Biology subjects

Taube, J.

Publications and source records attributed to Taube, J..

9 recordsLinked to original sources

bioRxiv2026

KDM6A is enzymatically active at the Golgi apparatus where it is necessary for maintenance of Golgi apparatus morphology

KDM6A and KDM6B, lysine demethylases, play a central role in regulation of transcription through their demethylation activity towards H3K27me3 and have also been shown to be dynamically regulated upon epithelial-mesenchymal transition (EMT). In particular, KDM6A has been implicated in a variety of malignancies and is frequently mutated in cancers including those in kidney, bladder, colorectal, and breast. KDM6A and KDM6B function as part of the COMPASS-like protein complex (CLC) which includes methyltransferases KMT2C/KMT2D and the regulatory WRAD-subcomplex. KDM6A total protein is known to be suppressed by TGF-{beta} in MCF10A breast cells; however, our examination of protein localization by immunofluorescence and LC-MS/MS reveals that KDM6A expression is lost in the nucleus but retained in the Golgi apparatus, independent of other CLC complex members. Importantly, KDM6A isolated from a biochemically-separated subcellular membranous fraction possesses the catalytic JmjC domain and is enzymatically active, indicating that KDM6A may have non-nuclear substrates. Further, knockdown of KDM6A and treatment with TGF-{beta} similarly alter Golgi apparatus morphology, in a cell type specific manner, suggesting context-dependent regulatory functions. These findings support a model in which KDM6A is necessary to maintain Golgi apparatus morphology and is enzymatically active outside of the nucleus.

cell biology↗

bioRxiv2026

Blindness reshapes mental time travel: From perceptual scenes to conceptual scaffolds

How can humans remember and imagine without vision? Mental time travel, the ability to re-experience past events and envision future ones, is widely assumed to rely on visual imagery and the construction of mental scenes. Blindness provides a critical test of this assumption. Across behavioral interviews, language analyses, and multimodal neuroimaging in congenitally blind, late-blind, and sighted individuals, we show that blind individuals, even those blind from birth, mentally time travel as vividly as sighted people, but construct their inner worlds differently. Sighted participants relied on perceptual detail and activated classic scene-processing regions, whereas blind participants emphasized thoughts and emotions and recruited reorganized occipital cortex. Connectivity analyses revealed strengthened coupling between occipital and medial temporal regions, indicating adaptive reconfiguration of the episodic system. The brain does not require images to imagine: it flexibly builds internal experiences using the representational resources available. Summary ParagraphHow humans reconstruct events that are no longer available to the senses is a fundamental but unresolved question. Remembering the past and imagining the future, known as mental time travel, is a defining feature of human cognition, shaping identity and guiding decisions{superscript 1},{superscript 2}. Prevailing theories assume that such constructions depend on visual imagery, with the minds eye reconstructing events on a visuospatial stage3,. Blindness provides a critical test of this assumption. Across extensive behavioral interviews and multimodal neuroimaging, we find that mental time travel remains phenomenologically intact in blindness, but its scaffolding changes fundamentally. Sighted individuals rely on perceptual detail and activate regions specialized for visual scenes, whereas blind individuals, whether blind from birth or later in life, emphasize thoughts and emotions and reorganize occipital cortex for conceptual strategies,. These contrasting strategies map onto distinct neural signatures, revealing a dissociation between perceptual and conceptual routes to episodic simulation. Together, these findings reveal that the brains capacity to construct internal experience rests on conceptual scaffolding, not perceptual re-creation.

neuroscience↗

bioRxiv2025

Seeing more than schemas: the vmPFC represents imagery- rich mental scenarios

Mental imagery varies dramatically across individuals, from vivid scene construction to the complete absence of visual experience, as seen in aphantasia. While the ventromedial prefrontal cortex (vmPFC) is traditionally associated with abstract, schematic representations, emerging theories suggest it may also contribute to constructing vivid, visual mental content. To test this, we developed a novel 7T fMRI experiment varying imagery demands across conditions: Prior to scanning, participants memorized richly detailed scenarios, more constrained, stationary objects, and finally semantic definitions for each of three abstract German words (e.g., hope). During fMRI and eye-tracking, the same word was presented across trials, but participants vividly re-engaged with one of three distinct representations (i.e., scenarios, objects, and definitions), allowing for comparison across richly different cognitive modes triggered by identical visual input. Univariate analyses confirmed previous findings; highlighting the roles of the vmPFC, hippocampus, parahippocampal cortex, and visual-perceptual cortex in imagery-rich scenario construction. We further performed multivoxel pattern analysis (MVPA) to examine distributed neural representations, which can reveal the informational content of mental imagery beyond activation magnitude. Critically, the vmPFC was the only brain region where MVPA classifier accuracy was higher for scenario construction than for object and abstract conditions, directly supporting our hypothesis that the vmPFC encodes imagery-rich details rather than solely abstract, schematic information. Eye movement variability also distinguished between conditions. These findings advance our understanding of vmPFC function, emphasising its role in representing vivid mental content. HighlightsO_LI{middle dot} vmPFC distinctly represents imagery-rich scenarios in MVPA analysis C_LIO_LIUnivariate fMRI reveals increased HC and PHC activity during scenario construction C_LIO_LIEye movements vary by imagery type, distinguishing scenarios from objects and definitions C_LI

neuroscience↗

bioRxiv2025

Elucidating directed neural dynamics of scene construction across memory and imagination

