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Increasing evidence indicates that nobiletin (NOB) is a promising neuroprotective agent. Astrocyte activation plays a key role in neurodegenerative disorders. Thus, this study aims to investigate the effects of NOB on astrocyte activation and the potential mechanisms. In this study, astrocytes were exposed to hypoxia injury for 24 h to induce activation in vitro. Glial fibrillary acidic protein (GFAP) was chosen as a marker of astrocyte activation. To evaluate the effects of NOB on the migration of activated astrocytes, we used a scratch wound healing assay and Transwell migration assay. In addition, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), mitochondrial membrane potential, Nrf2 and HO-1 were measured to investigate the mechanisms of NOB in the activation of astrocytes. We found that NOB alleviated astrocyte activation and decreased GFAP expression during hypoxia. Simultaneously, NOB alleviated the migration of astrocytes induced by hypoxia. With NOB treatment, hypoxia-induced oxidative stress was partially reversed, including reducing the production of ROS and MDA. Furthermore, NOB significantly improved the mitochondrial dysfunction in activated astrocytes. Finally, NOB promoted Nrf2 nuclear translocation and HO-1 expression in response to continuous oxidative damage. Our study indicates, for the first time, that NOB alleviates the activation of astrocytes induced by hypoxia in vitro, in part by ameliorating oxidative stress and mitochondrial dysfunction. This provides new insights into the neuroprotective effects of NOB.

Background Pathological stimuli cause mitochondrial damage and leakage of mitochondrial DNA (mtDNA) into the cytosol, as demonstrated in many cell types. The cytosolic mtDNA then drives the activation of noninfectious inflammation. Retinal microvascular endothelial cells (RMECs) play an important role in the inner endothelial blood–retinal barrier (BRB). RMEC dysfunction frequently occurs in posterior-segment eye diseases, causing loss of vision. In this study, we investigated the involvement of cytosolic mtDNA in noninfectious immune inflammation in RMECs under pathological stimuli. Methods RMECs were stimulated with 100 ng/ml lipopolysaccharide (LPS), 200 μM hydrogen peroxide (H 2 O 2 ), or 25 mM d -glucose. After 24 h, immunofluorescent staining was used to detect the opening of the mitochondrial permeability transition pore (MPTP). Cytosolic mtDNA was detected with immunofluorescent staining and PCR after stimulation. mtDNA was then isolated and used to transfect RMECs in vitro, and the protein levels of cGAS were evaluated with western blotting. Real-time PCR was used to examine cGAS mRNA expression levels at different time points after mtDNA stimulation. The activation of STING was detected with immunofluorescent staining 6 h after mtDNA stimulation. Western blotting was used to determine the expression of STING and IFNβ, the phosphorylation status of TBK1, IRF3, and nuclear factor-κB (NF-κB) P65, and the nuclear translocation of IRF3 and NF-κB P65 at 0, 3, 6, 12, and 24 h. The mRNA expression of proinflammatory cytokines CCL4, CXCL10, and IFNB1, and transcription factor IRF1 were determined with real-time PCR, together with the concentrations of intercellular adhesion molecule 1 (ICAM-1) mRNA. Results Pathological stimuli caused mtDNA to leak into the cytosol by opening the MPTP in RMECs after 24 h. Cytosolic mtDNA regulated the expression of cGAS and the distribution of STING in RMECs. It promoted ICAM-1, STING and IFNβ expression, TBK1, IRF3, and NF-κB phosphorylation and the nuclear translocation in RMECs at 12 and 24 h after its transfection. The mRNAs of proinflammatory cytokines CCL4, CXCL10, and IFNB1, and transcription factor IRF1 were significantly elevated at 12 and 24 h after mtDNA stimulation. Conclusions Pathological stimulation induces mtDNA escape into the cytosol of RMECs. This cytoplasmic mtDNA is recognized by the DNA sensor cGAS, increasing the expression of inflammatory cytokines through the STING–TBK1 signaling pathway. Ba7zzwjjDYYV6NH7beoByS Video Abstract . (MP4 37490 kb)

