Biology subjects

Roberts, T.

Publications and source records attributed to Roberts, T..

16 recordsLinked to original sources

bioRxiv2025

Evidence for dimensional representations and anticipatory dynamics in facial expression perception

Expression recognition relies on the ability to distinguish subtle visual differences across a range of facial expressions. Here, we examine the neural representation of dynamic expressions as reflected by electroencephalography (EEG) data in human adults. We find that a wide range of expressions (i.e., 14 emotional and 10 conversational expressions) can be decoded from neural signals, and that their representational structure evinces the classic dimensions of valence and arousal. Critically, we recover, through EEG-based video reconstruction, dynamic representations whose content succeeds in capturing even fine differences across related expressions (e.g., happy-satiated versus schadenfreude). Further, time-resolved decoding reveals anticipatory dynamics that maximize accuracy before the occurrence of an apex expression in the visual stimulus. These results are validated against behavioral data, which yield static reconstructions consistent with their neural counterparts. Thus, our results shed light on the representational basis of expression recognition and serve to recover the dynamic content of visual experience.

neuroscience↗

bioRxiv2025

Dual Modes of Gene Regulation by CDK12

The process of transcription is driven forward by the activity of kinases including CDK7, CDK9 and CDK12. Accordingly, acute inhibition of any of these kinases results in profound downregulation of gene expression. Here, we discover that loss or inhibition of CDK12 also significantly upregulates a set of coding and non-coding loci, whose activation could contribute to the anti-proliferative effects of CDK12 inhibitors. Mechanistically, CDK12 inhibition impairs transcription elongation, leading to increased RNA polymerase II termination or arrest in long genes. However, short genes such as MYC and enhancer RNAs are highly transcribed in the absence of CDK12 activity. Indeed, in HER2+ breast cancer, a malignancy where CDK12 is co-amplified with HER2 and its expression correlates with disease status, CDK12 inhibition markedly elevates MYC expression to induce lethality. The dual effects of CDK12 inhibition elucidated herein clarify its role in transcriptional control and have significant translational implications.

cancer biology↗

bioRxiv2025

Loss of the tumor suppressor PTEN activates cell-intrinsic interferon signaling to drive immune resistance

Loss of the tumor suppressor PTEN is strongly associated with a lack of response to immune checkpoint blockade therapies in cancer patients, but the underlying mechanisms are not fully understood. We have developed a transformation model where knocking out PTEN in human mammary epithelial cells drives dependence on the p110{beta} subunit of PI3K and, notably, elicits a robust induction of endogenous retroviral elements (ERVs) and activation of the interferon signaling. This constitutive cell-intrinsic interferon response, hallmarked by hyperactivated STAT1, is also observed in human tumors with a PTEN-low status. We further find that PTEN deficiency renders cancer cells resistant to the cytotoxic effects of immune cells and interferon-{gamma}. Notably, PTEN loss also results in a dependency on an activated DNA damage response pathway, leading to an exquisite vulnerability to CDK12 inhibition. Our study suggests an interferon adaptation model in which tumors driven by PTEN deficiency inherently activate the interferon response, enabling them to adapt to interferon cytotoxicity and gain resistance to immunotherapies.

cancer biology↗

bioRxiv2025

Genome structural plasticity and copy number dynamics shape adaptive evolution in a barley fungal pathogen

Leaf rust, caused by Puccinia hordei, is one of the most important diseases of barley globally. Here, we report the first haplotype-resolved chromosome-level genome assembly for P. hordei. To gain deeper insight and understanding of the P. hordei genome, we generated such assemblies for two Australian isolates with contrasting virulence, one collected in the 1970s and one in 2001. The two haplotype-phased and chromosome-level assemblies were used to investigate genome architecture in P. hordei and to investigate variability and evolutionary relationships of 41 virulence-divergent isolates that were collected over a 54-year period (1966-2020) in Australia. We report, for the first time in a rust fungus, evidence of a conserved chromosome, chromosome 9, which is enriched for structural variation and accessory features that imply it functions as a compartmentalized core chromosome with regions subject to rapid diversification, potentially acting as a structural hotspot in adaptive evolution in P. hordei. Clear genetic stratification into clonal and recombining lineages was uncovered, with evidence of both long-term asexual propagation and recombination. Analyses of haplotype-resolved mating-type gene phylogenies and chromosome 9 k-mer profiles confirm divergence at key loci underpinning reproductive modes, distinguishing clonally derived from sexually recombined groups. We also identified pervasive copy number variation across the P. hordei genomes, with clonal lineage-specific duplications. Consistent with this finding, the study for the first time links copy number variation of the Cyp51 gene to fungicide insensitivity. This latter discovery is highly significant as it represents the first documented case of fungicide insensitivity in a rust pathogen in which an underlying genetic mechanism has been identified. Together, these findings illuminate how genome structure, recombination, and structural variation shape the evolution and adaptation of P. hordei, providing a guidance for future surveillance and management of this pathogen.

