Exercise Attenuate Diaphragm Atrophy in COPD Mice via Inhibiting the RhoA/ROCK Signaling.

Background: Exercise is an indispensable component of pulmonary rehabilitation with strong anti-inflammatory effects. However, the mechanisms by which exercise prevents diaphragmatic atrophy in COPD (chronic obstructive pulmonary disease) remain unclear. Methods: Forty male C57BL/6 mice were assigned to the control (n=16) and smoke (n=24) groups. Mice in the smoke group were exposed to the cigarette smoke (CS) for six months. They were then divided into model and exercise training groups for 2 months. Histological changes were observed in lung and diaphragms. Subsequently, agonist U46639 and antagonist Y27632 of RhoA/ROCK were subjected to mechanical stretching in LPS-treated C2C12 myoblasts. The expression levels of Atrogin-1, MuRF-1, MyoD, Myf5, IL-1ß, TNF-α, and RhoA/ROCK were determined by Western blotting. Results: Diaphragmatic atrophy and increased RhoA/ROCK expression were observed in COPD mice. Exercise training attenuated diaphragmatic atrophy, decreased the expression of MuRF-1, and increased MyoD expression in COPD diaphragms. Exercise also affects the upregulation of RhoA/ROCK and inflammation-related proteins. In in vitro experiments with C2C12 myoblasts, LPS remarkably increased the level of inflammation and protein degradation, whereas Y27632 or combined with mechanical stretching prevented this phenomenon considerably. Conclusion: RhoA/ROCK plays an important role in the prevention of diaphragmatic atrophy in COPD.

Obesogenic potentials of environmental artificial sweeteners with disturbances on both lipid metabolism and neural responses.

Artificial sweeteners (ASs) entered the environments after application and emissions. Recent studies showed that some ASs had obesogenic risks. However, it remained unclear whether such risks are common and how they provoke such effects. Presently, the effects of 8 widely used ASs on lipid accumulation were measured in Caenorhabditis elegans. Potential mechanisms were explored with feeding and locomotion behavior, lipid metabolism and neural regulation. Results showed that acesulfame (ACE), aspartame (ASP), saccharin sodium (SOD), sucralose (SUC) and cyclamate (CYC) stimulated lipid accumulation at µg/L levels, showing obesogenic potentials. Behavior investigation showed that ACE, ASP, SOD, SUC and CYC biased more feeding in the energy intake aspect against the locomotion in the energy consumption one. Neotame (NEO), saccharin (SAC) and alitame (ALT) reduced the lipid accumulation without significant obesogenic potentials in the present study. However, all 8 ASs commonly disturbed enzymes (e.g., acetyl-CoA carboxylase) in lipogenesis and those (e.g., carnitine palmitoyl transferase) in lipolysis. In addition, ASs disturbed PPARγ (via expressions of nhr-49), TGF-ß/DAF-7 (daf-7) and SREBP (sbp-1) pathways. Moreover, they also interfered neurotransmitters including serotonin (5-HT), dopamine (DA) and acetylcholine (ACh), with influences in Gsα (e.g., via expressions of gsα-1, ser-7), glutamate (e.g., mgl-1), and cGMP-dependent signaling pathways (e.g., egl-4). In summary, environmental ASs commonly disturbed neural regulation connecting behavior and lipid metabolism, and 5 out of 8 showed clear obesogenic potentials. ENVIRONMENTAL IMPLICATION: Artificial sweeteners (ASs) are become emerging pollutants after wide application and continuous emission. Recent studies showed that some environmental ASs had obesogenic risks. The present study employed Caenorhabditis elegans to explore the influences of 8 commonly used ASs on lipid metabolisms and also the underlying mechanisms. Five out of 8 ASs stimulated lipid accumulation at µg/L levels, and they biased energy intake against energy consumption. The other three ASs reduced the lipid accumulation. ASs commonly disturbed lipogenesis and lipolysis via PPARγ, TGF-ß and SREBP pathways, and also influenced neurotransmitters with Gsα, glutamate and cGMP-dependent signaling pathways.