BackgroundImmune-checkpoint inhibitors (ICIs) emerged as a novel class of drugs for the treatment of a broad spectrum of malignancies. ICIs can produce durable antitumor responses but they are also associated with immune-related adverse events (irAEs). Endocrinopathies have reported as one of the most common irAEs of ICIs.MethodsThis study aimed to quantify association of endocrine adverse events (AEs) and ICI therapy and also to characterize the profiles of ICI-related endocrine complications from real-world practice. Data from the first quarter of 2014 to first quarter of 2019 in FDA Adverse Event Reporting System (FAERS) database were gathered to conduct disproportionality analysis. The definition of endocrine AEs relied on the preferred terms (PTs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Two signal indices based on statistical shrinkage transformation, reporting odds ratios (ROR) and information component (IC), were used to evaluate correlations between ICIs and endocrine events. For ROR, it was defined a signal if the lower limit of the 95% confidence interval (ROR025) more than one, with at least 3 cases. For IC, lower end of the 95% confidence interval of IC (IC025) exceeding zero was deemed statistically significant.ResultsA total of 29,294,336 records were involved, among these 6260 records related to endocrine AEs after ICIs treatment were identified. In general, male had a slightly lower reporting frequencies for ICIs-related endocrinopathies compared with female but not significant (ROR = 0.98 95%CI: 0.93–1.04) and the difference varied in several common endocrine AEs. Notably, in general, ICI drugs were significantly associated with over-reporting frequencies of endocrine complications, corresponding to IC025 = 2.49 and ROR025 = 5.99. For monotherapy, three strategies (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing endocrine events. Different reporting frequencies emerged when anti-CTLA-4 therapy was compared with anti-PD-1/PD-L1 medications for endocrine toxicities, corresponding to ROR = 1.68 (95%CI 1.55–1.83), ROR = 2.54 (95%CI 2.20–2.93), respectively. Combination therapy was associated with higher risk of endocrinopathies compared with monotherapy (ROR = 2.00, 95%CI 1.89–2.11). When further analysis, the spectrum of endocrine AEs differed in immunotherapy regimens. Hypothyroidism (N = 885,14.14%), adrenal insufficiency(N = 730,11.66%), hypophysitis (N = 688,10.99%) and hyperthyroidism (N = 472,7.54%) were top 4 ranked endocrine events after ICI therapy and their reporting frequency also differed in ICI immunotherapies.ConclusionOur pharmacovigilance analysis shows a high reporting frequency of endocrine AEs provoked by ICI monotherapy (especially anti-CTLA-4 therapy) and further reinforced by combination therapy. In addition, treatment with different ICI immunotherapies may result in a unique and distinct profile of endocrinopathies. Early recognition and management of ICI-related endocrine irAEs is of vital importance in clinical practice.

Sodium‐ion batteries (SIBs) hold great potential in the application of large‐scale energy storage. With the coming commercialization of SIBs, developing advanced anode of particularly hard carbon is becoming increasingly urgent yet challenging. Hard carbon still suffers from unclear sodium storage mechanism, unsatisfactory performance, and low initial Coulombic efficiency (ICE). Herein, the current state‐of‐the‐art advances in designing hard carbon anodes for high‐performance SIBs is summarized. First, the formation process of hard carbon and typical sodium storage models of “insertion–adsorption,” “adsorption–insertion,” “adsorption–pore filling,” and “adsorption–insertion–pore filling” are introduced systematically. Then, the key strategies including morphological engineering, heteroatom doping, and graphitic structure regulation are presented to enhance the capacity of hard carbon based on the in‐depth understanding of sodium storage behaviors. Subsequently, to promote the practical application of hard carbon, more attention is paid to the methods of ICE improvement, including electrolyte optimization, defect and surface engineering, and presodiation. Whereafter, hard‐carbon‐based SIBs and their intriguing applications are briefly sketched. Finally, future directions and challenging perspectives of hard‐carbon anodes for SIBs are proposed from the viewpoints of storage mechanisms, electrode structures, and presodiation techniques. Recent status and advances of sodium storage mechanisms and strategies for improving sodium storage performance of hard carbons are summarized. The future perspectives and key challenges are highlighted with the goal of clarifying the sodium storage mechanism, enhancing the initial Coulombic efficiency, and pursuing the commercial applications of hard carbons.

