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Construction and development projects worldwide heavily rely on concrete as their primary building material, making it an essential component of global infrastructure and growth. The various key ingredients that compose concrete contribute differently to its overall environmental footprint. Moreover, rapid urban and industrial growth has strained ecological systems and depleted resources, necessitating environmentally friendly substitutes for traditional concrete ingredients. Waste foundry sand has emerged as a potential replacement for natural sand in concrete mixtures, offering a sustainable option. Since evaluating waste foundry sand effects on concrete through laboratory methods is resource-intensive, therefore, this research employs six distinct ensemble boosting algorithms including CatBoost, XGBoost, HistGBRT, NGBoost, LightGBM, Adaboost and MLR to predict key properties of concrete made with waste foundry sand: split tensile strength, compressive strength, and elastic modulus. This investigation utilized SHapley additive exPlanations (SHAP) method to precisely illustrate feature interdependencies, quantify their complex relationships, and establish a hierarchy of importance. The models' performance was then assessed using multiple robust metrics, including mean absolute error (MAE), root mean squared error (RMSE), correlation coefficient (R), Nash-Sutcliffe efficiency coefficient (NSE), Kling-Gupta efficiency (KGE), and Willmott's Index (WI). The findings reveal that the XGBoost model excels in estimating the compressive strength, achieving an RMSE of 2.845 MPa and an R-value of 0.958. CatBoost follows as the second-best performer, with an RMSE of 3.083 MPa and an R-value of 0.952. For the elastic modulus estimation, XGBoost again outperforms other models, yielding an RMSE of 0.992 GPa and an R-value of 0.990, while NGBoost secures the second position with an RMSE of 1.256 GPa and an R-value of 0.985. In predicting the split tensile strength, XGBoost once more demonstrates superior accuracy, recording an RMSE of 0.296 MPa and an R-value of 0.925, closely follows by LightGBM with an RMSE of 0.302 MPa and an R-value of 0.926. This research demonstrates the effectiveness of XGBoost algorithms in predicting key properties of concrete with waste foundry sand when relevant factors are considered.

Abstract Black carbon (BC) is considered as an important contributor to the Himalayan glaciers melt in the past few decades. However, the long‐term source apportionment of BC remains unclear. Here we present the first radiocarbon (14C)‐based annual variation of BC source apportionment in an ice core spanning the period of 1959–2012 drilled from the Southeastern Tibetan Plateau, a receptor site of South Asia outflow. We find fossil fuel combustion is a major contribution (73% ± 5%), yet the biomass burning fraction (ƒbiomass) has grown from 24% ± 4% to 30% ± 4% since 1990. Intriguingly, we further find the ƒbiomass demonstrating a robust correlation with South Asian wildfires linked to climate oscillations. Thus, for mitigating BC impacts on Himalayan glaciers, South Asia's transition from fossil fuels to clean energy is a more efficient and urgent strategy than reducing residential biomass burning.

Intestinal fibrosis is often observed in inflammatory bowel disease (IBD) and seriously affects intestinal health. Our previous study identified that triphenyl phosphate (TPhP), one kind of frequently used organophosphate flame retardants (OPFRs), induced IBD-like features in colon. Herein, we firstly observed extracellular matrix deposition in colon tissues, indicative of appearance of colonic fibrosis. Further studies showed that TPhP downregulated epithelial marker E-cadherin levels but upregulated alpha smooth muscle actin (α-SMA) in mouse colon tissues, and similar results were observed in cultured colon cells, indicating that fibrogenesis might be attributed to epithelial-mesenchymal transition (EMT). Further transcriptome and experimental data demonstrated that TPhP-induced EMT was closely associated with activated Wnt/β-catenin pathway. Moreover, FOXM1 facilitated the entrance of β-catenin into nucleus to regulate expression of Wnt target genes, promoting EMT initiation. Collectively, these findings demonstrated that TPhP induced colonic fibrosis in mice by activating EMT, and this work may provide new perspectives in exploring etiology of intestinal fibrosis and developing relevant treatment strategies.

Decellularized tissue-engineered vascular grafts (dTEVGs) exhibit superior biocompatibility, anti-infection properties and repair potential, contributing to better patency and making them a more ideal choice for arteriovenous grafts (AVGs) in hemodialysis compared to chemically synthesized grafts. However, the unsatisfactory reendothelialization and smooth muscle remodeling of current dTEVGs limit their advantages. In this study, we investigated the use of elastase to improve the porosity of elastic fiber layers in dTEVGs, aiming to promote cell infiltration and achieve superior reendothelialization and smooth muscle remodeling. Our findings revealed that elastase treatment induced scattered cracks and holes in the elastic fiber layers of dTEVGs. Porous dTEVGs demonstrated increased cell infiltration in rat subcutaneous tissue. In the rat AVG models, mildly elastase-treated dTEVGs significantly improved cell infiltration and graft remodeling, including adequate smooth muscle cell (SMC) repopulation, impressive reendothelization and regeneration of the extracellular matrix, without stenosis, dilation or disintegration of the grafts. This study demonstrates that porous dTEVGs promote reendothelization, smooth muscle remodeling and extracellular matrix regeneration while retaining a stable graft structure, enhancing durability and puncture resistance in hemodialysis.

Abstract Background Chronic kidney disease (CKD) is the third most common cause of death after cancer and heart disease. The continuous treatment of children with CKD was greatly challenged during the COVID-19 pandemic, which significantly impacted the CKD children’s prognosis and the caregivers’ psychological status. However, the influence mechanism of socioeconomic status, medical delay duration, traffic pressure, and online consultation duration on caregivers’ hope and psychological resilience still lacks relevant evidence. Methods This study investigated the general social information, hope, and psychological resilience of 247 caregivers with CKD in 13 provinces of China in March 2020. Factor analysis and an exploratory Structural Equation Model ( SEM ) were used to find the best-fit model, and Bootstrapping was used to calculate the 95% CI of indirect effects. Results The factor analysis obtained four common factors, namely, socioeconomic status (annual family income, education, and career stability), medical accessibility (online consultation duration, medical delay duration, and traffic pressure), hope (positive attitude, positive action, and intimate relationship) and psychological resilience (optimism, tenacity, and strength), with the cumulative contribution rate of 65.34%. Bootstrapping obtains the socioeconomic status β = 0.30 (95% CI [0.14, 0.47], P = 0.002), medical accessibility β = 0.31 (95% CI [0.12, 0.47], P = 0.002), and hope β = 0.40 (95% CI [0.27, 0.52], P = 0.002) has a direct impact on psychological resilience of CKD children caregivers, followed by medical accessibility β = 0.20 (95% CI [0.10, 0.38], P = 0.001) and hope β = 0.23 (95% CI [0.16, 0.32], P = 0.001) plays a mediating role between socioeconomic status and psychological resilience. The indirect impact effect β = 0.35 (95% CI [0.25, 0.50], P = 0.001) is greater than the direct impact effect β = 0.30 (95% CI [0.14, 0.47], P = 0.002). Conclusions Sufficient attention should still be given to children with immunodeficiency after the COVID-19 pandemic, such as CKD, to avoid infection of deadly. Secondly, the government should vigorously develop Primary medical institutions to ensure efficient treatment of severe patients in tertiary hospitals; Finally, the professional literacy of medical workers in remote diagnosis and treatment should be improved to enhance the country’s emergency response capacity for similar major public events and the requirements for normalised epidemic prevention and control.

