Lomeikaite, V. | Search bioRxiv

bioRxiv2025

Distinct Metabolic Signatures Linked to High-Resolution Computed Tomography Radiographic Phenotypes in Stable and Progressive Fibrotic Lung Disease

Rationale and ObjectivesThis study aimed to identify distinct metabolic signatures associated with disease progression by integrating high-resolution computed tomography (HRCT) visual scoring with comprehensive metabolomic profiling. Materials and MethodsThis single-center, cross-sectional study enrolled 60 idiopathic pulmonary fibrosis/interstitial lung disease (IPF/ILD) patients from December 2021 to October 2022. Participants underwent standardized pulmonary function testing, HRCT imaging, and peripheral blood collection for metabolomic analysis using one-dimensional hydrogen nuclear magnetic resonance (1H NMR) spectroscopy and ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). A comprehensive HRCT scoring system quantified total HRCT composite scores. Linear regression analysis integrated radiographic scores with metabolomic profiles, adjusted for multiple covariates ResultsStable IPF/ILD exhibited moderate negative correlations between the six most significant metabolites and HRCT scores (r = -0.27 to -0.51), along with a high abundance of specific phospholipids (triacylglycerol, monoacylglycerol, phosphatidylglycerol, phosphatidylethanolamine, diacylglycerol), sphingomyelin, ceramide, and acylcarnitine. In contrast, progressive disease showed weak positive correlations between the six most significant metabolites and HRCT scores (r = 0.19-0.26), and moderate negative correlation between specific triacylglycerol species and HRCT scores (r = -0.37-0.4). Furthermore, metabolomic analysis in individuals with progressive disease revealed both high and low abundances of specific phospholipid species (including high and low triacylglycerol species, as well as low levels of phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and phosphatidylinositol), along with high levels of certain sphingomyelin, ceramide, taurine, and purine bases, and low levels of xanthine and lactic acid observed. ConclusionIntegration of systematic HRCT visual scoring with metabolomic profiling successfully differentiated stable from progressive IPF/ILD through distinct molecular-radiographic signatures. FundingSupporting Effective Educator Development (SEED) grant

cell biology↗

bioRxiv2024

Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects

Huntingtons disease (HD), due to expansion of a CAG repeat in HTT, is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.

genetics↗