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Abstract. B7-H3 (CD276), an immune checkpoint protein of the B7 family, exhibits significant upregulation in solid tumors and hematologic malignancies, exerting a crucial role in their pathophysiology. The distinct differential expression of B7-H3 between tumors and normal tissues and its multifaceted involvement in tumor pathogenesis position it as a promising therapeutic target for tumors. In the context of acute myeloid leukemia (AML), B7-H3 is prominently overexpressed and closely associated with unfavorable prognoses, yet it has remained understudied. Despite various ongoing clinical trials demonstrating the potential efficacy of immunotherapies targeting B7-H3, the precise underlying mechanisms responsible for B7-H3-mediated proliferation and immune evasion in AML remain enigmatic. In view of this, we comprehensively outline the current research progress concerning B7-H3 in AML, encompassing in-depth discussions on its structural attributes, receptor interactions, expression profiles, and biological significance in normal tissues and AML. Moreover, we delve into the protumor effects of B7-H3 in AML, examine the intricate mechanisms that underlie its function, and discuss the emerging application of B7-H3-targeted therapy in AML treatment. By juxtaposing B7-H3 with other molecules within the B7 family, this review emphasizes the distinctive advantages of B7-H3, not only as a valuable prognostic biomarker but also as a highly promising immunotherapeutic target in AML.

Global inland surface water bodies such as lakes and reservoirs, important components of the hydrosphere and ecosphere, are increasingly affected by climate change. Generating bathymetric volume-area-height (BVAH) curves for global inland surface water bodies can enhance our understanding of their topography and climate impacts. However, accurately quantifying the topographic patterns of these water bodies remains challenging due to the difficulties in collecting comprehensive bathymetric data. Therefore, we collected and processed over 2000 bathymetric maps of global water bodies from over 50 different data sources and then developed the BVAH model. Finally, the BVAH hydrological curves of 16671 global inland surface water bodies (larger than 10 km2) were generated. The results include but are not limited to (1) For most targeted water bodies, area (A) and volume (V) exhibit significant power function relationships with surface heights (H), with optimal power values quantified as 1.42 for A and 2.42 for V. (2) The BVAH model outperforms GLOBathy in estimating area and volume changes, achieving higher correlation coefficients (CC) of approximately 0.962 for the area and 0.991 for volume, and demonstrating lower percentages of root mean squared errors (PRMSE) around 10.9% for the area and 4.8% for volume. (3) In the case study of the Xizang Plateau and various large global reservoirs, the BVAH curve database can capture dynamic volume changes. As a unified simulation of the bathymetric topographical patterns, our bathymetric dataset and corresponding BVAH curve database have great potential to contribute to effective water resource management and ecological conservation efforts worldwide.

Abstract Detecting genetic variants enables risk factor identification, disease screening, and initiation of preventative therapeutics. However, current methods, relying on hybridization or sequencing, are unsuitable for point-of-care settings. In contrast, CRISPR-based-diagnostics offer high sensitivity and specificity for point-of-care applications. While these methods have predominantly been used for pathogen sensing, their utilization for genotyping is limited. Here, we report a multiplexed CRISPR-based genotyping assay using LwaCas13a, PsmCas13b, and LbaCas12a, enabling the simultaneous detection of six genotypes. We applied this assay to identify genetic variants in the APOL1 gene prevalent among African Americans, which are associated with an 8–30-fold increase in the risk of developing kidney disease. Machine learning facilitated robust analysis across a multicenter clinical cohort of more than 100 patients, accurately identifying their genotypes. In addition, we optimized the readout using a multi-analyte lateral-flow assay demonstrating the ability for simplified genotype determination of clinical samples. Our CRISPR-based genotyping assay enables cost-effective point-of-care genetic variant detection due to its simplicity, versatility, and fast readout.

Abstract Per- and poly-fluoroalkyl substances (PFAS) have gained widespread attention due to their adverse effects on health and environment. Developing efficient technology to capture PFAS from contaminated sources remains a great challenge. In this study, we introduce a type of reusable polymeric sorbent (PFPE-IEX + ) for rapid, efficient, and selective removal of multiple PFAS impurities from various contaminated water sources. The resin achieves >98% removal efficiency ([PFPE-IEX + ] = 0.5–5 mg mL−1, [PFAS]0 = 1–10 ppb in potable water and landfill leachate) and >500 mg g−1 sorption capacity for the 11 types of examined PFAS. We achieve efficient PFAS removal without breakthrough and subsequent resin regeneration and demonstrate good PFAS recovery in a proof-of-concept cartridge setup. The outcomes of this study offer valuable guidance to the design of platforms for efficient and selective PFAS capture from contaminated water, such as drinking water and landfill leachate.

Abstract Background Cardiovascular disease (CVD) is a major health concern for middle-aged and older adults, with lifestyle and metabolic risk factors well-studied. However, the role of psychosocial factors in CVD remains underexplored. Objective This study aims to delve into the connection between psychosocial factors and the occurrence of CVD. Methods We utilized data from the UK Biobank, a large-scale study covering adults aged 38 to 73 recruited from various centers across the UK between 2006 and 2010. We employed Cox proportional hazards models to analyze the relationship between social isolation, loneliness, and incident CVD. CVD diagnoses were confirmed through hospital records and death-register data. Additionally, we conducted mediation analyses to assess the impact of low-grade inflammation. Results The study encompassed 427,942 participants free from CVD, 55.8% of whom are women. High levels of social isolation and loneliness were linked to a higher risk of CVD (HRs 1.11, 95% CI 1.06–1.16; HRs 1.17, 95% CI 1.11–1.23). Depression also emerged as a predictor of CVD onset (HRs 1.25, 95% CI 1.19–1.31), with each psychosocial factor independently contributing to increased CVD risk. Mediation analyses pinpointed inflammation as a crucial mediator, especially for loneliness (indirect effect proportion: 4.7%). Conclusions This study underscores the significance of psychosocial factors in relation to CVD. Integrating assessments for social isolation, loneliness, and depression into routine healthcare could potentially aid in CVD prevention among middle-aged and elderly individuals. Lay summary This study underscores the significance of psychosocial factors in relation to CVD, emphasizing the association between social isolation or loneliness and the heightened risk of CVD. Graphical abstract

In recent years, leadership rejection has become an important topic of widespread academic concern as a factor that constrains individual career development and affects the competitive advantage of organizations. Although studies have been conducted on the implementation effect of leadership rejection, the role mechanism of leadership rejection has been less studied. In this study, we examine the impact of leadership rejection on employees' proactive behaviors and analyze the mediating effects of organizational identification, psychological empowerment, and the moderating effects of power distance. The path analysis of the two-stage survey data of 295 employees indicates that leadership rejection reduces employees' proactive behaviors by lowering subordinates' identification with the organization on the one hand and by lowering employees' psychological empowerment on the other. For employees with high power distance, leadership rejection has a weaker negative impact on employee proactive behavior by enhancing organizational identification; for employees with low power distance, leadership rejection has a stronger negative impact on employee work engagement by reducing psychological empowerment.

