Biology subjects

Chen, S.

Publications and source records attributed to Chen, S..

At least 631 records · Page 35Linked to original sources

bioRxiv2022

A transcriptional complex of FtMYB102 and FtbHLH4 coordinately regulates the accumulation of rutin in Fagopyrum tataricum

Tartary buckwheat is rich in flavonoids, which not only play an important role in plant-environment interaction, but are also beneficial to human health. Rutin is a therapeutic flavonol which is massively accumulated in Tartary buckwheat. It has been demonstrated that transcription factors control rutin biosynthesis. However, the transcriptional regulatory network of rutin is not fully clear. In this study, through transcriptome and target metabolomics, we validated the role of FtMYB102 and FtbHLH4 TFs at the different developmental stages of Tartary buckwheat. The elevated accumulation of rutin in the sprout appears to be closely associated with the expression of FtMYB102 and FtHLH4. Yeast two-hybrid, transient luciferase activity and co-immunoprecipitation demonstrated that FtMYB102 and FtbHLH4 can interact and form a transcriptional complex. Moreover, yeast one-hybrid showed that both FtMYB102 and FtbHLH4 directly bind to the promoter of chalcone isomerase (CHI), and they can coordinately induce CHI expression as shown by transient luciferase activity assay. Finally, we transferred the FtMYB102 and FtbHLH4 into the hairy roots of Tartary buckwheat and found that they both can promote the accumulation of rutin. Our results indicate that FtMYB102 and FtbHLH4 can form a transcriptional complex by inducing CHI expression to coordinately promote the accumulation of rutin.

plant biology↗

bioRxiv2022

Inhibition of c-Jun in AgRP neurons mediates chronic stress-induced anxiety-like behaviors and colitis susceptibility

Psychiatric disorders, such as anxiety, are frequently associated with inflammatory bowel diseases (IBD), however, the neural mechanisms are unknown. Here, we showed that hypothalamic agouti-related protein (AgRP) neuronal activity was suppressed under chronic restraint stress (CRS), a condition known to induce anxiety-like behaviors and increase colitis susceptibility. Consistently, chemogenic activation (inhibition) of AgRP neurons reversed (mimicked) CRS-induced anxiety-like behaviors and colitis susceptibility. Furthermore, CRS inhibited AgRP neuronal activity by suppressing the expression of c-Jun. As expected, overexpression of c-Jun in these neurons protected against the CRS-induced these effects and knockdown of c-Jun in AgRP neurons (c-Jun{Delta}AgRP) promoted anxiety-like behaviors and colitis. Moreover, relieving the anxiety with cyamemazine (an anxiolytic drug) alleviated colitis susceptibility in c-Jun{Delta}AgRP mice. Finally, according to a proteomic analysis, the levels of the secreted protein thrombospondin 1 (THBS1) were negatively associated with the increased anxiety-like behaviors and colitis susceptibility, supplementing recombinant THBS1 rescued colitis in c-Jun{Delta}AgRP mice. Taken together, these results reveal a critical role of hypothalamic AgRP neuron-derived c-Jun in orchestrating chronic stress-induced anxiety-like behaviors and colitis susceptibility. These results provide a new perspective for understanding the neuronal mechanisms and potential therapeutic target for the comorbidity of psychiatric disorders, such as anxiety, and IBD.

neuroscience↗

bioRxiv2022

Deep Learning-based Pseudo-Mass Spectrometry Imaging Analysis for Precision Medicine

Liquid chromatography-mass spectrometry (LC-MS) based untargeted metabolomics provides systematic profiling of metabolic. Yet its applications in precision medicine (disease diagnosis) have been limited by several challenges, including metabolite identification, information loss, and low reproducibility. Here, we present the deepPseudoMSI project (https://www.deeppseudomsi.org/), which converts LC-MS raw data to pseudo-MS images and then processes them by deep learning for precision medicine, such as disease diagnosis. Extensive tests based on real data demonstrated the superiority of deepPseudoMSI over traditional approaches and the capacity of our method to achieve an accurate individualized diagnosis. Our framework lays the foundation for future metabolic-based precision medicine.

