The spatiotemporal matching pattern of Ezrin/Periaxin involved in myoblast differentiation and fusion and Charcot-Marie-Tooth disease-associated muscle atrophy.

BACKGROUND: Clinically, Charcot-Marie-Tooth disease (CMT)-associated muscle atrophy still lacks effective treatment. Deletion and mutation of L-periaxin can be involved in CMT type 4F (CMT4F) by destroying the myelin sheath form, which may be related to the inhibitory role of Ezrin in the self-association of L-periaxin. However, it is still unknown whether L-periaxin and Ezrin are independently or interactively involved in the process of muscle atrophy by affecting the function of muscle satellite cells. METHOD: A gastrocnemius muscle atrophy model was prepared to mimic CMT4F and its associated muscle atrophy by mechanical clamping of the peroneal nerve. Differentiating C2C12 myoblast cells were treated with adenovirus-mediated overexpression or knockdown of Ezrin. Then, overexpression of L-periaxin and NFATc1/c2 or knockdown of L-periaxin and NFATc3/c4 mediated by adenovirus vectors were used to confirm their role in Ezrin-mediated myoblast differentiation, myotube formation and gastrocnemius muscle repair in a peroneal nerve injury model. RNA-seq, real-time PCR, immunofluorescence staining and Western blot were used in the above observation. RESULTS: For the first time, instantaneous L-periaxin expression was highest on the 6th day, while Ezrin expression peaked on the 4th day during myoblast differentiation/fusion in vitro. In vivo transduction of adenovirus vectors carrying Ezrin, but not Periaxin, into the gastrocnemius muscle in a peroneal nerve injury model increased the numbers of muscle myosin heavy chain (MyHC) I and II type myofibers, reducing muscle atrophy and fibrosis. Local muscle injection of overexpressed Ezrin combined with incubation of knockdown L-periaxin within the injured peroneal nerve or injection of knockdown L-periaxin into peroneal nerve-injured gastrocnemius muscle not only increased the number of muscle fibers but also recovered their size to a relatively normal level in vivo. Overexpression of Ezrin promoted myoblast differentiation/fusion, inducing increased MyHC-I+ and MyHC-II + muscle fiber specialization, and the specific effects could be enhanced by the addition of adenovirus vectors for knockdown of L-periaxin by shRNA. Overexpression of L-periaxin did not alter the inhibitory effects on myoblast differentiation and fusion mediated by knockdown of Ezrin by shRNA in vitro but decreased myotube length and size. Mechanistically, overexpressing Ezrin did not alter protein kinase A gamma catalytic subunit (PKA-γ cat), protein kinase A I alpha regulatory subunit (PKA reg Iα) or PKA reg Iß levels but increased PKA-α cat and PKA reg II α levels, leading to a decreased ratio of PKA reg I/II. The PKA inhibitor H-89 remarkably abolished the effects of overexpressing-Ezrin on increased myoblast differentiation/fusion. In contrast, knockdown of Ezrin by shRNA significantly delayed myoblast differentiation/fusion accompanied by an increased PKA reg I/II ratio, and the inhibitory effects could be eliminated by the PKA reg activator N6-Bz-cAMP. Meanwhile, overexpressing Ezrin enhanced type I muscle fiber specialization, accompanied by an increase in NFATc2/c3 levels and a decrease in NFATc1 levels. Furthermore, overexpressing NFATc2 or knocking down NFATc3 reversed the inhibitory effects of Ezrin knockdown on myoblast differentiation/fusion. CONCLUSIONS: The spatiotemporal pattern of Ezrin/Periaxin expression was involved in the control of myoblast differentiation/fusion, myotube length and size, and myofiber specialization, which was related to the activated PKA-NFAT-MEF2C signaling pathway, providing a novel L-Periaxin/Ezrin joint strategy for the treatment of muscle atrophy induced by nerve injury, especially in CMT4F.

MoTI: A Multi-Stage Algorithm for Moving Object Identification in SLAM.

Simultaneous localization and mapping (SLAM) algorithms are widely applied in fields such as autonomous driving and target tracking. However, the effect of moving objects on localization and mapping remains a challenge in natural dynamic scenarios. To overcome this challenge, this paper proposes an algorithm for dynamic point cloud detection that fuses laser and visual identification data, the multi-stage moving object identification algorithm (MoTI). The MoTI algorithm consists of two stages: rough processing and precise processing. In the rough processing stage, a statistical method is employed to preliminarily detect dynamic points based on the range image error of the point cloud. In the precise processing stage, the radius search strategy is used to statistically test the nearest neighbor points. Next, visual identification information and point cloud registration results are fused using a method of statistics and information weighting to construct a probability model for identifying whether a point cloud cluster originates from a moving object. The algorithm is integrated into the front-end of the LOAM system, which significantly improves the localization accuracy. The MoTI algorithm is evaluated on an actual indoor dynamic environment and several KITTI datasets, and the results demonstrate its ability to accurately detect dynamic targets in the background and improve the localization accuracy of the robot.

