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Metal-nitrogen-carbon catalysts with hierarchically dispersed porosity are deemed as efficient geometry for oxygen reduction reaction (ORR). However, catalytic performance determined by individual and interacting sites originating from structural heterogeneity is particularly elusive and yet remains to be understood. Here, an efficient hierarchically porous Fe single atom catalyst (Fe SAs-HP) is prepared with Fe atoms densely resided at micropores and mesopores. Fe SAs-HP exhibits robust ORR performance with half-wave potential of 0.94 V and turnover frequency of 5.99 e −1 s −1 site −1 at 0.80 V. Theoretical simulations unravel a structural heterogeneity induced optimization, where mesoporous Fe-N 4 acts as real active centers as a result of long-range electron regulation by adjacent microporous sites, facilitating O 2 activation and desorption of key intermediate *OH. Multilevel operando characterization results identify active Fe sites undergo a dynamic evolution from basic Fe-N 4 to active Fe-N 3 under working conditions. Our findings reveal the structural origin of enhanced intrinsic activity for hierarchically porous Fe-N 4 sites. Here, authors report an inter-site structural heterogeneity induced effect of hierarchical single atom Fe catalysts for robust oxygen reduction. Dynamic evolutions and insights into structure-activity relationship are presented.

Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by hepatic steatosis and inflammation in individuals with no significant alcohol consumption history. Predominantly affecting middle-aged and elderly populations, particularly those with obesity or metabolic syndrome, this condition represents a spectrum ranging from benign fatty accumulation to progressive liver damage. In advanced stages, NAFLD may progress to cirrhosis and hepatocellular carcinoma. This study systematically examines the global incidence patterns and epidemiological characteristics of NAFLD in older adults(>60 years), while establishing predictive models for its future disease burden. Data on NAFLD in the Elderly(>60 years), from 1990 to 2021, was obtained from the Global Burden of Disease (GBD) study, encompassing 204 countries and territories. This dataset includes incidence rates of NAFLD. The Joinpoint regression model was utilized to detect turning points in the epidemiological trends of NAFLD, and decomposition analysis was performed to analyze the factors influencing these trends. To evaluate potential health disparities related to NAFLD, the Slope Index and Concentration Index were calculated. Additionally, the Norpred and Bayesian age-period-cohort (BAPC) models were employed to forecast future incidence rates of NAFLD. In 1990, the global NAFLD incidence in the elderly was 2819125(3972309 ± 1807520), with an ASIR of 568.46(803.33 ± 364.10). The global NAFLD prevalence in the elderly was 132549345(166820867 ± 102941502), with an ASPR of 27284.94(34321.92 ± 21200.69). The global NAFLD deaths in the elderly were 27864(45975 ± 15898), with an age-standardized death rate of 6.20(10.18 ± 3.55). The global NAFLD DALYs in the elderly were 559945(931920 ± 319045), with an age-standardized DALYs rate of 116.78(193.49 ± 66.73). In 2021, the global NAFLD incidence in the elderly was 7,012,128 (9,896,736 ± 4,480,162), with an ASIR of 636.90 (900.15 ± 406.76). The global NAFLD prevalence in the elderly was 366,363,498 (454,385,769 ± 287,891,088), with an ASPR of 33,576.22 (41,647.44 ± 26,372.13). The global NAFLD deaths in the elderly were 63,313 (99,891 ± 37,267), with an age-standardized death rate of 5.95 (9.39 ± 3.50). The global NAFLD DALYs in the elderly were 1,238,927 (1,973,042 ± 729,228), with an age-standardized DALYs rate of 113.95 (181.50 ± 66.91). From 1990 to 2021, the AAPC of ASIR for NAFLD in the elderly globally was 0.37(0.36 to 0.38), with a p-value < 0.05. The AAPC of ASPR for NAFLD in the elderly globally was 0.67(0.65 to 0.68), with a p-value < 0.05. The AAPC of age-standardized deaths rate for NAFLD in the elderly globally was -0.13(-0.16 to -0.1), with a p-value < 0.05. The AAPC of age-standardized DALYs rate for NAFLD in the elderly globally was -0.05(-0.07 to -0.02), with a p-value < 0.05. The decomposition analysis results indicate that population growth is the primary driver of increased disease burden in older NAFLD patients. It is expected that in the future, the disease burden of NAFLD in elderly people worldwide will continue to rise. Over the past three decades, the annual age-standardized incidence rate and total number of cases of NAFLD, including cirrhosis, have increased among the elderly population, irrespective of gender. This upward trend is consistent across all SDI regions. Furthermore, future projections indicate that both the annual age-standardized incidence rate and the case numbers of NAFLD, including cirrhosis, in the elderly are likely to continue rising.

