Biology subjects

Cui, Y.

Publications and source records attributed to Cui, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

ZapC crosslinks FtsZ filaments through a dual-binding mechanism modulated by the intrinsically disordered linker of FtsZ

Most bacteria divide through binary fission, which is mediated by a large protein complex called the divisome. Assembly of the divisome is initiated by formation a Z ring at midcell consisting of polymers of the bacterial tubulin FtsZ. A series of FtsZ-associated proteins (Zaps), which crosslink FtsZ filaments, promote Z ring formation in Escherichia coli. However, how these proteins interact with FtsZ is still unclear. In this study, we discover that ZapC binds to both FtsZs globular domain and its conserved C-terminal peptide (CCTP) to crosslink FtsZ filaments. An AlphaFold 3 structural model of the FtsZ-ZapC complex indicates that ZapC binds to the globular domain of FtsZ via a loop region connecting its N-terminal and C-terminal domains and to the CCTP of FtsZ via a hydrophobic pocket in the N-terminal domain. Substitutions in these regions of ZapC disrupt its binding to FtsZ, validating the dual binding mode. Strikingly, we find that the intrinsically disordered C-terminal linker (CTL) of FtsZ affects the interaction of FtsZ with ZapC as well as other partners, indicating an important role of the CTL in FtsZ functionality. Taken together, these results indicate that ZapC, although it exists as a monomer, can crosslink FtsZ filaments by a two-pronged mechanism, binding to the globular domain of FtsZ in one filament and to the CCTP of FtsZ in another filament. Furthermore, the CTL plays an important role in regulating FtsZ interaction with its partners. ImportanceBacterial cytokinesis requires the Z ring, a highly dynamic cytoskeletal element consisting of polymers of the bacterial tubulin FtsZ. Formation of a coherent and functional Z ring is facilitated by FtsZ-associated proteins (Zap), which can crosslink FtsZ polymers, but how these proteins work is still incompletely understood. In this study, we find that ZapC, one of the FtsZ crosslinkers, binds to both FtsZs globular domain and its conserved C-terminal peptide to crosslink FtsZ filaments. Moreover, the intrinsically disordered C-terminal linker (CTL) of FtsZ modulates its binding to ZapC and many other FtsZ binding proteins. These findings reveal a novel mechanism to crosslink FtsZ filaments and reveal an important and highly conserved role of the CTL in FtsZ functionality.

microbiology↗

bioRxiv2025

Ontology-aware DNA methylation classification with a curated atlas ofhuman tissues and cell types

AO_SCPLOWBSTRACTC_SCPLOWDNA methylation (DNAm) is a core gene regulatory mechanism that captures cellular responses to short- and long-term stimuli such as environmental exposures, aging, and cellular differentiation. Although DNAm has proven valuable as a baseline biomarker for aging by enabling robust characterization of disease-associated methylation shifts associated with age, its potential to reveal analogous shifts in the context of tissue remains underex-plored. A major obstacle has been the absence of comprehensive, curated reference atlases spanning diverse normal human tissues, limiting most existing work to disease-subtype differentiation or localized tissue comparisons. To bridge this gap, we assemble the largest and most diverse atlas of exclusively healthy human tissue and cell samples profiled by 450K arrays, comprising of 16,959 samples across 86 tissues and cell types. Leveraging this resource, we introduce an ontology-aware classification framework that identifies robust CpG features associated with tissue and cell identity while integrating known anatomical and functional relationships (e.g., prefrontal cortex in the brain, leukocytes in blood). Our novel application of Minipatch learning distills a set of 190 CpG sites that can accurately support multi-label classification. We further validate our approach through an ontology-based label transfer task, demonstrating the effectiveness of ontology-informed learning to accurately predict relevant labels for 31 tissues and cell types not seen during training. These findings underscore the potential of our framework to enhance our understanding of healthy methylation landscapes and facilitate future applications in disease detection and personalized medicine.

bioinformatics↗

bioRxiv2025

Phloem-Specific Translational Regulation of Soybean Nodulation: Insights from a Phloem-Targeted TRAP-Seq Approach

