Biology subjects

Brightling, C. E.

Publications and source records attributed to Brightling, C. E..

6 recordsLinked to original sources

bioRxiv2026

Topology-Based Query Framework for Longitudinal Omics Trajectories

1 Abstract 1.1 Background Many longitudinal omics studies contain only a small number of repeated measurements collected before, during, or after an intervention. Existing approaches, including mixed-effects models and generalized additive models, estimate temporal effects but do not generally provide a discrete representation of trajectory topology that can be queried directly across experimental groups. 1.2 Methods We developed LongOmicsTraj, an open-source R package for topology-based representation and querying of short longitudinal omics trajectories. The framework encodes the direction of change between adjacent visits as up, down, or flat, with the ordered sequence defining an Ordinal Trajectory State (OTS). LongOmicsTraj operates downstream of trajectory estimation and can therefore be applied to empirical summaries or model-derived visit-level estimates, including those from linear mixed-effects models, generalized additive models, and polynomial regression, following a maSigPro-style time-course formulation [1]. OTS labels provide a common representation for topology-based querying, cross-group comparison, and evaluation of higherlevel representations such as trajectory clusters. We evaluated the framework using controlled simulations and bronchial biopsy transcriptomic data from the GLUCOLD corticosteroid intervention study (GEO accession GSE36221), measured at baseline, 6 months, and 30 months. The biological analysis compared continued inhaled corticosteroid (ICS) treatment, ICS withdrawal after 6 months, and placebo. 1.3 Results In simulations, LongOmicsTraj recovered predefined stable, monotonic, transient, rebound, and oscillatory trajectories with high accuracy when longitudinal signal was sufficiently clear, with performance declining under high-noise conditions and depending partly on the upstream estimator. In GLUCOLD, comparator-aware topology queries reduced 20,358 measured transcripts to 168 genes showing a corticosteroid response that was maintained during continued treatment, reversed following withdrawal, and was not reproduced under placebo. The selected genes included established corticosteroid-response genes and were enriched for immune-cell migration, chemotaxis, cell adhesion, and extracellular-matrix organisation. Topology-aware evaluation of FlexMix trajectory clusters additionally revealed substantial within-cluster temporal heterogeneity, with topology purities of approximately 46% to 60%. 1.4 Conclusions LongOmicsTraj provides a compact, directly queryable representation of temporal direction and order in short longitudinal omics studies. It complements existing longitudinal estimation and clustering methods by making trajectory structure explicit, enabling structured cross-group queries and quantification of temporal heterogeneity within trajectory clusters.

bioinformatics↗

bioRxiv2026

Reported estimates of human airway dimensions are inconsistent across studies

RationaleRespiratory diseases are a source of immense socioeconomic burden globally. In silico approaches can predict changes in human lung function due to disease or response to therapy. By stratifying patient-specific response a priori, these models can enable clinical-scale deployment of precision medicine strategies. Key to this is developing accurate organ geometries on which the models can be simulated. However, we lack analyses assessing the clinical applicability of reported airway dimension estimates. ObjectiveTo investigate physiologically-/anatomically-relevant airway dimension estimates and evaluate consistency across reported literature. MethodsWe conducted a systematic review of 37 published datasets. Airway wall thickness estimates were mined for healthy subjects and patients, and standardised to the Horsfield order airway generations. We simulated dynamic lung function to quantitatively assess their physiological relevance. We created an online database to make all datasets available to the research community. Measurements and Main ResultsReported human airway wall thickness estimates are inconsistent across studies. K-means clustering divided estimates for healthy subjects and patients into three and four clusters, respectively. Only one of the clusters in each category yielded anatomically-relevant estimates. Pressure-volume curves generated to assess physiological relevance also showed that only one cluster in each category exhibited plausible physiology. Principal Component Analysis weakly implicated imaging modalities to explain this inconsistency. ConclusionsReported airway dimension estimates are inconsistent and lack standardisation. To support future modelling efforts, we report physiologically-relevant estimates and introduce an open-access airway-dimension database to help standardise geometric inputs and quantify how measurement variability propagates to functional predictions.

biophysics↗

bioRxiv2025

Bacteriophage diversity declines with COPD severity in the respiratory microbiome

