Biology subjects

Chu, T.

Publications and source records attributed to Chu, T..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Crypt and Villus Enterochromaffin Cells are Distinct Stress Sensors in the Gut

The crypt-villus structure of the small intestine serves as an essential protective barrier, with its integrity monitored by the guts sensory system. Enterochromaffin (EC) cells, which are rare sensory epithelial cells that release serotonin (5-HT), surveil the mucosal environment and signal both within and outside the gut. However, it remains unclear whether EC cells in intestinal crypts and villi respond to different stimuli and elicit distinct responses. In this study, we introduce a new reporter mouse model to observe the release and propagation of serotonin in live intestines. Using this system, we show that crypt EC cells exhibit two modes of serotonin release: transient receptor potential A1 (TRPA1)-dependent tonic serotonin release that controls basal ionic secretion, and irritant-evoked serotonin release that activates gut sensory neurons. Furthermore, we find that a thick protective mucus layer prevents TRPA1 receptors on crypt EC cells from responding to luminal irritants such as reactive electrophiles; if this mucus layer is compromised, then crypt EC cells become susceptible to activation by luminal irritants. On the other hand, villus EC cells detect oxidative stress through TRPM2 channels and co-release serotonin and ATP to activate nearby gut sensory fibers. Our work highlights the physiological importance of intestinal architecture and differential TRP channel expression in sensing noxious stimuli that elicit nausea and/or pain sensations in the gut.

physiology↗

bioRxiv2024

Discriminative histone imputation using chromatin accessibility

Histone modifications (HMs) play a pivot role in various biological processes, including transcription, replication and DNA repair, significantly impacting chromatin structure. These modifications underpin the molecular mechanisms of cell-specific gene expression and complex diseases. However, annotating HMs across different cell types solely using experimental approaches is impractical due to cost and time constraints. Herein, we present dHICA (discriminative histone imputation using chromatin accessibility), a novel deep learning framework that integrates DNA sequences and chromatin accessibility data to predict multiple HM tracks. Employing the Transformer architecture alongside dilated convolutions, dHICA boasts an extensive receptive field and captures more cell-type-specific information. dHICA not only outperforms state-of-the-art baselines but also achieves superior performance in cell-specific loci and gene elements, aligning with biological expectations. Furthermore, dHICAs imputations hold significant potential for downstream applications, including chromatin state segmentation and elucidating the functional implications of SNPs. In conclusion, dHICA serves as an invaluable tool for advancing the understanding of chromatin dynamics, offering enhanced predictive capabilities and interpretability.

bioinformatics↗

bioRxiv2023

Unveiling Elevated Spontaneous Mutation Rates in Phyllostachys edulis (Moso Bamboo) through Whole Genome Sequencing (WGS) and Investigating the Impact of Atmospheric and Room Temperature Plasma (ARTP) Induced Mutagenesis

Moso bamboo, recognized for its wide distribution and economic importance, encounters challenges in varietal enhancement due to its protracted sexual reproduction cycle. This study employed whole-genome resequencing to uncover spontaneous mutations in Moso bamboo and investigated mutagenesis using atmospheric and room temperature plasma (ARTP). Through the sequencing results, we identified the population of flowering bamboo as an asexual breeding line. Notably, the flowering Moso bamboo population, exclusively derived from asexual reproduction, exhibited a high spontaneous mutation rate (4.54 x 10-4 to 1.15 x 10-3/bp) during sexual reproduction, considering parental and cross-pollination effects. Genetic disparities between offspring and parents exhibited a bimodal distribution, indicating a substantial cross-pollination rate. ARTP mutagenesis increased structural variations in offspring, while changes in SNPs and INDELs were less pronounced. Sanger sequencing validated a gene subset, providing a foundation for spontaneous mutation rate investigation via whole-genome sequencing. These insights, particularly from mutagenized offspring sequencing, contribute to Moso bamboo breeding strategies. HighlightMoso bamboo breeding revolutionized--high spontaneous mutations in asexually derived flowering population. ARTP mutagenesis boosts structural variations, shaping innovative breeding approaches.

genetics↗

bioRxiv2023

Vessel normalization and maturation promotes nanoparticle delivery to solid tumors while minimizing metastases.

