Disrupted mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation are often associated with macrophage pyroptosis. It remains unclear how these forms of mitochondrial ...dysfunction relate to inflammasome activation and gasdermin-D (Gsdmd) cleavage, two central steps of the pyroptotic process. Here, we also found MMP collapse and ROS generation induced by Nlrp3 inflammasome activation as previous studies reported. The elimination of ROS alleviated the cleavage of Gsdmd, suggesting that Gsdmd cleavage occurs downstream of ROS release. Consistent with this result, hydrogen peroxide treatment augmented the cleavage of Gsdmd by caspase-1. Indeed, four amino acid residues of Gsdmd were oxidized under oxidative stress in macrophages. The efficiency of Gsdmd cleavage by inflammatory caspase-1 was dramatically reduced when oxidative modification was blocked by mutation of these amino acid residues. These results demonstrate that Gsdmd oxidation serves as a de novo mechanism by which mitochondrial ROS promote Nlrp3 inflammasome-dependent pyroptotic cell death.
Previous research has suggested that engaging in regular physical activity (PA) can help to reduce symptoms of depression and anxiety in university students. However, there is a lack of evidence ...regarding the impact of reducing sedentary behavior (SB) and increasing light-intensity PA (LPA) on these symptoms. This study aims to address this gap by using isotemporal substitution (IS) models to explore how substituting SB with LPA or moderate-to-vigorous PA (MVPA) affects depression and anxiety symptoms among university students.
The study recruited 318 university students with a mean age of 21.13 years. Accelerometers were used to objectively measure the time spent on SB, LPA, and MVPA, while depression and anxiety symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Self-rating Anxiety Scale (SAS). IS models using multivariable linear regression were employed to estimate the associations between different behaviors and depression and anxiety symptoms when 30 min of one behavior was substituted with another.
In the single-activity model, less SB (β = 0.321, 95% CI: 0.089, 1.297) and more MVPA (β = -0.142, 95% CI: -1.496, - 0.071) were found to be significantly and negatively associated with depression scores, while less SB (β = 0.343, 95% CI: 0.057, 1.014), LPA (β = 0.132, 95% CI: 0.049, 1.023), and more MVPA (β = -0.077, 95% CI: -1.446, - 0.052) were significantly and negatively correlated with anxiety scores. The IS analysis revealed that substituting 30 min of SB with LPA (β = -0.202, 95% CI: -1.371, - 0.146) or MVPA (β = -0.308, 95% CI: -0.970, - 0.073) was associated with improvements in depressive symptoms. Substituting 30 min of SB with MVPA (β = -0.147, 95% CI: -1.863, - 0.034) was associated with reduced anxiety symptoms.
Replacing 30 min of SB with MVPA may alleviate depression and anxiety symptoms in university students. Further research is needed to explore the long-term effects of PA interventions on the mental health disorders of this population.
Although prior studies have demonstrated that children with high levels of fundamental movement skill (FMS) are more active throughout the day, little is known about children's FMS and their physical ...activity (PA) during different segments of the school day (e.g., recess, lunch break, and physical education). The present study focused on FMS and moderate-to-vigorous PA (MVPA) during school day and identifies the association between children's FMS and MVPA during different segments of the school day in China.
A total of 322 children (boys n = 163, girls n = 159; M
= 8.12, SD = 1.22 years) from four elementary schools involved in this study. Children's FMS and MVPA were measured using the Test of Gross Motor Development-2nd edition (TGMD-2) and hip-mounted accelerometers. Data such as height, weight, and socio-economic status (SES) were also obtained. Multilevel mixed regression models were used to examine the cross-sectional associations between FMS and MVPA. Models were adjusted for gender, age, standardized body mass index, and SES.
Children engaged in 32.19 min of MVPA during the whole school day. Boys were more active than girls and had higher object-control skills competency. Locomotor skills were positively associated with children's long recess (B = 1.063) and short recess time (B = 1.502) MVPA. Object-control skills were positively correlated with children's MVPA time during long recess (B = 1.244) and physical education (PE) lessons (B = 1.171).
The findings highlight the importance of developing both locomotor and object-control skills in elementary schools to lead more MVPA engagement during different segments of the school day.
Abstract
Objectives
To evaluate the effect of different exercise interventions on depressive symptoms in children and adolescents.
Methods
Randomized controlled trials (RCT) published until May 2023 ...were screened in four databases. The Cochrane collaboration tool was used to assess the risk of bias for quality evaluation. Stata 16.0 software was used for both a pairwise meta-analysis and a series of frequentist network meta-analyses (NMA).
