Biology subjects

Zeng, F.

Publications and source records attributed to Zeng, F..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

TREVI: A Transcriptional Regulation-driven Variational Inference Model to Speculate Gene Expression Mechanism with Integration of Single-cell Multi-omics

Single-cell multi-omics technology enables the concurrent measurement of multiple molecular entities, making it critical for unraveling the inherent gene regulation mechanisms driving cell heterogeneity. However, existing multi-omics techniques have limitations in capturing the intricate regulatory interactions among these molecular components. In this study, we introduce TREVIXMBD (Transcriptional REgulation-driven Variational Inference), a novel method that integrates the well-established gene regulation structure with scRNA-seq and scATAC-seq data through an advanced Bayesian framework. TREVIXMBD models the generation of gene expression profiles in individual cells by considering the integrated influence of three fundamental biological factors: accessibility of cis-regulatory elements regions, transcription factor (TF) activities and regulatory weights. TF activities and regulatory weights are probabilistically represented as latent variables, which capture the inherent gene regulatory significance. Hence, in contrast to gene expression, TF activities and regulatory weights that depict the cell states from a more intrinsic perspective, can keep consistent across diverse datasets. TREVIXMBD exhibits superior performance when compared to baseline methods in a variety of biological analyses, including cell typing, cell development tracking, and batch effect correction, as validated through comprehensive benchmarking. Moreover, TREVIXMBD can reveal variations in TF-gene regulation relationships across cells. The pretrained TREVIXMBD model can work even when only scRNA-seq is available. Overall, TREVIXMBD introduces a pioneering biological-mechanism-driven framework for elucidating cell states at a gene regulatory level. The models structure is adaptable for the inclusion of additional biological factors, allowing for flexible and more comprehensive gene regulation analysis.

bioinformatics↗

bioRxiv2023

Biosynthesis of H-GDGTs linked to ocean oxygen deficiency

Archaeal membrane lipids GDGTs (glycerol dialkyl glycerol tetraethers) are biomarkers used for tracking Earths historical environmental changes. Among these GDGTs, the H-shaped GDGTs (H-GDGTs, or GMGTs) represent a less-explored and often overlooked subset, with its biosynthetic pathway and geological significance remaining elusive. Here, we identified the gene responsible for biosynthesizing H-GDGTs, which encodes to a radical S-adenosyl-L-methionine (SAM) enzyme, named as H-GDGTs bridge synthase (Hbs). Heterologous expression of the gene hbs in a methanogen, as well as in vitro activity assay using the purified Hbs enzyme were performed. Additionally, we found that the genes encoding Hbs are exclusively present in obligate anaerobic archaea genomes and the metagenomes obtained from oxygen-deficient environments, but not in oxic settings. The H-GDGTs lipids were also consistently enriched in the modern oxygen-deficient environments, and remarkably accumulated in ancient sediments during oceanic anoxic event-2 (OAE-2, [~]94 million years ago) period. Our findings indicate H-GDGTs holds significant promise as a novel biomarker for studying historical ocean oxygen deficiency supported by a well-established biological basis.

microbiology↗

bioRxiv2023

ISMI-VAE: A Deep Learning Model for Classifying Disease Cells Using Gene Expression and SNV Data

Various studies have linked several diseases, including cancer and Covid-19, to single nucleotide variations (SNV). Although scRNA-seq technology can provide SNV and gene expression data, few studies have integrated and analyzed these multimodal data. To address this issue, this paper introduces Interpretable Single-cell Multimodal Data Integration Based on Variational Autoencoder (ISMI-VAE). ISMI-VAE leverages latent variable models that utilize the characteristics of SNV and gene expression data to overcome high noise levels, and uses deep learning techniques to integrate multimodal information, map them to a low-dimensional space, and classify disease cells. Moreover, ISMI-VAE introduces an attention mechanism to reflect feature importance and analyze genetic features that could potentially cause disease. Experimental results on three cancer data sets and one Covid-19 data set demonstrate that ISMI-VAE surpasses the baseline method in terms of both effectiveness and interpretability, and can effectively identify disease-causing gene features.

