Biology subjects

Chen, Z.

Publications and source records attributed to Chen, Z..

At least 775 records · Page 43Linked to original sources

bioRxiv2020

In-House Forecasting of Crop Latitude Adaptation through a Daylength-sensing-based Environment Adaptation Simulator (DEAS)

Global climate change necessitates the accelerated breeding of new crop varieties that can sustain yields in new environments. As a proxy for environmental adaptation, the selection of crops that can adapt to different latitudes is an appealing strategy. However, such selection currently involves a lengthy procedure that severely restricts the rapid breeding of varieties. Here, we aimed to combine molecular technologies with an in-house streamlined screening method to facilitate rapid selection for latitude adaptation. We established the Daylength-sensing-based Environment Adaptation Simulator (DEAS) to measure crop latitude adaptation via the transcriptional dynamics of florigen genes at different latitudes. We used different statistical approaches to demonstrate that DEAS predicts the florigen expression profiles in rice with high accuracy. Furthermore, we demonstrated the potential for application of DEAS in different crops. Incorporating DEAS into the breeding programs of conventional and underutilized crops could help meet the future needs for crop adaptation and promote sustainable agriculture.

plant biology↗

bioRxiv2020

AlphaTracker: A Multi-Animal Tracking and Behavioral Analysis Tool

The advancement of behavioral analysis in neuroscience has been aided by the development of computational tools1,2. Specifically, computer vision algorithms have emerged as a powerful tool to elevate behavioral research3,4. Yet fully automatic analysis of social behavior remains challenging in two ways. First, existing tools to track and analyze behavior often focus on single animals, not multiple, interacting animals. Second, many available tools are not developed for novice users and require programming experience to run. Here, we unveil a computer vision pipeline called AlphaTracker, which requires minimal hardware requirements and produces reliable tracking of multiple unmarked animals. An easy-to-use user interface further enables manual inspection and curation of results. We demonstrate the practical, real-time advantages of AlphaTracker through the study of multiple, socially-interacting mice.

animal behavior and cognition↗

bioRxiv2020

Potentiating CD8+ T cell antitumor activity by targeting the PCSK9/LDLR axis

Metabolic regulation has proven to play a critical role in T cell antitumor immunity. Cholesterol metabolism is a key component of this response but remains largely unexplored. Herein, we found that the LDL receptor (LDLR), which has been previously identified as a transporter for cholesterol and fatty acids, plays a pivotal role in regulating CD8+ T cell antitumor activity, with the genetic ablation of LDLR significantly attenuating CD8+ T cell activation and clonal expansion. Additionally, we found that LDLR interacts with the T-cell receptor (TCR) signalosome and regulates TCR signaling, facilitating CD8+ T cell activation and effector function. Furthermore, we found that the tumor microenvironment downregulates CD8+ T cell LDLR levels and TCR signaling via tumor cell-derived PCSK9, which binds and prevents the recycling of LDLR and TCR into the plasma membrane. Our findings indicate that genetic deletion or pharmacological inhibition of PCSK9 in tumor cells can enhance the antitumor activity of CD8+ T cells by alleviating the tumor microenvironments suppressive effect on CD8+ T cells and consequently inhibit tumor progression. While previously established as a hyperlipidemia target, this study highlights PCSK9 as a potential target for cancer immunotherapy as well.

immunology↗

bioRxiv2020

BiTSC^2: Bayesian inference of Tumor clonal Tree by joint analysis of Single-Cell SNV and CNA data

The rapid development of single-cell DNA sequencing (scDNA-seq) technology has greatly enhanced the resolution of tumor cell profiling, providing an unprecedented perspective in characterizing intra-tumoral heterogeneity and understanding tumor progression and metastasis. However, prominent algorithms for constructing tumor phylogeny based on scDNA-seq data usually only take single nucleotide variations (SNVs) as markers, failing to consider the effect caused by copy number alterations (CNAs). Here, we propose BiTSC2, Bayesian inference of Tumor clonal Tree by joint analysis of Single-Cell SNV and CNA data. BiTSC2 takes raw reads from scDNA-seq as input, accounts for sequencing errors, models dropout rate and assigns single cells into subclones. By applying Markov Chain Monte Carlo (MCMC) sampling, BiTSC2 can simultaneously estimate the subclonal scCNA and scSNV genotype matrices, sub-clonal assignments and tumor subclonal evolutionary tree. In comparison with existing methods on synthetic and real tumor data, BiTSC2 shows high accuracy in genotype recovery and sub-clonal assignment. BiTSC2 also performs robustly in dealing with scDNA-seq data with low sequencing depth and variant dropout rate.