Clonorchis sinensis infections persist globally among humans. These pathogens mainly inhabit the intrahepatic biliary system. Most individuals with clonorchiasis exhibit mild symptoms. The absence of distinctive symptoms often results in delayed diagnosis and treatment, potentially leading to chronic infection. We herein report a case of a 29-year-old female presented with a year-long history of abdominal distention and dyspepsia. Imaging revealed intrahepatic bile duct dilatation, intrahepatic bile duct cyst, and associated deposits. One month post-cystectomy, the patient developed massive ascites and a significant increase in eosinophil count. After treatment, multiple worms were observed in the drainage tube. Morphological and DNA metagenomic analyses confirmed the presence of C. sinensis. Clinical manifestations of C. sinensis vary widely. Imaging serves as a valuable diagnostic tool in endemic areas, especially in detecting intrahepatic duct dilation where the flukes reside. In addition to intrahepatic bile duct dilation, abnormal echoes within the bile duct and the presence of floating objects in the gallbladder significantly aid in diagnosis. Clinicians may encounter these parasitic diseases unexpectedly, underscoring the importance of understating such cases in routine practice and contributing to our broader understanding of managing similar cases in clinical settings.

Abstract. Background:. Life's Simple 7, the former construct of cardiovascular health (CVH) has been used to evaluate adverse non-communicable chronic diseases (NCDs). However, some flaws have been recognized in recent years and Life's Essential 8 has been established. In this study, we aimed to analyze the association between CVH defined by Life's Essential 8 and risk of 44 common NCDs and further estimate the population attributable fractions (PAFs) of low-moderate CVH scores in the 44 NCDs. Methods:. In the UK Biobank, 170,726 participants free of 44 common NCDs at baseline were included. The Life's Essential 8 composite measure consists of four health behaviours (diet, physical activity, nicotine exposure, and sleep) and four health factors (body mass index, non-high density lipoprotein cholesterol, blood glucose, and blood pressure), and the maximum CVH score was 100 points. CVH score was categorized into low, moderate, and high groups. Participants were followed up for 44 NCDs diagnosis across 10 human system disorders according to the International Classification of Diseases 10th edition (ICD-10) code using linkage to national health records until 2022. Cox proportional hazard models were used in this study. The hazard ratios (HRs) and PAFs of 44 NCDs associated with CVH score were examined. Results:. During the median follow-up of 10.85 years, 58,889 incident NCD cases were documented. Significant linear dose-response associations were found between higher CVH score and lower risk of 25 (56.8%) of 44 NCDs. Low-moderate CVH (

Aim This study explored the effect and mechanism of MAFF and HDAC6 on renal fibrosis and inflammation in lupus nephritis (LN).Methods IL-33 treated renal epithelial cells and MRL/lpr mice were respectively used for in vitro and in vivo experiments. The expressions of HDAC6, MAFF, and KLF5 were measured in cells and renal tissues. Before and after cell transfection, the morphological changes in renal tissues were observed using Hematoxylin and eosin (H&E) and Masson staining. The proteinuria, serum creatinine (SCr), blood urea nitrogen (BUN), and double-stranded DNA (dsDNA) levels were detected by biochemical analysis. The expressions of fibrosis and inflammation related proteins (including α-SMA, Vimentin, IL-1β, IL-6, and TNF-α), p65, and iNOS were also detected. The relationship among MAFF, HDAC6, and KLF5 was determined by chromatin immunoprecipitation and dual luciferase reporter gene assay.Results Renal tissues and cell models had elevated expressions of HDAC6 and KLF5, and decreased MAFF expression. HDAC6 suppression or MAFF overexpression led to suppression of proteinuria, SCr, BUN, and dsDNA levels, as well as attenuation of inflammatory infiltration and collagen deposition. HDAC6 can suppress MAFF expression via deacetylation to abolish its suppression of KLF5 expression, thus increasing KLF5 expression. In vivo and in vitro experiments showed the suppressive effect of HDAC6 suppression on renal fibrosis and inflammation can be abolished by KLF5 overexpression.Conclusion HDAC6 suppresses MAFF expression via deacetylation to elevate KLF5 expression, which consequently enhances fibrosis and inflammatory response in LN.

Objectives: This study aimed to establish a droplet digital polymerase chain reaction (ddPCR) assay for South-East Asian (SEA) deletion based on a fully integrated digital PCR system DropXpert S6.Methods: A total of 151 whole blood samples, 10 chorionic villus samples, and 17 amniotic fluid samples were collected, including 106 SEA heterozygotes, 43 normal individuals, 10 Hb Bart's hydrops details, and 19 SEA deletions combined with other genotypes.Genotypes of these samples were determined by the Gap-PCR method. We perform a series of optimizations of the ddPCR system to ensure the performance of the entire ddPCR reaction, such as droplet stability, fluorescence clustering, sensitivity, and accuracy.Results: Our assay exhibited 99.4% (177/178) accuracy compared with the Gap-PCR method, and the minimum detection limit of DNA was 0.1 ng/μL.Both targets have reliable linearity, R2 = 0.9999 for the α-thalassemia SEA deletion allele and R2 = 1 for the wild-type allele. The coefficient of variation for α-thalassemia SEA deletion allele detection at 2 and 10 ng/μL concentrations was 5.42% and 1.91%, respectively. In contrast, the coefficient of variation for wild-type allele detection was 4.06% and 1.83%, demonstrating its high quantitative accuracy. In addition, the DropXpert S6 PCR system showed some advantages over other ddPCR instruments, such as reducing testing costs, simplifying and automating the workflow.Conclusions: The DropXpert S6 PCR system provided a highly accurate diagnosis for α-thalassemia SEA deletion and can be used to detect α-thalassemia as an alternative method.

Background Sepsis-induced acute kidney injury (S-AKI) is a common complication in critically ill patients. Therefore, reliable biomarkers for predicting S-AKI outcomes are necessary. Serum cell-free DNA (cfDNA) is a circulating extracellular DNA fragment used as a noninvasive screening tool for many diseases, including sepsis. This study aimed to investigate the prognostic value of cfDNA in S-AKI patients and its relationship with some other parameters.Methods A total of 89 S-AKI patients admitted to the intensive care unit (ICU) from June 2021 to December 2021 were enrolled in this study. The patients were categorized into the low cfDNA group (< 855 ng/ml) and high cfDNA group (≥ 855 ng/ml) and were followed up for three months. CfDNA was extracted from serum and quantified using Quant-iT PicoGreen dsDNA Reagent.Results Overall survival was significantly lower in the high cfDNA group than in the low cfDNA group (Log-Rank p = 0.012). Univariate Cox proportional hazard model showed that cfDNA was significantly associated with all-cause mortality (HR [hazard ratio] 2.505, 95% CI [95% confidence interval] 1.184–5.298, p = 0.016). Also, serum cfDNA was a significant risk factor for all-cause mortality after adjusting for covariates (HR 2.191, 95% CI 1.017–4.721, p = 0.045). Moreover, cfDNA was positively correlated with several baseline parameters, including serum creatine, aspartate aminotransferase, alanine aminotransferase, prothrombin time, and International Normalized Ratio.Conclusion High serum cfDNA level is associated with higher mortality among the S-AKI population, indicating that cfDNA is a valuable biomarker for S-AKI prognosis.

