Biology subjects

Warren, D.

Publications and source records attributed to Warren, D..

10 recordsLinked to original sources

bioRxiv2026

A shared functional organisation underlies vascular disease remodelling

Cardiovascular disease involves coordinated remodelling across multiple biological processes. Gene-level signatures vary substantially between studies because different combinations of genes can support similar biological processes. Pathway-level analyses can provide more stable representations of these processes but typically consider pathways independently. We hypothesised that grouping related pathways into conserved biological functions and quantifying their relative weighting would reveal a higher-order, transferable property of vascular tissue that we term functional organisation. We quantified the relative weighting of six conserved biological functions across independent transcriptomic datasets spanning human vascular disease, experimental models and therapeutic interventions. Vascular tissues exhibited a reproducible functional organisation defined by the balance of these functions. A dominant remodelling trajectory captured coordinated, nonlinear rebalancing of structural, immune, signalling and metabolic programmes, while a second dimension distinguished contractile/ECM organisation from immune activity. This organisation was preserved across independently reconstructed reference cohorts and remained robust to analytical sensitivity testing. When independent datasets were projected into this fixed framework, biological and clinical phenotypes occupied coherent positions along the remodelling landscape. Plaque-derived vascular, stromal and immune cell populations also occupied ordered functional positions, linking cellular heterogeneity to tissue-level organisation. The same organisational structure generalised across atherosclerosis, peripheral vascular disease and abdominal aortic aneurysm and revealed continuous biological heterogeneity within conventional clinical classifications. Genetic, pharmacological and dietary perturbations reproducibly shifted functional organisation, demonstrating that organisational state is dynamic and biologically responsive. Together, these findings identify functional organisation as a reproducible tissue-level property of vascular remodelling and provide a framework for understanding cardiovascular disease as coordinated rebalancing of biological functions rather than alteration of individual pathways in isolation.

bioinformatics↗

bioRxiv2026

Immune-cell depleted diffuse large B-cell lymphomas have reduced expression of MHC class I

Immunotherapy has transformed treatment for many cancers. In the aggressive and genetically heterogeneous diffuse large B-cell lymphoma (DLBCL), CD19 CAR T-cell therapy is highly effective, whereas immune checkpoint blockade has shown limited benefit. Loss of MHC expression is a common mechanism to escape T-cell cytotoxicity, and loss of MHC class I (MHC-I) and II are frequent in DLBCL. We applied imaging mass cytometry to diagnostic biopsies from younger, high-risk DLBCL patients to map the tumor microenvironment (TME) spatial architecture in relation to tumor cell MHC expression, mutational status, transcriptomic and proteomic profiles. Neighborhood analyses identified four TME subtypes: immune-cell depleted and three immune-infiltrated types (mixed, CD4 T cell-rich, CD8 T-cell/macrophage-rich). Depleted cases had shorter overall survival (p = 0.033) and increased expression of proteins involved in DNA replication and proliferation markers compared to infiltrated cases. Tumor cell MHC-I expression was heterogeneous. Cases with low frequency of MHC-I-pos tumor cells were enriched for the depleted TME type. MHC-I-pos tumor cells were surrounded by CD4 and CD8 T cells and M1 macrophages, whereas MHC-I-neg tumor cells were closer to other MHC-I-neg tumor cells. These findings suggest that TME-based classification incorporating tumor cell MHC-I status may improve individualized immunotherapy selection.

cancer biology↗

bioRxiv2026

Epidermal Growth Factor/c-Met receptor signalling crosstalk drives tunneling nanotube formation in A549 lung adenocarcinoma cells

