Biology subjects

Hong, N.

Publications and source records attributed to Hong, N..

At least 19 recordsLinked to original sources

bioRxiv2026

Circadian rhythm disruption alters rhythmic properties of clock and memory gene expression in the hippocampi of rats

Our modern environment - with its artificial lighting, irregular work hours, and frequent travel -- often disrupts our circadian rhythms, which can lead to health problems, particularly in learning and memory. This is especially concerning given the aging population and the rising prevalence of dementia. Yet, the biological mechanisms linking circadian disruption to cognitive impairment remain poorly understood. At the molecular level, genetic techniques have been used to attenuate or abolish expression of key genes involved in circadian rhythms and these manipulations have detrimental effects on memory function. However, whether environmentally induced circadian disruption, impairs memory via changes in overall gene expression levels in the hippocampus or rather via changes in the coordinated rhythmic patterns of circadian expression across groups of genes is less known. Here, we examined how environmental circadian disruption affects the expression of genes involved in the circadian clock and memory in the hippocampus of rats using a forced desynchrony model. Circadian disruption changed the rhythmic properties of gene expression in most genes assessed but had no measurable effect on average expression levels across the day. These findings suggest that the inability to maintain circadian synchrony rather than overall expression may underlie the cognitive deficits observed in circadian-related disorders.

neuroscience↗

bioRxiv2026

A layered standards framework for integrating single-cell and spatial omics data into brain cell atlases

The BRAIN Initiative Cell Atlas Network (BICAN) is generating large-scale multimodal datasets to profile cell types in the human, non-human primate, and mouse brain. The diversity of single-cell and spatial transcriptomic and epigenomic assays, combined with varied experimental contexts, multiple data-generating laboratories and distributed infrastructure, poses substantial challenges for data integration and reuse in BICAN. To address this, we implemented a standards framework that enables layered integration of these data into knowledge-ready products for interoperable brain cell atlases. This framework organizes data based on three progressively structured layers. First, we introduced an assay-agnostic modeling layer that unifies the representation of single-cell and spatial omics data using a common set of biological entities and processes assessed by diverse experimental techniques. Second, we implemented harmonized metadata standards that capture key experimental features linked to biospecimen provenance across heterogeneous tissue sources, species, and preparations, supporting integration and validation while minimizing burden on data contributors. Third, we present an extensible representation for data-driven cell type taxonomies that integrates molecular data with annotations, ontology mappings, and evidence. Together, these contributions represent an end-to-end framework that transforms heterogeneous datasets into structured, interoperable resources that support broad community reuse via mapping algorithms, annotation systems, and visualization platforms. This approach links biospecimen provenance with cell-level outputs and embeds these in a standardized taxonomy format, enabling downstream applications such as cross-dataset integration, reference mapping, and knowledge-driven analysis. More broadly, our work demonstrates a generalizable strategy for enabling an efficient data-to-knowledge pipeline in a large-scale consortium setting.

genomics↗

bioRxiv2026

Metabolic control of mitochondrial plasticity and extracellular vesicle biology drives Cryptococcus neoformans virulence

Metabolic adaptation to nutrient stress is a key but poorly understood driver of fungal virulence. Here, we show that a dominant East Asian lineage of Cryptococcus neoformans (VNIa-5), which disproportionately infects immunocompetent hosts, has undergone lineage-specific rewiring of glucose-responsive stress pathways. Integrating population genomics, transcriptomics, and experimental infection models, we demonstrate that VNIa-5s clinical dominance is not explained by environmental prevalence. Instead, selective activation of Snf1 signalling links glucose limitation to mitochondrial tubularisation, extracellular vesicle remodelling, and enhanced melanization. Under low-glucose conditions, VNIa-5 exhibits marked mitochondrial plasticity and extracellular vesicle compositional shifts resembling hypervirulent outbreak lineages of Cryptococcus gattii. Following experimental induction of dormancy, VNIa-5 shows significantly increased virulence in vivo compared with the closely related but clinically rare VNIa-31 subclade, with host survival tightly correlated with mitochondrial morphology. These findings identify metabolic stress integration as a central mechanism shaping cryptococcal virulence and disease in immunocompetent human hosts.

