Biology subjects

Matthews, N.

Publications and source records attributed to Matthews, N..

18 recordsLinked to original sources

bioRxiv2026

First density and abundance estimate for the only East African Population of Western bongo (Tragelaphus eurycerus eurycerus) in Semuliki National Park, Uganda

Information on Western bongo (Tragelaphus eurycerus eurycerus) across its range remains scarce and fragmented, leaving the status of populations poorly understood, limiting effective conservation planning. We conducted three camera-trap surveys across Semuliki National Park, Uganda, between October 2019 and August 2020 (90 camera locations; 11,640 camera days), during which we detected the only currently known population of Western bongo in East Africa. We assessed the status of this population using data from the final survey (March-August 2020), when bongos were detected, applying an individual identification system adapted from Eastern bongo (Tragelaphus eurycerus isaaci) and spatially explicit capture-recapture (SECR) modelling to estimate density and abundance. To reflect known aspects of bongo ecology, we incorporated sex and habitat covariates derived from remotely sensed data as predictors of density. Bongos were detected on 17 occasions, and we identified 18 individuals (11 females and 7 males), of which seven immature individuals (5 females and 2 males). The top-ranking SECR model included the tasseled cap greenness index and sex as predictors of density. The model estimated a population size of 56.49 individuals (SE = 7.69; 95% CI = 41.43-71.56), with an estimated density of 0.58 individuals km-2 (SE = 0.171; 95% CI = 0.32-1.09) within Semuliki National Park. These results provide the first quantitative baseline for this population and suggest the presence of an established breeding population, highlighting the need for structured monitoring to support its long-term conservation.

ecology↗

bioRxiv2026

A microbiota-responsive polyfunctional cytotoxic CD4⁺ T-cell state promotes mucosal inflammation in ulcerative colitis

Ulcerative colitis (UC) is characterised by chronic colonic inflammation with marked heterogeneity in disease severity and therapeutic outcomes. Here, we define a spatially organised, polyfunctional cytotoxic CD4 T-cell state associated with mucosal inflammation and adverse therapeutic outcomes in UC. Integrating ex vivo T-cell receptor stimulation with multi-cohort bulk and single-cell transcriptomics and multiparameter flow cytometry, we show that GZMB CD4 T cells are preferentially enriched in inflamed UC mucosa, but not peripheral blood, and co-express cytotoxic molecules, Th1- and Th17-associated cytokines and chemokines, and immunoregulatory receptors. Single-cell analyses implicate inflammatory cytokine and antigen-presentation signals in the acquisition or maintenance of this state. High-resolution spatial profiling localised this programme predominantly to Th17 cells, which were preferentially enriched within multicellular inflammatory and tertiary lymphoid structure-associated niches. Across independent patient cohorts, a transcriptional signature derived from this state increased with endoscopic disease severity and was associated with reduced response to anti-TNF and anti-IL-12/23p40 therapies. Adoptive transfer of Gzma/Gzmb-deficient rather than wild-type CD4 T cells into Rag2-deficient recipient mice markedly attenuated experimental colitis and abrogated the polyfunctional cytokine phenotype, demonstrating that granzyme-dependent effector activity is a key mechanism driving CD4+ T-cell-mediated intestinal inflammation. Finally, human host-microbiome analysis linked this programme to intestinal dysbiosis, while transfer of dysbiotic microbiota promoted the emergence of a corresponding state in vivo. Collectively, these findings define a microbiota-responsive, spatially organised polyfunctional cytotoxic CD4 T-cell programme that contributes to intestinal inflammation and is associated with disease severity and treatment resistance in UC.

immunology↗

bioRxiv2026

A dysregulated stromal remodelling programme characterises prior anti-TNF failure in ulcerative colitis

