Biology subjects

Li, B.

Publications and source records attributed to Li, B..

At least 19 recordsLinked to original sources

bioRxiv2018

Molecular profiles and mutation burden analysis in Chinese patients with gastric carcinoma

The goal of this work was to investigate the molecular profiles and mutation burden in Chinese patients with gastric carcinoma (GC). In total, we performed whole exome sequencing (WES) on 74 GC patients with tumor and adjacent normal formalin-fixed, paraffin-embedded (FFPE) tissue samples. The mutation spectrum of these samples showed a high concordance with TCGA and other studies on GC. We found the alterations of 17 DNA repair genes (including BRCA2, POLE and MSH3, etc.) were strongly correlated with the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) of GC patients. Patients with mutations of these genes tend to have high TMB (median of TMB = 12.77, p=2.3e-6) and TNB (median of TNB = 5.97, p= 2.8e-3). In addition, younger GC patients (age < 60) have lower TMB (p = 0.0021) and TNB (p = 0.034) than older patients (age >= 60). Furthermore, we found a list of 18 genes and two genomic regions (1p36.21 and Xq26.3) were associated with peritoneal metastasis (PM) of GC, and patients with amplification of 1p36.21 and Xq26.3 have a worse prognosis (p=0.002, 0.01, respectively). Our analysis provides GC patients with potential markers for single and combination therapies.

cancer biology↗

bioRxiv2018

Homogenization of capillary flow and oxygenation in deeper cortical layers correlates with increased oxygen extraction

Our understanding of how capillary blood flow and oxygen distribute across cortical layers to meet the local metabolic demand is incomplete. We addressed this question by using two-photon imaging of microvascular oxygen partial pressure (PO2) and flow in the whisker barrel cortex in awake mice at rest. Our measurements in layers I-V show that the capillary red-blood-cell flux and oxygenation heterogeneity, and the intracapillary resistance to oxygen delivery, all decrease with depth, reaching a minimum around layer IV, while the depth-dependent oxygen extraction fraction is increased in layer IV, where oxygen demand is presumably the highest. Our findings suggest that homogenization of physiological observables relevant to oxygen transport to tissue is an important part of the microvascular network adaptation to a local brain metabolism increase. These results will inform the biophysical models of layer-specific cerebral oxygen delivery and consumption and improve our understanding of diseases that affect the cerebral microcirculation.\n\nIMPACT STATEMENTHomogenization of cortical capillary blood flow and oxygenation underpins an important mechanism, by which the microvascular network adapts to an increase in the local brain oxidative metabolism.

neuroscience↗

bioRxiv2018

HiAlc Klebsiella pneumonia, one of potential chief culprits of non-alcoholic fatty liver disease: through generation of endogenous ethanol

Non-alcoholic fatty liver disease (NAFLD), a prelude of cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. NAFLD has been considerated to be associated with the composition of gut microbiota. However, causal relationship between change of gut microbiome and NAFLD remains unclear. Here we show that Klebsiella pneumoniae was significantly associated with NAFLD through inducing generation of endogenous ethanol. A strain of high alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) was initially isolated from fecal samples of patient with non-alcoholic steatohepatitis (NASH) accompanied with auto-brewery syndrome (ABS). Gavage of HiAlc Kpn was capable of inducing murine model of fatty liver disease (FLD) in which had typical pathological changes of hepatic steatosis and similar liver gene expression profiles to those of alcohol intake in mice. Data derived from germ-free mice by gnotobiotic gavage further demonstrated that the HiAlc Kpn is the major cause of the changes in FLD mice. Furthermore, using proteomic and metabolitic analysis, we found that HiAlc Kpn induced generation of endogenous alcohol through the 2,3-butanediol fermentation pathway. More interestingly, the blood alcohol concentration was elevated in FLD mice induced by HiAlc Kpn after glucose intake. Clinical analysis showed that HiAlc Kpn were observed in up to 60% of patients with NAFLD. Our results suggested that HiAlc Kpn make important contribution to NAFLD, possibly through generation of the endogenous alcohol. Thus, targeting these bacteria might provide a novel therapeutic for clinical treatment of NAFLD.\n\nIn BriefFatty liver disease induced by high alcohol-producing Klebsiella pneumoniae\n\nCompeting Financial Interest StatementThe authors declare no conflicts of interest.