Nanoparticle delivery to solid tumors is known to be an inefficient process and various studies have tried to increase efficacy, but mechanistic and comparative studies remain scarce. Here, we use pharmacological agents to study the effect of vessel normalization or vessel disintegration on nanoparticle delivery to solid tumors. Using a multiparametric approach, we find that vessel disintegration fails to improve nanoparticle delivery and instead seems to have a limiting effect. Vessel normalization, however, improves delivery efficacy for nanoparticles ranging from 20 to 60 nm diameter. The normalization of the tumor blood vessels results in reduced hypoxia, reduced necrosis and an increase in Plvap+ CD276+ endothelial cells, which have been linked with nanoparticle delivery. Interestingly, where vessel disintegration stimulated cancer cell intravasation and associated metastases, vessel normalization impeded these processes. Together, these data reveal that, vessel normalization may be a safer and more suited approach for improving nanoparticle delivery to solid tumors, but its efficacy is limited by nanoparticle diameter and tumor parameters. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/538559v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@17e5e08org.highwire.dtl.DTLVardef@14f82dcorg.highwire.dtl.DTLVardef@118708eorg.highwire.dtl.DTLVardef@18593d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

Evaluating performance and applications of sample-wise cell deconvolution methods on human brain transcriptomic data

Sample-wise deconvolution methods have been developed to estimate cell-type proportions and gene expressions in bulk-tissue samples. However, the performance of these methods and their biological applications has not been evaluated, particularly on human brain transcriptomic data. Here, nine deconvolution methods were evaluated with sample-matched data from bulk-tissue RNAseq, single-cell/nuclei (sc/sn) RNAseq, and immunohistochemistry. A total of 1,130,767 nuclei/cells from 149 adult postmortem brains and 72 organoid samples were used. The results showed the best performance of dtangle for estimating cell proportions and bMIND for estimating sample-wise cell-type gene expression. For eight brain cell types, 25,273 cell-type eQTLs were identified with deconvoluted expressions (decon-eQTLs). The results showed that decon-eQTLs explained more schizophrenia GWAS heritability than bulk-tissue or single-cell eQTLs alone. Differential gene expression associated with multiple phenotypes were also examined using the deconvoluted data. Our findings, which were replicated in bulk-tissue RNAseq and sc/snRNAseq data, provided new insights into the biological applications of deconvoluted data.

genomics↗

bioRxiv2022

Firing rate adaptation in continuous attractor neural networks accounts for theta phase shift of hippocampal place cells

Hippocampal place cells in freely moving rodents display both theta phase precession and procession, which is thought to play important roles in cognition, but the neural mechanism for producing theta phase shift remains largely unknown. Here we show that firing rate adaptation within a continuous attractor neural network causes the neural activity bump to oscillate around the external input, resembling theta sweeps of decoded position during locomotion. These forward and backward sweeps naturally account for theta phase precession and procession of individual neurons, respectively. By tuning the adaptation strength, our model explains the difference between "bimodal cells" showing interleaved phase precession and procession, and "unimodal cells" in which phase precession predominates. Our model also explains the constant cycling of theta sweeps along different arms in a T-maze environment, the speed modulation of place cells firing frequency, and the continued phase shift after transient silencing of the hippocampus. We hope that this study will aid an understanding of the neural mechanism supporting theta phase coding in the brain.

neuroscience↗

bioRxiv2022

Within-host genotypic and phenotypic diversity of contemporaneous carbapenem-resistant Klebsiella pneumoniae from blood cultures of patients with bacteremia

Carbapenem-resistant Klebsiella pneumoniae (CRKP) are major pathogens globally. It is unknown whether bloodstream infections (BSIs) by CRKP and other bacteria are commonly caused by single organisms or mixed microbial populations. We hypothesized that contemporaneous CRKP from blood cultures of individual patients are genetically and phenotypically distinct. We determined short-read whole genome sequences of 10 strains from single colonies from CRKP-positive blood cultures in each of 6 patients (Illumina HiSeq). All strains were sequence type (ST)-258 K. pneumoniae that were unique by core genome single nucleotide polymorphism phylogeny, antibiotic resistance and virulence genes, capsular polysaccharide (CPS) gene mutations, and/or plasmid loss. Strains from each of 3 patients that differed in antibiotic resistance, virulence and/or CPS gene content underwent long-read sequencing for genome completion (Oxford Nanopore), and were tested for phenotypes in vitro and pathogenicity during mouse BSIs. Genetically distinct strains within individual patients exhibited significant differences in carbapenem, beta-lactam/beta-lactamase inhibitor and other antibiotic responses, CPS production, mucoviscosity, and susceptibility to serum killing. In 2 patients, strains differed significantly in their ability to infect organs and cause mortality in mice. In conclusion, we identified genotypic and phenotypic variant ST258 K. pneumoniae strains from blood cultures of individual patients, which were not detected by the clinical laboratory at time of BSI diagnosis. The data support a new paradigm of CRKP population diversity during BSIs. If validated for other BSIs, within-host bacterial diversity may have profound implications for medical, microbiology laboratory and infection prevention practices, and for understanding emergence of antibiotic resistance and pathogenesis. IMPORTANCEIn processing positive microbiologic cultures, standard clinical laboratory practice is to test a single bacterial strain from each morphologically distinct colony. We performed comprehensive whole genome sequence analyses on 10 carbapenem-resistant Klebsiella pneumoniae (CRKP) strains from positive blood cultures from each of 6 patients. Our findings that all strains were genetically unique and that genetic variants manifested differences in phenotypes like antibiotic responsiveness and virulence suggest that CRKP bloodstream infections may be commonly caused by mixed bacterial populations. Results raise questions about laboratory protocols and treatment decisions that are directed against a single strain. The observation that pan-genome analyses revealed inter-strain differences that were not evident by studying core genomes has important implications for investigating nosocomial outbreaks and transmission. Data also suggest a model of pathogenesis of CRKP infections, in which environmental pressures in vivo may select for outgrowth of variants that manifest antibiotic resistance, tolerance or specific virulence attributes.

