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Yang, J.

Publications and source records attributed to Yang, J..

At least 955 records · Page 53Linked to original sources

A novel bat coronavirus reveals natural insertions at the S1/S2 cleavage site of the Spike protein and a possible recombinant origin of HCoV-19

The unprecedented epidemic of pneumonia caused by a novel coronavirus, HCoV-19, in China and beyond has caused public health concern at a global scale. Although bats are regarded as the most likely natural hosts for HCoV-191,2, the origins of the virus remain unclear. Here, we report a novel bat-derived coronavirus, denoted RmYN02, identified from a metagenomics analysis of samples from 227 bats collected from Yunnan Province in China between May and October, 2019. RmYN02 shared 93.3% nucleotide identity with HCoV-19 at the scale of the complete virus genome and 97.2% identity in the 1ab gene in which it was the closest relative of HCoV-19. In contrast, RmYN02 showed low sequence identity (61.3%) to HCoV-19 in the receptor binding domain (RBD) and might not bind to angiotensin-converting enzyme 2 (ACE2). Critically, however, and in a similar manner to HCoV-19, RmYN02 was characterized by the insertion of multiple amino acids at the junction site of the S1 and S2 subunits of the Spike (S) protein. This provides strong evidence that such insertion events can occur in nature. Together, these data suggest that HCoV-19 originated from multiple naturally occurring recombination events among those viruses present in bats and other wildlife species.

microbiology↗

Prostaglandin receptor EP2 is a novel molecular target for high-risk neuroblastoma

As the third-most common type of cancers in infants and young children, neuroblastoma accounts for nearly 10% of all childhood cancers. Despite remarkable advances in tumor diagnosis and management during the past decades, the five-year survival rates for patients with high-risk neuroblastoma remain below 50%. Developing new therapies for this devastating type of childhood cancer is an urgent unmet need. Cyclooxygenase (COX) via synthesizing prostaglandin E2 (PGE2) promotes tumor cell proliferation, survival, migration and invasion, and fosters an inflammation-enriched microenvironment that can facilitate angiogenesis, immune evasion and treatment resistance. However, which downstream PGE2 receptor subtype - namely EP1, EP2, EP3 and EP4 - is directly involved in COX activity-promoted neuroblastoma growth remains elusive. Analyzing five major neuroblastoma patient datasets: Versteeg-88, Kocak-649, SEQC-498, Primary NRC-283, and Oberthuer-251, we show that COX-1/PGE2/EP2 signaling axis is highly associated with the aggressiveness of human neuroblastoma. A time-resolved fluorescence resonance energy transfer (TR-FRET) method reveals EP2 as the key Gs-coupled receptor that mediates PGE2-initiated cAMP signaling in neuroblastoma cells with various risk factors. Taking advantage of novel, selective and bioavailable small-molecule antagonists that we recently developed to target the PGE2/EP2 signaling in vivo, we have demonstrated that pharmacological inhibition of the peripheral EP2 receptor substantially impairs the growth of human neuroblastoma xenografts and the associated angiogenesis in mice. Collectively, our results suggest that the PGE2/EP2 pathway contributes to the growth and malignant potential of human neuroblastoma cells; pharmacological inhibition on EP2 receptor by our drug-like compounds might provide a novel therapeutic strategy for this deadly pediatric cancer.

pharmacology and toxicology↗

Genome wide association study reveals plant loci controlling heritability of the rhizosphere microbiome

Host genetics has recently been shown to be a driver of plant microbiome composition. However, identifying the underlying genetic loci controlling microbial selection remains challenging. Genome wide association studies (GWAS) represent a potentially powerful, unbiased method to identify microbes sensitive to host genotype, and to connect them with the genetic loci that influence their colonization. Here, we conducted a population-level microbiome analysis of the rhizospheres of 200 sorghum genotypes. Using 16S rRNA amplicon sequencing, we identify rhizosphere-associated bacteria exhibiting heritable associations with plant genotype, and identify significant overlap between these lineages and heritable taxa recently identified in maize. Furthermore, we demonstrate that GWAS can identify host loci that correlate with the abundance of specific subsets of the rhizosphere microbiome. Finally, we demonstrate that these results can be used to predict rhizosphere microbiome structure for an independent panel of sorghum genotypes based solely on knowledge of host genotypic information.

