ABSTRACT
During the recent COVID-19 (CoV) global outbreak, there is a sharp decline of revenue of on-demand ride-hailing (ODR) platforms because people have serious worries of infection in the shared vehicles. Blockchain, which supports cryptocurrency and creates full traceability of the service history of each car and driver, may come to rescue by allowing the platform to offer only the "safe cars" to consumers. Motivated by the real world challenges associated with the CoV outbreak for the ODR platform, we build game-theoretical models based on the M/M/n queuing system to explore if and how blockchain can help. In the basic model, the ODR platform decides the service price and special hygiene level. Comparing between the cases with and without blockchain, we find that blockchain implementation increases both the service price and hygiene level. In addition, when the consumers' inherent worry of infection is substantially large, implementing blockchain achieves all-win for the ODR platform, drivers and consumers. In the extended models, we first consider the case when the special hygiene level is determined by the drivers under a mixed-leadership game and then explore the case when customers are risk averse. The main findings about blockchain adoption remain valid in both cases. However, when the drivers take charge of the special hygiene level, both optimal decisions are lower in most cases. It is also important to make efforts to reduce consumers' feeling volatility toward service valuation for improving the value of blockchain adoption and related performances.
ABSTRACT
Abnormal function of immune cells is one of the key mechanisms leading to severe clinical symptoms in coronavirus disease 2019 patients, and metabolic pathways can destroy the function of the immune system by affecting innate and adaptive immune responses. However, the metabolic characteristics of the immune cells of the SARS-CoV-2 infected organs in situ remaining elusive. We reanalyzed the metabolic-related gene profiles in single-cell RNA sequencing data, drew the metabolic landscape in bronchoalveolar lavage fluid immune cells, and elucidated the metabolic remodeling mechanism that might lead to the progression of COVID-19 and the cytokine storm. Enhanced glycolysis is the most important common metabolic feature of all immune cells in COVID-19 patients. CCL2+ T cells, Group 2 macrophages with high SPP1 expression and myeloid dendritic cells are among the main contributors to the cytokine storm produced by infected lung tissue. Two metabolic analysis methods, including Compass, showed that glycolysis, fatty acid metabolism, bile acid synthesis and purine and pyrimidine metabolism levels of CCL2+ T cells, Group 2 macrophages and myeloid dendritic cells were upregulated and correlated with cytokine storms of COVID-19 patients. This might be the key metabolic regulatory factor for immune cells to produce large quantities of cytokines.
ABSTRACT
Under COVID-19, lots of supply disruption cases have appeared which highlight the importance of supply risk management. In this paper, we explore the commonly seen “supply guarantee deposit payment (SGDP)” scheme in fashion supply chains with production disruptions. Under the SGDP scheme, the apparel manufacturer guarantees the fashion retailer that it will supply the product on time by paying a certain amount of deposit to the fashion retailer with consideration of interest rate. In return, the apparel manufacturer requests a certain minimum ordering quantity (MOQ) in the supply contract. We first consider the case with a single product and then extend the analysis to the multi-product case. We find that the SGDP scheme can achieve win-win channel coordination for the fashion supply chain in the presence of production disruption and we have identified the respective bounds for the required amount of deposit payment. The range for setting the channel coordinating deposit payment under SGDP, depending on the size of the quantity difference after the adoption of SGDP, may increase or decrease when the chance of production disruption increases. With uniformly and normally distributed demands, we further derive the value of supply chain coordination under SGDP from the perspectives of the retailer, manufacturer and the whole supply chain, respectively. The critical influence factors in fashion supply chains are also uncovered. To achieve win-win channel coordination for the fashion supply chain with n different products using SGDP, we prove that it is sufficient if we can control n + 1 contract parameters. Moreover, we show that the MOQ is critical in order to achieve channel coordination, no matter the fashion retailer is risk neutral or risk averse. Finally, we check the robustness of our main results by considering the degree of damage of disruption. The findings would have good implications for the new normal after COVID-19.
ABSTRACT
SARS-CoV-2 is a highly pathogenic virus that evades anti-viral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the mRNA entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the SL1 region of the SARS-CoV-2 5 UTR is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides (ASOs) inhibits viral translation and makes SARS-CoV-2 5 UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus own virulence mechanism against itself could force a critical trade off between drug resistance and pathogenicity.
