Biology subjects

Zhang, Q.

Publications and source records attributed to Zhang, Q..

At least 703 records · Page 39Linked to original sources

bioRxiv2019

Research of the mechanism on miRNA193 in exosomes promotes cisplatin resistance in esophageal cancer cells

PurposeChemotherapy resistance of esophageal cancer is a key factor affecting the postoperative treatment of esophageal cancer. Among the media that transmit signals between cells, the exosomes secreted by tumor cells mediate information transmission between tumor cells, which can make sensitive cells obtain resistance. Although some cellular exosomes play an important role in tumors acquired drug resistance, the related action mechanism is still not explored specifically.\n\nMethodsTo elucidate this process, we constructed a cisplatin-resistant esophageal cancer cell line, and proved that exosomes conferring cellular resistance in esophageal cancer can promote cisplatin resistance in sensitive cells. Through high-throughput sequencing analysis of the exosome and of cells after stimulation by exosomes, we determined that the miRNA193 in exosomes conferring cellular resistance played a key role in sensitive cells acquiring resistance to cisplatin. In vitro experiments showed that miRNA193 can regulate the cell cycle of esophageal cancer cells and inhibit apoptosis, so that sensitive cells can acquire resistance to cisplatin. An in vivo experiment proved that miRNA193 can promote tumor proliferation through the exosomes, and provide sensitive cells with slight resistance to cisplatin.\n\nResultsSmall RNA sequencing of exosomes showed that exosomes in drug-resistant cells have 189 up-regulated and 304 down-regulated miRNAs; transcriptome results showed that drug-resistant cells treated with drug-resistant cellular exosomes have 3446 high-expression and 1709 low-expression genes; correlation analysis showed that drug-resistant cellular exosomes mainly affect the drug resistance of sensitive cells through paths such as cytokine-cytokine receptor interaction, and the VEGF and Jak-STAT signaling pathways; miRNA193, one of the high-expression miRNAs in drug-resistant cellular exosomes, can promote drug resistance by removing cisplatins inhibition of the cell cycle of sensitive cells.\n\nConclusionSensitive cells can become resistant to cisplatin through acquired drug-resistant cellular exosomes, and miRNA193 can make tumor cells acquire cisplatin resistance by regulating the cell cycle.

cancer biology↗

bioRxiv2019

A Synthetic Biology Approach to Sequential Stripe Patterning and Somitogenesis

Reaction-diffusion (RD) based clock and wavefront model has long been proposed as the mechanism underlying biological pattern formation of repeated and segmented structures including somitogenesis. However, systematic molecular level understanding of the mechanism remains elusive, largely due to the lack of suitable experimental systems to probe RD quantitatively in vivo. Here we design a synthetic gene circuit that couples gene expression regulation (reaction) with quorum sensing (diffusion) to guide bacterial cells self-organizing into stripe patterns at both microscopic and colony scales. An experimentally verified mathematical model confirms that these periodic spatial structures are emerged from the integration of oscillatory gene expression as the molecular clock and the outward expanding diffusions as the propagating wavefront. Furthermore, our paired model-experiment data illustrate that the RD-based patterning is sensitive to initial conditions and can be modulated by external inducers to generate diverse patterns, including multiple-stripe pattern, target-like pattern and ring patterns with reversed fluorescence. Powered by our synthetic biology setup, we also test different topologies of gene networks and show that network motifs enabling robust oscillations are foundations of sequential stripe pattern formation. These results verified close connections between gene network topology and resulting RD driven pattern formation, offering an engineering approach to help understand biological development.

synthetic biology↗

bioRxiv2019

Establishment of the trans-resveratrol-induced mouse pulmonary fibrosis model and its comparison with the bleomycin-induced model

