Biology subjects

Zhang, S.

Publications and source records attributed to Zhang, S..

At least 433 records · Page 24Linked to original sources

bioRxiv2025

High-precision cell-type mapping and annotation of single-cell spatial transcriptomics with STAMapper

Recent advances in single-cell spatial transcriptomics (scST) have enabled the analysis of gene transcription levels in individual cells while preserving their spatial positions. Cell-type mapping and annotation are crucial in understanding the complex interactions between cells and their microenvironments within a spatial context. To this end, we develop a heterogeneous graph neural network, STAMapper, to transfer the cell-type labels from single-cell RNA-seq data to scST data. STAMapper captures both the expression similarity among cells and the expression relationships between cells and genes and adopts a graph attention classifier to conduct semi-supervised learning for more accurate cell-type prediction. We collected 81 scST datasets consisting of 344 slices and 16 paired scRNA-seq datasets from eight technologies and five tissues to validate the efficiency of STAMapper. STAMapper achieved the best performance on 75 out of 81 datasets compared to competing methods in accuracy. STAMapper demonstrated enhanced performance over manual annotations, particularly at the boundaries of cell clusters, enabled the unknown cell-type detection in scST data, and exhibited precise cell subtype annotations. Additionally, STAMapper provided biologically meaningful gene embeddings, facilitating the identification of shared or unique gene modules across datasets.

bioinformatics↗

bioRxiv2025

Melatonin attenuates kidney injury by alleviating lysosomal damage in diabetic kidney disease

Proteinuria-induced damage to renal tubular epithelial cells is one of the main causes of diabetic kidney disease (DKD), and the clearance of overloaded albumin by lysosomes is crucial for maintaining the homeostasis of renal tubular epithelial cells. Therefore, lysosomal damage is closely related to the pathogenesis of DKD, but effective prevention and treatment measures are still lacking. Melatonin (MLT) is secreted by the pineal gland and can not only regulate circadian rhythms but also maintain lysosomal homeostasis. In this study, we demonstrate the presence of significant lysosomal damage in renal tubules of DKD patients, which causes autophagy impairment and a concomitant oxidative stress imbalance; however, MLT can upregulate transcription factor EB (TFEB) to improve lysosomal damage and restore the biosynthesis in this organelle. Mechanistically, MLT may protect lysosomes via the upregulation of TFEB and the miR-205-5p-LRP-1 pathway in renal tubules, thus improving autophagy dysfunction and oxidative imbalance in DKD.

pathology↗

bioRxiv2025

VISTA-induced tumor suppression by a four amino acid intracellular motif

VISTA is a key immune checkpoint receptor under investigation for cancer immunotherapy; however, its signaling mechanisms remain unclear. Here we identify a conserved four amino acid (NPGF) intracellular motif in VISTA that suppresses cell proliferation by constraining cell-intrinsic growth receptor signaling. The NPGF motif binds to the adapter protein NUMB and recruits Rab11 endosomal recycling machinery. We identify and characterize a class of triple-negative breast cancers with high VISTA expression and low proliferative index. In tumor cells with high VISTA levels, the NPGF motif sequesters NUMB at endosomes, which interferes with epidermal growth factor receptor (EGFR) trafficking and signaling to suppress tumor growth. These effects do not require canonical VISTA ligands, nor a functioning immune system. As a consequence of VISTA expression, EGFR receptor remains abnormally phosphorylated and cannot propagate ligand-induced signaling. Mutation of the VISTA NPGF domain reverts VISTA-induced growth suppression in multiple breast cancer mouse models. These results define a mechanism by which VISTA represses NUMB to control malignant epithelial cell growth and signaling. They also define distinct intracellular residues that are critical for VISTA-induced cell-intrinsic signaling that could be exploited to improve immunotherapy.

