Occupational future time perspective and mental health problems across adolescence: Random-intercept cross-lagged panel analysis and alternative variations.

INTRODUCTION: Adolescence is a crucial developmental stage characterized by escalating mental health issues as well as an increasing awareness of future career possibilities. Occupational future time perspective has been shown to be a promotive factor for social functioning and mental health, and a component in evidence-based clinical practices and randomized controlled trial intervention studies. However, it requires more rigorous and ecological corroboration from longitudinal analysis at the within-person level. METHODS: Random intercept cross-lagged panel models with several adjustments and sensitivity analyses were applied to the longitudinal data from the Zurich Project on the Social Development from Childhood to Adulthood (Zurich, Switzerland), to analyze how occupational future time perspective and psychological/neurodevelopmental outcomes (attention deficit hyperactivity disorder symptoms/externalizing/internalizing problems) covaried across ages 13 (N = 1365), 15 (N = 1446), and 17 (N = 1305) in the years 2016, 2018, and 2020, after controlling for sex (52% male), SES, and school type. RESULTS: A small effect was found in a random intercept cross-lagged panel model whereby occupational future time perspective at age 15 predicted externalizing problems at age 17 (ß = .146, p = .05, [95% CI = 0.000, 0.292]), and in a random intercept (contemporaneous) reciprocal panel model specification attention deficit hyperactivity disorder symptoms at age 17 were contemporaneously associated with occupational future time perspective at age 17 (ß = -.310, p < .05, [95% CI = -0.580, -0.041]). No cross-lagged associations were found to be robust across different model specifications/adjustments. CONCLUSIONS: These findings suggest that improving occupational future time perspective may have limited impact on enhancing mental health, offering valuable insights for school-based interventions. Further research and replication are necessary to confirm these results.

A Novel Super-Toughness and Self-Healing Solid Polymer Electrolyte for Solid Sodium Metal Batteries.

Solid sodium metal batteries (SSMBs) offer an alternative promising power source for electrochemical energy storage due to their high energy density and high safety. However, the inherent sodium dendrite growth and poor mechanical properties of electrolytes seriously limit their application. Herein, a network structure composed of polyethylene oxide-based composite polymer electrolyte (CPE) is designed with liquid metal nanoparticles (LM) for SSMBs, in which LM can move in the solid electrolyte with the electric field driven. This effect can facilitate the inactivated sodium return to the metal sodium anode, and alloy with dendrites at the same time, which is beneficial for inhibiting the growth of dendrites. The symmetric cell with the CPE containing LM achieves good cyclic stability of more than 1800 and 800 h at 0.1 and 0.2 mA cm-2, respectively. The energy density of the pouch battery can reach 230 Wh kg-1. In sum, LM presents great potential to be employed as a performance reinforcement filler for CPEs, which paves the way for achieving high-performance SSMBs.

Xanthate-Mediated Oxidation of Li2S as the Lithium-Containing Cathode in Lithium-Sulfur Batteries with Extremely Low Overpotential.

Lithium-sulfide (Li2S) has long been pursued as a lithium-containing cathode material for high-energy-density lithium-sulfur (Li-S) batteries. Unfortunately, its direct oxidation generally has a large overpotential, giving rise to low energy efficiency. The use of redox mediators to accelerate the conversion of solid Li2S to polysulfides represents a possible solution to lower the initial oxidation overpotential. However, most reported redox mediators exhibit significantly higher redox potentials than the desirable value. Herein, it is serendipitously found that lithium ethyl xanthate (LiEX) formed from the reaction among Li2S, ethanol, and CS2 at room temperature is an efficient redox mediator. It has a redox potential (≈2.3 V vs Li+/Li) close to the electrochemical oxidation potential of Li2S (2.25 V vs Li+/Li), which enables fast Li2S oxidation reaction kinetics, and more importantly, lowers the Li2S oxidation potential from ≈3.6 to ≈2.3 V. When further integrated with an Ni-NC catalyst in a tandem catalysis scheme, a remarkable specific capacity of ≈1100 mAh g-1 at 0.2 mA cm-2 and long cycle life of 1400 cycles with ∼73% capacity retention is achieved, outperforming those of other Li2S-based cathode materials from recent literature.

