Biology subjects

Williams, J. M.

Publications and source records attributed to Williams, J. M..

15 recordsLinked to original sources

bioRxiv2026

Lipid Network Crosslinked Hydrogels: Controlling MaterialDynamics Across Multiple Length Scales Through Lipid Movement

Control over network dynamics at different length scales is a feature of natural materials challenging to replicate in synthetic hydrogels. Hydrogel viscoelasticity is commonly controlled by tuning the kinetics of reversible crosslinks; however, this strategy inherently links the resulting macroscale and nanoscale dynamics of the individual network components. Taking inspiration from biological materials that feature lipids as structural elements, we introduce Lipid Network Crosslinked (LINC) hydrogels that exploit the mobility of individual lipids within self-assembled liposomes as covalent, network-crosslinking points. These mobile, covalent crosslinks increase hydrogel stress relaxation rates over 20-fold compared to polymer-only hydrogels with equivalent crosslinking chemistries and stiffnesses. We demonstrate that liposome design parameters, including degree of surface functionalization and tail saturation, provide a means to independently control the macroscale storage moduli and stress relaxation behavior. Finally, as an application where control over network dynamics at different length scales is critical, we placed cell-adhesive ligands onto more mobile or less mobile network elements. Human neural progenitor cells cultured within LINC hydrogels of identical macroscale viscoelasticity significantly altered their phenotype in response to nanoscale ligand dynamics. These results establish LINC hydrogels as biomimetic materials that leverage nanoscale lipid mobility within a macroscale polymeric network to control dynamics at multiple length scales.

bioengineering↗

bioRxiv2026

Quantitative determination of longitudinal CNS cholesterol loss during myelin damage and repair

1.Cholesterol in the central nervous system (CNS) is largely unesterified (>99%) and is predominantly present in the myelin sheath ([~]70% of total CNS cholesterol). Damage to the myelin sheath can result in the conversion of cholesterol to cholesterol esters, which occurs in many neurological diseases, including multiple sclerosis. In this study, we measured longitudinal CNS free cholesterol and cholesterol ester levels in a genetic mouse model during postnatal myelination, demyelination, and remyelination using gas chromatography-mass spectrometry with single ion monitoring technique (GC-MS-SIM) and liquid chromatography mass spectrometry (LC-MS). Cholesterol levels in healthy mouse brains increased up to 38 weeks. In contrast, cholesterol in the healthy spinal cord increased during postnatal timepoints, but then remained steady out to 38 weeks. Interestingly, cholesterol esters in the spinal cord were highest at P1 and drastically reduced by P42, while the brain had similar levels during all postnatal time points. During demyelination, both brain and spinal cord cholesterol levels were significantly reduced as compared to healthy mice and failed to return to normal cholesterol levels even during remyelination. Absolute quantification of cholesterol esters during peak demyelination revealed that cholesterol esters comprise 19% of the total cholesterol pool in the brain and 65% in the spinal cord. The lack of recovery in CNS cholesterol levels after demyelination suggests that healthy de novo cholesterol synthesis pathways are disrupted in this model. Absolute quantification of CNS cholesterol is critical for revealing mechanisms of cholesterol regulation during disease and identifying targets for restoring cholesterol to promote myelin repair.

neuroscience↗

bioRxiv2025

A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense.

Patients with systemic lupus erythematosus (SLE) are susceptible to bacterial infections, but the underlying dysfunction remains unclear. We found that Staphylococcus aureus triggers mitochondria-dependent suicidal NETosis via lactate sensing in healthy neutrophils, but this response is defective in SLE. Herein, we show that chronic Toll-like receptor (TLR) 7/9 signaling represses mitochondrial lactate dehydrogenase B (LDHB), thereby impairing lactate sensing and downstream suicidal NETosis. Instead, SLE neutrophils default to vital NET release; a less bactericidal, type I interferon (IFN)-driven process amplified by staphylococcal pore-forming toxins and sustained by elevated systemic IFN levels observed in SLE. Combined treatment with hydroxychloroquine (HCQ) and interferon-alpha/beta receptor (IFNAR) blockade restores LDHB expression, NET homeostasis, and bacterial clearance in lupus-prone mice. Neutrophils from SLE patients exhibit similar defects, which are reversed by HCQ and the IFNAR-blocking antibody anifrolumab. These findings identify a clinically actionable immunometabolic checkpoint linking chronic autoimmune signaling to defective antibacterial defense in SLE.