Sequential Fusion Filter for State Estimation of Nonlinear Multi-Sensor Systems with Cross-Correlated Noise and Packet Dropout Compensation.

This paper is concerned with the problem of state estimation for nonlinear multi-sensor systems with cross-correlated noise and packet loss compensation. In this case, the cross-correlated noise is modeled by the synchronous correlation of the observation noise of each sensor, and the observation noise of each sensor is correlated with the process noise at the previous moment. Meanwhile, in the process of state estimation, since the measurement data may be transmitted in an unreliable network, data packet dropout will inevitably occur, leading to a reduction in estimation accuracy. To address this undesirable situation, this paper proposes a state estimation method for nonlinear multi-sensor systems with cross-correlated noise and packet dropout compensation based on a sequential fusion framework. Firstly, a prediction compensation mechanism and a strategy based on observation noise estimation are used to update the measurement data while avoiding the noise decorrelation step. Secondly, a design step for a sequential fusion state estimation filter is derived based on an innovation analysis method. Then, a numerical implementation of the sequential fusion state estimator is given based on the third-degree spherical-radial cubature rule. Finally, the univariate nonstationary growth model (UNGM) is combined with simulation to verify the effectiveness and feasibility of the proposed algorithm.

Cyanidin-3-glucoside protects against high glucose-induced injury in human nucleus pulposus cells by regulating the Nrf2/HO-1 signaling.

Cyanidin-3-glucoside (C3G) is a well-known natural anthocyanin with antioxidant and anti-inflammatory properties. In this study, we explored the role and action mechanism of C3G in high glucose (HG)-induced damage of human nucleus pulposus cells (HNPCs). Cell viability was assessed by CCK-8 assay. TUNEL assay was performed for detecting apoptotic rate. Western blot was performed to determine the expression levels of cl-caspase-3, caspase-3, Bax, Bim, collagen II, aggrecan, MMP-3, MMP-13, and ADAMTS5. Reactive oxygen species (ROS) generation was analyzed using DCFH-DA staining. The Nrf2 was knocked down or overexpressed in HNPCs through transfection with si-Nrf2 or pcDNA3.0-Nrf2. C3G treatment (12.5, 25, and 50 µM) improved cell viability of HNPCs under HG condition. HG-induced cell apoptosis of HNPCs was attenuated by C3G with decreased apoptotic rate and relative levels of cl-caspase-3/caspase-3, Bax, and Bim. C3G treatment caused significant increase in expression levels of collagen II and aggrecan and decrease in the relative levels of MMP-3, MMP-13, and ADAMTS5. After treatment with C3G, ROS generation in HNPCs was markedly reduced. Treatment with N-acetylcysteine (NAC) reversed HG-induced cell apoptosis and extracellular matrix (ECM) degradation. C3G treatment induced the expression of Nrf2 and HO-1 in HG-induced HNPCs. Moreover, knockdown of Nrf2 reversed the inhibitory effect of C3G on ROS production. Summarily, C3G exerted a protective effect on ROS-mediated cellular damage in HNPCs under HG condition, which was attributed to the induction of the Nrf2/HO-1 signaling pathway.

Sinus Tarsi Approach With Percutaneous Screw Fixation for Intra-Articular Calcaneal Fractures.

The aim of this study was to evaluate the outcomes of surgical treatment of intra-articular calcaneal fractures by using the sinus tarsi approach combined with percutaneous medial reduction by leverage technique and percutaneous screw fixation. We assessed the outcomes of 29 patients treated using sinus tarsi approach with percutaneous screw fixation. All patients were evaluated both clinically and radiologically. The Böhler and Gissane angle were evaluated postoperatively using radiographs. During the median follow-up period of 27.0 ± 10.3 months, no cases with failure to reduce or displace hardware were detected. All cases achieved the restoration of a normal Böhler and Gissane angle. The median preoperative Böhler angle was 12.3° ± 2.5° while postoperatively it was 30.5° ± 5.7° (p < .01). The median preoperative Gissane angle was 98.1° ± 7.5°, which was 125.9° ± 3.6° postoperatively (p < .01). At the last follow-up, the median American Orthopedic Foot and Ankle Society hindfoot score was 87.7 ± 5.9, and the median Maryland foot score was 88.6 ± 5.9. Our technique for intra-articular calcaneal fractures can effectively correct calcaneal tuberosity outward displacement, medial wall overlapping, and the hindfoot varus deformity with less soft tissue damage. This technique is a good alternative for the treatment of calcaneal fractures, resulting in minimal soft tissue damage, few wound complications, and excellent radiological and clinical outcomes.