cancer biology↗

bioRxiv2025

Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis

Mutations in mitochondrial DNA (mtDNA) can lead to mitochondrial and cellular dysfunction. However, recent studies suggest that there is purifying selection against mutant mtDNAs during transgenerational transmission. We investigated the mtDNA dynamics during ovarian follicle development. Using base-editing, we generated mice harboring a 3177 G>A mutation corresponding to the human Leber hereditary optic neuropathy (LHON)-related mtDNA mutation and confirmed the transgenerational reduction of mutant mtDNA. Using a mouse follicle culture system in which pathogenic mtDNA mutations were introduced in vitro followed by mtDNA sequencing and digital PCR, we found this germline heteroplasmy shift during early folliculogenesis was induced by the decrease of mutant mtDNA together with compensatory replication of wild-type mtDNA. In contrast, synonymous mtDNA mutations did not impact the mtDNA dynamics. These findings show that mice can eliminate certain pathogenic mtDNA mutations in the germline during early folliculogenesis, maintaining mitochondrial integrity across generations.

genetics↗

bioRxiv2024

A Prediction Method of Land Use Type Evolution Based on Long and Short-Term Memory Networks--Taking Gansu Province as an Example

In the context of escalating global climate change and human activities, understanding the driving mechanisms behind land use change and predicting future trends is crucial. This study takes Gansu Province as a case, using land use type data from 1990 to 2020 to construct a Long Short-Term Memory (LSTM) model to predict land use changes over the next decade (2021-2030). The results indicate that land use types in Gansu Province exhibit significant dynamic changes, with forest area continuously increasing, built-up land rapidly expanding, and areas of unused land and grassland significantly decreasing. These changes reflect the combined effects of ecological protection policies, urbanization, and land development. The models predictions suggest that built-up land has absorbed substantial areas of unused land, grassland, and cultivated land, with accelerated urbanization. Forest area growth is attributed to the implementation of ecological restoration policies, while grassland and water areas show fluctuating changes, and the area of unused land continues to decrease. The findings not only provide data support for land resource management and ecological protection, but also offer scientific evidence for the formulation of sustainable land use policies, which can serve as an important reference for the sustainable use and management of land resources in Gansu Province and similar regions.

bioengineering↗

bioRxiv2024

A molecularly defined brain circuit module for regulating the panic-like defensive state

Panic is an episode of strong defensive state, characterized by intense fear and severe physical symptoms such as elevated cardiorespiratory activities. How the brain generates panic state remains poorly understood. Here, we developed a robot-based experimental paradigm to evoke panic-like defensive state in mice. When stimulated by the robot, the mice exhibited jumping escapes and elevated cardiorespiratory activities. With this paradigm, we identified Cbln2-expressing (Cbln2+) neurons in the posterior hypothalamic nucleus (PHN) as a key neuronal population essential for the induction of panic-like defensive state. Activation of Cbln2+ PHN neurons induced behavioral and physical symptoms of panic-like defensive state. These neurons were strongly activated by noxious mechanical stimuli and encode jumping escape vigor. They were synaptically innervated by anxiety-associated brain areas and provoked panic-like defensive state via their projection to the periaqueductal gray. Together, our results reveal a molecularly defined circuit module that regulates the panic-like defensive state in mice.

neuroscience↗

bioRxiv2024

Actin dysregulation induces immune evasion via oxidative stress-activated PD-L1 in gastric cancer

Diffuse gastric adenocarcinoma (DGAC) is an aggressive malignancy with limited therapeutic options, poor prognosis, and poorly understood biology. CRACD, an actin polymerization regulator, is often inactivated in gastric cancer, including DGAC. We found that genetic engineering of murine gastric organoids with Cracd ablation combined with Kras mutation and Trp53 loss induced aberrant cell plasticity, hyperproliferation, and hypermucinosis, the features that recapitulate DGAC transcriptional signatures. Notably, CRACD inactivation remodeled the immune landscape for immune evasion through PD-L1 enrichment in tumor cells. Mechanistically, CRACD loss disrupted actin dynamics, generating reactive oxygen species that activated HIF1, which transactivated PD-L1. Pharmacologic inhibition of HIF1 or PD-L1 restored immune surveillance and suppressed tumorigenesis. These findings reveal a novel role of actin homeostasis in limiting cell plasticity and immune evasion, position CRACD as a potential biomarker for stratifying patients with DGAC, and highlight HIF1 and PD-L1 as actionable therapeutic targets.

cancer biology↗

bioRxiv2024

UTX Epigenetically Imposes a Cytolytic Effector Program in Autoreactive Stem-like CD8+ T cell Progenitors

