Biology subjects

Dahmen, U.

Publications and source records attributed to Dahmen, U..

5 recordsLinked to original sources

bioRxiv2026

Sepsis Subtypes in Blood and Liver Define Precision Strategy for CXCR2 Blockade

Sepsis is classified into distinct transcriptomic endotypes. Yet specific cellular drivers for those subtypes remain ambiguous. Although dysregulated CXCL8-CXCR1/2 signaling and neutrophil hyperactivation are implicated in severe endotypes, the therapeutic window and organ-specific consequences of CXCR2 antagonism remain unclear. To determine whether murine transcriptomic subtypes (MTSs) recapitulate human consensus transcriptomic subtypes (CTSs) and evaluate how subtype state dictates the efficacy and trade-offs of Danirixin in polymicrobial sepsis. We reanalyzed septic patients whole-blood CITE-seq data to characterize CXCL8- CXCR2 signaling. Using a severity-stratified murine polymicrobial model, we evaluated Danirixins efficacy. Endpoints included 7-day survival, cytokine profiling, and hepatic histology. Early (24-h) multi-compartment assessments of bacterial burden, NETosis, immune infiltration, and paired blood-liver bulk RNA sequencing informed MTS classification and mechanistic insights. Human CTS1 exhibited neutrophil and progenitor expansion, elevated CXCL8/CD11b expression, and reduced CXCR2, defining a hyperactivated, dysregulated myeloid state. Applying CTS-derived gene signatures to murine tissues identified three MTSs correlating with pathogen load and interleukin-6. Human CTS1 dysregulation was mirrored in murine MTS3. Crucially, Danirixin improved 7-day survival in MTS3 sepsis. Conversely, in MTS1, Danirixin attenuated systemic NETosis and hepatic injury but exacerbated bacterial dissemination, without improving survival. Murine transcriptomic subtypes translationally model human sepsis subtypes. In severely dysregulated host-response states (MTS3/CTS1), CXCR2 antagonism effectively mitigates maladaptive, neutrophil-driven immunopathology. However, in less severe subtypes, it compromises early bacterial containment. These findings therefore support for endotype-guided precision targeting of CXCR2 in sepsis. One Sentence SummaryTargeting CXCR2 improves sepsis survival only in a specific molecular subtype, showing that host traits dictate therapeutic outcomes.

systems biology↗

bioRxiv2025

Automated Segmentation of Hepatic Vessels and Lobules in Whole-Slide Images Using U-Net Models

Automated analysis of hepatic vascular structures and lobules within whole-slide histological images is critical for ensuring accurate and timely morphometric evaluations and facilitating advancements in computational liver histology. Nonetheless, the intricate morphology of the tissue, variability in staining techniques, and the requirements for high-resolution imaging present substantial challenges to the precision of segmentation processes. We present a robust deep-learning pipeline using adaptive patch extraction and specialized U-Net architectures for segmenting vessels, bile ducts, and lobules in Glutamine Synthetase and Picro-Sirius-Red stained porcine liver sections. Our architecture incorporates a weight-boosted nnU-Net framework to effectively manage class imbalances and improve the detection of smaller vascular structures. Geometric data transformations enhanced the robustness and generalizability of the segmentation models. Evaluations conducted through five-fold cross-validation, as well as assessments utilizing independent test datasets, resulted in Dice similarity scores: 0.960 for lobules, 0.801 for central veins, 0.909 for hepatic arteries, 0.609 for portal veins, and 0.710 for bile ducts. The developed segmentation pipeline additionally supports comprehensive morphometric analyses of structural parameters, including number and size (diameter, area) of vascular structures, bile ducts, and lobules. For e.g., the diameter of hepatic arteries ranges between 30-90 {micro}m. These findings underscore the practical relevance of adaptable segmentation frameworks in advancing computational histological analysis of liver tissue.

bioinformatics↗

bioRxiv2023

Cross-Species Variability in Lobular Geometry and Cytochrome P450 Hepatic Zonation: Insights into CYP1A2, CYP2E1, CYP2D6 and CYP3A4

This study explores the critical interplay between lobular geometry and the zonated distribution of cytochrome P450 (CYP) enzymes across species. We present an innovative approach to assess lobular geometry and zonation patterns using whole slide imaging (WSI). This method allows a detailed, systematic comparison of lobular structures and spatial distribution of key CYP450 enzymes and glutamine synthetase in four different species (mouse, rat, pig, and human). Our results shed light on species differences in lobular geometry and enzymatic zonation, providing critical insights for drug metabolism research. Based on our approach we could determine the minimum number of lobules required for a statistically representative analysis, an important piece of information when evaluating liver biopsies and deriving information from WSI.

pathology↗

bioRxiv2019

Metabolic control of YAP via the acto-myosin system during liver regeneration

The mechanisms of organ size control remain poorly understood. A key question is how cells collectively sense the overall status of a tissue. We addressed this problem focusing on mouse liver regeneration, which is controlled by Hippo signalling. Using digital tissue reconstruction and quantitative image analysis, we found that the apical surface of hepatocytes forming the bile canalicular network expands concomitant with an increase of F-actin and phospho-Myosin, to compensate an overload of bile acids. Interestingly, these changes are sensed by the Hippo transcriptional co-activator YAP, which localizes to the apical F-actin-rich region and translocates to the nucleus in dependence of the acto-myosin system. This mechanism tolerates moderate bile acid fluctuations under tissue homeostasis, but activates YAP in response to sustained bile acid overload. Using an integrated biophysical-biochemical model of bile pressure and Hippo signalling, we explained this behaviour by the existence of a mechano-sensory mechanism that activates YAP in a switch-like manner. We propose that the apical surface of hepatocytes acts as a self-regulatory mechano-sensory system that responds to critical levels of bile acids as readout of tissue status.

systems biology↗

bioRxiv2017

ModuleDiscoverer: Identification of regulatory modules in protein-protein interaction networks.

The identification of disease associated modules based on protein-protein interaction networks (PPINs) and gene expression data has provided new insights into the mechanistic nature of diverse diseases. A major problem hampering their identification is the detection of protein communities within large-scale, whole-genome PPINs. Current strategies solve the maximal clique enumeration (MCE) problem, i.e., the enumeration of all non-extendable groups of proteins, where each pair of proteins is connected by an edge. The MCE problem however is non-deterministic polynomial time hard and can thus be computationally overwhelming for large-scale, whole-genome PPINs.\n\nWe present ModuleDiscoverer, a novel approach for the identification of regulatory modules from PPINs in conjunction with gene-expression data. ModuleDiscoverer is a heuristic that approximates the community structure underlying PPINs. Based on a high-confidence PPIN of Rattus norvegicus and publicly available gene expression data we apply our algorithm to identify the regulatory module of a rat-model of diet induced non-alcoholic steatohepatitis (NASH). We validate the module using single-nucleotide polymorphism data from independent genome-wide association studies. Structural analysis of the module reveals 10 sub-modules. These sub-modules are associated with distinct biological functions and pathways that are relevant to the pathological and clinical situation in NASH.\n\nModuleDiscoverer is freely available upon request from the corresponding author.

systems biology↗