Prior anti-tumour necrosis factor (TNF) failure is associated with reduced efficacy of subsequent advanced therapies in ulcerative colitis (UC), but the biological basis of this treatment-refractory state remains unclear. We integrated clinical outcomes and baseline colonic transcriptomic data from UC patients in the UNIFI phase III trial programme with regulatory and signalling network inference, connectivity mapping, and single-cell-resolution spatial transcriptomics. Colonic transcriptomic analyses identified coordinated enrichment of extracellular matrix organisation, collagen remodelling and integrin-associated programmes, increased stromal cell representation and elevated inferred MAPK/EGFR activity in UC patients with prior anti-TNF failure. Causal network inference prioritised MAPK3 as a candidate regulator of this state, while connectivity mapping identified MEK/EGFR inhibitors as candidate perturbagens. MEK inhibition suppressed stromal pathways and reduced inferred MAPK/EGFR activity ex vivo. Spatial profiling of active UC and non-IBD colonic tissues localised these programmes to UC-enriched stromal niches. Ligand-receptor inference further identified reciprocal stromal-myeloid communication within these niches. Collectively, these findings define a stromal remodelling programme associated with prior anti-TNF failure and nominate MAPK/EGFR signalling as a potentially tractable component of treatment-refractory UC.

systems biology↗

bioRxiv2026

Siglec-15 is a glyco-immune checkpoint in prostate cancer regulating immune evasion and metastasis

Prostate cancer is a leading cause of cancer-related mortality in men, and effective treatment options are limited for advanced and metastatic disease. The sialoglycan immune checkpoint Siglec-15 has emerged as a key mediator of tumour-associated immune suppression in several malignancies; however, its expression and functional role in prostate cancer remain poorly defined. Here, using dual immunofluorescence and immunohistochemistry, we demonstrate that Siglec-15 is expressed by prostate tumour epithelial cells, immunosuppressive macrophage phenotypes, and bone-resorbing osteoclasts within the tumour microenvironment. Mechanistically, we show that direct Siglec-15 receptor crosslinking, either by antibodies or tumour cell-derived conditioned medium, promotes monocyte-to-macrophage differentiation, generating macrophages with immunosuppressive and pathogenic phenotypes. Using therapeutic antibodies, we show that Siglec-15 blockade suppresses supernatant-induced monocyte to macrophage differentiation, allowing for the recovery of CD8 T-cell activation. Furthermore, we reveal that macrophage colony-stimulating factor (M-CSF) driven monocyte-derived macrophage differentiation is partially dependent on Siglec-15 signalling, with Siglec-15 blockade enhancing CD8 T-cell responses. In addition, anti-Siglec-15 treatment suppressed osteoclast differentiation, highlighting a dual role for Siglec-15 in prostate cancer immune suppression and bone remodelling. Consistent with these in vitro findings, therapeutic Siglec-15 blockade significantly reduced subcutaneous tumour growth in a CD8 T-cell-dependent manner and prolonged survival in a mouse model of prostate cancer metastasis. Together, these findings identify Siglec-15 as a central regulator of the prostate cancer glyco-immune axis, linking tumour-associated macrophage immune suppression with osteoclast-mediated bone remodelling, providing a compelling rationale for the clinical development of Siglec-15-targeted therapies for patients with advanced disease.

cancer biology↗

bioRxiv2026

Spatial transcriptomic analysis reveals coordinated gene expression in ovarian clear cell carcinoma and adjacent endometriosis in UK and Japanese patients