Type 1 Diabetes Mellitus (T1D) is a chronic disease caused by an unremitting autoimmune attack on pancreatic beta cells. This autoimmune chronicity is mediated by stem-like progenitor CD8+ T cells that continually repopulate the pool of beta cell-specific cytolytic effectors. Factors governing the conversion of progenitors to effectors, however, remain unclear. T1D has been linked to a chromosomal region (Xp13-p11) that contains the epigenetic regulator UTX, which suggests a key role for UTX in T1D pathogenesis. Here, we show that T cell-specific UTX deletion in NOD mice protects against T1D development. In T cells of NOD mice and T1D patients, UTX ablation resulted in the accumulation of CD8+ progenitor cells with concomitant deficiency of effectors, suggesting a key role for UTX in poising progenitors for transition to effectors. Mechanistically, UTXs role in T1D was independent of its inherent histone demethylase activity but instead relied on binding with transcription factors (TCF1 and STAT3) to co-regulate genes important in the maintenance and differentiation of progenitor CD8+ T cells. Together, these findings identify a critical role for UTX in T1D and the UTX:TCF1:STAT3 complex as a therapeutic target for terminating the long-lived autoimmune response.

immunology↗

bioRxiv2024

Incomplete lineage sorting of segmental duplications defines the human chromosome 2 fusion site early during African great ape speciation

All great apes differ karyotypically from humans due to the fusion of chromosomes 2a and 2b, resulting in human chromosome 2. Yet, the structure, function, and evolutionary history of the genomic regions associated with this fusion remain poorly understood. Here, we analyze finished telomere-to-telomere chromosomes in great apes and macaques to show that the fusion was associated with multiple pericentric inversions, segmental duplications (SDs), and the rapid turnover of subterminal repetitive DNA. We characterized the fusion site at single-base-pair resolution and identified three distinct SDs that originated more than 5 million years ago. These three distinct SDs were differentially distributed among African great apes as a result of incomplete lineage sorting (ILS) and lineage-specific duplication. Most conspicuously, one of these SDs shares homology to a hypomethylated SD spacer sequence present in hundreds of copies in the subterminal heterochromatin of chimpanzees and bonobos. The fusion in human was accompanied by a systematic degradation of the three divergent -satellite arrays representing the ancestral centromere creating five distinct structural haplotypes in humans. CRISPR/Cas9-mediated depletion of the fusion site in human cell lines significantly alters the expression of 108 genes, indicating a potential regulatory consequence to this human-specific karyotypic change.

evolutionary biology↗

bioRxiv2024

Immune mechanisms of type 1 diabetes revealed by single-cell transcriptomics, bulk transcriptomics, and experimental validation

BackgroundType 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic {beta} cells. Understanding the immune mechanisms underlying T1D is crucial for developing effective diagnostic and therapeutic strategies. This study aimed to elucidate the immune mechanisms of T1D by integrating single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and experimental validation. MethodsscRNA-seq data (GSE200695) and bulk RNA-seq data (GSE9006) were obtained from the Gene Expression Omnibus (GEO) database. After data preprocessing, principal component analysis (PCA), and clustering, cell subtypes were annotated using ImmGenData as a reference. Receptor-ligand interactions were analyzed to identify key cell subtypes. Least absolute shrinkage and selection operator (LASSO) regression was performed to identify characteristic genes and construct a diagnostic model. Key genes were further validated using the training and validation sets. Functional enrichment and immune infiltration analyses were conducted for the key genes. In vitro experiments were performed to validate the findings using a high-glucose model in the monocytic cell line THP-1. siRNA-mediated knockdown of TRIB1 was performed to investigate its role in regulating monocyte activation and immune-related pathways under high-glucose conditions. Monocyte activation markers, inflammatory cytokines, apoptosis, and the expression of key genes and immune-related genes were assessed using immunofluorescence staining, ELISA, flow cytometry, qPCR, and Western blot. ResultsMonocytes were identified as the key cell subtype with the most interactions with other cell subtypes. Eleven characteristic genes were selected to construct a diagnostic model, which demonstrated high validation efficiency (AUC > 0.8). Three key genes (ACTG1, REL, and TRIB1) showed consistent expression trends in the training and validation sets. Functional analyses revealed that these genes were involved in immune regulation and PI3K/AKT/mTOR signaling. In vitro experiments confirmed that high glucose induced monocyte activation, as evidenced by increased expression of activation markers (CD86) and pro-inflammatory cytokines (IL-8 and TNF-). High glucose also increased monocyte apoptosis and altered the expression of key genes (ACTG1, REL, and TRIB1) and immune-related genes (CXCL16, TGFBR1, CTLA4, CD48, TMIGD2, and HLA-DPB1). Knockdown of TRIB1 attenuated high glucose-induced monocyte activation, as demonstrated by decreased expression of activation markers and pro-inflammatory cytokines. TRIB1 knockdown also modulated the expression of immune-related genes and PI3K/AKT/mTOR signaling under high-glucose conditions. ConclusionsThis study integrates scRNA-seq, bulk RNA-seq, and experimental validation to unravel the immune mechanisms of T1D. Key genes (ACTG1, REL, and TRIB1) and monocytes were identified as crucial players in T1D pathogenesis. The constructed diagnostic model showed high validation efficiency. In vitro experiments confirmed the role of TRIB1 in regulating monocyte activation and immune-related pathways in a high-glucose model. These findings provide novel insights into the immune mechanisms of T1D and potential diagnostic and therapeutic targets.