Ferroptosis is an iron-dependent form of regulated cell death induced by the lethal accumulation of lipid peroxidation, while the precise mechanism of ferroptosis in the pathogenesis of ulcerative colitis (UC) remains to be elucidated. This study aimed to explore the potential effect of hypoxia inducible factor-1α (HIF-1α) on ferroptosis in intestinal epithelial cells (IECs) in UC. The relationship between ferroptosis and HIF-1α was initially investigated using clinical UC colon samples. In vitro and in vivo models of acute intestinal inflammatory response were constructed using lipopolysaccharide (LPS) and dextran sulfate sodium (DSS), respectively. The effect of HIF-1α on ferroptosis in UC was determined by establishing HIF-1α overexpression (HIF1A-OE) or knockdown (shHIF1A) IEC lines, and the mechanism by which HIF-1α mediated the transcription of glutathione peroxidase 4 (GPX4) was explored by combining Co-immunoprecipitation (Co-IP) and Chromatin immunoprecipitation-qPCR (ChIP-qPCR). The results indicated that ferroptosis was present in IECs from UC patients and colitis mice. Elevated expression of HIF-1α ameliorated the secretion of inflammatory cytokines and ferroptosis in IECs in vitro. HIF-1α inhibited ferroptosis by transcriptional activation of the GPX4 gene in inflammatory IECs. HIF-1α ameliorated the general conditions of mice and intestinal barrier dysfunction and by suppressing ferroptosis in IECs of mice through upregulating the expression of GPX4. In conclusion, ferroptosis occurred in the IECs of UC patients and colitis mice. HIF-1α may improve UC by suppressing ferroptosis in IECs through regulating the transcription of GPX4.

In order to precisely deliver celastrol into mitochondria of tumor cells, improve antitumor efficacy of celastrol and overcome its troublesome problems in clinical application, a novel multistage-targeted celastrol delivery system (C-TL/HA) was developed via electrostatic binding of hyaluronic acid (HA) to celastrol-loaded cationic liposomes composed of natural soybean phosphatidylcholine and cholesterol modified with mitochondrial targeting molecular TPP. Study results in this article showed that C-TL/HA successfully transported celastrol into mitochondria, effectively activated apoptosis of mitochondrial pathway, exerted higher tumor inhibition efficiency and lower toxic side effects compared with free celastrol. More importantly, HA coating not only enabled this delivery system to have good stability and safety in vivo, but also increased drug uptake and facilitated tumor targeting through recognizing CD44 receptors rich on the surface of tumor cells. Conclusively, this HA-coated mitochondrial targeting liposomes may provide a prospect for the clinical application of celastrol in tumor therapy.

Sleep architecture is frequently disrupted after major surgery, leading to acute and chronic postoperative sleep disorders that may contribute to episodic hypoxia, hemodynamic instability, postoperative fatigue, cognitive dysfunction, depression. These all have potentially detrimental impacts on disease regression. Pain is a key driver of postoperative sleep disruption and opioids are widely used for pain management due to their potent analgesic and sedative effects. Opioids are conventionally believed to induce natural sleep and reduce sleep disorders. However, available evidence suggests that opioids can disrupt sleep architecture, leading to sleep deprivation, fragmentation and restriction. This systematic review investigates the detrimental effects of opioids on postoperative sleep and explores the underlying mechanisms responsible for sleep disorders. By synthesizing current evidence wehighlight the risks associated with opioid-centric pain management strategies and advocate for a more balanced approach that optimizes pain relief while mitigating opioid-induced sleep disruption.

