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Dai, M.

Publications and source records attributed to Dai, M..

At least 19 recordsLinked to original sources

The functional diversification of somatosensory neuron repertoires across Mammalia

The striking diversity of mammalian body forms and surfaces, lifestyles, and habitats prompts the question of how each species' somatosensory neuron repertoire accommodates such diversity. The visual and olfactory systems diversify by gaining and losing sensor/receptor genes and corresponding sensory cell types. Using multiomic single-cell analysis of dorsal root ganglia neurons from thirteen different mammalian species and cross-species functional studies enabled by cell-type-specific enhancer viruses, we show that mammals instead assemble species-specific, functionally distinct somatosensory neuron repertoires from a conserved set of neuron types (orthotypes). Repertoire diversification takes multiple forms: orthotype abundance scales with variable bodily traits like hair follicle density, facilitating relevant behaviors; sensor/receptor expression is shuffled across species, such that orthotypes can detect different stimuli in different species; and orthotypes split into functionally distinct, species-specific subtypes (paratypes). Thus, unlike other sensory systems, the mammalian somatosensory system diversifies through multifarious changes to conserved orthotypes, enabling adaptation to diverse habitats, lifestyles, and body forms.

neuroscience↗

Compression Sequencing enables ultra-sensitive and scalable scRNA-seq

Current sequencing methods are inefficient and bottlenecked by repeated sampling of highly abundant molecules, which dominate sequencing reads, limit assay throughput and sensitivity for rare targets. For example, single-cell RNA sequencing (scRNA-seq) can profile up to millions of cells, but remains severely constrained by sequencing cost, resulting in shallow gene coverage and high dropout rate. Here we report an information science-inspired method, Compression Sequencing, that tackles this fundamental inefficiency and enables highly improved (>100x) sequencing power. Our method works by performing an accurate and unbiased logarithmic transform on molecular abundances over a wide (5 logs) dynamic range, thus suppressing high-abundance targets and enriching rare ones, while maintaining quantitative accuracy. Applied to scRNA-seq libraries, our method allows ultra-sensitive detection of low-abundance transcripts (2-5x more UMIs), ultra-low sequencing cost (200x reduction), preserves accurate cell types and differential expression analysis over a 500-2,000 gene panel. In AML clinical samples, Compression Sequencing reproduces clinical diagnosis and additionally allows transcriptomic profiling at affordable cost (est. $10 per sample). Our approach thus enables ultra-sensitive and scalable single-cell analysis for large-scale functional genomics studies, drug discovery screens, AI cell model training, as well as affordable single-cell disease diagnostics.

bioengineering↗

The cellular and genetic basis of inflorescence divergence between maize and teosinte

The domestication of maize from teosinte involved dramatic remodeling of the ear, yet the cellular and genetic bases of this transformation remain unclear. Here, we generate a single-nucleus and spatial transcriptome atlas of developing maize and teosinte ears. Comparative analysis reveals divergence in cob-associated cell types, with enhanced cytokinin signaling and reduced growth-inhibitory signals collectively driving cob thickening and enlargement in maize. We further demonstrate that domestication expanded the spatial expression domain of key transcription factors in maize meristem cells, enhancing the potential for increasing kernel number. Additionally, we verified a major domestication gene, ZmSPD1, in which two nonsynonymous SNPs differentiate maize from teosinte and alter jasmonic acid (JA) levels in the ear, thereby suppressing spikelet abortion to effectively double kernel production. These findings provide a cell-resolved mechanistic framework for how cob architecture and kernel number were shaped during maize domestication, offering new insights into the formation of key agronomic traits.

plant biology↗

Evolutionary history and microbial cross-feeding shape lifestyle-stratified dominance of Bifidobacterium longum subspecies in infants

Bifidobacterium longum (Bl.) is a key early-life gut symbiont, yet its evolutionary origin and mechanisms underlying the global biogeographic distribution of its subspecies remain poorly resolved. Here, we compiled a global genomic atlas of >7,000 MAGs/genomes from infants, domesticated animals, non-human primates, and ancient humans. High-resolution phylogenomic and functional analyses expanded infant-associated subspecies to five. Compared with non-human primates, B. longum was more prevalent in domesticated animals and ancient humans dating from 150 to 1,500 years ago. Moreover, human- and livestock-derived lineages from the same geographic regions clustered together, suggesting potential host-associated transmission. Ecologically, Bl. infantis and Bl. longum predominated in non-Western and Western infants, respectively, independent of breastfeeding, delivery mode, or antibiotic exposure. Instead, their distribution was associated with co-occurring microbes and HMO-driven cross-feeding interactions. These findings explain subspecies differentiation in the gut microbiota of Western and non-Western infants and provide a framework for community-mediated interventions in early life.

