Biology subjects

Lyons, M.

Publications and source records attributed to Lyons, M..

9 recordsLinked to original sources

bioRxiv2026

Functional Assessment of Cardiac Beat Dynamics Under Dynamic Flow: Insights from the Mera Microphysiological System

Cardiac rhythm is a critical clinical indicator for cardiac arrhythmias and adverse events during drug toxicity studies. In vivo, cardiomyocyte responses to pharmacological agents occur within minutes and are strongly influenced by dynamic drug delivery through blood flow. However, conventional 2D and 3D static culture systems fail to replicate these fluid flow kinetics, limiting their physiological relevance for assessing beat rate responses. Here, we present Mera, an advanced microphysiological system (MPS) developed by Hooke Bio, designed for high-throughput, long-term culture and functional analysis of 3D cardiac spheroids composed of human induced pluripotent stem cell-derived cardiomyocytes and cardiac fibroblasts. Mera enables dynamic perfusion, allowing investigation of cardiomyocyte beat rates under physiologically relevant flow conditions. The platform supports up to 640 spheroids per run and integrates automated imaging, fluid handling, and user-friendly software, operating under controlled physiological conditions (37{degrees}C, 5% CO2). Flow rates are tunable between 0 and 12.5 mL/min to mimic in vivo environments. Pharmacological testing with verapamil, isoproterenol, calcium chloride, and propranolol demonstrated real-time, reversible modulation of beat rate under flow, including recovery following drug-induced suppression. System variability was comparable to a temperature-controlled reference platform, supporting robust statistical analysis. Dose-response studies yielded IC values consistent with literature, confirming physiological relevance. Collectively, these results demonstrate that Mera provides a reproducible, scalable, and human-relevant platform for cardiac drug testing. By enabling dynamic drug exposure and automated analysis, Mera represents a powerful new approach methodology (NAM) for improving the predictive assessment of cardiac safety and beat-rate modulation drug responses.

bioengineering↗

bioRxiv2025

Integrating Artificial Intelligence-Driven Digital Pathology and Genomics to Establish Patient-Derived Organoids as a Novel Alternative Model for Drug Response in Head and Neck Cancer

Patient-derived organoids (PDOs) are emerging as advanced 3D ex vivo novel alternative method (NAM) preclinical models, offering significant advantages over traditional cell lines and monolayer cultures for therapeutic development. In this study, we established PDOs from surgically resected fresh tissues of human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) across anatomical sites, tumor T-categories, and sample types. These PDOs faithfully recapitulate the tumors pathology, mutational profile, and drug response. To enable rapid classification of PDO identity, we developed a new convolutional neural network (CNN) model, TransferNet-PDO, which accurately distinguished tumor versus normal PDOs in culture using digital histopathology images (AUC[≥]0.88). PDOs maintained stable cultures and were cryopreserved between passages 5 and 12. Immunohistochemistry (IHC) staining (PanCK, p63, Cytokeratin 13, Ki67) confirmed squamous phenotype and histologic aggression of the original tumor. For tumors harboring TP53 mutations by whole-exome sequencing (WES), PDOs retained the corresponding p53 functional status as confirmed by IHC (enhanced or loss of expression). Somatic mutational landscape revealed that PDOs preserved driver somatic mutations, copy number variations (CNVs), and clonal architecture including low-prevalence subclones. Drug sensitivity assessment of PDOs showed that cisplatin reduced cell viability, whereas cetuximab and lenvatinib had minimal effects. Chemoradiation led to greater tumor organoid killing compared to radiation or chemotherapy alone. This study presents an integrated HNSCC PDO platform combining tissue biobanking, organoid establishment, multi-omics characterization, functional drug screening, and AI-driven histopathologic classification, providing a comprehensive and scalable system for translational cancer research.

cancer biology↗

bioRxiv2024

Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis.

