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Browsing by Author "Li, Wen"

Now showing 1 - 3 of 3
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    Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood–brain barrier, and invades the central nervous system
    Tian, Debin; Li, Wen; Heffron, C. Lynn; Wang, Bo; Mahsoub, Hassan M.; Sooryanarain, Harini; Hassebroek, Anna M.; Clark-Deener, Sherrie; LeRoith, Tanya; Meng, Xiang-Jin (Proceedings of the National Academy of Sciences, 2022-06-14)
    Hepatitis E virus (HEV) is an important but understudied zoonotic virus causing both acute and chronic viral hepatitis. A proportion of HEV-infected individuals also developed neurological diseases such as Guillain–Barre syndrome, neuralgic amyotrophy, encephalitis, and myelitis, although the mechanism remains unknown. In this study, by using an in vitro blood–brain barrier (BBB) model, we first investigated whether HEV can cross the BBB and whether the quasi-enveloped HEV virions are more permissible to the BBB than the nonenveloped virions. We found that both quasi-enveloped and nonenveloped HEVs can similarly cross the BBB and that addition of proinflammatory cytokine tumor necrosis factor alpha (TNF-α) has no significant effect on the ability of HEV to cross the BBB in vitro. To explore the possible mechanism of HEV entry across the BBB, we tested the susceptibility of human brain microvascular endothelial cells lining the BBB to HEV infection and showed that brain microvascular endothelial cells support productive HEV infection. To further confirm the in vitro observation, we conducted an experimental HEV infection study in pigs and showed that both quasi-enveloped and nonenveloped HEVs invade the central nervous system (CNS) in pigs, as HEV RNA was detected in the brain and spinal cord of infected pigs. The HEV-infected pigs with detectable viral RNA in CNS tissues had histological lesions in brain and spinal cord and significantly higher levels of proinflammatory cytokines TNF-α and interleukin 18 than the HEV-infected pigs without detectable viral RNA in CNS tissues. The findings suggest a potential mechanism of HEV-associated neuroinvasion.
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    How are Multilingual Systems Constructed: Characterizing Language Use and Selection in Open-Source Multilingual Software
    Li, Wen; Marino, Austin; Yang, Haoran; Meng, Na; Li, Li; Cai, Haipeng (ACM, 2023-12)
    For many years now, modern software is known to be developed in multiple languages (hence termed as multilingual or multi-language software). Yet to this date we still only have very limited knowledge about how multilingual software systems are constructed. For instance, it is not yet really clear how diferent languages are used, selected together, and why they have been so in multilingual software development. Given the fact that using multiple languages in a single software project has become a norm, understanding language use and selection (i.e, language proile) as a basic element of the multilingual construction in contemporary software engineering is an essential first step. In this paper, we set out to ill this gap with a large-scale characterization study on language use and selection in open-source multilingual software. We start with presenting an updated overview of language use in 7,113 GitHub projects spanning ive past years by characterizing overall statistics of language proiles, followed by a deeper look into the functionality relevance/justiication of language selection in these projects through association rule mining.We proceed with an evolutionary characterization of 1,000 GitHub projects for each of 10 past years to provide a longitudinal view of how language use and selection have changed over the years, as well as how the association between functionality and language selection has been evolving. Among many other indings, our study revealed a growing trend of using 3 to 5 languages in one multilingual software project and noticeable stableness of top language selections. We found a non-trivial association between language selection and certain functionality domains, which was less stable than that with individual languages over time. In a historical context, we also have observed major shifts in these characteristics of multilingual systems both in contrast to earlier peer studies and along the evolutionary timeline. Our indings ofer essential knowledge on the multilingual construction in modern software development. Based on our results, we also provide insights and actionable suggestions for both researchers and developers of multilingual systems.
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    Ribavirin Treatment Failure-Associated Mutation, Y1320H, in the RNA-Dependent RNA Polymerase of Genotype 3 Hepatitis E Virus (HEV) Enhances Virus Replication in a Rabbit HEV Infection Model
    Wang, Bo; Mahsoub, Hassan M. M.; Li, Wen; Heffron, C. Lynn; Tian, Debin; Hassebroek, Anna M. M.; LeRoith, Tanya; Meng, Xiang-Jin (American Society for Microbiology, 2023-02-21)
    HEV-3 causes chronic hepatitis E that requires antiviral therapy in immunosuppressed individuals. RBV is the main therapeutic option for chronic hepatitis E as an off-label use. Chronic hepatitis E virus (HEV) infection has become a significant clinical problem that requires treatment in immunocompromised individuals. In the absence of an HEV-specific antiviral, ribavirin (RBV) has been used off-label, but treatment failure may occur due to mutations in the viral RNA-dependent RNA polymerase (RdRp), including Y1320H, K1383N, and G1634R. Chronic hepatitis E is mostly caused by zoonotic genotype 3 HEV (HEV-3), and HEV variants from rabbits (HEV-3ra) are closely related to human HEV-3. Here, we explored whether HEV-3ra, along with its cognate host, can serve as a model to study RBV treatment failure-associated mutations observed in human HEV-3-infected patients. By utilizing the HEV-3ra infectious clone and indicator replicon, we generated multiple single mutants (Y1320H, K1383N, K1634G, and K1634R) and a double mutant (Y1320H/K1383N) and assessed the role of mutations on replication and antiviral activity of HEV-3ra in cell culture. Furthermore, we also compared the replication of the Y1320H mutant with the wild-type HEV-3ra in experimentally infected rabbits. Our in vitro analyses revealed that the effects of these mutations on rabbit HEV-3ra are altogether highly consistent with those on human HEV-3. Importantly, we found that the Y1320H enhances virus replication during the acute stage of HEV-3ra infection in rabbits, which corroborated our in vitro results showing an enhanced viral replication of Y1320H. Taken together, our data suggest that HEV-3ra and its cognate host is a useful and relevant naturally occurring homologous animal model to study the clinical relevance of antiviral-resistant mutations observed in human HEV-3 chronically-infected patients.IMPORTANCE HEV-3 causes chronic hepatitis E that requires antiviral therapy in immunosuppressed individuals. RBV is the main therapeutic option for chronic hepatitis E as an off-label use. Several amino acid changes, including Y1320H, K1383N, and G1634R, in the RdRp of human HEV-3 have reportedly been associated with RBV treatment failure in chronic hepatitis E patients. In this study, we utilized an HEV-3ra from rabbit and its cognate host to investigate the effect of these RBV treatment failure-associated HEV-3 RdRp mutations on viral replication efficiency and antiviral susceptibility. The in vitro data using rabbit HEV-3ra was highly comparable to those from human HEV-3. We demonstrated that the Y1320H mutation significantly enhanced HEV-3ra replication in cell culture and enhanced virus replication during the acute stage of HEV-3ra infection in rabbits. The rabbit HEV-3ra infection model should be useful in delineating the role of human HEV-3 RBV treatment failure-associated mutations in antiviral resistance.