Biology subjects

Niu, J.

Publications and source records attributed to Niu, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Developmental origins of thymic B-cell lymphomas

The thymus provides a specialized niche for lymphocyte differentiation, yet the developmental trajectories of its rare B-cell population and their relationship to thymic B-cell lymphomagenesis remain poorly understood. Here, we integrate single-cell multiomics and spatial profiling across human tissues to delineate a B-cell differentiation program selectively represented in the human thymus. This program links CCL17 and germinal center-like B-cell states along a trajectory distinct from canonical germinal center differentiation and can be recapitulated in vitro by signals operating in the thymic medulla. Extending this framework across human B-cell lymphomas, we identify an inherent malignant cell state in PMBCL that shares transcriptional and epigenetic features with CCL17 thymic B cells. This malignant state associates with early clonal positions in reconstructed B-cell receptor phylogenies and persists within tumor microenvironments distinct from the thymic niche. Together, these findings support a model in which thymus-specific B-cell differentiation programs are redeployed during thymic B-cell lymphomagenesis.

cancer biology↗

bioRxiv2026

Impaired astrocytic Cx43 syncytial network in lateral habenula affects synaptic connectivity and drives adolescent stress-induced depression

Adolescent depression is a major neuropsychiatric disorder induced by early life stress; the underlying cellular mechanisms instigating pathological circuit malformation remain unclear, and, consequently, effective therapeutic strategy is limited. Here, we analysed the contribution of astrocytes to early life stress-induced adolescent depression using a mouse model of parental separation. We identified a previously unrecognised regional specialisation of lateral habenula (LHb) astrocytes, characterised by compact cellular domains, abundant leaflets, and enhanced Cx43 gap junctional coupling. Parental separation selectively reduced astrocytic Cx43 expression and gap junctional communication in the LHb, which was accompanied by profound astrocytic atrophy and loss of leaflets. Single-cell sequencing further revealed that parental separation induces a broad reorganisation of LHb astrocyte transcriptional states, including metabolic, stress-response, and inflammatory programs; moreover, it specifically reduces astrocyte-neuron communication. Consistent with this, we found that structural remodelling of LHb astrocytes affected tripartite synapse geometry, resulting in impaired excitatory and inhibitory synaptic transmission, and neuronal Ca2+ hyperexcitability, all ultimately associated with depressive-like behaviours. Selective knockdown of astrocytic Cx43 in the LHb recapitulated these pathological changes and translated into depressive-like behaviours. Mechanistically, we found that impaired Cx43 gap junctional communication is associated with excessive astrocytic Ca2+ dynamics, resulting in Rac1-GTPase activation and decreased p-Ezrin levels. In vivo inhibition of LHb astrocytic Ca2+ signalling rescued astrocytic atrophy and depressive-like behaviours following parental separation. Together, our findings establish a Cx43-Ca2+-Rac1-p-Ezrin pathway that links gap junction malfunction to structural remodelling of astrocytes and disruption of neuron-astrocyte interactions in the developing LHb. Our study reveals astrocytic Ca2+ dysregulation as an active downstream effector of Cx43 dysfunction and identifies a regionally specialised astrocytic mechanism through which early-life stress disrupts synaptic transmission and neuronal function during adolescence, providing a potential cellular target for intervention in adolescent depression.

neuroscience↗

bioRxiv2026

Brain Controllability and Control Energy in Gray-White Matter Fusion Network

Objective: Brain network controllability provides a framework for understanding how structural organization shapes brain dynamics, yet current models mainly rely on white-matter connectivity and may overlook the contribution of gray-matter architecture. Approach: We constructed a fusion network combining diffusion tensor imaging-derived white-matter connectivity with gray-matter morphological similarity and investigated its controllability, biological associations, heritability, phenotype prediction, and control energy. Main results: Controllability derived from the fusion network preserved key topological properties of the white-matter network and was associated with neurotransmitter systems and cerebral metabolism. Compared with the white-matter connectivity-based network, fusion-based controllability showed a systematic shift toward higher heritability, improved prediction of several individual characteristics and cognitive functions, and lower modeled control energy for activating resting-state networks. Significance: These findings suggest that incorporating gray-matter morphological information into a DTI-supported network provides a complementary structural representation for studying brain network controllability and state transitions. The lower control energy represents a model-derived transition cost and should not be interpreted as a direct measure of physiological energy expenditure.