Abstract Amid the escalating global climatic challenges, hydrological risks significantly influence human settlement patterns, underscoring the imperative for an in-depth comprehension of hydrological change’s ramifications on human migration. However, predominant research has been circumscribed to the national level. The study delves into the nonlinear effects of hydrological risks on migration dynamics in 46,776 global subnational units. Meanwhile, leveraging remote sensing, we procured globally consistent metrics of hydrological intrusion exposure, offering a holistic risk assessment encompassing hazard, exposure, and vulnerability dimensions, thus complementing previous work. Here, we show that exposure is the primary migration driver, surpassing socioeconomic factors. Surrounding disparities further intensified exposure’s impact. Vulnerable groups, especially the economically disadvantaged and elderly, tend to remain in high-risk areas, with the former predominantly migrating within proximate vicinities. The nonlinear analysis delineates an S-shaped trajectory for hydrological exposure, transitioning from resistance to migration and culminating in entrapment, revealing dependence on settlement resilience and adaptability.

Accurately predicting soil temperature (Ts) serves as the foundation of geothermal applications, modern irrigation strategies in arid agricultural landscapes, and understanding ecosystem changes. Also, this parameter is crucial for estimating crop water requirements, thereby enabling efficient management of scarce water resources in these moisture-limited environments. Therefore, the development of a sophisticated intelligent algorithm based on boosting ensemble including XGBoost, CatBoost, LightGBM, and AdaBoost models which incorporates nine different scenarios from meteorological variables as input parameters, offers valuable insights into subsurface thermal dynamics at various depths for accurately predicting thermal gradients within the soil profile, is imperative for soil science investigations. To unravel the underlying mechanisms influencing the models' predictions of Ts, the SHapley Additive exPlanations (SHAP) methodology was employed. This algorithm quantifies the contributory significance of each input variable and facilitates the explication of input-output dependencies. In this study, the model's performance was evaluated at two meteorological monitoring sites, denoted as Penjwen and Bazian, situated within the geopolitical boundaries of the Kurdistan region in Iraq using a suite of statistical indicators, including the correlation coefficient (R), the root mean square error (RMSE), the Nash-Sutcliffe efficiency (NSE), and the mean absolute error (MAE). These metrics provided a comprehensive assessment of the model's predictive accuracy and reliability. Moreover, this localized analysis provided insights into the model's efficacy under specific regional climatic conditions. At station Penjwen, the results based on the RMSE values indicated that the LightGBM and CatBoost methods performed better than other models in Ts estimation at depths of 5 cm and 10 cm, with RMSE values of 2.502 °C and 2.164 °C, respectively. Also, at station Bazian, CatBoost and LightGBM approaches showed the best results at depths of 5 cm and 10 cm, with RMSE values of 2.069 °C and 1.786 °C, respectively. The study's findings suggest that meteorological variables can serve as effective inputs for predicting Ts using the proposed algorithms.

The rapid virulence variation of Magnaporthe oryzae (M. oryzae) to rice is a big challenge for rice blast control. Even though many studies have been done by scientists all over the world, the mechanism of virulence variation in M. oryzae remains elusive. AM16, an avirulent M. oryzae strain reported in our previous study, provides an excellent entry point to explore the mechanism of virulence variation in M. oryzae. In this study, we found that the Pmk1 and Mac1 had specific mutations in strain AM16. The AM16 strains overexpressing Pmk1Guy11 or (and) Mac1Guy11 allele from strain Guy11 displayed significantly increasing conidiation, functional appressorium formation, and restoring pathogenicity to rice. Moreover, we observed that the strains overexpressing Mac1Guy11 had stronger conidia forming capacity than that of the strains overexpressing Pmk1Guy11, while the appressorium formation rate of strains overexpressing Pmk1Guy11 was similar to that of strains overexpressing Pmk1Guy11-Mac1Guy11, much higher than that of the strains overexpressing Mac1Guy11. Taken together, our results reveal that the natural mutation of Pmk1 and Mac1 genes are important, but not the sole cause, for the loss of virulence in strain AM16. The functional difference between Pmk1 and Mac1 in the growth and development of M. oryzae was first discovered, providing new insight into the pathogenic mechanism of M. oryzae.

In recent decades, securing drinkable water sources has become a pressing concern for populations in various regions worldwide. Therefore, to address the growing need for potable water, contemporary water purification technologies can be employed to convert saline sources into drinkable supplies. Therefore, the prediction of important parameters of desalination plants is a key task for designing and implementing these facilities. In this regard, artificial intelligence techniques have proven to be powerful assets in this field. These methods offer an expedited and effective means of estimating effective parameters, thus catalyzing their implementation in real-world scenarios. In this study, the predictive accuracy of six different machine learning models, including Natural Gradient-based Boosting (NGBoost), Adaptive Boosting (AdaBoost), Categorical Boosting (CatBoost), Support vector regression (SVR), Gaussian Process Regression (GPR), and Extremely Randomized Tree (ERT) was evaluated for modelling the parameter of permeate flow as a key element in system efficiency, energy consumption, and water quality using six various input combinations of feed water salt concentration, condenser inlet temperature, feed flow rate, and evaporator inlet temperature. The next phase of this research employed the SHAP interpretability method to illustrate the impact of individual variables on the model's output. Moreover, the predictive performance of the developed frameworks was evaluated using a set of five dependable statistical measures: RMSE, NS, MAE, MAPE and R2. These indicators were utilized to provide a robust means of gauging the precision of the model's forecasts. A comparative analysis of the outcomes, as measured by the RMSE criteria, revealed that the SVR technique (RMSE = 0.125 L/(h·m2)) exhibited superior performance compared to NGBoost (RMSE = 0.163 L/(h·m2)), AdaBoost (RMSE = 0.219 L/(h·m2)), CatBoost (RMSE = 0.149 L/(h·m2)), GPR (RMSE = 0.156 L/(h·m2)), and ERT (RMSE = 0.167 L/(h·m2)) methodologies in predicting permeate flow rates. The modelling outcomes obtained during the evaluation stage demonstrated the efficacy of the SVR algorithm in enhancing the precision of permeate flow forecasts, utilizing relevant input variables.

