Biology subjects

Thomson, K.

Publications and source records attributed to Thomson, K..

8 recordsLinked to original sources

bioRxiv2026

Skiaviridae: a large DNA virus family that persistently infects thraustochytrid protists

Genomics and metagenomics have transformed our understanding of the diversity of large DNA viruses infecting eukaryotic microorganisms. Using long-read sequencing, we discovered ubiquitous, co-culturing nucleocytoviruses in several thraustochytrid protists. These viruses are closely related to SmDNAV, an 'orphan' virus of the thraustochytrid Sicyoidochytrium minutum. Transcriptomics, proteomics and electron microscopy demonstrate viral gene expression and particle formation in these cultures without obvious defects in culture growth. We also found SmDNAV-type viruses associated with previously sequenced thraustochytrids. Phylogenetic analysis reveals that the SmDNAV and SmDNAV-like genomes belong to a hitherto unrecognized order of Nucleocytoviricota, here named "Skiavirales". All fifteen identified skiavirus genomes lack numerous viral hallmark genes including DNA-dependent RNA polymerase; all but three also lack DNA polymerase family B (PolB). PolB phylogeny suggests a specific relationship between Skiavirales and the recently discovered mirusviruses, which belong to a different viral realm. Gene exchange between skiaviruses, co-occurring mirusviruses, and host nuclear genomes shows that persistent infection by diverse large DNA viruses provides an opportunity for virus-virus and virus-host co-evolution in thraustochytrids and, perhaps, other microbial eukaryotes.

evolutionary biology↗

bioRxiv2024

An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten

The ALPK3 gene encodes alpha-protein kinase 3, a cardiac pseudo-kinase of unknown function. Heterozygous truncating variants (ALPK3tv) can cause dominant adult-onset Hypertrophic Cardiomyopathy (HCM). Here we confirm an excess of ALPK3tv in sarcomere-gene negative HCM patients. Moreover, we generated a novel knock-in mouse model carrying an ALPK3tv (K201X). Homozygous animals displayed hypertrophy and systolic dysfunction. Heterozygous animals demonstrated no obvious baseline; however, they had an aggravated hypertrophic response upon chronic adrenergic challenge. Isolated cardiomyocytes from heterozygous and homozygous mice showed reduced basal sarcomere length with prolonged relaxation, whilst calcium transients showed increased diastolic calcium levels and prolonged re-uptake. We also observed reduced fractional shortening. Protein kinase A-mediated phosphorylation, including that of cardiac troponin I, was significantly decreased. In agreement with the cellular HCM phenotype, reduced ratios of myosin heads in the super-relaxed state were measured. Contractile and calcium handling defects were partly corrected by treatment with mavacamten, a novel myosin inhibitor. For the first time with a non-sarcomere HCM variant, we have demonstrated hallmark changes in cardiac contractility and calcium handling, some resembling sarcomere-positive HCM, while others are distinct and DCM-like. Mavacamten is able to partially rescue the cellular phenotype, hence could be beneficial to HCM patients with ALPK3tv.

genetics↗

bioRxiv2021

'Superbugs: A Pop-up Science Shop': Increasing public awareness and knowledge of antimicrobial resistance by taking science to the city

Superbugs: A Pop-up Science Shop was a public engagement event in the school summer holidays of 2019, organised by members of Cardiff Universitys School of Medicine. We transformed an empty retail unit in the centre of Wales largest shopping centre into an interactive and immersive microbiology experience. We aimed to facilitate opportunities for two-way dialogue to impart positive impact on the awareness of antibiotic resistance, whilst concurrently evaluating the efficacy of an engagement strategy focused on the utilisation of public spaces to attract public demographics diverse to those who would normally engage with STEM outreach. Over the course of 14 days, we welcomed 6,566 visitors, with 67% attending as part of the natural footfall of the shopping centre. We created 1,625 young Antibiotic Resistance Champions, located in over 200 schools. Through a multi-lateral evaluation strategy, we were able to collect quantitative and qualitative feedback on the success of our delivery model, and the impact on our stakeholders. Herein, we will discuss the evolution of Superbugs from concept, planning and design, to the logistics of delivering an engagement event of this scale. We will focus in particular on the learning outcomes of the project, and how this will shape the future of our Superbugs project, and engagement events beyond. Key MessagesO_LICreating a multi-disciplinary core team is essential to the success of large-scale engagement events as well as the support and development of large numbers of colleagues/volunteers C_LIO_LIUtilising themes of exhibition and gameplay alongside strong fear-empowerment messages is an impactful way to confer positive influence and behaviour around antimicrobial resistance (AMR) and the use of antibiotics C_LIO_LI Pop-up shop is an effective mode of delivery to capture diverse public demographics far beyond those who would traditionally engage with scientific outreach and science engagement. C_LI

