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Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m 6 A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore– elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC. Cuproptosis regulation in tumors is unclear. Here the authors find that copper promotes METTL16 lactylation, inducing cuproptosis via stabilizing FDX1 in gastric cancer. Targeting lactyl-METTL16 and cuproptosis offers a potential feasible strategy for cancer therapy.

Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore- elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.

Advances in protein therapy are hindered by the poor stability, inadequate pharmacokinetic (PK) profiles, and immunogenicity of many therapeutic proteins. Polyethylene glycol conjugation (PEGylation) is the most successful strategy to date to overcome these shortcomings, and more than 10 PEGylated proteins have been brought to market. However, anti-PEG antibodies induced by treatment raise serious concerns about the future of PEGylated therapeutics. Here, we demonstrate a zwitterionic polymer network encapsulation technology that effectively enhances protein stability and PK while mitigating the immune response. Uricase modified with a comprehensive zwitterionic polycarboxybetaine (PCB) network exhibited exceptional stability and a greatly prolonged circulation half-life. More importantly, the PK behavior was unchanged, and neither anti-uricase nor anti-PCB antibodies were detected after three weekly injections in a rat model. This technology is applicable to a variety of proteins and unlocks the possibility of adopting highly immunogenic proteins for therapeutic or protective applications.

During the operation of space gravitational wave detectors, the constellation configuration formed by three satellites gradually deviates from the ideal 60° angle due to the periodic variations in orbits. To ensure the stability of inter-satellite laser links, active compensation of the breathing angle variation within the constellation plane is achieved by rotating the optical subassembly through the telescope pointing mechanism. This paper proposes a high-performance robust composite control method designed to enhance the robust stability, disturbance rejection, and tracking performance of the telescope pointing system. Specifically, based on the dynamic model of the telescope pointing mechanism and the disturbance noise model, an H∞ controller has been designed to ensure system stability and disturbance rejection capabilities. Meanwhile, employing the method of an H∞ norm optimized disturbance observer (HODOB) enhances the nonlinear friction rejection ability of the telescope pointing system. The simulation results indicate that, compared to the traditional disturbance observer (DOB) design, utilizing the HODOB method can enhance the tracking accuracy and pointing stability of the telescope pointing system by an order of magnitude. Furthermore, the proposed composite control method improves the overall system performance, ensuring that the stability of the telescope pointing system meets the 10 nrad/Hz1/2 @0.1 mHz~1 Hz requirement specified for the TianQin mission.

Background Seizures are associated with a decrease in γ-aminobutyric type A acid receptors (GABAaRs) on the neuronal surface, which may be regulated by enhanced internalization of GABAaRs. When interactions between GABAaR subunit α-1 (GABRA1) and postsynaptic scaffold proteins are weakened, the α1-containing GABAaRs leave the postsynaptic membrane and are internalized. Previous evidence suggested that neuroplastin (NPTN) promotes the localization of GABRA1 on the postsynaptic membrane. However, the association between NPTN and GABRA1 in seizures and its effect on the internalization of α1-containing GABAaRs on the neuronal surface has not been studied before. Methods An in vitro seizure model was constructed using magnesium-free extracellular fluid, and an in vivo model of status epilepticus (SE) was constructed using pentylenetetrazole (PTZ). Additionally, in vitro and in vivo NPTN-overexpression models were constructed. Electrophysiological recordings and internalization assays were performed to evaluate the action potentials and miniature inhibitory postsynaptic currents of neurons, as well as the intracellular accumulation ratio of α1-containing GABAaRs in neurons. Western blot analysis was performed to detect the expression of GABRA1 and NPTN both in vitro and in vivo. Immunofluorescence co-localization analysis and co-immunoprecipitation were performed to evaluate the interaction between GABRA1 and NPTN. Results The expression of GABRA1 was found to be decreased on the neuronal surface both in vivo and in vitro seizure models. In the in vitro seizure model, α1-containing GABAaRs showed increased internalization. NPTN expression was found to be positively correlated with GABRA1 expression on the neuronal surface both in vivo and in vitro seizure models. In addition, NPTN overexpression alleviated seizures and NPTN was shown to bind to GABRA1 to form protein complexes that can be disrupted during seizures in both in vivo and in vitro models. Furthermore, NPTN was found to inhibit the internalization of α1-containing GABAaRs in the in vitro seizure model. Conclusion Our findings provide evidence that NPTN may exert antiepileptic effects by binding to GABRA1 to inhibit the internalization of α1-containing GABAaRs. Graphical Abstract

Herein, functionalized carbon nanospheres (CNs) are encapsulated within reduced graphene oxide (rGO) layers as a high-performance microwave-absorbing material. The obtained sandwich-like CNs@rGO nanocomposite is characterized by a well-matched characteristic impedance and multiple dielectric relaxation processes, resulting in a strong reflection loss (–33.09 dB at 14.01 GHz) and broad effective bandwidth of 12.2–17.6 GHz (5.4 GHz) with a low thickness of 2.0 mm, which is superior to many reported carbon absorbers and even some magnetic absorbers. This remarkable microwave absorption property is ascribed to the sandwich structure, indicating that the as-prepared sandwich-like CNs@rGO nanocomposites are potential candidates for lightweight microwave absorption materials.Graphic abstract