Clinical application of retrograde sural neurofasciocutaneous flap repair combined with jingulian capsules to treat foot and ankle soft tissue defects.

OBJECTIVES: To observe and analyse the efficacy of retrograde sural neurofasciocutaneous flap repair combined with Jingulian capsules to treat foot and ankle soft tissue defects. METHODS: One hundred and eighty patients with foot and ankle soft tissue defects were enrolled in the study from January 2016 to June 2019 in The Second Department of General Surgery,Baoding First Central Hospital. They were divided into a study group and a reference group with the same case number. The former group was provided combination treatment, i.e. retrograde sural neurofasciocutaneous flap repair combined with Jingulian capsules; the latter group was given vacuum sealing drainage. Then, the treatment outcomes of the two groups were compared. RESULTS: The study group needed fewer dressing changes, less preoperative preparation time and antibiotic use than the reference group, p<0.05. The study group had a significantly lower incidence of wound infections and flap necrosis than the reference group, p<0.05. The study group was significantly superior to the reference group regarding ankle function scores and the pain visual analogue scores (VAS) p<0.05. CONCLUSIONS: Retrograde sural neurofasciocutaneous flap repair combined with Jingulian capsules is a protocol that improves efficacy for soft tissue defects in the foot and ankle, which are worthy of promotion and practice.

Enhancing the Photoluminescence Property of Pr3+ Ions by Understanding the Polymorphous Influence of the K3Lu(PO4)2 Host.

Adjusting the local coordination environment of lanthanide luminescent ions is a useful method to manipulate the relevant photoluminescence (PL) property. K3Lu(PO4)2 is a phase-change material, and according to the stable temperature range from low to high, the related polymorphs are phase I [P21/m, coordination number (CN) of Lu3+ = 7], phase II (P21/m, CN = 6), and phase III (P3̅, CN = 6), respectively. Based on the temperature-dependent PL analysis of K3Lu(PO4)2:Pr3+, we find that Pr3+ ions occupy the noninversion sites (Cs) in the two low-temperature phases but preferentially enter into the inversion ones (C3i) in phase III. Compared to Pr3+-doped phase I (78 K), Pr3+ ions in phase III (300 K) manifest a weaker fluorescence intensity (170-fold lower). To enhance the room-temperature PL property of K3Lu(PO4)2:Pr3+, a polymorphous adjustment strategy was proposed by the use of the ion-doping method. By introducing the Gd3+ ions into the lattice, Pr3+-doped phase I is successfully stabilized to room temperature, manifesting a 27-fold fluorescence increase in comparison to K3Lu(PO4)2:Pr3+ (0.1 at. %). The finding discussed in this study highlights the significance of site engineering for luminescent ions and also presents the application value of phase-change hosts in the development of high-performance luminescent materials.

Angiogenic Factor AGGF1 Activates Autophagy with an Essential Role in Therapeutic Angiogenesis for Heart Disease.

AGGF1 is an angiogenic factor with therapeutic potential to treat coronary artery disease (CAD) and myocardial infarction (MI). However, the underlying mechanism for AGGF1-mediated therapeutic angiogenesis is unknown. Here, we show for the first time that AGGF1 activates autophagy, a housekeeping catabolic cellular process, in endothelial cells (ECs), HL1, H9C2, and vascular smooth muscle cells. Studies with Atg5 small interfering RNA (siRNA) and the autophagy inhibitors bafilomycin A1 (Baf) and chloroquine demonstrate that autophagy is required for AGGF1-mediated EC proliferation, migration, capillary tube formation, and aortic ring-based angiogenesis. Aggf1+/- knockout (KO) mice show reduced autophagy, which was associated with inhibition of angiogenesis, larger infarct areas, and contractile dysfunction after MI. Protein therapy with AGGF1 leads to robust recovery of myocardial function and contraction with increased survival, increased ejection fraction, reduction of infarct areas, and inhibition of cardiac apoptosis and fibrosis by promoting therapeutic angiogenesis in mice with MI. Inhibition of autophagy in mice by bafilomycin A1 or in Becn1+/- and Atg5 KO mice eliminates AGGF1-mediated angiogenesis and therapeutic actions, indicating that autophagy acts upstream of and is essential for angiogenesis. Mechanistically, AGGF1 initiates autophagy by activating JNK, which leads to activation of Vps34 lipid kinase and the assembly of Becn1-Vps34-Atg14 complex involved in the initiation of autophagy. Our data demonstrate that (1) autophagy is essential for effective therapeutic angiogenesis to treat CAD and MI; (2) AGGF1 is critical to induction of autophagy; and (3) AGGF1 is a novel agent for treatment of CAD and MI. Our data suggest that maintaining or increasing autophagy is a highly innovative strategy to robustly boost the efficacy of therapeutic angiogenesis.

