Biology subjects

Bates, C.

Publications and source records attributed to Bates, C..

7 recordsLinked to original sources

bioRxiv2026

Causal contributions of the dorsolateral prefrontal cortex and temporoparietal junction to source and reality monitoring

Source and reality monitoring enable individuals to distinguish the origins of remembered information, including whether information was self- or other-generated and whether it was perceived or imagined. Although the dorsolateral prefrontal cortex (dlPFC) and temporoparietal junction (TPJ) have been implicated in these processes, their independent causal contributions remain unclear. We investigated whether focal transcranial direct current stimulation (f-tDCS) of the left dlPFC and left TPJ differentially modulates source and reality monitoring. One hundred participants were randomly assigned to receive anodal or sham stimulation of the left dlPFC or TPJ before completing an episodic memory task manipulating agent (self, experimenter), context (spoken, imagined), and emotional valence (positive, negative). Discrimination sensitivity (d') and response criterion (c) were examined separately. For source monitoring, stimulation interacted with context and cortical region: anodal dlPFC stimulation was associated with a greater spoken-imagined difference in self-experimenter discrimination than sham stimulation, whereas no equivalent context-dependent effect emerged following TPJ stimulation. For reality monitoring, stimulation effects also differed by cortical target, with reduced spoken-imagined discrimination following anodal relative to sham TPJ stimulation and no significant effect of dlPFC stimulation. These effects were not accompanied by corresponding stimulation effects on response criterion. Independent of stimulation, source discrimination was substantially greater for spoken than imagined information, while reality-monitoring sensitivity was enhanced for self-generated relative to experimenter-generated negative information. Together, these findings provide evidence that the dlPFC and TPJ make dissociable contributions to source and reality monitoring, while highlighting the importance of contextual and affective features in determining how the origins of memories are evaluated.

neuroscience↗

bioRxiv2021

Reciprocal Priming between RTKs within Recycling Endosomes Orchestrates Cellular Signaling Outputs

Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling-dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR-mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGF-mediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers.

cell biology↗

bioRxiv2019

CoFe granules focus coordinated glycolytic mRNA localization and translation to fuel glucose fermentation

Glycolysis is a fundamental metabolic pathway for glucose catabolism across biology, and glycolytic enzymes are amongst the most abundant proteins in cells. Their expression at such levels provides a particular challenge. Here we demonstrate that the glycolytic mRNAs are localized to granules in yeast and human cells. Detailed live cell and smFISH studies in yeast show that the mRNAs are actively translated in granules, and this translation appears critical for the localization. Furthermore, this arrangement is likely to facilitate the higher level organisation and control of the glycolytic pathway. Indeed, the degree of fermentation required by cells is intrinsically connected to the extent of mRNA localization to granules. On this basis, we term these granules, Core Fermentation (CoFe) granules; they appear to represent translation factories allowing high-level co-ordinated enzyme synthesis for a critical metabolic pathway.

cell biology↗

bioRxiv2019

Dissociation of solid tumour tissues with cold active protease for single-cell RNA-seq minimizes conserved collagenase associated stress responses

BackgroundSingle-cell RNA sequencing (scRNAseq) is a powerful tool for studying complex biological systems, such as tumour heterogeneity and tissue microenvironments. However, the sources of technical and biological variation in primary solid tumour tissues and patient-derived mouse xenografts for scRNAseq, are not well understood. Here, we used low temperature (6{degrees}C) protease and collagenase (37{degrees}C) to identify the transcriptional signatures associated with tissue dissociation across a diverse scRNAseq dataset comprising 128,481 cells from patient cancer tissues, patient-derived breast cancer xenografts and cancer cell lines.\n\nResultsWe observe substantial variation in standard quality control (QC) metrics of cell viability across conditions and tissues. From FACS sorted populations gated for cell viability, we identify a sub-population of dead cells that would pass standard data filtering practices, and quantify the extent to which their transcriptomes differ from live cells. We identify a further subpopulation of transcriptomically \"dying\" cells that exhibit up-regulation of MHC class I transcripts, in contrast with live and fully dead cells. From the contrast between tissue protease dissociation at 37{degrees}C or 6{degrees}C, we observe that collagenase digestion results in a stress response. We derive a core gene set of 512 heat shock and stress response genes, including FOS and JUN, induced by collagenase (37{degrees}C), which are minimized by dissociation with a cold active protease (6{degrees}C). While induction of these genes was highly conserved across all cell types, cell type-specific responses to collagenase digestion were observed in patient tissues. We observe that the yield of cancer and non-cancer cell types varies between tissues and dissociation methods.\n\nConclusionsThe method and conditions of tumour dissociation influence cell yield and transcriptome state and are both tissue and cell type dependent. Interpretation of stress pathway expression differences in cancer single cell studies, including components of surface immune recognition such as MHC class I, may be especially confounded. We define a core set of 512 genes that can assist with identification of such effects in dissociated scRNA-seq experiments.

