Biology subjects

Liu, R.

Publications and source records attributed to Liu, R..

At least 307 records · Page 17Linked to original sources

bioRxiv2019

Arabidopsis ERF109 regulates auxin transport-related genes in root development

The transcription factor ERF109 acts as a crosstalk node between jasmonic acid signaling and auxin biosynthesis by directly regulating YUC2 and ASA1 during lateral root formation in Arabidopsis. However, whether ERF109 regulates the auxin transport remains unclear. Here we report a mechanism of ERF109-mediated auxin transport in root system. Through root transcriptome comparison between erf109, wild type, and 35S:ERF109, we found that the genes PIN2 and PIN4, encoding the major membrane-based efflux carriers of auxin, were enriched in the overexpression line. In the promoters of these auxin transport genes, GCC-box cis elements were found and potentially bound by ERF109. Moreover, PID, encoding a key regulator in polar auxin transport, was found upregulated in 35S:ERF109 and down regulated in erf109. Yeast-one-hybrid and chromatin immunoprecipitation assays showed that ERF109 directly bound to the GCC-box of PIN2, PIN4, and PID. Genetic analyses with double mutants confirmed the function of ERF109 in the regulation of auxin transport in Arabidopsis roots. Taken together, our results show that ERF109 modulates auxin transport by directly regulating PIN2, PIN4 and PID. This ERF109-mediated auxin transport likely works together with ERF109-mediated auxin synthesis to establish auxin maxima for lateral root initiation.

plant biology↗

bioRxiv2019

Linking light-dependent life history traits with population dynamics for Prochlorococcus and cyanophage

Prochlorococcus grow in diurnal rhythms driven by diel cycles. Their ecology depends on light, nutrients, and top-down mortality processes including lysis by viruses. Cyanophage, viruses that infect cyanobacteria, are also impacted by light. For example, extracellular viability and intra-cell infection kinetics of some cyanophage vary between light and dark conditions. Nonetheless, it remains unclear if light-dependent viral life history traits scale-up to influence population-level dynamics. Here we examined the impact of diel-forcing on both cellular- and population-scale dynamics in multiple Prochlorococcus-phage systems. To do so, we developed a light-driven population model including both cellular growth and viral infection dynamics. We then tested the model against measurements of experimental infection dynamics with diel forcing to examine the extent to which population level changes in both viral and host abundances could be explained by light-dependent life history traits. Model-data integration reveals that light-dependent adsorption can improve fits to population dynamics for some virus-host pairs. However, light-dependent variation alone does not fully explain realized host and virus population dynamics. Instead, we show evidence of a previously unrecognized lysis saturation at relatively high virus to cell ratios. Altogether, our study represents a quantitative approach to integrate mechanistic models to reconcile Prochlorococcus-virus dynamics spanning cellular to population scales.

microbiology↗

bioRxiv2019

Nucleus Basalis Stimulation Stabilizes Attractor Networks and Enhances Task Representation in Prefrontal Cortex

Acetylcholine in the neocortex is critical for executive function. Degeneration of the basal forebrain cholinergic system is associated with cognitive decline in aging and Alzheimers disease. Cholinergic agonists and acetylcholinesterase inhibitors improve cognitive performance as does intermittent electrical stimulation of the cortical source of acetylcholine, the Nucleus Basalis (NB) of Meynert. Here we tested how NB stimulation improves working memory behavior and alters its neural code. NB stimulation increased dorsolateral prefrontal activity during the delay period of working memory tasks but did not strengthen phasic responses to the optimal visual stimulus of each neuron. Unexpectedly, improvement of behavioral performance was not the result of increased neural selectivity. Tuning of neuronal responses broadened, which rendered an attractor network more stable and filtered distracting visual stimuli more effectively. Thus, the effects of acetylcholine on prefrontal neural activity and selectivity in working memory contrast those of dopamine and stabilize neural ensembles based on neuromodulatory tone.

neuroscience↗

bioRxiv2019

Deep spectral learning for label-free optical imaging oximetry with uncertainty quantification