microbiology↗

Mechanism of fatty acid uptake and inhibition in human FATP2

Fatty Acid Transport Protein 2 (FATP2) couples fatty acid uptake to intracellular activation and is associated with pathological lipid accumulation in cancer and nonalcoholic fatty liver disease. Here, we present cryo-electron microscopy structures of human FATP2 across its reaction cycle. Our structures suggest that FATP2 recruits fatty acids directly from the membrane interface through a hydrophobic tunnel. Catalysis involves a [~]130{degrees} rotation of the C-terminal domain, a transition trapped by the antihypertensive drugs isradipine and benidipine. Both drugs lock the enzyme in a thioester-forming state, but benidipine exhibits superior efficacy by extending a bulky moiety into the primary catalytic tunnel to sterically block substrate entry. Furthermore, we identify a product inhibition mechanism where excess acyl-CoA traps the enzyme, potentially limiting metabolic overload. These findings provide a structural framework for understanding vectorial fatty acid channeling and a scaffold for developing modulators of metabolic flux. HighlightsO_LICryo-EM structures of human FATP2 reveal a membrane-anchored lollipop topology C_LIO_LIEndogenous fatty acids within a hydrophobic tunnel delineate the fatty acid uptake pathway C_LIO_LIIsradipine and benidipine displace fatty acids to trap a non-productive conformation C_LIO_LIAcyl-CoA product inhibition may provide negative feedback via steric occlusion C_LI

biophysics↗

Cognitive function depends upon Satb2 gene dosage in cortical projection neurons

SATB2-associated syndrome (SAS) is a severe neurodevelopmental disorder caused by de novo heterozygous SATB2 mutations, yet how haploinsufficiency disrupts brain development remains poorly understood. While homozygous Satb2 loss causes profound embryonic cell-fate defects, we demonstrate using a heterozygous mouse model that SAS phenotypes emerge primarily during postnatal circuit maturation. Integrating chromatin profiling, transcriptomics, electrophysiology, and behavior, we show that SATB2 acts as a dose-sensitive chromatin regulator that binds conserved enhancer-promoter landscapes to orchestrate networks linked to human intelligence. Although excitatory neuron subtype specification is preserved, Satb2 heterozygotes adopt an intermediate epigenetic state that drives cell-type-specific dysregulation of genes enriched for intellectual disability risk variants. Consequently, mutant neurons exhibit simplified dendritic arborization, reduced intrinsic excitability, and weakened layer 2/3-to-layer 5 intracortical connectivity. These circuit deficits culminate in the disorganization of the somatosensory barrel cortex and severe impairments in whisker-dependent texture discrimination. Finally, by restricting Satb2 heterozygosity to the cortex, we decouple these cortical sensory deficits from subcortical vocalization phenotypes. Together, our work links SATB2 dosage to chromatin architecture and postnatal circuit maturation, revealing a critical, post-mitotic therapeutic window for intervention in SAS.

neuroscience↗

CellClick: an interactive platform for adjustable and accurate cell type annotation in single-cell and spatial omics data

Single-cell omics and spatial omics technologies are nowadays widely used in biological and medical research. In both single-cell and spatial omics data analysis, accurate cell type annotation is a key step for downstream analysis and scientific discoveries. However, high-quality cell annotation usually requires multiple rounds of manual analysis for result refinement, which poses great challenges to most researchers. Here, we present CellClick, an interactive platform for convenient and accurate cell type annotation in single-cell and spatial omics data. CellClick provides Data Preprocessing, Data Visualization, Cell Annotation, Annotation Validation, and Cell Reannotation modules, which facilitate automatic or user-guided cell selection and annotation. The feasibility of using CellClick to generate more accurate cell annotation results was exemplified by both scRNA-seq and spatial transcriptomics data.

