Biology subjects

Hebert, R.

Publications and source records attributed to Hebert, R..

4 recordsLinked to original sources

bioRxiv2026

Proteomic and Transcriptomic Differences in Ischemic Stroke Patients with Atrial Fibrillation Versus Carotid Atherosclerosis

BackgroundIschemic stroke occurring in the setting of atrial fibrillation (AF) or carotid atherosclerosis (CA) may reflect distinct underlying biological processes. We integrated proteomic, transcriptomic, and genetic data from different sources to identify circulating proteins and molecular pathways associated with ischemic stroke in patients with AF versus CA. MethodsWe conducted a nested proteomic study within the UK Biobank comparing plasma protein levels among ischemic stroke patients with AF (n=539) and CA (n=127). Linear regression models were used to evaluate 2,923 proteins measured using the Olink Explore platform (false discovery rate [FDR] <0.05). In a separate Yale cohort, we evaluated expression of genes encoding identified proteins in thrombectomy clot single-cell RNA sequencing data from ischemic stroke patients with AF (n=7) or CA (n=7), including cell type-specific expression patterns. We then used summary statistics to perform 2-sample Mendelian randomization analyses using cis-protein quantitative trait loci to evaluate associations between genetically predicted levels of proteins identified in prior analyses and ischemic stroke subtypes. Exploratory pathway enrichment analyses were also performed. ResultsTwelve circulating proteins differed significantly between ischemic stroke patients with AF versus CA. AF was associated with higher levels of NTproBNP, NPPB, and ACP5, and lower levels of APCS, ANGPT2, PAMR1, PRCP, PROS1, LARP1, F7, F10, and LEO1 (all FDR<0.05). Clot transcriptomic analyses showed corresponding differential expression of ACP5, PRCP, LARP1, ANGPT2, and LEO1 across AF versus CA patients. Pathway analyses suggested enrichment of coagulation-related pathways among proteins associated with CA and natriuretic peptide signaling pathways among proteins associated with AF. Mendelian randomization analyses demonstrated associations between genetically predicted protein levels and ischemic stroke subtypes (AF or CA), including cardioembolic stroke for NTproBNPand ischemic stroke for ANGPT2, ACP5, APCS, and PAMR1. ConclusionComplementary proteomic, transcriptomic, and genetic analyses identified differing molecular profiles among ischemic stroke patients with AF versus CA. These findings support established biomarkers, including NTproBNP and coagulation-related proteins, while identifying additional candidate pathways that may contribute to biological differences between these stroke-associated conditions. Further validation in clinically adjudicated and longitudinal cohorts is needed.

neuroscience↗

bioRxiv2025

Molecular Mechanisms of Gain-of-Function Mutations in {lambda} Cro Revealed by Molecular Dynamics Simulations

Transcription factors regulate gene expression by coordinating complex networks in organisms ranging from bacteriophages to humans. Bacteriophage {lambda} Cro is a 66-residue repressor that binds DNA as a dimer to block transcription. Because of its small size, simple structure, and well-characterized function, Cro has long served as a model system for understanding the structure/function relationship in transcription factors. Experiments have shown that a small set of mutations can convert it into a dual-function transcription factor capable of both repression and activation. One engineered variant retains activity when truncated to 63 amino acids but loses function at 59, highlighting how little sequence is required for complex regulatory behavior. To probe the molecular basis of this adaptability, we performed multi-microsecond all-atom molecular dynamics simulations of wild-type Cro and two engineered variants, Act3 and Act8. The simulations reveal that minimal sequence changes can reorganize interaction surfaces, shift DNA-binding modes, modulate binding affinities, and redistribute intramolecular communication pathways. These effects on DNA binding occur alongside changes that may broaden regulatory potential, offering insight into how compact transcription factors evolve new functions. Together, these observations provide a mechanistic framework for understanding how transcription factor sequence, structure, and dynamics reshape gene regulatory function.

biophysics↗

bioRxiv2025

Deciphering the Molecular Mechanisms of BPTF Interactions with Nucleosomes via Molecular Simulations

Many transcription factors regulate DNA accessibility and gene expression by recognizing post-translational modifications on histone tails within nucleosomes. These interactions are often studied in vitro using short peptide mimics of histone tails, which may overlook conformational changes that occur in the full nucleosomal context. Here, we employ molecular dynamics simulations to investigate the binding dynamics of the PHD finger and bromodomain of BPTF, both in solution and bound to either a histone H3 peptide or a full nucleosome. Our results show that BPTF adopts distinct conformational states depending on its binding context, with nucleosome engagement inducing compaction of the multidomain structure. PHD finger binding displaces the H3 tail from DNA, increasing H3 tail flexibility while promoting compensatory binding of the H4 tail to nucleosomal DNA. This redistribution of histone-DNA contacts weakens overall hydrogen bonding with DNA, suggesting localized destabilization of the nucleosome core. Despite electrostatic repulsion limiting direct reader-DNA contacts, strong Van der Waals interactions with the H3 tail stabilize binding. Our results provide atomistic insight into how BPTF engagement modulates nucleosome structure and may facilitate chromatin remodeling.

biophysics↗

bioRxiv2025

Non-invasive approach for endoluminal biopsy coupled with single-cell proteomics allows for immune characterization of intracranial aneurysms

The immune regulatory mechanisms driving the stability, growth, and rupture of intracranial aneurysms (IAs) remain incompletely understood. In this study, we employ endoluminal biopsy with single-cell proteomics to comprehensively profile the immune landscape of IAs across their pathologic states. Our findings reveal distinct immune signatures associated with aneurysm states. Stable, i.e. non-growing unruptured, IAs exhibit a balanced immune cell composition. Ruptured IAs are marked by significant neutrophil predominance. Notably, we highlight key immune markers in aneurysm instability, offering new insights into immune drivers of aneurysm progression. These findings provide a foundation for immune-targeted, non-invasive therapeutic strategies aimed at targeting IAs and preventing rupture.

physiology↗