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The biological role of miR-3188 has not yet been reported in the context of cancer. In this study, we observe that miR-3188 not only reduces cell-cycle transition and proliferation, but also significantly prolongs the survival time of tumour-bearing mice as well as sensitizes cells to 5-FU. Mechanistic analyses indicate that miR-3188 directly targets mTOR to inactivate p-PI3K/p-AKT/c-JUN and induces its own expression. This feedback loop further suppresses cell-cycle signalling through the p-PI3K/p-AKT/p-mTOR pathway. Interestingly, we also observe that miR-3188 direct targeting of mTOR is mediated by FOXO1 suppression of p-PI3K/p-AKT/c-JUN signalling. In clinical samples, reduced miR-3188 is an unfavourable factor and negatively correlates with mTOR and c-JUN levels but positively correlates with FOXO1 expression. Our studies demonstrate that as a tumour suppressor, miR-3188 directly targets mTOR to stimulate its own expression and participates in FOXO1-mediated repression of cell growth, tumorigenesis and NPC chemotherapy resistance. Although miR-related mechanisms have been implicated in nasopharyngeal carcinoma (NPC), a precise role for miR-3188 has not been reported in this context. Here, Zhao et al . show that FOXO1-induced miR-3188 acts as a tumour suppressor in NPC by regulating the axis mTOR/PI3K/Akt/c-Jun.

Space-based gravitational wave detection imposes extremely high requirements on displacement measurement accuracy, with its core measurement components being laser interferometers and inertial sensors. The laser interferometers detect gravitational wave signals by measuring the distance between two test masses (TMs) housed within the inertial sensors. Spatial alignment errors of the TMs relative to the laser interferometers can severely degrade the interferometric performance, primarily by significantly amplifying tilt-to-length (TTL) coupling noise and reducing interferometric efficiency. This paper presents a systematic analysis of the coupling mechanisms between TM alignment errors and TTL coupling noise. We first establish a comprehensive TTL noise model that accounts for alignment errors, then verify and analyze it through optical simulations. This research ultimately clarifies the coupling mechanisms of TM alignment errors in the context of space-borne gravitational wave missions and determines the allowable alignment tolerance specifications required to meet the gravitational wave detection sensitivity requirements. This work provides critical theoretical foundations and design guidance for the ground alignment procedures and on-orbit performance prediction of future space-based gravitational wave detection missions.

A persistent accumulation of damaged mitochondria is part of prion disease pathogenesis. Normally, damaged mitochondria are cleared via a major pathway that involves the E3 ubiquitin ligase parkin and PTEN-induced kinase 1 (PINK1) that together initiate mitophagy, recognize and eliminate damaged mitochondria. However, the precise mechanisms underlying mitophagy in prion disease remain largely unknown. Using prion disease cell models, we observed PINK1-parkin-mediated mitophagy deficiency in which parkin depletion aggravated blocked mitochondrial colocalization with LC3-II-labeled autophagosomes, and significantly increased mitochondrial protein levels, which led to inhibited mitophagy. Parkin overexpression directly induced LC3-II colocalization with mitochondria and alleviated defective mitophagy. Moreover, parkin-mediated mitophagy was dependent on PINK1, since PINK1 depletion blocked mitochondrial Parkin recruitment and reduced optineurin and LC3-II proteins levels, thus inhibiting mitophagy. PINK1 overexpression induced parkin recruitment to the mitochondria, which then stimulated mitophagy. In addition, overexpressed parkin and PINK1 also protected neurons from apoptosis. Furthermore, we found that supplementation with two mitophagy-inducing agents, nicotinamide mononucleotide (NMN) and urolithin A (UA), significantly stimulated PINK1-parkin-mediated mitophagy. However, compared with NMN, UA could not alleviate prion-induced mitochondrial fragmentation and dysfunction, and neuronal apoptosis. These findings show that PINK1-parkin-mediated mitophagy defects lead to an accumulation of damaged mitochondria, thus suggesting that interventions that stimulate mitophagy may be potential therapeutic targets for prion diseases.

