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Reilly, S.

Publications and source records attributed to Reilly, S..

4 recordsLinked to original sources

immgenT: A Comprehensive Reference of Convergent T-cell States in the Mouse

The immgenT collaborative project generated a comprehensive molecular atlas of T cells spanning virtually all mouse organs and disease states, profiling ~800,000 cells from 750 samples with RNA, 128-plex surface protein, and {beta}TCR sequence. Applying a deep generative model to joint RNA and protein data defined the landscape of T-cell states organized into eight lineages and 107 robust clusters, integrating similar cells from different contexts, and resolving prior nomenclatures. Analysis of effector molecules, transcription factors and modules showed that both immunological functions and regulatory programs are shared across cell states. This framework provides a stable, reusable reference, demonstrated by computationally integrating 16 external datasets from diverse biological contexts. A set of public web tools supports browsing of these data and mapping of any dataset onto the immgenT framework. These results propose a molecular classification of T cells organized around a set of shared states reused across immunological contexts.

immunology↗

Longitudinal Plasma Proteome Changes Before and After Catheter Ablation in Atrial Fibrillation

BackgroundProteins in human plasma serve as critical markers for predicting disease risk and guiding therapeutic development. Current prediction models for atrial fibrillation (AF) largely rely on electronic health records; however, the plasma proteome of patients with AF reflects key biological processes, including inflammation, that are not captured by clinical variables alone. Circulating inflammatory mediators contribute to electrical and structural remodelling in the atria, thereby sustaining the AF phenotype. Identification of plasma proteins associated with AF may therefore improve understanding of the inflammatory and other biological processes underlying AF pathophysiology. ObjectiveIn this study, we profiled the plasma proteome of patients with paroxysmal AF (pxAF), persistent AF (persAF), and non-AF controls using Olink assay technology. MethodsPlasma samples from 30 individuals were analysed with the Olink Reveal panel. Differential expression analysis of normalised protein expression (NPX) values was performed between groups, with differentially expressed proteins (DEPs) defined by P < 0.05. ResultsWe identified 87 DEPs in pxAF and 107 DEPs in persAF compared with controls. From these, we shortlisted 11 candidate proteins that were upregulated in persAF at baseline and showed reduced expression 12 months after catheter ablation. This subset of proteins is implicated in the regulation of inflammation (CCL23, CXCL10, IL33), metabolism (ALDH3A1, NDUFS6), cell-matrix adhesion (AFAP1L1, LGALS7, SPOCK1), and physiological signalling (NOS1, PROK1, PTH). ConclusionCollectively, these plasma proteins highlight systemic molecular mechanisms contributing to AF pathogenesis and represent potential AF-specific biomarkers warranting further investigation in larger clinical cohorts and mechanistic studies.

molecular biology↗

Atrial Proteomic Profiling Reveals a Switch Towards Profibrotic Gene Expression Program in CREM-IbΔC-X Mice with Persistent Atrial Fibrillation

BackgroundOverexpression of the CREM (cAMP response element-binding modulator) isoform CREM-Ib{Delta}C-X in transgenic mice (CREM-Tg) causes the age-dependent development of spontaneous AF. PurposeTo identify key proteome signatures and biological processes accompanying the development of persistent AF through integrated proteomics and bioinformatics analysis. MethodsAtrial tissue samples from three CREM-Tg mice and three wild-type littermates were subjected to unbiased mass spectrometry-based quantitative proteomics, differential expression and pathway enrichment analysis, and protein-protein interaction (PPI) network analysis. ResultsA total of 98 differentially expressed proteins were identified. Gene ontology analysis revealed enrichment for biological processes regulating actin cytoskeleton organization and extracellular matrix (ECM) dynamics. Changes in ITGAV, FBLN5, and LCP1 were identified as being relevant to atrial fibrosis and remodeling based on expression changes, co-expression patterns, and PPI network analysis. Comparative analysis with previously published datasets revealed a shift in protein expression patterns from ion-channel and metabolic regulators in young CREM-Tg mice to profibrotic remodeling factors in older CREM-Tg mice. Furthermore, older CREM-Tg mice exhibited protein expression patterns that resembled those of humans with persistent AF. ConclusionsThis study uncovered distinct temporal changes in atrial protein expression patterns with age in CREM-Tg mice consistent with the progressive evolution of AF. Future studies into the role of the key differentially abundant proteins identified in this study in AF progression may open new therapeutic avenues to control atrial fibrosis and substrate development in AF. Graphical abstractGraphical abstract summarizing key findings of this paper. The atrial proteome in 9-month-old CREM- Tg mice with chronic persistent AF (perAF) was compared with age-matched WT littermates. In addition, proteome changes in these old CREM-Tg mice were compared with proteome changes previously identified in young CREM-Tg mice with paroxysmal AF (pAF). Moreover, an interspecies comparison was performed between old CREM-Tg mice and human patients with perAF. The major findings are that in pAF, key changes were identified in proteins involved in metabolism, energy production, DNA synthesis, and cell proliferation and growth. On the other hand, in mice and humans with perAF, key changes were found in the expression of proteins involved in collagen production, extracellular matrix remodeling, actin cytoskeleton organization, and tissue repair. O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/575097v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@603dbaorg.highwire.dtl.DTLVardef@74a168org.highwire.dtl.DTLVardef@110b834org.highwire.dtl.DTLVardef@ad96e3_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

Genomic contributions to infant and toddler vocabulary scores: Implications for association with health-, cognition- and behaviour-related outcomes

BackgroundThe number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors, although mechanisms are not well understood. Here, we performed a meta-genome-wide association study within the EAGLE consortium and investigated polygenic overlap with later-life traits, including Attention-Deficit/Hyperactivity Disorder (ADHD) and cognition. MethodsWe studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months) and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated Single-Nucleotide Polymorphism heritability (SNP-h2), genetic correlations (rg) and modelled underlying genetic factor structures with multivariate models. ResultsContributions of common genetic variation to early-life vocabulary were modest (SNP-h2: 0.08(SE=0.01) to 0.24(SE=0.03)) and multi-factorial. Genetic overlap between infant expressive and toddler receptive vocabulary was near zero (rg=0.07(SE=0.10)), although both measures were genetically related to toddler expressive vocabulary (rg=0.69(SE=0.14) and rg=0.67(SE=0.16), respectively). Consistently, polygenic association patterns with later-life traits differed: Genetic links with cognition emerged only in toddlerhood (e.g. toddler receptive vocabulary and intelligence: rg=0.36(SE=0.12)), despite comparable study power for infant measures. Furthermore, increased polygenic ADHD risk was associated with larger infant expressive vocabulary (rg=0.23(SE=0.08)), as confirmed by ADHD-symptom-based follow-up analyses in the Avon Longitudinal Study of Parents and Children (ALSPAC-rg=0.54(SE=0.26)). Genetic relationships with toddler receptive vocabulary were, however, opposite (ALSPAC-rg=-0.74(SE=0.23)), highlighting developmental changes in genetic architectures. ConclusionsMultiple genetic components contribute to early-life vocabulary development, shaping polygenic association patterns with later-life ADHD symptoms and cognition.

genomics↗