Biology subjects

Yuan, Y.

Publications and source records attributed to Yuan, Y..

At least 271 records · Page 15Linked to original sources

bioRxiv2020

First high-quality reference genome of Amphicarpaea edgeworthii

Amphicarpaea edgeworthii, an annual twining herb, is a widely distributed species and an ideal model for studying complex flowering types and evolutionary mechanisms of species. Herein, we generated a high-quality assembly of A. edgeworthii by using a combination of PacBio, 10x Genomics libraries, and Hi-C mapping technologies. The final 11 chromosome-level scaffolds covered 90.61% of the estimated genome (343.78 Mb), which is the first chromosome-scale assembled genome of an amphicarpic plant. These data will be beneficial for the discovery of genes that control major agronomic traits, spur genetic improvement of and functional genetic studies in legumes, and supply comparative genetic resources for other amphicarpic plants.

genomics↗

bioRxiv2020

Deep learning of gene interactions from single cell time-course expression data

MotivationTime-course gene expression data has been widely used to infer regulatory and signaling relationships between genes. Most of the widely used methods for such analysis were developed for bulk expression data. Single cell RNA-Seq (scRNA-Seq) data offers several advantages including the large number of expression profiles available and the ability to focus on individual cells rather than averages. However, this data also raises new computational challenges. ResultsUsing a novel encoding for scRNA-Seq expression data we develop deep learning methods for interaction prediction from time-course data. Our methods use a supervised framework which represents the data as a 3D tensor and train convolutional and recurrent neural networks (CNN and RNN) for predicting interactions. We tested our Time-course Deep Learning (TDL) models on five different time series scRNA-Seq datasets. As we show, TDL can accurately identify causal and regulatory gene-gene interactions and can also be used to assign new function to genes. TDL improves on prior methods for the above tasks and can be generally applied to new time series scRNA-Seq data. Availability and ImplementationFreely available at https://github.com/xiaoyeye/TDL. Contactzivbj@cs.cmu.edu Supplementary informationSupplementary data are available at XXX online.

bioinformatics↗

bioRxiv2020

Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

Artemisinin-resistant malaria parasites have emerged and been spreading, posing a significant public health challenge. Anti-malarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a "selective starvation" strategy by selectively inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in Plasmodium falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. Comparison of the crystal structures of human GLUT3 and PfHT1 bound to C3361, a PfHT1-specific moderate inhibitor, revealed an inhibitor binding-induced pocket that presented a promising druggable site. We thereby designed small-molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship (SAR) studies, the TH-PF series was identified to selectively inhibit PfHT1 over GLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously targeting the orthosteric and allosteric sites of a transporter. Significance statementBlocking sugar uptake in P. falciparum by selectively inhibiting the hexose transporter PfHT1 kills the blood-stage parasites without affecting the host cells, indicating PfHT1 as a promising therapeutic target. Here, we report the development of novel small-molecule inhibitors that are selectively potent to the malaria parasites over human cell lines by simultaneously targeting the orthosteric and the allosteric binding sites of PfHT1. Our findings established the basis for the rational design of next-generation anti-malarial drugs.

pharmacology and toxicology↗

bioRxiv2020

KSHV-encoded vCyclin can modulate HIF1α levels to promote DNA replication in hypoxia

The cellular adaptive response to hypoxia, mediated by high HIF1 levels includes metabolic reprogramming, restricted DNA replication and cell division. In contrast to healthy cells, the genome of cancer cells, and Kaposis sarcoma associated herpesvirus (KSHV) infected cells maintains replication in hypoxia. We show that KSHV infection, despite promoting expression of HIF1 in normoxia, can also restricts transcriptional activity, and promoted its degradation in hypoxia. KSHV-encoded vCyclin, expressed in hypoxia, mediated HIF1a cytosolic translocation, and its degradation through a non-canonical lysosomal pathway. Attenuation of HIF1 levels by vCyclin allowed cells to bypass the block to DNA replication and cell proliferation in the hypoxia. These results demonstrated that KSHV utilizes a unique strategy to balance HIF1 levels to overcome replication arrest and induction of the oncogenic phenotype, which are dependent on the levels of oxygen in the microenvironment.

