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Liu, L.

Publications and source records attributed to Liu, L..

At least 37 records · Page 2Linked to original sources

Estimating heterogeneous treatment effects by balancing heterogeneity and fitness

Estimating heterogeneous treatment effects is an important problem in many medical and biological applications since treatments may have different effects on the prognoses of different patients. Recently, several recursive partitioning methods have been proposed to identify the subgroups that with different responds to a treatment, and they rely on a fitness criterion to minimize the error between the estimated treatment effects and the unobservable true effects. In this paper, we propose that a heterogeneity criterion, which maximizes the differences of treatment effects among the subgroups, also needs to be considered. Moreover, we show that better performances can be achieved when the fitness and the heterogeneous criteria are considered simultaneously. Selecting the optimal splitting points then becomes a multi-objective problem; however, a solution that achieves optimal in both aspects are often not available. To solve this problem, we propose a multi-objective splitting procedure to balance both criteria. The proposed procedure is computationally efficient and fits naturally into the existing recursive partitioning framework. Experimental results show that the proposed multi-objective approach performs consistently better than existing ones.\n\nAuthor summaryThe effects of a treatment are often not the same for different individuals with different gene expressions. Learning to predict the heterogeneous treatment effects from clinical and expression data is an important step towards personalized medical treatment. Existing computational methods are not ideal for the task because they do not address the interpretability of the model and do not consider the limited sample sizes in biological and medical applications. Our method addresses these issues and achieves superior performance in analyzing the treatment effects of radiotherapy on breast cancer patients.

bioinformatics

First report and multilocus genotyping of Enterocytozoon bieneusi from Tibetan pigs in southwestern China

Enterocytozoon bieneusi is a common intestinal pathogen and a major cause of diarrhea and enteric diseases in a variety of animals. While the E. bieneusi genotype has become better-known, there are few reports on its prevalence in the Tibetan pig. This study investigated the prevalence, genetic diversity, and zoonotic potential of E. bieneusi in the Tibetan pig in southwestern China. Tibetan pig feces (266 samples) were collected from three sites in the southwest of China. Feces were subjected to PCR amplification of the internal transcribed spacer (ITS) region. E. bieneusi was detected in 83 (31.2%) of Tibetan pigs from the three different sites, with 25.4% in Kangding, 56% in Yaan and 26.7% in Qionglai. Age group demonstrated the prevalence of E. bieneusi range from 24.4%(aged 0 to 1 years) to 44.4%(aged 1 to 2 years). Four genotypes of E. bieneusi were identified: two known genotypes EbpC (n=58), Henan-IV (n=24) and two novel genotypes, SCT01 and SCT02 (one of each). Phylogenetic analysis showed these four genotypes clustered to group 1 with zoonotic potential. Multilocus sequence typing (MLST) analysis three microsatellites (MS1, MS3, MS7) and one minisatellite (MS4) revealed 47, 48, 23 and 47 positive specimens were successfully sequenced, and identified ten, ten, five and five genotypes at four loci, respectively. This study indicates the potential danger of E. bieneusi to Tibetan pigs in southwestern China, and offers basic data for preventing and controlling infections.

genetics

Deconvolution of single-cell multi-omics layers reveals regulatory heterogeneity

Integrative analysis of multi-omics layers at single cell level is critical for accurate dissection of cell-to-cell variation within certain cell populations. Here we report scCAT-seq, a technique for simultaneously assaying chromatin accessibility and the transcriptome within the same single cell. We show that the combined single cell signatures enable accurate construction of regulatory relationships between cis-regulatory elements and the target genes at single-cell resolution, providing a new dimension of features that helps direct discovery of regulatory patterns specific to distinct cell identities. Moreover, we generated the first single cell integrated maps of chromatin accessibility and transcriptome in human pre-implantation embryos and demonstrated the robustness of scCAT-seq in the precise dissection of master transcription factors in cells of distinct states during embryo development. The ability to obtain these two layers of omics data will help provide more accurate definitions of \"single cell state\" and enable the deconvolution of regulatory heterogeneity from complex cell populations.

genomics

Two Isoforms of the Guanine Nucleotide Exchange Factor, Daple/CCDC88C Cooperate as Tumor Suppressors

