Re-examining rotavirus innate immune evasion: Potential applications of the reverse genetics system

Rotaviruses represent one of the most successful pathogens in the world, with high infectivity and efficient transmission between the young of many animal species, including humans. To overcome host defenses, rotaviruses have evolved a plethora of strategies to effectively evade the innate immune response, establish initial infection in the small intestine, produce progeny, and shed into the environment. Previously, studying the roles and relative contributions of specific rotaviral factors in innate immune evasion had been challenging without a plasmid-only reverse genetics system. Although still in its infancy, current reverse genetics technology will help address important research questions regarding rotavirus innate immune evasion, host range restriction, and viral pathogenesis. In this review, we summarize the current knowledge about the antiviral host innate immune defense mechanisms, countermeasures of rotavirus-encoded factors, and strategies to better understand these interactions using the rotavirus reverse genetics system

A Study of Oscillating Water Column Wave Energy Converters Array Configurations Based on Simulation

Wave energy is a potentially important renewable clean source of energy that can help solve the energy demand throughout the world. A great deal of research has been conducted in the last few decades and it is now reaching the point of full implementation. In order to compete with other energy sources, we must first demonstrate that it is commercially viable. So far, researchers and developers have been able to demonstrate proof of concept utilizing a small number of wave energy converters (WECs) deployed in the open ocean or on shore. However, to make this source of energy commercially viable, the deployment of a large number of WECs is necessary. Regardless of the type of WEC used, the deployment of these devices has to be carefully thought out, since the direction of the wave fronts varies throughout the year and once the WECs are installed, they will remain fixed in those locations and they will experience only relatively small displacements on the ocean surface. When a group of WECs is deployed on the ocean surface, their motion resulting from the excitation force due to the arrival of a wave front will affect other WECs in the vicinity. Furthermore, depending on the angle of arrival of the wave front, the interaction between WECs will vary and the energy conversion capability will be affected. This interaction has been coined as the q factor by researchers in the field. In this thesis, we consider the deployment of an oscillating water column (OWC) WECs developed by researchers from the Polytechnic of Lisbon in Portugal and their Spanish collaborators, namely, the MarmokA5. Our deployment strategy has as its main objective the maximization of average power of the array of WECs. When we consider an array configuration, namely, its geometric configuration, distance between WECs, angle of arrival of the wave front, and sea state, we implement a mathematical model of the array produced by ANSYS AQWA in Simulink to compute the average power generated by the array. We evaluate array power generation performance by varying the form of its configuration and the number of WECs in it. The results of our strategy suggest that they can be incorporated into more formal mathematical objective function to optimize WEC array generated power

m6A modifications regulate intestinal immunity and rotavirus infection

N6-methyladenosine (m6A) is an abundant mRNA modification and affects many biological processes. However, how m6A levels are regulated during physiological or pathological processes such as virus infections, and the in vivo function of m6A in the intestinal immune defense against virus infections are largely unknown. Here, we uncover a novel antiviral function of m6A modification during rotavirus (RV) infection in small bowel intestinal epithelial cells (IECs). We found that rotavirus infection induced global m6A modifications on mRNA transcripts by down-regulating the m6a eraser ALKBH5. Mice lacking the m6A writer enzymes METTL3 in IECs

CityFlow: A Multi-Agent Reinforcement Learning Environment for Large Scale City Traffic Scenario

Traffic signal control is an emerging application scenario for reinforcement learning. Besides being as an important problem that affects people's daily life in commuting, traffic signal control poses its unique challenges for reinforcement learning in terms of adapting to dynamic traffic environment and coordinating thousands of agents including vehicles and pedestrians. A key factor in the success of modern reinforcement learning relies on a good simulator to generate a large number of data samples for learning. The most commonly used open-source traffic simulator SUMO is, however, not scalable to large road network and large traffic flow, which hinders the study of reinforcement learning on traffic scenarios. This motivates us to create a new traffic simulator CityFlow with fundamentally optimized data structures and efficient algorithms. CityFlow can support flexible definitions for road network and traffic flow based on synthetic and real-world data. It also provides user-friendly interface for reinforcement learning. Most importantly, CityFlow is more than twenty times faster than SUMO and is capable of supporting city-wide traffic simulation with an interactive render for monitoring. Besides traffic signal control, CityFlow could serve as the base for other transportation studies and can create new possibilities to test machine learning methods in the intelligent transportation domain.Comment: WWW 2019 Demo Pape

Rotavirus NSP1 contributes to intestinal viral replication, pathogenesis, and transmission