HighlightsA dual-atom nanozyme (DAN) was successfully prepared based on Fe and Mn bimetallic single-atom embedded in N-doped carbon material and modified with hydrophilic polymer.The DAN possess excellent enzyme catalytic activity and attenuate dramatically inflammation by inhibiting the reactive oxygen species (ROS)/NLRP3 signal axis.The DAN break the vicious cycle in dry eye disease and is a potential strategy for treating dry eye disease.Dry eye disease (DED) is a major ocular pathology worldwide, causing serious ocular discomfort and even visual impairment. The incidence of DED is gradually increasing with the high-frequency use of electronic products. Although inflammation is core cause of the DED vicious cycle, reactive oxygen species (ROS) play a pivotal role in the vicious cycle by regulating inflammation from upstream. Therefore, current therapies merely targeting inflammation show the failure of DED treatment. Here, a novel dual-atom nanozymes (DAN)-based eye drops are developed. The antioxidative DAN is successfully prepared by embedding Fe and Mn bimetallic single-atoms in N-doped carbon material and modifying it with a hydrophilic polymer. The in vitro and in vivo results demonstrate the DAN is endowed with superior biological activity in scavenging excessive ROS, inhibiting NLRP3 inflammasome activation, decreasing proinflammatory cytokines expression, and suppressing cell apoptosis. Consequently, the DAN effectively alleviate ocular inflammation, promote corneal epithelial repair, recover goblet cell density and tear secretion, thus breaking the DED vicious cycle. Our findings open an avenue to make the DAN as an intervention form to DED and ROS-mediated inflammatory diseases.

Efficiently removing excess reactive oxygen species (ROS) generated by various factors on the ocular surface is a promising strategy for preventing the development of dry eye disease (DED). The currently available eye drops for DED treatment are palliative, short-lived and frequently administered due to the short precorneal residence time. Here, we developed nanozyme-based eye drops for DED by exploiting borate-mediated dynamic covalent complexation between n-FeZIF-8 nanozymes (n-Z(Fe)) and poly(vinyl alcohol) (PVA) to overcome these problems. The resultant formulation (PBnZ), which has dual-ROS scavenging abilities and prolonged corneal retention can effectively reduce oxidative stress, thereby providing an excellent preventive effect to alleviate DED. In vitro and in vivo experiments revealed that PBnZ could eliminate excess ROS through both its multienzyme-like activity and the ROS-scavenging activity of borate bonds. The positively charged nanozyme-based eye drops displayed a longer precorneal residence time due to physical adhesion and the dynamic borate bonds between phenyboronic acid and PVA or o-diol with mucin. The in vivo results showed that eye drops could effectively alleviate DED. These dual-function PBnZ nanozyme-based eye drops can provide insights into the development of novel treatment strategies for DED and other ROS-mediated inflammatory diseases and a rationale for the application of nanomaterials in clinical settings. Graphical Abstract Highlights Modification of dynamic covalent bonds based on borate bonds can improve the solubility and dispersion of Fe-based nanozymes in solution. The nanozyme-based eye drops enable reactive groups to bind to the chemical groups present in the mucin layer to confer carrier adhesion, thereby increasing the retention time of the carrier on the ocular surface. Nanozyme-based eye drops have synergistic effects on Fe-based nanozymes, and borate bonds effectively neutralize excess ROS in the microenvironment of the ocular surface, thereby reducing oxidative stress and direct oxidative damage. Nanozyme-based eye drops could effectively alleviate DED and may be a promising nanotherapeutic strategy for DED treatment.

The development of non‐antibiotic pharmaceuticals with biocompatible and efficient antibacterial properties is of great significance for the treatment of bacterial keratitis. In this study, we have developed antibacterial iron‐doped nanozymes (Fe3+‐doped nanozymes, FNEs) with distinguished capacity to fight against bacterial infections. The iron‐doped nanozymes are composed of Fe3+ doped zeolitic imidazolate framework‐8 (Fe/ZIF‐8) and polyethylene imide (PEI), which were functionally coated on the surface of Fe/ZIF‐8 and imparted the FNEs with improved water dispersibility and biocompatibility. FNEs possess a significant spontaneous peroxidase‐mimic activity without the need for external stimulation, thus elevating cellular reactive oxygen species level by catalyzing local H2O2 at the infection site and resulting in bacteria damaged to death. FNEs eliminated 100% of Staphylococcus aureus within 6 h, and significantly relieved inflammation and bacterial infection levels in mice bacterial keratitis, exhibiting higher bioavailability and a superior therapeutic effect compared to conventional antibiotic eye drops. In addition, the FNEs would not generate drug resistance, suggesting that FNEs have great potential in overcoming infectious diseases caused by antimicrobial resistant bacteria. A functionalized antibacterial iron‐doped nanozyme with spontaneous peroxidase ‐mimic activity was fabricated to treat bacterial keratitis. The iron‐doped nanozymes could elevate cellular reactive oxygen species level and result in bacteria damaged to death, thus exhibiting an excellent therapeutic effect in bacterial keratitis.

