Crystal structure of the CoV-Y domain of SARS-CoV-2 nonstructural protein 3.

Replication of the coronavirus genome starts with the formation of viral RNA-containing double-membrane vesicles (DMV) following viral entry into the host cell. The multi-domain nonstructural protein 3 (nsp3) is the largest protein encoded by the known coronavirus genome and serves as a central component of the viral replication and transcription machinery. Previous studies demonstrated that the highly-conserved C-terminal region of nsp3 is essential for subcellular membrane rearrangement, yet the underlying mechanisms remain elusive. Here we report the crystal structure of the CoV-Y domain, the most C-terminal domain of the SARS-CoV-2 nsp3, at 2.4 Å-resolution. CoV-Y adopts a previously uncharacterized V-shaped fold featuring three distinct subdomains. Sequence alignment and structure prediction suggest that this fold is likely shared by the CoV-Y domains from closely related nsp3 homologs. NMR-based fragment screening combined with molecular docking identifies surface cavities in CoV-Y for interaction with potential ligands and other nsps. These studies provide the first structural view on a complete nsp3 CoV-Y domain, and the molecular framework for understanding the architecture, assembly and function of the nsp3 C-terminal domains in coronavirus replication. Our work illuminates nsp3 as a potential target for therapeutic interventions to aid in the on-going battle against the COVID-19 pandemic and diseases caused by other coronaviruses.

Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models.

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of this manuscript's publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration. However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization. Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines. Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity. Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases.

Sigma-1 Receptors in Depression: Mechanism and Therapeutic Development.

Depression is the most common type of neuropsychiatric illness and has increasingly become a major cause of disability. Unfortunately, the recent global pandemic of COVID-19 has dramatically increased the incidence of depression and has significantly increased the burden of mental health care worldwide. Since full remission of the clinical symptoms of depression has not been achieved with current treatments, there is a constant need to discover new compounds that meet the major clinical needs. Recently, the roles of sigma receptors, especially the sigma-1 receptor subtype, have attracted increasing attention as potential new targets and target-specific drugs due to their translocation property that produces a broad spectrum of biological functions. Even clinical first-line antidepressants with or without affinity for sigma-1 receptors have different pharmacological profiles. Thus, the regulatory role of sigma-1 receptors might be useful in treating these central nervous system (CNS) diseases. In addition, long-term mental stress disrupts the homeostasis in the CNS. In this review, we discuss the topical literature concerning sigma-1 receptor antidepressant mechanism of action in the regulation of intracellular proteostasis, calcium homeostasis and especially the dynamic Excitatory/Inhibitory (E/I) balance in the brain. Furthermore, based on these discoveries, we discuss sigma-1 receptor ligands with respect to their promise as targets for fast-onset action drugs in treating depression.

Characteristics, sources and health risk assessment of atmospheric carbonyls during multiple ozone pollution episodes in urban Beijing: Insights into control strategies.

Carbonyls have attracted continuous attention due to their critical roles in atmospheric chemistry and their potential hazards to the ecological environment and human health. In this study, atmospheric carbonyls were measured during several ground-level-ozone (O3) pollution episodes at three urban sites (CRAES, IEP and BJUT) in Beijing in 2019 and 2020. Comparative analysis revealed that the carbonyl concentrations were 20.25 ± 6.91 ppb and 13.43 ± 5.13 ppb in 2019 and 2020 in Beijing, respectively, with a significant spatial trend from north to south, and carbonyl levels in urban Beijing were in an upper-intermediate range in China, and higher than those in other countries reported in the literature. A particularly noteworthy phenomenon is the consistency of carbonyl concentrations with variations in O3 concentrations. On O3 polluted days, the carbonyl concentrations were 1.3-1.5 times higher than those on non-O3 polluted days. Secondary formation contributed more to formaldehyde (FA) and acetaldehyde (AA) on O3 polluted days, while the anthropogenic emissions were more significant for acetone (AC) on non-O3 polluted days. Vehicle exhaust and solvent utilization were the main primary contributors to carbonyls. Due to reduced anthropogenic emissions caused by the COVID-19 lockdown and the "Program for Controlling Volatile Organic Compounds in 2020" in China, the contributions of primary emissions to carbonyls decreased in 2020 in Beijing. Human cancer risks to exposed populations from FA and AA increased with elevated O3 levels, and the risks still remained on non-O3 polluted days. The residents around the BJUT site might experience relatively higher human cancer risks than those around the other two sites. The findings in this study confirmed that atmospheric carbonyl pollution and its potential human health hazards cannot be ignored in urban Beijing; therefore, more strict control strategies for atmospheric carbonyls are urgently needed to better protect human health in Beijing in the future.