Soybean (Glycine max) root nodulation is a symbiotic process that requires complex molecular and cellular coordination. The phloem plays a crucial role not only in nutrient transport but also in long-distance signaling that regulates nodulation. However, the molecular mechanisms underlying phloem-specific regulation during nodulation remain poorly characterized. Here, we developed a phloem-specific Translating Ribosome Affinity Purification sequencing (TRAP-seq) system to investigate the translational dynamics of phloem-associated genes during nodulation. Using a phloem-specific promoter (Glyma.01G040700) combined with the GAL4-UAS amplification system, we successfully captured the translatome of soybean root phloem at early (72 hours post-inoculation, hpi) and late (21 days post-inoculation, dpi) nodulation stages. Differential expression analysis revealed dynamic translational reprogramming, with 2,636 differentially expressed genes (DEGs) at 72 hpi and 8,422 DEGs at 21 dpi. Gene ontology and pathway enrichment analyses showed stage-specific regulatory shifts, including early activation of ethylene and defense pathways and late-stage enhancement of nutrient transport and vascular development. Transcription factor analysis identified GmbHLH121 as a key phloem-specific regulator of nodulation. Functional validation using RNAi knockdown and overexpression experiments demonstrated that GmbHLH121 negatively regulates nodule formation, likely acting downstream of or independently from early nodulation signaling pathways. Additionally, we uncovered dynamic regulation of cell wall-modifying enzymes (PME and PMEI) in the phloem, implicating their role in modulating plasmodesmata permeability and facilitating symplastic connectivity during nodulation. Our findings highlight the critical role of phloem-mediated translational regulation in coordinating root nodulation, emphasizing the phloem as an active regulatory hub for long-distance signaling and symbiotic efficiency.

plant biology↗

bioRxiv2025

Integrated spatial morpho-transcriptomics predicts functional traits in pancreatic cancer

Analyses of patient-derived cell lines have greatly enhanced discovery of molecular biomarkers and therapeutic targets. However, characterization of cellular morphological properties is limited. We studied cell morphologies of human pancreatic adenocarcinoma (PDAC) cell lines and their associations with drug sensitivity, gene expression, and functional properties. By integrating live cell and spatial mRNA imaging, we identified KRAS inhibitor-induced morphological changes specific for drug-resistant cells that correlated with gene expression changes. We then categorized a large panel of patient-derived PDAC cell lines into morphological (e.g., polygonal, irregular, spheroid) and organizational (e.g., tightly aggregated, multilayered, dispersed) subtypes and found differences in gene expression, therapeutic targeting potential, and metastatic proclivity. In human PDAC tissues, we identified prognostic expression signatures associated with distinct cancer cell organization patterns. In summary, we highlight the potential of cell morphological information in rapid, cost-effective assays to aid precision oncology efforts leveraging patient-derived in vitro models and tissues.

cancer biology↗

bioRxiv2025

Physical Activity and Depressive Mood Shared the Structural Connectivity between Motor and Reward Network: a population-based study from the UK Biobank

BackgroundExercise has been revealed to leave a positive effect on alleviating depressive symptoms by various existing studies. However, the neural basis behind this phenomenon remains unknown, as well as its underlying biological mechanism.AimsUsing a large neuroimaging cohort from UK Biobank, this study aimed to identify structural connectivity (SC) patterns simultaneously linked with physical activity and depression, as well as its biological interpretation.Method492 participants with major depression disorder (MDD) and 535 healthy controls (HC) were extracted from the UK Biobank dataset. Partial least squares regression was first utilized to explore a replicable SC pattern simultaneously associated with physical activity and depressive mood. The neuromaps toolbox was applied to interpret the biological ontologies of the identified SC pattern. Neuroimaging-transcriptome association and enrichment analyses were conducted to explore its underlying genetic basis, pathways and cell types. The reproducibility and generalizability were tested on another independent MDD dataset (N=3,496) and bipolar disorder (BD) dataset (N=81).ResultsA SC pattern linked with exercise was identified to be both significantly correlated with depressive mood and group discriminative between MDDs and HCs, which primarily located between the motor-related regions and reward-related regions. This pattern was associated with multiple neurotransmitter receptors, such as serotonin and GABA receptors, and enriched in pathways like synaptic signaling and astrocytes cell type. The SC pattern and genetic results were also replicated in another independent MDD dataset and present commonalities with BD.ConclusionsThis study not only initially identified a reproducible shared SC pattern between physical activity and depressive mood, but also elucidated the underlying biological mechanisms, which enhanced our understanding of how exercise helps alleviate depression and may inform the development of novel neuromodulation targets.

