Nuclear KRT19 is a transcriptional corepressor promoting histone deacetylation and liver tumorigenesis.

BACKGROUND AND AIMS: Epigenetic reprogramming and escape from terminal differentiation are poorly understood enabling characteristics of liver cancer. Keratin 19 (KRT19), classically known to form the intermediate filament cytoskeleton, is a marker of stemness and worse prognosis in liver cancer. This study aimed to address the functional roles of KRT19 in liver tumorigenesis and to elucidate the underlying mechanisms. APPROACH AND RESULTS: Using multiplexed genome editing of hepatocytes in vivo, we demonstrated that KRT19 promoted liver tumorigenesis in mice. Cell fractionation revealed a previously unrecognized nuclear fraction of KRT19. Tandem affinity purification identified histone deacetylase 1 and REST corepressor 1, components of the corepressor of RE-1 silencing transcription factor (CoREST) complex as KRT19-interacting proteins. KRT19 knockout markedly enhanced histone acetylation levels. Mechanistically, KRT19 promotes CoREST complex formation by enhancing histone deacetylase 1 and REST corepressor 1 interaction, thus increasing the deacetylase activity. ChIP-seq revealed hepatocyte-specific genes, such as hepatocyte nuclear factor 4 alpha ( HNF4A ), as direct targets of KRT19-CoREST. In addition, we identified forkhead box P4 as a direct activator of aberrant KRT19 expression in liver cancer. Furthermore, treatment of primary liver tumors and patient-derived xenografts in mice suggest that KRT19 expression has the potential to predict response to histone deacetylase 1 inhibitors especially in combination with lenvatinib. CONCLUSIONS: Our data show that nuclear KRT19 acts as a transcriptional corepressor through promoting the deacetylase activity of the CoREST complex, resulting in dedifferentiation of liver cancer. These findings reveal a previously unrecognized function of KRT19 in directly shaping the epigenetic landscape in cancer.

Transformer-Based Multi-Modal Data Fusion Method for COPD Classification and Physiological and Biochemical Indicators Identification.

As the number of modalities in biomedical data continues to increase, the significance of multi-modal data becomes evident in capturing complex relationships between biological processes, thereby complementing disease classification. However, the current multi-modal fusion methods for biomedical data require more effective exploitation of intra- and inter-modal interactions, and the application of powerful fusion methods to biomedical data is relatively rare. In this paper, we propose a novel multi-modal data fusion method that addresses these limitations. Our proposed method utilizes a graph neural network and a 3D convolutional network to identify intra-modal relationships. By doing so, we can extract meaningful features from each modality, preserving crucial information. To fuse information from different modalities, we employ the Low-rank Multi-modal Fusion method, which effectively integrates multiple modalities while reducing noise and redundancy. Additionally, our method incorporates the Cross-modal Transformer to automatically learn relationships between different modalities, facilitating enhanced information exchange and representation. We validate the effectiveness of our proposed method using lung CT imaging data and physiological and biochemical data obtained from patients diagnosed with Chronic Obstructive Pulmonary Disease (COPD). Our method demonstrates superior performance compared to various fusion methods and their variants in terms of disease classification accuracy.

Paeoniflorin alleviates lipopolysaccharide-induced disseminated intravascular coagulation by inhibiting inflammation and coagulation activation.

Lipopolysaccharide (LPS) is a toxic component of the outer membrane of gram-negative bacteria that can activate the blood coagulation system, leading to disseminated intravascular coagulation (DIC). DIC is a syndrome characterized by thromboembolism and multiple organ failure. Herein, the beneficial effect of paeoniflorin (PF) on the alleviation of LPS-induced DIC was investigated with an experimental DIC mouse model. Briefly, mice were randomly divided into the following six groups: (1) control; (2) LPS; (3) heparin; (4) low-PF treatment; (5) medium-PF treatment; and (6) high-PF treatment. The histological morphology of the liver and kidney was observed, and the coagulation indicators (such as prothrombin time), function indicators (such as alanine transferase), and inflammatory factors (such as TNF-α) were detected. Additionally, an in vitro cell inflammation model using RAW 264.7 murine macrophages was established. Activation of the nuclear factor kappa B (NF-κB) signaling pathway and tumor necrosis factor-α (TNF-α) were determined by western blotting. Based on our findings, PF could significantly improve the histological morphology of the liver and kidney, indicating that PF protects the liver and kidney against damage induced by LPS. Additionally, PF improved the function and coagulation indicators and reduced the production of inflammatory factors. In vitro, PF inhibited the expression of TNF-α by suppressing NF-κB signaling pathway activation. Collectively, our findings support the hypothesis that PF has anti-inflammatory and anticoagulation effects for the alleviation of LPS-induced DIC. PF is thus a potential co-treatment option for DIC.

Mesenchymal stem cells promote human melanocytes proliferation and resistance to apoptosis through PTEN pathway in vitiligo.

BACKGROUND: Vitiligo is an acquired chronic and recurrent skin disease that causes a depigmentation disorder, resulting in selective destruction of melanocytes (MC). However, the mechanism that leads to melanocyte dysfunction and death remains unclear. METHODS: We performed RNA sequencing, immunohistochemistry, and immunoblotting to characterize the patterns of phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway activation in vitiligo. We also cocultured primary melanocytes with mesenchymal stem cells (MSCs) in a Transwell system to explore how MSCs inhibit the PTEN/PI3K/AKT pathway in melanocytes. RESULTS: We identified that vitiligo normal-lesional junction skin presented with high expression of PTEN, which led to the inhibition of AKT phosphorylation (p-AKT) at S-473. Furthermore, PTEN overexpression led to oxidative stress-induced apoptosis in melanocytes. Coculturing with MSCs enhanced the cell proliferation of human melanocytes and repressed PTEN expression, which inhibited oxidative stress-induced apoptosis. CONCLUSION: We report that vitiligo patients present with high PTEN expression, which may play a role in the impairment of melanocytes. Furthermore, our study provides evidence that MSCs target the PTEN/PI3K/AKT pathway to regulate cell proliferation and apoptosis in human melanocytes, indicating that MSCs may serve as a promising therapy for vitiligo.

Clinical studies on event-related potentials (ERPs) N400 and the related factors in patients with poststroke depression (PSD).

OBJECTIVE: To evaluate event-related potentials (ERPs), N400, and the related factors in patients with poststroke depression (PSD). METHODS: Eighty-five stroke patients with depression, conforming to the diagnoses standard of Chinese Classification of Mental Diseases (3rd edition) (CCMD-3), were treated with fluoxetine hydrochloride for 3 months and another 85 stroke patients without depression were selected as the control group. The traits about N400 and blood platelet 5-HT concentrations of all patients were measured. RESULTS: There were significant differences between the incubation periods and average amplitudes of N400 in patients with PSD and those in patients without PSD (p < 0.01), while the blood platelet 5-HT concentrations of PSD patients were much lower than those of the patients without PSD (p < 0.01). For PSD patients, the N400 incubation periods were significantly shortened, averaged amplitudes were significantly increased (p < 0.01), and the blood platelet 5-HT concentrations were significantly raised after 3 months' treatment. CONCLUSIONS: For ERPs N400 in PSD patients, the incubation period is significantly prolonged and the average amplitude is reduced. Blood platelet 5-HT concentration may influence ERPs N400 in PSD patients. SIGNIFICANCE: N400 detections are helpful to the early diagnostic of PSD, and provide objective electrophysiology indexes for follow-up visits.