Pulmonary Hypertension Induces Serotonin Hyperreactivity and Metabolic Reprogramming in Coronary Arteries via NOX1/4-TRPM2 Signaling Pathway.

BACKGROUND: Clinical evidence revealed abnormal prevalence of coronary artery (CA) disease in patients with pulmonary hypertension (PH). The mechanistic connection between PH and CA disease is unclear. Serotonin (5-hydroxytryptamine), reactive oxygen species, and Ca2+ signaling have been implicated in both PH and CA disease. Our recent study indicates that NOXs (NADPH [nicotinamide adenine dinucleotide phosphate] oxidases) and TRPM2 (transient receptor potential cation channel subfamily M member 2) are key components of their interplay. We hypothesize that activation of the NOX-TRPM2 pathway facilitates the remodeling of CA in PH. METHODS: Left and right CAs from chronic hypoxia and monocrotaline-induced PH rats were collected to study vascular reactivity, gene expression, metabolism, and mitochondrial function. Inhibitors or specific siRNA were used to examine the pathological functions of NOX1/4-TRPM2 in CA smooth muscle cells. RESULTS: Significant CA remodeling and 5-hydroxytryptamine hyperreactivity in the right CA were observed in PH rats. NOX1/4-mediated reactive oxygen species production coupled with TRPM2-mediated Ca2+ influx contributed to 5-hydroxytryptamine hyperresponsiveness. CA smooth muscle cells from chronic hypoxia-PH rats exhibited increased proliferation, migration, apoptosis, and metabolic reprogramming in an NOX1/4-TRPM2-dependent manner. Furthermore, the NOX1/4-TRPM2 pathway participated in mitochondrial dysfunction, involving mitochondrial DNA damage, reactive oxygen species production, elevated mitochondrial membrane potential, mitochondrial Ca2+ accumulation, and mitochondrial fission. In vivo knockdown of NOX1/4 alleviated PH and suppressed CA remodeling in chronic hypoxia rats. CONCLUSIONS: PH triggers an increase in 5-hydroxytryptamine reactivity in the right CA and provokes metabolic reprogramming and mitochondrial disruption in CA smooth muscle cells via NOX1/4-TRPM2 activation. This signaling pathway may play an important role in CA remodeling and CA disease in PH.

Estimation of Knee Joint Angle from Surface EMG Using Multiple Kernels Relevance Vector Regression.

In wearable robots, the application of surface electromyography (sEMG) signals in motion intention recognition is a hot research issue. To improve the viability of human-robot interactive perception and to reduce the complexity of the knee joint angle estimation model, this paper proposed an estimation model for knee joint angle based on the novel method of multiple kernel relevance vector regression (MKRVR) through offline learning. The root mean square error, mean absolute error, and R2_score are used as performance indicators. By comparing the estimation model of MKRVR and least squares support vector regression (LSSVR), the MKRVR performs better on the estimation of the knee joint angle. The results showed that the MKRVR can estimate the knee joint angle with a continuous global MAE of 3.27° ± 1.2°, RMSE of 4.81° ± 1.37°, and R2 of 0.8946 ± 0.07. Therefore, we concluded that the MKRVR for the estimation of the knee joint angle from sEMG is viable and could be used for motion analysis and the application of recognition of the wearer's motion intentions in human-robot collaboration control.

SARS-CoV-2 causes a significant stress response mediated by small RNAs in the blood of COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a serious impact on the world. In this study, small RNAs from the blood of COVID-19 patients with moderate or severe symptoms were extracted for high-throughput sequencing and analysis. Interestingly, the levels of a special group of tRNA-derived small RNAs (tsRNAs) were found to be dramatically upregulated after SARS-CoV-2 infection, particularly in coronavirus disease 2019 (COVID-19) patients with severe symptoms. In particular, the 3'CCA tsRNAs from tRNA-Gly were highly consistent with the inflammation indicator C-reactive protein (CRP). In addition, we found that the majority of significantly changed microRNAs (miRNAs) were associated with endoplasmic reticulum (ER)/unfolded protein response (UPR) sensors, which may lead to the induction of proinflammatory cytokine and immune responses. This study found that SARS-CoV-2 infection caused significant changes in the levels of stress-associated small RNAs in patient blood and their potential functions. Our research revealed that the cells of COVID-19 patients undergo tremendous stress and respond, which can be reflected or regulated by small non-coding RNA (sncRNAs), thus providing potential thought for therapeutic intervention in COVID-19 by modulating small RNA levels or activities.

