Biology subjects

Yang, Q.

Publications and source records attributed to Yang, Q..

At least 253 records · Page 14Linked to original sources

bioRxiv2022

A comparative atlas of single-cell chromatin accessibility in the human brain

The human brain contains an extraordinarily diverse set of neuronal and glial cell types. Recent advances in single cell transcriptomics have begun to delineate the cellular heterogeneity in different brain regions, but the transcriptional regulatory programs responsible for the identity and function of each brain cell type remain to be defined. Here, we carried out single nucleus ATAC-seq analysis to probe the open chromatin landscape from over 1.1 million cells in 42 brain regions of three neurotypical adult donors. Integrative analysis of the resulting data identified 107 distinct cell types and revealed the cell-type-specific usage of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly 1/3 of them displayed sequence conservation as well as chromatin accessibility in the mouse brain. On the other hand, nearly 40% cCREs were human specific, with chromatin accessibility associated with species-restricted gene expression. Interestingly, these human specific cCREs were enriched for distinct families of retrotransposable elements, which displayed cell-type-specific chromatin accessibility. We uncovered strong associations between specific brain cell types and neuropsychiatric disorders. We futher developed deep learning models to predict regulatory function of non-coding disease risk variants.

neuroscience↗

bioRxiv2022

Oral Feeding of Nanoplastics reduces Brain function of Mice by Inducing Intestinal IL-1β-producing Macrophages

Background and AimsNanoplastics (NPs) as contaminants in food and water have drawn an increasing public attention. However, little is known about how NPs shape the gut immune landscape after entering the body. The objective of the study was to explore indirect effects caused by the interaction of NPs with the mammalian gut and whole immune system after entering the body. MethodsIn this study, we fabricated NPs ([~]500 nm) and microplastics (MPs) ([~]2 m) and aimed to evaluate their in vivo effects by feeding them in mice. The mechanism was then investigated by various technology including single-cell RNA sequencing of gut and brain tissue. ResultsThe results suggested that NPs showed a better ability to induce gut macrophage activation than did MPs. In addition, NPs triggered gut interleukin 1 beta (IL-1{beta})-producing macrophage reprogramming via inducing lysosomal damage after phagocytosis. More importantly, IL-1{beta} released from the intestine could affect brain immunity, leading to microglial activation and Th17 differentiation, all of which correlated with a decline in cognitive and short-term memory in NPs-fed mice ConclusionsThus, this study provides new insight into the mechanism of action of the gut-brain axis and delineates the way NPs reduce brain function, highlights the importance to fix the plastic pollution problem worldwide.

immunology↗

bioRxiv2022

Homotopic local-global parcellation of the human cerebral cortex from resting-state functional connectivity

Resting-state fMRI is commonly used to derive brain parcellations, which are widely used for dimensionality reduction and interpreting human neuroscience studies. We previously developed a model that integrates local and global approaches for estimating areal-level cortical parcellations. The resulting local-global parcellations are often referred to as the Schaefer parcellations. However, the lack of homotopic correspondence between left and right Schaefer parcels has limited their use for brain lateralization studies. Here, we extend our previous model to derive homotopic areal-level parcellations. Using resting-fMRI and task-fMRI across diverse scanners, acquisition protocols, preprocessing and demographics, we show that the resulting homotopic parcellations are as homogeneous as the Schaefer parcellations, while being more homogeneous than five publicly available parcellations. Furthermore, weaker correlations between homotopic parcels are associated with greater lateralization in resting network organization, as well as lateralization in language and motor task activation. Finally, the homotopic parcellations agree with the boundaries of a number of cortical areas estimated from histology and visuotopic fMRI, while capturing sub-areal (e.g., somatotopic and visuotopic) features. Overall, these results suggest that the homotopic local- global parcellations represent neurobiologically meaningful subdivisions of the human cerebral cortex and will be a useful resource for future studies. Multi-resolution parcellations estimated from 1479 participants are publicly available (GITHUB_LINK).

neuroscience↗

bioRxiv2022

HSPB1 facilitates chemoresistance through inhibiting ferroptotic cancer cell death and regulating NF-κB signaling pathway in breast cancer

Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients. However, the underlying mechanism remains elusive. Here, we identified novel functional roles of heat shock protein beta-1 (HSPB1), regulating the chemoresistance and ferroptotic cell death in breast cancer. Based on TCGA and GEO databases, HSPB1 expression was upregulated in breast cancer tissues and associated with poor prognosis of breast cancer patients, which was considered as an independent prognostic factor for breast cancer. Functional assays revealed that HSPB1 could promote cancer growth and metastasis in vitro and in vivo. Furthermore, HSPB1 facilitated doxorubicin resistance through protecting breast cancer cells from drug-induced ferroptosis. Mechanistically, HSPB1 could bind with Ik{beta}- and promote its ubiquitination-mediated degradation, leading to increased nuclear translocation and activation of NF-{kappa}B signaling. In addition, HSPB1 overexpression led to enhanced secretion of IL6, which further facilitated breast cancer progression. These findings revealed that HSPB1 upregulation might be a key driver to progression and chemoresistance through regulating ferroptosis in breast cancer, while targeting HSPB1 could be an effective strategy against breast cancer.

cancer biology↗

bioRxiv2022

Gap-free nuclear and mitochondrial genomes of Ustilaginoidea virens strain JS60-2, a fungal pathogen causing rice false smut

Rice false smut (RFS), caused by Ustilaginoidea virens, has become a major disease in recent years, and mycotoxins produced by U. virens often threaten food safety. To study fungal pathogenesis and identify potential targets for developing new fungicides, gap-free nuclear and complete mitochondrial genomes of U. virens JS60-2 were sequenced and assembled. Using the second and third generation sequencing data, we assembled a 38.02-Mb genome that consists of seven contigs with the contig N50 being 6.32-Mb. In total, 8,486 protein-coding genes were annotated in the genome, including 21 secondary metabolism gene clusters. We also assembled the complete mitochondrial genome, which is 102,498 bp, with 28% GC content. The JS60-2 genomes assembled in this study will facilitate research on U. virens and contribute to RFS control.

genomics↗

bioRxiv2022

A genome wide association study identifies a new variant associated with word reading fluency in Chinese children

Reading disability exhibited defects in different cognitive domains, including word reading fluency, word reading accuracy, phonological awareness, rapid automatized naming, and morphological awareness. To identify the genetic basis of Chinese reading disability, we conducted a genome wide association study (GWAS) of the cognitive traits related to Chinese reading disability in 2284 unrelated Chinese children. Among the traits analyzed in the present GWAS, we detected one genome wide significant association (p<5x10-8) on reading fluency for one SNP on 4p16.2, within EVC genes (rs6446395, p=7.55x10-10). Rs6446395 also showed significant association with word reading accuracy (p=3.39x10-4), phonological awareness (p=7.12x10-3), and rapid automatized naming (p=4.71x10-3), implying multiple effects of this variant. Gene-based analyses identified a gene to be associated with reading fluency at the genome-wide level. The eQTL data showed that rs6446395 affected EVC expression in the cerebellum. Our study discovered a new candidate susceptibility variant for reading ability and provide new insights into the genetics of development dyslexia in Chinese Children.

genetics↗

bioRxiv2022

A genome-wide association study identified new variants associated with mathematical abilities in Chinese children

Mathematical ability is moderately heritable, and it is a complex trait which can be evaluated in several different categories. A few genetic studies have been published on general mathematical ability. However, no genetic study focused on specific mathematical ability categories. In this study, we separately performed genome-wide association studies (GWASs) on 11 mathematical ability categories in 1 146 students from Chinese elementary schools. We identified 7 genome-wide significant single nucleotide polymorphisms (SNPs) with strong linkage disequilibrium (LD) among each other (all r2>0.8) associated with mathematical reasoning ability (top SNP: rs34034296, p=2.01x10-8, nearest gene: CUB and Sushi multiple domains 3, CSMD3). We replicated one SNP (rs133885) from 585 SNPs previously reported to be associated with general mathematical ability associated with division ability in our data (p=1.053x10-5). In the gene- and gene-set enrichment analysis by MAGMA, we found three significant enrichments of associations with three mathematical ability categories for three genes. We also observed four significant enrichments of associations with four mathematical ability categories for three gene sets. Our results suggest new candidate genetic loci for the genetics of mathematical ability.

