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Apurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno‐associated virus (AAV)‐mediated OTOF gene replacement therapy is extensively validated in Otof‐deficient mice. However, the clinical safety and efficacy of AAV‐OTOF is not reported. Here, AAV‐OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non‐human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV‐OTOF is delivered into one cochlea of a 5‐year‐old deaf patient and into the bilateral cochleae of an 8‐year‐old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure‐tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5‐year‐old patient can be restored to the normal range at 1 month after AAV‐OTOF injection, while the 8‐year‐old patient can hear the conversational sounds. Most importantly, the 5‐year‐old patient can hear and recognize speech only through the AAV‐OTOF‐injected ear. This study is the first to demonstrate the safety and efficacy of AAV‐OTOF in patients, expands and optimizes current OTOF‐related gene therapy and provides valuable information for further application of gene therapies for deafness. This study evaluates the efficacy and safety of an adeno‐associated virus (AAV) based gene therapy AAV‐OTOF in patients with DFNB9 deafness. AAV‐OTOF injection can restore the hearing function of the previous deaf ear to a normal level with safety. This proof of concept study provides clinical gene therapy data for DFNB9 deafness and also supplies support for other inner ear gene therapies.

Apolipoprotein C3 (apoC3) and apolipoprotein A5 (apoA5), encoded by APOA1/C3/A4/A5 gene cluster, are two critical regulators of plasma triglyceride (TG) metabolism. Deficiency of apoC3 or apoA5 led to significant decreased or increased plasma TG levels, respectively. Recent studies indicated apoC3 and apoA5 also played roles in plasma remnant cholesterol, high density lipoprotein (HDL) and hepatic TG metabolisms. Moreover, large scale population genetic studies indicated that loss of function mutations in APOC3 and APOA5 gene conferred decreased and increased risk of coronary artery disease (CAD), respectively. This manuscript mainly reviewed existing evidences suggesting the opposite role of apoC3 and apoA5 in lipid metabolism and CAD risk, and discussed the potential correlation between these two apolipoproteins.

In this paper, we propose a vehicle routing problem with time windows (TWVRP). In this problem, we consider a hard time constraint that the fleet can only serve customers within a specific time window. To solve this problem, a hybrid ant colony (HACO) algorithm is proposed based on ant colony algorithm and mutation operation. The HACO algorithm proposed has three innovations: the first is to update pheromones with a new method; the second is the introduction of adaptive parameters; and the third is to add the mutation operation. A famous Solomon instance is used to evaluate the performance of the proposed algorithm. Experimental results show that HACO algorithm is effective against solving the problem of vehicle routing with time windows. Besides, the proposed algorithm also has practical implications for vehicle routing problem and the results show that it is applicable and effective in practical problems.

To establish a bleeding prediction model for the use of low molecular weight heparin anticoagulation in cancer patients, aiming to help medical staff to individually evaluate the timing of low molecular weight heparin use in cancer patients. This retrospective cohort study enrolled 731 cancer patients (aged ≥18 years) from January to December 2021 receiving LMWH for venous thromboe-mbolism (VTE) prophylaxis at a tertiary general hospital in Southwest China. Participants were stratified into bleeding (n = 19) and non-bleeding (n = 712) cohorts based on ISTH-defined clinical outcomes. Risk factors identified through multivariablebinary logistic regression, with subsequent development and internal validation performed using R software (version 4.3.2). Univariate analysis of bleeding risk factors revealed statistically significant differences (P < 0.05) in body weight, nonsteroidal anti-inflammatory drug (NSAIDs) use, LMWH dosage, prothrombin time (PT), creatinine clearance, platelet count, Padua score, and HAS-BLED bleeding risk score. Based on clinical relevance, the final model incorporated LMWH dosage, platelet count, and HAS-BLED bleeding risk score as assessment items. The model demonstrated excellent predictive ability for bleeding events, with an ROC-AUC (95% CI) of 0.90 (0.82-0.97). The model showed good discrimination (Hosmer-Lemeshow, P = 0.854 > 0.05) and decision making capability, with strong diagnostic performance (accuracy: 0.83, sensitivity: 0.83, specificity: 0.79, positive predictive value: 0.99). The model had a low probability of missed diagnoses and high sensitivity and specificity. This study developed an optimized bleeding risk prediction model by enhancing the HAS-BLED score through the integration of three key variables: HAS-BLED score, LMWH dosage, and platelet count, demonstrating a robust application prospect for anticoagulation management in cancer patients.

With the development of the Internet, it is more convenient for people to obtain information, which also facilitates the spread of rumors. It is imperative to study the mechanisms of rumor transmission to control the spread of rumors. The process of rumor propagation is often affected by the interaction of multiple nodes. To reflect higher-order interactions in rumor-spreading, hypergraph theories are introduced in a Hyper-ILSR (Hyper-Ignorant–Lurker–Spreader–Recover) rumor-spreading model with saturation incidence rate in this study. Firstly, the definition of hypergraph and hyperdegree is introduced to explain the construction of the model. Secondly, the existence of the threshold and equilibrium of the Hyper-ILSR model is revealed by discussing the model, which is used to judge the final state of rumor propagation. Next, the stability of equilibrium is studied by Lyapunov functions. Moreover, optimal control is put forward to suppress rumor propagation. Finally, the differences between the Hyper-ILSR model and the general ILSR model are shown in numerical simulations.

