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Biology subjects

Jones, D. L.

Publications and source records attributed to Jones, D. L..

At least 19 recordsLinked to original sources

4-Dimensional Chess: Acoustic Localisation Reveals Nested Spatio-temporal Strategies in an Arboreal Communication Network

1. Adaptive behavioural strategies require animals to simultaneously navigate social and ecological domains across multiple spatial and temporal scales. Although drones and computer vision have recently transformed the study of wild animal societies, many nocturnal species and those occupying structurally complex habitats remain inaccessible to these approaches, limiting our understanding of behaviour in natural settings. 2. We aimed to determine how behavioural strategies are organised across nested spatial and temporal scales within a wild communication network. 3. We used three-dimensional acoustic localisation and source separation to track individual male Hyperolius sp. A, a nocturnal African reed frog, within a natural rainforest chorus and quantify patterns of site fidelity, movement, spatial organisation, and call-timing interactions. 4. Males exhibited significant site fidelity across nights, while chorus spatial structure varied with local caller density. Within nights, individuals followed a stereotyped behavioural sequence, descending from elevated arboreal refugia before settling into lower calling positions near breeding sites. At finer temporal scales, call-timing interactions varied according to both local competitor density and the proximity of neighbouring rivals. 5. These findings demonstrate that behavioural strategies emerge across nested spatial and temporal scales and that long-term spatial positioning, short-term movement decisions, and moment-to-moment signalling interactions are tightly linked within natural communication networks. More broadly, acoustic localisation provides a powerful framework for studying behaviour in species and habitats that remain difficult to observe using conventional approaches.

animal behavior and cognition↗

Hippocampal stimulation timed to memory reactivation shapes human sleep oscillatory dynamics and consolidation

Memory consolidation during sleep depends on the precisely timed coordination of hippocampal reactivation with cortical slow oscillations and spindles. In humans this coupling has been characterised correlationally, while causal investigations have required intracranial stimulation in restricted patient cohorts or used non-invasive approaches targeting cortical regions, often obscuring the underlying sleep rhythms. Here we stimulated the human hippocampus during sleep for the first time, applying temporal interference stimulation to the left hippocampal head either concurrently with or prior to induced memory reactivation. Stimulation concurrent with reactivation reduced associative memory forgetting relative to mistimed stimulation and enhanced fast spindle amplitude, preserving the association between slow oscillation-spindle coupling and memory. This behavioural benefit was mediated by a distributed, left-lateralised set of spindle and coupling features. Non-invasively engaging deep hippocampal circuits during sleep offers both a means to probe human memory and a scalable basis for intervention where consolidation fails.

neuroscience↗

Cytoskeletal-nuclear control of alveolar fibroblast identity directs lung regeneration

Respiratory mechanics direct cell fate in the lung, but the mechanisms by which these mechanical signals are sensed and transmitted to the nucleus to control cell state remain unclear. We paired in vivo perturbations of respiratory mechanics with single-cell genomics and found that alveolar fibroblasts are highly sensitive to physical changes in their microenvironment, exhibiting persistent shifts in their transcriptional identity after injury. Surprisingly, transmission of these signals through the nuclear envelope was not essential for maintaining transcriptional or epigenetic stability during homeostasis. However, severing mechanical-nuclear signaling promoted the normalization of alveolar fibroblast identity after acute injury, resulting in improved epithelial regeneration and reduced dysplastic remodeling. These studies reveal the importance of mechanical-nuclear signaling in the regulation of alveolar cell identity and function and reveal that targeting this complex can enhance tissue regeneration.

cell biology↗

Inflammatory Fibroblasts Promote Repair After Injury Through Epithelial Proliferation

