Biology subjects

Guo, Z.

Publications and source records attributed to Guo, Z..

At least 199 records · Page 11Linked to original sources

bioRxiv2021

PPAR-delta acts as a metabolic master checkpoint for metastasis in pancreatic cancer

SO_SCPLOWUMMARYC_SCPLOWIn pancreatic cancer, emerging evidence suggests that PPAR-{delta} overexpression is associated with tumor progression and metastasis, but a mechanistic link is still missing. Here we now show that PPAR-{delta} acts as the integrating upstream regulator for the metabolic rewiring, which is preceding the subsequent initiation of an invasive/metastatic program. Specifically, paracrine and metabolic cues regularly found in the metastasis-promoting tumor stroma consistently enhance, via induction of PPAR-{delta} activity, the glycolytic capacity and reserve of pancreatic cancer cells, respectively, accompanied by decreased mitochondrial oxygen consumption. Consequently, genetic or pharmacological inhibition of PPAR-{delta} results in reduced invasiveness and metastasis. Mechanistically, PPAR-{delta} acts by shifting the MYC/PGC1A balance towards MYC, enhancing metabolic plasticity. Targeting MYC similarly prevents the metabolic switch and subsequent initiation of invasiveness. Therefore, our data demonstrate that PPAR-{delta} is a key initiator for the metabolic reprogramming in pancreatic cancer, thereby acting as a checkpoint for the phenotypic change towards invasiveness. These findings provide compelling evidence for a novel treatment strategy to combat pancreatic cancer progression.

cancer biology↗

bioRxiv2021

METTL3 promotes homologous recombination repair and modulates chemotherapeutic response by regulating the EGF/Rad51 axis

METTL3 and N6-methyladenosine (m6A) are involved in many types of biological and pathological processes, including DNA repair. However, the function and mechanism of METTL3 in DNA repair and chemotherapeutic response remain largely unknown. In present study, we identified that METTL3 participates in the regulation of homologous recombination repair (HR), which further influences chemotherapeutic response in breast cancer (BC) cells. Knockdown of METTL3 sensitized BC cells to Adriamycin (ADR) treatment and increased accumulation of DNA damage. Mechanically, we demonstrated that inhibition of METTL3 impaired HR efficiency and increased ADR-induced DNA damage by regulating m6A modification of EGF/RAD51 axis. METTL3 promoted EGF expression through m6A modification, which further upregulated RAD51 expression, resulting in enhanced HR activity. We further demonstrated that the m6A "reader," YTHDC1, bound to the m6A modified EGF transcript and promoted EGF synthesis, which enhanced HR and cell survival during ADR treatment. Our findings reveal a pivotal mechanism of METTL3-mediated HR and chemotherapeutic drug response, which may contribute to cancer therapy.

biochemistry↗

bioRxiv2021

Acoustic and postural displays in a miniature and transparent teleost fish, Danionella dracula

Acoustic communication is widespread across vertebrates, including among fishes. We report robust acoustic displays during aggressive interactions for a laboratory colony of Danionella dracula, a relatively recently discovered miniature and transparent species of teleost fish closely related to zebrafish (Danio rerio). Males produce bursts of pulsatile, click-like sounds and a distinct postural display, extension of a hypertrophied lower jaw, during aggressive but not courtship interactions. Females lack a hypertrophied lower jaw and show no evidence of sound production or jaw extension in such contexts. Novel pairs of size-matched or -mismatched males were combined in resident-intruder assays where sound production and jaw extension could be linked to individuals. Resident males produce significantly more sound pulses and extend their jaw more often than intruders in both dyad contexts, and relatively larger males are significantly more sonic and exhibit more jaw extensions in size-mismatched pairs. The majority of highest sound producers in both contexts also show increased jaw extension during periods of heightened sonic activity. These studies firmly establish D. dracula as a sound-producing species that modulates both acoustic and postural displays during aggressive interactions based on either residency or body size, providing a foundation for further investigating the role of multimodal displays in a new model clade for neurogenomic studies of aggression, courtship, and other social interactions.

