Biology subjects

Li, Q.

Publications and source records attributed to Li, Q..

At least 685 records · Page 38Linked to original sources

bioRxiv2020

Inactivation of LCN2/EGR1 Promotes Oligodendrocyte Progenitor Cell Differentiation and Remyelination after White Matter Injury

The insufficient remyelination due to the impaired oligodendrocyte precursor cell differentiation and maturation is highly associated with irreversible white matter injury and neurological deficits. Consequently, inhibitory components and microenvironment for remyelination might serve as potential therapeutic targets for treating white matter injury after acute central nervous system injury and neurodegeneration diseases. Lipocalin-2 was recently reported to corelate with white matter in both atypical, acute white matter injured disease subarachnoid hemorrhage and typical, chronic white matter injured disease multiple sclerosis. To elucidate the role and underlying mechanism of Lipocalin-2 in oligodendrocyte precursor cell differentiation and remyelination, we used genetic inhibition and a constitutive conditional knockout model with subarachnoid hemorrhage or multiple sclerosis. We found that the genetic inhibition of the increase in Lipocalin-2 promoted oligodendrocyte precursor cell differentiation, remyelination, and functional recovery after subarachnoid hemorrhage or multiple sclerosis. Unexpectedly, the inhibition of Lipocalin-2 did not reduce glial activation and inflammation. Lipocalin-2 was shown to activate Early Growth Response Protein 1 in oligodendrocyte precursor cells, which is partly regulated by its receptor SLC22A17. In the conditional knockout of Early Growth Response Protein 1 in oligodendrocyte precursor cells, we discovered enhanced oligodendrocyte precursor cell differentiation in developing and injured white matter; consistently, the specific inactivation of Early Growth Response Protein 1 promoted remyelination and neurological recovery after subarachnoid hemorrhage or multiple sclerosis. Thus, we propose that following white matter injury in humans, the increase in Lipocalin-2 activates Early Growth Response Protein 1 and consequently impair oligodendrocyte precursor cell differentiation and myelin repair. Our results suggest that therapies specifically inactivating Lipocalin-2/ Early Growth Response Protein 1 signal in oligodendroglial lineage cells could represent a novel strategy to enhance differentiation and remyelination in white matter injury patients.

neuroscience↗

bioRxiv2019

Advanced Whole Genome Sequencing Using a Complete PCR-free Massively Parallel Sequencing (MPS) Workflow

BackgroundSystematic errors can be introduced from DNA amplification during massively parallel sequencing (MPS) library preparation and sequencing array formation. Polymerase chain reaction (PCR)-free genomic library preparation methods were previously shown to improve whole genome sequencing (WGS) quality on the Illumina platform, especially in calling insertions and deletions (InDels). We hypothesized that substantial InDel errors continue to be introduced by the remaining PCR step of DNA cluster generation. In addition to library preparation and sequencing, data analysis methods are also important for the accuracy of the output data.In recent years, several machine learning variant calling pipelines have emerged, which can correct the systematic errors from MPS and improve the data performance of variant calling. ResultsHere, PCR-free libraries were sequenced on the PCR-free DNBSEQ arrays from MGI Tech Co., Ltd. (referred to as MGI) to accomplish the first true PCR-free WGS which the whole process is truly not only PCR-free during library preparation but also PCR-free during sequencing. We demonstrated that PCR-based WGS libraries have significantly (about 5 times) more InDel errors than PCR-free libraries.Furthermore, PCR-free WGS libraries sequenced on the PCR-free DNBSEQ platform have up to 55% less InDel errors compared to the NovaSeq platform, confirming that DNA clusters contain PCR-generated errors.In addition, low coverage bias and less than 1% read duplication rate was reproducibly obtained in DNBSEQ PCR-free using either ultrasonic or enzymatic DNA fragmentation MGI kits combined with MGISEQ-2000. Meanwhile, variant calling performance (single-nucleotide polymorphisms (SNPs) F-score>99.94%, InDels F-score>99.6%) exceeded widely accepted standards using machine learning (ML) methods (DeepVariant or DNAscope). ConclusionsEnabled by the new PCR-free library preparation kits, ultra high-thoughput PCR-free sequencers and ML-based variant calling, true PCR-free DNBSEQ WGS provides a powerful solution for improving WGS accuracy while reducing cost and analysis time, thus facilitating future precision medicine, cohort studies, and large population genome projects.