Tunneling nanotubes (TNTs) are actin-based cytoplasmic connections that can mediate intercellular transfer of various cellular cargo and have been implicated in cancer progression and chemoresistance. However, the signalling mechanisms driving their formation remain poorly understood. Given the frequent dysregulation of EGFR and c-Met signalling in non-small cell lung cancer (NSCLC), and prior evidence of TNTs in lung adenocarcinoma patient samples, we investigated the role of EGFR and c-Met receptor signalling crosstalk in TNT induction in A549 lung adenocarcinoma cells. Stimulation with EGF, HGF, or in combination induced a concentration dependent increase in the formation of TNTs. TNTs exhibited typical characteristics, including F-actin expression, non-adherence to the substratum and facilitated intercellular trafficking of lysosomes, mitochondria, and lipid vesicles. EGFR was identified as a novel component of TNTs, but had little co-localisation with the c-Met receptor. Co-stimulation with HGF and EGF did not produce consistent additive or synergistic effects on TNT formation, suggesting shared downstream signalling. Furthermore, although EGFR and c-Met inhibition blocked EGF- and HGF-induced TNTs respectively, inhibition of both receptors was required to suppress TNTs following dual HGF/EGF treatment. Interestingly, blocking the EGF receptor alongside c-Met resulted in a more potent inhibition of HGF-induced TNTs, indicating crosstalk. Furthermore, inhibition of downstream MEK and PI3K pathways reduced HGF- or EGF- induced TNT formation, but dual inhibition was required to completely block TNT formation in HGF+EGF co-stimulated cells. These findings reveal a novel convergence of EGFR and c-Met and their downstream MAPK/PI3K pathways in TNT regulation, which can have important clinical implications in combinatorial receptor and cell signalling pathway targeting in NSCLC.

cancer biology↗

bioRxiv2025

Predicting the distribution of common wild mammal species across Europe - are there sufficient occurrence data?

ContextKnowledge of where wildlife species are and in what number is critical to support robust contingency planning for diseases affecting animal and human health. For common widespread species in particular, comprehensive surveillance is impractical and challenging to coordinate. This is where models can be useful, to fill in the gaps and direct survey efforts to maximise understanding. The ENETWILD project was commissioned by EFSA in 2017 to review available data and modelling methods to predict distributions for key species involved in diseases of concern (e.g., wild boar and African swine fever). Here, we outline the latest methodology to predict species distributions based on occurrence data and outline the areas where further data would be most helpful. MethodWe present a generic framework to model the distribution of common mammal species in Europe, using global data. Based on occurrence records from large scale repositories, our method first attempts to address known biases to produce a presence-absence dataset and then applies random forest modelling to predict habitat suitability. We apply this approach to twelve species spanning distinct survey methodologies within mammal recording (visual observation, trapping, and bats/audio monitoring). ResultsModel performance was acceptable across all species within the limits of the available training data (AUC close to or above 0.7). However, beyond these limits the reliability of prediction was substantially reduced. Assessment of the available data suggested large areas of Eastern and Southern (particularly mountainous) parts of Europe have a distinct environmental signature not sufficiently captured by the existing sampling. ConclusionsWithin Europe there remain environmental conditions which are not well represented by existing surveillance, predominantly in Eastern and Southern regions. To reliably apply a robust modelling approach to a Europe-wide context targeted data collection is required.

ecology↗

bioRxiv2025

G-quadruplexes represent promising new targets to overcome multidrug-resistant fungal infections

The growing emergence of antifungal resistance has prompted the identification of novel antifungal targets. G-quadruplexes (G4s), four-stranded secondary structures that form in DNA and RNA, have arisen as a drug target to treat bacterial, viral, and parasitic infections. Here, we provide the first demonstration that G4s form in fungi and represent a promising new target for antifungal development. We found that PhenDC3 and pyridostatin (PDS), ligands that bind to and stabilise G4s, potently inhibited the metabolism of fungal pathogens in different ways. These pathogens included the pan azole-resistant Aspergillus fumigatus isolate TR34/L98H and Candida auris. Notably, PhenDC3 could synergise with amphotericin B, was protective in an in vivo model of fungal infection, and was well-tolerated by human cells. However, continuous exposure to PhenDC3 resulted in some cross-resistance to current antifungals and this needs to be explored further. PhenDC3 could also increase the number of RNA G4s in live A. fumigatus. Further, we demonstrated the structural flexibility of DNA sequences found in cyp51A and cyp51B, with these sequences capable of forming duplexes, hairpins, G4s and i-motifs. Finally, PhenDC3, but not PDS, caused duplex DNA structures in cyp51A to transition into antiparallel G4 structures potentially associated with PhenDC3s increased antifungal potency. Taken together, G4s represent an exciting antifungal target, but a more detailed understanding of their biological roles is essential.

microbiology↗

bioRxiv2024

Using correlative and mechanistic species distribution models to predict vector-borne disease risk for the current and future environmental and climatic change: a case study of West Nile Virus in the UK.