immunology↗

bioRxiv2025

Temporal dynamics of CNS cholesterol esters correlate with demyelination and remyelination

Elevated cholesterol ester levels have been observed in the CNS of patients with neurological diseases, yet the source of cholesterol ester accumulation and whether it is directly linked to demyelination remains undefined. This study investigates the temporal dynamics of cholesterol esters using the Plp1-iCKO-Myrf mouse model, which features distinct phases of demyelination and remyelination. Our findings reveal that cholesterol ester levels increased with demyelination in both the brain and the spinal cord. In the brain, cholesterol esters declined to normal levels during remyelination, whereas cholesterol esters remained elevated in the spinal cord, which had limited remyelination. Expression of both acetyl-CoA-acyltransferase 1 (ACAT1) and lecithin-cholesterol acyltransferase (LCAT) were elevated during demyelination, suggesting the potential involvement of both proteins in the formation of cholesterol esters. Co-localization studies revealed that ACAT1 is predominantly expressed by microglia and LCAT is predominantly expressed by astrocytes during demyelination highlighting the active roles of glia cells in cholesterol ester metabolism. In addition, we showed that administering the remyelinating drug, Sob-AM2, effectively reduced the level of cholesterol ester accumulation in the brain during demyelination underscoring the potential that manipulating cholesterol ester regulatory pathways may offer for restoring cholesterol homeostasis and promoting remyelination in demyelinating diseases.

neuroscience↗

bioRxiv2024

Making the Monitoring Framework of the Kunming-Montreal Global Biodiversity Framework fit for purpose.

The Kunming-Montreal Global Biodiversity Framework (GBF) is the most ambitious agreement on biodiversity conservation and sustainable use to date. It calls for a whole-of government and whole-of-society approach to halt and reverse biodiversity loss worldwide. The Monitoring Framework of the GBF lays out how Parties to the Convention on Biological Diversity (CBD) are expected to report their progress. A CBD expert group provided guidance on its implementation, including a gap analysis to identify the strengths and limitations of the indicators in the Monitoring Framework. We present the results of the gap analysis, highlight where more work is needed and provide recommendations on implementing and improving monitoring to allow effective and comprehensive tracking of the GBFs ambition. We find that with the headline and binary indicators, which Parties are required to use, the Monitoring Framework fully covers 19% of the GBFs ambition and partially covers an additional 40%. Including disaggregations of the headline indicators improves coverage to 22% fully and an additional 41% partially. Adding optional (component and complementary) indicators brings full coverage to 29% with an additional 47% partial coverage. No indicators are available for 12% of the GBF. In practice, the coverage of the Monitoring Framework will depend on which indicators (headline and binary as well as component and complementary) and disaggregations are used by countries. Disaggregations are particularly relevant to monitor the cross-cutting considerations defined under section C. Substantial investment is required to collect the necessary data to compute indicators, infer change, and effectively monitor progress. We highlight important next steps to progressively improve the efficacy of the Monitoring Framework.

