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Abstract Reactive oxygen species (ROS)‐induced oxidative DNA damages have been considered the main cause of mutations in genes, which are highly related to carcinogenesis and tumour progression. Extracellular vesicles play an important role in cancer metastasis. However, the precise role of DNA oxidative damage in extracellular vesicles (EVs)‐mediated cancer cell migration and invasion remains unclear. Here, we reveal that ROS‐mediated DNA oxidative damage signalling promotes tumour metastasis through increasing EVs release. Mechanistically, 8‐oxoguanine DNA glycosylase (OGG1) recognises and binds to its substrate 8‐oxo‐7,8‐dihydroguanine (8‐oxoG), recruiting NF‐κB to the synaptotagmin 7 (SYT7) promoter and thereby triggering SYT7 transcription. The upregulation of SYT7 expression leads to increased release of E‐cadherin‐loaded EVs, which depletes intracellular E‐cadherin, thereby inducing epithelial‐mesenchymal transition (EMT). Notably, Th5487, the inhibitor of DNA binding activity of OGG1, blocks the recognition and transmission of oxidative signals, alleviates SYT7 expression and suppresses EVs release, thereby preventing tumour progression in vitro and in vivo. Collectively, our study illuminates the significance of 8‐oxoG/OGG1/SYT7 axis‐driven EVs release in oxidative stress‐induced tumour metastasis. These findings provide a deeper understanding of the molecular basis of cancer progression and offer potential avenues for therapeutic intervention.

Legacy colliery spoil tip failures pose a significant hazard that can result in harm to persons or damage to property and infrastructure. In this research, the 2020 Wattstown tip landslide caused by heavy rainfall was examined to investigate the likely mechanisms and developmental factors contributing to colliery spoil tip failures in Welsh coalfields. To achieve this, an integrated method was proposed through the combination of remote sensing mapping, stability chart analysis, 2D limit equilibrium (LE) modelling, and 3D finite difference method (FDM) analysis. Various water table geometries were incorporated into these models to ascertain the specific groundwater condition that triggered the occurrence of the 2020 landslide. In addition, sensitivity analyses were carried out to assess the influence of the colliery spoil properties (i.e., cohesion, friction angle, and porosity) on the slope stability analysis. The results indicate that the landslide was characterised by a shallow rotational failure mode and spatially constrained by the critical water table and an underlying geological interface. In addition, the results also imply that the landslide was triggered by the rise of water table associated with heavy rainfall. Through sensitivity analysis, it was found that the properties of the colliery spoil played an important role in confining the extent of the landslide and controlling the process of its development. The findings underscore the detrimental effects of increased pore pressures, induced by heavy rainfall, on the stability of colliery tips, highlighting the urgent needs for local government to enhance water management strategies for this region.

Exposure to PM2.5 pollution poses substantial health risks, with the precise quantification of exposure being fundamental to understanding the environmental inequalities therein. However, the absence of high-resolution spatiotemporal ambient population data, coupled with an insufficiency of attribute data, impedes a comprehension of the environmental inequality of exposure risks at a fine scale. Within the purview of a conceptual framework that interlinks social strata and citizenship identity with environmental inequality, this study examines the environmental inequality of PM2.5 exposure with a focus on the city of Xi’an. Quantitative metrics of the social strata and citizenship identities of the ambient population are derived from housing price data and mobile phone big data. The fine-scale estimation of PM2.5 concentrations is predicated on the kriging interpolation method and refined by leveraging an advanced dataset. Employing geographically weighted regression models, we examine the environmental inequality pattern at a fine spatial scale. The key findings are threefold: (1) the manifestation of environmental inequality in PM2.5 exposure is pronounced among individuals of varying social strata and citizenship identities within our study area, Xi’an; (2) nonlocal residents situated in the northwestern precincts of Xi’an are subject to the most pronounced PM2.5 exposure; and (3) an elevated socioeconomic status is identified as an attenuating factor, capable of averting the deleterious impacts of PM2.5 exposure among nonlocal residents. These findings proffer substantial practical implications for the orchestration of air pollution mitigation strategies and urban planning initiatives. They suggest that addressing the wellbeing of the marginalized underprivileged cohorts, who are environmentally and politically segregated under the extant urban planning policies in China, is of critical importance.