Traditional methods for algae removal in drinking water treatment, such as coagulation and sedimentation, face challenges due to the negative charge on algae cells’ surfaces, resulting in ineffective removal. Ultrasonic cavitation has shown promise in enhancing coagulation performance by disrupting extracellular polymer structures and improving cyanobacteria removal through various mechanisms like shear force and free radical reactions. However, the short lifespan and limited mass transfer distance of free radicals in conventional ultrasonic treatment lead to high energy consumption, limiting widespread application. To overcome these limitations and enhance energy efficiency, advanced carbon-based materials were developed and tested. Nitrogen-doped functional groups on nanodiamond surfaces were found to boost sonosensitivity by increasing the production of reactive oxygen species at the sonosensitizer-water interface. Utilizing low-power ultrasound (0.12 W/mL) in combination with N-ND treatment for 5 min, removal rates of Microcystis aeruginosa cells in water exceeded 90 %, with enhanced removal of algal organic matters and microcystins in water. Visualization through confocal microscopy highlighted the role of positively charged nitrogen-doped nanodiamonds in aggregating algae cells. The synergy between cell capturing and catalysis of N-ND indicates that efficient mass transfer of free radicals from the sonosensitizer’s surface to the microalgae’s surface is critical for promoting cyanobacteria floc formation. This study underscores the potential of employing a low-intensity ultrasound and N-ND system in effectively improving algae removal in water treatment processes.

Amid the burgeoning lunar economy, habitat establishment is vital for exploration. The investigation into lunar habitat morphology requires systematic organization. To systematically and comprehensively delve into lunar habitats morphological design, this study analyzes spatial elements and relationships through the profiling of lunar habitats. It comprehensively analyzes spatial elements and relationships, laying the groundwork for a dedicated performance evaluation system. It provides theoretical and technical references for lunar habitat forms in the early design phase. First, it summarizes four basic types of lunar habitat profiles. Second, it selects 23 factors influencing lunar habitat profile design, using the Delphi method to filter six major ones. Third, various simulation experiments assess each type’s performance under factors. Fourth, the TOPSIS method analyzes comprehensive performance. This study has developed a comprehensive performance evaluation system and an integrated experimental methodology for assessing the architectural profile morphology of lunar habitat structures. Employing the evaluation system, a comprehensive experimental analysis was conducted on four basic types in the current phase. This analysis yielded two design suggestions for profile elements and three optimization directions for profile design. The discussion offers insights for future evaluations, considering mission innovation and technological advancements.

Abstract. Background:. Prenatal and postnatal factors may have joint effects on cardiovascular health, and we aimed to assess the joint association of birth weight and ideal cardiovascular health metrics (ICVHMs) prospectively in adulthood with incident cardiovascular disease (CVD). Methods:. In the UK Biobank, 227,833 participants with data on ICVHM components and birth weight and without CVD at baseline were included. The ICVHMs included smoking, body mass index, physical activity, diet information, total cholesterol, blood pressure, and hemoglobin A1c. The Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) in men and women. Results:. Over a median follow-up period of 13.0 years (2,831,236 person-years), we documented 17,477 patients with incident CVD. Compared with participants with birth weights of 2.5–4.0 kg, the HRs (95% CIs) of CVD among those with low birth weights was 1.08 (1.00–1.16) in men and 1.23 (1.16–1.31) in women. The association between having a birth weight

Abstract Many wide-gap organic semiconductors exhibit imbalanced electron and hole transport, therefore efficient organic light-emitting diodes require a multilayer architecture of electron- and hole-transport materials to confine charge recombination to the emissive layer. Here, we show that even for emitters with imbalanced charge transport, it is possible to obtain highly efficient single-layer organic light emitting diodes (OLEDs), without the need for additional charge-transport and blocking layers. For hole-dominated emitters, an inverted single-layer device architecture with ohmic bottom-electron and top-hole contacts moves the emission zone away from the metal top electrode, thereby more than doubling the optical outcoupling efficiency. Finally, a blue-emitting inverted single-layer OLED based on thermally activated delayed fluorescence is achieved, exhibiting a high external quantum efficiency of 19% with little roll-off at high brightness, demonstrating that balanced charge transport is not a prerequisite for highly efficient single-layer OLEDs.

Abstract Dense matching of remote sensing images is crucial for 3D reconstruction. This study proposes an enhanced dense matching method employing the CPS image denoising algorithm, aiming to boost the SGM algorithm's accuracy and efficiency in remote sensing image matching. The stereo image pair's quality is evaluated using the PSNR index, and a decision-making criterion based on the CPS algorithm is incorporated to determine the need for denoising. Preprocessing steps, including image cropping and pixel coordinate transformation, significantly reduce computational requirements. An epipolar line model, minimizing the disparity between two pixels, is used for calculations. This model is employed to construct an epipolar image, enhancing the accuracy and efficiency of the process. The study conducted experimental validation and analysis of the mismatch rate, running time, and denoising effect of the algorithm using the Middlebury 2021 stereo datasets. Additionally, the matching results of the World-View3 satellite stereo image pairs were visualized and analyzed. The experimental results indicate that the proposed algorithm reduces the average mismatch rate by 13.1% and increases the running speed by about 3 to 4 times compared to the SGBM algorithm. Specifically, the denoising effect reduces the mismatch rate of the reconstructed image by an average of 8.97%. The results indicate that the CPS method effectively addresses dense matching challenges in the presence of image blur and noise, thereby improving the operational efficiency and accuracy of the dense matching algorithm.

Background: Identification of individuals with prediabetes who are at high risk of developing diabetes allows for precise interventions. We aimed to determine the role of nuclear magnetic resonance (NMR)-based metabolomic signature in predicting the progression from prediabetes to diabetes. Methods: This prospective study included 13,489 participants with prediabetes who had metabolomic data from the UK Biobank. Circulating metabolites were quantified via NMR spectroscopy. Cox proportional hazard (CPH) models were performed to estimate the associations between metabolites and diabetes risk. Supporting vector machine, random forest, and extreme gradient boosting were used to select the optimal metabolite panel for prediction. CPH and random survival forest (RSF) models were utilized to validate the predictive ability of the metabolites. Results: During a median follow-up of 13.6 years, 2525 participants developed diabetes. After adjusting for covariates, 94 of 168 metabolites were associated with risk of progression to diabetes. A panel of nine metabolites, selected by all three machine-learning algorithms, was found to significantly improve diabetes risk prediction beyond conventional risk factors in the CPH model (area under the receiver-operating characteristic curve, 1 year: 0.823 for risk factors + metabolites vs 0.759 for risk factors, 5 years: 0.830 vs 0.798, 10 years: 0.801 vs 0.776, all p < 0.05). Similar results were observed from the RSF model. Categorization of participants according to the predicted value thresholds revealed distinct cumulative risk of diabetes. Conclusions: Our study lends support for use of the metabolite markers to help determine individuals with prediabetes who are at high risk of progressing to diabetes and inform targeted and efficient interventions. Funding: Shanghai Municipal Health Commission (2022XD017). Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212501). Shanghai Municipal Human Resources and Social Security Bureau (2020074). Clinical Research Plan of Shanghai Hospital Development Center (SHDC2020CR4006). Science and Technology Commission of Shanghai Municipality (22015810500).