cancer biology↗

bioRxiv2020

The de novo genome of the "Spanish" slug Arion vulgaris Moquin-Tandon, 1855 (Gastropoda: Panpulmonata): massive expansion of transposable elements in a major pest species

BackgroundThe "Spanish" slug, Arion vulgaris Moquin-Tandon, 1855, is considered to be among the 100 worst pest species in Europe. It is common and invasive to at least northern and eastern parts of Europe, probably benefitting from climate change and the modern human lifestyle. The origin and expansion of this species, the mechanisms behind its outstanding adaptive success and ability to outcompete other land slugs are worth to be explored on a genomic level. However, a high-quality chromosome-level genome is still lacking. FindingsThe final assembly of A. vulgaris was obtained by combining short reads, linked reads, Nanopore long reads, and Hi-C data. The genome assembly size is 1.54 Gb with a contig N50 length of 8.6 Mb. We found a recent expansion of transposable elements (TEs) which results in repetitive sequences accounting for more than 75% of the A. vulgaris genome, which is the highest among all known gastropod species. We identified 32,518 protein coding genes, and 2,763 species specific genes were functionally enriched in response to stimuli, nervous system and reproduction. With 1,237 single-copy orthologs from A. vulgaris and other related mollusks with whole-genome data available, we reconstructed the phylogenetic relationships of gastropods and estimated the divergence time of stylommatophoran land snails (Achatina) and Arion slugs at around 126 million years ago, and confirmed the whole genome duplication event shared by them. ConclusionsTo our knowledge, the A. vulgaris genome is the first land slug genome assembly published to date. The high-quality genomic data will provide valuable genetic resources for further phylogeographic studies of A. vulgaris origin and expansion, invasiveness, as well as molluscan aquatic-land transition and shell formation.

genomics↗

bioRxiv2020

The SC-SNc pathway boosts appetitive locomotion in predatory hunting

Appetitive locomotion is essential for organisms to approach rewards, such as food and prey. How the brain controls appetitive locomotion is poorly understood. In a naturalistic goal-directed behavior--predatory hunting, we demonstrate an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to boost appetitive locomotion. The SC-SNc pathway transmitted locomotion-speed signals to dopamine neurons and triggered dopamine release in the dorsal striatum. Activation of this pathway increased the speed and frequency of approach during predatory hunting, an effect that depended on the activities of SNc dopamine neurons. Conversely, synaptic inactivation of this pathway impaired appetitive locomotion but not defensive or exploratory locomotion. Together, these data revealed the SC as an important source to provide locomotion-related signals to SNc dopamine neurons to boost appetitive locomotion.

neuroscience↗

bioRxiv2020

An End-to-end Oxford Nanopore Basecaller Using Convolution-augmented Transformer

Oxford Nanopore sequencing is fastly becoming an active field in genomics, and its critical to basecall nucleotide sequences from the complex electrical signals. Many efforts have been devoted to developing new basecalling tools over the years. However, the basecalled reads still suffer from a high error rate and slow speed. Here, we developed an open-source basecalling method, CATCaller, by simultaneously capturing global context through Attention and modeling local dependencies through dynamic convolution. The method was shown to consistently outper-form the ONT default basecaller Albacore, Guppy, and a recently developed attention-based method SACall in read accuracy. More importantly, our method is fast through a heterogeneously computational model to integrate both CPUs and GPUs. When compared to SACall, the method is nearly 4 times faster on a single GPU, and is highly scalable in parallelization with a further speedup of 3.3 on a four-GPU node.

bioinformatics↗

bioRxiv2020

A benchmarking study of SARS-CoV-2 whole-genome sequencing protocols using COVID-19 patient samples

The COVID-19 pandemic is a once-in-a-lifetime event, exceeding mortality rates of the flu pandemics from the 1950s and 1960s. Whole-genome sequencing (WGS) of SARS-CoV-2 plays a critical role in understanding the disease. Performance variation exists across SARS-CoV-2 viral WGS technologies, but there is currently no benchmarking study comparing different WGS sequencing protocols. We compared seven different SARS-CoV-2 WGS library protocols using RNA from patient nasopharyngeal swab samples under two storage conditions. We constructed multiple WGS libraries encompassing three different viral inputs: 1,000,000, 250,000 and 1,000 copies. Libraries were sequenced using two distinct platforms with varying sequencing depths and read lengths. We found large differences in mappability and genome coverage, and variations in sensitivity, reproducibility and precision of single-nucleotide variant calling across different protocols. We ranked the performance of protocols based on six different metrics. Our results indicated that the most appropriate protocol depended on viral input amount and sequencing depth. Our findings offer guidance in choosing appropriate WGS protocols to characterize SARS-CoV-2 and its evolution.

