SARS-CoV-2 NSP12 utilizes various host splicing factors for replication and splicing regulation (preprint)

Background The RNA-dependent RNA polymerase (RdRp) is a crucial element in the replication and transcription of RNA viruses. Although the RdRps of lethal human coronaviruses SARS-CoV-2, SARS-CoV, and MARS-CoV have been extensively studied, the molecular mechanism of the catalytic subunit NSP12, which is involved in pathogenesis, remains unclear. Results In this study, the biochemical and cell biological results demonstrate the interactions between SARS-CoV-2 NSP12 and seven host proteins, including three splicing factors (SLU7, PPIL3, and AKAP8), suggesting that the polymerase activity and stability of SARS-CoV-2 RdRp were affected by them to varying degrees. Furthermore, the entry efficacy of SARS-CoV-2 pseudovirus considerably decreased when SLU7 or PPIL3 was knocked out, indicating that abnormal splicing of the host genome was responsible for this occurrence. In addition, NSP12 and its homologues from SARS-CoV and MARS-CoV suppressed thealternative splicing (AS) of cellular genes, which were influenced by the three splicing factors. Conclusions Overall, our research illustrates that SARS-CoV-2 NSP12 can engage with various splicing factors, thereby impacting virus entry, replication, and gene splicing. This not only improves our understanding of how viruses cause diseases but also lays the foundation for the development of antiviral therapies.

Self-assembling short immunostimulatory duplex RNAs with broad-spectrum antiviral activity.

The current coronavirus disease 2019 (COVID-19) pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type III interferon (IFN-I and IFN-III). These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique sequence motif (sense strand, 5'-C; antisense strand, 3'-GGG) that mediates end-to-end dimer self-assembly. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases did not affect their ability to induce IFN. Unlike previously described immunostimulatory small interfering RNAs (siRNAs), their activity is independent of Toll-like receptor (TLR) 7/8, but requires the RIG-I/IRF3 pathway that induces a more restricted antiviral response with a lower proinflammatory signature compared with immunostimulant poly(I:C). Immune stimulation mediated by these duplex RNAs results in broad-spectrum inhibition of infections by many respiratory viruses with pandemic potential, including severe acute respiratory syndrome coronavirus (SARS-CoV)-2, SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus (HCoV)-NL63, and influenza A virus in cell lines, human lung chips that mimic organ-level lung pathophysiology, and a mouse SARS-CoV-2 infection model. These short double-stranded RNAs (dsRNAs) can be manufactured easily, and thus potentially could be harnessed to produce broad-spectrum antiviral therapeutics.

Analysis of response measures and effects of anti-cancer clinical trialon COVID-19 major public health emergency

At the beginning of 2020, with the outbreak of the nationspread coronavirus pneumonia (COVID-19), the national economy and people's lives have been deeply affected, as well as the clinical trial industry, which has brought unprecedented challenges to the management of research institutions and the implementation of clinical trial projects. This study analyzes the measures of chinese major research institutions in response to the requirements of the prevention and control of new coronavirus pneumonia. We select 76-day of 2020.01.23-2020.04.08 as time frame, to sum up the ongoing projects, treatment methods, followup medications, and loss of follow-ups of our research center, and aim to explore the feasibility of reducing the impact of clinical trials during the epidemic, as well as to accumulate experience for the remote execution of clinical trials in the future, and provide a reference for establishing relevant strategy for clinical trials under a special.

One-Year and Consequences of COVID-19 in Cancer Patients: a Cohort Study (preprint)

Background The study aim was to investigate one-year all-cause mortality and health consequences of cancer COVID-19 patients in China, stratified by primary tumor subtype.Methods In this multicenter cohort study, 166 cancer COVID-19 patients were studied along with 498 gender- and age-matched non-cancer COVID-19 patients in four hospitals in Wuhan, China, admitted 2020/01/01-2020/03/18, as well as with 498 parallel gender-, age-, and cancer subtype- matched non-COVID cancer patients hospitalized between 2019/01/01-2020/03/17. All patients were followed-up with a telephone survey to assess health consequences. Cox proportional hazards regression were used for risk analysis.Results In the three cohorts of median age of 65 ± 1 year and 49% male, the one-year all-cause mortality and hospital mortality rates of Cancer COVID-19 Cohort, 30% and 20% respectively, were significantly higher than COVID-19 Cohort (9% and 8%), and Cancer Cohort (16% and 2%). The 12-month all-cause post-discharge mortality rate of Cancer COVID-19 Cohort (11%) was higher than COVID-19 Cohort (0.4%), but similar to Cancer Cohort (15%). The high 1-year all-cause mortality was among hematologic malignancies (65%) and then nasopharyngeal, brain and skin tumors (45%), digestive system (43%), and lung (32%). the rate was low among genitourinary (14%), female genital (13%), breast (11%), and thyroid (0). As for patients having at least one symptom at the 1-year follow-up, Cancer COVID-19 Cohort (23%, 26/114) is similar to COVID-19 Cohort (30%, 130/432).Discussion Cancer COVID-19 patients showed a high rate of hospitalization mortality, but not after discharged, signifying the strong acute adverse effect of COVID-19 on cancer patients while little was in long-term effect. Risk stratification showed that hematologic malignancies, nasopharyngeal, brain, digestive system and lung tumors were high risk, while genitourinary, female genital, breast and thyroid were low risk which was similar to non-cancer COVID-19.Conclusions COVID-19 had little effect of 1-year mortality and sequelae for cancer survivors discharged from SARS-CoV-2 virus infection. Different tumor subtypes had different effect of COVID-19. COVID-19 patients with thyroid, breast, female genital, genitourinary tumor had low risk mortality which was similar to non-cancer patients.

Quarantine Vehicle Scheduling for Transferring High-Risk Individuals in Epidemic Areas.

In a large-scale epidemic outbreak, there can be many high-risk individuals to be transferred for medical isolation in epidemic areas. Typically, the individuals are scattered across different locations, and available quarantine vehicles are limited. Therefore, it is challenging to efficiently schedule the vehicles to transfer the individuals to isolated regions to control the spread of the epidemic. In this paper, we formulate such a quarantine vehicle scheduling problem for high-risk individual transfer, which is more difficult than most well-known vehicle routing problems. To efficiently solve this problem, we propose a hybrid algorithm based on the water wave optimization (WWO) metaheuristic and neighborhood search. The metaheuristic uses a small population to rapidly explore the solution space, and the neighborhood search uses a gradual strategy to improve the solution accuracy. Computational results demonstrate that the proposed algorithm significantly outperforms several existing algorithms and obtains high-quality solutions on real-world problem instances for high-risk individual transfer in Hangzhou, China, during the peak period of the novel coronavirus pneumonia (COVID-19).