Latest Publications
Speeding up Inference of Homologous Recombination in Bacteria
Felipe J Medina-Aguayo, Xavier Didelot, Richard G Everitt
Bacteria reproduce clonally but most species recombine frequently, so that the ancestral process is best captured using an ancestral recombination graph. This graph model is often too complex to be used in an inferential setup, but it can be approximated for example by the ClonalOrigin model. Inference in the ClonalOrigin model is performed via a Reversible-Jump Markov Chain Monte Carlo algorithm, however this often performs poorly due to the complexity of the target distribution since it needs to explore spaces of different dimensions. Recent developments in Bayesian computation methodology have provided ways to improve existing methods and code, but are not well-known outside the statistics community. We show how exploiting one of these new computational methods can lead to faster inference under the ClonalOrigin model.
Metabolic profiling and antibacterial activity of tree wood extracts obtained under variable extraction conditions
Diana Vinchira-Villarraga, Sabrine Dhaouadi, Vanja Milenkovic, Jiaqi Wei, Emily R. Grace, Katherine G. Hinton, Amy J. Webster, Andrea Vadillo-Dieguez, Sophie E. Powell, Naina Korotania, Leonardo Castellanos, Freddy A. Ramos, Richard J. Harrison, Mojgan Rabiey & Robert W. Jackson
This study aimed to develop a methodological approach to obtain extracts from different tree species with the highest reproducibility and chemical diversity possible, to ensure proper coverage of the trees’ metabolome. Each tree species has a unique metabolic profile, which means that no single protocol is universally effective. Extraction at 50 °C for three cycles using 80% methanol or chloroform/methanol/water showed the best results and is suggested for studying wood metabolome. These observations highlight the need to tailor extraction protocols to each tree species to ensure comprehensive metabolome coverage for metabolic profiling.
Delivery determinants of an Acinetobacter baumannii type VI secretion system bifunctional peptidoglycan hydrolase
Valeriya Bezkorovayna, Brooke K. Hayes, Francesca N. Gillett, Amy Wright, David I. Roper, Marina Harper, Sheena McGowan, John D. Boyce
Acinetobacter baumannii is a Gram-negative opportunistic pathogen and is a common cause of nosocomial infections.). Here we define the regions of interaction between Tae17 and its cognate delivery protein VgrG17 and identify that amino acids G1069 and W1075 in VgrG17 are essential for Tae17 delivery via the T6SS, the first time such specific delivery determinants of T6SS cargo effectors have been defined. Furthermore, we determine that the Tae17 effector is a multidomain, bifunctional, peptidoglycan-degrading enzyme that has both amidase activity, which targets the sugar-peptide bonds, and lytic transglycosylase activity, which targets the peptidoglycan sugar backbone. Moreover, we show that the Tae17 transglycosylase activity is more important than amidase activity for the killing of Escherichia coli. This study provides molecular insight into how the T6SS allows A. baumannii strains to gain dominance in polymicrobial communities and thus improve their chances of survival and transmission.
Mike Tildesley publications
The impact of natural climate variability on the global distribution of Aedes aegypti : a mathematical modelling study
Kaye, A. R., Obolski, U., Sun, L., Hart, W. S., Hurrell, J. W., Tildesley, M. J. and Thompson, R. N.
Aedes aegypti spread pathogens affecting humans, including dengue, Zika, and yellow fever viruses. Anthropogenic climate change is altering the spatial distribution of Ae aegypti and therefore the locations at risk of vector-borne disease. In addition to climate change, natural climate variability, resulting from internal atmospheric processes and interactions between climate system components (eg, atmosphere–land and atmosphere–ocean interactions), determines climate outcomes. However, the role of natural climate variability in modifying the effects of anthropogenic climate change on future environmental suitability for Ae aegypti has not been assessed fully. In this study, we aim to assess uncertainty arising from natural climate variability in projections of Ae aegypti suitability up to the year 2100. Lancet Planetary Health. December 2024
The time between symptom onset and various clinical outcomes : a statistical analysis of MERS-CoV patients in Saudi Arabia
Althobaity, Yehya, Alkhudaydi, Muhammad, Hill, Edward M., Thompson, Robin N. and Tildesley, Michael J
In this study, we investigate the impact of demographic characteristics on MERS-CoV cases in Saudi Arabia, specifically focusing on the time intervals between symptom onset and key events such as hospitalization, case confirmation, reporting and death. Importantly, we observe age-based differences in the risk of hospitalization and other measures of infection severity, including the probability of death conditional on hospitalization. Careful quantification of epidemiological characteristics, including inference of key epidemiological periods and assessments of differences between cases of different ages, plays a crucial role in understanding the progression of MERS-CoV outbreaks and formulating effective public health strategies to mitigate their impact.
Transcription factor deformed wings is an Atg8a-Interacting protein that regulates autophagy
Kołodziej, Marta, Tsapras, Panagiotis, Cameron, Alexander and Nezis, Ioannis P
LC3 (microtubule-associated protein 1 light chain 3, called Atg8 in yeast and Drosophila) is one of the most well-studied autophagy-related proteins. LC3 controls the selectivity of autophagic degradation by interacting with LIR (LC3-interacting region) motifs also known as AIM (Atg8-interacting motifs) on selective autophagy receptors that carry cargo for degradation. Although the function of Atg8 family proteins is primarily cytoplasmic, they are also enriched in the nucleus. Here, we used yeast two-hybrid screening, and we identified transcription factor Deformed wings (Dwg) as an Atg8a-interacting protein in Drosophila. Dwg-Atg8a interaction is LIR motif-dependent. We have created Dwg Y129A/I132A LIR mutant flies and shown that they exhibit elevated autophagy, improved resistance to oxidative stress, and starvation. Our results provide novel insights into the transcriptional regulation of autophagy in Drosophila.
Gladiolin produced by pathogenic Burkholderia synergizes with amphotericin B through membrane lipid rearrangements
Claudia Simm, Tzong-Hsien Lee, Harshini Weerasinghe, Dean Walsh, Ioanna T Nakou, Madhu Shankar, Wai Chung Tse, Rebecca Inman, Robert J Mulder, Freya Harrison, Marie-Isabel Aguilar, Gregory L Challis, Ana Traven
Amphotericin B (AmpB) is an effective but toxic antifungal drug.. AmpB disrupts fungal membranes by two proposed mechanisms: ergosterol sequestration from the membrane and pore formation. Whether these two mechanisms operate in conjunction and how they could be potentiated remains to be fully understood. Here, we report that gladiolin, a polyketide antibiotic produced by Burkholderia gladioli, is a strong potentiator of AmpB and acts synergistically against Cryptococcus and Candida species, including drug-resistant C. auris. Gladiolin also synergizes with AmpB against drug-resistant fungal biofilms, while exerting no mammalian cytotoxicity.. Collectively, our findings shed light on AmpB’s mechanism of action and characterize gladiolin as an AmpB potentiator, showing an antifungal mechanism distinct from its proposed antibiotic activity. We shed light on the synergistic mechanism at the membrane, and provide insights into potentiation strategies to improve AmpB’s activity/toxicity relationship.