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Xu, Z.

Publications and source records attributed to Xu, Z..

At least 325 records · Page 18Linked to original sources
bioRxiv2022

Characterization of the Tau Interactome in Human Brain Reveals Isoform-Dependent Interaction with 14-3-3 Family Proteins

Tau phosphorylation and aggregation is the final common pathway for neuronal toxicity across multiple neurodegenerative diseases including Alzheimer disease, progressive supranuclear palsy, and corticobasal degeneration. We have previously shown that the fetal brain expresses high levels of phosphorylated tau, and even tau aggregates, without apparent toxic effects. The mechanisms for this remarkable resilience, however, remain unclear. In order to identify potential mediators of this resilience, we used bead-linked total tau immunoprecipitation in human fetal, adult, and Alzheimer disease brains. We then used heterologous transfection in HEK 293T cells followed by coimmunoprecipitation, mass photometry, and nuclear magnetic resonance (NMR) to further characterize the interaction of tau with one of our top hits, 14-3-3-{beta}. We found significant differences between the tau interactome in fetal and AD brain, with little difference between adult and AD. There were significant differences in tau interaction with 14-3-3 family proteins between fetal and AD brain. We then determined that the 14-3-3 isoform with the highest difference, 14-3-3-{beta}, preferentially interacts with 4R tau in vitro, forming a complex consisting of two 14-3-3-{beta}, and one tau molecule. NMR studies using 15N-labeled phosphorylated tau showed that the binding site for 14-3-3 was in the microtubule binding region of tau, which is truncated in 3R tau through the exclusion of exon 10. Our findings suggest that there are marked differences between the phospho-tau interactome in fetal and Alzheimer disease brain, including differences in interaction with the critical 14-3-3 family of protein chaperones, which may explain, in part, the resilience of fetal brain to tau toxicity.

neuroscience↗
bioRxiv2022

Diving Behavior Reveals Humidity Sensing Ability of Water Deprived Planarians

Humidity sensing ability is crucial to terrestrial animals for fitting the environment. Researchers made great progress in recent study about humidity sensing mechanisms of terrestrial animals. However, it is poorly understood whether humidity sensing exists in aquatic animals. Here, we demonstrate that the aquatic planarians, one of the primitive forerunners of later animals, has the ability of humidity sensing and is capable of using the ability to perceive the water beneath itself from a drought place to seek survival. The behavior we discovered is described as diving because the worms twist its body to break away from the mucus that make them adhere to the drought place and drop into the water. The behavior is triggered by rapidly increasing humidity. This finding suggests that humidity sensing ability exists in the lower aquatic animals, and the ability might be used to seek for water when aquatic animals are facing desiccation. The finding also suggests that survival-seeking and decision-making behavior have appeared in the primitive planarian worms.

animal behavior and cognition↗
bioRxiv2022

Bacillus velezensis SQR9 sways the rhizosphere community and its sociality toward cooperation and plant growth promotion

According to the Lotka-Volterra competition model, intraspecific competition in plant-associated microbial communities should be stronger than interspecific competition. However, there is limited information on whether microbial communities follow this pattern and how disturbance by a newcomer affects them. Given the increasing popularity of probiotics, filling this knowledge gap could help guide future coexistence research. Here, we show that inoculation with a known probiotic, B. velezensis SQR9 shifts species co-occurrence patterns by decreasing the diversity of more distant species and promoting the growth of more closely related species, especially within the Bacillus community. By testing the sociality of Bacillus rhizosphere isolates, we then demonstrated that SQR9 increases the frequency of cooperative interactions in the Bacillus community, which may contribute to the promotion of plant growth. Finally, we provide an ecosystem framework comprising the strains genetic relatedness, metabolic niche space and social compatibility for the efficient and reliable assembly of Bacillus consortia. These findings shed new light on the ecological mechanisms underlying the beneficial effects of probiotics on host fitness.

microbiology↗
bioRxiv2022

Integrative multispecies omics reveals a hierarchy of cold-responsive network launched by circadian components in rosids

