Oridonin inhibits SARS-CoV-2 replication by targeting viral proteinase and polymerase.

COVID-19 has become a global public health crisis since its outbreak in China in December 2019. Currently there are few clinically effective drugs to combat SARS-CoV-2 infection. The main protein (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 are involved in the viral replication, and might be prospective targets for anti-coronavirus drug development. Here, we investigated the antiviral activity of oridonin, a natural small-molecule compound, against SARS-CoV-2 infection in vitro. The time-of-addition analysis showed that oridonin efficiently inhibited SARS-CoV-2 infection by interfering with the genome replication at the post-entry stage. Mechanistically, the inhibition of viral replication by oridonin depends on the oxidation activity of α, ß-unsaturated carbonyl. Further experiments showed that oridonin not only effectively inhibited SARS-CoV-2 Mpro activity, but also had some inhibitory effects on PLpro-mediated deubiquitinating and viral polymerase-catalyzed RNA elongation activities at high concentrations. In particular, oridonin could inhibit the bat SARS-like CoV and the newly emerged SARS-CoV-2 omicron variants (BA.1 and BA.2), which highlights its potential as a pan-coronavirus antiviral agent. Overall, our data provide strong evidence that oridonin is an efficient antiviral agent against SARS-CoV-2 infection.

Global age-structured spatial modeling for emerging infectious diseases like COVID-19.

Modeling the global dynamics of emerging infectious diseases (EIDs) like COVID-19 can provide important guidance in the preparation and mitigation of pandemic threats. While age-structured transmission models are widely used to simulate the evolution of EIDs, most of these studies focus on the analysis of specific countries and fail to characterize the spatial spread of EIDs across the world. Here, we developed a global pandemic simulator that integrates age-structured disease transmission models across 3,157 cities and explored its usage under several scenarios. We found that without mitigations, EIDs like COVID-19 are highly likely to cause profound global impacts. For pandemics seeded in most cities, the impacts are equally severe by the end of the first year. The result highlights the urgent need for strengthening global infectious disease monitoring capacity to provide early warnings of future outbreaks. Additionally, we found that the global mitigation efforts could be easily hampered if developed countries or countries near the seed origin take no control. The result indicates that successful pandemic mitigations require collective efforts across countries. The role of developed countries is vitally important as their passive responses may significantly impact other countries.

How to avoid a local epidemic becoming a global pandemic.

Here, we combine international air travel passenger data with a standard epidemiological model of the initial 3 mo of the COVID-19 pandemic (January through March 2020; toward the end of which the entire world locked down). Using the information available during this initial phase of the pandemic, our model accurately describes the main features of the actual global development of the pandemic demonstrated by the high degree of coherence between the model and global data. The validated model allows for an exploration of alternative policy efficacies (reducing air travel and/or introducing different degrees of compulsory immigration quarantine upon arrival to a country) in delaying the global spread of SARS-CoV-2 and thus is suggestive of similar efficacy in anticipating the spread of future global disease outbreaks. We show that a lesson from the recent pandemic is that reducing air travel globally is more effective in reducing the global spread than adopting immigration quarantine. Reducing air travel out of a source country has the most important effect regarding the spreading of the disease to the rest of the world. Based upon our results, we propose a digital twin as a further developed tool to inform future pandemic decision-making to inform measures intended to control the spread of disease agents of potential future pandemics. We discuss the design criteria for such a digital twin model as well as the feasibility of obtaining access to the necessary online data on international air travel.

Healthy cities initiative in China: Progress, challenges, and the way forward.

China implemented the first phase of its National Healthy Cities pilot program from 2016-20. Along with related urban health governmental initiatives, the program has helped put health on the agenda of local governments while raising public awareness. Healthy City actions taken at the municipal scale also prepared cities to deal with the COVID-19 pandemic. However, after intermittent trials spanning the past two decades, the Healthy Cities initiative in China has reached a crucial juncture. It risks becoming inconsequential given its overlap with other health promotion efforts, changing public health priorities in response to the pandemic, and the partial adoption of the Healthy Cities approach advanced by the World Health Organization (WHO). We recommend aligning the Healthy Cities initiative in China with strategic national and global level agendas such as Healthy China 2030 and the Sustainable Development Goals (SDGs) by providing an integrative governance framework to facilitate a coherent intersectoral program to systemically improve population health. Achieving this alignment will require leveraging the full spectrum of best practices in Healthy Cities actions and expanding assessment efforts. Funding: Tsinghua-Toyota Joint Research Fund "Healthy city systems for smart cities" program.

Assessment of nucleotide/nucleoside analog intervention in primer-dependent viral RNA-dependent RNA polymerases.

Nucleotide/nucleoside analogs (NAs) are important compounds used in antiviral drug development. To understand the action mode of NA drugs, we present an enzymology protocol to initially evaluate the intervention mechanism of the NTP forms of NAs on a coronaviral RNA-dependent RNA polymerase (RdRP). We describe the preparation of SARS-CoV-2 RdRP proteins and RNA constructs, followed by a primer-dependent RdRP assay to assess NTP forms of NAs. Two representative NA drugs, sofosbuvir and remdesivir, are used for demonstration of this protocol. For complete details on the use and execution of this protocol, please refer to Wu et al. (2021).

Remdesivir overcomes the S861 roadblock in SARS-CoV-2 polymerase elongation complex.

Remdesivir (RDV), a nucleotide analog with broad-spectrum features, has exhibited effectiveness in COVID-19 treatment. However, the precise working mechanism of RDV when targeting the viral RNA-dependent RNA polymerase (RdRP) has not been fully elucidated. Here, we solve a 3.0-Å structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRP elongation complex (EC) and assess RDV intervention in polymerase elongation phase. Although RDV could induce an "i+3" delayed termination in meta-stable complexes, only pausing and subsequent elongation are observed in the EC. A comparative investigation using an enterovirus RdRP further confirms similar delayed intervention and demonstrates that steric hindrance of the RDV-characteristic 1'-cyano at the -4 position is responsible for the "i+3" intervention, although two representative Flaviviridae RdRPs do not exhibit similar behavior. A comparison of representative viral RdRP catalytic complex structures indicates that the product RNA backbone encounters highly conserved structural elements, highlighting the broad-spectrum intervention potential of 1'-modified nucleotide analogs in anti-RNA virus drug development.

Reduction of Human Mobility Matters during Early COVID-19 Outbreaks: Evidence from India, Japan and China.

Mobility restrictions have been a heated topic during the global pandemic of coronavirus disease 2019 (COVID-19). However, multiple recent findings have verified its importance in blocking virus spread. Evidence on the association between mobility, cases imported from abroad and local medical resource supplies is limited. To reveal the association, this study quantified the importance of inter- and intra-country mobility in containing virus spread and avoiding hospitalizations during early stages of COVID-19 outbreaks in India, Japan, and China. We calculated the time-varying reproductive number (Rt) and duration from illness onset to diagnosis confirmation (Doc), to represent conditions of virus spread and hospital bed shortages, respectively. Results showed that inter-country mobility fluctuation could explain 80%, 35%, and 12% of the variance in imported cases and could prevent 20 million, 5 million, and 40 million imported cases in India, Japan and China, respectively. The critical time for screening and monitoring of imported cases is 2 weeks at minimum and 4 weeks at maximum, according to the time when the Pearson's Rs between Rt and imported cases reaches a peak (>0.8). We also found that if local transmission is initiated, a 1% increase in intra-country mobility would result in 1430 (±501), 109 (±181), and 10 (±1) additional bed shortages, as estimated using the Doc in India, Japan, and China, respectively. Our findings provide vital reference for governments to tailor their pre-vaccination policies regarding mobility, especially during future epidemic waves of COVID-19 or similar severe epidemic outbreaks.

Guidelines for Modeling and Reporting Health Effects of Climate Change Mitigation Actions.

