The senescence-associated secretome of Hedgehog-deficient hepatocytes drives MASLD progression.

The burden of senescent hepatocytes correlates with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms driving senescence and how it exacerbates MASLD are poorly understood. Hepatocytes experience lipotoxicity and become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine whether the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA-Seq analysis of liver samples from human and murine cohorts with MASLD confirmed that hepatocyte populations in MASLD livers were depleted of Smo+ cells and enriched with senescent cells. When fed a choline-deficient, amino acid-restricted high-fat diet (CDA-HFD) to induce MASLD, Smo- mice had lower antioxidant markers and developed worse DNA damage, senescence, steatohepatitis, and fibrosis than did Smo+ mice. Sera and hepatocyte-conditioned medium from Smo- mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo- hepatocytes with TP reduced senescence and lipotoxicity, whereas inhibiting TP in Smo+ hepatocytes had the opposite effect and exacerbated hepatocyte senescence, steatohepatitis, and fibrosis in CDA-HFD-fed mice. We conclude that inhibition of Hedgehog signaling in hepatocytes promoted MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence.

Osr1 Regulates Macrophage-mediated Liver Inflammation in Nonalcoholic Fatty Liver Disease Progression.

BACKGROUND & AIMS: Liver macrophage-mediated inflammation contributes to the pathogenesis of the nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Odd skipped-related 1 (Osr1) is a putative transcription factor previously reported to be involved in NASH progression; however, the underlying mechanisms remain unknown. The current study focused on the role of Osr1 in macrophage polarization and metabolism and its associated functions in the inflammation-induced pathogenesis of NASH. METHODS: OSR1/Osr1 expression patterns were compared in normal and NASH patients and mouse livers. NASH was established and compared between hepatocyte-specific Osr1 knockout (Osr1ΔHep), macrophage-specific Osr1 knockout (Osr1ΔMφ), and wild-type (Osr1F) mice fed with 3 different chronic obesogenic diets and methionine choline-deficient diet. Using genetic and therapeutic strategies in vitro and in vivo, the downstream targets of Osr1 and the associated mechanisms in inflammation-induced NASH were established. RESULTS: Osr1 was expressed in both hepatocytes and macrophages and exhibited different expression patterns in NASH. In NAFLD and NASH murine models, deleting Osr1 in myeloid cells (Osr1ΔMφ), but not hepatocytes, aggravated steatohepatitis with pronounced liver inflammation. Myeloid Osr1 deletion resulted in a polarization switch toward a pro-inflammatory phenotype associated with reduced oxidative phosphorylation activity. These inflamed Osr1ΔMφ macrophages promoted steatosis and inflammation in hepatocytes via cytokine secretion. We identified 2 downstream transcriptional targets of Osr1, c-Myc, and PPARγ and established the Osr1-PPARγ cascade in macrophage polarization and liver inflammation by genetic study and rosiglitazone treatment in vivo. We tested a promising intervention strategy targeting Osr1-PPARγ by AAV8L-delivered Osr1 expression or rosiglitazone that significantly repressed NAFLD/NASH progression in Osr1F and Osr1ΔMφ mice. CONCLUSIONS: Myeloid Osr1 mediates liver immune homeostasis and disrupting Osr1 aggravates the progression of NAFLD/NASH.

Revealing Personality Triggers for Media Vicarious Traumatization: A Fuzzy-Set Qualitative Comparative Analysis.

People may experience media vicarious traumatization due to frequent exposure to media coverage of disasters. Currently, the influential relationship between personality traits and media vicarious traumatization still lacks systematic and in-depth research. Based on the MU5735 airplane crash, this study explored the effects of configurations of personality traits on media vicarious traumatization by analyzing data from 331 Chinese university students (Mage = 22.63 years, SD = 2.67, range = 18 to 29, n = 186 male and n = 145 female) using Fuzzy-set Qualitative Comparative Analysis (fsQCA). The results revealed that five combinations of the Big Five personality traits could lead to media vicarious traumatization, the combinations of configurations are: (1) high conscientiousness, high agreeableness, and high neuroticism; (2) high conscientiousness, high extraversion, and high agreeableness; (3) high extraversion, high neuroticism, low conscientiousness, and low agreeableness; (4) high openness, high extraversion, high agreeableness, and high neuroticism; (5) high extraversion, high agreeableness, low openness, and low neuroticism. Furthermore, sociodemographic variables (gender, age, and education) interacted with personality traits and also resulted in different configurations of media vicarious traumatization. This study indicates the asymmetric relationships between personality traits and media vicarious traumatization, identifies the vulnerable groups to facilitate targeted trauma interventions for university students according to different configurations, and provides a reference for public psychological relief efforts in emergencies.

