ORCID Profile
0000-0002-2038-1045
Current Organisation
University of Tokyo
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Publisher: Proceedings of the National Academy of Sciences
Date: 07-07-2014
Abstract: One of the goals of modern molecular medicine is delivery and expression of heterologous genes in living organisms. RNA-based delivery vectors are a safer choice than DNA vectors, but they are prone to degradation and are highly dependent on efficient delivery methods. One of the ways to improve RNA vector performance is to increase the level of expression of the encoded proteins. We followed this approach and modified standard alphavirus replicon-based expression systems to make the transcribed subgenomic RNA additionally lifiable by viral replication enzymes. Higher levels of subgenomic RNA synthesis increased the replicons’ expression efficiency at least 10-fold. Such replicons can be widely applied for development of efficient DNA and RNA vaccines and protein production in vitro.
Publisher: American Society for Microbiology
Date: 15-08-2018
DOI: 10.1128/JVI.00838-18
Abstract: Alphaviruses utilize a broad spectrum of cellular factors for efficient formation and function of replication complexes (RCs). Our data demonstrate for the first time that the hypervariable domain (HVD) of chikungunya virus nonstructural protein 3 (nsP3) is intrinsically disordered. It binds at least 3 families of cellular proteins, which play an indispensable role in viral RNA replication. The proteins of each family demonstrate functional redundancy. We provide a detailed map of the binding sites on CHIKV nsP3 HVD and show that mutations in these sites or the replacement of CHIKV HVD by heterologous HVD change cell specificity of viral replication. Such manipulations with alphavirus HVDs open an opportunity for development of new irreversibly attenuated vaccine candidates. To date, the disordered protein fragments have been identified in the nonstructural proteins of many other viruses. They may also interact with a variety of cellular factors that determine critical aspects of virus-host interactions.
Publisher: Wageningen University and Research
Date: 22-07-2022
DOI: 10.18174/SESMO.18127
Abstract: Solar geoengineering, also known as Solar Radiation Modification (SRM), has been proposed to alter Earth’s radiative balance to reduce the effects of anthropogenic climate change. SRM has been identified as a research priority, as it has been shown to effectively reduce surface temperatures, while substantial uncertainties remain around side effects and impacts. Global modeling studies of SRM have often relied on idealized scenarios to understand the physical processes of interventions and their widespread impacts. These extreme or idealized scenarios are not directly policy-relevant and are often physically implausible (such as imposing global solar reduction to counter the warming of an instantaneous quadrupling of CO2). The climatic and ecological impacts of politically relevant and potentially plausible SRM approaches have rarely been modeled and assessed. Nevertheless, commentators and policymakers often falsely assume that idealized or extreme scenarios are proposed solutions to climate change. This paper proposes 18 scenarios that appear to be broadly plausible from political and Earth System perspectives and encompass futures that could be both warnings or perhaps desirable. We place these scenarios into four groups following broader strategic contexts: (1) Global Management (2) Regional Emergencies (3) Coordinated Regional Interventions and (4) Reactive Global Interventions. For each scenario, relevant model experiments are proposed. Some may be performed with existing setups of global climate models, while others require further specification. Developing and performing these model experiments – and assessing likely resulting impacts on society and ecosystems – would be essential to inform public debate and policymakers on the real-world issues surrounding SRM.
Publisher: American Society for Microbiology
Date: 02-2018
DOI: 10.1128/JVI.01965-17
Abstract: Venezuelan equine encephalitis virus (VEEV) is a representative member of the New World alphaviruses. It is transmitted by mosquito vectors and causes highly debilitating disease in humans, equids, and other vertebrate hosts. Despite a continuous public health threat, very few compounds with anti-VEEV activity in cell culture and in mouse models have been identified to date, and rapid development of virus resistance to some of them has been recorded. In this study, we investigated the possibility of using a modified nucleoside analog, β- d - N 4 -hydroxycytidine (NHC), as an anti-VEEV agent and defined the mechanism of its anti-VEEV activity. The results demonstrate that NHC is a very potent antiviral agent. It affects both the release of genome RNA-containing VEE virions and their infectivity. Both of these antiviral activities are determined by the NHC-induced accumulation of mutations in virus-specific RNAs. The antiviral effect is most prominent when NHC is applied early in the infectious process, during the lification of negative- and positive-strand RNAs in infected cells. Most importantly, only a low-level resistance of VEEV to NHC can be developed, and it requires acquisition and cooperative function of more than one mutation in nsP4. These adaptive mutations are closely located in the same segment of nsP4. Our data suggest that NHC is more potent than ribavirin as an anti-VEEV agent and likely can be used to treat other alphavirus infections. IMPORTANCE Venezuelan equine encephalitis virus (VEEV) can cause widespread epidemics among humans and domestic animals. VEEV infections result in severe meningoencephalitis and long-term sequelae. No approved therapeutics exist for treatment of VEEV infections. Our study demonstrates that β- d - N 4 -hydroxycytidine (NHC) is a very potent anti-VEEV compound, with the 50% effective concentration being below 1 μM. The mechanism of NHC antiviral activity is based on induction of high mutation rates in the viral genome. Accordingly, NHC treatment affects both the rates of particle release and the particle infectivity. Most importantly, in contrast to most of the anti-alphavirus drugs that are under development, resistance of VEEV to NHC develops very inefficiently. Even low levels of resistance require acquisition of multiple mutations in the gene of the VEEV-specific RNA-dependent RNA polymerase nsP4.
No related grants have been discovered for Masahiro Sugiyama.