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Xie, S.

Publications and source records attributed to Xie, S..

At least 109 records · Page 6Linked to original sources
bioRxiv2023

Human FAM111A inhibits vaccinia virus replication by degrading viral uncoating factor I3 and is antagonized by poxvirus host range factor SPI-1

Poxviruses are large double-stranded DNA viruses that infect a wide range of animals including humans. Since the eradication of smallpox, other members of the poxvirus family, such as monkeypox virus (MPXV) are still posing a great threat to public health. Vaccinia virus (VACV) is a prototypic poxvirus used as the vaccine strain for smallpox eradication. VACV encodes a serine protease inhibitor 1 (SPI-1) conserved in all orthopoxviruses, which has been recognized as a host range factor for modified vaccinia virus Ankara (MVA), an approved smallpox vaccine and a promising vaccine vector. FAM111A, a nuclear protein that regulates host DNA replication, was shown to restrict the replication of VACV-{Delta}SPI-1 in human cells. Nevertheless, the detailed antiviral mechanisms of FAM111A were unresolved. Here, we show that FAM111A is a potent restriction factor for VACV-{Delta}SPI-1 and MVA. Deletion of FAM111A rescued the replication of MVA and VACV-{Delta}SPI-1 and overexpression of FAM111A significantly reduced viral DNA replication and virus titers but did not affect viral early gene expression. The antiviral effect of FAM111A necessitated its trypsin-like protease domain and DNA binding domain but not the PCNA-interacting motif. We further discovered that FAM111A translocated into the cytoplasm upon VACV infection and this process was mediated by the cGAS-STING signaling pathway. Infection-triggered FAM111A degraded the nuclear pore complex via its protease activity, translocated to the cytoplasm, and interacted with and promoted the degradation of virus DNA binding protein I3 in a DNA-dependent manner. Interestingly, the protease activity of FAM111A was only needed for nuclear export but not I3 degradation as further analysis showed I3 was degraded through autophagy. Moreover, VACV SPI-1 was found primarily in the nucleus of infected cells and antagonized FAM111A by prohibiting its nuclear export. MPXV and lumpy skin disease virus SPI-1s also inhibited human FAM111A. Our findings reveal the detailed mechanism by which FAM111A functions to restrict a cytoplasmic DNA virus and provide explanations for the immune evasive function of VACV SPI-1.

microbiology↗
bioRxiv2022

Japanese Encephalitis Virus NS1 Protein regulates the expression and distribution of TIM-1 to promote viral infection

Japanese encephalitis virus (JEV) is a mosquito-borne Flavivirus, which may cause severe encephalitis in humans, horses, and other animals. TIM-1 has been identified to be a receptor that promotes various viruses to enter into target cells in recent years. In the present study, we found that TIM-1 protein was significantly increased in A549 cells at the late stage of JEV infection, while the transcription levels of TIM-1 remained unaltered. Interestingly, we found that NS1 protein plays a key role in increasing the expression of TIM-1 in cells infected with JEV. Further, we found that the NS1 protein also efficiently regulates TIM-1 protein to distribute in the cytoplasm in JEV-infected cells, and the amount of TIM-1 protein located on the cell membrane was reduced instead. As a consequence, NS1 protein antagonize TIM-1 mediated viral restriction for further viral infection and propagation in the late stage of infection. In molecular mechanism, the molecular weight of TIM-1 increased a bit in the present of NS1. Expression of NEU1 down-regulated TIM-1 expression and oseltamivir treatment increased the expression of TIM-1. Therefore, our data indicated that JEV NS1 protein facilitated the sialylation modification of TIM-1 to up-regulate the level of TIM-1 expression and regulate its distribution. Collectively, our study revealed that JEV NS1 protein regulates the expression and distribution of TIM-1 by facilitating its sialylation to antagonize TIM-1-mediated JEV restriction for further infection. Understanding the functional interplays between TIM-1 and NS1 proteins will offer new insights into virushost interaction. IMPORTANCET-cell immunoglobulin and mucin domain protein 1 (TIM-1) is known to promote cellular entry of various enveloped viruses. We discovered a novel phenomenon of dynamic expression and functional regulation of TIM-1 during JEV infection. Firstly, TIM-1 protein increased in the cytoplasm at the late stage of JEV infection. Furthermore, JEV NS1 protein up-regulated the intracellular expression of TIM-1 and antagonize TIM-1-mediated viral restriction for further viral infection. In molecular mechanism, JEV NS1 protein facilitated the sialylation of TIM-1 to increase the level of TIM-1 expression and cytoplasm distribution. Taken together, at the late stage of infection, JEV employs a strategy in which NS1 promotes JEV release by promoting the sialylation of TIM-1, causing it to be primarily localized in the cytoplasm. Therefore, we discovered new functions of TIM-1 and JEV NS1 during the process of JEV infection, and provide a new insight into the interactions between JEV and cell hosts.