Abstract Rheumatoid arthritis (RA) is a chronic and inflammatory autoimmune disease. Macrophage pyroptosis, a proinflammatory form of cell death, is critically important in RA; however, the detailed mechanism underlying pyroptosis induction is not yet well understood. Here, we report that DNA polymerase β (Pol β), a key enzyme in base excision repair, plays a pivotal role in RA pathogenesis. Our data shows that Pol β expression is significantly decreased in peripheral blood mononuclear cells (PBMCs) from active RA patients and collagen-induced arthritis (CIA) mice, and Pol β deficiency increases the incidence of RA, macrophage infiltration, and bone destruction in CIA mouse models. In vitro, experiments showed that Pol β deficiency exacerbated macrophage pyroptosis induced by LPS plus ATP, while overexpression of Pol β inhibited macrophage pyroptosis. Further characterization revealed that Pol β knockout resulted in DNA damage accumulation and cytosolic dsDNA leakage, which activated the cGAS-STING-NF-κB signaling pathway and upregulated the expression of NLRP3, IL-1 β, and IL-18. In conclusion, our findings clarify the influence of Pol β on the development of RA and provide a detailed explanation for the STING-NF-κB pathway to induce macrophage pyroptosis.

A fire whirl, a unique fire behavior, occurs when a vertical vortex of flames skyrockets due to specific surrounding temperatures and thermal gradient conditions during a fire. Compared with conventional fire plumes, fire whirls exhibit a higher air entrainment rate, tangential velocity, and axial velocity, thus presenting greater risks and destructive capabilities. Thus, studying the combustion characteristics of fire whirls becomes necessary. This experiment employed a small-scale, fixed-frame fire whirl generator. We investigated how varying air-inlet widths and fuel pan diameters influence the fire whirl’s combustion characteristics. Experimental images indicated a negative correlation between the fire whirl’s flame height and the air-inlet width, and a positive correlation with the fuel pan diameter. Our findings showed that the burning rate of the fire whirl during the quasi-steady-state combustion phase initially increased and then decreased as the air-inlet width expanded, peaking at a width of 7 cm. The data demonstrated a corresponding power-law relationship between the fire whirl’s dimensionless flame height and excess temperature. Ultimately, our results indicated a positive correlation between the 2/5 power of the fire whirl’s dimensionless heat release rate and the dimensionless flame height. The ratios of maximum to mean flame height and mean to continuous flame height are 1.35 and 1.5, respectively. Significantly, these ratios remain unaffected by the air-inlet width, fuel pan diameter, environmental temperature, and heat release rate.

Soft X-ray spectromicroscopy at the O K-edge, U N4,5-edges and Ce M4,5-edges has been performed on focused ion beam sections of spent nuclear fuel for the first time, yielding chemical information on the sub-micrometer scale. To analyze these data, a modification to non-negative matrix factorization (NMF) was developed, in which the data are no longer required to be non-negative, but the non-negativity of the spectral components and fit coefficients is largely preserved. The modified NMF method was utilized at the O K-edge to distinguish between two components, one present in the bulk of the sample similar to UO2 and one present at the interface of the sample which is a hyperstoichiometric UO2+x species. The species maps are consistent with a model of a thin layer of UO2+x over the entire sample, which is likely explained by oxidation after focused ion beam (FIB) sectioning. In addition to the uranium oxide bulk of the sample, Ce measurements were also performed to investigate the oxidation state of that fission product, which is the subject of considerable interest. Analysis of the Ce spectra shows that Ce is in a predominantly trivalent state, with a possible contribution from tetravalent Ce. Atom probe analysis was performed to provide confirmation of the presence and localization of Ce in the spent fuel.