Measurement of blood oxygen saturation (sO2) by optical imaging oximetry provides invaluable insight into local tissue functions and metabolism. Despite different embodiments and modalities, all label-free optical imaging oximetry utilize the same principle of sO2-dependent spectral contrast from hemoglobin. Traditional approaches for quantifying sO2 often rely on analytical models that are fitted by the spectral measurements. These approaches in practice suffer from uncertainties due to biological variability, tissue geometry, light scattering, systemic spectral bias, and variations in experimental conditions. Here, we propose a new data-driven approach, termed deep spectral learning (DSL) for oximetry to be highly robust to experimental variations, and more importantly to provide uncertainty quantification for each sO2 prediction. To demonstrate the robustness and generalizability of DSL, we analyze data from two visible light optical coherence tomography (vis-OCT) setups across two separate in vivo experiments in rat retina. Predictions made by DSL are highly adaptive to experimental variabilities as well as the depth-dependent backscattering spectra. Two neural-network-based models are tested and compared with the traditional least-squares fitting (LSF) method. The DSL-predicted sO2 shows significantly lower mean-square errors than the LSF. For the first time, we have demonstrated en face maps of retinal oximetry along with pixel-wise confidence assessment. Our DSL overcomes several limitations in the traditional approaches and provides a more flexible, robust, and reliable deep learning approach for in vivo non-invasive label-free optical oximetry.

bioengineering↗

bioRxiv2019

Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against autoimmune diseases

TNF- signaling plays a central role in the pathogenesis of various diseases, particularly autoimmune diseases. Screening of a library composed of FDA approved drugs led to the identification of Terfenadine and its active metabolite Fexofenadine as inhibitors of TNF- signaling. Both Fexofenadine and Terfenadine inhibited TNF/NF-{kappa}B signaling in vitro and in vivo, and ameliorated disease symptoms in various autoimmune disease models, including TNF- transgenic mice, collagen-induced arthritis, and inflammatory bowel disease. Subsequent studies identified cytosolic phospholipase A2 (cPLA2) as a novel target of Fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished Fexofenadines anti-TNF activity. Collectively, these findings not only provide new insights into the understanding of Fexofenadine action and underlying mechanism, but also provide new therapeutic interventions for various TNF- and cPLA2-associated pathologies and conditions, particularly autoimmune diseases.

molecular biology↗

bioRxiv2019

Characterization of the workplace chemical exposome using untargeted LC-MS/MS: a case study

Western people now spend close to 90% of their time indoors, one-quarter of which occurs at their place of employment. As such, interactions between employees and the workplace built environment have significant potential impact on employee health and safety. However, the range of workers daily chemical exposures is still poorly understood. Likewise, the influence of workers themselves and of worker behavior on the chemical composition of the workplace is still unknown. In this case study, we used untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) to compare the chemical signatures of three different types of workplaces: scientific research buildings, office buildings, and one mixed-purpose building. Our results identified differential signatures of public building surfaces based on building purpose, sampling location and surface materials. Overall, these results are helping define the influence of human behavior on the workplace chemical environment and identify the chemical hazards to which people are exposed throughout their workday. HighlightsO_LIImplementation of untargeted liquid chromatography-tandem mass spectrometry to study workplace chemical exposures. C_LIO_LIShared chemical signatures were identified based on building purpose. C_LIO_LIDifferential chemical signatures were identified based on surface material and sampling location. C_LIO_LIAnnotated molecules include pharmaceuticals, illicit drugs, food chemicals, constituents of paints and stains, and cleaning products. C_LI

biochemistry↗

bioRxiv2019

Genotypic frequencies at equilibrium for polysomic inheritance under double-reduction

Polyploids are organisms whose genomes consist of more than two complete sets of chromosomes. Both autopolyploids and allopolyploids may display polysomic inheritance. A peculiarity of polysomic inheritance is multivalent formation during meiosis resulting in double-reduction, which occurs when sister chromatid fragments are segregated into the same gamete. Double-reduction can result in gametes carrying identical-by-descent alleles and slightly increasing homozygosity. This will cause the genotypic frequencies to deviate from expected values and will thus bias the results of standard population genetic analytical methods used in molecular ecology and selective breeding. In this study, we extend existing double-reduction models to account for any even level of ploidy, and derive the symbolic expressions for genotypic frequencies via two methods. Inbreeding coefficients and heterozygosity under double-reduction and inbreeding are also calculated. Numerical solutions obtained by computer simulations are compared with analytical solutions predicted by the model to validate the model.

genetics↗

bioRxiv2018

Multi-plane Imaging of Neural Activity From the Mammalian Brain Using a Fast-switching Liquid Crystal Spatial Light Modulator

We report a novel two-photon fluorescence microscope based on a fast-switching liquid crystal spatial light modulator and a pair of galvo-resonant scanners for large-scale recording of neural activity from the mammalian brain. The utilized imaging technique is capable of monitoring large populations of neurons spread across different layers of the neocortex in awake and behaving mice. During each imaging session, all visual stimulus driven somatic activity could be recorded in the same behavior state. We observed heterogeneous response to different types of visual stimuli from ~ 3,300 excitatory neurons reaching from layer II/III to V of the striate cortex.

