Biology subjects

Sherlock, M.

Publications and source records attributed to Sherlock, M..

6 recordsLinked to original sources

bioRxiv2026

Enterovirus RNase L inhibiting RNAs are highly conserved with limited phylogenetic distribution

RNA molecules form specific 3D structures that facilitate a variety of functions through interactions with other macromolecules. Many RNA viral genomes maintain these structures to interact with and evade host immunity machinery. One such element, the competitive inhibitor RNA (ciRNA), discovered in the protein coding region of the poliovirus serotype 1 (PV1) genome, inhibits a host antiviral protein, ribonuclease L (RNase L). Although some functionally essential structural motifs of the PV1 ciRNA have been studied, the extent of its evolutionary conservation and other structural requirements remained unexplored. Here we combined bioinformatic and biochemical techniques to further define the requirements of a functional ciRNA and assess its phylogenetic distribution. We systematically mutated ciRNA structural features, verifying that ciRNA inhibitory activity requires a conserved loop E motif and a long-range base-pairing interaction, but its peripheral stems are dispensable and in fact a circularly permuted version maintains function. A structure-based homology search identified potential ciRNAs across the Picornaviridae family, but only a subset of those tested were functional--all are in Enterovirus coxsackiepol. When structural features needed for function were transposed from PV1 ciRNA to an RNA unable to inhibit RNase L, the chimeric RNAs did not gain wild-type function, and chemical probing data revealed that these nonfunctional RNAs are unable to form the correct secondary structure. Overall, the dual constraints of encoding a protein and forming a specific functional structure appear to not only limit the sequence diversity, but also the phylogenetic distribution, of ciRNAs.

microbiology↗

bioRxiv2025

Drivers of individual plant species contributions to β-diversity are scale-dependent

Species introductions and native extirpations are driving biotic homogenisation in plant communities by reducing {beta}-diversity. Individual species vary in their contributions to {beta}-diversity (Species Contribution to {beta}-Diversity; species-{beta}), yet our understanding of how species characteristics shape these contributions remains limited. Additionally, although the ecological processes influencing {beta}-diversity are known to vary with spatial scale, we lack understanding of how species contributions, or their underlying determinants, change across scales. Here, we modelled how plant functional traits, phylogenetic relatedness, and introduction status influence their contributions to {beta}-diversity using plant community data from 429 plots surveyed from 2017-2023 across three nested spatial scales (up to 1 km2) in nine sites spanning four countries. We extended the analysis to broader spatial extents (100 km2 to the entire UK) using GBIF occurrence data. We found that functional traits associated with competitive ability influenced species-{beta}, but the direction and strength of their effects varied with scale. Likewise, phylogenetic novelty increased species-{beta} at small scales but reduced it at larger ones. After accounting for traits and phylogeny, introduced species consistently contributed less to {beta}-diversity than native species--especially at broader spatial extents. These results demonstrate that species ecological and evolutionary characteristics shape their contributions to {beta}-diversity, but that these effects are scale-dependent. Our findings highlight the importance of scale-explicit approaches in understanding both the determinants of {beta}-diversity, and how we can combat its loss to mitigate biotic homogenisation.

ecology↗

bioRxiv2025

Shotgun metagenomic analysis of the oral microbiomes of children with noma reveals a novel disease-associated organism

Noma is a rapidly progressive orofacial gangrene that predominantly affects children living in extreme poverty. Despite its documentation since antiquity and its designation as a World Health Organisation Neglected Tropical Disease in 2023, the microbiological cause of noma remains poorly understood, with no specific organisms confidently identified as definitive aetiological agents. Here, we present the first deep shotgun metagenomic profiling of oral saliva microbiomes from 19 Nigerian children with acute noma. Our analyses reveal marked microbial dysbiosis in noma microbiomes, with machine learning and multivariate statistical analyses indicating significant enrichment of Treponema, Porphyromonas, and Bacteroides, alongside depletion of Streptococcus and Rothia, as key microbial signatures of noma disease. From the dataset we recovered 40 high-quality Treponema metagenome-assembled genomes (MAGs) spanning 19 species, 14 of which were novel. Notably, a novel species designated Treponema sp. A was detected in 15 of the 19 noma participants and was entirely absent from global healthy saliva metagenomes. Re-analysis of previously published 16S rRNA datasets from children with noma in Niger also revealed Treponema sp. A to be highly prevalent in noma cases but rare in controls. This study identifies Treponema--particularly Treponema sp. A--as a strong candidate organism associated with noma pathogenesis. Additionally, analysis of antimicrobial resistance determinants detected in noma metagenomes revealed concerning levels of resistance to antibiotics commonly used in noma treatment, particularly {beta}-lactams and metronidazole, especially among Prevotella species. These findings provide the first high-resolution microbial framework for noma and offer a foundation for future research into its pathogenesis and the development of novel diagnostics, therapeutics, and preventive strategies in endemic settings.