Globally, vector-borne diseases have significant impacts on both animal and human health, and these are predicted to increase with the effects of climate change. Understanding the drivers of such diseases can help inform surveillance and control measures to minimise risks both now and in the future. In this study, we illustrate a generalised approach for assessing disease risk combining species distribution models of vector and wildlife hosts with data on livestock and human populations using the potential emergence of West Nile Virus (WNV) in the UK as a case study. Currently absent in the UK, WNV is an orthoflavivirus with a natural transmission cycle between Culex mosquitos (Cx. pipiens and Cx. modestus) and birds. It can spread into non-target hosts (e.g., equids, humans) via mosquito bites where it can cause febrile disease with encephalitis and mortality in severe cases. We compared six correlative species distribution models and selected the most appropriate for each vector based on a selection of performance measures and compared this to mechanistic species distribution models and known distributions. We then combined these with correlative species distribution models of representative avian hosts, equines, and human population data to predict risk of WNV occurrence. Our findings highlighted areas at greater risk of WNV due to higher habitat suitability for both avian hosts and vectors, and considered how this risk could change by 2100 under a best-case Shared Socioeconomic Pathway (SSP1) and worst-case (SSP5) future climate scenario. Generally, WNV risk in the future was found to increase in south-eastern UK and decrease further north. Overall, this paper presents how current and future vector distributions can be modelled and combined with projected host distributions to predict areas at greater risk of novel diseases. This is important for policy decision making and contingency preparedness to enable adaptation to changing environments and the resulting shifts in vector-borne diseases that are predicted to occur.

ecology↗

bioRxiv2023

Extracellular vesicles stimulate smooth muscle cell migration by presenting collagen VI.

The extracellular matrix (ECM) supports blood vessel architecture and functionality and undergoes active remodelling during vascular repair and atherogenesis. Vascular smooth muscle cells (VSMCs) are essential for vessel repair and, via their secretome, can invade from the vessel media into the intima to mediate ECM remodelling. Accumulation of fibronectin (FN) is a hallmark of early vascular repair and atherosclerosis. Here we show that FN stimulates VSMCs to secrete small extracellular vesicles (sEVs) by activating the {beta}1 integrin/FAK/Src pathway as well as Arp2/3-dependent branching of the actin cytoskeleton. We found that sEVs are trapped by the ECM in vitro and colocalise with FN in symptomatic atherosclerotic plaques in vivo. Functionally, ECM-trapped sEVs induced the formation of focal adhesions (FA) with enhanced pulling forces at the cellular periphery preventing cellular spreading and adhesion. Proteomic and GO pathway analysis revealed that VSMC-derived sEVs display a cell adhesion signature and are specifically enriched with collagen VI on the sEV surface. In vitro assays identified collagen VI as playing a key role in cell adhesion and invasion directionality. Taken together our data suggests that the accumulation of FN is a key early event in vessel repair acting to promote secretion of collage VI enriched sEVs by VSMCs. These sEVs stimulate directional invasion, most likely by triggering peripheral focal adhesion formation and actomyosin contraction to exert sufficient traction force to enable VSMC movement within the complex vascular ECM network. Figure AbstractVascular smooth muscle cells sense fibronectin via {beta}1 integrin and secrete small extracellular vesicles loaded with collagen VI. These extracellular vesicles are entrapped in the extracellular matrix and induce formation of peripheral focal adhesions presenting adhesion complex ECM proteins including collagen VI, LGALS3BP, EDIL3 and TGFBI. Focal adhesions anchor the extracellular matrix to actin fibrils in the cell. Contraction of the actin fibrils generates the mechanical force for directional cell invasion through the matrix. This figure was created with BioRender (https://biorender.com/). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/551257v3_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1355004org.highwire.dtl.DTLVardef@1186e9forg.highwire.dtl.DTLVardef@106ad30org.highwire.dtl.DTLVardef@1543518_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Hepatocyte Growth Factor and β1-integrin signalling axis drives tunneling nanotube formation in A549 lung adenocarcinoma cells