A novel analytical model is proposed and validated in this paper to predict the velocity deficit in the wake downwind of a wind turbine. The model is derived by employing mass and momentum conservation and assuming a cosine-shaped distribution for the velocity deficit. In this model, a modified wake growth rate rather than a constant one is chosen to take into account the effects of the ambient turbulence and the mechanical turbulence generated. The model was tested against field observations, wind-tunnel measurements in different thrust operations and high-resolution large-eddy simulations (LES) for two aerodynamic roughness lengths. It was found that the normalized velocity deficit predicted by the proposed model shows good agreement with experimental and numerical data in terms of shape and magnitude in the far wake region ( x / d 0 > 3 ). Based on the proposed model, predictions from multiple views and at different locations are demonstrated to show the spatial distribution of streamwise velocity downwind of a wind turbine. The result shows that the model is suitable for predicting streamwise velocity fields and thus could provide some references for the selection of wind turbine spacing.

Wetlands, as a crucial component of urban green spaces, provide important leisure services for residents. Construction of wetlands has increased with the rapid urban expansion and population growth in China over recent decades, especially in semi-arid regions with scarce water resources. However, the residents’ satisfaction with wetland leisure demand remains unclear. This study evaluated the residents’ satisfaction with wetland leisure demand by a framework of physical calculation, taking Yinchuan City, the capital city of Ningxia Hui Autonomous Region, in the semi-arid region of Western China as a case study area. Spatial variations in residents’ satisfaction and their causes were revealed by a supply–demand relationship between the population capacity of wetlands and the total population of communities under a framework of physical calculation. The results indicated that 4.22% of the study area, which covered 7.38% of the total population, was fully satisfied with wetland leisure demand. Residents’ satisfaction in the urban area as a whole is low at 0.49, with a concentric distribution pattern increasing as the distance from the central urban area increases. The high population density and scanty wetlands mainly induced a relative-low residents’ satisfaction in the central urban area, accounting for 12.02% of the area and 32.70% of the population. Meanwhile, a relative-high residents’ satisfaction in the outer ring of the central urban area accounting for 59.10% of the area and 20.63% of the population was primarily due to the adequate capacity of wetlands. Medium residents’ satisfaction was mainly attributed to the road network density, which partially transferred local wetland leisure demand to adjacent areas. Wetland constructions and internal structural optimization to improve the capacity for leisure in densely populated central urban areas could provide a feasible path to alleviate unbalanced conditions. These results could deepen the understanding of supply–demand dynamics in the wetland leisure service and provide valuable information for optimizing wetland allocation in urban construction in semi-arid regions.

Dynamically controlling electromagnetic waves at will is highly desired in many applications, but most previously realized mechanically reconfigurable metasurfaces are of restricted wave-control capabilities due to the limited tuning ranges of structural properties (e.g., lattice constant or meta-atoms). Here, we present mechanically reconfigurable metasurfaces in which both lattice constants and local reflection phases of constitutional meta-atoms can be synchronously controlled based on the kirigami rotation transformation, thereby exhibiting extended tuning ranges and thus wave-control capabilities. In particular, such metasurfaces can exhibit continuously varied and even re-formed reflection-phase profiles along with the kirigami rotation transformation, serving as ideal platforms to achieve reconfigurable beam steering in pre-designed manners. Using this concept, we design and fabricate two kirigami metasurfaces, working as a beam flipper and as a beam splitter for microwaves, respectively, and experimentally characterize their wave-manipulation functionalities. Experimental results are in good agreement with full-wave simulations. The proposed idea is so general that it can be applied to realize reconfigurable metasurfaces with different materials/configurations or in high frequency regimes, for controlling electromagnetic waves and other classical waves (e.g., acoustic waves). Jiang et al. propose a kirigami-based, mechanically reconfigurable metasurface that utilizes simple uniform stretching to achieve unexpected and dynamic beam steering functions. This unique approach modifies the geometric phase and lattice constant synchronously based on the rotation of anisotropic meta-atoms, exhibiting extended degree of freedom and wave-tuning ranges.

The acid deposition has been considered to be a severe environmental issue in China. The pH, electrical conductivity (EC), and concentrations of water soluble ions (NO3-, Cl−, Ca2+, K+, F−, NH4+, Mg2+, SO42-, and Na+) in the precipitation samples collected from 320 cities during 2011–2016 across China were measured. The mean concentrations of F−, NO3-, and SO42- were in the order of winter (6.10, 19.44, and 45.74 µeq L−1) > spring (3.45, 13.83, and 42.61 µeq L−1) > autumn (2.67, 9.73, and 28.85 µeq L−1) > summer (2.04, 7.66, and 19.26 µeq L−1). Secondary ions (SO42-, NO3-, and NH4+) and F− peaked in the Yangtze River Delta (YRD) and Sichuan basin (SB). Crustal ions (i.e. Ca2+, Mg2+), Na+, and Cl− showed the highest concentrations in the semi-arid regions and the coastal cities. The statistical methods confirmed that the mean anthropogenic contribution ratios to SO42-, F−, NO3-, and NH4+ at a national scale were 46.12 %, 71.02 %, 79.10 %, and 82.40 %, respectively. However, Mg2+ (70.51 %), K+ (77.44 %), and Ca2+ (82.17 %) mostly originated from the crustal source. Both Na+ (70.54 %) and Cl− (60.42 %) were closely linked to sea salt aerosols. On the basis of the stepwise regression (SR) analysis, it was proposed that most of the secondary ions and F− were closely related to gross industrial production (GIP), total energy consumption (TEC), vehicle ownership, and N fertilizer use, but the crustal ions (Ca2+ and K+) were mainly controlled by the dust events. The influence of dust days, air temperature, and wind speed on ions increased from southeast China (SEC) to central China, and then to northwest China (NWC), whereas the influence of socioeconomic factors on acid ions (SO42- and NO3-) displayed the higher value in east China.