Biology subjects

Bahry, E.

Publications and source records attributed to Bahry, E..

7 recordsLinked to original sources

bioRxiv2026

Tau spreading coordinates intercellular lipid flux enhancing neuronal resilience to lipid toxicity

The presence of intrinsically disordered proteins (IDPs) in the extracellular environment of the brain suggests that protein disorder may serve functions beyond those confined to the intracellular space. Tau, a prototypical IDP linked to tauopathies, a class of neurodegenerative diseases, is continuously released and spreads between cells in the brain, yet the biological significance of this extracellular phase remains unresolved. Here, we show that spreading tau coordinates neutral lipid homeostasis by promoting neuronal lipid efflux and enhancing resilience to lipid toxicity. Integrating transcriptomics and lipidomics, we demonstrate that tau spreading reprograms lipid transport pathways and triggers redistribution of triacylglycerol pools, remodeling neutral lipid metabolism. Mechanistically, cellular uptake of spreading tau drives its accumulation within neutral lipid-rich compartments and promotes neuronal lipid efflux. The exported lipids are enriched in peroxidized species that are subsequently transferred to astrocytes, reducing neuronal lipid stress and revealing a pathway through which tau regulates lipid homeostasis. Our findings reframe spreading tau as a regulator of intercellular lipid flux and position protein disorder as an active mediator of cell-to-cell communication in coordinating tissue metabolism. Loss of this homeostatic function is likely to contribute to the early metabolic dysfunction associated with tauopathy.

neuroscience↗

bioRxiv2026

Efficient CRISPR/Cas9-mediated homology independent sequence replacement in vivo and non-dividing primary cells

Precise sequence replacement in non-dividing cells remains a major challenge for genome editing. Here we show that REPLACE (Rational end-joining protocol delivering a targeted sequence exchange), a homology-independent CRISPR/Cas9-based replacement strategy, enables exon- and gene-scale substitution in primary cells, in vivo tissues and post-mitotic human cardiomyocytes. REPLACE uses two guide RNAs to excise a defined genomic region and inserts a donor lacking homology arms through non-homologous end joining (NHEJ). In primary mouse hepatocytes, REPLACE mediated exon replacement in 35% of all cells. In adult mouse liver, editing efficiency could be increased to [~]20% when Cas9-sgRNA ribonucleoproteins were delivered via engineered virus-like particles (eVLPs) together with an adeno-associated virus (AAV) donor. REPLACE also supported large-segment replacement, enabling one-step exchange of a [~]27-kb mouse Ace2 interval with the human ACE2 coding region in zygotes, followed by germline transmission and tissue-specific expression. Finally, we applied REPLACE to a disease-relevant mutation that is not readily addressable by base editing and was poorly corrected by prime editing in post-mitotic cardiomyocytes. At the LMNA locus, REPLACE corrected the K117fs frameshift mutation in patient-derived post-mitotic cardiomyocytes with precise exon replacement and restored Lamin A/C protein expression and nuclear lamina localization. These findings establish REPLACE as a versatile platform for homology-independent sequence replacement and as a complementary approach for genetic correction in settings where homology-directed repair (HDR), base editing (BE) or prime editing (PE) are inefficient or not applicable.

genomics↗

bioRxiv2026

A generative AI framework for disease-specific lung microtissue bioengineering

Generative Lung Architecture Modeling (GLAM) is an integrated bioengineering framework that couples high-resolution three-dimensional tissue imaging with generative artificial intelligence to de novo design and 3D-bioprint anatomically detailed lung microtissue models. Native extracellular 3D matrix architectures of pulmonary parenchyma were extracted from healthy, fibrotic, and emphysematous in vivo mouse disease models and processed through a computational pipeline containing pre-trained image segmentation and 3D mesh generation. The resulting datasets were used to train a U-Net generative diffusion model with attention layers capable of synthesizing healthy and diseased lung tissue architectures. Microtissue cubes of about 200 - 300 {micro}m edge length of native and synthetic datasets were fabricated through high-resolution two-photon stereolithography with gelatin-methacryloyl biomaterial ink and successfully seeded with cells, demonstrating biological compatibility. In closing the loop between biological imaging, generative modeling, and high-resolution biofabrication, this integrated framework establishes generative AI as a functional design layer for tissue engineering. The resulting lung microtissues retained architectural features of the native and original tissues, making them an application-ready platform for customizable and scalable fabrication of biological tissue surrogates for preclinical modeling, drug testing, and precision regenerative bioengineering.

bioengineering↗

bioRxiv2024

Analysis of developmental gene expression using smFISH and in silico staging of C. elegans embryos

