Biology subjects

Zhao, Y.

Publications and source records attributed to Zhao, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2018

Extensive Expansion of the Speedy gene Family in Homininae and Functional Differentiation in Humans

BackgroundThe cell cycle plays important roles in physiology and disease. The Speedy/RINGO family of atypical cyclins regulates the cell cycle. However, the origin, evolution and function of the Speedy family are not completely understood. Understanding the origins and evolution of Speedy family would shed lights on the evolution of complexity of cell cycles in eukaryotes.\n\nResultsHere, we performed a comprehensive identification of Speedy genes in 258 eukaryotic species and found that the Speedy subfamily E was extensively expanded in Homininae, characterized by emergence of a low-Spy1-identify domain. Furthermore, the Speedy gene family show functional differentiation in humans and have a distinct expression pattern, different regulation network and co-expressed gene networks associated with cell cycle and various signaling pathways. Expression levels of the Speedy gene family are prognostic biomarkers among different cancer types.\n\nConclusionsOverall, we present a comprehensive view of the Speedy genes and highlight their potential function.

evolutionary biology↗

bioRxiv2018

Mechanisms of gene death in the Red Queen race revealed by the analysis of de novo microRNAs

The prevalence of de novo coding genes is controversial due to the length and coding constraints. Non-coding genes, especially small ones, are freer to evolve de novo by comparison. The best examples are microRNAs (miRNAs), a large class of regulatory molecules ~22 nt in length. Here, we study 6 de novo miRNAs in Drosophila which, like most new genes, are testis-specific. We ask how and why de novo genes die because gene death must be sufficiently frequent to balance the many new births. By knocking out each miRNA gene, we could analyze their contributions to each of the 9 components of male fitness (sperm production, length, competitiveness etc.). To our surprise, the knockout mutants often perform better in some components, and slightly worse in others, than the wildtype. When two of the younger miRNAs are assayed in long-term laboratory populations, their total fitness contributions are found to be essentially zero. These results collectively suggest that adaptive de novo genes die regularly, not due to the loss of functionality, but due to the canceling-out of positive and negative fitness effects, which may be characterized as \"quasi-neutrality\". Since de novo genes often emerge adaptively and become lost later, they reveal ongoing period-specific adaptations, reminiscent of the \"Red-Queen\" metaphor for long term evolution.

evolutionary biology↗

bioRxiv2018

Testing the Red Queen hypothesis on de novo new genes - Run or die in the evolution of new microRNAs

The Red Queen hypothesis depicts evolution as the continual struggle to adapt. According to this hypothesis, new genes, especially those originating from non-genic sequences (i.e., de novo genes), are eliminated unless they evolve continually in adaptation to a changing environment. Here, we analyze two Drosophila de novo miRNAs that are expressed in a testis-specific manner with very high rates of evolution in their DNA sequence. We knocked out these miRNAs in two sibling species and investigated their contributions to different fitness components. We observed that the fitness contributions of miR-975 in D. simulans seem positive, in contrast to its neutral contributions in D. melanogaster, while miR-983 appears to have negative contributions in both species, as the fitness of the knockout mutant increases. As predicted by the Red Queen hypothesis, the fitness difference of these de novo miRNAs indicates their different fates.

evolutionary biology↗

bioRxiv2018

Single-cell Transcriptomic Landscape of Nucleated Cells in Umbilical Cord Blood

Umbilical cord blood (UCB) transplant is a therapeutic option for both pediatric and adult patients with a variety of hematologic diseases such as several types of blood cancers, myeloproliferative disorders, genetic diseases, and metabolic disorders. However, the level of cellular heterogeneity and diversity of nucleated cells in the UCB has not yet been assessed in an unbiased and systemic fashion. In the current study, nucleated cells from UCB were subjected to single-cell RNA sequencing, a technology enabled simultaneous profiling of the gene expression signatures of thousands of cells, generating rich resources for further functional studies. Here, we report the transcriptomic maps of 19,052 UCB cells, covering 11 major cell types. Many of these cell types are comprised of distinct subpopulations, including distinct signatures in NK and NKT cell types in the UCB. Pseudotime ordering of nucleated red blood cells (NRBC) identifies wave-like activation and suppression of transcription regulators, leading to a polarized cellular state, which may reflect the NRBC maturation. Progenitor cells in the UBC also consist two subpopulations with divergent transcription programs activated, leading to specific cell-fate commitment. Collectively, we provide this comprehensive single-cell transcriptomic landscape and show that it can uncover previously unrecognized cell types, pathways and gene expression regulations that may contribute to the efficacy and outcome of UCB transplant, broadening the scope of research and clinical innovations.