Previously Aznar et al., showed that Daple enables Wnt/Frizzled receptors to transactivate trimeric G proteins during non-canonical Wnt signaling via a novel G-protein binding and activating (GBA) motif. By doing so, Daple serves as a double-edged sword; earlier during oncogenesis it suppresses neoplastic transformation and tumor growth, but later it triggers epithelial messenchymal transition (EMT). We have identified and characterized two isoforms of the human Daple/CCDC88c gene. While both isoforms cooperatively suppress tumor growth via their GBA motif, only the full-length transcript triggers EMT and invasion. Aspirin suppresses the full-length transcript and protein but upregulates the short isoform. Both isoforms are suppressed during colon cancer progression, and their reduced expression carries additive prognostic significance. These findings provide insights into the opposing roles of Daple during cancer progression and define the G protein regulatory GBA motif as one of the minimal modules essential for Daples role as a tumor suppressor.

cancer biology

Further expansion of methane metabolism in the Archaea

The recent discovery of key methane-metabolizing genes in the genomes from the archaeal phyla Bathyarchaeota and Verstraetearchaeota has expanded our understanding of the distribution of methane metabolism outside of the phylum Euryarchaeota. Here, we recovered two near-complete crenarchaeotal metagenome-assembled genomes (MAGs) from circumneutral hot springs that contain genes for methanogenesis, including the genes that encode for the key methyl-coenzyme M reductase (MCR) complex. These newly recovered archaea phylogenetically cluster with Geoarchaeota (deep lineage of archaeal order Thermoproteales), and the MCR-encoding genes clustered with the recently reported methanogens within the Verstraetearchaeota. In addition, genes encoding hydroxybutyryl-CoA dehydratase were identified in the newly recovered methanogens, indicating they might carry out the {beta}-oxidation process. Together, our findings further expanded the methane metabolism outside the phylum Euryarchaeota.

microbiology

Biogenesis of a young, 22-nt microRNA in Phaseoleae species by precursor-programmed uridylation

Phased, secondary siRNAs (phasiRNAs) represent a class of small RNAs in plants generated via distinct biogenesis pathways, predominantly dependent on the activity of 22 nt miRNAs. Most 22 nt miRNAs are processed by DCL1 from miRNA precursors containing an asymmetric bulge, yielding a 22/21 nt miRNA/miRNA* duplex. Here we show that miR1510, a soybean miRNA capable of triggering phasiRNA production from numerous NB-LRRs, previously described as 21 nt in its mature form, primarily accumulates as a 22 nt isoform via monouridylation. We demonstrate that in Arabidopsis, this uridylation is performed by HESO1. Biochemical experiments showed that the 3 terminus of miR1510 is only partially 2-O-methylated, because of the terminal mispairing in the miR1510/miR1510* duplex that inhibits HEN1 activity in soybean. miR1510 emerged in the Phaseoleae ~41 to 42 MYA with a conserved precursor structure yielding a 22 nt monouridylated form, yet a variant in mung bean is processed directly in a 22 nt mature form. This analysis of miR1510 yields two observations: (1) plants can utilize post-processing modification to generate abundant 22 nt miRNA isoforms to more efficiently regulate target mRNA abundances; (2) comparative analysis demonstrates an example of selective optimization of precursor processing of a young plant miRNA.

plant biology

Inhibition of EV71 replication by L3HYPDH, a newly identified interferon-stimulated gene product

Enterovirus 71 (EV71) is the common causative agent of hand-foot-mouth disease (HFMD). Despite evidence in mice model suggested that the interferon (IFN) signaling pathways play a role in defending against this virus, knowledge on the IFN-mediated antiviral response is still limited. Here we identified an IFN-stimulated gene (ISG) called L3HYPHD, whose expression inhibits EV71 replication. Mapping assay indicated that amino acids 61-120 and 295-354 are critical for its optimal antiviral activity. Mechanismly, L3HYPDH specifically inhibits protein translation mediated by EV71 internal ribosome entry site (IRES). Our data thus uncovered a new mechanism utilized by the host cell to restrict EV71 replication.

microbiology

Knockdown of GAS5 restores ox-LDL-induced impaired autophagy flux via upregulating miR-26a in human endothelial cells