Subject(s)
COVID-19 , Graft vs Host DiseaseABSTRACT
Background The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial.Methods: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6-minute walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102).Findings: Within 3 months, MSC administration exerted numerical improvement in whole-lung lesion volume compared with the placebo, leading to a significant difference of −10.82% (95% CI: −20.69%, −1.46%, P=0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point, with a significant difference of − 9.02% (95%CI: − 17.44%, − 0.10%, P=0.045) at month 9. More interestingly, 17.86% (10/56) of patients in the MSC group had normal CT images at month 12 ( P= 0.013), but none in the placebo group. The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time, particularly sleep difficulties at month 3 (OR 0.19, 95% CI 0.07,0.50; P=0.001), and usual activity at month 12 (OR 0.15, 95% CI 0.03,0.79; P=0.018). Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.55%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups.Interpretation: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients.Trial Registration: This trial was registered with ClinicalTrials.gov (NCT04288102).Funding The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Ethics Committee of the Fifth Medical Center, Chinese PLA General Hospital (2020-013-D).
Subject(s)
COVID-19 , Lung Diseases , NeoplasmsABSTRACT
PURPOSE: Although denosumab is a safe and effective treatment for osteoporosis in various clinical trials, few studies have investigated its efficacy in specific clinical situations. The effect of non-compliance with the standard six-month dosing regimen for denosumab on bone mineral density (BMD) was assessed in a retrospective study of patients prescribed denosumab during the COVID-19 pandemic. PATIENTS AND METHODS: Between February 2019 and September 2020, 638 patient records were reviewed, with 236 patients meeting the eligibility criteria. Patients were divided into three groups: those who received denosumab injections between five and seven months after their initial subcutaneous injection, those who received denosumab injections between seven and nine months after their initial subcutaneous injection, and those who received denosumab injections more than nine months after their initial subcutaneous injection. A multivariate regression study was conducted to compare the BMD shift (at least one year apart) before and after two denosumab injections between the three pre-specified groups in both the lumbar spine (LS) and the femoral neck (FN). RESULTS: The difference between LS BMD indicates that there is a statistical difference between subjects who received denosumab injections between 5 and 7 months (near-standard dosing interval) and more than 9 months (P=0.03), but not in FN BMD, and no clinically significant association was identified. CONCLUSION: The results of this study show that in special clinical situations, such as the COVID-19 pandemic, clinicians may have some flexibility to prescribe denosumab, but the interval between injections should not exceed 9 months.
ABSTRACT
Objective To assess the safety and efficacy of human umbilical cord-derived MSCs (UC-MSCs) for severe COVID-19 patients with lung damage. Design, Multicentre , randomised, double-blind, placebo-controlled trial. Setting Two hospitals in Wuhan, China, 5 March 2020 to 28 March 2020. Participants 101 severe COVID-19 patients with lung damage aged between 18-74 years. Intervention Patients were randomly assigned at a 2:1 ratio to receive either UC-MSCs (40 million cells per infusion) or placebo on days 0, 3, and 6. Main outcome measures The primary endpoints were safety and an altered proportion of whole lung lesion size from baseline to day 28, measured by chest computed tomography. Secondary outcomes were reduction of consolidation lesion sizeand lung function improvement (6-minute walk test, maximum vital capacity, diffusing capacity). Primary analysis was done in the modified intention-to-treat (mITT) population and safety analysis was done in all patients who started their assigned treatment. Results 100 patients were finally recruited to receive either UC-MSCs (n = 65) or placebo (n = 35). The patients receiving UC-MSCs exhibited a trend of numerical improvement in whole lung lesion size from baseline to day 28 compared with the placebo cases (the median difference was -13.31%, 95%CI -29.14%, 2.13%, P=0.080). UC-MSCs administration significantly reduced the proportions of consolidation lesion size from baseline to day 28 compared with the placebo (median difference: -15.45%, 95% CI -30.82%, -0.39%, P=0.043). The 6-minute walk test showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m, 95% CI 0.00, 57.00, P=0.057). The incidence of adverse events was similar, and no serious adverse events were observed in the two groups. Conclusions UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability.
