Biology subjects

Williams, S. E.

Publications and source records attributed to Williams, S. E..

15 recordsLinked to original sources

bioRxiv2026

A near-ubiquitous plasmid characterises Second Pandemic Yersinia pestis

Yersinia pestis, the causative agent of plague, crippled population across Eurasia in three well-described historical pandemics: The Justinianic plague (541-780), the Second Pandemic (1346-1840) and the Third Pandemic (1894-). The Second Pandemic was the deadliest, with the Black Death (1346-1351) killing up to 60% of Europe's population, far exceeding the population mortality of the Third pandemic, despite few genomic differences between their plague strains. To identify unique genetic variation that could help explain the high death toll of the Second Plague pandemic, we used variation-graph based pan-genomics on a large dataset of 110 new and 12 published shotgun sequenced ancient plague genomes to comprehensively characterise the pangenome diversity of the Second Pandemic plague. Our pangenomic approach revealed the presence of a cryptic 34kb plasmid, pTP33, in almost all strains from the Second Pandemic, but undetectable in all other ancient strains. We find that pTP33 is a phage-plasmid-like derived element with homologues in Enterobacterales bacteria with established insect- or invertebrate-associated lifestyle phases. Our results suggest that pTP33 widened the range and infectivity of vector species available for plague transmission, consistent with reported effects on biofilm formation and bacterial retention. We hypothesise that pTP33 broadened the vector range of Y. pestis beyond the classical rat/flea cycle, facilitating the establishment of new rodent-ectoparasite plague reservoirs, which, critically, increased the risk of flea- or lice-mediated plague transmission between humans. Taken together, our findings offer a biological explanation for differences in transmission dynamics and population mortality between the Second and Third plague pandemics.

genomics↗

bioRxiv2026

RetroMol: Parsing a shared encoding from natural products and their biosynthetic gene clusters

Natural products such as polyketides and nonribosomal peptides (NRPs) are important sources of bioactive compounds, including many antibiotics. Many of them are assembled by modular enzyme complexes and further modified and diversified by tailoring reactions encoded by biosynthetic gene clusters (BGCs). Although natural products and their coding BGCs describe different data modalities of the same biochemical process, a unified language to jointly describe their biochemistry is lacking. Here we introduce a sequence-based representation of the core biosynthesis of modular natural products, which we call primary sequences, that bridges chemical structures and BGCs. We also present RetroMol, an algorithm that parses either natural product structures or their encoding BGCs into their primary sequences of natural product building blocks. RetroMol allows for similarity scoring between natural products and BGCs, enabling the retrieval of compounds, BGCs, and a combination of the two, based on their biosynthetic similarity. This can, for instance, be used to retrieve biosynthetically similar but structurally dissimilar compounds, or link natural products to candidate coding BGCs in large experimental datasets. We demonstrate the latter by rediscovering the nocardichelin B BGC as a proof of principle. We also exemplify the utility of biosynthetic similarity by showing various pairs of biosynthetically similar compounds with low structural similarity. Together, these results establish primary sequences as a shared biosynthetic encoding for natural product comparison and BGC prioritization.

bioinformatics↗

bioRxiv2026

Comparing Machine Learning Approaches for Predicting CFD-Derived Stroke Risk Indicators in Atrial Fibrillation Patients

Non-valvular atrial fibrillation (AF) is associated with a five-fold increased risk of stroke, mainly due to impaired contractility of the left atrium (LA) leading to blood stasis and subsequent thrombus formation within the left atrial appendage (LAA). Current AF stroke risk stratification schemes, such as the CHA2DS2-VASc/ CHA2DS2-VA score, use comorbidities and do not capture mechanistic factors like blood flow dynamics and hypercoagulability. To address this, we developed a multiphase computational fluid dynamics (CFD) model of the LA, incorporating patient-specific geometries; modelling of the coagulation cascade; and non-Newtonian blood behaviour within the LAA. Using 84 simulation cases generated via Latin Hypercube Sampling of physiological blood parameters and 21 patient-derived LA anatomies, we trained surrogate machine learning models, including Ridge regression, XGBoost, Gaussian Process Emulators (GPEs), and deep learning networks, to predict CFD outputs such as blood viscosity in and fibrin concentrations in the LAA. Deep learning achieved R{superscript 2} values up to 0.90, with the accuracy increasing when both physiological parameters and the raw CT image were included. Other models showed uneven performance with R2 values below 0.7, highlighting the role of nonlinearities between parameters. The study presents a novel CFD model that captures the transition from blood stasis to clot formation, representing the full thrombotic continuum underlying stroke risk in AF, and a deep learning approach to enable efficient prediction of mechanistic outputs of clinical value for stroke risk stratification in AF patients. Author SummaryAtrial fibrillation is a common heart rhythm disorder that greatly increases the risk of stroke. In many patients, blood can pool inside a small pouch of the heart called the left atrial appendage, where clots may form and later travel to the brain. Current clinical tools used to estimate stroke risk mainly rely on a patients medical history and do not directly assess the mechanistic processes that lead to clot formation. In this study, we developed a computer model that simulates how blood flows and clots inside the heart using patient-specific heart anatomies derived from medical imaging. Our model combines blood flow, blood biochemistry, and the changing physical properties of blood during clot formation. We then used machine learning methods to predict these complex simulation results more efficiently. Deep learning models performed best, particularly when both clinical parameters and heart imaging data were included. Our work provides a new way to study the full process linking abnormal blood flow to clot formation in atrial fibrillation. In the future, this approach could support more personalised and mechanistic assessment of stroke risk and help guide treatment decisions.

