Biology subjects

Zhu, D. Y.

Publications and source records attributed to Zhu, D. Y..

5 recordsLinked to original sources

bioRxiv2025

Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision

Oct4, Sox2, and Klf4 (OSK) Yamanaka factors induce pluripotency and reverse age-related epigenetic changes, yet the mechanisms by which they promote rejuvenation remain poorly explored. Oxidative stress contributes to CNS aging and retinal pigmented epithelium (RPE) degeneration in age-related macular degeneration. We find that OSK expression in RPE restores retinal structure and visual function in aged mice and promotes oxidative resilience through a non-canonical, Tet2-independent pathway. Integrative functional genomics identifies GSTA4, a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a necessary and sufficient OSK effector. Dynamic GSTA4 regulation by OSK recapitulates a stem cell derived stress resilience program. GSTA4 overexpression alone enhances mitochondrial resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline. GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis driven by Yamanaka factors that circumvents reprogramming, providing therapeutic insights for age-related diseases. HIGHLIGHTSO_LIOSK-GSTA4 provides a dynamic, Tet2-independent stress-resilience axis. C_LIO_LIFunctional genomics pinpoints GSTA4 as a direct downstream effector activated by OSK. C_LIO_LIRPE aging involves progressive accumulation of 4-HNE that can be detoxified by GSTA4. C_LIO_LIEnhancing GSTA4 rejuvenates RPE cells, restores vision and is associated with lifespan-extending interventions. C_LI

genetics↗

bioRxiv2023

Autoencoder Model for Translating Omics Signatures

The development of effective therapeutics and vaccines for human diseases requires a systematic understanding of human biology. While animal and in vitro culture models have successfully elucidated the molecular mechanisms of diseases in many studies, they yet fail to adequately recapitulate human biology as evidenced by the predominant likelihood of failure in clinical trials. To address this broadly important problem, we developed AutoTransOP, a neural network autoencoder framework to map omics profiles from designated species or cellular contexts into a global latent space, from which germane information can be mapped between different contexts. This approach performs as well or better than extant machine learning methods and can identify animal/culture-specific molecular features predictive of other contexts, without requiring homology matching. For an especially challenging test case, we successfully apply our framework to a set of inter-species vaccine serology studies, where no 1-1 mapping between human and non-human primate features exists.

bioinformatics↗

bioRxiv2022

Spateo: multidimensional spatiotemporal modeling of single-cell spatial transcriptomics

Cells do not live in a vacuum, but in a milieu defined by cell-cell communication that can be measured via emerging high-resolution spatial transcriptomics approaches. However, analytical tools that fully leverage such data for kinetic modeling remain lacking. Here we present Spateo (aristoteleo/spateo-release), a general framework for quantitative spatiotemporal modeling of single-cell resolution spatial transcriptomics. Spateo delivers novel methods for digitizing spatial layers/columns to identify spatially-polar genes, and develops a comprehensive framework of cell-cell interaction to reveal spatial effects of niche factors and cell type-specific ligand-receptor interactions. Furthermore, Spateo reconstructs 3D models of whole embryos, and performs 3D morphometric analyses. Lastly, Spateo introduces the concept of "morphometric vector field" of cell migrations, and integrates spatial differential geometry to unveil regulatory programs underlying various organogenesis patterns of Drosophila. Thus, Spateo enables the study of the ecology of organs at a molecular level in 3D space, beyond isolated single cells.

systems biology↗

bioRxiv2020

Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics

The rising threat of pandemic viruses, such as SARS-CoV-2, requires development of new preclinical discovery platforms that can more rapidly identify therapeutics that are active in vitro and also translate in vivo. Here we show that human organ-on-a-chip (Organ Chip) microfluidic culture devices lined by highly differentiated human primary lung airway epithelium and endothelium can be used to model virus entry, replication, strain-dependent virulence, host cytokine production, and recruitment of circulating immune cells in response to infection by respiratory viruses with great pandemic potential. We provide a first demonstration of drug repurposing by using oseltamivir in influenza A virus-infected organ chip cultures and show that co-administration of the approved anticoagulant drug, nafamostat, can double oseltamivirs therapeutic time window. With the emergence of the COVID-19 pandemic, the Airway Chips were used to assess the inhibitory activities of approved drugs that showed inhibition in traditional cell culture assays only to find that most failed when tested in the Organ Chip platform. When administered in human Airway Chips under flow at a clinically relevant dose, one drug - amodiaquine - significantly inhibited infection by a pseudotyped SARS-CoV-2 virus. Proof of concept was provided by showing that amodiaquine and its active metabolite (desethylamodiaquine) also significantly reduce viral load in both direct infection and animal-to-animal transmission models of native SARS-CoV-2 infection in hamsters. These data highlight the value of Organ Chip technology as a more stringent and physiologically relevant platform for drug repurposing, and suggest that amodiaquine should be considered for future clinical testing.

microbiology↗

bioRxiv2019

Microtubule growth rates are sensitive to global and local changes in microtubule plus-end density

The microtubule (MT) cytoskeleton plays critically important roles in numerous cellular functions in eukaryotes, and it does so across a functionally diverse and morphologically disparate range of cell types [1]. In these roles, MT assemblies must adopt distinct morphologies and physical dimensions to perform specific functions [2-5]. As such, these macromolecular assemblies--as well as the dynamics of the individual MT polymers from which they are made--must scale and change in accordance with cell size and geometry. As first shown by Inoue using polarization microscopy, microtubules assemble to a steady state in mass, leaving enough of their subunits soluble to allow rapid growth and turnover. This suggests some negative feedback that limits the extent of assembly, for example decrease in growth rate, or increase in catastrophe rate, as the soluble subunit pool decreases. Such feedbacks might be global or local. Although these ideas have informed the field for decades, they have not been observed experimentally. Here we describe an experimental system designed to examine these long-standing ideas and determine a role for MT plus-end density in regulating MT growth rates.

molecular biology↗