Biology subjects

Lawless, D.

Publications and source records attributed to Lawless, D..

3 recordsLinked to original sources

bioRxiv2026

Multi-omics integration identifies a reproducible inflammatory host-response axis in pediatric sepsis

Sepsis is a major cause of morbidity and mortality in children, yet biological heterogeneity in host responses has limited progress toward targeted therapies and patient stratification. Multiomics integration can combine complementary molecular layers to identify coordinated disease programs not captured by individual assays. Here, we integrated genomic, bulk transcriptomic, proteomic and metabolomic data from blood samples of 22 children with culture-confirmed bacterial sepsis enrolled in the Swiss Pediatric Sepsis Study. Multi-Omics Factor Analysis identified a dominant host-response axis reflecting systemic inflammation. This axis was driven primarily by transcriptomic variation and supported by coordinated proteomic and metabolomic signals, including circulating inflammatory mediators and altered amino-acid metabolism. It was associated with C-reactive protein and a severity score proxy. Projection into an independent pediatric sepsis cohort (n = 22) reproduced the inflammatory and severity-related interpretation of this axis. Single-omic projections showed that the integrated signal could be approximated from individual layers, particularly transcriptomics. In three external pediatric whole-blood transcriptomic datasets, the RNA-derived projection separated septic shock from healthy controls and increased across clinical inflammatory syndromes. These findings define a reproducible inflammatory host-response axis in pediatric sepsis and support multi-omics-guided selection of molecular readouts suitable for clinical translation.

immunology↗

bioRxiv2020

A mitochondrial mutational signature of temperature and longevity in ectothermic and endothermic vertebrates.

The variation in the mutational spectrum of the mitochondrial genome (mtDNA) among species is not well understood. Recently, we demonstrated an increase in A>G substitutions on a heavy chain (hereafter AH>GH) of mtDNA in aged mammals, interpreting it as a hallmark of age-related oxidative damage. In this study, we hypothesized that the occurrence of AH>GH substitutions may depend on the level of aerobic metabolism, which can be inferred from an organisms body temperature. To test this hypothesis, we used body temperature in endotherms and environmental temperature in ectotherms as proxies for metabolic rate and reconstructed mtDNA mutational spectra for 1350 vertebrate species. Our results showed that temperature was associated with increased rates of AH>GH and asymmetry of AH>GH in different species of ray-finned fishes and within geographically distinct clades of European anchovy. Analysis of nucleotide composition in the most neutral synonymous sites of fishes revealed that warm-water species were expectedly more A-poor and G-rich compared to cold-water species. Finally, we extended our analyses to all vertebrates and observed higher AH>GH and increased asymmetry of AH>GH in warm-blooded (mammals and birds) compared to cold-blooded (Actinopterygii, amphibia, reptilia) vertebrate classes. Overall, our findings suggest that temperature, through its influence on metabolism and oxidative damage, shapes the mutational properties and nucleotide content of the mtDNA in all vertebrates.

evolutionary biology↗

bioRxiv2018

Characterising RAG1 and RAG2 with predictive genomics

While widespread genome sequencing ushers in a new era of preventive medicine, the tools for predictive genomics are still lacking. Time and resource limitations mean that human diseases remain uncharacterised because of an inability to predict clinically relevant genetic variants. The structural or functional impact of a coding variant is mirrored by allele frequencies amongst the general population. Studies in protein function frequently target sites that are evolutionarily preserved. However, rare diseases are often attributable to variants in genes that are highly conserved. An immunological disorder exemplifying this challenge occurs through damaging mutations in RAG1 and RAG2. RAG deficiency presents at an early age with a distinct phenotype of life-threatening immunodeficiency or autoimmunity. Many tools exist for variant pathogenicity prediction but these cannot account for the probability of variant occurrence. We present variants in RAG1 and RAG2 proteins which are most likely to be seen clinically as disease-causing. Our method of mutation rate residue frequency builds a map of most probable mutations allowing preemptive functional analysis. We compare the accuracy of our predicted probabilities to functional measurements and provide the method for application to any monogenic disorder.\n\nFundingThis work is funded by the University of Leeds 110 Anniversary Research Scholarship and by the National Institute for Health Research (NIHR, grant number RG65966). Dr. Jolan Walter has received federal funding. The authors declare no conflict of interest.\n\nAcknowledgementsWe gratefully acknowledge the participation of all NIHR BioResource volunteers, and thank the NIHR BioResource centres and staff for their contribution. We thank the National Institute for Health Research and NHS Blood and Transplant. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.\n\nEthics statementThe study was performed in accordance with the Declaration of Helsinki. The NIHR BioResource projects were approved by Research Ethics Committees in the UK and appropriate national ethics authorities in non-UK enrolment centres.

genomics↗