BackgroundOxidized low-density lipoprotein (ox-LDL)-induced endothelial cell (EC) injury and autophagy dysfunction play a vital role in the development of atherosclerosis. LncRNAs have been identified to participate in the regulation of pathogenesis of atherosclerosis. However, it remains largely undefined whether growth-arrest specific transcript 5 (GAS5) could influence ox-LDL-induced autophagy dysfunction in ECs.\n\nMethodsThe expressions of GAS5 and miR-26a in the plasma samples of patients with atherosclerosis and ox-LDL-treated human aortic endothelial cells (HAECs) were detected by qRT-PCR. Luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull down were performed to validate whether GAS5 could directly interact with miR-26a. The effects of ox-LDL, GAS5 or combined with miR-26a on apoptosis and autophagy were evaluated by flow cytometry analysis and western blot, respectively.\n\nResultsGAS5 expression was upregulated and miR-26a was downregulated in the plasma samples of patients with atherosclerosis and ox-LDL-treated HAECs. There was reciprocal inhibition between GAS5 and miR-26a expressions in ox-LDL-treated HAECs. We further demonstrated that GAS5 directly interacted with miR-26a in ox-LDL-treated HAECs. Additionally, ox-LDL administration induced apoptosis and impaired autophagy flux in HAECs. Rescue experiments demonstrated that GAS5 knockdown restored ox-LDL-induced impaired autophagy flux by upregulating miR-26a in HAECs.\n\nConclusionKnockdown of GAS5 restores ox-LDL-induced impaired autophagy flux via upregulating miR-26a in human endothelial cells, revealing a novel regulatory mechanism for ox-LDL-induced impaired autophagy flux in ECs through ceRNA crosstalk.

biochemistry

Single-cell RNA-seq reveals profibrotic macrophages in lung fibrosis

Myeloid cells localize to peripheral tissues in a wide range of pathologic contexts. However, appreciation of distinct myeloid subtypes has been limited by the signal averaging inherent to bulk sequencing approaches. Here we applied single-cell RNA sequencing (scRNA-seq) to map cellular heterogeneity in lung fibrosis induced by bleomycin injury in mice. We first developed a computational framework that enables unbiased, granular cell-type annotation of scRNA-seq. This approach identified a macrophage subpopulation that was specific to injured lung and notable for high expression of Cx3cr1+ and MHCII genes. We found that these macrophages, which bear a gene expression profile consistent with monocytic origin, progressively acquire alveolar macrophage identity and localize to sites of fibroblast accumulation. Probing their functional role, in vitro studies showed a trophic effect of these cells on fibroblast activation, and ablation of Cx3cr1-expressing cells suppressed fibrosis in vivo. We also found by gene set analysis and immunofluorescence that markers of these macrophages were upregulated in samples from patients with lung fibrosis compared with healthy controls. Taken together, our results uncover a specific pathologic subgroup of macrophages with markers that could enable their therapeutic targeting for fibrosis.

immunology

The expression tractability of a biological trait

Understanding how gene expression is translated to phenotype is central to modern molecular biology, but the success is contingent on the intrinsic tractability of the specific traits under examination. However, an a priori estimate of trait tractability from the perspective of gene expression is unavailable. Motivated by the concept of entropy in a thermodynamic system, we here propose such an estimate (ST) by gauging the number (N) of different expression states that underlie the same trait abnormality, with large ST corresponding to large N. By analyzing over 200 yeast morphological traits we show that ST is constrained by natural selection, which builds co-regulated gene modules to minimize the total number of possible expression states. We further show that ST is a good measure of the titer of recurrent patterns of an expression-trait relationship, predicting the extent to which the trait could be deterministically understood with gene expression data.

genomics

The homoeologous genes for the Rec8-like meiotic cohesin in wheat: structure, function, and evolutionary implication

