Biology subjects

Pearson, S.

Publications and source records attributed to Pearson, S..

13 recordsLinked to original sources

bioRxiv2026

Genome-wide dissection of tillering responsiveness to neighbour proximity in sorghum

Tillering plasticity is a key adaptive trait in sorghum influencing resource use efficiency via a plants ability to adjust branching to neighbour density. Neighbour detection through red:far-red (R:FR) light sensing regulates this plasticity. While molecular pathways regulating tiller outgrowth are partly known, the genetic architecture underlying density-responsive tillering has not been resolved in any grass species. A sorghum diversity panel (n = 895) was evaluated over two growing seasons (2023 and 2024) with plant spacing ranging from 5 to 60 cm. A linear mixed model incorporating neighbour distance and tiller counts estimated genotype-specific response. GWAS was conducted on isolated plants (no neighbours within 60 cm) and on estimated responsiveness to neighbours. GWAS identified 52 baseline tillering QTLs and 50 for spacing responsiveness, with 10 overlapping, suggesting shared genetic control. Comparison with 41 R:FR pathway candidate genes revealed enrichment in responsiveness QTLs (5/50, 10%) versus baseline (0/52, 0%) (Fishers exact test, P = 0.025). Our model identified 40 unique density-responsive tillering QTL regions. Reducing genotype response to neighbour absence could be a selection target to develop water-efficient sorghum varieties where controlled architecture may be more valuable than natural plasticity.

plant biology↗

bioRxiv2025

Is Evolution Predictable? Experiments in an Evolutionary Video Game

The outcome of evolution sometimes appears to be predictable, as in the evolution of the same characteristics independently in convergent evolution. Other times, evolutions path depends on starting conditions or chance events, and some forms evolve just once and never appear again. Is convergence, and by implication, predictability, a common characteristic of the evolutionary process? We aimed to answer this question by using an evolutionary video game titled Project Hastur as a study system. In this video game, the enemies evolve traits to help them combat the players strategy. We determined whether the same environmental pressures (in this case, player strategy) lead to predictable evolution. We conducted a series of experiments with three different playing styles and four different evolutionary treatments with varying kinds of selection pressure, each with several replicates. For each replicate, enemies from the first and final generations were categorized into types using k-means clustering. The Euclidean distance between the cluster centroids and the sum of squares values were recorded for each replicate and compared among evolutionary treatments using Wilcoxon rank sum tests. Evolutionary predictability was evaluated using permutation tests. We found that fitness functions in Project Hastur led to incredible, but unpredictable, diversity. The fitness landscape changes between replicates, even within the same experimental treatment and regardless of player strategy, resulting in enemies with an unpredictable array of trait values.

evolutionary biology↗

bioRxiv2025

Complete telomere-to-telomere genomes of cowpea reveal insights into centromere evolution in Phaseoleae

Cowpea (Vigna unguiculata) is a versatile legume crop providing a critical source of grain, vegetable and forage globally. Cultivated cowpea is classified into two main subspecies, subsp. sesquipedalis for fresh-pod vegetable and subsp. unguiculata for grain production. Here, we present two complete telomere-to-telomere (T2T) assemblies for the grain-type inbred lines HJD and vegetable-type FC6 through integrating PacBio HiFi reads, Oxford Nanopore ultra-long reads, and Hi-C data. The T2T genomes demonstrated improved contiguity, completeness, and accuracy compared to existing genomes, revealing clear telomeric and centromeric features. Comparative analysis of the T2T genomes highlighted inversions underlying subspecies divergence in cowpea. Evolutionary analysis uncovered contraction of gene families related to symbiosis in HJD, consist with its reduced root nodules compared to FC6. Distribution and composition of tandem repeat arrays and transposable elements in centromeric regions were largely conserved in cowpea, but displayed pronounced variation among Phaseoleae. Furthermore, frequent shifts of centromeric locations coincided with inversions found in Phaseoleae. Overall, this study provides a set of fundamental resources for cowpea improvement and enhances our understanding of cowpea subspecies divergence and genome evolution in Phaseoleae.