pathology↗

bioRxiv2025

Using landscape biodiversity metrics to assess rewilding: a space-for-time comparison between the Knepp Estate and an agricultural baseline at Boothby Wildland

O_LIThe biodiversity crisis is often framed in terms of the reduction of species found at a site: a (alpha) diversity. However, changes in species composition across a landscape - b (beta) diversity - caused by biotic homogenisation are part of the same crisis. Much biotic homogenisation in British terrestrial landscapes in the post-war period (1945 onwards) has been driven by agricultural conversion and intensification. Restoration efforts must therefore contend with restoring agricultural land to some desired state, and rewilding has emerged as a potential solution to this problem. C_LIO_LIHere we quantify rewilding success by comparing a- and b-diversity of plant assemblages across two study systems in different stages of rewilding. Boothby Wildland is an arable farm recently given over to rewilding, while the Knepp Estate is an ex-arable and dairy farm currently >20 years into rewilding. We assessed a-diversity within, and b- diversity across, these two landscapes using 3 years of plant survey data (2022-2024). C_LIO_LIWe confirmed expected differences between a baseline and rewilded landscape and explored the changes in a brand new rewilded landscape in its early years of progress. As expected, the plant community at the Knepp Estate is relatively stable while that of Boothby Wildland is changing rapidly, and we discuss the landscape impacts of different herbivory regimes on recovery. C_LIO_LISynthesis and applications. We also show that spatial metrics for SESMPD and SESMNTD can distinguish between a rewilded and degraded landscape. This suggests that changes in the structure of biodiversity across landscapes can be quantified using analyses that account for spatial structure in metrics. We call for further research to see if a spatial approach of this kind can be used as a general metric of success in rewilding. C_LI

ecology↗

bioRxiv2023

A conserved class of viral RNA structures regulate translation reinitiation through dynamic ribosome interactions

Certain viral RNAs encode proteins downstream of the main protein coding region, expressed through "termination-reinitiation" events, dependent on RNA structure. RNA elements located upstream of the first stop codon within these viral mRNAs bind the ribosome, preventing ribosome recycling and inducing reinitiation. We used bioinformatic methods to identify new examples of viral reinitiation-stimulating RNAs and experimentally verified their secondary structure and function. We determined the structure of a representative viral RNA-ribosome complex using cryoEM. 3D classification and variability analyses reveal that the viral RNA structure can sample a range of conformations while remaining tethered to the ribosome, which enabling the ribosome to find a reinitiation start site within a limited range of mRNA sequence. Evaluating the conserved features and constraints of this entire RNA class in the context of the cryoEM reconstruction provides insight into mechanisms enabling reinitiation, a translation regulation strategy employed by many other viral and eukaryotic systems.

molecular biology↗

bioRxiv2020

A structured viral RNA uses molecular mimicry and conformational dynamics to coordinate multiple functions

Viruses require multifunctional structured RNAs to hijack their hosts biochemistry, but their mechanisms can be obscured by the difficulty of solving conformationally dynamic RNA structures. Using cryo-EM, we visualized the structure of the mysterious viral tRNA-like structure (TLS) from brome mosaic virus (BMV), which affects replication, translation, and genome encapsidation. Structures in isolation and bound to tyrosyl-tRNA synthetase (TyrRS) show that this [~]55 kDa purported tRNA mimic undergoes large conformational rearrangements to bind TyrRS in a form that differs dramatically from tRNA. Our studies reveal how viral RNAs can use a combination of static and dynamic RNA structures to bind host machinery through highly noncanonical interactions and highlights the utility of cryo-EM for visualizing small conformationally dynamic structured RNAs.

biophysics↗