Non-neutralizing antibodies to SARS-Cov-2-related linear epitopes induce psychotic-like behavior in mice.

Objective: An increasing number of studies have reported that numerous patients with coronavirus disease 2019 (COVID-19) and vaccinated individuals have developed central nervous system (CNS) symptoms, and that most of the antibodies in their sera have no virus-neutralizing ability. We tested the hypothesis that non-neutralizing anti-S1-111 IgG induced by the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could negatively affect the CNS. Methods: After 14-day acclimation, the grouped ApoE-/- mice were immunized four times (day 0, day 7, day 14, day 28) with different spike-protein-derived peptides (coupled with KLH) or KLH via subcutaneous injection. Antibody level, state of glial cells, gene expression, prepulse inhibition, locomotor activity, and spatial working memory were assessed from day 21. Results: An increased level of anti-S1-111 IgG was measured in their sera and brain homogenate after the immunization. Crucially, anti-S1-111 IgG increased the density of microglia, activated microglia, and astrocytes in the hippocampus, and we observed a psychomotor-like behavioral phenotype with defective sensorimotor gating and impaired spontaneity among S1-111-immunized mice. Transcriptome profiling showed that up-regulated genes in S1-111-immunized mice were mainly associated with synaptic plasticity and mental disorders. Discussion: Our results show that the non-neutralizing antibody anti-S1-111 IgG induced by the spike protein caused a series of psychotic-like changes in model mice by activating glial cells and modulating synaptic plasticity. Preventing the production of anti-S1-111 IgG (or other non-neutralizing antibodies) may be a potential strategy to reduce CNS manifestations in COVID-19 patients and vaccinated individuals.

SARS-CoV-2 N Protein Triggers Acute Lung Injury via Modulating Macrophage Activation and Infiltration in in vitro and in vivo.

Background: SARS-CoV-2-induced acute lung injury but its nucleocapsid (N) and/or Spike (S) protein involvements in the disease pathology remain elusive. Methods: In vitro, the cultured THP-1 macrophages were stimulated with alive SARS-CoV-2 virus at different loading dose, N protein or S protein with/without TICAM2-siRNA, TIRAP-siRNA or MyD88-siRNA. The TICAM2, TIRAP and MyD88 expression in the THP-1 cells after N protein stimulation were determined. In vivo, naïve mice or mice with depletion macrophages were injected with N protein or dead SARS-CoV-2. The macrophages in the lung were analyzed with flow cytometry, and lung sections were stained with H&E or immunohistochemistry. Culture supernatants and serum were harvested for cytokines measurements with cytometric bead array. Results: Alive SARS-CoV-2 virus or N protein but not S protein induced high cytokine releases from macrophages in a time or virus loading dependent manner. MyD88 and TIRAP but not TICAM2 were highly involved in macrophage activation triggered by N protein whilst both inhibited with siRNA decreased inflammatory responses. Moreover, N protein and dead SARS-CoV-2 caused systemic inflammation, macrophage accumulation and acute lung injury in mice. Macrophage depletion in mice decreased cytokines in response to N protein. Conclusion: SARS-CoV-2 and its N protein but not S protein induced acute lung injury and systemic inflammation, which was closely related to macrophage activation, infiltration and release cytokines.

Development of HPLC-CAD method for simultaneous quantification of nine related substances in ursodeoxycholic acid and identification of two unknown impurities by HPLC-Q-TOF-MS.