genomics↗

bioRxiv2025

MotifPeeker: R package for benchmarking epigenomic profiling methods using motif enrichment as a key metric

MotifPeeker benchmarks epigenomic profiling methods targeting transcription factors (TFs) where no "gold standard" reference exists, using motif enrichment as a key metric. With minimal input, users can analyse their data in a single function and receive an intuitive HTML report. Availability and ImplementationMotifPeeker is available on Bioconductor ([≥] v3.21) at https://bioconductor.org/packages/MotifPeeker. The complete source code is available on GitHub at https://github.com/neurogenomics/MotifPeeker, with full documentation provided at https://neurogenomics.github.io/MotifPeeker. Additionally, the MotifPeeker Docker image is hosted on GitHub at https://github.com/neurogenomics/MotifPeeker/pkgs/container/motifpeeker.

bioinformatics↗

bioRxiv2024

Rational design of peak calling parameters for TIP-seq based on pA-Tn5 insertion patterns improves predictive power

Epigenomic profiling provides insights into the regulatory mechanisms that govern gene expression. At a fundamental level, these mechanisms are determined by proteins that bind the DNA or modify the chromatin. Techniques such as ChIP-seq and CUT&Tag have been instrumental in mapping the binding sites of such proteins across the genome. Recent advances have led to the development of TIP-seq, a highly sensitive method devised to increase the number of unique reads per sample. Its design results in novel library features, which have not yet been explored with comparative analytics. Through the extensive assessment of bioinformatics tools and parameters we have developed an analysis pipeline that is ideally suited for TIP-seq data, including linear deduplication, read prioritisation and read shifting. Using transcription factor binding profiles (TFs), we show that our optimised pipeline greatly reduces the width of peaks to below 50% and more precisely aligns the peak summit with known motifs. A tutorial of the optimised peak calling is available on GitHub at https://github.com/neurogenomics/peak_calling_tutorial.git. Our methodological advancement substantially improves TIP-seq data quality, and the thoughtful design of analysis parameters is widely applicable to all pA-Tn5 based profiling assays.

bioinformatics↗

bioRxiv2024

Estimating the seroprevalence of tuberculosis (Mycobacterium bovis) infection in a wild deer population in southwest England

Bovine tuberculosis (bTB) is a major disease of cattle that is subject to an eradication strategy in England. To inform control policies and manage the epidemic, all potential sources of infection for cattle must be identified and understood. The causative agent of bTB, Mycobacterium bovis, has a wide host range including several deer species. While transmission between cattle and deer has been implicated in some localised endemic regions, the role of deer in the epidemiology of bTB in England is poorly understood. This paper presents the results of a serological survey to estimate the prevalence of M. bovis in a large wild deer population in the High bTB Risk Area of southwest England. Blood samples were collected post-mortem over a 12-month period from wild deer during annual deer management controls in the Exmoor area and tested for M. bovis serum antibodies. Overall, 432 samples were collected and 69 (16.0%) were seropositive. The true seroprevalence in our sample was estimated to be 29.2% (95% CrI 21.1-38.6%), using Bayesian Latent Class Analysis to account for imperfect diagnostic test accuracy. Prevalence did not appear to differ between sexes nor between species, although the sample was predominantly red deer. The lowest prevalence was observed in animals aged under 1-year. Whilst these results provide valuable insights into M. bovis seroprevalence in this wild deer population, they should be interpreted alongside other relevant information such as ecology, species-specific epidemiology and disease pathology, deer density and cattle management to inform potential transmission risks between cattle and wild deer.

zoology↗

bioRxiv2024

Plasma membrane transporter Progressive Ankylosis Protein Homolog (ANKH/Ankh) mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation and ageing

A considerable body of recent evidence supports citrate transport as a major regulator of organismal lifespan and healthspan. Citrate accumulates outside senescent cells in vitro and in vivo. However, the detailed mechanism of senescent cell extracellular citrate (EC) accumulation is not clear. We show here that EC is partially mediated by a newly described plasma membrane citrate transporter ANKH/SLC62A1 (progressive human ankylosis - ANKH) in senescent fibroblasts. Analogous to interleukin 6 (IL-6), EC and/or ANKH are regulated by telomere dysfunction, the p38 mitogen-activated kinase axis, transforming growth factor beta and p53, but in contrast not by steroids, sodium butyrate, or Ataxia Telangiectasia Mutated (ATM). ANKH was upregulated in other senescent cell types relevant to ageing but not keratinocytes. In contrast, EC and ANKH were inhibited in dividing and senescent fibroblasts by interleukin 1 (IL-1) in parallel with increased IL-6 secretion. Loss- and gain of function mutations of ANKH/Ank are associated with disease and interestingly, Ank is also downregulated in both aged mouse liver and brain tissues in parallel with increased senescence markers and several cytokines, suggesting that inflammatory cytokines could inhibit EC production in vivo. These data identify ANKH/Ank as a novel regulator of senescence-derived EC in both humans and mice. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/609895v3_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1eed642org.highwire.dtl.DTLVardef@1349040org.highwire.dtl.DTLVardef@1ea867aorg.highwire.dtl.DTLVardef@22d251_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Nanoscale photobiotinylation, pulldown and sequencing of region-specific DNA from intact cells.