Background & Aims: The EAT-Lancet Commission in 2019 advocated a plant-centric diet for health and environmental benefits, but its relation to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. We aimed to discover the metabolite profile linked to the EAT-Lancet diet and its association with MASLD risk, considering genetic predisposition. Methods: We analyzed data from 105,752 UK Biobank participants with detailed dietary and metabolomic information. We constructed an EAT-Lancet diet index and derived a corresponding metabolomic signature through elastic net regression. A weighted polygenic risk score for MASLD was computed from associated risk variants. The Cox proportional hazards model was employed to estimate hazard ratios (HRs) and 95% CIs for the risk of MASLD (defined as hospital admission or death). Results: During a median follow-up period of 11.6 years, 1,138 cases of MASLD were documented. Participants in the highest group for the EAT-Lancet diet index had a multivariable HR of 0.79 (95% CI 0.66–0.95) for MASLD compared to the lowest group. The diet's impact was unaffected by genetic predisposition to MASLD (p = 0.42). Moreover, a robust correlation was found between the metabolomic signature and the EAT-Lancet diet index (Pearson r = 0.29; p

A new seismic repair method for reinforced concrete columns, which uses carbon fiber reinforced polymer (CFRP) grids and sprayed engineered cementitious composite (ECC) to form a composite reinforcement jacket, was proposed to improve the seismic performance of concrete columns damaged by earthquakes. Five specimen columns with 250 mm × 250 mm cross section and 1160 mm height were prepared and four different damage degree (no-damage, minor damage, moderate damage and severe damage) was controlled by the comparative specimen under the same amplitude-increasing lateral loading protocol and constant axial load. The pre-damaged columns were repaired and strengthened with three layers of CFRP grids and 25 mm thickness of sprayed ECC. The repaired columns were tested to failure and the effectiveness of the repairing schemes was evaluated by comparing load-carrying capacities, ductility, and energy dissipation. Based on the OpenSees seismic analysis software, a finite element model has been proposed to predict the seismic performance of the strengthened columns. The experimental results showed that the yield load, peak load, and ultimate load of the strengthened RC columns with no damage and slightly damage have significantly increased compared to the control specimen, with an increase range of 15% to 18%. For moderately damaged and severely damaged strengthened columns, the increase in the three characteristic load values is very small, or even reduced. Except for the severely damaged strengthened column, the ductility and energy consumption of other specimens have been improved to varying degrees. The analysis results indicated that the simulated values are in good agreement with the experimental ones, and the established finite element analysis model can be used to predict the seismic performance of strengthened columns.

The People’s Republic of China’s (PRC) fiscal system is characterized by very high expenditure decentralization and heavy reliance on transfers to finance public services. The government’s embrace of inclusiveness and equalization as national goals has raised questions about whether transfers can deliver equalization. This paper seeks to answer this question by analyzing newly available fiscal data compiled from government websites. We find the allocation of central transfers remains strongly region based, resulting in high intra-regional inequality among provinces. Poorer provinces also tend to retain more central transfers at their own (provincial) level. Those provinces with greater pretransfer inequality tend to exert greater equalization efforts, but these are not necessarily proportional to their pretransfer inequality. As a result, some localities are left out of the PRC’s countrywide equalization program. These equalization patterns remained highly persistent during the coronavirus disease shock in 2020. Collectively, the findings highlight that the PRC’s complex intergovernmental fiscal system still poses challenges for equalization.

Purpose: The aim of the current study was to investigate the association of accelerometer-measured sleep duration and different intensities of physical activity (PA) with the risk of incident type 2 diabetes in a population-based prospective cohort study. Methods: Altogether, 88,000 participants (mean age = 62.2 ± 7.9 years, mean ± SD) were included from the UK Biobank. Sleep duration (short: 8 h/day) and PA of different intensities were measured using a wrist-worn accelerometer over a 7-day period between 2013 and 2015. PA was classified according to the median or World Health Organization-recommendation: total volume of PA (high, low), moderate-to-vigorous PA (MVPA) (recommended, not recommended), and light-intensity PA (high, low). Incidence of type 2 diabetes was ascertained using hospital records or death registries. Results: During a median follow-up of 7.0 years, 1615 incident type 2 diabetes cases were documented. Compared with normal sleep duration, short (hazard ratio (HR) = 1.21, 95% confidence interval (95%CI): 1.03–1.41) but not long sleep duration (HR = 1.01, 95%CI: 0.89–1.15) was associated with excessive type 2 diabetes risk. This increased risk among short sleepers seems to be protected against by PA. Compared with normal sleepers with high or recommended PA, short sleepers with low volume of PA (HR = 1.81, 95%CI: 1.46–2.25), not recommended (below the World Health Organization-recommended level of) MVPA (HR = 1.92, 95%CI: 1.55–2.36), or low light-intensity PA (HR = 1.49, 95%CI: 1.13–1.90) had a higher risk of type 2 diabetes, while short sleepers with a high volume of PA (HR = 1.14, 95%CI: 0.88–1.49), recommended MVPA (HR = 1.02, 95%CI: 0.71–1.48), or high light-intensity PA (HR = 1.14, 95%CI: 0.92–1.41) did not. Conclusion: Accelerometer-measured short but not long sleep duration was associated with a higher risk of incident type 2 diabetes. A higher level of PA, regardless of intensity, potentially ameliorates this excessive risk.

Abstract Background Type 2 diabetes (T2D) is associated with an increased risk of premature death. Whether multifactorial risk factor modification could attenuate T2D-related excess risk of death is unclear. We aimed to examine the association of risk factor target achievement with mortality and life expectancy among patients with T2D, compared with individuals without diabetes. Methods In this longitudinal cohort study, we included 316 995 participants (14 162 with T2D and 302 833 without T2D) free from cardiovascular disease (CVD) or cancer at baseline between 2006 and 2010 from the UK Biobank. Participants with T2D were categorised according to the number of risk factors within target range (non-smoking, being physically active, healthy diet, guideline-recommended levels of glycated haemoglobin, body mass index, blood pressure, and total cholesterol). Survival models were applied to calculate hazard ratios (HRs) for mortality and predict life expectancy differences. Results Over a median follow-up of 13.8 (IQR 13.1–14.4) years, deaths occurred among 2105 (14.9%) participants with T2D and 18 505 (6.1%) participants without T2D. Compared with participants without T2D (death rate per 1000 person-years 4.51 [95% CI 4.44 to 4.57]), the risk of all-cause mortality among those with T2D decreased stepwise with an increasing number of risk factors within target range (0–1 risk factor target achieved: absolute rate difference per 1000 person-years 7.34 [4.91 to 9.78], HR 2.70 [2.25 to 3.25]; 6–7 risk factors target achieved: absolute rate difference per 1000 person-years 0.68 [-0.62 to 1.99], HR 1.16 [0.93 to 1.43]). A similar pattern was observed for CVD and cancer mortality. The association between risk factors target achievement and all-cause mortality was more prominent among participants younger than 60 years than those 60 years or older (P for interaction = 0.012). At age 50 years, participants with T2D who had 0–1 and 6–7 risk factors within target range had an average 7.67 (95% CI 6.15 to 9.19) and 0.99 (-0.59 to 2.56) reduced years of life expectancy, respectively, compared with those without T2D. Conclusions Individuals with T2D who achieved multiple risk factor targets had no significant excess mortality risk or reduction in life expectancy than those without diabetes. Early interventions aiming to promote risk factor modification could translate into improved long-term survival for patients with T2D.