bioinformatics↗

bioRxiv2024

Structured light projection using image guide fibers for in situ photo-biofabrication

Light-based biofabrication techniques have revolutionized the field of tissue engineering and regenerative medicine. Specifically, the projection of structured light, where the spatial distribution of light is controlled at both macro- and micro-scale, has enabled precise fabrication of complex three-dimensional structures with high resolution and speed. However, despite almost two decades of progress, biofabrication processes have been mostly limited to benchtop devices which limit the flexibility in terms of where the fabrication can occur. Here, we demonstrate a Fiber-assisted Structured Light (FaSt-Light) projection apparatus for rapid in situ crosslinking of photoresins. This approach uses image-guide fiber bundles which can project bespoke images at multiple wavelengths, enabling flexibility and spatial control of different photoinitiation systems and crosslinking chemistries and also the location of fabrication. We demonstrate coupling of different sizes of fibers and different lenses attached to the fibers to be able to project small (several mm) or large (several cm) images for material crosslinking. FaSt-Light allows control over the cross-section of the crosslinked resins and enables the introduction of microfilaments which can further guide cellular infiltration, differentiation and anisotropic matrix production. The proposed approach could lead to a new range of in situ biofabrication techniques which improve the translational potential of photo-fabricated tissues and grafts.

bioengineering↗

bioRxiv2024

SUMO E1 covalent allosteric inhibitors modulate polyamine synthesis via the MAT2A-AdoMetDC axis

Upregulation of protein SUMOylation is associated with various diseases, and SUMOylation inhibitors are promising drug candidates. We performed the first virtual screening of SUMO E1 covalent allosteric inhibitors (CAIs) and identified two SUMO E1 CAIs with new scaffolds and covalent warheads. We further demonstrated that these new CAIs perturbed the SUMOylation pathway and protein SUMOylation. Specifically, these CAIs affected the SUMOylation of the methionine adenosyltransferases MAT2A. The inhibition of MAT2A SUMOylation unexpectedly stimulated polyamine synthesis. Lastly, we showed that the combination of SUMO E1 CAIs with a polyamine synthesis inhibitor had synergistic effects in inhibiting T47D cells. Our work demonstrated the first cost-effective virtual screening of SUMO E1 CAIs, found that the downregulation of MAT2A SUMOylation increases polyamine synthesis, and SUMO E1 CAIs can synergize with polyamine synthesis inhibitors. This work would be of great value to the study of SUMOylation, covalent/allosteric drugs, and the polyamine metabolism network.

pharmacology and toxicology↗

bioRxiv2024

Cytoplasmic calcium influx mediated by Lr14a regulates stomatal immunity against leaf rust in wheat

