The Role of Microglia with Mitochondrial Dysfunction and Its Therapeutic Prospects in Alzheimer's Disease.

Alzheimer's disease (AD), a primary cause of dementia, is rapidly emerging as one of the most financially taxing, lethal, and burdensome diseases of the 21st century. Increasing evidence suggests that microglia-mediated neuroinflammation plays a key role in both the initiation and progression of AD. Recently, emerging evidence has demonstrated mitochondrial dysfunction, particular in microglia where precedes neuroinflammation in AD. Multiple signaling pathways are implicated in this process and pharmaceutical interventions are potentially involved in AD treatment. In this review, advance over the last five years in the signaling pathways and pharmaceutical interventions are summarized and it is proposed that targeting the signaling pathways in microglia with mitochondrial dysfunction could represent a novel direction for AD treatment.

Circ-ZNF236 mediates stem cells from apical papilla differentiation by regulating LGR4-induced autophagy.

AIM: Human stem cells from the apical papilla (SCAPs) are an appealing stem cell source for tissue regeneration engineering. Circular RNAs (circRNAs) are known to exert pivotal regulatory functions in various cell differentiation processes, including osteogenesis of mesenchymal stem cells. However, few studies have shown the potential mechanism of circRNAs in the odonto/osteogenic differentiation of SCAPs. Herein, we identified a novel circRNA, circ-ZNF236 (hsa_circ_0000857) and found that it was remarkably upregulated during the SCAPs committed differentiation. Thus, in this study, we showed the significance of circ-ZNF236 in the odonto/osteogenic differentiation of SCAPs and its underlying regulatory mechanisms. METHODOLOGY: The circular structure of circ-ZNF236 was identified via Sanger sequencing, amplification of convergent and divergent primers. The proliferation of SCAPs was detected by CCK-8, flow cytometry analysis and EdU incorporation assay. Western blotting, qRT-PCR, Alkaline phosphatase (ALP) and Alizarin red staining (ARS) were performed to explore the regulatory effect of circ-ZNF236/miR-218-5p/LGR4 axis in the odonto/osteogenic differentiation of SCAPs in vitro. Fluorescence in situ hybridization, as well as dual-luciferase reporting assays, revealed that circ-ZNF236 binds to miR-218-5p. Transmission electron microscopy (TEM) and mRFP-GFP-LC3 lentivirus were performed to detect the activation of autophagy. RESULTS: Circ-ZNF236 was identified as a highly stable circRNA with a covalent closed loop structure. Circ-ZNF236 had no detectable influence on cell proliferation but positively regulated SCAPs odonto/osteogenic differentiation. Furthermore, circ-ZNF236 was confirmed as a sponge of miR-218-5p in SCAPs, while miR-218-5p targets LGR4 mRNA at its 3'-UTR. Subsequent rescue experiments revealed that circ-ZNF236 regulates odonto/osteogenic differentiation by miR-218-5p/LGR4 in SCAPs. Importantly, circ-ZNF236 activated autophagy, and the activation of autophagy strengthened the committed differentiation capability of SCAPs. Subsequently, in vivo experiments showed that SCAPs overexpressing circ-ZNF236 promoted bone formation in a rat skull defect model. CONCLUSIONS: Circ-ZNF236 could activate autophagy through increasing LGR4 expression, thus positively regulating SCAPs odonto/osteogenic differentiation. Our findings suggested that circ-ZNF236 might represent a novel therapeutic target to prompt the odonto/osteogenic differentiation of SCAPs.

Electric-Eel-Type Bi-Ionic Gradient Battery.

Electric eels generate electricity with a discharge voltage of up to 860 V under ionic gradients, providing a fascinating example to inspire viable and flexible power sources. However, hitherto reported eel-related devices are strictly restricted by complicated fabrication and environmental energy input. Herein, an electric-eel-type bi-ionic gradient battery (BGB) is performed by cationic and anionic polyelectrolyte hydrogels featuring simplified units and self-energy supply. Benefiting from ionic bonds with opposite charges in the polymer chain, bianion gradients as well as ion selective migration pathways are synchronously constructed and integrated units are enabled. As a result, an open-circuit voltage of 0.54 V and a short-circuit current density of 13 µA cm-2 are generated by a BGB unit. Moreover, a voltage output up to 60 V is derived from integrated BGB devices, demonstrating the potential to drive wearable and implantable electronics. In this case, these artificial electric systems could overcome the great challenges of environmentally friendly, biocompatible, low-cost, and soft power sources, providing in-depth insights into the development of clean and sustainable power generation technologies.

Poster Session: Investigating temporal evolutions of perceptual choice within biological and artificial neural networks.