microbiology↗

bioRxiv2022

A lymphatic-stem cell interactome regulates intestinal stem cell activity

Barrier epithelia depend on resident stem cells for homeostasis, defense and repair. Intestinal stem cells (ISCs) of the small and large intestines respond to their local microenvironments (niches) to fulfill a continuous demand for tissue turnover, yet the complexity of their niches is still unfolding. Here, we report an extensive lymphatic network that intimately associates with ISCs within these niches. Devising a lymphatic:organoid coculture system, we show that lymphatic-secreted factors maintain ISCs while inhibiting precocious differentiation. Employing a new deconvolution algorithm, BayesPrism, to pair single-cell and spatial transcriptomics, we cartograph the lymphatic ligand:ISC receptor interactomes at high resolution. We unearth crypt lymphatics as a major source of WNT-signaling factors (WNT2, R-SPONDIN-3) known to drive ISC behavior, and REELIN, a hitherto unappreciated ISC regulator secreted by crypt lymphatics. Together, our studies expose lymphatics as a central hub for niche factors that govern the regenerative potential of ISCs.

cell biology↗

bioRxiv2021

Structural and functional characterizations of altered infectivity and immune evasion of SARS-CoV-2 Omicron variant

The SARS-CoV-2 Omicron with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the Spike (S) from Omicron reveals amino acid substitutions forging new interactions that stably maintain an "active" conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of viral fusion step. Alterations in local conformation, charge and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Apart from already existing mutations, we have identified three new immune escape sites: 1) Q493R, 2) G446S and 3) S371L/S373P/S375F that confers greater resistance to five of the six classes of RBD-antibodies. Structure of the Omicron S bound with human ACE2, together with analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.

biophysics↗

bioRxiv2021

Graph Transformer for drug response prediction

BackgroundPrevious models have shown that learning drug features from their graph representation is more efficient than learning from their strings or numeric representations. Furthermore, integrating multi-omics data of cell lines increases the performance of drug response prediction. However, these models showed drawbacks in extracting drug features from graph representation and incorporating redundancy information from multi-omics data. This paper proposes a deep learning model, GraTransDRP, to better drug representation and reduce information redundancy. First, the Graph transformer was utilized to extract the drug representation more efficiently. Next, Convolutional neural networks were used to learn the mutation, meth, and transcriptomics features. However, the dimension of transcriptomics features is up to 17737. Therefore, KernelPCA was applied to transcriptomics features to reduce the dimension and transform them into a dense presentation before putting them through the CNN model. Finally, drug and omics features were combined to predict a response value by a fully connected network. Experimental results show that our model outperforms some state-of-the-art methods, including GraphDRP, GraOmicDRP. Availability of data and materialshttps://github.com/chuducthang77/GraTransDRP.

bioinformatics↗

bioRxiv2020

Accurate imputation of histone modifications using transcription

The role of histone modifications in transcription remains incompletely understood. Here we used experimental perturbations combined with sensitive machine learning tools that infer the distribution of histone marks using maps of nascent transcription. Transcription predicted the variation in active histone marks and complex chromatin states, like bivalent promoters, down to single-nucleosome resolution and at an accuracy that rivaled the correspondence between independent ChIP-seq experiments. Blocking transcription rapidly removed two punctate marks, H3K4me3 and H3K27ac, from chromatin indicating that transcription is required for active histone modifications. Transcription was also required for maintenance of H3K27me3 consistent with a role for RNA in recruiting PRC2. A subset of DNase-I hypersensitive sites were refractory to prediction, precluding models where transcription initiates pervasively at any open chromatin. Our results, in combination with past literature, support a model in which active histone modifications serve a supportive, rather than a regulatory, role in transcription.