bioengineering↗

bioRxiv2026

The nightshift lowdown: can ants buffer climate change through shifts in vertical and temporal activity?

Temperature fluctuations across space and time create a multidimensional thermal landscape within which organisms are exposed to local climates while conducting their daily activities. Tropical species are considered to be particularly sensitive to climate change, with narrow thermal safety margins - the buffer between operative and lethal temperatures. In tropical rainforests, however, species can hypothetically mediate thermal exposure via activity over two local thermal dimensions: vertical (ground-canopy) and temporal (day-night). Such spatiotemporal flexibility could protect species from elevated temperatures and improve thermal safety margins, but this mechanism has not been previously investigated. We test this hypothesis using rainforest ants at a warm lowland and cool upland site (100, 1200 m a.s.l.) in the Australian Wet Tropics. At lowland and upland sites, we quantified microclimate, foraging activity, community composition, and thermal ecology of ants across vertical and temporal dimensions. To assess spatiotemporal flexibility as a climate change mitigation strategy, we calculated thermal safety margins (TSM) as the difference between a species upper thermal limit (CTmax) and mean activity temperature (Te). For each species in each of their spatiotemporal niches (ground-arboreal-day-night) we test whether shifting activity to cooler niches increases TSM using the hottest niches (arboreal and/or daytime) as a baseline. At both lowland and upland sites, ant species were highly stratified vertically, but the large majority (77 - 87.5%) were active both day and night, indicating widespread temporal generalisation. Shifting activity to cooler parts of the thermal landscape substantially improved TSMs: in the lowlands, species with arboreal diurnal foraging increased their TSM by an average of 4.4 {degrees}C ({+/-} 1.7 SE) by shifting to the ground and 6.7 {degrees}C ({+/-} 1.63 SE) by shifting to nocturnal foraging. Improvements were more modest in the uplands: arboreal diurnal foragers increased TSM by 2.1 {degrees}C ({+/-} 2.07 SE) and 2 {degrees}C ({+/-} 0.28 SE) for ground and nocturnal shifts respectively. We therefore demonstrate that foraging niche flexibility is an important climate-change mitigation trait and is most beneficial in the lowlands. Lowland diurnal canopy specialists, however, are most at risk. This represents a large proportion of tropical rainforest biodiversity, supporting previous hypotheses of lowland biotic attrition under climate change.

ecology↗

bioRxiv2025

Hemidesmosomes regulate epidermal differentiation during embryogenesis

In skin epidermis, integrins mediate adhesion of basal keratinocytes to the underlying basement membrane. While high expression of integrins has been correlated with stemness, there is limited direct evidence that integrins mediate keratinocyte retention within the basal layer. Here, we generate mosaic, epidermal-specific loss of integrin-{beta}4 (encoded by Itgb4) or its ligand, laminin-3{beta}3{gamma}2 (Lama3), using an in utero lentiviral-mediated approach. Although mutations in these genes cause postnatal skin blistering in mice and humans, we observe no evidence of epidermal-dermal separation embryonically. Despite no weobvious alterations to apicobasal polarity, Itgb4-deficient basal cells show mild defects in oriented cell divisions, with increased oblique divisions and altered telophase correction. However, differentiation via cellular delamination--where basal keratinocytes lose adhesion to the underlying basement membrane and transit into the suprabasal layer--is elevated upon Itgb4 and Lama3 loss. Notably, hyperactive Notch signaling both decreases integrin-{beta}4 expression and increases delamination. These findings conclusively demonstrate a causal role for hemidesmosomes in regulating epidermal differentiation through both mitotic and non-mitotic mechanisms and shed additional light on the programs regulating delamination. HighlightsO_LIEmbryonic loss of integrin-{beta}4 impairs hemidesmosome maturation, but does not cause blistering in the embryonic epidermis C_LIO_LIIntegrin-{beta}4 is dispensable for keratinocyte polarity but promotes telophase correction C_LIO_LIHemidesmosome adhesions regulate differentiation through delamination C_LI Summary StatementHemidesmosomes are specialized integrin complexes that anchor the epidermis to the basement membrane. We show that hemidesmosomal integrin-6{beta}4 and laminin-3{beta}3{gamma}2 regulate epidermal differentiation by promoting basal cell retention in embryogenesis.