genomics↗

bioRxiv2024

Type I interferon drives a cellular state inert to TCR-stimulation and could impede effective T-cell differentiation in cancer

Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium of the oral cavity, pharynx, or larynx and is linked to exposure to classical carcinogens and human papillomavirus (HPV) infection. Due to molecular, immunological, and clinical disparities between HPV+ and HPV-HNSCC, they are recognized as distinct cancer types. While immune checkpoint inhibition (ICI) has demonstrated efficacy in recurrent/metastatic HNSCC, response variability persists irrespective of HPV status. To gain insights into the CD8+ T-cell landscape of HPV-HNSCC, we performed multimodal sequencing (RNA and TCR) of CD8+ tumor-infiltrating lymphocytes (TILs) from treatment-naive HPV-HNSCC patients. Additionally, we subjected cells to ex vivo TCR-stimulation, facilitating the tracing of clonal transcriptomic responses. Our analysis revealed a subset of CD8+ TILs highly enriched for interferon-stimulated genes (ISG), which were found to be clonally related to a subset of granzyme K (GZMK)-expressing cells. Trajectory inference suggests ISG transition via GZMK cells towards terminal effector states. However, unlike GZMK cells, which rapidly an effector-like phenotype in response to TCR stimulation, ISG cells remain transcriptionally inert. Consequently, ISG cells may impede effective T-cell differentiation within the TME. Although, the functional consequences of ISG cells are poorly understood, we revealed that they possess receptors and ligands enabling cell-cell communication networks with key TME immunomodulators such as dendritic cells. Additionally, ISG cells were found to be a core feature across various tumor entities and were specifically enriched within tumor tissue. Thus, our findings illuminate the complexity of T-cell heterogeneity in HPV-HNSCC and reveal an overlooked population of IFN-stimulated CD8+ TILs. Further exploration of their functional significance may offer insights into therapeutic strategies for HPV-HNSCC and other cancer types.

immunology↗

bioRxiv2022

IL-17A promotes epithelial cell IL-33 production during nematode lung migration

The early migratory phase of pulmonary helminth infections is characterized by tissue injury leading to the release of the alarmin IL-33 and subsequent induction of type 2 immune responses. We recently described a role for IL-17A, through regulation of IFN{gamma}, as an important inducer of type 2 responses during infection with the lung-migrating rodent nematode Nippostrongylus brasiliensis. Here, we aimed to investigate the interaction between IL-17A and IL-33 during the early lung migratory stages of N. brasiliensis infection. In this brief report, we demonstrate that deficiency of IL-17A leads to impaired IL-33 expression and secretion early in infection, independent of IL-17A suppression of IFN{gamma}. Impaired IL-33 production was evident in lung epithelial cells, but not innate immune cells. Therefore, our results demonstrate that IL-17A can drive IL-33 during helminth infection, highlighting an additional mechanism through which IL-17A can regulate pulmonary type 2 immunity.

immunology↗

bioRxiv2022

The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia

Honeycombing (HC) is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). HC refers to cystic airways (HC airways) located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic HC airway cells and fibrotic uninvolved airway cells (distant from sites of UIP and morphologically intact) in 10 UIP specimens; 6 non-fibrotic airway cell specimens served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 UIP and 6 mucinous adenocarcinoma (MA) specimens. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to HC airway cells, showing deregulation of SLITs and ROBO pathway as the strongest category. We find that BPIFB1 is the most significantly increased secretome-associated protein in UIP, whereas MUC5AC is the most significantly increased in MA. We conclude that spatial proteomics demonstrates that the fibrotic uninvolved airway cells are abnormal. In addition, fibrotic HC airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach will generate novel and testable hypotheses to decipher fibrosis progression.

pathology↗

bioRxiv2021

Collateral damage: Identification and characterisation of spontaneous mutations causing deafness from a targeted knockout programme

