Biology subjects

Ye, Y.

Publications and source records attributed to Ye, Y..

At least 127 records · Page 7Linked to original sources

bioRxiv2022

Characterizing the landscape of viral expression in cancer by deep learning

About 15% of human cancer cases are attributed to viral infections. To date, virus expression in tumor tissues has been mostly studied by aligning tumor RNA sequencing reads to databases of known viruses. To allow identification of divergent viruses and rapid characterization of the tumor virome, we develop viRNAtrap, an alignment-free pipeline to identify viral reads and assemble viral contigs. We utilize viRNAtrap, which is based on a deep learning model trained to discriminate viral RNAseq reads, to explore viral expression in cancers and apply it to 14 cancer types from The Cancer Genome Atlas (TCGA). Using viRNAtrap, we uncover expression of unexpected and divergent viruses that have not previously been implicated in cancer and disclose human endogenous viruses whose expression is associated with poor overall survival. The viRNAtrap pipeline provides a way forward to study viral infections associated with different clinical conditions.

bioinformatics↗

bioRxiv2022

Early-Life Stress Impairs Perception and Neural Encoding of Rapid Signals in the Auditory Pathway

In children, early ear infections are a risk factor for later speech perception deficits. This is likely because auditory deprivation during a developmental critical period (CP) induces long-lasting deficits in perception and ACx encoding of temporally-varying sounds. CPs also create susceptibility to early-life stress (ELS) in neural regions involved with cognition and anxiety. As CP mechanisms are shared by sensory cortices and higher neural regions, ACx and temporal encoding may also be susceptible to ELS. To examine the effects of ELS on temporal processing, we developed a model of ELS in the Mongolian gerbil, a well-established model for auditory processing. ELS induction impaired the behavioral detection of short gaps in sound, which are critical for speech perception. This was accompanied by reduced neural responses to gaps in ACx, the auditory periphery, and auditory brainstem. These ELS effects presumably degrade the fidelity of sensory representations available to higher regions, and could contribute to ELS-induced problems with cognition.

neuroscience↗

bioRxiv2022

Ubiquitin-based pathway acts inside chloroplasts to regulate photosynthesis

Photosynthesis is the energetic basis for most life on Earth, and in plants it operates inside double-membrane-bound organelles called chloroplasts. The photosynthetic apparatus comprises numerous proteins encoded by the nuclear and organellar genomes. Maintenance of this apparatus requires the action of internal chloroplast proteases, but a role for the nucleocytosolic ubiquitin-proteasome system (UPS) was not expected owing to the barrier presented by the double-membrane envelope. Here, we show that photosynthesis proteins (including those encoded internally by chloroplast genes) are ubiquitinated, and processed via the CHLORAD pathway: they are degraded by the 26S proteasome following CDC48-dependent retrotranslocation to the cytosol. This demonstrates that the reach of the UPS extends to the interior of endosymbiotically-derived chloroplasts, where it acts to regulate one of the most fundamental processes of life. One Sentence SummaryThe ubiquitin-proteasome system targets proteins inside chloroplasts, including chloroplast-encoded photosynthesis subunits.

plant biology↗

bioRxiv2022

Route of mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells

Respiratory tract resident memory T cells (Trm), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory Trm. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron-based nanoparticles. Here we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influence influenza-specific cell-mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 Trm in lung and draining lymph node. Contralateral, compared to ipsilateral, intramuscular boosting broadened the distribution of LN Trm and T follicular helper cells, but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory, but augmented distribution to the respiratory mucosa. Of note, combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung Trm. Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung Trm that can be further enhanced by an additional intranasal immunization.

immunology↗

bioRxiv2022

Deciphering Hierarchical Chromatin Structures and Preference of Genomic Positions in Single Mouse Embryonic Stem Cells

The exploration of single-cell 3D genome maps reveals that chromatin domains are indeed physical structures presenting in single cells and domain boundaries vary from cell to cell. However, exhaustive analysis of regulatory factor binding or elements for preference of the formation of chromatin domains in single cells has not yet emerged. To this end, we first develop a hierarchical chromatin domain structure identification algorithm (named as HiCS) from individual single-cell Hi-C maps, with superior performance in both accuracy and efficiency. The results suggest that in addition to the known CTCF-cohesin complex, Polycomb, TrxG, pluripotent protein families and other multiple factors also contribute to shaping chromatin domain boundaries in single embryonic stem cells. Different cooperation patterns of regulatory factors decipher the preference of genomic position categories forming boundaries. And the most extensive six types of retrotransposons differentially distributed in these genomic position categories with preferential localization.