Perceptual decisions involve a process that evolves over time until it reaches a decision boundary. It's important to understand how this process unfolds. Recent psychophysical data indicates that the visual system extracts motion axis information faster than motion direction information (Kwon et al., 2015, J Vision). To understand the underlying mechanisms, we developed a biophysically realistic cortical network model of decision making. We generalized the two-variable reduced spiking neural network (Wong et al., 2006, J Neuroscience) to four-variable. The network input is based on motion energy (Adelson et al., 1985, Josa a) and the temporal profile of surround influence (Tadin et al., 2006, J Neuroscience). The model reproduces the prior experimental findings, showing the motion axis extraction before direction extraction. It reveals a stronger axis-wise inhibitory connection between the selective neural populations than the direction-wise inhibitory connection. We further designed a recurrent deep neural network to validate the neural population connectivity pattern. Our model provides a quantitative explanation for the temporal evolution of motion direction judgments. The results show that the spatiotemporal filtering for visual motion integration, the center-surround antagonism, and stronger axis-wise inhibitory connection between the selective neural populations can explain how the visual system can extract motion axis orientation before detecting motion direction.

Dynamic Surface Reconstruction of Amphoteric Metal (Zn, Al) Doped Cu2 O for Efficient Electrochemical CO2 Reduction to C2+ Products.

The recognition of the surface reconstruction of the catalysts during electrochemical CO2 reduction (CO2RR) is essential for exploring and comprehending active sites. Although the superior performance of Cu-Zn bimetallic sites toward multicarbon C2+ products has been established, the dynamic surface reconstruction has not been fully understood. Herein, Zn-doped Cu2 O nano-octahedrons are used to investigate the effect of the dynamic stability by the leaching and redeposition on CO2RR. Correlative characterizations confirm the Zn leaching from Zn-doped Cu2 O, which is redeposited at the surface of the catalysts, leading to dynamic stability and abundant Cu-Zn bimetallic sites at the surface. The reconstructed Zn-doped Cu2 O catalysts achieve a high Faradaic efficiency (FE) of C2+ products (77% at -1.1 V versus reversible hydrogen electrode (RHE)). Additionally, similar dynamic stability is also discovered in Al-doped Cu2 O for CO2RR, proving its universality in amphoteric metal-doped catalysts. Mechanism analyses reveal that the OHC-CHO pathway can be the C-C coupling processes on bare Cu2 O and Zn-doped Cu2 O, and the introduction of Zn to Cu can efficiently lower the energy barrier for CO2RR to C2 H4 . This research provides profound insight into unraveling surface dynamic reconstruction of amphoteric metal-containing electrocatalysts and can guide rational design of the high-performance electrocatalysts for CO2RR.

Ketogenic Diet as a Promising Non-Drug Intervention for Alzheimer's Disease: Mechanisms and Clinical Implications.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is mainly characterized by cognitive deficits. Although many studies have been devoted to developing disease-modifying therapies, there has been no effective therapy until now. However, dietary interventions may be a potential strategy to treat AD. The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with adequate protein. KD increases the levels of ketone bodies, providing an alternative energy source when there is not sufficient energy supply because of impaired glucose metabolism. Accumulating preclinical and clinical studies have shown that a KD is beneficial to AD. The potential underlying mechanisms include improved mitochondrial function, optimization of gut microbiota composition, and reduced neuroinflammation and oxidative stress. The review provides an update on clinical and preclinical research on the effects of KD or medium-chain triglyceride supplementation on symptoms and pathophysiology in AD. We also detail the potential mechanisms of KD, involving amyloid and tau proteins, neuroinflammation, gut microbiota, oxidative stress, and brain metabolism. We aimed to determine the function of the KD in AD and outline important aspects of the mechanism, providing a reference for the implementation of the KD as a potential therapeutic strategy for AD.

Competitor-Weighted Centrality and Small-World Clusters in Competition Networks on Firms' Innovation Ambidexterity: Evidence from the Wind Energy Industry.

A firm's embedding structures in a technology competition network can influence its propensity for innovation ambidexterity. Using PCT (patent cooperation treaty) patent data of wind energy companies between 2010 and 2019, we adopted social network analysis and fixed-effects panel negative binomial regression to examine the impacts of network structural features on firm innovation ambidexterity. The results show that competitor-weighted centrality contributes to a firm's propensities for both incremental and radical green innovation. In contrast, a firm's embeddedness in small-world clusters can moderate the effect of the firm's competitor-weighted centrality positively on its incremental innovation but negatively on its radical innovation. The study makes three theoretical contributions. First, it enriches the understanding of how the competition network affects innovation ambidexterity. Second, it provides new insights into the relationship between competition network structures and technology innovation strategy. Finally, it contributes to bridging the research on the social embeddedness perspective and green innovation literature. The findings of this study have important implications for enterprises in the wind energy sector regarding how competitive relationships affect green technology innovation. The study underscores the importance of considering the competitiveness of a firm's rivals and the embedded structural features when devising green innovation strategies.