animal behavior and cognition↗

bioRxiv2021

Scrutiny of human lung infection by SARS-CoV-2 and associated human immune responses in humanized mice

There is an urgent need for animal models of COVID-19 to study immunopathogenesis and test therapeutic intervenes. In this study we showed that NSG mice engrafted with human lung (HL) tissue (NSG-L mice) could be infected efficiently by SARS-CoV-2, and that live virus capable of infecting Vero cells was found in the HL grafts and multiple organs from infected NSG-L mice. RNA-seq examination identified a series of differentially expressed genes, which are enriched in viral defense responses, chemotaxis, interferon stimulation, and pulmonary fibrosis between HL grafts from infected and control NSG-L mice. Furthermore, when infecting humanized mice with human immune system (HIS) and autologous HL grafts (HISL mice), the mice had bodyweight loss and hemorrhage and immune cell infiltration in HL grafts, which were not observed in immunodeficient NSG-L mice, indicating the development of anti-viral immune responses in these mice. In support of this possibility, the infected HISL mice showed bodyweight recovery and lack of detectable live virus at the later time. These results demonstrate that NSG-L and HISL mice are susceptible to SARS-CoV-2 infection, offering a useful in vivo model for studying SARS-CoV-2 infection and the associated immune response and immunopathology, and testing anti-SARS-CoV-2 therapies.

immunology↗

bioRxiv2021

Base-resolution prediction of transcription factor binding signals by a deep learning framework

Transcription factors (TFs) play an important role in regulating gene expression, thus the identification of the sites bound by them has become a fundamental step for molecular and cellular biology. In this paper, we developed a deep learning framework leveraging existing fully convolutional neural networks (FCN) to predict TF-DNA binding signals at the base-resolution level, called FCNsignal. The proposed FCNsignal can simultaneously achieve the following tasks: (i) modeling the base-resolution signals of binding regions; (ii) discriminating binding or non-binding regions; (iii) locating TF-DNA binding regions; (iv) predicting binding motifs. The experimental results on 53 TF ChIP-seq datasets and 6 chromatin accessibility ATAC-seq datasets show that our proposed framework outperforms some existing state-of-the-art methods. In addition, we explored to use the trained FCNsignal to locate all potential TF-DNA binding regions on a whole chromosome and predict DNA sequences of arbitrary length, and the results show that our framework can find most of the known binding regions and accept sequences of arbitrary length. Furthermore, we demonstrated the potential ability of our framework in discovering causal disease-associated single-nucleotide polymorphisms (SNPs) through a series of experiments. Author summaryIdentification of transcription factor binding sites (TFBSs) is fundamental to study gene regulatory networks in biological systems, as TFs activate or suppress the transcription of genes by binding to specific TFBSs. With the development of high-throughput sequencing technologies and deep learning (DL), several DL-based approaches have been developed for systematically studying TFBSs, achieving impressive performance. Nevertheless, these methods either excessively focus on discriminating binding or non-binding sequences or individually accomplish multiple TFBSs-associated tasks. In this work, we provide an integrated framework, which utilizes the FCN architecture to predict TF-DNA binding signals at the base-resolution level, to simultaneously study multiple TFBSs-associated tasks. More importantly, we also demonstrate that our proposed framework has the ability to locate all potential TF-DNA binding regions from DNA sequences of arbitrary length. We hope that our framework can provide a new perspective on studying the mechanism of TF-DNA binding and its related tasks.

bioinformatics↗

bioRxiv2021

Emergence of an adaptive epigenetic cell state in human bladder urothelial carcinoma evolution

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) facilitates therapy resistance and immune evasion to affect clinical prognosis directly. However, the molecular and cellular mechanism generating ITH in BLCA remains elusive. Here we show that a TM4SF1-positive cancer subpopulation (TPCS) drives ITH diversification in BLCA. By extensive profiling of the epigenome and transcriptome of BLCA from 79 donors across all stages, we elucidated the evolution trajectories of luminal and basal BLCA. TPCS emerges from the basal trajectory and shows extensive transcriptional plasticity with a distinct epigenomic landscape. Clinically, TPCS were enriched in advanced stage patients and associated with poor prognosis. Our results showed how cancer adapts to its environment by adopting a stem cell-like epigenomic landscape.

