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Koch, K.

Publications and source records attributed to Koch, K..

9 recordsLinked to original sources

A synthetic MALDI-TOF MS atlas for microbial classification across hospitals

Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) mass spectrometry (MS) is central to routine clinical microbiology for species identification. Its combination with machine learning is constrained by fragmented public datasets, species imbalance and acquisition-related variability. Synthetic datasets could provide more training data, but they must preserve the spectral information needed to make predictions on real samples. Here, we present an open, synthetic MALDI-TOF MS atlas comprising 4.3 million spectra across 43 clinically relevant bacterial species. To construct the atlas, we harmonised public repositories from three countries and trained a species- and institution-conditioned concept-bottleneck generative variational autoencoder (CBGM-VAE) on 179,086 measured spectra. We assessed the atlas as both a stand-alone training resource and a complement to real data, using bacterial species classification as a functional benchmark. Evaluation comprised 7,269 real spectra from more than 7 countries, 24 institutions and multiple acquisition platforms, covering: temporal, technical, biological and combined shifts. A neural network trained only on synthetic spectra achieved F1 scores ranging from 0.788 to 1.000 across external cohorts. When synthetic spectra were combined with real training data, classification performance improved or matched using real data only. These findings demonstrate that the atlas retains transferable information and can complement measured data. The openly released atlas provides a reusable resource for supervised learning and benchmarking. It can also be explored for pretraining representation-learning and foundation models in MALDI-TOF MS research.

microbiology↗

Expression patterns and interaction profiles of heterotrimeric transducin subunits in the retina of the European robin ( Erithacus rubecula )

The heterotrimeric G-protein transducin (Gt) is mediating phototransduction in rod and cone cells of the vertebrate retina, but its expression patterns in migratory songbirds is unknown. We characterised Gt expression in the European robin, a night-migratory songbird known for its light-dependent magnetoreception. One well-supported hypothesis of magnetoreception involves radical-pair formation in the blue light receptor cryptochrome type 4a. The - and {gamma}-subunits of cone specific transducin have been identified as possible interaction partners of cryptochrome 4a. Therefore, we analysed the expression patterns of various G-protein subunits in bird photoreceptors by combining single cell RNA sequencing and immunohistochemistry. Protein-protein interaction was tested by pulldown, co-immunoprecipitation, and NanoBiT luminescence assays. G-protein subunits Gt{beta}1 and Gt{beta}3 are predominantly expressed in rods and cones, and Gt{gamma}T2 was the principal isoform in cones, whereas Gt{gamma}11 was associated with rods. In contrast, we did not detect Gt{gamma}10 expression in either photoreceptor type. Interaction assays demonstrated that all three {beta}{gamma} combinations; {beta}{gamma}T2, {beta}{gamma}10, and {beta}{gamma}11, can associate in vitro. These findings indicate that {beta}{gamma} dimer formation in vivo is likely constrained by the photoreceptor-specific expression of the respective subunits. The absence of Gt{gamma}10 expression in rods and cones does not support a role in photoreceptor-based magnetoreception.

Molecular Biology↗

ToxCastLite: A portable semantic evidence graph linking in vitro bioactivity, in vivo toxicity, and exposure-use context

MotivationThe ToxCast database is a valuable resource for computational toxicology and new approach methodologies (NAMs), but the approximately 100 GB MySQL distribution is difficult to use for portable local analysis and cross-domain evidence mining. Many practical questions concern chemicals, in vitro bioactivity, in vivo toxicological evidence, and exposure-relevant product-use context rather than raw database keys. ResultsWe present ToxCastLite, a portable semantic evidence-access system that combines assay-scoped SQLite databases with a compact RDF layer for GraphDB-based querying. The system streams large ToxCast/invitrodb MySQL dumps into curated SQLite profiles, reducing the footprint to approximately 3 GB for focused use cases such as developmental neurotoxicity. Dense numerical evidence, including concentration-response rows, remains in SQLite, while the RDF projection exposes linked semantic entities such as chemicals, assays, endpoints, model results, potency parameters (AC50), and MC6 quality flags. We further extend the graph with CPDat v4.0 product-use and functional-use evidence and ToxRefDB v3.0 in vivo toxicity evidence, including processed studies, point-of-departure records, effect summaries, and observation summaries. These layers are linked through DSSTox Substance Identifiers, enabling integrated queries across NAM bioactivity, curated animal-study evidence, and exposure/use context. A Streamlit prototype supports exploration through a locally deployed LLM that translates natural-language questions into SPARQL, grounded by a versioned RDF schema to reduce hallucination risk. Case studies in developmental neurotoxicity demonstrate how ToxCastLite identifies concordance between high-confidence in vitro DNT activity and positive in vivo apical evidence, detects in vitro DNT activity beyond available DNT-specific in vivo evidence, and prioritizes chemicals where NAM signals, ToxRefDB evidence, and CPDat product-use context intersect. For selected results, users can drill down from the semantic graph to the underlying SQLite records and retrieve concentration-response curves for expert inspection without manually writing SQL or SPARQL. AvailabilityProject website at toxcast-lite.github.io/. Contactarif.doenmez@iuf-duesseldorf.de