plant biology↗

SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development

SARS-CoV-2 and SARS-CoV share a common human receptor ACE2. Protein-protein interaction structure modeling indicates that spike-RBD of the two viruses also has similar overall binding conformation and binding free energy to ACE2. In vitro assays using recombinant ACE2 proteins and ACE2 expressing cells confirmed the two coronaviruses similar binding affinities to ACE2. The above studies provide experimental supporting evidences and possible explanation for the high transmissibility observed in the SARS-CoV-2 outbreak. Potent ACE2-blocking SARS-CoV neutralizing antibodies showed limited cross-binding and neutralizing activities to SARS-CoV-2. ACE2-non-blocking SARS-CoV RBD antibodies, though with weaker neutralizing activities against SARS-CoV, showed positive cross-neutralizing activities to SARS-CoV-2 with an unknown mechanism. These findings suggest a trade-off between the efficacy and spectrum for therapeutic antibodies to different coronaviruses, and hence highlight the possibilities and challenges in developing broadly protecting antibodies and vaccines against SARS-CoV-2 and its future mutants.

microbiology↗

Exploring spatiotemporal changes in ecosystem service values and hotspots in Southwest of China, Mekong Region

Xishuangbanna in the southwestern border of China is located in the upper reaches of the Mekong River between the Indo-China Peninsula and the East Asian continent. It is the largest tropical rain forest and monsoon forest in China. They have an irreplaceable ecological service function and are an important barrier to maintaining the ecological security of the Mekong River transboundary basin of the Lancang River. Based on three sets of remote sensing data (1996, 2003, 2010 and 2016), this study has made an exploration on spatio-temporal changes of Xishuangbanna, and also made an assessment on different ecosystem values of six types of ecosystem in Xishuangbanna based on related theories of ecological economics. Results showed that the values of Xishuangbanna ecosystem services in 1996, 2003, 2010, and 2016 were 70.4014billion yuan, 70.2115 billion yuan, 68.5129 billion yuan and 63.6098 billion yuan, respectively. The total value shows a continuous decreasing trend, reflecting the continuous decline in the ability of the Xishuangbanna ecosystem to provide services to humans. If divided by ecosystem types, forest and rubber were two types that have the greatest proportion of service values. In the perspective of service types, soil formation and protection account for the largest proportion, followed by gas regulation and biodiversity protection. Studying Xishuangbannas ecosystem service values is helpful to explore the sustainable development of resources and economy. HighlightThis paper used coefficient of sensitivity to determine the dependence of ESV on the change of ecosystem value coefficient over time. The total amount of ESV shows a continuous downward trend, indicating that the ecological environment of Xishuangbanna is still severe. The temporal-spatial change of ESV was analyzed for two decades.

ecology↗

Tracing Evolutionary Ages of Cancer-Driving Sites by Cancer Somatic Mutations

Evolutionary understanding of cancer genes may provide insights on the nature and evolution of complex life and the origin of multicellularity. In this study, we focus on the evolutionary ages of cancer-driving sites, and try to explore to what extent the amino acids of cancer-driving sites can be traced back to the most recent common ancestor (MRCA) of the gene. According to gene phylostraigraphy analysis, we use the definition of gene age (tg) by the most ancient phylogenetic position that can be traced back, in most cases based on the large-scale homology search of protein sequences. Our results are shown that the site-age profile of cancer-driving sites of TP53 is correlated with the number of cancer types the somatic mutations may affect. In general, those amino acid sites mutated in most cancer types are much ancient. These sites frequently mutated in cancerous cells are possibly responsible for carcinogenesis; some may be very important for basic growth of single-cell organisms, and others may contribute to complex cell regulation of multicellular organisms. The further cancer genomics analysis also indicates that ages of cancer-driving sites are ancient but may have a broad range in early stages of metazoans.

evolutionary biology↗

Twist, Snail, and Sox9 form an allosterically regulated complex, the EMTosome, on a bipartite E-box site.

Epithelial-Mesenchymal transition (EMT) of primary tumor cells is a critical trans-differentiation event that contributes to dissemination and metastasis. The process of EMT is controlled by specific DNA-binding transcription factors (TFs) that reprogram the tumor transcriptome. In particular, the canonical EMT-TFs Twist and Snail can induce an EMT program when overexpressed in cancer cells, and both are found upregulated in metastatic cancers. Twist and Snail bind DNA directly, by recognition to variants of the E-Box sequence CANNTG. However, it is unclear how this binding is regulated. We have used a biochemical approach to dissect DNA binding and protein-protein interactions that occur amongst these proteins. We find that Twist preferentially recognizes a dyad repeat of E-boxes that are not directly bound by Snail. Our data suggest that Twist use its WR domain to recruit Snail into a binding complex through the Snail zinc-finger motifs. We analyzed Twist-Snail complexes in the breast carcinoma cell line SUM1315 and found evidence that it contains an additional protein partner, Sox9. Notably, we report that a native Twist complex can be displaced from its dyad binding site by consensus DNA binding sites for Snail and Sox9 even though these proteins do not contact the Twist dyad site. Taken together, our findings suggest that Snail and Sox9 interact with Twist to regulate its DNA binding ability via protein-protein interactions, thereby allosterically regulating Twist DNA binding. We designate this ternary complex EMTosome. These results may inform efforts to therapeutically target the EMT program in order to target cancer metastasis.

