Biology subjects

Chao, Z.

Publications and source records attributed to Chao, Z..

10 recordsLinked to original sources

bioRxiv2026

Cell-free membrane systems reveal electrostatic control of ion transport in TMEM165 and disease-associated CaCA2 variants

Ion transport across intracellular membranes is essential for cellular homeostasis, yet organellar transport mechanisms remain difficult to resolve in native cells. Here, we establish a cell-free membrane system to interrogate full-length intracellular transporters under defined chemical conditions. Using cell-free protein synthesis, human Golgi transporter TMEM165 and its yeast homolog GDT1 were synthesized in membranes and analyzed by fluorescence and electrochemical measurements. The platform controlled protein identity, ion composition, and transmembrane pH gradients. TMEM165 transport was regulated by pH gradients, consistent with proton-coupled transport shaped by the electrostatic environment of the transport pathway. Disruption of a conserved acidic residue decreased pH sensitivity, broadened ion permeability, and altered steady-state transport behavior, indicating impaired proton coupling and selectivity. These findings identify conserved acidic residues as key regulators of TMEM165 function. More broadly, this work establishes a strategy for reconstructing organellar membrane proteins, resolving disease mechanisms, and engineering transport function in defined synthetic systems.

biophysics↗

bioRxiv2026

Accurate and scalable decontamination of imaging-based spatial transcriptomics via optimal transport

Imaging-based spatial transcriptomics enables molecule-resolved profiling of gene expression and tissue organization in situ. However, segmentation errors, transcript spillover and three-dimensional cell overlap can introduce misassigned transcripts into cell-level expression profiles, compromising biological interpretation and obscuring genuine signals. Existing methods either remove suspect expression at the cost of signal loss or lack a biologically grounded criterion for transcript assignment. Here we present CellDot, an optimal-transport framework that determines the fate of each transcript by retaining it in its host cell, reassigning it to a plausible neighboring cell or removing it as background. By integrating reference-guided expression compatibility with spatial information and data-adaptive constraints, CellDot enables accurate and traceable molecule-level correction while preserving biologically meaningful variation. In evaluations across multiple human tumor datasets, CellDot exhibited superior performance compared to existing decontamination methods, successfully restoring spatial expression patterns that matched independent cross-platform measurements. Moreover, it significantly enhanced the recovery of cellular states, intercellular communication, and spatial niche programs. Our experiments using real data demonstrated CellDot's scalability and established it as the only method applicable to a whole-transcriptome Atera dataset, underscoring its distinct advantages in the field of spatial transcriptomics.

bioinformatics↗

bioRxiv2026

CellART: a unified framework for extracting single-cell information from high-resolution spatial transcriptomics

Understanding how different cell types assemble into tissues and organs, as well as how they interact to transmit and receive biological signals, is essential for advancing biomedical and biological research. Recent advancements in spatial transcriptomics (ST) technologies have opened new avenues for investigating biological systems by achieving subcellular spatial resolution. Since cells are the fundamental units of life, extracting single-cell information from high-resolution ST data is crucial. However, existing ST platforms often capture sparse transcript counts per spot or measure only a limited number of genes, complicating the extraction of comprehensive single-cell information. In this study, we introduce CellART, a unified framework designed to extract single-cell information across diverse high-resolution ST platforms, including VisiumHD, Xenium, MERFISH, and Stereo-seq. By leveraging multimodal data, such as staining images, spatial transcriptomics data, and single-cell RNA sequencing references, CellART simultaneously performs cell segmentation and cell type annotation through a seamless integration of deep learning and probabilistic modeling. We demonstrate the efficiency, generalizability, and robustness of CellART across various high-resolution spatial transcriptomics platforms, capable of processing datasets containing millions of spots. Comprehensive experiments validate the biological relevance and accuracy of the recovered cellular information within spatial configurations. Notably, we highlight the utility of CellART in breast and colorectal cancer datasets, showcasing its ability to fully leverage high-resolution ST data. By enhancing cellular resolution, CellART facilitates the identification of transient cancer cell states and immune cell subtypes. Furthermore, CellART enables investigations into cancer-immune cell communication, uncovering both established interactions and novel ligand-receptor pairs. The outputs of CellART are compatible with widely used community tools, facilitating a variety of downstream analyses.

bioinformatics↗

bioRxiv2026

STAT: A multi-agent framework for integrated and interactive spatial transcriptomics analysis

