Search bioRxiv⌕ Search

Biology subjects

Yeung-Levy, S.

Publications and source records attributed to Yeung-Levy, S..

4 recordsLinked to original sources

CellFluxV2: An Image Generative Foundation Model for Virtual Cell Modeling

Building a virtual cell that simulates cellular behavior in silico is a central goal of computational biology. We introduce CellFluxV2, an image-generative model that predicts how cell morphologies change in response to chemical and genetic perturbations. A core innovation of CellFluxV2 is to learn distribution-level transformations from unperturbed to perturbed cells within the same experimental batch using flow matching, enabling it to disentangle true perturbation effects from confounding batch effects. Incorporating three methodological advances, CellFluxV2 achieves up to a 77% improvement in image fidelity over diffusion- and GAN-based baselines, while maintaining biological fidelity comparable to ground-truth images. Scaling up CellFluxV2, we establish the first scaling laws in image-based virtual cell modeling, demonstrating that performance improves consistently with both dataset size and model capacity. Furthermore, the scaled-up model generalizes well to out-of-distribution perturbations and exhibits two novel capabilities: batch-effect correction and cell-state interpolation. Together, these results position CellFluxV2 as a powerful foundation model advancing the vision of a virtual cell, unlocking novel opportunities for in silico drug screening.

bioinformatics↗

Cryogenic electron tomography and elemental analysis of mitochondrial granules in human retinal ganglion cells

Combining three-dimensional (3D) visualization with elemental analysis of vitrified cells can provide crucial insights into subcellular structures and elemental compositions in their native environments. We present a coordinated approach using cryogenic electron energy loss spectroscopy (cryoEELS) and cryogenic electron tomography (cryoET) to characterize the elemental distribution and ultrastructure of vitrified cells. We applied this method to examine calcium disposition in the mitochondria of cultured human retinal ganglion cells (RGCs) exposed to pro-calcifying conditions relevant to optic disc drusen pathology. Our cryoEELS analysis revealed mitochondrial granules with elevated calcium signals, offering direct evidence of mitochondrial calcification. Additionally, cryoET coupled with artificial intelligence-based analysis enabled quantification of the volume and spatial distribution of these calcium granules. This integrated workflow can be broadly applied to various cell types, facilitating the study of ultrastructure and elemental distribution in subcellular structures under diverse physiological and pathological conditions, as well as in response to therapeutic interventions.

biophysics↗

CryoViT: Efficient Segmentation of Cryogenic Electron Tomograms with Vision Foundation Models

Cryogenic electron tomography (cryoET) directly visualizes subcellular structures in 3D at the nanometer scale. Quantitative analyses of cryoET data can reveal structural biomarkers of diseases, provide novel mechanistic insights, and inform the effects of treatments on phenotype. However, existing automated annotation approaches primarily focus on localizing molecular features with few methods accurately quantifying complex structures such as organelles. We address this challenge with CryoViT, a paradigm shift from traditional convolutional neural networks that leverages vision transformers to enhance the segmentation of large pleomorphic structures that can occupy almost the entire field of view in high-magnification images, such as mitochondria. CryoViT is powered by a large-scale vision foundation model and overcomes limitations of popular U-Net based methods, particularly when training data are scarce. We demonstrate the efficacy of CryoViT on a large cryoET dataset of neurons differentiated from iPSCs derived from Huntington disease (HD) patients and cultured HD mouse model neurons.

bioinformatics↗

Global organelle profiling reveals subcellular localization and remodeling at proteome scale

Defining the subcellular distribution of all human proteins and its remodeling across cellular states remains a central goal in cell biology. Here, we present a high-resolution strategy to map subcellular organization using organelle immuno-capture coupled to mass spectrometry. We apply this proteomics workflow to a cell-wide collection of membranous and membrane-less compartments. A graph-based representation of our data reveals the subcellular localization of over 7,600 proteins, defines spatial protein networks, and uncovers interconnections between cellular compartments. We demonstrate that our approach can be deployed to comprehensively profile proteome remodeling during cellular perturbation. By characterizing the cellular landscape following hCoV-OC43 viral infection, we discover that many proteins are regulated by changes in their spatial distribution rather than by changes in their total abundance. Our results establish that proteome-wide analysis of subcellular remodeling provides essential insights for the elucidation of cellular responses. Our dataset can be explored at organelles.czbiohub.org.

cell biology↗