Chronic obstructive pulmonary disease (COPD) severity correlates with airway microbial dysbiosis, yet bacteriophage roles remain unexplored. We characterised the lung virome by re-analysing 135 sputum metagenomes from 99 COPD patients and 36 healthy controls. We identified 1,308 viral operational taxonomic units, revealing progressively lower viral diversity correlating with disease severity. Whilst viral and bacterial diversity typically showed strong positive correlations, patients with frequent exacerbations uniquely exhibited decoupled viral-bacterial relationships, indicating disrupted ecological dynamics. Phages infecting anaerobic oral bacteria showed disproportionately lower abundance--Porphyromonas phages were 40-fold less abundant despite only 4-fold lower bacterial abundance--whilst pathogen-associated phages showed no significant differences. We detected virulence factor-encoding phages, including two neuA-carrying Haemophilus phages in 7.4% of Haemophilus-colonised patients, associated with 82-fold higher bacterial abundance. These findings establish altered bacteriophage ecology as an unrecognised feature of COPD pathobiology, with differential phage-bacteria relationships that reshape lung microbial ecosystems, offering new perspectives for microbiome-targeted interventions.

microbiology↗

bioRxiv2020

Lysyl oxidase-like 2 (LOXL2) is Increased in Asthma and Contributes to Asthmatic Airway Remodelling

Airway smooth muscle cells (ASM) are fundamental to asthma pathogenesis, influencing bronchoconstriction, airway hyper-responsiveness, and airway remodelling. Extracellular matrix (ECM) can influence tissue remodelling pathways, however, to date no study has investigated the effect of ASM ECM stiffness and crosslinking on the development of asthmatic airway remodelling. We hypothesised that TGF{beta} activation by ASM is influenced by ECM in asthma and sought to investigate the mechanisms involved. This study combines in vitro and in vivo approaches: human ASM cells were used in vitro to investigate basal TGF{beta} activation and expression of ECM crosslinking enzymes. Human bronchial biopsies from asthmatic and non-asthmatic donors were used to confirm LOXL2 expression ASM. A chronic ovalbumin model of asthma was used to study the effect of LOXL2 inhibition on airway remodelling. We found that ASM cells from asthmatics activated more TGF{beta} basally than non-asthmatic controls and that diseased cell-derived ECM influences levels of TGF{beta} activated. Our data demonstrate that the ECM crosslinking enzyme LOXL2 is increased in asthmatic ASM cells and in bronchial biopsies. Crucially, we show that LOXL2 inhibition reduces ECM stiffness and TGF{beta} activation in vitro, and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an ovalbumin mouse model of asthma. These data are the first to highlight a role for LOXL2 in the development of asthmatic airway remodelling and suggest that LOXL2 inhibition warrants further investigation as a potential therapy to reduce remodelling of the airways in severe asthma.

cell biology↗

bioRxiv2020

Pathophysiological regulation of lung function by the free fatty acid receptor FFA4

Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with a significant number of patients being inadequately controlled by current frontline treatments means that there is a need to define novel therapeutic targets for these conditions1. Here we investigate a member of the G protein-coupled receptor (GPCR) family, FFA4, which responds to free circulating fatty acids, including dietary omega-3 fatty acids found in fish oils2–4. Although usually associated with metabolic responses linked with food intake, we show that FFA4 is expressed in the lung where it is coupled to Gq/11-signalling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated, at least in part, by the release of the prostaglandin PGE2 that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. Importantly, in acute and chronic ozone models of pollution-mediated inflammation, and in house-dust mite and cigarette smoke-induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, whilst this response was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was very similar to that observed in mice and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation. Hence, our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy that might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗

bioRxiv2018

Cohort Profile: Extended Cohort for E-health, Environment and DNA (EXCEED)

EXCEED is a longitudinal population-based cohort which facilitates investigation of genetic, environmental and lifestyle-related determinants of a broad range of diseases and of multiple morbidity through data collected at baseline and via electronic healthcare record linkage. Recruitment has taken place in Leicester, Leicestershire and Rutland since 2013 and is ongoing, with 10 156 participants aged 30-69 to date. The population of Leicester is diverse and additional recruitment from the local South Asian community is ongoing. Participants have consented to follow-up for up to 25 years through electronic health records (EHR). Data available includes baseline demographics, anthropometry, spirometry, lifestyle factors (smoking and alcohol use) and longitudinal health information from primary care records, with additional linkage to other EHR datasets planned. Patients have consented to be contacted for recall-by-genotype and recall-by-phenotype sub-studies, providing an important resource for precision medicine research. We welcome requests for collaboration and data access by contacting the study management team via exceed@le.ac.uk.

epidemiology↗