ecology↗

bioRxiv2024

Millennial-scale societal shifts drive the widespread loss of a marine ecosystem

Degradation of marine ecosystems by human activities is a global problem, with only recent recognition that exploitation of ecosystems over millennia can result in their functional extinction and loss from human memory. To reconstruct the historical distribution of oyster reefs in China, and the context behind loss, we extracted information from archaeological records and historical documents (pre-modern Chinese literature, administration reports, art, maps, newspapers) spanning [~]7600 years, then constrained records with past coastlines and habitable environmental conditions. Oyster reefs were extensively distributed along >750 km of coastline in the Pearl River Delta, and their exploitation underpinned the regions development into Chinas first economic hub in the 6th century. Millennial-scale overexploitation alongside societal shifts were central in their regional extirpation by the 19th century, but the enduring cultural importance of oysters is maintained by aquaculture expansion. Informed conservation practices can be developed from reconstructing the temporal interplay between human societies and the natural environment.

ecology↗

bioRxiv2023

Lipidomic analysis reveals differences in the extent of remyelination in the brain and spinal cord

During demyelination, lipid-rich myelin debris is released in the central nervous system (CNS) and must be phagocytosed and processed before new myelin can form. Although myelin comprises over 70% lipids, relatively little is known about how the CNS lipidome changes during demyelination and remyelination. In this study, we obtained a longitudinal lipidomic profile of the brain, spinal cord, and serum using a genetic mouse model of demyelination, known as Plp1-iCKO-Myrf mice. This model has distinct phases of demyelination and remyelination over the course of 24 weeks, in which loss of motor function peaks during demyelination. Using principal component analysis (PCA) and volcano plots, we have demonstrated that the brain and spinal cord have different remyelination capabilities and that this is reflected in different lipidomic profiles over time. We observed that plasmalogens (ether-linked phosphatidylserine and ether-linked phosphatidylcholine) were elevated specifically during the early stages of active demyelination. In addition, we identified lipids in the brain that were altered when mice were treated with a remyelinating drug, which may be CNS biomarkers of remyelination. The results of this study provide new insights into how the lipidome changes in response to demyelination, which will enable future studies to elucidate mechanisms of lipid regulation during demyelination and remyelination.

neuroscience↗

bioRxiv2023

PAX8 and transient Wnt signalling are critical for induction and completion of human renal mesenchymal-to-epithelial transition

During kidney development, nephron epithelia arise de novo from fate-committed mesenchymal progenitors through a mesenchymal-to-epithelial transition (MET). Downstream of fate specification, transcriptional mechanisms that drive establishment of epithelial morphology through MET are poorly understood. We used human renal organoids derived from induced pluripotent stem cells, which recapitulate nephrogenesis, to investigate mechanisms controlling the renal MET programme. Multi-ome profiling of organoids revealed dynamic changes in gene expression and chromatin accessibility driven by transcriptional activators and repressors throughout renal MET. CRISPR-interference-based gene perturbation revealed that PAX8 is essential for initiation of MET in human renal organoids, contrary to mouse, by activating a cell adhesion programme. Furthermore, while Wnt/{beta}-Catenin signalling specifies nephron fate, we find that it must be attenuated to allow HNF1B and TEAD transcription factors to drive completion of MET. These results reveal how the developing kidney balances fate-commitment and morphogenesis with implications for understanding both developmental kidney diseases and aberrant epithelial plasticity following adult renal tubular injury.

developmental biology↗

bioRxiv2023

Trial Averaging for Deep EEG Classification

Many signals, particularly of biological origin, suffer from a signal-to-noise ratio sufficiently low that it can be difficult to classify individual examples reliably, even with relatively sophisticated machine-learning techniques such as deep learning. In some cases, the noise can be high enough that it is even difficult to achieve convergence during training. We considered this problem for one data type that often suffers from such difficulties, namely electroencephalography (EEG) data from cognitive neuroscience studies in humans. One solution to increase signal-to-noise is, of course, to perform averaging among trials, which has been employed before in other studies of human neuroscience but not, to our knowledge, investigated rigorously, particularly not in deep learning. Here, we parametrically studied the effects of different amounts of trial averaging during training and/or testing in a human EEG dataset, and compared the results to that of a related algorithm, Mixup. Broadly, we found that even a small amount of averaging could significantly improve classification, particularly when both training and testing data were subjected to averaging. Simple averaging clearly outperformed Mixup, although the benefits of averaging differed across classification categories. Overall, our results confirm the value of averaging during training and testing when single-trial classification is not strictly necessary for the application in question. HighlightsO_LIAveraging trials can dramatically improve performance in classification of EEG data C_LIO_LIThe benefits can be seen when averaging on both training and test datasets C_LIO_LISimple trial averaging outperformed a popular related algorithm, Mixup C_LIO_LIHowever, effects of averaging differed across different stimulus categories C_LI

