Biology subjects

French, R.

Publications and source records attributed to French, R..

9 recordsLinked to original sources

bioRxiv2026

Co-infections and cryptic pathogens uncovered by metatranscriptomics in New Zealands severe acute respiratory infections

Severe acute respiratory infections (SARI) are a leading cause of hospitalisation and mortality globally. Many SARI cases remain undiagnosed because kit-based PCR diagnostic panels are typically limited to one or a small number of known pathogens and may fail to identify low-abundance infections or novel, poorly characterised organisms. Here, we used metatranscriptomic sequencing to profile the total infectome of 300 PCR-negative SARI nasopharyngeal samples collected through sentinel hospital-based surveillance in New Zealand between 2014-2021. Our analysis revealed actively transcribing potential pathogens in 43% of SARI cases, comprising 10 RNA viruses, three DNA viruses, nine bacterial species and four fungal species. Notably, co-infections occurred in 26% of cases, revealing polymicrobial infections missed by routine diagnostics. Human rhinoviruses were the most frequently identified, despite not being detected by PCR, and multiple common-cold coronaviruses, human parechovirus A1 and parainfluenza virus type 4, were identified, although these were not included in the PCR screening panel. We also detected a range of bacterial and fungal species and uncovered highly expressed virulence and antimicrobial resistance genes. Infectome composition and diversity were shaped by key demographic and epidemiological factors, with strongest effects observed for age and year of sample collection, indicating that host characteristics and temporal dynamics influence both microbial richness and community structure. These findings highlight the limitations of current diagnostic strategies and the value of metatranscriptomics for comprehensive microbial identification. Integrating such genomic approaches into both clinical and public health frameworks could improve diagnostic accuracy, enabling more sensitive detection and characterisation of potential pathogens while also strengthening surveillance and outbreak response.

genomics↗

bioRxiv2025

5-ethynyluridine perturbs nuclear RNA metabolism to promote the nuclear accumulation of TDP-43 and other RNA binding proteins

TDP-43, an essential nucleic acid binding protein and splicing regulator, is broadly disrupted in neurodegeneration. TDP-43 nuclear localization and function depend on the abundance of its nuclear RNA targets and its recruitment into large ribonucleoprotein complexes, which restricts TDP-43 nuclear efflux. To further investigate the interplay between TDP-43 and nascent RNAs, we aimed to employ 5-ethynyluridine (5EU), a widely used uridine analog for click chemistry labeling of newly transcribed RNAs. Surprisingly, 5EU induced the nuclear accumulation of TDP-43 and other RNA-binding proteins and attenuated TDP-43 mislocalization caused by disruption of the nuclear transport apparatus. RNA FISH demonstrated 5EU-induced nuclear accumulation of polyadenylated and GU-repeat-rich RNAs, suggesting increased retention of both processed and intronic RNAs. TDP-43 eCLIP confirmed that 5EU preserved TDP-43 binding at predominantly GU-rich intronic sites. RNAseq revealed significant 5EU-induced changes in alternative splicing, accompanied by an overall reduction in splicing diversity, without any major changes in RNA stability or TDP-43 splicing regulatory function. These data suggest that 5EU may impede RNA splicing efficiency and subsequent nuclear RNA processing and export. Our findings have important implications for studies utilizing 5EU and offer unexpected confirmation that the accumulation of endogenous nuclear RNAs promotes TDP-43 nuclear localization.