Autobiographical memory (AM) and imagination both rely on the brains ability to construct vivid, coherent mental representations of past or imagined experiences. A central cognitive process underlying these functions is scene construction--the mental generation of spatially organized, imagery-rich representations of environments. Using ultra-high field 7T fMRI combined with Dynamic Causal Modeling (DCM), we examined directed effective connectivity among key nodes of the default mode network: the ventromedial prefrontal cortex (vmPFC), hippocampus, and precuneus during object imagery, single-scene construction, and AM retrieval. Our results revealed distinct patterns of network dynamics depending on task demands. During AM retrieval, effective connectivity was characterized by vmPFC-driven top-down modulation primarily targeting the precuneus, supporting the temporal and self-relevant structuring of episodic memory. In contrast, extended scenario imagination engaged hippocampal bidirectional influences with both vmPFC and precuneus, reflecting the dynamic simulation and integration of unfolding events. Single Scene construction shifted network leadership to the precuneus, which exerted modulatory effects on both vmPFC and hippocampus, consistent with its pivotal role in spatial integration and the generation of coherent mental scenes. Object imagery showed minimal stable connectivity within this network, suggesting limited engagement of the hippocampal-default mode circuit during simpler visual representations. Together, our findings highlight a flexible, task-dependent reorganization of effective connectivity within the vmPFC- hippocampus-precuneus network during the construction of rich mental experiences. Scene construction emerges as a unifying mechanism linking memory and imagination, with the direction and strength of neural interactions adapting according to whether temporal or spatial demands predominate. HighlightsO_LIAutobiographical memory is reflected by vmPFC-driven effective connectivity C_LIO_LIEffective connectivity varies flexibly amongst vmPFC, hippocampus and precuneus C_LIO_LIScene construction emerges as a core process across memory and imagination C_LI

neuroscience↗

bioRxiv2025

From single scenes to extended scenarios: the role of the ventromedial prefrontal cortex in the construction of imagery-rich events

Mental events are fundamental to daily cognition, including the recollection of past experiences, the anticipation of future scenarios, and engagement in imaginative, fictitious thought. Typically, these temporally extended mental events unfold within coherent spatial contexts, rich in naturalistic scenes and objects. However, there remains a significant gap in understanding how these events are represented in the brain. This study aimed to investigate the neural patterns involved in the construction of temporally extended mental events. Using ultra-high field functional magnetic resonance imaging, we examined brain regions previously implicated in this cognitive process, including the ventromedial prefrontal cortex (vmPFC), hippocampus, and posterior neocortex. We employed a novel experimental paradigm in which participants engaged in three forms of mental imagery: single objects (e.g., "a black espresso"), single scenes (e.g., "a busy cafe"), and extended scenarios (e.g., "meeting a friend for coffee"). We identified a shared neural network - comprising the vmPFC, hippocampus, and posterior neocortex - engaged across all forms of mental imagery. However, we observed a hierarchical organization in their contributions: the posterior neocortex supported the construction of objects, scenes, and scenarios, while the hippocampus primarily contributed to scenes and scenarios. The vmPFC exhibited a stepwise increase in activation, peaking during scenario construction. These findings suggest that the construction of mental events emerges from the close interaction of perceptual details provided by the posterior neocortex, spatial coherence from the hippocampus, and the integration of those elements into a coherent, temporally extended mental event by the vmPFC - the "movies" of the mind.

neuroscience↗

bioRxiv2025

Ophiobolin A selectively alters mitochondria, metabolism and redox biology in breast cancer and mammary epithelial cells which have undergone epithelial to mesenchymal transition