microbiology↗

bioRxiv2025

Label-free Tracking of Subcortical White Matter Degradation In Vivo Using Third Harmonic Generation Microscopy in a Mouse Model of Multiple Sclerosis

Early detection and characterization of myelin degradation in the white matter (WM) is important for understanding neurodegenerative diseases such as multiple sclerosis (MS) and dementia. Here, we demonstrate a label-free in vivo imaging technique using third harmonic generation (THG) microscopy at 1320-nm excitation, which enables visualization of subcellular myelin structural changes deep in the mouse brain. By applying longitudinal THG imaging of the same axons in the cuprizone mouse model of MS, we captured the formation, evolution, and regression of myelin blisters in the corpus callosum through intact cortex - a depth inaccessible to other optical methods. We also confirmed the utility of conducting THG imaging in parallel with three-photon excited fluorescence imaging, which allowed us to determine that myelin blistering events were not correlated with the location of microglia cell bodies. Further, we used post-mortem immunohistochemistry to establish the ability to identify and measure the intranodal distance at nodes of Ranvier using in vivo THG imaging, and we found increased intranodal distances after cuprizone administration. We also developed a novel quantitative metric based on spatial concentration of the brightest THG signal that occurs before more overt changes like myelin blistering. Overall, THG microscopy offers a powerful method for detailed tracking of subcortical myelin dynamics, providing new opportunities to investigate disease mechanisms and potential therapeutic interventions in MS and other neurodegenerative diseases.

bioengineering↗

bioRxiv2025

Multimodal optical imaging and modulation through Smart Dura in non-human primates

Multimodal neural interfaces that integrate electrical and optical functionalities are promising tools for neuroscientific and clinical applications that involve recording and manipulating neuronal activity. However, most technologies for multimodal implementation are largely restricted to small animal models and lack the ability to translate to the larger brains of non-human primates (NHPs). Smart Dura, a recently developed large-scale neural interface for NHPs, enables high-density electrophysiological recordings and broad optical accessibility, providing multiscale information with enhanced spatiotemporal resolution. In this paper, the multimodal capabilities of Smart Dura are demonstrated through integration with multiphoton imaging, optical coherence tomography angiography (OCTA), and intrinsic signal optical imaging (ISOI), as well as optical manipulations such as photothrombotic lesioning and optogenetics. Through the transparent Smart Dura, in vivo fluorescence vascular imaging is achieved down to depths of 200 and 550 m using two-photon and three-photon microscopy, respectively. When combined with simultaneous electrophysiology, Smart Dura also enables assessment of vascular and neural dynamics via OCTA and ISOI, the induction of ischemic stroke, and the application of optogenetic neuromodulation across a wide cortical area of 20 mm in diameter. These capabilities support comprehensive investigations of brain dynamics in NHPs, advancing translational neurotechnology for human applications.

neuroscience↗

bioRxiv2025

Smart Dura: a functional artificial dura for multimodal neural recording and modulation

A multi-modal neural interface capable of long-term recording and stimulation is essential for advancing brain monitoring and developing targeted therapeutics. Among the traditional electrophysiological methods, micro-electrocorticography (ECoG) is appealing for chronic applications because it provides a good compromise between invasiveness and high-resolution neural recording. When combining ECoG with optical technologies, such as calcium imaging and optogenetics, this multi-modal approach enables the simultaneous collection of neural activity from individual neurons and the ability to perform cell-specific manipulation. While previous efforts have focused on multi-modal interfaces for small animal models, scaling these technologies to larger brains, of primates, remains challenging. In this paper, we present a multi-modal neural interface, named Smart Dura, a functional version of the commonly used artificial dura with integrated electrophysiological electrodes for large cortical area coverage for the NHP brain. The Smart Dura is fabricated using a thin-film microfabrication process to monolithically integrate a micron-scale electrode array into a soft, flexible, and transparent substrate with high-density electrodes (up to 256 electrodes) while providing matched mechanical compliance with the native tissue and achieving high optical transparency (exceeding 97%). Our in vivo experiments demonstrate electrophysiological recording capabilities combined with neuromodulation, as well as optical transparency via multiphoton imaging. This work paves the way toward a chronic neural interface that can provide large-scale, bidirectional interfacing for multimodal and closed-loop neuromodulation capabilities to study cortical brain activity in non-human primates, with the potential for translation to humans.

