Study of fusion peptide release for the spike protein of SARS-CoV-2.

The spike protein of SARS-CoV-2 can recognize the ACE2 membrane protein on the host cell and plays a key role in the membrane fusion process between the virus envelope and the host cell membrane. However, to date, the mechanism for the spike protein recognizing host cells and initiating membrane fusion remains unknown. In this study, based on the general assumption that all three S1/S2 junctions of the spike protein are cleaved, structures with different forms of S1 subunit stripping and S2' site cleavage were constructed. Then, the minimum requirement for the release of the fusion peptide was studied by all-atom structure-based MD simulations. The results from simulations showed that stripping an S1 subunit from the A-, B- or C-chain of the spike protein and cleaving the specific S2' site on the B-chain (C-chain or A-chain) may result in the release of the fusion peptide, suggesting that the requirement for the release of FP may be more relaxed than previously expected.

Harringtonine: A more effective antagonist for Omicron variant.

Fusion with host cell membrane is the main mechanism of infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we propose that a new strategy to screen small-molecule antagonists blocking SARS-CoV-2 membrane fusion. Using cell membrane chromatography (CMC), we found that harringtonine (HT) simultaneously targeted SARS-CoV-2 S protein and host cell surface TMPRSS2 expressed by the host cell, and subsequently confirmed that HT can inhibit membrane fusion. HT effectively blocked SARS-CoV-2 original strain entry with the IC50 of 0.217 µM, while the IC50 in delta variant decreased to 0.101 µM, the IC50 in Omicron BA.1 variant was 0.042 µM. Due to high transmissibility and immune escape, Omicron subvariant BA.5 has become the dominant strain of the SARS-CoV-2 virus and led to escalating COVID-19 cases, however, against BA.5, HT showed a surprising effectiveness. The IC50 in Omicron BA.5 was even lower than 0.0019 µM. The above results revealed the effect of HT on Omicron is very significant. In summary, we characterize HT as a small-molecule antagonist by direct targeting on the Spike protein and TMPRSS2.

Hospital red blood cell and platelet supply and utilization from March to December of the first year of the COVID-19 pandemic: The BEST collaborative study.

BACKGROUND: At the start of the coronavirus disease 2019 (COVID-19) pandemic, widespread blood shortages were anticipated. We sought to determine how hospital blood supply and blood utilization were affected by the first wave of COVID-19. STUDY DESIGN AND METHODS: Weekly red blood cell (RBC) and platelet (PLT) inventory, transfusion, and outdate data were collected from 13 institutions in the United States, Brazil, Canada, and Denmark from March 1st to December 31st of 2020 and 2019. Data from the sites were aligned based on each site's local first peak of COVID-19 cases, and data from 2020 (pandemic year) were compared with data from the corresponding period in 2019 (pre-pandemic baseline). RESULTS: RBC inventories were 3% lower in 2020 than in 2019 (680 vs. 704, p < .001) and 5% fewer RBCs were transfused per week compared to 2019 (477 vs. 501, p < .001). However, during the first COVID-19 peak, RBC and PLT inventories were higher than normal, as reflected by deviation from par, days on hand, and percent outdated. At this time, 16% fewer inpatient beds were occupied, and 43% fewer surgeries were performed compared to 2019 (p < .001). In contrast to 2019 when there was no correlation, there was, in 2020, significant negative correlations between RBC and PLT days on hand and both percentage occupancy of inpatient beds and percentage of surgeries performed. CONCLUSION: During the COVID-19 pandemic in 2020, RBC and PLT inventories remained adequate. During the first wave of cases, significant decreases in patient care activities were associated with excess RBC and PLT supplies and increased product outdating.

