Formation in Pigment Cells

Iridosomes, the guanine crystal-forming organelles of pigment-producing iridophores, are among the most versatile, visually striking yet mechanistically uncharacterized organelles in vertebrate biology. Lysosome-related organelles (LROs) support cell type-specific functions by adapting endolysosomal pathways for specialized roles. Here, we show that iridosomes represent a previously unrecognized subtype of LROs. Using transcriptomic profiling of zebrafish iridophores, CRISPR-Cas9-mediated gene disruption, and cryogenic transmission electron microscopy, we define the molecular program underlying iridosome biogenesis. Iridosomes have evolved unique adaptations for crystal growth while retaining core features of other LROs. Key regulators, including RAB32a, AP3M2, and HPS5, are essential for crystal formation, with gene knockouts causing reduced crystal number, altered morphology, and distinct maturation defects. We further identify hallmark LRO features in iridosomes, including intraluminal vesicles and pH-regulated developmental transitions. Cross-species transcriptomic analysis confirms that iridosomes share an LRO signature across vertebrates, including teleost fish and reptiles, suggesting ancient evolutionary origins. These findings establish iridosomes as crystalline LROs and as a model for investigating how cells construct structurally specialized organelles through coordinated trafficking, acid-base regulation, and crystallization, with implications for LRO evolution and human disease.

developmental biology↗

bioRxiv2025

ESM-Effect: An Effective and Efficient Fine-Tuning Framework towards accurate prediction of Mutation's Functional Effect

Predicting functional properties of mutations like the change in enzyme activity remains challenging and is not well captured by traditional pathogenicity prediction. Yet such functional predictions are crucial in areas like targeted cancer therapy where some drugs may only be administered if a mutation causes an increase in enzyme activity. Current approaches either leverage static Protein-Language Model (PLM) embeddings or complex multi-modal features (e.g., static PLM embeddings, structure, and evolutionary data) and either (1) fall short in accuracy or (2) involve complex data processing and pre-training. Standardized datasets and metrics for robust benchmarking would benefit model development but do not yet exist for functional effect prediction. To address these challenges we develop ESM-Effect, an optimized PLM-based functional effect prediction framework through extensive ablation studies. ESM-Effect fine-tunes ESM2 PLM with an inductive bias regression head to achieve state-of-the-art performance. It surpasses the multi-modal state-of-the-art method PreMode, indicating redundancy of structural and evolutionary features, while training 6.7-times faster. In addition, we develop a benchmarking framework with robust test datasets and strategies, and propose a novel metric for prediction accuracy termed relative Bin-Mean Error (rBME): rBME emphasizes prediction accuracy in challenging, non-clustered, and rare gain-of-function regions and correlates more intuitively with model performance than commonly used Spearmans rho. Finally, we demonstrate partial generalization of ESM-Effect to unseen mutational regions within the same protein, illustrating its potential in precision medicine applications. Extending this generalization across different proteins remains a promising direction for future research. ESM-Effect is available at: https://github.com/moritzgls/ESM-Effect.

bioinformatics↗

bioRxiv2023

S100A1ct: a synthetic peptide derived from human S100A1 protein improves cardiac contractile performance and survival in pre-clinical heart failure models

BackgroundThe EF-hand Ca2+ sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. S100A1s ability to recognize and modulate the activity of targets such as SERCA2a and RyR2 in cardiomyocytes has mostly been ascribed to its hydrophobic C-terminal -helix (residues 75-94). Objective: We therefore hypothesized that a synthetic peptide consisting of residues 75-94 of S100A1 and an N-terminal solubilization tag (S100A1ct) could mimic the performance enhancing effects of S100A1 and may be suitable as a peptide therapeutic to improve the function of diseased hearts. Methods and Results: Applying an integrative translational research pipeline, ranging from computational molecular modeling to large animal cardiac disease models, we characterize S100A1ct as a cell-penetrating peptide with positive inotropic and antiarrhythmic properties in normal and failing myocardium in vitro and in vivo. This activity translates into improved contractile performance and survival in pre-clinical heart failure models with reduced ejection fraction after S100A1ct systemic administration. Mechanistically, S100A1ct exerts a fast and sustained dose-dependent enhancement of cardiomyocyte Ca2+ cycling and prevents {beta}-adrenergic receptor triggered Ca2+ imbalances by targeting SERCA2a and RyR2 activity. Modeling suggests that S100A1ct may stimulate SERCA2a by interacting with the sarcoplasmic transmembrane segments of the multi-span integral membrane Ca2+ pump. Incorporation of a cardiomyocyte targeting peptide tag into S100A1ct (cor-S100A1ct) further enhanced its biological and therapeutic potency in vitro and in vivo. Conclusion: S100A1ct peptide is a promising lead for the development of a novel peptide-based therapeutic against heart failure with reduced ejection fraction.