neuroscience↗

bioRxiv2024

Sparsity of population activity in the hippocampus is task-invariant across the tri-synaptic circuit and dorsal-ventral axis

Evidence from neurophysiological and genetic studies demonstrates that activity sparsity - the proportion of neurons that are active at a given time in a population - systematically varies across the canonical trisynaptic circuit of the hippocampus. Recent work has also shown that sparsity varies across the hippocampal dorsoventral (long) axis, wherein activity is sparser in ventral than dorsal regions. While the hippocampus has a critical role in long-term memory (LTM), whether sparsity across the trisynaptic circuit and hippocampal long axis is task-dependent or invariant remains unknown. Importantly, representational sparsity has significant implications for neural computation and theoretical models of learning and memory within and beyond the hippocampus. Here we used functional molecular imaging to quantify sparsity in the rat hippocampus during performance of the Morris water task (MWT) and contextual fear discrimination (CFD) - two popular and distinct assays of LTM. We found that activity sparsity is highly reliable across memory tasks, wherein activity increases sequentially across the trisynaptic circuit (DG < CA3 < CA1) and decreases across the long axis (ventral < dorsal). These results have important implications for models of hippocampal function and suggest that activity sparsity is a preserved property in the hippocampal system across cognitive settings.

neuroscience↗

bioRxiv2023

The chromatin accessibility dynamics during cell fate specifications in zebrafish early embryogenesis

Chromatin accessibility plays a critical role in the regulation of cell fate decisions. Although gene expression changes have been extensively profiled at the single-cell level during early embryogenesis, the dynamics of chromatin accessibility at cis-regulatory elements remain poorly studied. Here, we used a plate-based single-cell ATAC-seq method to profile the chromatin accessibility dynamics of over 10, 000 nuclei from zebrafish embryos. We investigated several important time points immediately after zygotic genome activation (ZGA), covering key developmental stages up to dome. The results revealed key chromatin signatures in the first cell fate specifications when cells start to differentiate into enveloping layer (EVL) and yolk syncytial layer (YSL) cells. Finally, we uncovered many potential cell-type specific enhancers and transcription factor motifs that are important for the cell fate specifications.

genomics↗

bioRxiv2023

Differentiation and migration of hematopoietic stem and progenitor cells cross multiple tissues

Hematopoiesis requires the coordinated differentiation of hematopoietic stem cells and progenitor cells (HSPCs) in multiple tissues. Although differentiation of HSPCs in bone marrow (BM) has been well-studied, our knowledge about the migration and differentiation of HSPCs cross tissues is limited. Here, we collected and integrated single-cell RNA-seq data of human CD34+ cells, which represent HSPCs, from BM, peripheral blood (PB), thymus and mobilized PB (mPB), to investigate the hematopoiesis cross tissues. We constructed a cell atlas of HSPCs cross tissues and found most HSPC subsets in BM had counterparts in PB, indicating migration of HSPCs from BM to PB has a much broad spectrum. We found B progenitors highly expressed CXCR4 for anchoring in BM, while cells with low expression of CXCR4 facilitate their migration out of BM. Among the HSPC subsets from thymus, we only found the counterparts of the earliest thymic progenitors (ETPs) in BM and PB, potentially indicating that ETPs were the subsets that migrated from BM to PB and thymus. We found interaction signaling including CD99-CD99, CXCL12-CXCR4 and CCL19-CCR7 played important roles in ETP homing to thymus. Briefly, these data provided a single unified developmental spectrum of hematopoiesis cross different tissues, connected by cell migration.