neuroscience↗

bioRxiv2026

Kinesin-1 holoenzyme assembly coordinates cargo-adaptor recognition with heavy-chain autoinhibition

Kinesin-1 is a major microtubule-based molecular motor that transports diverse cellular cargoes, yet how assembly of its subunits is coupled to cargo recognition and motor regulation remains poorly understood. Mammalian kinesin-1 functions as a heterotetrameric holoenzyme composed of kinesin heavy chains (KIF5s) and kinesin light chains (KLCs), but the structural principles linking holoenzyme assembly to motor regulation remain unclear. Here, using KIF5C as a model system, we define the molecular mechanisms underlying kinesin-1 holoenzyme assembly and cargo-adaptor regulation. We identify a conserved coiled-coil interface between KIF5C and KLC1 that mediates their 2:2 assembly, with quantitative mutagenesis revealing key hydrophobic determinants of complex formation. We further demonstrate that the mitochondrial adaptor TRAK2 directly engages the KIF5C CC4 cargo-binding platform through a defined 2:2 interaction required for mitochondrial recruitment of KIF5C. Although KLC1 and TRAK2 bind distinct regions of KIF5C, KLC1 modulates TRAK2 association through steric and conformational effects, revealing how holoenzyme composition influences cargo-adaptor accessibility. Mechanistically, we identify a previously unrecognized intramolecular interaction between the KIF5C CC1 and CC4 domains that forms a stalk-mediated autoinhibitory latch. TRAK2 and KLC1 release this inhibitory interaction through distinct mechanisms. Together, our study establishes a molecular framework in which kinesin-1 holoenzyme assembly regulates cargo-adaptor recognition and autoinhibitory remodeling, providing mechanistic insight into how molecular motors coordinate cargo engagement with activation.

biochemistry↗

bioRxiv2026

A brain-tumour axis links chronic stress to gastric cancer progression through NPY signalling

Chronic stress promotes gastric tumour growth, but the central neural pathways remain largely enigmatic. Here, we identify a brain-tumour axis, implicating the central amygdala (CeA) activity in promoting gastric cancer growth through sympathetic neuropeptide Y (NPY) signalling occurring within the tumour. Using clinical datasets, patient samples, pathway tracing, electrophysiology and chemogenetic manipulation, we demonstrate that stress selectively increases NPY Y1 receptor (NPY1R) synthesis in the patients gastric cancer tissue; moreover, the NPY1R density correlates with advanced cancer stage and poor prognosis. In mice, daily constraint chronic stress enhances CeA excitability and promotes sympathetic neurotransmitter norepinephrine release within the tumour microenvironment. Norepinephrine, in turn, increases tumour endogenous NPY/NPY1R production and the activation of downstream MAPK/Erk1/2 signalling pathway, which drives cancer cell proliferation and invasion. Manipulating CeA neuronal activity alone can regulate tumour growth, whereas selectively blocking tumour NPY1R prevents stress-induced tumour progression in vivo and cancer cell migration in vitro. This study identifies a central-to-peripheral circuit linking chronic stress to gastric cancer growth, and highlights NPY1R as a potential therapeutic target.