The Rec8-like cohesin is a cohesion protein essential for orderly chromosome segregation in meiosis. Here, we cloned two Rec8-like homoeologous genes (homoeoalleles) from tetraploid wheat (TtRec8-A1 and TtRec8-B1) and one from hexaploid wheat (TaRec8-D1), and performed expression and functional analyses of the homoeoalleles. Also, we identified other two Rec8 homoeoalleles in hexaploid wheat (TaRec8-A1 and TaRec8-B1) and the one in Aegilops tauschii (AetRec8-D1) by comparative analysis. The coding DNA sequences (CDS) of these six Rec8 homoeoalleles are all 1,827 bp in length, encoding 608 amino acids. They differed from each other primarily in introns although single nucleotide polymorphisms were detected in CDS. Substantial difference was observed between the homoeoalleles from the subgenome B (TtRec8-B1 and TaRec8-B1) and those from the subgenomes A and D (TtRec8-A1, TaRec8-A1, and TaRec8-D1). TtRec8-A1 expressed dominantly over TtRec8-B1, but comparably to TaRec8-D1. Therefore, the Rec8 homoeoalleles from the subgenomes A and D may be functionally more active than the one from the subgenome B in wheat. The structural variation and differential expression of the Rec8 homoeoalleles indicate a unique cross-genome coordination of the homoeologous genes in the polyploid, and imply the distinction of the wheat subgenome B from other subgenomes in the origin and evolution.\n\nHIGHLIGHTThis work revealed the structural and expression patterns of the Rec8-like homoeologous genes in polyploid wheat, implying a unique origin and evolutionary route of the wheat B subgenome.

genetics

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

The anthelmintic niclosamide is a potent TMEM16A antagonist that fully bronchodilates airways

There is an unmet need in severe asthma where approximately 40% of patients exhibit poor {beta}-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca2+-activated-Cl- channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ~580,000 compounds. The anthelmintics niclosamide, nitazoxanide and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting {beta}-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully bronchodilated airways, while the {beta}-agonist isoproterenol showed only partial effects. Thus, antagonists of TMEM16A and repositioning of niclosamide and nitazoxanide represent an important additional treatment for patients with severe asthma and COPD that is poorly controlled with existing therapies. It is of note that drug repurposing has also attracted wide interest in niclosamide and nitazoxanide as a new treatment for cancer and infectious disease. For the first time we identify TMEM16A as a molecular target for these drugs and thus provide fresh insights into their mechanism for the treatment of these disorders in addition to respiratory disease.

physiology

NormExpression: an R package to normalize gene expression data using evaluated methods

Data normalization is a crucial step in the gene expression analysis as it ensures the validity of its downstream analyses. Although many metrics have been designed to evaluate the current normalization methods, the different metrics yield inconsistent results. In this study, we designed a new metric named Area Under normalized CV threshold Curve (AUCVC) and applied it with another metric mSCC to evaluate 14 commonly used normalization methods, achieving consistency in our evaluation results using both bulk RNA-seq and scRNA-seq data from the same library construction protocol. This consistency has validated the underlying theory that a sucessiful normalization method simultaneously maximizes the number of uniform genes and minimizes the correlation between the expression profiles of gene pairs. This consistency can also be used to analyze the quality of gene expression data. The gene expression data, normalization methods and evaluation metrics used in this study have been included in an R package named NormExpression. NormExpression provides a framework and a fast and simple way for researchers to evaluate methods (particularly some data-driven methods or their own methods) and then select a best one for data normalization in the gene expression analysis.

bioinformatics

Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors

Proliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the synthesis of serine from glucose, phosphoglycerate dehydrogenase (PHGDH) controls flux through the biosynthetic pathway for this important amino acid and represents a putative target in oncology. To discover inhibitors of PHGDH, a coupled biochemical assay was developed and optimized to enable high-throughput screening for inhibitors of human PHGDH. Feedback inhibition was minimized by coupling PHGDH activity to two downstream enzymes (PSAT1 and PSPH), providing a significant improvement in enzymatic turnover. Further coupling of NADH to a diaphorase/resazurin system enabled a red-shifted detection readout, minimizing interference due to compound autofluorescence. With this protocol, over 400,000 small molecules were screened for PHGDH inhibition, and following hit validation and triage work, a piperazine-1-thiourea was identified. Following rounds of medicinal chemistry and SAR exploration, two probes (NCT-502 and NCT-503) were identified. These molecules demonstrated improved target activity and encouraging ADME properties, enabling both in vitro and in vivo assessment of the biological importance of PHGDH, and its role in the fate of serine in PHGDH-dependent cancer cells.

