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The practical capacity of lithium-oxygen batteries falls short of their ultra-high theoretical value. Unfortunately, the fundamental understanding and enhanced design remain lacking, as the issue is complicated by the coupling processes between Li 2 O 2 nucleation, growth, and multi-species transport. Herein, we redefine the relationship between the microscale Li 2 O 2 behaviors and the macroscopic electrochemical performance, emphasizing the importance of the inherent modulating ability of Li + ions through a synergy of visualization techniques and cross-scale quantification. We find that Li 2 O 2 particle distributed against the oxygen gradient signifies a compatibility match for the nucleation and transport kinetics, thus enabling the output of the electrode’s maximum capacity and providing a basis for evaluating operating protocols for future applications. In this case, a 150% capacity enhancement is further achieved through the development of a universalizing methodology. This work opens the door for the rules and control of energy conversion in metal-air batteries, greatly accelerating their path to commercialization. To realize the theoretical energy density of lithium-oxygen batteries, this work uses the relationship between microscopic phenomena and macroscopic performance. By adjusting lithium-ion concentration, alignment of transport and nucleation kinetics improves and discharge capacity of the electrodes maximized.

Lipid transport and ATP synthesis are critical for the progression of non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) forms complexes with NAFLD-relevant transcripts. It associates with intron 24 of Apob pre-mRNA, with the 3′UTR of Uqcrb , and with the 5′UTR of Ndufb6 mRNA, thereby regulating the splicing of Apob mRNA and the translation of UQCRB and NDUFB6. Hepatocyte-specific HuR knockout reduces the expression of APOB, UQCRB, and NDUFB6 in mice, reducing liver lipid transport and ATP synthesis, and aggravating high-fat diet (HFD)-induced NAFLD. Adenovirus-mediated re-expression of HuR in hepatocytes rescues the effect of HuR knockout in HFD-induced NAFLD. Our findings highlight a critical role of HuR in regulating lipid transport and ATP synthesis. Human antigen R (HuR) is a RNA binding protein involved in the regulation of many cellular functions. Here the authors show that, hepatocyte specific deletion of HuR exacerbates high-fat diet-induced NAFLD in mice by regulating transcripts involved in lipid transport and ATP synthesis.

Neurological impairments resulting from bilirubin encephalopathy represent a hallmark of bilirubin’s neurotoxic effects. Earlier research suggests that bilirubin may contribute to Alzheimer’s disease (AD) pathology by inducing neuronal necrosis and abnormal tau phosphorylation. Nevertheless, the precise mechanisms linking bilirubin to neurodegeneration in both neonates and adults remain unclear. To address this, we established two complementary models: a pathological jaundice model using UGT1A1 ⁻/⁻ neonatal mice and an adult bilirubin exposure model via lateral ventricle injection, followed by brain tissue sequencing. Integrating bioinformatics analyses with multiple AD datasets, we uncovered regulatory effects of bilirubin exposure on neurodegenerative processes across age groups. Machine learning approaches identified two key genes, BCL2-binding component 3 ( Bbc3 ) and Mitogen-activated protein kinase kinase kinase 10 ( Map3k10 ), as central mediators of bilirubin-induced neuroinjury in pathological jaundice. In adults, bilirubin exposure also promoted neuroinflammation. Notably, effector memory CD8⁺ T cells emerged as critical drivers of AD-associated neuroinflammation, and four additional biomarkers were identified to construct a high-performance diagnostic model. Together, these findings highlight potential biomarkers for diagnosing and monitoring bilirubin-induced neurological damage and provide a basis for developing targeted diagnostic and therapeutic strategies for AD.

HER2+ breast cancer (BC) is characterized by rapid growth, early recurrence, early metastasis, and chemoresistance. Trastuzumab is the most effective treatment for HER2+ BC and effectively reduces the risk of recurrence and death of patients. Resistance to trastuzumab results in cancer recurrence and metastasis, leading to poor prognosis of HER2+ BC. In the present study, we found that non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG) expression was highly upregulated in trastuzumab-resistant HER2+ BC. Ectopic NCAPG was positively correlated with tumor relapse and shorter survival in HER2+ BC patients. Moreover, overexpression of NCAPG promoted, while silencing of NCAPG reduced, the proliferative and anti-apoptotic capacity of HER2+ BC cells both in vitro and in vivo, indicating NCAPG reduces the sensitivity of HER2+ BC cells to trastuzumab and may confer trastuzumab resistance. Furthermore, our results suggest that NCAPG triggers a series of biological cascades by phosphorylating SRC and enhancing nuclear localization and activation of STAT3. To summarize, our study explores a crucial role for NCAPG in trastuzumab resistance and its underlying mechanisms in HER2+ BC, and suggests that NCAPG could be both a potential prognostic marker as well as a therapeutic target to effectively overcome trastuzumab resistance.