Hippocampal circAnk3 Deficiency Causes Anxiety-like Behaviors and Social Deficits by Regulating the miR-7080-3p/IQGAP1 Pathway in Mice.

BACKGROUND: Circular RNAs are highly enriched in the synapses of the mammalian brain and play important roles in neurological function by acting as molecular sponges of microRNAs. circAnk3 is derived from the 11th intron of the ankyrin-3 gene, Ank3, a strong genetic risk factor for neuropsychiatric disorders; however, the function of circAnk3 remains elusive. In this study, we investigated the function of circAnk3 and its downstream regulatory network for target genes in the hippocampus of mice. METHODS: The DNA sequence from which circAnk3 is generated was modified using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9) technology, and neurobehavioral tests (anxiety and depression-like behaviors, social behaviors) were performed in circAnk3+/- mice. A series of molecular and biochemical assays were used to investigate the function of circAnk3 as a microRNA sponge and its downstream regulatory network for target genes. RESULTS: circAnk3+/- mice exhibited both anxiety-like behaviors and social deficits. circAnk3 was predominantly located in the cytoplasm of neuronal cells and functioned as a miR-7080-3p sponge to regulate the expression of Iqgap1. Inhibition of miR-7080-3p or restoration of Iqgap1 in the hippocampus ameliorated the behavioral deficits of circAnk3+/- mice. Furthermore, circAnk3 deficiency decreased the expression of the NMDA receptor subunit GluN2a and impaired the structural plasticity of dendritic synapses in the hippocampus. CONCLUSIONS: Our results reveal an important role of the circAnk3/miR-7080-3p/IQGAP1 axis in maintaining the structural plasticity of hippocampal synapses. circAnk3 might offer new insights into the involvement of circular RNAs in neuropsychiatric disorders.

Effects of external diaphragm pacing combined with conventional rehabilitation therapies in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

BACKGROUND: Numerous randomized controlled trials (RCTs) have reported the benefits of external diaphragm pacing combined with conventional rehabilitation therapies (EDP-CRTs) on pulmonary function and exercise capacity in patients with chronic obstructive pulmonary disease (COPD). However, evidence-based regarding its effects remains unclear. OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the effects of EDP-CRTs versus CRTs on patients with COPD. DESIGN: Systematic review and meta-analysis. DATA SOURCES AND METHODS: We performed a systematic review and meta-analysis, searching PubMed, Embase, Cochrane Central Register of Controlled Trials, Scopus, China Biology Medicine Disc, Chinese National Knowledge Infrastructure, Wan-Fang Database, and Chinese Scientific Journal Database from inception to 10 September 2023. RCTs investigating the effects of EDP-CRTs versus CRTs on COPD patients were included. The primary outcome was pulmonary function, including forced expiratory volume in 1 s (FEV1), the percentage of predicted values of FEV1 (FEV1%pred), and FEV1/forced vital capacity (FVC)%. Secondary outcomes included arterial blood gas analysis [the partial pressure of arterial oxygen (PaO2) and the partial pressure of arterial carbon dioxide (PaCO2)]; dyspnea [modified Medical Research Council Dyspnea Scale (mMRC)]; exercise capacity [6-min walking distance (6MWD)]; and quality of life [COPD assessment test (CAT)]. RevMan 5.3 software was used for meta-analysis. The quality of the included studies was assessed using the revised Cochrane Risk of Bias tool for randomized trials (RoB 2.0). The certainty of the evidence was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: In total, 13 studies/981 participants were included. The pooled results revealed significant benefits of EDP-CRTs versus CRTs on the FEV1 [standardized mean difference (SMD) = 1.07, 95% confidence interval (CI) = 0.58-1.56], FEV1%pred [weighted mean difference (WMD) = 6.67, 95% CI = 5.69-7.64], the FEV1/FVC% (SMD = 1.24, 95% CI = 0.48-2.00), PaO2 (SMD = 1.29, 95% CI = 0.74-1.84), PaCO2 (SMD = -1.88, 95% CI = -2.71 to -1.04), mMRC (WMD = -0.55, 95% CI = -0.65 to -0.45), 6MWD (SMD = 1.63, 95% CI = 0.85-2.42), and CAT (WMD = -1.75, 95% CI = -3.16 to -0.35), respectively. Planned subgroup analysis suggested that EDP-CRTs had a better effect on FEV1, FEV1/FVC%, 6MWD, and CAT in the duration of 2-4 weeks. CONCLUSION: EDP-CRTs have better effects on pulmonary function, PaCO2, dyspnea, exercise capacity, and quality of life in COPD patients than CRTs, and the duration to achieve the most effective treatment is 2-4 weeks. TRIAL REGISTRATION: This systematic review and meta-analysis protocol was prospectively registered with PROSPERO (No. CRD42022355964).