genomics↗

bioRxiv2019

Effects of Endophytic Fungus MF23 on Dendrobium nobile Lindl. in an artificial primary environment

The quality of Dendrobium nobile Lindl. is related to the endophytic fungus. It had reported that the mycorrhizal fungus MF23 helps to increase the content of dendrobine, but few studies had explained the mechanism of the phenomenon. In previous study, we verified the symbiotic mechanism of the mycorrhizal fungus MF23 with D. nobile on the agar medium. In this study, the research carried on the bark medium, nearly like the natural environment, which had special meaning because of its benefits for the widely application. As a result, it showed a significant effect especially in the later period of the cultivation, suggesting that mycorrhizal fungus MF23 had a promotion for D. nobile in the natural environment, which enabled the application of the technique in the experimental field. It also implied that post-modification enzyme genes might play an important role in stimulating biosynthesis of dendrobine.

genetics↗

bioRxiv2019

Mesoscale Dynamics of Spectrin and Acto-Myosin shape Membrane Territories during Mechanoresponse

The spectrin cytoskeleton is a major component of the cell cortex. While ubiquitously expressed, its dynamic interaction with the other cortex components, including the plasma membrane or the acto-myosin cytoskeleton, is poorly understood. Here, we investigated how the spectrin cytoskeleton re-organizes spatially and dynamically under the membrane during changes in cell mechanics. We found spectrin and acto-myosin cytoskeletons to be spatially distinct but cooperating during mechanical challenges, such as cell adhesion and contraction, or compression, stretch and osmolarity fluctuations, creating a cohesive cortex supporting the plasma membrane. Actin territories control protrusions and contractile structures while spectrin territories concentrate in retractile zones and low-actin density/inter-contractile regions, acting as a fence to organize membrane trafficking events. We unveil here the existence of a dynamic interplay between acto-myosin and spectrin cytoskeletons necessary to support a mesoscale organization of the lipid bilayer into spatially-confined cortical territories during cell mechanoresponse.

cell biology↗

bioRxiv2019

MB-GAN: Microbiome Simulation via Generative Adversarial Network

Simulation is a critical component of experimental design and evaluation of analysis methods in microbiome association studies. However, statistically modeling the microbiome data is challenging since that the complex structure in the real data is difficult to be fully represented by statistical models. To address this challenge, we designed a novel simulation framework for microbiome data using a generative adversarial network (GAN), called MB-GAN, by utilizing methodology advancements from the deep learning community. MB-GAN can automatically learn from a given dataset and compute simulated datasets that are indistinguishable from it. When MB-GAN was applied to a case-control microbiome study of 396 samples, we demonstrated that the simulated data and the original data had similar first-order and second-order properties, including sparsity, diversities, and taxa-taxa correlations. These advantages are suitable for further microbiome methodology development where high fidelity microbiome data are needed.

bioinformatics↗

bioRxiv2019

Global non-animal peroxidases analysis provides insights into the evolutionary study of this gene family in green lineage