neuroscience↗

bioRxiv2025

Macrogenetic atlas of prokaryotes

Macrogenetics investigates patterns and predictors of intraspecific genetic variation across diverse taxa, offering a framework for understanding species diversity and addressing evolutionary hypotheses. Here, we present a macrogenetic atlas of prokaryotes (MAP), integrating genomic data from 15,235 prokaryotic species (30 parameters in 12 categories) and population genetic data from 786 species (22 parameters in 7 categories), together with phylogenetic, phenotypic, and ecological information. MAP enables quantitative species characterization, straightforward cross-species comparisons, and easy generation, testing, and refinement of evolutionary hypotheses. For example, our analyses show that long- and short-range genetic linkage capture distinct evolutionary dynamics and independently shape genetic diversity. Further, we propose that as within-species diversity increases, epistatic selection increasingly contributes to shaping genetic diversity, exemplified by convergent selection-driven structures (ecospecies) identified in Streptococcus mitis and S. oralis. Overall, MAP represents a widely applicable resource (www.genomap.cn) and offers novel insights into the drivers of macroevolution and the life cycle of prokaryotic species.

microbiology↗

bioRxiv2025

ZapA employs a two-pronged mechanism to facilitate Z ring formation in Escherichia coli

The tubulin-like protein FtsZ assembles into the Z ring which leads to the assembly and activation of the division machinery in most bacteria. ZapA, a widely conserved protein that interacts with FtsZ, plays a pivotal role in organizing FtsZ filaments into a coherent Z ring. Previous studies revealed that ZapA forms a dumbbell-like tetramer that binds cooperatively to FtsZ filaments and aligns them in parallel, leading to the straightening and organization of FtsZ filament bundles. However, how ZapA interacts with FtsZ remains obscure. In this study, we uncover how ZapA interacts with FtsZ to facilitate Z ring formation in Escherichia coli. We find that mutations affecting surface exposed residues at the junction between adjacent FtsZ subunits in a filament as well as in an N-terminal motif of FtsZ weaken its interaction with ZapA in vivo and in vitro, indicating that ZapA binds to these regions of FtsZ. Consistent with this, ZapA prefers FtsZ polymers over monomeric FtsZ molecules and site-specific crosslinking confirmed that the dimer head domain of ZapA is in contact with the junction of FtsZ subunits. As a result, disruption of the putative interaction interfaces between FtsZ and ZapA abolishes the midcell localization of ZapA. Taken together, our results suggest that ZapA tetramers grab the N-terminal tails of FtsZ and then bind to the junctions between FtsZ subunits in the filament to straighten and crosslink parallel FtsZ filaments into the Z ring. SignificanceZapA is a widely conserved FtsZ-associated protein that promotes the organization of the Z ring, the key cytoskeletal element in the bacterial divisome. Although ZapA is known to crosslink FtsZ filaments, how it interacts with FtsZ remains enigmatic. In this study, we find that E. coli ZapA utilizes a dual binding mode in which it binds the junction between FtsZ subunits in a filament and to an N-terminal motif in FtsZ so that it can straighten and crosslink parallel FtsZ filaments simultaneously. Since the junction is formed when FtsZ polymerizes and falls apart when FtsZ depolymerizes, this interaction mode indicates that ZapA employs the polymerization dynamics of FtsZ to organize the filaments into the Z ring.

microbiology↗

bioRxiv2024

In vivo multiplex imaging of dynamic neurochemical networks with designed far-red dopamine sensors

Neurochemical signals like dopamine (DA) play a crucial role in a variety of brain functions through intricate interactions with other neuromodulators and intracellular signaling pathways. However, studying these complex networks has been hindered by the challenge of detecting multiple neurochemicals in vivo simultaneously. To overcome this limitation, we developed a single-protein chemigenetic DA sensor, HaloDA1.0, which combines a cpHaloTag-chemical dye approach with the G protein-coupled receptor activation-based (GRAB) strategy, providing high sensitivity for DA, sub-second response kinetics, and an extensive spectral range from far-red to near-infrared. When used together with existing green and red fluorescent neuromodulator sensors, Ca2+ indicators, cAMP sensors, and optogenetic tools, HaloDA1.0 provides high versatility for multiplex imaging in cultured neurons, brain slices, and behaving animals, facilitating in-depth studies of dynamic neurochemical networks.

