ABSTRACT
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the current global pandemic of the COVID-19, which has persisted partly through the emergence of new variants. A non-infectious, convenient, and reproducible in vitro system is needed to assess drug susceptibility of new variants of concern and potential drug resistance mutations. Method(s): The SARS-CoV-2 replicon protocol was adapted and optimized based on {Zhang 2021}. The replicon RNA was produced by in vitro transcription of full-length replicon DNA assembled by ligation of plasmid fragments encoding for the SARS-CoV-2 non-structural proteins (Nsps), nucleoprotein and gaussia luciferase reporter protein. Wild-type and mutant replicon RNAs were transfected into Huh7-1CN cells by electroporation and treated with remdesivir (RDV). To determine EC50 values, luciferase activity was determined at 48 hours post transfection. A recombinant SARS-CoV-2 virus rescue system {Xie 2020} was used to generate matching Nsp mutants for comparison with the replicon system. Result(s): The selected substitutions reflective of Omicron BA.5 sub-lineage BF.7 variant: the triple mutants (Nsp12 (P323L) +Nsp13 (R392C) + Nsp14 (I42V), and a single Nsp12 L247F mutant as well as several specific Nsp12 mutations identified by in vitro resistance selection with RDV or RDV parent nucleoside analog GS-441524 were cloned into the replicon and tested for susceptibility to RDV. RDV inhibited the SARS-CoV-2 wild-type replicon with a mean EC50 value of 14.7 +/- 3.5 nM (N=9). The Nsp12 P323L substitution, a common polymorphism in all major variants of concern including Omicron, was fully susceptible to RDV with a 0.6-fold change in EC50 from the wild-type. The Omicron BF.7 triple mutants and L247F were also fully susceptible to RDV with 0.5- and 0.4-fold changes, respectively. Nsp12 substitutions F480L, V557L, V792I, S759A+V792I, and C799F resulting from in vitro resistance selections with RDV showed minimal to moderate levels of reduced susceptibility to RDV (1.8 to 18.3-fold change) (Table 1). The RDV EC50 fold changes correlated between the noninfectious replicon and recombinant infection virus system (Table 1). Conclusion(s): The replicon system is a convenient and reproducible model to test the susceptibility of SARS-CoV-2 mutant variants to RDV and potentially other antivirals. The common Nsp12 polymorphisms in all variants including the highly transmissible Omicron variant were fully susceptible to RDV.
ABSTRACT
Cities account for more than 70% of global carbon emissions and play an important role in mitigating climate change and achieving carbon peak and carbon neutrality. As the Paris Agreement emphasizes the need to reach global peaking of greenhouse gas emissions as soon as possible, it is significant to predict carbon emissions at the city level. However, the current COVID-19 pandemic has dramatically impacted global socioeconomic development and carbon emissions, downplaying the reference value for most urban carbon emission prediction models. In fact, existing studies on urban carbon emission prediction have also suffered from some shortcomings, such as unclear analyses of the impact of the pandemic, single scenario prediction, unified setting of growth rates, and failure to provide decision support for the government's carbon peak work. Therefore, a multi-scenario study on urban carbon emission prediction and carbon peak in the post-pandemic period would provide local governments with scientific data to make their carbon peak action plan. To that end, we set five-carbon emission scenarios: business as usual (BAU), high emissions (HE), extremely high emissions (EHE), low emissions (LE) and extremely low emissions (ELF). Based on the Monte Carlo method, we adjust the probabilities of different periods and different carbon emission scenarios to simulate uncertain evolution of carbon emissions as well as carbon emission reduction. Combining multi-scenario analyses with the Mann-Kendall trend test and Theil Sen's trend slope estimation method, we predict carbon emissions of the Pearl River Delta Urban Agglomeration (PRD) from 2021 to 2035 and analyze the evolution path of PRD's carbon emissions as well as its potential for carbon peak and carbon emission reduction from 2006 to 