VALOR: Vision-Audio-Language Omni-Perception Pretraining Model and Dataset.

In this paper, we propose the Vision-Audio-Language Omni-peRception pretraining model (VALOR) for multimodal understanding and generation. Unlike widely-studied vision-language pretraining models, VALOR jointly models the relationships among vision, audio, and language in an end-to-end manner. It consists of three separate encoders for single modality representations and a decoder for multimodal conditional text generation. We design two pretext tasks to pretrain the VALOR model: Multimodal Grouping Alignment (MGA) and Multimodal Grouping Captioning (MGC). MGA projects vision, language, and audio into the same common space, simultaneously building vision-language, audio-language, and audiovisual-language alignment. MGC learns to generate text tokens under conditions of vision, audio, or both. To promote vision-audio-language pretraining research, we construct a large-scale, high-quality tri-modality dataset named VALOR-1M, containing 1 million audible videos with human-annotated audiovisual captions. Extensive experiments show that VALOR can learn strong multimodal correlations and generalize to various downstream tasks (e.g., retrieval, captioning, and question answering) with different input modalities (e.g., vision-language, audio-language, and audiovisual-language). VALOR achieves new state-of-the-art performance on a series of public cross-modality benchmarks. Code and data are available on the project page at https://casia-iva-group.github.io/projects/VALOR.

Electroencephalogram-based adaptive closed-loop brain-computer interface in neurorehabilitation: a review.

Brain-computer interfaces (BCIs) represent a groundbreaking approach to enabling direct communication for individuals with severe motor impairments, circumventing traditional neural and muscular pathways. Among the diverse array of BCI technologies, electroencephalogram (EEG)-based systems are particularly favored due to their non-invasive nature, user-friendly operation, and cost-effectiveness. Recent advancements have facilitated the development of adaptive bidirectional closed-loop BCIs, which dynamically adjust to users' brain activity, thereby enhancing responsiveness and efficacy in neurorehabilitation. These systems support real-time modulation and continuous feedback, fostering personalized therapeutic interventions that align with users' neural and behavioral responses. By incorporating machine learning algorithms, these BCIs optimize user interaction and promote recovery outcomes through mechanisms of activity-dependent neuroplasticity. This paper reviews the current landscape of EEG-based adaptive bidirectional closed-loop BCIs, examining their applications in the recovery of motor and sensory functions, as well as the challenges encountered in practical implementation. The findings underscore the potential of these technologies to significantly enhance patients' quality of life and social interaction, while also identifying critical areas for future research aimed at improving system adaptability and performance. As advancements in artificial intelligence continue, the evolution of sophisticated BCI systems holds promise for transforming neurorehabilitation and expanding applications across various domains.

Nonocclusive mesenteric ischemia after percutaneous kyphoplasty: A case report.

