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Nanoscale dynamics of enhancer-promoter interactions during exit from pluripotency
No full textThis Zenodo repository contains data generated for our manuscript. It contains: fig1.csv: Color/shift corrected, pairwise enhancer-promoter coordinates [µm] and distances [µm], in naive and primed mouse embryonic stem cells (mESCs), measured with a spinning disk confocal microscope. Related to Fig 1. fig2.csv: Multiway enhancer-promoter coordinates [µm] and distances for promoters with all their enhnacers [µm], in naive and primed mESCs, measured with a STED mircoscope. Related to Fig 2 D-G and Supplementary Fig S9. fig3.csv: Coordinates [µm] and distances between the promoter [µm] (Nanog or Dppa3), its closest ehnacer and closest intron RNA, in naive mESCs, measured with a STED microscope in confocal mode. Related to Fig 3 and Supplementary Fig S10 C. figS10.csv: Coordinates [µm] and distances between the Nanog promoter [µm], its 3 enhancers (-5, -45, +60) and closest intron RNA, in naive mESCs, measured with a STED microscope. Related to Supplementary Fig S10 D. region_coordinates_mm9.bed: Target names (promoters and enhnacers by the distance from their promoter) and the coordinates of the probed genomic region in mm9
IL-36 signaling as a drug target in Crohn's disease patients with IL36RN mutations
No full textThis archive contains transcriptomic raw count data and accompanying metadata used to reproduce the analyses presented in the publication: Hecker J et al. IL-36 signaling as a drug target in Crohn's disease patients with IL36RN mutations. EMBO Mol Med. 2025
PocketVina enables scalable and highly accurate physically valid docking through multi-pocket conditioning
No full textSampling physically valid ligand-binding poses remains a major challenge in molecular docking, particularly for unseen or structurally diverse targets. We introduce PocketVina, a fast and memory-efficient, search-based docking framework that combines pocket prediction with systematic multi-pocket exploration. We evaluate PocketVina across four established benchmarks—PDBbind2020 (timesplit and unseen), DockGen, Astex, and PoseBusters—and observe consistently strong performance in sampling physically valid docking poses. PocketVina achieves state-of-the-art performance when jointly considering ligand r.m.s.d. and physical validity (PB-valid), while remaining competitive with deep learning–based approaches in terms of r.m.s.d. alone, particularly on structurally diverse and previously unseen targets. PocketVina also maintains state-of-the-art physically valid docking accuracy across ligands with varying degrees of flexibility. We further introduce TargetDock-AI, a benchmarking dataset we curated, consisting of over 500,000 protein–ligand pairs, and a partition of the dataset labeled with PubChem activity annotations. On this large-scale dataset, PocketVina successfully discriminates active from inactive targets, outperforming a deep learning baseline while requiring significantly less GPU memory and runtime. PocketVina offers a robust and scalable docking strategy that requires no task-specific training and runs efficiently on standard GPUs, making it well-suited for high-throughput virtual screening and structure-based drug discovery
MRI-scale histology validates spatial sensitivity of in-vivo MRI-based axon radius estimation
Get PDFThe axon radius holds promise as a clinical MRI biomarker for neurological disorders. However, in-vivo MRI estimation appears infeasible on clinical scanners and lacks experimental validation. Crucially, existing histology is only sparsely sampled, enabling primarily qualitative assessment. Here, we use large-scale human brain histology, sampling 46 million axons across 35 corpus callosum regions with MRI-like sizes. By demonstrating a significant spatial correlation with histology on an advanced research scanner, we provide quantitative proof that MRI radius estimates reflect underlying microstructure—a critical milestone. The next milestone—translation to clinical scanners—appears feasible with now-available high-gradient systems according to simulations, but would require substantial SNR gains. Yet, we also identify a sensitivity bottleneck in current modeling that may offer a complementary path to improved sensitivity through future modeling advances. Overall, we provide promising evidence for the validity of MRI-based axon radius estimation and identify challenges that must be solved for clinical adoption
Ex-vivo dataset for validation of MRI-based axon radius mapping
No full textThe dataset provides histological axon radius distributions and ex-vivo dMRI data used in "MRI-scale histology validates spatial sensitivity of in-vivo MRI-based axon radius estimation" (Imaging Neuroscience, 2025, https://doi.org/10.1162/IMAG.a.1030). The dataset includes axon radius distributions of two human corpus callosum tissue samples scanned with histology (light microscopy); one of the samples was also scanned with ex-vivo diffusion MRI