Fatigue assessment of sedentary office workers using smartphones: a preliminary study.

Objectives. Smartphone-based gait assessment provides a novel method to evaluate fatigue. This study aimed to examine self-reported fatigue and gait parameters recorded using a smartphone before and after an 8-h work day in bank workers, and identify the relationship between self-reported fatigue and gait parameters. Methods. One hundred bank workers (aged 20-45 years) were tested before and after an 8-h work day using a reaction time test, self-reported fatigue scale and gait test. Spearman correlation coefficient analysis and partial least squares regression were used to identify the relationship between self-reported fatigue and gait parameters. Results. Reaction time and self-reported fatigue increased significantly after work. Gait parameters (step frequency, minimum acceleration, acceleration root mean square, step regularity and step counts) decreased; step time and step time variability increased significantly (p < 0.05). We found a significant correlation between changes (Δ) for Δwork engagement and Δstep frequency (r = -0.20, p < 0.05), Δwork engagement and Δstep time (r = 0.21, p < 0.05), and Δwork tasks and Δstep symmetry (r = -0.20, p < 0.05). Conclusion. This study suggests that step frequency, step time and step symmetry measured using a smartphone have the potential to be used as predictors of work fatigue.

Chloral Hydrate Alters Brain Activation Induced by Methamphetamine-Associated Cue and Prevents Relapse.

Methamphetamine is a highly addictive drug and its abuse leads to serious health and social problems. Until now, no effective medications are yet available for the treatment of methamphetamine addiction. Our study reveals that chloral hydrate, a clinical sedative drug, suppresses the seeking desire for methamphetamine. After 5 days of continuous administration (subanesthetic dose 50 mg/kg and 100 mg/kg), methamphetamine-seeking behavior of rats was inhibited in the condition place preference and intravenous self-administration tests. Furthermore, chloral hydrate treatment robustly suppressed cue-induced methamphetamine relapse. The whole brain c-fos immunostaining revealed that chloral hydrate treatment suppressed neuronal activity in the rhomboid thalamic nucleus (Rh), dorsal endopiriform nucleus (dEn), and claustrum (Cl) while enhanced zona incerta (ZI) activity during cue-induced methamphetamine relapse. Therefore, chloral hydrate could remodel neural network activity and serve as a potential medicine to treat methamphetamine addiction.

Ketogenic diet ameliorates cognitive impairment and neuroinflammation in a mouse model of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative disorder that causes dementia and affects millions of people worldwide. Although it has devastating outcomes for patients and tremendous economic costs to society, there is currently no effective treatment available. AIMS: The high-fat, low-carbohydrate ketogenic diet (KD) is an established treatment for refractory epilepsy with a proven efficacy. Although the considerable interest has emerged in recent years for applying KD in AD patients, only few interventional studies in animals and humans have addressed the effects of KD on cognitive impairments, and the results were inconclusive. The aim of this study was to explore the impact of KD on cognitive functions and AD pathology in 5XFAD mice-a validated animal model of AD. RESULTS: Four months of a ketogenic diet improved spatial learning, spatial memory and working memory in 5XFAD mice. The improvement in cognitive functions was associated with a restored number of neurons and synapses in both the hippocampus and the cortex. Ketogenic diet treatment also reduced amyloid plaque deposition and microglial activation, resulting in reduced neuroinflammation. The positive effect of ketogenic diet on cognitive functions depended on the starting time and the duration of the diet. A shorter period (2 months) of ketogenic diet treatment had a weaker effect. Ketogenic diet initiated at late stage of AD (9 months of age) displayed no effect on cognitive improvement. CONCLUSIONS: These findings indicate positive effects of ketogenic diet on both cognitive function and histopathology in Alzheimer's disease, which could be due to reduced microglial activation and neuroinflammation. Our findings provide new insights and therapeutic interventions for the treatment of Alzheimer's disease.

Efficacy of Lycium barbarum L. on plasma lipid concentration in adults: A protocol for systematic review and meta-analysis.

