Biology subjects

Walters, B.

Publications and source records attributed to Walters, B..

5 recordsLinked to original sources

bioRxiv2026

Spatial uncoupling of endothelial calcium signaling from phospha-tidylserine externalization in vascular injury

Ca2+ is both the signal that spreads injury information through the endothelium and the trigger for phospholipid scrambling that makes a membrane procoagulant. How a blood vessel can disseminate the first without broadcasting the second is unknown. Here, we combine single-cell laser injury in endothelial monolayers with imaging of intact mesenteric vessels in vitro and intravital Ca2+ imaging in vivo. Injury generated a coherent Ca2+ wavefront that spread rapidly before progressively slowing and terminating at a reproducible boundary 197 {+/-} 7 m from the wound, engaging 50 {+/-} 8 cells. The first ring of neighboring cells exhibited a distinct response that was prevented by carbenoxolone, whereas propagation beyond this ring required extracellular ATP, purinergic receptor activation, and IP3-dependent Ca2+ release. Wavefront kinematics were consistent with ATP diffusion. In vivo, injury elicited vasoconstriction and bidirectional Ca2+ waves propagating 205 {+/-} 28 m before terminating. Remarkably, despite widespread Ca2+ elevations, phosphatidylserine (PS) externalization remained confined to the wounded cell in monolayers and intact vessels in vitro. In contrast, ionomycin-induced Ca2+ overload exposed phosphatidylserine in nearly all endothelial cells. These findings reveal an unexpected spatial uncoupling between endothelial Ca2+ signaling and phospholipid scrambling, demonstrating that Ca2+ dependent scramblase activation is subject to additional spatial regulation. The endothelium can therefore propagate injury signals across a broad field of cells while maintaining a highly localized procoagulant membrane response.

physiology↗

bioRxiv2025

Theoretical Morphology of Avian Wing Planform Reveals Variable Optimisation to Flight Style

Bird wings exhibit a broad degree of functional and shape variation, though the exact nature of the form-function relationship is uncertain. Recent analysis suggests that functional variability is explained by linear non-shape-based traits and that shape variation is largely explained by phylogeny. We assay the relationship between wing planform shape and functional performance using a theoretical morphospace approach that eschews assumptions of the functional optimality of empirical morphologies. Empirical properties are considered post hoc relative to their positions in the functional performance landscapes. We produce a theoretical morphospace of wing planform shapes and compare the functional performance and optimality of theoretical shapes with 1139 extant taxa. These tests cover flight metrics and combinations linked with 7 flight niches. Metrics pertaining to agile flight strongly constrain shape, with hovering, diving and hawking birds developing optimal planforms. Marine soarers are suboptimal for metrics linked with efficient and manoeuvrable flight. Many taxa, principally passerines, remain suboptimal for all studied metrics and combinations. This suggests flight performance constrains planforms unevenly across birds. Phylomorphospace analysis suggests planform shape is only weakly influenced by phylogeny and functional optimality correlates closely with flight styles. This suggests wing shape remains a determining factor in how birds fly.

paleontology↗

bioRxiv2024

CNValidatron, automated validation of CNV calls using computer vision

BackgroundLarge rare copy number variants (CNVs) are a main source of genetic variation in the genome and are important in both evolution and disease risk. CNVs can be detected using different data sources, including genome sequencing, genotyping arrays and quantitative PCR experiments, but in most large cohorts, genotyping arrays remain the most prevalent source. Current methods to call CNVs from genotyping array data suffer from high false positive rates and while multiple approaches, including QC filtering, visual inspection of intensity tracks, and wet-lab validation are commonly applied to counter this problem, such methods are often non-specific (QC filtering) or inefficient (visual and wet-lab validations) at a genome-wide scale. ResultsWe have assembled the largest collection of human-verified CNV calls using visual validation, totaling almost 60,000 calls from 22,500 samples from three cohorts genotyped on several different arrays. Across all cohorts our visual validation found the majority of CNV calls to be false positive (53.7%) or unclear (9.7%). The false positive fraction varied substantially across datasets and genomic regions, and we show that existing filtering methods based on QC metrics are inefficient in removing false calls. Given the supremacy of visual validation over existing filtering methods in controlling the false positive fraction, we used a subset of our visual validation dataset to train a convolutional neural network to automate the validation of CNVs through machine vision. We tested the efficacy of the model using the remainder of the dataset and found the performance exceeded 90% in most measures, approximating that of a human analyst. Cross-validation with genome sequencing data found our visual validation to be highly accurate, with only 1.7% of calls supported by the sequencing dataset deemed as false by the human analyst, and a further 7.5% deemed as unclear. ConclusionsVisual inspection is the only effective validation approach for CNV calls. Our model is capable of automating this task at scale with very high accuracy, as shown by testing both within-sample and out-of-sample. The software is available as an R package at https://github.com/SinomeM/CNValidatron_fl.

bioinformatics↗

bioRxiv2022

Working memory and reaction time variability mediate the relationship between polygenic risk and ADHD traits in a general population sample

Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population sample derived from the Adolescent Brain and Cognition Developmental study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population sample that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.

neuroscience↗

bioRxiv2021

Toxoplasma infection alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

Toxoplasma gondii is a single celled parasite thought to infect 1 in 3 worldwide. During chronic infection, T. gondii can migrate to the brain where it promotes low-grade neuroinflammation with the capacity to induce changes in brain morphology and behavior. Consequently, infection with T. gondii has been linked with a number of neurocognitive disorders including schizophrenia (SZ), dementia, and Parkinsons disease. Beyond neuroinflammation, infection with T. gondii can modulate the production of neurotransmitters, such as dopamine. To further dissect these pathways and examine the impact of altered dopaminergic sensitivity in T. gondii-infected mice on both behavior and gene expression, we developed a novel mouse model, based on stimulant-induced (cocaine) hyperactivity. Employing this model, we found that infection with T. gondii did not alter fear behavior but did impact motor activity and neuropsychiatric-related behaviurs. While both behaviors may help reduce predator avoidance, consistent with previous studies, the latter finding is reminiscent of neurocognitive disorders. Applying RNASeq to two relevant brain regions, striatum and hippocampus, we identified a broad upregulation of immune responses. However, we also noted significant associations with more meaningful neurologically relevant terms were masked due to the sheer number of terms incorporated in multiple testing correction. We therefore performed a more focused analysis using a curated set of neurologically relevant terms revealing significant associations across multiple pathways. We also found that T. gondii and cocaine treatments impacted the expression of similar functional pathways in the hippocampus and striatum although, as indicated by the low overlap among differentially expressed genes, largely via different proteins. Furthermore, while most differentially expressed genes reacted to a single condition and were mostly upregulated, we identified gene expression patterns indicating unexpected interactions between T. gondii infection and cocaine exposure. These include sets of genes which responded to cocaine exposure but not upon cocaine exposure in the context of T. gondii infection, suggestive of a neuroprotective effect advantageous to parasite persistence. Given its ability to uncover such complex relationships, we propose this novel model offers a new perspective to dissect the molecular pathways by which T. gondii infection contributes to neuropsychiatric disorders such as schizophrenia.

microbiology↗