Elucidating regulators and molecular mechanisms underlying gene transcriptional and post-transcriptional co-regulatory network is key to understand plant cold-stress responses. Previous studies were mainly conducted on single species and whether the regulators and mechanisms are conserved across different species remains elusive. Here, we selected three species that diverged at early evolution of rosids (93-115 million years ago) and integrated phylotranscriptome and ChIP/DAP-seq datasets to identify cold-responsive regulators and their regulatory networks. First, we found over ten thousand cold-responsive genes including differentially expressed genes (DEGs) and alternative splicing genes (DASGs) in each species. Among the DEGs, genes encoding a set of transcription factors (TFs) (AP2/ERF, MYB, WRKY, NAC, etc.) and RNA binding proteins (RBPs) (Ribosomal, RRM, DEAD, Helicase_C, etc.) are conserved in cold responses in rosids. Compared to TFs, RBPs show a delayed cold-responsive pattern, likely suggesting a hierarchical regulation of DEGs and DASGs. Between DEGs and DASGs, we identified 259 overlapping DE-DASG orthogroups and interestingly, pathway analysis on each dataset of DEGs, DASGs, and DE-DASGs coincidently shows an enrichment of circadian rhythm. Evidentially, many circadian components are cold-regulated at both transcriptional and post-transcriptional levels. Moreover, we reasoned 226 cold-responsive genes regulated by at least two of five circadian components (CCA1, LHY, RV4, RVE8, and RVE7) in rosids. Finally, we unveiled a conserved hierarchical network in dynamic transcriptional and post-transcriptional regulation of cold-responsive genes launched by circadian components in rosids. Together, our results provide insights into core regulators and mechanisms underlying cold-responsive regulatory network across rosids, despite a long evolutionary history.

plant biology↗
bioRxiv2022

DeepAIR: a deep-learning framework for effective integration of sequence and 3D structure to enable adaptive immune receptor analysis

Structural docking between the adaptive immune receptors (AIRs), including T cell receptors (TCRs) and B cell receptors (BCRs), and their cognate antigens is one of the most fundamental processes in adaptive immunity. However, current methods for predicting AIR-antigen binding largely rely on sequence-derived features of AIRs, omitting the structure features that are essential for binding affinity. In this study, we present a deep-learning framework, termed DeepAIR, for the accurate prediction of AIR-antigen binding by integrating both sequence and structure features of AIRs. DeepAIR consists of three feature encoders (a trainable-embedding-layer-based gene encoder, a transformer-based sequence encoder, and a pre-trained AlphaFold2-based structure encoder), a gating-based attention mechanism to extract important features, and a tensor fusion mechanism to integrate obtained features. We train and evaluate DeepAIR on three downstream prediction tasks, including the prediction of AIR-antigen binding affinity, the prediction of AIR-antigen binding reactivity, and the classification of the immune repertoire. On five representative datasets, DeepAIR shows outstanding prediction performance in terms of AUC (area under the ROC curve) in predicting the binding reactivity to various antigens, as well as the classification of immune repertoire for nasopharyngeal carcinoma (NPC) and inflammatory bowel disease (IBD). DeepAIR is freely available for academic purposes at https://github.com/TencentAILabHealthcare/DeepAIR. We anticipate that DeepAIR can serve as a useful tool for characterizing and profiling antigen binding AIRs, thereby informing the design of personalized immunotherapy. HighlightsO_LIIntegrating predicted AIR structures using AlphaFold2 significantly improves the prediction accuracy of the binding reactivity between AIRs and antigens. C_LIO_LIDeepAIR is featured by a novel deep learning architecture that leverages both the gating-based attention mechanism and tensor fusion mechanism to effectively extract and integrate informative features from three feature encoders, including a trainable embedding-layer-based gene encoder, a transformer-based sequence encoder, and a pre-trained AlphaFold2-based structure encoder. C_LIO_LIDeepAIR is implemented as a biologically interpretable deep learning framework that highlights the key residues in both and {beta} chains that are critical for predicting the AIR-antigen binding. C_LI

immunology↗
bioRxiv2022

A global view of aging and Alzheimer's pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