The Impact of COVID-19 Control Measures on Air Quality in Guangdong Province

COVID-19 control measures had a significant social and economic impact in Guangdong Province, and provided a unique opportunity to assess the impact of human activities on air quality. Based on the monitoring data of PM2.5, PM10, NO2, and O3 concentrations from 101 air quality monitoring stations in Guangdong Province from October 2019 to April 2020, the PSCF (potential source contribution factor) analysis and LSTM (long short-term memory) neural network were applied to explore the impact of epidemic control measures on air quality in Guangdong Province. Results showed that during the lockdown, the average concentration of PM2.5, PM10, NO2, and O3 decreased by 37.84%, 51.56%, 58.82%, and 24.00%, respectively. The ranges of potential sources of pollutants were reduced, indicating that air quality in Guangdong Province improved significantly. The Pearl River Delta, characterized by a high population density, recorded the highest NO2 concentration values throughout the whole study period. Due to the lockdown, the areas with the highest concentrations of O3, PM2.5, and PM10 changed from the Pearl River Delta to the eastern and western Guangdong. Moreover, LSTM simulation results showed that the average concentration of PM2.5, PM10, NO2, and O3 decreased by 46.34%, 54.56%, 70.63%, and 26.76%, respectively, which was caused by human-made impacts. These findings reveal the remarkable impact of human activities on air quality and provide effective theoretical support for the prevention and control of air pollution in Guangdong Province.

3,4-Dihydroxyphenylethanol ameliorates lipopolysaccharide-induced septic cardiac injury in a murine model

3,4-Dihydroxyphenylethanol (DOPET) is a polyphenol found in olive oil. The present study evaluated the protective role of DOPET on LPS provoked septic cardiac injury in a murine model. Four groups were used in the study (n = 3): control, LPS, DOPET alone, and DOPET + LPS. LPS (15 mg/kg;i.p.);they were used to induce cardiac sepsis. The cardiac markers like LDH, CK-MB, and troponin-T, as well as inflammatory cytokines like TNF-α and IL-6 were measured in the serum. The antioxidants and oxidative stress parameters were measured in cardiac tissues. RT-PCR and western blot methods were done to evaluate the expression of inflammatory mediators and apoptotic markers. DOPET significantly decreased the cardiac markers (LDH, CK-MB, and troponin-T) and TNF-α and IL-6 level in the serum. DOPET effectively reduced the levels of MDA and NO in LPS intoxicated rats. DOPET also increased the levels of antioxidants like SOD, CAT, GPx, and GSH in LPS intoxicated rats. The mRNA levels of TNF-α, IL-6, and NF-κB were significantly downregulated by DOPET in cardiac tissues of LPS rats. The protein expression of Bcl-2 was upregulated, and Bax and caspase-3 were downregulated by DOPET. DOPET effectively attenuates LPS-induced cardiac dysfunction through its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.

Targeting PSD95/nNOS by ZL006 alleviates social isolation-induced heightened attack behavior in mice.

RATIONALE: Deregulated attack behaviors have devastating social consequences; however, satisfactory clinical management for the behavior is still an unmet need so far. Social isolation (SI) has been common during the COVID-19 pandemic and may have detrimental effects on mental health, including eliciting heightened attack behavior. OBJECTIVES: This study aims to explore whether injection of ZL006 can alleviate SI-induced escalation of attack behavior in mice. METHODS: Pharmacological tools, biochemical methods, and behavioral tests were used to explore the potential therapeutic effects of ZL006 targeting postsynaptic density 95 (PSD95)/neuronal nitric oxide synthase (nNOS) pathway on escalation of attack behavior induced by SI in mice. RESULTS: ZL006 mitigated SI-induced escalated attack behaviors and elevated nitric oxide (NO) level in the cortex of the SI mice. The beneficial effects of ZL006 lasted for at least 72 h after a single injection of ZL006. Potentiation of NO levels by L-arginine blocked the effects of ZL006. Moreover, a sub-effective dose of 7-NI in combination with a sub-effective dose of ZL006 decreased both SI-induced escalated attack behaviors and NO levels in mice subjected to SI. CONCLUSIONS: Our study highlights the importance of the PSD95/nNOS pathway in mediating SI-induced escalation of attack behavior. ZL006 may be a promising therapeutic strategy for treating aggressive behaviors.

Antibacterial Activity and Protection Efficiency of Polyvinyl Butyral Nanofibrous Membrane Containing Thymol Prepared through Vertical Electrospinning.