Coupled grey and green infrastructure (CGGI) is increasingly recognized as a viable approach to sustainable urban stormwater management. This study evaluates CGGI and grey infrastructure (GREI)-only schemes with various degree of centralization of the layout (DCL) in addressing urban flood and drainage issues in a historical and cultural district (HCD) which typically consists of high impervious surfaces, dense urban structures, and fragile heritage buildings. Yongqing Fang Community in Guangzhou, China, was selected as a case study in which the performance of the Grey-only and CGGI schemes are evaluated and compared. The results obtained indicated that the CGGI scheme was more advantageous in terms of cost-effectiveness and scalability, yielding potential savings of $30,500 to $163,400. Moreover, the fully decentralized layout of the two schemes could result in cost savings of 29.0% and 29.6%, respectively, over the fully centralized layout. However, CGGI shows marginally lower adaptability in response to extreme rainfall events compared to that of GREI-only solutions. Technical resilience (Tech-R) of GREI-only scored higher by 0.1% to 0.8%, 0.5% to 3.5%, and 0.7% to 4.8% for 10-year, 50-year, and 100-year rainfall scenarios, respectively. Nonetheless, CGGI schemes demonstrated superior adaptability in structural failure scenarios, and reduced surface overflow by 22.6%, 19.0%, and 18.4% compared to GREI for the same scenarios. In both the CGGI and GREI-only schemes, decentralized layouts are likely to outperform centralized layouts in both extreme rainfall events and in failure scenarios. These findings underscore the importance of decentralized layout of the drainage infrastructure which could enhance the hydrological performance of integrated drainage infrastructures, offering insights for due considerations in designing multi-objective infrastructures for urban flood mitigation in HCDs.

Abstract Background Steroid-resistant nephrotic syndrome (SRNS) are monogenic in some cases, however, there are still no clear guidelines on genetic testing in the clinical practice of SRNS in children. Methods Three hundred thirty-two children were diagnosed with SRNS, and all children underwent genetic testing, including gene panels and/or whole-exome/genome sequencing (WES/WGS), during treatment. We analysed the relationship between clinical manifestation and genotype, and compared different genetic testing methods’ detection rates and prices. Results In this study, 30.12% (100/332) of children diagnosed with SRNS had monogenic causes of the disease. With 33.7% (122/332) of children achieving complete remission, 88.5% (108/122) received steroids combined with tacrolimus (TAC). In detectability, WES increased by 8.69% (4/46) on gene panel testing, while WGS increased by 4.27% (5/117) on WES, and WES was approximately 1/7 of the price of WGS for every further 1% increase in pathogenicity. Conclusions We verified that steroids combined with TAC were the most effective option in paediatric SRNS. In detection efficiency, we found that WGS was the highest, followed by WES. The panel was the lowest, but the most cost-effective method when considering the economic-benefit ratio, and thus it should be recommended first in SRNS.

The accurate forecasting of vegetable prices is crucial for policy formulation, market decisions, and agricultural market stability. Traditional time-series models often require manual parameter tuning and struggle to effectively handle the complex non-linear characteristics of vegetable price data, limiting their predictive accuracy. This study conducts a comprehensive analysis of the performance of traditional methods, deep learning approaches, and cutting-edge large language models in vegetable-price forecasting using multiple predictive performance metrics. Experimental results demonstrate that large language models generally outperform other methods, but do not have consistent performance for all kinds of vegetables across different time scales. As a result, we propose a novel vegetable-price forecasting method based on mixture of expert models (VPF-MoE), which combines the strengths of large language models and deep learning methods. Different from the traditional single model prediction method, VPF-MoE can dynamically adapt to the characteristics of different vegetable types, dynamically select the best prediction method, and significantly improve the accuracy and robustness of the prediction. In addition, we optimized the application of large language models in vegetable-price forecasting, offering a new technological pathway for vegetable-price prediction.

The Xiao Jiang River, as a crucial element of ecological restoration in the upper reaches of the Yangtze River, plays an indispensable role in agricultural water utilization and water ecology within its watersheds. The water quality status of the Xiao Jiang River not only impacts local water-ecological equilibrium and economic benefits but also holds paramount importance for sustaining ecosystem health in the Yangtze River basin. Plankton surveys and environmental physicochemical detection were conducted in the major channel region of the Xiao Jiang River in dry and wet periods in 2022 to better understand the diversity of eukaryotic plankton and its community structure characteristics. Environmental DNA is an emerging method that combines traditional ecology with second-generation sequencing technology. It can detect species from a single sample that are difficult to find by traditional microscopy, making the results of plankton diversity studies more comprehensive. For the first time, environmental DNA was used to investigate eukaryotic plankton in the Xiao Jiang River . The results showed that a total of 881 species of plankton from 592 genera in 17 phyla were observed. During the dry period, 480 species belonging to 384 genera within17 phyla were detected, while, during the wet period, a total of 805 species belonging to 463 genera within 17 phyla were recorded. The phylum Ciliophora dominated the zooplankton, while the phylum Chlorophyta and Bacillariophyta dominated the phytoplankton. The presence of these dominant species indicate that the water quality conditions in the study area are oligotrophic and mesotrophic. Principal coordinate analysis and difference test showed that the number of plankton ASVs, abundance, species richness, dominating species, and diversity indices differed between the dry and wet periods. Spearman correlation analysis and redundancy analysis (RDA) of relative abundance data with environmental physicochemical factors revealed that water temperature (WT), dissolved oxygen (DO), potential of hydrogenacidity (pH), ammonia nitrogen (NH3-N), total nitrogen (TN), electrical conductivity (EC) and the determination of redox potential (ORP) were the main environmental physicochemical factors impacting the plankton community structure. The results of this study can serve as a provide data reference at the plankton level for water pollution management in the Xiao Jiang River, and they are extremely important for river ecological restoration and biodiversity recovery in the Yangtze River basin.

The indiscriminate evolution of urban configurations aggravates flood vulnerabilities, threatening sustainable urban expansion. Present methodologies fall short in supplying urban planners with flood mitigative strategies centered on urban configuration facets. Leveraging the power of the XGBoost algorithm, this study posits an advanced optimization schema, adroitly balancing the dual objectives of mitigating urban flooding and enhancing economic growth, with minimal disruption to established urban layouts. Shenzhen serves as the investigative ground, where the model displays exceptional accuracy, resilience, and interpretability in predicting Pluvial Flooding Susceptibility (PFS) and Economic Contribution (EC). Model interpretation divulges the profound influence of three-dimensional urban configuration elements, primarily the Building Congestion Degree, on PFS and EC. Pareto solution exploration for multi-objective optimization unveils the ideal urban configuration interval. To minimize PFS while maximizing EC, the research suggests pertinent measures: augmenting vegetation density, regulating the impervious coverage ratio within 50–70%, limiting two- and three-dimensional building density thresholds, and moderately escalating urban drainage network density. Additionally, it encourages a comprehensive appreciation of function-oriented land usage and intrinsic site topographical characteristics to reconcile varied urban development goals during planning. By fusing data-derived insights with multi-objective optimization, this research anticipates influencing urban planning models, thus enhancing decision-making related to urban configuration and fostering flood-resilient, sustainable, and economically prosperous urban habitats.