Effects of pulmonary-based Qigong exercise in stable patients with chronic obstructive pulmonary disease: a randomized controlled trial.

BACKGROUND: Physical exercise training is the central component of pulmonary rehabilitation. This study aimed to further investigate the rehabilitative effects of pulmonary-based Qigong exercise (PQE) in stable patients with chronic obstructive pulmonary disease (COPD). METHODS: In this randomized, assessor-blinded clinical trial, 44 participants with stable COPD were randomly assigned to 2 groups in a 1:1 ratio. Participants in the control group received usual care for 3 months. Participants in the intervention group received usual care combined with PQE (60 min each time, 2 times per day, 7 days per week, for 3 months). The outcome included exercise capacity, lung function test, skeletal muscle strength, dyspnea, and quality of life were measured before and after intervention. RESULTS: A total of 37 participants completed the trial. Compared to the control group, after 3 months of PQE, the mean change in exercise capacity, skeletal muscle strength, and quality of life were statistically significant (P < 0.05, for each), but no significant differences were observed in lung function (except for the forced expiratory volume in one second) and dyspnea (P > 0.05, for each). CONCLUSION: The findings of study suggest that the proposed program of 3 months of PQE intervention has significant improvement in exercise capacity, skeletal muscle strength, and quality of life of COPD-stable patients. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (Trial ID: ChiCTR-1800017405 on 28 July 2018; available at https://www.chictr.org.cn/showproj.html?proj=28343 ).

Role of Nrf2 and exercise in alleviating COPD-induced skeletal muscle dysfunction.

Chronic obstructive pulmonary disease (COPD) is a complex chronic respiratory disease with cumulative impacts on multiple systems, exhibiting significant extrapulmonary impacts, and posing a serious public health problem. Skeletal muscle dysfunction is one of the most pronounced extrapulmonary effects in patients with COPD, which severely affects patient prognosis and mortality primarily through reduced productivity resulting from muscle structural and functional alterations. Although the detailed pathogenesis of COPD has not been fully determined, some researchers agree that oxidative stress plays a significant role. Oxidative stress not only catalyzes the progression of pulmonary symptoms but also drives the development of skeletal muscle dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2), is a key transcription factor that regulates the antioxidant response and plays an enormous role in combating oxidative stress. In this review, we have summarized current research on oxidative stress damage to COPD skeletal muscle and analyzed the role of Nrf2 in improving skeletal muscle dysfunction in COPD through exercise. The results suggest that oxidative stress drives the occurrence and development of skeletal muscle dysfunction in COPD. Exercise may improve skeletal muscle dysfunction in patients with COPD by promoting the dissociation of Kelch-like ECH-associated protein 1 (Keap1) and Nrf2, inducing sequestosome1(p62) phosphorylation to bind with Keap1 competitively leading to Nrf2 stabilization and improving dynamin-related protein 1-dependent mitochondrial fission. Nrf2 may be a key target for exercise anti-oxidative stress to alleviate skeletal muscle dysfunction in COPD.

Neurodevelopmental defects in human cortical organoids with N-acetylneuraminic acid synthase mutation.

