42 research outputs found
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 virusāhost interactions and novel approaches to modulate host inflammation and antiviral responses
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An enhanced broad-spectrum peptide inhibits Omicron variants in vivo.
The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) poses a major challenge to vaccines and antiviral therapeutics due to their extensive evasion of immunity. Aiming to develop potent and broad-spectrum anticoronavirus inhibitors, we generated A1-(GGGGS)7-HR2m (A1L35HR2m) by introducing an angiotensin-converting enzyme 2 (ACE2)-derived peptide A1 to the N terminus of the viral HR2-derived peptide HR2m through a long flexible linker, which showed significantly improved antiviral activity. Further cholesterol (Chol) modification at the C terminus of A1L35HR2m greatly enhanced the inhibitory activities against SARS-CoV-2, SARS-CoV-2 VOCs, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) pseudoviruses, with IC50 values ranging from 0.16 to 5.53 nM. A1L35HR2m-Chol also potently inhibits spike-protein-mediated cell-cell fusion and the replication of authentic Omicron BA.2.12.1, BA.5, and EG.5.1. Importantly, A1L35HR2m-Chol distributed widely in respiratory tract tissue and had a long half-life (>10 h) in vivo. Intranasal administration of A1L35HR2m-Chol to K18-hACE2 transgenic mice potently inhibited Omicron BA.5 and EG.5.1 infection both prophylactically and therapeutically
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 Spikeās 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 cisātrans 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
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