Spatial transcriptomics analysis often involves a myriad of computational methods across diverse platforms, leading analysts to spend excessive time on data assembly rather than deriving biological insights. Current AI solutions tend to either oversimplify spatial data into generic single-cell tables or operate autonomously without opportunities for intermediate review, thus hindering the visual and iterative analyses essential for spatial biology. In response to these challenges, we introduce STAT, a multi-agent framework designed to make spatial analysis more conversational and user-friendly while maintaining transparency and control. STAT integrates a persistent session, a shared interactive tissue viewer, and a staged skill-aware pipeline, enabling a more intuitive analytical experience. In a comprehensive benchmark evaluation encompassing eleven analytical task categories across three spatial platforms and both cell- and spot-resolution data, STAT demonstrates superior performance compared to a vanilla large language model and existing autonomous spatial analysis agents, excelling in task completion, analytical quality, and token efficiency. Notably, STAT enables multi-task spatial analysis of a mixed-resolution breast cancer cohort and successfully reproduces key findings from a published Visium HD colorectal cancer study using natural language prompts alone. STAT thus facilitates trustworthy and scientifically rigorous spatial transcriptomics analysis, allowing researchers to focus more on biological interpretation.

bioinformatics↗

bioRxiv2026

A telomere-to-telomere (T2T) pig genome assembly reveals Y chromosome diversity and structural variations of Wuzhishan pigs

BackgroudWuzhishan (WZS) pigs are native to Hainan Province of China, and serve as both important agricultural resources and biomedical models. Although the published WZS pig genome (T2T-pig1.0) even achieving telomere-to telomere (T2T) completeness, substantial genetic diversity still exists within the same pig breed, another WZS pig genome named WZS-T2T was assembled in this study. ResultsMultiple sequencing data were used to assemble genome, and finally yielded a [~]2.68 Gb telomere-to-telomere genome, with N50 length [~]142.87 Mb, and annotated protein coding genes of 23,100. Compared to T2T-pig1.0, QV and BUSCO value was higher, and the Y chromosome (ChrY) length was longer in WZS-T2T than that of T2T-pig1.0. ChrY of two WZS pigs shared 11 genes, including sex differentiation-related genes of SHOX, PRKX, and DDX3X, and SRY; however, energy metabolism gene SLC25A4 and the macrophage-related receptor gene CSF2RA of ChrY were specific to WZS-T2T. An inversion SV on chromosome 10 with length [~]33.86 Mb was identified between two WZS pigs, and three proofs were proposed for proving the accuracy sequence orientation of WZS-T2T.The genetic diversity was consistent with LD decay speed in population different analysis. WZS pigs exhibited higher genetic diversity than other four pig populations (Tunchang pigs, Yuxi black pigs, Large White pig, and Duroc pigs) examined in this study, and presented slower LD decay compared to other four breeds. ConclusionsTherefore, WZS-T2T provided a higher-quality assembly, and potential advantages of both agricultural production and biomedical targets for WZS pigs.

genomics↗

bioRxiv2023

Diverse Configurations of Erroneous Predictive Coding Across Brain Hierarchies in a Non-Human Primate Model of Autism Spectrum Disorder

In autism spectrum disorder (ASD), atypical sensory experiences are often associated with irregularities in predictive coding, which proposes that the brain creates hierarchical sensory models via a bidirectional process of predictions and prediction errors. However, it remains unclear how these irregularities manifest across different functional hierarchies in the brain. To address this, we used high-density electrocorticography (ECoG) in a non-human primate model of ASD during an auditory task with two layers of temporal control, and applied a quantitative model to quantify the integrity of predictive coding across two distinct hierarchies. Our results demonstrate that ASD is characterized by sensory hypersensitivity and unstable predictions across two brain hierarchies, and reveal the associated spatio-spectro-temporal neural signatures. Importantly, we observe diverse configurations of underestimation or overestimation of sensory regularities within these hierarchies. This work provides a multi-layered biomarker for ASD, contributing to our understanding of its diverse symptoms.

neuroscience↗

bioRxiv2023

Recreating the Biological Steps of Viral Infection on a Bioelectronic Platform to Profile Viral Variants of Concern