Ursodeoxycholic acid has gained increasing attention due to its recent discovery of the preventive effect on SARS-CoV-2 infection. Ursodeoxycholic acid has been included in various pharmacopoeias as an old drug, and the latest European Pharmacopoeia lists nine potential related substances (impurities A∼I). However, existing methods in pharmacopoeias and literature can only quantify up to five of these impurities simultaneously, and the sensitivity is inadequate, as the impurities are isomers or cholic acid analogues lacking chromophores. Herein, a novel gradient RP-HPLC method coupled to charged aerosol detection (CAD) was developed and validated for the simultaneous separation and quantification of the nine impurities in ursodeoxycholic acid. The method proved sensitive and allowed the quantification of the impurities as low as 0.02 %. Relative correction factors of the nine impurities were all within the range of 0.8-1.2 in the gradient mode by optimizing chromatographic conditions and CAD parameters. In addition, this RP-HPLC method is fully compatible with LC-MS due to the volatile additives and high percentage of the organic phase, which can be directly used for the identification of impurities. The newly developed HPLC-CAD method was successfully applied to commercial bulk drug samples, and two unknown impurities were identified by HPLC-Q-TOF-MS. The effect of CAD parameters on the linearity and correction factors was also discussed in this study. Overall, the established HPLC-CAD method can improve the methods in current pharmacopoeias and literature and contributes to understanding the impurity profile for process improvement.

Optimization of empty container allocation for inland freight stations considering stochastic demand.

In the post-COVID-19 epidemic era (PCEE), the supply of empty containers will face stronger uncertainty. Estimating the amount of self-owned and leased empty containers that need to be allocated to each inland freight station in a specific area becomes a critical issue for liner companies in PCEE. However, owing to the high degree of unpredictability of the demand and the limited flexibility of empty container relocation, the abovementioned issue has not been fully addressed. This paper provides a model for empty container allocation without knowing the probability distribution function of empty container demand in advance. The abovementioned model can jointly optimize the quantities of self-owned empty containers and leased containers allocated to each inland freight station. To solve the model, a largest-debt-first policy is adopted to simplify the complicated model, and a differential evolutionary (DE) algorithm is developed to solve the simplified model. Compared with some commonly used algorithms, DE has advantages considering the ability to explore the optimal solution. In addition, the utility of the largest-debt-first policy proposed in this paper is compared with that of the traditional method. Experimental results show that in the case of high demand fluctuations, the proposed policy is better in controlling the operational and management costs. Overall, the theory and method proposed in this paper can effectively help the carrier set a reasonable regional empty container stock level and determine the number of self-owned and leased empty containers.

The SARS-CoV-2 envelope protein disrupts barrier function in an in vitro human blood-brain barrier model.

Patients with coronavirus disease 2019 (COVID-19) have been frequently reported to exhibit neurological manifestations and disruption of the blood-brain barrier (BBB). Among the risk factors for BBB breakdown, the loss of endothelial cells and pericytes has caused widespread concern. Recent studies have revealed that severe acute respiratory syndrome coronavirus 2 envelope (S2E) protein caused cell death. We tested the hypothesis that the S2E protein alone could induce BBB dysfunction. The S2E protein bound to human BBB-related cells and inhibited cell viability in a dose- and time-dependent manner. Importantly, the S2E protein disrupted barrier function in an in vitro BBB model composed of HCMEC/D3 (brain endothelial cell line), HBVP (brain vascular pericyte), and U87MG (astrocyte cell line) cells and suppressed the expression of major genes involved in maintaining endothelial permeability and function. In addition, the S2E protein crossed the HCMEC/D3 monolayer. The S2E protein triggered inflammatory responses in HCMEC/D3 and U87MG cells. Taken together, these results show for the first time that the S2E protein has a negative impact on the BBB. Therapies targeting the S2E protein could protect against and treat central nervous system manifestations in COVID-19 patients.

Research progress on association between COVID-19 and herpes zoster

The infection caused by SARS-CoV-2 may result in a series of skin damages. In addition, some patients report the re-activation of the varicella-zoster virus, which might be related to T cell immune dysfunction caused by SARS-CoV-2 infection. Recently, studies reported herpes zoster occurrence after inoculating the COVID-19 vaccine. At present, the mechanism of interaction between COVID-19, COVID-19 vaccine and herpes zoster remains unclear, and more high-quality studies are required to further define the relationship.

