Programmed cell death protein-1 (PD-1) protects liver damage by suppressing IFN-γ expression in T cells in infants and neonatal mice.

BACKGROUND: Biliary atresia (BA) is a severe cholangiopathy possibly resulting from virus-induced and immune-mediated injury of the biliary system. IFN-γ, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death protein-1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. METHODS: Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. RESULTS: PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver (PD-1+CD4+T cells in liver vs. IFN-γ concentration, r = - 0.25, p = 0.05; PD-1+CD8+T cells in liver vs. IFN-γ concentration, r = - 0.39, p = 0.004). Blockade of PD-1 increased IFN-γ expression in CD4+ T and CD8+ T cells (RRV vs. anti-PD-1 treated RRV mice: 11.59 ± 3.43% vs. 21.26 ± 5.32% IFN-γ+ in hepatic CD4+T cells, p = 0.0003; 9.33 ± 4.03% vs. 22.55 ± 7.47% IFN-γ+ in hepatic CD8+T cells, p = 0.0001), suppressed bilirubin production (RRV vs. anti-PD-1 treated RRV mice: 285.4 ± 47.93 vs. 229.8 ± 45.86 µmol/L total bilirubin, p = 0.01) and exacerbated liver immunopathology. CONCLUSIONS: PD-1 plays a protective role in infants with BA by suppressing IFN-γ production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.

MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease.

Mitophagy is a major quality control pathway that removes unwanted or dysfunctional mitochondria and plays an essential role in vascular health. Here we show that MCM8 expression is significantly decreased in children with Kawasaki disease (KD) who developed coronary artery aneurysms. Mechanistically, we discovered that nitric oxide signaling promotes TRIM21-mediated MCM8 ubiquitination, which disrupts its interaction with MCM9 and promotes its cytosolic export. In the cytosol, MCM8 relocates to the mitochondria pore-forming proteins and promotes their ubiquitination by TRIM21. In addition, MCM8 directly recruits LC3 via its LC3-interacting region (LIR) motif and initiates mitophagy. This suppresses mitochondrial DNA-mediated activation of type I interferon via cGAS and STING. Mice that are deficient in Mcm8, Trim21 and Nos2 or reconstituted with the East-Asian-specific MCM8-P276 variant develop more severe coronary artery vasculopathy in the Lactobacillus casei extract-induced KD model. Collectively, the data suggest that MCM8 protects vascular health in the KD setting.

3D Heterostructure Constructed by Few-Layered MXenes with a MoS2 Layer as the Shielding Shell for Excellent Hybrid Capacitive Deionization and Enhanced Structural Stability.

Two-dimensional (2D) layered transition-metal carbides (MXenes) are attractive faradic materials for an efficient capacitive deionization (CDI) process owing to their high capacitance, excellent conductivity, and remarkable ion storage capacity. However, the easy restacking property and spontaneous oxidation in solution by the dissolved oxygen of MXenes greatly restrict their further application in the CDI domain. Herein, a three-dimensional (3D) heterostructure (MoS2@MXene) is rationally designed and constructed, integrating the collective advantages of MXene flakes and MoS2 nanosheets through the hydrothermal method. In such a design, the well-dispersed MXene flakes can effectively reduce the aggregation of MoS2 nanosheets, boost electrical conductivity, and provide efficient charge transfer paths. Furthermore, MoS2 nanosheets as the high-capacity interlayer spacer can prevent the self-restacking of MXene flakes and provide more active sites for ion intercalation. Meanwhile, the strong chemical interactions between MXene flakes and MoS2 nanosheets contribute to accelerating the charge transfer kinetics and enhancing structural stability. Consequently, the resulting MoS2@MXene heterostructure electrode possesses high specific capacitance (171.4 F g-1), fast charge transfer and permeation rate, abundant Na+ diffusion channels, and superior electrochemical stability. Moreover, the hybrid CDI cell (AC//MoS2@MXene) with AC as the anode and MoS2@MXene as the cathode delivers outstanding desalination capacity (35.6 mg g-1), rapid desalination rate (2.6 mg g-1 min-1), excellent charge efficiency (90.2%), and good cyclic stability (96% retention rate). Most importantly, the MoS2@MXene electrode can keep good structural integrity after the long-term repeated desalination process due to the effective shielding effect of the MoS2 layer to protect MXenes from being further oxidized. This work presents the flexible structural engineering to realize excellent ion transfer and storage process by constructing the 3D heterostructure.

Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.