Biology subjects

Davis, G.

Publications and source records attributed to Davis, G..

9 recordsLinked to original sources

bioRxiv2026

A Multiscale Model of Collective Decision-Making in Hybrid Aspen Tree Tissues Describes Bud-Dormancy Break

The mechanisms underlying cellular coordination within tissues remain enigmatic. Most models focus on interactions between just two levels of organization - cell and tissue - and do not leverage data across deeper hierarchies that best represent living processes, with many spatial and temporal scales interacting. Integrating many scales, from molecular to cellular to tissular to organismal to populational, may be necessary to fully elucidate tissue function, especially in cases of sparse data at each level. Here, we investigate multiscale, robust regulation of tissue-level decision-making, using experimental studies of cold induced dormancy release in terminal buds of hybrid aspen trees as our case study. We develop a network model of terminal bud meristematic tissue, incorporating expression data from a key cold induced regulator gene, FLOWERING LOCUS T (FT1), which controls bud dormancy release, combined with data on variability in cell-to-cell communication controlled by FT1 mediated regulation of plasmodesmata. The model can explain dormancy breaking under constant temperature, but not variable temperature. We introduce constraints from organismal-level data and show how the presence of coordinated cellular interactions within individual plant tissues is necessary to reproduce data of population-level statistics. Our findings demonstrate how mechanisms of tissue function may be better constrained when data are used across more scales. They also hint at potential tantalizing new insights such as how tissue function might not be solely dictated bottom-up from molecular interactions, but also top-down from constraints imposed by the organismal and population context. Both implications illustrate the critical importance of incorporating cross-scale information processing in modeling biological decision-making. Significance StatementBiological hierarchies involve decision-making mediated via nested feedback loops. Data-informed modeling of this hierarchal complexity remains challenging. Here, we leverage unique features of plant biology - stationary growth, prolonged decision-making, and physical structure - to study multiscale dynamics determining cellular mechanisms of bud dormancy breaking in aspen trees. We examine how tissue function can be driven bottom-up from gene regulatory networks and top-down from organismal population-level statistics. Modeling experimental data collected at genetic, cellular, and organismal levels, reveals how population-level data allow constraining mechanisms of cellular coordination within individual plants when cellular data are sparse. Our findings demonstrate how multiscale methods can combat data sparsity and suggest new ways to study cellular coordination within organisms could be dictated by organismal population-level constraints.

synthetic biology↗

bioRxiv2026

Prostaglandin E2 Reverses Myofibroblast Differentiation in Eosinophilic Esophagitis

Background & AimsUnchecked inflammation in Eosinophilic esophagitis (EoE) leads to esophageal fibrosis and eventual stricture. Differentiated fibroblasts, termed myofibroblasts, are the main effector cells in fibrosis, responsible for secreting extracellular matrix proteins leading to tissue stiffness. Regulating myofibroblasts has not been explored as a therapeutic possibility in the fibrostenotic esophagus. Herein, we aim to investigate the efficacy of Prostaglandin E2 (PGE2) in dedifferentiation of the EoE myofibroblast. MethodsWe evaluated the efficacy and mechanism of myofibroblast dedifferentiation using fetal esophageal fibroblasts (FEF3), patient-derived fibroblasts, and a murine model of EoE. ResultsFibrosis markers (SMA, FN1, and COL1A1) and contractility of myofibroblasts were significantly decreased by PGE2 via the cAMP pathway. PGE2 treatment decreased nuclear accumulation of phospho-Smad2/3-YAP complex and induced phospho-YAP proteasomal degradation. Transcriptome analyses of FEF3 treated with TGF{beta} or PGE2 revealed that the Integrin1 pathway, and specifically thrombospondin 1 (THBS-1), was significantly upregulated by TGF{beta} and downregulated by PGE2, as supported by pseudo-bulk single-cell RNA-seq of EoE biopsies. THBS-1 was shown to be regulated by PGE2 via the cAMP/YAP pathway, and its knockdown induced myofibroblasts dedifferentiation. In a murine model of EoE, Butaprost, agonist of the E-prostanoid G protein-coupled receptor 2, treatment significantly reduced the expression of THBS-1, SMA, and FN1 along with a decrease in YAP nuclear translocation. Additionally, collagen fiber organization in the lamina propria was markedly reduced. ConclusionPGE2 promotes dedifferentiation of myofibroblasts in EoE via the cAMP/YAP/ THBS-1 pathway. Our data suggest that PGE2 is a promising treatment strategy for EoE with stenosis. What You Need to KnowO_ST_ABSBackground and ContextC_ST_ABSIn Eosinophilic esophagitis, unchecked inflammation and tissue stiffness drives fibroblast differentiation and fibrostenosis of the esophagus, yet targeting myofibroblasts as regulators of extracellular matrix deposition in fibrostenotic disease remains clinically unexplored. New FindingsProstaglandin E2 promotes dedifferentiation of myofibroblasts in eosinophilic esophagitis via the cAMP/YAP pathway, with Thrombospondin-1 identified as a critical YAP regulated target driving fibrostenosis. LimitationsThis study focused on fibroblast-specific mechanisms. The effects of PGE2 on esophageal epithelial differentiation, barrier function, and immune cell recruitment in EoE remain to be determined. Clinical Research RelevanceThis study demonstrates proof-of-concept that pharmacological reversal of established fibrosis is achievable in EoE. PGE2 and its EP2-selective agonists represent translatable therapeutic targets for fibrostenotic EoE--a patient population that remains treatment-refractory to current immunosuppressive approaches. Basic Research RelevanceThe cAMP/YAP/THBS-1 signaling in fibroblasts emerges as a critical therapeutic target for esophageal fibrosis. Importantly, this work demonstrates that terminally differentiated myofibroblasts retain remarkable plasticity and can dedifferentiate--challenging the paradigm that fibrosis is irreversible.