Dissecting the genetic components that contribute to the two main subphenotypes of steroid-sensitive nephrotic syndrome (SSNS) using genome-wide association studies (GWAS) strategy is important for understanding the disease. We conducted a multicenter cohort study (360 patients and 1835 controls) combined with a GWAS strategy to identify susceptibility variants associated with the following two subphenotypes of SSNS: steroid-sensitive nephrotic syndrome without relapse (SSNSWR, 181 patients) and steroid-dependent/frequent relapse nephrotic syndrome (SDNS/FRNS, 179 patients). The distribution of two single-nucleotide polymorphisms (SNPs) in ANKRD36 and ALPG was significant between SSNSWR and healthy controls, and that of two SNPs in GAD1 and HLA-DQA1 was significant between SDNS/FRNS and healthy controls. Interestingly, rs1047989 in HLA-DQA1 was a candidate locus for SDNS/FRNS but not for SSNSWR. No significant SNPs were observed between SSNSWR and SDNS/FRNS. Meanwhile, chromosome 2:171713702 in GAD1 was associated with a greater steroid dose (>0.75 mg/kg/d) upon relapse to first remission in patients with SDNS/FRNS (odds ratio = 3.14; 95% confidence interval, 0.97–9.87; P = 0.034). rs117014418 in APOL4 was significantly associated with a decrease in eGFR of greater than 20% compared with the baseline in SDNS/FRNS patients (P = 0.0001). Protein–protein intersection network construction suggested that HLA-DQA1 and HLA-DQB1 function together through GSDMA. Thus, SSNSWR belongs to non-HLA region-dependent nephropathy, and the HLA-DQA/DQB region is likely strongly associated with disease relapse, especially in SDNS/FRNS. The study provides a novel approach for the GWAS strategy of SSNS and contributes to our understanding of the pathological mechanisms of SSNSWR and SDNS/FRNS.

Retrieval-augmented generation (RAG) addresses the problem of knowledge cutoff and overcomes the inherent limitations of pre-trained language models by retrieving relevant information in real time. However, challenges related to efficiency and accuracy persist in current RAG strategies. A key issue is how to select appropriate methods for user queries of varying complexity dynamically. This study introduces a novel adaptive retrieval-augmented generation framework termed Layered Query Retrieval (LQR). The LQR framework focuses on query complexity classification, retrieval strategies, and relevance analysis, utilizing a custom-built training dataset to train smaller models that aid the large language model (LLM) in efficiently retrieving relevant information. A central technique in LQR is a semantic rule-based approach to distinguish between different levels of multi-hop queries. The process begins by parsing the user’s query for keywords, followed by a keyword-based document retrieval. Subsequently, we employ a natural language inference (NLI) model to assess whether the retrieved document is relevant to the query. We validated our approach on multiple single-hop and multi-hop datasets, demonstrating significant improvements in both accuracy and efficiency compared to existing single-step, multi-step, and adaptive methods. Our method exhibits high accuracy and efficiency, particularly on the HotpotQA dataset, where it outperforms the Adaptive-RAG method by improving accuracy by 9.4% and the F1 score by 16.14%. The proposed approach carefully balances retrieval efficiency with the accuracy of the LLM’s responses.

The increasing challenges of urbanization and climate change have driven the need for innovative stormwater management solutions. Rain gardens, as a nature-based solution (NBS), have emerged as a critical component in urban water management, particularly in enhancing hydrological regulation, water quality, and ecosystem services. This bibliometric review examines the application of rain gardens in urban environments, focusing on their roles in stormwater management, pollutant removal, and ecological enhancement. Data from 728 academic papers published between 2000 and 2023 were analyzed using the Web of Science (WoS) Core Collection, employing bibliometric tools such as the “Bibliometrix” R package and CiteSpace. The analysis highlights the increasing global interest in rain gardens, particularly since 2015, with China and the United States leading research efforts. Key findings reveal that rain gardens significantly reduce runoff, improve water quality, and contribute to urban biodiversity. In addition, their integration into public spaces offers landscape esthetics and social benefits, enhancing the quality of life in urban areas. However, challenges remain in optimizing their design for diverse climates and long-term performance. The study underscores the need for further research on plant–soil interactions, pollutant removal mechanisms, and the broader ecological and social contributions of rain gardens. This review provides insights into the evolution of rain garden research and identifies future directions for advancing sustainable urban stormwater management.

Abstract Objective Diabetic kidney disease (DKD) is characterized by the abnormal deposition of oxidized low-density lipoprotein (ox-LDL), which contributes to podocyte damage. Klotho, an aging suppressor that plays a critical role in protecting podocytes in DKD, is mainly expressed in kidney tubular epithelium and secreted in the blood. However, it has not been established whether Klotho can alleviate podocyte injury by inhibiting renal ox-LDL deposition, and the potential molecular mechanisms require further investigation. Methods We conducted a comprehensive analysis of serum and kidney biopsy samples obtained from patients diagnosed with DKD. Additionally, to explore the underlying mechanism of Klotho in the deposition of ox-LDL in the kidneys, we employed a mouse model of DKD with the Klotho genotype induced by streptozotocin (STZ). Furthermore, we conducted meticulous in vitro experiments on podocytes to gain further insights into the specific role of Klotho in the deposition of ox-LDL within the kidney. Results Our groundbreaking study unveiled the remarkable ability of the soluble form of Klotho to effectively inhibit high glucose-induced ox-LDL deposition in podocytes affected by DKD. Subsequent investigations elucidated that Klotho achieved this inhibition by reducing the expression of the insulin/insulin-like growth factor 1 receptor (IGF-1R), consequently leading to a decrease in the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1) and an enhancement of mitochondrial function. Ultimately, this series of events culminated in a significant reduction in the expression of the oxidized low-density lipoprotein receptor (OLR1), thereby resulting in a notable decrease in renal ox-LDL deposition in DKD. Conclusion Our findings suggested that Klotho had the potential to mitigate podocyte injury and reduced high glucose-induced ox-LDL deposition in glomerulus by modulating the IGF-1R/RAC1/OLR1 signaling. These results provided valuable insights that could inform the development of novel strategies for diagnosing and treating DKD. Graphical Abstract

BackgroundThis study aims to explore the clinical value of low disease activity state (LDAS) in the treat-to-target strategy of pediatric systemic lupus erythematosus (pSLE) and find the risk factors for never reaching LDAS.MethodsA total of 272 children with SLE who were diagnosed and followed up in two tertiary hospitals in China during the period from January 2012 to December 2019 were involved in this study, and the clinical presentation, pathology, and treatment were retrospectively studied.ResultsThe male-to-female ratio was 1:5.2, the age at diagnosis was 11.1 years (IQR, 9.8–13.1 years), the disease duration was 1.0 month (IQR, 0.5–2.0 months), and follow-up was 36.5 months (IQR, 25.7–50.9 months). During follow-up, 230 children achieved LDAS, and 42 were never been in. Male (P = 0.018), mucosal ulcer (P = 0.048), liver function damage (P = 0.026), cardiac effusion (P = 0.034), anemia (P = 0.048), urine red blood cells (P = 0.017), urinary leukocytes (P = 0.032), and endothelial cell proliferation in renal biopsy (P = 0.004)—these indexes have statistical differences between the two groups in the baseline. At baseline, endothelial cell proliferation (P = 0.02) is an independent risk factor for never achieving LDAS by multivariate logistic analysis. During follow-up, non-compliance was a risk factor for never achieving LDAS by comparing between groups. Children with biologics achieved LDAS at a higher rate than children without biologics (P = 0.038). The proportion of organ damage in patients never been in LDAS was significantly higher than that in patients who achieved LDAS (P < 0.001).ConclusionEndothelial cell proliferation in renal biopsy and non-compliance during follow-up were independent risk factors for never achieving LDAS. At the end of the follow-up, the organ damage in the remission group was similar to that in the LDAS group, indicating that LDAS can be used as a target for pSLE treatment.