Pulmonary fibrosis (PF) is a progressive, fatal disease, and its pathogenic mechanism has not yet been identified. The bleomycin (BLM)-induced animal model has several shortcomings that cannot be overcome. We accidentally found that the continuous oral administration of trans-resveratrol (TR) at levels above the prescribed dose can induce PF within a certain period of time, and this model can be successfully replicated in mice, as indicated by the hydroxyproline (HYP) test and pathological analysis. The TR model requires no anesthesia or surgery and thus causes less damage to mice than the BLM model. The progress of fibrosis in the TR model was slow but progressed steadily compared with the BLM model, and the TR model was more comparable to human PF. Although the pathogenesis is not understood, the TR-induced PF model indicated that there may be a close relationship between PF and tumors and antitumor drugs, which requires further exploration.

pharmacology and toxicology↗

bioRxiv2019

Viral manipulation of functionally distinct neurons from mice to humans

Recent success in identifying gene regulatory elements in the context of recombinant adeno-associated virus vectors have enabled cell type-restricted gene expression. However, within the cerebral cortex these tools are presently limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple novel enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we identified enhancers that target the breadth of its expression, including two that are selective for parvalbumin and vasoactive intestinal peptide cortical interneurons. Demonstrating the functional utility of these elements, we found that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across species, from mice to humans. Finally, we demonstrate that our selection method is generalizable to other genes and characterize four additional PV-specific enhancers with exquisite specificity for distinct regions of the brain. Altogether, these viral tools can be used for cell-type specific circuit manipulation and hold considerable promise for use in therapeutic interventions.

neuroscience↗

bioRxiv2019

Tensor Factorization-based Prediction with an Application to Estimating the Risk of Chronic Diseases

Tensor factorization has emerged as a powerful method to address the challenges of high dimensionality regarding disease development and comorbidity. Chronic diseases have a high likelihood to co-occur, making patients suffering from one chronic disease to have an elevated risk for the other diseases in the course of aging. Individualized prediction of chronic diseases can help patients prevent new diseases and reduce the healthcare costs. Despite rich results of risk assessment models for chronic diseases, individualized risk prediction considering the complex mechanisms of disease development and comorbidity remains to be under-researched. This research aims to develop tensor factorization-based machine learning models to predict the onset of new chronic diseases for individual patients through incorporating the comorbidity patterns with the clinical and sequential factors revealed in the electronic health records (EHR) data. We propose two tensor factorization-based methods to incorporate the clinical and sequential factors to reveal the latent patterns of co-occurring chronic diseases. The efficacy of the proposed methods was validated through predicting the onset of new chronic diseases for individual patients using the EHR data for 23 years from a major hospital in Hong Kong. The proposed methods consistently outperform benchmark predictive models. The top 10 predictions of new chronic diseases have approximately 60% recall. Tensor factorization is an appropriate method for predicting the onset of chronic diseases at the individual level. The proposed predictive models could inform proactive health management programs for at-risk patients with different chronic conditions at discharge.\n\nAuthor summaryThe existing risk assessment models mainly focused on the prediction of single diseases in the population base. Chronic disease risk prediction considering the complex mechanisms of disease development and comorbidity is under-researched. To support and inform clinical decision making for healthcare professionals in the aging society, this study provides an innovative approach to mapping an interconnected web of chronic illnesses and investigated the performance of chronic disease prediction using 2 years worth of patient assessment records and 23 years admission history data from a major hospital in Hong Kong. We proposed matrix and tensor-based methods to represent the high-order interrelations of patients, chronic diseases and additional features, which can reveal the latent patterns of co-occurring chronic diseases to enable more effective prediction. The proposed methods exhibit state-of-the-art performance in predicting the onset of new chronic diseases for individual patients.

bioinformatics↗

bioRxiv2019

Assembly of novel, nuclear dimers of the PI3-Kinase regulatory subunits underpins the pro-proliferative activity of the Cdc42-activated tyrosine kinase, ACK

