Development of antiviral agents targeting the RNA polymerase of influenza virus

abstractMicrobiologyDoctoralDoctor of Philosoph

Cellular Sensors and Viral Countermeasures: A Molecular Arms Race between Host and SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic that has caused disastrous effects on the society and human health globally. SARS-CoV-2 is a sarbecovirus in the Coronaviridae family with a positive-sense single-stranded RNA genome. It mainly replicates in the cytoplasm and viral components including RNAs and proteins can be sensed by pattern recognition receptors including toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and NOD-like receptors (NLRs) that regulate the host innate and adaptive immune responses. On the other hand, the SARS-CoV-2 genome encodes multiple proteins that can antagonize the host immune response to facilitate viral replication. In this review, we discuss the current knowledge on host sensors and viral countermeasures against host innate immune response to provide insights on virus–host interactions and novel approaches to modulate host inflammation and antiviral responses

Research on Active Collision Avoidance and Hysteresis Reduction of Intelligent Vehicle Based on Multi-Agent Coordinated Control System

This paper provides a multi-agent coordinated control system to improve the real-time performance of intelligent vehicle active collision avoidance. At first, the functions and characteristics of longitudinal and lateral collision avoidance agents are analyzed, which are the main components of the multi-agent. Then, a coordinated solution mechanism of an intelligent vehicle collision avoidance system is established based on hierarchical control and blackboard model methods to provide a reasonable way to avoid collision in complex situations. The multi-agent coordinated control system can handle the conflict between the decisions of different agents according to the rules. Comparing with existing control strategies, the proposed system can realize multi decisions and planning at the same time; thus, it will reduce the operation time lag during active collision avoidance. Additionally, fuzzy sliding mode control theory is introduced to guarantee accurate path tracking in lateral collision avoidance. Finally, co-simulation of Carsim and Simulink are taken, and the results show that the real-time behavior of intelligent vehicle collision avoidance can be improved by 25% through the system proposed

Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan

A mysterious outbreak of atypical pneumonia in late 2019 was traced to a seafood wholesale market in Wuhan of China. Within a few weeks, a novel coronavirus tentatively named as 2019 novel coronavirus (2019-nCoV) was announced by the World Health Organization. We performed bioinformatics analysis on a virus genome from a patient with 2019-nCoV infection and compared it with other related coronavirus genomes. Overall, the genome of 2019-nCoV has 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV. The phylogenetic trees of their orf1a/b, Spike, Envelope, Membrane and Nucleoprotein also clustered closely with those of the bat, civet and human SARS coronaviruses. However, the external subdomain of Spike’s receptor binding domain of 2019-nCoV shares only 40% amino acid identity with other SARS-related coronaviruses. Remarkably, its orf3b encodes a completely novel short protein. Furthermore, its new orf8 likely encodes a secreted protein with an alpha-helix, following with a beta-sheet(s) containing six strands. Learning from the roles of civet in SARS and camel in MERS, hunting for the animal source of 2019-nCoV and its more ancestral virus would be important for understanding the origin and evolution of this novel lineage B betacoronavirus. These findings provide the basis for starting further studies on the pathogenesis, and optimizing the design of diagnostic, antiviral and vaccination strategies for this emerging infection

Polyacrylate Backbone Promotes Photoinduced Reversible Solid-To-Liquid Transitions of Azobenzene-Containing Polymers

The development of polymers with efficient photoinduced reversible solid-to-liquid transitions is desirable for the design of healable materials, reconfigurable devices, and switchable adhesives. Herein, we demonstrate that an azobenzene-containing polyacrylate P-H exhibits more efficient photoinduced reversible solid-to-liquid transitions than its polymethacrylate analogue P-Me. The side chain of P-H or P-Me contains a hexamethylene spacer, a photoresponsive azobenzene group, and an n-decyl tail. Both P-H and P-Me show reversible cis–trans photoisomerization. Solid transP-H and P-Me change to liquid cis ones via UV-light-induced trans-to-cis isomerization; liquid cisP-H and P-Me revert to solid trans ones via visible-light-induced cis-to-trans back isomerization. Differential scanning calorimetry and rheology measurements revealed that photoinduced reversible solid-to-liquid transitions occur because P-H and P-Me have photoswitchable glass transition temperatures. Although P-Me exhibits a slightly faster rate for trans-to-cis photoisomerization than P-H due to fewer aggregates in solid state, cisP-H flows 20 times faster than cisP-Me because P-H has a more flexible polymer backbone. The low viscosity of cisP-H makes photoinduced solid-to-liquid transition efficient and enables the design of rapidly healable coatings. Our study shows that the design of a flexible backbone is a new strategy to develop rapidly healable polymers with more efficient photoinduced solid-to-liquid transitions