Li-air batteries have the potential to be the most promising next-generation energy storage solutions due to their high theoretical energy density. However, the practical capacity remains far below this theoretical value due to the insolubility and insulating properties of the main discharge product, Li2O2. Therefore, it is critical to understand the formation mechanism of discharge products, particularly their nucleation, growth, and the factors influencing the morphology and distribution. Modeling and simulation are widely applied to probe the battery mechanisms, offering cost-effective and efficient means to capture the complex processes involved, which enables quantitative characterization of product behaviors. Herein, this work first reviews the growth models of products in non-aqueous Li-air batteries from both macro and meso perspectives, highlighting how these models describe product growth. Subsequently, the effects of side reactions on product composition and battery performance are considered. Finally, the limitations in current models and potential directions for future research are outlined.

Infection is a leading cause of mortality in idiopathic inflammatory myopathies (IIMs). This study aimed to develop a nomogram for predicting severe infection risk in IIM patients. Patients with IIMs admitted to Zhongshan Hospital, Fudan University, from January 2015 to January 2022 were enrolled. They were randomly divided into derivation (70%) and validation (30%) sets. Univariate and multivariate Cox regression identified independent risk factors for severe infection, and the Akaike information criterion (AIC) was applied for model selection. A nomogram was constructed to predict severe infection risks at 6 months, 1 year, and 3 years. Predictive accuracy and discriminative ability were evaluated using the concordance index (C-index), calibration curves, and the area under the receiver operating characteristic curve (AUC). Decision curve analysis (DCA) assessed clinical utility. Kaplan-Meier (K-M) curves were used to analyze survival differences between high- and low-risk groups stratified by nomogram scores. Among 263 IIM patients, 81 experienced 106 severe infection events, with lower respiratory tract infections being the most common (47.2%). Independent risk factors included age at onset (HR 1.024, 95% CI 1.002-1.046, =0.036), lactate dehydrogenase (HR 1.002, 95% CI 0.999-1.005, =0.078), HRCT score (HR 1.004, 95% CI 1.001-1.006, =0.002), and lymphocyte count (HR 0.48, 95% CI 0.23-0.99, =0.048). The nomogram demonstrated strong predictive performance, with AUCs of 0.84, 0.83, and 0.78 for 6 months, 1 year, and 3 years in the derivation set, and 0.91, 0.77, and 0.64 in the validation set. Calibration curves showed good agreement between predicted and observed risks, while DCA demonstrated significant net benefit over individual predictors. Kaplan-Meier curves revealed significant differences in the cumulative risk of severe infection between high- and low-risk groups. Further validation in DM and ASS subgroups demonstrated that the nomogram effectively predicted severe infections, with AUCs of 0.86, 0.81, and 0.73 for DM and 0.86, 0.83, and 0.74 for ASS at 6 months, 1 year, and 3 years, respectively. We have developed a new nomogram to predict severe infection risk in IIM patients at 6 months, 1 year, and 3 years. This model aids clinicians and patients in formulating treatment and follow-up strategies.

Background Bladder cancer (BLCA) is a malignancy that frequently metastasizes and leads to poor patient prognosis. It is essential to understand the molecular mechanisms underlying the progression and metastasis of BLCA and identify potential biomarkers. Methods The expression of peptidase inhibitor 16 (PI16) was analysed using quantitative PCR, immunoblotting and immunohistochemistry assays. The functional roles of PI16 were evaluated using wound healing, transwell, and human umbilical vein endothelial cell tube formation assays, as well as in vivo tumour models. The effects of PI16 on nuclear factor κB (NF-κB) signalling activation were examined using luciferase reporter gene systems, immunoblotting and immunofluorescence assays. Co-immunoprecipitation was used to investigate the interaction of PI16 with annexin-A1 (ANXA1) and NEMO. Results PI16 expression was downregulated in bladder cancer tissues, and lower PI16 levels correlated with disease progression and poor survival in patients with BLCA. Overexpressing PI16 inhibited BLCA cell growth, motility, invasion and angiogenesis in vitro and in vivo, while silencing PI16 had the opposite effects. Mechanistically, PI16 inhibited the activation of the NF-κB pathway by interacting with ANXA1, which inhibited K63 and M1 ubiquitination of NEMO. Conclusions These results indicate that PI16 functions as a tumour suppressor in BLCA by inhibiting tumour growth and metastasis. Additionally, PI16 may serve as a potential biomarker for metastatic BLCA.