RATIONALE: Percutaneous kyphoplasty (PKP) is a minimally invasive technique employed for treating vertebral compression fractures. Although PKP is simple and relatively safe, severe complications are possible. Here, we report a new, severe complication linked to this procedure, namely nonocclusive mesenteric ischemia (NOMI). PATIENT CONCERNS: An 83-year-old female patient, previously in good health, fell backward, landing on her buttocks, and subsequently experienced persistent low-back pain that exacerbated during turning or sitting up. DIAGNOSES: Lumbar spine radiography revealed wedge deformity of the L1 vertebral body. Lumbar spine magnetic resonance imaging indicated a fresh compression fracture of the L1 vertebral body. INTERVENTIONS: On the 2nd day following the trauma, the patient underwent PKP under local anesthesia. Anesthesia was satisfactory, and the procedure progressed smoothly. OUTCOMES: The patient experienced mild discomfort in the right abdomen within the 1st hour to 3 days postoperatively, mild abdominal distension on the 4th day, and sudden severe abdominal pain on the 5th day. Immediate abdominal computed tomography revealed ischemic changes in the ascending colon and hepatic flexure, accompanied by hepatic portal venous gas. An hour later, abdominal pain spontaneously subsided. Approximately 5 hours later, an enhanced abdominal computed tomography revealed no filling defects in the mesenteric vasculature, absence of luminal narrowing or occlusion, enhanced intestinal walls, and a notable improvement in hepatic portal venous gas. Considering NOMI and ischemia related to superior mesenteric artery spasm, vasodilator therapy (papaverine hydrochloride) was initiated, leading to favorable outcomes. On day 17, pathological examination of the hepatic flexure revealed moderate, acute, and chronic mucosal inflammation, along with interstitial fibrous tissue proliferation, providing clear evidence supporting ischemic changes. She was discharged on day 18 after a successful recovery. LESSONS: The occurrence of NOMI after PKP is uncommon. Yet, once it happens, delayed diagnosis or misdiagnosis can lead to serious consequences such as intestinal necrosis and abdominal infection, even endangering the patient's life. We currently lack experience in preventing this complication, but timely diagnosis and appropriate intervention are effective measures in treating such complications.

Brazing of TC4 Alloy Using Ti-Zr-Ni-Cu-Sn Amorphous Braze Fillers.

In order to address the issues of excessive brittle intermetallic compounds (IMC) formation in the TC4 brazed joints, two types of novel Ti-Zr-Cu-Ni-Sn amorphous braze fillers were designed. The microstructure and shear strength of the TC4/Ti-Zr-Ni-Cu-Sn/TC4 brazed joints were studied by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffractometer (XRD) and electronic universal materials testing machine. The results show that the optimized Ti35Zr25Ni15Cu20Sn5 braze filler whose chemical composition is closer to the eutectic point possesses a lower melting point compared with the equiatomic Ti23.75Zr23.75Ni23.75Cu23.75Sn5. This was beneficial to the sufficient diffusion of Cu and Ni elements with the base metal during brazing and reduces the residual (Ti,Zr)2(Ni,Cu) content in the joint, which helps to improve the joint performance. The room-temperature and high-temperature shear strength of the TC4 brazed joints using the near eutectic component Ti35Zr25Ni15Cu20Sn5 filler reached a maximum of 472 MPa and 389 MPa at 970 °C/10 min, which was 66% and 48% higher than that of the TC4 joints brazed with the equiatomic Ti23.75Zr23.75Ni23.75Cu23.75Sn5 braze filler. Microstructural evolution and the corresponding mechanical response were in-depth discussed.

Sensitive detection of synthetic response to cancer immunotherapy driven by gene paralog pairs.

Emerging immunotherapies such as immune checkpoint blockade (ICB) and chimeric antigen receptor T-cell (CAR-T) therapy have revolutionized cancer treatment and have improved the survival of patients with multiple cancer types. Despite this success many patients are unresponsive to these treatments or relapse following treatment. CRISPR activation and knockout (KO) screens have been used to identify novel single gene targets that can enhance effector T cell function and promote immune cell targeting and eradication of tumors. However, cancer cells often employ multiple genes to promote an immunosuppressive pathway and thus modulating individual genes often has a limited effect. Paralogs are genes that originate from common ancestors and retain similar functions. They often have complex effects on a particular phenotype depending on factors like gene family similarity, each individual gene's expression and the physiological or pathological context. Some paralogs exhibit synthetic lethal interactions in cancer cell survival; however, a thorough investigation of paralog pairs that could enhance the efficacy of cancer immunotherapy is lacking. Here we introduce a sensitive computational approach that uses sgRNA sets enrichment analysis to identify cancer-intrinsic paralog pairs which have the potential to synergistically enhance T cell-mediated tumor destruction. We have further developed an ensemble learning model that uses an XGBoost classifier and incorporates features such as gene characteristics, sequence and structural similarities, protein-protein interaction (PPI) networks, and gene coevolution data to predict paralog pairs that are likely to enhance immunotherapy efficacy. We experimentally validated the functional significance of these predicted paralog pairs using double knockout (DKO) of identified paralog gene pairs as compared to single gene knockouts (SKOs). These data and analyses collectively provide a sensitive approach to identify previously undetected paralog pairs that can enhance cancer immunotherapy even when individual genes within the pair has a limited effect.

Magnetic fibrin nanofiber hydrogel delivering iron oxide magnetic nanoparticles promotes peripheral nerve regeneration.

Peripheral nerve injury is a debilitating condition that have a profound impact on the overall quality of an individual's life. The repair of peripheral nerve defects continues to present significant challenges in the field. Iron oxide magnetic nanoparticles (IONPs) have been recognized as potent nanotools for promoting the regeneration of peripheral nerves due to their capability as biological carriers and their ability to template the hydrogel structure under an external magnetic field. This research used a fibrin nanofiber hydrogel loaded with IONPs (IONPs/fibrin) to promote the regeneration of peripheral nerves in rats. In vitro examination of PC12 cells on various concentrations of IONPs/fibrin hydrogels revealed a remarkable increase in NGF and VEGF expression at 2% IONPs concentration. The biocompatibility and degradation of 2% IONPs/fibrin hydrogel were assessed using the in vivo imaging system, demonstrating subcutaneous degradation within a week without immediate inflammation. Bridging a 10-mm sciatic nerve gap in Sprague Dawley rats with 2% IONPs/fibrin hydrogel led to satisfactory morphological recovery of myelinated nerve fibers. And motor functional recovery in the 2% IONPs/fibrin group was comparable to autografts at 6, 9 and 12 weeks postoperatively. Hence, the composite fibrin hydrogel incorporating 2% IONPs exhibits potential for peripheral nerve regeneration.

Deciphering the anammox microbial community succession with humic acid exposure to optimize large anammox granules for robust nitrogen removal.

The robustness of the anaerobic ammonia oxidation (anammox) process in treating wastewater with high concentrations of humic acids (HAs), including landfill leachate and sludge anaerobic digestion liquid, has been paid great attention. This study revealed that the anammox sludge granule size of 1.0-2.0 mm could be robust under the HA exposure with high concentrations. The total nitrogen removal efficiency (NRE) was 96.2% at the HA concentration of 20-100 mg/L, while the NRE was 88.5% at the HA concentration of 500 mg/L, with reduced by 7.7%. The increased extracellular polymeric substances (EPS) content which was stimulated by the HA exposure favored the formation of large granules (1.0-2.0 mm) by enveloping medium and micro granules (0.2-1.0 mm). The abundance of anammox bacteria Candidatus Brocadia was found to be higher (14.2%) in large anammox granules sized 1.0-2.0 mm, suggesting a potentially high anammox activity. However, the abundance of denitrifiers Denitratisoma increased by 4.3% in ultra-large anammox granules sized >2.0 mm, which could be attributed to the high EPS content for heterotrophic denitrifiers metabolism as organic matter. The feedback mechanism of the anammox community for maintaining the ecological function under the HA exposure resulted in a closely related microbial community, with positive and negative correlations in the ecological network increased by 64.3%. This study revealed that the HA exposure of the anammox system resulted in the anammox granules of 1.0-2.0 mm size being the dominant granules with robust nitrogen removal, providing significant guidance for the optimization of anammox granules for an efficient treatment of HA-containing wastewater in anammox applications.

The association between problematic short video use and suicidal ideation and self-injurious behaviors: the mediating roles of sleep disturbance and depression.