The operation of the electricity system faces the difficulty of minimizing ice damage to transmission lines. Due to the uncertainty of transmission line icing thickness, accurate prediction of icing thickness is very important to guide transmission line planning and power grid anti-icing design effectively. Scientific and reasonable early warning assessment of conductor icing is also helpful to make timely and accurate response measures to the possible freezing disaster risk, so as to effectively ensure the safe and stable operation of power grid and reduce the occurrence of the freezing disaster. Based on this, this paper proposes a multi-factor prediction model based on GM (1, 6) grey theory, which considers the transmission line conductor icing model under the influence of multiple meteorological factors. Based on the conductor icing model, the conductor icing degree can be predicted in real time according to meteorological parameters, so as to realize the purpose of transmission line conductor icing disaster risk early warning. It is worth noting that the paper improves the traditional grey model by adding random data functions, which makes the model solve the problem of inaccurate prediction of small samples. Finally, a case study is carried out, and the icing disaster risk is divided into five levels. It is found that the maximal prediction error of icing thickness based on GM (1, 6) grey theory multi-factor prediction model is 10.06%(The average value is only 4.22%), and the accuracy of transmission line conductor icing disaster risk early warning is 88.9%. In addition, a certain safety margin value is added to the predicted value near the critical value of icing thickness, reducing the probability of judging the high-risk level as low-risk. Applying risk early warning method in ice areas can guide the anti-ice work of transmission line.

Abstract Background Rett Syndrome (RTT) is a rare, severe, and progressive developmental disorder with intellectual disability. Anesthesia in RTT patients presents a range of challenges. We report a child with RTT who received dental treatment under muscle relaxant-free general anesthesia in our ambulatory center. Case presentation A 15-year-old girl with RTT was admitted to our dental clinic with multiple dental caries and residual roots. Dental treatment was scheduled under ambulatory general anesthesia. After anesthesia induction, a nasal tube was initiated under the guidance of a fiberoptic bronchoscope. Multimodal analgesia, body temperature monitoring, and postoperative nausea and vomiting prevention were applied. No muscle relaxants were used throughout the process. The endotracheal tube was successfully removed after the operation and the patient was discharged home the same day. Conclusion An individualized anesthesia strategy enabled a quick and safe recovery for this RTT patient after dental treatment under muscle relaxant-free general anesthesia.

Hypoxia is one of the factors severely affect renal function, and, in severe cases, it can lead to renal fibrosis. Although much progress has been made in identifying the molecular mediators of fibrosis, the mechanisms that govern renal fibrosis remain unclear, and there have been no effective therapeutic anti-fibrotic strategies to date. Mammals exposed to low oxygen in the plateau environment for a long time are prone to high-altitude disease, while yaks have been living in the plateau for generations do not develop kidney fibrosis caused by low oxygen. It has been suggested that metabolic reprogramming occurs in renal fibrosis and that pyruvate dehydrogenase kinase 1 (PDK1) plays a crucial role in metabolic reprogramming as an important node between glycolysis and the tricarboxylic acid cycle. The aim of this study was to investigate the effects of hypoxia on the renal tissues and renal interstitial fibroblasts of yaks. We found that, at the tissue level, HIF-1α, PDK1, TGF-β1, Smad2, Smad3, and α-SMA were mainly distributed and expressed in tubular epithelial cells but were barely present in the renal mesenchymal fibroblasts of healthy cattle and yak kidneys. Anoptical density analysis showed that in healthy cattle kidneys, TGF-β1, Smad2, and Smad3 expression was significantly higher than in yak kidneys (p < 0.05), and HIF-1α and PDK1 expression was significantly lower than in yak kidneys (p < 0.05). The results at the protein and gene levels showed the same trend. At the cellular level, prolonged hypoxia significantly elevated PDK1 expression in the renal mesangial fibroblasts of cattle and yak kidneys compared with normoxia (p < 0.05) and was proportional to the degree of cellular fibrosis. However, PDK1 expression remained stable in yaks compared with renal interstitial fibroblast-like cells in cattle during the same hypoxic time period. At the same time, prolonged hypoxia also promoted changes in cellular phenotype, promoting the proliferation, activation, glucose consumption, lactate production, and anti-apoptosis in the both of cattle and yaks renal interstitial fibroblasts The differences in kidney structure and expression of PDK1 and HIF-1α in kidney tissue and renal interstitial fibroblasts induced by different oxygen concentrations suggest that there may be a regulatory relationship between yak kidney adaptation and hypoxic environment at high altitude. This provides strong support for the elucidation of the regulatory relationship between PDK1 and HIF-1α, as well as a new direction for the treatment or delay of hypoxic renal fibrosis; additionally, these findings provide a basis for further analysis of the molecular mechanism of hypoxia adaptation-related factors and the adaptation of yaks to plateau hypoxia.

Summary: Large prospective studies are required to better elucidate the associations of physical activity, sedentary behaviors (SBs), and sleep with overall cancer and site-specific cancer risk, accounting for the interactions with genetic predisposition. The study included 360,271 individuals in UK Biobank. After a median follow-up of 12.52 years, we found higher total physical activity (TPA) level and higher sleep scores were related to reduced risk of cancer while higher SB level showed a positive association with cancer. Compared with high TPA-healthy sleep group and low SB-healthy sleep group, low TPA-poor sleep group and high SB-poor sleep group had the highest risk for overall cancer, breast cancer, and lung cancer. Adherence to a more active exercise pattern was associated with a lower risk of cancer irrespective of genetic risk. Our study suggests that improving the quality of sleep and developing physical activity habits might yield benefits in mitigating the cancer risk.

Promoters are one of the most critical elements in regulating gene expression. They are considered essential biotechnological tools for heterologous protein production. The one most widely used in plants is the 35S promoter from cauliflower mosaic virus. However, our study for the first time discovered the 35S promoter reduced the expression of exogenous proteins under increased antibiotic stress. We discovered an endogenous strong promoter from duckweed named LpSUT2 that keeps higher initiation activity under antibiotic stress. Stable transformation in duckweed showed that the gene expression of eGFP in the LpSUT2:eGFP was 1.76 times that of the 35S:eGFP at 100 mg.L-1 G418 and 6.18 times at 500 mg.L-1 G418. Notably, with the increase of G418 concentration, the gene expression and the fluorescence signal of eGFP in the 35S:eGFP were weakened, while the LpSUT2:eGFP only changed slightly. This is because, under high antibiotic stress, the 35S promoter was methylated, leading to the gene silencing of the eGFP gene. Meanwhile, the LpSUT2 promoter was not methylated and maintained high activity. This is a previously unknown mechanism that provides us with new insights into screening more stable promoters that are less affected by environmental stress. These outcomes suggest that the LpSUT2 promoter has a high capacity to initiate the expression of exogenous proteins. In conclusion, our study provides a promoter tool with potential application for plant genetic engineering and also provides new insights into screening promoters.