Fibroblast heterogeneity after lung injury is a well observed phenomenon made highly relevant by the widespread application of single cell RNA-sequencing. The characterization of homeostatic and injury associated states has led to the identification of a population of fibroblasts that emerge during inflammation and express cytokines that may potentially amplify the inflammatory circuit. However, whether these cells actively contribute to inflammation or serve an alternative function within the broader injury-repair cascade remains unclear. By integrating several robust murine lung injury data sets we establish the persistence of the inflammatory fibroblast across multiple injury models and identify a role for these cells in lung repair after injury through effects on alveolar epithelial proliferation. We validate this observation in-vivo using a genetic model of spontaneous lung fibrosis and in-vitro with mixed alveolar organoid cultures of various homeostatic and injury associated fibroblasts wherein we identify a mesenchymal-epithelial BMP signaling axis as a key driver of the AT2 cell injury repair response. Finally, we present supporting evidence from human disease, reinforcing the relevance of this fibroblast subset in pathological settings. These findings extend critical observations made prior to the single-cell era and contribute to our evolving understanding of fibroblast heterogeneity as a key feature of lung repair.

molecular biology↗

Cross-species consensus atlas of the primate basal ganglia

The basal ganglia (BG) are conserved brain regions essential for motor control, learning, emotion, and cognition, and are implicated in neurological and psychiatric disease. Yet a unified cross-species taxonomy of BG cell types is lacking, limiting translation of BG circuit mechanisms, interpretation of human genetic risk, and development of cell type-targeted tools. We present a multiomic consensus atlas of 1.8 million nuclei from human, macaque, and marmoset spanning eight BG structures. Integrating cross-species gene expression, open chromatin, and spatial profiling enables definition of conserved and divergent cell types. Alignment to existing mouse and human atlases identifies 61 homologous cell types conserved over 80 million years. We identify a STRd D2 StrioMat Hybrid medium spiny neuron (MSN) type with molecular, electrophysiological, and morphological features that clarify hybrid MSN identities. Comparative cis-regulatory analysis reveals conserved sequence grammars that encode cell identity and inform viral targeting strategies, providing a foundational resource for BG evolution, function, and disease.

neuroscience↗

Mechanical force-mediated cellular crosstalk maintains the integrity of the lung gas exchange niche

Respiratory motion imposes a constant mechanical strain that has important but poorly defined impact on tissue niches in the lung. We developed a reversible bronchial ligation model to induce and reverse unilateral blockade of lung mechanical motion in vivo and show that this leads to transcriptomic changes in multiple cell lineages that are not normalized upon reinitiation of respiratory motion. Perturbation of mechanosignaling specifically in alveolar epithelial type I (AT1) cells alters the transcriptomic state and fate of their niche neighbors, demonstrating that AT1 cells act as a node that propagates a mechanical cascade throughout the lung alveolus. Mechanically perturbed AT1 cells induce a distinct capillary endothelial cell state that persists after reactivation of respiratory motion, which is mediated by an integrin/TGF-{beta} network within the alveolus that is vulnerable to pharmacological intervention. Importantly, AT1 mechanosignaling and intercellular communication are altered in chronic human lung diseases, highlighting the critical role of an AT1-driven mechanosensing network in lung disease biology. Thus, mechanosensing cells propagate biophysical signals that regulate tissue function and program tissue responses in disease.

cell biology↗

An injury-induced tissue niche shaped by mesenchymal plasticity coordinates the regenerative and disease response in the lung

Severe lung injury causes basal stem cells to migrate and outcompete alveolar stem cells resulting in dysplastic repair and a loss of gas exchange function. This "stem cell collision" is part of a multistep process that is now revealed to generate an injury-induced tissue niche (iTCH) containing Keratin 5+ epithelial cells and plastic Pdgfra+ mesenchymal cells. Temporal and spatial single cell analysis reveals that iTCHs are governed by mesenchymal proliferation and Notch signaling, which suppresses Wnt and Fgf signaling in iTCHs. Conversely, loss of Notch in iTCHs rewires alveolar signaling patterns to promote euplastic regeneration and gas exchange. The signaling patterns of iTCHs can differentially phenotype fibrotic from degenerative human lung diseases, through apposing flows of FGF and WNT signaling. These data reveal the emergence of an injury and disease associated iTCH in the lung and the ability of using iTCH specific signaling patterns to discriminate human lung disease phenotypes.

cell biology↗

Real-time pooled optical screening with single-cell isolation capability.

