Biology subjects

Milne, R.

Publications and source records attributed to Milne, R..

4 recordsLinked to original sources

bioRxiv2024

Different liposomal formulations of 5-Fluorouracil result in variations to gastrointestinal toxicities

5-Fluorouracil (5FU) treatment can induce severe mucositis, gastrointestinal toxicity. New formulations of 5-FU increase cancer cytotoxicity, such as neutral liposomes (NL), cationic liposomes (CL), and polyethylenimine copper (PEI-Cu) complexes. However, gastrointestinal toxicity for these new formulations remains unclear. We aim to determine if new formulations in 5FU reduce mucositis by reducing intestinal goblet cell and nerve integrity. Sprague Dawley rats were randomly assigned to groups: saline (n=6), 5FU (n=6 ), NL-5FU (n=5), CL-5FU (n=5), PEI-CU-5FU (n=6), NL-PEI-Cu-5FU (n=5) CL-PEI-Cu-5FU (n=5) (Formulations were equivalent to 10mg/kg 5FU in saline). Treatment was administered daily for 5 days. Rats where humanely killed 2 days after treatment. Haematoxylin and Eosin staining for histological change, Alcian Blue-PAS staining for mucin composition, and immunohistochemistry with S100 antibody for nerve integrity were performed. Statistical analysis using Kruskal-Wallis test with Dunns post-test and Mann Whitney U test d were performed. Effect size was determined using Cohens D test. In the jejunum, inflammatory infiltrate increased in PEI-Cu-5FU rats compared to 5-FU controls (p=0.0011). S100 positive nerve bundles increased in NL-5FU rats compared to saline control (p<0.05). S100 positive cells increased in CL-PEI-Cu-5FU rats compared to saline controls. PEI-Cu-5FU formulation was associated with increased inflammatory infiltrate potentially in response to damage in the jejunum. However, liposomal formulations increased S100 positive neural cells, which may offer protection through increased gastrointestinal motility and contraction. While these formulations of 5FU increase cancer cytotoxicity, the gastrointestinal toxicity remains similar. However, further close monitoring of 5FU formulations for gastrointestinal toxicity is warranted.

molecular biology↗

bioRxiv2021

Induction of transposable element expression is central to innate sensing

Evidence indicates that transposable elements (TEs) stimulate innate sensing pathways in various pathologies but it is not clear whether they are sensed during normal physiological responses. Here we show that, during activation with an exogenous pathogen associated molecular pattern (PAMP), dendritic cells (DCs) epigenetically remodel heterochromatin at TEs by depleting the methyltransferase Suv39h1 and reducing histone-3 lysine-9 trimethylation (H3K9me3). TLR4 signaling activates TE expression to enhance innate responses through the DNA sensor cGAS. Cytosolic cGAS-bound DNA comprised LINE1 TEs as the predominant endogenous ligands. Concordantly, LINE1 inhibition attenuated the type-I IFN response to LPS and rescued influenza virus infection. We propose that in healthy cells, exogenous PAMPs epigenetically activate self-derived PAMPs (LINE1) that engage cGAS to enhance responses. These data explain why pathogens employ redundant and broad innate immune countermeasures, to suppress activation of host PAMPs and illustrate a hitherto unappreciated role for host genome-derived PAMPs in response to pathogens.

immunology↗

bioRxiv2021

Local overfishing patterns have regional effects on health of coral, and economic transitions can promote its recovery

Overfishing has the potential to severely disrupt coral reef ecosystems worldwide, while harvesting at more sustainable levels instead can boost fish yield without damaging reefs. The dispersal abilities of reef species mean that coral reefs form highly connected environments, and the viability of reef fish populations depends on spatially explicit processes such as the spillover effect and unauthorized harvesting inside marine protected areas. However, much of the literature on coral conservation and management has only examined overfishing on a local scale, without considering how different spatial patterns of fishing levels can affect reef health both locally and regionally. Here, we simulate a coupled human-environment model to determine how coral and herbivorous reef fish respond to overfishing across multiple spatial scales. We find that coral and reef fish react in opposite ways to habitat fragmentation driven by overfishing, and that a potential spillover effect from marine protected areas into overfished patches helps coral populations far less than it does reef fish. We also show that ongoing economic transitions from fishing to tourism have the potential to revive fish and coral populations over a relatively short timescale, and that large-scale reef recovery is possible even if these transitions only occur locally. Our results show the importance of considering spatial dynamics in marine conservation efforts, and demonstrate the ability of economic factors to cause regime shifts in human-environment systems.

ecology↗

bioRxiv2018

Alcohol consumption is associated with widespread changes in blood DNA methylation: analysis of cross-sectional and longitudinal data

BackgroundDNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart.\n\nMethodsUsing the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined using baseline peripheral blood samples from 5,606 adult Melbourne Collaborative Cohort Study (MCCS) participants. For a subset of 1,088 of them, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. Independent data from the LOLIPOP (N=4,042) and KORA (N=1,662) cohorts were used to replicate associations discovered in the MCCS.\n\nResultsCross-sectional analyses identified 1,414 CpGs associated with alcohol intake at P<10-7, 1,243 of which had not been reported previously. Of these 1,243 novel associations, 1,078 were replicated (P<0.05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated (P<0.05) 403 of 518 associations that had been reported previously. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1,414 CpGs, 530 were differentially methylated (P<0.05) in former compared with current drinkers. Longitudinal associations between the change in alcohol intake and the change in methylation were observed for 513 of the 1,414 cross-sectional associations.\n\nConclusionOur study indicates that, for middle-aged and older adults, alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with changes in alcohol consumption.

epidemiology↗