bioengineering↗

bioRxiv2018

Comparative metabonomic investigations of Schistosoma japonicum from SCID mice and BALB/c mice: clues to developmental abnormality of schistosome in the immunodeficient host

It has been discovered that the development of schistosome is hampered in immunodeficient mice, e.g. nude mice lacking T-lymphocytes and the severe combined immune deficient (SCID) mice lacking both T- and B-lymphocytes. However, its still unresolved about the underlying regulatory mechanisms of the retarded growth and development of schistosomes in their immunodeficient definitive host. In this study, therefore, five replicates of male or female Schistosoma japonicum samples with twenty male or female worms in each sample, were collected from SCID mice or BALB/c mice at five weeks post infection and used to perform metabonomic analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS) platform, for elucidating the growth and development regulation of schistosome in their definitive hosts from the metabolomic aspect. Based on the identified 1015 ion features in ESI+ mode and 342 ion features in ESI-mode, multivariate modelling methods including the Principal Component Analysis (PCA), Partial Least Squares Discriminant Analysis (PLS-DA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) identified distinct metabolic profiles that clearly differentiated both male and female worms in SCID mice from those in BALB/c mice, respectively. Common and uniquely perturbed metabolites and their involved metabolic pathways were identified in male and female worms from SCID mice when compared with those from BALB/c mice. The results also revealed that more differential metabolites were found in female worms (one metabolite was up-regulated and forty metabolites were down-regulated) than male worms (nine metabolites were up-regulated and twenty metabolites were down-regulated) between SCID mice and BALB/c mice. The top five increased metabolites of male worms in SCID mice when compared with those in BALB/c mice were PC(22:6/20:1), L-allothreonine, L-serine, glycerophosphocholine and 5-aminoimidazole ribonucleotide. And the top five decreased metabolites of male worms in SCID mice when compared with those in BALB/c mice were PC(16:0/0:0), PAF C-16, PE(18:1/0:0), adenosine and butenoyl PAF. Most of the differential metabolites of female worms in SCID mice had lower levels when compared with the normal female worms in BALB/c mice, except for retinyl ester with a higher level. The top five decreased metabolites of female worms in SCID mice when compared with those in BALB/c mice were adrenic acid, 5-phosphoribosylamine, PC(16:0/0:0), PC(22:6/20:1) and ergothioneine. The involved metabolic pathways of the differential metabolites in male worms between SCID mice and BALB/c mice mainly included taurine and hypotaurine metabolism, glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, alpha-linolenic acid metabolism, etc. The involved metabolic pathways of differential metabolites in female worms included mainly pyrimidine metabolism, sphingolipid metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, etc. These findings suggested a correlation between the retarded growth and development of schistosome in SCID mice and their perturbed metabolic profiles, which also provided a new insight into the regulation mechanisms of growth and development of S. japonicum worms from the metabolic level, and provided clues for discovery of drugs or vaccines against the parasites and parasitic disease.\n\nAuthor summaryThe growth and development of schistosome has been discovered hampered in the immunodeficient hosts. But it remains unresolved about the molecular mechanisms involved in this. In this study, we tested and compared the metabolic profiles of the male and female Schistosoma japonicum worms collected from SCID mice or BALB/c mice at five weeks post infection using liquid chromatography tandem mass spectrometry (LC-MS/MS) platform. There were 1015 ion features in ESI+ mode and 342 ion features in ESI-mode were identified, and distinct metabolic profiles were found to clearly differentiate both male and female worms in SCID mice from those in BALB/c mice, respectively. The results also found more differential metabolites in female worms than in male worms between SCID mice and BALB/c mice. The enriched metabolic pathways of the differential metabolites in male worms between SCID mice and BALB/c mice included taurine and hypotaurine metabolism, glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, alpha-linolenic acid metabolism, etc. And the enriched metabolic pathways of differential metabolites in female worms included pyrimidine metabolism, sphingolipid metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, etc. The findings in this study suggested an association between the developmentally stunted schistosome and their perturbed metabolites and metabolic pathways, which provided a new insight into the regulation mechanisms of growth and development of S. japonicum worms from the metabolic level, and clues for discovery of drugs or vaccines against the parasites and disease.

biochemistry↗

bioRxiv2018

Comparative genetic architectures of schizophrenia in East Asian and European populations

