On Low-Complexity Quickest Intervention of Mutated Diffusion Processes Through Local Approximation (preprint)

We consider the problem of controlling a mutated diffusion process with an unknown mutation time. The problem is formulated as the quickest intervention problem with the mutation modeled by a change-point, which is a generalization of the quickest change-point detection (QCD). Our goal is to intervene in the mutated process as soon as possible while maintaining a low intervention cost with optimally chosen intervention actions. This model and the proposed algorithms can be applied to pandemic prevention (such as Covid-19) or misinformation containment. We formulate the problem as a partially observed Markov decision process (POMDP) and convert it to an MDP through the belief state of the change-point. We first propose a grid approximation approach to calculate the optimal intervention policy, whose computational complexity could be very high when the number of grids is large. In order to reduce the computational complexity, we further propose a low-complexity threshold-based policy through the analysis of the first-order approximation of the value functions in the ``local intervention'' regime. Simulation results show the low-complexity algorithm has a similar performance as the grid approximation and both perform much better than the QCD-based algorithms.

Cell transcriptomic atlas of the non-human primate Macaca fascicularis.

Studying tissue composition and function in non-human primates (NHPs) is crucial to understand the nature of our own species. Here we present a large-scale cell transcriptomic atlas that encompasses over 1 million cells from 45 tissues of the adult NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a species phylogenetically close to humans. To demonstrate the utility of the atlas, we have reconstructed the cell-cell interaction networks that drive Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases, and intersected our data with human genetic disease orthologues to establish potential clinical associations. Our M. fascicularis cell atlas constitutes an essential reference for future studies in humans and NHPs.

High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors.

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 µmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

Linear epitopes of SARS-CoV-2 spike protein elicit neutralizing antibodies in COVID-19 patients (preprint)

SARS-CoV-2 outbreak is a world-wide pandemic. The Spike protein plays central role in cell entry of the virus, and triggers significant immuno-response. Our understanding of the immune-response against S protein is still very limited. Herein, we constructed a peptide microarray and analyzed 55 convalescent sera, three areas with rich linear epitopes were identified. Potent neutralizing antibodies enriched from sera by 3 peptides, which do not belong to RBD were revealed.