The expression of O-GlcNAc transferase (OGT) and its catalytic product, O-GlcNAcylation (O-GlcNAc), are elevated in many types of cancers, including prostate cancer (PC). Inhibition of OGT serves as a potential strategy for PC treatment alone or combinational therapy. PC is the second common cancer type in male worldwide, for which chemotherapy is still the first-line treatment. However, the function of inhibition of OGT on chemotherapeutic response in PC cells is still unknown. In this study, we show that inhibition of OGT by genetic knockdown using shRNA or by chemical inhibition using OGT inhibitors sensitize PC cells to docetaxel, which is the most common chemotherapeutic agent in PC chemotherapy. Furthermore, we identified that microRNA-140 (miR-140) directly binds to OGT mRNA 3′ untranslated region and inhibits OGT expression. Moreover, docetaxel treatment stimulates miR-140 expression, whereas represses OGT expression in PC cells. Overexpression of miR-140 enhanced the drug sensitivity of PC cells to docetaxel, which could be reversed by overexpression of OGT. Overall, this study demonstrates miR-140/OGT axis as therapeutic target in PC treatment and provides a promising adjuvant therapeutic strategy for PC therapy.

Abstract Background Hand injury is commonly associated with multiple soft tissue defects. Polyfoliate flaps grafting is the optimal approach for multiple wounds.The feasibility of clinical using of free thoracodorsal artery polyfoliate perforator flaps for repairing multiple soft tissue defects in the hand needs to be confirmed in clinical practice. Methods Fifteen patients with hand soft tissue defects that were repaired using free thoracodorsal artery polyfoliate perforator flaps from January 2015 to February 2018 was retrospectively analysed. The survival rate, the operative time, the appearance and sensory recovery of the flaps, and hand function were evaluated. Results The flaps of all 15 patients survived. Vascular crisis occurred in one patient, and the flap was saved after exploratory operation. The 15 patients were followed up for 12–26 months. Sensation in the flaps was partially recovered in all 15 patients. The wound in the donor area was closed directly with sutures. Mean score of scars at the donor site were assessed using the modified Vancouver scar scale (VSS) was 2.7. A puffed appearance in the recipient area was noted in four patients. To obtain a more satisfactory appearance, revision of the flap was performed once in these four patients. The Total Active Movement (TAM) evaluation system was used to assess the results, which were considered excellent in seven patients, good in six patients, fair in two patients, and poor in none of the patients. Ten of the 15 patients returned to their primary jobs. Conclusion Free thoracodorsal artery polyfoliate perforator flaps are appropriate for repairing multiple soft tissue defects in the hand, offer a satisfactory appearance, require a short operative time, and have little impact on the function and aesthetics of the donor site.

The experimental study on the combustion characteristics of paper stack fires was carried out in a low-pressure chamber. The variability of which with different environmental pressures and stacking methods were investigated. The mass of each group of experimental paper strips was 107 g. Three iron frames had the same volume, but different lengths and widths, and the strips were placed evenly in the frames to simulate different ways of paper stacking. The combustion tests of the paper stack were conducted at four ambient pressures of 101 kPa, 80 kPa, 60 kPa, and 40 kPa, respectively. The parameters measured during the experiments included mass loss, heat release rate (HRR), and flame temperature. The experimental results showed that the stacking type and pressure significantly affected the properties of the paper stack fire. For instance, the burning rate was influenced by the cross-sectional combustion area, pressure, and load height. There was a linear relationship between the ratio of the peak burning rate to the characteristic length of the bottom surface and the pressure-load height. The intensity factor of the paper stack fire was closely related to the environmental pressure: the paper stack fire under atmospheric pressure was generally a fast-growing one, which was a medium-growing fire under about 80 kPa. In comparison, that was a slow-growing fire when the pressure was 60 kPa.