neuroscience↗

bioRxiv2024

Uncovering the signaling networks of disseminated glioblastoma cells in vivo with INSIGHT

Dysregulation of intracellular signaling networks underpins cancer. However, a systems-level elucidation of how signaling networks within distinct cell subpopulations drive cancer progression in vivo has been unattainable due to technical limitations. We developed INSIGHT (INvestigating SIGnaling network of specific cell subpopulation in Heterogeneous Tissue), a new platform technology combining fluorescence-activated cell sorting with ultra-sensitive mass spectrometry to enable phosphoproteomic characterization of rare and discrete cell subpopulations from fixed tissues. We demonstrated the broad utility of INSIGHT by analyzing the oligodendroglial cell-specific signaling network in the mouse brain. We then applied INSIGHT to investigate the rare, disseminated tumor cell subpopulation in glioblastoma patient-derived xenograft models. INSIGHT uncovered a global rewiring of signaling networks with tumor cell dissemination, marked by a transition from proliferation-associated signaling in the primary tumor cells to signaling associated with postsynapse, neuronal migration, and ion homeostasis in disseminated tumor cells. We reveal interconnections between signaling circuitries within the networks, with numerous proteins, including GluA2, exhibiting altered phosphorylation without protein expression changes, emphasizing the role of post-translational modifications in glioblastoma dissemination. We validated key phosphorylation changes and inferred differentially active kinases with tumor spread to offer new systems-level insights into glioblastoma dissemination mechanisms in vivo. INSIGHT is generally applicable to a wide range of biological systems without genetic engineering and provides quantitative phosphorylation and protein expression data for selected cell subpopulations from heterogeneous tissues.

systems biology↗

bioRxiv2024

Sub-cellular Imaging of the Entire Protein-Coding Human Transcriptome (18933-plex) on FFPE Tissue Using Spatial Molecular Imaging

Single-cell RNA-seq revolutionized single-cell biology, by providing a complete whole transcriptome view of individual cells. Regrettably, this was accomplished only for individual, tissue-dissociated cells. High-plex spatial biology has begun to recover the x, y, and z-coordinates of single-cells, but typically at the expense of far less than whole transcriptome coverage. To solve this problem, Bruker Spatial Biology has accomplished a commercial-grade panel (CosMx(R) Spatial Molecular Imager Whole Transcriptome Panel (WTx)), using 37,872 imaging barcodes, capable of sub-cellular imaging of the entire human protein-coding transcriptome. The imaging barcodes are encoded with 156 bits of information (4 on-cycles and 35 dark-cycles per code), at a Hamming Distance of 4 from each other to achieve a very low false-code detection. Key to achieving this high-plex capability was the ability to manufacture imaging barcodes that require no in-tissue amplification (every barcode is manufactured under GMP to contain exactly 30 fluorescent dyes) and uniform, size-exclusion purified, extremely small imaging barcodes ([~] 20 nm). A detailed study of six different human FFPE tissue types was performed (Colon, Pancreas, Hippocampus, Skin, Breast, Kidney), yielding over 5.4 billion transcripts from 2.7 million cells. We counted over 1,550 transcripts-per-cell on average and observed 900 unique genes per cell (measured as the median). Single fixed-cells containing well over 10,000 subcellularly imaged transcripts were accomplished. Advancing single-cell imaging to the whole transcriptome level opens a single unified approach to accomplish essentially all single-cell experiments, both imaging and non-imaging. Depending upon the sample type (e.g. fixed-cells, organoids, tissue sections, etc.), the transcripts per cell and genes per cell measured using the whole transcriptome panel often exceeds that obtained by the highest-resolution single-cell RNA-seq, can be performed on a single 5 {micro}m FFPE tissue section, with no dissociation bias (every cell is counted). Pathway analysis within the tumor bed of a colon adenocarcinoma sample found evidence of enrichment in pathways suggestive of an aggressive tumor type, and localized ligand-receptor analysis showed spatially restricted patterns related to adhesion, migration, and proliferation. The high-dimensional whole transcriptome data is streamed directly to a cloud-based Spatial Informatics Platform, allowing for the scalable processing of millions-of-single-cells and billions-of-transcripts per operation. The WTx data are combined with high-resolution antibody-based cell-morphology imaging and data-driven machine-learning cell segmentation algorithms, to generate the most complete view of single cell and sub-cellular spatial biology that has ever been obtained.