SUMOylation of Vps34 by SUMO1 promotes phenotypic switching of vascular smooth muscle cells by activating autophagy in pulmonary arterial hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a life-threatening disease without effective therapies. PAH is associated with a progressive increase in pulmonary vascular resistance and irreversible pulmonary vascular remodeling. SUMO1 (small ubiquitin-related modifier 1) can bind to target proteins and lead to protein SUMOylation, an important post-translational modification with a key role in many diseases. However, the contribution of SUMO1 to PAH remains to be fully characterized. METHODS: In this study, we explored the role of SUMO1 in the dedifferentiation of vascular smooth muscle cells (VSMCs) involved in hypoxia-induced pulmonary vascular remodeling and PAH in vivo and in vitro. RESULTS: In a mouse model of hypoxic PAH, SUMO1 expression was significantly increased, which was associated with activation of autophagy (increased LC3b and decreased p62), dedifferentiation of pulmonary arterial VSMCs (reduced α-SMA, SM22 and SM-MHC), and pulmonary vascular remodeling. Similar results were obtained in a MCT-induced PAH model. Overexpression of SUMO1 significantly increased VSMCs proliferation, migration, hypoxia-induced VSMCs dedifferentiation, and autophagy, but these effects were abolished by inhibition of autophagy by 3-MA in aortic VSMCs. Furthermore, SUMO1 knockdown reversed hypoxia-induced proliferation and migration of PASMCs. Mechanistically, SUMO1 promotes Vps34 SUMOylation and the assembly of the Beclin-1-Vps34-Atg14 complex, thereby inducing autophagy, whereas Vps34 mutation K840R reduces Vps34 SUMOylation and inhibits VSMCs dedifferentiation. DISCUSSION: Our data uncovers an important role of SUMO1 in VSMCs proliferation, migration, autophagy, and phenotypic switching (dedifferentiation) involved in pulmonary vascular remodeling and PAH. Targeting of the SUMO1-Vps34-autophagy signaling axis may be exploited to develop therapeutic strategies to treat PAH.

Rhythmic low-field magnetic stimulation may improve depression by increasing brain-derived neurotrophic factor.

BACKGROUND: Low-field magnetic stimulation (LFMS) has mood-elevating effect, and the increase of brain-derived neurotrophic factor (BDNF) is associated with antidepressant treatment. We evaluated the effects and association with BDNF of rhythmic LFMS in the treatment of major depressive disorder (MDD). METHODS: A total of 22 MDD patients were randomized to rhythmic alpha stimulation (RAS) or rhythmic delta stimulation (RDS), with 5 sessions per week, lasting for 6 weeks. Outcomes assessments included the 17-item Hamilton Depression Rating Scale (HAMD-17), the Hamilton Anxiety Rating Scale (HAMA), and the Clinical Global Impressions-Severity scale (CGI-S) at baseline and at weeks 1, 2, 3, 4, and 6. Serum BDNF level was measured at baseline and at weeks 2, 4, and 6. RESULTS: HAMD-17, HAMA, and CGI-S scores were significantly reduced with both RAS and RDS. RAS patients had numerically greater reductions in HAMD-17 scores than RDS patients (8.9 ± 7.4 vs. 6.2 ± 6.2, effect size [ES]=0.40), while RDS patients had greater improvement in HAMA scores (8.2 ± 8.0 vs. 5.3 ± 5.8, ES=0.42). RAS was associated with clinically relevant advantages in response (54.5% vs. 18.2%, number-needed-to-treat [NNT]=3) and remission (36.4% vs. 9.1%, NNT=4). BDNF increased significantly during the 6-week study period (p<0.05), with greater increases in RAS at weeks 4 and 6 (ES=0.66-0.76) and statistical superiority at week 2 (p=0.034, ES=1.23). Baseline BDNF in the 8 responders (24.8±9.0 ng/ml) was lower than in the 14 nonresponders (31.1±7.3 ng/ml, p=0.083, ES=-0.79), and BDNF increased more in responders (8.9±7.8 ng/ml) than in nonresponders (1.8±3.5 ng/ml, p=0.044). The change in BDNF at week 2 was the most strongly predicted response (p=0.016). CONCLUSIONS: Rhythmic LFMS was effective for MDD. BDNF may moderate/mediate the efficacy of LFMS.