Author summarySchizophrenia is a severe psychiatric disorder with a lifetime risk of about 1% world-wide. Most large schizophrenia genetic studies have studied people of primarily European ancestry, potentially missing important biological insights. Here we present a study of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide significant schizophrenia associations in 19 genetic loci. Over the genome, the common genetic variants that confer risk for schizophrenia have highly similar effects in those of East Asian and European ancestry (rg=0.98), indicating for the first time that the genetic basis of schizophrenia and its biology are broadly shared across these world populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries revealed 208 genome-wide significant schizophrenia associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping more precisely isolated schizophrenia causal alleles in 70% of these loci. Despite consistent genetic effects across populations, polygenic risk models trained in one population have reduced performance in the other, highlighting the importance of including all major ancestral groups with sufficient sample size to ensure the findings have maximum relevance for all populations.

genetics↗

bioRxiv2018

Bioinformatics workflows for genomic analysis of tumors from Patient Derived Xenografts (PDX): challenges and guidelines

Bioinformatics workflows for analyzing genomic data obtained from xenografted tumor (e.g., human tumors engrafted in a mouse host) must address several challenges, including separating mouse and human sequence reads and accurate identification of somatic mutations and copy number aberrations when paired normal DNA from the patient is not available. We report here data analysis workflows that address these challenges and result in reliable identification of somatic mutations, copy number alterations, and transcriptomic profiles of tumors from patient derived xenograft models. We validated our analytical approaches using simulated data and by assessing concordance of the genomic properties of xenograft tumors with data from primary human tumors in The Cancer Genome Atlas (TCGA). The commands and parameters for the workflows are available at https://github.com/TheJacksonLaboratory/PDX-Analysis-Workflows.

bioinformatics↗

bioRxiv2018

Mismatch-repair signature mutations activate gene enhancers across colorectal cancer epigenomes

Commonly-mutated genes have been found for many cancers, but less is known about mutations in cis-regulatory elements. We leverage gains in tumor-specific enhancer activity, coupled with allele-biased mutation detection from H3K27ac ChIP-seq data, to pinpoint potential enhancer-activating mutations in colorectal cancer (CRC). Analysis of a genetically-diverse cohort of CRC specimens revealed that microsatellite instable (MSI) samples have a high indel rate within active enhancers. Enhancers with indels show evidence of positive selection, increased target gene expression, and a subset is highly recurrent. The indels affect short homopolymer tracts of A/T and increase affinity for FOX transcription factors. We further demonstrate that signature mismatch-repair (MMR) mutations activate enhancers using a xenograft tumor metastasis model, where mutations are induced naturally via CRISPR/Cas9 inactivation of MLH1 prior to tumor cell injection. Our results suggest that MMR signature mutations activate or augment enhancers in CRC tumor epigenomes to provide a selective advantage.

cancer biology↗

bioRxiv2018

Deep convolutional neural networks for accurate somatic variant calling

We present NeuSomatic, the first convolutional neural network approach for somatic mutation detection, which significantly outperforms previous methods on different sequencing platforms, sequencing strategies, and tumor purities. NeuSomatic summarizes sequence alignments into small matrices and incorporates more than a hundred features to capture mutation signals effectively. It can be used universally as a stand-alone somatic mutation detection method or with an ensemble of existing methods to achieve the highest accuracy.

genomics↗

bioRxiv2018

Transcriptomic responses of the marine cyanobacterium Prochlorococcus to viral lysis products

Marine phytoplankton contributes to about one half of global primary production, and a significant proportion of their photosynthetically fixed organic carbon is released after viral infection as dissolved organic matter (DOM). This DOM pool is known to be consumed by heterotrophic microorganisms; however, its impact on the uninfected co-occurring phytoplankton remains largely unknown. Here, we conducted transcriptomic analyses to study the effects of viral lysis products on the unicellular cyanobacterium Prochlorococcus, which is the most abundant photosynthetic organism on Earth. While Prochlorococcus growth was not affected by viral lysis products, many tRNAs increased in abundance, which was also seen after amino acid addition, suggesting that amino acids are one of the compounds in viral lysis products that affected the expression of tRNA genes. The decreased transcript abundances of N metabolism genes also suggested that Prochlorococcus responded to organic N compounds, consistent with abundant amino acids in viral lysis products. The addition of viral lysis products to Prochlorococcus reduced the maximum photochemical efficiency of photosystem II and CO2 fixation while increased its respiration rate, consistent with differentially expressed genes related to photosynthesis and respiration. One of the highest positive fold-changes was observed for the 6S RNA, a non-coding RNA functioning as a global transcriptional regulator in bacteria. The high level of 6S RNA might be responsible for some of the observed transcriptional responses. Taken together, our results revealed the transcriptional regulation of Prochlorococcus in response to viral lysis products and suggested its metabolic potential to utilize organic N compounds.\n\nImportancePhotosynthetic microorganisms called phytoplankton are abundant in the oceans and contribute to about one half of global CO2 fixation. Phytoplankton are frequently infected by viruses and after infection their organic carbon is released into the ocean as dissolved organic matter (DOM). Marine DOM is important for the marine food web because it supports the growth of heterotrophic microorganisms. However, the impact of viral DOM on the uninfected phytoplankton is largely unknown. In this study, we conducted transcriptomic analyses and identified many differentially expressed genes when viral DOM was added to the marine cyanobacterium Prochlorococcus. One effect of viral DOM is that the carbon fixation of Prochlorococcus was reduced by ~16%, which might affect carbon cycling in the worlds oceans since Prochlorococcus is the most abundant photosynthetic organism on Earth.