genetics↗

bioRxiv2022

Clustering of CaV1.3 L-type calcium channels by Shank3

Clustering of neuronal L-type voltage-gated Ca2+ channels (LTCC) in the plasma membrane is increasingly implicated in creating highly localized Ca2+ signaling nanodomains. For example, LTCC activation can increase phosphorylation of the nuclear CREB transcription factor by increasing Ca2+ concentrations within a nanodomain close to the channel, without requiring bulk Ca2+ increases in the cytosol or nucleus. However, the molecular basis for LTCC clustering is poorly understood. The postsynaptic scaffolding protein Shank3 specifically associates with one of the major neuronal LTCCs, the CaV1.3 calcium channel, and is required for optimal LTCC-dependent excitation-transcription coupling. Here, we co-expressed CaV1.3 1 subunits with two distinct epitope-tags with or without Shank3 in HEK cells. Co-immunoprecipitation studies using the cell lysates revealed that Shank3 can assemble multiple CaV1.3 1 subunits in a complex under basal conditions. Moreover, CaV1.3 LTCC complex formation was facilitated by CaV{beta} subunits ({beta}3 and {beta}2a), which also interact with Shank3. Shank3 interactions with CaV1.3 LTCCs and multimeric CaV1.3 LTCC complex assembly were disrupted following addition of Ca2+ and calmodulin (Ca2+/CaM) to cell lysates, perhaps simulating conditions within an activated CaV1.3 LTCC nanodomain. In intact HEK293T cells, co-expression of Shank3 enhanced the intensity of membrane-localized CaV1.3 LTCC clusters under basal conditions, but not after Ca2+channel activation. Live cell imaging studies also revealed that Ca2+ influx through LTCCs disassociated Shank3 from CaV1.3 LTCCs clusters and reduced the CaV1.3 cluster intensity. Deletion of the PDZ domain from Shank3 prevented both binding to CaV1.3 and the changes in multimeric CaV1.3 LTCC complex assembly in vitro and in HEK293 cells. Finally, we found that shRNA knock-down of Shank3 expression in cultured rat primary hippocampal neurons reduced the intensity of surface-localized CaV1.3 LTCC clusters in dendrites. Taken together, our findings reveal a novel molecular mechanism contributing to neuronal LTCC clustering under basal conditions.

neuroscience↗

bioRxiv2022

Biophysical and Structural Characterization of a Viral Genome Packaging Motor

Like many dsDNA viruses, bacteriophage {lambda} replicates its genome as a concatemer consisting of multiple copies of covalently linked dsDNA genomes. To encapsidate a single genome within a nascent procapsid, {lambda} must: 1) find its own dsDNA amongst the multitude of host nucleic acids; 2) identify the genomic start site; 3) cut the DNA; 4) bring the excised DNA to a procapsid; 5) translocate DNA into the capsid; 6) cut DNA again at a packaging termination site, 7) disengage from the newly filled capsid; and 8) bring the remainder of the genomic concatemer to fill another empty procapsid. These disparate genome processing tasks are carried out by a single virus-encoded enzyme complex called terminase. While it has been shown that {lambda} terminase initially forms a tetrameric complex to cut DNA, it is not clear whether the same configuration translocates DNA. Here, we describe biophysical and initial structural characterization of a {lambda} terminase translocation complex. Analytical ultracentrifugation (AUC) and small angle X-ray scattering (SAXS) indicate that between 4 and 5 protomeric subunits assemble a cone-shaped terminase complex with a maximum dimension of [~]230 and radius of gyration of [~]72 [A]. Two-dimensional classification of cryoEM images of {lambda} terminase are consistent with these dimensions and show that particles assume a preferred orientation in ice. The orientations appear to be end-on, as terminase rings resemble a starfish with approximate pentameric symmetry. While [~]5-fold symmetry is apparent, one of the five "arms" appears partially displaced with weaker more diffuse density in some classes, suggesting flexibility and/or partial occupancy. Charge detection mass spectrometry (CDMS) is consistent with a pentameric complex, with evidence that one motor subunit is weakly bound. Kinetic analysis indicates that the complex hydrolyzes ATP at a rate comparable to the rates of other phage packaging motors. Together with previously published data, these results suggest that {lambda} terminase assembles conformationally and stoichiometrically distinct complexes to carry out different genome processing tasks. We propose a "symmetry resolution" pathway to explain how terminase transitions between these structurally and functionally distinct states.

biophysics↗

bioRxiv2022

Regulation of the Phage Lambda Viral Packaging Motor's Grip and DNA End-clamp Mechanism

Many dsDNA viruses utilize ATP-powered "terminase" motors to package their genomes into procapsid shells. Here we use a single-molecule DNA grip/slip assay with rapid solution exchange to probe effects of nucleotide binding/dissociation in phage lambda motors containing both the large (TerL) and small (TerS) terminase subunits. Both subunits are required for packaging in vivo, but for some viruses (e.g., phages T4, HK97) packaging can be measured in vitro with only the catalytic TerL subunit. TerS facilitates initiation of packaging in vivo, but it has remained unclear if it plays any role during translocation. Surprisingly we measure frequent DNA gripping and high motor-DNA friction even in the absence of nucleotide. Such behavior was not observed in phage T4 motors containing only TerL, for which motor-DNA interactions were measured to be much weaker and significant gripping and friction was only observed with nucleotide present. For the lambda TerL/TerS holoenzyme, binding of nucleotide (ATP analogs or ADP) further increases gripping and friction, indicating there are both nucleotide independent and dependent interactions. Our findings suggest that TerS plays an important role in motor processivity, and that ATP-independent DNA gripping explains pausing observed during lambda packaging. We propose TerS acts as a "sliding clamp" to limit back slipping when TerL loses grip. Additionally, we show that the lambda packaging complex has a "DNA end clamp" mechanism that prevents the viral genome from completely exiting the capsid once packaging has initiated.

