Oxidized galectin-1 in SLE fails to bind the inhibitory receptor VSTM1 and increases reactive oxygen species levels in neutrophils

Inhibitory immune receptors set thresholds for immune cell activation,and their deficiency predisposes a person to autoimmune responses.However,the agonists of inhibitory immune receptors remain largely unknown,representing untapped sources of treatments for autoimmune diseases.Here,we show that V-set and transmembrane domain-containing 1(VSTM1)is an inhibitory receptor and that its binding by the competent ligand soluble galectin-1(Gal1)is essential for maintaining neutrophil viability mediated by downregulated reactive oxygen species production.However,in patients with systemic lupus erythematosus(SLE),circulating Gal1 is oxidized and cannot be recognized by VSTM1,leading to increased intracellular reactive oxygen species levels and reduced neutrophil viability.Dysregulated neutrophil function or death contributes significantly to the pathogenesis of SLE by providing danger molecules and autoantigens that drive the production of inflammatory cytokines and the activation of autoreactive lymphocytes.Interestingly,serum levels of glutathione,an antioxidant able to convert oxidized Gal1 to its reduced form,were negatively correlated with SLE disease activity.Taken together,our findings reveal failed inhibitory Gal1/VSTM1 pathway activation in patients with SLE and provide important insights for the development of effective targeted therapies.

Synchronization transition of a modular neural network containing subnetworks of different scales

Time delay and coupling strength are important factors that affect the synchronization of neural networks.In this study,a modular neural network containing subnetworks of different scales was constructed using the Hodgkin–Huxley(HH)neural model;i.e.,a small-scale random network was unidirectionally connected to a large-scale small-world network through chemical synapses.Time delays were found to induce multiple synchronization transitions in the network.An increase in coupling strength also promoted synchronization of the network when the time delay was an integer multiple of the firing period of a single neuron.Considering that time delays at different locations in a modular network may have different effects,we explored the influence of time delays within each subnetwork and between two subnetworks on the synchronization of modular networks.We found that when the subnetworks were well synchronized internally,an increase in the time delay within both subnetworks induced multiple synchronization transitions of their own.In addition,the synchronization state of the small-scale network affected the synchronization of the large-scale network.It was surprising to find that an increase in the time delay between the two subnetworks caused the synchronization factor of the modular network to vary periodically,but it had essentially no effect on the synchronization within the receiving subnetwork.By analyzing the phase difference between the two subnetworks,we found that the mechanism of the periodic variation of the synchronization factor of the modular network was the periodic variation of the phase difference.Finally,the generality of the results was demonstrated by investigating modular networks at different scales.

Regioselective umpolung addition of dicyanobenzene to α,β-unsaturated alkenes enabled by electrochemical reduction

An umpolung addition of dicyanobenzene toα,β-unsaturated alkenes has been developed using an elec-troreductive strategy.This electrochemical protocol is well compatible with a broad range of convention-ally challenging substrates,includingα,β-unsaturated esters,nitriles and trisubstituted enones.Moreover,good to excellent regioselectivities are observed in the reaction of cinnamates with dicyanobenzene.Synthetic utility of this electrochemical approach is further demonstrated by direct late-stage functionali-zation of(S)-verbenone and 16-dehydropregnenolone acetate.