bioinformatics↗

bioRxiv2022

Enhanced recovery of single-cell RNA-sequencing reads for missing gene expression data

Droplet-based 3 single-cell RNA-sequencing (scRNA-seq) methods have proved transformational in characterizing cellular diversity and generating valuable hypotheses throughout biology1,2. Here we outline a common problem with 3 scRNA-seq datasets where genes that have been documented to be expressed with other methods, are either completely missing or are dramatically under-represented thereby compromising the discovery of cell types, states, and genetic mechanisms. We show that this problem stems from three main sources of sequencing read loss: (1) reads mapping immediately 3 to known gene boundaries due to poor 3 UTR annotation; (2) intronic reads stemming from unannotated exons or pre-mRNA; (3) discarded reads due to gene overlaps3. Each of these issues impacts the detection of thousands of genes even in well-characterized mouse and human genomes rendering downstream analysis either partially or fully blind to their expression. We outline a simple three-step solution to recover the missing gene expression data that entails compiling a hybrid pre-mRNA reference to retrieve intronic reads4, resolving gene collision derived read loss through removal of readthrough and premature start transcripts, and redefining 3 gene boundaries to capture false intergenic reads. We demonstrate with mouse brain and human peripheral blood datasets that this approach dramatically increases the amount of sequencing data included in downstream analysis revealing 20 - 50% more genes per cell and incorporates 15-20% more sequencing reads than with standard solutions5. These improvements reveal previously missing biologically relevant cell types, states, and marker genes in the mouse brain and human blood profiling data. Finally, we provide scRNA-seq optimized transcriptomic references for human and mouse data as well as simple algorithmic implementation of these solutions that can be deployed to both thoroughly as well as poorly annotated genomes. Our results demonstrate that optimizing the sequencing read mapping step can significantly improve the analysis resolution as well as biological insight from scRNA-seq. Moreover, this approach warrants a fresh look at preceding analyses of this popular and scalable cellular profiling technology.

genomics↗

bioRxiv2022

A cocktail containing two synergetic antibodies broadly neutralizes SARS-CoV-2 and its variants including Omicron BA.1 and BA.2

Neutralizing antibodies (NAbs) can prevent and treat infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, continuously emerging variants, such as Omicron, have significantly reduced the potency of most known NAbs. The selection of NAbs with broad neutralizing activities and the identification of conserved critical epitopes are still urgently needed. Here, we identified an extremely potent antibody (55A8) by single B-cell sorting from convalescent SARS-CoV-2-infected patients that recognized the receptor-binding domain (RBD) in the SARS-CoV-2 spike (S) protein. 55A8 could bind to wild-type SARS-CoV-2, Omicron BA.1 and Omicron BA.2 simultaneously with 58G6, a NAb previously identified by our group. Importantly, an antibody cocktail containing 55A8 and 58G6 (2-cocktail) showed synergetic neutralizing activity with a half-maximal inhibitory concentration (IC50) in the picomolar range in vitro and prophylactic efficacy in hamsters challenged with Omicron (BA.1) through intranasal delivery at an extraordinarily low dosage (25 g of each antibody daily) at 3 days post-infection. Structural analysis by cryo-electron microscopy (cryo-EM) revealed that 55A8 is a Class III NAb that recognizes a highly conserved epitope. It could block angiotensin-converting enzyme 2 (ACE2) binding to the RBD in the S protein trimer via steric hindrance. The epitopes in the RBD recognized by 55A8 and 58G6 were found to be different and complementary, which could explain the synergetic mechanism of these two NAbs. Our findings not only provide a potential antibody cocktail for clinical use against infection with current SARS-CoV-2 strains and future variants but also identify critical epitope information for the development of better antiviral agents.

immunology↗

bioRxiv2022

Direct N-Me Aziridination Reaction Enables Pinpointing C=C Bonds in Lipids with Mass Spectrometry