Field-free spin-orbit torque-driven domain wall motion in magnetic thin films with perpendicular magnetic anisotropy (PMA) requires the domain walls to have Néel character. Conventionally, Néel domain walls are stabilized by the Dzyaloshinskii-Moriya interaction (DMI) in ultrathin films. Here, in a europium iron garnet thin film with PMA and an additional uniaxial in-plane anisotropy, we demonstrate two bistable Néel domain wall states in the absence of DMI, and the capability to toggle the wall states with an in-plane field pulse and consequently their directions of motion under a current pulse. We present a phase diagram for the bistable Néel domain wall states as a function of in-plane field pulse width and amplitude. By fitting the experimental data to an analytical model of Néel wall reversal through the nucleation and propagation of Bloch lines, we extract the length of the initial reversed domain wall segment and Bloch line nucleation energy barrier. Current-driven motion of in-plane anisotropy stabilized Néel walls is qualitatively different from that of DMI-stabilized ones owing to the different symmetry of the effective fields that stabilize the Néel configuration. Furthermore, we present a proof of principle demonstration for 2-bit random number generation based on the stochastic reversal of domain wall chirality. These results provide critical insight into the topological energy barrier of Bloch lines and identify paths towards domain wall-based memory and computing devices. Neel domain walls are typically stabilized by an interfacial Dzyaloshinskii-Moriya interaction, with a chirality that is fixed by the sample materials. Here, Song, Huang and coauthors demonstrate the existence of two bistable Néel domain wall states with opposite chiralities, and the switching between these via magnetic field pulses

Highlights Crucial role of local microstrain was deciphered to boost oxygen electrocatalysis via quantitatively riveting asymmetric Fe–N 3 S 1 sites on carbon hollow nanospheres with specific curvature. The local microstrain accelerates kinetics of *OH reduction on Fe–N 3 S 1 , enabling much enhanced intrinsic activity, selectivity and stability toward oxygen electrocatalysis. The strained Fe–N 3 S 1 sites were monitored to transformed into Fe–N 3 –S 1 sites, further dynamically mitigating the overadsorption of *OH intermediates. Disrupting the symmetric electron distribution of porphyrin-like Fe single-atom catalysts has been considered as an effective way to harvest high intrinsic activity. Understanding the catalytic performance governed by geometric microstrains is highly desirable for further optimization of such efficient sites. Here, we decipher the crucial role of local microstrain in boosting intrinsic activity and durability of asymmetric Fe single-atom catalysts (Fe–N 3 S 1 ) by replacing one N atom with S atom. The high-curvature hollow carbon nanosphere substrate introduces 1.3% local compressive strain to Fe–N bonds and 1.5% tensile strain to Fe–S bonds, downshifting the d -band center and accelerating the kinetics of *OH reduction. Consequently, highly curved Fe–N 3 S 1 sites anchored on hollow carbon nanosphere (FeNS-HNS-20) exhibit negligible current loss, a high half-wave potential of 0.922 V vs. RHE and turnover frequency of 6.2 e −1  s −1 site −1 , which are 53 mV more positive and 1.7 times that of flat Fe–N–S counterpart, respectively. More importantly, multiple operando spectroscopies monitored the dynamic optimization of strained Fe–N 3 S 1 sites into Fe–N 3 sites, further mitigating the overadsorption of *OH intermediates. This work not only sheds new light on local microstrain-induced catalytic enhancement, but also provides a plausible direction for optimizing efficient asymmetric sites via geometric configurations.

The pathophysiological differences between menstrually-related migraine (MRM) and pure menstrual migraine (PMM) are largely unclear. The aim of this study was to investigate the potential differences in brain structure and function between PMM and MRM. Forty-eight menstrual migraine patients (32 MRM; 16 PMM) were recruited for this study. Voxel-based morphometry (VBM) was applied on structural magnetic resonance imaging (sMRI), and the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) in resting state functional MRI (rsfMRI) were calculated. No significant between-group difference was observed in the grey matter volume (GMV). MRM patients exhibited lower ALFF values at the dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex (mPFC) than PMM patients. Moreover, the MRM group showed significantly higher ReHo values in the DLPFC. Higher values in the mPFC were related to higher expression of calcitonin gene-associated peptide (CGRP) in the PMM group (r = 0.5, P  = 0.048). Combined ALFF and ReHo analyses revealed significantly different spontaneous neural activity in the DLPFC and mPFC, between MRM and PMM patients, and ALFF values in the mPFC were positively correlated with CGRP expression, in the PMM group. This study enhances our understanding of the relationship between neural abnormalities and CGRP expression in individuals with PMM.