genomics↗

bioRxiv2023

Single cell analyses of cancer cells identified two regulatorily and functionally distinct categories in differentially expressed genes among tumor subclones

To explore the feature of cancer cells and tumor subclones, we analyzed 101,065 single-cell transcriptomes from 12 colorectal cancer (CRC) patients and 92 single cell genomes from one of these patients. We found cancer cells, endothelial cells and stromal cells in tumor tissue expressed much more genes and had stronger cell-cell interactions than their counterparts in normal tissue. We identified copy number variations (CNVs) in each cancer cell and found correlation between gene copy number and expression level in cancer cells at single cell resolution. Analysis of tumor subclones inferred by CNVs showed accumulation of mutations in each tumor subclone along lineage trajectories. We found differentially expressed genes (DEGs) between tumor subclones had two populations: DEGCNV and DEGreg. DEGCNV, showing high CNV-expression correlation and whose expression differences depend on the differences of CNV level, enriched in housekeeping genes and cell adhesion associated genes. DEGreg, showing low CNV-expression correlation and mainly in low CNV variation regions and regions without CNVs, enriched in cytokine signaling genes. Furthermore, cell-cell communication analyses showed that DEGCNV tends to involve in cell-cell contact while DEGreg tends to involve in secreted signaling, which further support that DEGCNV and DEGreg are two regulatorily and functionally distinct categories.

genomics↗

bioRxiv2022

Dynamics, signals and influencing factors of CD4 T cell activation revealed by single cell RNA-seq

T cell activation is a key event in adaptive immunity. However, factors affecting T cell activation have not been systematically analyzed. Here, we analyzed stimulated CD4 T cells with anti-CD3/CD28 under several conditions to explore the factors affecting T cell activation. We defined stimulated T overlapped with resting T on UMAP as inert T. Inert T expressed activated T specific genes and cytokines, indicating it is a special functional state. Stimulated T derived from peripheral CD4 T has higher fraction of effector T (TEFF) while stimulated T derived from CD4 TN has higher fraction of proliferation T and interferon highly expressed T (IFNhi T). CD4 T was more likely to differentiate into TEFF and less likely to differentiate into heat shock protein specific T (HSPhi T) and IFNhi T in the presence of CD8 T. Interestingly, CXCR4low T responded to stimulation more efficiently than CXCR4hi T. These information facilitates we design stimulation to obtain ideal activated T.

immunology↗

bioRxiv2022

Novel Viroid-like RNAs Naturally Infect a Filamentous Fungus

Viroids have been found to naturally infect only plants, resulting in big losses for some crops, but whether viroids or viroid-like RNAs naturally infect non-plant hosts remains unknown. Here we report the existence of a set of exogenous, single-stranded circular RNAs, ranging in size between 157-450 nucleotides (nt), isolated from the fungus Botryosphaeria dothidea and nominated Botryosphaeria dothidea circular RNAs (BdcRNAs). BdcRNA(s) replicate autonomously in the nucleus via a rolling-circle replication mechanism following symmetric pathways with distribution patterns depending on strand polarity and species. BdcRNAs can modulate to different degrees specific biological traits (e.g., alter morphology, decrease growth rate, attenuate virulence, and increase or decrease tolerance to osmotic stress and oxidative stress) of the host fungus by regulating related metabolic pathways. Overall, BdcRNA(s) have genome characteristics similar to those of viroids and exhibit pathogenic effects on the fungal hosts. These novel viroid-like RNAs infecting fungi are proposed to be termed as mycoviroids. BdcRNA(s) may be regarded as additional inhabitants at the frontier of life in terms of genomic complexity, and represent a new class of acellular entities endowed with regulatory functions, and novel epigenomic carriers of biological information. Significance statementSeveral viroids have been transfected into unicellular and filamentous fungi to assess whether they can replicate, but no natural infections of fungi with viroid or viroid-like RNAs have been reported before. Here we describe a set of exogenous circular RNAs (cRNAs) in a phytopathogenic fungus. These cRNAs display molecular and biological features which might represent a new class of viroid-like cRNAs endowed with regulatory functions, and novel epigenomic carriers of biological information. This is the first report of infectious viroid-like RNAs (or exogenous small cRNAs) in a life kingdom (fungi) other than plants. We also present a subcellular analysis of cRNAs in a fungus for the first time and provide useful understanding in how cRNAs replicate, move, and are distributed in fungal cells.