Dermal fibrosis is a cardinal feature of systemic sclerosis (SSc) for which there are limited treatment strategies. This is in part due to our fragmented understanding of how dermal white adipose tissue (DWAT) contributes to skin fibrosis. We identified elevated sine oculis homeobox homolog 1 (SIX1) expression in SSc skin samples from the GENISOS and PRESS cohorts, the expression of which correlated with adipose-associated genes and molecular pathways. SIX1 localization studies identified increased signals in the DWAT area in SSc and in experimental models of skin fibrosis. Global and adipocyte specific Six1 deletion abrogated end-stage fibrotic gene expression and dermal adipocyte shrinkage induced by SQ bleomycin treatment. Further studies revealed a link between elevated SIX1 and increased expression of SERPINE1 and its protein PAI-1 which are known pro-fibrotic mediators. However, SIX1 deletion did not appear to affect cellular trans differentiation. Taken together these results point at SIX1 as a potential target for dermal fibrosis in SSc. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSkin thickening and tightening are leading causes of morbidity in systemic sclerosis (SSc). The authors previously reported that the aberrantly expressed developmental transcription factor sine oculis homeobox homology 1 (SIX1) drives pulmonary fibrosis. However, the contribution of SIX1 to skin fibrosis and associated dermal fat loss remains unknown. Added value of this studyThe role of dermal fat loss in skin fibrosis is not fully understood. Studies have shown that adipocytes can transition to mesenchymal cells promoting fibrosis, consistent with loss of the dermal white adipose layer. Our research provides insight into a novel molecular mechanism of lipodystrophy important for skin fibrosis in SSc. We identified the upregulation of SIX1 in adipocytes in skin from patients with SSc which was associated with the progression of skin fibrosis. We found elevated Six1 in mouse dermal adipocytes of early fibrotic skin. Ubiquitous and adipose-specific loss of Six1 decreased markers of experimental skin fibrosis in mice which recapitulate cardinal features of SSc dermal fibrosis. Increased SIX1 expression is linked with elevated levels of Serpine1 the gene that codes for the protein plasminogen activator inhibitor (PAI)-1. This is important since PAI-1 is a known pro-fibrotic agent in the skin that contributes to the deposition of extracellular matrix (ECM) products. Implications of all the available evidenceFat atrophy may represent a targetable contributor to early systemic sclerosis manifestations. This is as it precedes skin fibrosis and the use of topical agent which are usually lipophilic can help us target dermal adipocytes. Our results show that SIX1 could be an important early marker for skin fibrosis in SSc that can also be targeted therapeutically.

molecular biology↗

bioRxiv2024

Reproducing within-reef variability in coral dynamics with a metacommunity modelling framework

Reef systems span spatial scales from 10s to 100s and even 1000s of kilometres, with substantial spatial variability across these scales. Managing and predicting the future of coral reefs requires insights into reef functioning at all spatial scales. However, investigations of reef functioning often consider individual reefs as the smallest unit (10s of kilometres), despite substantial spatiotemporal variability occurring within-reefs (100s of meters). We developed C[~]scape, a coral metacommunity modelling framework that integrates the demography of corals with population-level responses to physical and environmental spatial layers, to simulate a mosaic of interacting coral communities across a heterogenous seascape. Coral communities are linked using biophysical connectivity modelling. Coral community growth is modelled with a logistic growth model, with the intrinsic growth parameter determined from taxa-specific Integral Projection Models to incorporate demographic mechanisms. Site-specific coral habitat parameters, derived from satellite-based geomorphic and benthic habitat maps, define the maximum coral cover and are used to modulate community growth spatially and temporally as a function of the available space suitable for corals. These parameters are a proxy for the many interacting physical and environmental factors -- e.g., depth, light, wave exposure, temperature, and substrate type -- that drive within-reef variability in coral demography. Using a case study from the Great Barrier Reef, we show that modulating community growth using site-specific habitat parameters enables more accurate hindcasts of coral cover dynamics, while overlooking within-reef variability may lead to misleading conclusions about metacommunity dynamics. More generally, C[~]scape provides a valuable framework for predicting spatiotemporal dynamics of coral communities within and between reefs, offering a mechanistic approach to test a range of management and restoration options.

ecology↗

bioRxiv2023

Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma

BackgroundAcral melanoma (AM) has distinct characteristics as compared to cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICI). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. MethodsWe characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-{gamma}-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. Results72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3+CD8+PD1+ intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low vs high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared to responders across cancers, including acral melanoma, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. ConclusionsA unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.

cell biology↗

bioRxiv2022

Mera: A scalable high throughput automated micro-physiological system

There is an urgent need for scalable Microphysiological Systems (MPSs)1 that can better predict drug efficacy and toxicity at the preclinical screening stage. Here we present Mera, an automated, modular and scalable system for culturing and assaying microtissues with interconnected fluidics, inbuilt environmental control and automated image capture. The system presented has multiple possible fluidics modes. Of these the primary mode is designed so that cells may be matured into a desired microtissue type and in the secondary mode the fluid flow can be re-orientated to create a recirculating circuit composed of inter-connected channels to allow drugging or staining. We present data demonstrating the prototype system Mera using an Acetaminophen/HepG2 liver microtissue toxicity assay with Calcein AM and Ethidium Homodimer (EtHD1) viability assays. We demonstrate the functionality of the automated image capture system. The prototype microtissue culture plate wells are laid out in a 3 x 3 or 4 x 10 grid format with viability and toxicity assays demonstrated in both formats. In this paper we set the groundwork for the Mera system as a viable option for scalable microtissue culture and assay development.

bioengineering↗

bioRxiv2020

Reef Cover: a coral reef classification for global habitat mapping from biophysical remote sensing.

