Targeting myeloid-derived suppressor cells promotes antiparasitic T-cell immunity and enhances the efficacy of PD-1 blockade (15 words).

Immune exhaustion corresponds to a loss of effector function of T cells that associates with cancer or chronic infection. Here, our objective was to decipher the mechanisms involved in the immune suppression of myeloid-derived suppressor cells (MDSCs) and to explore the potential to target these cells for immunotherapy to enhance checkpoint blockade efficacy in a chronic parasite infection. We demonstrated that programmed cell-death-1 (PD-1) expression was significantly upregulated and associated with T-cell dysfunction in advanced alveolar echinococcosis (AE) patients and in Echinococcus multilocularis-infected mice. PD-1 blockade ex vivo failed to reverse AE patients' peripheral blood T-cell dysfunction. PD-1/PD-L1 blockade or PD-1 deficiency had no significant effects on metacestode in mouse model. This was due to the inhibitory capacities of immunosuppressive granulocytic MDSCs (G-MDSCs), especially in the liver surrounding the parasite pseudotumor. MDSCs suppressed T-cell function in vitro in an indoleamine 2, 3 dioxygenase 1 (IDO1)-dependent manner. Although depleting MDSCs alone restored T-cell effector functions and led to some limitation of disease progression in E. multilocularis-infected mice, combination with PD-1 blockade was better to induce antiparasitic efficacy. Our findings provide preclinical evidence in support of targeting MDSC or combining such an approach with checkpoint blockade in patients with advanced AE. (200 words).

Immunological Characteristics of Hepatic Dendritic Cells in Patients and Mouse Model with Liver Echinococcus multilocularis Infection.

The cestode Echinococcus multilocularis, which mainly dwells in the liver, leads to a serious parasitic liver disease called alveolar echinococcosis (AE). Despite the increased attention drawn to the immunosuppressive microenvironment formed by hepatic AE tissue, the immunological characteristics of hepatic dendritic cells (DCs) in the AE liver microenvironment have not been fully elucidated. Here, we profiled the immunophenotypic characteristics of hepatic DC subsets in both clinical AE patients and a mouse model. Single-cell RNA sequencing (scRNA-Seq) analysis of four AE patient specimens revealed that greater DC numbers were present within perilesional liver tissues and that the distributions of cDC and pDC subsets in the liver and periphery were different. cDCs highly expressed the costimulatory molecule CD86, the immune checkpoint molecule CD244, LAG3, CTLA4, and the checkpoint ligand CD48, while pDCs expressed these genes at low frequencies. Flow cytometric analysis of hepatic DC subsets in an E. multilocularis infection mouse model demonstrated that the number of cDCs significantly increased after parasite infection, and a tolerogenic phenotype characterized by a decrease in CD40 and CD80 expression levels was observed at an early stage, whereas an activated phenotype characterized by an increase in CD86 expression levels was observed at a late stage. Moreover, the expression profiles of major immune checkpoint molecules (CD244 and LAG3) and ligands (CD48) on hepatic DC subsets in a mouse model exhibited the same pattern as those in AE patients. Notably, the cDC and pDC subsets in the E. multilocularis infection group exhibited higher expression levels of PD-L1 and CD155 than those in the control group, suggesting the potential of these subsets to impair T cell function. These findings may provide valuable information for investigating the role of hepatic DC subsets in the AE microenvironment and guiding DC targeting treatments for AE.

Platelet-derived microparticles and their cargos: The past, present and future.

All eukaryotic cells can secrete extracellular vesicles, which have a double-membrane structure and are important players in the intercellular communication involved in a variety of important biological processes. Platelets form platelet-derived microparticles (PMPs) in response to activation, injury, or apoptosis. This review introduces the origin, pathway, and biological functions of PMPs and their importance in physiological and pathological processes. In addition, we review the potential applications of PMPs in cancer, vascular homeostasis, thrombosis, inflammation, neural regeneration, biomarkers, and drug carriers to achieve targeted drug delivery. In addition, we comprehensively report on the origin, biological functions, and applications of PMPs. The clinical transformation, high heterogeneity, future development direction, and limitations of the current research on PMPs are also discussed in depth. Evidence has revealed that PMPs play an important role in cell-cell communication, providing clues for the development of PMPs as carriers for relevant cell-targeted drugs. The development history and prospects of PMPs and their cargos are explored in this guidebook.

Upregulation of LAG3 modulates the immune imbalance of CD4+ T-cell subsets and exacerbates disease progression in patients with alveolar echinococcosis and a mouse model.