The tyrosine kinase ACK is an oncogene associated with poor prognosis in human cancers. ACK promotes proliferation, in part, by contributing to the activation of Akt, the major PI3-Kinase effector. We show that ACK also regulates PI3-Kinase directly, via interactions with the PI3-Kinase regulatory subunits. ACK interacts with all five regulatory subunit isoforms and directly phosphorylates p85, p85{beta}, p55 and p50 on Tyr607 (or equivalent). Phosphorylation of p85{beta} at this residue promotes cell proliferation but, counterintuitively, ACK does not stimulate PI3-Kinase catalytic activity. We show that ACK stabilizes p85 levels by promoting an interaction between the p85 nSH2 domain and pTyr607, protecting p85 from ubiquitination. We demonstrate that ACK interacts with p85 exclusively in nuclear-enriched cell fractions where the increased levels of the regulatory subunits, together with the nSH2-pTyr607 interaction, promote formation of dimeric p85. We postulate that these novel dimers undertake nuclear functions that contribute to Cdc42-ACK driven oncogenesis. We propose that ACK shapes PI3-Kinase signalling by dampening the PIP3 response, whilst continuing to drive cell proliferation through Akt activation and hereto unexplored but crucial functions of nuclear dimeric p85. These new regulatory subunit dimers represent a previously undescribed mode of regulation for PI3-Kinase and potentially reveal additional avenues for therapeutic intervention.

molecular biology↗

bioRxiv2019

Vector bionomics and vectorial capacity as emergent properties of mosquito behaviors and ecology

Mosquitoes are important vectors for pathogens of humans and other vertebrate animals. Some aspects of adult mosquito behavior and mosquito ecology play an important role in determining the capacity of vector populations to transmit pathogens. Here, we re-examine factors affecting the transmission of pathogens by mosquitoes using a new approach. Unlike most previous models, this framework considers the behavioral states and state transitions of adult mosquitoes through a sequence of activity bouts. We developed a new framework for individual-based simulation models called MBITES (Mosquito Bout-based and Individual-based Transmission Ecology Simulator). In MBITES, it is possible to build models that simulate the behavior and ecology of adult mosquitoes in exquisite detail on complex resource landscapes generated by spatial point processes. We also developed an ordinary differential equation model which is the Kolmogorov forward equations for models developed in MBITES under a specific set of simplifying assumptions. While infection of the mosquito and pathogen development are one possible part of a mosquitos state, that is not the main focus. Using extensive simulation using some models developed in MBITES, we show that vectorial capacity can be understood as an emergent property of simple behavioral algorithms interacting with complex resource landscapes, and that relative density or sparsity of resources and the need to search can have profound consequences for mosquito populations capacity to transmit pathogens.

ecology↗

bioRxiv2019

Cortical RORβ is required for layer 4 transcriptional identity and barrel integrity.

Retinoic Acid-Related Orphan Receptor Beta (ROR{beta}) is a transcription factor (TF) and marker of layer 4 (L4) neurons, which are distinctive both in transcriptional identity and the ability to form aggregates such as barrels in rodent somatosensory cortex. However, the relationship between transcriptional identity and L4 cytoarchitecture is largely unknown. We find ROR{beta} is required in the cortex for L4 aggregation into barrels and thalamocortical afferent (TCA) segregation. Interestingly, barrel organization also degrades with age. Loss of ROR{beta} delays excitatory input and disrupts gene expression and chromatin accessibility, with downregulation of L4 and upregulation of L5 genes, suggesting a shift in cellular identity. Expression and binding site accessibility change for many other TFs, including closure of neurodevelopmental TF binding sites and increased expression and binding capacity of activity-regulated TFs. Lastly, a putative target of ROR{beta}, Thsd7a, is downregulated without ROR{beta}, and Thsd7a knockout alone disrupts TCA organization in adult barrels.

neuroscience↗

bioRxiv2019

Systematic Pan-Cancer Analysis Reveals the Functional Roles of Ferroptosis Across Cancers