bioinformatics↗

bioRxiv2022

Trophoblast and blood vessel organoid cultures recapitulate the role of WNT2B in promoting intravillous vascularization in human intrauterine and ectopic pregnancy

Tubal ectopic pregnancy (TEP), a pregnancy complication caused by aberrant implantation in fallopian tubes, accounts for 9-13% pregnancy-related deaths. The lack of models for human TEP hampers the understanding of its pathological mechanisms. Here, we employed multiple models to investigate the crosstalk between human trophoblast development and intravillous vascularization. We found that the severity of TEP, the size of placental villi, and the depth of trophoblast invasion are correlated with the extent of intravillous vascularization. We identified a key pro-angiogenic factor secreted by trophoblasts, WNT2B, that promotes villous vasculogenesis, angiogenesis, and vascular network expansion. In an organoid coculture model consisting of trophoblast organoids and blood vessel organoids, knockdown of WNT2B in trophoblast organoids compromises their pro-angiogenic effect on the development of blood vessel organoids. These organoid-based models reveal an important role for WNT-mediated angiogenesis in pregnancies and could be employed to investigate the commutations between trophoblasts and endothelial/endothelial progenitor cells.

cell biology↗

bioRxiv2022

The structure of insulin granule core determines secretory capacity being reduced in type-2 diabetes

Exocytosis in excitable cells is essential for their physiological functions. Although the exocytotic machinery controlling cellular secretion has been well investigated, the function of the vesicular cargo, i.e. secretory granular content remains obscure. Here we combine dSTORM imaging and single-domain insulin antibody, to dissect the in situ structure of insulin granule cores (IGCs) at nano level. We demonstrate that the size and shape of the IGCs can be regulated by the juxta-granular molecules Nucleobindin-2 and Enolase-1, that further contribute to the stimulated insulin secretion. IGCs located at the plasma membrane are larger than those in the cytosol. The IGCs size is decreased by [~]20% after glucose stimulation due to the release of the peripheral part of IGCs through incomplete granule fusion. Importantly, the reduction of the IGCs size is also observed in non-stimulatory pancreatic {beta}-cells from diabetic db/db mice, Akita (Ins2+/-) mice and human Type-2 diabetic donors, in accordance with impaired secretion. These findings overall highlight the structure of exocytotic insulin cores as a novel modality amenable to targeting in the stimulated exocytosis in {beta}-cells with impaired insulin secretion.

physiology↗

bioRxiv2022

Chromosome-scale genome assembly of the diploid oat Avena longiglumis reveals the landscape of repetitive sequences, genes and chromosome evolution in grasses

BackgroundOat (Avena sativa, 2n=6x=42) is an important crop, and with its wild relatives including A. longiglumis (ALO, 2n=6x=14), has advantageous agronomic and nutritional traits. A de-novo chromosome-level ALO genome assembly was made to investigate diversity and structural genome variation between Avena species and other Poaceae in an evolutionary context, and develop genomic resources to identify the pangenome and economic traits within Pooideae. ResultsThe 3.85 gigabase ALO genome (seven pseudo-chromosomes), contained 40,845 protein-coding genes and 87% repetitive sequences (84.21% transposable elements). An LTR retrotransposon family was abundant at all chromosome centromeres, and genes were distributed without major terminal clusters. Comparisons of synteny with A. eriantha and A. strigosa showed evolutionary translocations of terminal segments including many genes. Comparison with rice (x=12) and the ancestral grass karyotype showed synteny and features of chromosome evolution including fusions, translocations and insertions of syntenic blocks across Pooideae species. With a genome size 10 times larger than rice, ALO showed relatively uniform expansion along the chromosome arms, with few gene-poor regions along arms, and no major duplications nor deletions. Linked gene networks were identified (mixed-linkage glucans and cellulose synthase genes), and CYP450 genes may be related to salt-tolerance. ConclusionsThe high-continuity genome assembly shows gene, chromosomal structural and copy number variation, providing a reference for the Avena pangenome, defining the full spectrum of diversity. Chromosomal rearrangements and genome expansion demonstrate features of evolution across the genus and grass BOP-clade, contributing to exploitation of gene and genome diversity through precision breeding.