genomics↗

bioRxiv2020

The APETALA2 transcription factor LsAP2 regulates seed shape in lettuce

Seeds are major vehicles of propagation and dispersal in plants. A number of transcription factors, including APETALA2 (AP2), play crucial roles during the seed development process in various plant species. However, genes essential for seed development and the regulatory networks during seed development remain unclear in lettuce. Here, we identified a lettuce AP2 (LsAP2) gene that was highly expressed at the early stages of seed development. LsAP2 knockout plants obtained by the CRISPR/Cas9 system were used to explore the biological function of LsAP2. Compared with wild-type, the seeds of the Lsap2 mutant plants had increased length and decreased width, and developed an extended tip at the seed top. After further investigating the seed structural characteristics of Lsap2 mutant plants, we proposed a new function of LsAP2 in seed dispersal. Moreover, we identified several interactors of LsAP2. Our results showed that LsAP2 directly interacted with the lettuce homolog of BREVIPEDICELLUS (LsBP) and promoted the expression of LsBP. Transcriptome analysis revealed that LsAP2 might also be involved in brassinosteroid biosynthesis and signaling pathways. Taken together, our data indicate that LsAP2 has a significant function in regulating seed shape in lettuce.

plant biology↗

bioRxiv2020

Role and Dynamics of Vacuolar pH during Cell-in-Cell mediated Death

The non-autonomous cell death by entosis was mediated by the so-called cell-in-cell structures, which were believed to kill the internalized cells by a mechanism dependent on acidified lysosomes. However, the precise values and roles of pH critical for the death of the internalized cells remained undetermined yet. We creatively employed keima, a fluorescent protein that displays different excitation spectra in responding to pH changes, to monitor the pH dynamics of the entotic vacuoles during cell-in-cell mediated death. We found that different cells varied in their basal intracellular pH, and the pH was relatively stable for entotic vacuoles containing live cells, but sharply dropped to a narrow range along with the inner cell death. In contrast, the lipidation of entotic vacuoles by LC3 displayed previously underappreciated complex patterns associated with entotic and apoptotic death, respectively. The pH decline seemed to play distinct roles in the two types of inner cell deaths, where apoptosis is preceded with moderate pH decline while a profound pH decline is likely to be determinate for entotic death. Whereas the cancer cells seemed to be lesser tolerant to acidified environments than non-cancerous cells, manipulating vacuolar pH could effectively control inner cell fates and switch the ways whereby inner cell die. Together, this study demonstrated for the first time the pH dynamics of entotic vacuoles that dictate the fates of internalized cells, providing a rationale for tuning cellular pH as a potential way to treat cell-in-cell associated diseases such as cancer.

cell biology↗

bioRxiv2020

Temporal patterns in the evolutionary genetic distance of SARS-CoV-2 during the COVID-19 pandemic

BackgroundDuring the pandemic of coronavirus disease 2019 (COVID-19), the genetic mutations occurred in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cumulatively or sporadically. In this study, we employed a computational approach to identify and trace the emerging patterns of the SARS-CoV-2 mutations, and quantify accumulative genetic distance across different periods and proteins. MethodsFull-length human SARS-CoV-2 strains in United Kingdom were collected. We investigated the temporal variation in the evolutionary genetic distance defined by the Hamming distance since the start of COVID-19 pandemic. FindingsOur results showed that the SARS-CoV-2 was in the process of continuous evolution, mainly involved in spike protein (S protein), the RNA-dependent RNA polymerase (RdRp) region of open reading frame 1 (ORF1) and nucleocapsid protein (N protein). By contrast, mutations in other proteins were sporadic and genetic distance to the initial sequenced strain did not show an increasing trend.

bioinformatics↗

bioRxiv2020

Ontology-Aware Deep Learning Enables Ultrafast, Accurate and Interpretable Source Tracking among Sub-Million Microbial Community Samples from Hundreds of Niches