This study presents a comprehensive methodology for the implementation of Nature-based Solutions (NbS) in the context of urban flood mitigation, specifically within the heritage city of Guangzhou, China. The investigation delves into the roles of urban morphology and impermeability in exacerbating flood risk through enhanced runoff accumulation and reduced infiltration. A key focus is the spatial heterogeneity of flood susceptibility, influenced by the disparate distribution of various building types and demographic segments. This research integrates susceptibility and vulnerability assessments with spatial analysis of NbS and multi-criteria decision-making, facilitating the identification of pivotal zones for NbS application. Findings underscore the critical role of urban design in flood risk management and reveal the efficacy of vegetation-based strategies, namely vegetated swales and bioretention cells, which account for 8.41% and 7.08% of the total area, respectively, in curbing urban flood impacts. Recommendations for heritage city innovation include the prioritization of vegetation-integrated road layouts coupled with a gradual enhancement of grey infrastructure in historical areas. The study culminates in providing strategic insights for policymakers and urban planners in heritage cities, underscoring the necessity of a balanced approach to technical feasibility and conservation imperatives in NbS deployment.

Objective Currently, little is known regarding changes in family situation with concurrent changes in working life. This study aimed to examine whether changes in family situation (based on living with children and/or marrying/divorcing) were associated with changes in working life and whether the associations were influenced by sex, genetics and early life environment.Design Prospective cohort study.Setting and participants Data from Swedish national registers of 16 410 twins were used. Fixed-effects logistic regression models assessing ORs with 95% CIs were applied to examine associations between changes in family situation and working life controlling for time-invariant effects and adjusted for covariates, and conditional models to account for confounding of genetics and early life environment.Results Changes in individuals life situation from being single and living without children to married and living with children were associated with transitioning from unsustainable (ie, having unemployment or sickness absence/disability pension) to sustainable working life (men: OR 2.40, 95% CI 2.26 to 2.56; women: OR 1.68, 95% CI 1.59 to 1.78). Changes from being married to single, in contrast, attenuated the likelihood of transitioning to a sustainable working life. Moreover, changes in men’s working life seem to be more dependent on changes in family situation compared with women. Genetic factors and early life environment play a role in the associations.Conclusions Family formation increases the likelihood of a more stable working life whereas divorce is a risk factor for work interruptions. Our study emphasises that family formation improves the work life situation and to a higher degree for men.

Abstract The global rise in life expectancy transforms age structure consequently having impact to the sustainability of social protection systems and working life. This descriptive study aimed to illustrate the annual prevalence of sustainable working life across Swedish residential regions, and investigate differences between age groups, sex, or being identical or fraternal twin. The study sample included 81,231 twins with linkage to national register data on sickness absence, disability pension, unemployment, and residential regions. Regions were classified by Swedish municipalities into nine groups. Sustainable working life were then followed in 1998, 2003, 2008, and 2013. Annual prevalence and Generalized Estimating Equation (GEE) with log linear models for interaction test were used. Medium to large size municipalities (15–24%) had higher annual prevalence of sustainable working life than smaller municipalities (1–7%). Young adults in medium to large size municipalities had high annual prevalence of sustainable working life. We found no differences for sexes or being identical or fraternal twin. To conclude, annual prevalence of sustainable working life in 1998, 2003, 2008 and 2013 differed by region being highest in medium to large size municipalities which may have importance for targeting policies, regulations, and practices in a region-specific way. Further studies on residential regions and sustainable working life would be merited to confirm associations and other influential factors.

Abstract Background The maturation of microRNAs (miRNAs) successively undergoes Drosha, Dicer, and Argonaute ˗mediated processing, however, the intricate regulations of the individual miRNA maturation are largely unknown. Retinoid x receptor alpha (RXRα) belongs to nuclear receptors that regulate gene transcription by binding to DNA elements, however, whether RXRα binds to miRNAs to exert physiological functions is not known. Results In this work, we found that RXRα directly binds to the precursor of miR-103 (pre-miR-103a-2) via its DNA-binding domain with a preferred binding sequence of AGGUCA. The binding of RXRα inhibits the processing of miR-103 maturation from pre-miR-103a-2. Mechanistically, RXRα prevents the nuclear export of pre-miR-103a-2 for further processing by inhibiting the association of exportin-5 with pre-miR-103a-2. Pathophysiologically, the negative effect of RXRα on miR-103 maturation correlates to the positive effects of RXRα on the expression of Dicer, a target of miR-103, and on the inhibition of breast cancer. Conclusions Our findings unravel an unexpected role of transcription factor RXRα in specific miRNA maturation at post-transcriptional level through pre-miRNA binding, and present a mechanistic insight regarding RXRα role in breast cancer progression.

Background: Recent studies from targeted and untargeted metabolomics have consistently revealed that diet-related metabolites, including carnitine (C0), several species of acylcarnitines (AcyCNs), amino acids, ceramides, and lysophosphatidylcholines (LPCs) may serve as potential multiple myeloma (MM) biomarkers. However, most of these approaches had some intrinsic limitations, namely low reproducibility and compromising the accuracy of the results. Objective: This study developed and validated a precise, efficient, and reliable liquid chromatography tandem mass spectrometric (LC-MS/MS) method for measuring these 28 metabolic risk factors in human serum. Design: This method employed isopropanol to extract the metabolites from serum, gradient elution on a hydrophilic interaction liquid chromatographic column (HILIC) for chromatographic separation, and multiple reaction monitor (MRM) mode with positive electrospray ionization (ESI) for mass spectrometric detection. Results: The correlation coefficients of linear response for this method were more than 0.9984. Analytical recoveries ranged from 91.3 to 106.3%, averaging 99.5%. The intra-run and total coefficients of variation were 1.1–5.9% and 2.0–9.6%, respectively. We have simultaneously determined the serological levels of C0, several subclasses of AcyCNs, amino acids, ceramides, and LPCs within 15 min for the first time. Conclusion: The established LC-MS/MS method was accurate, sensitive, efficient, and could be valuable in providing insights into the association between diet patterns and MM disease and added value in further clinical research.

Lost circulation is one of the important problems that restricts the speed and efficiency of oil and gas drilling and production. In this study, a resin plugging system was successfully developed for lost circulation formation. The resin plugging system showed excellent performance under high temperature and pressure conditions. The experimental results showed that the compressive strength of the resin plugging material can reach 9.23 MPa after curing, which is significantly higher than that of the traditional polymer gel material. The resin material can achieve effective curing in the temperature range of 60 °C to 100 °C, and the curing time decreases with the increase of temperature and only needs 3.46 h at 140 °C. The microstructure results showed that the resin material can form a chain or three-dimensional network structure after curing, which can effectively increase the toughness and strength of the cured plugging layer. Infrared and thermogravimetric analysis further confirmed the thermal stability of the chemical bonds in the material, and the initial decomposition temperature was about 241 °C, indicating that it had good thermal stability at about 300 °C. In addition, the effects of curing temperature, salinity, and drilling fluid pollution on the properties of the resin plugging agent were also investigated. The results showed that curing agent dosage and curing temperature are the key factors affecting curing time, while salinity and drilling fluid pollution affect the curing strength and overall properties of the materials. After adding 20% KCl polysulfonate drilling fluid, the compressive strength of the consolidated body decreased to 4.55 MPa. This study can provide an efficient and reliable plugging solution for malignant loss formation.