PurposeOvarian clear cell carcinoma (OCCC) is strongly associated with endometriosis and shows geographic variation in incidence. We investigated whether OCCC and adjacent endometriosis exhibit distinct transcriptional states and whether these patterns differ between United Kingdom (UK) and Japanese cohorts. Experimental DesignWe performed whole-transcriptome spatial profiling on specimens from 16 OCCC cases (8 UK, 8 Japan) in which tumor and endometriosis were both present. Gene expression was analyzed in tumor, endometriosis and stroma. ARID1A status was assessed by immunohistochemistry. ResultsMedian age was 59 years (range 26-82). 13/16 cases (81.3%) had early-stage disease. Tissue compartment rather than cohort of origin was the dominant source of variation across endometriosis and tumor regions. Endometriosis was enriched for inflammatory and immune-related pathways compared to tumor, whilst there was greater representation of chromatin and protein-DNA complex assembly pathways in tumor regions. These patterns were conserved across both cohorts and after stratification by ARID1A status. Mesenchymal-associated gene expression scores also significantly differed across stroma, endometriosis and tumor with clear compartmental separation. Cell type deconvolution analyses showed clear compositional differences between stromal and epithelial disease compartments. ConclusionsOCCC and coexisting endometriosis are transcriptionally distinct, with the dominant contrast being compartmental rather than geographic. ARID1A alone is unlikely to account for the principal spatial transcriptional states identified here. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between OCCC and coexisting endometriosis or represent different stages of endometriosis-associated tumorigenesis. Translational RelevanceOvarian clear cell carcinoma often arises in association with endometriosis, yet the biological transition between these lesions remains poorly understood. Using spatial transcriptomics in matched tumor and adjacent endometriosis from Japanese and UK cohorts, we showed that endometriosis is characterized by inflammatory and antigen-presentation features, whereas tumor regions showed chromatin-organization and oncogenic transcriptional states. These patterns were largely maintained irrespective of ARID1A status and geographic background. In addition, spatial deconvolution suggested differences in local immune composition, with tumor regions showing relatively greater neutrophil- and T cell-associated signals. Together, our data suggest that OCCC and coexisting endometriosis share a spatially linked tissue context, but that tumor regions have distinct transcriptional profile and microenvironment that may be involved in the malignant transformation and inform interpretation of molecular classification in endometriosis-associated OCCC.

pathology↗

bioRxiv2025

Single-cell atlas of the developing Down syndrome brain cortex

Down syndrome (DS), caused by trisomy of chromosome 21, is the leading genetic cause of intellectual disability, yet the mechanisms disrupting fetal brain development remain unclear. We performed single-cell transcriptomic and chromatin accessibility profiling of approximately 250,000 cells from 15 DS and 15 control human fetal cortices (10-20 weeks post-conception). Our analysis revealed a subtype-specific reduction in RORB/FOXP1-expressing excitatory neurons and widespread disruption of neurodevelopmental transcriptional programs. Chromosome 21 transcription factors BACH1, PKNOX1, and GABPA emerged as dosage-sensitive hubs regulating genes linked to intellectual disability. Antisense oligonucleotide-mediated normalization of these factors in human neural progenitors in vitro partially rescued target gene expression. Benchmarking a humanized in vivo model captured additional molecular and cellular signatures of DS, complementing the in vitro model. Together, this resource defines the gene-regulatory landscape underlying cortical development in DS and highlights candidate molecular targets and preclinical models for future intervention studies. HighlightsO_LISingle-cell atlas of Down syndrome fetal cortex links transcriptional dysregulation to reduction of layer 4 neurons C_LIO_LIChromosome 21 transcription factors PKNOX1, BACH1, and GABPA drive intellectual disability gene dysregulation C_LIO_LITransplanted human cells model late-stage DS phenotypes, bypassing scarcity of fetal tissue C_LIO_LIASO targeting chromosome 21 transcription factors restores DS-associated molecular signatures C_LI

neuroscience↗

bioRxiv2025

Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors

For all drugs, effective target engagement requires sufficient intracellular concentrations of drug to be reached, but whether tumour heterogeneity impacts drug distribution and efficacy is poorly studied. PARP inhibitors have transformed treatment of high-grade serous ovarian carcinoma (HGSOC), but resistance remains a clinical hurdle in this highly heterogeneous tumour type. We developed a patient-derived explant multi-modal imaging pipeline, which demonstrated that cell-intrinsic PARP inhibitor accumulation is highly variable, both between patients and within tumours. Spatial transcriptomics revealed enrichment of apoptotic and lysosomal signatures in high-drug regions. Rucaparib, an intrinsically fluorescent PARP inhibitor, accumulates heterogeneously at the single-cell level, with rucaparib-high cells demonstrating increased drug response relative to rucaparib low. Mechanistically, lysosomal sequestration creates a rucaparib reservoir that determines drug levels in the nucleus. Perturbation of lysosomal content altered intracellular levels of weak base PARP inhibitors rucaparib and niraparib, but not olaparib. Together these data suggest that lysosomes act as a reservoir for a subset of PARP inhibitor drugs to improve drug response.