cancer biology

Combined aptamer and transcriptome sequencing of single cells

The transcriptome and proteome encode distinct information that is important for characterizing heterogeneous biological systems. We demonstrate a method to simultaneously characterize the transcriptomes and proteomes of single cells at high throughput using aptamer probes and droplet-based single cell sequencing. With our method, we differentiate distinct cell types based on aptamer surface binding and gene expression patterns. Aptamers provide advantages over antibodies for single cell protein characterization, including rapid, in vitro, and high-purity generation via SELEX, and the ability to amplify and detect them with PCR and sequencing.

cell biology

Architecture of human interphase chromosome determines the spatiotemporal dynamics of chromatin loci

By incorporating the information of human chromosome inferred from Hi-C experiments into a heteropolymer model of chromatin chain, we generate a conformational ensemble to investigate its spatiotemporal dynamics. The heterogeneous loci interactions result in hierarchical organization of chromatin chain, which obeys compact space-filling (SF) statistics at intermediate length scale. Remarkably, the higher order architecture of the chromatin, characterized by the single universal Flory exponent ({nu} = 1/3) for condensed homopolymers, provides quantitative account of the dynamical properties of the chromosome. The local chromosome structures, exemplified by topologically associated domains (~ 0.1 - 1 Mb), display dynamics with fast relaxation time ([lsim] 50 sec), whereas the long-range spatial reorganization of the entire chromatin [Formula] occurs on a much longer time scale ({gtrsim} hour), suggestive of glass-like behavior. This key finding provides the dynamic basis of cell-to-cell variability. Active forces, modeled using stronger isotropic white noises, accelerate the relaxation dynamics of chromatin domain described by the low frequency modes. Surprisingly, they do not significantly change the local scale dynamics from those under passive condition. By linking the spatiotemporal dynamics of chromosome with its organization, our study highlights the importance of physical constraints in chromosome architecture on the sluggish dynamics.\n\nSignificance StatementChromosomes are giant chain molecules made of hundreds of megabase-long DNA intercalated with proteins. Structure and dynamics of interphase chromatin in space and time hold the key to understanding the cell type-dependent gene regulation. In this study, we establish that the crumpled and space-filling organization of chromatin fiber in the chromosome territory, characterized by a single universal exponent used to describe polymer sizes, is sufficient to explain the complex spatiotemporal hierarchy in chromatin dynamics as well as the subdiffusive motion of the chromatin loci. While seemingly a daunting problem at a first glance, our study shows that relatively simple principles, rooted in polymer physics, can be used to grasp the essence of dynamical properties of the interphase chromatin.

biophysics

Prediction of potential disease-associated microRNAs using structural perturbation method

MotivationThe identification of disease-related microRNAs(miRNAs) is an essential but challenging task in bioinformatics research. Similarity-based link prediction methods are often used to predict potential associations between miRNAs and diseases. In these methods, all unobserved associations are ranked by their similarity scores. Higher score indicates higher probability of existence. However, most previous studies mainly focus on designing advanced methods to improve the prediction accuracy while neglect to investigate the link predictability of the networks that present the miRNAs and diseases associations. In this work, we construct a bilayer network by integrating the miRNA-disease network, the miRNA similarity network and the disease similarity network. We use structural consistency as an indicator to estimate the link predictability of the related networks. On the basis of the indicator, a derivative algorithm, called structural perturbation method (SPM), is applied to predict potential associations between miRNAs and diseases.\n\nResultsThe link predictability of bilayer network is higher than that of miRNA-disease network, indicating that the prediction of potential miRNAs-diseases associations on bilayer network can achieve higher accuracy than based merely on the miRNA-disease network. A comparison between the SPM and other algorithms reveals the reliable performance of SPM which performed well in a 5-fold cross-validation. We test fifteen networks. The AUC values of SPM are higher than some well-known methods, indicating that SPM could serve as a useful computational method for improving the identification accuracy of miRNA-disease associations. Moreover, in a case study on breast neoplasm, 80% of the top-20 predicted miRNAs have been manually confirmed by previous experimental studies.\n\nAvailability and Implementationhttps://github.com/lecea/SPM-code.git\n\nContactlinyuan.lv@gmail.com, zouquan@nclab.net.\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics