The Asymmetric Correlation and Causality between the European Union Carbon Market and Fossil Energy Markets before and after COVID-19 (preprint)

This paper analyzes the correlation and causality between the European Union carbon emission allowance market and international fossil energy markets. Asymmetric correlation is examined using local Gaussian correlation and asymmetric causality is assessed using a quantile Granger causality test. Empirical results show that, after the COVID-19 outbreak, the EU carbon emission market is more correlated to the crude oil market, but it is less linked to the coal futures market. In contrast to the UK natural gas futures market, the EU carbon emission market shows contagion with the US natural gas market. During the COVID-19 pandemic, unidirectional causality from the EU carbon emission market to the fossil energy market has been becoming bidirectional.JEL classification: C22, I18, O13, O52, Q43

Epidemiological Characteristics of COVID-19 Deaths In China: An Analysis of Environmental Factors (preprint)

Background: As of April 2020, most of the confirmed cases outside Hubei province have been cured or confirmed dead in China. We aimed to understand environmental factors leading to COVID-19-related mortality in non-Hubei region. Methods: : We collected spatial-temporal and environmental data of 99 cases of COVID-19-related deaths outside of Hubei province in Mainland China between January 22, 2020 and April 6, 2020. A descriptive analysis, including a spatial-temporal distribution of daily reported diagnosed cases and related deaths, was conducted. We analyzed the possible environmental factors that affect the provincial-level case fatality rate (CFR) of COVID-19 outside Hubei, China. Results: Among the 99 reported deaths, 59 (59.6%) were male and 40 (40.4%) were female. The mean age at death was 71.30 (SD 12.98) years and 74 deaths were among those 65 years or older. The CFR was negatively correlated with temperature (r=-0.679, P <0.001) and humidity (r=-0.607, P =0.002), while latitude was positively correlated with the CFR (r=0.636, P =0.001). There were no statistically significant associations between CFR and the social environment factors. Conclusion: Higher CFR of COVID-19 was associated with lower temperature, lower humidity, and higher latitude. Continual analysis of daily reported diagnoses and mortality data can help healthcare professionals and policy makers understand the trends within a country in order to better prepare nationwide prevention and care guidelines, along with adequately appropriate funds accordingly.

A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase (preprint)

A worldwide effort is ongoing to discover drugs against the Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2), which has so far caused >3.5 million fatalities (https://covid19.who.int/). The virus essential RNA-dependent RNA polymerase complex is targeted by several nucleoside/tide analogues whose mechanisms of action and clinical potential are currently evaluated. The guanosine analogue AT-527, a double prodrug of its 5'-triphosphate AT-9010, is currently in phase III clinical trials as a COVID19 treatment. Here we report the cryo-EM structure at 2.98 Å resolution of the SARS-CoV-2 nsp12-nsp7-(nsp8)2 complex with RNA showing AT-9010 bound at three sites of nsp12. At the RdRp active-site, one AT-9010 is incorporated into the RNA product. Its 2'-methyl group prevents correct alignment of a second AT-9010 occupying the incoming NTP pocket. The 2'-F, 2'-methyl 3'-OH ribose scaffold explains the non-obligate RNA chain-termination potency of this NA series for both HCV NS5 and SARS-CoV RTCs. A third AT-9010 molecule 5'-diphosphate binds to a coronavirus-specific pocket in the nsp12 N-terminus NiRAN domain, a SelO pseudo-kinase structural and functional homologue. This unique binding mode impedes NiRAN-mediated UMPylation of SARS-CoV-2 nsp8 and nsp9 proteins. Our results suggest a mechanism of action for AT-527 in line with a therapeutic use for COVID19.

Protein-primed RNA synthesis in SARS-CoVs and structural basis for inhibition by AT-527 (preprint)

How viruses from the Coronaviridae family initiate viral RNA synthesis is unknown. Here we show that the SARS-CoV-1 and -2 Nidovirus RdRp-Associated Nucleotidyltransferase (NiRAN) domain on nsp12 uridylates the viral cofactor nsp8, forming a UMP-Nsp8 covalent intermediate that subsequently primes RNA synthesis from a poly(A) template; a protein-priming mechanism reminiscent of Picornaviridae enzymes. In parallel, the RdRp active site of nsp12 synthesizes a pppGpU primer, which primes (-)ssRNA synthesis at the precise genome-poly(A) junction. The guanosine analogue 5'-triphosphate AT-9010 (prodrug: AT-527) tightly binds to the NiRAN and inhibits both nsp8-labeling and the initiation of RNA synthesis. A 2.98 A resolution Cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-(nsp8)2 /RNA/NTP quaternary complex shows AT-9010 simultaneously binds to both NiRAN and RdRp active site of nsp12, blocking their respective activities. AT-527 is currently in phase II clinical trials, and is a potent inhibitor of SARS-CoV-1 and -2, representing a promising drug for COVID-19 treatment.