Biology subjects

Zhou, S.

Publications and source records attributed to Zhou, S..

At least 19 recordsLinked to original sources

bioRxiv2018

Metabolome-scale genome-wide association studies reveal chemical diversity and genetic control of maize specialized metabolites

One Sentence SummaryHPLC-MS metabolite profiling of maize seedlings, in combination with genome-wide association studies, identifies numerous quantitative trait loci that influence the accumulation of foliar metabolites.\n\nAbstractCultivated maize (Zea mays) retains much of the genetic and metabolic diversity of its wild ancestors. Non-targeted HPLC-MS metabolomics using a diverse panel of 264 maize inbred lines identified a bimodal distribution in the prevalence of foliar metabolites. Although 15% of the detected mass features were present in >90% of the inbred lines, the majority were found in <50% of the samples. Whereas leaf bases and tips were differentiated primarily by flavonoid abundance, maize varieties (stiff-stalk, non-stiff-stalk, tropical, sweet corn, and popcorn) were differentiated predominantly by benzoxazinoid metabolites. Genome-wide association studies (GWAS), performed for 3,991 mass features from the leaf tips and leaf bases, showed that 90% have multiple significantly associated loci scattered across the genome. Several quantitative trait locus hotspots in the maize genome regulate the abundance of multiple, often metabolically related mass features. The utility of maize metabolite GWAS was demonstrated by confirming known benzoxazinoid biosynthesis genes, as well as by mapping isomeric variation in the accumulation of phenylpropanoid hydroxycitric acid esters to a single linkage block in a citrate synthase-like gene. Similar to gene expression databases, this metabolomic GWAS dataset constitutes an important public resource for linking maize metabolites with biosynthetic and regulatory genes.

genetics↗

bioRxiv2018

A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

Bromodomains (BRDs) are evolutionary conserved epigenetic protein interaction modules which recognize (\"read\") acetyl-lysine, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective tool small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan(R) and demonstrate the utility of the set using studies of muscle cell differentiation and triple negative breast cancer (TNBC). We identified cross talk between histone acetylation and the glycolytic pathway resulting in a vulnerability of TNBC cell lines to inhibition of BRPF2/3 BRDs under conditions of glucose deprivation or GLUT1 inhibition. This chemical probe set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.

cell biology↗

bioRxiv2018

Improving Whole-Brain Neural Decoding of fMRI with Domain Adaptation

In neural decoding, there has been a growing interest in machine learning on whole-brain functional magnetic resonance imaging (fMRI). However, the size discrepancy between the feature space and the training set poses serious challenges. Simply increasing the number of training examples is infeasible and costly. In this paper, we proposed a domain adaptation framework for whole-brain fMRI (DawfMRI) to improve whole-brain neural decoding on target data leveraging pre-existing source data. DawfMRI consists of three steps: 1) feature extraction from whole-brain fMRI, 2) source and target feature adaptation, and 3) source and target classifier adaptation. We evaluated its eight possible variations, including two non-adaptation and six adaptation algorithms, using a collection of seven task-based fMRI datasets (129 unique subjects and 11 cognitive tasks in total) from the OpenNeuro project. The results demonstrated that appropriate source domain can help improve neural decoding accuracy for challenging classification tasks. The best-case improvement is 8.94% (from 78.64% to 87.58%). Moreover, we discovered a plausible relationship between psychological similarity and adaptation effectiveness. Finally, visualizing and interpreting voxel weights showed that the adaptation can provide additional insights into neural decoding.

neuroscience↗

bioRxiv2018

Impact of acetolactate synthase inactivation on 1,3-propanediol fermentation by Klebsiella pneumoniae