bioinformatics↗

bioRxiv2023

Molecular Evolution and Interaction of 14-3-3 Proteins with H+-ATPases in Plant Abiotic Stresses

Environmental stresses severely affect plant growth and crop productivity. Regulated by 14-3-3 proteins (14-3-3s), H+-ATPases (AHA) are important proton pumps that can induce diverse secondary transport via channels and co-transporters for the abiotic stress response of plants. Many studies demonstrated the roles of 14-3-3s and AHAs in coordinating the processes of plant growth, phytohormone signaling, and stress responses. However, the molecular evolution of 14-3-3s and AHAs has not been summarized in parallel with insights across multiple plant species. Here, we review the roles of 14-3-3s and AHAs in cell signaling to enhance plant responses to diverse environmental stresses. We analyzed the molecular evolution of key proteins that are associated with 14-3-3s and AHAs in plant growth and hormone signaling. The results revealed evolution, duplication, contraction, and expansion of 14-3-3s and AHAs in green plants. We also discussed the stress-specific expression of those 14-3-3s and AHAs in a eudicot (Arabidopsis thaliana), a monocot (Hordeum vulgare) and a moss (Physcomitrium patens) under abiotic stresses. We propose that 14-3-3s and H+-ATPases respond to abiotic stresses through many important targets and signaling components of phytohormones, which could be promising to improve plant tolerance to single or multiple environmental stresses. HighlightWe review the response and adaptation of 14-3-3s and AHAs to diverse environmental stimuli and we analyze the evolutionary features and molecular functions of 14-3-3s and AHAs.

plant biology↗

bioRxiv2023

TREM2 promotes glioma progression and angiogenesis mediated by microglia/brain macrophages

TREM2, a myeloid cell-specific signaling molecule, controls essential functions of microglia and impacts on the pathogenesis of Alzheimers disease and other neurodegenerative disorders. TREM2 is also highly expressed in tumor-associated macrophages and plays detrimental roles in an experimental mouse sarcoma model. Here we studied whether TREM2 influences glioma progression. We found a sex- dependent effect of TREM2: the glioma volume is significantly attenuated in TREM2- deficient male but not female mice injected with GL261-EGFP glioma cells. The accumulation of glioma-associated microglia/macrophages (GAMs) and vascularization is reduced in male TREM2-deficient mice. A transcriptomic analysis of glioma tissue revealed that TREM2 deficiency suppresses angiogenic genes and MHC clusters. In an organotypic slice model devoid of functional vascularization, the tumor size was not affected by TREM2-deficiency. In human resection samples from glioblastoma, TREM2 is upregulated in GAMs. Based on the TCGA and CGGA databases, the TREM2 expression levels are negatively correlated with survival. Thus, the TREM2-dependent crosstalk between GAMs and the vasculature formation promotes glioma growth. Graphic abstractTREM2-dependent crosstalk between glioma-associated microglia/macrophages and the vasculature formation promotes glioma growth in male glioma mouse model. Created with BioRender.com O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/540621v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@65bec7org.highwire.dtl.DTLVardef@1d00961org.highwire.dtl.DTLVardef@117ee5eorg.highwire.dtl.DTLVardef@227994_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Specification of distinct cell types in a sensory-adhesive organ for metamorphosis in the Ciona larva

The papillae of tunicate larvae contribute sensory, adhesive, and metamorphosis-regulating functions that are crucial for the biphasic lifestyle of these marine, non-vertebrate chordates. We have identified additional molecular markers for at least five distinct cell types in the papillae of the model tunicate Ciona, allowing us to further study the development of these organs. Using tissue-specific CRISPR/Cas9-mediated mutagenesis and other molecular perturbations, we reveal the roles of key transcription factors and signaling pathways that are important for patterning the papilla territory into a highly organized array of different cell types and shapes. We further test the contributions of different transcription factors and cell types to the production of the adhesive glue that allows for larval attachment during settlement, and to the processes of tail retraction and body rotation during metamorphosis. With this study, we continue working towards connecting gene regulation to cellular functions that control the developmental transition between the motile larva and sessile adult of Ciona.