Cancer Biology↗

bioRxiv2026

Chromosome-scale genome assembly of diploid halophyte Thinopyrum bessarabicum excludes J genome from polyploid Thinopyrum ancestry

Wild relatives of wheat harbour genetic diversity essential for improving resilience to climate-driven stresses, yet their deployment is hampered by unresolved evolutionary relationships and the absence of reference genomes. Here we present a chromosome-scale reference genome for Thinopyrum bessarabicum, a diploid halophyte and high-priority donor for wheat salt tolerance breeding. A key unresolved question is whether the diploid J genome contributed directly to the subgenome composition of extant polyploid Thinopyrum species, and which genomic features underpin its exceptional salt tolerance. Using this resource, we show that the diploid J genome of Th. bessarabicum is not represented among the subgenomes of polyploid Thinopyrum species, resolving a long-standing ambiguity in Triticeae genomics. Gene-level resolution of the reciprocal 4/5 chromosomal translocation across six related Triticeae species identifies conserved breakpoint gene pairs, supporting a single ancestral rearrangement. Genome-wide gene content analysis shows that halophytic capacity is underpinned by quantitative expansion of conserved stress-response gene families. Salt tolerance phenotyping validates chromosome 5J as a tolerance locus in both Th. bessarabicum and wheat introgression lines. A physically anchored marker framework and dual-reference skim-sequencing pipeline enable precise megabase-resolution characterisation of Th. bessarabicum introgressions in wheat, providing a genomic foundation for deploying J-genome diversity in crop improvement.

plant biology↗

bioRxiv2026

Photo-downregulation of SIRT4 mitigates aging in mice by enhancing H3K9ac via fatty acid metabolism

As organisms age, mitochondrial metabolic activity declines, and disrupted gene expression regulation mediated by histone acetylation induces the emergence of senescent physiological phenotypes in tissues. In this study, we found that periodic exposure to red light significantly increased histone H3 Lys9 acetylation (H3K9ac) levels in the tissues and organs of aged mice. Following red light exposure, silent information regulation factor 4 (SIRT4) protein levels in keratinocytes were notably reduced, whereas glycolysis, fatty acid metabolism, and the tricarboxylic acid (TCA) cycle were significantly activated in keratinocytes. The reduction in mitochondrial SIRT4 levels enhances the acetylation of mitochondrial metabolic proteins, particularly malonyl-CoA decarboxylase (MCD), a potent inhibitor of the key rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) in fatty acid oxidation. This process promotes mitochondrial fatty acid oxidation and TCA cycle. Additionally, the decrease in SIRT4 activates SIRT1 through feedback mechanisms, thereby alleviating its inhibition on PPAR- in senescent keratinocytes and comprehensively activating the expression of genes related to lipid metabolism. This lipid metabolism activation ultimately facilitates the accumulation of acetyl-CoA within keratinocytes, increases H3K9ac levels, and reshapes the expression patterns of senescence-related genes. Eventually, cellular aging is effectively mitigated by the synergistic regulation of metabolism, inflammation, and gene expression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/717004v2_ufig1.gif" ALT="Figure 1"> View larger version (82K): org.highwire.dtl.DTLVardef@ba3865org.highwire.dtl.DTLVardef@1cc9a58org.highwire.dtl.DTLVardef@1a90e7borg.highwire.dtl.DTLVardef@1f5e88f_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical AbstractMechanism of anti-aging action of red light: Red light can reduce SIRT4 signalling in keratinocytes, thereby reactivating lipid metabolism and increasing levels of acetyl-CoA. This promotes histone acetylation, which in turn remodels the expression of age-related inflammatory factors and genes.

cell biology↗

bioRxiv2026

Influenza A virus membrane fusion is regulated by the balance between receptor binding and cleavage