The spill fires caused by liquid fuel leaks greatly threaten the safety of fuel transportation and storage. In this work, the effect of fuel temperature on the spread characteristics of flowing flames was investigated through n-butanol spilling fire experiments. The spill fire spread can be divided into three stages at different temperatures and leakage rates (I) full spread, (II) gradually extinguished spread, and (III) unable to spread. The oscillation of the flame is related to the fuel thickness and the discharge rate. As the discharge rate or temperature increases, the spread mode changes from pulsation to uniform. With an increase in temperature, the surface flow of the flame is reduced, leading to a decrease in both the preheating time and pulsation amplitude. However, the rate of liquid surface detachment from the flame increases with increasing temperature. The view factor of flame spread can be calculated by the solid flame model, and the flame influences the heat radiation spread state with stable phases or peaks. The research findings presented in this paper hold significant implications for the development of fire safety regulations pertaining to fuel leakage fires.

Abstract 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.

Methyltransferase-like 3 (METTL3) and N6-methyladenosine (m6A) are involved in many types of biological and pathological processes, including DNA repair. However, the function and mechanism of METTL3 in DNA repair and chemotherapeutic response remain largely unknown. In present study, we identified that METTL3 participates in the regulation of homologous recombination repair (HR), which further influences chemotherapeutic response in both MCF-7 and MDA-MB-231 breast cancer (BC) cells. Knockdown of METTL3 sensitized these BC cells to Adriamycin (ADR; also named as doxorubicin) treatment and increased accumulation of DNA damage. Mechanically, we demonstrated that inhibition of METTL3 impaired HR efficiency and increased ADR-induced DNA damage by regulating m6A modification of EGF/RAD51 axis. METTL3 promoted EGF expression through m6A modification, which further upregulated RAD51 expression, resulting in enhanced HR activity. We further demonstrated that the m6A ‘reader,’ YTHDC1, bound to the m6A modified EGF transcript and promoted EGF synthesis, which enhanced HR and cell survival during ADR treatment in BC. Our findings reveal a pivotal mechanism of METTL3-mediated HR and chemotherapeutic drug response, which may contribute to cancer therapy.

Reactive oxygen species (ROS) are a group of highly oxidative molecules that induce DNA damage, affecting DNA damage response (DDR) and gene expression. It is now recognized that DNA base excision repair (BER) is one of the important pathways responsible for sensing oxidative stress to eliminate DNA damage, in which FEN1 plays an important role in this process. However, the regulation of FEN1 under oxidative stress is still unclear. Here, we identified a novel RNA G-quadruplex (rG4) sequence in the 5′untranslated region (5′UTR) of FEN1 mRNA. Under oxidative stress, the G bases in the G4-forming sequence can be oxidized by ROS, resulting in structural disruption of the G-quadruplex. ROS or TMPyP4, a G4-structural ligand, disrupted the formation of G4 structure and affected the expression of FEN1. Furthermore, pull-down experiments identified a novel FEN1 rG4-binding protein, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), and cellular studies have shown that hnRNPA1 plays an important role in regulating FEN1 expression. This work demonstrates that rG4 acts as a ROS sensor in the 5′UTR of FEN1 mRNA. Taken together, these results suggest a novel role for rG4 in translational control under oxidative stress.

A pre-stressing design and a simple fabrication technology to substantially improve the strength of ceramic components are presented. Residual surface compressive stress is generated in ceramic components by pressureless sintering of a green bulk coated with a thin layer of low coefficient of thermal expansion (CTE). The stress level can be controlled by changing the cross-section area ratio, Young's modulus ratio and CTE ratio of the coating. Pre-stressed ZrO2 ceramics coated with Al2O3 can achieve a flexural strength of 1330 ± 52 MPa, 45% higher than their uncoated counterpart. Similarly, the flexural strength of building porcelain tiles is increased by 70%, from 67 ± 3 MPa to 114 ± 5 MPa. The damage tolerance of pre-stressed ZrO2 ceramics is excellent with a high residual strength of ∼1200 MPa in a thermal shock test at 325 °C. This simple technique can improve the mechanical performance of ceramic components with no limitation of size and shape. Keywords: Pre-stressed ceramics, Coating, Strength, Thermal shock resistance