Urban microclimate faces serious challenges due to increased urbanization and frequent heatwave events. Many studies focused on investigating the holistic quantitative relationships between urban morphology factors and heat island intensity at the city scale, but less effort has been devoted to exploring the relationships on a block scale. Additionally, there is a lack of fast prediction methods for urban microclimate for local climate zones (LCZ) planning and design. To address these challenges, this study proposes a Long Short-Term Memory Networks (LSTM) model to predict the effects of urban morphology factors on the air temperature under local climate zones. The effects of the spatial morphology features on the air temperature were characterized and quantified employing a post-interpretation method. The Pearl River New Town (PRNT), the downtown area of Guangzhou, China, was considered as the research area for the model implementation. The results showed that air temperature prediction accuracy is the best when using the historical three-time step data, with R2 of 0.975. LCZ A has the highest prediction accuracy, with an R2 of 0.990. LCZ 5 has the lowest accuracy, with an R2 of 0.881. Moreover, the effect of urban morphology factors on air temperature was found to be greater than the effect of land cover type. In this regard, the sky view factor (SVF) has the highest impact, followed by the aspect ratio (AR) and the pervious surface fraction (PSF). Nevertheless, the warming effect in built type was stronger than that in land cover. During the heatwave period, the maximum and minimum temperature changes were recorded in LCZ 4 and LCZ A, respectively, with values of 9.7 °C and 8.6 °C. It was shown that low-rise areas are more resilient than high-rise areas during heatwave periods. This is because low-rise areas generally exhibit a smaller increase in air temperature. These findings provide a better understanding of the relationship between urban microclimate and urban form, and a method of rapidly predicting the microclimate of a neighborhood block. It provides guidance and support, with great significance for climate-friendly urban planning.

Abstract Background Previous research has demonstrated flavonoid intake was closely related to hyperuricemia. The purpose of this study was to examine whether flavonoid intake was associated with serum uric acid and hyperuricemia in U.S. adults. Methods The study sample consisted of 8,760 participants enrolled in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2010. Flavonoid consumption was measured using a two-day recall questionnaire on dietary intake. Hyperuricemia was defined based on the serum uric acid levels, determined as ≥ 7 mg/dL for males and ≥ 6 mg/dL for females. The study utilized multivariate linear regression to determine the correlation between flavonoid consumption and serum uric acid levels. Additionally, analyses involving multivariate logistic regression and restricted cubic splines (RCS) were conducted to evaluate the potential link between flavonoid consumption and hyperuricemia. All analyses were adjusted for possible confounding variables. Results The study revealed a negative correlation between serum uric acid levels and elevated levels of anthocyanidins and flavanones, with significant p-trends of

Abstract We aimed to investigate transitions to and from sickness absence, or disability pension among individuals with back, neck, or shoulder pain and/or with common mental disorders (CMDs), and the role of familial (genetics and shared environment) influences on the transitions. Swedish twins born 1935–1985 who responded to pain and CMDs survey items (N = 41,516) were followed on average 8.7 years for sickness absence states in national registers. Multi-state Cox regression models were applied for three exposure groups: pain, CMDs, and presence of both, compared to unexposed. Exposure discordant twin pairs, stratified by zygosity, were analysed to assess the role of familial factors. Hazard Ratios (HR) with 95% confidence intervals and transition intensities were calculated. HRs were similar for transitions between states among those with pain or CMDs. The highest HRs were for transitions from entry to sickness absence and sickness absence to disability pension among those with both pain and CMDs (HRs: 1.61 and 1.43, respectively). Higher HRs for dizygotic compared to monozygotic twins for the first transition to sickness absence and for altering back to not being sickness absent indicate familial confounding. Back, neck, or shoulder pain and/or CMDs indicate a higher risk to become sickness absent and for repeated sickness absence episodes over time compared to unaffected.

The mathematical form of many optimization problems in engineering is constrained optimization problems. In this paper, an improved genetic algorithm based on two-direction crossover and grouped mutation is proposed to solve constrained optimization problems. In addition to making full use of the direction information of the parent individual, the two-direction crossover adds an additional search direction and finally searches in the better direction of the two directions, which improves the search efficiency. The grouped mutation divides the population into two groups and uses mutation operators with different properties for each group to give full play to the characteristics of these mutation operators and improve the search efficiency. In experiments on the IEEE CEC 2017 competition on constrained real-parameter optimization and ten real-world constrained optimization problems, the proposed algorithm outperforms other state-of-the-art algorithms. Finally, the proposed algorithm is used to optimize a single-stage cylindrical gear reducer.

Urban flooding risks, often overlooked by conventional methods, can be profoundly affected by city configurations. However, explainable Artificial Intelligence could provide insights into how urban configurations affected urban flooding. This study, taking entered on Shenzhen City, deploys an XGBoost, integrating SHapley Additive exPlanation and Partial Dependency Plots, to assess how urban morphology influences urban flooding susceptibility. The models and strategies presented in this study aimed to adapt to extreme storms from the perspective of city spatial configuration planning. The findings underscore the varying impact of disaster variables on urban flooding, with morphological attributes becoming highly significant during severe inundations. In the analysis, mean building volume emerged as a pivotal parameter, with a mean SHAP value of 0.0107 m and a contribution ratio of 9.70 %. The study indicates that building configurations should be optimized to minimize urban flooding risks. It is recommended that the Mean Building Volume (MBV) be maintained within the range of 1.25 km3 to 2.5 km3, and the Standard Deviation of Building Volume (SDBV) be kept below 2.814 km3. By harnessing explainable Artificial Intelligence algorithms, this study offers insights into the intricate relationship between urban forms and flood risk, thereby informing the development of effective urban flooding adaptation strategies.

Designing a transcranial electrical stimulation (tES) strategy requires considering multiple objectives, such as intensity in the target area, focality, stimulation depth, and avoidance zone. These objectives are often mutually exclusive. In this paper, we propose a general framework, called multi-objective optimization via evolutionary algorithm (MOVEA), which solves the non-convex optimization problem in designing tES strategies without a predefined direction. MOVEA enables simultaneous optimization of multiple targets through Pareto optimization, generating a Pareto front after a single run without manual weight adjustment and allowing easy expansion to more targets. This Pareto front consists of optimal solutions that meet various requirements while respecting trade-off relationships between conflicting objectives such as intensity and focality. MOVEA is versatile and suitable for both transcranial alternating current stimulation (tACS) and transcranial temporal interference stimulation (tTIS) based on high definition (HD) and two-pair systems. We comprehensively compared tACS and tTIS in terms of intensity, focality, and steerability for targets at different depths. Our findings reveal that tTIS enhances focality by reducing activated volume outside the target by 60%. HD-tTIS and HD-tDCS can achieve equivalent maximum intensities, surpassing those of two-pair tTIS, such as 0.51 V/m under HD-tACS/HD-tTIS and 0.42 V/m under two-pair tTIS for the motor area as a target. Analysis of variance in eight subjects highlights individual differences in both optimal stimulation policies and outcomes for tACS and tTIS, emphasizing the need for personalized stimulation protocols. These findings provide guidance for designing appropriate stimulation strategies for tACS and tTIS. MOVEA facilitates the optimization of tES based on specific objectives and constraints, advancing tTIS and tACS-based neuromodulation in understanding the causal relationship between brain regions and cognitive functions and treating diseases. The code for MOVEA is available at https://github.com/ncclabsustech/MOVEA.

