Impacts of Greenhouse Gases and Anthropogenic Aerosols Changes on Surface Air Temperature in East Asia under Different Post-pandemic Period Emission Scenarios

In order to know how surface air temperature (SAT) changes in East Asia under different emission scenarios after the COVID-19 outbreak, in this paper, we investigated the impacts of greenhouse gases (GHGs) and anthropogenic aerosols changes on SAT in East Asia by using the aerosol-climate coupled model BCC-AGCM 2.0_CUACE/Aero, combining with the post-pandemic emission scenarios proposed by Covid multi-Earth system model intercomparison project (CovidMIP scenarios for short, including fossil-fueled recovery, moderate green stimulus, strong green stimulus, hereinafter as FFF, MGG, SGG, respectively). We assessed the impacts of changes in GHGs and anthropogenic aerosols together and separately on SAT in East Asia and its typical subregions during 2020‒2050. The results show that by mid-21st-century, SAT in East Asia will increase by 0.81±0.083°C under Baseline (same as SSP2-4.5 scenario), i.e., SAT difference between 2045‒2050 and 2020‒2025), and there will be more intense warming in all the three scenarios in East Asia, in which the largest SAT difference (SAT-d) compared to Baseline is 0.33±0.11°C under SGG and the smallest SAT-d is 0.07±0.14°C under FFF. To further explore the mechanism of these SAT-d, we analyzed the trend of surface longwave and shortwave net radiation flux driven by GHGs and anthropogenic aerosols there. It is found that in early period (2020‒2035), the role of aerosol changes is bigger than that of GHG changes in dominating SAT-d, particularly sulfate, whose reduction will become the main contributor to SAT-d by affecting the net solar flux at surface. In later period (2036‒2050), because of GHGs’ longer atmospheric lifetime than aerosols, the role of decreasing GHGs concentrations will determine the drop in SAT-d through affecting the net longwave flux at surface.

Reconstruction of the cell pseudo-space from single-cell RNA sequencing data with scSpace (preprint)

Tissues are highly complicated with spatial heterogeneity in gene expression. However, the cutting-edge single-cell RNA-seq technology eliminates the spatial information of individual cells, which contributes to the characterization of cell identities. Herein, we propose s ingle- c ell s patial p osition a ssociated c o- e mbeddings (scSpace), an integrative algorithm to distinguish spatially variable cell subclusters by reconstructing cells onto a pseudo-space with spatial transcriptome references (Visium, STARmap, Slide-seq, etc.). We demonstrated that scSpace can define biologically meaningful cell subpopulations neglected by single-cell RNA-seq or spatially resolved transcriptomics. The use of scSpace to uncover the spatial association within single-cell data, reproduced, the hierarchical distribution of cells in the brain cortex and liver lobules, and the regional variation of cells in heart ventricles and the intestinal villus. scSpace identified cell subclusters in intratelencephalic neurons, which were confirmed by their biomarkers. The application of scSpace in melanoma and Covid-19 exhibited a broad prospect in the discovery of spatial therapeutic markers.

COVID-19 vaccine and Menstrual conditions in female: data analysis of the Vaccine Adverse Event Reporting System (preprint)

Background: In reports of adverse reactions following vaccination with the coronavirus disease 2019(COVID-19) vaccines, there have been fewer reports of concern for menstrual disorders in female. Objective: Our study used Vaccine Adverse Event Reporting System(VAERS)to investigate and analyze the relationship between COVID-19 Vaccines and menstrual disorders in female. Methods: We collected reports of menstrual disorders in VAERS from July 2, 1990 to November 12, 2021, and performed a stratified analysis. The potential relationship between COVID-19 vaccine and reports of menstrual disorders was evaluated using the Reporting Odds Ratio (ROR) method. Results: A total of 14,431 reports of menstrual disorders were included in the study, and 13,118 were associated with COVID-19 vaccine. The ROR was 7.83 (95% confidence interval [95%CI]:7.39-8.28). The most commonly reported event was Menstruation irregular (4998 reports), and a higher percentage of female aged 30-49 years reported menstrual disorders (42.55%) after exposure to COVID-19 Vaccines. Both for all reports of menstrual disorders (ROR=5.82; 95%CI:4.93-6.95) and excluding reports of unknown age (ROR=13.02; 95%CI:10.89-15.56), suggest that female age may be associated with menstrual disorders after vaccination with the COVID-19 Vaccines. Conclusion: Our study suggests a potential safety signal among female who received the COVID-19 vaccine, which may cause menstrual disorders in young adult female (30-49 years old). However, due to the well-known limitations of spontaneous reporting data, it is challenging to directly define menstrual disorders as an adverse event of the COVID-19 Vaccines, and reports of adverse reactions to COVID-19 Vaccines in this age group should continue to be tracked.