cell biology↗

bioRxiv2025

Endothelial cell MHC molecules are necessary and sufficient to reject 3D-printed human skin grafts in an advanced human immune system mouse

Vascularized skins were 3D-printed using single donor human fibroblasts, pericytes, keratinocytes and endothelial cells (ECs), the latter either unmodified (WT-ECs) or deleted of MHC molecules (KO-ECs). Adult MISTRG6 immunodeficient mice neonatally inoculated with adult human hematopoietic stem cells (HSCs) received printed skin allogeneic to the HSCs and were boosted 3 weeks post-grafting with human peripheral blood mononuclear cells (PBMCs) autologous to the HSCs. HSC inoculation alone produced low levels of circulating human myeloid and lymphoid cells without affecting grafts; PBMC boosting dramatically increased circulating human CD4+ T cells and boosted CD8+ T cells only in mice with WT-EC grafts. These grafts became infiltrated by human macrophages, dendritic cells, CD4+ and CD8+ T cells, and showed evidence of rejection. Shared T cell clones were present in skin and spleen. KO-EC grafts had minimal infiltration of graft or spleen without rejection despite MHC molecule expression on other graft cell types.

immunology↗

bioRxiv2025

Amino acids activate parallel chemosensory pathways in Drosophila

Amino acids (AAs) are essential dietary macronutrients that impact an organisms fitness in a concentration-dependent manner, but the mechanisms mediating AA detection to drive consumption are less clear. In Drosophila, we identified the full repertoire of taste cells and receptors involved in feeding initiation towards a glutamate-rich AA mixture, tryptone, using in vivo calcium imaging and the proboscis extension response (PER). We found that AA attraction occurs through sweet cells, whereas feeding aversion is mediated through Ionotropic Receptor 94e (IR94e) cells and bitter cells, dependent on concentration. Further, our results corroborate previous findings that ionotropic receptors IR76b, IR51b, and IR94e detect AAs in their respective cell types. Additionally, we describe a new role for the appetitive IR56d receptor and bitter gustatory receptors in detecting AAs. This work establishes a cellular and molecular framework of AA feeding initiation and highlights redundancy in aversive pathways that regulate AA feeding.

neuroscience↗

bioRxiv2024

Taste cells expressing Ionotropic Receptor 94e reciprocally impact feeding and egg laying in Drosophila

Chemosensory cells across the body of Drosophila melanogaster evaluate the environment and play a crucial role in neural circuits that prioritize feeding, mating, or egg laying. Previous mapping of gustatory receptor neurons (GRNs) on the fly labellum identified a set of neurons in L-type sensilla defined by expression of Ionotropic Receptor 94e (IR94e), but the impact of IR94e GRNs on behavior remained unclear. To understand their behavioral output, we used optogenetics and chemogenetics to activate IR94e neurons and found that they drive mild suppression of feeding but enhanced egg laying. In vivo calcium imaging revealed that IR94e GRNs respond strongly to certain amino acids, including glutamate. Furthermore, we found that IR94e is necessary and sufficient for the detection of amino acid ligands, and co-receptors IR25a and IR76b are also required for IR94e GRN activation. Finally, IR94e mutants show behavioral changes to solutions containing amino acids, including increased consumption and decreased egg laying. Overall, our results suggest that IR94e GRNs on the fly labellum discourage feeding and encourage egg laying as part of an important behavioral switch in response to certain chemical cues.

neuroscience↗

bioRxiv2022

On the reliability of wearable technology: A tutorial on measuring heart rate and heart rate variability in the wild

Wearable sensors are quickly making their way into psychophysiological research, as they allow collecting longitudinal and ecologically valid data. The present tutorial considers fidelity of physiological measurement with wearable sensors, focusing on reliability. We elaborate why ensuring reliability for wearables is important and offer statistical tools for assessing wearable reliability for between participants and within-participant designs. The framework offered here is illustrated using several brands of commercially available heart rate sensors. Our hope is that by systematically quantifying measurement reliability, researchers will be able to make informed choices about specific wearable devices and measurement procedures that meet their research goals.

neuroscience↗

bioRxiv2022

QUAS-R: Glutamine (Q) Uptake Assay with Single cell Resolution reveals metabolic heterogeneity with immune populations.

