Biology subjects

Williams, G. R.

Publications and source records attributed to Williams, G. R..

8 recordsLinked to original sources

bioRxiv2026

First estimates of the population growth rate of the parasitic honey bee mite Tropilaelaps mercedesae in Apis mellifera colonies

A parasitic mite of honey bee brood (Tropilaelaps mercedesae), is spreading through populations of Apis mellifera honey bees in new regions and poses a major threat to honey bee health. Despite its clear threat, the biology of this mite is poorly understood, with gaps on such fundamental issues as how fast its populations can grow. This leaves the beekeeping world underprepared to plan for its arrival and management. In this study, we documented the growth of T. mercedesae populations in untreated A. mellifera colonies in Thailand and South Korea, and did the same for another parasitic mite (Varroa destructor) when possible. We found that the population growth of T. mercedesae was variable but could reach high levels (daily r of 0.010, 0.036, and 0.057), while the population growth of V. destructor (r = 0.021) matched previous estimates. Our results indicate that T. mercedesae populations can grow rapidly but they do not always attain this potential. Based on our results, humidity should be studied as a potential driver of population growth. If future work can reveal key drivers of T. mercedesae population growth, this would help predict infestations and help design management strategies that exploit the pests biological vulnerabilities.

zoology↗

bioRxiv2026

Poly(acrylamido) PEG-alternatives Enhance mRNA-LNP Efficacy in Immune Cells and Evade anti-PEG Antibodies During Repeated Dosing

Following the successes of the messenger RNA (mRNA) lipid nanoparticle (LNP) vaccines during the COVID-19 pandemic, mRNA-LNPs are being explored for many critical disease indications including infectious disease vaccination, cancer immunotherapies, and protein replacement therapies. LNPs require a polymer coating to provide stability in storage, and to minimise clearance from the body by reducing protein adsorption after injection. Poly(ethylene glycol)-lipids (PEG-lipids) have fulfilled this role to date, however increasing prevalence of antibodies against PEG in the general population jeopardises the efficacy of future PEGylated LNP doses and increases the likelihood of adverse pseudo-allergic responses. There is, therefore, an urgent unmet need to develop LNPs with new surfaces of PEG-alternative polymers which can evade anti-PEG antibodies, particularly where repeat dosing is required. Here, we present a family of polymer lipids, poly(acrylamido) (PAM) lipids, which effectively replace conventional PEG-lipids in mRNA-LNP formulations. We identify key design parameters to show that PAM-lipid monomer chemistry, molar mass and end-group all have critical effects on LNP size, polydispersity and in vitro transfection efficiencies, while having little impact on LNP morphology or internal structure. We determine that side-group (monomer) chemistry is a key mediator in alleviating anti-polymer antibody cross-reactivity. Compared to clinical benchmark PEGylated LNPs, several PAM-LNPs displayed improved transfection efficacy across multiple mRNA cargos in diverse cell types, organs, and routes of administration, both in vitro and in vivo. In particular, mRNA transfection improved in immune cells both in vitro (up-to 120-fold), and in vivo (up-to 5-fold), including superior mRNA expression in lymph nodes (2.5-fold). In part, this is likely because PAMs increase LNP uptake/association with primary immune cells (BMDCs), and increase biodistribution to the lymphoid tissues (LNs, spleen). Crucially, PAM-LNPs avoid circulating anti-PEG antibodies to recover lost mRNA efficacy after repeated dosing in vivo, 300% higher than PEG-LNPs. Overall, our findings establish the PAM-lipid family as a versatile platform of chemically varied PEG-alternatives, towards the next generation of therapeutic mRNA-LNP technologies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/708093v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@107de1aorg.highwire.dtl.DTLVardef@186b6eforg.highwire.dtl.DTLVardef@1542371org.highwire.dtl.DTLVardef@e2d47f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Design and development of a SARS and MERS Combination Vaccine