Hippo signaling pathway activation during SARS-CoV-2 infection contributes to host antiviral response.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, causes respiratory failure and damage to multiple organ systems. The emergence of viral variants poses a risk of vaccine failures and prolongation of the pandemic. However, our understanding of the molecular basis of SARS-CoV-2 infection and subsequent COVID-19 pathophysiology is limited. In this study, we have uncovered a critical role for the evolutionarily conserved Hippo signaling pathway in COVID-19 pathogenesis. Given the complexity of COVID-19-associated cell injury and immunopathogenesis processes, we investigated Hippo pathway dynamics in SARS-CoV-2 infection by utilizing COVID-19 lung samples and human cell models based on pluripotent stem cell-derived cardiomyocytes (PSC-CMs) and human primary lung air-liquid interface (ALI) cultures. SARS-CoV-2 infection caused activation of the Hippo signaling pathway in COVID-19 lung and in vitro cultures. Both parental and Delta variant of concern (VOC) strains induced Hippo pathway. The chemical inhibition and gene knockdown of upstream kinases MST1/2 and LATS1 resulted in significantly enhanced SARS-CoV-2 replication, indicating antiviral roles. Verteporfin, a pharmacological inhibitor of the Hippo pathway downstream transactivator, YAP, significantly reduced virus replication. These results delineate a direct antiviral role for Hippo signaling in SARS-CoV-2 infection and the potential for this pathway to be pharmacologically targeted to treat COVID-19.

Comprehensive Fragment Screening of the SARS‐CoV‐2 Proteome Explores Novel Chemical Space for Drug Development

SARS‐CoV‐2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti‐virals. Within the international Covid19‐NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR‐detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure‐based drug design against the SCoV2 proteome.

Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development.

SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome.

Effect of Exergame Training on Working Memory and Executive Function in Older Adults

Background: As the population ages, cognitive impairment and dementia have become one of the greatest health threats in older adults. Prior studies suggest that exergaming could improve cognitive function in older adults. To date, few long-term exergames intervention studies on older adults during the COVID-19 epidemic exist. This study aimed to investigate the effects of exergame on cognitive function in Chinese older adults, and to examine whether exergame was more effective than aerobic dancing for executive function and working memory. Methods: 55 participants (mean age = 65.4 ±3.7 years) were randomly assigned to an exergame training (ET) group, an aerobic dancing training (ADT) group, or a control (CON) group. The ET and ADT groups received 36 sessions (three 75-min training sessions per week, exercise intensity = 65 to 75% HRmax) during a 12-week period. The outcome measures for cognitive function included working memory measured by the N-back test, and executive function measured by the Stroop test. Results: The ET group showed a significantly positive effect in working memory, relative to the ADT (accuracy in 1-back test: ES = 0.76, p < 0.01), and CON group (accuracy in 1-back test: ES = 0.87, p = 0.02). Moreover, the performance in the Stroop test showed some improvements in executive function after intervention in the ET and ADT groups (Stroop intervention effect: ES = 0.38;p = 0.25). Conclusions: Exergame had a positive benefit in improving cognitive functions in older adults without cognitive impairment. Long-term exergame training could improve working memory in older adults. Exergame and aerobic dancing can efficiently improve inhibitory control of executive function in older adults. Maintaining an active lifestyle is protective of cognitive health in older adults.

Backbone and Ile, Leu, Val methyl group resonance assignment of CoV-Y domain of SARS-CoV-2 non-structural protein 3.

The worldwide COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonstructural protein 3 (nsp3) has 1945 residues and is the largest protein encoded by SARS-CoV-2. It comprises more than a dozen independent domains with various functions. Many of these domains were studied in the closely-related virus SARS-CoV following an earlier outbreak. Nonetheless structural and functional information on the C-terminal region of nsp3 containing two transmembrane and three extra-membrane domains remains incomplete. This part of the protein appears to be involved in initiation of double membrane vesicle (DMV) formation, membranous organelles the virus builds to hide its replication-transcription complex from host immune defenses. Here we present the near-complete backbone and Ile, Leu, and Val methyl group chemical shift assignments of the most C-terminal domain of nsp3, CoV-Y. As the exact function and binding partners of CoV-Y remain unknown, our data provide a basis for future NMR studies of protein-protein interactions to elucidate the molecular mechanism of DMV formation.