neuroscience↗

bioRxiv2023

Intranasal mRNA-LNP vaccination protects hamsters from SARS-CoV-2 infection

Intranasal vaccination represents a promising approach for preventing disease caused by respiratory pathogens by eliciting a mucosal immune response in the respiratory tract that may act as an early barrier to infection and transmission. This study investigated immunogenicity and protective efficacy of intranasally administered messenger RNA (mRNA)-lipid nanoparticle (LNP) encapsulated vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Syrian golden hamsters. Intranasal mRNA-LNP vaccination systemically induced spike-specific binding (IgG and IgA) and neutralizing antibodies with similar robustness to intramuscular controls. Additionally, intranasal vaccination decreased viral loads in the respiratory tract, reduced lung pathology, and prevented weight loss after SARS-CoV-2 challenge. This is the first study to demonstrate successful immunogenicity and protection against respiratory viral infection by an intranasally administered mRNA-LNP vaccine.

immunology↗

bioRxiv2021

A single dose of replication-competent VSV-vectored vaccine expressing SARS-CoV-2 S1 protects against virus replication in a hamster model of severe COVID-19

The development of effective countermeasures against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the agent responsible for the COVID-19 pandemic, is a priority. We designed and produced ConVac, a replication-competent vesicular stomatitis virus (VSV) vaccine vector that expresses the S1 subunit of SARS-CoV-2 spike protein. We used golden Syrian hamsters as animal model of severe COVID-19 to test the efficacy of the ConVac vaccine. A single vaccine dose elicited high levels of SARS-CoV-2 specific binding and neutralizing antibodies; following intranasal challenge with SARS-CoV-2, animals were protected from weight loss and viral replication in the lungs. No enhanced pathology was observed in vaccinated animals upon challenge, but some inflammation was still detected. The data indicate rapid control of SARS-CoV-2 replication by the S1-based VSV-vectored SARS-CoV-2 ConVac vaccine.

immunology↗

bioRxiv2021

A workflow for simultaneous detection of coding and non-coding transcripts by ribosomal RNA-depleted RNA-Seq.

RNA sequencing offers unprecedented access to the transcriptome. Key to this is the identification and quantification of many different species of RNA from the same sample at the same time. In this study we describe a novel protocol for simultaneous detection of coding and non-coding transcripts using modifications to the Ion Total RNA-Seq kit v2 protocol, with integration of QIASeq FastSelect rRNA removal kit. We report highly consistent sequencing libraries can be produced from both frozen high integrity mouse hippocampal tissue and the more challenging post-mortem human tissue. Removal of rRNA using FastSelect was highly efficient, resulting in less than 1.5% rRNA content in the final library, significantly better than other reported rRNA removal techniques. We identified >30,000 unique transcripts from all samples, including protein-coding genes and many unique species of non-coding RNA, in biologically-relevant proportions. Furthermore, normalized sequencing read count for select genes significantly negatively correlated with Ct values from RT-qPCR analysis from the same samples. These results indicate that this protocol accurately and consistently identifies and quantifies a wide variety of transcripts simultaneously. The highly efficient rRNA depletion, coupled with minimized sample handling and without complicated and high-loss size selection protocols, makes this protocol useful to researchers wishing to investigate whole transcriptomes.

molecular biology↗

bioRxiv2020

Deep-Learning-Based Multivariate Pattern Analysis (dMVPA): A Tutorial and a Toolbox

