Liver-derived extracellular vesicles from patients with hepatitis B virus-related acute-on-chronic liver failure impair hepatic regeneration by inhibiting on FGFR2 signaling via miR-218-5p.

BACKGROUND: Impaired liver regeneration in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients is closely related to prognosis; however, the mechanisms are not yet defined. Liver-derived extracellular vesicles (EVs) may be involved in the dysregulation of liver regeneration. Clarifying the underlying mechanisms will improve the treatments for HBV-ACLF. METHODS: EVs were isolated by ultracentrifugation from liver tissues of HBV-ACLF patients (ACLF_EVs) after liver transplantation, and their function was investigated in acute liver injury (ALI) mice and AML12 cells. Differentially expressed miRNAs (DE-miRNAs) were screened by deep miRNA sequencing. The lipid nanoparticle (LNP) system was applied as a carrier for the targeted delivery of miRNA inhibitors to improve its effect on liver regeneration. RESULTS: ACLF_EVs inhibited hepatocyte proliferation and liver regeneration, with a critical role of miR-218-5p. Mechanistically, ACLF_EVs fused directly with target hepatocytes and transferred miR-218-5p into hepatocytes, acting by suppressing FGFR2 mRNA and inhibiting the activation of ERK1/2 signaling pathway. Reducing the level of miR-218-5p expression in the liver of ACLF mice partially restored liver regeneration ability. CONCLUSION: The current data reveal the mechanism underlying impaired liver regeneration in HBV-ACLF that promotes the discovery of new therapeutic approaches.

Efficacy of Matrine, Rotenone, and Pyrethrin Against Red Imported Fire Ant Solenopsis invicta (Hymenoptera: Formicidae) and Their Impact on Aquatic Organisms.

Chemicals, including toxic bait and dusts, are the main means of controlling the red imported fire ant Solenopsis invicta (abbreviation 'RIFA'), which is a serious invasive pest. To identify environmentally friendly chemicals for controlling RIFA, we tested the toxicity and horizontal transfer of three botanical insecticides-matrine, rotenone, and pyrethrin-and their impact on aquatic organisms (i.e., three fish and one shrimp). The LD50 value of matrine, rotenone, and pyrethrin was 0.24, 50.929, and 13.590 ng/ant, respectively. Matrine, rotenone, and pyrethrin had effective horizontal transfer and caused significant secondary mortality. After exposure to donor workers, 90.75%, 90.75%, and 100% of recipient workers in the 0.025% matrine, 1.0% rotenone, and 0.3% pyrethrin dust treatments, respectively, died within 48 h. Furthermore, 0.025% matrine dust caused significant tertiary mortality (49.5%). Tertiary mortality caused by 1.0% rotenone and 0.3% pyrethrin dusts was very low, only 7.75% and 18.5%, respectively. In a field trial, the comprehensive mortality effect of 0.05% matrine, 1.50% rotenone, and 0.375% pyrethrin dust was 74.96%, 30.10%, and 29.27%, respectively, after 14 d of treatment. Matrine had low toxicity to the fish Hypophthalmichthys molitrix, and 37.5 mg/L pyrethrin had low toxicity to the fish Cirrhinus molitorella, H. molitrix, and Oreochromis niloticus. However, rotenone was highly toxic to all three fish. The shrimp Neocaridina denticulate was not sensitive to matrine, rotenone, or pyrethrin. Matrine dust has highly effective horizontal transfer, and 0.05% matrine dust has great potential for managing RIFA in organic farms, aquaculture farms of H. molitrix, and water resource regions.

Multi-region sequencing with spatial information enables accurate heterogeneity estimation and risk stratification in liver cancer.

BACKGROUND: Numerous studies have used multi-region sampling approaches to characterize intra-tumor heterogeneity (ITH) in hepatocellular carcinoma (HCC). However, conventional multi-region sampling strategies do not preserve the spatial details of samples, and thus, the potential influences of spatial distribution on patient-wise ITH (represents the overall heterogeneity level of the tumor in a given patient) have long been overlooked. Furthermore, gene-wise transcriptional ITH (represents the expression pattern of genes across different intra-tumor regions) in HCC is also under-explored, highlighting the need for a comprehensive investigation. METHODS: To address the problem of spatial information loss, we propose a simple and easy-to-implement strategy called spatial localization sampling (SLS). We performed multi-region sampling and sequencing on 14 patients with HCC, collecting a total of 75 tumor samples with spatial information and molecular data. Normalized diversity score and integrated heterogeneity score (IHS) were then developed to measure patient-wise and gene-wise ITH, respectively. RESULTS: A significant correlation between spatial and molecular heterogeneity was uncovered, implying that spatial distribution of sampling sites did influence ITH estimation in HCC. We demonstrated that the normalized diversity score had the ability to overcome sampling location bias and provide a more accurate estimation of patient-wise ITH. According to this metric, HCC tumors could be divided into two classes (low-ITH and high-ITH tumors) with significant differences in multiple biological properties. Through IHS analysis, we revealed a highly heterogenous immune microenvironment in HCC and identified some low-ITH checkpoint genes with immunotherapeutic potential. We also constructed a low-heterogeneity risk stratification (LHRS) signature based on the IHS results which could accurately predict the survival outcome of patients with HCC on a single tumor biopsy sample. CONCLUSIONS: This study provides new insights into the complex phenotypes of HCC and may serve as a guide for future studies in this field.