The biological functions of lipids largely depend on their chemical structures. The position of C=C bonds is an essential attribute that determines the structures of unsaturated lipids. Here, we developed a new type of chemical derivatization method for C=C bond using aziridination reaction. This new cyclization method for the C=C bonds in lipids based on the direct N-Me aziridination reaction of olefins using N-methyl-O-tosylhydroxylamine (TsONHCH3) as the aminating reagent. When combined with the tandem MS analysis, this novel activation approach for C=C bonds enables the accurate identification their positions in different kinds of unsaturated lipids. Furthermore, an integrated workflow has been established for comprehensively identifying the C=C bond positional isomers of lipids in complicated biological sample. This work provided a new chemical approach for the structural lipidomics.

biochemistry↗

bioRxiv2022

Insulated expression of periplasmic uricase in E. coli Nissle 1917 for the treatment of hyperuricemia

Hyperuricemia is a prevalent disease worldwide that is characterized by elevated urate levels in the blood owing to purine metabolic disorders, which can result in gout and comorbidities. As approximately one-third of urate is excreted by the small intestine and cleared by intestinal microorganisms, modulating the gut microbiota could be an attractive approach for hyperuricemia and gout treatment. In this study, we engineered a probiotic E. coli Nissle 1917 (EcN) strain, EcN C6, which expresses periplasmic uricase at an "insulated site", for urate degeneration. Oral administration of EcN C6 successfully alleviated hyperuricemia, related symptom and gut microbiota in a purine-rich food-induced hyperuricemia rat model and a uox-knockout mouse model. Importantly, the expression of periplasmic uricase in the insulated site did not influence the probiotic properties or global gene transcription of EcN, suggesting that EcN C6 is a safe, effective and low cost therapeutic candidate for hyperuricemia treatment.

synthetic biology↗

bioRxiv2022

Multi-omic profiling of the leukemic microenvironment shows bone marrow interstitial fluid is distinct from peripheral blood plasma

The bone marrow is the place of hematopoiesis with a microenvironment that supports lifelong maintenance of stem cells and high proliferation. It is not surprising that this environment is also favourable for malignant cells emerging in the bone marrow or metastasizing to it. While the cellular composition of the bone marrow microenvironment has been extensively studied, the extracellular matrix and interstitial fluid components have received little attention. Since the sinusoids connect the bone marrow interstitial fluid to the circulation, it is often considered to have the same composition as peripheral blood plasma. Stark differences in the cellular composition of the bone marrow and peripheral blood with different secretory capacities would however suggest profound differences. In this study we set out to better define if and how the bone marrow interstitial fluid (BMIF) compares to the peripheral blood plasma (PBP) and how both are remodeled during chemotherapy. We applied a multi-omic strategy to quantify the metabolite, lipid and protein components as well as the proteolytic modification of proteins to gain a comprehensive understanding of the two compartments. We found that the bone marrow interstitial fluid is clearly distinct from peripheral blood plasma, both during active pediatric acute lymphoblastic leukemia and following induction chemotherapy. Either compartment was shaped differently by active leukemia, with the bone marrow interstitial fluid being rich in extracellular vesicle components and showing protease dysregulation while the peripheral blood plasma showed elevation of immune regulatory proteins. Following chemotherapy, the BMIF showed signs of cellular remodeling and impaired innate immune activation while the peripheral blood plasma was characterized by restored lipid homeostasis.

cancer biology↗

bioRxiv2022

The mouse claustrum synaptically connects cortical network motifs

Spatially distant areas of cerebral cortex coordinate their activity into networks that are integral to cognitive processing. A common structural motif of cortical networks is co-activated frontal and posterior cortical regions. Knowledge of the neural circuit mechanisms underlying such widespread inter-areal cortical coordination is lacking. Using anesthetized mouse functional magnetic resonance imaging (fMRI) we discovered that mouse frontal cortical functional connectivity reflects the common cortical network motif in its functional connectivity to posterior cortices, but also demonstrates significant functional connectivity with the claustrum. Exploring whether the claustrum may synaptically support such network architecture, we used a channelrhodopsin-assisted electrophysiological circuit mapping approach to assess the strength of synaptic connectivity of 35 unique frontal cortico-claustral-cortical connections through 1,050 subtype-identified claustrum projection neurons. We observed significant trans-claustral synaptic connectivity from the anterior cingulate cortex and prelimbic prefrontal cortex back to originating frontal cortical regions as well as to posteriorly-lying visual and parietal association cortices contralaterally. The infralimbic prefrontal cortex possessed significant trans-claustral synaptic connectivity with the posteriorly-lying retrosplenial cortex, but to a far lesser degree with visual and parietal association cortices. These data reveal discrete extended cortical pathways through the claustrum that are positioned to support cortical network motifs central to cognitive control functions.