Infection with the cestode Echinococcus multilocularis (E. multilocularis) causes alveolar echinococcosis (AE), a tumor-like disease predominantly affecting the liver but able to spread to any organ. T cells develop functional defects during chronic E. multilocularis infection, mostly due to upregulation of inhibitory receptors such as T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and programmed death-1 (PD-1). However, the role of lymphocyte activation gene-3 (LAG3), an inhibitory receptor, in AE infection remains to be determined. Here, we discovered that high expression of LAG3 was mainly found in CD4+ T cells and induced regulatory T cells (iTregs) in close liver tissue (CLT) from AE patients. In a mouse model of E. multilocularis infection, LAG3 expression was predominantly found in T helper 2 (Th2) and Treg subsets, which secreted significantly more IL-4 and IL-10, resulting in host immune tolerance and disease progression at a late stage. Furthermore, LAG3 deficiency was found to drive the development of effector memory CD4+ T cells and enhance the type 1 CD4+ T-cell immune response, thus inhibiting metacestode growth in vivo. In addition, CD4+ T cells from LAG3-deficient mice produced more IFN-γ and less IL-4 when stimulated by E. multilocularis protoscoleces (EmP) antigen in vitro. Finally, adoptive transfer experiments showed that LAG3-knockout (KO) CD4+ T cells were more likely to develop into Th1 cells and less likely to develop into Tregs in recipient mice. Our work reveals that high expression of LAG3 accelerates AE disease progression by modulating the immune imbalance of CD4+ T-cell subsets. These findings may provide a novel immunotherapeutic strategy against E. multilocularis infection.

Bone collision detection method for robot assisted fracture reduction based on vibration excitation.

BACKGROUND AND OBJECTIVE: In the process of robotic fracture reduction, there is a risk of unintended collision of broken bones, which is not conducive to ensuring the safety of the reduction system. In order to solve this problem, this paper proposed a vibration-based collision detection method for fracture reduction process. METHODS: Based on the two degree-of-freedom vibration response model, the factors affecting the respond of the vibration, including the excitation voltage, the clamping length at the proximal and distal ends, the mass and tensile force of the soft tissue, were obtained. The effects of these factors on the vibration transfer performance of broken bones and soft tissue were investigated by single factor experiments. RESULTS: The results showed that, in terms of peak value, the increase of excitation voltage would make the vibration amplitude increase linearly, and the increase of soft tissue mass and tension increased the vibration transmission capacity of soft tissue in the frequency range of 500-1000 Hz. In terms of peak frequency, the clamping length at the distal end had the greatest influence, which reached 74 Hz, followed by 45 Hz at the proximal end. While the influence of other factors was little. According to single factor experiments, the excitation frequency in the verification experiments was determined as 677 Hz. Under the vibration interference with the acceleration amplitude of 1.2 G, this method achieved correct detection. CONCLUSION: This research developed a broken bone collision detection method based on vibration excitation. The method can correctly detect the collision of broken bones with strong anti-interference ability. It is of great significance to improve the safety of fracture reduction process.

Echinococcus granulosus: The establishment of the metacestode in the liver is associated with control of the CD4+ T-cell-mediated immune response in patients with cystic echinococcosis and a mouse model.

The larval stage of the tapeworm Echinococcus granulosus sensu lato (E. granulosus s.l.) caused a chronic infection, known as cystic echinococcosis (CE), which is a worldwide public health problem. The human secondary CE is caused by the dissemination of protoscoleces (PSCs) when fertile cysts are accidentally ruptured, followed by development of PSCs into new metacestodes. The local immune mechanisms responsible for the establishment and established phases after infection with E. granulosus s.l. are not clear. Here, we showed that T cells were involved in the formation of the immune environment in the liver in CE patients and Echinococcus granulosus sensu strict (E. granulosus s.s.)-infected mice, with CD4+ T cells being the dominant immune cells; this process was closely associated with cyst viability and establishment. Local T2-type responses in the liver were permissive for early infection establishment by E. granulosus s.s. between 4 and 6 weeks in the experimental model. CD4+ T-cell deficiency promoted PSC development into cysts in the liver in E. granulosus s.s.-infected mice. In addition, CD4+ T-cell-mediated cellular immune responses and IL-10-producing CD8+ T cells play a critical role in the establishment phase of secondary E. granulosus s.s. PSC infection. These data contribute to the understanding of local immune responses to CE and the design of new therapies by restoring effective immune responses and blocking evasion mechanisms during the establishment phase of infection.