bioinformatics↗

Endothelial YAP/TAZ rewiring under cardiometabolic stress drives sex-divergent vascular remodeling in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is widely linked to endothelial dysfunction, yet the molecular pathways translating cardiometabolic stress into microvascular remodeling remain poorly defined. Here, we identify endothelial YAP/TAZ signaling as a mechanistic regulator of sex-divergent vascular responses in HFpEF. Plasma proteomics from the UK Biobank revealed elevated circulating YAP1 levels associated with heart failure and increased mortality, particularly in male patients, where YAP1 coincided with increased levels of the endothelial activation marker ESM1. In a hypertensive cardiorenal mouse model, endothelial YAP/TAZ deletion preserved cardiac function, whereas endothelial TAZ gain-of-function aggravated disease. Under cardiometabolic stress (TNF and high glucose), endothelial cells exhibited sex-specific rewiring of YAP/TAZ-dependent transcriptional programs. Male endothelial cells showed increased extracellular YAP1 release, angiogenic instability with impaired extracellular matrix remodeling, whereas female cells adopted an immune-primed, stress-adaptive phenotype. Mechanistically, cardiometabolic stress uncoupled canonical YAP-TEAD transcription and engaged alternative cofactors, including VGLL3 and VGLL4, thereby reshaping the endothelial secretome and propagating sex-divergent microvascular remodeling. These findings identify endothelial YAP/TAZ rewiring as a molecular switch that converts cardiometabolic stress into sex-divergent microvascular remodeling in HFpEF and connect this process to circulating YAP1 and ESM1 in patients.

cell biology↗

Inhibitory control and error processing in Obsessive-Compulsive Disorder: A mega-analysis of task-based fMRI data by the ENIGMA-OCD consortium

ObjectiveObsessive-compulsive disorder (OCD) is a chronic condition in which impaired inhibitory control and excessive error monitoring may contribute to the maintenance of obsessions and compulsions. This mega-analysis investigates neural activation during response inhibition and error processing using adult and pediatric data from the ENIGMA-OCD consortium and the ABCD study. MethodsIndividual participant data was uniformly processed using HALFpipe to extract statistical maps for response inhibition and error processing contrasts. Bayesian multilevel models were used to assess regional and whole-brain effects of OCD, with additional analyses examining the association between the OCD clinical profile and task-related activation. ResultsAcross inhibitory control tasks, both individuals with OCD and control participants showed robust activation in regions implicated in response inhibition and error processing. During response inhibition, compared to controls, adults with OCD showed stronger somatomotor cortex activation, while children with OCD showed stronger occipital cortex activation. Children with likely OCD from the ABCD cohort showed reduced activity in the frontoparietal network in the anterior insula/frontal operculum region. During error processing, relative to controls, adults with OCD showed weaker activation in fronto-striatal regions, while children with OCD showed stronger activation in frontoparietal and attention networks. Greater OCD symptom severity was associated with weaker task-related activation in adults and stronger activation in children during response inhibition. ConclusionCase-control differences in brain activation during inhibitory control varied by age group and task contrast. Symptom severity emerged as the main clinical correlate of activation during inhibition, suggesting that inhibitory control deficits in OCD may be both state-dependent and developmentally specific.

neuroscience↗

Preconditioning of human iPSCs with doxorubicin causes genome-wide transcriptional reprogramming in iPSC-derived cardiomyocytes linked to mitochondrial dysfunction and impaired cardiac regeneration