Joint Optimization Decision of Online Retailers’ Pricing and Live-Streaming Effort in the Postepidemic Era

The isolation requirements of the coronavirus epidemic and the intuitive display advantages of live-streaming have led to an increasing number of retailers shifting to social live-streaming platforms and e-commerce live-streaming platforms to promote and sell their products in real time. However, the provision of live-streaming services will also incur high live-streaming effort costs. In this paper, we develop two decision models for retailers to sell goods through a single online shop and both online shop and live-streaming room;we also present the optimal decisions of pricing and live-streaming efforts. Furthermore, we identify the profitability conditions for retailers to determine when to provide live-streaming services. In addition, we examine the impact of the provision of live-streaming services on the optimal price and live-streaming effort. We obtain three findings. First, there is a unique optimal decision on the price and live-streaming effort under certain conditions. Second, when the effect coefficient of the live-streaming room reaches a certain threshold, there are enough customers who enter the live-streaming room to watch and buy and it is profitable for retailers to provide live-streaming service. Finally, the optimal price and live-streaming effort increase with the increase in average return loss, the effect coefficient of live-streaming effort, and the extra return rate and decrease with the increase in the proportion of customers who choose to buy in the online shop and the price discount coefficient in the live-streaming room.

SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation.

Background: Infection of SARS-CoV-2 may cause acute respiratory syndrome. It has been reported that SARS-CoV-2 nucleocapsid protein (N-protein) presents early in body fluids during infection. The direct involvement of N-protein in lung injury is poorly understood. Methods: Recombinant N-protein was pretreated with polymyxin B, a lipopolysaccharide (LPS)-neutralizing agent. C57BL/6, C3H/HeJ (resistant to LPS), and C3H/HeN (control for C3H/HeJ) mice were exposed to N-protein via intratracheal administration to examine acute lung injury. In vitro, bone marrow-derived macrophages (BMDMs) were cultured with N-protein to study phosphorylation of nuclear factor kappa B (NF-ĸB) p65, macrophage polarization, and expression of proinflammatory cytokines. Results: N-protein produced acute lung injury in C57BL/6 mice, with elevated protein permeability, total cell count, neutrophil infiltration, and proinflammatory cytokines in the bronchioalveolar lavage. N-protein also induced lung injury in both C3H/HeJ and C3H/HeN mice, indicating that the effect could not be attributed to the LPS contamination. N-protein triggered phosphorylation of NF-ĸB p65 in vitro, which was abolished by both N-protein denaturation and treatment with an antibody for N-protein, demonstrating that the effect is N-protein specific. In addition, N-protein promoted M1 macrophage polarization and the expression of proinflammatory cytokines, which was also blocked by N-protein denaturation and antibody for N-protein. Furthermore, N-protein induced NF-ĸB p65 phosphorylation in the lung, while pyrrolidine dithiocarbamate, an NF-ĸB inhibitor, alleviated the effect of N-protein on acute lung injury. Conclusions: SARS-CoV-2 N-protein itself is toxic and induces acute lung injury in mice. Both N-protein and NF-ĸB pathway may be therapeutic targets for treating multi-organ injuries in Coronavirus disease 2019 (COVID-19).

The Spring Festival Effect: The change in NO2 column concentration in China caused by the migration of human activities

The Spring Festival is the most important holiday in China, and human activity and population mobility may contribute greatly to air quality. According to the satellite-based tropospheric nitrogen dioxide (NO2) column and ground-based observational concentration of NO2 in megacities from 2013 to 2018 around the Spring Festival, we found that NO2 concentration obviously decreases, presenting a “tide phenomenon”, particularly in the megacities, with the tropospheric NO2 column density decreasing by 31.8%–44.5%. The tropospheric NO2 column density in Beijing decreased by 41.6% and rebounded by 22.3% after the festival. Vehicle sources were among the important causes of NOx emissions in the megacities, and traffic intensity decreased significantly during the festival. As the coronavirus disease 2019 (COVID-19) pandemic progresses, the traffic intensity in urban areas is decreasing significantly, with the tropospheric NO2 column density decreasing by 56.2% and rebounding by only 6.8% in 2020, without the “tide phenomenon”.

