Biology subjects

Li, S.

Publications and source records attributed to Li, S..

At least 1,225 records · Page 68Linked to original sources

bioRxiv2019

Sleep deprivation selectively down-regulates astrocytic 5-HT2B receptors and triggers depressive-like behaviors via stimulating P2X7 receptors

Chronic loss of sleep damages health and disturbs quality of life. The long-lasting sleep deprivation (SD) as well as sleep abnormalities is a substantial risk factor for major depressive disorder (MDD), although the underlying mechanisms are not clear. In our previous studies, we report the activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome induced by long-term SD is P2X7 receptors (P2X7R) dependent, and antidepressant fluoxetine could alleviate this neuroinflammasome via 5-HT2B receptors (5-HT2BR) in astrocytes. Here, we discovered that the chronic SD activates astroglial P2X7 receptors, which in turn selectively down-regulated expression of 5-HT2BR in astrocytes. Stimulation of P2X7R induced by SD suppressed the phosphorylation of AKT and FoxO3a selectively in astrocytes, but not in neurones. The over-expression of FoxO3a in astrocytes inhibited expression of 5-HT2BR. Down-regulation of 5-HT2BR instigated by SD suppressed activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2 (cPLA2). This latter cascade promoted the release of arachidonic acid (AA) and prostaglandin E2 (PGE2). The depressive-like behaviours induced by SD were alleviated in P2X7R-KO mice. Our study reveals the mechanism underlying chronic SD-induced depressive-like behaviors and highlights that blocking P2X7 receptors or activating 5-HT2BR in astrocytes could play a key role for exploring the therapeutic strategies aimed at the depression evoked by sleep disorders.\n\nMain PointsChronic SD selectively down-regulates expression of 5-HT2BR through activation of P2X7R in astrocytes. SD promotes the release of AA and PGE2 via the decreased 5-HT2BR, these factors induce depressive-like behaviors.

neuroscience↗

bioRxiv2019

A 3D High Resolution Generative Deep-learning Network for Fluorescence Microscopy Image

Deep learning technology enables us acquire high resolution image from low resolution image in biological imaging free from sophisticated optical hardware. However, current methods require a huge number of the precisely registered low-resolution (LR) and high-resolution (HR) volume image pairs. This requirement is challengeable for biological volume imaging. Here, we proposed 3D deep learning network based on dual generative adversarial network (dual-GAN) framework for recovering HR volume images from LR volume images. Our network avoids learning the direct mappings from the LR and HR volume image pairs, which need precisely image registration process. And the cycle consistent network makes the predicted HR volume image faithful to its corresponding LR volume image. The proposed method achieves the recovery of 20x/1.0 NA volume images from 5x/0.16 NA volume images collected by light-sheet microscopy. In essence our method is suitable for the other imaging modalities.

neuroscience↗

bioRxiv2019

A cold shock protein from a thermophile bacterium promotes the high-temperature growth of bacteria and fungi through binding to diverse RNA species

High temperatures deleteriously affect cells by damaging cellular structures and changing the behavior of diverse biomolecules, and extensive research about thermophilic microorganisms has elucidated some of the mechanisms that can overcome these effects and allow thriving in high-temperature ecological niches. We here used functional genomics methods to screen out a cold-shock protein (CspL) from a high-productivity lactate producing thermophile strain (Bacillus coagulans strain 2-6) grown at 37{degrees}C and 60{degrees}C. We subsequently made the highly striking finding that transgenic expression of CspL conferred massive increases in high temperature growth of other organisms including E. coli (2.4-fold biomass increase at 45{degrees}C) and the eukaryote S. cerevisiae (a 2.7-fold biomass increase at 34{degrees}C). Pursuing these findings, we used bio-layer interferometry assays to characterize the nucleotide-binding function of CspL in vitro, and used proteomics and RNA-Seq to characterize the global effects of CspL on mRNA transcript accumulation and used RIP-Seq to identify in vivo RNA targets of this nucleotide-binding protein (e.g. rpoE, and rmf, etc.). Finally, we confirmed that a nucleotide-binding-dead variant form of CspL does not have increased growth rates or biomass accumulation effects at high temperatures. Our study thus establishes that CspL can function as a global RNA chaperone.

