MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p47phox–oxidative stress pathway in neutrophils

Objectives Chronic-plus-binge ethanol feeding activates neutrophils and exacerbates liver injury in mice. This study investigates how recent excessive drinking affects peripheral neutrophils and liver injury in alcoholics, and how miR-223, one of the most abundant microRNAs (miRNAs) in neutrophils, modulates neutrophil function and liver injury in ethanol-fed mice. Designs Three hundred alcoholics with (n=140) or without (n=160) recent excessive drinking and 45 healthy controls were enrolled. Mice were fed an ethanol diet for 10 days followed by a single binge of ethanol. Results Compared with healthy controls or alcoholics without recent drinking, alcoholics with recent excessive drinking had higher levels of circulating neutrophils, which correlated with serum levels of alanine transaminase (ALT) and aspartate transaminase (AST). miRNA array analysis revealed that alcoholics had elevated serum miR-223 levels compared with healthy controls. In chronic-plus-binge ethanol feeding mouse model, the levels of miR-223 were increased in both serum and neutrophils. Genetic deletion of the miR-223 gene exacerbated ethanol-induced hepatic injury, neutrophil infiltration, reactive oxygen species (ROS) and upregulated hepatic expression of interleukin (IL)-6 and phagocytic oxidase (phox) p47phox. Mechanistic studies revealed that miR-223 directly inhibited IL-6 expression and subsequently inhibited p47phox expression in neutrophils. Deletion of the p47phox gene ameliorated ethanol-induced liver injury and ROS production by neutrophils. Finally, miR-223 expression was downregulated, while IL-6 and p47phox expression were upregulated in peripheral blood neutrophils from alcoholics compared with healthy controls. Conclusions miR-223 is an important regulator to block neutrophil infiltration in alcoholic liver disease and could be a novel therapeutic target for the treatment of this malady

Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice

ASXL1 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies, and its alterations are associated with poor prognosis. De novo ASXL1 mutations cause Bohring-Opitz syndrome characterized by multiple congenital malformations. We show that Asxl1 deletion in mice led to developmental abnormalities including dwarfism, anophthalmia, and 80% embryonic lethality. Surviving Asxl1(-/-) mice lived for up to 42 days and developed features of myelodysplastic syndrome (MDS), including dysplastic neutrophils and multiple lineage cytopenia. Asxl1(-/-) mice had a reduced hematopoietic stem cell (HSC) pool, and Asxl1(-/-) HSCs exhibited decreased hematopoietic repopulating capacity, with skewed cell differentiation favoring granulocytic lineage. Asxl1(+/-) mice also developed mild MDS-like disease, which could progress to MDS/myeloproliferative neoplasm, demonstrating a haploinsufficient effect of Asxl1 in the pathogenesis of myeloid malignancies. Asxl1 loss led to an increased apoptosis and mitosis in Lineage(-)c-Kit(+) (Lin(-)c-Kit(+)) cells, consistent with human MDS. Furthermore, Asxl1(-/-) Lin(-)c-Kit(+) cells exhibited decreased global levels of H3K27me3 and H3K4me3 and altered expression of genes regulating apoptosis (Bcl2, Bcl2l12, Bcl2l13). Collectively, we report a novel ASXL1 murine model that recapitulates human myeloid malignancies, implying that Asxl1 functions as a tumor suppressor to maintain hematopoietic cell homeostasis. Future work is necessary to clarify the contribution of microenvironment to the hematopoietic phenotypes observed in the constitutional Asxl1(-/-) mice

Prognosis for patients with apical hypertrophic cardiomyopathy: A multicenter cohort study based on propensity score matching

Background: Apical hypertrophic cardiomyopathy (AHCM) is a subtype of HCM, and few studies on the prognosis in AHCM are available.Aims: This study aimed to explore the clinical prognosis for AHCM and non-AHCM patients through clinical data based on propensity score matching (PSM) in a large cohort of Chinese HCM patients.Methods: The cohort study included 2268 HCM patients, 226 AHCM and 2042 non-AHCM patients from 13 tertiary hospitals, who were treated between 1996 and 2021. Fifteen demographic and clinical variables of 226 AHCM patients and 2042 non-AHCM patients were matched using 1:2 PSM. A Cox proportional hazard regression model was constructed to assess the effect of AHCM on mortality.Results: During a median follow-up of 5.1 (2.4–8.4) years, 353 (15.6%) of the 2268 HCM patients died, of whom 205 died due to cardiovascular mortality/cardiac transplantation and 94 experienced sudden cardiac death (SCD). In the matched cohort, the ACHM patients had lower rates of all-cause mortality (P = 0.003), cardiovascular mortality/cardiac transplantation (P = 0.03), and SCD (P = 0.02) than the non-AHCM patients. Furthermore, the Cox proportional hazard regression model showed that AHCM was an independent prognostic predictor of all-cause HCM mortality (P = 0.004) and a univariable prognostic predictor of cardiovascular mortality/cardiac transplantation (P = 0.03) and for SCD (P = 0.03). However, AHCM was not significant in multivariable Cox regression models in relation to cardiovascular mortality/cardiac transplantation and SCD.Conclusion: AHCM had a favorable prognosis both before and after matching, with lower all-cause mortality, cardiovascular mortality/cardiac transplantation, and SCD than non-AHCM

Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice

De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood mortality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss as well as conditional deletion in osteoblasts and their progenitors led to significant bone loss and a markedly decreased number of bone marrow stromal cells (BMSCs) compared with wild-type littermates. Asxl1(-/-) BMSCs displayed impaired self-renewal and skewed differentiation, away from osteoblasts and favoring adipocytes. RNA-sequencing analysis revealed altered expression of genes involved in cell proliferation, skeletal development, and morphogenesis. Furthermore, gene set enrichment analysis showed decreased expression of stem cell self-renewal gene signature, suggesting a role of Asxl1 in regulating the stemness of BMSCs. Importantly, re-introduction of Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1(-/-) BMSCs. Our study unveils a pivotal role of ASXL1 in the maintenance of BMSC functions and skeletal development

An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia

Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation

Environmental Settings and Harmful Algal Blooms in the Sea Area Adjacent to the Changjiang River Estuary

The characteristics of the environmental settings of the sea area adjacent to the Changjiang River estuary include complex currents and water masses, the diluted water plume and its redirection, upwelling, front, and nutrients and their sources. The Changjiang River estuary characteristics also include the phytoplankton community, which can affect the growth, migration, assembling, resting and competition of algae to form red tides in this area.. The features of red tide events recorded in this area in terms of time, location and causative species were analyzed, and the main findings on the red tides during the recent cruises in this area are also introduced.Nagasaki University Major Research Project: Restoration of Marine Environment and Resources in East Asi

Simulation analysis and effect evaluation of excavation and support of underground cavern group

According to the main construction procedures of underground caverns, an analysis model for the excavation of a certain pumping station underground cavern group was established, and its excavation and support process are dynamically simulated. The calculation schemes of unsupport and support are compared with indicators such as plastic zone, bolt axial force and displacement field distribution. The analysis results show that after the support, the plastic zone distribution and deformation characteristics of the rock around the cave are greatly improved. The bolt axial force also meets the requirements, indicating that the support parameters and support methods are reasonable. The supporting effect has been well simulated and realized