Biology subjects

Newton, R.

Publications and source records attributed to Newton, R..

10 recordsLinked to original sources

bioRxiv2026

The nuclear transport receptor Impβ is a regulator of actin polymerization

Nuclear transport receptors are best known for mediating nucleocytoplasmic transport (NCT) through nuclear pore complexes. Here, we uncover an unexpected function of the primary import receptor importin-{beta} (Imp{beta}) as a direct regulator of the actin cytoskeleton. Imp{beta} associates with stress fibers and the cell cortex and promotes actin polymerization through direct interactions. Disrupting Imp{beta}-actin binding impairs stress fiber formation and suppresses cell migration well before NCT is affected. In 3D spheroids, perturbing Imp{beta} further compromises tissue integrity, as reflected in changes to nuclear curvature and ellipticity. Together, these findings identify Imp{beta} as a regulator of actin organization in both 2D and 3D contexts, revealing a direct link between the nuclear transport machinery and the cytoskeleton.

cell biology↗

bioRxiv2025

Inflammatory cytokines promote interferon regulatory factor (IRF) transcriptional activity in human pulmonary epithelial cells through the induction of IRF1 by nuclear factor-κB

Transcription factors of the interferon regulatory factor (IRF) family play key roles during viral and bacterial infections. However, IRF regulation by inflammatory cytokines, including interleukin (IL)-1{beta} and tumor necrosis factor (TNF) , remains underexplored. Since airway epithelial cells (AECs) modulate lung inflammation, IRF expression was characterized in pulmonary A549 and bronchial BEAS-2B epithelial cells, plus primary human AECs grown in submersion or highly differentiated air-liquid interface culture. Whereas most IRF mRNAs were expressed across models, IRF4 and IRF8 showed consistently low expression, and IRF6 was only expressed highly in primary cells. IRF3 and IRF9 were highly expressed in each model, and while protein expression was confirmed in A549 cells, this remained primarily cytoplasmic post-IL-1{beta} treatment. IRF2 was constitutively nuclear in A549 cells and showed moderate/high mRNA expression in each model. IRF1 mRNA was induced by IL-1{beta}-in primary and A549 cells, where IL-1{beta} and TNF dramatically increased IRF1 protein expression. TNF also increased IRF1 protein in BEAS-2B cells. In A549 cells, an IRF reporter system combined with RNA silencing did not support transcriptional roles for IRF2 or IRF3 but suggested a modest role for IRF9 following IL-1{beta} stimulation. IL-1{beta}-induced IRF1 localized to the nucleus of A549 cells revealing a major transcriptional role. IRF1 expression induced by IL-1{beta}/TNF required NF-{kappa}B and four novel 5' enhancer regions to IRF1 bound the NF-{kappa}B subunit, p65. These regions drove IL-1{beta}/TNF-inducible reporter activity via consensus NF-{kappa}B motifs. Three such regions recruited RNA polymerase-2 and were flanked by the active chromatin mark, histone 3 lysine 27 acetylation which, given the high levels of genetic conservation, support involvement in IRF1 transcription. Finally, IRF1 expression, transcription rate, and enhancer activity induced by IL-1{beta}/TNF were relatively unaffected by glucocorticoid co-treatment. IRF1-dependent gene expression could therefore be insensitive to glucocorticoid and may contribute to glucocorticoid-resistant diseases such as severe asthma.

molecular biology↗

bioRxiv2022

Emerging variants of canine enteric coronavirus associated with seasonal outbreaks of severe canine gastroenteric disease

Canine enteric coronavirus (CECoV) variants have an emerging role in severe outbreaks of canine gastroenteritis. Here we used syndromic health data from a sentinel network of UK veterinary practices to identify an outbreak of severe canine gastroenteritis. Affected dogs frequently presented with vomiting, diarrhoea and inappetence. Data from sentinel diagnostic laboratories showed similar seasonal increases in CECoV diagnosis. Membrane glycoprotein (M) gene sequence analysis implied wide geographical circulation of a new CECoV variant. Whole genome sequencing suggested the main circulating 2022 variant was most closely related to one previously identified in 2020 with additional spike gene recombination; all variants were unrelated to CECoV-like viruses recently associated with human respiratory disease. Identifying factors that drive population-level evolution, and its implications for host protection and virulence, will be important to understand the emerging role of CECoV variants in canine and human health, and may act as a model for coronavirus population adaptation more widely.

genomics↗

bioRxiv2021

Seed-coat thickness explains contrasting germination responses to smoke and heat by Leucadendron species