1,3-Propanediol (1,3-PDO) is an important compound that is mainly used in industry for polymer production. Fermentation of 1,3-PDO from glycerol by marine Klebsiella pneumoniae is accompanied by formation of 2,3-butanediol (2,3-BDO) as one of the main byproduct. The first step in the formation of 2,3-BDO from pyruvate is catalyzed by acetolactate synthase (ALS), an enzyme that competes with 1,3-PDO oxidoreductase for the cofactor NADH. This study aimed to analyze the impact of engineering the 2,3-BDO formation pathway via inactivation of ALS on 1,3-PDO fermentation by marine K. pneumoniae HSL4. An ALS mutant was generated using Red recombinase assisted gene replacement. The ALS specific activities of K. pneumoniae {Delta}ALS were notably lower than that of the wild-type strain. Fed-batch fermentation of the mutant strain resulted in a 1,3-PDO concentration, productivity and conversion of 72.04 g L-1, 2.25 g L-1 h-1, and 0.41 g g-1, a slightly increase compared with the parent strain. Moreover, inactivation of ALS decreased meso-2,3-BDO formation to trace amounts, significantly increased 2S,3S-BDO and lactate production, and a pronounced redistribution of intracellular metabolic flux was apparent.

microbiology↗

bioRxiv2018

Base pair editing of goat embryos: nonsense codon introgression into FGF5 to improve cashmere yield

The ability to alter single bases without DNA double strand breaks provides a potential solution for multiplex editing of livestock genomes for quantitative traits. Here, we report using a single base editing system, Base Editor 3 (BE3), to induce nonsense codons (C-to-T transitions) at four target sites in caprine FGF5. All five progenies produced from microinjected single-cell embryos had alleles with a targeted nonsense mutation and yielded expected phenotypes. The effectiveness of BE3 to make single base changes varied considerably based on sgRNA design. Also, the rate of mosaicism differed between animals, target sites, and tissue type. PCR amplicon and whole genome resequencing analyses for off-target changes caused by BE3 were low at a genome-wide scale. This study provides first evidence of base editing in livestock, thus presenting a potentially better method to introgress complex human disease alleles into large animal models and provide genetic improvement of complex health and production traits in a single generation.

genetics↗

bioRxiv2018

Pan-cancer analysis of RNA binding proteins (RBPs) reveals the involvement of the core pre-mRNA splicing and translation machinery in tumorigenesis

RNA binding proteins (RBPs) are key regulators of posttranscriptional processes such as RNA maturation, transport, localization, turnover and translation. Despite their dysregulation in various diseases including cancer, the landscape of RBP expression and regulatory mechanisms in human cancer has not been well characterized. Here, we analyzed mRNA expression of 1487 RBPs in ~6700 clinical samples across 16 human cancer types and found that there were significantly more upregulated RBPs than downregulated ones in tumors when compared to their adjacent normal tissues. Across almost all of the 16 cancer types, 109 RBPs were consistently upregulated (cuRBPs) while only 41 RBPs were consistently downregulated (cdRBPs). Integrating expression with the copy number and DNA methylation data, we found that the overexpression of cuRBPs is largely associated with the amplification of copy number, whereas the downregulation of cdRBPs may be a result of epigenetic silencing mediated by DNA methylation. Furthermore, our results indicated that cuRBPs could work together to promote cancer progression potentially through the involvement of splicing and translation machinery, while cdRBPs might function independently to suppress tumorigenesis. Additionally, we focused on colon cancer and identified several novel potential oncogenic RBPs, such as PABPC1L which might promote cancer development via regulating the core splicing machinery. In summary, we showed distinct expression landscapes, regulatory mechanisms and characteristics of cuRBPs and cdRBPs and implicated several novel RBPs in cancer pathogenesis. Moreover, our results suggest that the involvement of the core pre-mRNA splicing and translation machinery could be critical in tumorigenesis.

systems biology↗

bioRxiv2018

Identification of pathogens in culture-negative infective endocarditis with metagenomic analysis

Pathogens identification is critical for the proper diagnosis and precise treatment of infective endocarditis. Although blood and valve cultures are the gold standard for IE pathogens detection, many cases are culture-negative, especially in patients who had received long-term antibiotic treatment, and precise diagnosis has therefore become a major challenge in the clinic. Metagenomic sequencing can provide both information on the pathogenic strain and the antibiotic susceptibility profile of patient samples without culturing, offering a powerful method to deal with culture-negative cases. In this work, we assessed the feasibility of a metagenomic approach to detect the causative pathogens in resected valves from IE patients.\n\nUsing our in-house developed bioinformatics pipeline, we analyzed the sequencing results generated from both next-generation sequencing and Oxford Nanopore Technologies MinION nanopore sequencing for the direct identification of pathogens from the resected valves of seven clinically culture-negative IE patients according to the modified Duke criteria. Moreover, we were able to simultaneously characterize respective antimicrobial resistance features. This provides clinicians with valuable information to diagnose and treat IE patients after valve replacement surgery.