Haploinsufficiency of Klippel-Trenaunay syndrome gene Aggf1 inhibits developmental and pathological angiogenesis by inactivating PI3K and AKT and disrupts vascular integrity by activating VE-cadherin.

Aggf1 is the first gene identified for Klippel-Trenaunay syndrome (KTS), and encodes an angiogenic factor. However, the in vivo roles of Aggf1 are incompletely defined. Here we demonstrate that Aggf1 is essential for both physiological angiogenesis and pathological tumour angiogenesis in vivo. Two lines of Aggf1 knockout (KO) mice showed a particularly severe phenotype as no homozygous embryos were observed and heterozygous mice also showed embryonic lethality (haploinsufficient lethality) observed only for Vegfa and Dll4. Aggf1+/- KO caused defective angiogenesis in yolk sacs and embryos. Survived adult heterozygous mice exhibit frequent haemorrhages and increased vascular permeability due to increased phosphorylation and reduced membrane localization of VE-cadherin. AGGF1 inhibits VE-cadherin phosphorylation, increases plasma membrane VE-cadherin in ECs and in mice, blocks vascular permeability induced by ischaemia-reperfusion (IR), restores depressed cardiac function and contraction, reduces infarct sizes, cardiac fibrosis and necrosis, haemorrhages, edema, and macrophage density associated with IR. Mechanistically, AGGF1 promotes angiogenesis by activating catalytic p110α subunit and p85α regulatory subunit of PI3K, leading to activation of AKT, GSK3ß and p70S6K. AKT activation is significantly reduced in heterozygous KO mice and isolated KO ECs, which can be rescued by exogenous AGGF1. ECs from KO mice show reduced capillary angiogenesis, which is rescued by AGGF1 and AKT. Tumour growth/angiogenesis is reduced in heterozygous mice, which was associated with reduced activation of p110α, p85α and AKT. Together with recent identification of somatic mutations in p110α (encoded by PIK3CA), our data establish a potential mechanistic link between AGGF1 and PIK3CA, the two genes identified for KTS.

The establishment of the objective diagnostic markers and personalized medical intervention in patients with major depressive disorder: rationale and protocol.

BACKGROUND: Major depressive disorders (MDD) is a common mental disorder with high prevalence, frequent relapse and associated with heavy disease burden. Heritability, environment and their interaction play important roles in the development of MDD. MDD patients usually display a wide variation in clinical symptoms and signs, while the diagnosis of MDD is relatively subjective. The treatment response varies substantially between different subtypes of MDD patients and only half respond adequately to the first antidepressant. This study aims to define subtypes of MDD, develop multi-dimension diagnostic test and combined predictors for improving the diagnostic accuracy and promoting personalized intervention in MDD patients. METHODS/DESIGN: This is a multi-center, multi-stage and prospective study. The first stage of this study is a case-control study, aims to explore the risk factors for developing MDD and then define the subtypes of MDD using 1200 MDD patients and 1200 healthy controls with a set of questionnaire. The second stage is a diagnostic test, aims to indentify and replicate the potential indicators to assist MDD diagnosis using 600 MDD patients and 300 healthy controls from the first stage with a set of questionnaire, neuropsychological assessment and a series of biomarkers. The third stage is a 96-week longitudinal study, including 8-week acute period treatment and 88-week stable period treatment, aims to identify overall predictors of treatment effectiveness on MDD at week 8 post treatment and to explore the predictors on MDD prognosis in the following 2 years using 600 MDD patients from the first stage with a set of questionnaire, neuropsychological assessment and a series of biomarkers. The primary outcome measure is the change of the total score of 17-Item Hamilton Rating Scale for Depression. DISCUSSION: This study will provide strong and suitable evidence for enhancing the accuracy of MDD diagnosis and promoting personalized treatment for MDD patients in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02023567 ; registration date: December 2013.

Construction of an auxiliary scoring model for myelosuppression in patients with lung cancer chemotherapy based on random forest algorithm.