Ferroptosis is a type of cell death that related to cancer, however, the characteristics of ferroptosis in cancers are still uncertain. Based on the data in The Cancer Genome Atlas, we found that most ferroptosis regulator genes (FRGs) were differentially expressed in tumors, copy number alterations (CNA) and DNA methylation contributed to their aberrant expression. We established the ferroptosis potential index (FPI) to reveal the functional roles of ferroptosis and noticed that the FPI was higher in tumors than in normal tissues in most cancers, and was associated with subtypes and clinical features. The FPI was negatively correlated with several metabolism pathways but positively associated with several important metastasis-related pathways and immune-related pathways. Higher FPI predicted worse prognosis in several tumors, while FPI and FRGs impacted drug sensitivity. Our study presents a systematical analysis of ferroptosis and its regulatory genes, and highlights the potential of ferroptosis-based cancer therapy.

cancer biology↗

bioRxiv2019

Systematical analysis reveals the novel function of Cyp2c29 in liver injury

As a severe lethal cancer, hepatocellular carcinoma (HCC) usually originates from chronic liver injury and inflammation, in which the discovery of key genes is important for HCC prevention. Here, we analyzed the time serial (from 0 week to 30 weeks) transcriptome data of liver injury samples in diethylnitrosamine (DEN)-induced HCC mouse model. Through expression and function analyses, we identified that Cyp2c29 was a key gene continuously downregulated during liver injury. Overexpression of Cyp2c29 suppressed the NF-{kappa}B activation, proinflammatory cytokine production and hepatocyte proliferation by increasing its production 14,15-epoxyeicosatrienoic acid (14,15-EET). Furthermore, in vivo Cyp2c29 protected against liver inflammation in liver injury mice models by reversing the expression on functions of cell proliferation, metabolism and inflammation including suppressing NF-{kappa}B pathway and compensatory proliferation. CYP2C8 and CYP2C9, two human homologs of mouse Cyp2c29, were decreased in human HCC progression and positively correlated with HCC patient survival. Therefore, through systematical analysis and verification, we identified that Cyp2c29 is a novel gene in liver injury and inflammation, which may be a potential biomarker for HCC prevention and prognosis.

bioinformatics↗

bioRxiv2019

Visualizing in vitro-in vivo correlation of miktoarm copolymer nanomicelles in cancer cellular uptake and trafficking

In this study, a clear correlation between the in vitro and in vivo cellular uptake and trafficking was discovered by delivering miktoarm copolymer nanomicelles (MCNs) to cancer cells and tumor tissues. To monitor this process, two different FRET pairs, DiO and DiI, DiD and DiR, were loaded into MCNs to monitor the Forster resonance energy transfer (FRET) efficiency. The change in FRET efficiency in vitro and in vivo demonstrated a similar sequence of events for the transport of MCNs: hyperbranched block PCL inserted into cytomembrane, while the loaded hydrophobic fluorescence probes were released and followed by time-dependent intracellular clustering within endocytic vesicles. Additionally, uptake of loaded fluorescence probes with successively increasing ratios of copolymers suggested that with the increase of mass ratio of copolymer to fluorescence probes, cellular uptake of probes significantly decreased. This result was also consistent with the uptake behavior in cancer tissues. Collectively, the interaction between MCNs and cellular membrane dictated the uptake and trafficking of core-loaded hydrophobic probes. This concept paves a new way to analyze in vitro-in vivo correlation of other nanocarriers for endocytosis mechanism studies as well as further novel copolymers design in biomedical applications.

pharmacology and toxicology↗

bioRxiv2019

The inverse relationship between fibronectin and neuroligins in the embryonic rat colon

Our previous study identified that the abnormal expression of fibronectin (FN), neuroligin-1 (NL1) and neuroligin-2 (NL2) in the colons of children with Hirschsprung disease (HSCR), but the correlated relationship between the three in the development of the enteric nervous system (ENS) remains unclear. Colons of Wistar rats and PC12 neurons were used to investigate the relationship between FN and the neuroligins (NLs). Colon tissues from thirty healthy embryonic rats, including fifteen at embryonic day 16 (E16), eight at E18, seven at E20, and fifteen newborn rats within 24 hours (Ep0) were analyzed to determine the correlated expression of FN and NLs using Western blot (WB) analysis and real-time fluorescence quantitative PCR (qRT-PCR) methods. Small interfering ribonucleic acid (siRNA) targeting and gene plasmids were used to explore the functional interaction between FN and NLs by using PC12 neuron cells. Furthermore, we used recombinant FN and NL proteins to confirm their interactions. Our studies showed that there were downregulatory effects between FN and the NLs in the embryonic rat colon and different cell lines, indicating that FN and NLs could directly regulate each other, and there is a negative linear correlation between them. The imbalanced interaction between extracellular matrix and synapse-related genes may provide a new perspective for the pathogenesis and treatment of HSCR and neuronal intestinal malformations (NIMs).