Viral mutation rates frequently outpace the development of technologies used to detect and identify harmful variants; for SARS Coronavirus-2 (SARS-CoV-2), these are called variants of concern (VOC). Given the continual emergence of VOC, there is a critical need to develop platforms that can identify the presence of a virus and readily identify its propensity for infection. We present an electronic biomembrane sensing platform that recreates the multifaceted and sequential biological cues that give rise to distinct SARS-CoV-2 virus host cell entry pathways and reports the progression of entry steps of these pathways as electrical signals. Within these electrical signals, two necessary entry processes mediated by the viral Spike protein, virus binding and membrane fusion, can be distinguished. Remarkably, we find that closely related VOC exhibit distinct fusion signatures that correlate with trends reported in cell-based infectivity assays, allowing us to report quantitative differences in fusion characteristics among them that inform their infectivity potentials. This cell-free biomimetic infection platform also has a virus-free option that equally reports infectivity potential of the Spike proteins. We used SARS-CoV-2 as our prototype, but we anticipate that this platform will extend to other enveloped viruses and cell lines to quantifiably explore virus/host interactions. This advance should aid in faster determination of entry characteristics and fusogenicities of future VOC, necessary for rapid response.

bioengineering↗

bioRxiv2023

Global disinhibition and corticospinal plasticity for drastic recovery after spinal cord injury

The induction of large-scale plasticity in the adult brain should be key for recovery from severe damage of the central nervous system. Here, drastic motor recovery was observed after subhemisection spinal cord injury in macaques that received intensive training and cortical electrical stimulation. During recovery, movement-related activity increased in ipsilesional sensorimotor areas and functional connectivity from ipsilesional to contralesional areas was strengthened. Electrical stimulation applied widely across bilateral sensorimotor areas induced muscle twitches in affected and intact forelimbs. The interhemispheric inhibition observed before injury was switched to facilitation. Furthermore, massive re-routing occurred in corticospinal axons from the contralesional motor cortex. Such global disinhibition and massive plasticity would open the workspace for the reorganization of motor networks to recruit novel areas for recovery. One Sentence SummaryGlobal disinhibition and corticospinal plasticity for drastic recovery after spinal cord injury in macaque monkeys.

neuroscience↗

bioRxiv2020

Uclacyanin proteins are required for lignified nanodomain formation within Casparian strips

Casparian strips (CS) are cell wall modifications of vascular plants restricting extracellular free diffusion into and out the vascular system. This barrier plays a critical role in controlling the acquisition of nutrients and water necessary for normal plant development. CS are formed by the precise deposition of a band of lignin approximately 2 m wide and 150 nm thick spanning the apoplastic space between adjacent endodermal cells. Here, we identified a copper-containing protein, Uclacyanin1 (UCC1) that is sub-compartmentalised within the CS. UCC1 forms a central CS nanodomain in comparison with other CS-located proteins that are found to be mainly accumulated at the periphery of the CS. We found that loss-of-function of two uclacyanins (UCC1 and UCC2) reduces lignification specifically in this central CS nanodomain, revealing a nano-compartmentalised machinery for lignin polymerisation. This lack of lignification leads to increased endodermal permeability, and consequently to a loss of mineral nutrient homeostasis.

plant biology↗

bioRxiv2018

Identification of Novel Genes and Variations Associated to Glycolytic Potential Based on Pig Model

In livestock, glycolytic potential (GP) is a critical indicator for evaluating the meat quality. To date, two major genes protein kinase AMP-activated {gamma}3 non-catalytic subunit gene (PRKAG3) and phosphorylase kinase catalytic subunit gamma 1(PHKG1), and corresponding cause mutations influencing GP have been confirmed in pigs. Therefore, the aim of this study to identify the novel candidate genes and variations related to GP-related traits using a four-hybrid pig model [Pietrain (P)x Duroc (D)] x[(Landrace) x(Yorkshire)]. We totally constructed six RNA-seq libraries using longissimus dorsi (LD) muscles, and each library contained two higher GP (H) or two lower GP (L) individuals. A total of 525, 698 and 135 differentially expressed genes (DEGs) were identified between H11 vs L11, H9 vs L9, and H5 vs L5 groups using PossionDis method, respectively. Notably, we found 97 non-redundant DEGs were mapped to GP related QTLs from three paired comparison groups. Moreover, 69 DEGs were identified between H (H11, H9 and H5) and L (L11, L9 and L5) groups using NOIseq method. Additionally, 1,076 potential specific SNPs were figured out between H and L groups, and approximately 40 large Indels with a length [≥] 5bp were identified in each sequencing library. In conclusion, our data provide foundation for further confirming the key genes and the functional mutations affecting GP-related traits in pigs, and also pave the way for elucidating the underling molecular regulatory mechanisms of glycogen metabolism in future study. Moreover, this study might provide valuable information for study on human glycogen storage diseases.

genomics↗