Results
A total of 35 RCTs and 5393 participants were included. Aerobic exercise had the most significant effect on depressive symptoms (66.2%), followed by group training (62.5%), resistance exercise (59.0%), and aerobic combined with resistance exercise (57.9%). Furthermore, children and adolescents younger than 15 years showed significant improvement in depressive symptoms (SMD=-0.41, 95% CI (-0.63, -0.19), P < 0.01). The study also found a significant improvement in depression among healthy, obesity, and depressed populations (SMD=-0.25, 95% CI (-0.41, -0.08), P < 0.01); SMD=-0.15, 95% CI (-0.31, -0.00), P < 0.01; SMD=-0.75, 95% CI (-1.32, -0.19), P < 0.01). Additionally, 30 min of exercise had a significant effect (SMD=-0.14, 95% CI (-0,81, -0.01), P < 0.01), and 40–50 min of exercise had the best effect (SMD=-0.17, 95% CI (-0,33, -0.02), P < 0.01). Lastly, exercise frequency of three times per week was significant in children and adolescents (SMD=-0.42, 95% CI (-0,66, -0.18), P < 0.01).
Conclusion
Exercise significantly improves depressive symptoms in children and adolescents, with aerobic exercise having the most significant effect. A 12-week, three-times-a-week, 40-50-minute exercise intervention was found to be more effective in younger children and adolescents.
Guidelines recommend endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as an initial investigatory technique for mediastinal nodal staging in lung cancer. However, ...EBUS-TBNA can be limited by the inadequacy of intact tissues, which might restrict its diagnostic yield in mediastinal lesions of certain aetiologies. We have previously shown that EBUS-guided transbronchial mediastinal cryobiopsy can provide intact samples with greater volume.
This randomised study determined the diagnostic yield and safety of transbronchial mediastinal cryobiopsy monitored by endosonography for the diagnosis of mediastinal lesions. Patients with a mediastinal lesion of ≥1 cm in the short axis were recruited. Following identification of the mediastinal lesion by linear EBUS, fine-needle aspiration and cryobiopsy were sequentially performed in a randomised order. Primary end-points were diagnostic yield, defined as the percentage of patients for whom mediastinal biopsy provided a definite diagnosis, and procedure-related adverse events.
In total, 197 patients were enrolled and randomly allocated. The overall diagnostic yield was 79.9% and 91.8% for TBNA and transbronchial mediastinal cryobiopsy, respectively (p=0.001). Diagnostic yields were similar for metastatic lymphadenopathy (94.1%
95.6%, p=0.58), while cryobiopsy was more sensitive than TBNA in uncommon tumours (91.7%
25.0%, p=0.001) and benign disorders (80.9%
53.2%, p=0.004). No significant differences in diagnostic yield were detected between "TBNA first" and "Cryobiopsy first" groups. We observed two cases of pneumothorax and one case of pneumomediastinum.
Transbronchial cryobiopsy performed under EBUS guidance is a safe and useful approach that offers diagnostic histological samples of mediastinal lesions.
Childhood and adolescent overweight and obesity are global public health issues. Previous studies on exercise and overweight and obese children have produced inconsistent findings and lacked ...comparisons between different exercise modalities and intensities. Therefore, a network meta-analysis is necessary to provide evidence-based intervention programs. This study aims to identify the effects of different exercise modalities and intensities on changes in body composition in overweight and obese children and adolescents.
A search for randomized controlled trials was conducted on Web of Science, PubMed, Scopus, and Embase involving exercise interventions aimed at improving body composition (body fat percentage, BMI, fat mass, fat-free mass, body weight) in overweight and obese children and adolescents. A random effects network meta-analysis was performed using STATA 14.0 software within a frequentist framework. The literature quality was assessed using the Cochrane Risk of Bias Tool 2.0.
Thirty-two papers involving 1,452 participants were included. There were six types of intervention involved in the study, including moderate intensity aerobic exercise, high-intensity aerobic exercise, moderate intensity resistance exercise, high-intensity resistance exercise, moderate intensity combined exercise, and high-intensity combined exercise. The network meta-analysis results revealed that high-intensity combined exercise was the best exercise mode for improving BMI mean difference in kg/m
= -1.65, 95% CI (-3.27, -0.02) and reducing fat mass mean difference in kg = -2.87, 95% CI (-4.84, -0.91). Moderate intensity combined exercise was the best mode for weight loss mean difference in kg = -4.58, 95% CI (-5.94, -3.22) and improvement in body fat percentage mean difference in% = -2.52, 95% CI (-3.83, -1.20). High-intensity resistance exercise had the optimal effect in increasing fat-free mass mean difference in kg = 1.10, 95% CI (0.22, 1.99).
In conclusion, the study found that combined exercise, whether moderate or high intensity, was more effective than any other exercise modality in improving body fat percentage and BMI, reducing fat mass and weight. Resistance exercise was the most effective in increasing fat-free mass.