The race-specific resistance gene Lr14a in wheat confers a unique type of heterogenous resistance reaction. It encodes an ankyrin-repeat transmembrane domain protein that confers immunity against the fungal pathogen Puccinia triticina. Here, we show that Lr14a functions as a calcium-permeable channel, mediating cytoplasmic Ca{superscript 2} influx that is crucial for leaf rust resistance in wheat. Infection with avirulent isolates induced Lr14a expression predominantly in mesophyll cells while triggering cell death in guard cells in wheat. This study revealed a mechanism by which the product of an R gene regulates stomatal immunity non-cell autonomously through the mediation of calcium signaling.

plant biology↗

bioRxiv2024

Temperature-sensitive cortical condensation modulates mechano-response at Tricellular Junctions

A general mechanism to maintain epithelial integrity during cell movements is to couple adhesion strength with mechanical force. Mechanosensitive proteins are recruited to adhesion sites to reinforce cell-cell or cell-matrix linkage in response to elevated tension. However, subcellular mechanisms for highly dynamic protein transport into and out of tension-bearing structures remain elusive. Furthermore, it is still unknown whether mechanosensitivity can be modulated by physiological signals in vivo. Here we revealed a direct "edge-to-vertex" route of Canoe/Afadin transport to tricellular junctions under tension, which relies on an obligatory binding partner Mbt/PAK. Without Mbt/PAK, Canoe/Afadin becomes insensitive to cytoskeletal tension and forms "tactoid-shaped" condensates directly at bicellular junctions. Remarkably, a temporary increase in temperature within the physiological range dissolves these condensates, allowing Canoe/Afadin to regain mechanosensitivity and enrichment at tricellular junctions. Functionally, the localization of Mbt/PAK at cell junctions oscillates during synchronous cell division within embryonic mitotic domains, enabling dynamic adjustments of Canoe/Afadin mechanosensitivity to preserve epithelial integrity in rapidly dividing tissues. Collectively, our findings suggest a physiological process in which the state of protein condensation, regulated by biochemical inputs, can supersede mechanical signals to modulate adhesion strength during cell division.

cell biology↗

bioRxiv2024

Lineage-associated Human Divergently-Paired Genes (DPGs) Exhibit Regulatory Characteristics and Evolutionary Trends

Divergently-paired genes (DPGs) represent one of the minimal co-transcriptional units (the rest include tandemly- and convergently-paired genes) of clustered genes; the former and the latter constitute greater than 10% and 75% of the total human genes, respectively. Our previous studies have shown that vertebrate DPGs are more conserved, both organizationally and functionally than invertebrates. Three critical questions remain to be addressed: (1) what are the conserved DPGs over vertebrate lineages, especially among mammals and primates? (2) being bidirectionally transcribed, to what extent do DPGs share their promoter sequences and how mechanistically and stringently are their co-expression regulated within the shared inter-TSS (transcription start site) sequence space? and (3) based on the recently released high-quality human genome assemblies, how do human-associated DPGs distribute over selected primate lineages and what are their possible functional consequences biologically? Our study begins by identifying 1399 human DPGs (12% of all human protein-coding genes), and presents findings from this analysis. First, 1136, 1118, 925, and 830 human DPGs are shared genetically with primates, mammals, avians, and fish, respectively. DPGs are not only functionally enriched toward direct protein-DNA interactions and cell cycle synchronization but also exhibit obvious lineage association, narrow in principle toward synchronization of certain core molecular mechanisms and cellular processes. Second, their inter-TSS distances and expression variables affect both co-expression strength and disparity between the two genes. Finally, our results based on a comparison among the primate DPGs reveal that the human-associated DPGs exhibit intensive diversification in co-expression, duplication, and definite involvement in neural development. Within humans, 55 and 357 DPGs are associated to the Chinese (YAO) and the European (CHM13) assemblies, respectively. Our results offer novel insights into comprehending the structure-function selection of gene clusters over evolutionary time scales, as well as a deeper understanding of the regulatory characteristics of co-expressed neighboring genes.

genomics↗

bioRxiv2024

Multi-scale parameterization of neural rhythmicity with lagged Hilbert autocoherence