The non-animal peroxidases belong to a superfamily of oxidoreductases that reduce the hydrogen peroxide and oxidize numerous substrates. Since their initial characterization in 1992, several advances have provided an understanding into the origin and evolutionary history of this family of proteins. Here, we report for the first time an exhaustive evolutionary analysis of non-animal peroxidases using integrated in silico and biochemical strategies. Thanks to the availability of numerous genomic sequences from many species belonging to different kingdoms together with expert and exhaustive annotation of peroxidase sequences centralized in a dedicated database, we have deepened our understanding of the evolutionary process underlying non-animal peroxidases through phylogenetic reconstructions. We analysed the distribution of all non-animal peroxidases in more than 200 eukaryotic organisms in silico. First, we show that the presence or absence of non-animal peroxidases can be correlated with the presence or absence of certain organelles or with specific biological processes. Examining a wide range of organisms, we confirmed that ascorbate peroxidases (APx) and cytochromes c peroxidases (CcP) were detected respectively in chloroplast and mitochondria containing organisms. Plants, which contain both organelles, are an exception and contain only APxs without CcP. Class III peroxidases (CIII Prx) were only detected in plants and Class II peroxidases (CII Prx) in fungi related to wood decay and plant degradation. Moreover, we demonstrate that biochemical activities (APx, CcP and CIII Prx) assayed in protein extracts obtained from 30 different eukaryotic organisms strongly support the distribution of the sequences resulting from our in silico analysis. The biochemical results confirmed both the presence and classification of non-animal peroxidase encoding sequences.

evolutionary biology↗

bioRxiv2019

qKW9 encodes a pentatricopeptide repeat protein affecting photosynthesis and grain filling in maize

Kernel weight is an important yield component in maize that was selected during domestication. Many kernel weight genes have been identified through mutant analysis, and are mostly involved in the biogenesis and functional maintenance of organelles or other fundamental cellular activities. However, only a limited number of loci underlying quantitative variation in kernel weight have been cloned. Here we characterize a maize kernel weight QTL, qKW9 and find that it encodes a DYW motif pentatricopeptide repeat protein involved in C-to-U editing of NdhB, a subunit of the chloroplast NADH dehydrogenase-like complex. In a null qKW9 background, C-to-U editing of NdhB was abolished, and photosynthesis was reduced, suggesting that qKW9 regulates kernel weight by controling the maternal source of photosynthate for grain filling. Characterization of qKW9 highlights the importance of optimizing photosynthesis on maize grain yield production.

plant biology↗

bioRxiv2019

Estimating genetic inheritance in case-control studies

Case-control genetic association study is an efficient tool to search for the deleterious genetic variants predispose to human complex diseases, where the additive mode of inheritance is commonly assumed. However, how the genetic variants influence the occurrence of a certain disease is impossible to know beforehand. We show numerically that the existing procedures using the Hardy-Weinberg equilibrium test to choose the genetic model might be inconsistent. We propose a new method to choose the genetic model by adopting co-dominant code for risk allele and logistic regression model. Extensive computer simulation results demonstrate superiorities of the new method. Applications to six single nucleotide polymorphisms(SNPs) for breast cancer and eight SNPs for Type 2 Diabetes further show good performances of proposed method. In order to specify a genetic model for an allele, our method has some merits and is consistent as sample size is large. We propose to apply our method in related fields.

genetics↗

bioRxiv2019

Effect of antenatal tetramethylpyrazine on lung development and YAP expression in a rat model of experimental congenital diaphragmatic hernia

Tetramethylpyrazine (TMP) is a chemical compound found in extracts derived from the Chinese medicinal plant. Due to its remarkable therapeutic effects, availability, and low cost and toxicity, TMP has been used to treat cardiovascular diseases and pulmonary hypertension in China. The aim of this study was to investigate the therapeutic effects and underlying mechanism of TMP on lung development using a rat model of nitrofen-induced congenital diaphragmatic hernia (CDH). Pregnant rats were divided into three groups: control, CDH, and CDH+TMP. Nitrofen was used to induce CDH. In the CDH and CDH+TMP, Fetuses only with left diaphragmatic hernias were chosen for analysis. Lung and body weight were recorded and lung histologic evaluations, image analysis, and western blot analysis of YAP, p-YAP and LATS1 were performed after lung processing. A marked abnormal structure was observed, as evidenced by pulmonary hypoplasia and vascular remodeling, in the CDH. These abnormalities were improved in the CDH+TMP. There were significant differences between the CDH and CDH+TMP in percentage of medial wall thickness, arteriole muscularization, radial alveolar counts, AA%, and alveolar septal thickness. YAP expression was markedly increased in the CDH compared to the control, which was not affected by antenatal TMP administration. However, prenatal TMP intervention significantly increased expression of LATS1 and phosphorylation of YAP in the CDH fetuses. Our results demonstrate that antenatal TMP administration improved vascular remodeling and promoted lung development in a rat model of CDH, potentially through increasing expression of LATS1 and phosphorylation of YAP.