Mice carrying targeted mutations are important for investigating gene function and the role of genes in disease, but the process of culturing embryonic stem cells during the making of a targeted allele offers opportunities for spontaneous mutations to arise. Identifying spontaneous mutations relies on the detection of phenotypes segregating independently of targeted alleles, and many phenotypes are easy to miss if not specifically looked for. Here we present data from a large, targeted knockout programme in which mice were analysed through a phenotyping pipeline. Twenty-five lines out of 1311 displayed different deafness phenotypes that did not segregate with the targeted allele. We have identified 8 different mutations causing deafness in 16 of these 25 lines and characterised the resulting phenotypes. Our data show that spontaneous mutations with observable effects on phenotype are a common side effect of intensive breeding programmes, including those underlying targeted mutation programmes.

genetics↗

bioRxiv2020

The magnitude of airway remodelling is not altered by distinct allergic inflammatory responses in BALB/c vs C57BL/6 mice, but matrix composition differs

Allergic airway inflammation is heterogenous with variability in immune phenotypes observed across asthmatic patients. Inflammation has been thought to directly contribute to airway remodelling in asthma, but clinical data suggests that neutralising type 2 cytokines does not necessarily alter disease pathogenesis. Here, we utilised C57BL/6 and BALB/c mice to investigate the development of allergic airway inflammation and remodelling. Exposure to an allergen cocktail for up to 8 weeks led to type 2 and type 17 inflammation, characterized by airway eosinophilia and neutrophilia and increased expression of chitinase-like proteins in both C75BL/6 and BALB/c mice. However, BALB/c mice developed much greater inflammatory responses than C57BL/6 mice, effects possibly explained by a failure to induce pathways that regulate and maintain T cell activation in C57BL/6 mice, as shown by whole lung RNA transcript analysis. Allergen administration resulted in a similar degree of airway remodelling between mouse strains but with differences in collagen subtype composition. Increased collagen III was observed around the airways of C57BL/6 but not BALB/c mice while allergen-induced loss of basement membrane collagen IV was only observed in BALB/c mice. This study highlights a model of type 2/type 17 airway inflammation in mice whereby development of airway remodelling can occur in both BALB/c and C57BL/6 mice despite differences in immune response dynamics between strains. Importantly, compositional changes in the ECM between genetic strains of mice may help us better understand the relationships between lung function, remodelling and airway inflammation.

immunology↗

bioRxiv2019

IL-17A both initiates (via IFNγ suppression) and limits the pulmonary type 2 immune response to nematode infection

Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production and neutrophilia. Using N. brasiliensis infection we confirm previous observations that Il17a-KO mice exhibit an impaired type-2 immune response. Neutrophil depletion and reconstitution studies demonstrated that neutrophils contribute to the subsequent eosinophilia but are not responsible for the ability of IL-17A to promote type-2 cytokine responses. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifn{gamma} signature in the Il17a-KO mice confirmed by enhanced IFN{gamma} protein production. Depletion of early IFN{gamma} rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFN{gamma} promotes type-2 immunity. Notably, when IL-17A was blocked later in infection, the type-2 response increased. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris, revealed that IL-17A promotes a type-2 immune response in the lung even when a parasite lifecycle is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity which supports the development of a protective type-2 immune response but subsequently limits the magnitude of that response.