cancer biology↗

bioRxiv2021

Comparative transcriptomic analysis of maize ear heterosis during the inflorescence meristem differentiation stage

Heterosis is widely used in many crops; however, its genetic mechanisms are only partly understood. Here, we sampled inflorescence meristem (IM) ears from the single-segment substitution maize (Zea mays) line lx9801hlEW2b, containing a heterotic locus hlEW2b associated with ear width, the receptor parent lx9801, the test parent Zheng58, and their corresponding hybrids. After transcriptomic analysis, 1638 genes were identified in at least one hybrid with nonadditively expressed patterns and different expression levels between the two hybrids. In particular, 2263 (12.89%) and 2352 (14.65%) genes showed allele-specific expression (ASE) in Zheng58 x lx9801 and Zheng58 x lx9801hlEW2b, respectively. A functional analysis showed that these genes were enriched in development-related processes and biosynthesis and catabolism processes, which are potentially associated with heterosis. Additionally, nonadditive expression and ASE may fine-tune the expression levels of crucial genes (such as WUS and KNOX that control IM development) controlling auxin metabolism and ear development to optimal states, and transcriptional variation may play important roles in maize ear heterosis. The results provide new information that increases our understanding of the relationship between transcriptional variation and heterosis formation during maize ear development, which may be helpful in clarifying the genetic and molecular mechanisms of heterosis.

genetics↗

bioRxiv2021

MM-Deacon: Multimodal molecular domain embedding analysis via contrastive learning

AO_SCPLOWBSTRACTC_SCPLOWMolecular representation learning plays an essential role in cheminformatics. Recently, language model-based approaches have been popular as an alternative to traditional expert-designed features to encode molecules. However, these approaches only utilize a single modality for representing molecules. Driven by the fact that a given molecule can be described through different modalities such as Simplified Molecular Line Entry System (SMILES), The International Union of Pure and Applied Chemistry (IUPAC), and The IUPAC International Chemical Identifier (InChI), we propose a multimodal molecular embedding generation approach called MM-Deacon (multimodal molecular domain embedding analysis via contrastive learning). MM-Deacon is trained using SMILES and IUPAC molecule representations as two different modalities. First, SMILES and IUPAC strings are encoded by using two different transformer-based language models independently, then the contrastive loss is utilized to bring these encoded representations from different modalities closer to each other if they belong to the same molecule, and to push embeddings farther from each other if they belong to different molecules. We evaluate the robustness of our molecule embeddings on molecule clustering, cross-modal molecule search, drug similarity assessment and drug-drug interaction tasks.

bioinformatics↗

bioRxiv2021

Effect of ORF7 of SARS-CoV-2 on the chemotaxis of monocytes and neutrophils in vitro

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most significant public health threats in worldwide. Patients with severe COVID-19 usually have pneumonia concomitant with local inflammation and sometimes a cytokine storm. Specific components of the SARS-CoV-2 virus trigger lung inflammation, and recruitment of immune cells to the lungs exacerbates this process, although much remains unknown about the pathogenesis of COVID-19. Our study of lung type II pneumocyte cells (A549) demonstrated that ORF7, an open reading frame (ORF) in the genome of SARS-CoV-2, induced the production of CCL2, a chemokine that promotes the chemotaxis of monocytes, and decreased the expression of IL-8, a chemokine that recruits neutrophils. A549 cells also had an increased level of IL-6. The results of our chemotaxis transwell assay suggested that ORF7 augmented monocyte infiltration and reduced the number of neutrophils. We conclude that the ORF7 of SARS-CoV-2 may have specific effects on the immunological changes in tissues after infection. These results suggest that the functions of other ORFs of SARS-CoV-2 should also be comprehensively examined.

cell biology↗

bioRxiv2021

BMSC-Derived Exosomal MiRNAs Can Modulate Bone Restoration in Diabetic Rats with Femoral Defects

