Biology subjects

Guy, A.

Publications and source records attributed to Guy, A..

6 recordsLinked to original sources

bioRxiv2025

Single JAK2-V617F hematopoietic stem cells can initiate MPN in transplantations into non-conditioned recipient mice

Myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem cells (HSC) that are most frequently caused by acquired somatic mutations in JAK2. A number of conditional mouse models of JAK2-V617F-driven MPN have been generated that rely on Cre-LoxP mediated activation, resulting in polyclonal disease. To more closely mimic the monoclonal origin of human MPN, transplantations of single purified JAK2-mutant HSCs or bone marrow (BM) at limiting dilutions into lethally irradiated recipient mice have been previously performed. However, irradiation is known to alter the BM microenvironment and also to induce transient aplasia accompanied by elevated cytokine levels that promotes the expansion of the mutant clone. To overcome these limitations, we examined whether JAK2-V617F-mutant HSCs are able to engraft and initiate MPN in non-conditioned recipients. We found that BM from two different MPN models, one expressing the human JAK2-V617F, and another expressing the mouse Jak2-V617F, efficiently engrafted and initiated MPN in non-irradiated immunocompromised Rag2-/- recipients. MPN evolved even in transplantations at limiting dilutions, showing high competitiveness of single JAK2-mutant HSCs. Thus, JAK2-V617F mutant HSCs can outcompete resident non-mutated HSCs in the absence of elevated cytokine levels and without the need of emptying stem cell niches by irradiation. However, only BM from mice expressing the mouse Jak2-V617F engrafted and initiated disease in non-conditioned C57BL/6 mice, while BM from mice expressing the human JAK2-V617F was rejected, indicating that mouse Jak2-V617F is ignored by the immune surveillance. These results provide a possible explanation why JAK2-V617F is so frequently found in healthy individuals with clonal hematopoiesis.

cancer biology↗

bioRxiv2025

Machine Learning Reveals Immediate Disruption in Mosquito Flight when exposed to Olyset Nets

Insecticide-treated nets (ITNs) remain a critical intervention in controlling malaria transmission, yet the behavioural adaptations of mosquitoes in response to these interventions are not fully understood. This study examined the flight behaviour of insecticide-resistant (IR) and insecticide-susceptible (IS) Anopheles gambiae strains around an Olyset net (OL), a permethrin-impregnated ITN, versus an untreated net (UT). Using machine learning (ML) models, we classified mosquito flight trajectories with high accuracy (0.838) and ROC AUC (0.925). Contrary to assumptions that behavioural changes at OL would intensify over time, our findings show an immediate onset of convoluted, erratic flight paths for both IR and IS mosquitoes around the treated net. SHAP analysis identified three key predictive features of OL exposure: frequency of zero-crossings in flight angle change, first quartile of flight angle change, and zero-crossings in horizontal velocity. These suggest disruptive flight patterns, indicating insecticidal irritancy. While IS mosquitoes displayed rapid, disordered trajectories and mostly died within 30 minutes, IR mosquitoes persisted throughout the 2-hour experiments but exhibited similarly disturbed behaviour, suggesting resistance does not fully mitigate disruption. Our findings challenge literature suggesting permethrins repellency in solution form, instead supporting an irritant or contactdriven effect when incorporated into net fibres. This study highlights the value of ML-based trajectory analysis for understanding mosquito behaviour, refining ITN configurations and evaluating novel active ingredients aimed at disrupting mosquito flight behaviour. Future work should extend these methods to other ITNs to further illuminate the complex interplay between mosquito behaviour and insecticidal intervention.

animal behavior and cognition↗

bioRxiv2023

Physics-informed deep generative learning for quantitative assessment of the retina

Disruption of retinal vasculature is linked to various diseases, including diabetic retinopathy and macular degeneration, leading to vision loss. We present here a novel algorithmic approach that generates highly realistic digital models of human retinal blood vessels based on established biophysical principles, including fully-connected arterial and venous trees with a single inlet and outlet. This approach, using physics-informed generative adversarial networks (PI-GAN), enables the segmentation and reconstruction of blood vessel networks that requires no human input and out-performs human labelling. Our findings highlight the potential of PI-GAN for accurate retinal vasculature characterization, with implications for improving early disease detection, monitoring disease progression, and improving patient care.