In recent years, multivariate pattern analysis (MVPA) has been hugely beneficial for cognitive neuroscience by making new experiment designs possible and by increasing the inferential power of functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and other neuroimaging methodologies. In a similar time frame, "deep learning" (a term for the use of artificial neural networks with convolutional, recurrent, or similarly sophisticated architectures) has produced a parallel revolution in the field of machine learning and has been employed across a wide variety of applications. Traditional MVPA also uses a form of machine learning, but most commonly with much simpler techniques based on linear calculations; a number of studies have applied deep learning techniques to neuroimaging data, but we believe that those have barely scratched the surface of the potential deep learning holds for the field. In this paper, we provide a brief introduction to deep learning for those new to the technique, explore the logistical pros and cons of using deep learning to analyze neuroimaging data - which we term "deep MVPA," or dMVPA - and introduce a new software toolbox (the "Deep Learning In Neuroimaging: Exploration, Analysis, Tools, and Education" package, DeLINEATE for short) intended to facilitate dMVPA for neuroscientists (and indeed, scientists more broadly) everywhere.

neuroscience↗

bioRxiv2018

Oral iron exacerbates colitis and influences the intestinal microbiome

Inflammatory bowel disease (IBD) is associated with anaemia and oral iron replacement to correct this can be problematic, intensifying inflammation and tissue damage. The intestinal microbiota also plays a key role in the pathogenesis of IBD, and iron supplementation likely influences gut bacterial diversity in patients with IBD. Here, we assessed the impact of dietary iron, using chow diets containing either 100, 200 or 400 ppm, fed ad libitum to adult female C57BL/6 mice in the presence or absence of colitis induced using dextran sulfate sodium (DSS), on (i) clinical and histological severity of acute DSS-induced colitis, and (ii) faecal microbial diversity, as assessed by sequencing the V4 region of 16S rRNA. Increasing or decreasing dietary iron concentration from the standard 200 ppm exacerbated both clinical and histological severity of DSS-induced colitis. DSS-treated mice provided only half the standard levels of iron ad libitum (i.e. chow containing 100 ppm iron) lost more body weight than those receiving double the amount of standard iron (i.e. 400 ppm); p<0.01. Faecal calprotectin levels were significantly increased in the presence of colitis in those consuming 100 ppm iron at day 8 (5.94-fold) versus day-10 group (4.14-fold) (p<0.05), and for the 400 ppm day-8 group (8.17-fold) versus day-10 group (4.44-fold) (p<0.001). In the presence of colitis, dietary iron at 400 ppm resulted in a significant reduction in faecal abundance of Firmicutes and Bacteroidetes, and increase of Proteobacteria, changes which were not observed with lower dietary intake of iron at 100 ppm. Overall, altering dietary iron intake exacerbated DSS-induced colitis; increasing the iron content of the diet also led to changes in intestinal bacteria diversity and composition after colitis was induced with DSS.

physiology↗

bioRxiv2017

Mice lacking NF-κB1 exhibit marked DNA damage responses and more severe gastric pathology in response to parenteral tamoxifen administration.

BackgroundTamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-{kappa}B subunits. Nfkb1-/- mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2-/- mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF-{kappa}B subunits.\n\nMethodsGroups of 5 female C57BL/6 (WT), Nfkb1-/-, Nfkb2-/- and c-Rel-/- mice were administered 150mg/kg TAM by IP injection. 72 hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of 6 female WT and Nfkb1-/- mice were exposed to 12Gy {gamma}-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 hours after irradiation.\n\nResultsTAM induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1-/- mice than WT mice. Nfkb1-/- mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by {gamma}H2AX. To determine investigate whether the difference in gastric epithelial DNA damage response of Nfkb1-/- mice was unique to TAM induced DNA damage, or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following {gamma}-irradiation. 6 hours after {gamma}-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1-/- mice.\n\nConclusionsNF-{kappa}B1 mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1-/- mice to DNA damage.

immunology↗