developmental biology↗

bioRxiv2023

Extraction of biological signals by factorization enables the reliable analysis of single-cell transcriptomics

Accurately and reliably capturing actual biological signals from single-cell transcriptomics is vital for achieving legitimate scientific results, which is unfortunately hindered by the presence of various kinds of unwanted variations. Here we described a deep auto-regressive factor model known as scPhenoXMBD, demonstrated that each genes expression can be split into discrete components that represent biological signals and unwanted variations, which effectively mitigated the effects of unwanted variations in the data of single-cell sequencing. Using scPhenoXMBD, we evaluated various factors affecting IFN {beta} -stimulated immune cells and demonstrated that biological signal extraction facilitates the identification of IFN{beta}-responsive pathways and genes. Numerous experiments were conducted to show that scPhenoXMBD could be utilized successfully in enhancing cell clustering stability, obtaining identical cell populations from diverse data sources, advancing the single-cell CRISPR screening of functional elements, and minimizing the influence of inter-subject discrepancies in the cell-disease relationships. scPhenoXMBD is anticipated to be a dependable and repeatable method for the precise analysis of single-cell data.

bioinformatics↗

bioRxiv2023

Comprehensive Multi-omics Analysis Reveals the Core Role of Glycerophospholipid Metabolism in Rheumatoid Arthritis Development

ObjectivesRheumatoid arthritis (RA) is a chronic autoimmune disease with complex causes and recurrent attacks that can easily develop into chronic arthritis. Our study aims to elucidate potential mechanism among control, new-onset RA (NORA) and chronic RA (CRA) with multi-omics analysis. MethodsA total of 162 subjects were included in our study, 121 subjects were used for 16S rRNA, ITS sequencing and metabolomics analysis and 41 subjects were used for transcriptomics analysis. Enrichment analysis was based on significant difference metabolites and genes. Protein-protein interaction network and correlation analyses were performed to interpret the interactions among intestinal flora, metabolites and genes. We applied three models to distinguish between NORA and CRA using computational OR values, LASSO and random forest, respectively. ResultsOur results demonstrated intestinal flora disturbance in RA development, with significantly increased abundance of Escherichia-Shigella and Proteobacteria in NORA. We also found that the diversity was significantly reduced in CRA compared to NORA through fungi analysis. Moreover, we identified 28 differential metabolites between NORA and CRA. Pathway enrichment analysis revealed significant dysregulation of glycerophospholipid metabolism and phenylalanine metabolism pathways in RA patients. Next, we identified 40 differentially expressed genes between NORA and CRA, which acetylcholinesterase (ACHE) was the core gene and significantly enriched in glycerophospholipid metabolism pathway. Correlation analysis showed a strong negatively correlation between glycerophosphocholine and inflammatory characteristics. ConclusionsThese findings revealed that glycerophospholipid metabolism plays a crucial role in the development and progression of RA, providing new ideas for early clinical diagnosis and optimizing treatment strategies.

immunology↗

bioRxiv2022

Lactate-derived HDAC6 Lactylation as a new target for neuronal protection in cerebral ischemic reperfusion injury

Lactylation is a newly found lactate-derived post-translational modification, which is firstly reported on histone protein lysine residues to regulate gene expression. Here, we provided evidence that higher serum lactate level was possibly associated with better prognosis in ischemic stroke patients. Meanwhile, inhibition of endogenous lactate increased the infarct volume and decreased protein pan-lactylation in the affected brain tissue in cerebral ischemia mice. We further demonstrated that downregulating lactylation level of Hdac6 (Histone Deacetylase 6) in neurons exacerbated ischemic neuronal injury. The underlying mechanisms involved Hdac6 lactylation disturbing calcium homeostasis through binding BiP (Binding immunoglobulin protein), an endoplasmic reticulum-related protein. Collectively, our findings identified a new effect of lactate for neuroprotection through Hdac6 lactylation during cerebral ischemic reperfusion injury which introduced a potential therapeutic approach against ischemic stroke.