developmental biology↗

bioRxiv2019

Prediction of liquid-liquid phase separation proteins using machine learning

The liquid-liquid phase separation (LLPS) of bio-molecules in cell underpins the formation of membraneless organelles, which are the condensates of protein, nucleic acid, or both, and play critical roles in cellular functions. The dysregulation of LLPS might be implicated in a number of diseases. Although the LLPS of biomolecules has been investigated intensively in recent years, the knowledge of the prevalence and distribution of phase separation proteins (PSPs) is still lag behind. Development of computational methods to predict PSPs is therefore of great importance for comprehensive understanding of the biological function of LLPS. Here, a sequence-based prediction tool using machine learning for LLPS proteins (PSPredictor) was developed. Our model can achieve a maximum 10-CV accuracy of 96.03%, and performs much better in identifying new PSPs than reported PSP prediction tools. As far as we know, this is the first attempt to make a direct and more general prediction on LLPS proteins only based on sequence information.

bioinformatics↗

bioRxiv2019

A novel vaccine targeting the viral protease cleavage sites protects Mauritian cynomolgus macaques against vaginal SIVmac251 infection

After over three decades of research, an effective anti-HIV vaccine remains elusive. Unconventional and novel vaccine strategies are needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provides greater than 80% protection of Mauritian cynomolgus macaques (MCMs) against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses are correlated with vaccine efficacy. The PCS vaccine does not induce immune activation and inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune environment generated by the PCS vaccine predicts vaccine efficacy. Our study demonstrates for the first time that a novel vaccine which targets viral maturation, but lacks full Env and Gag proteins as immunogens, can prevent intravaginal infection in a highly stringent NHP/SIV challenge model. Targeting HIV maturation thus offers a novel approach to developing an effective HIV vaccine. One Sentence SummaryThe anti-PCS T cell responses and the immune environment induced by the novel PCS vaccine are key correlates of vaccine efficacy

microbiology↗

bioRxiv2019

Learning cis-regulatory principles of ADAR-based RNA editing from CRISPR-mediated mutagenesis

Adenosine-to-inosine (A-to-I) RNA editing catalyzed by ADAR enzymes occurs in double-stranded RNAs (dsRNAs). How the RNA sequence and structure (i.e., the cis-regulation) determine the editing efficiency and specificity is poorly understood, despite a compelling need towards functional understanding of known editing events and transcriptome engineering of desired adenosines. We developed a CRISPR/Cas9-mediated saturation mutagenesis approach to generate comprehensive libraries of point mutations near an editing site and its editing complementary sequence (ECS) at the endogenous genomic locus. We used machine learning to integrate diverse RNA sequence features and computationally predicted structures to model editing levels measured by deep sequencing and identified cis-regulatory features of RNA editing. As proof-of-concept, we applied this integrative approach to three editing substrates. Our models explained over 70% of variation in editing levels. The models indicate that RNA sequence and structure features synergistically determine the editing levels. Our integrative approach can be broadly applied to any editing site towards the goal of deciphering the RNA editing code. It also provides guidance for designing and screening of antisense RNA sequences that form dsRNA duplex with the target transcript for ADAR-mediated transcriptome engineering.

molecular biology↗

bioRxiv2019

Lysyl oxidase promotes neuronal ferroptosis exacerbating seizure-induced hippocampal damage