BackgroundThe anthracycline doxorubicin (Dox) is a widely used genotoxic chemotherapeutic drug with known dose-limiting cardiotoxic effects. How Dox-induced damage either to cardiomyocytes or to cardiac stem cells, which may compromise cardiac regeneration, contributes to cardiotoxicity remains poorly understood. MethodsHere we used a human induced pluripotent stem cell (iPSC)-based model system to determine the sensitivity of stem cells (iPSCs) and iPSC-derived derived cardiomyocytes (iCMs) applying different treatment regimens of Dox. Next to a broad range of methods to determine cellular and mitochondrial functions we performed an in-depth whole genome transcriptome profiling in iPSCs as well as iCMs. ResultsAs compared to their differentiated counterparts, iPSCs are highly sensitive against even short pulse-treatments with low Dox concentrations. Using such rather mild treatment conditions, we observed major mitochondrial impairments as demonstrated by increased mitochondrial fragmentation, persistent loss of mitochondrial membrane potential, and reduced ATP levels, while neither a markedly increased nuclear DNA damage response nor apoptosis were detected. Albeit mitochondrial dysfunction was not accompanied by changes in mitochondrial ultrastructure or altered OXPHOS complex assembly, mitochondrial genome (mtDNA) organization was altered. This points to a possible role of mtDNA remodelling for contributing to the high susceptibility of iPSCs to Dox. Whole genome transcriptome profiling revealed major differences in the transcriptional response to Dox treatment between iPSCs and iCMs. We could show that a moderate and transient exposure of iPSCs to Dox is sufficient to cause major transcriptional changes as for example reflected by the downregulation of numerous pivotal genes regulating cellular homeostasis and energy metabolism in iPSCs. Furthermore, pulse-treatment with Dox at the iPSC stage, termed preconditioning here, shifts the global transcriptional landscape of iCMs towards the expression of genes associated with impaired cardiac muscle regeneration, disrupted energy metabolism, altered muscle contraction, and increased fibrosis. ConclusionsOur findings support the hypothesis that Dox-induced mitochondrial dysfunction and transcriptional preconditioning in stem cells results in an impaired regenerative capacity after differentiation. This highlights a potential critical role of stem cells in mediating Dox-induced cardiotoxicity.

cell biology↗

Molecular and functional characterization of different BrainSphere models for use in neurotoxicity testing on microelectrode arrays

The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently developed which are based on human induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differentiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction protocols yielded nearly 100 % nestin-positive hiPSC-derived neural progenitor cells (hiNPCs) yet with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed applying such MEA-based spike sorting. These models are not only promising tools in toxicology but also for drug development and disease modeling.

neuroscience↗

White Matter Microstructure and its Relation to Clinical Features of Obsessive-Compulsive Disorder: Findings from the ENIGMA OCD Working Group

ImportanceMicrostructural alterations in cortico-subcortical connections are thought to be present in Obsessive-Compulsive Disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. ObjectiveTo investigate microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. Design, Setting, and ParticipantsIn this cross-sectional case-control magnetic resonance study, we investigated diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA-OCD Working Group. Main Outcomes and MeasuresWe extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohens d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. ResultsAdult OCD patients showed significant FA reduction in the sagittal stratum (d=-0.21, z=-3.21, p=0.001) and posterior thalamic radiation (d=-0.26, z=-4.57, p<0.0001). In the sagittal stratum only, lower FA was associated with a younger age of onset (z=2.71, p=0.006), longer duration of illness (z=-2.086, p=0.036) and a higher percentage of medicated patients in the cohorts studied (z=-1.98, p=0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to matched controls. Conclusions and RelevanceMicrostructural alterations in projection and association fibers to posterior brain regions were found in adult OCD, and related to disease course and medication status. Such results are relevant to models positing deficits in connectivity as a crucial mechanism in OCD. KEY POINTSO_ST_ABSQuestionC_ST_ABSDo patients with Obsessive-Compulsive Disorder (OCD) show white matter microstructural alterations, and are these alterations related to clinical features? FindingsData from 19 sites of the ENIGMA-OCD Consortium were included, involving 700 adult patients and 645 adult controls, 174 pediatric patients and 144 pediatric controls. Diffusion tensor imaging data were meta-analyzed using a harmonized data processing and analysis protocol. Adult, but not pediatric, patients showed alterations in the sagittal stratum and posterior thalamic radiation; sagittal stratum differences were associated with clinical features. MeaningMicrostructural abnormalities found in adult but not in the pediatric cohort, are related to illness duration and medication status.

neuroscience↗

Shared vulnerability for connectome alterations across psychiatric and neurological brain disorders

Macroscale white matter pathways form the infrastructure for large-scale communication in the human brain, a prerequisite for healthy brain function. Conversely, disruptions in the brains connectivity architecture are thought to play an important role in a wide range of psychiatric and neurological brain disorders. Here we show that especially connections important for global communication and network integration are involved in a wide range of brain disorders. We report on a meta-analytic connectome study comprising in total 895 patients and 1,016 controls across twelve neurological and psychiatric disorders. We extracted disorder connectome fingerprints for each of these twelve disorders, which were then combined into a cross-disorder disconnectivity involvement map, representing the involvement of each brain pathway across brain disorders. Our findings show connections central to the brains infrastructure are disproportionally involved across a wide range of disorders. Connections critical for global network communication and integration display high disturbance across disorders, suggesting a general cross-disorder involvement and importance of these pathways in normal function. Taken together, our cross-disorder study suggests a convergence of disconnectivity across disorders to a partially shared disconnectivity substrate of central connections.

neuroscience↗