Abstract
Gasdermin B (GSDMB) has been reported to be associated with immune diseases in humans, but the detailed molecular mechanisms remain unsolved. The N-terminus of GSDMB by itself, unlike other ...gasdermin family proteins, does not induce cell death. Here, we show that GSDMB is highly expressed in the leukocytes of septic shock patients, which is associated with increased release of the gasdermin D (GSDMD) N-terminus. GSDMB expression and the accumulation of the N-terminal fragment of GSDMD are induced by the activation of the non-canonical pyroptosis pathway in a human monocyte cell line. The downregulation of GSDMB alleviates the cleavage of GSDMD and cell death. Consistently, the overexpression of GSDMB promotes GSDMD cleavage, accompanied by increased LDH release. We further found that GSDMB promotes caspase-4 activity, which is required for the cleavage of GSDMD in non-canonical pyroptosis, by directly binding to the CARD domain of caspase-4. Our study reveals a GSDMB-mediated novel regulatory mechanism for non-canonical pyroptosis and suggests a potential new strategy for the treatment of inflammatory diseases.
Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC despite its serious adverse ...effects. Here, we report that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib’s benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP–activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug’s current use in HCC.
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•Low-dose sorafenib safely suppresses NASH progression in mice•Low-dose sorafenib resolves NASH in monkeys without detectable toxicities•AMPK activation is required for the therapeutic effects of sorafenib in NASH•Sorafenib activates AMPK by acting as a mitochondrial uncoupler
Jian et al. show that low-dose sorafenib safely and effectively suppressed NASH progression in both mice and monkeys. Mechanistically, induction of mitochondrial uncoupling and subsequent AMPK activation primarily underlies the therapeutic effects of sorafenib in NASH.
Background Anxiety, depression, and stress are the most common mental health problems in childhood. Exercise interventions in childhood help to promote mental health. Objective To investigate the ...relationship between exercise interventions and improvement of negative emotions such as anxiety, depression, and stress in children (5-12 years). Methods Articles were searched in five electronic databases from their inception to January 2023. The meta-analysis was performed using Stata 16.0. Results Twenty-three intervention studies included 6830 children. 1) The exercise intervention group was significantly better than the control group in improving negative emotions (Standard Mean Difference SMD=-0.25, 95% Confidence Intervals CI: -0.34 to -0.15, P < 0.01). Exercise intervention improved different kinds of negative emotions: anxiety (SMD=-0.19, 95% CI: -0.33 to -0.06, P < 0.01), depression (SMD=-0.22, 95% CI: -0.43 to -0.01, P < 0.01), and stress (SMD=-0.33, 95% CI: -0.53 to -0.14, P < 0.01); it was most effective at relieving problematic stress. Exercise interventions lasting 20-45 min were most effective in improving children's negative emotions (SMD=-0.38, 95% CI: -0.56 to -0.20, P < 0.01). An exercise intervention period of 10 weeks was more effective in improving children's negative mood (SMD=-0.26, 95% CI: -0.34 to -0.17, P = 0.274). Conclusion Exercise interventions may improve negative emotions such as anxiety, depression, and stress in children. These findings may have clinical implications for children with negative affect. However, these studies showed a large heterogeneity, and the results should be interpreted with caution. Future studies should report the variability of exercise interventions by gender, age group, and type, intensity, and place of exercise. Keywords: Exercise, Children, Negative emotion, Meta-analysis
In nanostructure assemblies, the superposition of current paths forms microscopic electric circuits, and different circuit networks produce varying results, particularly when utilized as transistor ...channels for computing applications. However, the intricate nature of assembly networks and the winding paths of commensurate currents hinder standard circuit modeling. Inspired by the quantum collapse of superposition states for information decoding in quantum circuits, the implementation of analogous current path collapse to facilitate the detection of microscopic circuits by modifying their network topology is explored. Here, the superposition and collapse of current paths in gate‐all‐around polysilicon nanosheet arrays are demonstrated to enrich the computational resources within transistors by engineering the channel length and quantity. Switching the ferroelectric polarization of Hf0.5Zr0.5O2 gate dielectric, which drives these transistors out‐of‐equilibrium, decodes the output polymorphism through circuit topological modifications. Furthermore, a protocol for the single‐electron readout of ferroelectric polarization is presented with tailoring the channel coherence. The introduction of lateral path superposition results into intriguing metal‐to‐insulator transitions due to transient behavior of ferroelectric switching. This ability to adjust the current networks within transistors and their interaction with ferroelectric polarization in polycrystalline nanostructures lays the groundwork for generating diverse current characteristics as potential physical databases for optimization‐based computing.
Superposition and collapse of nanostructured in‐transistor current networks are demonstrated to be read and decoded by quantum tunneling and ferroelectric switching in gate‐all‐around polysilicon nanosheet arrays and planar‐gated nanofilms. The drain current output is therefore endowed with polymorphism due to the interplay of the polysilicon and Hf0.5Zr0.5O2 nanostructures.
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