cancer biology↗

bioRxiv2025

A common algorithm for confidence judgements across visual, auditory and audio-visual decisions

Most studies investigating the computational basis of decision confidence have focused on simple visual perceptual tasks, leaving open questions about how confidence is formed in decisions involving other sensory modalities or those requiring the integration of information across modalities. To address these gaps, we used computational modelling to analyse confidence judgements in perceptual decisions involving visual, auditory, and audio-visual stimuli. Drawing on research into visual confidence, we adapted models from the literature to evaluate their fit to our data, comparing three popular classes: unscaled evidence strength, scaled evidence strength, and Bayesian models. Our results show that the scaled evidence strength models consistently outperformed the other model classes across all tasks and could also be used to predict behaviour in the audio-visual task from the unidimensional auditory and visual model fits. These findings suggest that confidence judgements across different perceptual decisions rely on a shared algorithm that dynamically accounts for both sensory uncertainty and evidence strength, without the computation of posterior probabilities. Additionally, we investigated the algorithms used for multidimensional (audio-visual) confidence judgements specifically, showing that participants integrated both the visual and auditory dimensions of the stimulus, rather than relying solely on the most informative modality, and used a modality-independent measure of sensory uncertainty to adjust their confidence. Overall, our findings provide evidence for a common algorithm underlying confidence judgements across modalities and demonstrate the broad applicability of the scaled evidence strength algorithm, even in tasks requiring the integration of distinct sensory information.

neuroscience↗

bioRxiv2024

Multiscale single-cell assessment of the fibrotic niche in idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease characterised by excessive extracellular matrix deposition within the lung. Recent advances in single-cell RNA sequencing have identified distinct fibrotic populations, yet their origins and spatial relationships remain incompletely understood. MethodsUsing spatial transcriptomics and Hyperion imaging mass cytometry we compared the cellular composition in formalin fixed paraffin embedded fibrotic lesions (n=9 patients) with control lung (n=9), and cellular interactions were inferred using CellChat V2 ligand-receptor analysis. Monolayers of airway epithelial cells were used to identify changes in keratin (KRT) expression following cell detachment and cyclical mechanical stretch. ResultsSpatial multiomics profiling of human lung cells confirmed the in situ localisation of previously described IPF-enriched populations, and identified a previously unrecognized KRT5low/KRT17 epithelial population derived from airway basal cells that progressively acquiring molecular features of aberrant basaloid cells, forming a unique fibrotic niche enriched with the Secreted Phosphoprotein 1 (SPP1) positive macrophages. Functional studies demonstrated that epithelial detachment and cyclical mechanical stretch drive KRT5 reduction, providing a mechanism for the emergence of this transitional state. In addition, we also identified distinct immune-stromal niches enriched in lymphocytes and alveolar fibroblasts. ConclusionThese findings delineate distinct fibrotic epithelial niches in IPF and support a model in which epithelial loss induces aberrant basaloid differentiation and fibroblast activation, with subsequent airway traction and epithelial detachment generating a secondary niche enriched in basal-derived KRT5low/KRT17 cells and SPP1 macrophages.