neuroscience↗

bioRxiv2022

Molecular Control of Circuit Plasticity and the Permanence of Imprinted Odor Memory

Behavioral imprinting is a distinct form of learning that has a lifelong impact on social interactions and affectional behaviors1-4. Unlike other forms of memory, imprinting does not require conspicuous association of stimuli; exposure per se appears sufficient to induce memories that neither undergo extinction nor are altered by experience later in life. The site of storage of imprinted memory and the mechanisms that control its formation and permanence are unknown. Here we uncover a molecular mechanism that controls olfactory imprinting, which underlies behaviors including kin and nest recognition, maternal attachment, and homing5-10. We show that odor exposure during the perinatal period converts an innately aversive odor into a homing signal. The behavioral change is associated with odor-induced changes in the projection patterns of olfactory sensory neuron (OSN) expressing the cognate receptors for the exposed odor. We show that the Wnt signaling receptor Frizzled1 (Fzd1) acts as a master regulator of the critical period of OSN development and is responsible for closing the critical period to prevent further changes in the neural circuit. In Fzd1 knockout mice axon projection patterns are continually modified by sensory experience. As Fzd1 knockout abolishes the developmental critical period, it also abolishes odor imprinting. Specific knockout of Fzd1 in the OSNs have the same effect. Mechanistically, Fzd1 controls the critical period through an autoregulated shutdown and by controlling an activity-driven regulon in the OSNs. The transient expression and the subsequent downregulation of Fzd1 leads to the irreversible closure of the critical period to lock in circuits established during the critical period. The evidence suggests that imprinted odor memory is stored in the patterns of connectivity at the first synapse in the olfactory bulb. Early odor experience induces changes in the OSN projection to alter connectivity with innate circuits to establish a life-long memory.

neuroscience↗

bioRxiv2022

PPML-Omics: a Privacy-Preserving federated Machine Learning system protects patients' privacy from omic data

Modern machine learning models towards various tasks with omic data analysis give rise to threats of privacy leakage of patients involved in those datasets. Despite the advances in different privacy technologies, existing methods tend to introduce too much computational cost (e.g. cryptographic methods) or noise (e.g. differential privacy), which hampers either model usefulness or accuracy in protecting privacy in biological data. Here, we proposed a secure and privacy-preserving machine learning method (PPML-Omics) by designing a decentralized version of the differential private federated learning algorithm. We applied PPML-Omics to analyze data from three sequencing technologies, and addressed the privacy concern in three major tasks of omic data, namely cancer classification with bulk RNA-seq, clustering with single-cell RNA-seq, and the integration of spatial gene expression and tumour morphology with spatial transcriptomics, under three representative deep learning models. We also examined privacy breaches in depth through privacy attack experiments and demonstrated that PPML-Omics could protect patients privacy. In each of these applications, PPML-Omics was able to outperform methods of comparison under the same level of privacy guarantee, demonstrating the versatility of the method in simultaneously balancing the privacy-preserving capability and utility in practical omic data analysis. Furthermore, we gave the theoretical proof of the privacy-preserving capability of PPML-Omics, suggesting the first mathematically guaranteed method with robust and generalizable empirical performance in protecting patients privacy in omic data.

bioinformatics↗

bioRxiv2022

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer's disease

The pathology of Alzheimers disease (AD) is associated with the extracellular amyloid-{beta} (A{beta}) plaques that perturb the mechanical properties of brain tissue. Microglia sense and integrate biochemical cues in their local microenvironment, intimate linking with AD progress. However, neither the microglial mechanosensing pathway nor its impact on AD pathogenesis is well studied. Here, we showed that the mechanosensitive ion channel Piezo1 is increased in microglia upon stiffness stimuli of A{beta} fibrils. The upregulation of Piezo1 in A{beta} plaque-associated microglia was observed in AD mouse models and human patients. Microglia lacking Piezo1 disturbed microglial clustering, phagocytosis, and compaction of A{beta} plaques, resulting in the exacerbation of A{beta} and neurodegenerative pathologies in AD. Conversely, pharmacological activation of Piezo1 ameliorated brain A{beta} burden and cognitive impairment in the 5xFAD mouse. Together, our results reveal Piezo1, as a mechanosensor of A{beta} fibrils stiffness in microglia, could represent a promising therapeutic target for AD.