AIM: To evaluate the effect of symmetrical arc incision correcting corneal astigmatism in femtosecond laser-assisted phacoemulsification (FLACS). METHODS: This study enrolled patients with cataract combined with regular corneal astigmatism of >0.75 D, who underwent FLACS. Symmetrical arc incision was set at 8 mm diameter and 85% depth. The follow-up time was 3-24mo (4.92±3.49mo). Pentacam recorded the corneal astigmatism and higher-order aberration at pre-operation and post-operation. The changes in corneal astigmatism were analyzed by Alpins method. The correlation of astigmatism type, age, corneal horizontal diameter, corneal thickness, arc incision length, and correction index (CI) was analyzed, and the residual corneal astigmatism was compared with the residual whole eye astigmatism. RESULTS: Totally 79 patients (102 eyes) were enrolled, 10 patients had corneal epithelial injury, 1 patient occurred corneal epithelial hyperplasia. The corneal astigmatism was 1.23±0.38 D pre-operation, and decreased to 0.76±0.39 D post-operation (t=10.146, P=0.000). Corneal high-order aberration was 0.17±0.08 μm pre-operation and 0.24±0.11 μm post-operation (t=-5.186, P=0.000). The residual corneal astigmatism and residual whole eye astigmatism were no significant difference (t=-0.347, P=0.729). Using Alpin's method, the following were determined: target-induced astigmatism (TIA) =1.23±0.38 D, surgery-induced astigmatism (SIA) =0.77±0.45 D, difference vector (DV)=0.77±0.39 D, and CI=0.54±0.28. Age, astigmatism size, corneal horizontal diameter, corneal thickness, and arc incision length were not correlated with CI. The CI for against the rule astigmatism (ATR) was better than that for with the rule astigmatism (WTR; P=0.001). CONCLUSION: Femtosecond laser-assisted astigmatic keratotomy has better CI of ATR, but increase higher-order corneal aberration. CI is not ideal, it's not a perfect choice if we pursue ideal correction effect.

Abstract Spatial transcriptomics (ST) technologies generate multiple data types from biological samples, namely gene expression, physical distance between data points, and/or tissue morphology. Here we developed three computational-statistical algorithms that integrate all three data types to advance understanding of cellular processes. First, we present a spatial graph-based method, pseudo-time-space (PSTS), to model and uncover relationships between transcriptional states of cells across tissues undergoing dynamic change (e.g. neurodevelopment, brain injury and/or microglia activation, and cancer progression). We further developed a spatially-constrained two-level permutation (SCTP) test to study cell-cell interaction, finding highly interactive tissue regions across thousands of ligand-receptor pairs with markedly reduced false discovery rates. Finally, we present a spatial graph-based imputation method with neural network (stSME), to correct for technical noise/dropout and increase ST data coverage. Together, the algorithms that we developed, implemented in the comprehensive and fast stLearn software, allow for robust interrogation of biological processes within healthy and diseased tissues.

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown promise in reducing the risk of atrial fibrillation (AF). However, the results are controversial and the underlying metabolic mechanism remains unclear. Emerging evidence implied that SGLT2 inhibitors have extra beneficial metabolic effects on circulating metabolites beyond glucose control, which might play a role in reducing the risk of AF. Hence, our study aimed to investigate the effect of circulating metabolites mediating SGLT2 inhibition in AF by Mendelian randomization (MR). Methods A two-sample and two-step MR study was conducted to evaluate the association of SGLT2 inhibition with AF and the mediation effects of circulating metabolites linking SGLT2 inhibition with AF. Genetic instruments for SGLT2 inhibition were identified as genetic variants, which were both associated with the expression of SLC5A2 gene and glycated hemoglobin level (HbA1c). Positive control analysis on type 2 diabetes mellitus (T2DM) was conducted to validate the selection of genetic instruments. Results Genetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of T2DM (odds ratio [OR] = 0.63 [95% CI 0.45, 0.88], P = 0.006) and AF (0.51 [0.27, 0.97], P = 0.039). Among 168 circulating metabolites, two metabolites were both associated with SGLT2 inhibition and AF. The effect of SGLT2 inhibition on AF through the total concentration of lipoprotein particles (0.88 [0.81, 0.96], P = 0.004) and the concentration of HDL particles (0.89 [0.82, 0.97], P = 0.005), with a mediated proportion of 8.03% (95% CI [1.20%, 14.34%], P = 0.010) and 7.59% ([1.09%, 13.34%], P = 0.011) of the total effect, respectively. Conclusions This study supported the association of SGLT2 inhibition with a reduced risk of AF. The total concentration of lipoprotein particles and particularly the concentration of HDL particles might mediate this association. Further mechanistic and clinical studies research are needed to understand the mediation effects of circulating metabolites especially blood lipids in the association between SGLT2 inhibition and AF.

Abstract Background The gut microbiota plays a crucial role in regulating host metabolism and producing uremic toxins in patients with end-stage renal disease (ESRD). Our objective is to advance toward a holistic understanding of the gut ecosystem and its functional capacity in such patients, which is still lacking. Results Herein, we explore the gut microbiome of 378 hemodialytic ESRD patients and 290 healthy volunteers from two independent cohorts via deep metagenomic sequencing and metagenome-assembled-genome-based characterization of their feces. Our findings reveal fundamental alterations in the ESRD microbiome, characterized by a panel of 348 differentially abundant species, including ESRD-elevated representatives of Blautia spp., Dorea spp., and Eggerthellaceae, and ESRD-depleted Prevotella and Roseburia species. Through functional annotation of the ESRD-associated species, we uncover various taxon-specific functions linked to the disease, such as antimicrobial resistance, aromatic compound degradation, and biosynthesis of small bioactive molecules. Additionally, we show that the gut microbial composition can be utilized to predict serum uremic toxin concentrations, and based on this, we identify the key toxin-contributing species. Furthermore, our investigation extended to 47 additional non-dialyzed chronic kidney disease (CKD) patients, revealing a significant correlation between the abundance of ESRD-associated microbial signatures and CKD progression. Conclusion This study delineates the taxonomic and functional landscapes and biomarkers of the ESRD microbiome. Understanding the role of gut microbiota in ESRD could open new avenues for therapeutic interventions and personalized treatment approaches in patients with this condition.

The exocyst is a hetero-octameric complex that exhibits significant functional diversity in regulating biological processes and defense responses. In plants, the EXO70 proteins are important components of the exocyst complex and are involved in membrane trafficking, biotic and abiotic interactions, as well as cell wall formation. A previous study has indicated that a member of the EXO subfamily, EXO70E2, interacts with RIN4 to mediate plant immunity. In this study, we found that EXO70E2 interacts with the RING-type E3 ligase Botrytis susceptible1 interactor (BOI), and the C-terminal domain of BOI is necessary for its interaction with EXO70E2. Moreover, the protein level of EXO70E2 was degraded and ubiquitinated by BOI in vitro. Collectively, our study reveals a mechanism for regulating the stability of EXO70E2 by a RING-type E3 ligase BOI-mediated ubiquitination.

Polyamines play a pivotal role in cancer cell proliferation. The excessive polyamine requirement of these malignancies is satisfied through heightened biosynthesis and augmented extracellular uptake via the polyamine transport system (PTS) present on the cell membrane. Meanwhile, photodynamic therapy (PDT) emerges as an effective anti-cancer treatment devoid of drug resistance. Recognizing these intricacies, our study devised a novel polyamine-derived photosensitizer (PS) for targeted photodynamic treatment, focusing predominantly on pancreatic cancer cells. We synthesized and evaluated novel spermine-derived fluorescent probes (N2) and PS (N3), exhibiting selectivity towards pancreatic cancer cells via PTS. N3 showed minimal dark toxicity but significant phototoxicity upon irradiation, effectively causing cell death in vitro. A significant reduction in tumor volume was observed post-treatment with no pronounced dark toxicity using the pancreatic cancer CDX mouse model, affirming the therapeutic potential of N3. Overall, our findings introduce a promising new strategy for cancer treatment, highlighting the potential of polyamine-derived PSs in PDT.