ObjectivesThis study was conducted in order to design and develop a framework utilizing deep learning (DL) to differentiate papillary renal cell carcinoma (PRCC) from chromophobe renal cell carcinoma (ChRCC) using convolutional neural networks (CNNs) on a small set of computed tomography (CT) images and provide a feasible method that can be applied to light devices.MethodsTraining and validation datasets were established based on radiological, clinical, and pathological data exported from the radiology, urology, and pathology departments. As the gold standard, reports were reviewed to determine the pathological subtype. Six CNN-based models were trained and validated to differentiate the two subtypes. A special test dataset generated with six new cases and four cases from The Cancer Imaging Archive (TCIA) was applied to validate the efficiency of the best model and of the manual processing by abdominal radiologists. Objective evaluation indexes [accuracy, sensitivity, specificity, receiver operating characteristic (ROC) curve, and area under the curve (AUC)] were calculated to assess model performance.ResultsThe CT image sequences of 70 patients were segmented and validated by two experienced abdominal radiologists. The best model achieved 96.8640% accuracy (99.3794% sensitivity and 94.0271% specificity) in the validation set and 100% (case accuracy) and 93.3333% (image accuracy) in the test set. The manual classification achieved 85% accuracy (100% sensitivity and 70% specificity) in the test set.ConclusionsThis framework demonstrates that DL models could help reliably predict the subtypes of PRCC and ChRCC.

This paper focuses on the back analysis of an ancient, catastrophic rock avalanche located in the small city of Lettopalena (Chieti, Italy). The integrated use of various investigation methods was employed for landslide analysis, including the use of traditional manual surveys and remote sensing (RS) mapping for the identification of geological structures. The outputs of the manual and RS surveys were then utilised to numerically model the landslide using a 2D distinct element method. A series of numerical simulations were undertaken to perform a sensitivity analysis to investigate the uncertainty of discontinuity properties on the slope stability analysis and provide further insight into the landslide failure mechanism. Both numerical modelling and field investigations indicate that the landslide was controlled by translational sliding along a folded bedding plane, with toe removal because of river erosion. This generated daylighting of the bedding plane, creating kinematic freedom for the landslide. The formation of lateral and rear release surfaces was influenced by the orientation of the discrete fracture network. Due to the presence of an anticline, the landslide region was constrained in the middle-lower section of the slope, where the higher inclination of the bedding plane was detected. The landslide is characterized by a step-path slip surface at the toe of the slope, which was observed both in the modelling and the field. This paper highlights the combined use of a geological model and numerical modelling to provide an improved understanding of the origin and development of rock avalanches under the influence of river erosion, anticline structures, and related faults and fractures.

Abstract Background Skin barrier functions develop after birth and may be related to skin disorders in infants. We aimed to assess associations between dynamic trends of four skin barrier functional parameters in early life with infant atopic dermatitis (AD). Methods Based on the prospective cohort MKNFOAD (NCT02889081), we examined transepidermal water loss (TEWL), stratum corneum hydration (SCH), skin pH, and sebum content at five anatomical sites (cheek, forehead, forearm, abdomen, and lower leg) in 418 term infants at birth, 42 days, and 6 months. Trend differences by sex and association with AD at age 1 year were tested using variance analyses. Associations of the parameters with AD risk were tested using discrete time survival analysis, adjusting extensive covariates including parental history of allergy, infant’s sex, birth weight (kg), and delivery mode. Odds ratios (ORs) and 95% confidence interval (CIs) were reported. Results Overall TEWL and SCH appeared trends of increase while skin surface pH and sebum content showed trends of decrease within the first six postnatal months. Sex differences were significant for sebum content only (p

