Biology subjects

Demarest, P.

Publications and source records attributed to Demarest, P..

6 recordsLinked to original sources

bioRxiv2024

Vibrotactile auricular vagus nerve stimulation alters limbic system connectivity in humans: A pilot study

Vibration offers a potential alternative modality for transcutaneous auricular vagus nerve stimulation (taVNS). However, mechanisms of action are not well-defined. The goal of this study was to evaluate the potential of vibrotactile stimulation as a method for activating central brain regions akin to other vagal nerve stimulation methodologies. To do so, intracranial electrophysiological signals were recorded in human subjects to perform a parametric characterization of vibrotactile taVNS and investigate changes in coherence across key brain regions. We hypothesized that vibrotactile taVNS would increase coherence between limbic brain areas, similar to areas activated by classic electrical VNS approaches. Our specific regions of interest included the orbitofrontal cortex, anterior cingulate cortex, amygdala, hippocampus, and parahippocampal gyrus. Patients with intractable epilepsy undergoing stereotactic electroencephalography (sEEG) monitoring participated in the study. Vibrotactile taVNS was administered across five vibration frequencies following a randomized stimulation on/off pattern, and sEEG signals were recorded throughout. Spectral coherence in response to stimulation was defined across four canonical frequency bands, theta, alpha, beta, and broadband gamma. At the group level, vibrotactile taVNS resulted in significantly increased global low-frequency coherence. Anatomically, multiple limbic brain regions exhibited notably increased coherence during taVNS compared to baseline. The percentage of total electrode pairs demonstrating increased coherence was also quantified at the individual level. 20 Hz vibration resulted in the highest percentage of responder pairs across low-frequency coherence measures, but notable inter-subject variability was present. Overall, vibrotactile taVNS induced significant low-frequency coherence increases involving several limbic system structures. Further, parametric characterization revealed the presence of inter-subject variability in terms of identifying the optimal vibration frequency. These findings encourage continued research into vibrotactile stimulation as an alternative modality for noninvasive vagus nerve stimulation.

neuroscience↗

bioRxiv2024

Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas

Despite the potential of targeted epigenetic therapies, most cancers do not respond to current epigenetic drugs. The Polycomb repressive complex EZH2 inhibitor tazemetostat was recently approved for the treatment of SMARCB1-deficient epithelioid sarcomas, based on the functional antagonism between PRC2 and loss of SMARCB1. Through the analysis of tazemetostat-treated patient tumors, we recently defined key principles of their response and resistance to EZH2 epigenetic therapy. Here, using transcriptomic inference from SMARCB1-deficient tumor cells, we nominate the DNA damage repair kinase ATR as a target for rational combination EZH2 epigenetic therapy. We show that EZH2 inhibition promotes DNA damage in epithelioid and rhabdoid tumor cells, at least in part via its induction of the transposase-derived PGBD5. We leverage this collateral synthetic lethal dependency to target PGBD5-dependent DNA damage by inhibition of ATR but not CHK1 using elimusertib. Consequently, combined EZH2 and ATR inhibition improves therapeutic responses in diverse patient-derived epithelioid and rhabdoid tumors in vivo. This advances a combination epigenetic therapy based on EZH2-PGBD5 synthetic lethal dependency suitable for immediate translation to clinical trials for patients.

cancer biology↗

bioRxiv2024

Does Vibrotactile Stimulation of the Auricular Vagus Nerve Enhance Working Memory? A Behavioral and Physiological Investigation

BackgroundWorking memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular VNS (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact. ObjectiveWe aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter. MethodThis study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control). ResultsIn 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metric d compared to the baseline but not to the sham. Moreover, we found that the reduction rate of d with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham. ConclusionOur findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory. HighlightsO_LIVibrotactile stimulation of the auricular vagus nerve increases general arousal. C_LIO_LIVibrotactile stimulation of the auricular vagus nerve mitigates arousal decreases as subjects continuously perform working memory tasks. C_LIO_LI6 Hz Vibrotactile auricular vagus nerve stimulation is a potential intervention for enhancing working memory performance. C_LI