Femto-seq is a novel nanoscale optical method that can be used to obtain DNA sequence information from targeted regions around a specific locus or other nuclear regions of interest. Two-photon excitation is used to photobiotinylate femtoliter volumes of chromatin within the nucleus, allowing for subsequent isolation and sequencing of DNA, and bioinformatic mapping of any nuclear region of interest in a select set of cells from a heterogenous population.

genomics↗

bioRxiv2022

Primary Omicron infection elicits weak antibody response but robust cellularimmunity in children

Omicron variants of SARS-CoV-2 are globally dominant and infection rates are very high in children. We determined immune responses following Omicron BA.1/2 infection in children aged 6-14 years and related this to prior and subsequent SARS-CoV-2 infection or vaccination. Primary Omicron infection elicited a weak antibody response with poor functional neutralizing antibodies. Subsequent Omicron reinfection or COVID-19 vaccination elicited increased antibody titres with broad neutralisation of Omicron subvariants. Prior pre-Omicron SARS-CoV-2 virus infection or vaccination primed for robust antibody responses following Omicron infection but these remained primarily focussed against ancestral variants. Primary Omicron infection thus elicits a weak antibody response in children which is boosted after reinfection or vaccination. Cellular responses were robust and broadly equivalent in all groups, providing protection against severe disease irrespective of SARS-CoV-2 variant. Immunological imprinting is likely to act as an important determinant of long-term humoral immunity, the future clinical importance of which is unknown.

immunology↗

bioRxiv2022

Telomerase deficiency in humans is associated with systemic age-related changes in energy metabolism

Underlying mechanisms of plasma metabolite signatures of human ageing and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis Congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, DKC1) and progressive telomere attrition. We show extracellular citrate is repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo; leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, citrate and senescence factors only weakly distinguished DC patients from controls, whereas other tricarboxylic acid cycle metabolites, lactate and especially pyruvate distinguished them with high significance, consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data has similarities with age-related disease signatures in humans. Our results have implications for the early diagnosis of telomere dysfunction and anti-senescence therapeutics. HighlightsO_LIExtracellular citrate is regulated by telomere function in vitro and in vivo. C_LIO_LIDyskeratosis Congenita (DC) is a human disease characterized by systemic telomere attrition, which showed an age-related plasma energetic profile, distinct from age-related disease and that of centenarians. C_LIO_LIThe DC profile strikingly out-performed senescence factors in discriminating DC from controls, and pyruvate associated with a low lactate:pyruvate ratio is potentially a useful and cheap minimally invasive diagnostic aid for DC and telomere dysfunction. C_LIO_LIMechanistically DC systemic metabolism is indicative of a shift to reduced pyruvate dehydrogenase activity, glycolysis and/or increased citrate and lactate production followed by further metabolism in the kidneys and liver. C_LI

cell biology↗

bioRxiv2021

Modeling the trajectory of SARS-CoV-2 spike protein evolution in continuous latent space using a neural network and Gaussian process

Viral vaccines can lose their efficacy as the genomes of targeted viruses rapidly evolve, resulting in new variants that may evade vaccine-induced immunity. This process is apparent in the emergence of new SARS-CoV-2 variants which have the potential to undermine vaccination efforts and cause further outbreaks. Predictive vaccinology points to a future of pandemic preparedness in which vaccines can be developed preemptively based in part on predictive models of viral evolution. Thus, modeling the trajectory of SARS-CoV-2 spike protein evolution could have value for mRNA vaccine development. Traditionally, in silico sequence evolution has been modeled discretely, while there has been limited investigation into continuous models. Here we present the Viral Predictor for mRNA Evolution (VPRE), an open-source software tool which learns from mutational patterns in viral proteins and models their most statistically likely evolutionary trajectories. We trained a variational autoencoder with real-time and simulated SARS-CoV-2 genome data from Australia to encode discrete spike protein sequences into continuous numerical variables. To simulate evolution along a phylogenetic path, we trained a Gaussian process model with the numerical variables to project spike protein evolution up to five months in advance. Our predictions mapped primarily to a sequence that differed by a single amino acid from the most reported spike protein in Australia within the prediction timeframe, indicating the utility of deep learning and continuous latent spaces for modeling viral protein evolution. VPRE can be readily adapted to investigate and predict the evolution of viruses other than SARS-CoV-2 in temporal, geographic, and lineage-specific pathways.