OBJECTIVE: To construct an auxiliary scoring model for myelosuppression in patients with lung cancer undergoing chemotherapy based on a random forest algorithm, and to evaluate the predictive performance of the model. METHODS: Patients with lung cancer who received chemotherapy in Shanxi Province Cancer Hospital from January 2019 to January 2022 were retrospectively selected as research subjects, and their general demographic information, disease-related indicators, and laboratory test results before chemotherapy were collected. Patients were divided into a training set (136 cases) and a validation set (68 cases) in a ratio of 2:1. R software was used to establish a scoring model of myelosuppression in lung cancer patients in the training set, and the receiver operating characteristic curve, accuracy, sensitivity, and balanced F-score were used in the two data sets to evaluate the predictive performance of the model. RESULTS: Among the 204 lung cancer patients enrolled, 75 patients developed myelosuppression during the follow-up period after chemotherapy, with an incidence of 36.76%. The factors in the constructed random forest model were ranked in order of age (23.233), bone metastasis (21.704), chemotherapy course (19.259), Alb (13.833), and gender (11.471) according to the mean decrease accuracy. The areas under the curve of the model in the training and validation sets were 0.878 and 0.885, respectively (all P < 0.05). The predictive accuracy of the validated model was 82.35%, the sensitivity and specificity were 84.00% and 81.40%, respectively, and the balanced F-score was 77.78% (all P < 0.05). CONCLUSION: The risk assessment model for the occurrence of myelosuppression in patients with lung cancer chemotherapy based on a random forest algorithm can provide a reference for the accurate identification of high-risk patients.

Gender-specific associations between types of childhood maltreatment and major depressive disorder: A matched case-control study.

INTRODUCTION: Major depressive disorder (MDD) has been found to be nearly twice as prevalent in females as in males. One hypothesis proposed that abused females were particularly prone to MDD. We aim to examine the sex-specific associations between various types of childhood trauma and MDD. METHODS: In this study, 290 outpatients diagnosed with MDD were recruited from Beijing Anding Hospital, and 290 healthy volunteers were recruited from neighborhoods nearby the hospital, with sex, age, and family history matched. Childhood Trauma Questionnaire-Short Form (CTQ-SF) developed by Bernstein et al. was used to assess the severity of five different types of childhood abuse and neglect. McNemar's test and conditional logistic regression models with potential confounders (i.e., marital status, educational level, and body mass index) controlled were used to explore the sex-specific associations between different types of childhood maltreatment and MDD. RESULTS: In the full sample, patients with MDD showed a significant higher rate of any childhood maltreatment (i.e., emotional abuse, sexual abuse, physical abuse, emotional neglect, and physical neglect). Among females, all types of childhood abuse were statistically significant. For males, significant differences were only found in emotional abuse and in emotional neglect. CONCLUSION: It would appear that MDD in the outpatients is associated with any type of childhood trauma in women and emotional abuse or neglect in men.

Continuous exposure to isoprenaline reduced myotube size by delaying myoblast differentiation and fusion through the NFAT-MEF2C signaling pathway.

We aimed to explore whether superfluous sympathetic activity affects myoblast differentiation, fusion, and myofiber types using a continuous single-dose isoprenaline exposure model in vitro and to further confirm the role of distinct NFATs in ISO-mediated effects. Compared with delivery of single and interval single, continuous single-dose ISO most obviously diminished myotube size while postponing myoblast differentiation/fusion in a time- and dose-dependent pattern, accompanied by an apparent decrease in nuclear NFATc1/c2 levels and a slight increase in nuclear NFATc3/c4 levels. Overexpression of NFATc1 or NFATc2, particularly NFATc1, markedly abolished the inhibitory effects of ISO on myoblast differentiation/fusion, myotube size and Myh7 expression, which was attributed to a remarkable increase in the nuclear NFATc1/c2 levels and a reduction in the nuclear NFATc4 levels and the associated increase in the numbers of MyoG and MEF2C positive nuclei within more than 3 nuclei myotubes, especially in MEF2C. Moreover, knockdown of NFATc3 by shRNA did not alter the inhibitory effect of ISO on myoblast differentiation/fusion or myotube size but partially recovered the expression of Myh7, which was related to the slightly increased nuclear levels of NFATc1/c2, MyoG and MEF2C. Knockdown of NFATc4 by shRNA prominently increased the number of MyHC +, MyoG or MEF2C + myoblast cells with 1 ~ 2 nuclei, causing fewer numbers and smaller myotube sizes. However, NFATc4 knockdown further deteriorated the effects of ISO on myoblast fusion and myotube size, with more than 5 nuclei and Myh1/2/4 expression, which was associated with a decrease in nuclear NFATc2/c3 levels. Therefore, ISO inhibited myoblast differentiation/fusion and myotube size through the NFAT-MyoG-MEF2C signaling pathway.

Early Predictive Value of NT-proBNP Combined With Echocardiography in Anthracyclines Induced Cardiotoxicity.