In a pooled optical screen, a genetically diverse library of living cells is imaged and characterised for phenotypic variations without knowing the genotype of the cells. The genotypes are identified in situ after the cells have been fixed or by physical extraction of interesting phenotypes followed by sequencing. Mother-machine microfluidics devices are efficient tools in pooled optical screens since many strains can be imaged in the same field of view, but the throughput is often limited. In this work, we show a method to extract single bacterial cells from a compact 100,000-trap mother-machine-based fluidic device using an optical tweezer. Unlike previous devices, the fluids in our design are routed in 3D to enable fast loading of cells, increased trap density, and faster imaging. We have also developed software that allows real-time analysis of the phenotyping data.

biophysics↗

Make Like a Tree and Leave: How Will Tree Species Loss and Climate Change Alter Future Temperate Broadleaved Forests?

Forest creation has the potential to reduce biodiversity loss and mitigate climate change but, tree disease emergence may counteract this. Further, given decadal timescales required for forest establishment, climate change is increasingly likely to act as a filter on plant community assembly. In the temperate lowlands succession takes 30 to 50 years for non-forest land to establish woodland plant assemblages, while the timescales required for new forest to sequester carbon suggest unassisted succession will be too slow for net zero 2050 targets. However, if plantations can establish faster than succession it would be beneficial to recommend planting native species as soon as possible. We explore scenarios of broadleaved woodland development across Wales, UK, as a case study area. We use a suite of empirical species niche models for British plants to estimate the potential species composition of forests with, and without, projected climate change. Additionally, we examine how tree canopy composition alters if Fraxinus excelsior is widely impacted by ash-dieback (Hymenoscyphus fraxineus). The results suggest soil total carbon and nitrogen could achieve baseline broadleaved forest values in less than 30 years. However only timber and woody flora species groups showed diversity surpassing baseline broadleaved forest diversity, with nectar plants and ancient woodland indicator species failing to reach baseline equivalents within 30 years; although complete congruence is unlikely given baseline forests could be hundreds of years old. Where Fraxinus excelsior was removed from the species pool we predicted that a scrub phase will persist or, if present, Acer pseudoplatanus will become the canopy dominant. The heavier shade cast this species is likely to result in differences in species composition of the understory and ground flora diversity is likely to decrease. Reliance on unassisted succession will also depend critically on (a) dispersal from local source populations and (b) on establishment filters that could be severe in landscapes with high management intensity history. These findings indicate that leaving the UKs fragmented habitats to relying on already degraded successional processes could lead to poor afforestation outcomes. HighlightsO_LIAfforestation can mitigate global change but tree disease makes outcomes uncertain C_LIO_LIAfforestation methods establishment timescales and time for benefits to occur C_LIO_LIWe model afforestation and predict how soils and plants change with climate C_LIO_LIAsh loss from die-back is replaced by low low-canopy woodland / scrub over 30 years C_LIO_LIAfforestation achieves baseline forest values for some variables within 30 years C_LI

ecology↗

A diversity of diversities: evaluating the relationships between below and aboveground biodiversity