[Simulation Analysis of the Impact of COVID-19 Pandemic Control on Air Quality in Henan Province based on Machine Learning Algorithm].

To reduce the risks of COVID-19 on society and the health of the general public, necessary prevention and control measures were implemented throughout China in 2020. Consequently, air quality was greatly improved due to lower emissions. However, the improvement of air quality could also be closely related to meteorological conditions. During quarantine (January 27 to February, 2020), reductions were observed in the concentration of all air pollutants in Henan Province (PM2.5, PM10, SO2, CO, and NO2 decreased by 36.89%, 34.18%, 19.43%, 29.85%, and 58.51%, respectively) relative to measurements taken from January 1 to 26, 2020. The only exception was for the concentration of O3, which increased by 69.64%. This study evaluates the importance of meteorological conditions in air pollution, through simulation with a long-and-short-term memory network (LSTM) and a machine learning algorithm. Results show that meteorological conditions play a crucial role in air pollutant formation. Given favorable meteorological factors, the concentrations of pollutants could be reduced by 15%-30%, while the reduction due to anthropogenic emission control ranges from 6%-40%. During the epidemic, meteorological conditions and human emissions accounted for 34.84% and 34.81% of the increase in O3 concentration, respectively. The results show that primary pollutant concentrations are more sensitive to the intensity of anthropogenic emissions. However, secondary pollutants are more dependent on meteorological factors. Furthermore, a nonlinear relationship has been identified between O3 concentration and to emission intensity. Further investigation into the causes of the rise in O3 concentration is necessary to gain a greater understanding and better control of particulate matter and O3 pollution.

Risk factors and prediction nomogram model for psychosocial and behavioural problems among children and adolescents during the COVID-19 pandemic: A national multicentre study: Risk Factors of Childhood Psychosocial Problems.

BACKGROUND: We aimed to explore the risk profiles attributable to psychosocial and behavioural problems during the coronavirus disease 2019 pandemic. To this end, we created a risk-prediction nomogram model. METHODS: A national multicentre study was conducted through an online questionnaire involving 12,186 children (6-11 years old) and adolescents (12-16 years old). Respondents' psychosocial and behavioural functioning were assessed using the Achenbach Child Behaviour Checklist (CBCL). Data were analysed using STATA software and R-language. RESULTS: The positive detection rate of psychological problems within Wuhan was greater than that outside Wuhan for schizoid (P = 0.005), and depression (P = 0.030) in children, and for somatic complaints (P = 0.048), immaturity (P = 0.023), and delinquent behaviour (P = 0.046) in adolescents. After graded multivariable adjustment, seven factors associated with psychological problems in children and adolescents outside Wuhan were parent-child conflict (odds ratio (OR): 4.94, 95% confidence interval (95% CI): 4.27-5.72), sleep problems (OR: 4.05, 95% CI: 3.77-4.36), online study time (OR: 0.41, 95% CI: 0.37-0.47), physical activity time (OR: 0.510, 95% CI: 0.44-0.59), number of close friends (OR: 0.51, 95% CI: 0.44-0.6), time spent playing videogames (OR: 2.26, 95% CI: 1.90-2.69) and eating disorders (OR: 2.71, 95% CI: 2.35-3.11) (all P < 0.001). Contrastingly, within Wuhan, only the first four factors, namely, parent-child conflict (5.95, 2.82-12.57), sleep problems (4.47, 3.06-6.54), online study time (0.37, 0.22-0.64), and physical activity time (0.42, 0.22-0.80) were identified (all P < 0.01). Accordingly, nomogram models were created with significant attributes and had decent prediction performance with C-indexes over 80%. LIMITATION: A cross-sectional study and self-reported measures. CONCLUSIONS: Besides the four significant risk factors within and outside Wuhan, the three additional factors outside Wuhan deserve special attention. The prediction nomogram models constructed in this study have important clinical and public health implications for psychosocial and behavioural assessment.