Stable operation over wide temperature ranges is still a great challenge for lithium-sulfur batteries facing actual operating environments. Electrocatalysis is an effective strategy to address the sluggish reaction kinetics of lithium polysulfides at low temperatures and exacerbated shuttling effect at high temperatures; however, its practicality is still restricted by the structural stability of the support electrodes. In this work, a binder with wide temperature range adaptability is designed with a structure-modulated stable electrocatalytic mechanism, which can achieve effective adsorption and accelerated conversion of lithium polysulfides, and high-temperature self-repair and low-temperature internal support of electrodes. Lithium-sulfur batteries with the binder have a specific capacity of 780 mAh g −1 (5 C, 8375 mA g −1 ), and 470 mAh g −1 (0.1 C, 167.5 mA g −1 ) even at −40 °C. This work realizes the stable operation across a temperature range of 100 °C solely by the innovative development of binder, which provides a unique perspective for wide-temperature range lithium-sulfur battery design. Complex environments with varying temperatures remain a major challenge for batteries. Here, authors develop a polymer composite binder with dynamic active sites and phase change properties, enabling lithium sulfur batteries to operate stably over a wide temperature range of −40 °C to 60 °C.

HighlightsA novel N-doped strategy of C2N3− in situ trimerization between the 2D MXene interlayers was first proposed.The ultra-fast pseudocapacitive behavior of Ti3C2Tx/Na3TCM anode was managed and verified.The as-fabricated sodium-ion capacitor delivers excellent electrochemical performance by anode/cathode mass matching.2D MXenes are attractive for energy storage applications because of their high electronic conductivity. However, it is still highly challenging for improving the sluggish sodium (Na)-ion transport kinetics within the MXenes interlayers. Herein, a novel nitrogen-doped Ti3C2Tx MXene was synthesized by introducing the in situ polymeric sodium dicyanamide (Na-dca) to tune the complex terminations and then utilized as intercalation-type pseudocapacitive anode of Na-ion capacitors (NICs). The Na-dca can intercalate into the interlayers of Ti3C2Tx nanosheets and simultaneously form sodium tricyanomelaminate (Na3TCM) by the catalyst-free trimerization. The as-prepared Ti3C2Tx/Na3TCM exhibits a high N-doping of 5.6 at.% in the form of strong Ti–N bonding and stabilized triazine ring structure. Consequently, coupling Ti3C2Tx/Na3TCM anode with different mass of activated carbon cathodes, the asymmetric MXene//carbon NICs are assembled. It is able to deliver high energy density (97.6 Wh kg−1), high power output (16.5 kW kg−1), and excellent cycling stability (≈ 82.6% capacitance retention after 8000 cycles).

System parameters identification of nonlinear bistable structures has attracted considerable interest because the performance enhancement of energy harvesting and vibration control is significantly dependent on the model parameter of nonlinear systems. Therefore, a two-stage subspace method is proposed to identify the critical parameters in the system equation of nonlinear bistable piezoelectric structures. The dynamic equation of nonlinear bistable piezoelectric structures is separated into an underlying linear electromechanical coupling equation and a nonlinear mechanical equation. At first, for the underlying linear electromechanical coupling equation, a force–displacement subspace is constructed to identify the linear mass, damping and stiffness. Meanwhile, a velocity–voltage subspace is created for the identification of the electromechanical coupling coefficient. Next, for the nonlinear mechanical equation, the nonlinear restoring force in bistable structures can be estimated by the extended nonlinear frequency response function. Numerical simulation on a magnetic coupled bistable piezoelectric structure is performed to investigate the influence of frequency-swept responses, the noise intensity and polynomial order on identification accuracy. Experimental measurement of a magnetic coupled asymmetric bistable piezoelectric beam is conducted under different excitation conditions. Experimental results demonstrate the effectiveness of the proposed identification method.

