Biology subjects

Tu, A.

Publications and source records attributed to Tu, A..

3 recordsLinked to original sources

bioRxiv2026

Function-oriented microglial transcriptional scores in Alz-heimer's disease: resolving terminal functions beyond activa-tion states

Alzheimer's disease (AD) staging based on amyloid-{beta}, tau, and neurodegeneration does not capture heterogeneous microglial functions. Existing transcriptomic scores indicate microglial activation or state similarity but do not resolve post-activation functions and are not directly comparable across scales. Herein, we develop a function-oriented framework comprising seven harmful-and seven adaptive-associated gene modules, selected from predefined mechanisms and direct functional evidence. Using SEA-AD micro-glia/perivascular macrophage nuclei, we compute do-nor-brain-region pseudobulk scores on a fixed P10-P90 reference scale and validate them against matched protein, activity, and tissue endpoints. H3 is related to cytokine/chemokine proteins; H4 and A5 are related to the same isoprostane readout in opposite directions; and A3 is related to dense-core plaque fraction. Benchmark comparison shows modest incremental fit but distinct out-come-specific information. In external GSE146639, eight modules remained FDR-significant, although harmful and adaptive arms are highly collinear; H7 and A2 are replicated in external proteomics. Downsampling, leave-one-gene-out, and alternative scoring analyses supports technical stability, and single-cell reconstruction supported a state-resolved basis. These scores summarize relative engagement of damage-related and adaptive programmes, enabling mechanistic comparison across donors and brain regions, but remain observational, are not intended for clinical decision-making, and require further validation.

neuroscience↗

bioRxiv2026

Prevalent glutamyl-endopeptidases in the commensal skin microbiome have itch-relevant activity

Atopic dermatitis (AD) is frequently accompanied by pruritus, which has predominantly been attributed to skin colonization by Staphylococcus aureus, particularly through cleavage of protease-activated receptor 1 (PAR1) by the glutamyl endopeptidase (GEP) V8 protease. Whether related GEPs from other skin-associated staphylococci contribute to this process remains unclear. Here, we analyzed 273 staphylococcal isolates from skin swabs of 10 AD patients with pruritus, dominated by S. aureus and Staphylococcus epidermidis. Genome mining using a custom hidden Markov model identified 678 candidate GEPs, which were clustered and resolved into five structurally distinct protease architectures. Representative proteases (V8, Esp, SplB, Csp, and Hsp) were expressed and characterized. Esp displayed GEP activity and PAR1 tethered-ligand cleavage comparable to V8, generating noncanonical cleavage products, while Csp cleaved PAR1 with reduced but substantial efficiency. All representative proteases significantly disrupted barrier integrity in an epithelial barrier model. Analysis of isolate genomes and publicly available Staphylococcus genomes showed that V8 and Esp are highly conserved and largely species-restricted, whereas Csp is more broadly distributed across species. These findings identify Esp and Csp as functional GEP virulence factors in S. epidermidis and S. capitis, capable of activating itch signaling and compromising barrier function. Our study suggests that GEP-mediated pruritus and barrier dysfunction in AD may arise not only from pathogens like S. aureus, but also from commensals or opportunistic pathogens such as S. epidermidis and S. capitis. ImportanceStaphylococcus aureus colonization on the skin is closely associated with itch in atopic dermatitis (AD) through a secreted protease that cleaves PAR1 on sensory neurons. However, AD patients can experience pruritus without S. aureus colonization. This raises the question of whether other skin-colonizing staphylococci contribute to this process. We identify glutamyl endopeptidase homologs, including Esp from Staphylococcus epidermidis and Csp from Staphylococcus capitis, that cleave the same itch receptor and disrupt epithelial barrier integrity. These serine proteases are distributed across staphylococcal species that colonize human skin. Therefore, itch and barrier dysfunction in AD may not be restricted to S. aureus but instead arise from the proteolytic activity of multiple staphylococcal species. This functional redundancy means that other staphylococcal species can sustain GEP-driven itch and barrier dysfunction even in the absence of S. aureus, suggesting that therapeutic strategies targeting only S. aureus may overlook these alternative drivers of disease.

microbiology↗

bioRxiv2021

Mouse models of immune dysfunction: Their neuroanatomical differences reflect their anxiety-behavioural phenotype

Extensive evidence supports the role of the immune system in modulating brain function and behaviour. However, past studies have revealed striking heterogeneity in behavioural phenotypes produced from immune system dysfunction. Using magnetic resonance imaging (MRI), we studied the neuroanatomical differences among 11 distinct genetically-modified mouse lines (n=371), each deficient in a different element of the immune system. We found a significant and heterogeneous effect of immune dysfunction on the brains of both male and female mice. However, by imaging the whole brain and using bayesian hierarchical modelling, we were able to identify patterns within the heterogeneous phenotype. Certain structures -- such as the corpus callosum, midbrain, and thalamus -- were more likely to be affected by immune dysfunction. A notable brain-behaviour relationship was identified with neuroanatomy endophenotypes across mouse models clustering according to anxiety-like behaviour phenotypes reported in literature, such as altered volume in brains regions associated with promoting fear response (e.g., the lateral septum and cerebellum). Interestingly, genes with preferential spatial expression in the most commonly affected regions are also associated with multiple sclerosis and other immune-mediated diseases. In total, our data suggest that the immune system modulates anxiety behaviour through well-established brain networks.

neuroscience↗