Psychosocial and behavioral problems of children and adolescents in the early stage of reopening schools after the COVID-19 pandemic: a national cross-sectional study in China.

This study aims to explore the psychosocial and behavioral problems of children and adolescents in the early stage of reopening schools. In this national cross-sectional study, a total of 11072 students from China were naturally divided into two groups based on their schooling status: reopened schools (RS) and home schooling (HS) group. The psychosocial and behavioral functioning were measured by Achenbach Child Behaviour Checklist (CBCL) and compared in these two groups. Multivariable logistic regression analyses were conducted to explore the independent predictors associated with the psychosocial and behavioral problems. Our results showed that the students in the RS group had more adverse behaviors than that of HS group. The RS group had the higher rates of parent-offspring conflict, prolonged homework time, increased sedentary time and sleep problems (all p < 0.001). When separate analyses were conducted in boys and girls, the RS group had the higher scores for (1) overall behavioral problems (p = 0.02 and p = 0.01), internalizing (p = 0.02 and p = 0.02) and externalizing (p = 0.02 and p = 0.004) behaviors in the 6-11 age group; (2) externalizing (p = 0.049 and p = 0.006) behaviors in the 12-16 age group. Multivariable regression showed parent-offspring conflict and increased sedentary time were the most common risk factors, while physical activity and number of close friends were protective factors for behavior problems in RS students (p < 0.01 or 0.05). The present study revealed that students' psychosocial and behavioral problems increased in the early stage of schools reopened unexpectedly. These findings suggest that close attention must be paid and holistic strategies employed in the school reopening process of post-COVID-19 period.

Study on the influence of operational and management processes of a water reclamation plant since COVID-19 situation.

Reusing treated wastewater can effectively alleviate water shortages and water contamination problems but depends on ensuring the safety of the reclaimed water that is produced. The operating and management conditions for water reclamation plants in China have been changed since the outbreak of the COVID-19 epidemic in China at the end of 2019 to prevent emerging viruses being spread through wastewater treatment processes and the reclaimed water that is produced. Removal of pathogens and trace organic compounds (e.g., pharmaceuticals and personal care products and endocrine disrupting chemicals) in a real water reclamation plant after the start of COVID-19 epidemic was studied. Disinfection byproduct formation caused by chlorine being added to meet disinfection requirements was also assessed. The pathogenic microorganism concentrations in effluent were <2 (most probable number)/L, and the removal rates for most trace organic compounds were >80% when advanced treatments were performed using ozone, ultraviolet light, and chlorine doses of 2 mg/L, 20.5 mJ/cm2, and 2-3 mg/L, respectively. The main disinfection byproduct produced at a chlorine dose of 2 mg/L and a residence time of 1 h was chloroform (at concentrations <15 µg/L). The results indicated that the water reclamation processes with modified conditions gave high pathogen and trace organic compound removal rates and reasonably well-controlled disinfection byproduct concentrations.

Enhancing the filtration efficiency and wearing time of disposable surgical masks using TENG technology.

The COVID-19 pandemic has caused an unprecedented human and health crisis. And the shortage of protective equipment, especially the personal protective disposable surgical masks, has been a great challenge. Here, we developed an effective and simple scheme to prolong the lifetime of disposable surgical masks without changing their current structure, which is beneficial to solve the shortage of personal masks. After electrifying the meltblown PP filter by the new-developed single-electrode-based sliding triboelectric nanogenerator (TENG) charge replenishment (NGCR) technology, the processed filter is bipolar charged and has a filtration efficiency beyond 95% for the particulate matter (PM) ranging from PM0.3 to PM10.0. Further, we demonstrate the 80 °C dry heating is an effective decontamination method. This method is compatible with single-electrode-based sliding TENG charge replenishment technology. The 80 °C dry heating and the NGCR technology can make up an effective regeneration procedure for the mask. Even after ten cycles of simulated 4 h wearing process and such regeneration procedure, the filtration efficiency of the disposable surgical masks PM0.3 is still higher than 95%.