Biallelic genetic variants in N-acetylneuraminic acid synthase (NANS), a critical enzyme in endogenous sialic acid biosynthesis, are clinically associated with neurodevelopmental disorders. However, the mechanism underlying the neuropathological consequences has remained elusive. Here, we found that NANS mutation resulted in the absence of both sialic acid and protein polysialylation in the cortical organoids and notably reduced the proliferation and expansion of neural progenitors. NANS mutation dysregulated neural migration and differentiation, disturbed synapse formation, and weakened neuronal activity. Single-cell RNA sequencing revealed that NANS loss of function markedly altered transcriptional programs involved in neuronal differentiation and ribosomal biogenesis in various neuronal cell types. Similarly, Nans heterozygous mice exhibited impaired cortical neurogenesis and neurobehavioral deficits. Collectively, our findings reveal a crucial role of NANS-mediated endogenous sialic acid biosynthesis in regulating multiple features of human cortical development, thus linking NANS mutation with its clinically relevant neurodevelopmental disorders.

Anti-inflammatory effects of acupuncture in the treatment of chronic obstructive pulmonary disease.

Numerous randomised controlled trials have suggested the positive effects of acupuncture on chronic obstructive pulmonary disease (COPD). However, the underlying therapeutic mechanisms of acupuncture for COPD have not been clearly summarized yet. Inflammation is central to the development of COPD. In this review, we elucidate the effects and underlying mechanisms of acupuncture from an anti-inflammatory perspective based on animal studies. Cigarette smoke combined with lipopolysaccharide is often used to establish animal models of COPD. Electroacupuncture can be an effective intervention to improve inflammation in COPD, and Feishu (BL13) and Zusanli (ST36) can be used as basic acupoints in COPD animal models. Different acupuncture types can regulate different types of inflammatory cytokines; meanwhile, different acupuncture types and acupoint options have similar effects on modulating the level of inflammatory cytokines. In particular, acupuncture exerts anti-inflammatory effects by inhibiting the release of inflammatory cells, inflammasomes and inflammatory cytokines. The main underlying mechanism through which acupuncture improves inflammation in COPD is the modulation of relevant signalling pathways: nuclear factor-κB (NF-κB) (e.g., myeloid differentiation primary response 88/NF-κB, toll-like receptor-4/NF-κB, silent information regulator transcript-1/NF-κB), mitogen-activated protein kinase signalling pathways (extracellular signal-regulated kinase 1/2, p38 and c-Jun NH2-terminal kinase), cholinergic anti-inflammatory pathway, and dopamine D2 receptor pathway. The current synthesis will be beneficial for further research on the effect of acupuncture on COPD inflammation. Please cite this article as: Jiang LH, Li PJ, Wang YQ, Jiang ML, Han XY, Bao YD, Deng XL, Wu WB, Liu XD. Anti-inflammatory effects of acupuncture in the treatment of chronic obstructive pulmonary disease. J Integr Med. 2023; 21(6): 518-527.

Methamphetamine exposure drives cell cycle exit and aberrant differentiation in rat hippocampal-derived neurospheres.

Introduction: Methamphetamine (METH) abuse by pregnant drug addicts causes toxic effects on fetal neurodevelopment; however, the mechanism underlying such effect of METH is poorly understood. Methods: In the present study, we applied three-dimensional (3D) neurospheres derived from the embryonic rat hippocampal tissue to investigate the effect of METH on neurodevelopment. Through the combination of whole genome transcriptional analyses, the involved cell signalings were identified and investigated. Results: We found that METH treatment for 24 h significantly and concentration-dependently reduced the size of neurospheres. Analyses of genome-wide transcriptomic profiles found that those down-regulated differentially expressed genes (DEGs) upon METH exposure were remarkably enriched in the cell cycle progression. By measuring the cell cycle and the expression of cell cycle-related checkpoint proteins, we found that METH exposure significantly elevated the percentage of G0/G1 phase and decreased the levels of the proteins involved in the G1/S transition, indicating G0/G1 cell cycle arrest. Furthermore, during the early neurodevelopment stage of neurospheres, METH caused aberrant cell differentiation both in the neurons and astrocytes, and attenuated migration ability of neurospheres accompanied by increased oxidative stress and apoptosis. Conclusion: Our findings reveal that METH induces an aberrant cell cycle arrest and neuronal differentiation, impairing the coordination of migration and differentiation of neurospheres.