BACKGROUND: Prior work suggests that problematic short video use was associated with adverse psychological, physiological, and educational outcomes. With the prevailing of short video platforms, the potential relationships between this problematic behavior and suicidal ideation and self-injurious behaviors have yet to be thoroughly examined. Besides, considering the potential dual nature of problematic short video use, particularly its positive aspects, a potential mechanism may exist linking such problematic behavior to SI and SIBs, ultimately driving individuals towards extreme outcomes. Nevertheless, such mediation paths have not been rigorously examined. Thus, the current study aimed to investigate their relationships and delve into the underlying mechanism, specifically identifying potential mediators between sleep disturbance and depression. METHODS: A quantitative cross-sectional study design was employed to model data derived from a large sample of first- and second-year university students residing in mainland China (N = 1,099; Mage = 19.80 years; 51.7% male). RESULTS: Results showed that problematic short video use has a dual impact on SI and SIBs. On the one hand, problematic short video use was directly related to the decreased risk of suicidal ideation, attempts, and NSSI. On the other hand, such problematic behavior was indirectly associated with the increased risk of NSSI through sleep disturbance, and it indirectly related to the elevated risk of suicidal ideation, attempts, and NSSI through depression. Besides, on the whole, problematic short video use was positively associated with NSSI but not suicidal ideation and attempts. CONCLUSIONS: These findings indicated that problematic short video use had a dual impact on SI and SIBs. Consequently, it is paramount to comprehend the genuine magnitude of the influence that such problematic behavior holds over these intricate psychological conditions.

Hepatocyte-specific CCAAT/enhancer binding protein α restricts liver fibrosis progression.

Metabolic dysfunction-associated steatohepatitis (MASH) - previously described as nonalcoholic steatohepatitis (NASH) - is a major driver of liver fibrosis in humans, while liver fibrosis is a key determinant of all-cause mortality in liver disease independent of MASH occurrence. CCAAT/enhancer binding protein α (CEBPA), as a versatile ligand-independent transcriptional factor, has an important function in myeloid cells, and is under clinical evaluation for cancer therapy. CEBPA is also expressed in hepatocytes and regulates glucolipid homeostasis; however, the role of hepatocyte-specific CEBPA in modulating liver fibrosis progression is largely unknown. Here, hepatic CEBPA expression was found to be decreased during MASH progression both in humans and mice, and hepatic CEBPA mRNA was negatively correlated with MASH fibrosis in the human liver. CebpaΔHep mice had markedly enhanced liver fibrosis induced by a high-fat, high-cholesterol, high-fructose diet or carbon tetrachloride. Temporal and spatial hepatocyte-specific CEBPA loss at the progressive stage of MASH in CebpaΔHep,ERT2 mice functionally promoted liver fibrosis. Mechanistically, hepatocyte CEBPA directly repressed Spp1 transactivation to reduce the secretion of osteopontin, a fibrogenesis inducer of hepatic stellate cells. Forced hepatocyte-specific CEBPA expression reduced MASH-associated liver fibrosis. These results demonstrate an important role for hepatocyte-specific CEBPA in liver fibrosis progression, and may help guide the therapeutic discoveries targeting hepatocyte CEBPA for the treatment of liver fibrosis.

Pubertal exposure to Microcystin-LR arrests spermatogonia proliferation by inducing DSB and inhibiting SIRT6 dependent DNA repair in vivo and in vitro.

The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2 µg/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.

Daily life affective dynamics as transdiagnostic predictors of mental health symptoms: An ecological momentary assessment study.