microbiology↗

bioRxiv2021

Comprehensive mapping of the alternative polyadenylation site usage and its dynamics at single cell resolution

Alternative polyadenylation (APA) plays an important role in post-transcriptional gene regulation such as transcript stability and translation efficiency. However, our knowledge about APA dynamics at single cell level is largely unexplored. Here we developed single cell polyadenylation sequencing (scPolyA-seq), a strand-specific approach for sequencing 3 end of transcripts, to investigate the landscape of APA at single cell level. By analyzing several cell lines, we found many genes using multiple polyA sites in bulk data are prone to use only one polyA site in each single cell. Interestingly, cell cycle was significantly enriched in genes showing high variation of polyA site usages. We further identified 414 genes showing polyA site usage switch after cell synchronization. Genes showing cell cycle associated polyA site usage switch were grouped into 6 clusters, with cell phase specific functional categories enriched in each cluster. Furthermore, scPolyA-seq could facilitate study of APA in various biological processes.

bioinformatics↗

bioRxiv2021

Mesenchymal stem cell subpopulations and their heterogeneity of response to inductions revealed by single-cell RNA-seq

Mesenchymal stem/stromal cells (MSCs) are promising cell source for regenerative medicine and treatment of autoimmune disorders. Comparing MSCs from different tissues at single cell level is fundamental for optimizing clinical applications. Here we analyzed single cell RNA-seq data of MSCs from 4 tissues, namely umbilical cord, bone marrow, synovial tissue and adipose tissue. We identified 3 major cell subpopulations, namely osteo-MSCs, chondro-MSCs, adipo/myo-MSCs, across all MSC samples. MSCs from umbilical cord exhibited the highest immunosuppression, potentially indicating it is the best immune modulator for autoimmune diseases. The differentiation potentials of MSC subpopulations, which are strongly associated with their subtypes and tissue sources, showed pronounced subpopulation differences. We found MSC subpopulations expanded and differentiated when their subtypes consist with induction directions, while the other subpopulations shrank. We identified the genes and transcription factors underlying each induction at single cell level and subpopulation level, providing better targets for improving induction efficiency.

genetics↗

bioRxiv2021

JAG1 intracellular domain acts as a transcriptional cofactor that forms an oncogenic transcriptional complex with DDX17/SMAD3/TGIF2

Jagged1 (JAG1) is a Notch ligand that contact-dependently activates Notch receptors and regulates cancer progression. The JAG1 intracellular domain (JICD1) is generated from JAG1, such as the formation of NOTCH1 intracellular domain (NICD1), however, the role of JICD1 in tumorigenicity has not been comprehensively elucidated. Herein, we revealed that JICD1 induced astrocytes to acquire several cancer stem cell properties, including tumor formation, invasiveness, stemness, and resistance to chemotherapy and radiotherapy. The transcriptome, ChIP-sequencing, and proteomic analyses revealed that JICD1 increased SOX2 expression by forming a transcriptional complex with DDX17, SMAD3, and TGIF2. Furthermore, JICD1-driven tumorigenicity was directly regulated by SOX2. Therefore, our results demonstrated that, like NICD1, JICD1 acts as a transcriptional cofactor in the formation of the DDX17/SMAD3/TGIF2 transcriptional complex, leading to oncogenic transformation.

molecular biology↗

bioRxiv2021

Re-investigation of classic T cell subsets and identification of novel cell subpopulations by single-cell RNA sequencing