Visible-Light-Mediated Intermolecular [2 + 2]-Cycloaddition Reaction of 3-Alkylideneindolin-2-one with Alkenes via Triplet Energy Transfer for the Synthesis of 3-Spirocyclobutyl Oxindoles.

[2 + 2]-Cycloaddition is the most straightforward approach to the construction of cyclobutanes. In this paper, the intermolecular [2 + 2]-cycloaddition reaction of 3-alkylideneindolin-2-ones with alkenes was achieved. This reaction can be used in the synthesis of 3-spirocyclobutyl oxindoles, polycyclic oxindoles, and late stage modification of some drug molecules.

Morphine Re-arranges Chromatin Spatial Architecture of Primate Cortical Neurons.

The expression of linear DNA sequence is precisely regulated by the three-dimensional (3D) architecture of chromatin. Morphine-induced aberrant gene networks of neurons have been extensively investigated; however, how morphine impacts the 3D genomic architecture of neurons is still unknown. Here, we applied digestion-ligation-only high-throughput chromosome conformation capture (DLO Hi-C) technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons. After receiving continuous morphine administration for 90 days on rhesus monkeys, we discovered that morphine re-arranged chromosome territories, with a total of 391 segmented compartments being switched. Morphine altered over half of the detected topologically associated domains (TADs), most of which exhibited a variety of shifts, followed by separating and fusing types. Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops. Moreover, all identified differentially expressed genes from the RNA sequencing data were mapped to the specific TAD boundaries or differential loops, and were further validated for changed expression. Collectively, an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated with morphine effects. Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.

Cardiolipin and OPA1 Team up for Methamphetamine-Induced Locomotor Activity by Promoting Neuronal Mitochondrial Fusion in the Nucleus Accumbens of Mice.

Mitochondria are highly dynamic organelles with coordinated cycles of fission and fusion occurring continuously to satisfy the energy demands in the complex architecture of neurons. How mitochondria contribute to addicted drug-induced adaptable mitochondrial networks and neuroplasticity remains largely unknown. Through liquid chromatography-mass spectrometry-based lipidomics, we first analyzed the alteration of the mitochondrial lipidome of three mouse brain areas in methamphetamine (METH)-induced locomotor activity and conditioned place preference. The results showed that METH remodeled the mitochondrial lipidome of the hippocampus, nucleus accumbens (NAc), and striatum in both models. Notably, mitochondrial hallmark lipid cardiolipin (CL) was specifically increased in the NAc in METH-induced hyperlocomotor activity, which was accompanied by an elongated giant mitochondrial morphology. Moreover, METH significantly boosted mitochondrial respiration and ATP generation as well as the copy number of mitochondrial genome DNA in the NAc. By screening the expressions of mitochondrial dynamin-related proteins, we found that repeated METH significantly upregulated the expression of long-form optic atrophy type 1 (L-OPA1) and enhanced the interaction of L-OPA1 with CL, which may promote mitochondrial fusion in the NAc. On the contrary, neuronal OPA1 depletion in the NAc not only recovered the dysregulated mitochondrial morphology and synaptic vesicle distribution induced by METH but also attenuated the psychomotor effect of METH. Collectively, upregulated CL and OPA1 cooperate to mediate METH-induced adaptation of neuronal mitochondrial dynamics in the NAc, which correlates with the psychomotor effect of METH. These findings propose a potential therapeutic approach for METH addiction by inhibiting neuronal mitochondrial fusion.

Integrated lipidomic and transcriptomic analysis reveals clarithromycin-induced alteration of glycerophospholipid metabolism in the cerebral cortex of mice.