BACKGROUND: Affective dynamics have been identified as a correlate of a broad span of mental health issues, making them key candidate transdiagnostic factors. However, there remains a lack of knowledge about which aspects of affective dynamics - especially as they manifest in the course of daily life - relate to a general risk for mental health issues versus specific symptoms. METHODS: We leverage an ecological momentary assessment (EMA) study design with four measures per day over a two-week period to explore how negative affect levels, inertia, lability, and reactivity to provocation and stress in the course of daily life relate to mental health symptoms in young adults (n = 256) in the domains of anxiety, depression, psychosis-like symptoms, behaviour problems, suicidality, and substance use. RESULTS: Dynamic structural equation modelling (DSEM) suggested that negative affect levels in daily life were associated with depression, anxiety, indirect and proactive aggression, psychosis, anxiety, and self-injury; negative affective lability was associated with depression, physical aggression, reactive aggression, suicidal ideation, and ADHD symptoms; negative affective inertia was associated with depression, anxiety, physical aggression, and cannabis use; and emotional reactivity to provocation was related to physical aggression. LIMITATIONS: The cross-sectional design, the limited span of mental health issues included, and the convenience nature and small size of the sample are limitations. CONCLUSIONS: Findings suggest that a subset of mental health symptoms have shared negative affective dynamics patterns. Longitudinal research is needed to rigorously examine the directionality of the effects underlying the association between affective dynamics and mental health issues.

Enhanced bacterial cellulose production in Gluconacetobacter xylinus by overexpression of two genes (bscC and bcsD) and a modified static culture.

Bacterial cellulose (BC), a nanostructured material, is renowned for its excellent properties. However, its production by bacteria is costly due to low medium utilization and conversion rates. To enhance the yield of BC, this study aimed to increase BC yield through genetic modification, specifically by overexpressing bcsC and bcsD in Gluconacetobacter xylinus, and by developing a modified culture method to reduce medium viscosity by adding water during fermentation. As a result, BC yields of 5.4, 6.2, and 6.8 g/L were achieved from strains overexpressing genes bcsC, bcsD, and bcsCD, significantly surpassing the yield of 2.2 g/L from wild-type (WT) strains. In the modified culture, the BC yields of all four strains increased by >1 g/L with the addition of 20 mL of water during fermentation. Upon comparing the properties of BC, minimal differences were observed between the WT and pbcsC strains, as well as between the static and modified cultures. In contrast, BC produced by strains overexpressing bcsD had a denser microstructural network and exhibited demonstrated higher tensile strength and elongation-to-break. Compared to WT, BC from bcsD overexpressed strains also displayed enhanced crystallinity, higher degree of polymerization and improved thermal stability.

Associations Between Reward and Future-Related Orientations and General and Specific Mental Health Issues in Adolescence.

Adolescence is characterised by a peak in sensation seeking accompanied by gradually developing self-control skills. Adolescents typically show steeper delay discounting performance than other age groups; a feature that is transdiagnostically related to a variety of mental health disorders. However, delay discounting performance is not a singular mental process but involves both risk/reward and future orientation elements, usually operationalised as probability/risk and time discounting tasks, respectively. To clarify the specific relations between the risk/reward and future orientation elements of delay discounting and different types of mental health problems, two bi-factor models and a series of structural equation models (SEMs) were fitted to multi-informant (parent and adolescent self-reported) mental health data from a large UK study. A transdiagnostic promotive role of future orientation was found using bi-factor modelling to separate general and dimension-specific mental health variation; however, this was limited to parent reports. In addition, future orientation was negatively associated with conduct problems and ADHD symptoms, but positively associated with emotional problems. Risk aversion was negatively associated with conduct problems, but positively associated with emotional and peer problems. The findings highlight that risk/reward and future orientation elements of delay discounting play partly distinct roles in different mental health problems and can serve both promotive and risk roles during adolescence. Findings also illuminate which elements of delay discounting should be intervention targets for different mental health concerns.

Diabetes Mellitus to Accelerated Atherosclerosis: Shared Cellular and Molecular Mechanisms in Glucose and Lipid Metabolism.

