Biology subjects

Varga, D.

Publications and source records attributed to Varga, D..

7 recordsLinked to original sources

bioRxiv2026

Extracellular vesicles from triple negative breast cancer cells disrupt the blood-brain barrier via miR-146a-5p- and TGF-β1-mediated downregulation of endothelial Paqr5

Brain metastases are a common and often fatal complication of certain cancer types, such as triple-negative breast cancer. However, the molecular pathways driving brain metastasis formation, including the migration of cancer cells from the bloodstream to the brain parenchyma across the blood-brain barrier, are not yet fully defined. Therefore, using highly relevant mouse and human model systems, the mechanisms by which triple-negative breast cancer cells and their released extracellular vesicles modulate the blood-brain barrier-forming endothelium to increase its permissiveness to tumour cell entry into the brain are investigated. It is observed that extracellular vesicles derived from tumour cells are taken up by cerebral endothelial cells, where they induce miR-146a-5p- and TGF-{beta}1-mediated downregulation of PAQR5/mPR{gamma}, a membrane progesterone receptor. This, in turn, leads to disruption of interendothelial tight junctions, particularly through repression of claudin-5 expression, a critical protein for maintaining barrier function. Altogether this identifies a novel mechanism by which triple-negative breast cancer-derived extracellular vesicles compromise blood-brain barrier integrity, thereby facilitating transendothelial migration of cancer cells and promoting brain metastasis development. Moreover, this study is the first to highlight the role of membrane progesterone receptors in regulating the blood-brain barrier. Table of contents O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/701753v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@113c0a8org.highwire.dtl.DTLVardef@1cd5625org.highwire.dtl.DTLVardef@1d2b3c2org.highwire.dtl.DTLVardef@178a97_HPS_FORMAT_FIGEXP M_FIG Extracellular vesicles from triple-negative breast cancer cells induce miR-146a-5p- and TGF-1-mediated downregulation of PAQR5/mPR{gamma}, a membrane progesterone receptor, in blood-brain barrier-forming endothelial cells. This results in disruption of interendothelial tight junctions, thereby promoting enhanced migration of cancer cells into the brain. This mechanism highlights the role of membrane progesterone receptors in regulating the blood-brain barrier. C_FIG

cancer biology↗

bioRxiv2023

Visual to default network pathways: A double dissociation between semantic and spatial cognition

Processing pathways between sensory and default mode network (DMN) regions support recognition, navigation, and memory but their organisation is not well understood. We show that functional subdivisions of visual cortex and DMN sit at opposing ends of parallel streams of information processing that support visually-mediated semantic and spatial cognition, providing convergent evidence from univariate and multivariate task responses, intrinsic functional and structural connectivity. Participants learned virtual environments consisting of buildings populated with objects, drawn from either a single semantic category or multiple categories. Later, they made semantic and spatial context decisions about these objects and buildings during functional magnetic resonance imaging. A lateral ventral occipital to frontotemporal DMN pathway was primarily engaged by semantic judgements, while a medial visual to medial temporal DMN pathway supported spatial context judgements. These pathways had distinctive locations in functional connectivity space: the semantic pathway was both further from unimodal systems and more balanced between visual and auditory-motor regions compared with the spatial pathway. When semantic and spatial context information could be integrated (in buildings containing objects from a single category), regions at the intersection of these pathways responded, suggesting that parallel processing streams interact at multiple levels of the cortical hierarchy to produce coherent memory-guided cognition.

neuroscience↗

bioRxiv2022

Phase separated ribosome nascent chain complexes paused in translation are capable to continue expression of proteins playing role in genotoxic stress response upon DNA damage

EDTA- and RNase-resistant ribonucleoprotein complexes of arrested ribosomes with protruding nascent polypeptide chains have recently been described in yeast and human cells. These complexes have been termed assemblysomes, a type of soluble condensates distinct from other known granules. Here, we use bioinformatics to identify additional proteins that likely form assemblysomes during translation. We characterize soluble condensates of the DNA helicase Sgs1, one such identified protein and a key player in the repair of DNA double-strand breaks in yeast. We show that paused ribosome-associated nascent chains of Sgs1 in condensates are able to resume translation upon UV irradiation, consistent with the return of mRNA to the ribosome pool. By extending our studies to human cell lines, we found that EDTA-resistant pellets of ribosomes from the human prostate cancer cell line DU145 are sensitive to treatment with 1,6-hexanediol, which is known to dissolve liquid-liquid phase-separated condensates. In addition, transmission electron microscopy shows that 1,6-hexanediol dissolves ring ribosomal structures from the cytoplasm of radioresistant A549 cells while making the cells more sensitive to X-rays. These results suggest that the stress response is based on a conserved mechanism involving the regulated return of phase-separated paused ribosome-nascent chain complexes to translating ribosomes.

molecular biology↗

bioRxiv2021

Context Free and Context-Dependent Conceptual Representation in the Temporal Lobes

How concepts are coded in the brain is a core issue in cognitive neuroscience. Studies have focused on how individual concepts are processed, but the way in which conceptual representation changes to suit the context is unclear. We parametrically manipulated the association strength between words, presented in pairs one word at a time using a slow event-related fMRI design. We combined representational similarity analysis and computational linguistics to probe the neurocomputational content of these trials. Individual word meaning was maintained in supramarginal gyrus (associated with verbal short-term memory) when items were judged to be unrelated, but not when a linking context was retrieved. Context-dependent meaning was instead represented in left lateral prefrontal gyrus (associated with controlled retrieval), angular gyrus and ventral temporal lobe (regions associated with integrative aspects of memory). Analyses of informational connectivity, examining the similarity of activation patterns across trials between sites, showed that control network regions had more similar multivariate responses across trials when association strength was weak, reflecting a common controlled retrieval state when the task required more unusual associations. These findings indicate that semantic control and representational sites amplify contextually-relevant meanings in trials judged to be related.