Interactions between influenza A virus (IAV) and its host receptor, sialic acid, influence multiple stages of infection through the opposing activities of hemagglutinin (HA) and neuraminidase (NA). Multivalent HA binding to low-affinity receptors generates high avidity and attachment specificity, while NA-mediated receptor cleavage promotes penetration through sialylated respiratory mucus and progeny virion release. The role of receptor interactions in post-attachment entry, particularly during genome delivery through HA-mediated endosomal membrane fusion, remains unresolved due to conflicting data, limited control of receptor conditions, and difficulty separating attachment from fusion at low efficiency. Here, we address this question using a flow-cytometry based assay that quantifies time-resolved lipid mixing in hundreds of individual virion-membrane pairs per second, combined with programmable control of receptor density and chemistry on target membranes. We show that HA-receptor interactions regulate membrane fusion efficiency by promoting productive fusion-peptide insertion by HA. This effect depends on receptor context: within a defined regime, lipid-mixing efficiency increases with receptor density whereas NA activity reduces it by depleting receptors. Receptor type and HA-receptor binding avidity further modulate lipid-mixing outcomes, establishing a direct link between HA-receptor interactions and fusion efficiency. Together, these results identify receptor binding as an active regulator of membrane fusion and provide a framework that reconciles prior conflicting observations. More broadly, they extend the functional interplay between HA and NA to the level of membrane fusion, with implications for viral adaptation and host specificity. Significance StatementWe resolve a long-standing question by showing that host receptor binding by HA and cleavage by NA regulate influenza A virus membrane fusion, the entry step delivering the viral genome into the cell. HA-receptor engagement promotes productive HA membrane insertion, leading to fusion. Receptor density, HA-receptor affinity, and NA catalytic activity tune fusion outcomes. These results were enabled by two methodological advances: precise control of receptor presentation on target membranes and sensitive measurement of attachment and membrane fusion at the single-virion level. By defining how the opposing activities of HA and NA regulate fusion, this study extends their functional interplay to a key step in entry and provides new insight into how these proteins coevolve during viral adaptation.

microbiology↗

bioRxiv2026

Reassessment of RNF43 Function Reveals No Impact on Endogenous EGFR or BRAF Protein Stability

RNF43 is best known for removing the Wnt-receptor complex from the cell surface, thereby maintaining Wnt-signaling at minimal essential levels. Recent studies reported that RNF43-mutant colorectal cancers carrying the common BRAFV600E mutation, respond more effectively to combined BRAF/EGFR inhibition. To determine whether RNF43 directly regulates EGFR or BRAF protein abundance, multiple pancreatic and colorectal cancer cell line models were generated in which RNF43 was knocked out, repaired, or stably overexpressed. Total and cell surface EGFR levels, as well as endogenous BRAF expression, were quantified. Across all models, no consistent evidence emerges that RNF43 modulates endogenous EGFR or BRAF levels. R-spondins likewise fail to alter EGFR levels or internalization. Notably, elevated EGFR expression observed in a subset of RNF43 knockout clones is induced by unintended CRISPR/Cas9 vector integration rather than the absence of RNF43 itself, highlighting a previously underappreciated artefact that can confound interpretations of EGFR regulation in genome edited lines. Overall, the data argue against a direct and general role for RNF43 in controlling EGFR or BRAF protein abundance, contradicting recent reports that propose degradation of these targets. Further studies are required to resolve these discrepancies and clarify the mechanistic basis underlying these conflicting observations.

cell biology↗

bioRxiv2025

Gene Delivery Mediated by Backbone-Degradable RAFT Copolymers

Cationic polymers present an attractive platform for gene delivery. However, these highly charged macromolecules can also lead to cytotoxicity. Therefore, there is a strong unmet need to develop efficacious polymeric gene delivery vehicles with high biocompatibility. Here, we leveraged recent advances in polymer chemistry to develop backbone-degradable cationic copolymers and evaluate their potential as gene delivery vehicles. Specifically, polycations were prepared via copolymerization with macrocyclic allylic sulfides which can participate in PET-RAFT polymerization via radical ring-opening cascade copolymerization to install degradable backbone segments. A polymer library with varying degradability was prepared and evaluated using a model GFP plasmid to transfect U-2 OS cells. Incorporation of degradable groups into the copolymer backbone improved transfection efficiency 10-fold at low amine/phosphate (N/P) ratios without increasing cytotoxicity, thereby enhancing their value as gene delivery carriers. We hypothesize that degradability may enhance the complexs disassembly kinetics in the cytosol, enabling more efficient payload release.