molecular biology↗

bioRxiv2024

KLF6 in Pulmonary Hypertension: The Dual Role of Friend and Foe

BackgroundPulmonary arterial hypertension (PAH) is a severe lung condition with unmet clinical needs, marked by endothelial damage, excessive repair, and arterial narrowing, though mechanisms remain unclear. MethodsThis study investigates Kruppel-like transcription factor 6 (KLF6), known for its role in tissue injury response and cancer onset, in PAH through functional and expression analyses in human pulmonary artery endothelial cells (HPAECs) and human and rodent PAH lung tissues. FindingsKLF6 expression increased in early experimental PAH in response to hypoxia and inflammation, while the expression of endothelial homeostasis regulators KLF2 and KLF4, previously linked to PAH, decreased. KLF6 overexpression enhanced pulmonary endothelial survival and angiogenesis through broad transcriptomic remodelling, including changes in genes governing endothelial homeostasis and arterial identity (e.g., SOX17, ERG, BMPR2) and promoted human pulmonary artery smooth muscle cells (HPASMCs) proliferation, which was inhibited by bosentan and imatinib. KLF6 functional and transcriptomic responses differed from those of KLF2 and KLF4. Comparative analysis of RNA-seq PAH databases and spatial transcriptomic analysis of human idiopathic PAH (IPAH) tissues highlighted strong association of KLF6 with vascular remodelling, especially with the formation of angioproliferative (plexiform) lesions. High KLF6 expression was observed in IPAH vascular endothelium and IPAH blood-derived endothelial progenitor cells. Single nucleus RNA-seq in PAH associated with Alveolar Capillary Dysplasia confirmed disease-related elevated KLF6 expression in arterial endothelial cells. InterpretationAccumulation and reorganization of KLF6+ endothelial cells characterize human PAH. KLF6 drives endothelial repair and an apoptosis-resistant, angioproliferative endothelial phenotype. Targeting KLF6 could be a novel therapeutic approach for PAH. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSPulmonary arterial hypertension (PAH) is a progressive and life-shortening lung disease with no cure. In PAH development, endothelial damage is believed to initiate an abnormal repair process, leading to extensive vascular remodelling and the formation of complex angio-proliferative (plexiform) lesions. We conducted a systematic search of the PubMed database to identify transcription factors potentially involved in driving endothelial repair and promoting an apoptosis-resistant, angio-proliferative vascular phenotype. Previous research has linked the loss of endothelial homeostasis in PAH to the inhibition of transcription factors KLF2 and KLF4. While KLF6 is known to play a vital role in vascular development and supports endothelial repair, its specific role in PAH remains unexplored. Added value of this studyThis study is the first to establish a connection between KLF6 and PAH pathogenesis. Our findings reveal that KLF6 activation is a key feature of an apoptosis-resistant, angio-proliferative endothelial phenotype characteristic of human PAH-associated plexogenic arteriopathy. Furthermore, we identify both overlapping and unique activation patterns and transcriptional programs regulated by KLF2, KLF4, and KLF6 in lung endothelial cells, highlighting KLF6s unique role in driving endothelial dysfunction in PAH. Implications of all the available evidenceTargeting KLF6 offers a promising therapeutic strategy to counteract excessive vascular repair and prevent the vascular remodelling in PAH. FUNDINGPhD studentship from the University of Hafr Al Batin, KSA, and the Saudi Cultural Bureau in London (UKSACB) (Rehab Alharbi). Spatial transcriptomic reagents were funded by the British Heart Foundation Centre of Research Excellence Award and Senior BHF Fellowship FS/18/52/33808 (Allan Lawrie). Human samples used in this research project were obtained from the Imperial College Healthcare Tissue Bank (ICHTB) supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.

cell biology↗

bioRxiv2022

Modality Independent or Modality Specific? Common Computations Underlie Confidence Judgements in Visual and Auditory Decisions