microbiology↗

bioRxiv2019

Mercator: An R Package for Visualization ofDistance Matrices

SummaryUnsupervised data analysis in many scientific disciplines is based on calculating distances between observations and finding ways to visualize those distances. These kinds of unsupervised analyses help researchers uncover patterns in large-scale data sets. However, researchers can select from a vast number of different distance metrics, each designed to highlight different aspects of different data types. There are also numerous visualization methods with their own strengths and weaknesses. To help researchers perform unsupervised analyses, we developed the Mercator R package. Mercator enables users to see important patterns in their data by generating multiple visualizations using different standard algorithms, making it particularly easy to compare and contrast the results arising from different metrics. By allowing users to select the distance metric that best fits their needs, Mercator helps researchers perform unsupervised analyses that use pattern identification through computation and visual inspection.\n\nAvailability and ImplementationMercator is freely available at the Comprehensive R Archive Network (https://cran.r-project.org/web/packages/Mercator/index.html)\n\nContactKevin.Coombes@osumc.edu\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2019

Mining the human tonsillar microbiota as autoimmune modulator

Palatine tonsils are important lymphoid organs featuring constant cross-talks between the commensal microorganisms and immune system, and have been implicated as critical autoimmunity origins for immune-related diseases, including rheumatoid arthritis (RA), a common autoimmune disorder. However, there was no evidence to show link between tonsillar microbiota and RA. Here, we identified a significant dysbiosis of RA tonsillar microbiota, with loss of Streptococcus salivarius and its functional molecules salivaricins (a type of antibacterial peptides). Consistent with the niche-preference, S. salivarius and salivaricins administrated intranasally or intraorally conferred prophylactic and therapeutic efficacies against experimental arthritis. Moreover, we demonstrated, for the first time, that S. salivarius and salivaricins exerted immunosuppressive capacities via inhibiting CD4+effector T cell subsets and autoantibody production in mice and human. These results uncover a communication between tonsillar microbiota and host autoimmunity, and identify the active components from tonsillar microbes in modulating immune homeostasis.\n\nOne sentence summaryTonsillar microbiota regulate host autoimmunity via antibacterial peptides

microbiology↗

bioRxiv2019

Persistent Elevation of Electrical Pain Threshold following Continuous Theta Burst Stimulation over Primary Somatosensory Cortex in Humans

BackgroundPrimary somatosensory cortex (S1) is involved in pain processing and thus its suppression using neuromodulatory techniques such as continuous theta burst stimulation (cTBS) might be a potential pain management strategy in patients with neuropathic pain. S1 cTBS is known to elevate pain threshold in young adults. However, the persistence of this effect is unknown.\n\nObjective/HypothesisWe hypothesized persistent elevation of pain threshold following cTBS over S1 in healthy, young adults.\n\nMethodsWe recruited ten subjects in a sham-controlled crossover design and recorded their electrical pain threshold (EPT) for 40 min following cTBS over S1. We assessed corticospinal excitability (CSE) to rule out the involvement of primary motor cortex due to spread of current.\n\nResultscTBS over S1 elevated EPT without modulating CSE compared to sham stimulation. EPT was elevated for 40 min post-cTBS.\n\nConclusionsS1 can be focally targeted using cTBS for a longer lasting pain relief in patients.

neuroscience↗

bioRxiv2019

Measurement of Atom Resolvability in CryoEM Maps with Q-scores

CryoEM density maps are now at the point where resolvability of individual atoms can be achieved. However, resolvability is not necessarily uniform throughout the map. We introduce a quantitative parameter to characterize the resolvability of individual atoms in cryoEM maps, the map Q-score. Q-scores can be calculated for atoms in proteins, nucleic acids, water, ligands, and other solvent atoms, using models fitted to or derived from cryoEM maps. Q-scores can also be averaged to represent larger features such as entire residues and nucleotides. Averaged over entire models, Q-scores correlate very well with the estimated resolution of cryoEM maps for both protein and RNA. Assuming the models they are calculated from are well-fitted to the map, Q-scores can thus be used as another measure to indicate resolvability of features in cryoEM maps at various scales, from entire complexes down to individual atoms. Q-score analysis of multiple cryoEM maps of the same proteins derived from different labs confirms reproducibility of structural features down to water and ion atoms.

biochemistry↗

bioRxiv2019

Ribosolve: Rapid determination of three-dimensional RNA-only structures

The discovery and design of biologically important RNA molecules is dramatically outpacing three-dimensional structural characterization. To address this challenge, we present Ribosolve, a hybrid method integrating moderate-resolution cryo-EM maps, chemical mapping, and Rosetta computational modeling, and demonstrate its application to thirteen previously unknown 119-to 338-nucleotide protein-free RNA-only structures: full-length Tetrahymena ribozyme, hc16 ligase with and without substrate, full-length V. cholerae and F. nucleatum glycine riboswitch aptamers with and without glycine, Mycobacterium SAM-IV riboswitch with and without S-adenosylmethionine, and computer-designed spinach-TTR-3, eterna3D-JR_1, and ATP-TTR-3 with and without AMP. Blind challenges, prospective compensatory mutagenesis, internal controls, and simulation benchmarks validate the Ribosolve models and establish that modeling convergence is quantitatively predictive of model accuracy. These results demonstrate that RNA-only 3D structure determination can be rapid and routine.