Poor growth and disease transmission of small sea urchins Strongylocentrotus intermedius in summer greatly hamper the production efficiency of the longline culture. Reducing the adverse effects of high stocking density while maintaining high biomass is essential to address these problems. Here, we conducted a laboratory experiment to simulate the multi-layer culture for sea urchins at ambient high temperatures (from 22.2 to 24.5 °C) in summer for ~ 7 weeks. Survival, body size, lantern growth, gut weight, food consumption, Aristotle's lantern reflex, 5-hydroxytryptamine concentration, pepsin activity and gut morphology were subsequently evaluated. The present study found that multi-layer culture led to significantly larger body size than those without multi-layer culture (the control group). This was probably because of the greater feeding capacity (indicated by lantern growth and Aristotle's lantern reflex) and food digestion (indicated by morphology and pepsin activity of gut) in the multi-layer cultured sea urchins. These results indicate that multi-layer is an effective approach to improving the growth efficiency of sea urchins at high temperatures. We assessed whether eliminating interaction further improve these commercially important traits of sea urchins in multi-layer culture. This study found that eliminating interactions displayed greater body size and Aristotle's lantern reflex than those not separated in the multi-layer culture. This approach also significantly reduced the morbidity compared with the control group. These novel findings indicate that eliminating interactions in multi-layer culture greatly contributes to the growth and disease prevention of sea urchins at high temperatures. The present study establishes a new technique for the longline culture of sea urchins in summer and provides valuable information into the longline culture management of other commercially important species (e.g. scallops, abalones and oysters).

Interaction among sea urchins remains largely uninvestigated, although the aggregation of sea urchins is common. In the present study, 1, 15 and 30 sea urchins Strongylocentrotus intermedius (11.06 ± 0.99 mm in test diameter) were placed in a 1 m 2 circular tank, respectively. Movement behaviors were recorded for 12 min to investigate potential interactions among sea urchins. After the 12-min control period, we added food cues into the tank and recorded the changes in sea urchins’ behaviors. For the first time, we here quantified the interactions among sea urchins in laboratory and found that the interactions varied with food cues and with different densities. The sea urchins dispersed in random directions after being released. There was no significant difference in the movement speed and the displacement of sea urchins among the three density groups (1, 15 and 30 ind/m 2 ). The interaction occurred when sea urchins randomly contacted with the conspecifics and slowed down the movement speed. The speed of sea urchins after physical contacts decreased by an average of 40% in the density of 15 ind/m 2 and 17% in the density of 30 ind/m 2 . This interaction resulted in significantly higher randomness in the movement direction and lower movement linearity in 15 and 30 ind/m 2 than in 1 ind/m 2 . After the introduction of food cues, the movement speed, displacement and dispersal distance of sea urchin groups decreased significantly in all the three densities. The dispersal distance and expansion speed of sea urchins were significantly lower in 30 ind/m 2 than those in 15 ind/m 2 . The present study indicates that the interaction among sea urchins limits the movement of individual sea urchin and provides valuable information into how large groups of sea urchins are stable in places where food is plentiful.

Hard carbons are promising anodes for sodium‐ion batteries. However, there is still considerable controversy regarding the sodium storage behaviors in hard carbons, which are mainly attributed to the varied precursors, confused pyrolysis mechanism, and different characterization methods. Herein, benefiting from the flexible molecular structure of polymers, a series of hard carbons with carefully tuned microstructures are fabricated by adjusting the ratio of aryl and alkyl groups in the epoxy resins. The results of dynamic mechanical analysis, in‐situ Fourier transform infrared spectra, and synchronous thermal gravimetric‐infrared spectrum‐gas chromatography/mass spectrometry reveal that replacing the alkyl with aryl groups in the resin can enhance the crosslink density, inhibit the degradation and rearrangement process, and further lead to a more disordered microstructure. In addition, it is suggested that accessible channels provided by sufficiently wide interlayer spacing are necessary for closed pore filling. The optimized anode delivers a high capacity of 375 mAh/g in half cell with an initial Coulombic efficiency of 80.61%, and an energy density of 252 Wh/kg is attained in full cell. Finally, a reliable relationship among precursor–pyrolysis mechanism–structure–performance is established, and the sodium storage mechanism of “adsorption–insertion–pore filling” is well proved. The composition of precursors is precisely controlled based on the flexible molecular structure of polymers. Replacing the alkyl with aryl groups can enhance the crosslink density, inhibit the two‐step degradation and rearrangement process, and lead to hard carbons with more accessible channels to internal pores, thereby resulting in an extended plateau region during discharging.