microbiology↗

bioRxiv2018

Detection of adaptive divergence in populations of the stream mayfly Ephemera strigata with machine learning

Adaptive divergence is a key mechanism shaping the genetic variation of natural populations. A central question linking ecology with evolutionary biology concerns the role of environmental heterogeneity in determining adaptive divergence among local populations within a species. In this study, we examined adaptive the divergence among populations of the stream mayfly Ephemera strigata in the Natori River Basin in northeastern Japan. We used a genome scanning approach to detect candidate loci under selection and then applied a machine learning method (i.e. Random Forest) and traditional distance-based redundancy analysis (dbRDA) to examine relationships between environmental factors and adaptive divergence at non-neutral loci. We also assessed spatial autocorrelation at neutral loci to quantify the dispersal ability of E. strigata. Our main findings were as follows: 1) random forest shows a higher resolution than traditional statistical analysis for detecting adaptive divergence; 2) separating markers into neutral and non-neutral loci provides insights into genetic diversity, local adaptation and dispersal ability and 3) E. strigata shows altitudinal adaptive divergence among the populations in the Natori River Basin.

evolutionary biology↗

bioRxiv2018

Bidirectional Control of Coronary Vascular Resistance by Eicosanoids via a Novel GPCR

Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We identified G protein-coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor antagonistically regulated by two endogenous eicosanoids: 15-HETE, which stimulates GPR39 to increase mVSMC intracellular calcium and augment microvascular CVR, and 14,15-EET, which inhibits these actions. Furthermore, zinc ion acts as an allosteric modulator of GPR39 to potentiate the efficacy of the two ligands. Our findings will have a major impact on understanding the roles of eicosanoids in cardiovascular physiology and disease, and provide an opportunity for the development of novel GPR39-targeting therapies for cardiovascular disease.\n\nOne Sentence SummaryGPR39 is a microvascular smooth muscle cell receptor regulated by two vasoactive eicosanoids with opposing actions.

physiology↗

bioRxiv2018

RT States: systematic annotation of the human genome using cell type-specific replication timing programs

The replication timing (RT) program has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows to characterize the RT program in the entire human genome in a high-throughput and high-resolution fashion. These experiments suggest that RT changes dynamically during development in coordination with gene activity. Since RT is such a fundamental biological process, we believe that an effective quantitative profile of the local RT program from a diverse set of cell types in various developmental stages and lineages can provide crucial biological insights for a genomic locus. In the present study, we explored recurrent and spatially coherent combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We found that a Hidden Markov Model with 15 hidden states provide a good model to describe these genome-wide RT profiling data. Each of the hidden state represents a unique combination of RT profiles across different cell types which we refer to as \"RT states\". To understand the biological properties of these RT states, we inspected their relationship with chromatin states, gene expression, functional annotation and 3D chromosomal organization. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome.\n\nAUTHOR SUMMARYThe replication timing (RT) program is an important cellular mechanism and has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows us to characterize the RT program in the entire human genome. Results from these experiments suggest that RT changes dynamically across different developmental stages. Since RT is such a fundamental biological process, we believe that the local RT program from a diverse set of cell types in various developmental stages can provide crucial biological insights for a genomic locus. In the present study, we explored combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We developed a statistical model consist of 15 \"RT states\" to describe these genome-wide RT profiling data. To understand the biological properties of these RT states, we inspected the relationship between RT states and other types of functional annotations of the genome. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome.

bioinformatics↗

bioRxiv2018

Mining unknown porcine protein isoforms by tissue-based map of proteome enhances the pig genome annotation

A lack of the complete pig proteome has left a gap in our knowledge of the pig genome and has restricted the feasibility of using pigs as a biomedical model. We developed the tissue-based proteome maps using 34 major normal pig tissues. A total of 7,319 unknown protein isoforms were identified and systematically characterized, including 3,703 novel protein isoforms, 669 protein isoforms from 460 genes symbolized beginning with LOC, and 2,947 protein isoforms without clear NCBI annotation in current pig reference genome. These newly identified protein isoforms were functionally annotated through profiling the pig transcriptome with high-throughput RNA sequencing (RNA-seq) of the same pig tissues, further improving the genome annotation of corresponding protein coding genes. Combining the well-annotated genes that having parallel expression pattern and subcellular witness, we predicted the tissue related subcellular components and potential function for these unknown proteins. Finally, we mined 3,656 orthologous genes for 49.95% of unknown protein isoforms across multiple species, referring to 65 KEGG pathways and 25 disease signaling pathways. These findings provided valuable insights and a rich resource for enhancing studies of pig genomics and biology as well as biomedical model application to human medicine.

