Biology subjects

Beck, G.

Publications and source records attributed to Beck, G..

5 recordsLinked to original sources

bioRxiv2026

Metabolomic Network Analysis Reveals Reorganization of Lipid and Steroid Programs Linked to Right Ventricular-Pulmonary Vascular Function in Pulmonary Hypertension

BackgroundPulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways. MethodsWe applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients. ResultsWGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, {beta}-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites. ConclusionsThese findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.

physiology↗

bioRxiv2025

Organoid Pharmacotyping of Pancreatic Cancer Enables Functional Precision Oncology and Drug Repurposing

PurposePancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with limited benefit from current cytotoxic regimens and poor predictive value of genomics alone. Patient-derived organoids (PDOs) represent a promising platform for functional precision oncology, yet systematic pharmacotyping of genomically annotated PDAC PDOs remains sparse. Experimental DesignWe established a clinically annotated panel of ten treatment-naive PDAC PDOs spanning well-, moderately-, and poorly differentiated tumors. PDOs were evaluated for morphologic and genomic fidelity and screened against 1,813 clinically relevant small molecules in a high-throughput 384-well format. Drug sensitivities were quantified at the compound and drug-family levels and integrated with histologic grade, pathway-level mutational profiles, and available clinical treatment information. ResultsPDOs preserved hallmark tumor features, including glandular organization and subclonal mutational architecture. Pharmacotyping revealed both shared and subtype-specific vulnerabilities. Classical (well/moderately differentiated) PDOs showed enriched mutations in DNA repair, mitotic spindle, and chromatin-regulatory pathways and were preferentially sensitive to topoisomerase inhibitors, microtubule poisons, and HDAC inhibitors. In contrast, basal (poorly differentiated) PDOs displayed coordinated defects in mitochondrial function, vesicle trafficking, and ubiquitin-mediated proteostasis, at the pathway level, that conferred a previously unrecognized vulnerability to cardiac glycosides. Sensitivities to standard PDAC agents were heterogeneous across models, underscoring the limited predictive value of genotype alone and the need for functional drug testing. ConclusionsThis integrated genomic and pharmacologic analysis demonstrates that PDO pharmacotyping identifies biologically grounded, actionable vulnerabilities in PDAC, including novel therapeutic opportunities in basal, chemo-resistant tumors. These findings support PDO-guided functional profiling as a clinically relevant platform for refining drug selection and expanding treatment options for patients with PDAC. SignificancePDAC is dominated by chemoresistance and lacks reliable genomic predictors of therapy response. By integrating high-throughput drug screening with mutation-informed pathway analysis in patient-derived organoids, we identify differentiation-linked therapeutic liabilities, including a previously unrecognized vulnerability to cardiac glycosides in basal PDAC. These results highlight PDO pharmacotyping as a powerful functional complement to genomics for guiding treatment selection in pancreatic cancer.

cancer biology↗

bioRxiv2025

Tegmental atrophy in isolated REM sleep behaviour disorder: Ex vivo-informed in vivo imaging

Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is an early-stage synucleinopathy characterized by brainstem pathology. In rodents, the pontine tegmentum contains an REM sleep centre, the sublaterodorsal nucleus (SLD), which expresses corticotropin-releasing hormone binding protein (CRHBP). While the involvement of brainstem pathophysiology is thus implicated in iRBD, its solid evidence remains scarce in humans due to the difficulty in identifying small brainstem nuclei with conventional MRI technology alone. Here, we aimed to detect tegmental atrophy in iRBD with voxel-based morphometry (VBM) analysis combined with a novel human brainstem atlas. Structural MRIs from 98 patients with iRBD and 114 controls were analysed to investigate grey matter volume (GMV) using VBM. Our unique approach involved detailed assessments of the VBM results, guided by a high-resolution MRI-based atlas of the human brainstem. This brainstem atlas was founded on ex vivo MRI of 10 postmortem human specimens. We validated it with CRHBP immunostaining, which aided in identifying putative REM sleep-regulating nuclei in humans. We applied this brainstem atlas to identify atrophy in specific brainstem regions in iRBD and correlate their volumes with clinical measures, including autonomic functions. VBM revealed a focal cluster of grey matter atrophy in the dorsal pontine tegmentum of iRBD patients, including the laterodorsal tegmental nucleus, ventral part (LDTgV) and the pedunculopontine tegmental nucleus (PTg). Our atlas-based analysis confirmed the LDTgV as the site of most conspicuous atrophy, revealing a significant volume reduction in iRBD patients compared to controls with a moderate effect size (Cohens d = 0.46, Bonferroni-corrected p = 0.019). Furthermore, greater atrophy in the LDTgV and the PTg was associated with more severe autonomic dysfunction as measured by Scales for Outcomes in Parkinsons Disease-Autonomic dysfunction (SCOPA-AUT) scores (partial r = -0.237, p = 0.019 and partial r = -0.236, p = 0.019, respectively). Histological analysis confirmed that the LDTgV is selectively enriched with CRHBP-positive neurons, a putative marker for REM sleep-on neurons. We provided novel evidence for the involvement of LDTgV, the putative human homolog of the murine SLD, in iRBD. The present findings advance our understanding of the neuroanatomical basis of iRBD and will contribute to the development of early biomarkers for -synucleinopathies.

neuroscience↗

bioRxiv2024

α-Synuclein acts as a cholesteryl-ester sensor on lipid droplets regulating organelle size and abundance.

While aggregated alpha-Synuclein (Syn) is commonly associated with Parkinsons disease, its physiological function as a membrane-binding protein is poorly understood. Here, we show that endogenous Syn binds lipid droplets (LDs) in multiple human cell lines and in stem cell-derived dopaminergic neurons. LD-binding encompasses Syn residues 1-100, which masks their detection by immunofluorescence microscopy, probably explaining the scarcity of similar observations in earlier studies. Syn-LD interactions are highly temperature-sensitive and selective for cholesteryl-ester-rich LDs. They promote the formation of Syn multimers that dissociate from LDs at non-permissive temperatures. Syn remains LD-bound throughout starvation-induced lipolysis, whereas siRNA-knockdown diminishes LD abundance and compromises cell viability upon nutrient depletion, without affecting LD biosynthesis. Reciprocally, excess Syn stimulates LD accumulation in dependence of lipid availability, restricts organelle size and ensures intracellular LD organization, which strictly depends on functional membrane-binding. Supporting a general role of Syn in cellular lipid and cholesterol metabolism, our results point to additional loss-of-function similarities between Parkinsons, Alzheimers and Gauchers disease.

cell biology↗

bioRxiv2022

Conformational change in the monomeric alpha-synuclein imparts fibril polymorphs

-Synuclein (Syn) inclusions are a pathological hallmark of several neurodegenerative disorders. While cryo-electron microscopy studies have revealed distinct fibril polymorphs across different synucleinopathies, the molecular switches controlling polymorphism remained unveiled. In this study, we found that fibril morphology is associated with the conformational state of monomeric Syn. Through systematic manipulation of the ionic strength and temperature, we pinpoint two distinct polymorphs: a twisted morphology at low ionic strength and temperature, and a rod-like morphology at higher ionic strength and temperature. Most strikingly, we found that a specific conformational change in the C-terminal domain of the monomeric Syn serves as the master switch for the formation of polymorphs. Interestingly, this conformational change can be triggered by calcium binding to the C-terminus, connecting environmental factors to specific fibril architectures. Our results unmask the C-terminal domain as a key player for orchestrating Syn fibril morphology, providing significant insights into the fibrogenesis of Syn. Significance StatementThe Syn C-terminus domain acts as the master switch programming its fibril polymorphism.

biophysics↗