developmental biology↗

bioRxiv2025

DIFFERENTIAL ROLES OF RAD18 IN REPRESSING CARCINOGEN- AND ONCOGENE-DRIVEN MUTAGENESIS IN VIVO

The DNA repair protein RAD18 activates Y-family Trans-Lesion Synthesis (TLS) DNA polymerases that are DNA damage-tolerant and potentially error-prone. RAD18 is also frequently overexpressed and pathologically activated in cancer cells. However, the extent to which RAD18 shapes cancer genomes and impacts tumorigenesis is unclear. Therefore, we tested the effect of Rad18 status on chemically-induced and oncogene-driven tumorigenesis. In a chemically-induced oral carcinogenesis model, acute (2-16 days) 4NQO-treatment induces expression of Rad18 and TLS polymerase mRNAs in mouse oral epithelial cells prior to emergence of oral squamous cell carcinomas (OSCCs). Chronic (8 week) 4NQO-treatment leads to onset of oral tumors that is accelerated in Rad18-/- mice when compared with Rad18+/+ animals. Analysis of OSCC exomes reveals increased levels of G(C)>T(A) transversions in Rad18-/- tumors when compared with Rad18+/+. Therefore, Rad18 promotes error-free bypass of 4NQO-induced DNA lesions and suppresses 4NQO-induced oral carcinogenesis. In a KrasG12D-induced lung carcinogenesis model, Rad18-deficiency did not affect rates or incidence of oncogene-induced lung tumors or mutations. Taken together, we demonstrate that Rad18 has context-specific tumor-suppressive activity. Given the prevalence of 4NQO-like environmental exposures, RAD18 is highly likely to shape human cancer genomes and perhaps influence other aspects of the tumorigenic process.

cancer biology↗

bioRxiv2025

Ontogeny of the vagal gut-brain axis

Gut-brain communication is a key component of homeostasis which regulates behaviors such as appetite and reward. Intestinal entero-endocrine cells (EECs) translate nutrient intake into signals which affect sensation and behavior, in part through synapse-like contacts with vagal nodose neurons. This direct neuroepithelial circuit regulates feeding (1-3), yet its genesis and role in higher order behaviors remains unknown. We find that EECs first contact nodose neurons in utero, and these interactions require brain-derived neurotrophic factor (BDNF). We show that BDNF regulates the dynamics of these interactions, which underlie EEC-evoked optogenetic excitation of the circuit. In addition to feeding, we discover that this circuit regulates sociability and inhibitory behavioral control. These studies define the ontogeny of a direct gut-brain circuit responsible for early physiology and behavior.

developmental biology↗

bioRxiv2024

Maramycin, a cytotoxic isoquinolinequinone terpenoid produced through heterologous expression of a bifunctional indole prenyltransferase /tryptophan indole-lyase in S. albidoflavus

Isoquinolinequinones represent an important family of natural alkaloids with profound biological activities. Heterologous expression of a rare bifunctional indole prenyltransferase /tryptophan indole-lyase enzyme from Streptomyces mirabilis P8-A2 in S. albidoflavus J1074 led to the activation of a putative isoquinolinequinone biosynthetic gene cluster and production of a novel isoquinolinequinone alkaloid, named maramycin (1). The structure of maramycin was determined by analysis of spectroscopic (1D/2D NMR) and MS spectrometric data. The prevalence of this bifunctional biosynthetic enzyme was explored and found to be a recent evolutionary event with only a few representatives in Nature. Maramycin exhibited moderate cytotoxicity against human prostate cancer cell lines, LNCaP and C4-2B. The discovery of maramycin (1) enriched the chemical diversity of natural isoquinolinequinones and also provided new insights into crosstalk between the host biosynthetic genes and the heterologous biosynthetic genes in generating new chemical scaffolds.