Research On Equilibrium Strategy and Emergency Management of Three Oligarch Battery Manufacturers Under Cooperative Promotion and Low-Carbon Policy (preprint)

As a crucial technology of solving energy shortage and environment contamination, battery technology is increasingly paid attention to by people. Among various batteries, lithium battery and Zinc-nickel battery are the most competitive and promising ones, especially the Zinc-nickel battery, which will induce shock to current battery industry chain. Meanwhile, the drastic change of exterior environment, such as 5G, Sharing Economy, low-carbon policy, trade protectionism and covid-19 has brought huge challenge to the management of battery industry chain. In this context, this paper set up a battery supply chain, including two zinc-nickel battery manufacturers and a lithium battery manufacturer. Against the background of cooperative promotion of big data and low-carbon policy, this paper constructs a cooperative game model under non cooperative game and demand disturbance respectively, analysing and discussing equilibrium strategy of supply chain. The results show that the price set by the manufacturer increases with the improvement of its technical level when consumers are more sensitive to technical level; with the increase of the Carbon Emission Technology Renewal Coefficient, the optimal price of all the three manufacturers will drop; when the market promotion rate is in the middle range, the price of zinc-nickel battery will be higher than that of lithium battery. In the demand disturbance model, the supply chain determines different optimal prices according to the different ranges of demand disturbance.

SARS-CoV-2 viral shedding characteristics and potential evidence for the priority for faecal specimen testing in diagnosis

This study aimed to identify the specimen type that has high positivity and its proper sampling time for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing to promote diagnostic efficiency. All SARS-CoV-2-infected patients with a laboratory-confirmed diagnosis in Zhoushan City were followed up for viral shedding in respiratory tract specimens and faecal samples. Positivity was analysed both qualitatively and quantitatively by proper statistical approaches with strong testing power. Viral shedding in respiratory tract and faecal specimens was prolonged to 45 and 40 days after the last exposure, respectively. The overall positive rate in respiratory tract specimens was low and relatively unstable, being higher in the early-to-mid stage than in the mid-to-late stage of the disease course. Compared with respiratory tract specimens, faecal samples had a higher viral load, higher overall positive rate, and more stable positivity in different disease courses and varied symptomatic status. Faecal specimens have the potential ability to surpass respiratory tract specimens in virus detection. Testing of faecal specimens in diagnosis, especially for identifying asymptomatic carriers, is recommended. Simultaneously, testing respiratory tract specimens at the early-to-mid stage is better than testing at the mid-to-late stage of the disease course. A relatively small sample size was noted, and statistical approaches were used to address it. Information was missing for both specimen types at different stages of the disease course due to censored data. Our research extends the observed viral shedding in both specimen types and highlights the importance of faecal specimen testing in SARS-CoV-2 diagnosis. Healthcare workers, patients, and the general public may all benefit from our study findings. Disposal of sewage from hospitals and residential areas should be performed cautiously because the virus sheds in faeces and can last for a long time.