microbiology↗

bioRxiv2018

Ethylene signaling regulates natural variation in the abundance of antifungal acetylated diferuloylsucroses and Fusarium graminearum resistance in maize seedling roots

O_LIThe production and regulation of defensive specialized metabolites plays a central role in pathogen resistance in maize (Zea mays) and other plants. Therefore, identification of genes involved in plant specialized metabolism can contribute to improved disease resistance.\nC_LIO_LIWe used comparative metabolomics to identify previously unknown antifungal metabolites in maize seedling roots, and investigated the genetic and physiological mechanisms underlying their natural variation using quantitative trait locus (QTL) mapping and comparative transcriptomics approaches.\nC_LIO_LITwo maize metabolites, smilaside A (3,6-diferuloyl-3',6'-diacetylsucrose) and smiglaside C (3,6-diferuloyl-2',3',6'-triacetylsucrose), that may contribute to maize resistance against Fusarium graminearum and other fungal pathogens were identified. Elevated expression of an ethylene receptor gene, ETHYLENE INSENSITIVE 2 (ZmEIN2), co-segregated with decreased smilaside A/smiglaside C ratio. Pharmacological and genetic manipulation of ethylene availability and sensitivity in vivo indicated that, whereas ethylene was required for the production of both metabolites, the smilaside A/smiglaside C ratio was negatively regulated by ethylene sensitivity. This ratio, rather than the absolute abundance of these two metabolites, was important for maize seedling root defense against F. graminearum.\nC_LIO_LIEthylene signaling regulates the relative abundance of the two F. graminearum-resistance-related metabolites and affects resistance against F. graminearum in maize seedling roots.\nC_LI

plant biology↗

bioRxiv2018

Let-7i-5p regulation of cell morphology and migration through distinct signaling pathways in normal and pathogenic fibroblasts from urethra

Pelvic fracture urethral distraction defects (PFUDD) is a common disease that could severely affect patients life quality, yet little is known about the molecular mechanism associated with pathogenic fibrosis in PFUDD. In this study, we found that let-7i-5p could regulate different cellular events in normal and pathogenic fibroblasts through three distinct signaling pathways. Interestingly, those regulations are compromised during the translation from mRNA to protein, and partially based on pathogenic status of the fibroblasts. By analyzing the molecular mechanism associated with its function, we conclude that let-7i-5p plays an essential role in regulating cell shape and tissue elasticity, cell migration, cell morphology and cytoskeleton, and could serve as a potential target for clinical treatment of urethral stricture patients.

molecular biology↗

bioRxiv2018

STREAM: Single-cell Trajectories Reconstruction, Exploration And Mapping of omics data

Single-cell transcriptomic assays have enabled the de novo reconstruction of lineage differentiation trajectories, along with the characterization of cellular heterogeneity and state transitions. Several methods have been developed for reconstructing developmental trajectories from single-cell transcriptomic data, but efforts on analyzing single-cell epigenomic data and on trajectory visualization remain limited. Here we present STREAM, an interactive pipeline capable of disentangling and visualizing complex branching trajectories from both single-cell transcriptomic and epigenomic data.

genomics↗

bioRxiv2018

Repurposing cytarabine for treating primary effusion lymphoma by targeting KSHV latent and lytic replications