Driven by the change in intense land use and land cover (LULC) due to fast urbanization, urban flooding events have become the most frequent and influential hazards over the last few decades. Accurately predicting possible flood-prone locations under the dynamic fluctuations of LULC is crucial for sustainable urban development. However, there has been sparse studies on systematic integration of LULC changes into anticipate urban development scenarios coupled with flooding vulnerability assessment. Therefore, this study proposed a robust and powerful cascade modeling chain consisting of Maximum Entropy, System Dynamics and Patch-generating Land Use Simulation in combination with shared socio-economic pathways for projecting temporal and spatial dynamic changes associated with urban flooding vulnerability. Taking Guangdong Hong Kong Macao Greater Bay Area (GBA) as case study, the results showed that the increase in urban flooding was largely caused by the expansion of construction land. Overall, a substantial distinction within the scenarios was observed and the flooding vulnerability was ranked in the order of SSP126

Nephrotic syndrome (NS) is a relatively rare and serious presentation of IgA nephropathy (IgAN) (NS-IgAN). Previous research has suggested that the pathogenesis of NS-IgAN may involve circulating immune imbalance and kidney injury; however, this has yet to be fully elucidated. To investigate the cellular and molecular status of NS-IgAN, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) and kidney cells from pediatric patients diagnosed with NS-IgAN by renal biopsy. Consistently, the proportion of intermediate monocytes (IMs) in NS-IgAN patients was higher than in healthy controls. Furthermore, flow cytometry confirmed that IMs were significantly increased in pediatric patients with NS. The characteristic expression of VSIG4 and MHC class II molecules and an increase in oxidative phosphorylation may be important features of IMs in NS-IgAN. Notably, we found that the expression level of CCR2 was significantly increased in the CMs, IMs, and NCMs of patients with NS-IgAN. This may be related to kidney injury. Regulatory T cells (Tregs) are classified into two subsets of cells: Treg1 (CCR7high, TCF7high, and HLA-DRlow) and Treg2 (CCR7low, TCF7low, and HLA-DRhigh). We found that the levels of Treg2 cells expressed significant levels of CCR4 and GATA3, which may be related to the recovery of kidney injury. The state of NS in patients was closely related to podocyte injury. The expression levels of CCL2, PRSS23, and genes related to epithelial-mesenchymal transition were significantly increased in podocytes from NS-IgAN patients. These represent key features of podocyte injury. Our analysis suggests that PTGDS is significantly downregulated following injury and may represent a new marker for podocytes. In this study, we systematically analyzed molecular events in the circulatory system and kidney tissue of pediatric patients with NS-IgAN, which provides new insights for targeted therapy in the future.

Large-scale crop phenology monitoring is critical for agronomic planning and yield prediction applications. Synthetic Aperture Radar (SAR) remote sensing is well-suited for crop growth monitoring due to its nearly all-weather observation capability. Yet, the capability of the dual-polarimetric SAR data for wheat phenology estimation has not been thoroughly investigated. Here, we conducted a comprehensive evaluation of Sentinel-1 SAR polarimetric parameters’ sensibilities on winter wheat’s key phenophases while considering the incidence angle. We extracted 12 polarimetric parameters based on the covariance matrix and a dual-pol-version H-α decomposition. All parameters were evaluated by their temporal profile and feature importance score of Gini impurity with a decremental random forest classification process. A final wheat phenology classification model was built using the best indicator combination. The result shows that the Normalized Shannon Entropy (NSE), Degree of Linear Polarization (DoLP), and Stokes Parameter g2 were the three most important indicators, while the Span, Average Alpha (α2¯), and Backscatter Coefficient σVH0 were the three least important features in discriminating wheat phenology for all three incidence angle groups. The smaller-incidence angle (30–35°) SAR images are better suited for estimating wheat phenology. The combination of NSE, DoLP, and two Stokes Parameters (g2 and g0) constitutes the most effective indicator ensemble. For all eight key phenophases, the average Precision and Recall scores were above 0.8. This study highlighted the potential of dual-polarimetric SAR data for wheat phenology estimation. The feature importance evaluation results provide a reference for future phenology estimation studies using dual-polarimetric SAR data in choosing better-informed indicators.

Abstract The aim was to investigate occurrence and duration of sickness absence (SA) among young employees with previous depression/anxiety in private and public sectors. This population-based prospective study included 11,519 Swedish twin individuals of age 19–29 years that were followed regarding SA during 2006–2016. Data on previous depression/anxiety came from two screening surveys in 2005. Data on SA and employment sector were received from national registries. Descriptive statistics and logistic regression were used, also controlling for familial factors. Proportion of employees with SA was significantly higher among those with, as compared to those without, previous depression/anxiety, regardless the employment sector. Individuals with previous depression/anxiety had increased risk for future SA, in both private (OR 2.25, 95% CI 1.90–2.66) and public sectors (OR 2.10, 95% CI 1.73–2.54). Familial factors played a role in the association among employees in the private sector. A higher proportion of long-term SA was observed among employees with previous depression/anxiety in the private as compared to the public sector. To conclude, previous depression/anxiety tends to increase risk for SA among young employees in both employment sectors, whereas long-term SA seemed to be more prevalent among those in the private as compared to the public sector.

Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome (NS) of different etiologies is critical for early clinical guidance. We employed whole-exome sequencing (WES) to detect monogenic causes of NS in a multicenter cohort of 637 patients. In this study, a genetic cause was identified in 30.0% of the idiopathic steroid-resistant nephrotic syndrome (SRNS) patients. Other than congenital nephrotic syndrome (CNS), there were no significant differences in the incidence of monogenic diseases based on the age at manifestation. Causative mutations were detected in 39.5% of patients with focal segmental glomerulosclerosis (FSGS) and 9.2% of those with minimal change disease (MCD). In terms of the patterns in patients with different types of steroid resistance, a single gene mutation was identified in 34.8% of patients with primary resistance, 2.9% with secondary resistance, and 71.4% of children with multidrug resistance. Among the various intensified immunosuppressive therapies, tacrolimus (TAC) showed the highest response rate, with 49.7% of idiopathic SRNS patients achieving complete remission. Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern, and only 31.4% of patients with monogenic disease achieved a partial remission on TAC. During an average 4.1-year follow-up, 21.4% of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease (ESRD). Collectively, this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients, especially those with primary and/or multidrug resistance.