biophysics↗

bioRxiv2019

Endocytic Clathrin Coats Develop Curvature at Early Stages of Their Formation

Sculpting a flat patch of membrane into an endocytic vesicle requires curvature generation on the cell surface, which is the primary function of endocytic protein complexes. The mechanism through which membrane curvature is imposed during formation of clathrin-coated vesicles is an ongoing controversy. Using super-resolved live cell fluorescence imaging, we demonstrate that curvature generation by clathrin-coated pits can be detected in real time within cultured cells and tissues of developing metazoan organisms. We found that the footprint of clathrin coats increase monotonically during formation of curved pits at different levels of plasma membrane tension. Our findings are only compatible with models that predict curvature generation at early stages of endocytic clathrin-coated pit formation. Therefore, clathrin-coated vesicle formation does not necessitate a dynamically unstable clathrin lattice that would allow an abrupt flat-to-curved transition. SummaryEndocytic clathrin coats acquire curvature without a flat-to-curved transition that requires an extensive reorganization of the clathrin lattice.

biophysics↗

bioRxiv2019

An integrative ENCODE resource for cancer genomics

ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting how SUB1, a previously uncharacterized RBP, drives aberrant tumor expression and amplifies the effect of MYC, a well-known oncogenic TF. Furthermore, we show how our annotation allows us to place oncogenic transformations in the context of a broad cell space; here, many normal-to-tumor transitions move towards a stem-like state, while oncogene knockdowns show an opposing trend. Finally, we organize the resource into a coherent workflow to prioritize key elements and variants, in addition to regulators. We showcase the application of this prioritization to somatic burdening, cancer differential expression and GWAS. Targeted validations of the prioritized regulators, elements and variants using siRNA knockdowns, CRISPR-based editing, and luciferase assays demonstrate the value of the ENCODE resource.

genomics↗

bioRxiv2019

Direct Metatranscriptome RNA-seq and Multiplex RT-PCR Amplicon Sequencing on Nanopore MinION - Promising Strategies for Multiplex Identification of Viable Pathogens in Food

Viable pathogenic bacteria are major biohazards that pose a significant threat to food safety. Despite the recent developments in detection platforms, multiplex identification of viable pathogens in food remains a major challenge. A novel strategy is developed through direct metatranscriptome RNA-seq and multiplex RT-PCR amplicon sequencing on Nanopore MinION to achieve real-time multiplex identification of viable pathogen in food. Specifically, this study reports an optimized universal Nanopore sample extraction and library preparation protocol applicable to both Gram-positive and Gram-negative pathogenic bacteria, demonstrated using a cocktail culture of E. coli O157:H7, Salmonella enteritidis, and Listeria monocytogenes, which were selected based on their impact on economic loss or prevalence in recent outbreaks. Further evaluation and validation confirmed the accuracy of direct metatranscriptome RNA-seq and multiplex RT-PCR amplicon sequencing using Sanger sequencing and selective media. The study also included a comparison of different bioinformatic pipelines for metatranscriptomic and amplicon genomic analysis. MEGAN without rRNA mapping showed the highest accuracy of multiplex identification using the metatranscriptomic data. EPI2ME also demonstrated high accuracy using multiplex RT-PCR amplicon sequencing. In addition, a systemic comparison was drawn between Nanopore sequencing of the direct metatranscriptome RNA-seq and RT-PCR amplicons. Both methods are comparable in accuracy and time. Nanopore sequencing of RT-PCR amplicon has higher sensitivity, but Nanopore metatranscriptome sequencing excels in read length and dealing with complex microbiome and non-bacterial transcriptome backgrounds. To the best of our knowledge, this is the first report of metatranscriptome sequencing of cocktail microbial RNAs on the emerging Nanopore platform. Direct RNA-seq and RT-PCR amplicons sequencing of metatranscriptome enable the direct identification of nucleotide analogs in RNAs, which is highly informative for determining microbial identities while detecting ecologically relevant processes. The information pertained in this study could be important for future revelatory research, including predicting antibiotic resistance, elucidating host-pathogen interaction, prognosing disease progression, and investigating microbial ecology, etc.