Oncogenic Kaposis sarcoma-associated herpesvirus (KSHV) is etiologically linked to primary effusion lymphoma (PEL), an aggressive and non-treatable malignancy commonly found in AIDS patients. In this study, we performed a high throughput screening of 3,731 characterized compounds, and identified cytarabine approved by FDA for treating numerous types of cancer as a potent inhibitor of KSHV-induced PEL. We showed the high efficacy of cytarabine in the growth inhibition of various PEL cells by inducing cell cycle arrest and apoptosis. Cytarabine inhibited host DNA and RNA syntheses and therefore induced cellular cytotoxicity. Furthermore, cytarabine inhibited viral DNA and RNA syntheses and induced the the rapid degradation of KSHV major latent protein LANA, leading to the suppression of KSHV latent replication. Importantly, cytarabine effectively inhibited active KSHV replication and virion production in PEL cells. Finally, cytarabine treatments not only effectively inhibited the initiation and progression of PEL tumors, but also induced regression of grown PEL tumors in a xenograft mouse model. Together, our study has identified cytarabine as novel therapeutic agent for treating PEL as well as eliminating KSHV persistent infection.\n\nImportancePrimary effusion lymphoma is an aggressive malignancy caused by Kaposis sarcoma-associated herpesvirus. The outcome of primary effusion lymphoma is dismal without specific treatment. Through a high throughput screening of characterized compounds, we identified a FDA-approved compound cytarabine as a potent inhibitor of primary effusion lymphoma. We showed that cytarabine induced regression of PEL tumors in a xenograft mouse model. Cytarabine inhibited host and viral DNA and RNA syntheses, resulting in the induction of cytotoxicity. Of interest, cytarabine induced the degradation of KSHV major latent protein LANA, hence suppressing KSHV latent replication, which is required for PEL survival. Furthermore, cytarabine inhibited KSHV lytic replication program, preventing virion production. Our findings identified cytarabine as novel therapeutic agent for treating PEL as well as for eliminating KSHV persistent infection. Since cytarabine is already approved by the FDA, it might be an ideal candidate for repurposing for PEL therapy and for further evaluation in advanced clinical trials.

microbiology↗

bioRxiv2018

Integrative visual omics of the white-rot fungus Polyporus brumalis exposes the biotechnological potential of its oxidative enzymes for delignifying raw plant biomass.

White-rot fungi are wood decayers able to degrade all polymers from lignocellulosic biomass including cellulose, hemicelluloses, and lignin. The white-rot fungus Polyporus brumalis efficiently breaks down lignin and is regarded as having a high potential for the initial treatment of plant biomass in its conversion to bio-energy. We performed integrative multi-omics analyses by combining data from the fungal genome, transcriptomes, and secretomes. We found the fungus possessed an unexpectedly large set of genes coding for enzymes related to lignin degradation, and that these were highly expressed and massively secreted under solid-state fermentation conditions. The examination of interrelated multi-omics patterns revealed the coordinated regulation of lignin-active peroxidases and H2O2-generating enzymes along with the activation of cellular mechanisms for detoxification, which combined to result in the efficient lignin breakdown by the fungus.\n\nImportancePlant biomass conversion for green chemistry and bio-energy is a current challenge for a modern sustainable bioeconomy. The complex polyaromatic lignin polymers in raw biomass feedstocks (i.e. agriculture and forestry by-products) are major obstacles for biomass conversions. From a biotechnological aspect, these compounds could be a potential source of aromatic platform molecules for bio-based polymers. Here we describe the extraordinary ability of Polyporus brumalis for lignin degradation using its enzymatic arsenal to break down wheat straw, a lignocellulosic substrate that is considered as a biomass feedstock worldwide. We observed unusual expansions of gene families coding for; 1) Class II peroxidases involved in lignin degradation; and 2) GMC oxidoreductases/dehydrogenases involved in generating the hydrogen peroxide required for lignin peroxidase activity. Our findings suggested the fungus massively mobilizes this oxidative machinery during growth on wheat straw. Overall, we identified sets of co-regulated enzymes, which could potentially augment the efficiency of biotechnological plant biomass conversions.

bioengineering↗

bioRxiv2018

Fusarium graminearum-Induced Shoot Elongation and Root Reduction in Maize Seedlings Correlate with Later Seedling Blight Severity