Breast cancer progression is facilitated by the epithelial to mesenchymal transition (EMT), generating cancer cells with enhanced metastatic capacity and resistance to chemotherapeutics. EMT is known to impart changes in metabolic pathways and mitochondrial function. Here, we show a natural product possesses EMT-specific cytotoxic activity via alterations in metabolic and mitochondrial functions. The fungus-derived sesterterpenoid, ophiobolin A (OpA), possesses nanomolar cytotoxic activity and a high therapeutic index, although its target and mechanism of action remain unknown. Here, we utilized a model of mammary epithelial cells and breast cancer cell lines with and without EMT features to characterize the mechanism of selectivity towards EMT(+) cells by OpA and to identify novel targets for the treatment of EMT-enriched breast cancer. Proteins interacting with OpA in EMT(+) cells were identified through proteomic studies. We utilized trans-mitochondrial cybrids to determine that mitochondria mediate sensitivity to OpA. Furthermore, we report effects on glycolysis, oxidative metabolism, and disruption of metabolite abundance in the TCA cycle. Alterations to mitochondrial iron concentrations and glutathione production, mediated partly by OpA engagement with the metabolic proteins CISD3 and SLC25A40, were also detected in EMT(+) cells. Antioxidant mechanisms are activated by OpA in EMT(+) cells via the NRF2-ARE pathway, verified by decreased cytotoxicity in EMT(+) cells pretreated with the NRF2 activator CDDO. Collectively, we conclude that OpA selectivity toward EMT is mediated by the mitochondria, and at sub-cytotoxic levels, generates a metabolic shift leading to cell death countered by antioxidant mechanisms.

cancer biology↗

bioRxiv2025

PANoptosis, a combination of inflammatory cell death mechanisms, induced 1 by Ophiobolin A in breast cancer cell lines

An unmet challenge in managing breast cancer is treatment failure due to resistance to apoptosis-inducing chemotherapies. Thus, it is important to identify novel non-apoptotic therapeutic agents. Several non-apoptotic programmed cell death pathways utilize specific cellular signaling events to trigger lytic and pro-inflammatory cell death. PANoptosis, which encompasses pyroptosis, apoptosis and necroptosis, is of paramount importance in the regulation of cell death and immune responses. Our study illustrates that ophiobolin A (OpA) is an anti-cancer agent that triggers lytic cell death in breast cancer cells, including triple-negative breast cancer (TNBC), via a mechanism dependent on RIPK1. This study reveals that OpA induces typical pyroptosis-like characteristics, including cellular swelling, plasma membrane rupture, GSDMD cleavage and release of cytokines in breast cancer cells. The involvement of caspase 3, RIPK1, and GSDMD suggests that PANoptosis is activated upon OpA treatment in breast cancer. The induction of pro-inflammatory cell death suggests potential applications for OpA in cancer treatment.

cancer biology↗

bioRxiv2021

Epithelial-mesenchymal plasticity through loss of CTCF motif accessibility and protein expression

Epithelial-mesenchymal transition (EMT) and its reversal, mesenchymal-epithelial transition (MET) drive tissue reorganization critical for early development. In carcinomas, processing through EMT, MET or partial states promotes migration, invasion, dormancy, and metastatic colonization. As a reversible process, EMT is inherently regulated at epigenetic and epigenomic levels. To understand the epigenomic nature of reversible EMT and its partial states, we characterized chromatin accessibility dynamics, transcriptomic output, protein expression, and cellular phenotypes during stepwise reversible EMT. We found that the chromatin insulating protein machinery, including CTCF, is suppressed and re-expressed, coincident with broad alterations in chromatin accessibility, during EMT/MET and is lower in triple-negative breast cancer cell lines with EMT features. Through analysis of chromatin accessibility using ATAC-seq, we identify that early phases of EMT are characterized by enrichment for AP-1 family member binding motifs but also by diminished enrichment for CTCF binding motifs. Through loss-of-function analysis we demonstrate that suppression of CTCF alters cellular plasticity, facilitating entrance into a partial EMT state. These findings are indicative of a role of CTCF and chromatin reorganization for epithelial-mesenchymal plasticity.

cell biology↗

bioRxiv2020

Gene expression and chromatin accessibility during progressive EMT and MET linked to dynamic CTCF engagement

BackgroundEpithelial-mesenchymal transition (EMT) facilitates cellular movements critical for proper development; however, in a carcinoma, EMT promotes metastatic dissemination. Stable intermediate states (partial-EMT) are increasingly implicated in metastatic dissemination while reversal of EMT, termed mesenchymal-epithelial transition (MET), is increasingly implicated in metastatic colonization. To understand the partial and reversible nature of EMT, we characterized chromatin accessibility dynamics, transcriptome changes, protein expression patterns, as well as E-cadherin expression, localization, and gene-level dynamics in mammary epithelial cells undergoing stepwise reversible EMT. ResultsWhile shorter EMT induction induced internalization of E-cadherin protein, surface expression was recovered upon MET without loss of transcript or bulk protein. Conversely, a longer EMT induced stable repression of E-cadherin indicated by loss of chromatin accessibility and induced global expansion of accessible sites across the genome, facilitated by increased engagement of multiple transcription factor families, including AP-1 and SMAD. We observe enrichment for binding sites for the insulator proteins CTCF and BORIS was significantly diminished in both stemness-enriched partial-EMT and partial-MET states and determined that CTCF repression imparts alterations in some histone covalent modifications concomitant with those observed during TGF{beta}-induced EMT. ConclusionsThese findings are indicative of a major role for chromatin looping and reorganization in plasticity, stemness, and partial EMT phenotypes.

cell biology↗