SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases.

The replication machinery of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely associated with the endoplasmic reticulum (ER) in host cells. Activation of the unfolded protein response (UPR) is a strategy hijacked by coronavirus to facilitate its replication and suppress host innate immunity. Here, we have found that SARS-CoV-2 ORF8 protein accumulates in the ER and escapes the degradation system by forming mixed disulfide complexes with ER oxidoreductases. ORF8 induces the activation of three UPR pathways through targeting key UPR components, remodels ER morphology and accelerates protein trafficking. Moreover, small molecule reducing agents release ORF8 from the mixed disulfide complexes and facilitate its degradation, therefore mitigate ER stress. Our study reveals a unique mechanism by which SARS-CoV-2 ORF8 escapes degradation by host cells and regulates ER reshaping. Targeting ORF8-involved mixed disulfide complexes could be a new strategy to alleviate SARS-CoV-2 induced ER stress and related diseases.

Transcriptional Start Site Coverage Analysis in Plasma Cell-Free DNA Reveals Disease Severity and Tissue Specificity of COVID-19 Patients.

Symptoms of coronavirus disease 2019 (COVID-19) range from asymptomatic to severe pneumonia and death. A deep understanding of the variation of biological characteristics in severe COVID-19 patients is crucial for the detection of individuals at high risk of critical condition for the clinical management of the disease. Herein, by profiling the gene expression spectrum deduced from DNA coverage in regions surrounding transcriptional start site in plasma cell-free DNA (cfDNA) of COVID-19 patients, we deciphered the altered biological processes in the severe cases and demonstrated the feasibility of cfDNA in measuring the COVID-19 progression. The up- and downregulated genes in the plasma of severe patient were found to be closely related to the biological processes and functions affected by COVID-19 progression. More importantly, with the analysis of transcriptome data of blood cells and lung cells from control group and cases with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, we revealed that the upregulated genes were predominantly involved in the viral and antiviral activity in blood cells, reflecting the intense viral replication and the active reaction of immune system in the severe patients. Pathway analysis of downregulated genes in plasma DNA and lung cells also demonstrated the diminished adenosine triphosphate synthesis function in lung cells, which was evidenced to correlate with the severe COVID-19 symptoms, such as a cytokine storm and acute respiratory distress. Overall, this study revealed tissue involvement, provided insights into the mechanism of COVID-19 progression, and highlighted the utility of cfDNA as a noninvasive biomarker for disease severity inspections.

Double lock of a potent human therapeutic monoclonal antibody against SARS-CoV-2.

Receptor recognition and subsequent membrane fusion are essential for the establishment of successful infection by SARS-CoV-2. Halting these steps can cure COVID-19. Here we have identified and characterized a potent human monoclonal antibody, HB27, that blocks SARS-CoV-2 attachment to its cellular receptor at sub-nM concentrations. Remarkably, HB27 can also prevent SARS-CoV-2 membrane fusion. Consequently, a single dose of HB27 conferred effective protection against SARS-CoV-2 in two established mouse models. Rhesus macaques showed no obvious adverse events when administrated with 10 times the effective dose of HB27. Cryo-EM studies on complex of SARS-CoV-2 trimeric S with HB27 Fab reveal that three Fab fragments work synergistically to occlude SARS-CoV-2 from binding to the ACE2 receptor. Binding of the antibody also restrains any further conformational changes of the receptor binding domain, possibly interfering with progression from the prefusion to the postfusion stage. These results suggest that HB27 is a promising candidate for immuno-therapies against COVID-19.