Epilepsy is a serious neurological disorder and characterized by recurrent and unprovoked seizures. A critical pathological factor in the seizure genesis is neuronal loss. However, mechanisms which lead to neuronal death remain elusive. Our present investigation depicted that ferroptosis, a recently discovered iron- and lipid peroxidation-dependent cell death, probably served as a mechanism in murine models of kainic acid (KA)-induced seizures. And treatment with ferroptosis inhibitors ferrostatin-1 (Fer-1), liproxstatin-1 (Lipo-1) or deferoxamine (DFO) significantly suppressed seizure severity and frequency. Using gene expression profiling in HT22 cells after glutamate exposure (a validated ferroptotic cell death model), we identified lysyl oxidase (Lox) as a novel inducer of ferroptosis. Mechanistically, Lox promoted ferroptosis via activation of extracellular regulated protein kinase (ERK)-dependent 5-lipoxygenase (Alox5) phosphorylation at serine 663 residue signaling, subsequent leading to lipid reactive oxygen species (ROS) accumulation. In a murine model of KA-induced seizure, we illustrated that administration of {beta}-aminopropionitrile (BAPN), a specific Lox inhibitor, remarkably prevented seizure generation. Overall, these findings highlight Lox, a novel identified ferroptotic regulator in neurons, serves as a potential target for seizure-related disease including epilepsy.

neuroscience↗

bioRxiv2019

Meta-analysis of Scandinavian Schizophrenia Exomes

Rare genetic variants may play a prominent role in schizophrenia. We report on the to date largest whole exome sequencing study of schizophrenia case-control samples from related populations and combine with other available sequence data, analysing in total 34,084 individuals (14,302 cases). Three genes showed significant association at FDR < 0.10 (SETD1A, TAF13 and MKI67) and gene-set analyses highlighted the involvement of the synaptome and excitatory neurons, and demonstrated shared architecture with high-functioning autism.

genetics↗

bioRxiv2019

SPOP Promotes Ubiquitination and Degradation of MyD88 to Suppress the Innate Immune Response

As a canonical adaptor for Toll-like receptor (TLR) family, MyD88 has crucial roles in host defence against infection of microbial pathogens and its dysregulation might induce autoimmune diseases. Here we demonstrate that the Cullin 3-based ubiquitin ligase adaptor SPOP recognizes the intermediate domain and degrades chMyD88 through the proteasome pathway. Knockdown or genetic ablation of chSPOP leads to aberrant elevation of the chMyD88 protein. Consequently, ChSPOP negatively regulates the activity of NF-{kappa}B pathway and thus the production of IL-1{beta} and IL-8 upon LPS challenge. Furthermore, SPOP deficiency mice are more susceptible to infection of Salmonella typhimurium. Collectively, these findings demonstrate chMyD88 as a bona fide substrate of chSPOP and uncover a mechanism by which chSPOP suppresses the innate immune signaling.\n\nAuthor SummaryMyD88 is a central adaptor mediating the initiate of innate immune response and production of proinflammatory cytokines that restrain pathogens and activate adaptive immunity. Although MyD88 is crucial for the host to prevent pathogenic infection, misregulation of MyD88 abundance might lead to autoimmune diseases. Thus, degradation of MyD88 is a canonical mechanism to terminate cytokines production. Here we characterized a novel E3 ligase SPOP that target MyD88 for degradation. SPOP attenuated IL1{beta} and IL8 production through K48-linked polyubiquitination and degradation of MyD88 and thus impaired immune responses. SPOP deficient mice show more susceptibility to infection by Salmonella typhimurium. These findings demonstrate that SPOP is a negative regulator of MyD88-dependent pathway activation triggered by LPS and Salmonella typhimurium, which helps the host to maintain immune homeostasis.

immunology↗

bioRxiv2019

A statistical framework for measuring reproducibility and replicability of high-throughput experiments from multiple sources

SO_SCPLOWUMMARYC_SCPLOWReplication is essential to reliable and consistent scientific discovery in high-throughput experiments. Quantifying the replicability of scientific discoveries and identifying sources of irreproducibility have become important tasks for quality control and data integration. In this work we introduce a novel statistical model to measure the reproducibility and replicability of findings from replicate experiments in multi-source studies. Using a nested copula mixture model that characterizes the interdependence between replication experiments both across and within sources, our method quantifies reproducibility and replicability of each candidate simultaneously in a coherent framework. Through simulation studies, an ENCODE ChIP-seq dataset and a SEQC RNA-seq dataset, we demonstrate the effectiveness of our method in diagnosing the source of discordance and improving the reliability of scientific discoveries.