neuroscience↗

bioRxiv2022

Neural and cognitive correlates of performance in dynamic multi-modal settings

The endeavour to understand human cognition has largely relied upon investigation of task-related brain activity. However, resting-state brain activity can also offer insights into individual information processing and performance capabilities. Previous research has identified electroencephalographic resting-state characteristics (most prominently: the individual alpha frequency; IAF) that predict cognitive function. However, it has largely overlooked a second component of electrophysiological signals: aperiodic 1/f activity. The current study examined how both oscillatory and aperiodic resting-state EEG measures, alongside traditional cognitive tests, can predict performance in a dynamic and complex, semi-naturalistic cognitive task. Participants resting-state EEG was recorded prior to engaging in a Target Motion Analysis (TMA) task in a simulated submarine control room environment (CRUSE), which required participants to integrate dynamically changing information over time. We demonstrated that the relationship between IAF and cognitive performance extends from simple cognitive tasks (e.g., digit span) to complex, dynamic measures of information processing. Further, our results showed that individual 1/f parameters (slope and intercept) differentially predicted performance across practice and testing sessions, whereby flatter slopes were associated with improved performance during learning, while higher intercepts were linked to better performance during testing. In addition to the EEG predictors, we demonstrate a link between cognitive skills most closely related to the TMA task (i.e., spatial imagery) and subsequent performance. Overall, the current study highlights (1) how resting-state metrics - both oscillatory and aperiodic - have the potential to index higher-order cognitive capacity, while (2) emphasising the importance of examining these electrophysiological components within more dynamic settings and over time.

neuroscience↗

bioRxiv2022

Heterotypic vaccination responses against SARS-CoV-2 Omicron BA.2

The Omicron sub-lineage BA.2 of SARS-CoV-2 has recently become dominant across many areas in the world in the on-going waves of COVID-19. Compared to the ancestral/wild-type (WT) virus, Omicron lineage variants, both BA.1 and BA.2, contain high number of mutations, especially in the spike protein, causing significant immune escape that leads to substantial reduction of vaccine and antibody efficacy. Because of this antigenic drift, BA.2 exhibited differential resistance profile to monoclonal antibodies than BA.1. Thus, it is important to understand whether the immunity elicited by currently available vaccines are effective against the BA.2 subvariant. We directly tested the heterotypic vaccination responses against Omicron BA.2, using vaccinated serum from animals receiving WT- and variant-specific mRNA vaccine in lipid nanoparticle (LNP) formulations. Omicron BA.1 and BA.2 antigen showed similar reactivity to serum antibodies elicited by two doses of WT, B.1.351 and B.1.617 LNP-mRNAs. Neutralizing antibody titers of B.1.351 and B.1.617 LNP-mRNA were ~2-fold higher than that of WT LNP-mRNA. Both homologous boosting with WT LNP-mRNA and heterologous boosting with BA.1 LNP-mRNA substantially increased waning immunity of WT vaccinated mice against both BA.1 and BA.2 subvariants. The BA.1 LNP-mRNA booster was ~3-fold more efficient than WT LNP-mRNA at elevating neutralizing antibody titers of BA.2. Together, these data provided a direct preclinical evaluation of WT and variant-specific LNP-mRNAs in standard two-dose and as boosters against BA.1 and BA.2 subvariants.

immunology↗

bioRxiv2022

Dual-Resolving of Lipid Positional and Geometric Isomers of C=C Bonds via Bifunctional Photocycloaddition-Photoisomerization Reaction System and Mass Spectrometry