cell biology↗

bioRxiv2024

Linking phenology, harvest index and genetics to improve chickpea grain yield

Phenology is critical to crop adaptation. We grew 24 chickpea genotypes in 12 environments to analyse: the environmental and genotypic drivers of phenology; associations between phenology and yield; and phenotypes associated with allelic variants of three flowering related candidate loci: CaELF3a; a cluster of three FT genes on chromosome 3; and a region on chromosome 4 with an orthologue of the floral promoter GIGANTEA. A simple model with 3 genotype-specific parameters explained the differences in flowering response to daylength. Environmental factors causing flower abortion, such as low temperature and radiation and high humidity, led to a longer flowering-to-podding interval. Late podding associated with poor partition to grain, limiting yield in favourable environments. Sonali, carrying the early allele of Caelf3a (elf3a), was generally the earliest to set pod, had low biomass but the highest harvest index. Genotypes combining the early variants of GIGANTEA and FT orthologues FTdel, where a deletion in the intergenic region of FTa1-FTa2 was associated with slow development, usually featured early reproduction and high harvest index, returning high yield in favourable environments. We emphasise the importance of pod set, rather than flowering, as a target for breeding, agronomic, and modelling applications. HighlightThis paper analyses the environmental and genetic controls of chickpea phenology and its effects on grain yield, in a multi-environment trial including 24 genotypes with varying combinations of flowering related genes.

plant biology↗

bioRxiv2024

The Discovery of Small Molecule Inhibitors of cFLIP that Sensitise Tumour Cells to TRAIL

The TNF-related apoptosis-inducing ligand (TRAIL) has potential as a therapeutic agent as it has previously been shown to induce apoptosis in triple-negative breast cancer. Recombinant human TRAIL has shown promise in pre-clinical studies of breast cancer. TRAIL exhibits specificity for triple-negative and treatment-resistant disease subsets. However, several studies have demonstrated that patient tumours exhibit resistance to TRAIL and TRAIL-receptor agonists. We have previously demonstrated that suppression of the TRAIL-receptor inhibitor cFLIP can sensitise breast cancer stem cells to apoptosis inducers, but development of pharmacological inhibitors of cFLIP have been impeded by concerns over structural similarities between cFLIP and the pro-apoptotic procaspase-8. We used molecular dynamics to model the interactions between cFLIP, procaspase-8 and the TRAIL-receptor Death Inducing Signalling Complex (TRAIL-DISC), followed by virtual pharmacophore screening and in-cell viability assays to identify a small-molecule (OH14, 3) that selectively inhibited cFLIP binding to the DISC and promoted TRAIL-mediated apoptosis in breast cancer cell lines. When used in combination with TRAIL, OH14 significantly impaired breast cancer cell viability in primary derived and established cell culture. Given the relatively low (micromolar) potency of the initial hit compound inhibitor OH14 (3), limiting its utility as a preclinical development candidate, we carried out structure-activity relationship studies to find a cFLIP inhibitor with more potent cellular activity. Our findings confirm the proof-of-principle that selective pharmacological inhibition of cFLIP can be used to target a vulnerability in breast cancer cells.

cancer biology↗

bioRxiv2024

Variations in clustering of multielectrode local field potentials in the motor cortex of macaque monkeys during a reach-and-grasp task

There is experimental evidence of varying correlation among the elements of the neuromuscular system over the course of the reach-and-grasp task. Several neuromuscular disorders are accompanied by anomalies in muscular coupling during the task. The aim of this study was to investigate if modifications in correlations and clustering can be detected in the Local Field Potential (LFP) recordings of the motor cortex during the task. To this end, we analyzed the LFP recordings from a previously published study on monkeys which performed a reach-and-grasp task for targets with a vertical or horizontal orientation. LFP signals were recorded from the motor and premotor cortex of macaque monkeys as they performed the task. We found very robust changes in the correlations of the multielectrode LFP recordings which corresponded to task epochs. Mean LFP correlation increased significantly during reaching and then decreased during grasp. This pattern was very robust for both left and right arm reaches irrespective of target orientation. A hierarchical cluster analysis supported the same conclusion - a decreased number of clusters during reach followed by an increase for grasp. A sliding window computation of the number of clusters was performed to probe the predictive capacities of these LFP clusters for upcoming task events. For a very high percentage of trials (95.3%), there was a downturn in cluster number following the Pellet Drop (GO signal) which reached a minimum shortly preceding the Start of grasp, hence indicating that cluster analyses of LFP signals could provide online indications of the Start of grasp.