Circular RNA circHIPK3 is downregulated in diabetic cardiomyopathy and overexpression of circHIPK3 suppresses PTEN to protect cardiomyocytes from high glucose-induced cell apoptosis.

It has been reported that circHIPK3 can be downregulated by high glucose, suggesting its potential involvement in diabetes and diabetic complications. This study aimed to explore the role of circHIPK3 in diabetic cardiomyopathy (DC). PTEN is a kind of tumor suppressor gene, which is very commonly lost in human cancer. We detected the expression of circHIPK3 and PTEN in plasma samples from DC patients, diabetic patients without complications diabetes mellitus (DM) and health controls by RT-qPCR and ELISA. In vitro cell experiment, AC16 cells (cardiomyocytes) were treated with high glucose, followed by expression analysis of circHIPK3 and PTEN mRNA by RT-qPCR. CircHIPK3 or PTEN expression vector were used to overexpress circHIPK3 and PTEN in AC16 cells to explore the relationship between them. The role of circHIPK3 and PTEN in regulating the apoptosis of AC16 cells was analyzed by cell apoptosis assay. The result showed that CircHIPK3 was downregulated in diabetes and further downregulated in DC. In AC16 cells, high glucose treatment decreased the expression levels of circHIPK3. Across DC samples, the expression of circHIPK3 was inversely correlated with PTEN. In AC16 cells, overexpression of circHIPK3 decreased the expression levels of PTEN. CircHIPK3 may suppress AC16 cell apoptosis induced by high glucose and inhibited the role of PTEN in cell apoptosis. Therefore, circHIPK3 may downregulate PTEN to protect cardiomyocytes from high glucose-induced cell apoptosis.

General filtering method for electronic speckle pattern interferometry fringe images with various densities based on variational image decomposition.

Filtering off speckle noise from a fringe image is one of the key tasks in electronic speckle pattern interferometry (ESPI). In general, ESPI fringe images can be divided into three categories: low-density fringe images, high-density fringe images, and variable-density fringe images. In this paper, we first present a general filtering method based on variational image decomposition that can filter speckle noise for ESPI fringe images with various densities. In our method, a variable-density ESPI fringe image is decomposed into low-density fringes, high-density fringes, and noise. A low-density fringe image is decomposed into low-density fringes and noise. A high-density fringe image is decomposed into high-density fringes and noise. We give some suitable function spaces to describe low-density fringes, high-density fringes, and noise, respectively. Then we construct several models and numerical algorithms for ESPI fringe images with various densities. And we investigate the performance of these models via our extensive experiments. Finally, we compare our proposed models with the windowed Fourier transform method and coherence enhancing diffusion partial differential equation filter. These two methods may be the most effective filtering methods at present. Furthermore, we use the proposed method to filter a collection of the experimentally obtained ESPI fringe images with poor quality. The experimental results demonstrate the performance of our proposed method.

Structure of Zeste-DNA Complex Reveals a New Modality of DNA Recognition by Homeodomain-Like Proteins.

Drosophila Zeste is a DNA binding protein important for chromatin-targeted regulation of gene expression. It is best studied in the context of transvection-a mechanism of interallelic gene regulation involving paired chromosomes-and repression of the expression of white by Zeste mutants. Both of these functions depend on the DNA binding and self-association properties of Zeste, but the underlying structural basis remains unknown. Here we report the crystal structure of the DNA binding domain of Zeste in complex with a 19-bp DNA duplex containing the consensus recognition sequence motif. The structure reveals a helix-turn-helix Myb/homeodomain-like fold with the Zeste-specific insertion sequence forming a short helix and a long loop. Direct base contacts by the major groove binding helix principally account for the sequence-specific recognition, and backbone contacts via the Zeste-specific insertion are mainly responsible for the length requirement and the orientation of DNA. Our structural and biochemical characterizations of the DNA binding property of Zeste uncover an altered DNA binding modality of homeodomain-like proteins, and the structural information should facilitate the unraveling of the intricate mechanism of Zeste in regulation of gene expression.