cell biology↗

bioRxiv2019

Residue retention promotes soil carbon accumulation in minimum tillage systems: Implications for conservation tillage

Crop residue retention and minimum tillage (including no-tillage, NT, and reduced tillage, RT) are common conservation tillage practices that have been extensively practised for improving soil health and reducing the negative environmental impact caused by intensive farming. However, the complex effect of conservation tillage practices on soil organic carbon (SOC) storage has not been systematically analyzed, and particularly, the synergistic effect of crop residue retention and minimum tillage on SOC storage remains nonexistent. We conducted a global meta-analysis using a dataset consisting of 823 pairs of data points from 164 studies. We analyzed the effect of crop residue retention and minimum tillage on SOC storage and how the above effects were influenced by various soil/environmental (soil sampling depth, soil texture, and climate) and management conditions (cropping intensity and treatment duration). We found that either residue retention or minimum tillage alone increased SOC stock, while the former increased SOC more. The NT and RT increased SOC stock by 10 and 6%, respectively, in comparison to conventional tillage (CT). The NT plus residue retention (NTS) and RT plus residue retention (RTS) resulted in 20 and 26% more increase in SOC than NT and RT, respectively. Compared with CT, NTS and RTS further increased SOC stock by 29 and 27%, respectively. The above effects were greater in the topsoil than in the subsoil. Availability of initial soil nutrient played a greater role in affecting SOC stock than climatic conditions and management practices. Both residue retention and NT increased SOC rapidly in the first 6 years regardless of soil texture or climate condition, followed by a period of slower sequestration phase before reaching a slow steady rate. Double cropping generally increased SOC stock across all conservation tillage practices as compared to single or multiple cropping. Therefore, we conclude that minimum tillage coupled with residue retention in a double cropping system is the most beneficial management system for increasing cropland SOC storage, which can inform sustainable soil management practices aimed at increasing global C sequestration.

ecology↗

bioRxiv2019

Genome-wide identification and transcriptomic analysis of microRNAs across various amphioxus organs using deep sequencing

Amphioxus is the closest living invertebrate proxy of the vertebrate ancestor. Systematic gene identification and expression profile analysis of amphioxus organs is thus important for clarifying the molecular mechanisms of organ function formation and further understanding the evolutionary origin of organs and genes in vertebrates. The precise regulation of microRNAs (miRNAs) is crucial for the functional specification and differentiation of organs. In particular, those miRNAs that are expressed specifically in organs (OSMs) play key roles in organ identity, differentiation, and function. In this study, the genome-wide miRNA transcriptome was analyzed in eight organs of adult amphioxus Branchiostoma belcheri using deep sequencing. A total of 167 known miRNAs and 23 novel miRNAs (named novel_mir), including 139 conserved miRNAs, were discovered, and 79 of these were identified as OSMs. Additionally, analyses of the expression patterns of eight randomly selected known miRNAs demonstrated the accuracy of the miRNA deep sequencing that was used in this study. Furthermore, potentially OSM-regulated genes were predicted for each organ type. Functional enrichment of these predicted targets, as well as further functional analyses of known OSMs, was conducted. We found that the OSMs were potentially to be involved in organ specific functions, such as epidermis development, gonad development, muscle cell development, proteolysis, lipid metabolism and generation of neurons. Moreover, OSMs with non-organ specific functions were detected, and primarily include those related to innate immunity and response to stimuli. These findings provide insights into the regulatory roles of OSMs in various amphioxus organs.