Regulation of transcription during embryogenesis is key to development and differentiation. To study transcript expression throughout Caenorhabditis elegans embryogenesis at single-molecule resolution, we developed a high-throughput single-molecule fluorescence in situ hybridization (smFISH) method that relies on computational methods to developmentally stage embryos and quantify individual mRNA molecules in single embryos. We applied our system to sdc-2, a zygotically transcribed gene essential for hermaphrodite development and dosage compensation. We found that sdc-2 is rapidly activated during early embryogenesis by increasing both the number of mRNAs produced per transcription site and the frequency of sites engaged in transcription. Knockdown of sdc-2 and dpy-27, a subunit of the dosage compensation complex (DCC), increased the number of active transcription sites for the X chromosomal gene dpy-23 but not the autosomal gene mdh-1, suggesting that the DCC reduces the frequency of dpy-23 transcription. The temporal resolution from in silico staging of embryos showed that the deletion of a single DCC recruitment element near the dpy-23 gene causes higher dpy-23 mRNA expression after the start of dosage compensation, which could not be resolved using mRNAseq from mixed-stage embryos. In summary, we have established a computational approach to quantify temporal regulation of transcription throughout C. elegans embryogenesis and demonstrated its potential to provide new insights into developmental gene regulation.

developmental biology↗

bioRxiv2023

VoltRon: A Spatial Omics Analysis Platform for Multi-Resolution and Multi-omics Integration using Image Registration

The growing number of spatial omic technologies have created a demand for computational tools capable of managing, storing, and analyzing spatial datasets with multiple modalities and spatial resolutions. Meanwhile, computer vision is becoming an integral part of processing spatial data readouts where image registration and spatial data alignment of tissue sections are essential prior to data integration. Hence, there is a need for computational platforms that analyze data across spatial datasets with diverse resolutions as well as those that manipulate and process images of microanatomical tissue structures. To this end, we have developed VoltRon, a novel R package for spatial omics analysis with a unique data structure that accommodates data readouts with many levels of spatial resolutions (i.e., multi-resolution) including regions of interest (ROIs), spots, single cells, and even subcellular entities such as molecules. To connect and integrate these spatially diverse omic profiles, VoltRon accounts for spatial organization of tissue blocks (samples), layers (sections) and assays given a multi-resolution collection of spatial data readouts. An easy-to-use computer vision toolbox, OpenCV, is fully embedded in VoltRon that allows users to both automatically and manually register spatial coordinates across adjacent layers for data transfer without the need for external software tools. VoltRon is implemented in the R programming language and is freely available at https://github.com/BIMSBbioinfo/VoltRon.

bioinformatics↗

bioRxiv2021

A noncatalytic activity of the H4K20 demethylase DPY-21 regulates condensin DC binding

Condensin is a multi-subunit SMC complex that binds to and compacts chromosomes. Here we addressed the regulation of condensin binding dynamics using C. elegans condensin DC, which represses X chromosomes in hermaphrodites for dosage compensation. We established fluorescence recovery after photobleaching (FRAP) using the SMC4 homolog DPY-27 and showed that a well-characterized ATPase mutation abolishes its binding. Next, we performed FRAP in the background of several chromatin modifier mutants that cause varying degrees of X-chromosome derepression. The greatest effect was in a null mutant of the H4K20me2 demethylase DPY-21, where the mobile fraction of condensin DC reduced from [~]30% to 10%. In contrast, a catalytic mutant of dpy-21 did not regulate condensin DC mobility. Hi-C data in the dpy-21 null mutant showed little change compared to wild type, uncoupling Hi-C measured long-range DNA contacts from transcriptional repression of the X chromosomes. Together, our results indicate that DPY-21 has a non-catalytic role in regulating the dynamics of condensin DC binding, which is important for transcription repression.

cell biology↗

bioRxiv2021

RS-FISH: Precise, interactive and scalable smFISH spot detection using Radial Symmetry

Fluorescent in-situ hybridization (FISH)-based methods are powerful tools to study molecular processes with subcellular resolution, relying on accurate identification and localization of diffraction-limited spots in microscopy images. We developed the Radial Symmetry-FISH (RS-FISH) software that accurately, robustly, and quickly detects single-molecule spots in two and three dimensions, making it applicable to several key assays, including single-molecule FISH (smFISH), spatial transcriptomics, and spatial genomics. RS-FISH allows interactive parameter tuning and scales to large sets of images as well as tera-byte sized image volumes such as entire brain scans using straight-forward distributed processing on workstations, clusters, and in the cloud.

bioinformatics↗