cancer biology↗

Microtubule Assembly and Pole Coalescence: Early Steps in C. elegans Oocyte Meiosis I Spindle Assembly

How oocytes assemble bipolar meiotic spindles in the absence of centrosomes as microtubule organizing centers remains poorly understood. We have used live cell imaging in C. elegans to investigate requirements for the nuclear lamina and for conserved regulators of microtubule dynamics during oocyte meiosis I spindle assembly, assessing these requirements with respect to recently identified spindle assembly steps. We show that the nuclear lamina is required for microtubule bundles to form a cage-like structure that appears shortly after oocyte nuclear envelope breakdown and surrounds the oocyte chromosomes, although bipolar spindles still assembled in its absence. Although two conserved regulators of microtubule nucleation, RAN-1 and {gamma}-tubulin, are not required for bipolar spindle assembly, both contribute to normal levels of spindle-associated microtubules and spindle assembly dynamics. Finally, the XMAP215 ortholog ZYG-9 and the nearly identical minus-end directed kinesins KLP-15/16 are required for proper assembly of the early cage-like structure of microtubule bundles, and for early spindle pole foci to coalesce into a bipolar structure. Our results provide a framework for assigning molecular mechanisms to recently described steps in C. elegans oocyte meiosis I spindle assembly.

cell biology↗

Trophectoderm Potency is Retained Exclusively in Human Naïve Cells

Classical mouse embryology has established a paradigm of early development driven by sequential lineage bifurcations. Accordingly, mouse embryonic stem cells derived from early epiblast have lost the potency to produce extraembryonic trophectoderm. We show in contrast that human naive epiblast cells readily make trophectoderm. Inhibition of ERK signalling, instrumental in naive stem cell propagation, unexpectedly potentiates trophectoderm formation, an effect enhanced by Nodal inhibition. Transcriptome analyses authenticate conversion into trophectoderm with subsequent production of syncitiotrophoblast, cytotrophoblast and trophoblast stem cells. Genetic perturbations indicate that NANOG suppresses and TFAP2C enables trophectoderm induction. Consistent with post-implantation progression, trophectoderm potential is extinguished in conventional human pluripotent stem cells, which instead make amnion. Finally, human embryo epiblasts from late blastocysts efficiently generate trophectoderm and differentiated trophoblast. Thus, pluripotent cells in the human embryo retain extraembryonic lineage plasticity and regenerative potential until implantation. Harnessing this unanticipated regulative capacity may be beneficial for assisted reproduction technology.

developmental biology↗

Convergent genetic architecture underlies parallel pelvic reduction in genetically highly structured stickleback species

Repeated and independent adaptation to specific environmental conditions from standing genetic variation is common. However, if genetic variation is limited, the evolution of similar locally adapted traits may be restricted to genetically different and potentially less optimal solutions or prevented from happening altogether. Using a quantitative trait locus (QTL) mapping approach, we identified the genomic regions responsible for the repeated pelvic reduction (PR) in three crosses between nine-spined stickleback populations expressing full and reduced pelvic structures. In one cross, PR mapped to linkage group 7 (LG7) containing the gene Pitx1, known to control pelvic reduction also in the three-spined stickleback. In the two other crosses, PR was polygenic and attributed to ten novel QTL, of which 90% were unique to specific crosses. When screening the genomes from 27 different populations for deletions in the Pitx1 regulatory element, these were only found in the population in which PR mapped to LG7, even though the morphological data indicated large effect QTL for PR in several other populations as well. Consistent with the available theory and simulations parameterised on empirical data, we hypothesise that the observed variability in genetic architecture of PR is due to heterogeneity in the spatial distribution of standing genetic variation caused by >2x stronger population structuring among freshwater populations and >10x stronger genetic isolation by distance in the sea in nine-spined sticklebacks as compared to three-spined sticklebacks.

evolutionary biology↗

Theoretical and empirical quantification of the accuracy of polygenic scores in ancestry divergent populations