Analysis of neural activity in different frequency bands is ubiquitous in systems and cognitive neuroscience. Recent analytical breakthroughs and theoretical developments rely on phase maintenance of oscillatory signals without considering whether or not this assumption is met. Lagged (auto)coherence, the coherence between a signal and itself at increasing temporal delays, has been proposed as a way to quantify the rhythmicity, or periodicity, of a signal. However, current Fourier-based lagged autocoherence algorithms suffer from poor spectral accuracy and resolution, aliasing effects that become more pronounced at higher frequencies, and conflation with amplitude covariation, especially in frequency ranges in which the signal-to-noise ratio is low. We introduce a continuous estimator, lagged Hilbert autocoherence (LHaC), which addresses these limitations by using multiplication in the frequency domain for precise bandpass filtering, computing instantaneous analytic signals via the Hilbert transform, and thresholding using the amplitude covariation of phase-shuffled surrogate data. While LHaC and lagged Fourier autocoherence (LFaC) estimate distinct theoretical quantities, we compare their empirical behavior in simulations with controlled rhythmic structure. These analyses show that LHaC provides more spectrally resolved estimates of rhythmicity and is more sensitive to the duration of transient, short-lived oscillatory events. We further demonstrate the utility of LHaC for identifying frequency-specific differences in rhythmicity between conditions and tracking learning-related changes in neural oscillations. Lagged Hilbert autocoherence thus offers a refined and practically useful approach to characterizing neurophysiological rhythmicity.

neuroscience↗

bioRxiv2024

A Novel Efficient Algorithm for Common Variants Genotyping from Low-Coverage Sequencing Data

Low-coverage whole-genome sequencing (LC-WGS) combined with imputation represents a cost-effective genotyping strategy for genome-wide association studies (GWAS) in population genetics. In this study, the Limpute algorithm was developed specifically for genotyping from low-coverage sequencing data, it extracts variant information from low-coverage sequencing data by the novel virtual probes and subsequently performs imputation through cross-reference between samples. Compared to the currently dominant algorithm for low-coverage sequencing data, GLIMPSE2, Limpute achieved similar imputation performance within common variants (r2>0.87) while the GLIMPSE2 has a runtime approximately five times longer than that of the Limpute. Furthermore, to fully evaluate the accuracy of genotype imputation by Limpute, we utilized high-coverage whole-genome sequencing data (30x), microarray data, and high-coverage whole-exome sequencing data (30x) as validation sets respectively. The results demonstrated that Limpute has a good imputation performance for common variants using low-coverage sequencing data (1x: r2 > 0.87; 3x: r2 > 0.92; 5x: r2 > 0.93). In summary, we present a highly efficient, low-cost algorithm for genotyping from low-coverage sequencing data, offering substantial support for genetic research.

bioinformatics↗

bioRxiv2024

DGKα and ζ Deficiency Causes Regulatory T-Cell Dysregulation, Destabilization, and Conversion to Pathogenic T-Follicular Helper Cells to Trigger IgG1-Predominant Autoimmunity

Regulatory T cells (Tregs) actively engage in immune suppression to prevent autoimmune diseases but also inhibit anti-tumor immunity. Although Tregs express a TCR repertoire with relatively high affinities to self, they are normally quite stable and their inflammatory programs are intrinsically suppressed. We report here that diacylglycerol (DAG) kinases (DGK) ( and ( are crucial for homeostasis, suppression of proinflammatory programs, and stability of Tregs and for enforcing their dependence on CD28 costimulatory signal. Treg-specific deficiency of both DGK( and ( derails signaling, metabolic, and transcriptional programs in Tregs to cause dysregulated phenotypic and functional properties and to unleash conversion to pathogenic exTregs, especially exTreg-T follicular helper (Tfh) 2 cells, leading to uncontrolled effector T cell differentiation, deregulated germinal center (GC) B-cell responses and IgG1/IgE predominant antibodies/autoantibodies, and multiorgan autoimmune diseases. Our data not only illustrate the crucial roles of DGKs in Tregs to maintain self-tolerance but also unveil a Treg-to-self-reactive-pathogenic-exTreg-Tfh-cell program that is suppressed by DGKs and that could exert broad pathogenic roles in autoimmune diseases if unchecked.

immunology↗