It is known that the study of the qualitative properties of a matrix A (which depend only on the sign pattern of A) can be turned into the study of the graph theoretical properties of the signed digraph S(A). The unde...It is known that the study of the qualitative properties of a matrix A (which depend only on the sign pattern of A) can be turned into the study of the graph theoretical properties of the signed digraph S(A). The underlying digraph of the signed digraph of a strong sign nonsingular matrix (abbreviated S NS matrix) with a negative main diagonal is called an S NS digraph. In the study of S NS digraphs, the minimal forbidden configuration (or MFC for short) plays an important role. Three (classes of) MFS's were constructed by Thomassen, Brualdi and Shader, and Shao. In this paper, we show that a digraph D is an S2NS digraph if and only if its 'cycle linear system' is solvable. This simplifies a parallel result obtained by Shao and Hu. As an application of the result, a graph theoretical characterization for a digraph to be an S NS digraph is given. At the end of the paper, we construct infinitely many new MFCs to show that for each even number k(k>0), there are basic MFCs with fc terminal components (here, with no loss of generality, we assume that the number of the initial components of a digraph is no less than that of its terminal components throughout the following).展开更多
Dengue viruses(DENV)have spread throughout the world and pose a huge threat to human life.The most widespread serotype is type 2 DENV(DENV 2),which has no specific treatment.NS2B-NS3 protease plays a pivotal role in D...Dengue viruses(DENV)have spread throughout the world and pose a huge threat to human life.The most widespread serotype is type 2 DENV(DENV 2),which has no specific treatment.NS2B-NS3 protease plays a pivotal role in DENV replication because of its function in cleavage of the viral polyprotein;thus,it is considered a promising target for antiviral discovery.In this study,we developed a high-throughput screening system based on the NS2B-NS3 protease to identify candidates from an FDA-approved drug library.Eltrombopag was screened out of 3273 drugs,and demonstrated inhibition on DENV 2 at the micromolar level in vitro,significantly reducing viral loads in the targeted organs of challenged mice following intraperitoneal injection.Further mechanistic analysis showed that eltrombopag allosterically binds to the DENV 2 NS2B-NS3 protease in a reversible,noncompetitive manner,therefore inhibiting DENV 2 at the post-infection stage.In addition,eltrombopag inhibited the NS2B-NS3 proteases of DENV 4 and Zika virus,suggesting its potential as a broadspectrum antiviral agent.This study repurposed eltrombopag as a promising antiviral agent against DENV,providing an alternative for antiviral development against flaviviruses.展开更多
基金Supported by the Doctoral Fund of the Xiamen University (No.Y01007).
文摘It is known that the study of the qualitative properties of a matrix A (which depend only on the sign pattern of A) can be turned into the study of the graph theoretical properties of the signed digraph S(A). The underlying digraph of the signed digraph of a strong sign nonsingular matrix (abbreviated S NS matrix) with a negative main diagonal is called an S NS digraph. In the study of S NS digraphs, the minimal forbidden configuration (or MFC for short) plays an important role. Three (classes of) MFS's were constructed by Thomassen, Brualdi and Shader, and Shao. In this paper, we show that a digraph D is an S2NS digraph if and only if its 'cycle linear system' is solvable. This simplifies a parallel result obtained by Shao and Hu. As an application of the result, a graph theoretical characterization for a digraph to be an S NS digraph is given. At the end of the paper, we construct infinitely many new MFCs to show that for each even number k(k>0), there are basic MFCs with fc terminal components (here, with no loss of generality, we assume that the number of the initial components of a digraph is no less than that of its terminal components throughout the following).
基金supported by the National Natural Science Foundation of China(Grant No.82130101)the Youth Innovation Promotion Association of CAS(Grant No.2021333).
文摘Dengue viruses(DENV)have spread throughout the world and pose a huge threat to human life.The most widespread serotype is type 2 DENV(DENV 2),which has no specific treatment.NS2B-NS3 protease plays a pivotal role in DENV replication because of its function in cleavage of the viral polyprotein;thus,it is considered a promising target for antiviral discovery.In this study,we developed a high-throughput screening system based on the NS2B-NS3 protease to identify candidates from an FDA-approved drug library.Eltrombopag was screened out of 3273 drugs,and demonstrated inhibition on DENV 2 at the micromolar level in vitro,significantly reducing viral loads in the targeted organs of challenged mice following intraperitoneal injection.Further mechanistic analysis showed that eltrombopag allosterically binds to the DENV 2 NS2B-NS3 protease in a reversible,noncompetitive manner,therefore inhibiting DENV 2 at the post-infection stage.In addition,eltrombopag inhibited the NS2B-NS3 proteases of DENV 4 and Zika virus,suggesting its potential as a broadspectrum antiviral agent.This study repurposed eltrombopag as a promising antiviral agent against DENV,providing an alternative for antiviral development against flaviviruses.