Polygenic scores (PGS) have been widely used to predict complex traits and risk of diseases using variants identified from genome-wide association studies (GWASs). To date, most GWASs have been conducted in populations of European ancestry, which limits the use of GWAS-derived PGS in non-European populations. Here, we develop a new theory to predict the relative accuracy (RA, relative to the accuracy in populations of the same ancestry as the discovery population) of PGS across ancestries. We used simulations and real data from the UK Biobank to evaluate our results. We found across various simulation scenarios that the RA of PGS based on trait-associated SNPs can be predicted accurately from modelling linkage disequilibrium (LD), minor allele frequencies (MAF), cross-population correlations of SNP effect sizes and heritability. Altogether, we find that LD and MAF differences between ancestries explain alone up to ~70% of the loss of RA using European-based PGS in African ancestry for traits like body mass index and height. Our results suggest that causal variants underlying common genetic variation identified in European ancestry GWASs are mostly shared across continents.

genetics↗

The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for human complex diseases

There is increasing interest about the interplay between host genetics and gut microbiome on human complex diseases, with prior evidence mainly derived from animal models. In addition, the shared and distinct microbiome features among human complex diseases remain largely unclear. We performed a microbiome genome-wide association study to identify host genetic variants associated with gut microbiome in a Chinese population with 1475 participants. We then conducted bi-directional Mendelian randomization analyses to examine the potential causal associations between gut microbiome and human complex diseases. We found that Saccharibacteria (also known as TM7 phylum) could potentially improve renal function by affecting renal function biomarkers (i.e., creatinine and estimated glomerular filtration rate). In contrast, atrial fibrillation, chronic kidney disease and prostate cancer, as predicted by the host genetics, had potential causal effect on gut microbiome. Further disease-microbiome feature analysis suggested that gut microbiome features revealed novel relationship among human complex diseases. These results suggest that different human complex diseases share common and distinct gut microbiome features, which may help re-shape our understanding about the disease etiology in humans.

microbiology↗

Cross-Species Integration of Transcriptomic Effects of Tobacco and Nicotine Exposure Helps to Prioritize Genetic Effects on Human Tobacco Consumption

Computational advances have fostered the development of new methods and tools to integrate gene expression and functional evidence into human-genetic association analyses. Integrative functional genomics analysis for altered response to alcohol in mice provided the first evidence that multi-species analysis tools, such as GeneWeaver, can identify or confirm novel alcohol-related loci. The present study describes an integrative framework to investigate how highly-connected genes linked by their association to tobacco-related behaviors, contribute to individual differences in tobacco consumption. Data from individuals of European ancestry in the UKBiobank (N=139,043) were used to examine the relative contribution of orthologs of a set of genes that are transcriptionally co-regulated by tobacco or nicotine exposure in model organism experiments to human tobacco consumption. Multi-component mixed linear models using genotyped and imputed single nucleotide variants indicated that: (1) variation within human orthologs of these genes accounted for 2-5% of the observed heritability (meta h2SNP-Total=0.08 [95% CI: 0.07, 0.09]) of tobacco/nicotine consumption across three independent folds of unrelated individuals (enrichment ranging from 0.85 - 2.98), and (2) variation around (5, 10, 15, 25, and 50 Kb regions) the set of co-transcriptionally regulated genes accounted for 5-36% of the observed SNP-heritability (enrichment ranging from 1.60 - 31.45). Notably, the effects of variants in co-transcriptionally regulated genes were enriched in tobacco GWAS. These findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption.

genetics↗

Visual impairment, spectacle wear and academic performance among junior high school students in western China

In September 2013, 2248 students from 36 junior high schools in Shaanxi Province underwent assessment of visual acuity (VA), completed a questionnaire about their spectacle use and were administered a standardized mathematics examination. Among 2,248 students (mean age 13.6 years, 52% male), visual impairment was present in 699 (31%, 95% Confidence Interval 29-33%). Spectacle wear was observed in 360 of 966 children needing glasses (37%). Ownership of spectacles among children needing glasses was associated with poorer uncorrected vision in the better-seeing eye (P <0.001) and paternal educational (p=0.001), but not age, sex, boarding at school, both parents having out-migrated for work or maternal education. Spectacle ownership among children with visual impairment was associated with better test performance (P=0.035). Therefore, visual impairment and non-wear of spectacle were common. Wearing spectacles was associated with better academic performance in this cross-sectional analysis, consistent with recent trial results among younger children.

scientific communication and education↗

Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration.

