BRG1 promotes progression of B-cell acute lymphoblastic leukemia by disrupting PPP2R1A transcription.

Despite advancements in chemotherapy and the availability of novel therapies, the outcome of adult patients with B-cell acute lymphoblastic leukemia (B-ALL) remains unsatisfactory. Therefore, it is necessary to understand the molecular mechanisms underlying the progression of B-ALL. Brahma-related gene 1 (BRG1) is a poor prognostic factor for multiple cancers. Here, the expression of BRG1 was found to be higher in patients with B-ALL, irrespective of the molecular subtype, than in healthy individuals, and its overexpression was associated with a poor prognosis. Upregulation of BRG1 accelerated cell cycle progression into the S phase, resulting in increased cell proliferation, whereas its downregulation facilitated the apoptosis of B-ALL cells. Mechanistically, BRG1 occupies the transcriptional activation site of PPP2R1A, thereby inhibiting its expression and activating the PI3K/AKT signaling pathway to regulate the proto-oncogenes c-Myc and BCL-2. Consistently, silencing of BRG1 and administration of PFI-3 (a specific inhibitor targeting BRG1) significantly inhibited the progression of leukemia and effectively prolonged survival in cell-derived xenograft mouse models of B-ALL. Altogether, this study demonstrates that BRG1-induced overactivation of the PPP2R1A/PI3K/AKT signaling pathway plays an important role in promoting the progression of B-ALL. Therefore, targeting BRG1 represents a promising strategy for the treatment of B-ALL in adults.

Clinical phenotypes and outcomes of patients with left ventricular thrombus: an unsupervised cluster analysis.

BACKGROUND: Left ventricular thrombus (LVT) can develop in a diverse group of patients with various underlying causes, resulting in divergent natural histories and trajectories with treatment. Our aim was to use cluster analysis to identify unique clinical profiles among patients with LVT and then compare their clinical characteristics, treatment strategies, and outcomes. METHODS: We conducted a retrospective study involving 472 patients with LVT whose data were extracted from a tertiary center's echocardiography database, from March 2011 to January 2021. We used the TwoStep cluster analysis method, examining 19 variables. RESULTS: Our analysis of the 472 patients with LVT revealed two distinct patient clusters. Cluster 1, comprising 247 individuals (52.3%), was characterized by younger patients with a lower incidence of traditional cardiovascular risk factors and relatively fewer comorbidities compared with Cluster 2. Most patients had LVT attributed to an underlying ischemic condition, with a larger proportion being due to post-acute myocardial infarction in Cluster 1 (68.8%), and due to ischemic cardiomyopathy in Cluster 2 (57.8%). Notably, patients in Cluster 2 exhibited a reduced likelihood of LVT resolution (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.44-0.77, p < 0.001) and a higher risk of all-cause mortality (HR 2.27, 95% CI 1.43-3.60, p = 0.001). These associations persisted even after adjusting for variables such as anticoagulation treatment, the presence of left ventricular aneurysms, and specific LVT characteristics such as mobility, protrusion, and size. CONCLUSION: Through TwoStep cluster analysis, we identified two distinct clinical phenotypes among patients with LVT, each distinguished by unique baseline clinical attributes and varying prognoses.

The impact of MCCK1, an inhibitor of IKBKE kinase, on acute B lymphocyte leukemia cells.

B-cell acute lymphoblastic leukemia (B-ALL) is a malignant blood disorder, particularly detrimental to children and adolescents, with recurrent or unresponsive cases contributing significantly to cancer-associated fatalities. IKBKE, associated with innate immunity, tumor promotion, and drug resistance, remains poorly understood in the context of B-ALL. Thus, this research aimed to explore the impact of the IKBKE inhibitor MCCK1 on B-ALL cells. The study encompassed diverse experiments, including clinical samples, in vitro and in vivo investigations. Quantitative real-time fluorescence PCR and protein blotting revealed heightened IKBKE mRNA and protein expression in B-ALL patients. Subsequent in vitro experiments with B-ALL cell lines demonstrated that MCCK1 treatment resulted in reduced cell viability and survival rates, with flow cytometry indicating cell cycle arrest. In vivo experiments using B-ALL mouse tumor models substantiated MCCK1's efficacy in impeding tumor proliferation. These findings collectively suggest that IKBKE, found to be elevated in B-ALL patients, may serve as a promising drug target, with MCCK1 demonstrating potential for inducing apoptosis in B-ALL cells both in vitro and in vivo.

Advances in Mechanism of HIV-1 Immune Reconstitution Failure: Understanding Lymphocyte Subpopulations and Interventions for Immunological Nonresponders.

In individuals diagnosed with AIDS, the primary method of sustained suppression of HIV-1 replication is antiretroviral therapy, which systematically increases CD4+ T cell levels and restores immune function. However, there is still a subset of 10-40% of people living with HIV who not only fail to reach normal CD4+ T cell counts but also experience severe immune dysfunction. These individuals are referred to as immunological nonresponders (INRs). INRs have a higher susceptibility to opportunistic infections and non-AIDS-related illnesses, resulting in increased morbidity and mortality rates. Therefore, it is crucial to gain new insights into the primary mechanisms of immune reconstitution failure to enable early and effective treatment for individuals at risk. This review provides an overview of the dynamics of key lymphocyte subpopulations, the main molecular mechanisms of INRs, clinical diagnosis, and intervention strategies during immune reconstitution failure, primarily from a multiomics perspective.

Drosophila Larvae-Inspired Soft Crawling Robot with Multimodal Locomotion and Versatile Applications.