bioengineering↗

bioRxiv2024

Diversity and structure of the deep-sea sponge microbiome in the equatorial Atlantic Ocean

Sponges (phylum Porifera) harbour specific microbial communities that drive the ecology and evolution of the host. Understanding the structure and dynamics of these communities is emerging as a primary focus in marine microbial ecology research. Much of the work to date has focused on sponges from warm and shallow coastal waters, while sponges from the deep ocean remain less well-studied. Here, we present a metataxonomic analysis of the microbial consortia associated with 23 deep-sea sponges. We identify a high abundance of archaea relative to bacteria across these communities, with certain sponge microbiomes comprising more than 90% archaea. Specifically, the archaeal family Nitrosopumilaceae are prolific, comprising over 99% of all archaeal reads. Our analysis revealed sponge microbial communities mirror the host sponge phylogeny, indicating a key role for host taxonomy in defining microbiome composition. Our work confirms the contribution of both evolutionary and environmental processes to the composition of microbial communities in deep-sea sponges. ImportanceThe deep ocean is the largest biome on Earth, accounting for >90% of the planets marine environment. Despite this it remains a largely unexplored ecosystem, with less than 0.01% of the deep seafloor having been quantitatively sampled. Deep-sea sponges are ancient metazoans which harbour complex microbial communities and much still remains to be learned about the composition and diversity of these unique microbiomes. In an effort to address this, here we report a metataxonomic analysis of the microbial consortia associated with 23 deep-sea sponges from the equatorial Atlantic Ocean. Our findings reveal intricate, species-specific microbial communities dominated by ammonia-oxidizing archaea. This study highlights the significant role sponges play in shaping microbial consortia, providing new insights into deep-sea ecosystem dynamics. Importantly, our findings provide a scientific basis for understanding the evolutionary relationships between sponges and their symbiotic microorganisms.

microbiology↗

bioRxiv2022

Discovery and biosynthetic assessment of Streptomyces ortus sp nov. isolated from a deep-sea sponge

The deep sea is known to host novel bacteria with the potential to produce a diverse array of undiscovered natural products. Understanding these bacteria is thus of broad interest in ecology and could also underpin applied drug discovery, specifically in the area of antimicrobials. Here, we isolate a new strain of Streptomyces from the tissue of the deep-sea sponge Polymastia corticata collected at a depth of 1869 m from the Gramberg seamount in the Atlantic Ocean. This strain, which was given the initial designation A15ISP2-DRY2T, has a genome size of 9.29 Mb with a GC content of 70.83%. Phylogenomics determined that A15ISP2-DRY2T represents a novel species within the genus Streptomyces as part of the Streptomyces aurantiacus clade. The biosynthetic potential of A15ISP2-DRY2T was assessed relative to other members of the aurantiacus clade via comparative gene cluster family (GCF) analysis. This revealed a clear congruent relationship between phylogeny and GCF content. A15ISP2-DRY2T contains six unique GCFs absent elsewhere in the clade. Culture-based assays were used to demonstrate the antibacterial activity of A15ISP2-DRY2T against two drug-resistant human pathogens. We thus determine A15ISP2-DRY2T to be a novel bacterial species with considerable biosynthetic potential and propose the systematic name Streptomyces ortus sp. nov. Impact StatementThe Streptomyces genus has contributed more to our antibiotic arsenal than any other group of bacteria or fungi. Despite decades of exploration, global analysis has suggested they still possess more undiscovered biosynthetic diversity than any other bacterial group. Isolating novel species of Streptomyces is therefore a priority for antibiotic discovery. Here we isolate a novel strain from a deep-sea sponge and use comparative cluster analysis to identify six biosynthetic clusters unique to our deep-sea strain. This work demonstrates the utility of continuing to isolate novel Streptomyces strains for antibiotic discovery and, for the first time, we used species tree-gene cluster tree reconciliation to assess the contribution of vertical evolution on the biosynthetic gene cluster content of Streptomyces.