Classic T cell subsets are defined by a small set of cell surface markers, while single cell RNA sequencing (scRNA-seq) clusters cells using genome-wide gene expression profiles. The relationship between scRNA-seq Clustered-Populations (scCPops) and cell surface marker-defined classic T cell subsets remain unclear. Here, we interrogated 6 bead-enriched T cell subsets with 62,235 single cell transcriptomes and re-grouped them into 9 scCPops. Bead-enriched CD4 Naive and CD8 Naive were mainly clustered into their scCPop counterparts, while cells from the other T cell subsets were assigned to multiple scCPops including mucosal-associated invariant T cells and natural killer T cells. The multiple T cell subsets that form a single scCPop exhibited similar expression pattern, but not vice versa, indicating scCPops are much homogeneous cell populations with similar cell states. Interestingly, we discovered and named IFNhi T, a new T cell subpopulation that highly expressed Interferon Signaling Associated Genes (ISAGs). We further enriched IFNhi T by FACS sorting of BST2 for scRNA-seq analyses. IFNhi T cluster disappeared on tSNE plot after removing ISAGs, while IFNhi T cluster showed up by tSNE analyses of ISAGs alone, indicating ISAGs are the major contributor of IFNhi T cluster. BST2+ T cells and BST2- T cells showing different efficiencies of T cell activation indicates high level of ISAGs may contribute to quick immune responses.

genomics↗

bioRxiv2020

Impacted Spike Frequency Adaptation Associated with Reduction of KCNQ2/3 Promotes Seizure Activity in Temporal Lobe Epilepsy

Although numerous epilepsy-related genes have been identified by unbiased genome-wide screening based on samples from both animal models and patients, the druggable targets for temporal lobe epilepsy (TLE) are still limited. Meanwhile, a large number of candidate genes that might promote or inhibit seizure activities are waiting for further validation. In this study, we first analyzed two public databases and determined the significant down-regulations of two M-type potassium channel genes (KCNQ2/3) expressions in hippocampus samples from TLE patients. Then we reproduced the similar pathological changes in the pilocarpine mouse model of TLE and further detected the decrease of spike frequency adaptation driven by impacted M-currents on dentate gyrus granule neurons. Finally, we employed a small-scale simulation of dentate gyrus network to investigate potential functional consequences of disrupted neuronal excitability. We demonstrated that the impacted spike frequency adaptation of granule cells facilitated the epileptiform activity among the entire network, including prolonged seizure duration and reduced interictal intervals. Our results identify a new mechanism contributing to ictogenesis in TLE and suggest a novel target for the anti-epileptic drug discovery.

neuroscience↗

bioRxiv2020

Integrated decoding hematopoiesis and leukemogenesis at single-cell resolution and its clinical implication

Integrated analyses of hematopoiesis and leukemogenesis could provide new biological and clinical insights1,2. Here we constructed a comprehensive cell atlas using [~]100,000 single cell transcriptomes of bone marrow mononuclear cells and its subsets from 5 healthy samples and 13 leukemia samples. Trajectory analysis showed hematopoietic stem cells continuously differentiated through tree-like structure into 7 lineages. Although our single cell analyses showed the major cellular heterogeneity were inter-patients, there were distinct leukemia cell subpopulations within patient. We developed counterpart composite index (CCI) for projecting leukemia cell subpopulation into reference hematopoietic cells, to identify their healthy counterparts that could predict leukemia subtype and clinical outcome. Interestingly, we found the trajectories of leukemogenesis were similar to that of their healthy counterparts, indicating lineage relationship of leukemia cell subpopulations. Single cell analyses of leukemia patient at diagnosis, refractory, remission and relapse vividly presented dynamics of cell population and the underlying genes. Single cell transcriptomic variants analyses showed the relapsed leukemia cells, whose healthy counterparts were closer to the root of hematopoietic tree, were derived from an early minor leukemia cell population. This study not only increased our understanding of hematopoiesis and leukemogenesis, but also provided an approach for leukemia classification and clinical outcome prediction.

genomics↗