genomics↗

bioRxiv2018

RNA polymerase mapping in plants identifies enhancers enriched in causal variants

Promoter-proximal pausing and divergent transcription at promoters and enhancers, which are prominent features in animals, have been reported to be absent in plants based on a study of Arabidopsis thaliana. Here, our PRO-Seq analysis in cassava (Manihot esculenta) identified peaks of transcriptionally-engaged RNA polymerase II (Pol2) at both 5 and 3 ends of genes, consistent with paused or slowly-moving Pol2, and divergent transcription at potential intragenic enhancers. A full genome search for bi-directional transcription using an algorithm for enhancer detection developed in mammals (dREG) identified many enhancer candidates. These sites show distinct patterns of methylation and nucleotide variation based on genomic evolutionary rate profiling characteristic of active enhancers. Maize GRO-Seq data showed RNA polymerase occupancy at promoters and enhancers consistent with cassava but not Arabidopsis. Furthermore, putative enhancers in maize identified by dREG significantly overlapped with sites previously identified on the basis of open chromatin, histone marks, and methylation. We show that SNPs within these divergently transcribed intergenic regions predict significantly more variation in fitness and root composition than SNPs in chromosomal segments randomly ascertained from the same intergenic distribution, suggesting a functional importance of these sites on cassava. The findings shed new light on plant transcription regulation and its impact on development and plasticity.

genomics↗

bioRxiv2018

Coordinative Metabolism of Glutamine Carbon and Nitrogen in proliferating Cancer Cells Under Hypoxia

Under hypoxia, most of glucose is converted to secretory lactate, which leads to the lack of carbon source from glucose and thus the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid releasing potentially toxic ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate under hypoxia. We found that glutamine nitrogen is indispensable to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. The specific metabolic pathway occurs in vivo and is required for tumor growth. Such a metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism.\n\nSignificanceTumor cells often addict to glutamine, and particularly utilize its carbon for lipogenesis under hypoxia. We reveal that tumor cells package the excessive glutamine-nitrogen into secretory dihydroorotate, instead of toxic ammonia. This specifically reprogrammed pathway supports in vivo tumor growth, and could offer diagnostic markers and therapeutic targets for cancers.

biochemistry↗

bioRxiv2018

Identification of Novel Genes and Variations Associated to Glycolytic Potential Based on Pig Model

In livestock, glycolytic potential (GP) is a critical indicator for evaluating the meat quality. To date, two major genes protein kinase AMP-activated {gamma}3 non-catalytic subunit gene (PRKAG3) and phosphorylase kinase catalytic subunit gamma 1(PHKG1), and corresponding cause mutations influencing GP have been confirmed in pigs. Therefore, the aim of this study to identify the novel candidate genes and variations related to GP-related traits using a four-hybrid pig model [Pietrain (P)x Duroc (D)] x[(Landrace) x(Yorkshire)]. We totally constructed six RNA-seq libraries using longissimus dorsi (LD) muscles, and each library contained two higher GP (H) or two lower GP (L) individuals. A total of 525, 698 and 135 differentially expressed genes (DEGs) were identified between H11 vs L11, H9 vs L9, and H5 vs L5 groups using PossionDis method, respectively. Notably, we found 97 non-redundant DEGs were mapped to GP related QTLs from three paired comparison groups. Moreover, 69 DEGs were identified between H (H11, H9 and H5) and L (L11, L9 and L5) groups using NOIseq method. Additionally, 1,076 potential specific SNPs were figured out between H and L groups, and approximately 40 large Indels with a length [≥] 5bp were identified in each sequencing library. In conclusion, our data provide foundation for further confirming the key genes and the functional mutations affecting GP-related traits in pigs, and also pave the way for elucidating the underling molecular regulatory mechanisms of glycogen metabolism in future study. Moreover, this study might provide valuable information for study on human glycogen storage diseases.