microbiology↗

bioRxiv2020

A yeast BiFC-seq method for genome-wide interactome mapping

Genome-wide physical protein-protein interaction (PPI) mapping remains a major challenge for current technologies. Here, we report a high-efficiency yeast bimolecular fluorescence complementation method coupled with next-generation DNA sequencing (BiFC-seq) for interactome mapping. We applied this technology to systematically investigate an intraviral network of Ebola virus (EBOV). Two-thirds (9/13) of known interactions of EBOV were recaptured and five novel interactions were discovered. Next, we used BiFC-seq method to map the interactome of the tumor protein p53. We identified 97 interactors of p53 with more than three quarters are novel. Furthermore, in more complex background, we screened potential interactors by pooling two BiFC-libraries together, and revealing a network of 229 interactions among 205 proteins. These results show that BiFC-seq is a highly sensitive, rapid and economical method in genome-wide interactome mapping.

genomics↗

bioRxiv2020

Single-cell screening of SARS-CoV-2 target cells in pets, livestock, poultry and wildlife

A few animals have been suspected to be intermediate hosts of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a large-scale single-cell screening of SARS-CoV-2 target cells on a wide variety of animals is missing. Here, we constructed the single-cell atlas for 11 representative species in pets, livestock, poultry, and wildlife. Notably, the proportion of SARS-CoV-2 target cells in cat was found considerably higher than other species we investigated and SARS-CoV-2 target cells were detected in multiple cell types of domestic pig, implying the necessity to carefully evaluate the risk of cats during the current COVID-19 pandemic and keep pigs under surveillance for the possibility of becoming intermediate hosts in future coronavirus outbreak. Furthermore, we screened the expression patterns of receptors for 144 viruses, resulting in a comprehensive atlas of virus target cells. Taken together, our work provides a novel and fundamental strategy to screen virus target cells and susceptible species, based on single-cell transcriptomes we generated for domesticated animals and wildlife, which could function as a valuable resource for controlling current pandemics and serve as an early warning system for coping with future infectious disease threats.

cell biology↗

bioRxiv2020

Reconstructing SARS-CoV-2 response signaling and regulatory networks

Several molecular datasets have been recently compiled to characterize the activity of SARS-CoV-2 within human cells. Here we extend computational methods to integrate several different types of sequence, functional and interaction data to reconstruct networks and pathways activated by the virus in host cells. We identify key proteins in these networks and further intersect them with genes differentially expressed at conditions that are known to impact viral activity. Several of the top ranked genes do not directly interact with virus proteins. We experimentally tested treatments for a number of the predicted targets. We show that blocking one of the predicted indirect targets significantly reduces viral loads in stem cell-derived alveolar epithelial type II cells (iAT2s). Software and interactive visualizationhttps://github.com/phoenixding/sdremsc

systems biology↗

bioRxiv2020

The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

SARS-CoV-2 infection have caused global pandemic and claimed over 5,000,000 tolls1-4. Although the genetic sequences of their etiologic viruses are of high homology, the clinical and pathological characteristics of COVID-19 significantly differ from SARS5,6. Especially, it seems that SARS-CoV-2 undergoes vast replication in vivo without being effectively monitored by anti-viral immunity7. Here, we show that the viral protein encoded from open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all the viral proteins, can directly interact with MHC-I molecules and significantly down-regulates their surface expression on various cell types. In contrast, ORF8a and ORF8b of SARS-CoV do not exert this function. In the ORF8-expressing cells, MHC-I molecules are selectively target for lysosomal degradation by an autophagy-dependent mechanism. As a result, CTLs inefficiently eliminate the ORF8-expressing cells. Our results demonstrate that ORF8 protein disrupts antigen presentation and reduces the recognition and the elimination of virus-infected cells by CTLs8. Therefore, we suggest that the inhibition of ORF8 function could be a strategy to improve the special immune surveillance and accelerate the eradication of SARS-CoV-2 in vivo.

microbiology↗

bioRxiv2020

Single-cell regulatory landscape and disease vulnerability map of adult Macaque cortex

Single cell approaches have increased our knowledge about the cell type composition of the non-human primate (NHP), but a detailed characterization of area-specific regulatory features remains outstanding. We generated single-cell chromatin accessibility (single-cell ATAC) and transcriptomic data of 358,237 cells from prefrontal cortex (PFC), primary motor cortex (M1) and primary visual cortex (V1) of adult cynomolgus monkey brain, and integrated this dataset with Stereo-seq (Spatio-Temporal Enhanced REsolution Omics-sequencing) of the corresponding cortical areas to assign topographic information to molecular states. We identified area-specific chromatin accessible sites and their targeted genes, including the cell type-specific transcriptional regulatory network associated with excitatory neurons heterogeneity. We reveal calcium ion transport and axon guidance genes related to specialized functions of PFC and M1, identified the similarities and differences between adult macaque and human oligodendrocyte trajectories, and mapped the genetic variants and gene perturbations of human diseases to NHP cortical cells. This resource establishes a transcriptomic and chromatin accessibility combinatory regulatory landscape at a single-cell and spatially resolved resolution in NHP cortex.

neuroscience↗

bioRxiv2020

RefKA: A fast and efficient long-read genome assembly approach for large and complex genomes

Recent advances in long-read sequencing have the potential to produce more complete genome assemblies using sequence reads which can span repetitive regions. However, overlap based assembly methods routinely used for this data require significant computing time and resources. Here, we have developed RefKA, a reference-based approach for long read genome assembly. This approach relies on breaking up a closely related reference genome into bins, aligning k-mers unique to each bin with PacBio reads, and then assembling each bin in parallel followed by a final bin-stitching step. During benchmarking, we assembled the wheat Chinese Spring (CS) genome using publicly available PacBio reads in parallel in 168 wall hours on a 250 CPU system. The maximum RAM used was 300 Gb and the computing time was 42,000 CPU hours. The approach opens applications for the assembly of other large and complex genomes with much-reduced computing requirements. The RefKA pipeline is available at https://github.com/AppliedBioinformatics/RefKA

bioinformatics↗

bioRxiv2020

Cancer SIGVAR: A semi-automated interpretation tool for germline variants of hereditary cancer-related genes

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology published guidelines in 2015 for the clinical interpretation of Mendelian disorder sequence variants based on 28 criteria. ClinGen Sequence Variant Interpretation (SVI) Working Groups have developed many adaptations or refinements of these guidelines to improve the consistency of interpretation. We combined the most recent adaptations to expand the criteria from 28 to 48 and developed a tool called Cancer SIGVAR to help healthcare workers and genetic counselors interpret the clinical significance of cancer germline variants, which is critical for the clinical diagnosis and treatment of hereditary cancer. Our tool can accept VCF files as input and realize fully automated interpretation based on 21 criteria and semi-automated interpretation based on 48 criteria. We validated our tool on the ClinVar and CLINVITAE benchmark databases for the accuracy of fully automated interpretation, achieving an average consistency for pathogenic and benign assessment up to 93.40% and 82.54%, respectively. We compared Cancer SIGVAR with a similar tool, InterVar, and analyzed the main differences in criteria and implementation. In addition, to verify the performance of semi-automated interpretation based on 48 criteria, we selected 911 variants from two benchmark databases and reached an average classification consistency of 98.35%. Our findings highlight the need to optimize automated interpretation tools based on constantly updated guidelines.

genetics↗

bioRxiv2020

Single-cell atlas of a non-human primate reveals new pathogenic mechanisms of COVID-19

Stopping COVID-19 is a priority worldwide. Understanding which cell types are targeted by SARS-CoV-2 virus, whether interspecies differences exist, and how variations in cell state influence viral entry is fundamental for accelerating therapeutic and preventative approaches. In this endeavor, we profiled the transcriptome of nine tissues from a Macaca fascicularis monkey at single-cell resolution. The distribution of SARS-CoV-2 facilitators, ACE2 and TMRPSS2, in different cell subtypes showed substantial heterogeneity across lung, kidney, and liver. Through co-expression analysis, we identified immunomodulatory proteins such as IDO2 and ANPEP as potential SARS-CoV-2 targets responsible for immune cell exhaustion. Furthermore, single-cell chromatin accessibility analysis of the kidney unveiled a plausible link between IL6-mediated innate immune responses aiming to protect tissue and enhanced ACE2 expression that could promote viral entry. Our work constitutes a unique resource for understanding the physiology and pathophysiology of two phylogenetically close species, which might guide in the development of therapeutic approaches in humans. Bullet pointsO_LIWe generated a single-cell transcriptome atlas of 9 monkey tissues to study COVID-19. C_LIO_LIACE2+TMPRSS2+ epithelial cells of lung, kidney and liver are targets for SARS-CoV-2. C_LIO_LIACE2 correlation analysis shows IDO2 and ANPEP as potential therapeutic opportunities. C_LIO_LIWe unveil a link between IL6, STAT transcription factors and boosted SARS-CoV-2 entry. C_LI

cell biology↗

bioRxiv2020

Cell type-specific histone acetylation profiling of Alzheimer's Disease subjects and integration with genetics

We profile genome-wide histone 3 lysine 27 acetylation (H3K27ac) of 3 major brain cell types from hippocampus and dorsolateral prefrontal cortex (dlPFC) of subjects with and without Alzheimers Disease (AD). We confirm that single nucleotide polymorphisms (SNPs) associated with late onset AD (LOAD) prefer to reside in the microglial histone acetylome, which varies most strongly with age. We observe acetylation differences associated with AD pathology at 3,598 peaks, predominantly in an oligodendrocyte-enriched population. Strikingly, these differences occur at the promoters of known early onset AD (EOAD) risk genes (APP, PSEN1, PSEN2, BACE1), late onset AD (LOAD) risk genes (BIN1, PICALM, CLU, ADAM10, ADAMTS4, SORL1 and FERMT2), and putative enhancers annotated to other genes associated with AD pathology (MAPT). More broadly, acetylation differences in the oligodendrocyte-enriched population occur near genes in pathways for central nervous system myelination and oxidative phosphorylation. In most cases, these promoter acetylation differences are associated with differences in transcription in oligodendrocytes. Overall, we reveal deregulation of known and novel pathways in AD and highlight genomic regions as therapeutic targets in oligodendrocytes of hippocampus and dlPFC.

genetics↗

bioRxiv2020

Integrated analysis of gene correlation reveals disordered relationship between metabolism and immunity in tumor microenvironment

BackgroundMetabolism reprogramming and immune evasion are the most fundamental hallmarks for cancer survival. The complex interactions between metabolism and immune systems in tumors and their microenvironment is complicated. Researching on the correlation changes between metabolic and immune related-genes in normal and tumor tissues would help to reveal these complex interactions. MethodsIn this study, the mRNA profiles across 11 cancer types was obtained from The Cancer Genome Atlas (TCGA). Then, the spearmans correlation coefficient was calculated between metabolic and immune related-genes for each sample group. ResultsOur results showed that the number of correlated gene pairs was reduced significantly in tumor tissues compared with those of normal tissue, especially in KIRC, KIRP and STAD. Functional enrichment analysis for the universal (the pairs appeared in more than 2 cancer types) and specific (the pairs only in one specific cancer type) gene pairs across cancer types revealed top pathways which appeared in tumor and normal samples, such as phosphatidylinositol signaling system and inositol phosphate metabolism. Thereinto, the pairs in normal tissues missing in tumors may indicate they are important factors affecting immune system, such as, DGKs and PIP4ks. The correlation analysis between immune checkpoint and metabolism genes also showed a reduced correlation in tumor and had the tissue specificity, such as, FUT8 was strongly correlated with PDCD1 in the HC of STAD and they had a weaker correlation in other normal tissues and tumor types. ConclusionsOur study provides a novel strategy for investigating interaction of tumor immune and metabolism in microenvironment and offers some key points for exploring new targets including metabolic targets and immunomodulator of immune checkpoints.

bioinformatics↗

bioRxiv2020

Dampened PI3K/AKT signaling contributes to cancer resistance of the naked mole rat

Mammalian species have a dramatically different susceptibility to cancer. However, how cancer-resistant species resist oncogenic transformation is not fully understood. Here, we performed a comprehensive analysis of oncogene-induced transcriptional changes in the fibroblasts of a cancer-prone species, the mouse, and three cancer-resistant species, the human, the blind mole rat, and the naked mole rat. We report that multiple cellular processes are more refractory to oncogene-induced transcriptional changes in blind mole-rat, naked mole-rat, or human cells compared to mouse cells, such as cell division, cell adhesion, extracellular matrix organization, and metabolism. Strikingly, naked mole rat cells are more resistant to Ras-induced transcriptional changes compared to the other three species. As a mechanism, we found that critical genes in the PI3K pathway including Akt1 and Pik3ca are downregulated in naked mole rat cells. Activating the PI3K/AKT pathway in the naked mole rat cells renders them susceptible to tumorigenic transformation. This study provides multiple new insights into anti-cancer mechanisms in cancer-resistant species of mammals. Significance statementAnimal species differ greatly in their cancer susceptibility. Cancer rates in the mouse range from 50-90%, while two other rodent species, the naked mole rat and the blind mole rat have only a few cancer cases ever reported. Here we examined the mechanisms responsible these differences by comparing changes in transcription patters in response to oncoproteins in the mouse, naked mole rat, blind mole rat and human cells. The most striking finding was that the naked mole rat cells were resistant to transcriptional changes induced by oncogenic Ras. We found that pathways downstream of Ras were naturally attenuated in the naked mole rat. This finding identifies a novel mechanism that evolved to provide tumor resistance to the naked mole rat.

cancer biology↗

bioRxiv2020

Causal dynamical modelling predicts novel regulatory genes of FOXP3 in human regulatory T cells

Regulatory T cells (Tregs), characterized as a CD4+CD25+FOXP3+ subset of T cells, are vital to the induction of immune tolerance and the maintenance of immune homeostasis. While target genes of Treg master regulator FOXP3 have been identified, the upstream regulatory machinery of FOXP3 still remains largely unknown. Here we dynamically model causal relationships among genes from available time-series genome-scale datasets, to predict direct or indirect regulatory genes of FOXP3 in human primary Tregs. From the whole genome, we selected five top ranked candidates for further experimental validation. Following knockdown, three out of the five candidates indeed showed significant effects on the mRNA expression of FOXP3. Further experiments showed that one out of these three predicted candidates, namely nuclear receptor binding factor 2 (NRBF2), also affected FOXP3 protein expression. These results open new doors to identify potential new mechanisms of immune related diseases.

systems biology↗

bioRxiv2020

Functional Plasticity and Evolutionary Adaptation of Allosteric Regulation

Allostery is a fundamental regulatory mechanism of protein function. Despite notable advances, understanding the molecular determinants of allostery remains an elusive goal. Our current knowledge of allostery is principally shaped by a structure-centric view which makes it difficult to understand the decentralized character of allostery. We present a function-centric approach using deep mutational scanning to elucidate the molecular basis and underlying functional landscape of allostery. We show that allosteric signaling exhibits a high-degree of functional plasticity and redundancy through myriad mutational pathways. Residues critical for allosteric signaling are surprisingly poorly conserved while those required for structural integrity are highly conserved, suggesting evolutionary pressure to preserve fold over function. Our results suggest multiple solutions to the thermodynamic conditions of cooperativity, in contrast to the common view of a finely-tuned allosteric residue network maintained under selection.

biochemistry↗

bioRxiv2020

Validity of Two-Dimensional Static Footprint in Medial Longitudinal Arch Evaluation and the Characteristics of Athletes' Footprints

BackgroundWe aimed to explore the validity of two-dimensional static footprint analysis in medial longitudinal arch evaluation as well as the characteristics of athletes footprints to provide a basis for the evaluation and selection of athletes. MethodsExperiment One: Twenty-nine high level athletes (runners and jumpers) and forty normal college students were selected. Based on the X-ray photos taken of the medial foot, we measured the calcaneal inclination angle, the calcaneal-first metatarsal angle and the ratio of height to length of the medial longitudinal arch. We collected indicators of two-dimensional static footprints. Experiment Two: 106 high level athletes (runners and jumpers) and 104 normal college students were selected. We also collected indicators of two-dimensional static footprints. ResultsThe average measuring the Interclass Correlation Efficient (ICC) of calcaneal inclination angle, calcaneal-first metatarsal angle, the ratio of height to length of the medial longitudinal arch, the width of ball, arch and heel, the length of footprint and each toe, Chippaux-Smirak Index (CSI) and Staheli Index (SAI) were higher than 0.800. Regardless of athletes or college students, male or female, the correlation between CSI, SAI and calcaneal inclination angle, calcaneal-first metatarsal angle, the ratio of height to length of the medial longitudinal arch was statistically significant (P<0.05). College students CSI of the right foot is significantly higher than that of the left foot regardless of gender (P<0.05). ConclusionsWe prove the qualification of CSI and SAI in medial longitudinal arch evaluation and explain that the relative height of medial longitudinal arch is an important indicator in track and field.

genetics↗