The exosomal miRNAs of BMSCs participate in hyperglycemia induced poor healing of bone defects. Here, we demonstrate that exosomes derived from BMSCs harvested from diabetes mellitus(DM) rats suppressed bone formation when administered to normal rats with bone defects. Using high-throughput sequencing analysis of microRNA molecules, high miR-140-3p levels were expressed in exosomes released by N-BMSCs. Using TargetScan software and luciferase activity assays, plxnb1 was identified as the downstream molecular target of exosomal miR-140-3p that regulated osteogenesis. Transplantation of exosomes that overexpressed miR-140-3p into DM rats promoted the restoration of bone defects. Furthermore, miR-140-3p significantly promoted the differentiation of DM-BMSCs into osteoblasts and inhibited the expression p-RohA and p-ROCK in the plexin B1 signaling pathway. Taken together, these observations suggest that DM decreases the levels of exosomal miR-140-3p, which impedes bone formation and the differentiation of BMSCs. MiR-140-3p may represent a potential therapeutic target for DM related to abnormal bone metabolism.

cell biology↗

bioRxiv2021

Three-dimensional microenvironment regulates gene expression, function, and tight junction dynamics of iPSC-derived blood-brain barrier microvessels

The blood-brain barrier (BBB) plays a pivotal role in brain health and disease. In the BBB, brain microvascular endothelial cells (BMECs) are connected by tight junctions which regulate paracellular transport, and express specialized transporter systems which regulate transcellular transport. However, existing in vitro models of the BBB display variable physiological accuracy across a wide range of characteristics including gene/protein expression and barrier function. Here, we use an isogenic family of fluorescently-labeled iPSC-derived BMEC-like cells (iBMECs) and brain pericyte-like cells (iPCs) within two-dimensional confluent monolayers (2D) and three-dimensional (3D) tissue-engineered microvessels to explore how 3D microenvironment regulates gene expression and function of the in vitro BBB. We show that 3D microenvironment (shear stress, cell-ECM interactions, and cylindrical geometry) increases BBB phenotype and endothelial identity, and alters angiogenic and cytokine responses in synergy with pericyte co-culture. Tissue-engineered microvessels incorporating junction-labeled iBMECs enable study of the real-time dynamics of tight junctions during homeostasis and in response to physical and chemical perturbations.

bioengineering↗

bioRxiv2021

Optical Cellular Micromotion: A New Paradigm to Measure Tumour Cells Invasion in 3D Tumour Environments

Measuring tumour cell invasiveness through three-dimensional (3D) tissues, particularly at the single cell level, can provide important mechanistic understanding and assist in identifying therapeutic targets of tumour invasion. However, current experimental approaches, including standard in vitro invasion assays, have limited physiological relevance and offer insufficient insight about the vast heterogeneity in tumour cell migration through tissues. To address these issues, here we report on the concept of optical cellular micromotion, where digital holographic microscopy (DHM) is used to map the optical thickness fluctuations at sub-micron scale within single cells. These fluctuations are driven by the dynamic movement of subcellular structures including the cytoskeleton and inherently associated with the biological processes involved in cell invasion within tissues. We experimentally demonstrate that the optical cellular micromotion correlates with tumour cells motility and invasiveness both at the population and single cell levels. In addition, the optical cellular micromotion significantly reduced upon treatment with migrastatic drugs that inhibit tumour cell invasion. These results demonstrate that micromotion measurements can rapidly and non-invasively determine the invasive behaviour of single tumour cells within tissues, yielding a new and powerful tool to assess the efficacy of approaches targeting tumour cell invasiveness. Significance StatementTumour cells invasion through tissues is a key hallmark of malignant tumour progression and its measurement is essential to unraveling biological processes and screening for new approaches targeting cell motility. To address the limitations of current approaches, we demonstrate that sub-micron scale mapping of the dynamic optical thickness fluctuations within single cells, referred to as optical cellular micromotion, correlates with their motility in ECM mimicking gel, both at the population and single cell levels. We anticipate that 3D optical micromotion measurement will provide a powerful new tool to address important biological questions and screen for new approaches targeting tumour cell invasiveness.

bioengineering↗

bioRxiv2021

Miniature inverted-repeat transposable elements drive rapid microRNA diversification in angiosperms

