Biology subjects

Hill, L. J.

Publications and source records attributed to Hill, L. J..

5 recordsLinked to original sources

bioRxiv2026

Cross-omics profiling reveals cortical neuronal dysfunction following neonatal intraventricular haemorrhage that is attenuated by decorin treatment

Neonatal intraventricular haemorrhage (IVH) is a form of haemorrhagic stroke which is most common in premature infants and can cause mortality and lifelong disability. The reaction of brain tissue to extraneous blood is known to trigger several complications including post-haemorrhagic hydrocephalus (PHH), furthering the likelihood of neurological disability and death. The molecular response of the neuron-rich cortex to blood within the first 24 hours of injury, and how this may precipitate secondary brain injury or neurodegeneration, remains poorly defined. This lack of understanding may reduce the development of novel therapeutics aiming to limit the injury caused by neonatal IVH. Here, we utilised a proteome and transcriptome cross-omics approach to characterise cortical responses to blood in a neonatal mouse model of IVH to improve understanding of the effects and drivers of IVH-induced brain injury. The pleiotropic proteoglycan decorin, a well-characterised modulator of the inflammatory cytokine transforming growth factor beta 1, was also studied to identify if it can have any beneficial effects in the cortex. Cross-omics analysis between the transcriptome and proteome highlighted ferroptosis-associated signatures as a key post-IVH cortical injury mechanism. IVH caused a marked depletion of cortical neurons, neurofilaments, and synaptic vesicle proteins, observed through transcriptomics, immunostaining, and proteomics, which were attenuated by decorin treatment. Decorin also produced an enhanced phagocytic response potentially through activation of microglia. These findings highlight the vulnerability of cortical neurons to early injury following IVH in neonates and support decorin as a potential neuroprotective agent. They also suggest that ferroptosis-associated pathways may contribute to early cortical injury and represent a potential therapeutic target in this context.

neuroscience↗

bioRxiv2025

NRF2 upregulation by CDDO-Me protects AC16 human cardiomyocytes against doxorubicin-induced toxicity.

Doxorubicin (DOX) is an effective anticancer therapeutic but exhibits dose-dependent, potentially life-threatening cardiotoxicity. The specific mechanisms driving this cardiotoxicity are not fully understood but can include the induction of oxidative stress and subsequent cell death mechanism activation. This has prompted the exploration of NRF2, a master co-ordinator of antioxidant and largely cytoprotective pathways, as a potential approach for the alleviation of DOX-induced cardiotoxicity. Here, NRF2 was pharmacologically activated via CDDO-Me (hitherto referred to as CDDO) to reduce the negative consequences on AC16 human cardiomyocyte cell health and functions. NRF2 intracellular dynamics were quantitatively measured using live-cell imaging, demonstrating rapid ([~]10 min) yet sustained ([≥]24 h) induction of NRF2 expression and functional downstream activity. Genetic perturbations of the NRF2-KEAP1 system highlight that CDDO acts specifically through NRF2 to exert AC16 cytoprotection from DOX whilst not promoting human lung and pancreatic cancer cell line viability. Via RNA-seq analysis, we reveal that CDDO dampens DOX-mediated effects on p53 signalling, apoptosis and ferroptosis. This study provides novel insight into NRF2 dynamics in the widely utilised AC16 cells whilst further elucidating the molecular mechanisms contributing to DOX cardiotoxicity and potential NRF2-orchestrated defence. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/675420v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@18c0bb5org.highwire.dtl.DTLVardef@154c707org.highwire.dtl.DTLVardef@d6c127org.highwire.dtl.DTLVardef@122ef0d_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Promiscuous endosymbionts in deep-sea corals and crinoids are shaped by nitrogen cycling

Crinoids are commonly associated with corals, but whether they physiologically interact is unclear. Like corals, crinoids host symbiotic microorganisms but little is known about the crinoid microbiome. Here, we reveal the microbiomes of the deep-sea corals Desmophyllum pertusum and Solenosmilia variabilis and, notably, their associated feather star crinoid, Koehlermetra (of the family Thalassometridae) in the Campos Basin, Brazil. We showed that the same endosymbiotic members of the families Endozoicomonadaceae and Nitrosopumilaceae interchangeably inhabit the internal and external structures of the corals and crinoid, indicating promiscuity in symbioses. The metagenome-assembled genome of the novel and dominant Endozoicomonas promiscua sp. nov. suggest that these symbionts may drive dissimilatory nitrate reduction to ammonia, which could be a source of energy for ammonia-oxidizing archaea (AOA) of the family Nitrosopumilaceae. Thus, nitrogen cycling may determine the microorganisms that are hosted by deep-sea corals, which may be provided by their associated crinoids. These findings provide important insight about the complex ecological interactions that could lead to promiscuous symbiosis. TeaserDeep-sea corals and crinoids share symbiotic microbes that cycle nitrogen, potentially supporting each other in the nutrient-poor deep sea.

microbiology↗

bioRxiv2024

Mathematical Models of Retinal Drug Delivery

PurposeWet age-related macular degeneration (AMD) causes vision loss when vascular endothelial growth factor (VEGF) stimulates blood vessel growth into the light-sensitive retina. Anti-VEGF treatments such as ranibizumab are currently administered to treat wet AMD via intravitreal injections, which are unpleasant, expensive and risk complications. We explored the efficacy of topically administered ranibizumab, with cell penetrating peptides (CPPs). MethodsEx vivo pig eyes were divided into 3 groups and treated with 1. topical or 2. intravitreal ranibizumab and CPP, or 3. intravitreal ranibizumab. ELISAs measured ranibizumab and VEGF concentrations in the aqueous and vitreous at 20 min, 40 min, 1 hr and 3.5 hr (n = 3, per group). An ordinary differential equation model was formulated to describe the evolving concentrations of ranibizumab, VEGF and their compounds in the tear, aqueous and vitreal compartments. ResultsExperimental -- Topical: aqueous ranibizumab levels increased significantly, coincident with a significant drop in aqueous VEGF. Vitreal ranibizumab increased significantly, while vitreal VEGF remained constant. Intravitreal (with and without CPP): vitreal ranibizumab reached high concentrations, coincident with a significant drop in vitreal VEGF. Mathematical -- topical treatment may provide sustained, moderate suppression of vitreal VEGF levels, while intravitreal treatment provides strong suppression which lessens between treatments. ConclusionsCPP allows topical ranibizumab to penetrate the cornea but reduces ranibizumab availability and efficacy in neutralising VEGF for intravitreal treatment. Combined intravitreal/topical treatment presents a promising approach. Treatment efficacy would be enhanced if ranibizumabs rate of binding to VEGF or tear residence time could be increased.

systems biology↗

bioRxiv2020

High temperature inhibits cnidarian-dinoflagellate symbiosis establishment through nitric oxide signaling

Disclaimer StatementThe authors have withdrawn their manuscript after further experiments based on reviewer comments did not support the conclusions of the paper. Therefore, the authors do not wish this work to be cited as reference for the project. The authors thank the anonymous reviewer for a critical assessment. If you have any questions, please contact the corresponding authors.

microbiology↗