The aim of this study was to investigate the effects of hypoxia-induced phenotype, glucose metabolism, ROS levels, and the PDK1-mediated regulation of TGF-β/Smad signaling in yellow cattles, yaks, and those overexpressing PDK1 PASMCs using growth curves, flow cytometry, scratch experiments, glucose and lactic acid assays, RT-qPCR, and Western blotting. The results showed that hypoxia significantly promoted proliferation, migration, antiapoptosis, ROS levels, glucose consumption, and lactate production in yellow cattle PASMCs (p < 0.05), and the cells were dedifferentiated from the contractile phenotype; conversely, hypoxia had no significant effect on yak PASMCs (p > 0.05). PDK1 overexpression significantly promoted proliferation, antiapoptosis, glucose consumption, and lactate production in yak PASMCs under normoxia and hypoxia (p < 0.05), decreased their migration levels under hypoxia (p < 0.05), and dedifferentiated the contractile phenotype of the cells. Overexpression of PDK1 in yak PASMCs is detrimental to their adaptation to hypoxic environments. Yak PASMCs adapted to the effects of hypoxia on lung tissue by downregulating the expression of genes related to the PDK1 and TGF-β/Smad signaling pathways. Taken together, the regulation of PDK1-mediated TGF-β/Smad signaling may be involved in the process of yaks’ adaptation to the hypoxic environment of the plateau, reflecting the good adaptive ability of yaks. The present study provides basic information to further elucidate the mechanism of PDK1-mediated TGF-β/Smad signaling induced by hypoxia in the lungs of yaks, as well as target genes for the treatment of plateau diseases in humans and animals.

Bistatic radar exhibits spatial isomerism and diverse configurations, leading to unique clutter characteristics distinct from those of monostatic radar. The clutter rank serves as a pivotal indicator of clutter characteristics, enabling the quantification of clutter severity. Space-time adaptive processing (STAP) is a critical technique to detect moving targets, and clutter rank determines the number of independent and identically distributed (IID) training samples and the degree of freedom (DOF) for effective suppression of clutter that STAP requires. Therefore, the accurate estimation of clutter rank for bistatic radar can provide a crucial indicator for designing and constructing STAP processors, thereby facilitating fast and efficient clutter suppression in bistatic radar systems. This study is based on the idea that clutter rank is the number of prolate spheroidal wave function (PSWF) orthogonal bases utilized for approximating the clutter signal. Firstly, the challenge of utilizing PSWF orthogonal bases for approximating the clutter signal in bistatic radar is elucidated. This pertains to the fact that, unlike monostatic radar clutter, bistatic radar clutter is not capable of being expressed as a single-frequency signal. The clutter rank estimation for bistatic radar is thus derived as the frequency bandwidth estimation. Secondly, to achieve this estimation, the frequency distribution of each individual scattering unit is investigated, thereby determining their extending frequency broadening (EFB) as compared to that of single-frequency. Subsequently, the integral average of EFB across the entire range bin is computed, ultimately enabling the acquisition of bistatic radar’s frequency bandwidth. Finally, the estimation method is extended to non-side-looking mode and limited observation areas with pattern modulation. Simulation experiments confirm that our proposed method provides accurate clutter rank estimations, surpassing 99% proportions of large eigenvalues across various bistatic configurations, observation modes, and areas.

Accurate and early diagnosis of monkeypox virus (MPXV) is crucial for controlling epidemics and treating affected individuals promptly. This study aimed to assess the analytical and clinical performance of the MolecisionTM Monkeypox Virus qPCR Assay, Biorain Monkeypox Virus ddPCR Assay, and MAGLUMI® Monkeypox Virus Ag (chemiluminescence immunoassay, CLIA) Assay. Additionally, it aimed to compare the clinical application of antigen and nucleic acid assays to offer insights into using commercial monkeypox assay kits. Specimens from 117 clinical patients, serial diluted virus cell culture supernatant, and artificially created positive samples were tested to evaluate the performance of these assay kits for MPXV diagnostics. The Biorain Monkeypox Virus ddPCR Assay had a limit of detection (LoD) of 3.89 CCID50/mL, while the MolecisionTM Monkeypox Virus qPCR Assay had an LoD of 15.55 CCID50/mL. The MAGLUMI® Monkeypox Virus Ag (CLIA) Assay had an LoD of 0.500 pg/mL. The accuracy of the MolecisionTM Monkeypox Virus qPCR Assay was comparable to the Biorain Monkeypox Virus ddPCR Assay, and the MAGLUMI® Monkeypox Virus Ag (CLIA) Assay demonstrated high sensitivity. The specificity of all three MPXV diagnostic assays for clinical specimens with potential cross-reacting substances was 100%. In conclusion, this study provides valuable insights into the clinical application of monkeypox assays, supporting efforts to mitigate and control the spread of monkeypox.

Abstract Immune checkpoint inhibitor (ICI) therapy has had limited success (

Abstract Background Glioma is a lethal brain cancer and lacking effective therapies. Challenges include no effective therapeutic target, intra- and intertumoral heterogeneity, inadequate effective drugs, and an immunosuppressive microenvironment, etc. Deciphering the pathogenesis of gliomas and finding out the working mechanisms are urgent and necessary for glioma treatment. Identification of prognostic biomarkers and targeting the biomarker genes will be a promising therapy. Methods From our RNA-sequencing data of the oxidative phosphorylation (OXPHOS)-inhibition sensitive and OXPHOS-resistant cell lines, we found that the scaffolding protein caveolin 1 (CAV1) is highly expressed in the resistant group but not in the sensitive group. By comprehensive analysis of our RNA sequencing data, Whole Genome Bisulfite Sequencing (WGBS) data and public databases, we found that CAV1 is highly expressed in gliomas and its expression is positively related with pathological processes, higher CAV1 predicts shorter overall survival. Results Further analysis indicated that (1) the differentiated genes in CAV1-high groups are enriched in immune infiltration and immune response; (2) CAV1 is positively correlated with tumor metastasis markers; (3) the methylation level of CAV1 promoters in glioma group is lower in higher stage than that in lower stage; (4) CAV1 is positively correlated with glioma stemness; (5) higher expression of CAV1 renders the glioma cells’ resistant to oxidative phosphorylation inhibitors. Conclusion Therefore, we identified a key gene CAV1 and deciphered its function in glioma progression and prognosis, proposing that CAV1 may be a therapeutic target for gliomas. Graphical Abstract

Abstract Ferroptosis, a newform of programmed cell death, driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes and is extremely dependent on iron ions, which is differs characteristics from traditional cell death has attracted greater attention. Based on the curiosity of this new form of regulated cell death, there has a tremendous progress in the field of mechanistic understanding of ferroptosis recent years. Ferroptosis is closely associated with the development of many diseases and involved in many diseases related signaling pathways. Not only a variety of oncoproteins and tumor suppressors can regulate ferroptosis, but multiple oncogenic signaling pathways can also have a regulatory effect on ferroptosis. Ferroptosis results in the accumulation of large amounts of lipid peroxides thus involving the onset of oxidative stress and energy stress responses. The MAPK pathway plays a critical role in oxidative stress and AMPK acts as a sensor of cellular energy and is involved in the regulation of the energy stress response. Moreover, activation of AMPK can induce the occurrence of autophagy-dependent ferroptosis and p53-activated ferroptosis. In recent years, there have been new advances in the study of molecular mechanisms related to the regulation of ferroptosis by both pathways. In this review, we will summarize the molecular mechanisms by which the MAPK-AMPK signaling pathway regulates ferroptosis. Meanwhile, we sorted out the mysterious relationship between MAPK and AMPK, described the crosstalk among ferroptosis and MAPK-AMPK signaling pathways, and summarized the relevant ferroptosis inducers targeting this regulatory network. This will provide a new field for future research on ferroptosis mechanisms and provide a new vision for cancer treatment strategies. Video Abstract