bioinformatics↗

bioRxiv2019

RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, discovering novel VA-regulated genes

Vitamin A (VA) deficiency remains prevalent in resource limited countries, affecting over 250 million preschool aged children. Vitamin A deficiency is associated with reduced intestinal barrier function and increased risk of mortality due to mucosal infection. Using Citrobacter rodentium (C. rodentium) infection in mice as a model for diarrheal diseases in humans, previous reports showed reduced pathogen clearance and survival in vitamin A deficient (VAD) mice compared to their vitamin A sufficient (VAS) counterparts. ObjectivesTo characterize and compare the impact of preexisting VA deficiency on gene expression patterns in the small intestine (SI) and the colon, and to discover novel target genes in VA-related biological pathways. MethodsVAD mice were generated by feeding VAD diet to pregnant C57/BL6 dams and their post-weaning offspring. RNAseq were performed using the total mRNAs extracted from SI and colon. Differentially Expressed Gene (DEG), Gene Ontology (GO) enrichment, and Weighted Gene Co-expression Network Analysis (WGCNA) were performed to characterize expression and co-expression patterns. ResultsDEGs compared between VAS and VAD groups detected 49 SI and 94 colon genes. By GO information, SI DEGs were significantly enriched in categories relevant to retinoid metabolic process, molecule binding, and immune function. Immunity related pathways, including "humoral immune response" and "complement activation" were positively associated with VA in SI. Three co-expression modules showed significant correlation with VA status in SI; these modules contained four known retinoic acid targets. In addition, other SI genes of interest (e.g. Mbl2, Cxcl14, and Nr0b2) in these modules were suggested as new candidate genes regulated by VA. Furthermore, our analysis showed that markers of two cell types in SI, mast cells and Tuft cells, were significantly altered by VA status. In colon, "cell division" was the only enriched category and was negatively associated with VA. Thus, comparison of co-expression modules between SI and colon indicated distinct networks under the regulation of dietary VA and suggest that preexisting VAD could have a significant impact on the host response to a variety of disease conditions.

physiology↗

bioRxiv2019

Genomic profiling of circulating tumor DNA reveals genetics and residual disease in NK/T lymphoma

BackgroundExtranodal NK/T-cell lymphoma, nasal type (ENTKL), is an aggressive hematological malignancy with poor prognosis. Early detection of tumors at initial diagnosis or during routine surveillance is important for improving survival outcomes. Molecular profiling of circulating tumor DNA (ctDNA) is a promising noninvasive tool for monitoring disease status. Here, we investigated the feasible of ctDNA detection in ENTKL. MethodsPlasma ctDNA was assessment were based on blood specimens that were collected from 65 patients recently diagnosed with ENKTL at the hematology medical center of Xinqiao Hospital, longitudinal samples collected under chemotherapy also included. Gene mutation spectrum of ENKTL was analyzed via cancer personalized profiling sequencing (CAPP-Seq). This study is registered with ClinicalTrials.gov (ChiCTR1800014813) ResultsFrom February 2017 to September 2019, 65 patients were enrolled, we found that the most frequently mutated genes were KMT2D (23.1%), APC (12.3%), ATM (10.8%), ASXL3 (9.2%), JAK3 (9.2%), SETD2 (9.2%), TP53 (9.2%), NOTCH1 (7.7%). The mutation frequencies of KMT2D was significantly higher in stage III-IV, and mutations in KMT2D, ASXL3 and JAK3 were significantly correlated with the metabolic tumor burden of the patients. Compared with tumor tissue DNA, ctDNA profiling showed good concordance. Serial ctDNA analysis showed that treatment with chemotherapy could decrease the number and mutation allele frequency of genes. Compared with PET/CT, ctDNA has more advantages for tracking residual disease in patients. In addition, we also found that mutated KMT2D predicted poor prognosis in patients. ConclusionCollectively, our results provide evidence that ctDNA may serve as a novel precision medicine biomarker in ENKTL.

genomics↗