O_LITo predict how biodiversity will respond to global change, it is crucial to understand the relative roles of abiotic drivers and biotic interactions in driving associations between the biodiversity of disparate taxa. It is particularly challenging to understand diversity-diversity links across domains and habitats, because data are rarely available for multiple above- and below-ground taxa across multiple sites. C_LIO_LIHere we analyse data from a unique biodiversity dataset gathered across a variety of oceanic temperate terrestrial habitats in Wales, comprising 300 sites with co-located soil microbial, plant, bird, and pollinator surveys along with climate and soil physicochemical information. Soil groups are analysed using metabarcoding of the 16S, ITS1 and 18S DNA regions, allowing in depth characterisation of microbial and soil animal biodiversity. C_LIO_LIWe explore biodiversity relationships along three aspects of community composition: First, we assess correlation between the alpha diversity of different groups. Second, we assess whether biotic turnover between sites is correlated across different groups. Finally, we investigate the co-occurrence of individual taxa across sites. In each analysis, we assess the contribution of linear or non-linear environmental effects. C_LIO_LIWe find that a positive correlation between alpha diversity of plants, soil bacteria, soil fungi, soil heterotrophic protists, bees and butterflies is in fact driven by complex non-linear responses to abiotic drivers. In contrast, environmental variation did not account for positive associations between the diversity of plants and both birds and AM fungi, suggesting a role for biotic interactions. C_LIO_LIBoth the diversity and taxon-level associations between the differing soil groups remained even after accounting for non-linear environmental gradients. Aboveground, spatial factors played larger roles in driving biotic communities, while linear environmental gradients were sufficient to explain many group- and taxon-level relationships. C_LIO_LISynthesis. Our results show how non-linear responses to environmental gradients drive many of the relationships between plant biodiversity and the biodiversity of above- and belowground biological communities. Our work shows how different aspects of biodiversity might respond non-linearly to changing environments and identifies cases where management-induced changes in one community could either influence other taxa or lead to loss of apparent biological associations. C_LI

ecology↗

The septate junction component Bark beetle is required for Drosophila intestinal barrier function and homeostasis

Age-related loss of intestinal barrier function has been found across species, and the causes remain unknown. The intestinal epithelial barrier is maintained by tight junctions (TJs) in mammals and septate junctions (SJs) in insects. Specialized tricellular junctions (TCJs) are found at the nexus of three adjacent cell membranes, and we showed previously that aging results in mis-localization of the tricellular SJ (tSJ) component Gliotactin (Gli) in enterocytes (ECs) of the Drosophila melanogaster intestine. In embryonic epithelia, the tSJ protein Bark beetle (Bark) recruits Gli to tSJs, which prompted us to investigate Bark function in the intestine. Bark protein localization decreases at tSJs in aged flies. EC-specific bark depletion in young flies led to hallmarks of intestinal aging and shortened lifespan, whereas depletion of bark in progenitor cells reduced Notch activity, biasing differentiation toward the secretory lineage. Together, our data implicate Bark in EC maturation, maintenance of intestinal barrier integrity, and homeostasis. Understanding the assembly and maintenance of tSJs to ensure barrier integrity may lead to strategies to improve tissue integrity when function is compromised.

cell biology↗

Genetic mapping reveals Pou2af2-dependent tuning of tuft cell differentiation and intestinal type 2 immunity

Chemosensory epithelial tuft cells contribute to innate immunity at barrier surfaces, but their differentiation from epithelial progenitors is not well understood. Here we exploited differences between inbred mouse strains to identify an epithelium-intrinsic mechanism that regulates tuft cell differentiation and tunes innate type 2 immunity in the small intestine. Balb/cJ (Balb) mice had fewer intestinal tuft cells than C57BL/6J (B6) mice and failed to respond to the tuft cell ligand succinate. A majority of this differential succinate response was determined by a single genetic locus from 50-67Mb on chromosome 9 (Chr9). Congenic Balb mice carrying the B6 Chr9 locus had elevated baseline numbers of tuft cells and responded to succinate. The Chr9 locus includes Pou2af2, a transcriptional cofactor essential for tuft cell development. Epithelial crypts expressed a previously unannotated short isoform of Pou2af2 that uses a novel transcriptional start site and encodes a non-functional protein. Low tuft cell numbers and the resulting lack of succinate response in Balb mice was explained by a preferential expression of the short isoform. Physiologically, differential Pou2af2 isoform usage tuned innate type 2 immunity in the small intestine. Balb mice maintained responsiveness to helminth pathogens while ignoring commensal Tritrichomonas protists and reducing norovirus burdens. One Sentence SummaryGenetic mapping identifies Pou2af2 isoform usage as a novel regulator of tuft cell differentiation that tunes intestinal innate type 2 immunity.