genomics↗

bioRxiv2024

A genome-wide ATLAS of liver chromatin architecture reveals that sex dictates diet-induced nucleosome dynamics

The three-dimensional organization of the genome plays an important role in cellular function. Alterations between open and closed chromatin states contributes to DNA binding, collaborative transcriptional activities and informs post-transcriptional processing. The liver orchestrates systemic metabolic control and has the ability to mount a rapid adaptive response to environmental challenges. We interrogated the chromatin architecture in liver under different dietary cues. Using ATAC-seq, we mapped over 120,000 nucleosome peaks, revealing a remarkably preserved hepatic chromatin landscape across feeding conditions. Stringent analysis of nucleosome rearrangements in response to diet revealed that sex is the dominant factor segregating changes in chromatin accessibility. A lipid-rich diet led to a more accessible chromatin confirmation at promoter regions in female mice along with enrichment of promoter binding CCAAT-binding domain proteins. Male liver exhibited stronger binding for nutrient sensing nuclear receptors. Integrative analysis with gene expression corroborated a role for chromatin states in informing functional differences in metabolic traits. We distinguished the impact of gonadal sex and chromosomal sex as determinants of chromatin modulation by diet using the Four Core Genotypes mouse model. Our data provide mechanistic evidence underlying the regulation for the critical sex-dimorphic GWAS gene, Pnpla3. In summary, we provide a comprehensive epigenetic resource in murine liver that uncovers the complexity of chromatin dynamics in response to diet and sex. HighlightsATAC-Seq, RNA-Seq, and FCG model-integrated analysis unravel sex differences in chromatin accessibility and transcriptome responses to dietary challenges. Lipid-rich diet led to sex-biased chromatin confirmation at promoter regions. Gonadal sex emerged as the most prevalent determinant of the sex bias hepatic chromatin modulation by lipid-rich diets. The critical sex-dimorphic GWAS gene Pnpla3 is suppressed by testosterone, which underlies hepatic differences in expression between the sexes.

molecular biology↗

bioRxiv2024

NOLC1 Suppresses Immuno-chemotherapy by Inhibiting p53-mediated Ferroptosis in Gastric Cancer

Gastric cancer (GC) is one of the most malignant cancers, and cisplatin (Cis)-based chemotherapy remains the main clinical treatment for GC. However, Cis resistance often occurs, largely limiting its therapeutic efficacy in tumors. Therefore, a better understanding of the drug resistance mechanism could reveal new approaches for improving GC treatment efficacy. Here, we define the integrative role of nucleolar and coiled-body phosphoprotein 1 (NOLC1), a molecular chaperone that is significantly upregulated in GC tissues and Cis-resistant GC cells. Knocking down NOLC1 increased GC sensitivity to Cis by regulating ferroptosis. Mechanistically, NOLC1 binds to the p53 DNA binding domain (DBD), decreasing p53 nuclear accumulation stimulated by Cis and suppressing p53 transcriptional functions. Then, the p53-mediated ferroptosis is suppressed. Furthermore, the silence of NOLC1 promoted ferroptosis-induced immunogenic cell death (ICD) and reprogrammed the immunosuppressive tumor microenvironment, thereby increasing sensitivity to anti-programmed cell death-1 (PD-1) therapy plus Cis. The combination of anti-PD-1 plus Cis effectively inhibited GC growth without significant side effects. In summary, our findings reveal that targeting NOLC1 may be a novel therapeutic strategy for GC and may increase the efficacy of chemotherapy combined with immune checkpoint inhibitor (ICI) therapy.

cancer biology↗

bioRxiv2024

HumanTestisDB: A Comprehensive Atlas of Testicular Transcriptomics and Cellular Interactions