BACKGROUND: Modeling suggests that climate change mitigation actions can have substantial human health benefits that accrue quickly and locally. Documenting the benefits can help drive more ambitious and health-protective climate change mitigation actions; however, documenting the adverse health effects can help to avoid them. Estimating the health effects of mitigation (HEM) actions can help policy makers prioritize investments based not only on mitigation potential but also on expected health benefits. To date, however, the wide range of incompatible approaches taken to developing and reporting HEM estimates has limited their comparability and usefulness to policymakers. OBJECTIVE: The objective of this effort was to generate guidance for modeling studies on scoping, estimating, and reporting population health effects from climate change mitigation actions. METHODS: An expert panel of HEM researchers was recruited to participate in developing guidance for conducting HEM studies. The primary literature and a synthesis of HEM studies were provided to the panel. Panel members then participated in a modified Delphi exercise to identify areas of consensus regarding HEM estimation. Finally, the panel met to review and discuss consensus findings, resolve remaining differences, and generate guidance regarding conducting HEM studies. RESULTS: The panel generated a checklist of recommendations regarding stakeholder engagement: HEM modeling, including model structure, scope and scale, demographics, time horizons, counterfactuals, health response functions, and metrics; parameterization and reporting; approaches to uncertainty and sensitivity analysis; accounting for policy uptake; and discounting. DISCUSSION: This checklist provides guidance for conducting and reporting HEM estimates to make them more comparable and useful for policymakers. Harmonization of HEM estimates has the potential to lead to advances in and improved synthesis of policy-relevant research that can inform evidence-based decision making and practice. https://doi.org/10.1289/EHP6745.

Author Correction: Near-real-time monitoring of global CO2 emissions reveals the effects of the COVID-19 pandemic.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20254-5.

Near-real-time monitoring of global CO2 emissions reveals the effects of the COVID-19 pandemic.

The COVID-19 pandemic is impacting human activities, and in turn energy use and carbon dioxide (CO2) emissions. Here we present daily estimates of country-level CO2 emissions for different sectors based on near-real-time activity data. The key result is an abrupt 8.8% decrease in global CO2 emissions (-1551 Mt CO2) in the first half of 2020 compared to the same period in 2019. The magnitude of this decrease is larger than during previous economic downturns or World War II. The timing of emissions decreases corresponds to lockdown measures in each country. By July 1st, the pandemic's effects on global emissions diminished as lockdown restrictions relaxed and some economic activities restarted, especially in China and several European countries, but substantial differences persist between countries, with continuing emission declines in the U.S. where coronavirus cases are still increasing substantially.

Global COVID-19 pandemic demands joint interventions for the suppression of future waves.

Emerging evidence suggests a resurgence of COVID-19 in the coming years. It is thus critical to optimize emergency response planning from a broad, integrated perspective. We developed a mathematical model incorporating climate-driven variation in community transmissions and movement-modulated spatial diffusions of COVID-19 into various intervention scenarios. We find that an intensive 8-wk intervention targeting the reduction of local transmissibility and international travel is efficient and effective. Practically, we suggest a tiered implementation of this strategy where interventions are first implemented at locations in what we call the Global Intervention Hub, followed by timely interventions in secondary high-risk locations. We argue that thinking globally, categorizing locations in a hub-and-spoke intervention network, and acting locally, applying interventions at high-risk areas, is a functional strategy to avert the tremendous burden that would otherwise be placed on public health and society.

Global supply-chain effects of COVID-19 control measures.

Countries have sought to stop the spread of coronavirus disease 2019 (COVID-19) by severely restricting travel and in-person commercial activities. Here, we analyse the supply-chain effects of a set of idealized lockdown scenarios, using the latest global trade modelling framework. We find that supply-chain losses that are related to initial COVID-19 lockdowns are largely dependent on the number of countries imposing restrictions and that losses are more sensitive to the duration of a lockdown than its strictness. However, a longer containment that can eradicate the disease imposes a smaller loss than shorter ones. Earlier, stricter and shorter lockdowns can minimize overall losses. A 'go-slow' approach to lifting restrictions may reduce overall damages if it avoids the need for further lockdowns. Regardless of the strategy, the complexity of global supply chains will magnify losses beyond the direct effects of COVID-19. Thus, pandemic control is a public good that requires collective efforts and support to lower-capacity countries.

Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.

Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.