bioinformatics↗

BBB-Permeable Near-Infrared Oxazine Fluorophores for White Matter Tract Imaging

Preserving critical functional tissue remains a major challenge in fluorescence-guided surgery (FGS), particularly in neurosurgery where injury to white matter tracts can lead to lasting neurological deficits. Probes for preventing iatrogenic injury of the peripheral nervous system have highlighted the potential of real-time intraoperative guidance for nerve-sparing surgery, supporting improved preservation of critical functional tissue, but analogous tools for the central nervous system remain limited. While there are some awake mapping and MRI based techniques that try to minimize the resection of white matter tracts (WMTs), they do not provide surgeons with real-time visualization. To address this gap, we rationally translated a peripheral nerve targeted oxazine fluorophore platform into a library of novel oxazine dyes that can penetrate the blood-brain barrier (BBB), exhibit specificity for white matter tissue and maintain spectral compatibility with clinically relevant imaging systems. Guided by our fluorophore medicinal chemistry platform, this work includes library design, photophysical property characterization, in vivo WMTs specificity screening, and in vivo imaging window assessment of the lead candidates to evaluate neurosurgical workflow compatibility. The lead candidate identified from this library demonstrated strong in vivo WMTs-specific fluorescence intensity, contrast and imaging window compatible with neurosurgical workflows, establishing BBB-permeable oxazine fluorophores as a promising scaffold for future structure-sparing neurosurgical FGS.

bioengineering↗

A graph-based pangenome reveals the genetic basis of climate-resilient and horticultural traits in pear

Climate change poses an increasing threat to the cultivation of deciduous fruit trees, placing greater demands on modern pear breeding. Using pear germplasm adapted to diverse environments, we assembled 11 chromosome-level genomes. In combination with 13 publicly accessible pear genomes, we analyzed presence-absence variations (PAVs) and constructed a graph-based pangenome for pear. By performing a PAV-eQTL analysis of the fruit of 123 pear accessions, we identified PAVs significantly associated with expression levels of genes that may be involved in regulating agronomic traits. Population analysis of 268 pear accessions revealed two stop-gained variants in DAM1 of independent origin, which may function in advancing the blooming date and reducing the chilling requirement. We detected complex PAVs at the NOR1 locus, including two copy-number variations and one deletion. These PAVs contributed to the rapid diversification of the NOR1 locus and the fruit development period through regulating ARF5 and other ripening-related genes. We revealed the selection history of the NOR1 locus and developed novel pear individuals that accumulated alleles for low chilling requirement, early blooming date, and short fruit development period. The results provide valuable resources for pear genomics research and offer a guideline for breeding modern pears with climate resilience.

plant biology↗

APEX1 Protects Cardiomyocytes Against Oxidative Stress by Regulating p53 Protein Stability

Withdrawal statementThe authors have withdrawn this manuscript because the preprint was uploaded to bioRxiv before all co-authors had been fully informed and had provided their explicit consent to make the manuscript publicly available as a preprint. Following internal discussions, the authors have reached a consensus that they do not wish this version to be publicly available. We therefore kindly request that this preprint be withdrawn on the bioRxiv platform. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

molecular biology↗

Developmental dysregulation of chandelier cell excitability in a mouse model of Dravet Syndrome

Chandelier cells (ChCs) are a rare and highly specialized sub-type of inhibitory neuron in the cerebral cortex that specifically and exclusively form synapses onto the axon initial segment of excitatory neurons and thereby exert powerful control of excitability. We applied a newly developed, cell type-specific enhancer element to label ChCs and assess their electrophysiological and morphological properties across development in Dravet Syndrome (Scn1a+/- mice), a prominent neurodevelopmental disorder defined by epilepsy and features of autism spectrum disorder. Dravet Syndrome is known to predominantly impact GABAergic interneurons. We found that ChCs from juvenile Scn1a+/- mice (postnatal day, P18-21) exhibit impaired excitability, and that deficits largely persist in young adulthood (P35-56). These findings are distinct from prior observations in the more common subtype of parvalbumin-positive interneurons, basket cells. We found no differences in the axonal or dendritic morphology of ChCs at either time point. Our results suggest a role for ChCs in the pathogenesis of Dravet Syndrome and constitute the first targeted study of ChC function in a specific genetically-defined neurodevelopmental disorder.

neuroscience↗

LARIS enables accurate and efficient ligand and receptor interaction analysis in spatial transcriptomics