Humans possess the ability to evaluate their confidence in a range of different decisions. In this study, we investigated the computational processes that underlie confidence judgements and the extent to which these computations are the same for perceptual decisions in the visual and auditory modalities. Participants completed two versions of a categorisation task with visual or auditory stimuli and made confidence judgements about their category decisions. In each modality, we varied both evidence strength, (i.e., the strength of the evidence for a particular category) and sensory uncertainty (i.e., the intensity of the sensory signal). We evaluated several classes of models which formalise the mapping of evidence strength and sensory uncertainty to confidence in different ways: 1) unscaled evidence strength models, 2) scaled evidence strength models, and 3) Bayesian models. Our model comparison results showed that across tasks and modalities, participants take evidence strength and sensory uncertainty into account in a way that is consistent with the scaled evidence strength class. Notably, the Bayesian class provided a relatively poor account of the data across modalities, particularly in the more complex categorisation task. Our findings suggest that a common process is used for evaluating confidence in perceptual decisions across domains, but that the parameter settings governing the process are tuned differently in each modality. Overall, our results highlight the impact of sensory uncertainty on confidence and the unity of metacognitive processing across sensory modalities. Author SummaryIn this study, we investigated the computational processes that describe how people derive a sense of confidence in their decisions. In particular, we determined whether the computations that underlie the evaluation of confidence for a visual decision are the same as those for an auditory decision. We tested a range of different models from 3 distinct classes which make different predictions about the computations that are used. We found that a single class of models provided the best account of confidence, suggesting a common process for evaluating confidence across sensory modalities. Even though these computations are governed by the same general process, our results suggest that the process is still fine-tuned within each modality.

neuroscience↗

bioRxiv2022

CDK4/6 inhibition and dsRNA sensor agonism co-operate to enhance anti-cancer effects through ER stress and immune modulation of tumour cells

Cytoplasmic pattern recognition receptors (PRRs) for double-stranded RNA (RIG-I/MDA5) are key mediators of anti-viral responses. PRR agonists, such as dsRNA oncolytic Reovirus type 3 Dearing (Rt3D), potently activate RNA sensors. We used an unbiased cytotoxicity screen to reveal synergistic drug-virotherapy combinations and found potent effects of Rt3D combined with the CDK4/6 inhibitor, palbociclib. The combination augmented oncolytic virus-induced endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and the expression and activation/signaling of RNA sensors. Combined Rt3D-palbociclib treatment potently increased interferon production and signaling, and knockdown studies implicated key UPR proteins and the RNA sensor, RIG-I, as essential to the phenotype observed. Further experiments, using canonical RIG-I agonists and an ER stress inducer, thapsigargin, confirmed cross-talk between RNA sensing and ER stress pathways that augmented cancer cell death and interferon production. Combined Rt3D-palbociclib also increased innate immune activation within tumour cells and IFN-induced HLA expression. Analysis of the immunopeptidome revealed changes to HLA-captured peptides with Rt3D-palbociclib, including altered expression of peptides from cancer/testis antigens (CTA) and endogenous retroviral elements (ERVs). Our findings highlight cross-talk between UPR signaling and RNA-mediated PRR activation as a means of enhancing anti-cancer efficacy with potential pro-immunogenic consequences. This has implications for future clinical development of PRR agonists and oncolytic viruses, and broadens the therapeutic remit of CDK4/6 inhibitors to include roles as both ER stress and dsRNA PRR sensitizers.

cancer biology↗

bioRxiv2020

Mutational processes impact the evolution of anti-EGFR antibody resistance in colorectal cancer

Anti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRC) but acquired resistance invariably evolves. Which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis, a transient cetuximab-induced increase in mutagenesis, contributes in patients is unknown. We investigated this in exome sequencing data of 42 baseline and progression biopsies from cetuximab treated CRCs. Mutation loads did not increase from baseline to progression. Evidence for a contribution of cetuximab-induced mutagenesis was limited. However, the mutational Signature 17 was a key contributer of specific KRAS/NRAS and EGFR driver mutations that are common at acquired resistance. Signature 17 activity before treatment predicted shorter progression free survival. This demonstrates the utility of mutational signatures to predict cancer drug resistance evolution. SIGNIFICANCEDrug resistance evolution occurs ubiquitously in solid tumours during treatment with targeted drugs. Biomarkers that can be assessed prior to treatment to predict the time to resistance evolution and the genetic resistance mechanisms that will evolve have not been described. We identified the mutational Signature 17 as the first candidate biomarker that predicts shorter time to progression and several specific KRAS/NRAS and EGFR mutations that will likely evolve in CRCs during cetuximab treatment. Understanding the mutational mechanism underlying Signature 17 may open opportunities to delay resistance acquisition. The potential of mutational signatures to predict resistance to a broader range of drugs in other tumor types should be assessed.