Fire stimulates germination of most seeds in fire-prone vegetation. Fruits of Leucadendron (Proteaceae) are winged achenes or nutlets that correlate with their requirements for smoke and/or heat in promoting germination. We describe five possible smoke-heat dormancy-release/germination syndromes among plants, of which Leucadendron displays three (no response, smoke only, smoke and heat). As seed-coat thickness varies with seed-storage location (plant or soil) and morphology (winged or wingless), we tested its possible role in water uptake and germination. Species with winged seeds achieved 100% germination in the absence of smoke/heat, seed coats were an order of magnitude thinner, and their permeability greatly exceeded that of nutlets. As seed-coat thickness increased a) imbibitional water uptake declined at a decreasing rate, and b) the response to smoke, and to a lesser extent heat, increased linearly to reach levels of germination approaching those of winged seeds. For species responsive to smoke and heat, there was no additive effect when applied together, suggesting that they may have promoted the same physiological process. By what mechanisms a) the smoke response is greater the thicker the seed coat, and b) smoke chemicals could increase water permeability to explain the non-additive effect of smoke and heat, warrant further investigation. HighlightWe show Leucadendron seeds are either plant-stored with thin, highly permeable seed-coats that germinate readily; or soil-stored and the thicker their seed-coat, the lower their permeability and greater their need for smoke/heat to promote germination.

plant biology↗

bioRxiv2021

Antibody response patterns to Helicobacter pylori infection in a rural Ugandan population cohort.

BackgroundHelicobacter pylori (H. pylori) establishes life-long infection in humans in the absence of treatment and has been associated with a variety of gastrointestinal conditions including peptic ulcer and gastric cancer. Antibody responses to H. pylori antigens are found to be associated with disease risk, however, data from Africa are scarce. MethodsTo assess the seroprevalence of H. pylori and characterise antibody response patterns, we measured serum IgG antibody levels to 14 antigens among 7,211 individuals in a rural Ugandan population cohort. Multivariate-adjusted linear regression models were fitted to investigate the influence of age, sex, and co-infection on antibody seroreactivity levels. ResultsH. pylori seroprevalence was 95% in our study population, with 94% of individuals seropositive in childhood (<15 years). In H. pylori positive individuals, we found a markedly high seroprevalence (~99%) and antibody levels to the high-risk antigens CagA and VacA, in addition to Cag{delta}. HSV-2 co-infection was significantly associated with higher IgG levels of CagA and VacA (OR=1.10, 95% C. I=1.05-1.16). HIV infection was associated with lowered IgG levels to CagA (OR=0.86, 95% C.I.=0.80-0.93), and HPV infection was associated with increased IgG levels to VacA (OR=1.16, 95% C.I.=1.11-1.21). ConclusionsH. pylori in this population is ubiquitous from childhood, with a high prevalence and high seroreactivity levels of high-risk antigens, suggesting chronic active inflammatory responses in individuals that are indicative of risk of disease. Further investigation is warranted to fully understand the relationship between host, immunogenicity, and clinical outcomes to better stratify by risk and improve treatment. Key MessagesO_LIAntibody responses to H. pylori antigens are found to be associated with risk of gastric cancer, however, despite the high seroprevalence in African populations, data from Africa are scarce. This is the first study of antibody response patterns and their determinants from an African population. C_LIO_LIOur study shows a population where H. pylori is ubiquitous from childhood, and seroprevalence of virulent antigens is distinctively high suggesting an increased of disease compared to other populations. C_LIO_LIWe observe inter-individual variation in virulent antibody responses partly influenced by co-infection. C_LIO_LIWe highlight crucial insights into antibody-based biomarkers of disease risk and reinforce the need for population-based H. pylori screening and treatment programmes for gastric cancer control. C_LI

immunology↗

bioRxiv2020

Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

Genome-wide association studies (GWAS) for kidney function have uncovered hundreds of risk loci, primarily in populations of European ancestry. We conducted the first GWAS of estimated glomerular filtration rate (eGFR) in Africa in 3288 Ugandans and replicated the findings in 8224 African Americans. We identified two loci associated with eGFR at genome-wide significance (p<5x10-8). The most significantly associated variant (rs2433603, p=2.4x10-9) in GATM was distinct from previously reported signals. A second association signal mapping near HBB (rs141845179, p=3.0x10-8) was not significant after conditioning on a previously reported SNP (rs334) for eGFR. However, fine-mapping analyses highlighted rs141845179 to be the most likely causal variant at the HBB locus (posterior probability of 0.61). A trans-ethnic GRS of eGFR constructed from previously reported lead SNPs was not predictive into the Ugandan population, indicating that additional large-scale efforts in Africa are necessary to gain further insight into the genetic architecture of kidney disease.

genetics↗

bioRxiv2019

HBV seroepidemiology data for Africa provides insights into transmission and prevention

