Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Objective To explore the effect of transcranial direct current stimulation(tDCS) with differ-ent stimulation models over primary motor cortex(M1) on motor skill acquisition after sports fatigue in basketball players. Methods Twenty-nine basketball players(9 females and 20 males;age:19.79±0.77 year;training experience:3.40±2.16 year) received the concurrent dual-site anodal tDCS over M1,anodal tDCS over left M1(cathodal tDCS over right M1) and sham stimulation session in a coun-terbalanced order,with an interval between two sessions no less than one week. The tDCS lasted 10 min at the intensity of 2 mA,while the sham was only given for the first 30 s. In each session,sports fatigue was induced by the maximal incremental cycling exercise protocol,followed by tDCS. Subsequently,the motor skill acquisition was evaluated using the serial reaction time task(SRTT) and basketball shooting accuracy test. Results In the basketball shooting accuracy test,the shooting accura-cy increased significantly after concurrent dual-site anodal tDCS over M1 compared with sham stimula-tion(P=0.010). For SRTT,the mean errors(block 2,3 and 7) of each block decreased significantly af-ter concurrent dual-site anodal tDCS over M1,in comparison with the sham stimulation(P values<0.05 for all). Conclusion Concurrent dual-site anodal tDCS over M1 can effectively improve motor skill ac-quisition after sports fatigue in basketball players.

Objective To explore the effect of transcranial direct current stimulation(tDCS) with differ-ent stimulation models over primary motor cortex(M1) on motor skill acquisition after sports fatigue in basketball players. Methods Twenty-nine basketball players(9 females and 20 males;age:19.79±0.77 year;training experience:3.40±2.16 year) received the concurrent dual-site anodal tDCS over M1,anodal tDCS over left M1(cathodal tDCS over right M1) and sham stimulation session in a coun-terbalanced order,with an interval between two sessions no less than one week. The tDCS lasted 10 min at the intensity of 2 mA,while the sham was only given for the first 30 s. In each session,sports fatigue was induced by the maximal incremental cycling exercise protocol,followed by tDCS. Subsequently,the motor skill acquisition was evaluated using the serial reaction time task(SRTT) and basketball shooting accuracy test. Results In the basketball shooting accuracy test,the shooting accura-cy increased significantly after concurrent dual-site anodal tDCS over M1 compared with sham stimula-tion(P=0.010). For SRTT,the mean errors(block 2,3 and 7) of each block decreased significantly af-ter concurrent dual-site anodal tDCS over M1,in comparison with the sham stimulation(P values<0.05 for all). Conclusion Concurrent dual-site anodal tDCS over M1 can effectively improve motor skill ac-quisition after sports fatigue in basketball players.