genomics↗

bioRxiv2020

Identification of Relevant Genetic Alterations in Cancer using Topological Data Analysis

Large-scale cancer genomic studies enable the systematic identification of mutations that lead to the genesis and progression of tumors, uncovering the underlying molecular mechanisms and potential therapies. While some such mutations are recurrently found in many tumors, many others exist solely within a few samples, precluding detection by conventional recurrence-based statistical approaches. Integrated analysis of somatic mutations and RNA expression data across 12 tumor types reveals that mutations of cancer genes are usually accompanied by substantial changes in expression. We use topological data analysis to leverage this observation and uncover 38 elusive candidate cancer-associated genes, including inactivating mutations of the metalloproteinase ADAMTS12 in lung adenocarcinoma. We show that ADAMTS12-/- mice have a five-fold increase in the susceptibility to develop lung tumors, confirming the role of ADAMTS12 as a tumor suppressor gene. Our results demonstrate that data integration through topological techniques can increase our ability to identify previously unreported cancer-related alterations.

cancer biology↗

bioRxiv2020

Bayesian Inference of Cell Composition and Gene Expression Reveals Tumor-Microenvironment Interactions

Understanding the interactions between cells in their environment is a major challenge in genomics. Here we developed BayesPrism, a Bayesian method to jointly predict cellular composition and gene expression in each cell type, including heterogeneous malignant cells, from bulk RNA-seq using scRNA-seq as prior information. We conducted an integrative analysis of 1,412 bulk RNA-seq samples in primary glioblastoma, head and neck squamous cell carcinoma, and melanoma using single-cell datasets of 85 patients. We identified cell types correlated with clinical outcomes and explored spatial heterogeneity in malignant cell states and non-malignant cell type composition. We refined subtypes using gene expression in malignant cells, after excluding confounding non-malignant cell types. Finally, we identified genes whose expression in malignant cells correlated with infiltration of macrophages, T cells, fibroblasts, and endothelial cells across multiple tumor types. Our work introduces a new lens that uses scRNA-seq to accurately infer cellular composition and expression in large cohorts of bulk data.

genomics↗

bioRxiv2019

Minutes-timescale 3D isotropic imaging of entire organs at subcellular resolution by content-aware compressed-sensing light-sheet microscopy

Instant 3D imaging of entire organs and organisms at cellular resolution is a recurring challenge in life science. Here we report on a computational light-sheet microscopy able to achieve minute-timescale mapping of entire macro-scale organs at high spatial resolution, thereby overcoming the throughput limit of current 3D microscopy implementations. Through combining a dual-side confocally-scanned Bessel light-sheet illumination which provides thinner-and-wider optical sectioning of deep tissues, with a content-aware compressed sensing (CACS) computation pipeline which further improves the contrast and resolution based on a single acquisition, our method yields 3D images with high, isotropic spatial resolution and rapid acquisition improved by two-orders of magnitude. We demonstrate the imaging of whole brain ([~]400 mm3), entire gastrocnemius and tibialis muscles ([~]200 mm3) of mouse at subcellular resolution (0.5-m isovoxel) and ultra-high throughput of 5[~]10 minutes per sample. Various system-level cellular analyses, such as mapping cell populations at different brain sub-regions, tracing long-distance projection neurons over the entire brain, and calculating neuromuscular junction occupancy across whole muscle, were also readily enabled by our method.

bioengineering↗

bioRxiv2019

Transcriptome analysis of the Larimichthys polyactis under heat and cold stress

The small yellow croaker (Larimichthys polyactis) is an important marine economic fish that is widely distributed in the East Sea, Yellow Sea and Bohai of China. However, the wild populations of small yellow croaker are severely depleted, and there is currently a developing large-scale artificial propagation of this fish for aquaculture. However, the current variety of small yellow croaker that is cultivated is not capable to coping with large fluctuations in temperature. Therefore, it is important to understand the molecular mechanisms that are activated in response to temperature stress in the small yellow croaker. Here, we conducted transcriptomic analysis of the liver of small yellow croaker under heat and cold stress. A total of 270,844,888, 265,727,006 and 259,666,218 clean reads were generated from heat temperature group, low temperature group and control group, respectively, and comparing expression of genes in these transcriptomes,10,878 unigenes that were differential expressed were identified. Sixteen of the differentially expressed unigenes were validated by qRT-PCR. Pathway enrichment analysis identified that the ER pathway, immune signaling pathway and metabolic response pathway were affected by temperature stress. The results of this study provide a comprehensive overview of temperature stress-induced transcriptional patterns in liver tissues of the small yellow croaker. In addition, these results can guide future molecular studies of heat and cold stress response in this species for improving the stock used for aquaculture.