Background The COVID-19 pandemic significantly impacted individuals with type 2 diabetes (T2D), especially in China, where stringent public health measures disrupted healthcare access and heightened psychological stress. The long-term associations of pandemic-related post-traumatic stress disorder (PTSD) symptoms with self-care behaviors, fear of hypoglycemia (FoH), and depressive symptoms in T2D patients remain underexplored. This study examines these associations in Chinese adults with T2D in the post-pandemic period. Methods We conducted a cross-sectional study with 242 adults with T2D at community health centers in Huai’an, China. Data on PTSD symptoms (Impact of Event Scale-Revised), self-care behaviors (Summary of Diabetes Self-Care Activities-6), FoH (Hypoglycemia Fear Survey II-Worry Scale), and depressive symptoms (Patient Health Questionnaire-9) were collected. Generalized linear models adjusted for demographic and clinical factors analyzed associations between PTSD symptoms and self-care, FoH, and depressive symptoms. Results The prevalence of PTSD in the sample was 10.33% ( n  = 25). Higher PTSD scores were significantly associated with poorer dietary adherence (β = -0.0036, 95% CI: -0.0066 to -0.0005) and foot care (β = -0.0365, 95% CI: -0.0494 to -0.0235), as well as increased FoH (β = 0.0171, 95% CI: 0.0055 to 0.0287) and depressive symptoms (β = 0.0148, 95% CI: 0.0076 to 0.0220). No significant associations were found with physical activity, blood glucose testing, or medication adherence (all P  > 0.05). Conclusions COVID pandemic-related PTSD symptoms may be associated with certain worsened self-care behaviors, heightened FoH, and increased depressive symptoms among patients with T2D. These findings suggest that addressing mental health by integrating psychological support into chronic-care models could help improve diabetes outcomes, particularly for vulnerable groups facing future public health challenges.

The ELMOD3 gene is implicated in causing autosomal recessive/dominant non-syndromic hearing loss in humans. However, the etiology has yet to be completely elucidated. In this study, we generated a patient-derived iPSC line carrying ELMOD3 c.512A>G mutation. In addition, the patient-derived iPSC line was corrected by CRISPR/Cas9 genome editing system. Then we applied RNA sequencing profiling to compare the patient-derived iPSC line with different controls, respectively (the healthy sibling-derived iPSCs and the CRISPR/Cas9 corrected iPSCs). Functional enrichment and PPI network analysis revealed that differentially expressed genes (DEGs) were enriched in the gene ontology, such as sensory epithelial development, intermediate filament cytoskeleton organization, and the regulation of ion transmembrane transport. Our current work provided a new tool for studying how disruption of ELMOD3 mechanistically drives hearing loss.

The system differential response method for inverse estimation has received much attention in the hydrology literature. However, its underlying mechanisms remain largely unexplored, highlighting the need for this study. This study proposes the relation degree coefficient (RC) concept describing the nonlinear relationships between different variables and demonstrates that the selective information extraction ability of the method was first demonstrated from a theoretical perspective. Synthetic cases were conducted to demonstrate the method performance under various variables to be estimated. The results show that the useful information is extracted from the relationship between the variables to be estimated and the observed discharge. In addition, there is a general trend that suggests that incorporating more variables into the inversion estimation can lead to enhanced estimation performance.

Di(2‐ethylhexyl) phthalate (DEHP) is used as plasticizer and is ubiquitously found in the environment. Exposure to DEHP has been linked to an increased incidence of type 2 diabetes. Pancreatic β‐cell dysfunction is a hallmark of type 2 diabetes; however, it is unknown whether DEHP exposure contributes to this risk. Here, we aimed to investigate the cytotoxic effects of DEHP on INS‐1 cells and to further explore the related underlying mechanisms. INS‐1 cells were exposed to 0, 5, 25, 125 or 625 μM DEHP for 24 hrs. Cell viability, glucose‐stimulated insulin secretion, reactive oxygen species (ROS) generation, cellular antioxidant response, Ca2+ homoeostasis and the levels of genes and proteins involved in endoplasmic reticulum (ER) stress were measured. The results showed that DEHP decreased insulin secretion and content and induced apoptosis in INS‐1 cells in a dose‐dependent manner. Furthermore, ROS generation was increased and Nrf2‐dependent antioxidant defence protection was dysregulated in INS‐1 cells after DEHP exposure. Most importantly, DEHP effectively depleted ER Ca2+ and triggered the ER stress response as demonstrated by the elevated transcription and translation of the ER chaperone GRP78 and GRP94, the increased phosphorylation of protein kinase R‐like endoplasmic reticulum kinase (PERK) and its downstream substrate eukaryotic translation initiation factor 2α (eIF2α), as well as the increased levels of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). Taken together, DEHP exerted toxic effects on INS‐1 cells by inducing apoptosis, which is dependent on the activation of the PERK–ATF4–CHOP ER stress signalling pathway and the suppression of Nrf2‐dependent antioxidant protection.