Objective: Determine the predictive value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) combined with echocardiography in the diagnosis of anthracyclines-induced chronic cardiotoxicity. Methods: A total of 80 female breast cancer patients from January 2019 to October 2021 were included in our hospital. Twenty-six patients with cardiotoxicity were divided into the cardiac impairment group, and the 54 patients without cardiotoxicity were classified into the normal control group. NT-proBNP levels and cardiac echocardiography were measured before the start of the chemotherapy cycle, in cycle 3 of the chemotherapy, and after the chemotherapy cycle in all patients. Results: After three cycles of chemotherapy and chemotherapy, the levels of NT-proBNP in patients of the two groups were significantly higher than those before chemotherapy (P < 0.05). The levels of NT-proBNP in the cardiac injury group after three cycles of chemotherapy and chemotherapy were higher than those in the normal control group at the same time point (P < 0.05). The LVEF of patients in the cardiac impairment group after chemotherapy was lower than that before chemotherapy, and the LVEF after chemotherapy was lower than that in the normal control group (P < 0.05). NT-proBNP had a negative correlation with LVEF (r = -0.549, P < 0.001). The AUC of NT-proBNP in combination with LVEF for predicting cardiotoxicity in our patient was 0.898(95%CI:0.829-0.966). Conclusion: NT-proBNP combined with echocardiography has clinical significance in the detection of anthracyclines-induced cardiotoxicity, and it can detect early myocardial injury induced by anthracyclines, with early prediction value. It is important to protect heart function and judge prognosis.

Endothelial cell metabolic memory causes cardiovascular dysfunction in diabetes.

AIMS: The aim of this study was to identify the molecular mechanism for hyperglycaemia-induced metabolic memory in endothelial cells (ECs), and to show its critical importance to development of cardiovascular dysfunction in diabetes. METHODS AND RESULTS: Hyperglycaemia induces increased nuclear factor-κB (NF-κB) signalling, up-regulation of miR-27a-3p, down-regulation of nuclear factor erythroid-2 related factor 2 (NRF2) expression, increased transforming growth factor-ß (TGF-ß) signalling, down-regulation of miR-29, and induction of endothelial-to-mesenchymal transition (EndMT), all of which are memorized by ECs and not erased when switched to a low glucose condition, thereby causing perivascular fibrosis and cardiac dysfunction. Similar metabolic memory effects are found for production of nitric oxide (NO), generation of reactive oxygen species (ROS), and the mitochondrial oxygen consumption rate in two different types of ECs. The observed metabolic memory effects in ECs are blocked by NRF2 activator tert-butylhydroquinone and a miR-27a-3p inhibitor. In vivo, the NRF2 activator and miR-27a-3p inhibitor block cardiac perivascular fibrosis and restore cardiovascular function by decreasing NF-κB signalling, down-regulating miR-27a-3p, up-regulating NRF2 expression, reducing TGF-ß signalling, and inhibiting EndMT during insulin treatment of diabetes in streptozotocin-induced diabetic mice, whereas insulin alone does not improve cardiac function. CONCLUSIONS: Our data indicate that disruption of hyperglycaemia-induced EC metabolic memory is required for restoring cardiac function during treatment of diabetes, and identify a novel molecular signalling pathway of NF-κB/miR-27a-3p/NRF2/ROS/TGF-ß/EndMT involved in metabolic memory.

Astragaloside IV improves angiogenesis under hypoxic conditions by enhancing hypoxia­inducible factor­1α SUMOylation.

Improving angiogenic capacity under hypoxic conditions is essential for improving the survival of skin grafts, as they often lack the necessary blood supply. The stable expression levels of hypoxia­inducible factor­1α (HIF­1α) in the nucleus directly affect the downstream vascular endothelial growth factor (VEGF) signaling pathway and regulate angiogenesis in a hypoxic environment. Astragaloside IV (AS­IV), an active component isolated from Astragalus membranaceus, has multiple biological effects including antioxidant and anti­diabetic effects, and the ability to provide protection from cardiovascular damage. However, the mechanisms underlying these effects have not previously been elucidated. The present study investigated whether AS­IV promotes angiogenesis via affecting the balance between ubiquitination and small ubiquitin­related modifier (SUMO) modification of HIF­1α. The results demonstrated that persistent hypoxia induces changes in expression levels of HIF­1α protein and significantly increases the proportion of dysplastic blood vessels. Further western blotting experiments showed that rapid attenuation and delayed compensation of SUMO1 activity is one of the reasons for the initial increase then decrease in HIF­1α levels. SUMO1 overexpression stabilized the presence of HIF­1α in the nucleus and decreased the extent of abnormal blood vessel morphology observed following hypoxia. AS­IV induces vascular endothelial cells to continuously produce SUMO1, stabilizes the HIF­1α/VEGF pathway and improves angiogenesis in hypoxic conditions. In summary, the present study confirmed that AS­IV stimulates vascular endothelial cells to continuously resupply SUMO1, stabilizes the presence of HIF­1α protein and improves angiogenesis in adverse hypoxic conditions, which may improve the success rate of flap graft surgery following trauma or burn.

