Tebbutt, S. | Search bioRxiv

bioRxiv2026

Circulating miR-4532 is associated with loss of ambulation in dysferlinopathy

BackgroundLimb-girdle muscular dystrophies (LGMDs) are inherited myopathies characterized mainly by progressive weakness of the proximal muscles of the shoulder and pelvic girdle areas, leading to functional decline and eventual loss of independent ambulation. Dysferlinopathy (LGMD2B) is an autosomal recessive LGMD subtype, is caused by mutations in the DYSF gene that lead to lack of dysferlin which results in muscle death and chronic muscle fiber degeneration. Preservation of ambulation is a key clinical milestone, as loss of independent gait markedly reduces quality of life and complicates care management. Although patients often perceive functional decline before their initial clinical presentation, current clinical assessments typically detect disease progression after substantial muscle damage has occurred. MethodsIn this multigroup case-control study, we profiled plasma miRNAs from 49 genetically confirmed dysferlinopathy patients (24 ambulatory, 25 non-ambulatory) and 25 age- and sex-matched healthy controls. Total RNA was extracted from blood samples and hybridized to Affymetrix GeneChip miRNA 3.1 arrays. After quality control and filtering, differential expression analysis was performed using linear models for microarrays, adjusting for age and sex, with a false discovery rate cutoff of 10%. Results14 miRNAs were significantly altered between dysferlinopathy patients and controls. Notably, miR-4532 was upregulated in ambulatory patients relative to controls, whereas it was downregulated in non-ambulatory patients compared with ambulatory patients, although expression levels remained higher than in controls. Levels of miR-4532 were positively associated with circulating monocyte levels in ambulatory patients only. ConclusionThese results suggest that miR-4532 may be a circulating marker associated with ambulatory status in dysferlinopathy. Its known involvement in inflammatory signaling and muscle regeneration pathways underscores its potential as an early indicator for disease activity.

bioinformatics↗

bioRxiv2025

Spatiotemporal-multimodal integration reveals BCG-induced skin-blood crosstalk

Tuberculosis (TB) remains the leading cause of infectious death. The Bacille Calmette-Guerin (BCG) vaccine has been the only licensed vaccine available for TB prevention. Despite BCG being administered intradermally for over a century to >100 million individuals annually, the molecular events in the skin following BCG administration have not been investigated; as a result, measurable correlates of protection that could predict vaccine effectiveness already early after vaccination are lacking. Here we show that BCG immediately (within one day after vaccination) induces dynamic molecular waves that drive the acute human host response across space (layers of the skin and systemically in blood) and time (days). Integration of this data across space and time identified robust networks of interactive modules related to immune surveillance (e.g. Langerhans cells), cell trafficking (e.g. endothelial cells, ITGB5), and trained immunity (e.g. neutrophils, macrophages, {gamma}{delta}-T cell). Importantly, not only were we able to identify BCG-activated pathways associated with trained immunity such as mTOR signaling and glycolysis/gluconeogenesis, we were able to pinpoint the time-point and precise location (skin layer) of the initial activation of theses pathways. Combining tissue biopsies of human skin (spatial genomics) with liquid biopsies (cell-free blood plasma RNASeq) following BCG vaccination our data both confirmed known evidence (e.g. prominent {gamma}{delta}-T cell induction at the site of BCG administration; negative correlation of blood vs tissue myeloid-derived suppressor cells), but also generated promising new leads such as baseline levels of B cells, platelets and nuocytes in the skin prior to BCG administration predict eventual outcome, and that these predictive differences in baseline cellular composition can be captured non-invasively using high resolution images of the site of injection (dermatoscopy). Given this data represents the first holistic view of the acute molecular response to BCG in the skin in a human population at medium to high TB risk, we anticipate our findings of the immediate/early events following BCG vaccination, including non-invasive predictive assessment will support acceleration of vaccine development in the fight against TB.

systems biology↗