genomics↗

bioRxiv2022

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

Oriented cell divisions balance self-renewal and differentiation in stratified epithelia such as the skin epidermis. During peak epidermal stratification, the distribution of division angles among basal keratinocyte progenitors is bimodal, with planar and perpendicular divisions driving symmetric and asymmetric daughter cell fates, respectively. An apically-polarized, evolutionarily-conserved spindle orientation complex that includes the scaffolding protein LGN/Pins/Gpsm2 plays a central role in promoting perpendicular divisions and stratification, but little is known about the molecular regulation of planar divisions. Here, we demonstrate that the LGN paralog, AGS3/Gpsm1, is a novel negative regulator of LGN, and inhibits perpendicular divisions. Static and ex vivo live imaging reveal that AGS3 overexpression displaces LGN from the apical cortex and increases planar orientations, while AGS3 loss prolongs cortical LGN localization and leads to a perpendicular orientation bias. Genetic epistasis experiments in double mutants confirm that AGS3 operates through LGN. Finally, clonal lineage tracing shows that LGN and AGS3 promote asymmetric and symmetric fates, respectively, while also influencing differentiation through delamination. Collectively, these studies shed new light into how spindle orientation influences epidermal stratification.

developmental biology↗

bioRxiv2021

Long-term changes in populations of rainforest birds in the Australia Wet Tropics bioregion: a climate-driven biodiversity emergency

Many authors have suggested that the vulnerability of montane biodiversity to climate change worldwide is significantly higher than in most other ecosystems. Despite the extensive variety of studies predicting severe impacts of climate change globally, few studies have empirically validated the predicted changes in distribution and population density. Here, we used 17 years of bird monitoring across latitudinal/elevational gradients in the rainforest of the Australian Wet Tropics World Heritage Area to assess changes in local abundance and distribution. We used relative abundance in 1977 surveys across 114 sites ranging from 0-1500m above sea level and utilised a trend analysis approach (TRIM) to investigate elevational shifts in abundance of 42 species between 2000 - 2016. The local abundance of most mid and high elevation species has declined at the lower edges of their distribution by >40% while lowland species increased by up to 190% into higher elevation areas. Upland-specialised species and regional endemics have undergone dramatic population declines of almost 50%. The "Outstanding Universal Value" of the Australian Wet Tropics World Heritage Area, one of the most irreplaceable biodiversity hotspots on Earth, is rapidly degrading. These observed impacts are likely to be similar in many tropical montane ecosystems globally.

ecology↗

bioRxiv2020

The schizophrenia-associated variant in SLC39A8 alters N-glycosylation in the mouse brain

A missense mutation (A391T) in the manganese transporter SLC39A8 is strongly associated with schizophrenia in genomic studies, though the molecular connection to the brain remains hypothetical. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a knock-in mouse model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain. N-linked glycosylation was most significantly impaired, with effects differing between regions. RNAseq analysis showed negligible regional variation, consistent with changes in the activity of glycosylation enzymes rather than gene expression. Finally, nearly one third of detected glycoproteins were differentially N-glycosylated in the cortex, including members of several pathways previously implicated in schizophrenia such as cell adhesion molecules and neurotransmitter receptors. These findings provide a mechanistic link between a risk allele and biochemical changes in the brain, furthering our molecular understanding of the pathophysiology of schizophrenia.

neuroscience↗

bioRxiv2019

A schizophrenia risk locus alters brain metal transport and plasma glycosylation

A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers of disease. SummaryA common variant in the manganese transporter SLC39A8 is associated with numerous phenotypes including schizophrenia. Mealer et. al. presents an in-depth analysis of brain MRI and plasma glycomics in human carriers of the common variant, identifying several manganese-related changes with potential for diagnostic and therapeutic biomarker development.

biochemistry↗

bioRxiv2019

Telophase correction refines division orientation in stratified epithelia

During organogenesis, precise control of spindle orientation ensures a proper balance of proliferation and differentiation. In the developing murine epidermis, planar and perpendicular divisions yield symmetric and asymmetric fate outcomes, respectively. Classically, division axis specification involves centrosome migration and spindle rotation, events that occur early in mitosis. Here, we identify a previously uncharacterized orientation mechanism that occurs during telophase, correcting erroneous oblique orientations that unexpectedly persist into anaphase. The directionality of reorientation--towards either planar or perpendicular--correlates with the maintenance or loss of basal contact by the apical daughter. While the conserved scaffolding protein Pins/LGN is believed to function primarily through initial spindle positioning, we now show it also functions actively during telophase to reorient oblique divisions toward perpendicular. The ability to undergo telophase correction is also critically dependent upon an LGN-independent pathway involving the tension-sensitive adherens junction proteins vinculin, a-catenin and afadin, and correction directionality is influenced by local cell density. Failure of this reorientation mechanism impacts tissue architecture, as excessive oblique divisions induce precocious differentiation. The division orientation plasticity provided by telophase correction may provide a means for progenitors to dynamically respond to extrinsic cues provided by neighboring cells in order to adapt to local tissue needs.

cell biology↗