bioengineering↗

bioRxiv2023

A transposase-derived gene required for human brain development

DNA transposable elements and transposase-derived genes are present in most living organisms, including vertebrates, but their function is largely unknown. PiggyBac Transposable Element Derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase-derived gene with retained nuclease activity in human cells. Vertebrate brain development is known to be associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood. Here, we show that PGBD5 contributes to normal brain development in mice and humans, where its deficiency causes disorder of intellectual disability, movement, and seizures. In mice, Pgbd5 is required for the developmental induction of post-mitotic DNA breaks and recurrent somatic genome rearrangements. In the brain cortex, loss of Pgbd5 leads to aberrant differentiation and gene expression of distinct neuronal populations, including specific types of glutamatergic neurons, which explains the features of PGBD5 deficiency in humans. Thus, PGBD5 might be a transposase-derived enzyme required for brain development in mammals. One-Sentence SummaryPiggyBac Transposable Element Derived 5 (PGBD5) is required for brain development in humans and mice through genetic and epigenetic mechanisms.

neuroscience↗

bioRxiv2023

Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy

Essential epigenetic dependencies have become evident in many cancers. Based on the functional antagonism between BAF/SWI/SNF and PRC2 in SMARCB1-deficient sarcomas, we and colleagues recently completed the clinical trial of the EZH2 inhibitor tazemetostat. However, the principles of tumor response to epigenetic therapy in general, and tazemetostat in particular, remain unknown. Using functional genomics of patient tumors and diverse experimental models, we sought to define molecular mechanisms of tazemetostat resistance in SMARCB1-deficient sarcomas and rhabdoid tumors. We found distinct classes of acquired mutations that converge on the RB1/E2F axis and decouple EZH2-dependent differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest despite EZH2 inhibition, and suggests a general mechanism for effective EZH2 therapy. This also enables us to develop combination strategies to circumvent tazemetostat resistance using cell cycle bypass targeting via AURKB, and synthetic lethal targeting of PGBD5-dependent DNA damage repair via ATR. This reveals prospective biomarkers for therapy stratification, including PRICKLE1 associated with tazemetostat resistance. In all, this work offers a paradigm for rational epigenetic combination therapy suitable for immediate translation to clinical trials for epithelioid sarcomas, rhabdoid tumors, and other epigenetically dysregulated cancers. SignificanceGenomic studies of patient epithelioid sarcomas, rhabdoid tumors, and their cell lines identify mutations converging on a common pathway that is essential for response to EZH2 inhibition. Resistance mutations decouple drug-induced differentiation from cell cycle control. We identify complementary epigenetic combination strategies to overcome resistance and improve durability of response, supporting their investigation in clinical trials.

cancer biology↗

bioRxiv2022

Childhood cancer mutagenesis caused by a domesticated DNA transposase

Genomic rearrangements are a hallmark of most solid tumors, including medulloblastoma, one of the most common brain tumors in children. Childhood cancers involve dysregulated cell development, but their mutational causes remain largely unknown. One of the most common forms of medulloblastoma is caused by ectopic activation of Sonic Hedgehog (SHH) signaling in cerebellar granule cell progenitors, associated with genetic deletions, amplifications, and other oncogenic chromosomal rearrangements. Here, we show that PiggyBac Transposable Element Derived 5 (Pgbd5) promotes tumor development in multiple developmentally-accurate mouse models of SHH medulloblastoma. Most mice with Pgbd5 deficiency do not develop tumors, while Pgbd5-deficient mice maintain largely normal cerebellar development. Mouse medulloblastomas expressing Pgbd5 exhibit significantly increased numbers of somatic structural DNA rearrangements, with PGBD5-specific transposon sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. Therefore, this study identifies PGBD5 as a primary medulloblastoma mutator and provides a genetic mechanism responsible for the generation of somatic oncogenic DNA rearrangements in childhood cancer. One-Sentence SummaryInduction of somatic oncogenic mutations by the DNA transposase PGBD5 in cerebellar progenitor cells promotes medulloblastoma development.

cancer biology↗