biophysics↗

bioRxiv2022

Designing a Minimal Artificial Glycolytic Pathway

The canonical glycolysis generates two molecules of acetyl-coenzyme A (acetyl-CoA) from one glucose through eleven cascade biochemical reactions. Here, we designed and constructed a Minimal Artificial Glycolytic (MAG) pathway consisting of only three types of biochemical reactions, with phosphoketolase as the core, combined with phosphatase and isomerase as auxiliary enzymes. It could theoretically achieve a 100% carbon yield to acetyl-CoA from any monosaccharide by integrating one-carbon condensation reaction. We tested the MAG pathway in vitro and in vivo, demonstrating the catabolism of typical C1-C6 carbohydrates to acetyl-CoA with yields from 82% to 95%. This novel glycolytic pathway provides a promising route for biomanufacturing with stoichiometric productivity from multiple carbon sources in the future.

synthetic biology↗

bioRxiv2022

Exposure to BA.4/BA.5 Spike glycoprotein drives pan-Omicron neutralization in vaccine-experienced humans and mice

The SARS-CoV-2 Omicron variant and its sublineages show pronounced viral escape from neutralizing antibodies elicited by vaccination or prior SARS-CoV-2 variant infection owing to over 30 amino acid alterations within the spike (S) glycoprotein. We and others have recently reported that breakthrough infection of vaccinated individuals with Omicron sublineages BA.1 and BA.2 are associated with distinct patterns of cross-neutralizing activity against SARS-CoV-2 variants of concern (VOCs). BA.2 breakthrough infection mediated overall stronger cross-neutralization of BA.2 and its descendants (BA.2.12.1, BA.4, and BA.5) compared to BA.1 breakthrough infection. Here we characterized the effect of Omicron BA.4/BA.5 S glycoprotein exposure on the magnitude and breadth of the neutralizing antibody response upon breakthrough infection in vaccinated individuals and in mice upon booster vaccination. We show that immune sera from triple mRNA-vaccinated individuals with subsequent Omicron BA.4/BA.5 breakthrough infection display broad and robust neutralizing activity against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/BA.5. Administration of a prototypic BA.4/BA.5-adapted mRNA booster vaccine to mice following SARS-CoV-2 wild-type strain-based primary immunization is associated with similarly broad neutralizing activity. Immunization of naive mice with a bivalent mRNA vaccine (wild-type + Omicron BA.4/BA.5) induces strong and broad neutralizing activity against Omicron VOCs and previous variants. These findings suggest that when administered as boosters, mono- and bivalent Omicron BA.4/BA.5-adapted vaccines may enhance neutralization breadth, and in a bivalent format may also have the potential to confer protection to individuals with no pre-existing immunity against SARS-CoV-2.

immunology↗

bioRxiv2022

Nucleobase adduct-containing metabolites are MR1 ligands that stimulate self-reactive MR1T cells

MR1T lymphocytes are a recently identified population of T cells that recognize unknown self-antigens presented by the non-polymorphic MHC-I-related molecule, MR1. MR1T cells can kill tumor cells and modulate the functions of other immune cells with promising therapeutic applications. By integrating genetic, pharmacological and biochemical approaches we identified carbonyl stress and alterations of nucleobase metabolism in tumor target cells that promote recognition by MR1 T cells. We dissected these pathways and found that nucleobase adduct-containing metabolites are self-antigens stimulating MR1T cells. Several nucleobase adducts are presented by MR1 molecules and stimulate individual MR1T cells. Our data suggest that MR1T cells are surveyor of cellular metabolic alterations occurring in conditions of metabolic stress, such as cancer, and lay the groundwork for the development of novel HLA-unrestricted T cell-based therapies.

immunology↗

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

The redlegged earth mite draft genome provides new insights into pesticide resistance evolution and demography in its invasive Australian range