Thermal transport is a key performance metric for thorium dioxide in many applications where defect-generating radiation fields are present. An understanding of the effect of nanoscale lattice defects on thermal transport in this material is currently unavailable due to the lack of a single crystal material from which unit processes may be investigated. In this work, a series of high-quality thorium dioxide single crystals are exposed to 2 MeV proton irradiation at room temperature and 600 °C to create microscale regions with varying densities and types of point and extended defects. Defected regions are investigated using spatial domain thermoreflectance to quantify the change in thermal conductivity as a function of ion fluence as well as transmission electron microscopy and Raman spectroscopy to interrogate the structure of the generated defects. Together, this combination of methods provides important initial insight into defect formation, recombination, and clustering in thorium dioxide and the effect of those defects on thermal transport. These methods also provide a promising pathway for the quantification of the smallest-scale defects that cannot be captured using traditional microscopy techniques and play an outsized role in degrading thermal performance.

The DNA lesions caused by oxidative damage are principally repaired by the base excision repair (BER) pathway. 8-oxoguanine DNA glycosylase 1 (OGG1) initiates BER through recognizing and cleaving the oxidatively damaged nucleobase 8-oxo-7,8-dihydroguanine (8-oxoG). How the BER machinery detects and accesses lesions within the context of chromatin is largely unknown. Here, we found that the symmetrical dimethylarginine of histone H4 (producing H4R3me2s) serves as a bridge between DNA damage and subsequent repair. Intracellular H4R3me2s was significantly increased after treatment with the DNA oxidant reagent H2O2, and this increase was regulated by OGG1, which could directly interact with the specific arginine methyltransferase, PRMT5. Arginine-methylated H4R3 could associate with flap endonuclease 1 (FEN1) and enhance its nuclease activity and BER efficiency. Furthermore, cells with a decreased level of H4R3me2s were more susceptible to DNA-damaging agents and accumulated more DNA damage lesions in their genome. Taken together, these results demonstrate that H4R3me2s can be recognized as a reader protein that senses DNA damage and a writer protein that promotes DNA repair.

Colorectal cancer: pathways to drug resistance The interaction between two signaling pathways may be related to resistance to a leading cancer drug in colorectal cancer cells. The drug 5-fluorouracil (5-FU) is widely used to limit malignant cell proliferation, but some cancers, including colorectal cancers, are resistant to 5-FU. Zhigang Guo at Nanjing Normal University, China, and co-workers have uncovered the signaling pathways behind 5-FU resistance in colorectal cancer cell lines. They found that 5-FU-resistant cells expressed high levels of two proteins indicative of an over-active Wnt signaling pathway, a crucial pathway in healthy development, the disruption of which is implicated in many diseases. This upregulated pathway suppressed another signaling pathway, leading to reduced cancer cell death. This interaction between the pathways could prove to be a valuable therapeutic target to limit resistance to 5-FU.

This paper proposes a novel method to incorporate unfavorable orientations of discontinuities into machine learning (ML) landslide prediction by using GIS-based kinematic analysis. Discontinuities, detected from photogrammetric and aerial LiDAR surveys, were included in the assessment of potential rock slope instability through GIS-based kinematic analysis. Results from the kinematic analysis, coupled with several commonly used landslide influencing factors, were adopted as input variables in ML models to predict landslides. In this paper, various ML models, such as random forest (RF), support vector machine (SVM), multilayer perceptron (MLP) and deep learning neural network (DLNN) models were evaluated. Results of two validation methods (confusion matrix and ROC curve) show that the involvement of discontinuity-related variables significantly improved the landslide predictive capability of these four models. Their addition demonstrated a minimum of 6% and 4% increase in the overall prediction accuracy and the area under curve (AUC), respectively. In addition, frequency ratio (FR) analysis showed good consistency between landslide probability that was characterized by FR values and discontinuity-related variables, indicating a high correlation. Both results of model validation and FR analysis highlight that inclusion of discontinuities into ML models can improve landslide prediction accuracy.