Latest Publications
Quantifying vector diversion effects in zoonotic systems: A modelling framework for arbovirus transmission between reservoir and dead-end hosts
Emma L. Fairbanks, Matthew Baylis, Janet M. Daly, Michael J. Tildesley
Vector-borne disease transmission involves complex interactions between vectors, reservoir hosts and dead-end hosts. We present a mathematical model for the vectorial capacity that incorporates multiple host types and their interactions, focusing specifically on West Nile virus transmission by Culex pipiens mosquitoes. Our model integrates climate-dependent parameters affecting vector biology with vector control interventions to predict transmission potential under various scenarios. We demonstrate how vector control interventions targeting one host type can significantly impact transmission dynamics across all host populations. By examining the effects of different vector control tool modes of action (repellency, preprandial killing, disarming and postprandial killing), we develop target product profiles that minimise unintended consequences of vector control. Notably, we identify the optimal intervention characteristics needed to prevent repellency on dead-end hosts from inadvertently increasing transmission among reservoir hosts. This research provides valuable insights for public health officials designing targeted vector control strategies and offers a flexible modelling framework that can be adapted to other vector-borne diseases with complex host dynamics.
Bayesian spatio-temporal modelling for infectious disease outbreak detection
Matthew Adeoye, Xavier Didelot, Simon E.F. Spencer
The Bayesian analysis of infectious disease surveillance data from multiple locations typically involves building and fitting a spatio-temporal model of how the disease spreads in the structured population. Here we present new generally applicable methodology to perform this task. We introduce a parsimonious representation of seasonality and a biologically informed specification of the outbreak component to avoid parameter identifiability issues. We develop a computationally efficient Bayesian inference methodology for the proposed models, including techniques to detect outbreaks by computing marginal posterior probabilities at each spatial location and time point. We show that it is possible to efficiently integrate out the discrete parameters associated with outbreak states, enabling the use of dynamic Hamiltonian Monte Carlo (HMC) as a complementary alternative to a hybrid Markov chain Monte Carlo (MCMC) algorithm. Furthermore, we introduce a robust Bayesian model comparison framework based on importance sampling to approximate model evidence in high-dimensional space. The performance of our methodology is validated through systematic simulation studies, where simulated outbreaks were successfully detected, and our model comparison strategy demonstrates strong reliability. We also apply our new methodology to monthly incidence data on invasive meningococcal disease from 28 European countries. The results highlight outbreaks across multiple countries and months, with model comparison analysis showing that the new specification outperforms previous approaches.
CDCA7 facilitates MET1-mediated CG DNA methylation maintenance in centromeric heterochromatin via linker histone H1
Shuya Wang, Tong Li, Matthew Naish, Russell Chuang, Evan K. Lin, Christian Fonkalsrud, Yan He, Suhua Feng, Ian R. Henderson, Steven E. Jacobsen
DNA methylation is a conserved epigenetic modification essential for maintaining genome stability. However, how methyltransferases maintain CG methylation within compact chromatin, including centromeres, remains unclear. In humans, CDCA7 is necessary for the inheritance of DNA methylation at juxta-centromeres. Mutations that impair its ability to bind chromatin result in Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) syndrome, characterized by centromeric instability. To investigate whether CDCA7 function is conserved, we identified two Arabidopsis thaliana orthologs, CDCA7α and CDCA7β. The loss of both copies results in CG hypomethylation at pericentromeric regions and centromeric satellite repeat arrays. Machine learning analysis suggested that heterochromatic nucleosomes, with enrichment of H1, H2A.W, and H3K9me2, depend heavily on CDCA7 proteins for CG methylation maintenance of the associated DNA. Loss of H1 restores heterochromatic DNA methylation in cdca7α cdca7β mutants, indicating that CDCA7α and CDCA7β mainly remodel H1-containing nucleosomes for methyltransferases to access DNA. Notably, in h1.1 h1.2 mutants, CG methylation shows a significant increase in centromeres, which reveals a new inhibitory role of H1 in DNA methylation maintenance within satellite repeat arrays. Centromeric DNA hypermethylation is lost in h1.1 h1.2 cdca7α cdca7β quadruple mutants, demonstrating that CDCA7α and CDCA7β can act independently of H1 to enhance MET1 activity at nucleosomes. Overall, these findings establish CDCA7α and CDCA7β as conserved regulators of DNA methylation within heterochromatin and centromeric satellite repeat arrays.
Pineal gland senescence: an emerging ageing-related pathology?
Emma Short, Ramzi Ajjan, Thomas M Barber, Sunil Bhandari, Paul Chazot, Jennifer L. Garrison, Anushka Goyal, Robert Huckstepp, Noordin Jamal, Venkateswarlu Kanamarlapudi, Alpar Lazar, Thomas Lee, Adriana A. S. Tavares, Jeremy J Tree, Jack Wellington, Stuart RG Calimport, Barry Bentley
An ageing-related pathology has recently been described as one that develops and/or progresses with increasing chronological age, that is associated with, or contributes to, functional decline and that is evidenced by studies in humans. The pineal gland is a photo-neuroendocrine organ whose primary function is to produce and secrete melatonin in response to light-dark cycle environmental cues. The gland may undergo ageing-related structural and morphological changes, including calcification, gliosis, cyst formation, and reduced density of β-adrenergic receptors, which are hypothesised to reduce melatonin secretion. Pineal gland senescence describes the ageing-related decline in neuroendocrine function, with reduced secretion of melatonin, which may contribute to ageing-related sleep disorders and disruption of other circadian-driven physiological functions and may have secondary effects such as contributing to cognitive and mood disorders related to sleep disturbance.
Reply to Kohl: Moving beyond the 19th-century view of domestication
The Staphylococcus aureus LXG-domain toxins EsxX and SAR0287 do not promote virulence in a zebrafish larval infection model
Fatima Ulhuq, Amy K. Tooke, Chriselle Mendonca, Guillermina Casabona, Johann Habersetzer, Yaping Yang, Margarida C. Gomes, Felicity Alcock, Serge Mostowy, Tracy Palmer
The Staphylococcus aureus type VIIb secretion system (T7SSb) is a multiprotein secretion system that secretes toxins with antibacterial activity, but which is also required for full virulence in animal models of infection. S. aureus strains carry one of four T7SSb locus types, named essC1 to essC4, each of which encodes a characteristic LXG-family substrate at the T7SS locus. In essC2 strains, this LXG-domain protein is EsxX, which has a glycine zipper sequence in its C-terminus and has potent antibacterial, membrane-depolarizing activity. In this work, we recognize conserved features of the essC2 and essC3 systems, identifying the LXG protein SAR0287 as structurally and functionally similar to EsxX. Using a zebrafish larval hindbrain ventricle infection model, we demonstrate that the T7SSb of essC2 and essC3 representative strains contributes to bacterial replication and zebrafish mortality. However, there is no significant loss of virulence in the model system if EsxX or SAR0287 is absent. These findings indicate that there is no discernible role for either toxin in this virulence model.