Diabetes is one of the critical independent risk factors for the progression of cardiovascular disease, and the underlying mechanism regarding this association remains poorly understood. Hence, it is urgent to decipher the fundamental pathophysiology and consequently provide new insights into the identification of innovative therapeutic targets for diabetic atherosclerosis. It is now appreciated that different cell types are heavily involved in the progress of diabetic atherosclerosis, including endothelial cells, macrophages, vascular smooth muscle cells, dependence on altered metabolic pathways, intracellular lipids, and high glucose. Additionally, extensive studies have elucidated that diabetes accelerates the odds of atherosclerosis with the explanation that these two chronic disorders share some common mechanisms, such as endothelial dysfunction and inflammation. In this review, we initially summarize the current research and proposed mechanisms and then highlight the role of these three cell types in diabetes-accelerated atherosclerosis and finally establish the mechanism pinpointing the relationship between diabetes and atherosclerosis.

MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction.

BACKGROUND: Micheliolide (MCL), which is the active metabolite of parthenolide, has demonstrated promising clinical application potential. However, the effects and underlying mechanisms of MCL on atherosclerosis are still unclear. METHOD: ApoE-/- mice were fed with high fat diet, with or without MCL oral administration, then the plaque area, lipid deposition and collagen content were determined. In vitro, MCL was used to pretreat macrophages combined by ox-LDL, the levels of ferroptosis related proteins, NRF2 activation, mitochondrial function and oxidative stress were detected. RESULTS: MCL administration significantly attenuated atherosclerotic plaque progress, which characteristics with decreased plaque area, less lipid deposition and increased collagen. Compared with HD group, the level of GPX4 and xCT in atherosclerotic root macrophages were increased in MCL group obviously. In vitro experiment demonstrated that MCL increased GPX4 and xCT level, improved mitochondrial function, attenuated oxidative stress and inhibited lipid peroxidation to suppress macrophage ferroptosis induced with ox-LDL. Moreover, MCL inhibited KEAP1/NRF2 complex formation and enhanced NRF2 nucleus translocation, while the protective effect of MCL on macrophage ferroptosis was abolished by NRF2 inhibition. Additionally, molecular docking suggests that MCL may bind to the Arg483 site of KEAP1, which also contributes to KEAP1/NRF2 binding. Furthermore, Transfection Arg483 (KEAP1-R483S) mutant plasmid can abrogate the anti-ferroptosis and anti-oxidative effects of MC in macrophages. KEAP1-R483S mutation also limited the protective effect of MCL on atherosclerosis progress and macrophage ferroptosis in ApoE-/- mice. CONCLUSION: MCL suppressed atherosclerosis by inhibiting macrophage ferroptosis via activating NRF2 pathway, the related mechanism is through binding to the Arg483 site of KEAP1 competitively.

A Dynamically Stable Sulfide Electrolyte Architecture for High-Performance All-Solid-State Lithium Metal Batteries.

All-solid-state batteries employing sulfide solid electrolyte and Li metal anode are promising because of their high safety and energy densities. However, the interface between Li metal and sulfides suffers from catastrophic instability which stems the practical use. Here, a dynamically stable sulfide electrolyte architecture to construct the hierarchy of interface stability is reported. By rationally designing the multilayer structures of sulfide electrolytes, the dynamic decomposing-alloying process from MS4 (M = Ge or Sn) unit in sulfide interlayer can significantly prohibit Li dendrite penetration is revealed. The abundance of highly electronic insulating decompositions, such as Li2 S, at the sulfide interlayer interface helps to well constrain the dynamic decomposition process and preserve the long-term polarization stability is also highlighted. By using Li6 PS5 Cl||Li10 SnP2 S12 ||Li6 PS5 Cl electrolyte architecture, Li metal anode shows an unprecedented critical current density over 3 mA cm-2 and achieves the steady over-potential for ≈900 hours. Based upon the merits, the Li||LiNi0.8 Co0.1 Mn0.1 O2 battery delivers a remarkable 75.3% retention even after 600 cycles at 1 C (1C-0.95 mA cm-2 ) under a low stack pressure of 15 MPa.