Clinical effect of millimeter wave applied to acupoints on treatment of COVID-19

OBJECTIVE: To retrospectively observe the clinical effect of integrated Chinese and Western medicine combined with millimeter wave therapy on treatment of non-critical COVID-19 patients. METHODS: A total of 47 patients with COVID-19 who were treated in the People's Hospital of Hong'an County from Feb 2, 2020 to Feb 19, 2020 were enrolled in the study, the patients were given integrated Chinese and Western medicine therapies such as oxygen therapy, antiviral treatment, supportive treatment and Chinese patent medicine, and the millimeter wave therapy was applied to the acupoints twice a day. The respiratory function indexes such as oxygenation index and oxyhemoglobin saturation, chest CT, number of times of cough in a day and blood test indexes were collected after the millimeter wave treatment system was used for 1 day (T1), 3 days (T2), 10 days (T3) and 14 days (T4). RESULTS: The oxygenation index and blood oxygen saturation of the 47 patients were significantly higher at T2, T3 and T4 than at T1 after the integrated Chinese and Western medicine combined with millimeter wave therapy (P<0.05). There was significant difference in the percentage of the patients with grade 3 chest CT among all the time points except for T2 and T1 (P<0.05). There were significant differences in the number of times of cough and body temperature between the time points and T1 (P<0.05). The lactic dehydrogenase(LDH) level was slowly reduced, and there was significant difference between T4 and T1 (P<0.05). There were no significant differences in the white blood cell, lymphocyte, hemoglobin, potassium, sodium and chlorine at the admission. 4 patients were tested positive at T4, and the negative conversion ratio was 91.5%. CONCLUSION: The integrated Chinese and Western medicine combined with millimeter wave therapy can achieve remarkable effect on improvement of clinical symptoms of the COVID-19 patients such as oxygenation index and promote the nucleic acid to turn negative, and it has certain clinical application value.

Investigation on sleep and mental health of patients with Parkinson's disease during the Coronavirus disease 2019 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is adversely affecting sleep quality and mental health, especially in individuals with chronic disease such as Parkinson's disease (PD). METHODS: We conducted a quantitative study, which included 119 Chinese PD patients who had been treated in an outpatient neurology clinic in Wuhan and 169 age- and sex-matched healthy controls. The questionnaire survey focused on the impact of the COVID-19 pandemic on sleep, mental status, symptoms, and daily life and medical treatment of PD patients. RESULTS: Compared to healthy controls, PD patients had significantly higher scores in both the Pittsburgh Sleep Quality Index (PSQI) (8.13 vs 5.36, p < 0.001) and the Hospital Anxiety and Depression Scale (HADS) -Depression (4.89 vs 3.82, p = 0.022), as well as a higher prevalence of sleep disturbances with PSQI > 5 points (68.9% vs 44.4%, p < 0.001). Sleep disturbance was identified in 68.9% of PD patients. A logistic regression analysis showed that sleep disturbance of PD patients was independently associated with exacerbation of PD symptoms (OR = 3.616, 95%CI= (1.479, 8.844), p = 0.005) and anxiety (OR = 1.379, 95%CI= (1.157, 1.642), p < 0.001). Compared to male PD patients, female ones had higher PSQI scores (9.28 ± 4.41 vs 7.03 ± 4.01, p = 0.009) and anxiety (32.8% vs 0.1%, p = 0.002) and depression prevalence (34.5% vs 11.5%, p = 0.003). CONCLUSION: The findings of the present study emphasize the importance of mental and sleep health interventions in PD patients during the COVID-19 pandemic. Additional attention should be paid to the difficulty encountered by PD patients in seeking medical treatment.

COVID-19: Clinical aspects and therapeutics responses.

COVID-19 has created havoc in the world by causing thousands of demises in a short period of time. Up till now, several attempts have been made for potential therapeutics against SARS-COV2. In this retrospective, single-center study, we extracted data from 122 COVID-19, RT-PCR confirmed patients. who were treated with a new treatment strategy of lianhuaqingwen with Arbidol Hydrochloride. The patients were either asymptomatic or had mild symptoms for COVID-19 disease. Of 122 patients 21 (17.21%) patients developed severe conditions of COVID-19, while total 111 (90.9%) experienced mild symptoms such as fever in 93 (76.22%) patients, cough in 23 (20.17%) and muscle pain were observed in total 8 (7%) patients. Furthermore our newly applied drugs combination (Lianhuaqingwen and Arbidol Hydrochloride) showed therapeutic effects in 5-7 days in patients with mild symptoms with 98% recovery rate. These results indicate that COVID-19 patients with mild symptoms can be treated with Lianhuaqingwen and Arbidol Hydrochloride. However, extensive clinical investigations are required to confirm the effectiveness of these drugs.