cancer biology↗

bioRxiv2020

Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

Aneuploidy, the loss and gain of whole and part chromosomes, is near-ubiquitous in cancer genomes and likely defines cancer cell biology. However, the temporal evolutionary dynamics that select for aneuploidy remain uncharacterised. Here we perform longitudinal genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that represent distinct stages of tumour evolution through metastasis and treatment. Adenomas typically had few copy number alterations (CNAs) and most were subclonal, whereas cancers had many clonal CNAs, suggesting that progression goes through a CNA bottleneck. Individual CRC glands from the same tumour typically had very similar karyotypes, despite evidence of ongoing instability at the cell level in patient tumours, cell lines and organoids. CNAs in metastatic lesions sampled from liver and other organs, after chemotherapy or targeted therapies, and in late recurrences were typically similar to the primary tumour. Mathematical modelling and statistical inference indicated that these data are consistent with the action of negative selection on CNAs that traps cancer cell genomes on a fitness peak defined by the specific pattern of chromosomal aberrations. These data suggest that the initial progression of colorectal cancer requires the traversal of a rugged fitness landscape and subsequent CNA evolution, including metastatic dissemination and therapeutic resistance, is constrained by negative selection.

cancer biology↗

bioRxiv2019

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

Mismatch repair deficient (dMMR) gastro-oesophageal adenocarcinomas (GOAs) show better outcomes than their MMR-proficient counterparts and high immunotherapy sensitivity. The hypermutator-phenotype of dMMR tumours theoretically enables high evolvability but how these cancers evolve has not been investigated in detail. We applied multi-region exome sequencing (MSeq) to four treatment-naive dMMR GOAs. This revealed extreme intratumour heterogeneity (ITH), exceeding ITH in other cancer types >20-fold, but also long phylogenetic trunks which may explain the exquisite immunotherapy sensitivity of dMMR tumours. Subclonal driver mutations were common and parallel evolution occurred in RAS, PIK3CA, SWI/SNF-complex genes and in immune evasion regulators. MSeq data and evolution analysis of single region-data from 64 MSI GOAs showed that chromosome 8 gains were among the earliest genetic events and that the hypermutator-phenotype remained active during progression. MSeq may be necessary for biomarker development in these heterogeneous cancers. Comparison with other MSeq-analysed tumour types revealed mutation rates and their timing as major determinants of phylogenetic tree morphologies.

cancer biology↗

bioRxiv2019

Rapid recalibration of temporal order judgements: Response bias accounts for contradictory results

Recent findings indicate that timing perception is systematically changed after only a single presentation of temporal asynchrony. This effect is known as rapid recalibration. In the synchrony judgement task, similar timing relationships in consecutive trials seem more synchronous (positive rapid recalibration; Van der Burg et al., 2013, 2015). Interestingly, the direction of this effect is reversed for temporal order judgements (negative rapid recalibration; Roseboom, 2019). We aimed to determine whether negative rapid recalibration of temporal order judgements (TOJs) reflects genuine rapid temporal recalibration, or a choice-repetition bias unrelated to timing perception. In our first experiment we found no evidence of rapid recalibration of TOJs, but positive rapid recalibration of associated confidence. This suggests that timing perception had rapidly recalibrated, but that this was undetectable in TOJs, plausibly because the positive recalibration effect was obfuscated by a large negative bias effect. In our second experiment, we dissociated participants previous TOJ from the most recently presented timing relationship, mitigating the choice-repetition bias effect, and found evidence of positive rapid recalibration of TOJs. We therefore conclude that timing perception is rapidly recalibrated positively for both synchrony and temporal order judgements. It remains unclear whether rapid recalibration occurs at the level of sensory processing, leading to similar effects in all subsequent judgements, or reflects a generalised decision-making strategy.