Conventional single-cell genomics approaches are limited by throughput and thus may have failed to capture aspects of the molecular signatures and dynamics of rare cell types associated with aging and diseases. Here, we developed EasySci, an extensively improved single-cell combinatorial indexing strategy, for investigating the age-dependent dynamics of transcription and chromatin accessibility across diverse brain cell types. We profiled [~]1.5 million single-cell transcriptomes and [~]400,000 single-cell chromatin accessibility profiles across mouse brains spanning different ages, genotypes, and both sexes. With a novel computational framework designed for characterizing cellular subtypes based on the expression of both genes and exons, we identified > 300 cell subtypes and deciphered their underlying molecular programs and spatial locations especially for rare cell types (e.g., pinealocytes, tanycytes). Leveraging these data, we generated a global readout of age-dependent changes at cell subtype resolution, providing insights into cell types that expand (e.g., rare astrocytes and vascular leptomeningeal cells in the olfactory bulb, reactive microglia, and oligodendrocytes) or are depleted (e.g., neuronal progenitors, neuroblasts, committed oligodendrocyte precursors) as age progresses. Furthermore, we explored cell-type-specific responses to genetic perturbations associated with Alzheimers disease (AD) and identified rare cell types depleted (e.g., mt-Cytb+, mt-Rnr2+ choroid plexus epithelial cells) or enriched (e.g., Col25a1+, Ndrg1+ interbrain and midbrain neurons) in both AD models. Key findings are consistent between males and females, validated across the transcriptome, chromatin accessibility, and spatial analyses. Finally, we profiled a total of 118,240 single-nuclei transcriptomes from twenty-four post-mortem human brain samples derived from control and AD patients, revealing highly cell-type-specific and region-specific gene expression changes associated with AD pathogenesis. Critical AD-associated gene signatures were validated in both human and mice. In summary, these data comprise a rich resource for exploring cell-type-specific dynamics and the underlying molecular mechanisms in normal and pathological mammalian aging.

genomics↗
bioRxiv2022

Polygenic scoring accuracy varies across the genetic ancestry continuum in all human populations

Polygenic scores (PGS) have limited portability across different groupings of individuals (e.g., by genetic ancestries and/or social determinants of health), preventing their equitable use. PGS portability has typically been assessed using a single aggregate population-level statistic (e.g., R2), ignoring inter-individual variation within the population. Here we evaluate PGS accuracy at individual-level resolution, independent of its annotated genetic ancestries. We show that PGS accuracy varies between individuals across the genetic ancestry continuum in all ancestries, even within traditionally "homogeneous" genetic ancestry clusters. Using a large and diverse Los Angeles biobank (ATLAS, N= 36,778) along with the UK Biobank (UKBB, N= 487,409), we show that PGS accuracy decreases along a continuum of genetic ancestries in all considered populations and the trend is well-captured by a continuous measure of genetic distance (GD) from the PGS training data; Pearson correlation of -0.95 between GD and PGS accuracy averaged across 84 traits. When applying PGS models trained in UKBB "white British" individuals to European-ancestry individuals of ATLAS, individuals in the highest GD decile have 14% lower accuracy relative to the lowest decile; notably the lowest GD decile of Hispanic/Latino American ancestry individuals showed similar PGS performance as the highest GD decile of European ancestry ATLAS individuals. GD is significantly correlated with PGS estimates themselves for 82 out of 84 traits, further emphasizing the importance of incorporating the continuum of genetic ancestry in PGS interpretation. Our results highlight the need for moving away from discrete genetic ancestry clusters towards the continuum of genetic ancestries when considering PGS and their applications.

