Biology subjects

Weil, A. G.

Publications and source records attributed to Weil, A. G..

3 recordsLinked to original sources

bioRxiv2026

Connectome-wide mega-analysis identifies a reproducible functional network signature of temporal lobe epilepsy

Resting-state functional magnetic resonance imaging (MRI) studies have reported abnormal intrinsic functional connectivity (FC) across distributed circuits in patients with temporal lobe epilepsy (TLE), indicating a system-level impact of the disorder. However, findings remain inconsistent due to limited sample sizes and methodological heterogeneity, leaving the structural determinants and clinical relevance of FC alterations unresolved. To identify a robust and reproducible FC signature, we conducted a data-driven, connectome-wide mega-analysis in a large multicentre cohort of 652 participants (297 TLE, 73 disease controls, and 282 healthy controls) with multimodal 3T MRI and deep clinical phenotyping. We identified convergent FC reconfigurations at both group and individual levels that preferentially involved densely connected hubs, manifesting as hyperconnectivity in frontoparietal association systems and hypoconnectivity in temporal and paralimbic systems. Integrating structural cortical wiring features further revealed that these extensive alterations were constrained by corticocortical proximity, microstructural similarity, and white matter connectivity. Clinically, the FC phenotype tracked symptom burden and disease progression, informed postsurgical seizure outcome, and distinguished TLE from other focal epilepsies. Collectively, these findings systematically delineate a neurobiologically grounded, hub-centric pattern of intrinsic network disruption in TLE, anchored in temporolimbic and adjacent transmodal systems, with potential utility for individualized phenotypic stratification and outcome prognostication.

neuroscience↗

bioRxiv2025

Personalized Biomarkers of Multiscale Functional Alterations in Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) presents with substantial inter-patient variability in clinical and neuroimaging manifestations. This multicenter study examined inter-individual differences in spatial patterns of intrinsic brain function in TLE using normative modeling at multiple spatial scales and evaluated the effectiveness of individual functional deviations for clinical diagnosis and postsurgical outcome prediction. We analyzed multimodal MRI data on 298 healthy controls, 282 TLE patients, and 45 disease controls with extratemporal epilepsy. Cortical function was profiled at local, regional, and global scales using brain signal variability, regional homogeneity, and node strength. We estimated patient-specific W-score maps to index deviations from normative metrics. Compared to healthy controls, patients with TLE showed considerable variations in patterns of functional alterations across the cortex, with the highest overlap in the ipsilateral mesiotemporal regions. Connectome-based simulation revealed the paralimbic and medial default mode regions as key disease epicenters. Functional changes were primarily underpinned by superficial white matter anomalies. Supervised pattern learning achieved classification AUCs of 0.76 for TLE versus disease controls, 0.74 for left versus right TLE, and 0.63 for seizure-free versus non-seizure-free TLE, with greater contralateral temporal functional deviations correlating with unfavorable postsurgical seizure outcome. Our findings reveal the heterogeneous impact of TLE on intrinsic cortical function. These biomarkers hold promise for clinical translation, guiding precision therapeutics and enhancing presurgical decision-making in TLE.

neuroscience↗

bioRxiv2023

H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs

Polycomb Repressive Complex 2 (PRC2)-mediated histone H3K27 tri-methylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, polycomb-regulated genes are connected through long-range 3D interactions which resolve upon differentiation. Here, we report that polycomb looping is controlled by H3K27me3 spreading and regulates target gene silencing and cell fate specification. Using glioma-derived H3 Lys-27-Met (H3K27M) mutations as tools to restrict H3K27me3 deposition, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened 3D interactions mirroring chromatin architecture of pluripotency, and stringent gene repression that maintains cells in progenitor states to facilitate tumor development. Conversely, H3K27me3 spread in pluripotent stem cells, following neural differentiation or loss of the H3K36 methyltransferase NSD1, dilutes cPRC1 concentration and dissolves polycomb loops. These results identify the regulatory principles and disease implications of polycomb looping and nominate histone modification-guided distribution of reader complexes as an important mechanism for nuclear compartment organization. Highlights{square} The confinement of H3K27me3 at PRC2 nucleation sites without its spreading correlates with increased 3D chromatin interactions. {square}The H3K27M oncohistone concentrates canonical PRC1 that anchors chromatin loop interactions in gliomas, silencing developmental programs. {square}Stem and progenitor cells require factors promoting H3K27me3 confinement, including H3K36me2, to maintain cPRC1 loop architecture. {square}The cPRC1-H3K27me3 interaction is a targetable driver of aberrant self-renewal in tumor cells.

molecular biology↗