Clarithromycin (CLA) has been widely used in the treatment of bacterial infection. Research reveals the adverse effects on the central nervous system among patients receiving CLA treatment; whereas, a relevant underlying mechanism remains considerably unclear. According to our research, an integrated lipidomic and transcriptomic analysis was applied to explore the effect of CLA on neurobehavior. CLA treatment caused anxiety-like behaviors dose-dependently during open field as well as elevated plus maze trials on mice. Transcriptomes and LC/MS-MS-based metabolomes were adopted for investigating how CLA affected lipidomic profiling as well as metabolic pathway of the cerebral cortex. CLA exposure greatly disturbed glycerophospholipid metabolism and the carbon chain length of fatty acids. By using whole transcriptome sequencing, we found that CLA significantly downregulated the mRNA expression of CEPT1 and CHPT1, two key enzymes involved in the synthesis of glycerophospholipids, supporting the findings from the lipidomic profiling. Also, CLA causes changes in neuronal morphology and function in vitro, which support the existing findings concerning neurobehavior in vivo. We speculate that altered glycerophospholipid metabolism may be involved in the neurobehavioral effect of CLA. Our findings contribute to understanding the mechanisms of CLA-induced adverse effects on the central nervous system. 1. Clarithromycin treatment caused anxiety-like behavior with dose-dependent response both in the open field and elevated plus maze test in mice; 2. Clarithromycin exposing predominately disturbed the metabolism of glycerophospholipids in the cerebral cortex of mice; 3. Clarithromycin application remarkably attenuated CEPT1 and CHPT1 gene expression, which participate in the last step in the synthesis of glycerophospholipids; 4. The altered glycerophospholipid metabolomics may be involved in the abnormal neurobehavior caused by clarithromycin.

Neonatal exposure to sevoflurane induces adolescent neurobehavioral dysfunction by interfering with hippocampal glycerophoslipid metabolism in rats.

Sevoflurane exposure in the neonatal period causes long-term developmental neuropsychological dysfunction, including memory impairment and anxiety-like behaviors. However, the molecular mechanisms underlying such effects have not been fully elucidated. In this study, we investigated the effect of neonatal exposure to sevoflurane on neurobehavioral profiles in adolescent rats, and applied an integrated approach of lipidomics and proteomics to investigate the molecular network implicated in neurobehavioral dysfunction. We found that neonatal exposure to sevoflurane caused cognitive impairment and social behavior deficits in adolescent rats. Lipidomics analyses revealed that sevoflurane significantly remodeled hippocampal lipid metabolism, including lysophatidylcholine (LPC) metabolism, phospholipid carbon chain length and carbon chain saturation. Through a combined proteomics analysis, we found that neonatal exposure to sevoflurane significantly downregulated the expression of lysophosphatidylcholine acyltransferase 1 (LPCAT1), a key enzyme in the regulation of phospholipid metabolism, in the hippocampus of adolescent rats. Importantly, hippocampal LPCAT1 overexpression restored the dysregulated glycerophospholipid (GP) metabolism and alleviated the learning and memory deficits caused by sevoflurane. Collectively, our evidence that neonatal exposure to sevoflurane downregulates LPCAT1 expression and dysregulates GP metabolism in the hippocampus, which may contribute to the neurobehavioral dysfunction in the adolescent rats.

ß-hydroxybutyrate reduces reinstatement of cocaine conditioned place preference through hippocampal CaMKII-α ß-hydroxybutyrylation.

Studies have shown the therapeutic effects of a ketogenic diet (KD) on epilepsy, but the effect of a KD on drug reinstatement is largely unclear. This study aims to investigate whether KD consumption possesses therapeutic potential for cocaine reinstatement and the molecular mechanism. We find that a KD significantly reduces cocaine-induced reinstatement in mice, which is accompanied by a markedly elevated level of ß-hydroxybutyrate (ß-OHB), the most abundant ketone body, in the hippocampus. The underlying mechanism is that ß-OHB posttranslationally modifies CaMKII-α with ß-hydroxybutyrylation, resulting in significant inhibition of T286 autophosphorylation and downregulation of CaMKII activity. Collectively, our results reveal that ß-hydroxybutyrylation is a posttranslational modification of CaMKII-α that plays a critical role in mediating the effect of KD consumption in reducing cocaine reinstatement.