scientific communication and education↗

bioRxiv2021

Human interictal epileptiform discharges are traveling waves reflecting ictal self-organization

Interictal epileptiform discharges (IEDs), also known as interictal spikes, are large intermittent electrophysiological events observed between seizures in patients with epilepsy. Though they occur far more often than seizures, IEDs are less studied, and their relationship to seizures remains unclear. To better understand this relationship, we examined multi-day recordings of microelectrode arrays implanted in human epilepsy patients, allowing us to precisely observe the spatiotemporal propagation of IEDs, spontaneous seizures, and how they relate. These recordings showed that the majority of IEDs are traveling waves, traversing the same path as ictal discharges during seizures, and with a fixed direction relative to seizure propagation. Moreover, the majority of IEDs, like ictal discharges, were bidirectional, with one predominant and a second, less frequent antipodal direction. These results reveal a fundamental spatiotemporal similarity between IEDs and ictal discharges. These results also imply that most IEDs arise in brain tissue outside the site of seizure onset and propagate toward it, indicating that the propagation of IEDs provides useful information for localizing the seizure focus.

neuroscience↗

bioRxiv2020

Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs

The discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that represent the salient features of human pharmacoresistant epilepsy and employing these models for preclinical testing of investigational ASDs. One such model that has garnered increased interest in recent years is the mouse variant of the Intra-Amygdala Kainate (IAK) microinjection model of mesial temporal lobe epilepsy (MTLE). In establishing a version of this model, several methodological variables were evaluated for their effect(s) on pertinent quantitative endpoints. Although administration of a benzodiazepine 40 minutes after kainate (KA) induced status epilepticus (SE) is commonly used to improve survival, data presented here demonstrates similar outcomes (mortality, hippocampal damage, latency periods, and 90-day SRS natural history) between mice given midazolam and those that were not. Using a version of this model that did not interrupt SE with a benzodiazepine, a 90-day natural history study was performed and survival, latency periods, SRS frequencies and durations, and SRS clustering data were quantified. Finally, an important step towards model adoption is to assess the sensitivities or resistances of SRSs to a panel of approved and clinically used ASDs. Accordingly, the following ASDs were evaluated for their effects on SRSs in these mice: phenytoin (20 mg/kg, b.i.d.), carbamazepine (30 mg/kg, t.i.d.), valproate (240 mg/kg, t.i.d.), diazepam (4 mg/kg, b.i.d.), and phenobarbital (25 and 50 mg/kg, b.i.d.). Valproate, diazepam, and phenobarbital significantly attenuated SRS frequency relative to vehicle controls at doses devoid of observable adverse behavioral effects. Only diazepam significantly increased seizure freedom. Neither phenytoin nor carbamazepine significantly altered SRS frequency or freedom under these experimental conditions. These data demonstrate that SRSs in this IAK model of MTLE are pharmacoresistant to two representative sodium channel-inhibiting ASDs (phenytoin and carbamazepine) but not to GABA receptor modulating ASDs (diazepam and phenobarbital) or a mixed-mechanism ASD (valproate). Accordingly, this model is being incorporated into the NINDS-funded ETSP testing platform for treatment resistant epilepsy. HighlightsO_LIAn intra-amygdala kainate model of TLE was evaluated for pharmacoresistant seizures C_LIO_LIAdministration of midazolam during status epilepticus did not affect mortality C_LIO_LIModel characteristics were evaluated over a 90-day natural history study C_LIO_LISpontaneous seizures were resistant to phenytoin and carbamazepine C_LIO_LISpontaneous seizures were sensitive to valproic acid, diazepam, and phenobarbital C_LI