genomics↗

bioRxiv2022

Staphylococcus aureus nt5 gene contributes to bacterial infection ability to form kidney abscess

Staphylococcus aureus (S. aureus) is a commonly conditional infection pathogen, in which several key virulence genes are responsible for bacterial infection ability. The S. aureus nt5 gene, encoding 5-nucleotidase, mediates bacterial nucleic acid pathway, yet it is nearly unknown of nt5 function for staphylococcal infection ability. Herein we have constructed S. aureus mutant with the gene nt5C166T silence (S. aureus {Delta}nt5) by a CRISPR RNA-guided base editing system to investigate bacterial infection ability in vitro and in vivo. As expected, several nt5-related genes are disturbed in S. aureus {Delta}nt5, in which gene transcription level of py is decreased compared with the wild-type S. aureus. Bacterial gene nt5 is downregulated and py/adk are upregulated when S. aureus is exposed to antibiotics daptomycin, which indicates nt5-mediated nucleic acid pathway is interfered upon with daptomycin treatment. Furthermore, the mutant {Delta}nt5 displays about a 40-fold reduction of bacterial loading in mouse kidney on a mouse sepsis model, and the infection ability of {Delta}nt5 is reduced than the wild-type bacteria. The gene nt5 contributes to S. aureus-infected abscess formation in mouse kidney, and the silence of nt5 gene promotes phagocytosis of S. aureus by mouse and human immunocytes. In general, our findings reveal nt5 silence impedes bacterial loading in kidney to form abscess but enhances S. aureus to be phagocytosed by host cell immune system in vitro and in vivo, which indicates that nt5 gene plays an important role in bacterial infection and immune evasion.

immunology↗

bioRxiv2022

Blocking Gi/o-coupled signaling eradicates cancer stem cells and sensitizes breast tumors to HER2-targeted therapies to inhibit tumor relapse

Cancer stem cells (CSCs) are a small subpopulation of cells within tumors that are resistant to anti-tumor therapies, making them a likely origin of tumor relapse after treatment. In many cancers including breast cancer, CSC function is regulated by G protein-coupled receptors (GPCRs), making GPCR signaling an attractive target for new therapies designed to eradicate CSCs. Yet, CSCs overexpress multiple GPCRs that are redundant in maintaining CSC function, so it is unclear how to target all the various GPCRs to prevent relapse. Here, in a model of HER2+ breast cancer (i.e., transgenic MMTV-Neu mice), we were able to block tumorsphere- and tumor-forming capability of CSCs by targeting GPCRs coupled to Gi/o proteins (Gi/o-GPCRs). Similarly, in HER2+ breast cancer cells, blocking signaling downstream of Gi/o-GPCRs in the PI3K/AKT and Src pathways also enhanced HER2-targeted elimination of CSCs. In a proof-of-concept study, when CSCs were selectively ablated (via a suicide gene construct), loss of CSCs from HER2+ breast cancer cell populations mimicked the effect of targeting Gi/o-GPCR signaling, suppressing their capacity for tumor initiation and progression and enhancing HER2-targeted therapy. Thus, targeting Gi/o-GPCR signaling in HER2+ breast cancer is a promising approach for eradicating CSCs, enhancing HER2+ targeted therapy and blocking tumor reemergence.

cancer biology↗

bioRxiv2022

Meta-analysis of Microbiome Association Networks Reveal Patterns of Dysbiosis in Diseased Microbiomes

The human gut microbiome is composed of a diverse and dynamic population of microbial species which play key roles in modulating host health and physiology. While individual microbial species have been found to be associated with certain disease states, increasing evidence suggests that higher-order microbial interactions may have an equal or greater contribution to host fitness. To better understand microbial community dynamics, we utilize complex networks to study interactions through a meta-analysis of microbial association networks between healthy and disease gut microbiomes. Taking advantage of the large number of metagenomes derived from healthy individuals and patients with various diseases, together with recent advances in network inference that can deal with sparse compositional data, we inferred microbial association networks based on co-occurrence of gut microbial species and made the networks publicly available as a resource (github repository named GutNet). Through our meta-analysis of inferred networks, we were able to identify network-associated features that help stratify between healthy and disease states such as the differentiation of various bacterial phyla and enrichment of Proteobacteria interactions in diseased networks. Additionally, our findings show that the contributions of taxa in microbial associations are disproportionate to their abundances and that rarer taxa of microbial species play an integral part in shaping dynamics of microbial community interactions. Overall, this meta-analysis revealed valuable insights into microbial community dynamics between healthy and disease phenotypes.

