Biology subjects

Shields, S.

Publications and source records attributed to Shields, S..

4 recordsLinked to original sources

bioRxiv2026

Distributions of host heterogeneity in susceptibility show signatures of pathogen geographic structure in an insect baculovirus

Segregated variation between populations is a fundamental evolutionary process leading to parasite specialization, yet the resulting impacts on infection heterogeneity within populations are theoretically and empirically understudied. We asked whether the distribution of host susceptibility to infection within populations carries the signatures of geographic structure from pathogen local adaptation, maladaptation, or generalism in a nuclear polyhedrosis virus that infects the Gulf Fritillary butterfly Dione vanillae. For this virus, there is genetic support for two geographically distinct groups within San Diego County, based on whole genome sequencing of 16 virus isolates. Reciprocal laboratory infections showed evidence of two contrasting viral life history strategies: a generalist phenotype that consistently infected variable hosts and a specialist that performed slightly better in its local host population. As predicted by our theoretical model, the more consistent infection displayed by the generalist across populations corresponded to lower heterogeneity in susceptibility within populations, modeled as gamma distribution. Furthermore, the generalist phenotype was collected over a wider geographic range despite having a tenfold-lower mean infection rate than the specialist, suggesting that a strategy of more consistent infection provides key fitness advantages across diverse host populations. Intriguingly, when there is variation in host susceptibility, interpretations of pathogen local adaptation are dose-dependent. Measuring infectivity across multiple doses enables estimation of the whole distribution of susceptibility, which provides more reliable identification of pathogen specialization to its local host. Our work demonstrates how trait distributions and not only their mean values can carry quantifiable signatures of eco-evolutionary processes in interspecific interactions.

ecology↗

bioRxiv2024

Oxidative stress promotes axonal atrophy through alterations in microtubules and EB1 function

Axons are crucial for transmitting neurochemical signals. As organisms age, the ability of neurons to maintain their axons declines; hence aged axons are more susceptible to damage or dysfunction. Understanding what causes axonal vulnerability is crucial for developing strategies to enhance overall resilience of neurons, and to prevent their deterioration during ageing or in age-related neurodegenerative diseases. Increasing levels of reactive oxygen species (ROS) causes oxidative stress, a hallmark of ageing and age-related diseases. Despite this association, a causal relationship between oxidative stress and neuronal ageing remains unclear, particularly how subcellular physiology is affected by ROS. By using Drosophila-derived primary neuronal cultures and a recently developed in vivo neuronal model of ageing, which involves the visualisation of Drosophila medulla neurons, we investigated the interplay between oxidative stress, neuronal ageing and the microtubule cytoskeleton. We find that oxidative stress as a key driver of axonal and synaptic decay, including the appearance of axonal swellings, microtubule alterations in both axons and synapses and the morphological transformation of axonal terminals during ageing. We demonstrate that increased ROS sensitises the microtubule plus end binding factor, end-binding protein 1 (EB1), leading to microtubule defects, affecting neuronal integrity. Furthermore, manipulating EB1 proved to be a valuable therapeutic strategy to prevent ageing hallmarks observed in conditions of elevated ROS. In summary, we demonstrate a mechanistic pathway linking cellular oxidative stress, the microtubule cytoskeleton and axonal deterioration during ageing and provide evidence of the therapeutic potential of enhancing microtubule plus end physiology to improve the resilience of axons.

neuroscience↗

bioRxiv2023

Microtubule decay is a driver of neuronal ageing and a promising target for intervention

Natural ageing is accompanied by a decline in motor, sensory and cognitive functions, all impacting life quality. Ageing is the predominant risk factor for many neurodegenerative diseases, including Parkinsons and Alzheimers disease. We need therefore to gain a better understanding of the cellular and physiological processes underlying age-related neuronal decay. However, gaining this understanding is a slow process due to the long time required to age mammalian or vertebrate model animals. Here we introduce a new cellular model within the Drosophila brain where neurons show typical ageing hallmarks known from the primate brain, including axonal swellings, cytoskeletal decay, a reduction in axonal calibre and morphological changes arising at synaptic terminals. In the fly brain, these changes occur within just a few weeks, ideal to study the underlying mechanisms. We observe that decay of the neuronal microtubule cytoskeleton clearly precedes other ageing hallmarks. We show that the microtubule-binding factors Tau, EB1 and Shot, are necessary for microtubule maintenance in axons and synapses. Their functional loss during ageing triggers microtubule bundle decay followed by the decline in axons and synapses. Genetic manipulations that improve microtubule networks, slow down other neuronal ageing hallmarks and confer aged specimens with the ability to outperform age-matched controls. Our work suggests therefore that microtubule networks are a key lesion site in ageing neurons and offer promising opportunities to improve neuronal decay in advanced age.

neuroscience↗

bioRxiv2019

A Multidimensional Systems Biology Analysis of Cellular Senescence in Ageing and Disease

Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of ageing and has been linked to ageing-related diseases like cancer. Senescent cells have been shown to accumulate in tissues of aged organisms which in turn can lead to chronic inflammation. Many genes have been associated with cell senescence, yet a comprehensive understanding of cell senescence pathways is still lacking. To this end, we created CellAge (http://genomics.senescence.info/cells), a manually curated database of 279 human genes associated with cellular senescence, and performed various integrative and functional analyses. We observed that genes promoting cell senescence tend to be overexpressed with age in human tissues and are also significantly overrepresented in anti-longevity and tumour-suppressor gene databases. By contrast, genes inhibiting cell senescence overlapped with pro-longevity genes and oncogenes. Furthermore, an evolutionary analysis revealed a strong conservation of senescence-associated genes in mammals, but not in invertebrates. Using the CellAge genes as seed nodes, we also built protein-protein interaction and co-expression networks. Clusters in the networks were enriched for cell cycle and immunological processes. Network topological parameters also revealed novel potential senescence-associated regulators. We then used siRNAs and observed that of 26 candidates tested, 19 induced markers of senescence. Overall, our work provides a new resource for researchers to study cell senescence and our systems biology analyses provide new insights and novel genes regarding cell senescence.

systems biology↗