bioengineering↗

bioRxiv2025

Mycobacterium tuberculosis m4C DNA methyltransferase Rv3204 promotes mycobacteria survival under oxidative stress

Reactive oxygen species (ROS) inflict cellular damage yet are pivotal mediators of signaling pathways. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), persists as a major global health threat, partly due to its capacity to neutralize host-derived ROS toxicity. While DNA methylation deficiency is known to attenuate Mtb virulence, the specific role of DNA methyltransferases in mycobacterial survival under oxidative stress remains poorly defined. Here, we demonstrate that the mycobacterial protein Rv3204 functions as an N4-methylcytosine (m4C) DNA methyltransferase. Deletion of the Rv3204 homolog (Ms_1939) in Mycobacterium smegmatis significantly impaired bacterial survival upon rifampicin exposure. This phenotype was associated with heightened intracellular ROS accumulation and a failure to upregulate transcription of ROS detoxification genes. Furthermore, the mutant exhibited downregulated expression of DNA repair genes and increased susceptibility to fluoroquinolone antibiotics (norfloxacin, ofloxacin). Crucially, the Ms_1939 deletion strain displayed elevated levels of DNA damage. To our knowledge, this is the first study establishing a direct link between an m4C DNA methyltransferase and ROS homeostasis in mycobacteria. Our findings identify Rv3204 as a potential novel therapeutic target for modulating ROS sensitivity in M. tuberculosis. ImportanceMycobacterium tuberculosis, the causative agent of tuberculosis, remains a major global health threat due in part to its ability to withstand host-derived oxidative stress. This study identifies Rv3204 as a novel N4-methylcytosine DNA methyltransferase essential for mycobacterial survival under oxidative stress. We demonstrate that deletion of Rv3204 homolog in M. smegmatis leads to elevated intracellular ROS, impaired transcriptional activation of antioxidant and DNA repair genes, increased DNA damage, and heightened susceptibility to fluoroquinolone antibiotics. Our findings establish a critical link between epigenetic regulation via m4C methylation and ROS homeostasis in mycobacteria--a relationship previously unexplored. This work not only advances our understanding of bacterial epigenetic mechanisms in stress adaptation but also positions Rv3204 as a promising target for novel anti-tuberculosis strategies aimed at disrupting redox balance and enhancing antibiotic efficacy. DATA summaryRaw data files have been deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) under accession number GSE139646 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139646).

genetics↗

bioRxiv2025

NuMA promotes constitutive heterochromatin compaction by stabilizing linker histone H1 on chromatin

Heterochromatin has been widely recognized to exert pivotal functions of silencing specific genes and maintenance of genome stability. However, the mechanisms underlying heterochromatin formation and maintenance remain to be fully elucidated. Here, we discovered that the critical mitotic regulator NuMA, as a nucleoskeleton protein, is required for constitutive heterochromatin organization at the level of nucleosomes in the interphase. Depletion of NuMA results in shortened nucleosome repeat length (NRL), dispersed nucleosome clutches and increased chromatin accessibility in heterochromatin regions. Afterwards, epigenetic maintenance and transcription repression in constitutive heterochromatin are disrupted upon NuMA-depletion, particularly the up-regulated transcription level of the non-coding long terminal repeat (LTR) elements, indicating the crucial roles of NuMA in cell differentiation and senescence. We revealed that such functions of NuMA rely on its interaction with linker histone H1, which stabilizes H1s binding to chromatin and facilitates nucleosome stacking. We provided direct structural evidence of NuMAs stabilization effect at the highest spatial resolution of nucleosomes through in situ cryo-ET. Notably, we found that NuMA oligomerizes into quasi-meshwork in nucleoplasm and highly co-localizes with H1 on the chromatin, providing the organization basis for NuMA as a nucleoskeleton protein in chromatin architecture regulation. Collectively, our findings illuminate the concerted effect of nucleoskeleton protein and linker histone on chromatin compaction at the level of nucleosomes, which unveil a new layer of mechanisms by which nucleoskeleton regulates heterochromatin formation and maintenance.