neuroscience↗

bioRxiv2017

Ultra-sensitive mutation detection and genome-wide DNA copy number reconstruction by error corrected circulating tumour DNA sequencing

Minimally invasive circulating free DNA (cfDNA) analysis can portray cancer genome landscapes but highly sensitive and specific genetic approaches are necessary to accurately detect mutations with often low variant frequencies. We developed a targeted cfDNA sequencing technology using novel off-the-shelf molecular barcodes for error correction, in combination with custom solution hybrid capture enrichment. Modelling based on cfDNA yields from 58 patients shows that our assay, which requires 25ng of cfDNA input, should be applicable to >95% of patients with metastatic colorectal cancer. Sequencing of a 163.3 kb target region including 32 genes detected 100% of single nucleotide variants with 0.15% variant frequency in cfDNA spike-in experiments. Molecular barcode error correction reduced false positive mutation calls by 98.6%. In a series of 28 patients with metastatic colorectal cancers, 80 out of 91 (88%) mutations previously detected by tumour tissue sequencing were called in the cfDNA. Call rates were similar for single nucleotide variants and small insertions/deletions. Mutations only called in cfDNA but not detectable in matched tumour tissue included, among others, a subclonal resistance driver mutation to anti-EGFR antibodies in the KRAS gene, multiple activating PIK3CA mutations in each of two patients (indicative of parallel evolution), and TP53 mutations originating from clonal haematopoiesis. Furthermore, we demonstrate that cfDNA off-target read analysis allows the reconstruction of genome wide copy number aberration profiles from 71% of these 28 cases. This error-corrected ultra-deep cfDNA sequencing assay with a target region that can be readily customized enables broad insights into cancer genomes and evolution.

genomics↗

bioRxiv2017

Auditory prediction errors as individual biomarkers of schizophrenia

Schizophrenia is a complex psychiatric disorder, typically diagnosed through symptomatic evidence collected through patient interview. We aim to develop an objective biologically-based computational tool which aids diagnosis and relies on accessible imaging technologies such as electroencephalography (EEG). To achieve this, we used machine learning techniques and a combination of paradigms designed to elicit prediction errors or Mismatch Negativity (MMN) responses. MMN, an EEG component elicited by unpredictable changes in sequences of auditory stimuli, has previously been shown to be reduced in people with schizophrenia and this is arguably one of the most reproducible neurophysiological markers of schizophrenia.\n\nEEG data were acquired from 21 patients with schizophrenia and 22 healthy controls whilst they listened to three auditory oddball paradigms comprising sequences of tones which deviated in 10% of trials from regularly occurring standard tones. Deviant tones shared the same properties as standard tones, except for one physical aspect: 1) duration-the deviant stimulus was twice the duration of the standard; 2) monaural gap-deviants had a silent interval omitted from the standard, or 3) inter-aural timing difference, which caused the deviant location to be perceived as 90{degrees} away from the standards.\n\nWe used multivariate pattern analysis, a machine learning technique implemented in the Pattern Recognition for Neuroimaging Toolbox (PRoNTo) to classify images generated through statistical parametric mapping (SPM) of spatiotemporal EEG data, i.e. event-related potentials measured on the two-dimensional surface of the scalp over time. Using support vector machine (SVM) and Gaussian processes classifiers (GPC), we were able classify individual patients and controls with balanced accuracies of up to 80.48% (p-values = 0.0326, FDR corrected) and an ROC analysis yielding an AUC of 0.87. Crucially, a GPC regression revealed that MMN predicted global assessment of functioning (GAF) scores (correlation = 0.73, R2 = 0.53, p = 0.0006)

neuroscience↗