Tunneling nanotubes (TNTs) are thin cytoplasmic protrusions involved in long-distance cellular communication. The presence of TNTs has been found in vivo and in vitro studies in non-small cell lung cancer (NSCLC). Cancer cells transport a range of organelles and signalling molecules along TNTs, to confer a survival phenotype for the recipient cell, contributing toward chemoresistance and malignancy. Despite its important role in cancer progression, the molecular mechanisms underlying TNT formation is not well defined. Within the tumour microenvironment (TME) of NSCLC, hepatocyte growth factor (HGF) and its receptor, c-Met, are mutationally upregulated causing growth, and invasion. In this study, we report a novel crosstalk between HGF/c-Met and {beta}1-integrin involved in the formation of functional TNTs in A549 cells. Through pharmacological inhibitor studies, we discovered Arp2/3 complex, MAPK and PI3K pathways were activated downstream of this crosstalk signalling axis. Furthermore, paxillin was recruited during this key process, localising at the protrusion site of HGF-induced TNTs, and therefore serving as the central link between the upstream and downstream regulators involved. Overall, these results demonstrate a novel strategy to inhibit TNT formation in NSCLC through targeting the HGF/c-Met and {beta}1-integrin signalling axis, thus highlighting the importance of personalised multi-drug targeting in NSCLC.

cancer biology↗

bioRxiv2020

What makes Hemidactylus invasions successful? A case study on the island of Curacao.

Hemidactylus spp. (House geckos) rank among the most successful invasive reptile species worldwide. Hemidactylus mabouia in particular has become ubiquitous across tropical urban settings in the Western Hemisphere. H. mabouia’s ability to thrive in close proximity to humans has led to the rapid displacement of native geckos in urban areas, however the mechanisms driving this displacement remain understudied. Here we combine data from nitrogen and carbon stable isotopes, stomach contents, and morphometric analyses of traits associated with feeding and locomotion to test alternate hypotheses of displacement between H. mabouia and a native gecko, Phyllodactylus martini, on the island of Curaçao. Consistent with expectations of direct food resource competition, we demonstrate substantial overlap of invertebrate prey resources between the species. Additionally, we found strong evidence from both diet content and stable isotope analyses that H. mabouia acts as a vertebrate predator, preying upon P. martini as well as other native and non-native reptiles. Finally, we show that H. mabouia possesses several morphological advantages, including larger sizes in feeding-associated traits and limb proportions that could offer a propulsive locomotor advantage on vertical surfaces. Together, these findings suggest the successful establishment of H. mabouia likely involves a combination of both exploitative interspecific competition and predation. Given the ubiquity of H. mabouia, illuminating the role of this species as both a competitor and a predator casts new concerns on the ecological and demographic impacts of this widespread urban invader.Competing Interest StatementThe authors have declared no competing interest.View Full Text

zoology↗

bioRxiv2019

A model for estimating traction force magnitude reveals differential regulation of actomyosin activity and matrix adhesion number in response to smooth muscle cell spreading

Decreased aortic compliance is associated with ageing and vascular disease, including atherosclerosis and hypertension. Ultimately, changes in aortic compliance are driven by altered ECM composition however, recent findings have identified a cellular component to decreased aortic compliance observed in ageing and hypertension. Vascular smooth muscle cells (VSMCs) line the blood vessel wall and VSMC contraction regulates vascular tone and contributes to aortic compliance. Mechanical cues derived from the ECM influence VSMC function, yet whether ECM rigidity influences VSMC force generation remains unclear. In this study, we describe the relationship between VSMC spreading, traction force magnitude and matrix rigidity. Importantly, we show that spreading predicts integrated traction force (integrated-TF) magnitude independently of matrix rigidity. Using linear regression analysis, we have generated a model for calculating integrated-TF from VSMC area. This model closely predicts the integrated traction force measured by live VSMC traction force microscopy. Vinculin staining analysis revealed that spreading strongly correlated with adhesion number per VSMC, suggesting that increased VSMC integrated-TF was due to enhanced matrix anchor points. Further analysis revealed that calculated integrated-TF per adhesion was reduced by matrix rigidity, however, adhesion number/m2 increased, resulting in the average integrated-TF/m2 remaining unaltered. As a result, the integrated-TF/VSMC spreading relationship is independent of matrix rigidity. Therefore, our study has identified and validated a novel model to predict and understand the mechanisms influencing VSMC traction force magnitude.

cell biology↗