Human safety, health management, and disease transmission prevention have become crucial tasks in the present COVID-19 pandemic situation. Masks are widely available and create a safer and disease transmission-free environment. This study presents a facile method of fabricating masks through electrospinning nontoxic polyvinyl butyral (PVB) polymeric matrix with the antibacterial component Thymol, a natural phenol monoterpene. Based on the results of Japanese Industrial Standards and American Association of Textile Chemists and Colorists methods, the maximum antibacterial value of the mask against Gram-positive and Gram-negative bacteria was 5.6 and 6.4, respectively. Moreover, vertical electrospinning was performed to prepare Thymol/PVB nanofiber masks, and the effects of parameters on the submicron particulate filtration efficiency (PFE), differential pressure, and bacterial filtration efficiency (BFE) were determined. Thorough optimization of the small-diameter nanofiber-based antibacterial mask led to denser accumulation and improved PFE and pressure difference; the mask was thus noted to meet the present pandemic requirements. The as-developed nanofibrous masks have the antibacterial activity suggested by the National Standard of the Republic of China (CNS 14774) for general medical masks. Their BFE reaches 99.4%, with a pressure difference of <5 mmH2O/cm2. The mask can safeguard human health and promote a healthy environment.

Potential antiviral activity of isorhamnetin against SARS-CoV-2 spike pseudotyped virus in vitro.

Coronavirus Disease 2019 (COVID-19) cases and deaths are still rising worldwide, there is currently no effective treatment for severe inflammation and acute lung injury caused by new coronavirus (SARS-COV-2) infection. Therapies to prevent or treat COVID-19, including antiviral drug and several vaccines, are still being development. Human angiotensin-converting enzyme 2 (ACE2), expressing in lung, has been confirmed to be a receptor for SARS-COV-2 infection, interventions for attachment of spike protein of SARS-CoV-2 to ACE2 may be a potential approach to prevent viral infections and it is considered as a potential target for drug development. In this study, we observed that seabuckthorn and its flavonoid compounds quercetin and isorhamnetin were shown strong retention to ACE2 overexpression HEK293 (ACE2h ) cells by CMC analysis. Based on drug receptor interaction analysis and viral entry studies in vitro, we evaluated the interaction of two flavonoid compounds and ACE2 as well as the inhibitory effect of the two compounds on viral entry. Surface plasmon resonance assay proved the effect that isorhamnetin bound to the ACE2, and its affinity (KD value) was at the micromolar level, that was, 2.51 ± 0.68 µM. Viral entry studies in vitro indicated that isorhamnetin inhibited SARS-CoV-2 spike pseudotyped virus entering ACE2h cells. Based on promising in vitro results, we proposed isorhamnetin to be a potential therapeutic candidate compound against COVID-19.

Survival Analysis and Risk Factors in COVID-19 Patients.

OBJECTIVE: The aim of this study is to evaluate the clinical characteristics and outcomes in 2019 coronavirus disease (COVID-19) patients and to help clinicians perform correct treatment and evaluate prognosis and guide the treatment. METHODS: Patients totaling 239 were diagnosed with COVID-19 and were included in this study. Patients were divided into the improvement group and the death group according to their outcome (improvement or death). Clinical characteristics and laboratory parameters were collected from medical records. Continuous variables were tested by an independent sample T test, and categorical variables were analyzed by the chi-square test or Fisher's exact test. The Cox proportional hazard regression model was used for survival analysis in death patients. The time-dependent area under curves (AUC) based on white blood cell count, lymphocyte count, neutrophil count by age, blood urea nitrogen, and C-reactive protein were plotted. RESULTS: Efficacy evaluation indicated that 99 (41.4%) patients had deteriorated, and 140 (58.6%) patients had improved. Oxygen saturation, hemoglobin levels, infection-related indicators, lymphocyte and platelet counts, C-reactive protein, serum albumin, liver and kidney function, and lactate dehydrogenase in improvement group were statistically significant between the improvement and death groups. A survival analysis revealed that comorbidities, lymphocyte counts, platelet count, serum albumin, C-reactive protein level, and renal dysfunction may be risk factors in patients with COVID-19. CONCLUSION: Patients with comorbidities, lower lymphocyte counts in hemogram, platelet count and serum albumin, high C-reactive protein level, and renal dysfunction may have higher risk for death. More attention should be given to risk management in the progression of COVID-19.