microbiology↗

bioRxiv2018

Modeling Spatial Correlation of Transcripts With Application to Developing Pancreas

Recently high-throughput image-based transcriptomic methods were developed and enabled researchers to spatially resolve gene expression variation at the molecular level for the first time. In this work, we develop a general analysis tool to quantitatively study the spatial correlations of gene expression in fixed tissue sections. As an illustration, we analyze the spatial distribution of single mRNA molecules measured by in situ sequencing on human fetal pancreas at three developmental time points 80, 87 and 117 days post-fertilization. We develop a density profile-based method to capture the spatial relationship between gene expression and other morphological features of the tissue sample such as position of nuclei and endocrine cells of the pancreas. In addition, we build a statistical model to characterize correlations in the spatial distribution of the expression level among different genes. This model enables us to infer the inhibitory and clustering effects throughout different time points. Our analysis framework is applicable to a wide variety of spatially-resolved transcriptomic data to derive biological insights.

bioinformatics↗

bioRxiv2018

Epigenetic Drift of H3K27me3 in Aging Links Glycolysis to Healthy Longevity

Epigenetic alteration has been implicated in aging. However, the mechanism by which epigenetic change impacts aging is unclear. H3K27me3, a highly conserved histone modification signifying transcriptional repression, is marked and maintained by Polycomb Repressive Complexes (PRCs). Here, we explore the mechanism by which age-modulated increase of H3K27me3 impacts adult lifespan. Using Drosophila, we reveal that aging leads to loss of fidelity in epigenetic marking and drift of H3K27me3 and consequential reduction in the expression of glycolytic genes with negative effects on energy production and redox state. Moreover, we show that a reduction of H3K27me3 by PRCs-deficiency promotes glycolysis and healthy lifespan. While perturbing glycolysis by gene mutation diminishes the pro-lifespan benefits mediated by PRCs-deficiency, transgenic increase of glycolytic genes in wild-type animals extends longevity. Together, we propose that epigenetic drift of H3K27me3 defines a new aging mechanism and that stimulation of glycolysis promotes metabolic health and longevity.

molecular biology↗

bioRxiv2017

Cyanophages exhibit rhythmic infection patterns under light-dark cycles

Most living organisms exhibit diurnal rhythms as an adaptation to the daily light-dark (diel) cycle. However, diurnal rhythms have not been found in viruses. Here, we studied the diel infection patterns of bacteriophages infecting the unicellular cyanobacteria Prochlorococcus and Synechococcus, which are the most abundant photosynthetic organisms in the oceans. With lab cultures, we found that cyanophages used three infection strategies in the dark: no adsorption, adsorption but no replication, and replication. Interestingly, the former two exhibited rhythmic infection patterns under light-dark cycles. We further showed in the South China Sea and the Western Pacific Ocean that cyanophage abundances varied rhythmically, with a peak at night. Moreover, diel transcriptional rhythms of many cyanophage genes were found in the North Pacific Subtropical Gyre, which also peaked at night. Our results suggested that cyanophage infection of Prochlorococcus is synchronized to the light-dark cycle, which may result in a synchronized release of dissolved organic matter to the marine food web.

microbiology↗

bioRxiv2017

Transcriptome Deconvolution of Heterogeneous Tumor Samples with Immune Infiltration

Transcriptomic deconvolution in cancer and other heterogeneous tissues remains challenging. Available methods lack the ability to estimate both component-specific proportions and expression profiles for individual samples. We present DeMixT, a new tool to deconvolve high dimensional data from mixtures of more than two components. DeMixT implements an iterated conditional mode algorithm and a novel gene-set-based component merging approach to improve accuracy. In a series of experimental validation studies and application to TCGA data, DeMixT showed high accuracy. Improved deconvolution is an important step towards linking tumor transcriptomic data with clinical outcomes. An R package, scripts and data are available: https://github.com/wwylab/DeMixT/.

bioinformatics↗