Fusarium graminearum seedling blight is a common disease of maize (Zea mays). Development of genetic resistance to seedling blight in maize germplasm requires efficient and accurate quantitative assessment of disease severity. Through artificial inoculation experiments under controlled growth conditions, we determined that host genotype, pathogen genotype, and infection dose influence the extent to which F. graminearum induces shoot elongation and inhibits root growth in maize seedlings. A comparison of fifteen maize inbred lines showed independent variation of these two fungus-induced effects on seedling growth. In a broader survey with nine commercial maize hybrids and three field-collected fungal isolates, there was significant correlation between these seedling growth responses, as well as with later seedling blight severity. Analysis of variance suggested that this variation and the observed correlative relationships were primarily driven by differing pathogenicity of the three fungal isolates. Together, our results indicate that F. graminearum-induced shoot elongation and root reduction in maize seedlings have distinct underlying physiological mechanisms, and that early observations of seedling growth responses can serve as a proxy for investigating natural variation in host resistance and pathogen aggressiveness at later growth stages.

plant biology↗

bioRxiv2018

Rainbow-seq: combining cell lineage tracking with single-cell RNA sequencing in preimplantation embryos

Single-cell RNA-seq experiments cannot record cell division history and therefore cannot directly connect intercellular differences at a later developmental stage to their progenitor cells. We developed Rainbow-seq to combine cell division lineage tracing with single-cell RNA-seq. With distinct fluorescent protein genes as lineage markers, Rainbow-seq enables each single-cell RNA-seq experiment to simultaneously read single-cell transcriptomes and decode the lineage marker genes. We traced the lineages deriving from each blastomere in two-cell mouse embryos and observed inequivalent contributions to the embryonic and abembryonic poles in 72% of the blastocysts evaluated. Rainbow-seq on four- and eight-cell embryos with lineage tracing triggered at two-cell stage exhibited remarkable transcriptome-wide differences between the two cell lineages at both stages, including genes involved in negative regulation of transcription and signaling. These data provide critical insights on cell fate choices in cleavage embryos. Rainbow-seq bridged a critical gap between cellular division history and single-cell RNA-seq assays.

developmental biology↗

bioRxiv2017

Transcriptome Analysis of Adult C. elegans Cells Reveals Tissue-specific Gene and Isoform Expression

The biology and behavior of adults differ substantially from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific isolation to identify the transcriptomes of C. elegans four major tissues (or \"tissue-ome\"), identifying ubiquitously expressed and tissue-specific \"super-enriched\" genes. These data newly reveal the hypodermis metabolic character, suggest potential worm-human tissue orthologies, and identify tissue-specific changes in the Insulin/IGF-1 signaling pathway. Tissue-specific alternative splicing analysis identified a large set of collagen isoforms and a neuron-specific CREB isoform. Finally, we developed a machine learning-based prediction tool for 70 sub-tissue cell types, which we used to predict cellular expression differences in IIS/FOXO signaling, stage-specific TGF-b activity, and basal vs. memory-induced CREB transcription. Together, these data provide a rich resource for understanding the biology governing multicellular adult animals

genomics↗

bioRxiv2017

Myosin IIA interacts with the spectrin-actin membrane skeleton to control red blood cell membrane curvature and deformability

The biconcave disc shape and deformability of mammalian red blood cells (RBCs) relies upon the membrane skeleton, a viscoelastic network of short, membrane-associated actin filaments (F-actin) cross-linked by long, flexible spectrin tetramers. Nonmuscle myosin II (NMII) motors exert force on diverse F-actin networks to control cell shapes, but a function for NMII contractility in the 2D spectrin-F-actin network in RBCs has not been tested. Here, we show that RBCs contain membrane skeleton-associated NMIIA puncta, identified as bipolar filaments by super-resolution fluorescence microscopy. NMIIA association with the membrane skeleton is ATP-dependent, consistent with NMIIA motor domains binding to membrane skeleton F-actin and contributing to membrane mechanical stability. In addition, the NMIIA heavy and light chains are phosphorylated in vivo in RBCs, indicating active regulation of NMIIA motor activity and filament assembly, while reduced heavy chain phosphorylation of membrane skeleton-associated NMIIA indicates assembly of stable filaments at the membrane. Treatment of RBCs with blebbistatin, an inhibitor of NMII motor activity, decreases the number of NMIIA filaments associated with the membrane and enhances local, nanoscale membrane oscillations, suggesting decreased membrane tension. Blebbistatin-treated RBCs also exhibit elongated shapes, loss of membrane curvature, and enhanced deformability, indicating a role for NMIIA contractility in promoting membrane stiffness and maintaining RBC biconcave disc cell shape. As structures similar to the RBC membrane skeleton are conserved in many metazoan cell types, these data demonstrate a general function for NMII in controlling specialized membrane morphology and mechanical properties through contractile interactions with short F-actin in spectrin-F-actin networks.\n\nSignificance statementThe biconcave disc shape and deformability of the mammalian RBC is vital to its circulatory function, relying upon a 2D viscoelastic spectrin-F-actin network attached to the membrane. A role for myosin II (NMII) contractility in generating tension in this network and controlling RBC shape has never been tested. We show that NMIIA forms phosphorylated bipolar filaments in RBCs, which associate with F-actin at the membrane. NMIIA motor activity is required for interactions with the spectrin-F-actin network, and regulates RBC biconcave shape and deformability. These results provide a novel mechanism for actomyosin force generation at the plasma membrane, and may be applicable to other cell types such as neurons and polarized epithelial cells with a spectrin-F-actin-based membrane skeleton.