BACKGROUND: Dyslipidemia is an important risk factor for atherosclerotic cardiovascular disease. Lycium barbarum L. are widely used as medicinal and functional food and may be particularly beneficial for patients with dyslipidemia. This systematic review protocol is designed to be used to evaluate the effects of Lycium barbarum L. on plasma lipid concentration through systematic reviews and meta-analysis. METHODS: The Following electronic databases will be searched from inception to October 2021: the China National Knowledge Infrastructure, PubMed, Cochrane Library, Web of Science, and Wan-fang database. All randomized controlled trial designs evaluated the effects of Lycium barbarum L. on plasma concentrations of lipids will be included. Two researchers will operate literature retrieval, screening, information extraction, quality assessment, and data analysis independently. The analysis will be conducted using Rstudio software (Version 1.4.1717). RESULTS: The findings will be submitted to a peer-reviewed publication. CONCLUSION: This study will provide practical and targeted evidence in investigating the impact of Lycium barbarum L. on plasma lipid concentration in adults. REGISTRATION NUMBER: INPLASY2021110043.

Numerical Investigation of the Composite Action of Axially Compressed Concrete-Filled Circular Aluminum Alloy Tubular Stub Columns.

This paper studied the composite action of concrete-filled circular aluminum alloy tubular (CFCAT) stub columns under axial compression. A fine-meshed finite three-dimensional (3D) solid element model making use of a tri-axial plastic-damage constitutive model of concrete and elastoplastic constitutive model of aluminum alloy was established. A parametric study utilizing the verified finite element (FE) model was carried out and the analytical results were exploited to investigate the composite actions of concrete-filled circular aluminum alloy tubular stub columns subjected axial compression. Compared with the concrete-filled steel tube (CFCST) stub columns, the aluminum alloy tube exerted a weaker constraint effect on the infilled concrete due to its lower elastic modulus. Based on the FE analytical results and regression method, the composite action model of concrete-filled circular aluminum alloy tubular stub columns was proposed. By generalizing the stress nephogram of the concrete-filled circular aluminum alloy tubular stub column at the limit state, a design formula was proposed to estimate the ultimate bearing capacity the columns using the superposition method. The predicted results of the proposed formula show a good agreement with both the experimental and FE analytical results. The comparison between the proposed formula and current design methods indicates that the proposed formula is more accurate and convenient to use.

Oriented Assembly of Anisotropic Nanosheets into Ultrathin Flowerlike Superstructures for Energy Storage.

The hierarchical ultrathin nanostructures are excellent electrode materials for supercapacitors because of their large surface area and their ability to promote ion and electron transport. Herein, we investigated nine l-amino acids (LAs) as inductive agents to synthesize a series of CoNi-OH/LAs materials for energy storage. With the different amino acids, the assembled CoNi-OH/LAs form a lamellar, flower-shaped, and bulk structure. Among all materials, the ultrathin flowerlike CoNi2-OH/l-asparagine (CoNi2-OH/l-Asn) exhibits an excellent specific capacity of 405.4 mAh g-1 (2608 F g-1) and a 100% retention rate after 3000 cycles. We also assembled asymmetrical supercapacitor CoNi2-OH/l-Asn//N-rGO devices, which demonstrated an energy density of 64.9 Wh kg-1 at 799.9 W kg-1 and superlong cycling stability (82.4% at 10 A g-1) over 5000 cycles.

Neuregulin1-ErbB4 Signaling in Spinal Cord Participates in Electroacupuncture Analgesia in Inflammatory Pain.

Chronic inflammatory pain is a severe clinical symptom that aggravates the life quality of patients and places a huge economic burden on individuals and society. As one complementary and alternative therapy, electroacupuncture (EA) is widely used in clinical practice to treat chronic inflammatory pain based on its safety and efficacy. Previous studies have revealed the potential role of adenosine, neuropeptides, and inflammatory factors in EA analgesia in various pain models, but the identity of some of the signaling pathways involved remain unknown. In the present study, we explored whether neuregulin1 (NRG1)-ErbB4 signaling is involved in EA analgesia in inflammatory pain. Repeated EA treatment at the acupoints Zusanli (ST36) and Sanyinjiao (SP6) for 3 consecutive days remarkably attenuated mechanical allodynia and thermal hyperalgesia in complete Freund's adjuvant (CFA)-treated mice, with an increased expression of NRG1 in spinal cord (SC). We found that ErbB4 kinase participated in both the EA and NRG1 mediated analgesic effects on inflammatory pain by pharmacological inhibition or genetic ablation ErbB4 in vivo. Intriguingly, the mice with conditional knockout of ErbB4 from PV+ interneurons in SC showed abnormal basal mechanical threshold. Meanwhile, NRG1 treatment could not relieve tactile allodynia in PV-Erbb4-/- mice or AAV-PV-Erbb4-/- mice after CFA injection. These experimental results suggest that regulating NRG1-ErbB4 signaling in SC could reduce pain hypersensitivity and contribute to EA analgesia in inflammatory pain.