genomics↗

bioRxiv2018

Hepatitis B Virus Inhibits Neutrophil Extracellular Traps Release by Modulating Reactive Oxygen Species Production and Autophagy

Neutrophils, an important component of the innate immune system, release extracellular traps (NETs) to eliminate invaded pathogens by trapping and killing microbes. A dysfunctional innate immune response is a major cause of persistent hepatitis B virus (HBV) infection. HBV has been shown to reduce neutrophil responses. The objectives of the present study were to determine whether HBV influenced NETs release and to identify the underlying mechanisms. Primary neutrophils and circulating blood samples were collected from 40 patients with a chronic hepatitis B infection (CHB) and 40 healthy controls to detect NETs release using a Quant-iT Pico Green dsDNA assay and to determine the levels of HBV-DNA and HBV markers. NETs release was decreased in patients with a CHB infection, and hepatitis B surface antigen, hepatitis B e antigen and hepatitis B core antibody levels negatively correlated with NETs release. The Quant-iT Pico Green dsDNA assay and western blotting were used to examine the effect of HBV proteins (HBV X protein, HBV C protein, HBV E protein and HBV S protein) on NETs release in vitro. Based on the flow cytometry and western blot data, HBV C protein and HBV E protein inhibited NETs release by decreasing reactive oxygen species (ROS) production and autophagy. Overall, HBV may inhibit NETs release by modulating ROS production and autophagy to escape the immune system and promote the establishment of a chronic infection.

immunology↗

bioRxiv2018

Neural mechanisms underlying the precision of visual working memory

The neural mechanisms associated with the limited capacity of working memory has long been studied, but it is still unclear how the brain maintains the fidelity of representations in working memory. Here, an orientation recall task for estimating the precision of visual working memory was performed both inside and outside an fMRI scanner. Results showed that the trial-by-trial recall error (in radians) was correlated with delay period activity in the lateral occipital complex (LOC) during working memory maintenance, regardless of the memory load. Moreover, delay activity in LOC also correlated with the individual participants precision of working memory from a separate behavioral experiment held two weeks prior. Furthermore, a region within the prefrontal cortex, the inferior frontal junction (IFJ), exhibited greater functional connectivity with LOC when the working memory load increased. Together, our findings provide unique evidence that the LOC supports visual working memory precision, while communication between the IFJ and LOC varys with visual working memory load.

neuroscience↗

bioRxiv2018

LFAQ: towards unbiased label-free absolute protein quantification by predicting peptide quantitative factors

Mass spectrometry (MS) has become a prominent choice for large-scale absolute protein quantification, but its quantification accuracy still has substantial room for improvement. A crucial issue is the bias between the peptide MS intensity and the actual peptide abundance, i.e., the fact that peptides with equal abundance may have different MS intensities. This bias is mainly caused by the diverse physicochemical properties of peptides. Here, we propose a novel algorithm for label-free absolute protein quantification, LFAQ, which can correct the biased MS intensities by using the predicted peptide quantitative factors for all identified peptides. When validated on datasets produced by different MS instruments and data acquisition modes, LFAQ presented accuracy and precision superior to those of existing methods. In particular, it reduced the quantification error by an average of 46% for low-abundance proteins.

bioinformatics↗

bioRxiv2018

Cold Shock Fail to Restrain Pre-formed Bacterial Biofilm

Environmental temperature fluctuation has great impact on the formation of bacterial biofilm, while little information is available for assessing the influence of sharp temperature shifts on the fate of pre-formed biofilm. In this study, experimental evidence is firstly explored on the response of Vibrio parahaemolyticus pre-formed biofilm under cold shock (4 {degrees}C and 10 {degrees}C). Surprisingly, biofilm biomass of V. parahaemolyticus significantly increased during the period of cold shock as revealed by crystal violet staining. Polysaccharides and proteins contents in extracellular polymeric substances were gradually enhanced after cold shocks and exhibited high consistency. RT-qPCR demonstrated the expression of flagella and virulence-related genes were up-regulated. Most of QS and T3SS genes were slightly up-regulated, and three T3SS genes (vcrD1, vcrD2{beta} and vopD1) were down-regulated. Furthermore, the biofilm structure of V parahaemolyticus have been analyzed by Confocal laser scanning microscopy (CLSM), which sharply changed under cold shocks. The correlation analysis further displayed the significant correlation (P < 0.01) among biofilm structure parameters, and weak correlation (P < 0.05) between biofilm related genes and biofilm structure parameters. In conclusion, our results novel discovered that V. parahaemolyticus biofilm related genes were actively expressed and biofilm biomass was continuously increased, biofilm structure was tremendously changed after cold shock. This study underscored the risk that biofilm cells had the ability to adapt to low temperature shift.\n\nIMPORTANCEBiofilms are widespread in natural environments, especially on the surface of food and medical biomaterials, which threaten human safety from persistent infections. Previous studies simply focused on biofilm formation of microorganisms under steady state, however, the actual environment frequently fluctuated. V. parahaemolyticus is a widely distributed foodborne pathogen, temperature play a great role in its survival. Researchers generally assume that cold environment can restrain biofilm formation and bacterial activity. This study explored the effects of V. parahaemolyticus biofilm upon a shift from 37 {degrees}C to 4 {degrees}C or 10 {degrees}C from two aspects. On the one hand, the changes of biofilm biomass and EPS contents, the expression of biofilm related genes directly described that pre-formed bacterial biofilm could not be controlled efficiently in cold environment. On the other hand, the CLSM images revealed biofilm morphological structure change, the correlation analysis showed inner relationship among biofilm structure parameters and biofilm related genes. These results suggested that cold shock fail to restrain pre-formed bacterial biofilm, therefore be a potential risk in nature environment.