Genomic data provide valuable insights into pest management issues such as resistance evolution, historical patterns of pest invasions and ongoing population dynamics. We assembled the first reference genome for the redlegged earth mite, Halotydeus destructor (Tucker, 1925), to investigate adaptation to pesticide pressures and demography in its invasive Australian range using whole-genome pool-seq data from regionally distributed populations. Our reference genome comprises 132 autosomal contigs, with a total length of 48.90 Mb. We observed a large complex of ace genes, which has presumably evolved from a long history of organophosphate selection in H. destructor and may contribute toward organophosphate resistance through copy number variation, target-site mutations, and structural variants. In the putative ancestral H. destructor ace gene, we identified three target-site mutations (G119S, A201S, and F331Y) segregating in organophosphate resistant populations. Additionally, we identified two new para sodium channel gene mutations (L925I and F1020Y) that may contribute to pyrethroid resistance. Regional structuring observed in population genomic analyses indicates that gene flow in H. destructor does not homogenise populations across large geographic distances. However, our demographic analyses were equivocal on the magnitude of gene flow; the short invasion history of H. destructor makes it difficult to distinguish scenarios of complete isolation vs. ongoing migration. Nonetheless, we identified clear signatures of reduced genetic diversity and smaller inferred effective population sizes in eastern vs. western populations, which is consistent with the stepping-stone invasion pathway of this pest in Australia. These new insights will inform development of diagnostic genetic markers of resistance, further investigation into the multifaceted organophosphate resistance mechanism, and predictive modelling of resistance evolution and spread.

genomics↗

bioRxiv2022

LC-MS/MS-PRM Quantification of IgG glycoforms using stable isotope labeled IgG1 Fc glycopeptide standard

Targeted quantification of proteins is a standard methodology with broad utility, but targeted quantification of glycoproteins has not reached its full potential. The lack of optimized workflows and isotopically labeled standards limits the acceptance of glycoproteomics quantification. In this paper, we introduce an efficient and streamlined chemoenzymatic synthesis of a library of isotopically labeled glycopeptides of IgG1 which we use for quantification in an energy optimized LC-MS/MS-PRM workflow. Incorporation of the stable isotope labeled N-acetylglucosamine enables an efficient monitoring of all major fragment ions of the glycopeptides generated under the soft collision induced dissociation (CID) conditions which reduces the CVs of the quantification to 0.7-2.8%. Our results document, for the first time, that the workflow using a combination of stable isotope labeled standards with intra-scan normalization enables quantification of the glycopeptides by an electron transfer dissociation (ETD) workflow as well as the CID workflow with the highest sensitivity compared to traditional workflows., This was exemplified by a rapid quantification (13-minute) of IgG1 Fc glycoforms from COVID-19 patients. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/501850v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@b5b18corg.highwire.dtl.DTLVardef@9b87b9org.highwire.dtl.DTLVardef@eba7ecorg.highwire.dtl.DTLVardef@15da596_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

Spatial mapping of human lung tissue reveals granuloma diversity and histopathological superstructure in tuberculosis

The histopathological hallmark of tuberculosis (TB) is the formation of immune cell enriched aggregates called granulomas, but the scope of granuloma heterogeneity in human TB is unknown. By spatially mapping individual immune cells across large regions of TB lung tissue, we report that in addition to necrotizing granulomas, the human TB lung contains abundant non-necrotizing leukocyte aggregates surrounding areas of necrotizing tissue. These cellular lesions were more diverse in composition than necrotizing lesions and could be stratified into four general classes based on cellular composition and spatial distribution of B cells and macrophages, indicating there are foci of distinct immune reactions adjacent to necrotizing granulomas. We further show that the specific cellular composition of non-necrotizing structures correlates with their proximity to necrotizing lesions. Together, our study shows that during tuberculosis diseased lung tissue develops a histopathological superstructure comprising at least four different types of non-necrotizing cellular aggregates organized as satellites of necrotizing granulomas.

immunology↗

bioRxiv2022

An Evidence-based Cognitive Model of Human Wayfinding under Uncertainty

Existing computational models lack adequate representation of the uncertainty experienced in human wayfinding tasks. They overly rely on optimized pathing algorithms, which reduces realism and limits insights on human responses to architectural designs. To address this, we developed an empirically grounded model that predicts human wayfinding uncertainty experience. Using data from 28 participants navigating an educational building with varying signage, we constructed the model (Study 1), and validated it with data from 11 other participants (Study 2). We found the wayfinding uncertainty correlated with the time elapsed since seeing the last helpful sign. The cognitive agent based on this model closely replicated human-reported uncertainty levels during wayfinding tasks under different signage conditions. Although the model more closely resembled human behavior compared to a shortest-route algorithm, additional environmental variables and heuristics are needed for better human outcome alignment. Our study showcases that evidence-based cognitive agent modeling can provide nuanced, human-like wayfinding behavior, enhancing the potential for effective computational design evaluation.

animal behavior and cognition↗