physiology↗

bioRxiv2018

Decreased green autofluorescence intensity of lung parenchyma is a potential non-invasive diagnostic biomarker for lung cancer

Early and non-invasive diagnosis is critical for enhancing the survival rates of lung cancer. In current study we determined the green autoflorescence (AF) of the pulmonary parenchyma of lung cancer patients, using 488 nm and 500 - 550 nm as excitation wavelength and emission wavelength, respectively. Our study has suggested that decreased green AF intensity of pulmonary parenchyma may be a potential diagnostic biomarker for lung cancer: First, the green AF intensity of the cancerous tissues is less than 40% of those of distant non-neoplastic tissues and peri-neoplastic tissues; second, the green AF intensity of both the distant non-neoplastic tissues and cancerous tissues of squamous carcinoma is significantly lower than that of adenocarcinoma; third, the AF intensity of the peri-neoplastic tissues of the lung cancer patients is negatively correlated with the stages of lung cancer; and fourth, our study on the AF spectrum of pulmonary parenchyma has suggested that the AF may result from the AF of the keratins or FAD of the pulmonary parenchyma. Collectively, our study has suggested that decreased green AF intensity of pulmonary parenchyma may become a novel biomarker for non-invasive diagnosis of lung cancer. The green AF intensity may also be used to non-invasively differentiate squamous carcinoma and adenocarcinoma, as well as the stages of lung cancer. Moreover, our diagnostic approach for lung cancer may be used for image-guided surgery of lung cancer for lesions that have not been identified by CT.

biophysics↗

bioRxiv2018

Identification of regulatory elements from nascent transcription using dREG

Our genomes encode a wealth of transcription initiation regions (TIRs) that can be identified by their distinctive patterns of actively elongating RNA polymerase. We previously introduced dREG to identify TIRs using PRO-seq data. Here we introduce an efficient new implementation of dREG that uses PRO-seq data to identify both uni- and bidirectionally transcribed TIRs with 70% improvements in accuracy, 3-4-fold higher resolution, and >100-fold increases in computational efficiency. Using a novel strategy to identify TIRs based on their statistical confidence reveals extensive overlap with orthogonal assays, yet also reveals thousands of additional weakly-transcribed TIRs that were not identified by H3K27ac ChIP-seq or DNase-I-hypersensitivity. Novel TIRs discovered by dREG were often associated with RNA polymerase III initiation, bound by pioneer transcription factors, or located in broad domains marked by repressive chromatin modifications. We provide a web interface to dREG that can be used by the scientific community (http://dREG.DNASequence.org).

bioinformatics↗

bioRxiv2018

Selectively increased autofluorescence at certain regions of skin may become a novel diagnostic biomarker for lung cancer

Early diagnosis is critical for improving the 5-year survival rate of lung cancer patients. Our current study tested our hypothesis that increased autofluorescence (AF) of skin and nails may become a novel diagnostic biomarker of lung cancer, which has generated the following findings: First, our study on a mouse model of lung cancer has shown that development of lung cancer led to a marked increase in the epidermal green AF of the mice. Second, the AF intensity of the untreated lung cancer patients was significantly higher than that of the healthy persons and the pulmonary infection patients at certain examined locations of the skin and fingernails. Third, the ‘Pattern of AF’ of healthy controls, pulmonary infection patients and untreated lung cancer patients was markedly different from each other. Fourth, when the number of the locations with increased AF was used as the sole diagnostic parameter, our ROC analysis showed that the AUC was 0.9067 for differentiating the healthy controls and the untreated lung cancer patients. Collectively, our study has indicated that development of lung cancer is sufficient to induce increases in the epidermal green AF of both mice and human subjects. Our study has also indicated that the ‘Pattern of AF’ of lung cancer patients could become a novel biomarker of lung cancer, which holds great promise for non-invasive, rapid and economic diagnosis and screening of lung cancer.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