The taxonomical structure of microbial community sample is highly habitat-specific, making it possible for source tracking niches where samples are originated. Current methods face challenges when the number of samples and niches are magnitudes more than current in use, under which circumstances they are unable to accurately source track samples in a timely manner, rendering them difficult in knowledge discovery from sub-million heterogeneous samples. Here, we introduce a deep learning method based on Ontology-aware Neural Network approach, ONN4MST (https://github.com/HUST-NingKang-Lab/ONN4MST), which takes into consideration the ontology structure of niches and the relationship of samples from these ontologically-organized niches. ONN4MSTs superiority in accuracy, speed and robustness have been proven, for example with an accuracy of 0.99 and AUC of 0.97 in a microbial source tracking experiment that 125,823 samples and 114 niches were involved. Moreover, ONN4MST has been utilized on several source tracking applications, showing that it could provide highly-interpretable results from samples with previously less-studied niches, detect microbial contaminants, and identify similar samples from ontologically-remote niches, with high fidelity.

bioinformatics↗

bioRxiv2020

In-vitro and in-vivo characterization of CRANAD-2 for multi-spectral optoacoustic tomography and fluorescence imaging of amyloid-beta deposits in Alzheimer mice

The abnormal deposition of fibrillar beta-amyloid (A{beta}) deposits in the brain is one of the major histopathological hallmarks of Alzheimers disease (AD). Here we characterize curcumin-derivative CRANAD-2 for multi-spectral optoacoustic tomography (MSOT) and fluorescence imaging of brain A{beta} deposits in the arcA{beta} mouse model of AD cerebral amyloidosis. CRANAD-2 shows a specific and quantitative detection of A fibrils in vitro, even in complex mixtures, and it is capable to distinguish between monomeric and fibrillar forms of A. In vivo epifluorescence and MSOT after intravenous CRANAD-2 administration demonstrated higher retention in arcA{beta} compared to non-transgenic littermate mice. Immunohistochemistry showed co-localization of CRANAD-2 and A{beta} deposits in arcA{beta} mouse brain sections, thus verifying the specificity of the probe. In conclusion, we demonstrate suitability of CRANAD-2 for fluorescence- and MSOT-based detection of A{beta} deposits in animal models of AD pathology, which facilitates mechanistic studies and the monitoring of putative treatments targeting A{beta} deposits.

neuroscience↗

bioRxiv2020

Spaceflight decelerates the epigenetic clock orchestrated with a global alteration in DNA methylome and transcriptome in the mouse retina

Astronauts exhibit an assortment of clinical abnormalities in their eyes during long-duration spaceflight. The purpose of this study was to determine whether spaceflight induces epigenomic and transcriptomic reprogramming in the retina or alters the epigenetic clock. The mice were flown for 37 days in animal enclosure modules on the International Space Station; ground-based control animals were maintained under similar housing conditions. Mouse retinas were isolated and both DNA methylome and transcriptome were determined by deep sequencing. We found that a large number of genes were differentially methylated with spaceflight, whereas there were fewer differentially expressed genes at the transcriptome level. Several biological pathways involved in retinal diseases such as macular degeneration were significantly altered. Our results indicated that spaceflight decelerated the retinal epigenetic clock. This study demonstrates that spaceflight impacts the retina at the epigenomic and transcriptomic levels, and such changes could be involved in the etiology of eye-related disorders among astronauts.

genomics↗

bioRxiv2020

Fast 3D printing of large-scale biocompatible hydrogel models

Large scale cell-laden hydrogel models hold great promise for tissue repair and organ transplantation, but their fabrication is faced with challenges in achieving clinically-relevant size and hierarchical structures. 3D bioprinting is an emerging technology, but its application in large, solid hydrogel fabrication has been limited by the slow printing speed that can affect the part quality and the biological activity of the encapsulated cells. Here we present a Fast hydrogeL prOjection stereolithogrAphy Technology (FLOAT) that allows the creation of a centimeter-sized, multiscale solid hydrogel model within minutes. Through precisely controlling the photopolymerization condition, we established low suction force-driven, high-velocity flow of the hydrogel prepolymer that supports the continuous replenishment of the prepolymer solution below the curing part and the nonstop part growth. We showed that this process is unique to the hydrogel prepolymer without externally supplemented oxygen. The rapid printing of centimeter-sized hydrogel models using FLOAT was shown to significantly reduce the part deformation and cellular injury caused by the prolonged exposure to the environmental stresses in layer-by-layer based printing methods. Media perfusion in the printed vessel network was shown to promote cell survival and metabolic function in the deep core of the large-sized hydrogel model over long term. The FLOAT is compatible with multiple photocurable hydrogel materials and the printed scaffold supports the endothelialization of prefabricated vascular channels. Together, these studies demonstrate a rapid 3D hydrogel printing method and highlight the potential of this method in the fabrication of large-sized engineered tissue models.