Advances in single-cell technology have enabled the detailed mapping of testicular cell transcriptomes, which is essential for understanding spermatogenesis. However, the fragmented nature of age-specific data from various literature sources has hindered comprehensive analysis. To overcome this, the Human Testis Database (HumanTestisDB) was developed, consolidating multiple human testicular sequencing datasets to address this limitation. Through extensive investigation, 38 unique cell types were identified, providing a detailed perspective on cellular variety. Furthermore, the database systematically categorizes samples into eight developmental stages, offering a structured framework to comprehend the temporal dynamics of testicular development. Each stage features comprehensive maps of cell-cell interactions, elucidating the complex communication network inside the testicular microenvironment at particular developmental stages. Moreover, by facilitating comparisons of interactions among various cell types at different stages, the database permits examining alterations that transpire during critical transitions in spermatogenesis. HumanTestisDB, available at https://shalab.njmu.edu.cn/humantestisdb, offers vital insights into testicular transcriptomics and interactions, serving as an essential resource for advancing research in reproductive biology.

cell biology↗

bioRxiv2024

A framework for target discovery in rare cancers

Functional genetic screens have uncovered dependencies in many cancers, but experimentally screened models for most cancers are far outnumbered by molecularly-profiled tumors, particularly for rare cancers. We used machine learning to infer gene dependencies from tumor transcriptional profiles, applying our model to the TCGA (11,373 tumors; 28 lineages), rare cancers (1,034 tumors, including 17 kidney cancer subtypes), and 509 previously unscreened cancer cell lines. Besides recovering dependencies previously identified in functional screens, we inferred drug response and synthetic essential relationships directly from tumors, including those associated with RB1 inactivation, KRAS mutation, and microsatellite instability. Via dependency prediction, we discovered and validated a shared reliance on oxidative phosphorylation in two previously unscreened rare cancers both driven by TFE3 gene fusions. We also nominate additional actionable vulnerabilities across various rare kidney cancers lacking experimental models. Our approach enables discovery of cancer vulnerabilities from transcriptomes, even in the absence of functional screening.

cancer biology↗

bioRxiv2024

Exploring the Role of Cotton CMF Genes in Salt Stress Tolerance: Insights from Phylogenetic, Expression, and Functional Analyses

Salt stress significantly limits cotton growth and development, making the improvement of salt tolerance critical. CMF genes, containing a single CCT domain, are promising targets for breeding programs. We identified 101 CMF genes from four cotton species. Phylogenetic analysis grouped these genes into six clusters closely related to Arabidopsis. Gene structure and motif analysis showed high conservation, while collinear analysis indicated segmental duplication as a key factor in CMF gene family expansion. Promoter analysis predicted involvement in light, abiotic stress, plant hormone responses, and growth. Expression analysis revealed differential expression of GhCMF genes across tissues, with some induced by abiotic stress. Co-expression network analysis indicated GhCMF14 interacts with other proteins to resist abiotic stress. Subcellular localization showed GhCMF14 in the nucleus. Silencing GhCMF14 enhanced salt tolerance, with higher chlorophyll and proline content, and lower MDA and H2O2 levels. This study provides insights into CMF gene regulation and their role in cotton salt stress tolerance.

plant biology↗

bioRxiv2024

Inter-Kingdom Interactions and Environmental Influences on the Oral Microbiome in Severe Early Childhood Caries