genomics↗

bioRxiv2018

Translation factor mRNA granules direct protein synthetic capacity to regions of polarized growth

mRNA localization serves key functions in localized protein production making it critical that the translation machinery itself is present at these locations. Here we show that translation factor mRNAs are localized to distinct granules within yeast cells. In contrast to many mRNP granules, such as P-bodies and stress granules, which contain translationally repressed mRNAs, these granules harbor translated mRNAs under active growth conditions. The granules require Pablp for their integrity and are inherited by developing daughter cells in a She2p/ She3p dependent manner. These results point to a model where roughly half the mRNA for certain translation factors are specifically directed in granules toward the tip of the developing daughter cell where protein synthesis is most heavily required, which has particular implications for filamentous forms of growth. Such a feedforward mechanism would ensure adequate provision of the translation machinery where it is to be needed most over the coming growth cycle. SummaryThis study shows that mRNAs encoding a range of translation factors are localized to granules that get transported into the yeast daughter cell using the She2p/She3p machinery. This likely supports an intensification of protein synthetic activity to facilitate apical polarized growth.

cell biology↗

bioRxiv2018

HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells

Hypoxia stimulates metastasis in cancer and is linked to poor patient prognosis. In tumours, oxygen levels vary and hypoxic regions exist within a generally well-oxygenated tumour. However, whilst the heterogeneous environment is known to contribute to metastatic progression, little is known about the mechanism by which heterogeneic hypoxia contributes to cancer progression. This is largely because existing experimental models do not recapitulate the heterogeneous nature of hypoxia. The primary effector of the hypoxic response is the transcription factor Hypoxia inducible factor 1-alpha (HIF1-alpha). HIF1-alpha is stabilised in response to low oxygen levels in the cellular environment and its expression is seen in hypoxic regions throughout the tumour.\n\nWe have developed a model system in which HIF1-alpha can be induced within a sub-population of cancer cells, thus enabling us to mimic the effects of heterogeneic HIF1-alpha expression.\n\nWe show that induction of HIF1-alpha not only recapitulates elements of the hypoxic response in the induced cells but also results in significant changes in proliferation, gene expression and mammosphere formation within the HIF1-alpha negative population.\n\nThese findings suggest that the HIF1-alpha expressing cells found within hypoxic regions are likely to contribute to the subsequent progression of a tumour by modifying the behaviour of cells in the non-hypoxic regions of the local micro-environment.

cancer biology↗

bioRxiv2017

Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect susceptibility to developmental polychlorinated biphenyl exposure in mice: Relevance to studies of human neurological disorders

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with the discovery of new sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but there is some evidence that high PCB exposure in adults increases the risk of Parkinsons disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect susceptibility to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity AhrbCyp1a2(-/-) mice were most susceptible compared with poor-affinity AhrdCyp1a2(-/-) and wild type AhrbCyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in multiple tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated immune suppression with reduced thymus and spleen weights and significantly reduced thyroxine at P14. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immuno-staining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity AhrdCyp1a2(-/-) while AhrbCyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinsons disease.

pharmacology and toxicology↗