Subject(s)
COVID-19 , Lung Diseases , Renal InsufficiencyABSTRACT
Background: Treatment of severe Corona Virus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC‑MSCs) to treat patients with severe COVID-19 with lung damage, based on our phase 1 data.Methods: In this randomised, double-blind, and placebo-controlled trial, we recruited 101 eligible patients with severe COVID-19 with lung damage aged between 18–74 years from two hospitals. Enrolled patients were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. We excluded patients with malignant tumours, shock, or other organ failure. The primary endpoint was an altered proportion of whole lung lesion areas from baseline to day 28, measured by chest computed tomography. Other imaging outcomes, 6-minute walk test, maximum vital capacity, diffusing capacity, plasma biomarkers, and adverse events were recorded and analysed. Primary analysis was done in the modified intention-to-treat (mITT) population and safety analysis was done in all patients who started their assigned treatment. Findings: From March 5, 2020, to March 28, 2020, 100 patients were finally enrolled and received either UC-MSCs (n = 65) or placebo (n = 35). During follow-up, the patients receiving UC-MSCs exhibited a trend of numerical improvement in whole lung lesions from baseline to day 28 compared with the placebo cases. UC-MSCs administration significantly reduced the proportions of consolidation lesions from baseline to day 28 in the treated patients compared with the placebo subjects. The 6-minute walk test showed an increased distance in patients treated with UC-MSCs. Notably, UC-MSCs delivery was well tolerated, with no serious adverse events.Interpretation: UC-MSCs treatment is a safe and potentially effective therapeutic approach for patients with severe COVID‑19. The trial suggests that UC-MSCs administration might benefit patients with COVID-19 with lung damage at the convalescent stage as well as the progression stage.Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT04288102.Funding Statement: This trial was supported by The National Key R&D Program of China (2020YFC0841900, 2020YFC0844000, 2020YFC08860900); The Innovation Groups of the National Natural Science Foundation of China (81721002); The National Science and Technology Major Project (2017YFA0105703).Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: Ethical approval was obtained from the institutional review boards of each participating hospital. Written informed consent was obtained from all the enrolled patients or their legal representatives if they were unable to provide consent.
Subject(s)
Lung Diseases , Neoplasms , Virus Diseases , COVID-19ABSTRACT
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a highly contagious virus that underlies the current COVID-19 pandemic. SARS-CoV-2 infection exhibits many features of viral immune evasion of host defense, and the SARS-CoV-2 nonstructural protein 1 (Nsp1) suppresses host defense by inhibiting host protein translation and could be a target for antiviral therapy against COVID-19. However, how SARS-CoV-2 circumvents this translational blockage for the production of its own proteins is an open question. Here we report a bipartite mechanism of SARS-CoV-2 Nsp1 in hijacking the host ribosome by a direct interaction with the small ribosomal subunit 40S through its C-terminal domain (CT) and in lifting this inhibition by a direct interaction with the 5' untranslated region (5’ UTR) of viral mRNA through its N-terminal domain (NT). We show that Nsp1-CT is sufficient for binding to 40S and inhibition of host protein translation, and that 5’ UTR of SARS-CoV-2 mRNA removes this inhibition by binding to Nsp1-NT, suggesting that the Nsp1-NT-UTR interaction is incompatible with the Nsp1-CT-40S interaction. Indeed, lengthening the linker between Nsp1-NT and Nsp1-CT of Nsp1 progressively reduced the ability of SARS-CoV-2 5’ UTR to escape the translational inhibition, supporting that the incompatibility is likely steric in nature. The short SL1 region of the 5’ UTR is required for viral mRNA translation in the presence of Nsp1. Thus, our data provide a comprehensive view on how Nsp1 switches infected cells from host mRNA translation to SARS-CoV-2 mRNA translation, and that Nsp1 and 5’ UTR may be targeted for anti-COVID-19 therapeutics.Funding: L.W. was supported by funding from an NIH T32 grant (5T32AI007512-34). T.-M.F. was supported by funding from an NIH T32 grant (5T32HL066987-18 to L.E.S.) and by start-up funds from the Ohio State University Comprehensive Cancer Center.Conflict of Interest: The authors declare no competing interests.