System level analysis of single cell data is rapidly transforming the field of immunometabolism. However, metabolic profiling of single cells and small populations by flow and mass cytometry is extremely limited by the availability of specific reagents such as antibodies and fluorescently nutrient analogues. Given the competitive demand for nutrients in pathogenic microenvironments including sites of infection, tumours and autoinflammation, there is a need to understand how and when immune cells access these nutrients. Fluorescent-tagging of nutrients is one approach to study nutrient transport but is extremely limited in its usefulness as tagging usually changes the transport characteristics and transporter specificity of the nutrient. Herein, we developed a completely new approach for single cell analysis of nutrient uptake where a fluorophore is attached to a functionalized amino acid after it has been transported across the plasma membrane and is within the cell. This in-cell biorthogonal labelling ensures that bona fide transport has been measured. System ASC transporter SLC1A5/ASCT2 transports multiple amino acids, most notably the crucial fuel glutamine, and has essential roles in supporting immune metabolism, signalling and function. This flow cytometry assay allows for rapid, sensitive, and quantitative measurement of SLC1A5-mediated uptake, which we used to interrogate the transport capacity of the complex immune subpopulations within the thymus, at a single cell resolution previously "unreachable". Taken together, our findings provide an easy procedure to assess which cells support their function via SLC1A5 mediated uptake of amino acids in a sensitive single cell assay. This assay is a significant addition to the single-cell metabolic toolbox required to decode the metabolic landscape of complex immune microenvironments.

immunology↗

bioRxiv2021

How the Zebra got its Rump Stripes: Salience at Distance and in Motion

Zebras stripes cannot protect them from predators, Darwin concluded, and current consensus tends to support his view1,2. In principle, stripes could support crypsis or aposematism, could dazzle, confuse or disrupt predators perception3-8, yet no such effects are manifest in predator-prey interactions9-11. Instead, narrow stripes covering zebras head, neck, limbs and flanks are an effective deterrent to tabanids12, vectors for equine disease13,14. Accordingly, while other potential benefits, e.g., thermoregulation15,16 and intraspecific communication17, cannot be excluded, zebra stripes likely evolved primarily to deter parasites18-20. Rump stripes, however, do not fit this, or any extant view. Typically horizontal and broader in sub-species with width variation, they are ill-suited to crypsis or parasite-deterrence12 and vary with hyaena threat18, perhaps shaped by an additional selective pressure. We observed that rump (and rear-flank) stripes remain highly conspicuous when viewed in motion or at distance, while other stripes do not. To study this striking effect, we filtered images of zebra to simulate acuity limitations in lion and hyaena photopic and mesopic vision. For mountain zebra and plains zebra without shadow striping, rump stripes were the most conspicuous image regions according to computational salience models, corroborated by human observers judgements of maximally attention-capturing image locations, which were strongly biased toward the rear. By hijacking exogenous attention mechanisms to force predator attention to the rear, salient rump stripes confer benefits to zebra, estimated here in pursuit simulations. Benefits of rump stripe salience may counteract anti-parasite benefits and costs of conspicuity to shape rump and shadow stripe variation. 1 HighlightsO_LIZebra stripes likely evolved to deter biting flies, but rump stripes are ill-suited to this. C_LIO_LIRump-stripes remain highly conspicuous when viewed at distance or in motion. C_LIO_LIComputational models and human observers judge rump stripes are most salient stripes. C_LIO_LISalient rump stripes drive predator attention to rear, hindering capture by predators. C_LIO_LIObserve this striking effect in moving zebra at: viscog.psychol.cam.ac.uk/resources-and-downloads C_LI

evolutionary biology↗

bioRxiv2018

Widespread cytoplasmic polyadenylation programs asymmetry in the germline and early embryo

BACKGROUNDThe program of embryonic development is launched by selective activation of a silent maternal transcriptome. In Caenorhabditis elegans, nuclei of the adult germline are responsible for the synthesis of at least two distinct mRNA populations; those required for housekeeping functions, and those that program the oocyte-to-embryo transition. We mapped this separation by changes to the length-distribution of poly(A)-tails that depend on GLD-2 mediated cytoplasmic polyadenylation and its regulators genome-wide.\n\nRESULTSMore than 1000 targets of cytoplasmic polyadenylation were identified by differential polyadenylation. Amongst mRNA with the greatest dependence on GLD-2 were those encoding RNA binding proteins with known roles in spatiotemporal patterning such as mex-5 and pos-1. In General, the 3 UTR of GLD-2 targets were longer, contained cytosine-patches, and were enriched for non-standard polyadenylation-motifs. To identify the deadenylase that initiated transcript silencing, we depleted the known deadenylases in the gld-2(0) mutant background. Only the loss of CCF-1 suppressed the short-tailed phenotype of GLD-2 targets suggesting that in addition to its general role in RNA turnover, this is the major deadenylase for regulatory silencing of maternal mRNA. Analysis of poly(A)-tail length-change in the embryo lacking specific RNA-binding proteins revealed new candidates for asymmetric expression in the first embryonic divisions.\n\nCONCLUSIONThe concerted action of RNA binding proteins exquisitely regulates GLD-2 activity in space and time. We present our data as interactive web resources for a model where GLD-2 mediated cytoplasmic polyadenylation regulates target mRNA at each stage of worm germline and early embryonic development.

developmental biology↗