Genomic epidemiology of SARS-CoV-2 in Pakistan (preprint)

Pakistan has been severely affected by the COVID-19 pandemic. To investigate the initial introductions and transmissions of the SARS-CoV-2 in the country, we performed the largest genomic epidemiology study of COVID-19 in Pakistan and generated 150 complete SARS-CoV-2 genome sequences from samples collected before June 1, 2020. We identified a total of 347 variants, 29 of which were over-represented in Pakistan. Meanwhile, we found over one thousand intra-host single-nucleotide variants. Several of them occurred concurrently, indicating possible interactions among them. Some of the hypermutable positions were not observed in the polymorphism data, suggesting strong purifying selections. The genomic epidemiology revealed five distinctive spreading clusters. The largest cluster consisted of 74 viruses which were derived from different geographic locations and formed a deep hierarchical structure, indicating an extensive and persistent nation-wide transmission of the virus that was probably contributed by a signature mutation of this cluster. Twenty-eight putative international introductions were identified, several of which were consistent with the epidemiological investigations. No progenies of any of these 150 viruses have been found outside of Pakistan, most likely due to the nonphmarcological intervention to control the virus. This study has inferred the introductions and transmissions of SARS-CoV-2 in Pakistan, which could provide a guidance for an effective strategy for disease control.

Comprehensive analysis of RNA-seq and whole genome sequencing data reveals no evidence for SARS-CoV-2 integrating into host genome (preprint)

SARS-CoV-2, as the causation of severe epidemic of COVID-19, is one kind of positive single-stranded RNA virus with high transmissibility. However, whether or not SARS-CoV-2 can integrate into host genome needs thorough investigation. Here, we performed both RNA sequencing (RNA-seq) and whole genome sequencing on SARS-CoV-2 infected human and monkey cells, and investigated the presence of host-virus chimeric events. Through RNA-seq, we did detect the chimeric host-virus reads in the infected cells. But further analysis using mixed libraries of infected cells and uninfected zebrafish embryos demonstrated that these reads are falsely generated during library construction. In support, whole genome sequencing also didn't identify the existence of chimeric reads in their corresponding regions. Therefore, the evidence for SARS-CoV-2's integration into host genome is lacking.

Differential transcriptomic landscapes of multiple organs from SARS-CoV-2 early infected rhesus macaques (preprint)

SARS-CoV-2 infection causes complicated clinic manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various tissues/organs examined, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Neuronal receptor NRP1 expression showed a significant induction by SARS-CoV-2 in cerebral cortex, which might be responsible for a higher infectivity and consequent inflammatory response. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.

Association of Chronic Acid Suppression and Social Determinants of Health with COVID-19 Infection (preprint)

Acid suppressants are a widely-used class of medications previously linked to an increased risk of aerodigestive infections. However, prior studies of these medications as potentially reversible risk factors for COVID-19 have been conflicting. We performed a case-control study involving clinician-abstracted data from 900 health records across 3 US medical centers. We incorporated sociobehavioral predictors of infectious exposure using geomapping to publicly-available data. We found no evidence for an association between chronic acid suppression and incident COVID-19 (adjusted odds ratio 1.04, 95% CI: 0.92-1.17, P =0.515). However, we identified several medical and social features as positive (Latinx ethnicity, BMI ≥ 30, dementia, public transportation use, month of the pandemic) and negative (female sex, concurrent solid tumor, alcohol use disorder) predictors of new-onset infection. These results place both medical and social factors on the same scale within the context of the COVID-19 pandemic, and underscore the importance of comprehensive models of disease.

Hypertension patients infected with COVID- 19 undergo a longer period of negative conversion:A retrospective study (preprint)

Purpose Previous studies have showed that age,sex and comorbidities might be associated with severity of patients infected with COVID-19 ,which endangers public health worldwide rapidly.The characteristics and length of negative conversion of Non-severe COVID-19 patients with or without hypertension is limited.This study aims to assess whether non-severe COVID-19 patients with hypertension undergone more longer period of negative conversion .Methods This single-center, retrospective study was performed in Xiantao first People’s Hospital Affiliated to Yangtze University(xiantao, hubei,China) by using medical records.Non-severe COVID-19 patients with a history of hypertension From January 23 to February15 were enrolled as group A. A Control group(group B) was matched (1:1) according to age,sex and the admission date.Data on clinical records, laboratory results, and radiological tests was collected. we conducted all analyses with SPSS software(22.0).Results  We enrolled 24 and 24 Non-severe COVID-19 patients with and without hypertension, respectively. The most common symptoms were fever and cough in both groups.The frequency of fatigue is more in patients with hypertension.The levels of AST,ALT and CRP were higher in group A.The mean periods of negative conversion for COVID-19 virus were 17 days(SD:5.5) and 15 days(SD:3.6)for patients with and without hypertension(P=0.021).The mean hospitalization periods were 16.8 days (SD:5.6) and 13.7 days (SD:3.8) , respectively (p=0.083) .Conclusion Non-severe COVID-19 patients with hypertension undergone a longer negative conversion for COVID-19 virus and spent more time on clearing COVID-19 virus.