Soft crawling robots have been widely studied and applied because of their excellent environmental adaptability and flexible movement. However, most existing soft crawling robots typically exhibit a single-motion mode and lack diverse capabilities. Inspired by Drosophila larvae, this paper proposes a compact soft crawling robot (weight, 13 g; length, 165 mm; diameter, 35 mm) with multimodal locomotion (forward, turning, rolling, and twisting). Each robot module uses 4 sets of high-power-density shape memory alloy actuators, endowing it with 4 degrees of motion freedom. We analyze the mechanical characteristics of the robot modules through experiments and simulation analysis. The plug-and-play modules can be quickly assembled to meet different motion and task requirements. The soft crawling robot can be remotely operated with an external controller, showcasing multimodal motion on various material surfaces. In a narrow maze, the robot demonstrates agile movement and effective maneuvering around obstacles. In addition, leveraging the inherent bistable characteristics of the robot modules, we used the robot modules as anchoring units and installed a microcamera on the robot's head for pipeline detection. The robot completed the inspection in horizontal, vertical, curved, and branched pipelines, adjusted the camera view, and twisted a valve in the pipeline for the first time. Our research highlights the robot's superior locomotion and application capabilities, providing an innovative strategy for the development of lightweight, compact, and multifunctional soft crawling robots.

Associations between postoperative cognitive dysfunction, serum interleukin-6 and postoperative delirium among patients after coronary artery bypass grafting: A mediation analysis.

BACKGROUND: POCD is a common complication among patients who underwent coronary artery bypass graft (CABG), it is linked to loss of independence and reduced quality of life. AIMS AND OBJECTIVES: To examine the association between postoperative cognitive dysfunction (POCD), postoperative delirium (POD) and interleukin-6 (IL-6). DESIGN: A prospective cohort study. METHODS: Patients who underwent elective isolated CABG were enrolled. POCD was assessed by a set of cognitive function tools. Delirium was assessed using the CAM-ICU. The logistic regression analyses were used to identify the predictive value of POD or IL-6 on POCD. The path analysis was used to analyse the relationship among POD, IL-6 and POCD. RESULTS: A total of 212 patients were enrolled, with 25.0% of patients developing POD and 32.5% developing POCD. The multiple logistic regression analysis revealed that patients with POD had a four-fold increased hazard of POCD (OR = 3.655), and patients with IL-6 ≥ 830.50 pg/mL at the 6th hours after surgery had a 5-fold increased risk of experiencing POCD (OR = 5.042). However, the mediation effect of POD between IL-6 and POCD was not statistically significant (ß = 0.059, p = .392). CONCLUSIONS: POD and IL-6 at the 6th hour after surgery (≥830.50 pg/mL) are two potent predictors for POCD, while POD did not play a mediation effect between IL-6 and POCD. RELEVANCE TO CLINICAL PRACTICE: Early identification of risk factors (e.g., delirium assessment and testing for serum IL-6 levels) by clinical nurses for POCD may contribute to the clinical practice for the targeted prevention nursing strategies.

Associations between varicose veins and heart failure: A genetic correlation and mendelian randomization study.

Varicose veins and heart failure (HF) are increasingly prevalent. Although numbers of observational studies have indicated that varicose veins might contribute to the risk of HF, the causal relationship between them remains unclear due to the uncontrolled confounding factors and reverse causation bias. Therefore, this study aimed to explore the potential causal relationship between varicose veins and HF. Based on publicly released genome-wide association studies (GWAS), gene correlation was assessed using linkage disequilibrium score (LDSC) regression, and we conducted a two-sample Mendelian randomization (TSMR) analysis to infer the causal relationship. We performed the Inverse variance weighted (IVW) method as the primary analysis, and used Weighted median, MR-Egger, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods to detect and correct for horizontal pleiotropy. LDSC revealed there was a positive genetic correlation between varicose veins and HF (rg = 0.1726184, Se = 0.04511803, P = .0001). The results of the IVW method indicated that genetically predicted varicose veins were associated with an increased risk of HF (odds ratio (OR) = 1.03; 95% confidence interval (CI): 1.01-1.06; P = .009). Our findings illustrated the significant causal effect of varicose veins on HF, suggesting that people with varicose veins might have a higher risk of HF. The results provided a novel and important perspective into the development mechanism of HF.

CAV3 alleviates diabetic cardiomyopathy via inhibiting NDUFA10-mediated mitochondrial dysfunction.

BACKGROUND: The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated. METHODS: Cardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and functional experiments. RESULTS: Our findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10. CONCLUSIONS: The current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.

Asymmetrical Interactions between Ni Single Atomic Sites and Ni Clusters in a 3D Porous Organic Framework for Enhanced CO2 Photoreduction.

3D porous organic frameworks, which possess the advantages of high surface area and abundant exposed active sites, are considered ideal platforms to accommodate single atoms (SAs) and metal nanoclusters (NCs) in high-performance catalysts; however, very little research has been conducted in this field. In the present work, a 3D porous organic framework containing Ni1 SAs and Nin NCs is prepared through the metal-assisted one-pot polycondensation of tetraaldehyde and hexaaminotriptycene. The single metal sites and metal clusters confined in the 3D space created a favorable micro-environment that facilitated the activation of chemically inert CO2 molecules, thus promoting the overall photoconversion efficiency and selectivity of CO2 reduction. The 3D-NiSAs/NiNCs-POPs, as a CO2 photoreduction catalyst, demonstrated an exceptional CO production rate of 6.24 mmol g-1 h-1, high selectivity of 98%, and excellent stability. The theoretical calculations uncovered that asymmetrical interaction between Ni1 SAs and Nin NCs not only favored the bending of CO2 molecules and reducing the CO2 reduction energy, but also regulated the electronic structure of the catalyst leading to the optimal binding strength of intermediates.