neuroscience↗

bioRxiv2022

Contrary neuronal recalibration in different multisensory cortical areas

The adult brain demonstrates remarkable multisensory plasticity by dynamically recalibrating information from multiple sensory sources. When a systematic visual-vestibular heading offset is experienced, the unisensory perceptual estimates recalibrate toward each other (in opposite directions) to reduce the conflict. The neural substrate of this recalibration is unknown. Here, we recorded single-neuron activity from the dorsal medial superior temporal (MSTd), parieto-insular vestibular cortex (PIVC), and ventral intraparietal (VIP) areas in three male rhesus macaques during visual-vestibular recalibration. Both visual and vestibular tuning in MSTd recalibrated-each according to their respective cues perceptual shifts. Vestibular tuning in PIVC also recalibrated together with corresponding perceptual shifts (cells were not visually tuned). By contrast, VIP neurons demonstrated a unique phenomenon: both vestibular and visual tuning recalibrated according to vestibular perceptual shifts. Such that, visual tuning shifted, surprisingly, contrary to visual perceptual shifts. Therefore, while unsupervised recalibration (to reduce cue conflict) occurs in early multisensory cortices, higher-level VIP reflects only a global shift, in vestibular space. In BriefThe neural bases of multisensory plasticity are currently unknown. Here, Zeng et al. studied neuronal recalibration to a systematic visual-vestibular cue conflict. In multisensory cortical areas MSTd and PIVC, single-unit responses to visual and vestibular stimuli recalibrated to reduce the cue conflict, along with their respective unisensory perceptual shifts. By contrast, in higher-level VIP, both visual and vestibular neuronal responses recalibrated with vestibular perceptual shifts. This led to a surprising recalibration of visual responses opposite in direction to visual perceptual shifts. This exposes differential aspects of multisensory plasticity across multisensory cortical areas, and reveals a novel hybrid of visual responses within a vestibular reference frame in parietal neurons. HighlightsO_LIIn the presence of a systematic heading conflict, visual and vestibular cues recalibrate towards one another to reduce the conflict. C_LIO_LIIn MSTd, neuronal responses to vestibular and visual cues recalibrated, each according to their respective cues perceptual shifts. C_LIO_LIIn PIVC, vestibular responses recalibrated according to vestibular perceptual shifts (cells were not visually tuned). C_LIO_LIIn VIP, neuronal responses to both vestibular and visual cues recalibrated together with vestibular perceptual shifts (opposite in direction to visual perceptual shifts). C_LIO_LIProfound differences in neuronal recalibration expose different functions across multisensory cortical areas. C_LI

neuroscience↗

bioRxiv2022

In silico labeling enables kinetic myelination assay in brightfield

Recent advances with deep neural networks have shown the feasibility of acquiring brightfield images with transmitted light and applying in-silico labeling to predict fluorescent images. We have developed a novel in-silico labeling method based on a generative adversarial network and outperforms the state-of-the-art Unet method in generating realistic fluorescent images and quantitatively recapitulating real staining signals, as demonstrated in a complex co-culture myelination assay. Furthermore, we have performed the assay in live mode with multiple kinetic points, applied in-silico labeling to predict fluorescent images from brightfield and quantified the kinetic phenotypic changes. Thus, the proposed approach provides a potential tool to study the kinetics of cellular phenotypic changes with brightfield imaging.

cell biology↗

bioRxiv2022

Mixed selectivity coding of content-temporal detail by dorsomedial posterior parietal neurons