HPVTIMER: A shiny web application for tumor immune estimation in human papillomavirus‐associated cancers

Abstract The tumor immune microenvironment (TIME) is closely associated with tumor formation, particularly linked to the human papillomavirus (HPV), and regulates tumor initiation, proliferation, infiltration, and metastasis. With the rise of immunotherapy, an increasing amount of sample data used for TIME exploration is available in databases. However, no currently available web tool enables a comprehensive exploration of the TIME of HPV‐associated cancers by leveraging these data. We have developed a web tool called HPV‐associated Tumor Immune MicroEnvironment ExploreR (HPVTIMER), which provides a comprehensive analysis platform that integrates over 10,000 genes and 2290 tumor samples from 65 transcriptome data sets across 8 cancer types sourced from the Gene Expression Omnibus (GEO) database. The tool features four built‐in analysis modules, namely, the differential expression analysis module, correlation analysis module, immune infiltration analysis module, and pathway analysis module. These modules enable users to perform systematic and vertical analyses. We used several analytical modules in HPVTIMER to briefly explore the role of CDKN2A in head and neck squamous cell carcinomas. We expect that HPVTIMER will help users explore the immune microenvironment of HPV‐associated cancers and uncover potential immune regulatory mechanisms and immunotherapeutic targets. HPVTIMER is available at http://www.hpvtimer.com/

Development of Three-Dimensional Human Intestinal Organoids as a Physiologically Relevant Model for Characterizing the Viral Replication Kinetics and Antiviral Susceptibility of Enteroviruses

Enteroviruses are important causes of hand, foot, and mouth disease, respiratory infections, and neurological infections in human. A major hurdle for the development of anti-enterovirus agents is the lack of physiologically relevant evaluation platforms that closely correlate with the in vivo state. We established the human small intestinal organoids as a novel platform for characterizing the viral replication kinetics and evaluating candidate antivirals for enteroviruses. The organoids supported productive replication of enterovirus (EV)-A71, coxsackievirus B2, and poliovirus type 3, as evidenced by increasing viral loads, infectious virus titers, and the presence of cytopathic effects. In contrast, EV-D68, which mainly causes respiratory tract infection in humans, did not replicate significantly in the organoids. The differential expression profiles of the receptors for these enteroviruses correlated with their replication kinetics. Using itraconazole as control, we showed that the results of various antiviral assays, including viral load reduction, plaque reduction, and cytopathic effect inhibition assays, were highly reproducible in the organoids. Moreover, itraconazole attenuated virus-induced inflammatory response in the organoids, which helped to explain its antiviral effects and mechanism. Collectively, these data showed that the human small intestinal organoids may serve as a robust platform for investigating the pathogenesis and evaluating antivirals for enteroviruses

Development of Three-Dimensional Human Intestinal Organoids as a Physiologically Relevant Model for Characterizing the Viral Replication Kinetics and Antiviral Susceptibility of Enteroviruses

Enteroviruses are important causes of hand, foot, and mouth disease, respiratory infections, and neurological infections in human. A major hurdle for the development of anti-enterovirus agents is the lack of physiologically relevant evaluation platforms that closely correlate with the in vivo state. We established the human small intestinal organoids as a novel platform for characterizing the viral replication kinetics and evaluating candidate antivirals for enteroviruses. The organoids supported productive replication of enterovirus (EV)-A71, coxsackievirus B2, and poliovirus type 3, as evidenced by increasing viral loads, infectious virus titers, and the presence of cytopathic effects. In contrast, EV-D68, which mainly causes respiratory tract infection in humans, did not replicate significantly in the organoids. The differential expression profiles of the receptors for these enteroviruses correlated with their replication kinetics. Using itraconazole as control, we showed that the results of various antiviral assays, including viral load reduction, plaque reduction, and cytopathic effect inhibition assays, were highly reproducible in the organoids. Moreover, itraconazole attenuated virus-induced inflammatory response in the organoids, which helped to explain its antiviral effects and mechanism. Collectively, these data showed that the human small intestinal organoids may serve as a robust platform for investigating the pathogenesis and evaluating antivirals for enteroviruses