microbiology↗

bioRxiv2018

Transient Overexpression of VEGF-A in Adipose Tissue Promotes Energy Expenditure via Activation of the Sympathetic Nervous System

Adipose-derived VEGF-A stimulates functional blood vessel formation in obese fat pads which in turn facilitates healthy expansion of the adipose tissue. However, the detailed mechanism(s) governing the process remains largely unknown. Here, we investigated the role of sympathetic nervous system activation in the process. To this end, we induced overexpression of VEGF-A in an adipose-specific doxycycline (Dox)-inducible transgenic mouse model for a short period of time during high fat-diet (HFD) feeding. We found that local overexpression of VEGF-A in adipose tissue stimulated lipolysis and browning rapidly after Dox induction. Immunofluorescent staining against tyrosine hydroxylase (TH) indicated higher levels of sympathetic innervation in adipose tissue of transgenic mice. In response to the increased norepinephrine (NE) level, expression of {beta}3-andrenoceptor was significantly upregulated and the downstream protein kinase A (PKA) pathway was activated, as indicated by the enhanced phosphorylation of the whole PKA substrates, in particular the hormone sensitive lipase (HSL) in adipocytes. As the result, the adipose tissue exhibited increased lipolysis, browning, and energy expenditure. Importantly, all these effects were abolished upon the treatment with {beta}3-adrenoceptor antagonist SR59230A. Collectively, these results demonstrate that transient overexpressed VEGF-A activates sympathetic nervous system which hence promotes lipolysis and browning in adipose tissue.

physiology↗

bioRxiv2018

Laboratory evolution from social to solitary behavior in the N2 reference strain is unnecessary for its fitness advantages

The standard reference Caenorhabditis elegans strain, N2, has evolved marked behavioral changes since its isolation from the wild 67 years ago. Laboratory-derived variation in two genes, npr-1 and glb-5, suppress aerotaxis behaviors on food, resulting in N2 animals evolving from social to solitary feeding strategies. We show here that the derived alleles of npr-1 and glb-5 can confer large fitness advantages in standard laboratory conditions, suggesting that the changes in feeding strategies were beneficial to the N2 strain. However, by using environmental manipulations that suppress social behaviors, we showed the fitness advantages of the derived alleles remained unchanged, suggesting selection on these alleles acted through biological traits unrelated to solitary behavior. Transcriptomics analysis, developmental timing assays, and feeding assays showed that N2 animals mature faster, produce more sperm, and eat more food than a strain containing ancestral alleles of these genes (CX12311) regardless of the behavioral strategies. The O2-sensing neurons URX, AQR, and PQR and the pheromone biosynthesis and lipid regulating enzyme encoded by daf-22 are necessary for the full fitness advantages. We suggest that changes to social/solitary behavior in N2 were a pleiotropic consequence of npr-1 and glb-5s ability to modify integrated O2 and pheromone neural circuits that regulate feeding rate and reproductive development. Together, our results demonstrate how laboratory evolution can lead to profound changes in a strain used as a model by for understanding a variety of fundamental biological processes.

evolutionary biology↗

bioRxiv2018

Staphylococcal superantigen-like protein 13 activates neutrophils via Formyl Peptide Receptor 2