Advances in spatially resolved transcriptomics provide unprecedented opportunities to characterise intercellular communication pathways. However, robust and computationally efficient incorporation of spatial information into intercellular communication inference remains challenging. Here, we present LARIS (Ligand And Receptor Interaction analysis in Spatial transcriptomics), an accurate and scalable method that identifies cell type-specific and spatially restricted ligand-receptor (LR) interactions at single-cell or bead resolution. LARIS is compatible with all spatial transcriptomic technologies and quantifies specificity, infers sender-receiver directionality, and detects how differential interactions vary across time and space. To compare LARIS with existing methods, we established a simulation framework to generate ground truth of LR interactions with defined tissue architecture and gene expression patterns. LARIS demonstrates superior performances over other methods in accuracy and scalability. We further applied LARIS to human tonsil and developing mouse cortex spatial transcriptomics datasets collected from various spatial techniques. This uncovered the signalling mechanisms shaping tissue organisation and their changes over time. LARIS reveals cell type-, niche-, and condition-specific signalling and scales to hundreds of thousands of cells in minutes. This provides an efficient and direct method for discovering the molecular interplay between apposed cells across development.

bioinformatics↗

Gut Microbiota-derived Adenosine Determines the Efficacy of Electroconvulsive Therapy for Depression

Electroconvulsive therapy (ECT) is a final procedure for major depressive disorders (MDD). However, the effectiveness of ECT in treating MDD patients varies. Here we identified gut microbiota as a potential restraining factor of ECT efficacy. By using a 5-day electroconvulsive shock (ECS) in depression mouse model of chronic restraint stress (CRS), it was observed that the antidepressant effect of ECS was suppressed after antibiotics (ABX)-induced microbiota dysbiosis, which also resulted in elevated c-Fos expression of CRH neurons in paraventricular nucleus of hypothalamus (PVN) and increased serum corticosterone levels after ECS. Metabolomic analysis revealed the critical involvement of microbiota associated purine metabolism, and the supplement of gut microbiota-derived adenosine was able to recover the antidepressant effect of ECS in ABX-treated CRS mouse model. Based on the neural tracing from colon to brain and the immunofluorescence staining, it was surmised a gut-brain axis originated from Adora1-expressing cells in colon mediate this biological process. Furthermore, adenosine supplement alleviated the further deterioration of post-ECS memory loss and impairment of synaptic plasticity induced by ABX-treatment as well. Our findings suggest a potential role of microbial adenosine metabolism in ECT efficacy determination and side effect protection, highlights potential application of adenosine supplement in antidepressant therapies of those depression patients with microbiota dysbiosis.

systems biology↗

AniMarkerDB: a comprehensive database for exploring cell types and marker genes in livestock and poultry at single-cell resolution

Single-cell RNA sequencing (scRNA-seq) has dramatically advanced the understanding of cellular heterogeneity. While numerous marker gene databases are available for humans and mice, a lack of systematic resources for livestock and poultry species remains, limiting progress in functional genomics, immunology, and breeding.. To address this challenge, we developed AniMarkerDB (https://animarkerdb.bio), a comprehensive and curated database dedicated to marker genes and immune-related epitopes in economically animals, including chicken, pig, and duck. AniMarkerDB integrates 7,010 marker gene across 37 tissues and 846 cell types, together with 71,442 immune epitope records from IEDB. All entries undergo rigorous literature curation, manual validation, and multi-level quality control, with standardized nomenclature and annotation to ensure data consistency and reusability. The platform supports flexible queries by species, tissue, cell type, or gene. It offers analytical tools for cross-species comparison model organisms such as human and mouse, interactive single-cell atlas visualization, and user-defined cell type annotation. Additionally, AniMarkerDB provides dynamic visualizations and export options, enabling researchers to efficiently obtain large-scale marker and epitope data for downstream applications such as infectious disease research, vaccine target design, and comparative immunology. Looking ahead, AniMarkerDB will expand species coverage and incorporate additional modalities, including single-cell atlases from healthy and disease models, establishing itself as a comprehensive and authoritative platform for animal cell biology, disease modeling, and translational research. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/682327v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@af7e7borg.highwire.dtl.DTLVardef@198d114org.highwire.dtl.DTLVardef@1c69ed2org.highwire.dtl.DTLVardef@e4fc43_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

Discrete interneuron subsets participate in GluN1/GluN3A excitatory glycine receptor (eGlyR)-mediated regulation of hippocampal network activity throughout development and evolution.