bioengineering↗

bioRxiv2020

The RNA-binding protein HuR promotes nonalcoholic steatohepatitis (NASH) progression by enhancing death signaling pathway

Hepatocyte death triggers liver inflammation, liver injury, and fibrosis, which contributes to non-alcoholic steatohepatitis (NASH) pathogenesis. However, whether RNA processing regulates death signaling pathway during NASH progression is not investigated. In this study, we show that HuR, a widely expressed RNA-binding protein, promotes NASH progression by increasing DR5/caspase8/caspase3-mediated hepatocyte death. Cytosolic HuR levels are abnormally elevated in human patients with NASH. Hepatocyte-specific deletion of HuR protects against MCD-induced NASH by decreasing liver steatosis, inflammation and cell death, whereas hepatic overexpression of HuR induces liver injury by increasing DR5-induced hepatocyte death. Furthermore, in primary hepatocytes, HuR deficiency ameliorates PA&TNF-induced hepatocyte death due to decreased DR5/caspase8/caspase 3 signaling pathway while overexpression of HuR induces hepatocyte death by increasing DR5/caspase8/caspase 3 signaling pathway. Mechanistically, HuR directly binds to 3'-UTR of DR5 transcript and promotes its mRNA stability, contributing to the hepatocyte death during NASH progression. Our data reveal a novel mechanism by which HuR promotes mRNA stability of DR5, which contributes to NASH progression.

physiology↗

bioRxiv2020

Mutating PINK1 gene by paired truncated sgRNA/Cas9-D10A in Cynomolgus Monkey

Mutations of PINK1 cause early-onset Parkinsons disease (PD) with selective neurodegeneration in humans. However,current PINK1 knockout mouse and pig models are unable to recapitulate the typical neurodegenerative phenotypes observed in PD patients, indicating that it is essential to generate PINK1 disease models in non-human primates (NHPs) that are highly close to humans, to investigate the unique function of PINK1 in primate brains. Paired single guide RNA (sgRNA)/Cas9-D10A nickases and truncated sgRNA/Cas9, both enabling the reduction of the off-target effect without apparently compromising the on-target editing, are two optimized strategies in applying the CRISPR/Cas9 system to establish disease animal models. Here, we combined the two strategies and injected Cas9-D10A mRNA and two truncated sgRNAs into one-cell-stage cynomolgus zygotes to target PINK1 gene. We show precise and efficient gene editing of the target site in the three new born cynomolgus monkeys. The frame shift mutations of PINK1 in mutant fibroblasts leaded to the reduction of the mRNA, However, western-blot and immunofluorescencestaining confirmed the PINK1 proteinlevels werecomparable to that in the wild-type fibroblasts. We further reprogramed mutant fibroblast into induced pluripotent stem cells (iPSCs) and they show similar ability of differentiation into dopamine (DA) neurons. Taken together, our results showed that coinjection of Cas9-D10A nickase mRNA and sgRNA into one-cell-stage cynomolgus embryos enable the generation of human disease models in NHPs and the target editing by paired truncated sgRNA/Cas9-D10A in PINK1 gene exon 2 did not impact the protein expression.

genetics↗

bioRxiv2020

Genome-wide characterization and expression profiling of B3 superfamily during flower induction stage in pineapple (Ananas comosus L.)

The B3 superfamily is a plant-specific family, which involves in growth and development process. By now, the identification of B3 superfamily in pineapple (Ananas comosus) has not reported. In this study, 57 B3 genes were identified and further phylogenetically classified into five subfamilies, all genes contained B3 domain. Chromosomal localization analysis revealed that 54 of 57 AcB3 genes were located on 21 chromosomes.Collinearity analysis indicated that the segmental duplication was the main event in the evolution of B3 gene superfamily and most of them were under purifying selection. Moreover, there were 7 and 39 pairs of orthologous B3s were identified between pineapple and Arabidopsis or rice, respectively, which indicated the closer genetic relationship between pineapple and rice. Most genes had cis-element of abscisic acid, ethylene, MeJA, light, and abiotic stress. qRT-PCR showed that the expression level of most AcB3 genes were up-regulated within 1 d after ethephon treatment and expressed high level in flower bud differentiation period in stem apex. This study provide a comprehensive understanding of AcB3s and a basis for future molecular studies of ethephon induced pineapple flowering.

plant biology↗