MicroRNAs (miRNAs) are rapidly evolving endogenous small RNAs programing organism function and behavior. Although models for miRNA origination have been proposed based on sporadic cases, the genomic mechanisms driving swift diversification of the miRNA repertoires in plants remain elusive. Here, by comprehensively analyzing 20 phylogenetically representative plant species, we identified miniature inverted-repeat transposable elements (MITEs) as the predominant genomic sources for de novo miRNAs in angiosperms. Our data illustrated a transposition-transcription process whereby properly sized MITEs transposed into active genic regions could be converted into new miRNAs, termed MITE-miRNAs, in as few as 20 generations. We showed that this molecular domestication mechanism leads to a possible evolutionary arms race between the MITEs and the host genomes that rapidly and continuously changes the miRNA repertoires. We found that the MITE-miRNAs are selected for targeting genes associated with plant adaptation and habitat expansion, thereby constituting a genomic innovation potentially underlying angiosperm megadiversity.

plant biology↗

bioRxiv2021

EnTrance: Exploration of Entropy Scaling Ball Cover Search in Protein Sequences

Biological sequence alignment using computational power has received increasing attention as technology develops. It is important to predict if a novel DNA sequence is potentially dangerous by determining its taxonomic identity and functional characteristics through sequence identification. This task can be facilitated by the rapidly increasing amounts of biological data in DNA and protein databases thanks to the corresponding increase in computational and storage costs. Unfortunately, the growth in biological databases has caused difficulty in exploiting this information. EnTrance presents an approach that can expedite the analysis of this large database by employing entropy scaling. This allows scaling with the amount of entropy in the database instead of scaling with the absolute size of the database. Since DNA and protein sequences are biologically meaningful, the space of biological sequences demonstrates the structure exploited by entropy scaling. As biological sequence databases grow, taking advantage of this structure can be extremely beneficial for reducing query times. EnTrance, the entropy scaling search algorithm introduced here, accelerates the biological sequence search exemplified by tools such as BLAST. EnTrance does this by utilizing a two step search approach. In this fashion, EnTrance quickly reduces the number of potential matches before more exhaustively searching the remaining sequences. Tests of EnTrance show that this approach can lead to improved query times. However, constructing the required entropy scaling indices beforehand can be challenging. To improve performance, EnTrance investigates several ideas for accelerating index build time that supports entropy scaling searches. In particular, EnTrance makes full use of the concurrency features of Go language greatly reducing the index build time. Our results identify key tradeoffs and demonstrate that there is potential in using these techniques for sequence similarity searches. Finally, EnTrance returns more matches and higher percentage identity matches when compared with existing tools.

bioinformatics↗

bioRxiv2021

The effect of histone deacetylase inhibitor Trichostatin A on IL-17A-induced transformation of MRC5 into myofibroblasts and its mechanism

ObjectiveTo elucidate potential IL-17A- and TSA-mediated regulation of fibroblasts transformation. MethodsMTT assay, HDAC1 activity assay, cell immunofluorescence and Western blot were employed to detect the expression of related indicators. ResultsMRC5 cells expressed only a small amount of Vimentin. IL-17A treatment upregulated MRC5 cell proliferation, in a concentration-dependent manner. TSA treatment, however, suppressed MRC5 cell proliferation. IL-17A treatment also upregulated HDAC1 activity in MRC5 cells, in a concentration-dependent manner. Using immunofluorescence, we demonstrated that IL-17A-treated MRC5 cells had markedly elevated Vimentin, Collagen-I and a-SMA levels, compared to controls. However, a combined treatment of IL-17A and TSA resulted in markedly reduced levels of the Vimentin, Collagen-I and a-SMA, compared to IL-17A alone, yet the amount was higher than controls. Using western blot analysis, we also revealed that the IL-17A-treated MRC5 cells had markedly elevated levels of Vimentin, a-SMA, HDAC1, p-Smad2, and p-Smad3, and markedly reduced level of Smad7, compared to controls. In TSA intervention group, the expression effect of the above protein was opposite. Moreover, no discernible difference was observed in the levels of Smad2 and Smad3 among the treated and un-treated groups. ConclusionIL-17A stimulates proliferation of MRC5 cells and increases HDAC1 activity and protein expression. It also transforms MRC5 cells into myofibroblasts via activation of the TGF -{beta}1/ Smads signaling network. TSA, on the other hand, strongly suppresses TGF -{beta}1/ Smads pathway-mediated fibrosis by ceasing HDAC1 activity and protein expression.