International goals for elimination of hepatitis B virus (HBV) infection set ambitious targets for 2030. In many African populations, HBV prevalence remains high ([≥]8%) despite the roll-out of infant HBV immunisation from the mid-1990s onwards. Enhanced efforts are now urgently required to improve an understanding of population epidemiology, in order to determine which interventions are most likely to be effective in advancing populations towards elimination goals. In populations with a high prevalence of infection, catch-up HBV vaccination of adults has sometimes been deployed as a preventive strategy. An alternative approach of test and treat could be applied as a tool to interrupt transmission. We used a systematic approach to investigate the relationship between prevalence of HBV infection (HBsAg) and exposure (anti-HBc) in Africa, and then applied a mathematical model to investigate the impact of catch-up vaccination and a test and treat strategy in Uganda, representing a high prevalence setting. We demonstrate a strong relationship between the prevalence of HBsAg and anti-HBc (p<0.0001), but with region-specific differences that may reflect different patterns of transmission. In high prevalence settings, catch-up vaccination may have a transient effect but this intervention does not contribute to a sustained decline in prevalence. In contrast, diagnosing and treating infection has a marked impact on reducing prevalence, equivalent to that of infant immunisation. Conclusion: We have developed a high-resolution picture of HBV epidemiology across Africa. Developing insights into regional differences provides an evidence base for the most effective interventions. In combination with robust neonatal immunisation programmes, testing and treating infection is likely to be of most impact in making advances towards elimination targets.

epidemiology↗

bioRxiv2017

Hepatitis B Virus Infection as a Neglected Tropical Disease

BACKGROUND BACKGROUND CURRENT STRATEGIES FOR HBV... APPLICATION OF NTD CRITERIA... RECOMMENDATIONS BASED ON NTD... CONCLUSIONS SUPPORTING INFORMATION LEGEND REFERENCES The Global Hepatitis Health Sector Strategy is aiming for elimination of viral hepatitis as a public health threat by 2030 [1], while enhanced elimination efforts for hepatitis are also promoted under the broader remit of global Sustainable Development Goals (SDGs) [2]. This is an enormous challenge for hepatitis B virus (HBV) given the estimated global burden of 260 million chronic carriers, of whom the majority are unaware of their infection [3] (Figure 1).\n\nWe here present HBV within the framework for ...

microbiology↗

bioRxiv2017

A Comparison Of Machine Learning And Bayesian Modelling For Molecular Serotyping

BackgroundStreptococcus pneumoniae is a human pathogen that is a major cause of infant mortality. Identifying the pneumococcal serotype is an important step in monitoring the impact of vaccines used to protect against disease. Genomic microarrays provide an effective method for molecular serotyping. Previously we developed an empirical Bayesian model for the classification of serotypes from a molecular serotyping array. With only few samples available, a model driven approach was the only option. In the meanwhile, several thousand samples have been made available to us, providing an opportunity to investigate serotype classification by machine learning methods, which could complement the Bayesian model.\n\nResultsWe compare the performance of the original Bayesian model with two machine learning algorithms: Gradient Boosting Machines and Random Forests. We present our results as an example of a generic strategy whereby a preliminary probabilistic model is complemented or replaced by a machine learning classifier once enough data are available. Despite the availability of thousands of serotyping arrays, a problem encountered when applying machine learning methods is the lack of training data containing mixtures of serotypes; due to the large number of possible combinations. Most of the available training data comprises samples with only a single serotype. To overcome the lack of training data we implemented an iterative analysis, creating artificial training data of serotype mixtures by combining raw data from single serotype arrays.\n\nConclusionsWith the enhanced training set the machine learning algorithms out perform the original Bayesian model. However, for serotypes currently lacking sufficient training data the best performing implementation was a combination of the results of the Bayesian Model and the Gradient Boosting Machine. As well as being an effective method for classifying biological data, machine learning can also be used as an efficient method for revealing subtle biological insights, which we illustrate with an example.

genomics↗

bioRxiv2017

gene-cocite: a web application for extracting, visualising and assessing the cocitations of a list of genes

BackgroundThe outcome from the analysis of high through-put genomics experiments is commonly a list of genes. The most basic measure of association is whether the genes in the list have ever been cocited together.\n\nResultsThe web application gene-cocite accepts a list of genes and returns a list of the papers which cocite any two or more of the genes. The proportion of the genes which are cocited with at least one other gene is given, and the p-value for the probability of this proportion of cocitations occurring by chance from a random list of genes of the same length calculated. An interactive graph with links to papers is displayed, showing how the genes in the list are related to each other by publications.\n\nConclusionsgene-cocite (http://sysbio.mrc-bsu.cam.ac.uk/gene-cocite) is designed to be an easy to use first step for biological researchers investigating the background of their list of genes.

bioinformatics↗