neuroscience↗

bioRxiv2020

Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans

Several related human coronaviruses (HCoVs) are endemic in the human population, causing mild respiratory infections1. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiologic agent of Coronavirus disease 2019 (COVID-19), is a recent zoonotic infection that has quickly reached pandemic proportions2,3. Zoonotic introduction of novel coronaviruses is thought to occur in the absence of pre-existing immunity in the target human population. Using diverse assays for detection of antibodies reactive with the SARS-CoV-2 spike (S) glycoprotein, we demonstrate the presence of pre-existing humoral immunity in uninfected and unexposed humans to the new coronavirus. SARS-CoV-2 S-reactive antibodies were readily detectable by a sensitive flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. These were predominantly of the IgG class and targeted the S2 subunit. In contrast, SARS-CoV-2 infection induced higher titres of SARS-CoV-2 S-reactive IgG antibodies, targeting both the S1 and S2 subunits, as well as concomitant IgM and IgA antibodies, lasting throughout the observation period of 6 weeks since symptoms onset. SARS-CoV-2-uninfected donor sera also variably reacted with SARS-CoV-2 S and nucleoprotein (N), but not with the S1 subunit or the receptor binding domain (RBD) of S on standard enzyme immunoassays. Notably, SARS-CoV-2-uninfected donor sera exhibited specific neutralising activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes, according to levels of SARS-CoV-2 S-binding IgG and with efficiencies comparable to those of COVID-19 patient sera. Distinguishing pre-existing and de novo antibody responses to SARS-CoV-2 will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.

immunology↗

bioRxiv2019

Enhanced prediction of gene and missense rare-variant pathogenicity by joint analysis of gene burden and amino-acid residue position

BackgroundAlthough rare-missense variants in Mendelian disease-genes have been noted to cluster in specific regions of proteins, it is not clear how to consider this information when evaluating the pathogenicity of a gene or variant. Here we introduce methods for gene-association and variant-interpretation that utilise this powerful signal. MethodsWe present a case-control rare-variant association test, ClusterBurden, that combines information on both variant-burden and variant-clustering. We then introduce a data-driven modelling framework to estimate mutational hotspots in genes with missense variant-clustering and integrate further in-silico predictors into the models. ResultsWe show that ClusterBurden can increase statistical power to scan for putative disease-genes, driven by missense variants, in simulated data and a 34-gene panel dataset of 5,338 cases of hypertrophic cardiomyopathy. We demonstrate that data-driven models can allow quantitative application of the ACMG criteria PM1 and PP3, to resolve a wide range of pathogenicity potential amongst variants of uncertain significance. A web application (Pathogenicity_by_Position) is accessible for missense variant risk prediction of six sarcomeric genes and an R package is available for association testing using ClusterBurden. ConclusionThe inclusion of missense residue position enhances the power of disease-gene association and improves rare-variant pathogenicity interpretation.

genetics↗

bioRxiv2019

CPO Complete, a novel test for fast, accurate phenotypic detection and classification of carbapenemases

Rapid, accurate detection of carbapenemase-producing organisms (CPOs) and the classification of their carbapenemases are valuable tools for reducing the mortality of the CPO-associated infections, preventing the spread of CPOs, and optimizing use of new {beta}-lactamase inhibitor combinations such as ceftazidime/avibactam and meropenem/vaborbactam. The current study evaluated the performance of CPO Complete, a novel, manual, phenotypic carbapenemase detection and classification test. The test was evaluated for sensitivity and specificity against 262 CPO isolates of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii and 67 non-CPO isolates. It was also evaluated for carbapenemase classification accuracy against 205 CPOs that produced a single carbapenemase class. The test exhibited 100% sensitivity 98.5% specificity for carbapenemase detection within 90 minutes and detected 74.1% of carbapenemases within 10 minutes. In the classification evaluation, 99.0% of carbapenemases were correctly classified. The test is technically simple and has potential for adaptation to automated instruments. With lyophilized kit storage at temperatures up to 38{degrees}C the CPO Complete test has the potential to provide rapid, accurate carbapenemase detection and classification in both limited resource and technologically advanced laboratories.

microbiology↗