Biology subjects

Wing, A.

Publications and source records attributed to Wing, A..

5 recordsLinked to original sources

bioRxiv2026

P2Y14 receptor agonist impairs, and antagonist improves whole-body glucose homeostasis and liver steatosis

Knockout of the UDP-glucose-activated P2Y14 receptor (P2Y14R) in adipocytes or whole-body has been reported to provide metabolic benefits in obese mice. We hypothesized that selective P2Y14R activation would lead to metabolic impairments, whereas pharmacological antagonism would improve metabolic deficits in diet-induced obese (DIO) mice. Here, we investigated the metabolic effects of a synthetic P2Y14R agonist, UDP-like methylene-bridged MRS2905. Acute P2Y14R activation with MRS2905 triggered a robust and prolonged hyperglycemic effect in lean and obese mice with impaired glucose homeostasis. Moreover, MRS2905 treatment of obese mice lowered fasting plasma insulin and increased glucagon levels, along with upregulation of liver JNK phosphorylation and the expression of rate-limiting gluconeogenic genes. The MRS2905-induced hyperglycemic effect was blunted in whole-body P2Y14R knockout mice compared with wild-type control. In contrast, a potent P2Y14R antagonist mono-ester prodrug (MRS4779) partially reversed the agonist-induced hyperglycemia and restored proper glucose homeostasis after acute treatment. Chronic MRS4779 administration in DIO mice reduced fat mass and improved various metabolic parameters including liver steatosis. Additionally, we examined the roles of P2Y14R in hepatocytes of DIO mice. Here, we report that P2Y14R was upregulated in liver and hepatocytes from obese mice compared to lean mice. Overnight fasting also upregulated hepatic P2Y14R expression. P2Y14R deletion from hepatocytes in DIO mice improved fasting blood glucose level and lipid metabolism without improving glucose homeostasis. These results suggest a novel P2Y14R function in hepatic lipid metabolism, and P2Y14R antagonists may prove useful for the treatment of obesity and obesity-related metabolic disorders.

physiology↗

bioRxiv2025

Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas

High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.

cancer biology↗

bioRxiv2024

Tracking Microcystis viruses and infection dynamics across distinct phases of a Microcystis-dominated bloom

Given the impact of viruses on microbial community composition and function, viruses have the potential to play a significant role in the fate of freshwater cyanobacterial harmful algal blooms (cHABs). Yet the role of viruses in cHABs remains poorly understood. We sought to address this knowledge gap with a metagenomic analysis of viruses of bloom-forming Microcystis aeruginosa across cHAB phases in the western basin of Lake Erie. Size-fractionation of the water allowed us to identify significant fraction-specific trends in viral diversity, which corresponded with Microcystis genetic diversity. Using a new machine-learning model, we predicted infections between viral and microbial host populations. We predicted hundreds of viral populations with infection histories including Microcystis and non-Microcystis hosts, suggesting extensive interconnectivity and the potential for virus-mediated cross-species exchange of genetic material within cHABs communities. Infection predictions revealed a broad host range for Lake Erie Microcystis viruses, challenging previous notions of "narrow" host-virus interactions in cHABs. Abundant viral genes belonging to predicted Microcystis viruses revealed their potential role in key metabolic pathways and adaptation to environmental changes. We observed significant turnover of predicted Microcystis virus populations across time. Viral diversity was highest in the viral fraction and lowest in the colony-associated fraction, suggesting that Microcystis colony formation and growth during cHABs leads to bottlenecks in viral diversity. These findings advance our understanding of uncultivated Microcystis virus diversity, their potential effects on host metabolism, potential influence on species interactions, and potential coevolutionary processes between microbial hosts and their viral predators within Microcystis-dominated cHABs. ImportanceUnderstanding interactions between viruses, their hosts, and environmental parameters may be key to identifying the mechanisms underlying the persistence and demise of cyanobacterial harmful algal blooms (cHABs). In this study we describe the viral diversity and host ranges of viruses predicted to infect Microcystis, describing the distribution of these properties across time, space, and different bloom-associated size fractions. Additionally, the study highlights abundant genes belonging to predicted Microcystis viruses and their potential roles in key metabolic pathways and adaptation to environmental changes. The observed turnover of Microcystis virus populations, with the highest diversity in viral fractions and the lowest in colony-associated fractions, suggests that Microcystis colony formation during blooms plays an important role in shaping viral diversity and community turnover. These findings contribute to a better understanding of the interplay between viruses, Microcystis, and their accompanying bacterial communities, shedding light on mechanisms driving bloom dynamics, species interactions, and coevolutionary processes.