biophysics↗

bioRxiv2025

A distinct class of eukaryotic demethylases safeguards the positional fidelity of N6-methyladenine (6mA)

DNA N6-methyladenine (6mA) has recently been rediscovered as an epigenetic mark in eukaryotes. Several demethylases responsible for 6mA removal have been identified in multicellular eukaryotes. However, despite the much higher abundance of 6mA in unicellular species, no such enzymes have been reported and the biological significance of 6mA removal in these organisms remain unclear. Here, we identify and functionally characterize DMT3 as a dedicated 6mA demethylase in unicellular eukaryotes. DMT3 targets both fully and hemi-methylated ApT dinucleotides on DNA. It is predominantly localized at transcription start sites (TSS), where it antagonizes the activity of the 6mA methyltransferase AMT1. Deletion or catalytic inactivation of DMT3 leads to genome-wide ectopic 6mA deposition specifically at TSS regions, driven by AMT1, and is accompanied by increased chromatin accessibility and elevated enrichment of transcription-associated histone marks. These epigenetic alterations disrupt gene expression, reduce osmotic stress resistance, and impair the initiation of sexual reproduction. Together, our findings uncover a critical 6mA demethylase in unicellular eukaryotes, and highlight the essential role of active 6mA removal in maintaining transcriptional and developmental integrity.

genetics↗

bioRxiv2025

DNA extracted from boiled archival fish bones yields high quality whole genome sequencing data

Archival samples provide a unique source of DNA, offering the potential to extend the temporal scale of genetic studies by decades to centuries. Fish hard structures, such as otoliths and scales, serve as records for fish collected during fisheries monitoring across a large spatiotemporal scale. Operculum bones are a type of fish hard structure that, although less commonly collected, have been utilized in genetic studies. However, the usefulness of archived operculum bones to provide high quality whole genome sequence information has not been thoroughly evaluated. Here, we applied a commercially available extraction protocol, with minor adjustments, to isolate genomic DNA from operculum bones of Eurasian perch collected up to 47 years ago, followed by standard short-read whole genome sequencing. By comparing the metrics of DNA and whole genome sequencing data of bones with contemporary muscle samples, we demonstrate that the application of a simple extraction protocol on boiled archival fish operculum bones yields high quality genomic information that is comparable to fresh tissue, highlighting the role of archival operculum bones as an overlooked repository of valuable genomic information.

molecular biology↗

bioRxiv2025

SpaBatch: Batch Alignment of Spatial Transcriptomics Data using Graph Deep Learning

Spatial transcriptomics (ST) has emerged as a transformative technology, enabling the simultaneous capture of gene expression and spatial context within tissues. However, batch effects arising from technical variability remain a significant barrier to integrating datasets generated from different experiments. To this end, we introduce a novel graph deep learning framework (SpaBatch) tailored for the batch alignment of multi-slice spatial transcriptomics data. SpaBatch is an innovative computational framework leveraging Variational Graph Autoencoders, self-supervised learning, and triplet learning with readout aggregation to enhance multi-slice spatial transcriptomics data integration. We validated our framework on multiple datasets encompassing various tissue types and experimental conditions. Through the adjustment of batch effects, SpaBatch facilitates the analysis of spatial transcriptome domains across multiple slices, showcasing its capability to reveal new biological insights in multi-slice spatial transcriptome studies.

bioinformatics↗

bioRxiv2025

Population-scale gene expression analysis reveals the contribution of expression diversity to the modern wheat improvement