Impact of urbanization on air quality in the Yangtze River Delta during the COVID-19 lockdown in China

The urban agglomeration of Yangtze River Delta (YRD) is symbol of China's rapid urbanization during the past decades. Urbanization can significantly impact land-cover properties, surface heating, and emissions of air pollutants. To control the spread of COVID-19, China imposed very rigorous restrictions, leading to dramatic reductions in air pollutants (except O3) from satellite and ground-based data. As such, inter-transportation of air pollutants was weak during the lockdown, which was conducive to discuss the impacts of urbanization on the air quality. During the lockdown, the rates of surface PM2.5, PM10, SO2, NO2 and CO reductions in different urban types ranged from 6.6% to 62.4% in the YRD. Urbanization exerted great impacts on the pollutant variations in urban agglomerations despite such large decreases in primary pollution in YRD. Lower values of AOD and tropospheric NO2 columns were noticeably observed over large cities during the lockdown. The extents of surface PM, SO2, NO2 and CO reductions in large cities (first-tier and second-tier) were found to be larger (4.7%-10.6%) than those in small-medium cities (third-tier and fourth-tier) during the lockdown, which was also the case for the extent of the increase (33.0% - 53.0%) in O3. PCA analysis revealed that the PM decreases in large cities made greater improvement in the air quality compared with the small cities during lockdown, while the urbanization had non-obvious influence on the photochemical reactions. It is imperative to adopt policies and programs to mitigate the air pollution in urban agglomerations in the fast urbanization process.

The use of therapeutic plasma exchange as adjunctive therapy in the treatment of coronavirus disease 2019: A critical appraisal of the current evidence.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a major pandemic. While vaccine development moves forward, optimal treatment continues to be explored. Efforts include an ever-expanding number of clinical trials along with newly proposed experimental and off-label investigational therapies; one of which is therapeutic plasma exchange (TPE). There have been a number of publications on TPE use as adjunctive therapy for coronavirus disease 2019 (COVID-19), but no prospective randomized controlled trials (RCTs) have been completed. This article critically appraises the current available evidence on TPE as a treatment modality for SARS-CoV-2 infection.

Characterization of the aerosol chemical composition during the COVID-19 lockdown period in Suzhou in the Yangtze River Delta, China.

To control the spread of COVID-19, rigorous restrictions have been implemented in China, resulting in a great reduction in pollutant emissions. In this study, we evaluated the air quality in the Yangtze River Delta during the COVID-19 lockdown period using satellite and ground-based data, including particle matter (PM), trace gases, water-soluble ions (WSIs) and black carbon (BC). We found that the impacts of lockdown policy on air quality cannot be accurately assessed using MODIS aerosol optical depth (AOD) data, whereas the tropospheric nitrogen dioxide (NO2) vertical column density can well reflect the influences of these restrictions on human activities. Compared to the pre-COVID period, the PM2.5, PM10, NO2, carbon monoxide (CO), BC and WSIs during the lockdown in Suzhou were observed to decrease by 37.2%, 38.3%, 64.5%, 26.1%, 53.3% and 58.6%, respectively, while the sulfur dioxide (SO2) and ozone (O3) increased by 1.5% and 104.7%. The WSIs ranked in the order of NO3- > NH4+ > SO42- > Cl- > Ca2+ > K+ > Mg2+ > Na+ during the lockdown period. By comparisons with the ion concentrations during the pre-COVID period, we found that the ions NO3-, NH4+, SO42-, Cl-, Ca2+, K+ and Na+ decreased by 66.3%, 48.8%, 52.9%, 56.9%, 57.9% and 76.3%, respectively, during the lockdown, in contrast to Mg2+, which increased by 30.2%. The lockdown policy was found to have great impacts on the diurnal variations of Cl-, SO42-, Na+ and Ca2+.

Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus.

BACKGROUND: The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019 and there is no sign that the epidemic is abating . The major issue for controlling the infectious is lacking efficient prevention and therapeutic approaches. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been reported to treat the disease, but the underlying mechanism remains controversial. PURPOSE: The objective of this study is to investigate whether CQ and HCQ could be ACE2 blockers and used to inhibit 2019-nCoV virus infection. METHODS: In our study, we used CCK-8 staining, flow cytometry and immunofluorescent staining to evaluate the toxicity and autophagy of CQ and HCQ, respectively, on ACE2 high-expressing HEK293T cells (ACE2h cells). We further analyzed the binding character of CQ and HCQ to ACE2 by molecular docking and surface plasmon resonance (SPR) assays, 2019-nCoV spike pseudotyped virus was also used to observe the viropexis effect of CQ and HCQ in ACE2h cells. RESULTS: Results showed that HCQ is slightly more toxic to ACE2h cells than CQ. Both CQ and HCQ could bind to ACE2 with KD = (7.31 ± 0.62)e-7 M and (4.82 ± 0.87)e-7 M, respectively. They exhibit equivalent suppression effect for the entrance of 2019-nCoV spike pseudotyped virus into ACE2h cells. CONCLUSIONS: CQ and HCQ both inhibit the entrance 2019-nCoV into cells by blocking the binding of the virus with ACE2. Our findings provide novel insights into the molecular mechanism of CQ and HCQ treatment effect on virus infection.

Psychological status of medical workforce during the COVID-19 pandemic: A cross-sectional study.

The pandemic of 2019 coronavirus disease (COVID-19) has burdened an unprecedented psychological stress on people around the world, especially the medical workforce. The study focuses on assess the psychological status of them. The authors conducted a single-center, cross-sectional survey via online questionnaires. Occurrence of fear, anxiety and depression were measured by the numeric rating scale (NRS) on fear, Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD), respectively. A total of 2299 eligible participants were enrolled from the authors' institution, including 2042 medical staff and 257 administrative staff. The severity of fear, anxiety and depression were significantly different between two groups. Furthermore, as compared to the non-clinical staff, front line medical staff with close contact with infected patients, including working in the departments of respiratory, emergency, infectious disease, and ICU, showed higher scores on fear scale, HAMA and HAMD, and they were 1.4 times more likely to feel fear, twice more likely to suffer anxiety and depression. The medical staff especially working in above-mentioned departments made them more susceptible to psychological disorders. Effective strategies toward to improving the mental health should be provided to these individuals.

Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China ;Clinical Infectious Diseases ;Oxford Academic

Abstract Background From December 2019 to February 2020, 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China. Related clinical features are needed. Methods We reviewed 69 patients who were hospitalized in Union hospital in Wuhan between January 16 to January 29, 2020. All patients were confirmed to be infected with SARS-CoV-2 and the final date of follow-up was February 4, 2020. Results The median age of 69 enrolled patients was 42.0 years (IQR 35.0-62.0), and 32 patients (46%) were men. The most common symptoms were fever (60[87%]), cough (38[55%]), and fatigue (29[42%]). Most patients received antiviral therapy (66 [98.5%] of 67 patients) and antibiotic therapy (66 [98.5%] of 67 patients). As of February 4, 2020, 18 (26.9%) of 67 patients had been discharged, and five patients had died, with a mortality rate of 7.5%. According to the lowest SpO2 during admission, cases were divided into the SpO2≥90% group (n=55) and the SpO2<90% group (n=14). All 5 deaths occurred in the SpO2<90% group. Compared with SpO2≥90% group, patients of the SpO2<90% group were older, and showed more comorbidities and higher plasma levels of IL6, IL10, lactate dehydrogenase, and c reactive protein. Arbidol treatment showed tendency to improve the discharging rate and decrease the mortality rate. Conclusions COVID-19 appears to show frequent fever, dry cough, and increase of inflammatory cytokines, and induced a mortality rate of 7.5%. Older patients or those with underlying comorbidities are at higher risk of death.