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a highly contagious virus that underlies the current COVID-19 pandemic. SARS-CoV-2 is thought to disable various features of host immunity and cellular defense. The SARS-CoV-2 nonstructural protein 1 (Nsp1) is known to inhibit host protein translation and could be a target for antiviral therapy against COVID-19. However, how SARS-CoV-2 circumvents this translational blockage for the production of its own proteins is an open question. Here, we report a bipartite mechanism of SARS-CoV-2 Nsp1 which operates by: (1) hijacking the host ribosome via direct interaction of its C-terminal domain (CT) with the 40S ribosomal subunit and (2) specifically lifting this inhibition for SARS-CoV-2 via a direct interaction of its N-terminal domain (NT) with the 5 untranslated region (5 UTR) of SARS-CoV-2 mRNA. We show that while Nsp1-CT is sufficient for binding to 40S and inhibition of host protein translation, the 5 UTR of SARS-CoV-2 mRNA removes this inhibition by binding to Nsp1-NT, suggesting that the Nsp1-NT-UTR interaction is incompatible with the Nsp1-CT-40S interaction. Indeed, lengthening the linker between Nsp1-NT and Nsp1-CT of Nsp1 progressively reduced the ability of SARS-CoV-2 5 UTR to escape the translational inhibition, supporting that the incompatibility is likely steric in nature. The short SL1 region of the 5 UTR is required for viral mRNA translation in the presence of Nsp1. Thus, our data provide a comprehensive view on how Nsp1 switches infected cells from host mRNA translation to SARS-CoV-2 mRNA translation, and that Nsp1 and 5 UTR may be targeted for anti-COVID-19 therapeutics.
Subject(s)
COVID-19ABSTRACT
In COVID-19 caused by SARS-CoV-2 infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of five healthy donors and 13 COVID-19 patients including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in COVID-19 patients showed a strong interferon-alpha response, and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ Effector-GNLY (Granulysin), CD8+ Effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during the disease progression.
Subject(s)
COVID-19ABSTRACT
The outbreak of COVID-19 originated in Wuhan has become a global epidemic of contagious diseases, which poses a serious threat to human life and health, especially for those with underlined diseases. However, Impacts of COVID-19 epidemic on HD center and HD patients are still unknown. In this report, we reviewed the whole course of the epidemic emerged in the HD center of Renmin Hospital, Wuhan University from January 14, 2020, the day the first case was confirmed, to February 17, 2020, the day the epidemic extinction. There are totally 37 cases among 230 HD patients and 4 cases among 33 staff being diagnosed with COVID-19. The epidemiology, clinical presentation and immune profile of dialysis patients contracted COVID-19 were further studied. We found that the two key measures we took in response to the epidemic, one was upgrading level of prevention and protection on January 21 and the other one starting universal screening, isolating, and distributing the infected cases on February 4, were effective in the epidemic control. No new COVID-19 case had been diagnosed since February 13. During the epidemic, 7 HD patients died, including 6 with COVID-19 and 1 without COVID-19. The presumed causes of death were not directly related to pneumonia, but due to cardiovascular and cerebrovascular diseases, hyperkalemia, etc. Most of the leukocytes in the peripheral blood of the HD patients infected with COVID-19 decreased, and the CT images of the chest mostly showed the ground glass like changes on the right side. The symptoms of most of the patients were mild, and there were no cases admitted to ICU. The frequency of lymphocytes in PBMCs and the serum level of inflammatory cytokines were assessed in HD patients contracted COVID-19 or not, non-HD COVID-19 patients, as well as healthy volunteers. The results showed that lymphocytes of T cell, Th cells, killer T cells, as well as NK cells in PBMCs of HD patients decreased significantly than other groups. HD patients with COVID-19 also displayed remarkable lower serum level of inflammatory cytokines than other COVID-19 patients. Our study indicates that HD patients are the highly susceptible population and HD centers are high risk area in the outbreak of COVID-19 epidemic. Measures of prevention, protection, screening, isolation, and distribution are essential in the epidemic management and should be taken in the early stage. HD Patients with COVID-19 are mostly clinical mild and unlikely progress to severe pneumonia due to the impaired cellular immune function and incapability of mounting cytokines storm. More attention should be paid to prevent cardiovascular events, which may be the collateral impacts of COVID-19 epidemic on HD patients.