biophysics↗

bioRxiv2022

Behaviour of pyrethroid-resistant Anopheles gambiae at the interface of two dual active-ingredient bed nets, assessed by room-scale infrared video tracking

BackgroundThe success of Insecticide Treated Bednets (ITNs) for malaria vector control in Africa relies on the behaviour of the major malaria vectors, Anopheles species. Research into mosquito behavioural traits influencing the performance of ITNs has focused largely on time or location of biting. Here we investigated less tractable behaviours including timings of net contact, willingness to refeed and longevity post exposure to two next-generation nets, PermaNet(R) 3.0 (P3) and Interceptor(R) G2 (IG2) in comparison with a standard pyrethroid only net (Olyset (OL)) and an untreated net. MethodsSusceptible and resistant Anopheles gambiae mosquitoes were exposed to the nets with a human volunteer host in a room scale assay. Mosquito movements were tracked for two hours using an infrared video system, collecting flight trajectory, spatial position and net contact data. Post-assay, mosquitoes were monitored for a range of sublethal insecticide effects. ResultsOL, P3 and IG2 all killed over 90% of susceptible mosquitoes 24 hours after exposure, but this effect was not seen with resistant mosquitoes where mortality ranged from 16% to 72%. Total mosquito activity was higher around untreated nets than ITNs. There was no difference in total activity, the number, or duration, of net contact, between any mosquito strain, with similar behaviours recorded in susceptible and resistant strains at all ITNs. Net contact was focussed predominantly on the roof for all bednets. We observed a steep decay in activity for both susceptible strains when P3 and OL were present and with IG2 for one of the two susceptible strains. All treated nets reduced the willingness of resistant strains to re-feed when offered blood one-hour post-exposure, with a more pronounced effect seen with P3 and OL than IG2. ConclusionResults indicate that the effects of ITNs on mosquito behaviour are consistent, with no major differences in responses between strains of different pyrethroid susceptibility.

animal behavior and cognition↗

bioRxiv2021

VIVID: a web application for variant interpretation and visualisation in multidimensional analyses

Large-scale comparative genomics- and population genetic studies generate enormous amounts of polymorphism data in the form of DNA variants. Ultimately, the goal of many of these studies is to associate genetic variants to phenotypes or fitness. We introduce VIVID, an interactive, user-friendly web application that integrates a wide range of approaches for encoding genotypic to phenotypic information in any organism or disease, from an individual or population, in three-dimensional (3D) space. It allows mutation mapping and annotation, calculation of interactions and conservation scores, prediction of harmful effects, analysis of diversity and selection, and 3-dimensional (3D) visualisation of genotypic information encoded in Variant Call Format (VCF) on AlphaFold2 protein models. VIVID enables the rapid assessment of genes of interest in the study of adaptive evolution and the genetic load, and it helps prioritising targets for experimental validation. We demonstrate the utility of VIVID by exploring the evolutionary genetics of the parasitic protist Plasmodium falciparum, revealing geographic variation in the signature of balancing selection in potential targets of functional antibodies.

bioinformatics↗

bioRxiv2019

Diffuse retro-reflective imaging for improved mosquito tracking around human baited bednets

Robust imaging techniques for tracking insects have been essential tools in numerous laboratory and field studies on pests, beneficial insects and model systems. Recent innovations in optical imaging systems and associated signal processing have enabled detailed characterisation of nocturnal mosquito behaviour around bednets and improvements in bednet design, a global essential for protecting populations against malaria. Nonetheless, there remain challenges around ease of use for large scale in situ recordings and extracting data reliably in the critical areas of the bednet where the optical signal is attenuated. Here we introduce a retro-reflective screen at the back of the measurement volume, which can simultaneously provide diffuse illumination, and remove optical alignment issues whilst requiring only one-sided access to the measurement space. The illumination becomes significantly more uniform, although, noise removal algorithms are needed to reduce the effects of shot noise particularly across low intensity bednet regions. By systematically introducing mosquitoes in front and behind the bednet in lab experiments we are able to demonstrate robust tracking in these challenging areas. Overall, the retro-reflective imaging setup delivers mosquito segmentation rates in excess of 90% compared to less than 70% with back-lit systems.

animal behavior and cognition↗