immunology↗

Special Nuclear Layer Contacts Among Starburst Amacrine Cells in the Mouse Retina

We observed novel classes of cell-cell contacts between retinal starburst amacrine neurons, from finely detailed morphological reconstructions of cells from an electron microscopic image volume of a mouse retina. These contacts have peculiar morphological patterns and traits, different among the respective On and Off starburst amacrine subpopulations, but both occur within the soma layers as opposed to their regular laminae of contact within the inner plexiform layer.

neuroscience↗

mTORC1 is required for differentiation of germline stem cells in the Drosophila melanogaster testis

Metabolism participates in the control of stem cell function and subsequent maintenance of tissue homeostasis. How this is achieved in the context of adult stem cell niches in coordination with other local and intrinsic signaling cues is not completely understood. The Target of Rapamycin (TOR) pathway is a master regulator of metabolism and plays essential roles in stem cell maintenance and differentiation. We observe differential expression of the Tor kinase in the Drosophila male germline, which correlates with restriction of mTORC1 activity to germline stem cells (GSCs) and early germ cells. Targeted RNAi-mediated downregulation of Tor in early germ cells causes a block and/or a delay in differentiation, resulting in an accumulation of germ cells with GSC-like features. These early germ cells also contain unusually large and dysfunctional autolysosomes. In addition, downregulation of Tor in adult male GSCs and early germ cells causes non-autonomous activation of mTORC1 in neighboring cyst cells, which correlates with a disruption in the coordination of germline and somatic differentiation. Our study identifies a previously uncharacterized role of the TOR pathway in regulating male germline differentiation.

developmental biology↗

Mechano-epigenetic regulation of extracellular matrix homeostasis via Yap and Taz

Cells integrate mechanical cues to direct fate specification to maintain tissue function and homeostasis. While disruption of these cues is known to lead to aberrant cell behavior and chronic diseases, such as tendinopathies, the underlying mechanisms by which mechanical signals maintain cell function is not well understood. Here, we show using a novel model of tendon de-tensioning that loss of tensile cues in vivo acutely changes nuclear morphology, positioning, and expression of catabolic gene programs. Using paired ATAC/RNAseq, we further identify that a loss of cellular tension rapidly reduces chromatin accessibility in the vicinity of Yap/Taz genomic targets while also increasing expression of genes involved in matrix catabolism. Overexpression of Yap results in a reduction of chromatin accessibility at matrix catabolic gene loci, while also reducing transcriptional levels. Concordantly, depletion of Yap/Taz elevates matrix catabolic expression. Finally, we demonstrate that overexpression of Yap not only prevents the induction of a broad catabolic program following a loss of cellular tension, but also preserves the underlying chromatin state from force-induced alterations. Taken together, these results provide novel mechanistic details by which mechanical signals regulate tendon cell function to preserve matrix homeostasis through a Yap/Taz axis. Significance StatementCells integrate mechanical signals to regulate biological outputs within tissues. These processes are required for tissue function and homeostasis. Here, we show how mechanical cues (e.g. tension) directs tendon cell function and fate at a transcriptional and epigenetic level. Furthermore, we show that disruption of these mechanical cues leads to a disease-like cell state, indicating these mechanosensitive pathways could be important for diseases driven by perturbed mechanical signaling, such as tendinopathy. Finally, we demonstrate that genetic perturbation of a single protein can preserve cell and chromatin state following a loss of tension, supporting novel avenues for the development of innovative mechano-therapeutics.

cell biology↗

Culture Associated DNA Methylation Changes Impact on Cellular Function of Human Intestinal Organoids