Rotavirus (RV)-encoded nonstructural protein 1 (NSP1), the product of gene segment 5, effectively antagonizes host interferon (IFN) signaling via multiple mechanisms. Recent studies with the newly established RV reverse genetics system indicate that NSP1 is not essential for the replication of the simian RV SA11 strain in cell culture. However, the role of NSP1 in RV infectio

When STING meets viruses: Sensing, trafficking and response

To effectively defend against microbial pathogens, the host cells mount antiviral innate immune responses by producing interferons (IFNs), and hundreds of IFN-stimulated genes (ISGs). Upon recognition of cytoplasmic viral or bacterial DNAs and abnormal endogenous DNAs, the DNA sensor cGAS synthesizes 2\u27,3\u27-cGAMP that induces STING (stimulator of interferon genes) undergoing conformational changes, cellular trafficking, and the activation of downstream factors. Therefore, STING plays a pivotal role in preventing microbial pathogen infection by sensing DNAs during pathogen invasion. This review is dedicated to the recent advances in the dynamic regulations of STING activation, intracellular trafficking, and post-translational modifications (PTMs) by the host and microbial proteins

Reverse genetics of murine rotavirus: A comparative analysis of the wild-type and cell-culture-adapted murine rotavirus VP4 in replication and virulence in neonatal mice

Small-animal models and reverse genetics systems are powerful tools for investigating the molecular mechanisms underlying viral replication, virulence, and interaction with the host immune response in vivo. Rotavirus (RV) causes acute gastroenteritis in many young animals and infants worldwide. Murine RV replicates efficiently in the intestines of inoculated suckling pups, causing diarrhea, and spreads efficiently to uninoculated littermates. Because RVs derived from human and other non-mouse animal species do not replicate efficiently in mice, murine RVs are uniquely useful in probing the viral and host determinants of efficient replication and pathogenesis in a species-matched mouse model. Previously, we established an optimized reverse genetics protocol for RV and successfully generated a murine-like RV rD6/2-2g strain that replicates well in both cultured cell lines and in the intestines of inoculated pups. However, rD6/2-2g possesses three out of eleven gene segments derived from simian RV strains, and these three heterologous segments may attenuate viral pathogenicity in vivo. Here, we rescued the first recombinant RV with all 11 gene segments of murine RV origin. Using this virus as a genetic background, we generated a panel of recombinant murine RVs with either N-terminal VP8* or C-terminal VP5* regions chimerized between a cell-culture-adapted murine ETD strain and a non-tissue-culture-adapted murine EW strain and compared the diarrhea rate and fecal RV shedding in pups. The recombinant viruses with VP5* domains derived from the murine EW strain showed slightly more fecal shedding than those with VP5* domains from the ETD strain. The newly characterized full-genome murine RV will be a useful tool for dissecting virus-host interactions and for studying the mechanism of pathogenesis in neonatal mice

Modification Method of Tooth Profile of Locomotive Traction Gear Based on Rodent Arm Variation

Locomotive traction gear is the key component to power transmission and speed control in locomotive transmission system, which plays an important role in locomotive running speed and load-carrying torque. Considering that there is not universal rule for the method of modification of locomotive gear at present, in this paper, the tooth profile modification is considered with the combination of the increased contact ratio and the variation of the moment arm of action. Based on the principle of modification, according to the load direction after modification, the change rule of moment arm of action after modification is determined, and the interval range of tooth profile modification is also determined. Taking a certain locomotive traction gear as an example, the results obtained through the method of modification which based on combining moment arm of action variation with the increase of contact ratio and the method based on the traditional empirical formula are compared through finite element simulation respectively, on this account to verify the superiority of the theory of modification, which has important theoretical significance for profile modification of locomotive traction gear

Nlrp9b Inflammasome Restricts Rotavirus Infection in Intestinal Epithelial Cells

Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide. Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-κB signalling, raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo, especially by NOD-like receptor (NLR) inflammasomes, is largely unknown. Here we uncover and mechanistically characterize the NLR Nlrp9b that is specifically expressed in intestinal epithelial cells and restricts rotavirus infection. Our data show that, via RNA helicase Dhx9, Nlrp9b recognizes short double-stranded RNA stretches and forms inflammasome complexes with the adaptor proteins Asc and caspase-1 to promote the maturation of interleukin (Il)-18 and gasdermin D (Gsdmd)-induced pyroptosis. Conditional depletion of Nlrp9b or other inflammasome components in the intestine in vivo resulted in enhanced susceptibility of mice to rotavirus replication. Our study highlights an important innate immune signalling pathway that functions in intestinal epithelial cells and may present useful targets in the modulation of host defences against viral pathogens