INO80-Dependent Remodeling of Transcriptional Regulatory Network Underlies the Progression of Heart Failure.

BACKGROUND: Progressive remodeling of cardiac gene expression underlies decline in cardiac function, eventually leading to heart failure. However, the major determinants of transcriptional network switching from normal to failed hearts remain to be determined. METHODS: In this study, we integrated human samples, genetic mouse models, and genomic approaches, including bulk RNA sequencing, single-cell RNA sequencing, chromatin immunoprecipitation followed by high-throughput sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing, to identify the role of chromatin remodeling complex INO80 in heart homeostasis and dysfunction. RESULTS: The INO80 chromatin remodeling complex was abundantly expressed in mature cardiomyocytes, and its expression further increased in mouse and human heart failure. Cardiomyocyte-specific overexpression of Ino80, its core catalytic subunit, induced heart failure within 4 days. Combining RNA sequencing, chromatin immunoprecipitation followed by high-throughput sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing, we revealed INO80 overexpression-dependent reshaping of the nucleosomal landscape that remodeled a core set of transcription factors, most notably the MEF2 (Myocyte Enhancer Factor 2) family, whose target genes were closely associated with cardiac function. Conditional cardiomyocyte-specific deletion of Ino80 in an established mouse model of heart failure demonstrated remarkable preservation of cardiac function. CONCLUSIONS: In summary, our findings shed light on the INO80-dependent remodeling of the chromatin landscape and transcriptional networks as a major mechanism underlying cardiac dysfunction in heart failure, and suggest INO80 as a potential preventative or interventional target.

Effects of different soil and water conservation measures on plant diversity and productivity in Loess Plateau.

Many soil and water conservation measures (SWCM) have been implemented in the Loess Plateau of China, and they have an impact on ecosystems all levels and involve complicated mechanisms. Previously, studies typically focused on a single factor's effect on diversity or productivity. With this background, the current investigation embarked on an extensive study, with vegetation survey conducted in the no measure plots (NM), vegetation measure plots (VM) and engineering measure plots (EM) in the Loess Plateau of China. We used structural equation models (SEM) to explain the mechanism by which SWCM affects plant productivity and diversity. VM have direct effects on plant diversity, and EM have direct effects on soil properties and community structure. The two measures also had indirect effects on plant functional traits and community structure. The results show that the changes in plant functional traits and community structure by SWCM decreased plant diversity, whereas the increase of productivity was primarily dominated by improvements in community structure, and we conclude that variability in plant diversity and productivity across different measures on the Loess Plateau was primarily due to the responses of different plants to variable soil properties and the community responses. It was also emphasized that vegetation measures were beneficial to the increase of biomass per plant, while engineering measures were more beneficial to the growth of dominant species. These findings provide a theoretical foundation for vegetation management and restoration after the application of different SWCM.

Positive correlation between VCA-IgM and Th1/Th2 immunocytokines in children with infectious mononucleosis.

OBJECTIVE: To analyze the correlation between immunoglobulin M (IgM) against viral capsid antigen (VCA) of Epstein-Barr virus (EBV) and T helper 1 and 2 (Th1/Th2) immunocytokines (ICKs) in children with infectious mononucleosis (IM). METHODS: This is a retrospective study. A total of 40 children with IM treated in our hospital from August 2019 to August 2021 were included in the research group, and another 42 children with upper respiratory tract infection treated during the same period were selected as the control group. The VCA-IgM positive (+) rate and Th1/Th2 ICKs in two groups were detected, and the correlation of VCA-IgM with Th1/Th2 ICKs in IM patients was analyzed. RESULTS: The research group was found to have an evidently higher VCA-IgM+ rate than the control group. Moreover, the accuracy of VCA-IgM in detecting IM was as high as 91.46%. In addition, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-6 and IL-10 presented markedly elevated levels in the research group than in the control group, and in VCA-IgM negative (-) patients compared with VCA-IgM+ patients. There was a positive connection between VCA-IgM and Th1/Th2 ICKs. CONCLUSIONS: IM children showed high VCA-IgM+ rate and imbalance of Th1/Th2 ICKs, and their VCA-IgM and Th1/Th2 ICKs are positively correlated. In addition, VCA-IgM has certain diagnostic value for IM.

CD19/CD22 Dual-Targeted CAR T-cell Therapy for Relapsed/Refractory Aggressive B-cell Lymphoma: A Safety and Efficacy Study.