cell biology↗

bioRxiv2017

T-bet+ CD11c+ B Cells Are Critical For Anti-Chromatin IgG Production In The Development Of Lupus

A hallmark of systemic lupus erythematosus is high titers of circulating autoantibody. A novel CD11c+ B cell subset has been identified that is critical for the development of autoimmunity. However, the role of CD11c+ B cells in the development of lupus is unclear. Chronic graft-versus-host disease (cGVHD) is a lupus-like syndrome with great autoantibody production. In the present study we investigated the role of CD11c+ B cells in the pathogenesis of lupus in the cGVHD model. Here, we found the percentage and absolute number of CD11c+ B cells and titer of sera anti-chromatin IgG and IgG2a antibody were increased in cGVHD mice. CD11c+ plasma cells from cGVHD mice produced large amounts of anti-chromatin IgG2a upon stimulation. Depletion of CD11c+ B cells reduced anti-chromatin IgG and IgG2a production. T-bet expression was further shown to be upregulated in CD11c+ B cells. Knockout of T-bet in B cells alleviated cGVHD. The percentage of T-bet+ CD11c+ B cells was elevated in lupus patients and positively correlated with serum anti-chromatin levels. Our findings suggest T-bet+ CD11c+ B cells contribute to the pathogenesis of lupus and provides potential target for therapeutic intervention.

immunology↗

bioRxiv2017

NLR1-V, a CC-NBS-LRR encoding gene, is a potential candidate gene of the wheat powdery mildew resistance gene Pm21

Wheat powdery mildew caused by Blumeria graminisb f. sp. tritici is one of the most destructive diseases all over the world. Pm21, transferred from the wild Haynaldia villosa to wheat, confers broad spectrum resistance throughout the whole stage, and this gene has been widely used in wheat production for more than 20 years. Cloning the candidate gene of Pm21 is the prerequisite for elucidating the resistance mechanism, and is a valuable attempt to clone the target genes from the evolutionarily distant wild species. In this study, an innovative approach, which combined cytogenetic stocks development, mutagenesis, RenSeq and PacBio, was tried successfully to clone an NBS-LRR type gene NLR1-V from the Pm21 locus. Firstly, a powdery mildew resistant cryptic alien introgression line HP33 involved very small 6VS segment was developed, and 6 independent susceptible mutants of T6VS {middle dot} 6AL was identified. Then, the transcriptome of H. villosa was obtained by NGS and the full-length NBS-LRR gene database was constructed by RenSeq-PacBio. In the following study, two expressed NLR genes were located to the Pm21 locus using the HP33 as the mapping material, and only NLR1-V showed polymorphism between the wild T6VS {middle dot} 6AL and its six mutants. The functional analysis indicated that silencing of NLR1-V could compromise the resistance of T6VS {middle dot} 6AL completely, and could also decrease the resistance of T6VS {middle dot} 6DL dramatically. Moreover, NLR1-V could recover the resistance of the susceptible mutant and increase the resistance in the susceptible wheat. The study implied that NLR1-V, a CC-NBS-LRR encoding gene, is a potential candidate gene of the powdery mildew resistance gene Pm21.

plant biology↗