Vitamin D deficiency is a candidate risk factor for a range of adverse health outcomes. In a genome-wide association study of 25 hydroxyvitamin D (25OHD) concentration in 417,580 Europeans we identified 143 independent loci in 112 1-Mb regions providing new insights into the physiology of vitamin D and implicating genes involved in (a) lipid and lipoprotein metabolism, (b) dermal tissue properties, and (c) the sulphonation and glucuronidation of 25OHD. Mendelian randomization models found no robust evidence that 25OHD concentration had causal effects on candidate phenotypes (e.g. BMI, psychiatric disorders), but many phenotypes had (direct or indirect) causal effects on 25OHD concentration, clarifying the relationship between 25OHD status and health.

genetics↗

A non-mosaic humanized mouse model of Down syndrome, trisomy of the long arm of human chromosome 21 in mouse chromosome background

Down syndrome (DS) is a complex human condition, and animal models trisomic for human chromosome 21 (HSA21) genes or orthologs provide insights into better understanding and treating DS. However, HSA21 orthologs are distributed into three mouse chromosomes, preventing us from generating mouse models trisomy of a complete set of HSA21 orthologs. The only existing humanized mouse DS model, Tc1, carries a HSA21 with over 20% of protein coding genes (PCGs) disrupted. More importantly, due to the human centromere, Tc1 is mosaic (a mix of euploid and trisomic cells), which makes every mouse unique and compromises interpretation of results. Here, we used mouse artificial chromosome (MAC) technology to "clone" the 34 MB long arm of HSA21 (HSA21q). Through multiple steps of microcell-mediated chromosome transfer we created a new humanized DS mouse model, Tc(HSA21q;MAC)1Yakaz ("TcMAC21"). Constitutive EGFP expression from the transchromosome and fluorescent in situ hybridization validate that TcMAC21, containing a hybrid chromosome of HSA21q and mouse centromere, is not mosaic. Whole genome sequencing shows that TcMAC21 contains a nearly complete copy of HSA21q with 93% of intact PCGs, while RNA-seq and additional mRNA/protein expression analyses confirm that PCGs are transcribed and regulated. A battery of tests show that TcMAC21 recapitulates many DS phenotypes including morphological anomalies in heart, craniofacial skeleton and brain, pathologies at molecular and cellular level, and impairments in learning, memory and synaptic plasticity. TcMAC21 is the most complete mouse model of DS extant and has potential for supporting a wide range of basic and preclinical research. Significance StatementIn the last 25 years, mouse models of trisomy 21 have supported research into Down syndrome, from defining the basis for developmental effects up to support for clinical trials. However, existing models have significant shortfalls, especially for preclinical studies. These deficiencies include incomplete or inappropriate representation of trisomic genes, absence of an extra chromosome, and mosaicism. Using cutting edge technologies we produced a mouse artificial chromosome containing the entire 34Mb long arm of human chromosome 21 and, with assisted reproductive technologies, established it in the germ line of mice. This trisomic mouse manifests developmental and functional features of Down syndrome, including hippocampal-based learning and memory deficits. This is the most complete model of Down syndrome produced to date.

genetics↗

Volumetric Segmentation and Characterisation of the Paracingulate Sulcus on MRI Scans

Many architectures of deep neural networks have been designed to solve specific biomedical problems, among which segmentation is a critical step to detect and locate the boundaries of the target object from an image. In this paper, we develop a deep learning based framework to automatically segment the paracingulate sulcus (PCS) from the MRI scan and estimate lengths for its segments. The study is the first work on segmentation and characterisation of the PCS, and the model achieves a Dice score of over 0.77 on segmentation, which demonstrates its potential for clinical use to assist human annotation. Moreover, the proposed architecture as a solution can be generalised to other problems where the object has similar patterns.

bioinformatics↗

Big data reveals deep associations in physical examination indicators and can help predict overall underlying health status

Because of lacking of the systematic investigation of correlations between the physical examination indicators (PEIs), currently most of them are independently used for disease warning. This results in very limited diagnostic values of general physical examination. Here, we first systematically analyzed the correlations between 221 PEIs in healthy and in 34 unhealthy states in 803,614 peoples in China. We revealed rich relevant between PEIs in healthy physical status (7,662 significant correlations, 31.5% of all). However, in disease conditions, the PEI correlations changed. We further focused on the difference of these PEIs between healthy and 35 unhealthy physical status, 1,239 significant PEI difference were discovered suggesting as candidate disease markers. Finally, we established machine learning algorithms to predict the health status by using 15%-16% PEIs by feature extraction, which reached 66%-99% precision predictions depending on the physical state. This new encyclopedia of PEI correlation provides rich information to chronic disease diagnosis. Our developed machine learning algorithms will have fundamental impact in practice of general physical examination.

pathology↗