Biology subjects

Pearson, L.

Publications and source records attributed to Pearson, L..

4 recordsLinked to original sources

bioRxiv2026

Population-scale subcellular proteomics reveals intracellular remodelling across the Alzheimer's disease-resilience spectrum

Proteome-wide analyses of human tissue have transformed our understanding of disease, but provide limited insight into protein localisation, a functionally informative dimension of the proteome. In Alzheimer's disease, amyloid-{beta} and tau exhibit aberrant localisation, yet whether spatial reorganisation extends proteome-wide has remained inaccessible to abundance-based proteomics. Here, we develop comparative subcellular proteomics applied to dorsolateral prefrontal cortex from 75 individuals spanning the Alzheimer's disease-resilience spectrum, modelling protein localisation across disease. We identify 217 disease-associated localisation shifts enriched for endolysosomal function, intracellular trafficking, and RNA processing, and resolve tau proteoforms within insoluble aggregates. Our strongest localisation candidates show only modest differences in whole-tissue abundance, highlighting disease biology inaccessible to conventional proteomics. We validate co-localisation of CSNK1A1 with pathological tau and identify an unexpected neuronal localisation pattern for SCAI, a cancer-associated protein not previously characterised in human brain, highlighting the discovery potential of subcellular proteomics in tissue.

neuroscience↗

bioRxiv2025

Performance anxiety is associated with biases in learning from reward and punishment in skilled individuals

Performance anxiety (PA) is common in high-stakes settings, from public speaking to the performing arts, yet its mechanisms remain poorly understood. Using behavioural analysis, computational modelling, and electroencephalography, we tested whether PA biases learning from reward and punishment under varying task uncertainty. Across three experiments with 95 skilled pianists, participants learned hidden melody dynamics through graded reward or punishment feedback. Bayesian hierarchical regression showed that increasing PA levels were associated with faster reward learning under high uncertainty (large action space) but faster punishment learning under low uncertainty (reduced action space). These learning biases--reflecting the interaction between PA and reinforcement type--were associated with reinforcement-driven modulation of motor variability and frontal theta (4-7 Hz) activity encoding feedback changes and signalling motor adjustments. The findings reveal that predisposition to PA in skilled individuals modulates reward- and punishment-based learning in a context-dependent manner governed by task uncertainty.

neuroscience↗

bioRxiv2025

Adaptive Increase of Amylase Gene Copy Number in Peruvians Driven by Potato-rich Diets

Summary/AbstractThe salivary amylase gene (AMY1) exhibits remarkable copy number variation linked to dietary shifts in human evolution. While global studies highlight its structural complexity and association with starch-rich diets, localized selection patterns remain under explored. Here, we analyzed AMY1 copy number in 3,723 individuals from 85 populations, revealing that Indigenous Peruvian Andean populations possess the highest AMY1 copy number globally. A genome-wide analysis showed significantly higher amylase copy numbers in Peruvian Andean genomes compared to closely related populations. Further, we identified positive selection (selection coefficient of 0.0124, log likelihood ratio of 11.1543) at the nucleotide level on a haplotype harboring at least five haploid AMY1 copies, with a Peruvian Andean-specific expansion coinciding with potato domestication ([~]6-10 kya). Using ultra-long-read sequencing, we demonstrated that previously described recombination-based mutational mechanisms drive the formation of high-copy AMY1 haplotypes observed in Andean population. Our study provides a framework for investigating structurally complex loci and their role in human dietary adaptation.

genetics↗

bioRxiv2022

Cellular Heterogeneity of Pluripotent Stem Cell Derived Cardiomyocyte Grafts is Mechanistically Linked to Treatable Arrhythmias

BackgroundExciting pre-clinical data have confirmed that human pluripotent stem cell derived cardiomyocytes (PSC-CMs) can remuscularise the injured or diseased heart, with several clinical trials now in planning or recruitment stages worldwide. However, ventricular arrhythmias are a predictable complication following engraftment of intramyocardially injected PSC-CMs. Therefore, there is an urgent unmet need to gain mechanistic insights and treatment strategies to control or prevent these engraftment arrhythmias (EAs). MethodsWe used a porcine model of myocardial infarction and PSC-CM transplantation to investigate efficacy of pharmacologic and catheter based anti-arrhythmic strategies in mitigating EAs. Furthermore, cell doses were robustly phenotyped using single cell ribonucleic acid sequencing and high parameter flow cytometry to identify cellular characteristics predictive of arrhythmogenesis. ResultsCombination therapy with amiodarone and ivabradine significantly reduced EA rate and burden following PSC-CM transplantation. Catheter ablation was also a feasible and effective treatment strategy which could be considered in the case of pharmacologically refractory arrhythmias. In addition, we show that EAs are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. We further describe two unique surface marker signatures, SIRPA+/CD90-/CD200+ and SIRPA+/CD90-/CD200-, which identify arrhythmogenic and non-arrhythmogenic cardiomyocytes respectively. ConclusionOur data deepens mechanistic understanding of EAs and suggests that modifications to current PSC-CM production and/or selection protocols could ameliorate this problem. We further show that current clinical pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish these arrhythmias, an important safety consideration given several impending clinical trials.

cell biology↗