Abstract Background Tubulointerstitial lesions play a pivotal role in the progression of IgA nephropathy (IgAN). Elevated N-acetyl-beta-D-glucosaminidase (NAG) in urine is released from damaged proximal tubular epithelial cells (PTEC) and may serve as a biomarker of renal progression in diseases with tubulointerstitial involvement. Methods We evaluated the predictive value of urinary NAG (uNAG) for disease progression in 213 biopsy-proven primary IgAN patients from January 2018 to December 2019 at Zhongshan Hospital, Fudan University. We compared the results with those of serum cystatin C (sCysC). Results Increased uNAG and sCysC levels were associated with worse clinical and histological manifestations. Only uNAG level was independently associated with remission status after adjustment. Patients with high uNAG levels (> 22.32 U/g Cr) had a 4.32-fold greater risk of disease progression. The combination of baseline uNAG and clinical data may achieve satisfactory risk prediction in IgAN patients with relatively preserved renal function (eGFR ≥ 60 ml/min/1.73 m2, area under the curve [AUC] 0.760). Conclusion Our results suggest that uNAG is a promising biomarker for predicting IgAN remission status.

Abstract Mechanistic target of rapamycin complex 1 (mTORC1) is a conserved serine/threonine kinase that integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activation requires tethering to lysosomes by the Ragulator‐Rag complex. However, the dynamic regulation of the interaction between Ragulator and Rag guanosine triphosphatase (GTPase) remains unclear. In this study, that LAMTOR1, an essential component of Ragulator, is dynamically ubiquitinated depending on amino acid abundance is reported. It is found that the E3 ligase TRAF4 directly interacts with LAMTOR1 and catalyzes the K63‐linked polyubiquitination of LAMTOR1 at K151. Ubiquitination of LAMTOR1 by TRAF4 promoted its binding to Rag GTPases and enhanced mTORC1 activation, K151R knock‐in or TRAF4 knock‐out blocks amino acid‐induced mTORC1 activation and accelerates the development of inflammation‐induced colon cancer. This study revealed that TRAF4‐mediated LAMTOR1 ubiquitination is a regulatory mechanism for mTORC1 activation and provides a therapeutic target for diseases involving mTORC1 dysregulation.

Background A healthy lifestyle is an important factor for preventing heart failure. However, the association between outdoor light exposure time and heart failure is still unknown. The aim of this study was to examine the association between outdoor light exposure time and the incidence of heart failure. Methods and Results This cohort study included participants from the UK Biobank recruited from 2006 to 2010 who were 40 to 70 years of age and free of heart failure at baseline. The mean follow‐up time was 12.61 years. The outdoor light exposure time was self‐reported at baseline. A restricted cubic spline was performed to examine the potential nonlinear relationship between outdoor light exposure and the incidence of heart failure. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% CIs. During a mean follow‐up of 12.61 years, 13 789 participants were first diagnosed with heart failure. There was a nonlinear (J‐shaped) trend between outdoor light time and heart failure risk. Cox proportional hazard regression models showed that, compared with participants who received an average of 1.0 to 2.5 hours of outdoor light per day, those with 2.5 hours had a higher risk of heart failure after the model was adjusted for age and sex (2.5 hours: HR, 1.11 [95% CI, 1.07–1.15]). These associations were still significant in the fully adjusted models (2.5 hours: HR, 1.07 [95% CI, 1.03–1.11]). Conclusions We found a J‐shaped association between outdoor light exposure time and the risk of incident heart failure, suggesting that moderate exposure to outdoor light may be a prevention strategy for heart failure.

Transmission towers serve as crucial safety pillars within the power transmission system, and their damage can lead to severe consequences. The structural failure of a tower undergoes a process from the initiation of local damage to overall failure, emphasizing the importance of conducting detailed local safety research. This paper introduces a nonlinear damage analysis method rooted in the continuous damage theory, specifically designed for critical areas of transmission towers. A material subroutine for elastic-plastic-damage constitutive equations is developed using commercial software, and thorough verification ensures the accuracy of both the subroutine and the algorithm. The proposed algorithm is then applied to analyze the damage in critical areas of a tower, simulating the plasticity-damage coupling evolution of the main leg during the collapse of the transmission tower. Regarding the treatment of bolt connections in the local model, it indicates that there is a small difference between the contact model and the rigid-joint model results. Taking computational efficiency into consideration, it is recommended to employ rigid-joint model to simulate the evolution of damage. The presented example illustrates damage occurring on the outer side of the main leg, ultimately leading to lateral damage under the combined influence of bending and torsion. This research offers a novel method for investigating the failure mechanisms of transmission towers under extreme weather conditions and proposes precise reinforcement strategies.

Structural analyses of transmission towers against tornados, which are of vital practical significance in design and maintenance of the structures in regions suffering from the convective weather, were rarely reported by the wind engineering community up to today. To balance the computing efficiency and the simulation accuracy, numerical calculations based on Wen’s tornadic velocity model are employed to analyze the tornado-induced structural responses of a 131-meter-high free-standing transmission tower in east China in this article. Results suggest that both the tornadic load and the structural response are noticeably greater in the lateral direction than in the longitudinal direction, and they are found to be highly nonstationary due to the traveling nature of the tornado. In addition, according to the present study, the transmission tower is not prone to the strength failure during the tornadic event and slight fatigue damages are accumulated on the tower body due to the tornadic action which can be timely warned using the structural health monitoring strategy based on field measurements of low-order structural natural frequencies. Besides the points mentioned above, the innovations of the present research additionally include the following: (1) tornado-induced structural responses and atmospheric boundary layer wind-induced structural behaviors have been compared to provide conclusions of theoretical significance; (2) a novel fatigue damage assessment method based on the high-circle fatigue damage accumulation theory has been applied to the analysis of tornado-induced structural damage; (3) the structural configuration of a key joint on a main chord has been optimized against the tornado based on the advanced response surface optimization method.

Abstract In vitro, ACE2 translocates to the nucleus to induce SARS-CoV-2 replication. Here, using digital spatial profiling of lung tissues from SARS-CoV-2-infected golden Syrian hamsters, we show that a specific and selective peptide inhibitor of nuclear ACE2 (NACE2i) inhibits viral replication two days after SARS-CoV-2 infection. Moreover, the peptide also prevents inflammation and macrophage infiltration, and increases NK cell infiltration in bronchioles. NACE2i treatment increases the levels of the active histone mark, H3K27ac, restores host translation in infected hamster bronchiolar cells, and leads to an enrichment in methylated ACE2 in hamster bronchioles and lung macrophages, a signature associated with virus protection. In addition, ACE2 methylation is increased in myeloid cells from vaccinated patients and associated with reduced SARS-CoV-2 spike protein expression in monocytes from individuals who have recovered from infection. This protective epigenetic scarring of ACE2 is associated with a reduced latent viral reservoir in monocytes/macrophages and enhanced immune protection against SARS-CoV-2. Nuclear ACE2 may represent a therapeutic target independent of the variant and strain of viruses that use the ACE2 receptor for host cell entry.