genomics↗

bioRxiv2018

The Big Five, Self-efficacy, and Self-control in Boxers

Inviting 210 boxers of national athletes in China as participants, this study applied the NEO Five-Factor Inventory and self-control and self-efficacy scales for athletes to examine the relationship between personality traits and self-control, as well as any effect of self-efficacy as a mediator between the two variables. The data analysis indicated that, firstly, the boxers overall level of self-control is high, and the higher the competitive level, the higher the level of self-control. Secondly, there were significant correlations among the Big Five, self-control, and self-efficacy. Thirdly, the mediation model showed that self-efficacy has a significant mediating effect between the Big Five and self-control. These results suggest that formulating training and intervention programs based on the personality traits of boxers and focusing on training their self-efficacy (1) to help them enhance their self-control ability, thereby improving athletic performance and promoting physical and mental health, and (2) to support the inclusion of personality traits, self-efficacy, and self-control among psychological indicators to be assessed in boxers.

scientific communication and education↗

bioRxiv2018

Understanding RNP remodelling uncovers RBPs functionally required for viral replication

The compendium of RNA-binding proteins (RBPome) has been greatly expanded by the development of RNA-interactome capture (RNA-IC). However, it remains unknown how responsive is the RBPome and whether these responses are biologically relevant. To answer these questions, we created comparative RNA-IC to analyse cells challenged with an RNA virus, called sindbis (SINV). Strikingly, the virus altered the activity of 245 RBPs, many of which were newly discovered by RNA-IC. Mechanistically, alterations in RNA binding upon SINV infection are caused by changes in the subcellular localisation of RBPs and RNA availability. Moreover, RBPome responses are crucial, as perturbation of dynamic RBPs modulates the capacity of the virus to infect the cell. For example, ablation of XRN1 causes cells to be refractory to infection, while GEMIN5 moonlights as a novel antiviral factor. Therefore, RBPome remodelling provides a mechanism by which cells can extensively rewire gene expression in response to physiological cues.\n\nHIGHLIGHTSO_LIA quarter of the RBPome remodels upon SINV infection.\nC_LIO_LIThe remodelling is caused by changes in protein localisation and RNA availability.\nC_LIO_LIRewiring of the RBPome is crucial for viral infection efficacy.\nC_LIO_LIWe discover RBPs with previously unknown anti- or pro-viral activity.\nC_LI

molecular biology↗

bioRxiv2018

Unaltered prion disease in mice lacking developmental endothelial locus-1 (Del 1)

Progression of prion diseases is driven by the accumulation of prions in the brain. Ablation of microglia or deletion of the eat-me-signal milk-fat globule EGF factor VIII (Mfge8) accelerate prion pathogenesis, suggesting that microglia defends the brain by phagocytosing prions. Like Mfge8, Developmental endothelial locus-1 (Del-1) is a secreted protein that acts as an opsonin bridging phagocytes and apoptotic cells to facilitate phagocytosis. We therefore asked whether Del-1 might play a role in controlling prion pathogenesis. We first determined the expression pattern of Del-1 in mice, and found that the brain expresses the highest level of Del-1. In mouse brains, Del-1 was mainly expressed by neurons. We then assessed the anti-inflammatory and phagocytosis-promoting functions of Del-1 in prion disease, and determined whether Del-1 complements Mfge8 in prion clearance in mice with a C57BL/6J genetic background. We found that Del-1 deficiency did not change prion disease progression and lesion patterns. Also, prion clearance and PrPSc deposition were unaltered in Del-1 deficient mice. Additionally, prioninduced neuroinflammation was not affected by Del-1 deficiency. We conclude that Del-1 is not a major determinant of prion pathogenesis in this context.

neuroscience↗

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

Characterization and identification of long non-coding RNAs based on feature relationship