microbiology↗
bioRxiv2022

Incorporating Pre-training Paradigm for Antibody Sequence-Structure Co-design

Antibodies are versatile proteins that can bind to pathogens and provide effective protection for human body. Recently, deep learning-based computational antibody design has attracted popular attention since it automatically mines the antibody patterns from data that could be complementary to human experiences. However, the computational methods heavily rely on the high-quality antibody structure data, which is quite limited. Besides, the complementarity-determining region (CDR), which is the key component of an antibody that determines the specificity and binding affinity, is highly variable and hard to predict. Therefore, data limitation issue further raises the difficulty of CDR generation for antibodies. Fortunately, there exists a large amount of sequence data of antibodies that can help model the CDR and alleviate the reliance on structured data. By witnessing the success of pre-training models for protein modeling, in this paper, we develop an antibody pre-trained language model and incorporate it into the (antigen-specific) antibody design model in a systemic way. Specifically, we first pre-train an antibody language model based on the sequence data, then propose a one-shot way for sequence and structure generation of CDR to avoid the heavy cost and error propagation from an autoregressive manner, and finally leverage the pre-trained antibody model for the antigen-specific antibody generation model with some carefully designed modules. Through various experiments, we show that our method achieves superior performance over previous baselines on different tasks, such as sequence and structure generation, antigen-binding CDR-H3 design.

molecular biology↗
bioRxiv2022

Perturbation of mitochondrial Ca2+ homeostasis activates cross-compartmental proteostatic response in Arabidopsis

Mitochondrial Ca2+ (mtCa2+) homeostasis is essential to mitochondrial functions. However, how mtCa2+ homeostasis is achieved and the consequences of impaired mtCa2+ homeostasis in plants is poorly understood. Here, we demonstrate a critical role for mitochondrial Ca2+ uniporter (MCU) in the control of mtCa2+ uptake for mtCa2+ homeostasis in planta by characterizing MCU mutants and overexpressed plants. Impaired MCU-controlled mtCa2+ homeostasis (iMUCH) in gain-of-function and loss-of-function MCU plants causes the misregulation of mitochondrial gene expression that triggers mitonuclear protein imbalance. Transcriptome integrated with proteomics analysis reveal activation of multiple compartmental UPR gene expression and decrease of cytosolic translation with selective repression of ribosome and RNA modification protein synthesis upon iMUCH. Intriguingly, TOR signalling is not involved in cytosolic translational response to iMUCH, but the reduction of eIF phosphorylation is evident under iMUCH induced mitochondrial stress. Thus, our study unveils the essential functions of MCU proteins for mtCa2+ homeostasis, and the involvement of MCU-controlled mtCa2+ homeostasis in mitochondrial stress dependent regulation of protein synthesis for cellular proteostasis that is connected to plant growth and stress resistance.

plant biology↗
bioRxiv2022

Aging and Obesity Prime the Methylome and Transcriptome of Adipose Stem Cells for Disease and Dysfunction

