Engineered Immunogens to Expose Conserved Epitopes Targeted by Broad Coronavirus Antibodies (preprint)

Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which can readily mutate to escape acquired immunity. Other regions in the spike S2 subunit, such as the fusion peptide and the stem helix, are highly conserved across sarbecoviruses and recognized by broadly reactive antibodies, providing hope that targeting these epitopes by vaccination could offer protection against both current and emergent viruses. Here we employed computational modeling to design epitope scaffolds that display the fusion peptide and the stem helix epitopes. The engineered proteins bound both mature and germline versions of multiple broad and protective human antibodies with high affinity. Binding specificity was confirmed both biochemically and via high resolution crystal structures. Finally, the epitope scaffolds showed potent engagement of antibodies and memory B-cells from subjects previously exposed to SARS-CoV2, illustrating their potential to elicit antibodies against the fusion peptide and the stem helix by vaccination.

Towards Exploring Large Molecular Space: An Efficient Chemical Genetic Algorithm

Generating molecules with desired properties is an important task in chemistry and pharmacy. An efficient method may have a positive impact on finding drugs to treat diseases like COVID-19. Data mining and artificial intelligence may be good ways to find an efficient method. Recently, both the generative models based on deep learning and the work based on genetic algorithms have made some progress in generating molecules and optimizing the molecule's properties. However, existing methods need to be improved in efficiency and performance. To solve these problems, we propose a method named the Chemical Genetic Algorithm for Large Molecular Space (CALM). Specifically, CALM employs a scalable and efficient molecular representation called molecular matrix. Then, we design corresponding crossover, mutation, and mask operators inspired by domain knowledge and previous studies. We apply our genetic algorithm to several tasks related to molecular property optimization and constraint molecular optimization. The results of these tasks show that our approach outperforms the other state-of-the-art deep learning and genetic algorithm methods, where the z tests performed on the results of several experiments show that our method is more than 99% likely to be significant. At the same time, based on the experimental results, we point out the insufficiency in the experimental evaluation standard which affects the fair evaluation of previous work. Supplementary Information The online version contains supplementary material available at 10.1007/s11390-021-0970-3.

Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV-2 and Exhibits Broad-Spectrum Antiviral Activity.

There is a pressing need for host-directed therapeutics that elicit broad-spectrum antiviral activities to potentially address current and future viral pandemics. Apratoxin S4 (Apra S4) is a potent Sec61 inhibitor that prevents cotranslational translocation of secretory proteins into the endoplasmic reticulum (ER), leading to anticancer and antiangiogenic activity both in vitro and in vivo. Since Sec61 has been shown to be an essential host factor for viral proteostasis, we tested Apra S4 in cellular models of viral infection, including SARS-CoV-2, influenza A virus, and flaviviruses (Zika, West Nile, and Dengue virus). Apra S4 inhibited viral replication in a concentration-dependent manner and had high potency particularly against SARS-CoV-2 and influenza A virus, with subnanomolar activity in human cells. Characterization studies focused on SARS-CoV-2 revealed that Apra S4 impacted a post-entry stage of the viral life-cycle. Transmission electron microscopy revealed that Apra S4 blocked formation of stacked double-membrane vesicles, the sites of viral replication. Apra S4 reduced dsRNA formation and prevented viral protein production and trafficking of secretory proteins, especially the spike protein. Given the potent and broad-spectrum activity of Apra S4, further preclinical evaluation of Apra S4 and other Sec61 inhibitors as antivirals is warranted.

Positioning a Handshake Bay for Twin Stacking Cranes in an Automated Container Terminal Yard Block

At automated container terminals (ACTs), twin automated stacking cranes (ASCs) can carry out the tasks—store and retrieve containers simultaneously in a yard block using a handshake bay, where a primary ASC stacks the container at the handshake bay and the other crane carries it to the destination bay. Although the handshake bay increases the degree of crane utilization, the ASCs will interfere with each other at the bay, decreasing the stacking efficiency. This study formulates a mixed-integer linear program (MILP) to position the handshake bay and simultaneously schedule the twin ASCs to minimize the tasks’ makespan. The proposed formulation considers the safe time interval to avoid crane collisions during adjacent crane movements. To solve the model, we developed a random-key genetic algorithm with a priority-based decoding scheme to optimize the task sequences and tasks assigned to the cranes. The priority-based GA can always generate feasible solutions by ranking the container-handling tasks. Numerical experiments prove that the safe temporal interval affects the makespan and the handshake bay’s position. An optimal handshake bay reduces 35% of the makespan compared with a nonoptimal bay, and the proposed algorithm is competitive compared with the on-the-shelf MILP solver and can solve medium- and large-scale instances in short computing time with gaps lower than 5% compared with ideal solutions.

Clinical characteristics and outcomes of hepatitis B virus carriers infected with COVID-19 at the Jinyintan hospital in WuHan, China (preprint)

Background: Coronavirus 2019 (COVID-19) is a novel infectious disease that was earliest reported in Wuhan, China, but has been later discovered everywhere in the world. On the other hand, Hepatitis B virus (HBV) is ubiquitous in China; having millions of HBV carriers, HBV infection has become a major problem of public health in China. In this study, we aim to describe the clinical features of HBV carriers infected with COVID-19 and to assess factors that may affect the progression and outcome of the disease.Methods: 72 patients diagnosed as infected with both COVID-19 and HBV at the Jinyintan Hospital of Wuhan have been involved in this study. Epidemiological characteristics, demographic features, clinical manifestations, laboratory test, treatment, management and final outcomes of these patients were collected and analyzed.Results: Among all 72 patients (40 male and 32 female, with a median age of 58.5 years old), 22 (30.56%) were diagnosed as severe cases and 50 (69.44%) non-severe cases. Fever is the most common symptom, followed by cough, chest tightness and sputum. Significant differences have been observed in the outcomes of laboratory tests including hematologic, biochemical, infection and coagulation parameters, and in indicators like Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Total Bilirubin (TBil), Direct Bilirubin (DBil), Indirect Bilirubin (IBil) and γ-glutamyl Transferase (GGT) at the admission and discharge of these patients. Especially, levels of Prealbumin (PA) and Serum Amyloid A (SAA) showed an obvious trend of decreasing, which is statistically significant.Conclusions: The clinical features of HBV carriers infected with COVID-19 have obvious systemic symptoms, such as fever, cough, and chest tightness. By comparing their liver functions tested on the dates of admission and discharge, we found that the SARS-CoV-2 virus, which causes COVID-19, does not directly activate the Hepatitis B virus, so that the risk of liver cell damage for HBV carriers infected with COVID-19 does not increase. Both PA and SAA seem to work as sensitive indicators and can be used to evaluate the prognosis and outcome of these patients.