pharmacology and toxicology↗

bioRxiv2023

SUMO interacting motif (SIM) of S100A1 is critical for S100A1 post-translational protein stability

S100A1 is a small EF-type Ca2+ sensor protein that belongs to the multigenic S100 protein family. It is abundantly expressed in cardiomyocytes (CMs) and has been described as a key regulator of CM performance due to its unique ability to interact with structural contractile proteins, regulators of cardiac Ca2+ cycling, and mitochondrial proteins. However, our understanding of the molecular mechanisms regulating S100A1 protein levels is limited. We used the bioinformatics tool GPS-SUMO2.0 to identify a putative SUMO interacting motif (SIM) on S100A1. Consistently, a S100A1:SUMO interaction assay showed a Ca2+-dependent interaction of S100A1 with SUMO proteins. In neonatal rat ventricular myocytes (NRVM) and COS1 cells, S100A1 protein abundance increased in the presence of overexpressed SUMO1 without affecting the S100A1 mRNA transcript. We then generated S100A1 truncation mutants, where the SIM motif was removed by truncation or in which the core residues of the SIM motif (residues 77-79) were deleted or replaced by alanine. In COS1 cells and NRVM, overexpression of these S100A1 mutants led to elevated S100A1 mutant mRNA levels but failed to produce respective protein levels. Protein expression of these mutants could be rescued from degradation by addition of the proteasome inhibitor MG-132. By using an information-driven approach to dock the three-dimensional structures of S100A1 and SUMO, we predict a novel interaction mode between the SIM in S100A1 and SUMO. This study shows an important role of SUMO:SIM-mediated protein:protein interaction in the regulation of post-translational protein stability, and provides mechanistic insights into the indispensability of the core SIM for S100A1 post-translational stability.

biochemistry↗

bioRxiv2021

A science friction story. Molecular interactions in semiflexible polymer networks

Established model theories, developed to capture the mechanical behavior of soft complex materials composed of semiflexible polymers assume entropic interactions between filaments to determine the mechanical response. In recent studies, the general accepted tube model has been challenged in terms of its basic assumption about filament-filament interactions, but also because of its predictions regarding the frequency dependence of the elastic modulus in the intermediate frequency regime. A central question is how molecular interactions and friction between network constituents influence the rheological response of isotropic entangled networks of semiflexible polymers. It was shown that friction forces between aligned pairs of actin filaments are not negligible. Here, we systematically investigate the influence of friction forces and attractive interactions on network rheology by means of a targeted surface modification. We show that these forces have a qualitative and quantitative influence on the viscoelastic properties of semiflexible polymer networks and contribute to the response to nonlinear deformations. By comparing two polymer model systems with respect to their surface compositions we give a possible explanation about the origin of acting forces on a molecular level.

biophysics↗

bioRxiv2018

Cortical network fingerprints predict deep brain stimulation outcome in dystonia

BackgroundDeep brain stimulation (DBS) is an effective evidence-based therapy for dystonia. However, no unequivocal predictors of therapy responses exist. We investigate whether patients optimally responding to DBS present distinct brain network organization and structural patterns.\n\nMethodsBased on a German multicentre cohort of eighty-two dystonia patients with segmental and generalized dystonia, who received DBS implantation in the globus pallidus internus patients were classified based on the clinical response 36 months after DBS, as superior-outcome group or moderate-outcome group, as above or below 70% motor improvement, respectively. Fifty-one patients met MRI-quality and treatment response requirements (mean age 51.3 {+/-} 13.2 years; 25 female) and were included into further analysis. From preoperative MRI we assessed cortical thickness and structural covariance, which were then fed into network analysis using graph theory. We designed a support vector machine to classify subjects for the clinical response based on group network properties and individual grey matter fingerprints.\n\nResultsThe moderate-outcome group showed cortical atrophy mainly in the sensorimotor and visuomotor areas and disturbed network topology in these regions. From all the structural integrity of the cortical mantle explained about 45% of the stimulation amplitude. Classification analyses achieved 88% of accuracy using individual grey matter atrophy patterns to predict DBS outcome.\n\nConclusionsThe analysis of cortical integrity and network properties could be developed into independent predictors to identify dystonia patients who benefit from DBS.

neuroscience↗