2035. Discussions are made on the possibility of achieving conditional areas' carbon peak goal in 2025 in Guangdong and China's carbon peak goal in 2030. We find that: (1) Carbon emissions of PRD increased rapidly from 2006 to 2016. Dynamic simulation shows that carbon emissions a significant peak in 2020 and decrease to 248.85 M similar to 270.06 Mt in 2035. Carbon intensity decreases by 84.18 degrees 4-85.21% from 2006 to 2035. Based on the emission reduction of the BAU scenario, the cumulative carbon emission reduction potential of the LF, scenario and ELF, scenario is as high as 304.86 M and 587.22 Mt from 2021 to 2035. Carbon emission reduction potential based on dynamic simulation of random combination scenario is between 81.68 and 128.25 Mt, with a probability of 67.65% to achieve further emission reduction. The probability of reducing 27.44 Mt carbon emissions is the largest. (2) Shenzhen, Zhuhai, Huizhou and Dongguan are four cities that show an inverted "U" shaped evolution path to achieve carbon peak. All of them reach the carbon peak no later than 2020. From 2006 to 2035, especially after the carbon peak, carbon emissions of these cities will decrease significantly. Their carbon emissions will reduce by 14.15 M-15.40 Mt, 9.17 M-9.94 Mt, 24.07 M-26.08 Mt and 22.36 M-24.24 Mt in 2035, respectively. The cumulative carbon emission reduction potential from 2021 to 2035 is -7.99 M-8.69 Mt, -3.48 M-4.87 Mt, -5.97 M-15.39 Mt and-8.77 M-12.62 Mt, respectively. However, being earlier to reach a carbon peak reduces their carbon emission reduction potential from 2021 to 2035. (3) Guangzhou, Foshan, Zhongshan, Jiangmen and Zhaoqing are five cities that could potentially reach carbon peaks but with divergent evolution paths. Some scenarios are at risk of not reaching a carbon peak. The possibility for Guangzhou, Foshan and Zhongshan to achieve the carbon peak target of conditional areas in Guangdong Province in 2025 is more than 96.01%, while that for Jiangmen and Zhaoqing is less than 20.08%. Moreover, there is a possibility of 2.04% for Jiangmen and Zhaoqing not to reach a carbon peak. In 2035, the emission reduction of the five cities will be 56.90 M-61.87 Mt, 44.35 M-48.16 Mt, 23.92 M-25.91 Mt, 33.78 M-36.58 Mt and 20.15 M-21.88 Mt, respectively. The cumulative carbon emission reduction potential of these cities from 2021 to 2035 is significant. which is -23.75M-26.60 Mt, 17.51 M-22.17 Mt, -6.64 M-12.19 Mt, -7.57 M-17.82 Mt and -3.86 M 11.79 Mt, respectively. (4) Being earlier to reach a carbon peak is conducive for cities to reduce carbon emissions. The curve of cumulative carbon emission reduction potential shows that the marginal potential of carbon emission reduction increases with time. So early adoption of emission reduction measures and early realization of carbon peak will promote carbon emission reduction. When making action plans for carbon peak, we should prevent cities from reaching false carbon peak during the platform period, pay attention to the demonstration and acceleration effect of carbon peak cities with relatively high carbon emissions, and explore the carbon emission reduction potential of cities that have difficulties in reaching carbon peak by optimizing their energy structure and utilization efficiency.
ABSTRACT
The outbreak of 2019 novel coronavirus disease (COVID-19) is spreading rapidly. In order to prevent cluster outbreaks, the government strengthened the management and control of personnel mobility, which had a great impact on the examination and treatment of breast cancer patients. This paper discusses how to realize scientific health management of breast cancer patients outside the hospital based on the existing epidemic situation, characteristics of breast cancer patients and public health safety factors. The breast cancer patients should synthetically consider the epidemic prevention situation of inhabitance, the disease stage and previous therapeutic schedule to decide the next therapeutic schedule. If necessary, after professional discussion and communication between doctors and patients online or offline, the hospital visiting time should be delayed through seeking alternative treatment schemes, and psychological counseling for patients should be paid attention to at the same time.