Considering that the precise delivery of Celastrol (Cst) into mitochondria to induce mitochondrial dysfunction may be a potential approach to improve the therapeutic outcomes of Cst on TNBC, a novel tumor mitochondria dual-targeted mixed-micelle nano-system was fabricated via self-synthesized triphenylphosphonium-modified cholesterol (TPP-Chol) and hyaluronic acid (HA)-modified cholesterol (HA-Chol). The Cst-loaded mixed micelles (Cst@HA/TPP-M) exhibited the characteristics of a small particle size, negative surface potential, high drug loading of up to 22.8%, and sustained drug release behavior. Compared to Cst-loaded micelles assembled only by TPP-Chol (Cst@TPP-M), Cst@HA/TPP-M decreased the hemolysis rate and upgraded the in vivo stability and safety. In addition, a series of cell experiments using the triple-negative breast cancer cell line MDA-MB-231 as a cell model proved that Cst@HA/TPP-M effectively increased the cellular uptake of the drug through CD44-receptors-mediated endocytosis, and the uptake amount was three times that of the free Cst group. The confocal results demonstrated successful endo-lysosomal escape and effective mitochondrial transport triggered by the charge converse of Cst@HA/TPP-M after HA degradation in endo-lysosomes. Compared to the free Cst group, Cst@HA/TPP-M significantly elevated the ROS levels, reduced the mitochondrial membrane potential, and promoted tumor cell apoptosis, showing a better induction effect on mitochondrial dysfunction. In vivo imaging and antitumor experiments based on MDA-MB-231-tumor-bearing nude mice showed that Cst@HA/TPP-M facilitated drug enrichment at the tumor site, attenuated drug systemic distribution, and polished up the antitumor efficacy of Cst compared with free Cst. In general, as a target drug delivery system, mixed micelles co-constructed by TPP-Chol and HA-Chol might provide a promising strategy to ameliorate the therapeutic outcomes of Cst on TNBC.

Purpose Bisphenols (BPs), including bisphenol A (BPA) and its analogs BPB, BPF, BPS, and BPAF, are essential industrial raw materials used in the production of consumer goods but pose significant public health risks. Bisphenols contribute to carcinogenesis due to their endocrine-disrupting properties, particularly in breast cancer. However, the relationship between BPs exposure and putative cancer risk, as well as the underlying molecular mechanisms, remains poorly understood. Methods This study employed network toxicology, molecular docking, molecular dynamics simulation, machine learning, and bioinformatics to systematically investigate the molecular mechanisms and potential targets associated with carcinogenic risks of five BPs. Results The findings revealed that BPs exposure increases cancer risk by targeting 26 core proteins, including RXRA, AKT2, and CYCS, leading to oxidative stress and modulation of cancer-related signaling pathways such as MAPK, PI3K/AKT, Ras, and VEGF. Molecular docking and dynamics simulations demonstrated stable binding interactions between RXRA and all five BPs. Analysis of the TCM database indicated that Ginseng , Turmeric , and Salvia miltiorrhiza can mitigate BPs-induced cancer risk by targeting these core proteins. Pan-cancer analysis showed that kidney renal clear cell carcinoma (KIRC) and low-grade glioma (LGG) are most strongly associated with BPs exposure. Diagnostic and prognostic models based on core targets exhibited high predictive accuracy, offering valuable clinical decision support. Single-cell sequencing revealed that core targets are primarily localized in immune cells in KIRC and glioma cells in LGG. Conclusion This study provides a theoretical foundation for evaluating cancer risk associated with BPs exposure and establishes a novel framework for understanding the pathogenesis and potential therapeutic strategies for environmental pollutants.