genetics↗

bioRxiv2019

An ultra-sensitive T-cell receptor detection method for TCR-Seq and RNA-Seq data

T-cell receptors (TCRs) recognizing antigens play vital roles in T-cell immunology. Surveying TCR repertoires by characterizing complementarity-determining region 3 (CDR3) can provide valuable insights into the immune community underlying pathologic conditions, which will benefit neoantigen discovery and cancer immunotherapy. Here we present a novel tool named CATT, which can apply on TCR sequencing (TCR-Seq), RNA-Seq, and single-cell TCR(RNA)-Seq data to characterize CDR3 repertoires. CATT integrated maximum-network-flow based micro-assembly algorithm, data-driven error correction model, and Bayes classification algorithm, to self-adaptively and ultra-sensitively characterize CDR3 repertoires with high accuracy. Benchmark results of datasets from in silico and real conditions demonstrated that CATT showed superior recall and precision compared with other prevalent tools, especially for datasets with short read length and small data size. By applying CATT on a TCR-Seq dataset from aplastic anemia patients, we found the skewing of TCR repertoire was due to the oligoclonal expansion of effector memory T-cells. CATT will be a powerful tool for researchers conducting TCR and immune repertoire studies. CATT is freely available at http://bioinfo.life.hust.edu.cn/CATT.

bioinformatics↗

bioRxiv2019

Emodin Attenuates Renal Interstitial Fibrosis via Regulation of TIMP1/MM9 Pathway in Rats

Emodin has a variety of pharmacological functions including anti-bacterial infection, anti-inflammatory, anti-oxidation, anti-tumor, regulation of gastrointestinal activities and anti-hepatic and lung fibrosis. However, the role of emodin in the regulation of renal interstitial fibrosis(RIF) remains poorly understood. In this study, we investigated the regulation of emodin in RIF and revealed the underlying molecular mechanisms. We established a unilateral ureter obstruction(UUO) model to simulate renal interstitial fibrosis in rats. We found that UUO rats were observed a large amount of inflammatory cell infiltration, more fibroblast proliferation, collagen fiber proliferation. Furthermore, we demonstrated that the up-regulation of TIMP1 and down-regulation of MMP9 were related to renal fibrosis. However, those phenomena in emodin-treated UUO rats were ameliorated. Collectively, our results provide new insights into the treatment of RIF and suggest that the TIMP1/MM9 signaling axis may be a potential therapeutic target for RIF.

molecular biology↗

bioRxiv2019

Unit quaternion description of spatial rotation in 3D electron cryo-microscopy

Electron cryo-microscopy (cryoEM) involves the estimation of orientations of projection images or three-dimensional (3D) volumes. However, the lack of statistical tools of rotations in cryoEM fails to answer the growing demands for adopting advanced statistical methods. In this study, we develop a comprehensive statistical tool specialized for cryoEM based on an unit quaternion description of spatial rotations. Some basic properties and definitions of the quaternion, as well as a way to use the unit quaternion to describe and perform rotations, are first recalled. Then, based on the unit quaternion, the distance and geodesic between rotations are designed for cryoEM to enable comparisons and interpolations between rotations, which are prerequisites of statistics of rotations in 3D cryoEM. Further, methods of directional statistics specialized for cryoEM are developed, including calculations of the average rotation, sampling, and inference with uniform and angular central Gaussian (ACG) distribution, as well as an estimation of the rotation precision. Finally, the method of handling molecular symmetry is introduced. Using the unit quaternion system for cryoEM, we provide comprehensive mathematical tools for the analysis of spatial rotations in cryoEM.

biophysics↗

bioRxiv2019

The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild type ACVR1. To explore the role of the NSC, we generated agonist-only Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSCs physiological role in corresponding knock-in mice. Impact StatementThe non-signaling complex formed by Activin A and ACVR1 is operant in vivo and is required to temper the degree of heterotopic ossification in the genetic disorder fibrodysplasia ossificans progressiva.

cell biology↗