Background & AimsHuman intestinal epithelial organoids (IEO) are a powerful tool to model major aspects of intestinal development, health and diseases, as patient derived cultures retain many features found in-vivo. A necessary aspect of the organoid model is the requirement to expand cultures in-vitro through several rounds of passaging. This is of concern, as the passaging of cells has been shown to affect cell morphology, ploidy, and function. In this study, we address concerns around long term passaging of IEO to better characterise and define effects on cell morphology and function. MethodsHere we have analysed 173 human IEO from two sampling sites, terminal ileum and sigmoid colon and examined the effect of culture duration on DNA methylation (DNAm), gene expression and cellular function including their response to proinflammatory cytokines and in-vitro cell differentiation. ResultsOur analyses revealed a major effect of culture duration on DNAm, leading to significant changes at 61,337 loci representing approximately 8% of all CpGs tested. Although global cellular functions such as gut segment-specific gene expression remained stable, a subset of methylation changes correlated with altered gene expression at baseline as well as in response to inflammatory cytokine exposure and in-vitro differentiation. Importantly, epigenetic changes were found to be enriched in genomic regions associated with colonic cancer and distant to the site of replication indicating similarities to malignant transformation. ConclusionsOur study reveals culture-associated epigenetic, transcriptomic and functional changes in human mucosa derived IEO and highlights the importance of considering passage number as a potentially confounding factor. SynopsisThis work describes cell culture induced changes to DNA methylation, gene expression and cellular function in human IEO. Globally organoids lost DNA methylation with time in culture while DNA methylation also became generally more variable. This work suggests a shifted epigenetic profile in organoids cultured long-term.

genomics↗

Lung injury epigenetically primes mesenchyme for amplified activation upon re-injury

The lungs have a remarkable capacity to repair. However, repetitive injury can lead to progressive fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multi-modal analyses on isolated lung mesenchyme during the initiation, progression and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrogenic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme retains specific epigenetic traits (memory) of prior activation, resulting in amplified induction of a fibrogenic program upon re-injury. We identify Runx1 as a critical driver of both fibrogenic activation and epigenetic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that Runx1 is spontaneously activated in standard culture conditions, previously masking these roles of Runx1. Genetic and pharmacological targeting of Runx1 dampens fibrogenic mesenchymal cell activation in cell and tissue models, confirming its functional importance. Finally, publicly available scRNAseq data reveal selective expression of Runx1 in the fibrogenic cell subpopulations that emerge in mouse and human fibrotic lung tissue. Collectively, our findings implicate Runx1 in both the initiation and memory of fibrogenic mesenchymal cell activation that together prime amplified mesenchymal cell responses upon repeated injury.

cell biology↗

Diverse soil RNA viral communities have the potential to influence grassland ecosystems across multiple trophic levels

Grassland ecosystems form 30-40%1 of total land cover and provide essential ecosystem services, including food production, flood mitigation and carbon storage2. Their productivity is closely related to soil microbial communities3, yet the role of viruses within these critical ecosystems is currently undercharacterised4 and in particular, our knowledge of soil RNA viruses is significantly limited5. Here, we applied viromics6 to characterise soil RNA viral communities along an altitudinal productivity gradient of peat, managed grassland and coastal soils. We identified 3,462 viral operational taxonomic units (vOTUs) and assessed their spatial distribution, phylogenetic diversity and potential host ranges. Soil types exhibited showed minimal similarity in viral community composition, but with >10-fold more vOTUs shared between managed grassland soils when compared with peat or coastal soils. Phylogenetic analyses of viral sequences predicted broad host ranges including bacteria, plants, fungi, vertebrates and invertebrates, contrasting with soil DNA viromes which are typically dominated by bacteriophages7. RNA viral communities therefore likely have the ability to influence soil ecosystems across multiple trophic levels. Our study represents an important step towards the characterisation of terrestrial RNA viral communities and the intricate interactions with their hosts, which will provide a more holistic view of the biology of economically and ecologically important terrestrial ecosystems.

ecology↗