bioinformatics↗

bioRxiv2022

Robust expansion of phylogeny for fast-growing genome sequence data

Massive sequencing of SARS-CoV-2 genomes has led to a great demand for adding new samples to a reference phylogeny instead of building the tree from scratch. To address such challenge, we proposed an algorithm TIPars by integrating parsimony analysis with pre-computed ancestral sequences. Compared to four state-of-the-art methods on four benchmark datasets (SARS-CoV-2, Influenza virus, Newcastle disease virus and 16S rRNA genes), TIPars achieved the best performance in most tests. It took only 21 seconds to insert 100 SARS-CoV-2 genomes to a 100k-taxa reference tree using near 1.4 gigabytes of memory. Its efficient and accurate phylogenetic placements and incrementation for phylogenies with highly similar and divergent sequences suggest that it will be useful in a wide range of studies including pathogen molecular epidemiology, microbiome diversity and systematics.

bioinformatics↗

bioRxiv2021

A spatiotemporal steroidogenic regulatory network in human fetal adrenal glands and gonads

Human fetal adrenal glands produce substantial amounts of dehydroepiandrosterone (DHEA), which is one of the most important precursors of sex hormones. However, the underlying biological mechanism remains largely unknown. Herein, we sequenced human fetal adrenal glands and gonads from 7 to 14 GW via the 10x Genomics single-cell transcriptome techniques and reconstructed their location information by Spatial Transcriptome, conducted COOL-seq for the MC2R+ inner zone steroidogenic cells during the time window of sex differentiation (8-12GW). We found that relative to gonads, adrenal glands begin to synthesize steroids early. The coordination among steroidogenic cells and multiple nonsteroidogenic cells promotes adrenal cortex construction and steroid synthesis. Notably, during the time window of sex differentiation (8-12 GW), key enzyme gene expression shifts to accelerate DHEA synthesis in males and cortisol synthesis in females. Furthermore, high SST+ expressions in the adrenal gland and testis amplify androgen synthesis in males. Our research highlights the robustness of the action of fetal adrenal glands on gonads to modify the process of sexual differentiation.

systems biology↗

bioRxiv2021

Mutations in RBD of SARS-CoV-2 Omicron variant result stronger binding to human ACE2 protein

The COVID-19 pandemic caused by the SARS-CoV-2 virus has led to more than 270 million infections and 5.3 million of deaths worldwide. Several major variants of SARS-CoV-2 have emerged and posed challenges in controlling the pandemic. The recently occurred Omicron variant raised serious concerns about reducing the efficacy of vaccines and neutralization antibodies due to its vast mutations. We have modelled the complex structure of the human ACE2 protein and the receptor binding domain (RBD) of Omicron Spike protein (S-protein), and conducted atomistic molecular dynamics simulations to study the binding interactions. The analysis shows that the Omicron RBD binds more strongly to the human ACE2 protein than the original strain. The mutations at the ACE2-RBD interface enhance the tight binding by increasing hydrogen bonding interaction and enlarging buried solvent accessible surface area.

bioinformatics↗

bioRxiv2021

A Graph Convolutional Network-based screening strategy for rapid identification of SARS-CoV-2 cell-entry inhibitors

The cell entry of SARS-CoV-2 has emerged as an attractive drug development target. We previously reported that the entry of SARS-CoV-2 depends on the cell surface heparan sulfate proteoglycan (HSPG) and the cortex actin, which can be targeted by therapeutic agents identified by conventional drug repurposing screens. However, this drug identification strategy requires laborious library screening, which is time-consuming and often limited number of compounds can be screened. As an alternative approach, we developed and trained a graph convolutional network (GCN)-based classification model using information extracted from experimentally identified HSPG and actin inhibitors. This method allowed us to virtually screen 170,000 compounds, resulting in [~]2000 potential hits. A hit confirmation assay with the uptake of a fluorescently labeled HSPG cargo further shortlisted 256 active compounds. Among them, 16 compounds had modest to strong inhibitory activities against the entry of SARS-CoV-2 pseudotyped particles into Vero E6 cells. These results establish a GCN-based virtual screen workflow for rapid identification of new small molecule inhibitors against validated drug targets. Graphical TOC Entry O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/471787v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1632bc4org.highwire.dtl.DTLVardef@1ce912borg.highwire.dtl.DTLVardef@9cdc86org.highwire.dtl.DTLVardef@521712_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2021