Confinement Effect and Efficiency of Concentrically Loaded RACFCST Stub Columns.

Recycled aggregate concrete-filled steel tubular (RACFST) columns are widely recognized as efficient structural members that can reduce the environmental impact of the building industry and improve the mechanical behavior of recycled aggregate concrete (RAC). The objective of this study is to investigate the behavior of recycled aggregate concrete-filled circular steel tubular (RACFCST) stub columns subjected to the axial loading. Three-dimensional finite element (FE) models were established using a triaxial plastic-damage constitutive model of RAC considering the replacement ratio of recycled aggregates. The FE analytical results revealed that the decreased ultimate bearing capacity of RACFCST stub columns compared with conventional concrete infilled steel tubular (CFST) columns was mainly due to the weakened confinement effect and efficiency. This trend will become more apparent with the larger replacement ratio of recycled aggregates. A practical design formula of the ultimate bearing capacity of RACFCST stub columns subjected to axial load was proposed on the basis of the reasonably simplified cross-sectional stress nephogram at the ultimate state. The derivation process incorporated the equilibrium condition and the superposition theory. The proposed equation was evaluated by comparing its accuracy and accessibility to some well-known design formulae proposed by other researchers and some widely used design codes.

Aggregation-induced chemiluminescence system for sensitive detection of mercury ions.

As mercury ions (Hg2+) are emanated to surroundings in the course of various natural events and human activities, an accurate sensing of Hg2+ is essential for human health and environmental protection. Herein, a new aggregation-induced chemiluminescence (CL) sensor for fast, sensitive, and selective detection of Hg2+ is developed, based on the CL enhancement of bis(2,4,6-trichlorophenyl)oxalate (TCPO)-H2O2 system by thiolate-protected gold complexes (Au(I)-thiolate complexes) in the aggregated state. Because Hg2+ has a strong interaction with hydrosulfuryl (-SH) groups in Au(I)-thiolate complexes, the aggregation is disrupted and the CL is quenched. The decrease of CL intensity is proportional to Hg2+ contents with a linear range of 0.005-10 µg mL-1 and the limit of detection (LOD) is 3 ng mL-1. To the best of our knowledge, this is the first AIE CL sensor for Hg2+ detection. The study opens up attractive perspectives for developing simple and rapid aggregation-induced CL methods in monitoring heavy metals.

Influence of Experimental Autoimmune Prostatitis on Sexual Function and the Anti-inflammatory Efficacy of Celecoxib in a Rat Model.

Experimental autoimmune prostatitis (EAP) is a well-established model induced by an autoimmune response to prostate antigen. The symptomatic, pathological, and immunological characteristics of EAP animals are highly consistent with human chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), which makes EAP an ideal model for this disease. Here, we investigate the influence of EAP on male rat sexual function and the efficacy of anti-inflammatory therapy with celecoxib. EAP rat models were established using male Wistar rats. Rats were randomly assigned to a normal control group, an EAP model group, or an EAP model with celecoxib treatment group (celecoxib group). Behavioral changes, sexual behavioral changes, and erectile function were estimated using an open-field test, a sucrose consumption test, mating experiments, and by intracavernous pressure/mean arterial pressure ratio (ICP/MAP). Histological changes in the prostate were observed by HE staining, and the serum inflammatory factors IL-1ß and TNF-α levels were measured by enzyme-linked immunosorbent assay. In addition, serotonin (5-hydroxytryptamine, 5-HT), 5-HT1A receptor, 5-HT2C receptor, and serotonin transporter (SERT) expression levels in the hippocampus and spinal cord (T13-L1, L5-S2) were examined by immunohistochemistry and western blot analysis. Results showed that EAP rats exhibited characteristics of depression, decreased sexual drive, premature ejaculation, and increased threshold of penile erection. Moreover, all these changes were effectively alleviated by celecoxib. Significant increases in prostatic interstitial infiltration by inflammatory cells and in serum IL-1ß and TNF-α levels were observed in EAP rats, and these were partially reduced by celecoxib. Additionally, the expression pattern of serotonin system regulators in the hippocampus and spinal cord were altered in EAP model rats, including a decrease in 5-HT levels and an increase in 5-HT1A receptor levels. In conclusion, autoimmune prostatitis impaired rat sexual function, and this was effectively prevented by anti-inflammatory therapy with celecoxib. Moreover, a serotonin system disorder in the central nervous system was likely mediated via inflammation in EAP rats.