genetics↗
bioRxiv2022

TRAF6 modulates PD-L1 expression through YAP1-TFCP2 signaling in melanoma

BackgroundImmunotherapy represented by the programmed death-1 (PD-1)/ligand 1 (PD-L1) monoclonal antibodies has led tumor treatment into a new era. However, the low overall response rate and high incidence of drug resistance largely damage the clinical benefits of existing immune checkpoint therapies. Recent studies correlate the response to PD-1/PD-L1 blockade with PD-L1 expression levels in tumor cells. Hence, identifying molecular targets and pathways controlling PD-L1 protein expression and stability in tumor cells is a major priority. MethodsIn this study, we first performed a Stress and Proteostasis CRISPR interference library-based screening to identify PD-L1 positive modulators. We then used in vitro and in vivo assays to investigate the biological function and mechanism of TRAF6 and its downstream YAP1/TFCP2 signaling in malignant melanoma. ResultsHere, we identified TRAF6 as a critical regulator of PD-L1 in melanoma cells. Suppression of TRAF6 expression down-regulates PD-L1 expression on the membrane surface of melanoma cells. We also found that PD-L1 protein abundance is regulated by YAP1/TFCP2 transcriptional complex. TRAF6 stabilizes YAP1 by K63 poly-ubiquitination modification, subsequently promoting the formation of YAP1/TFCP2 and PD-L1 transcription. Furthermore, inhibition of TRAF6 by Bortezomib enhanced cytolytic activity of CD8+ T cells by reduction of endogenous PD-L1. Notably, Bortezomib enhances anti-tumor immunity to an extent that is comparable to anti-PD-1 mAb therapies with no obvious toxicity. ConclusionsThese findings uncover a novel molecular mechanism for regulating PD-L1 protein abundance by a E3 ligase in cancer cells and reveal the potential of using TRAF6 inhibitors to stimulate internal anti-tumor immunological effect for TRAF6-PD-L1 overexpressing cancers.

cancer biology↗
bioRxiv2022

Multi-omics biomarkers aid prostate cancer prognostication

Effective biomarkers and diagnostic tools are urgently needed in clinical settings for improved management of prostate cancer patients, especially to reduce over-treatment of indolent tumors and for early identification of aggressive disease. Gene expression signatures are currently the "gold standard" to provide guide clinical decision, however their clinical utility and interpretability is questionable. Multi-modal molecular profiling provides an holistic approach to systematically unravel the biological complexity underlying cancer pathogenesis, hence biomarkers developed using such an integrated approach hold the potential to more accurately capture cancer-driving alterations than signatures based on a single omics modality. Currently, however, robust and reproducible multi-omics biomarkers are still lacking for prostate cancer. In this study, we analyzed transcriptomics and metabolomics profiles jointly in a prostate cancer cohort and identified two prognostic signatures with high statistical powers (signature 1: EGLN3, succinate, trans-4-hydroxyprolin; and signature 2: IL6, SLC22A2, histamine). Our approach leveraged a priori biological knowledge of the cellular metabolism and gene circuitry, enabling the identification of dysregulated network modules. Functional bioinformatics analyses suggest that these signatures can capture relevant molecular alterations in prostate cancer tissues, including dysregulations of cellular signaling, cell cycle progression, and immune system modulation, stratifying patients in distinct risk groups. Next, we trained two gene expression signatures as a proxy for the multi-omics ones, extending our investigation to publicly available data, further confirming their prognostic values in independent patient cohorts. In summary, the analysis of multi-modal molecular grounded in cellular network biology represents a promising approach for the development of robust prognostic biomarkers of detecting and discriminating high grade disease.

systems biology↗
bioRxiv2022

La revolution de l'ADN: biocompatible and biosafe DNA data storage

DNA data storage is an emerging technology that has the potential to replace bulky, fragile and energy-intensive current digital data storage media. Here, we report a storage strategy called DNA Drive, that organizes data on long double stranded replicative DNA molecules. The DNA Drive has unlimited storage capacity, and its encoding scheme ensures the biosafety of the process by limiting the potential of the DNA sequence to code for mRNA and proteins. Using our approach, we encoded two historical texts from the French Revolution, the Declaration of the Rights of Man and of the Citizen of 1789 and the Declaration of the Rights of Woman and of the Female Citizen published in 1791. In contrast to previous DNA storage strategies, the biocompatibility of the DNA Drive enables biological manipulation of the data including low cost copy. One-Sentence SummaryThe DNA Drive is a biosafe and biocompatible DNA data storage strategy with unlimited storage capacity.