Evaluating the Disaster Risk of the COVID-19 Pandemic Using an Ecological Niche Model

Since 2019, the novel coronavirus has spread rapidly worldwide, greatly affecting social stability and human health. Pandemic prevention has become China’s primary task in responding to the transmission of COVID-19. Risk mapping and the proposal and implementation of epidemic prevention measures emphasize many research efforts. In this study, we collected location information for confirmed COVID-19 cases in Beijing, Shenyang, Dalian, and Shijiazhuang from 5 October 2020 to 5 January 2021, and selected 15 environmental variables to construct a model that comprehensively considered the parameters affecting the outbreak and spread of COVID-19 epidemics. Annual average temperature, catering, medical facilities, and other variables were processed using ArcGIS 10.3 and classified into three groups, including natural environmental variables, positive socio-environmental variables, and benign socio-environmental variables. We modeled the epidemic risk distribution for each area using the MaxEnt model based on the case occurrence data and environmental variables in four regions, and evaluated the key environmental variables influencing the epidemic distribution. The results showed that medium-risk zones were mainly distributed in Changping and Shunyi in Beijing, while Huanggu District in Shenyang and the southern part of Jinzhou District and the eastern part of Ganjingzi District in Dalian also represented areas at moderate risk of epidemics. For Shijiazhuang, Xinle, Gaocheng and other places were key COVID-19 epidemic spread areas. The jackknife assessment results revealed that positive socio-environmental variables are the most important factors affecting the outbreak and spread of COVID-19. The average contribution rate of the seafood market was 21.12%, and this contribution reached as high as 61.3% in Shenyang. The comprehensive analysis showed that improved seafood market management, strengthened crowd control and information recording, industry-catered specifications, and well-trained employees have become urgently needed prevention strategies in different regions. The comprehensive analysis indicated that the niche model could be used to classify the epidemic risk and propose prevention and control strategies when combined with the assessment results of the jackknife test, thus providing a theoretical basis and information support for suppressing the spread of COVID-19 epidemics.

One-year mortality and consequences of COVID-19 in cancer patients: A cohort study.

The 1-year mortality and health consequences of COVID-19 in cancer patients are relatively underexplored. In this multicenter cohort study, 166 COVID-19 patients with cancer were compared with 498 non-cancer COVID-19 patients and 498 non-COVID cancer patients. The 1-year all-cause mortality and hospital mortality rates in Cancer COVID-19 Cohort (30% and 20%) were significantly higher than those in COVID-19 Cohort (9% and 8%, both P < .001) and Cancer Cohort (16% and 2%, both P < 0.001). The 12-month all-cause post-discharge mortality rate in survival discharged Cancer COVID-19 Cohort (8%) was higher than that in COVID-19 Cohort (0.4%, P < .001) but similar to that in Cancer Cohort (15%, P = .084). The incidence of sequelae in Cancer COVID-19 Cohort (23%, 26/114) is similar to that in COVID-19 Cohort (30%, 130/432, P = .13). The 1-year all-cause mortality was high among patients with hematologic malignancies (59%), followed by those who have nasopharyngeal, brain, and skin tumors (45%), digestive system neoplasm (43%), and lung cancers (32%). The rate was moderate among patients with genitourinary (14%), female genital (13%), breast (11%), and thyroid tumors (0). COVID-19 patients with cancer showed a high rate of in-hospital mortality and 1-year all-cause mortality, but the 12-month all-cause post-discharge mortality rate in survival discharged cancer COVID-19 patients was similar to that in Cancer Cohort. Comparing to COVID-19 Cohort, risk stratification showed that hematologic, nasopharyngeal, brain, digestive system, and lung tumors were high risk (44% vs 9%, P < 0.001), while genitourinary, female genital, breast, and thyroid tumors had moderate risk (10% vs 9%, P = .85) in COVID-19 Cancer Cohort. Different tumor subtypes had different effects on COVID-19. But if cancer patients with COVID-19 manage to survive their COVID-19 infections, then long-term mortality appears to be similar to the cancer patients without COVID-19, and their long-term clinical sequelae were similar to the COVID-19 patients without cancer.