The epigenome of stem cells occupies a critical interface between genes and environment, serving to regulate expression through modification by intrinsic and extrinsic factors. We hypothesized that aging and obesity, which represent major risk factors for a variety of diseases, synergistically modify the epigenome of adult adipose stem cells (ASCs). Using integrated RNA- and targeted bisulfite-sequencing in murine ASCs from lean and obese mice at 5- and 12- months of age, we identified global DNA hypomethylation with either aging or obesity, and a synergistic effect of aging combined with obesity. The transcriptome of ASCs in lean mice was relatively stable to the effects of age, but this was not true in obese mice. Functional pathway analyses identified a subset of genes with critical roles in progenitors and in diseases of obesity and aging. Specifically, Mapt, Nr3c2, App, and Ctnnb1 emerged as potential hypomethylated upstream regulators in both aging and obesity (AL vs YL and AO vs YO), and App, Ctnnb1, Hipk2, Id2, and Tp53 exhibited additional effects of aging in obese animals. Further, Foxo3 and Ccnd1 were potential hypermethylated upstream regulators of healthy aging (AL vs YL), and of the effects of obesity in young animals (YO vs YL), suggesting that these factors could play a role in accelerated aging with obesity. Finally, we identified candidate driver genes that appeared recurrently in all analyses and comparisons undertaken. Further mechanistic studies are needed to validate the roles of these genes capable of priming ASCs for dysfunction in aging- and obesity-associated pathologies.

cell biology↗
bioRxiv2022

The Role of Frontal Eye Field in Saccadic Mixed-strategy Decision-making

Game theory can predict the distribution of choices in aggregate during mixed-strategy games, yet the neural process mediating individual probabilistic choices remains poorly understood. Here, we examined the role of frontal eye field (FEF) in a decision-making task when macaques were trained to play a mixed-strategic game - Matching Pennies - against a computer opponent. Neuronal activities of FEF neurons predicted the animals upcoming saccadic choices and these activities became increasingly more selective as the choice deadline approached. Subthreshold electrical micro-stimulation applied in FEF also biased choices. Extended stimulation biased choices towards the preferred FEF vector whereas early termination of stimulation biased choices away from the preferred FEF vector. By contrast, micro-stimulation biased choices in the preferred direction during a non-strategic perceptual luminance discrimination task. We conclude that FEF is causally contributing to mixed-strategy decision-making process although the timing of FEF activation contributes to the decision process in a more non-linear manner during strategic compared to perceptual decision-making.

neuroscience↗
bioRxiv2022

Sister chromatid cohesion establishment during DNA replication termination

The cohesin complex tethers sister chromatids together from the moment they are generated in S-phase until their separation in anaphase1,2. This fundamental phenomenon, called sister chromatid cohesion, underpins orderly chromosome segregation. The replisome complex coordinates cohesion establishment with replication of parental DNA3. Cohesion can be established by cohesin complexes bound to DNA before replication4,5, but how replisome interaction with pre-loaded cohesin complexes results in cohesion is not known. Prevailing models suggest cohesion is established by replisome passage through the cohesin ring or by transfer of cohesin behind the replication fork by replisome components5. Unexpectedly, by visualising single replication forks colliding with pre-loaded cohesin complexes, we find that cohesin is pushed by the replisome to where a converging replisome is met. Whilst the converging replisomes are removed during DNA replication termination, cohesin remains on nascent DNA. We demonstrate that these cohesin molecules tether the newly replicated sister DNAs together. Our results support a new model where sister chromatid cohesion is established during DNA replication termination, providing important insight into the molecular mechanism of cohesion establishment.

biophysics↗
bioRxiv2022

The Chromosome-based Genome of Paspalum vaginatum Provides New Insights into Salt-stress Adaptation

Salinization is increasingly a major factor limiting production worldwide. Revealing the mechanism of salt tolerance could help to create salt-tolerant crops and improve their yields. We reported a chromosome-scale genome sequence of the halophyte turfgrass Paspalum vaginatum, and provided structural evidence that it shared a common ancestor with Z. mays and S. bicolor. A total of 107 P. vaginatum germplasms were divided into two groups (China and foreign group) based on the re-sequenced data, and the grouping findings were consistent with the geographical origin. Genome-wide association study (GWAS) of visually scored wilting degree and withering rates identified highly significant QTL on chromosome 6. Combination with RNA-seq, we identified a significantly up-regulated gene under salt stress, which encodes High-affinity K+ Transporter 7 (PvHKT7), as strong candidates underlying the QTL. Overexpression of this gene in Arabidopsis thaliana significantly enhanced salt tolerance by increasing K+ absorption. This study adds new insights into salt-stress adaptation of P. vaginatum and serve as a resource for salt-tolerant improvement of grain crops.