Staphylococcal Superantigen-Like (SSL) proteins, one of major virulence factor families produced by Staphylococcus aureus, were previously demonstrated to be immune evasion molecules that interfere with a variety of innate immune defenses. However, in contrast to these characterized SSLs, that inhibit immune functions, we show that SSL13 is a strong activator of neutrophils via the formyl-peptide receptor 2 (FPR2). Moreover, our data show that SSL13 acts as a chemoattractant, induces degranulation and oxidative burst in neutrophils. As with many other staphylococcal immune evasion proteins, SSL13 shows a high degree of human specificity. SSL13 is not able to efficiently activate mouse neutrophils, hampering in vivo experiments.\n\nIn conclusion, SSL13 is a neutrophil chemoattractant and activator that acts via the FPR2. Therefore, SSL13 is a unique SSL member that does not belong to the immune evasion class, but is a pathogen alarming molecule.

microbiology↗

bioRxiv2018

EZH2 co-opts gain-of-function p53 mutants to promote cancer growth and metastasis

With the unfolding of more and more cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target different mutants rather than develop strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation sequencing (RIP-seq) we identified EZH2 as a p53 mRNA-binding protein. EZH2 bound to the internal ribosome entry site (IRES) in the 5 untranslated region (5UTR) of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner. EZH2 augmented p53 GOF mutant-mediated cancer growth and metastasis by increasing p53 GOF mutant protein level. EZH2 overexpression associated with the worse outcome only in patients with p53-mutated cancer. Depletion of EZH2 by antisense oligonucleotides inhibited p53 GOF mutant-mediated cancer growth. Our findings reveal a non-methyltransferase function of EZH2 that controls protein translation of p53 GOF mutants, inhibition of which causes synthetic lethality in cancer cells expressing p53 GOF mutants.

cancer biology↗

bioRxiv2018

Ldb1 mediates trans enhancement in mammals

Singular olfactory receptor (OR) gene expression1,2 coincides with the formation of a multi-chromosomal enhancer hub that associates with the only transcribed OR allele in each cell3,4. This hub consists of converging transcriptional enhancers3, or \"Greek Islands\", defined by stereotypic binding of Lhx2 and Ebf on a shared, composite DNA motif5. How this multi-chromosomal hub, or any other genomic compartment, assembles is unknown, and so is the significance of compartmentalization in transcription. Here, we report that LIM domain binding protein 1 (Ldb1), which is recruited by Lhx2 and Ebf to Greek Islands, promotes robust and specific trans interactions between these enhancers. In addition to disrupting Greek Island hubs, Ldb1 deletion also causes significant downregulation of OR transcription. Thus, our data provide insight to the formation of genomic compartments, confirm the essential role of interchromosomal interactions in OR gene choice, and establish trans enhancement as a mechanism for mammalian gene activation.

genomics↗

bioRxiv2018

A statistical framework for cross-tissue transcriptome-wide association analysis

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to predict (impute) gene expression levels from genotypes from samples with matched genotypes and expression levels in a specific tissue. However, it is challenging to develop robust and accurate imputation models with limited sample sizes for any single tissue. Here, we first introduce a multi-task learning approach to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average 39% improvement in imputation accuracy and generated effective imputation models for an average 120% (range 13%-339%) more genes in each tissue. We then describe a summary statistic-based testing framework that combines multiple single-tissue associations into a single powerful metric to quantify overall gene-trait association at the organism level. When our method, called UTMOST, was applied to analyze genome wide association results for 50 complex traits (Ntotal=4.5 million), we were able to identify considerably more genes in tissues enriched for trait heritability, and cross-tissue analysis significantly outperformed single-tissue strategies (p=1.7e-8). Finally, we performed a cross-tissue genome-wide association study for late-onset Alzheimers disease (LOAD) and replicated our findings in two independent datasets (Ntotal=175,776). In total, we identified 69 significant genes, many of which are novel, leading to novel insights on LOAD etiologies.

genetics↗

bioRxiv2018

Increased H. pylori stool shedding and EPIYA-D cagA alleles are associated with gastric cancer in an East Asian hospital