neuroscience↗

bioRxiv2020

Distinct and Common Neural Coding of Semantic and Non-semantic Control Demands

The flexible retrieval of knowledge is critical in everyday situations involving problem solving, reasoning and social interaction. Current theories emphasise the importance of a left-lateralised semantic control network (SCN) in supporting flexible semantic behaviour, while a bilateral multiple-demand network (MDN) is implicated in executive functions across domains. No study, however, has examined whether semantic and non-semantic demands are reflected in a common neural code within regions specifically implicated in semantic control. Using functional MRI and univariate parametric modulation analysis as well as multivariate pattern analysis, we found that semantic and non-semantic demands gave rise to both similar and distinct neural responses across control-related networks. Though activity patterns in SCN and MDN could decode the difficulty of both semantic and verbal working memory decisions, there was no shared common neural coding of cognitive demands in SCN regions. In contrast, regions in MDN showed common patterns across manipulations of semantic and working memory control demands, with successful cross-classification of difficulty across tasks. Therefore, SCN and MDN can be dissociated according to the information they maintain about cognitive demands.

neuroscience↗

bioRxiv2020

Distinct default mode network subsystems show similarities and differences in the effect of task focus across reading and autobiographical memory

While reading, the mind can wander to unrelated autobiographical information, creating a perceptually-decoupled state detrimental to narrative comprehension. To understand how this mind-wandering state emerges, we asked whether retrieving autobiographical content necessitates functional disengagement from visual input. In Experiment 1, brain activity was recorded using functional magnetic resonance imaging (fMRI) in an experimental situation mimicking naturally occurring mind-wandering, allowing us to precisely delineate neural regions involved in memory and reading. Individuals read expository texts and ignored personally relevant autobiographical memories, as well as the opposite situation. Medial regions of the default mode network (DMN) were recruited during memory retrieval. In contrast, left temporal and lateral prefrontal regions of the DMN, as well as ventral visual cortex, were recruited when reading for comprehension. Experiment 2 used functional connectivity at rest to establish that (i) DMN regions linked to memory are more functionally decoupled from regions of ventral visual cortex than regions in the same network engaged when reading, and (ii) individuals reporting more mind-wandering and worse comprehension, while reading in the lab, showed increased functional decoupling between visually-connected DMN sites important for reading and a region of dorsal occipital cortex linked to autobiographical memory in Experiment 1. These data suggest we lose track of the narrative when our mind wanders because the generation of autobiographical mental content relies on cortical regions within the DMN which are functionally decoupled from ventral visual regions engaged during reading. Significance statementWhen the mind wanders during reading, we lose track of information from the narrative. We hypothesised that poor comprehension occurs because retrieving autobiographical memories reduces the perceptual coupling necessary to understand written words. We show that default mode network (DMN) areas involved in reading are functionally more connected to ventral visual regions than DMN regions important for autobiographical memory. Furthermore, individuals who mind-wander more, and comprehend less, have weaker connectivity between visually-coupled DMN regions linked to reading and dorsal occipital areas linked to autobiographical memory. These data suggest that when our minds wander during reading, retrieval of personally-relevant information activates DMN regions that are functionally disconnected from visual input, creating a perceptually decoupled state detrimental to comprehension.

neuroscience↗

bioRxiv2019

Quantification of DNA damage induced γH2AX focus formation via super-resolution dSTORM localization microscopy

In eukaryotic cells, each process, in which DNA is involved, should take place in the context of chromatin structure. DNA double-strand breaks (DSBs) are one of the most deleterious damages often leading to chromosomal rearrangement. In response to environmental stresses, cells have developed repair mechanisms to eliminate the DSBs. Upon DSB induction, several factors play roles in chromatin relaxation by catalysing the appropriate histone posttranslational modification (PTM) steps, therefore promoting the access of the repair factors to the DSBs. Among these PTMs, the phosphorylation of the histone variant H2AX at its Ser139 residue (also known as {gamma}H2AX) could be observed at the break sites. The structure of {gamma}H2AX focus has to be organized during the repair as it contributes to accessibility of specific repair proteins to the damaged site. Our aim was to develop a quantitative approach to analyse the morphology of individual repair foci by super-resolution dSTORM microscopy to gain insight into genome organization in DNA repair. We have established a specific dSTORM measurement process by developing a new analytical algorithm for gaining quantitative information about chromatin morphology and repair foci topology at individual {gamma}H2AX enriched repair focus. By this method we quantified unique repair foci to show the average distribution of {gamma}H2AX clusters. By monitoring {gamma}H2AX signal, we could reach 20 nm spatial resolution and resolve a single DNA damage spot, which allow us to identify different chromatin sub-clusters around the break site. Additionally, based on our new analysis method, we were able to show the number of nucleosomes in each sub-cluster that could allow us to define the possible chromatin structure and the nucleosome density around the break sites. This method is the first demonstration of a single-cell based quantitative measurement of a discrete repair focus, which could provide new opportunities to categorize spatial organization of dot patterns by parametric determination of topological similarity.

cell biology↗