Decades of studies implicating GluN3A N-methyl-D-aspartate receptor (NMDAR) subunits in physiological and pathological function have largely been interpreted through direct regulation of conventional glutamatergic NMDARs. However, emerging evidence indicates that GluN3A frequently assembles with GluN1 forming unconventional glutamate-insensitive NMDARs that operate as native excitatory glycine receptors (eGlyRs). Here we demonstrate that hippocampal somatostatin and neurogliaform interneurons (Sst-INs and NGFCs) express functional eGlyRs from early postnatal through adult ages. In the developing hippocampus eGlyR-mediated excitation of NGFCs with ambient glycine dramatically increases GABAergic tone, with consequences for the generation of giant depolarizing potentials (GDPs). In the mature hippocampus, eGlyR- mediated excitation of Sst-INs regulates sharp wave ripples (SWRs). Finally, we reveal evolutionary conservation of hippocampal Sst-IN eGlyRs and eGlyR- mediated SWR regulation in non-human primates confirming functional eGlyR availability for therapeutic potential in higher species. Our findings underscore that eGlyR mediated regulation of cell and circuit excitability through both cell autonomous and cell non-autonomous mechanisms must be considered to understand GluN3A roles in brain development, plasticity, and disease.

neuroscience↗

Single-cell transcriptome sequencing for opening the blood-brain barrier through specific mode electroacupuncture stimulation

BackgroundThe blood-brain barrier (BBB) interferes with the treatment of central nervous system disorders owing to the complexity of its structure and restrictive function. Thus, it is challenging to develop central nervous system drug delivery strategies. Specific mode electroacupuncture (EA) stimulation can effectively open the BBB in rats. MethodsHere, we used single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell population in the Sprague-Dawley rat cerebral cortex. ResultsWe identified 23 cell subsets and eight types of cells in the brain by cell annotation. scRNA-seq revealed transcriptional changes in the cerebral cortex under EA. ConclusionsOur findings offer valuable insights into the molecular and cellular modifications in the brain resulting from EA intervention and serve as a resource for drug delivery across healthy and diseased states. Innovative approaches to enhance BBB opening will lead to more effective therapeutic plans and enhanced drug delivery.

neuroscience↗

A novel, evolutionarily conserved inhibitory circuit selectively regulates dentate gyrus mossy cell function.

The mammalian dentate gyrus contributes to mnemonic function by parsing similar events and places. The disparate activity patterns of mossy cells and granule cells is believed to enable this function yet the mechanisms that drive this circuit dynamic remain elusive. We identified a novel inhibitory interneuron subtype, characterized by VGluT3 expression, with overwhelming target selectivity for mossy cells while also revealing that CCK, PV, SOM and VIP interneurons preferentially innervate granule cells. Leveraging pharmacology and novel enhancer viruses, we find that this target-specific inhibitory innervation pattern is evolutionarily conserved in non-human primates and humans. In addition, in vivo chemogenetic manipulation of VGluT3+ interneurons selectively alters the activity and functional properties of mossy cells. These findings establish that mossy cells and granule cells have unique, evolutionarily conserved inhibitory innervation patterns and suggest selective inhibitory circuits may be necessary to maintain DG circuit dynamics and enable pattern separation across species.

neuroscience↗

CRISPR-based shuttle cloning of 1,397 human genes into UAS vectors

The construction of genome-wide DNA libraries from publicly available resources is essential for leveraging functional genomics to investigate complex biological systems. However, all existing high-throughput cloning methods for transferring DNA fragments between vectors require PCR amplification of the DNA fragments, rendering the construction of genome-wide DNA libraries labor-intensive and time-consuming. By introducing a concept of CRISPRshuttle cassette, we herein present a method named CRISPR-based shuttle cloning (CRISPRshuttle cloning). This method enables the high-throughput transfer of numerous DNA fragments from original plasmids with identical backbones to a different vector background without the need for PCR amplification of the DNA fragments. The procedure comprises two-step test tube reactions followed by bacterial transformation. Using CRISPRshuttle we successfully generated a library of GAL4/UAS-based UAS-ORF plasmids covering 1,397 human genes conserved in Drosophila. This library may serve as a valuable resource for gain-of-function screening in cultured cells and for the creation of a transgenic UAS-ORF library in Drosophila.

molecular biology↗