synthetic biology↗
bioRxiv2022

Extraction and selection of high-molecular-weight DNA for long-read sequencing from Chlamydomonas reinhardtii

Recent advances in long-read sequencing technologies have enabled the complete assembly of eukaryotic genomes from telomere to telomere by allowing repeated regions to be fully sequenced and assembled, thus filling the gaps left by previous short-read sequencing methods. Furthermore, long-read sequencing can also help characterizing structural variants, with applications in the fields of genome evolution or cancer genomics. For many organisms, the main bottleneck to sequence long reads remains the lack of robust methods to obtain high-molecular-weight (HMW) DNA. For this purpose, we developed an optimized protocol to extract DNA suitable for long-read sequencing from the unicellular green alga Chlamydomonas reinhardtii, based on CTAB/phenol extraction followed by a size selection step for long DNA molecules. We provide validation results for the extraction protocol, as well as statistics obtained with Oxford Nanopore Technologies sequencing.

genomics↗
bioRxiv2022

Transformer Enables Reference Free And Unsupervised Analysis of Spatial Transcriptomics

The development of spatial transcriptomics technologies makes it possible to study tissue heterogeneity at the scale of spatial expressed microenvironment. However, most of the previous methods collapse the spatial patterns in the low spatial resolution. Existing reference based deconvolution methods integrate single-cell reference and spatial transcriptomics data to predict the proportion of cell-types, but the availability of suitable single-cell reference is often limited. In this paper, we propose a novel Transformer based model (TransfromerST) to integrate the spatial gene expression measurements and their spatial patterns in the histology image (if available) without single cell reference. TransfromerST enables the learning of the locally realistic and globally consistent constituents at nearly single cell resolution. TransfromerST firstly uses a transformer based variational autoencoder to explore the latent representation of gene expression, which is further embedded with the spatial relationship learned from adaptive graph Transformer model. The super-resolved cross-scale graph network improves the model-fit to enhanced structure-functional interactions. The public and in-house experimental results with multimodal spatial transcriptomics data demonstrate TransfromerST could highlight the tissue structures at nearly single cell resolution and detect the spatial variable genes and meta gene for each spatial domain. In summary, TransfromerST provides an effective and efficient alternative for spatial transcriptomics tissue clustering, super-resolution and gene expression prediction from histology image.

bioinformatics↗
bioRxiv2022

A microglia-CD4+ T cell partnership generates protective anti-tumor immunity to glioblastoma

The limited efficacy of immunotherapies against glioblastoma illustrates the urgent need to better understand the interactions between the central nervous system and the immune system. Here, we showed that a protective response to CTLA-4 therapy depended on a mutualistic relationship between microglia and CD4+ T cells. Suppression of gliomas by CD4+ T cells did not require tumor-intrinsic MHC-II expression, but rather was dependent on the selective expression of MHC-II and antigen presentation by local microglia that in turn, sustained CD4+ T cell tumoricidal effector functions. CD4+ T cell secretion of IFN{gamma} made the glioma cells vulnerable to enhanced tumor surveillance and phagocytosis by microglia via the AXL/MER tyrosine kinase receptors that were necessary for tumor suppression. This work illustrates a novel partnership between CD4+ T cells and microglia that unleashes the tumoricidal properties of microglia that can be harnessed to improve immunotherapies for glioblastoma.

immunology↗
bioRxiv2022

Apolipoprotein A1 and high-density lipoprotein limit low-density lipoprotein transcytosis by binding scavenger receptor B1