The ketogenic diet increases Neuregulin 1 expression via elevating histone acetylation and its anti-seizure effect requires ErbB4 kinase activity.

BACKGROUND: The ketogenic diet (KD)has been considered an effective treatment for epilepsy, whereas its underlying mechanisms remain obscure. We have previously reported that the KD feeding increased Neuregulin 1 (NRG1) expression in the hippocampus; disruption of NRG1 signaling by genetically deleting its receptor-ErbB4 abolished KD's effects on inhibitory synaptic activity and seizures. However, it is still unclear about the mechanisms underlying the effect of KD on NRG1 expression and whether the effects of KD require ErbB4 kinase activity. METHODS: The effects of the KD on NRG1 expression were assessed via western blotting and real-time PCR. Acetylation level at the Nrg1 promoter locus was examined using the chromatin immunoprecipitation technique. Kainic acid (KA)-induced acute seizure model was utilized to examine the effects of KD and histone deacetylase inhibitor-TSA on seizures. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The obligatory role of ErbB4 kinase activity in KD's effects on seizures and inhibitory synaptic activity was evaluated by using ErbB kinase antagonist and transgenic mouse-T796G. RESULTS: We report that KD specifically increases Type I NRG1 expression in the hippocampus. Using the chromatin immunoprecipitation technique, we observe increased acetylated-histone occupancy at the Nrg1 promoter locus of KD-fed mice. Treatment of TSA dramatically elevates NRG1 expression and diminishes the difference between the effects of the control diet (CD) and KD. These data indicate that KD increases NRG1 expression via up-regulating histone acetylation. Moreover, both pharmacological and genetic inhibitions of ErbB4 kinase activity significantly block the KD's effects on inhibitory synaptic activity and seizure, suggesting an essential role of ErbB4 kinase activity. CONCLUSION: These results strengthen our understanding of the role of NRG1/ErbB4 signaling in KD and shed light on novel therapeutic interventions for epilepsy.

Neuregulin 1/ErbB4 signaling contributes to the anti-epileptic effects of the ketogenic diet.

BACKGROUND: The ketogenic diet (KD) has been recognized as a potentially effective therapy to treat neuropsychiatric diseases, including epilepsy. Previous studies have indicated that KD treatment elevates γ-Amino butyric acid (GABA) levels in both human and murine brains, which presumably contributes to the KD's anti-seizure effects. However, this has not been systematically investigated at the synaptic level, and the underlying molecular mechanisms remain to be elucidated. METHODS: Kainic acid (KA)-induced acute and chronic seizure models were utilized to examine the effects of KD treatment on seizure threshold and epileptogenesis. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The effects of the KD on Neuregulin 1 (Nrg1) expression were assessed via RNA sequencing, real-time PCR and Western blotting. The obligatory role of Nrg1 in KD's effects on seizures was evaluated through disruption of Nrg1 signaling in mice by genetically deleting its receptor-ErbB4. RESULTS: We found that KD treatment suppressed seizures in both acute and chronic seizure models and enhanced presynaptic GABA release probability in the hippocampus. By screening molecular targets linked to GABAergic activity with transcriptome analysis, we identified that KD treatment dramatically increased the Nrg1 gene expression in the hippocampus. Disruption of Nrg1 signaling by genetically deleting its receptor-ErbB4 abolished KD's effects on GABAergic activity and seizures. CONCLUSION: Our findings suggest a critical role of Nrg1/ErbB4 signaling in mediating KD's effects on GABAergic activity and seizures, shedding light on developing new therapeutic interventions to seizure control.

[Early diagnosis and microsurgical treatment of hand glomus tumor in 30 female cases].

OBJECTIVE: To investigate the clinical features, early diagnosis and surgical treatment of the hand glomus tumor in the female. METHODS: Thirty female patients with the hand glomus tumor underwent early resection by microsurgery. The average age was 35 years ranging from 18 to 48 years. The course of disease was from 3 months to 3 years. All patients' tumors occured on single finger. RESULTS: In the 30 cases, there were 28 patients with localized eminences and hepatic plaques under the nail. The compression of distal phalanx could be seen on radiographs in 18 patients, definite and localised tenderness on nails could be found in all cases, the tenderness disappeared and no recurrence after 15 months of follow-up in all cases. CONCLUSION: The hepatic plaque under the nail and fixed tenderness point on the nail are of significance in diagnosis for the hand glomus tumor in the female, the early microsurgical resection is unique effective treatment to this disease.