BackgroundHelicobacter pylori infection induces chronic inflammation and tissue damage in the stomach, increasing risk for gastric cancer. Paradoxically, these tissue alterations may promote loss of H. pylori infection during cancer progression. H. pyloris role in cancer progression beyond initiation is unclear. Geographic variation in gastric cancer risk has been attributed to variation in carriage and type of the H. pylori oncogene cagA.\n\nMethodsTo investigate possible differences in H. pylori load in the stomach and shedding in stool, H. pylori load and cagA genotype were assessed using droplet digital PCR assays on gastric mucosa and stool samples from 49 urea breath test-positive individuals, including 25 gastric cancer and 24 non-cancer subjects at Henan Cancer Hospital, Henan, China.\n\nResultsQuantitation of H. pylori DNA indicated similar gastric loads among cancer and non-cancer cases, but the gastric cancer group had a median H. pylori load in the stool that was six times higher than that of the non-cancer subjects. While the cagA gene was uniformly present among study subjects, only 70% had the East Asian cagA allele, which was significantly associated with gastric cancer (Fishers Exact Test, p = 0.03).\n\nConclusionH. pylori persists in a subset of gastric cancer cases and thus may contribute to cancer progression. In this East Asian population with a high prevalence of the cagA gene, the East Asian allele could still provide a marker for gastric cancer risk.\n\nImpactThis study contributes to our understanding of H. pylori dynamics in the context of pathological changes.

microbiology↗

bioRxiv2018

All-optical electrophysiology reveals brain-state dependent changes in hippocampal subthreshold dynamics and excitability

A technology to record membrane potential from multiple neurons, simultaneously, in behaving animals will have a transformative impact on neuroscience research1. Parallel recordings could reveal the subthreshold potentials and intercellular correlations that underlie network behavior2. Paired stimulation and recording can further reveal the input-output properties of individual cells or networks in the context of different brain states3. Genetically encoded voltage indicators are a promising tool for these purposes, but were so far limited to single-cell recordings with marginal signal to noise ratio (SNR) in vivo4-6. We developed improved near infrared voltage indicators, high speed microscopes and targeted gene expression schemes which enabled recordings of supra- and subthreshold voltage dynamics from multiple neurons simultaneously in mouse hippocampus, in vivo. The reporters revealed sub-cellular details of back-propagating action potentials, correlations in sub-threshold voltage between multiple cells, and changes in dynamics associated with transitions from resting to locomotion. In combination with optogenetic stimulation, the reporters revealed brain state-dependent changes in neuronal excitability, reflecting the interplay of excitatory and inhibitory synaptic inputs. These tools open the possibility for detailed explorations of network dynamics in the context of behavior.

neuroscience↗

bioRxiv2018

Loss of SDHB reprograms energy metabolisms and inhibits high fat diet induced metabolic syndromes

Mitochondrial respiratory complex II utilizes succinate, key substrate of the Krebs cycle, for oxidative phosphorylation, which is essential for glucose metabolism. Mutations of complex II cause cancers and mitochondrial diseases, raising a critical question of the (patho-)physiological functions. To address the fundamental role of complex II in systemic energy metabolism, we specifically knockout SDHB in mice liver, a key complex II subunit that tethers the catalytic SDHA subunit and transfers the electrons to ubiquinone, and found that SHDB deficiency abolishes the assembly of complex II without affecting other respiration complexes while largely retaining SDHA stability. SHDB ablation reprograms energy metabolism and hyperactivates the glycolysis, Krebs cycle and {beta}-oxidation pathways, leading to catastrophic energy deficit and early death. Strikingly, sucrose supplementation or high fat diet resumes both glucose and lipid metabolism and prevent early death. Also, SDHB deficient mice are completely resistant to high fat diet induced obesity. Our findings reveal that the unanticipated role of complex II orchestrating both lipid and glucose metabolisms, and suggest that SDHB is an ideal therapeutic target for combating obesity.

molecular biology↗

bioRxiv2018

De novo haplotype reconstruction in viral quasispecies using paired-end read guided path finding

MotivationRNA virus populations contain closely related but different viral strains infecting an individual host. As the selection acts on clouds of mutants rather than single sequences, these viruses have abilities to escape host immune responses or develop drug resistance. Reconstruction of the viral haplotypes is a fundamental step to characterize the virus population, predict their viral phenotypes, and finally provide important information for clinical treatment and prevention. Advances of the next-generation sequencing technologies open up new opportunities to assemble full-length haplotypes. However, error-prone short reads, high similarity between related strains, unknown number of haplotypes pose computational challenges for reference-free haplotype reconstruction. There is still big room to improve the performance of existing haplotype assembly tools.\n\nResultsIn this work, we developed a de novo haplotype reconstruction tool PEHaplo for viral quasispecies data, which contains a group of related but different viral strains. PEHaplo employs paired-end reads to distinguish highly similar strains. We applied it to both simulated and real quasispecies data, and the results were benchmarked against several recently published haplotype reconstruction tools. The comparison shows that PEHaplo outperforms the benchmarked tools in a comprehensive set of metrics.\n\nAvailabilityThe source code and the documentation of PEHaplo is available at https://github.com/chjiao/PEHaplo.\n\nContactyannisun@msu.edu

bioinformatics↗