The dorsomedial posterior parietal cortex is part of a higher-cognition network implicated in elaborate processes underpinning memory formation, recollection, episodes reconstruction, and temporal information processing. Neural coding for complex episodic processing is however under-documented. Here we revealed a set of neural codes of neuroethogram in the primate parietal cortex. Analyzing neural responses in macaque dmPPC to naturalistic videos, we discovered several groups of neurons that are sensitive to different categories of ethogram-items and to low-level sensory features, and saccadic eye movement. We also discovered that the processing of category and feature information by these neurons is sustained by accumulation of temporal information over a long timescale up to 30 s, corroborating its reported long temporal receptive windows. We performed an additional behavioral experiment and found that saccade-related activities could not account for the mixed neuronal responses elicited by the video stimuli. We further observed monkeys scan-paths and gaze consistency are modulated by video content. Taken altogether, these neural findings explain how dorsomedial PPC weaves fabrics of ongoing experiences together in real-time. The high dimensionality of neural representations should motivate us to shift the focus of attention from pure selectivity neurons to mixed selectivity neurons, especially in increasingly complex naturalistic task designs. HIGHLIGHTSO_LINeural codes for "neuroethogram" in macaque dorsomedial parietal cortex C_LIO_LIParietal neural codes exhibit mixed selectivity of event features C_LIO_LIDorsomedial PPC neurons support a long temporal receptive window for episodes C_LIO_LISaccadic movement could not explain away mixed neuronal responses C_LIO_LIConsistency in scan-path and gaze shown across viewing repetitions C_LI

neuroscience↗

bioRxiv2022

scPheno: A deep generative model to integrate scRNA-seq with disease phenotypes and its application on prediction of COVID-19 pneumonia and severe assessment

Cell-to-cell variability is orchestrated by transcriptional variations participating in different biological processes. However, the dissection of transcriptional variability in specific biological process at single-cell level remains unavailable. Here, we present a deep generative model scPheno to integrate scRNA-seq with disease phenotypes to unravel the invisible phenotype-related transcriptional variations. We applied scPheno on COVID-19 blood scRNA-seq to separate transcriptional variations in regulating COVID-19 host immunity and transcriptional variations in maintaining cell-type identity. In silico, we found CLU+IFI27+S100A9+ monocyte as the efficient cellular marker for the prediction of COVID-19 diagnosis. Inspiringly, using only 4 genes upregulated in CLU+IFI27+S100A9+ monocytes can predict the COVID-19 diagnosis of individuals from different country with an accuracy up to 81.3%. We also found C1+CD163+ monocyte and 8 C1+CD163+ monocyte-upregulated genes as the efficient biomarkers for the prediction of severity assessment. Overall, scPheno is an effective method in dissecting the transcriptional basis of phenotype variations at single-cell level.

genomics↗

bioRxiv2021

Mechanical ventilation affects the microecology of the rat respiratory tract

BackgroundThe most common second strike in mechanically ventilated patients is a pulmonary infection caused by the ease with which bacteria can invade and colonize the lungs due to mechanical ventilation. At the same time, metastasis of lower airway microbiota may have significant implications in the development of intubation mechanical ventilation lung inflammation. Thus, we establish a rat model of tracheal intubation with mechanical ventilation and explore the effects of mechanical ventilation on lung injury and microbiological changes in rats. MethodsSprague-Dawley rats were randomized into control, Spontaneously Breathing (1, 3, 6 hours), Mechanical ventilation(1, 3, 6 hours) groups. Lung wet to dry weight ratio (W/D weight ratio) and Lung histopathological injury score were evaluated.16SrDNA sequencing was performed to explore respiratory flora changes. ResultsBacterial diversity was comparable between healthy and intubation mechanical ventilation rats, with time relation. Ordination analyses revealed that samples clustered more dispersing by tracheal intubation and mechanical ventilation. Finally, predicted metagenomes suggested a substantial increase in biofilm formation phenotype during early tracheal intubation and mechanical ventilation. ConclusionCollectively, these results establish a link between the duration of mechanical ventilation and alterations to the respiratory tract microecology. In future studies, we hope to discover the effectiveness of new immunomodulatory or probiotic bacteria to prevent airway diseases associated with ventilator therapy.

microbiology↗

bioRxiv2021

Sequential rescue and repair of stalled and damaged ribosome by bacterial PrfH and RtcB