microbiology↗

bioRxiv2019

Extent and context dependence of pleiotropy revealed by high-throughput single-cell phenotyping

Pleiotropy - when a single mutation affects multiple traits - is a controversial topic with far-reaching implications. Pleiotropy plays a central role in debates about how complex traits evolve and whether biological systems are modular or are organized such that every gene has the potential to affect many traits. Pleiotropy is also critical to initiatives in evolutionary medicine that seek to trap infectious microbes or tumors by selecting for mutations that encourage growth in some conditions at the expense of others. Research in these fields, and others, would benefit from understanding the extent to which pleiotropy reflects inherent relationships among phenotypes that correlate no matter the perturbation (vertical pleiotropy). Alternatively, pleiotropy may result from genetic changes that impose correlations between otherwise independent traits (horizontal pleiotropy). We distinguish these possibilities by using clonal populations of yeast cells to quantify the inherent relationships between single-cell morphological features. Then, we demonstrate how often these relationships underlie vertical pleiotropy and how often these relationships are modified by genetic variants (QTL) acting via horizontal pleiotropy. Our comprehensive screen measures thousands of pairwise trait correlations across hundreds of thousands of yeast cells and reveals ample evidence of both vertical and horizontal pleiotropy. Additionally, we observe that the correlations between traits can change with the environment, genetic background and cell-cycle position. These changing dependencies suggest a nuanced view of pleiotropy: biological systems demonstrate limited pleiotropy in any given context, but across contexts (e.g., across diverse environments and genetic backgrounds) each genetic change has the potential to influence a larger number of traits. Our method suggests that exploiting pleiotropy for applications in evolutionary medicine would benefit from focusing on traits with correlations that are less dependent on context.

evolutionary biology↗

bioRxiv2019

The nervous system is the major target for Gold nanoparticle-based therapy: Evidence from RNA sequencing data of C. elegans

The increasing use of gold nanoparticles (NPs) raises concerns about the potential effect of gold NPs exposure on human health. Therefore, gold NPs exposure is hard to evaluate at the organ level with current measurement technology. The bio-distribution assay showed that intestine was the organ with most gold NPs accumulated in C. elegans. However, our data indicated that 62.8% of the significant altered genes were function in the nervous system using tissue enrichment analysis. Notably, developmental stage analysis has demonstrated that NP exposure interfered with the development of animals. Furthermore, the transcription factors DAF-16 was regulating the oxidative stress genes induced by gold NPs. Therefore, we proposed the localization of the oxidative stress genes in the neuron cells and how their expression affect neuron communication. Our results demonstrate that the gold NPs-induced oxidative stress affects the nervous system via physical damage to the neurons and disruption of cell-to-cell communication. Future toxicology research on gold NPs should focus on neurons. O_FIG O_LINKSMALLFIG WIDTH=120 HEIGHT=200 SRC="FIGDIR/small/699785v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@19effeorg.highwire.dtl.DTLVardef@db10d9org.highwire.dtl.DTLVardef@2f4736org.highwire.dtl.DTLVardef@1ec2a52_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

neuroscience↗

bioRxiv2019

Partial absence of PD-1 expression by tumor-specific CD8+ T cells in EBV-driven lymphoepithelioma-like carcinoma: a case report

Lymphoepithelioma-like carcinoma (LELC) is an uncommon lung cancer, typically observed in young, non-smoking Asian populations. LELC is associated with Epstein-Barr virus (EBV) infection of lung tumor cells of epithelial origin, suggesting a carcinogenic role of EBV as observed in nasopharyngeal carcinoma (NPC). Here, we studied the antigen specificity and phenotype of CD8+ tumor infiltrating lymphocytes (TILs) in one LELC patient positive for EBV infection in lung tumor cells. Using MHC class I tetramers, we detected two populations of EBV-specific CD8+ TILs, which can be considered as tumor-specific CD8+ T cells, in the tumor of this patient. Transcriptomic analyses of these two populations reveal their distinct exhausted profiles and polyclonal TCR repertoire. High dimensional analyses at single cell level using mass cytometry showed showed that populations of tumor specific CD8+ TILs are phenotypically heterogeneous, although they consistently express CD39. Unexpectedly, although the LELC tumor cells expressed abundant PD-L1, these tumor-specific CD8+ TILs mostly did not express PD-1, suggesting that anti-PD1/PD-L1 immunotherapy may not be an appropriate strategy for disinhibiting EBV-specific cells for the treatment of LELC patients. These results might also help to explain low rates of checkpoint blockade immunotherapy response for NPC, despite the antigenicity of EBV for both tumor types.