The biological functions of lipids largely depend on their chemical structures. The position and configuration of C=C bonds are two of the essential attributes that determine the structures of unsaturated lipids. However, simultaneous identification of both attributes remains challenging. Here, we developed a bifunctional visible-light-activated photocycloaddition-photoisomerization reaction system, which enabled the dual-resolving of the positional and geometric isomerism of C=C bonds in lipids when combined with liquid chromatographic mass spectrometry. The dual-pathway reaction mechanism was demonstrated by experiments and density functional theory calculations. Based on this bifunctional reaction system, a workflow of deep structural lipidomics was established, and allowed the revealing of unique patterns of cis-trans-isomers in bacteria, as well as the tracking of C=C positional isomers changes in mouse brain ischemia. This study not only offers a powerful tool for deep lipid structural biology, but also provides a new paradigm for developing the multifunctional visible-light-induced reaction.

biochemistry↗

bioRxiv2022

Stem cells partner with matrix remodeling cells during regeneration

Stem cells enable regeneration by self-renewing and differentiating as instructed by a local microenvironment called a niche1-3. In most cases, the repair or replacement of tissues is fueled by tissue-specific or lineage-restricted stem cells that proliferate in response to local injury and apoptosis4-11. However, in organisms that regenerate using abundant adult pluripotent stem cells, the stem cell niches that support tissue repair have not been identified or characterized. Since these adult pluripotent stem cells are often more widely distributed and plentiful than lineage-restricted stem cells of other organisms, defining their microenvironments may uncover alternative forms of stem cell regulation12-14. Here we used unbiased spatial transcriptomics to define the cellular and molecular environments that support pluripotency in the highly regenerative freshwater planarian Schmidtea mediterranea. We determined that stem cells associate with a diverse collection of differentiated cell types, and these associations are highly dynamic during regeneration. We explored associations with two distinct cell types: secretory cells we term hecatonoblasts, and intestinal cells. While both cell types regulate stem cell proliferation, their spatial relationships to stem cells defy the concept of a single regenerative niche. Thus, the planarian stem cell pool is likely maintained by a dynamic collection of distinct microenvironments that cooperatively power whole-body regeneration.

developmental biology↗

bioRxiv2022

A genome-wide mutational constraint map quantified from variation in 76,156 human genomes

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders, but attempts to assess constraint for non-protein-coding regions have proven more difficult. Here we aggregate, process, and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD), the largest public open-access human genome reference dataset, and use this dataset to build a mutational constraint map for the whole genome. We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation across the genome. As expected, proteincoding sequences overall are under stronger constraint than non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association, and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, while non-coding constraint captures additional functional information underrecognized by gene constraint metrics. We demonstrate that this genome-wide constraint map provides an effective approach for characterizing the non-coding genome and improving the identification and interpretation of functional human genetic variation.

genetics↗

bioRxiv2022

Hiplot: a comprehensive and easy-to-use web service boosting publication-ready biomedical data visualization

Modern web techniques provide an unprecedented opportunity for leveraging complex biomedical data generating in clinical, omics, and mechanism experiments. Currently, the functions for carrying out publication-ready biomedical data visualization represent primary technical hurdles in the state-of-art omics-based web services, whereas the demand for visualization-based interactive data mining is ever-growing. Here, we propose an easy-to-use web service, Hiplot (https://hiplot.com.cn), equipping with comprehensive and interactive biomedical data visualization functions (230+) including basic statistics, multi-omics, regression, clustering, dimensional reduction, meta-analysis, survival analysis, risk modeling, etc. We used the demo and real datasets to demonstrate the usage workflow and the core functions of Hiplot. It permits users to conveniently and interactively complete a few specialized visualization tasks that previously could only be done by senior bioinformatics or biostatistics researchers. A modern web client with efficient user interfaces and interaction methods has been implemented based on the custom components library and the extensible plugin system. The versatile output can also be produced in different environments via using the cross-platform portable command-line interface (CLI) program, Hctl. A switchable view between the editable data table and the file uploader/path selection could facilitate data importing, previewing, and exporting, while the plumber-based response strategy significantly reduced the time costs for generating basic scientific graphics. Diversified layouts, themes/styles, and color palettes in this website allow users to create high-quality and publication-ready graphics. Researchers devoted to both life and data science may benefit from the emerging web service.

bioinformatics↗