Adjuvant corticosteroid therapy for critically ill patients with COVID-19 (preprint)

Addition of adjuvant corticosteroid therapy to standard antiviral treatment of patients with coronavirus disease (COVID-19) is common in clinical practice. However, evidence is scarce regarding the efficacy of adjuvant corticosteroids in patients who are critically ill. We retrospectively evaluated the effects of adjuvant corticosteroid treatment on the outcome of 244 critically ill patients with COVID-19, using a risk stratification model that adjusts for potential differences between the steroid group (n=151) and the non-steroid group (n=93). We observed that adjuvant corticosteroid therapy was independent from 28-day mortality, either in multivariate logistic regression of the entire cohort after adjustment for major mortality-associated variables (age, SpO2/FiO2, and lymphocyte count) and individual propensity score (adjusted OR: 1.05; 95% CI: -1.92-2.01), or in propensity score-matched (1:1 without replacement) case-control analysis (62 patients in 31 pairs; log-rank test P=0.17). Additionally, subgroup analyses of 147 (60%) patients who had dyspnea and 87 (36%) patients who had ARDS revealed corticosteroid treatment was not associated with clinical outcome (both, P>0.3). However, increased corticosteroids dosage was significantly associated with elevated mortality risk after adjustment for administration duration (P=0.003); every ten-milligram increase in hydrocortisone-equivalent dosage was associated with additional 4% mortality risk (adjusted HR: 1.04, 95% CI: 1.01-1.07). Our findings indicated that limited effect of corticosteroid therapy could pose to overall survival and prudent dose within effective limits may be recommended for critically ill patients under certain circumstances.

Structural basis for the inhibition of COVID-19 virus main protease by carmofur, an antineoplastic drug (preprint)

The antineoplastic drug Carmofur was shown to inhibit SARS-CoV-2 main protease (Mpro). Here the X-ray crystal structure of Mpro in complex with Carmofur reveals that the carbonyl reactive group of Carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC50 = 24.30 M) and it is a promising lead compound to develop new antiviral treatment for COVID-19.

Structure-Based Design, Synthesis and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease (preprint)

SARS-CoV-2 is the etiological agent responsible for the COVID-19 outbreak in Wuhan. Specific antiviral drug are urgently needed to treat COVID-19 infections. The main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, which makes it an attractive drug target. In an effort to rapidly discover lead compounds targeting Mpro, two compounds (11a and 11b) were designed and synthesized, both of which exhibited excellent inhibitory activity with an IC50 value of 0.05 M and 0.04 M respectively. Significantly, both compounds exhibited potent anti-SARS-CoV-2 infection activity in a cell-based assay with an EC50 value of 0.42 M and 0.33 M, respectively. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 [A] resolution, respectively. The crystal structures showed that 11a and 11b are covalent inhibitors, the aldehyde groups of which are bound covalently to Cys145 of Mpro. Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity which is promising drug leads with clinical potential that merits further studies.

Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target (preprint)

A novel coronavirus (2019-nCoV) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. Here we report the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8 at a resolution of 2.9-[A]. Additional to the conserved architecture of the polymerase core of the viral polymerase family and a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain featured in coronaviral RdRp, nsp12 possesses a newly identified {beta}-hairpin domain at its N-terminal. Key residues for viral replication and transcription are observed. A comparative analysis to show how remdesivir binds to this polymerase is also provided. This structure provides insight into the central component of coronaviral replication/transcription machinery and sheds light on the design of new antiviral therapeutics targeting viral RdRp. One Sentence SummaryStructure of 2019-nCov RNA polymerase.

Structure-based drug design, virtual screening and high-throughput screening rapidly identify antiviral leads targeting COVID-19 (preprint)

A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1-4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these inhibit Mpro with IC50 values ranging from 0.67 to 21.4 M. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.