Coral reef management and conservation stand to benefit from improved high-resolution global mapping. Yet classifications employed in large-scale reef mapping to date are typically poorly defined, not shared or region-specific. Here we present Reef Cover, a new coral reef geomorphic zone classification, developed to support global-scale coral reef habitat mapping in a transparent and version-based framework. We developed scalable classes by focusing on attributes that can be observed remotely, but whose membership rules also reflect knowledge of reef formation, growth and functioning. Bridging the divide between earth observation data and geo-ecological knowledge of reefs, Reef Cover maximises the trade-off between applicability at global scales, and relevance and accuracy at local scales. We use the Caroline and Mariana Island chains in the Pacific as a case study to demonstrate use of the classification scheme and its scientific and conservation applications. The primary application of Reef Cover is the Allen Coral Atlas global coral reef mapping project, but the system will support bespoke reef mapping conducted at a variety of spatial scales.

systems biology↗

bioRxiv2019

Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s Disease: Association with Alzheimer’s disease polygenic risk

Pathological changes in Alzheimers disease (AD) begin decades before dementia onset. Because locus coeruleus tau pathology is the earliest occurring AD pathology, targeting indicators of locus coeruleus (dys)function may improve midlife screening for earlier identification of AD risk. Pupillary responses during cognitive tasks are driven by the locus coeruleus and index cognitive effort. Several findings suggest task-associated pupillary response as an early marker of AD risk. Requiring greater effort suggests being closer to ones compensatory capacity, and adults with mild cognitive impairment (MCI) have greater pupil dilation during digit span tasks than cognitively normal individuals, despite equivalent task performance. Higher AD polygenic risk scores (AD-PRSs) are associated with increased odds of MCI and tau positivity. We hypothesized that AD-PRSs would be associated with pupillary responses in cognitively normal middle-aged adults. We demonstrated that pupillary responses during digit span tasks were heritable (h2=.30-.36) in 1119 men ages 56-66. We then examined associations between AD-PRSs and pupillary responses in a cognitively normal subset who all had comparable span capacities (n=539). Higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit recall) cognitive load condition; Cohens d=.36 for the upper versus lower quartile of the AD-PRS distribution. Results held up after controlling for APOE genotype. The results support pupillary response--and by inference, locus coeruleus dysfunction--as a genetically-mediated biomarker of early MCI/AD risk. In some studies, cognition predicted disease progression earlier than biomarkers. Pupillary responses might improve screening and early identification of genetically at-risk individuals even before cognitive performance declines.

genetics↗

bioRxiv2017

Bird interactions with drones, from individuals to large colonies

Drones are rapidly becoming a key part of the toolkit for a range of scientific disciplines, as well as a range of management and commercial applications. This presents a number of challenges in context of how drone use might impact nearby wildlife. Interactions between birds and drones naturally come to mind, since they share the airspace. This paper details initial findings on the interactions between drones and birds for a range of waterbird, passerine and raptor species, across of a range of scientific applications and natural environments. The primary aims of this paper are to provide guidance for those planning or undertaking drone monitoring exercises, as well as provide direction for future research into safe and effective monitoring with drones. Our study sites we all located within Australia and spanned a range of arid, semi-arid, dunefield, floodplain, wetland, woodland, forest, coastal heath and urban environments. We particularly focus on behavioral changes towards drones during breeding season, interactions with raptors, and effects on nesting birds in large colonies - three areas yet to be explored in published literature. In over 70 hours of flight, there were no incidents with birds. Although some aggressive behavior was encountered from solitary breeding birds. Several large breeding bird colonies were surveyed, and included in our observations is monitoring and counting of nests in a colony of over 200,000 Straw-necked Ibis, the largest drone-based bird monitoring exercise to date. In addition to providing observations of interactions with specific bird species, we recommend procedures for flight planning, safe flying and avoidance. This paper also provides a basis for a number of critical and emerging areas of research into bird-drone interactions, most notably, territorial breeding birds, safety around large raptors, and the effect of drones on the behaviour of birds in large breeding colonies.

ecology↗