Changes in gene expression are crucial for crop breeding, yet population genomics has primarily focused on sequence polymorphisms rather than gene expression diversity. The strategy of using single genome reference for RNA-seq analysis could not handle introgression bias, especially for hexaploidy wheat. Here, we conducted RNA-seq for 328 wheat lines, including representative diverse landraces and elite cultivars from China and the United States, to investigate the role of gene expression variation in shaping agronomic traits. Using pan-genome resources, we identified 20,615 more transcripts than using the Chinese Spring reference genome alone. We constructed a pan-gene atlas regulatory map through eQTL analysis, demonstrating that genes introgressed from wild relatives were under tight genetic control. Genes responding to environmental stress show higher activity after introgressed into the wheat genome, demonstrating how long-term breeding selection impacted the gene expression regulation of targeted introgression. Multi-omics modeling identified 231 high-confidence candidate genes for 34 field agronomic traits and the seedling resistance phenotypes of 8 powdery mildew isolates. More than one fifth of those candidates have no homolog in Chinese Spring reference genome. By utilizing the indexed KN9204 EMS library, 80% candidates showed significant trait difference between wild type and mutant lines. Furthermore, directional shifts in genes of which expression were changed by breeding improvement demonstrated distinct adaptations to local environments. Our study constructed a pan-gene atlas to correct the reference bias of reads mapping in RNA-seq studies and revealed the expression patterns of introgressed genes within the wheat genome and their regulatory mechanisms, which highlighted the impact of breeding selection on gene expression of the worlds most important crop.

plant biology↗

bioRxiv2025

Particular Amino Acid on Lateral Interface Maintains FtsZ Function Under Acid Stress in Streptococcus mutans

FtsZ is the core protein for cell division in bacteria that can polymerize into Z-rings and drive cytokinesis. Understanding how bacteria maintain the correct function of FtsZ under various environmental stresses is crucial for novel antibacterial drug discovery. Our previous study revealed that the FtsZ in S. mutans has higher self-assembly and GTPase activity under acidic stress, which may be responsible for the cariogenesis of S. mutans. However, the mechanism is still unknown. Here, we further reported the crystal structure of S. mutans FtsZ, revealing a unique lateral interface. Through protein polymerization and GTPase ability assay, we experimentally demonstrated that mutation of Arg68 on this lateral interface significantly reduced the functional activity of FtsZ in an acidic environment. The phenotype assay and rat caries model further showed that mutation of Arg68 effectively inhibited the acid resistance of S. mutans and the occurrence and progress of dental caries in vivo. By employing a molecular dynamics simulation analysis, we conclude that mutation of Arg68 disrupts the conformation change necessary for SmFtsZ polymerization under acidic conditions. Our study proposes a novel mechanism to maintain FtsZ function in bacteria and could be a potential target for antimicrobial drugs to inhibit the growth of S. mutans in an acidic environment. Significance StatementFtsZ is the core protein that drives cytokinesis. Maintaining the self-assembly and GTPase activity of FtsZ plays a critical role in cell growth under environmental stress. Currently, research on FtsZ function maintenance under stress mainly focuses on model organisms, with less on other pathogenic bacteria. This study reveals a novel structural mechanism for the acidic tolerance of FtsZ in S. mutans which survives in strongly acidic surroundings. Meanwhile, Arg68 on the lateral interface of SmFtsZ may be a potential therapeutic target to regulate microecology and combat S. mutans-associated dental caries.

microbiology↗

bioRxiv2025

Single-cell multiomics data integration and generation with scPairing

Single-cell multiomics technologies generate paired measurements of different cellular modalities, such as gene expression and chromatin accessibility. However, multiomics technologies are more expensive than their unimodal counterparts, resulting in smaller and fewer available multiomics datasets. Here, we present scPairing, a deep learning model inspired by Contrastive Language-Image Pre-Training, which embeds different modalities from the same single cells onto a common embedding space. We leverage the common embedding space to generate novel multiomics data following bridge integration, a method that uses an existing multiomics bridge to link unimodal data. Through extensive benchmarking, we show that scPairing constructs an embedding space that fully captures both coarse and fine biological structures. We then use scPairing to generate new multiomics data from retina, immune, and renal cells. Furthermore, we extend scPairing to generate trimodal data. Researchers can use these generated multiomics datasets to discover new biological relationships across modalities or confirm existing hypotheses.

bioinformatics↗