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Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8+ T cells. The cardiac-specific protein α-myosin, which is absent from the thymus3,4, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8+ T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.

Fecal microbiota transplantation (FMT) is a therapy that involves the transplantation of healthy human fecal microorganisms into the gut of patients to rebuild or consolidate the intestinal microecology. It has been utilized in many diseases. However, FMT had a limited effect on patients with small intestinal diseases because of the unique ecological characteristics of the microorganisms. Thus, we proposed a new microecology transplantation therapy called human intestinal fluid transplantation (HIFT). Human intestinal fluid can be collected through a nasojejunal tube and be made into capsules using the freeze-dried powder method. In addition, strict standards for donor screening and management have been established. We are currently developing a high-standard HIFT preparation system and conducting high-quality clinical studies to validate the safety and efficacy of HIFT combined with FMT.

With the rapid increase in the urban traffic volume, the traffic capacity of existing bridges could not meet the demands of urban planning in many cities, leading to the problem of reconstruction or expansion. Considering the sustainability principle in bridge structure construction while minimizing the environmental implications of the construction activities, a multi-technique hybrid method for the widening and splicing of new and old beam bridges was proposed. Firstly, according to the stress equations of the splicing interface between the new and old bridges, the control condition for the selection of the splicing materials was found, and a selection method based on the maximum stress at the splicing interface of the materials was proposed. Then, based on the control condition of the foundation settlement of the new bridges, the geometric parameters of the splicing structures, and the mechanical parameters of the splicing materials, equations for the minimum reinforcement ratio were derived according to the allowable stress value of the splicing materials. Lastly, the equivalent analogic orthotropic plate model of the splicing bridges was built, and based on that, a calculation method for the quantity of the splicing diaphragms was proposed. Also, the effectiveness of the proposed method was validated through a reconstruction and expansion project in Guangdong Province. The results showed that the maximum foundation settlements of the new bridges were smaller than the assumption values of the calculation after reconstruction of the old bridges, and no observable cracks were found in the splicing structures. The proposed method could serve as a reference for similar structure designs. [ABSTRACT FROM AUTHOR]

In this article, an almost sure central limit theorem for non-stationary Markov chains on a general state space is established by using the techniques of shift operator and harmonic function. [ABSTRACT FROM AUTHOR]