In bacteria, rescue of stalled ribosomes due to 3-truncated mRNAs is carried out by the ubiquitous trans-translation system as well as alternative ribosome-rescue factors such as ArfA and ArfB. It is unclear, however, how the stalled ribosomes caused by ribosomal damages are rescued. Here, we report that a bacterial system composed of PrfH and RtcB not only rescues a stalled ribosome resulting from a specific damage in the decoding center but also repairs the damage afterwards. Peptide release assays reveal that PrfH is only active with the damaged ribosome, but not with the intact one. A 2.55-angstrom cryo-EM structure of PrfH in complex with the damaged 70S ribosome provides molecular insight into specific recognition of the damage site by PrfH. RNA repair assays demonstrate that PrfH-coupled RtcB efficiently repairs the damaged 30S ribosomal subunit, but not the damaged tRNAs. Thus, our studies have uncovered a biological operation by a pair of bacterial enzymes, aiming to reverse the potentially lethal damage inflicted by an invading ribotoxin for cell survival.

biochemistry↗

bioRxiv2021

The Impact of a Dynamic Working Environment on Human Gut Microbiota

Gut microbiota dysbiosis is associated with a variety of diseases, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), metabolic diseases, allergic diseases, neurodevelopmental disorders and cancer. The human gut microbiota can be influenced by a variety of factors, including geography, dietary habits, living environment, age and altered lifestyle etc. This study was conducted to explore the gut microbiota compositions in officials who are in a stable working environment and train drivers who are in a dynamic working environment. Microbiota communities in the feces of 80 officials and 88 train drivers were analyzed using Illumina MiSeq sequencing targeting the V3-V4 region of 16S ribosomal RNA (rRNA) gene and ITS1 region of fungi. There were significant differences between the two groups in diversity and richness of gut microbiota, while the microbial community compositions of the two groups were similar. The relationship between gut microbiota and clinical characteristics was investigated. We found that more bacteria and fungi were positively correlated with clinical characteristics. Functional prediction analysis of the gut microbiota between the two groups by PICRUSt2 revealed significant differences between the official group and the train driver group. Elucidating these differences of the microbiome between the two groups will provide a foundation understanding of the impact of a dynamic environment on gut microbiota.

microbiology↗

bioRxiv2020

Differentiation independent neuroprotective role of Vcan+ oligodendrocyte precursor cells in poststroke cognitive impairment recovery

The cell type-specific molecular pathology of post-stroke cognitive impairment (PSCI) in the hippocampus has not been thoroughly elucidated. We analyzed 27,069 cells by using single-cell RNA sequencing, and four oligodendrocyte precursor cell (OPC) subtypes were identified, Vcan+ OPCs, which were determined to be the primary cluster among them. Additionally, we examined the features of endothelial cells (ECs) and found that Lcn2+ ECs might play neuroprotective roles via Vwf after stroke. These results may facilitate further studies attempting to identify new avenues of research and novel targets for PSCI treatment.

neuroscience↗

bioRxiv2020

Extensive MET alterations confer clinical response to MET inhibitors in gliomas

Activating alterations of the MET gene are well-characterized oncogenic drivers, and MET inhibitors could successfully treat several tumor types with MET alterations, including gliomas with PTPRZ1-MET fusion. However, the full diversity and prevalence of MET alterations in gliomas are still lacking to accurately identify a subset of patients likely to benefit from MET inhibitor treatment. Here, we interrogated genomic profiles of 1,351 gliomas, and further identify 60 cases harboring MET alterations, including MET fusions and various MET exon skipping events. MET RNA alterations, but not MET amplification, are highly enriched in the secondary glioblastomas (sGBM) with significantly worse prognosis. Further molecular analysis has shown that MET RNA alterations acting an additive effects of MET overexpression are induced in the course of glioma evolution. In vitro and clinical studies indicate cells and patients harboring MET alterations have better response to MET inhibitors. Collectively, these data suggest that a subgroup of gliomas harboring MET alterations likely to have benefit from MET-targeted therapy.

neuroscience↗