Yijinjing Qigong intervention shows strong evidence on clinical effectiveness and electroencephalography signal features for early poststroke depression: A randomized, controlled trial.

Objective: Although Traditional Chinese Yijinjing Qigong Exercise (YJJQE) as mind-body intervention is popularly used among adults to ameliorate depressive symptoms in China, no randomized controlled trials (RCTs) are available to evaluate the effects of YJJQE in patients with poststroke depression (PSD). This study aims to explore the clinical efficacy and the neurological and psychiatric mechanism in brain network functional connectivity underlying electroencephalography (EEG). Materials and methods: A total of 60 patients, diagnosed with mild PSD, were randomly (1:1) assigned to YJJQE group (n = 30) and control group of routine segmental rehabilitation training group (n = 30) for a 60-min exercise session once a day for 3 weeks. All outcome measures were collected at baseline and 3-weeks ending intervention. The primary outcome was the 24-item Hamilton Depression Scale (HAMD-24) score, evaluation at more time points for 1 month of follow-up. The secondary outcomes were EEG data in four frequency domains (δ, θ, α, and ß), global efficiency (GE), local efficiency (LE), GE/LE curve [areas under the curve (AUC)], Phase Lag Index (PLI), (HAMD-24) Score and EEG correlation analysis. Results: All patients showed no significant differences in baseline data. After 3 weeks and 1 month of follow-up, the YJJQE group demonstrated significant decreasing changes compared to the control group on the HAMD-24 scores (p < 0.001). Furthermore, the YJJQE group also showed a significant reduction in θ wave, and an increase in both GE and LE. Compared to the control group, the YJJQE Qigong group showed significantly greater functional connectivity in the δ, θ, and ß frequency bands in the brain network of the degree of phase synchronization (p < 0.001). HAMD-24 Score and EEG correlation analysis negative correlation in the Qigong group θ wave (p < 0.001). Conclusion: Our findings demonstrated that YJJQE is estimated to effectively alleviate the depressed mood of patients with PSD by promoting the efficiency in information transmission of network functional connectivity and its integration ability in different brain regions. Therefore, the YJJQE would be useful as a non-pharmacological treatment to prevent PSD. Clinical trial registration: [http://www.chictr.org.cn/showproj.aspx?proj=55789], identifier [ChiCTR2000035588].

Synapse differentiation-induced gene 1 regulates stress-induced depression through interaction with the AMPA receptor GluA2 subunit of nucleus accumbens in male mice.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are key regulators during the process of synaptic plasticity in major depression disorder (MDD). Synapse differentiation-induced gene 1 (SynDIG1) functions as an atypical AMPAR auxiliary subunit and regulates synaptic AMPAR content; however, the role of SynDIG1 in MDD remains elusive. In this study, we found that the SynDIG1 expression was significantly increased in the neurons of the nucleus accumbens (NAc) of male mice after chronic social defeat stress (CSDS). CSDS enhanced SynDIG1-GluA2 binding and promoted the surface expression of AMPAR subunit GluA2 in the NAc. Knockdown of SynDIG1 decreased the surface expression of GluA2 and reversed the alteration of dendrite spines in the neurons, eventually alleviating the depressive-like behaviors of the stressed mice. Moreover, intra-NAc injection of IP12, a specific peptide to disrupt the interaction of SynDIG1 with GluA2, rescued depressive-like behaviors. Collectively, SynDIG1 regulates the surface expression of GluA2 and dendritic remodeling in the NAc of male mice under CSDS, thus mediating the depressive-like behaviors.

A two-stage deep learning architecture for radiographic staging of periodontal bone loss.