microbiology↗

bioRxiv2023

Benchmarking combined informatics approaches for virus discovery: Caution is needed when combining in silico identification methods

BackgroundThe identification of viruses from environmental metagenomic samples using informatics tools has offered critical insights in microbiome studies. However, it remains difficult for researchers to know for their specific study which tool(s) and settings are best suited to maximize capture of viruses while minimizing false positives. Studies are increasingly combining multiple tool outputs attempting to recover more viruses, but no combined approach has been benchmarked for accuracy. Here, we benchmarked 63 viral identification rulesets against mock metagenomes composed of publicly available viral, bacterial, archaeal, fungal, and protist sequences. These rulesets are based on combinations of four single-tool rules and two multi-tool tuning rules. We applied these rulesets to various aquatic metagenomes and filtering strategies to evaluate the impact of habitat and viral enrichment on individual and combined tool performance. We provide a packaged pipeline for researchers that want to replicate our process. ResultsWe found that combining rules increased viral recall, but at the expense of increased false positives. Six of the 63 combinations tested had equivalent accuracies to the highest one (MCC=0.77, padj [≥] 0.05). All of the six high accuracy rulesets included VirSorter2, five included our "tuning removal" rule, and no high performing rulesets used more than four of our six rules. DeepVirFinder, VIBRANT, and VirSorter were each found once in these high accuracy rulesets, but never in combination with each other. Our validation suggests that the MCC plateau at 0.77 is caused by inaccurate labeling of the data that viral identification tools rely on for training and validation. In the aquatic metagenomes, our "highest MCC" ruleset identified a higher proportion of viral sequences in the virus-enriched samples (44-46%) than the non-enriched, cellular metagenomes (7-19%). ConclusionWhile improved algorithms may lead to more accurate viral identification tools, this should be done in tandem with curating accurately labeled viral gene and sequence databases. For most applications, we recommend the use of the ruleset that uses VirSorter2 and our empirically derived tuning removal rule. By providing a rigorous overview of the behavior of in silico viral identification strategies, our findings guide the use of existing viral identification tools and offer a blueprint for feature engineering of new tools that will lead to higher-confidence viral discovery in microbiome studies.

bioinformatics↗

bioRxiv2018

Microbial subnetworks related to short-term diel O2 fluxes within geochemically distinct freshwater wetlands

O2 concentrations often fluctuate over diel timescales within wetlands, driven by temperature, sunlight, photosynthesis, and respiration. These daily fluxes have been shown to impact biogeochemical transformations (e.g. denitrification), which are mediated by the residing microbial community. However, little is known about how resident microbial communities respond to diel dramatic physical and chemical fluxes in freshwater wetland ecosystems. In this study, total microbial (bacterial and archaeal) community structure was significantly related to diel time points in just one out of four distinct freshwater wetlands sampled. This suggests that daily environmental shifts may influence wetlands differentially based upon the resident microbial community and specific physical and chemical conditions of a freshwater wetland. However, when exploring at finer resolutions of the microbial communities within each wetland, subcommunities within two wetlands were found to correspond to fluctuating O2 levels. Microbial taxa that were found to be susceptible to fluctuating O2 levels within these subnetworks may have intimate ties to metabolism and/or diel redox cycles. This study highlights that freshwater wetland microbial communities are often stable in community structure when confronted with short-term O2 fluxes, however, specialist taxa may be sensitive to these same fluxes.

microbiology↗