cell biology↗

bioRxiv2021

Autism_genepheno: Text mining of gene-phenotypeassociations reveals new phenotypic profiles ofautism-associated genes

Autism is a spectrum disorder with wide variation in type and severity of symptoms. Understanding gene-phenotype associations is vital to unravel the disease mechanisms and advance its diagnosis and treatment. To date, several databases have stored a large portion of gene-phenotype associations which are mainly obtained from genetic experiments. However, a large proportion of gene-phenotype associations are still buried in the autism-related literature and there are limited resources to investigate autism-associated gene-phenotype associations. Given the abundance of the autism-related literature, we were thus motivated to develop Autism_genepheno, a text mining pipeline to identify sentence-level mentions of autism-associated genes and phenotypes in literature through natural language processing methods. We have generated a comprehensive database of gene-phenotype associations in the last five years autism-related literature that can be easily updated as new literature becomes available. We have evaluated our pipeline through several different approaches, and we are able to rank and select top autism-associated genes through their unique and wide spectrum of phenotypic profiles, which could provide a unique resource for the diagnosis and treatment of autism. The data resources and the Autism_genpheno pipeline are available at: https://github.com/maiziezhoulab/Autism_genepheno.

bioinformatics↗

bioRxiv2021

A global multiregional proteomic map of the human cerebral cortex

The Brodmann area (BA)-based map is one of the most widely used cortical maps for studies of human brain functions and in clinical practice; however, the molecular architecture of BAs remain unknown. The present study provided a global multiregional proteomic map of the human cerebral cortex by analyzing 29 BAs. These 29 BAs were grouped into 6 clusters based on similarities in proteomic patterns: the motor and sensory cluster, vision cluster, auditory cluster and Brocas area, Wernickes area cluster, cingulate cortex cluster, and heterogeneous function cluster. We identified 474 cluster-specific and 134 BA-specific signature proteins whose functions are closely associated with specialized functions and disease vulnerability of the corresponding cluster or BA. The findings of the present study could provide explanations for the functional connections between the anterior cingulate cortex and sensorimotor cortex and for anxiety-related function in the sensorimotor cortex. The brain transcriptomic and proteomic comparison indicated that they both could reflect the function of cerebral cortex, but showed different characteristics. These proteomic data are publicly available at the Human Brain Proteome Atlas (www.brain-omics.com). Our results may enhance our understanding of the molecular basis of brain functions and provide an important resource to support human brain research.

neuroscience↗

bioRxiv2021

Efficient Inhibition of SARS-CoV-2 Using Chimeric Antisense Oligonucleotides through RNase L Activation

There is an urgent need for effective antiviral drugs to alleviate the current COVID-19 pandemic. Here, we rationally designed and developed chimeric antisense oligonucleotides to degrade envelope and spike RNAs of SARS-CoV-2. Each oligonucleotide comprises a 3 antisense sequence for target recognition and a 5-phosphorylated 2-5 poly(A)4 for guided ribonuclease L (RNase L) activation. Since RNase L can potently cleave single strand RNA during innate antiviral response, the improved degradation efficiency of chimeric oligonucleotides was twice as much as classic antisense oligonucleotides in Vero cells, for both SARS-CoV-2 RNA targets. In pseudovirus infection models, one of chimeric oligonucleotides targeting spike RNA achieved potent and broad-spectrum inhibition of both SARS-CoV-2 and its recently reported N501Y and/or {Delta}H69/{Delta}V70 mutants. These results showed that the constructed chimeric oligonucleotides could efficiently degrade pathogenic RNA of SARS-CoV-2 facilitated by immune activation, showing promising potentials as antiviral nucleic acid drugs for COVID-19.

microbiology↗