Extended supplementary data for manuscript: Gene regulatory mechanisms of cellular memory of a single cocaine exposure in VTA dopaminergic neurons
No full textDrug addiction is a chronic brain disease with major global health and economic costs. Many drugs of abuse hijack reward circuitry, reinforcing drug-taking behaviour. While drug effects on synaptic plasticity are transient, the gene regulatory mechanisms driving long-term memory of drug exposure remain unclear. We assessed gene expression and chromatin accessibility in ventral tegmental area dopamine neurons (VTA-DNs) in a time-course following acute cocaine exposure. Expression changes persist for 14 days, including upregulation of addiction-associated neuropeptides, while AP-1 chromatin binding sites shift from early stimulus-driven activity to sustained silencing. We show downregulation of Foxa2 and its targets, followed by erosion of DN identity lasting up to 14 days, and sustained upregulation of Polycomb-repressed genes. We show that a single cocaine exposure is sufficient to trigger enduring transcriptional and epigenetic changes in reward-associated neurons as memory of drug exposure, and provide a high-resolution temporal map of cocaine-induced regulatory plasticity as groundwork for finding molecular targets that drive addiction onset
Clonally expanded effector CD4+ cytotoxic T lymphocytes are associated with severe neurological adverse events after immune checkpoint inhibitor therapy
No full textImmune checkpoint inhibitor (ICI) therapies present a pillar of modern cancer therapy but can cause severe and potentially fatal neurological immune-related adverse events (n-irAEs). Here, we performed single-cell RNA sequencing and T cell receptor profiling of PBMCs of a cohort of 17 cancer patients receiving ICI therapy. Our data suggest alterations in regulatory T cell frequencies and B cell states, and a significant enrichment of clonally expanded CD4+ cytotoxic T lymphocytes (CD4+ CTLs) with an effector gene expression profile in n-irAE patients
Sex-specific structural and functional cardiac remodeling during healthy aging assessed by cardiovascular magnetic resonance
Get PDFBACKGROUND: Aging as a major non-modifiable cardiac risk factor challenges future cardiovascular medicine and economic demands, which requires further assessments addressing physiological age-associated cardiac changes. OBJECTIVES: Using cardiovascular magnetic resonance (CMR), this study aims to characterize sex-specific ventricular adaptations during healthy aging. METHODS: The population included healthy volunteers who underwent CMR at 1.5 or 3 Tesla scanners applying cine-imaging with a short-axis coverage of the left (LV) and right (RV) ventricle. The cohort was divided by sex (female and male) and age (subgroups in years): 1 (19-29), 2 (30-39), 3 (40-49), and 4 (=50). Cardiac adaptations were quantitatively assessed by CMR indices. RESULTS: After the exclusion of missing or poor-quality CMR datasets or diagnosed disease, 140 of 203 volunteers were part of the final analysis. Women generally had smaller ventricular dimensions and LV mass, but higher biventricular systolic function. There was a significant age-associated decrease in ventricular dimensions as well as a significant increase in LV mass-to-volume ratio (LV-MVR, concentricity) in both sexes (LV-MVR in g/ml: age group 1 vs. 4: females 0.50 vs. 0.57, p=0.016, males 0.56 vs. 0.67, p=0.024). LV stroke volume index decreased significantly with age in both sexes, but stronger for men than for women (in ml/m(2): age group 1 vs. 4: females 51.76 vs. 41.94, p<0.001, males 55.31 vs. 40.78, p<0.001). Ventricular proportions (RV-to-LV-volume ratio) were constant between the age groups in both sexes. CONCLUSIONS: In both sexes, healthy aging was associated with an increase in concentricity and a decline in ventricular dimensions. Furthermore, relevant age-related sex differences in systolic LV performance were observed
Pluripotent stem cell-based drug discovery uncovers sildenafil as a treatment for mitochondrial disease
Get PDFMitochondrial disease encompasses inherited disorders affecting mitochondrial function. A severe and untreatable form of mitochondrial disease is Leigh syndrome (LS) causing psychomotor regression and metabolic crises. To accelerate drug discovery for LS, we screened a library of 5,632 repurposable compounds in induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) from LS patients. We identified phosphodiesterase 5 inhibitors (PDE5i) as leads, and prioritized sildenafil due to its safety profile. Sildenafil restored pathways regulating nervous system development, enhanced neurite outgrowth in LS neurons, and mitigated abnormal calcium responses in LS brain organoids under metabolic stress. In a mouse model of LS, sildenafil extended the lifespan and ameliorated metabolic and encephalopathy phenotypes. Chronic off-label compassionate treatment with sildenafil in six LS patients showed improvements in motor function and resistance to metabolic crises. These findings highlight the potential of iPSC-driven drug discovery and position sildenafil as a promising candidate for mitochondrial diseases