immunology↗

bioRxiv2019

Mitochondrial pyruvate carrier is required for optimal brown fat thermogenesis

Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to help maintain a constant body temperature and counteract metabolic disease in mammals. The metabolic adaptations required for thermogenesis are not fully understood. Here we explore how steady state levels of metabolic intermediates are altered in brown adipose tissue in response to cold exposure. Transcriptome and metabolome analysis revealed changes in pathways involved in amino acid, glucose, and TCA cycle metabolism. Using isotopic labeling experiments, we found that activated brown adipocytes increased labeling of pyruvate and TCA cycle intermediates from U13C-glucose. Although glucose oxidation has been implicated as being essential for thermogenesis, its requirement for efficient thermogenesis has not been directly tested. Here we show that mitochondrial pyruvate uptake is essential for optimal thermogenesis, as conditional deletion of Mpc1 in brown adipocytes leads to impaired cold adaptation. Isotopic labeling experiments using U13C-glucose showed that loss of MPC1 led to impaired labeling of TCA cycle intermediates, while labeling of glycolytic intermediates was unchanged. Loss of MPC1 in BAT increased 3-hydroxybutyrate levels in blood and BAT in response to the cold, suggesting that ketogenesis provides an alternative fuel source that partially compensates for impaired mitochondrial oxidation of cytosolic pyruvate. Collectively, these studies highlight that complete glucose oxidation is essential for optimal brown fat thermogenesis.

biochemistry↗

bioRxiv2018

Vector-Mediated Transport Producing Drug-like Peptides

Drugs that are structural mimetics of peptides (e.g. small molecules) have been plagued by problems associated with oral availability and transcellular movement. Vector-mediated transport, where a potentially therapeutic drug is covalently linked to another molecule that is a ligand for an active transport or transcytosis system, was developed as an approach for moving a drug across the blood-brain-barrier. We now report a vector approach that produced peptides with oral activity, blood-brain-barrier transport, and extended in vivo half-life. Generating these properties requires secondary structure stabilization into a {beta} hairpin, and the addition of a C-terminal dipeptide sequence composed of non-polar residues. Peptides with biological activity incompatible with these derivatizations were covalently linked to a model transport vector, producing a chimera with the therapeutic activity of the peptide and the transport properties of the vector. Our platform technology may be a general approach for the design of drug-like peptides.

pharmacology and toxicology↗

bioRxiv2018

Loss of TLE3 Promotes Mitochondrial Program in Beige Adipocytes and Improves Glucose Metabolism

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue are not well understood. Here we demonstrate that the transcriptional coregulator TLE3 is induced with aging and inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes prevents age- and diet-induced weight gain by promoting mitochondrial oxidative metabolism and increasing energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these enhancers are also enriched for EBF transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 mediates age-dependent beige adipose thermogenic decline through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.

developmental biology↗

bioRxiv2017

Identification of drug eQTL interactions from repeat transcriptional and environmental measurements in a lupus clinical trial

BackgroundCytokines are critical to human disease and are attractive therapeutic targets given their widespread influence on gene regulation and transcription. Defining the downstream regulatory mechanisms influenced by cytokines is central to defining drug and disease mechanisms. One promising strategy is to use interactions between expression quantitative trait loci (eQTLs) and cytokine levels to define target genes and mechanisms.\n\nResultsIn a clinical trial for anti-IL-6 in patients with systemic lupus erythematosus we measured interferon (IFN) status, anti-IL-6 drug exposure and genome-wide gene expression at three time points (379 samples from 157 individuals). First, we show that repeat transcriptomic measurements increases the number of cis eQTLs identified compared to using a single time point by 64%. Then, after identifying 4,818 cis-eQTLs, we observed a statistically significant enrichment of in vivo eQTL interactions with IFN status (p<0.001 by permutation) and anti-IL-6 drug exposure (p<0.001). We observed 210 and 72 interactions for IFN and anti-IL-6 respectively (FDR<20%). Anti-IL-6 interactions have not yet been described while 99 of the IFN interactions are novel. Finally, we found transcription factor binding motifs interrupted by eQTL interaction SNPs, pointing to key regulatory mediators of these environmental stimuli and therefore potential therapeutic targets for autoimmune diseases. In particular, genes with IFN interactions are enriched for ISRE binding site motifs, while those with anti-IL-6 interactions are enriched for IRF4 motifs.\n\nConclusionThis study highlights the potential to exploit clinical trial data to discover in vivo eQTL interactions with therapeutically relevant environmental variables.

genomics↗