Chimeric antigen receptor (CAR) T-cell therapies that target either CD19 or CD22 alone have potent antilymphoma effects. However, antigen escape-mediated relapse often occurs. CAR T cells targeting both CD19 and CD22 may overcome this limitation. In this study, we developed bispecific CAR T cells simultaneously recognizing CD19- and CD22-expressing targets and assessed their safety and efficacy profiles in patients with relapsed/refractory aggressive B-cell lymphoma. Twenty-four patients were screened, and 16 were found eligible for the study. CAR T-cell-associated toxicities were recorded. Responses, overall survival (OS), and progression-free survival (PFS) were assessed. Of the 16 eligible patients, 14 (87.5%) achieved objective response and 10 (62.5%) achieved complete response (CR). The 2-year OS and PFS rates were 77.3% and 40.2%, respectively. Achieving CR (P = 0.046) and the number of prior chemotherapy lines (n = 2; P = 0.047) were independent prognostic factors associated with favorable PFS. The 2-year OS and PFS among patients who achieved CR were higher than among those who did not (P = 0.015 and P < 0.001, respectively). The 2-year PFS among patients who received two prior lines of chemotherapy was higher than that among patients who received more than two lines of chemotherapy (P = 0.049); OS did not differ between the groups. Severe grade 4 cytokine-release syndrome (CRS) was observed in 1 patient; 4 and 11 patients had grades 1 and 2 CRS, respectively. No patients developed neurotoxicity. CD19/CD22 dual-targeted CAR T cells may be a safe, potent antilymphoma cell-based targeted immunotherapy.

Incidence and Risk Factors Associated with Infection after Chimeric Antigen Receptor T Cell Therapy for Relapsed/Refractory B-cell Malignancies.

Chimeric antigen receptor T cells (CAR-Ts) constitute a novel therapeutic strategy for relapsed/refractory B-cell malignancies. With the extensive application of CAR-T therapy in clinical settings, CAR-T-associated toxicities have become increasingly apparent. However, information regarding the associated infections is limited. We aimed to evaluate the incidence of infection during CAR-T therapy and identify the potential risk factors. Especially, we evaluated infections and the associated risk factors in 92 patients. The cohort included patients with acute lymphoblastic leukemia (n = 58) and non-Hodgkin lymphoma (n = 34). Fifteen cases of infection (predominantly bacterial) were observed within 28 days of CAR-T therapy, with an infection density of 0.5 infections for every 100 days-at-risk. Neutropenia before CAR-T therapy (P = .005) and prior infection (P = .046) were independent risk factors associated with infection within 28 days after CAR-T therapy; corticosteroid treatment during cytokine release syndrome (P = .013) was an independent risk factor during days 29-180 after CAR-T infusions. Moreover, the 2-year survival duration was significantly shorter in patients with infections than in those without (126 vs 409 days; P = .006). Our results suggested that effective anti-infection therapies may improve prognosis of patients who have a high infection risk. The risk of bacterial infections during the early stages of CAR-T therapy and the subsequent risk of viral infections thereafter should be considered to provide the appropriate treatment and improve patient prognosis.

Tubeimoside I Protects Dopaminergic Neurons Against Inflammation-Mediated Damage in Lipopolysaccharide (LPS)-Evoked Model of Parkinson's Disease in Rats.

Parkinson's disease (PD), a frequent degenerative disease in the elderly, is characterized by dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc). Neuroinflammation caused by over-activated microglia plays a crucial role in the pathogenesis of PD. Tubeimoside I (TBMS1) has a broad anti-inflammatory effect in peripheral tissues, but the effect on neuroinflammation has not been reported. Therefore, we explored whether TBMS1 could protect dopaminergic neurons by inhibiting the activation of microglia in lipopolysaccharide (LPS)-induced PD rat model. In addition, then, the effect and mechanism of TBMS1 on neuroinflammation were assessed in LPS-exposed murine microglial BV-2 cells. The results in vivo showed that TBMS1 suppressed microglial activation and dopaminergic neurons' reduction in LPS-injected PD rat model. In vitro study found that TBMS1 could inhibit LPS-induced inflammatory responses in BV-2 cells, and this effect was mediated by suppressing the phosphorylation of protein kinase B (AKT), nuclear factor-kappa B (NF-κB p65), p38 and extracellular regulated protein kinases (ERK1/2). Taken together, these results demonstrated for the first time that TBMS1 played a role in protecting dopaminergic neurons by inhibiting neuroinflammation mediated by microglia.