This work was conducted during the COVID-19 pandemic prior to the licensing of any vaccines against COVID-19. Although several COVID-19 vaccines are now commercially available, this research on the development of a combination Severe Acute Respiratory Syndrome-associated Coronavirus (SARS-CoV), SARS-coronavirus 2 (SARS-CoV-2), and Middle Eastern Respiratory Syndrome (MERS) is still relevant and shows how a combination vaccine can be designed, produced and rapidly tested in the laboratory. We present the development of a combination vaccine designed to provide immunity against Severe Acute Respiratory Syndrome-associated Coronavirus (SARS-CoV), SARS-coronavirus 2 (SARS-CoV-2), and Middle Eastern Respiratory Syndrome (MERS). The primary objective of this vaccine design is twofold: to mitigate the burden of coronavirus and to address the specific vulnerability of regions prone to recurrent MERS outbreaks. Our combination vaccine incorporates antigenic components from zoonotic sources, specifically SARS-CoV, SARS-CoV-2, and MERS. We assess the impact of combining different Spike proteins S1 subunit antigens, due to its recognised immunogenic potential, and adjuvants on serum antibody titres, virus neutralizing capabilities, and inter-antigen immune responses. We report a robust and broad antibody response against SARS-CoV-2 and related coronaviruses, which was amplified by different adjuvant formulations, including alum, MPLA, CpG, and Squalene-in-Water Emulsion.

immunology↗

bioRxiv2024

Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease

Musculoskeletal diseases are a major health burden. Development of bone-active therapies has been hindered by limited understanding of the cells and genes that regulate the skeleton. We exploited the value of cross-species analysis and developed single-cell methodologies in skeletal tissues to define the critical endosteal compartment that regulates bone turnover. Thirty-four distinct cell types were identified, and disease-relevant cells prioritised by enrichment for rare skeletal disorder genes and bone mineral density-associated genes in an extended UK Biobank GWAS. Functional validation was undertaken in over one thousand genetically modified mouse models. Endothelial and vascular smooth muscle cells were identified as novel skeletal disease-relevant cells alongside osteoblast, chondrocyte and osteoclast cell lineages. Hundreds of cell-specific genes with unappreciated roles in skeletal pathophysiology were identified. This comprehensive cellular and molecular framework underpins skeletal physiology and disease, and will help prioritise new therapeutic targets to accelerate development of novel therapies to treat musculoskeletal disease.

genetics↗

bioRxiv2020

Osteocyte Transcriptome Mapping Identifies a Molecular Landscape Controlling Skeletal Homeostasis and Susceptibility to Skeletal Disease

Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this program is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P=2.4x10-22) and are associated with the polygenic diseases osteoporosis (P=1.8x10-13) and osteoarthritis (P=1.6x10-7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.

systems biology↗

bioRxiv2020

A trans-eQTL network regulates osteoclast multinucleation and bone mass

Functional characterisation of cell-type specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans-regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (Pik3cb-/-, Atp8b2+/-, Igsf8-/-, Eml1-/-, Appl2-/-, Deptor-/-) and myeloid-specific Slc40a1{Delta}LysMCre knockout mice displayed abnormal bone phenotypes. We report antagonizing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast fusion and bone mass. Impact statementWe took advantage of the osteoclast whose multinucleation properties correlate with bone mass. We show that a trans-regulated gene network (MMnet) controls skeletal homeostasis through osteoclast multinucleation and function.

cell biology↗

bioRxiv2019

Decoding the genomic basis of osteoarthritis

Osteoarthritis causes pain and functional disability for a quarter of a billion people worldwide, with no disease-stratifying tools nor modifying therapy. Here, we use primary cartilage and synovium from osteoarthritis patients to construct a molecular quantitative trait locus map of gene expression and protein abundance. By integrating data across omics levels, we identify likely effector genes for osteoarthritis-associated genetic signals. We detect pronounced molecular differences between macroscopically intact and highly degenerated cartilage. We identify molecularly-defined patient subgroups that correlate with clinical characteristics, stratifying patients on the basis of their molecular profile. We construct and validate a 7-gene classifier that reproducibly distinguishes between these disease subtypes, and identify potentially actionable compounds for disease modification and drug repurposing.

genomics↗

bioRxiv2019

Accelerating functional gene discovery in osteoarthritis

Osteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by Crispr/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.

genetics↗