Dental caries arise from intricate interactions among oral microorganisms, impacting ecological stability and disease progression. This study delves into the bacterial-fungal dynamics in severe early childhood caries (S-ECC) among 61 children aged 3-4 years with complete deciduous dentition. We evaluated environmental factors such as saliva pH, buffering capacity, and trace elements (iron, fluoride). We examined the performance of 16S rRNA V1-V9 regions gene and internal transcribed spacer (ITS) primers for bacteria and fungi from plaque and saliva to characterize community compositions and diversity. Saliva pH and buffering capacity were also measured. Findings revealed significant shifts in bacterial diversity in S-ECC saliva samples, marked by decreased diversity and elevated abundance of cariogenic species, particularly Streptococcus mutans. Candida albicans was notably more prevalent in the S-ECC group, implicating its potential role in pathogenesis. Iron and fluoride concentrations showed no significant correlation with microbial community structure. Network analyses uncovered complex intra- and inter-kingdom interactions, underscoring cooperative and competitive dynamics. S-ECC children exhibited higher abundances of bacteria (Streptococcus mutans, Granulicatella, Actinomyces) and fungi (Candida albicans), with specific microbial taxa associated with reduced saliva pH. ImportanceThis study illuminates the intricate relationship between bacteria and fungi within the oral microbial community of children, specifically highlighting differences between those with severe early childhood caries (S-ECC) and those without caries. Through an extensive analysis of the microbial composition in both saliva and dental plaque, we identified a significant increase in the abundance of specific bacterial taxa (e.g., S. mutans, Granulicatella, Actinomyces) and fungal species (e.g., C. albicans) in the oral cavities of children with S-ECC. This finding underscores the potential role of these microorganisms in the development of caries. Contrary to previous studies that emphasize the importance of iron and fluoride in oral health, our research found no significant correlation between the concentrations of these elements and the composition of oral microbial communities. This result challenges conventional understanding and opens new avenues for future research. Additionally, we discovered an association between certain microbial species and reduced salivary pH, offering fresh insights into the relationship between the oral microenvironment and caries development. The implications of our findings are substantial for the development of prevention and intervention strategies targeting childhood caries. They also underscore the critical need for a deeper exploration of oral microbial interactions and their environmental influences.

microbiology↗

bioRxiv2024

STANCE: a unified statistical model to detect cell-type-specific spatially variable genes in spatial transcriptomics

A significant challenge in analyzing spatial transcriptomics data is the effective and efficient detection of spatially variable genes (SVGs), whose expression exhibits non-random spatial patterns in tissues. Many SVGs show spatial variation in expression that is highly correlated with cell type categories or compositions, leading to the concept of cell type-specific spatially variable genes (ctSVGs). Existing statistical methods for detecting ctSVGs treat cell type-specific spatial effects as fixed effects when modeling, resulting in a critical issue: the testing results are not invariant to the rotation of spatial coordinates. Additionally, an SVG may display random spatial patterns within a cell type, and a ctSVG may exhibit random spatial patterns from a general perspective, indicating that an SVG does not necessarily have to be a ctSVG, and vice versa. This poses challenges in real analysis when detecting SVGs or ctSVGs. To address these problems, we propose STANCE, a unified statistical model developed to detect both SVG and ctSVGs in spatial transcriptomics. By integrating gene expression, spatial location, and cell type composition through a linear mixed-effect model, STANCE enables the identification of both SVGs and ctSVGs in an initial stage, followed by a second stage test dedicated to ctSVG detection. Its design ensures robustness in complex scenarios and the results are spatial rotation invariant. We demonstrated the performance of STANCE through comprehensive simulations and analyses of three public datasets. The downstream analyses based on ctSVGs detected by STANCE suggest promising future applications of the model in spatial transcriptomics and various areas of genome biology. A software implementation of STANCE is available at https://github.com/Cui-STT-Lab/STANCE.

bioinformatics↗

bioRxiv2024

Overabundant endocannabinoids in neurons are detrimental to cognitive function

2-Arachidonoylglycerol (2-AG) is the most prevalent endocannabinoid involved in maintaining brain homeostasis. Previous studies have demonstrated that inactivating monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading 2-AG in the brain, alleviates neuropathology and prevents synaptic and cognitive decline in animal models of neurodegenerative diseases. However, we show that selectively inhibiting 2-AG metabolism in neurons impairs cognitive function in mice. This cognitive impairment appears to result from decreased expression of synaptic proteins and synapse numbers, impaired long-term synaptic plasticity and cortical circuit functional connectivity, and diminished neurogenesis. Interestingly, the synaptic and cognitive deficits induced by neuronal MAGL inactivation can be counterbalanced by inhibiting astrocytic 2-AG metabolism. Transcriptomic analyses reveal that inhibiting neuronal 2-AG degradation leads to widespread changes in expression of genes associated with synaptic function. These findings suggest that crosstalk in 2-AG signaling between astrocytes and neurons is crucial for maintaining synaptic and cognitive functions and that excessive 2-AG in neurons alone is detrimental to cognitive function.

neuroscience↗