bioinformatics↗

bioRxiv2021

3D UNet with GAN discriminator for robust localisation of the fetal brain and trunk in MRI with partial coverage of the fetal body

In fetal MRI, automated localisation of the fetal brain or trunk is a prerequisite for motion correction methods. However, the existing CNN-based solutions are prone to errors and may require manual editing. In this work, we propose to combine a multi-label 3D UNet with a GAN discriminator for localisation of both fetal brain and trunk in fetal MRI stacks. The proposed method is robust for datasets with both full and partial coverage of the fetal body.

bioengineering↗

bioRxiv2019

Parkinson’s disease: a systemic inflammatory disease accompanied by bacterial inflammagens

Parkinsons disease (PD) is a well-known neurodegenerative disease. Recently, the role of gingipains from Porphyromonas gingivalis was implicated in Alzheimers disease. Here we present evidence of systemic inflammation, accompanied by hypercoagulation; we also show that ginipains from P. gingivalis and its LPS may foster abnormal clotting, and that ginipains are present in PD blood, and thus that ginipains action on blood may be relevant to PD pathology. Bloods from both PD and healthy blood samples were analysed using thromboelastography (TEG), confocal and electron microscopies, and for cytokine and other circulating biomarkers. We also probed PD and healthy plasma clots with a polyclonal antibody for the bacterial protease, gingipain R1, from P. gingivalis. Low concentrations of recombinant gingipain R1 were also added to purified fluorescent fibrinogen. TEG, fibrin(ogen) amyloid formation and platelet ultrastructure analysis confirmed profound hypercoagulation, while the biomarker analysis confirmed significantly increased levels of circulating proinflammatory cytokines. We provide evidence for the presence of the protease, gingipain R1 in PD blood, implicating inflammatory microbial cell wall products in PD.

neuroscience↗

bioRxiv2019

Glycosylphosphatidylinositol Biosynthesis and Remodeling are Required for Neural Crest Cell, Cardiac and Neural Development.

The glycosylphosphatidylinositol (GPI) anchor attaches nearly 150 proteins to the cell surface. Patients with pathogenic variants in GPI biosynthetic pathway genes display an array of phenotypes including seizures, developmental delay, dysmorphic facial features and cleft palate. There is virtually no mechanism to explain these phenotypes. we identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypomorphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2). Pgap2 is one of the final proteins in the GPI biosynthesis pathway and is required for anchor maturation. We found the Clpex mutation results in a global decrease in surface GPI expression. Surprisingly, Pgap2 showed tissue specific expression with enrichment in the affected tissues of the Clpex mutant. We found the phenotype in Clpex mutants is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium, as is observed in the GPI anchored Folate Receptor 1-/- mouse. We showed folinic acid supplementation in utero can rescue the cleft lip phenotype in Clpex. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency in the Wnt1-Cre lineage. These mutants developed median cleft lip and palate demonstrating a cell autonomous role for GPI biosynthesis in NCC development.

developmental biology↗

bioRxiv2017

Thalamostriatal and cerebellothalamic pathways in a songbird, the Bengalese finch

The thalamostriatal system is a major network in the mammalian brain, originating principally from the intralaminar nuclei of thalamus. Functions of the thalamostriatal system remain unclear, but a subset of these projections provides a pathway through which the cerebellum communicates with the basal ganglia. Both the cerebellum and basal ganglia play crucial roles in motor control. Although songbirds have yielded key insights into the neural basis of vocal learning, it is unknown whether a thalamostriatal system exists in the songbird brain. Thalamic nucleus DLM is an important part of the song system, the network of nuclei required for learning and producing song. DLM receives output from song system basal ganglia nucleus Area X and sits within dorsal thalamus, the proposed avian homolog of the mammalian intralaminar nuclei that also receives projections from the cerebellar nuclei. Using a viral vector that specifically labels presynaptic axon segments, we show in Bengalese finches that dorsal thalamus projects to Area X, the basal ganglia nucleus of the song system, and to surrounding medial striatum. To identify the sources of thalamic input to Area X, we map DLM and cerebellar-recipient dorsal thalamus (DTCbN). Surprisingly, we find both DLM and immediately-adjacent subregions of DTCbN project to Area X. In contrast, a medial-ventral subregion of DTCbN projects to medial striatum outside Area X. Our results suggest the basal ganglia in the song system, like the mammalian basal ganglia, integrate feedback from the thalamic region to which they project as well as thalamic regions that receive cerebellar output.

neuroscience↗