BACKGROUND: Radiographic periodontal bone loss is one of the most important basis for periodontitis staging, with problems such as limited accuracy, inconsistency, and low efficiency in imaging diagnosis. Deep learning network may be a solution to improve the accuracy and efficiency of periodontitis imaging staging diagnosis. This study aims to establish a comprehensive and accurate radiological staging model of periodontal alveolar bone loss based on panoramic images. METHODS: A total of 640 panoramic images were included, and 3 experienced periodontal physicians marked the key points needed to calculate the degree of periodontal alveolar bone loss and the specific location and shape of the alveolar bone loss. A two-stage deep learning architecture based on UNet and YOLO-v4 was proposed to localize the tooth and key points, so that the percentage of periodontal alveolar bone loss was accurately calculated and periodontitis was staged. The ability of the model to recognize these features was evaluated and compared with that of general dental practitioners. RESULTS: The overall classification accuracy of the model was 0.77, and the performance of the model varied for different tooth positions and categories; model classification was generally more accurate than that of general practitioners. CONCLUSIONS: It is feasible to establish deep learning model for assessment and staging radiographic periodontal alveolar bone loss using two-stage architecture based on UNet and YOLO-v4.

mTOR regulates cocaine-induced behavioural sensitization through the SynDIG1-GluA2 interaction in the nucleus accumbens.

Behavioral sensitization is a progressive increase in locomotor or stereotypic behaviours in response to drugs. It is believed to contribute to the reinforcing properties of drugs and to play an important role in relapse after cessation of drug abuse. However, the mechanism underlying this behaviour remains poorly understood. In this study, we showed that mTOR signaling was activated during the expression of behavioral sensitization to cocaine and that intraperitoneal or intra-nucleus accumbens (NAc) treatment with rapamycin, a specific mTOR inhibitor, attenuated cocaine-induced behavioural sensitization. Cocaine significantly modified brain lipid profiles in the NAc of cocaine-sensitized mice and markedly elevated the levels of phosphatidylinositol-4-monophosphates (PIPs), including PIP, PIP2, and PIP3. The behavioural effect of cocaine was attenuated by intra-NAc administration of LY294002, an AKT-specific inhibitor, suggesting that PIPs may contribute to mTOR activation in response to cocaine. An RNA-sequencing analysis of the downstream effectors of mTOR signalling revealed that cocaine significantly decreased the expression of SynDIG1, a known substrate of mTOR signalling, and decreased the surface expression of GluA2. In contrast, AAV-mediated SynDIG1 overexpression in NAc attenuated intracellular GluA2 internalization by promoting the SynDIG1-GluA2 interaction, thus maintaining GluA2 surface expression and repressing cocaine-induced behaviours. In conclusion, NAc SynDIG1 may play a negative regulatory role in cocaine-induced behavioural sensitization by regulating synaptic surface expression of GluA2.

Silencing uridine diphosphate N-acetylglucosamine pyrophosphorylase gene impairs larval development in Henosepilachna vigintioctopunctata.

BACKGROUND: Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) diphosphorylase (UAP) catalyzes the formation of UDP-GlcNAc, the precursor for the production of chitin in ectodermally derived epidermal cells and midgut, for GlcNAcylation of proteins and for generation of glycosyl-phosphatidyl-inositol anchors in all tissues in Drosophila melanogaster. RESULTS: Here, we identified a putative HvUAP gene in Henosepilachna vigintioctopunctata. Knockdown of HvUAP at the second-, third- and fourth-instar stages impaired larval development. Most resultant HvUAP hypomorphs showed arrested development at the third-, fourth-instar larval or prepupal stages, and became paralyzed, depending on the age when treated. Some HvUAP-silenced larvae had weak and soft scoli. A portion of HvUAP-depleted beetles formed misshapen pupae. No HvUAP RNA interference pupae successfully emerged as adults. Dissection and microscopic observation revealed that knockdown of HvUAP affected gut growth and food ingestion, reduced cuticle thickness, and negatively affected the formation of newly generated cuticle layers during ecdysis. Furthermore, HvUAP deficiency inhibited development of the tracheal respiratory system and thinned tracheal taenidia. CONCLUSION: The phenotypical defects in HvUAP hypomorphs suggest that HvUAP is involved in the production of chitin. Moreover, our findings will enable the development of a double-stranded RNA-based pesticide to control H. vigintioctopunctata. © 2021 Society of Chemical Industry.