A steel modular building is a highly prefabricated form of steel construction. It offers rapid assembly, a high degree of industrialization, and an environmentally friendly construction site. To promote the application of multi-story steel modular buildings in earthquake fortification zones, it is imperative to conduct in-depth research on their seismic behavior. In this study, a seven-story modular steel building is investigated using shaking table tests. Three seismic waves (artificial ground motion, Tohoku wave, and Tianjin wave) are selected and scaled to four intensity levels (PGA = 0.035 g, 0.1 g, 0.22 g, 0.31 g). It is found that no residual deformation of the structure is observed after tests, and its stiffness degradation ratio is 7.65%. The largest strains observed during the tests are 540 × 10−6 in beams, 1538 × 10−6 in columns, and 669 × 10−6 in joint regions, all remaining below a threshold value of 1690 × 10−6. Amplitudes and frequency characteristics of the acceleration responses are significantly affected by the characteristics of the seismic waves. However, the acceleration responses at higher floors are predominantly governed by the structure’s low-order modes (first-mode and second-mode), with the corresponding spectra containing only a single peak. When the predominant frequency of the input ground motion is close to the fundamental natural frequency of the modular steel structure, the acceleration responses will be significantly amplified. Overall, the structure demonstrates favorable seismic resistance.

Prion diseases are a group of fatal neurodegenerative disorders characterized by the abnormal folding of cellular prion proteins into pathogenic forms. The development of these diseases is intricately linked to oxidative stress and mitochondrial dysfunction. Irisin, an endogenous myokine, has demonstrated considerable neuroprotective potential due to its antioxidative properties. However, the protective effects of irisin against prion diseases have yet to be clarified. Our findings indicate that treatment with exogenous irisin can mitigate the apoptosis induced by PrP 106–126. Additionally, irisin significantly reduces oxidative stress and alleviates the mitochondrial dysfunction triggered by PrP 106–126 . Furthermore, irisin treatment targets uncoupling protein 2 (UCP2) and activates the AMPK-Nrf2 pathway, substantially improving oxidative stress and mitochondrial dysfunction in N2a cells induced by PrP 106–126 . These results suggest that irisin represents a novel and promising therapeutic approach for treating prion diseases. Highlights PrP 106–126 induces mitochondrial dysfunction in a mtROS-dependent manner. Irisin alleviates PrP 106–126 -induced oxidative stress via UCP2 activation. UCP2 mediates irisin-induced AMPK-Nrf2 activation. Inhibition of oxidative stress rescues PrP 106–126 -induced cell death. PrP 106–126 exposure induces ROS accumulation, leading to mitochondrial dysfunction and cell death. Irisin has a protective effect against PrP 106–126 toxicity and depends on the activation of the UCP2-AMPK signaling pathway.

For the Taiji program or other LISA-like space-based gravitational wave (GW) detection missions, establishing laser links is a prerequisite for entering the normal science mode. There has been a lack of in-depth research on inter-satellite link acquisition under weak light and low-speed conditions. In this paper, we comprehensively analyze the impact of key parameters, including scan speed, track width, acquisition camera integration time, and jitter, on the acquisition process. By introducing laser spot location error under weak light conditions, we derive an analytical expression for the acquisition failure probability. Focusing on variations in scan speed and track width and carefully selecting the appropriate acquisition camera integration time, we then simulate the actual acquisition process to closely replicate real conditions. Analytical results of the acquisition failure probability align closely with the simulation results. Under the Taiji program’s parameter settings, the scan speed is set to 3.31 μrad/s, the track width to 0.87 μrad, and the integration time to 800ms. These parameters are optimized to minimize the mean acquisition time over multiple scans, resulting in a single link acquisition time of 223.77s. The analytical model can be used for the parameter design of inter-satellite laser link acquisition under weak light conditions.