cancer biology↗

bioRxiv2019

CELLULOSE SYNTHASE INTERACTIVE1- and Microtubule-Dependent Cell Wall Architecture Is Required for Acid Growth in Arabidopsis Hypocotyls

Auxin-induced cell elongation relies in part on the acidification of the cell wall, a process known as acid growth that presumably triggers expansin-mediated wall loosening via altered interactions between cellulose microfibrils. Cellulose microfibrils are a major determinant for anisotropic growth and they provide the scaffold for cell wall assembly. Little is known about how acid growth depends on cell wall architecture. To explore the relationship between acid growth-mediated cell elongation and plant cell wall architecture, two mutants (jia1-1 and csi1-3) that are defective in cellulose biosynthesis and cellulose microfibril organization were analyzed. The study revealed that cell elongation is dependent on CSI1-mediated cell wall architecture but not on the overall crystalline cellulose content. We observed a correlation between loss of crossed-polylamellate walls and loss of auxin- and fusicoccin-induced cell growth in csi1-3. Furthermore, induced loss of crossed-polylamellate walls via disruption of cortical microtubule mimics the effect of csi1 in acid growth. We hypothesize that CSI1- and microtubule-dependent crossed-polylamellate walls are required for acid growth in Arabidopsis hypocotyls.

plant biology↗

bioRxiv2019

CD155/CD96 promotes immunosuppression in lung adenocarcinoma (LUAD)

Lung adenocarcinoma (LUAD) remains one of the leading causes of death in patients with cancer. The association of CD155 with CD96 transmits an inhibitory signal and suppresses antitumor immune response. This study investigates the effect of CD155/CD96 on immune suppression in LUAD. We demonstrate that LUAD patients with high CD155 expression suffer from immune suppression and experience a poor prognosis, which coincides with an inhibited AKT-mTOR signaling pathway in CD8 T cells and subsequently up-regulated CD96 expression. Moreover, the inhibition effect can be reversed by CD96 blocking antibody. High CD155 expression inhibited the release of IFN{gamma} from CD8 cells. Moreover, Blocking CD96 restored IFN{gamma} production in CD8 T cells and neutralized the inhibition of IFN{gamma} production in CD8 T cells mediated by CD155. Animal experiments showed that CD155-mediated LUAD growth might depend on its suppression antitumor immune response in the tumor microenvironment in PDX mice. In conclusion, our results suggest that LUAD cells suppress antitumor immune response in the tumor microenvironment through CD155/CD96. CD155/CD96 could be a potential therapeutic target for LUAD patients.\n\nAbbreviationsLUAD: lung adenocarcinoma; IFN{gamma}: interferon gamma; PDX: patient-derived xenograft; NSCLC: non-small cell lung cancer; PRR: poliovirus receptor-related; MDSCs: myeloid-derived suppressor cells; PRR: poliovirus receptor-related; STR: short tandem repeat; IRS: immunoreactive score; SI: staining intensity; PP: percentage of positive cells; RT-PCR: reverse transcription-polymerase chain reaction; PBS: phosphate-buffered saline; PBMCs: peripheral blood mononuclear cells; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; rCD155: recombinant human CD155; LUAD cells: lung adenocarcinoma cells; TILs: tumor-infiltrating lymphocytes; GzmB: granzyme B; IL-2 (Interleukin-2); TNF- : tumor necrosis factor-alpha; PI: propidium Iodide; PDX: patient-derived xenograft; TIGIT: T cell immunoreceptor with Igand ITIM domains; WBC: white blood cells; MFI: mean fluorescence intensity; HPF: high power field

cancer biology↗

bioRxiv2019

H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions

Gene repression and silencers are poorly understood. We reasoned that H3K27me3-rich regions (MRRs) of the genome defined from clusters of H3K27me3 peaks may be used to identify silencers that can regulate gene expression via proximity or looping. MRRs were associated with chromatin interactions and interact preferentially with each other. MRR component removal at interaction anchors by CRISPR led to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. The MRR knockout cells also showed changes in phenotype associated with cell identity, and altered xenograft tumor growth. MRR-associated genes and long-range chromatin interactions were susceptible to H3K27me3 depletion. Our results characterized H3K27me3-rich regions and their mechanisms of functioning via looping.

genomics↗

bioRxiv2019

Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities

We conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.

neuroscience↗