neuroscience↗

bioRxiv2022

Human land-use impacts viral diversity and abundance in a New Zealand river

Although water-borne viruses have important implications for the health of humans and other animals, little is known about the impact of human land-use on viral diversity and evolution in water systems such as rivers. We used metagenomic next-generation sequencing to compare the diversity and abundance of viruses at sampling sites along a single river in New Zealand that differed in human land use impact, ranging from pristine to urban. From this we identified 504 putative virus species, of which 97% were novel. Many of the novel viruses were highly divergent, and likely included a new subfamily within the Parvoviridae. We identified at least 63 virus species that may infect vertebrates - most likely fish and water birds - from the Astroviridae, Birnaviridae, Parvoviridae and Picornaviridae. No putative human viruses were detected. Importantly, we observed differences in the composition of viral communities at sites impacted by human land-use (farming and urban) compared to native forest sites (pristine). At the viral species level, the urban sites had higher diversity (327 virus species) than the farming (n=150) and pristine sites (n=119), and more viruses were shared between the urban and farming sites (n=76) than between the pristine and farming or urban sites (n=24). The two farming sites had a lower viral abundance across all host types, while the pristine sites had a higher abundance of viruses associated with animals, plants and fungi. We also identified viruses linked to agriculture and human impact at the river sampling sites in farming and urban areas that were not present at the native forest sites. Overall, our study shows that human land-use can impact viral communities in rivers, such that further work is needed to reduce the impact of intensive farming and urbanization on water systems.

microbiology↗

bioRxiv2021

VCP protects neurons from proteopathic seeding

Uptake and spread of proteopathic seeds, such as S, Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery necessary for this process is poorly understood. Using a genome-wide CRISPR-Cas9 screen, we identified Valosin Containing Protein (VCP) as a suppressor of S seeding. Dominant mutations in VCP cause multisystem proteinopathy (MSP) with muscle and neuronal degeneration. VCP inhibition or disease mutations increase S seeding in cells and neurons. This is not associated with an increase in seed uptake and is similar to treatment with the lysosomal damaging agent, LLoME. Intrastriatal injection of S seeds into VCP disease mice enhances seeding efficiency compared with controls. This is not specific to S since VCP inhibition or disease mutations increased TDP-43 seeding in neurons. These data support that VCP protects against proteopathic spread of pathogenic aggregates. The spread of distinct aggregate species may dictate pleiotropic phenotypes and pathologies in VCP associated MSP.

neuroscience↗

bioRxiv2018

dmrff: identifying differentially methylated regions efficiently with power and control

A differentially methylated region (DMR) is a genomic region in which DNA methylation is consistently positively or negatively associated with a phenotype or exposure. We demonstrate that existing algorithms for identifying DMRs either fail to consistently control false positive rates (comb-p and DMRcate), suffer from low power (bumphunter) or lack modeling flexibility (seqlm). We introduce a new method, dmrff, that overcomes these shortcomings and can additionally be used to meta-analyze multiple datasets. When applied to investigate associations of age in multiple datasets, dmrff identifies novel DMRs near genes previously linked to age. An R implementation is available on Github (http://github.com/perishky/dmrff).

bioinformatics↗

bioRxiv2017

Histamine signaling via the metabotropic receptor Trapped in endoderm 1 regulates courtship initiation in Drosophila melanogaster.

Understanding the role of genes in directing behavior is one of the primary goals of neuroscience. Mating behavior in Drosophila is controlled by male-specific splicing of the master regulatory gene fruitless (fru), and the male-specific splice form, fruM, is both necessary and sufficient for all aspects of the courtship ritual. We have previously described the role of Trapped in endoderm 1 (Tre1) in courtship behavior. Tre1 encodes an orphan G-protein-coupled receptor that is essential for normal courtship behavior in male flies. We previously found that feminizing Tre1-expressing cells in males via expression of the female-specific splicing factor Transformer (TraF) resulted in rapid courtship initiation. Here we confirm that Tre1 is required in neurons for normal courtship behavior, and present genetic evidence that Tre1 acts through the downregulation of the E-cadherin Shotgun, and that the neurotransmitter histamine is the likely Tre1 ligand. Our findings are the first evidence for metabotropic histamine receptors in Drosophila, and the first to demonstrate a role for histamine in courtship.

genetics↗