Nano-Pore Structure and Fractal Characteristics of Shale Gas Reservoirs: A Case Study of Longmaxi Formation in Southeastern Chongqing, China.

Pore structure and fractal dimensions can characterize the adsorption, desorption and seepage characteristics of shale gas reservoirs. In this study, pore structure, fractal characteristics and influencing factors were studied of the Longmaxi formation shale gas reservoir in southeastern Chongqing, China. Scanning electron microscopy was used to describe the characteristics of various reservoirs. High pressure mercury intrusion and low temperature liquid N2 and CO2 adsorption experiments were used to obtain pore structure parameters. V-S model, FHH model and Menger sponge model were selected to calculate the micropore, mesopore and macropore fractal dimensions, respectively. The results show that organic matter pores, inter-granular pores, intra-granular pores and micro-fractures are developed within the shale, and the pore morphology is mostly ink pores and parallel plate pores with aperture essentially in the 1-2 nm and 2-50 nm ranges. Moreover, macropores are the most complex in these samples, with mesopores being less complex than macropores, and the micropores being the simplest. D1 (micropore fractal dimension) ranges from 2.31 to 2.50, D2 (mesopore fractal dimension) ranges from 2.74 to 2.83, D3 (macropore fractal dimension) ranges from 2.87 to 2.95, and Dt (comprehensive fractal dimension) ranges from 2.69 to 2.83 of fractal characteristics. D1 and D2 are mainly controlled by TOC content, while D3 and Dt are mainly controlled by brittle and clay mineral content. These results may be helpful for exploration and the development of shale gas in southeastern Chongqing, China.

Percutaneous endoscopic lumbar discectomy compared with other surgeries for lumbar disc herniation: A meta-analysis.

OBJECTIVE: This meta-analysis was performed to investigate whether percutaneous endoscopic lumbar discectomy (PELD) had a superior effect than other surgeries in the treatment of patients with lumbar disc herniation (LDH). METHOD: We searched PubMed, Embase, and Web of Science through February 2018 to identify eligible studies that compared the effects and complications between PELD and other surgical interventions in LDH. The outcomes included success rate, recurrence rate, complication rate, operation time, hospital stay, blood loss, visual analog scale (VAS) score for back pain and leg pain, 12-item Short Form Health Survey (SF12) physical component score, mental component score, Japanese Orthopaedic Association Score, Oswestry Disability Index. A random-effects or fixed-effects model was used to pool the estimate, according to the heterogeneity among the included studies. RESULTS: Fourteen studies (involving 2,528 patients) were included in this meta-analysis. Compared with other surgeries, PELD had favorable clinical outcomes for LDH, including shorter operation time (weight mean difference, WMD=-18.14 minutes, 95%CI: -25.24, -11.05; P < .001) and hospital stay (WMD = -2.59 days, 95%CI: -3.87, -1.31; P < .001), less blood loss (WMD = -30.14 ml, 95%CI: -43.16, -17.13; P < .001), and improved SF12- mental component score (WMD = 2.28, 95%CI: 0.50, 4.06; P = .012)) and SF12- physical component score (WMD = 1.04, 95%CI: 0.37, 1.71; P = .02). However, it also was associated with a significantly higher rate of recurrent disc herniation (relative risk [RR] = 1.65, 95%CI: 1.08, 2.52; P = .021). There were no significant differences between the PELD group and other surgical group in terms of success rate (RR = 1.01, 95%CI: 0.97, 1.04; P = .733), complication rate (RR = 0.86, 95%CI: 0.63, 1.18; P = .361), Japanese Orthopaedic Association Score score (WMD = 0.19, 95%CI: -1.90, 2.27; P = .861), visual analog scale score for back pain (WMD = -0.17, 95%CI: -0.55, 0.21; P = .384) and leg pain (WMD = 0.00, 95%CI: -0.10, 0.10; P = .991), and Oswestry Disability Index score (WMD = -0.29, 95%CI: -1.00, 0.43; P = .434). CONCLUSION: PELD was associated with better effects and similar complications with other surgeries in LDH. However, it also resulted in a higher recurrence rate. Considering the potential limitations in the present study, further large-scale, well-performed randomized trials are needed to verify our findings.