The significance of long non-coding RNAs (lncRNAs) in many biological processes and diseases has gained intense interests over the past several years. However, computational identification of lncRNAs in a wide range of species remains challenging; it requires prior knowledge of well-established sequences and annotations or species-specific training data, but the reality is that only a limited number of species have high-quality sequences and annotations. Here we first characterize lncRNAs by contrast to protein-coding RNAs based on feature relationship and find that the feature relationship between ORF (open reading frame) length and GC content presents universally substantial divergence in lncRNAs and protein-coding RNAs, as observed in a broad variety of species. Based on the feature relationship, accordingly, we further present LGC, a novel algorithm for identifying lncRNAs that is able to accurately distinguish lncRNAs from protein-coding RNAs in a cross-species manner without any prior knowledge. As validated on large-scale empirical datasets, comparative results show that LGC outperforms existing algorithms by achieving higher accuracy, well-balanced sensitivity and specificity, and is robustly effective (>90% accuracy) in discriminating lncRNAs from protein-coding RNAs across diverse species that range from plants to mammals. To our knowledge, this study, for the first time, differentially characterizes lncRNAs and protein-coding RNAs based on feature relationship, which is further applied in computational identification of lncRNAs. Taken together, our study represents a significant advance in characterization and identification of lncRNAs and LGC thus bears broad potential utility for computational analysis of lncRNAs in a wide range of species.

bioinformatics↗

bioRxiv2018

A particle-filter framework for robust cryoEM 3D reconstruction

Electron cryo-microscopy (cryoEM) is now a powerful tool in determining atomic structures of biological macromolecules under nearly natural conditions. The major task of single-particle cryoEM is to estimate a set of parameters for each input particle image to reconstruct the three-dimensional structure of the macromolecules. As future large-scale applications require increasingly higher resolution and automation, robust high-dimensional parameter estimation algorithms need to be developed in the presence of various image qualities. In this paper, we introduced a particle-filter algorithm for cryoEM, which was a sequential Monte Carlo method for robust and fast high-dimensional parameter estimation. The cryoEM parameter estimation problem was described by a probability density function of the estimated parameters. The particle filter uses a set of random and weighted support points to represent such a probability density function. The statistical properties of the support points not only enhance the parameter estimation with self-adaptive accuracy but also provide the belief of estimated parameters, which is essential for the reconstruction phase. The implementation of these features showed strong tolerance to bad particles and enabled robust defocus refinement, demonstrated by the remarkable resolution improvement at the atomic level.

biophysics↗

bioRxiv2018

Population coding of valence in the basolateral amygdala

The basolateral amygdala (BLA) plays an important role in associative learning, by representing both conditioned stimuli (CSs) and unconditioned stimuli (USs) of positive and negative valences, and by forming associations between CSs and USs. However, how such associations are formed and updated during learning remains unclear. Here we show that associative learning driven by reward and punishment profoundly alters BLA neuronal responses at population levels, reducing noise correlations and transforming the representations of CSs to resemble the distinctive valence-specific representations of USs. This transformation is accompanied by the emergence of prevalent inhibitory CS and US responses, and by the plasticity of CS responses in individual BLA neurons. During reversal learning wherein the expected valences are reversed, BLA population CS representations are remapped onto ensembles representing the opposite valences and track the switching in valence-specific behavioral actions. Our results reveal how signals predictive of opposing valences in the BLA evolve during reward and punishment learning, and how these signals might be updated and used to guide flexible behaviors.

neuroscience↗

bioRxiv2018

TRAF6 directs Foxp3 localization and facilitates Treg function through K63-type ubiquitination

Regulatory T cells (Treg) are crucial mediators of immune control. The characteristic gene expression and suppressive function of Treg depend considerably on the stable expression and activity of the transcription factor Foxp3. While transcriptional regulation of the Foxp3 gene has been studied in depth, both the expression and function of Foxp3 are also modulated at the protein level. However, the molecular players involved in posttranslational Foxp3 regulation are just beginning to be elucidated. Here we found TRAF6-deficient Tregs were dysfunctional in vivo; mice with Treg-restricted deletion of TRAF6 were resistant to B16 melanomas and displayed enhanced anti-tumor immunity. We further determined that Foxp3 undergoes lysine-63 chain (K63) ubiquitination at lysine 262 mediated by the E3 ligase TRAF6. When deprived of TRAF6 activity or rendered insensitive to K63 ubiquitination, Foxp3 displayed aberrant, perinuclear accumulation, disrupted function. Thus, Foxp3 ubiquitination by TRAF6 ensures proper localization of Foxp3 and facilitates Foxp3s gene-regulating activity in Tregs. These results implicate TRAF6 as a key posttranslational, Treg-stabilizing force that may be targeted in novel tolerance-breaking therapies.

immunology↗