genomics↗
bioRxiv2022

Circulating tumor DNA profiling approach based on in silico background elimination guides patient classification of multiple cancers

Circulating tumor DNA (ctDNA) analysis is increasingly providing a promising minimally invasive alternative to tissue biopsies in precision oncology. However, current methods of ctDNA mutation profiling have limited resolution because of the high background noise and false-positive rate caused by benign variants in plasma cell-free DNA (cfDNA), majorly generated during clonal hematopoiesis. Although personalized parallel white blood cell (WBC) genome sequencing suppresses the noise of clonal hematopoiesis variances observed in ctDNA based liquid biopsy, the system cost and complexity restrict its extensive application in clinical settings. To address this challenge, we describe a Matched WBC Genome sequencing Independent CtDNA profiling (MaGIC) approach, which enables the sensitive detection of recurrent tumor mutant information harbored by ctDNA from a bulk cfDNA background based on hybrid capture cfDNA deep sequencing, in silico background elimination, and a reliable readout measurement by the calculation the number of key mutated exons. Leveraging somatic mutation data from 10163 patients across 24 cancer types obtained from The Cancer Genome Atlas, we confirm that the MaGIC approaches are of ideal performance in prediction of prognosis by tissue biopsy samples of patients across multiple cancers. Meanwhile, MaGIC approaches enable the classification of prostate cancer patients from heathy cohorts by ctDNA sequencing data. We further profiled the ctDNAs of 80 plasma samples from 40 patients with nasopharyngeal carcinoma before and during chemotherapy by MaGIC approaches. The MaGICv2 can predict the chemosensitivity with high accuracy by simply using one liquid biopsy sample of each patient before a stereotypical treatment course. We anticipate that this new approach has the potential utility of ctDNA detection in multiple clinical cancer contexts, thus facilitating precise cancer therapy. TeaserA liquid biopsy analysis method for multifunctional patient classification such as diagnosis and chemosensitivity prediction.

cancer biology↗
bioRxiv2022

Comparative genomics of five Valsa species gives insights on their pathogenicity evolution

Valsa is a genus of ascomycetes fungi within the family Valsaceae that includes many wood destructive pathogens. The species such as Valsa mali and Valsa pyri that colonize fruit trees are threatening the global fruit production. Rapid host adaptation and fungicide resistance emergence are the main characteristics that make them devastating and hard to control. Efficient disease management can be achieved from early infection diagnosis and fungicide application, but lack of understandings of their genetic diversity and genomic features that underpin their pathogenicity evolution and drug resistance is essentially impeding the progress of effective and sustainable disease control. Here, we report genome assemblies of Valsa malicola, Valsa persoonii and Valsa sordida which represents close relatives of the two well known Valsa mali and Valsa pyri that cause canker disease with different host preferences. Comparative genomics analysis revealed that segmental rearrangements, inversions and translocations frequently occurred among Valsa spp. genomes. Genes identified in highly active regions exhibited high sequence differentiation and are enriched in membrane transporter proteins involved in anti-drug and nutrient transportation activities. Consistently, we also found membrane transporter gene families have been undergoing significant expansions in Valsa clade. Furthermore, unique genes that possessed or retained by each of the five Valsa species are more likely part of the secondary metabolic (SM) gene clusters which suggests SM one of the critical components that diverge along with the evolution of Valsa species. Repeat sequence content contributes significantly to genome size variation across the five species. The wide spread AT-rich regions resulted from repeat induced point C to T mutation (RIP) exhibited a specific proximity to secondary metabolic gene clusters and this positional proximity is correlated with the diversification of SM clusters suggesting a potential companion evolution between repeat sequence and secondary metabolism cluster. Lastly, we show that LaeA, the global regulator of secondary metabolic gene cluster, exhibiting diverged manner of regulation on the expression of clusters in vegetative and invasive mycelia of the devastating V. mali indicating the complexity of secondary metabolism in fungal species.

bioinformatics↗
bioRxiv2022

CHD-associated enhancers shape human cardiomyocyte lineage commitment

Enhancers orchestrate gene expression programs that drive multicellular development and lineage commitment. Thus, genetic variants at enhancers are thought to contribute to developmental diseases by altering cell fate commitment. However, while many variant-containing enhancers have been identified, studies to endogenously test the impact of these enhancers on lineage commitment have been lacking. We perform a single-cell CRISPRi screen to assess the endogenous roles of 25 enhancers and putative cardiac target genes implicated in genetic studies of congenital heart defects (CHD). We identify 16 enhancers whose repression leads to deficient differentiation of human cardiomyocytes (CMs). A focused CRISPRi validation screen shows that repression of TBX5 enhancers delays the transcriptional switch from mid- to late-stage CM states. Endogenous genetic deletions of two TBX5 enhancers phenocopy epigenetic perturbations. Together, these results identify critical enhancers of cardiac development and suggest that misregulation of these enhancers could contribute to cardiac defects in human patients. HIGHLIGHTSO_LISingle-cell enhancer perturbation screens during human cardiomyocyte differentiation. C_LIO_LIPerturbation of CHD-linked enhancers/genes causes deficient CM differentiation. C_LIO_LIRepression or knockout of TBX5 enhancers delays transition from mid to late CM states. C_LIO_LIDeficient differentiation coincides with reduced expression of known cardiac genes. C_LI

genomics↗
bioRxiv2022

A simple island biodiversity model is robust to trait dependence in diversification and colonization rates

The application of state-dependent speciation and extinction (SSE) models to phylogenetic trees has revealed an important role for traits in diversification. However, this role remains comparatively unexplored on islands, which can include multiple independent clades resulting from different colonization events. Here, we perform a robustness study to identify how trait-dependence in rates of island colonization, extinction and speciation (CES rates) affects the estimation accuracy of a phylogenetic model that assumes no rate variation between trait states. We extend the DAISIE (Dynamic Assembly of Islands through Speciation, Immigration and Extinction) simulation model to include state-dependent rates, and evaluate the robustness of the DAISIE inference model using simulated data. Our results show that when the CES rate differences between trait states are moderate, DAISIE shows negligible error for a variety of island diversity metrics. However, for large differences in speciation rates, we find large errors when reconstructing clade size variation and non-endemic species diversity through time. We conclude that for many biologically realistic scenarios with trait-dependent speciation and colonization, island diversity dynamics can be accurately estimated without the need to explicitly model trait dynamics. Nonetheless, our new simulation model may provide a useful tool for studying patterns of trait variation.

evolutionary biology↗
bioRxiv2021

Metabolic profiling of serum for osteoarthritis biomarkers

Osteoarthritis is a prevalent aging disease in the world, and in recent years it has shown a trend toward younger age, which is becoming a major health problem in the world and seriously endangers the health of the elderly. However, the etiology and pathogenesis of osteoarthritis are still unclear, causing great trouble for treatment. To screen out potential biomarkers that could be used as identification of osteoarthritis and explore the pathogenesis of osteoarthritis, we performed untargeted metabolomics analysis of nine New Zealand rabbit serum samples by LC-MS / MS, including three normal serum samples (control group) and six osteoarthritis serum samples (case group). Finally 44 differential metabolites were identified, and the ROC analysis results indicated that a total of 36 differential metabolites could be used as potential biomarkers. Further metabolic pathway enrichment analysis was performed on these differential metabolites, and we found that a total of 17 metabolic pathways were affected, which may provide directions for the study of osteoarthritis mechanisms.

bioinformatics↗
bioRxiv2021

Visual category representations in the infant brain

Visual categorization is a human core cognitive capacity 1,2 that depends on the development of visual category representations in the infant brain 3-7. However, the exact nature of infant visual category representations and their relationship to the corresponding adult form remains unknown 8. Our results clarify the nature of visual category representations from electroencephalography (EEG) data in 6- to 8-month-old infants and their developmental trajectory towards adult maturity in the key characteristics of temporal dynamics 2,9, representational format 10-12, and spectral properties 13,14. Temporal dynamics change from slowly emerging, developing representations in infants to quickly emerging, complex representations in adults. Despite those differences, infants and adults already partly share visual category representations. The format of infants representations is visual features of low to intermediate complexity, whereas adults representations also encode high complexity features. Theta band activity contributes to visual category representations in infants, and these representations are shifted to the alpha/beta band in adults. Together, we reveal the developmental neural basis of visual categorization in humans, show how information transmission channels change in development, and demonstrate the power of advanced multivariate analysis techniques in infant EEG research for theory building in developmental cognitive science.

neuroscience↗
bioRxiv2021

High Resolution Nanostructure with Two-stages of Exponential Energy Dissipation at the Ultrathin Osteochondral Interface Tissue of Human Knee Joint

Cartilage adheres to subchondral bone via a specific osteochondral interface tissue where forces are transferred from soft cartilage to hard bone without fatigue damage over a lifetime of load cycles. However, the fine structure and mechanical properties of osteochondral interface tissue remain unclear. Here, we identified an ultrathin [~]20-30 m calcified region with two-layered micro-nano structures of osteochondral interface tissue in human knee joint, which exhibited characteristic biomolecular compositions and complex nanocrystals assembly. Within this region, an exponential increase of modulus (3 orders of magnitude) was conducive to the force transmission which was verified by finite element simulations. The nanoscale heterogeneity of hydroxyapatite, along with enrichment of elastic-responsive protein-titin which is usually present in muscle, endowed the osteochondral tissue with excellent energy dissipation and fatigue resistance properties. Our results provide potential design for high-performance interface materials for osteochondral interface regeneration and functional coatings.

bioengineering↗
bioRxiv2021

The retromer complex regulates C. elegans development and mammalian ciliogenesis

The mammalian retromer is comprised of subunits VPS26, VPS29 and VPS35, and a more loosely-associated sorting nexin (SNX) heterodimer. Despite known roles for the retromer in multiple trafficking events in yeast and mammalian cells, its role in development is poorly understood, and its potential function in primary ciliogenesis remains unknown. Using CRISPR-Cas9 editing, we demonstrated that vps-26 homozygous knockout C. elegans have reduced brood sizes and impaired vulval development, as well as decreased body length which has been linked to defects in primary ciliogenesis. Since many endocytic proteins are implicated in the generation of primary cilia, we addressed whether the retromer regulates ciliogenesis in mammalian cells. We observed VPS35 localized to the primary cilium, and depletion of VPS26, VPS35 or SNX1/SNX5 led to decreased ciliogenesis. Retromer also coimmunoprecipitated with the capping protein, CP110, and was required for its removal from the mother centriole. Herein, we characterize new roles for the retromer in C. elegans development and in the regulation of ciliogenesis in mammalian cells, and suggest a novel role for the retromer in CP110 removal from the mother centriole.

cell biology↗
bioRxiv2021

Rapid visual CRISPR assay: a naked-eye colorimetric detection method for nucleic acids based on CRISPR/Cas12a and convolutional neural network

Rapid diagnosis based on naked-eye colorimetric detection remains challenging, but it could build new capacities for molecular point-of-care testing (POCT). In this study, we evaluated the performance of 16 types of single-stranded DNA-fluorophore-quencher (ssDNA-FQ) reporters for use with CRISPR/Cas12a based visual colorimetric assays. Among them, 9 ssDNA-FQ reporters were found to be suitable for direct visual colorimetric detection, with especially very strong performance using ROX-labeled reporters. We optimized the reaction concentrations of these ssDNA-FQ reporters for naked-eye read-out of assay results (no transducing component required for visualization). Subsequently, we developed a convolutional neural network algorithm standardize and to automate the analytical colorimetric assessment of images and integrated this into the MagicEye mobile phone software. A field-deployable assay platform named RApid VIsual CRISPR (RAVI-CRISPR) based on a ROX-labeled reporter with isothermal amplification and CRISPR/Cas12a targeting was established. We deployed RAVI-CRISPR in a single tube towards an instrument-less colorimetric POCT format that requires only a portable rechargeable hand warmer for incubation. The RAVI-CRISPR was successfully used for the single-copy detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and African swine fever virus (ASFV). Our study demonstrates this novel RAVI-CRISPR system for distinguishing different pathogenic nucleic acid targets with high specificity and sensitivity as the simplest-to-date platform for rapid pen-side testing.

molecular biology↗