Atherosclerosis results from the deposition and oxidation of low-density lipoprotein (LDL) and immune cell infiltration in the sub-arterial space leading to arterial occlusion. Numerous studies have shown that transcytosis transports circulating LDL across endothelial cells lining the blood vessels. LDL transcytosis is initiated by binding to either Scavenger Receptor B1 (SR-B1) or Activin A receptor-like kinase 1 (ALK1) on the apical side of endothelial cells leading to its transit and release on the basolateral side. Individuals with elevated levels of circulating high-density lipoprotein (HDL) are partly protected from atherosclerosis due to its ability to remove excess cholesterol and act as an antioxidant. Apolipoprotein A1 (APOA1), an HDL constituent, can bind to SR-B1, raising the possibility that APOA1/HDL may also compete with LDL for SR-B1 binding and thereby limit LDL deposition in the sub-arterial space. To examine this possibility, we used in vitro approaches to quantify the internalization and transcytosis of fluorescent LDL in coronary endothelial cells. Using microscale thermophoresis and affinity capture, we find that SR-B1 and APOA1 directly interact, and that binding is enhanced when using the cardioprotective variant of APOA1 termed Milano (APOA1-Milano). In a murine model, transiently increasing the levels of HDL reduced the acute deposition of fluorescently labeled LDL in the atheroprone inner curvature of the aorta. Reduced LDL deposition was also observed when increasing circulating wild-type APOA1 or the APOA1-Milano variant, with a more robust inhibition from the APOA1-Milano. The results suggest that HDL may limit SR-B1-mediated LDL transcytosis and deposition, adding to the mechanisms by which it can act as an atheroprotective particle.

biochemistry↗
bioRxiv2022

InterClone: Store, Search and Cluster Adaptive Immune Receptor Repertoires

B and T cell receptor repertoire data has the potential to fundamentally change the way we diagnose and treat a wide range of diseases. However, there are few resources for storing or analyzing repertoire data. InterClone provides tools for storing, searching, and clustering repertoire datasets. Efficiency is achieved by encoding the complementarity-determining regions of sequences as mmseqs2 databases. Single chain search or cluster results can be merged into paired (alpha-beta or heavy-light) results for analysis of single-cell sequencing data. We illustrate the use of InterClone with two recently reported examples: 1) searching for SARS-CoV-2 infection-enhancing antibodies in bulk COVID-19 and healthy donor repertoires; 2) identification of SARS-CoV-2 specific TCRs by clustering paired and bulk sequences from COVID-19, BNT162b2 vaccinated and healthy unvaccinated donors. The core functions of InterClone have been implemented as a web server and integrated database (https://sysimm.org/interclone). All source code is available upon request.

bioinformatics↗
bioRxiv2022

Propagation dynamics of electrotactic motility in large epithelial cell sheets

Directional migration initiated at the wound edge leads epithelial sheets to migrate in wound healing. How such coherent migration is achieved is not well understood. Here we used electric fields to induce robust migration of sheets of human keratinocytes and developed an in silico model to characterize initiation and propagation of epithelial collective migration. Electric fields initiate increase in migrations directionality and speed at the leading edge. The increases propagate across the epithelial sheets, resulting in directional migration of cell sheets as coherent units. Both the experimental and in silico models demonstrated vector-like integration of the electric and default directional cues at the free edge in space and time. The resultant collective migration is remarkably consistent in experiments and modeling, both qualitatively and quantitatively. The keratinocyte model thus faithfully reflects key features of epithelial migration as a coherent tissue in vivo, e.g. that leading cells lead, and that epithelium maintains cell- cell junction.

cell biology↗
bioRxiv2022

Testis-specific H2BFWT disrupts nucleosome integrity through reductions of DNA-histone interactions

During spermatogenesis, multiple testis-specific histone variants are involved in the dynamic chromatin transitions. H2BFWT is a primate testis-specific H2B variant with hitherto unclear functions, and SNPs of H2BFWT are closely associated with male non-obstructive infertility. Here, we found that H2BFWT is preferentially localized in the sub-telomeric regions and the promoters of genes highly expressed in testis from differentiated spermatogonia to early spermatocytes. Cryo-EM structural analysis shows that H2BFWT nucleosomes are defined by weakened interactions between H2A-H2BFWT dimer and H4, and between histone octamer and DNA. Furthermore, one of its SNPs, H2BFWTH100R further destabilizes nucleosomes and increases the nucleosome unwrapping rate by interfering with the interaction with H4K91. Our results suggest that H2BFWT may be necessary for the regulation of spermatogenesis-related gene expression by decreasing transcriptional barriers, and that H2BFWTH100R overdrives its nucleosome-destabilizing effects which causes infertility.

biochemistry↗