Self-assembling short immunostimulatory duplex RNAs with broad spectrum antiviral activity

The current COVID-19 pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type III interferon (IFN-I and IFN-III), in a wide range of human cell types. These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique conserved sequence motif (sense strand: 5-C, antisense strand: 3-GGG) that mediates end-to-end dimer self-assembly of these RNAs by Hoogsteen G-G base-pairing. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases did not affect their ability to induce IFN. Unlike previously described immunostimulatory siRNAs, their activity is independent of TLR7/8, but requires the RIG-I/IRF3 pathway that induces a more restricted antiviral response with a lower proinflammatory signature compared with poly(I:C). Immune stimulation mediated by these duplex RNAs results in broad spectrum inhibition of infections by many respiratory viruses with pandemic potential, including SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A, as well as the common cold virus HCoV-NL63 in both cell lines and human Lung Chips that mimic organ-level lung pathophysiology. These short dsRNAs can be manufactured easily, and thus potentially could be harnessed to produce broad-spectrum antiviral therapeutics at low cost.

immunology↗

bioRxiv2021

Mitoxantrone modulates a glycosaminoglycan-spike complex to inhibit SARS-CoV-2 infection

Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2 spike (S) protein also interacts with heparan sulfate, a negatively charged glycosaminoglycan (GAG) attached to certain membrane proteins on the cell surface. This interaction facilitates the engagement of spike with a downstream receptor to promote viral entry. Here, we show that Mitoxantrone, an FDA-approved topoisomerase inhibitor, targets a spike-GAG complex to compromise the fusogenic function of spike in viral entry. As a single agent, Mitoxantrone inhibits the infection of an authentic SARS-CoV-2 strain in a cell-based model and in human lung EpiAirway 3D tissues. Gene expression profiling supports the plasma membrane as a major target of Mitoxantrone but also underscores an undesired activity targeting nucleosome dynamics. We propose that Mitoxantrone analogs bearing similar GAG-binding activities but with reduced affinity for DNA topoisomerase may offer an alternative therapy to overcome breakthrough infections in the post-vaccine era.

cell biology↗

bioRxiv2021

Diversity and dynamics of the CRISPR-Cas systems associated with Bacteroides fragilis in human population

CRISPR-Cas systems are adaptive immune systems commonly found in prokaryotes that provide sequence-specific defense against invading mobile genetic elements (MGEs). The memory of these immunological encounters are stored in CRISPR arrays, where spacer sequences record the identity and history of past invaders. Analyzing such CRISPR arrays provide insights into the dynamics of CRISPR-Cas systems and the adaptation of their host bacteria to rapidly changing environments such as the human gut. In this study, we utilized 601 Bacteroides fragilis genome isolates from 12 healthy individuals, 6 of which include longitudinal observations, and 222 available B. fragilis reference genomes to update the understanding of B. fragilis CRISPR-Cas dynamics and their differential activities. Analysis of longitudinal genomic data showed that some CRISPR array structures remained relatively stable over time whereas others involved radical spacer acquisition during some periods, and diverse CRISPR arrays (associated with multiple isolates) co-existed in the same individuals with some persisted over time. Furthermore, features of CRISPR adaptation, evolution, and microdynamics were highlighted through an analysis of host-MGE network, such as modules of multiple MGEs and hosts, reflecting complex interactions between B. fragilis and its invaders mediated through the CRISPR-Cas systems. This work demonstrates the power of using culture-based population genomics to reveal the activities and evolution of the CRISPR-Cas systems associated with gut bacteria in human population. We made available of all annotated CRISPR-Cas systems and their target MGEs, and their interaction network as a web resource at https://omics.informatics.indiana.edu/CRISPRone/Bfragilis.

bioinformatics↗