The purpose of this study is to investigate the effect of urate-lowering therapies (ULTs) on renal uric acid excretion in gout patients. This prospective observational study involved 106 primary gout patients and 51 healthy controls. Gout patients received ULT with either xanthine oxidase inhibitors or the uricosuric agent benzbromarone. Parameters such as 24-h urinary uric acid, creatinine clearance, uric acid clearance, glomerular filtration load of uric acid, fractional excretion of uric acid, excretion of uric acid per volume of glomerular filtration, and urinary uric acid to urinary creatinine ratio were used to evaluate the pre- and post-treatment renal capacity for uric acid clearance in gout patients and were compared with the values in the healthy controls. Compared to healthy controls, gout patients had higher glomerular filtration load of uric acid and lower uric acid clearance, creatinine clearance, and fractional uric acid excretion. After ULT, both the xanthine oxidase inhibitor group and benzbromarone group patients showed reduction in glomerular filtration load of uric acid. Creatinine clearance was significantly improved in the xanthine oxidase inhibitor group. Excretion function was remarkably enhanced in patients who reached the treatment target (serum uric acid <6 mg/dl). Changes in glomerular uric acid filtration load were significantly correlated with changes in serum urate levels. Gout patients have impaired renal uric acid excretion. ULTs reduce renal urate load and enhance the renal capacity of uric acid clearance. Xanthine oxidase inhibitors showed superiority over benzbromarone in improving renal function.

To regenerate bone tissues, we investigated the osteogenic differentiation of induced-pluripotent-stem-cell-derived mesenchymal stem cells (iPSC-MSCs) and bone regeneration capacities using N-acetyl cysteine (NAC)-loaded biomimetic nanofibers of hydroxyapatite/silk fibroin (HAp/SF). The addition of HAp and NAC decreased the diameters of the electrospun fibers and enhanced the mechanical properties of the silk scaffold. The release kinetic curve indicated that NAC was released from NAC/HAp/SF nanofibers in a biphasic pattern, with an initial burst release stage and a later sustained release stage. This pattern of release of NAC encapsulated on the NAC/HAp/SF scaffolds prolonged the release of high concentrations of NAC, thereby largely affecting the osteogenic differentiation of iPSC-MSCs and bone regeneration. Thus, a new silk electrospun scaffold was developed. HAp was used as a separate nanocarrier for recharging the NAC concentration, which demonstrated the promising potential for the use of NAC/HAp/SF for bone tissue engineering.

The remarkable mechanisms of storiform fibrosis and the formation of high levels of IgG4 with a pathogenic germinal center (GC) in the inflammatory tissue of IgG4-RD remains unknown and may be responsible for the unsatisfactory therapeutic effect on IgG4-related diseases when using conventional therapy. To investigate the mechanisms of interleukin 6 (IL-6) inducing fibroblasts to produce cytokines for pathogenic GC formation in the development of IgG4-related disease (IgG4-RD). The clinical data and laboratory examinations of 56 patients with IgG4-RD were collected. IL-6 and IL-6R expression in the serum and tissues of patients with IgG4-RD and healthy controls were detected by ELISA, immunohistochemistry, and immunofluorescence. Human aorta adventitial fibroblasts (AAFs) were cultured and stimulated with IL-6/IL-6 receptor (IL-6R). The effect of IL-6/IL-6R on AAFs was determined by Luminex assays. The serum IL-6 and IL-6R levels were elevated in active IgG4-RD patients and IL-6 was positively correlated with the disease activity (e.g., erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and IgG4-RD responder index). IL-6 and IL-6R expression in the tissue lesions of IgG4-related retroperitoneal fibrosis and IgG4-related sialadenitis patients were also significantly higher than that in the normal tissues. In addition, there is a relative abundance of myofibroblasts as well as IgG4 plasma cells in the tissues of IgG4-related retroperitoneal fibrosis. α-SMA and B cell differentiation cytokines (i.e., B cell activating factor), and α-SMA and T follicular helper (Tfh) cell differentiation cytokines (e.g., IL-7, IL-12, and IL-23) were co-expressed in the local lesions. , IL-6/IL-6R significantly promoted the production of B cell activating factor, IL-7, IL-12, and IL-23 in AAFs in a dose-dependent manner. This effect was partially blocked by JAK1, JAK2, STAT3, and Akt inhibitors, respectively. IL-6/IL-6R trans-signaling in fibroblasts releases Tfh and B cell differentiation factors partially via the JAK2/STAT3, JAK1/STAT3, and JAK2/Akt pathways, which may be linked to the pathogenesis of IgG4-RD. This indicated that IL-6 and fibroblasts may be responsible for GC formation and fibrosis in the development of IgG4-RD. Blocking IL-6 with JAK1/2 inhibitors or inhibiting fibroblast proliferation might be beneficial for IgG4-RD treatment.