Abstract Background Proteinuria is an unfavorable clinical condition highly associated with a risk of renal and cardiovascular disease in chronic kidney disease (CKD). However, whether all proteinuria forms are linked to renal impairment are still unclear. Cubilin is an endocytic receptor highly expressed in renal proximal tubules mediating uptake of albumin, transferrin and α1-microglobulin. Methods Exome sequencing method initially identified candidate genes. With the application of exome sequencing combined with Sanger sequencing, we further focused on CUBN through bioinformatics analysis. The pathogenic effects of the potentially causative variants were verified utilizing complementary analysis of clinical data and systematic characterization of the variants’ expression and function with clinical samples and in vitro experiments in HEK293T cell lines along with in vivo experiments in mice. Results In this study, we identified four novel variants locating after the vitamin B12 (vitB12)-binding domain of Cubilin (encoded by CUBN, NM_001081.3: c.4397G > A (p.C1466Y), c.6796C > T (p.R2266X), c.6821 + 3A > G and c.5153_5154delCT (p.S1718X)) in two families. Moreover, the variants severely affected the expression and function of Cubilin in renal proximal tubules and caused albuminuria, increasing levels in urine transferrin and α1-microglobulin, but without progressive glomerular filtration barrier (GFB) impairment, vitB12 deficiencies or abnormal blood levels of HDL and albumin. Further mechanistic insights showed that the variants after the vitB12-binding domain of CUBN merely disrupted the association with Amnionless (AMN) that exhibited aberrant localization in cell cytoplasm rather than membrane. Conclusions Here, our findings suggested that different mutation types after the vitB12-binding domain of CUBN uncouple proteinuria from glomerular filtration barrier, that may be an unexpectedly common benign condition in humans and may not require any proteinuria-lowering treatment or renal biopsy.

Abstract Background The "Law on Doctors of the People's Republic of China," which was officially implemented on March 1, 2022, emphasizes the requirements for rational drug use and the necessity for appropriate management of off-label drug use. The safety and ethical considerations related to off-label drug use are different in children than in adults. There is so far no management guideline for pediatric off-label use of drugs in China, and the applicability of foreign guidelines is limited. Establishing a localized evidence-based management guideline for pediatric off-label use of drugs to support the national legislation and clinical practice is of critical importance. Methods We established a guideline working group, including experts from a broad range of disciplines and developed recommendations following the guidance of the World Health Organization Handbook and the Chinese Medical Association. The following themes were identified by questionnaires and expert interviews to be of great concern in the management of off-label drug use in children: general principles and characteristics of management of pediatric off-label drug use; establishment of expert committees; evidence evaluation; risk–benefit assessment; informed consent; monitoring and assessment of the risk; and monitoring and patient education. Two rounds of Delphi surveys were organized to determine the final recommendations of this guideline. We graded the recommendations based on the body of evidence, referring to the evaluation tool of the Evidence-based management (EBMgt) and the Oxford Center for Evidence-Based Medicine: Level of Evidence (March 2009). Results We developed the first guideline for the management of pediatric off-label use of drugs in China. Conclusions The guideline is to offer guidance for pediatricians, pharmacists, medical managers, policymakers, and primary care physicians on how to manage off-label drug use in pediatrics and to provide recommendations for Chinese healthcare policy in the future.

Nature-based solutions (NbSs) are considered to form an innovative stormwater management approach that has living resolutions grounded in natural processes and structures. NbSs offer many other environmental benefits over traditional grey infrastructure, including reduced air pollution and climate change mitigation. This review predominantly centers on the hydrological aspect of NbSs and furnishes a condensed summary of the collective understanding about NbSs as an alternatives for stormwater management. In this study, which employed the CIMO (Context, Intervention, Mechanism, Outcome) framework, a corpus of 187 NbS-related publications (2000–2023) extracted from the Web of Science database were used, and we expounded upon the origins, objectives, and significance of NbSs in urban runoff and climate change, and the operational mechanisms of NbSs (including green roofs, permeable pavements, bioretention systems, and constructed wetlands), which are widely used in urban stormwater management, were also discussed. Additionally, the efficacy of NbSs in improving stormwater quality and quantity is discussed in depth in this study. In particular, the critical role of NbSs in reducing nutrients such as TSS, TN, TP, and COD and heavy metal pollutants such as Fe, Cu, Pb, and Zn is emphasized. Finally, the main barriers encountered in the promotion and application of NbSs in different countries and regions, including financial, technological and physical, regulatory, and public awareness, are listed, and future directions for improving and strategizing NbS implementation are proposed. This review gathered knowledge from diverse sources to provide an overview of NbSs, enhancing the comprehension of their mechanisms and applications. It underscores specific areas requiring future research attention.

Sucrose non-fermenting–1-related protein kinase–1 (SnRK1) is a highly conserved serine–threonine kinase complex regulating plants’ energy metabolisms and resistance to various types of stresses. However, the downstream genes regulated by SnRK1 in these plant physiological processes still need to be explored. In this study, we found that the knockout of OsSnRK1a resulted in no obvious defects in rice growth but notably decreased the seed setting rate. The ossnrk1a mutants were more sensitive to blast fungus (Magnaporthe oryzae) infection and showed compromised immune responses. Transcriptome analyses revealed that SnRK1a was an important intermediate in the energy metabolism and response to biotic stress. Further investigation confirmed that the transcription levels of OsNADH-GOGAT2, which positively controls rice yield, and the defense-related gene pathogenesis-related protein 1b (OsPR1b) were remarkably decreased in the ossnrk1a mutant. Moreover, we found that OsSnRK1a directly interacted with the regulatory subunits OsSnRK1β1 and OsSnRK1β3, which responded specifically to blast fungus infection and starvation stresses, respectively. Taken together, our findings provide an insight into the mechanism of OsSnRK1a, which forms a complex with specific β subunits, contributing to rice seed set and resistance by regulating the transcription of related genes.

BackgroundImmunoglobulin A nephropathy (IgAN) is one of the most common kidney diseases leading to renal injury. Of pediatric cases, 25%–30% progress into end-stage kidney disease (ESKD) in 20–25 years. Therefore, predicting and intervening in IgAN at an early stage is crucial. The purpose of this study was to validate the availability of an international predictive tool for childhood IgAN in a cohort of children with IgAN treated at a regional medical centre.MethodsAn external validation cohort of children with IgAN from medical centers in Southwest China was formed to validate the predictive performance of the two full models with and without race differences by comparing four measures: area under the curve (AUC), the regression coefficient of linear prediction (PI), survival analysis curves for different risk groups, and R2D.ResultsA total of 210 Chinese children, including 129 males, with an overall mean age of 9.43 ± 2.71 years, were incorporated from this regional medical center. In total, 11.43% (24/210) of patients achieved an outcome with a GFR decrease of more than 30% or reached ESKD. The AUC of the full model with race was 0.685 (95% CI: 0.570–0.800) and the AUC of the full model without race was 0.640 (95% CI: 0.517–0.764). The PI of the full model with race and without race was 0.816 (SE = 0.006, P

Sponge City Construction (SCC) has been extensively explored for controlling frequent urban waterlogging and non-point source pollution. Assessing the “supply” and “demand” of SCC as a city-wide approach may aid in appropriate areal coverage to achieve optimal performance on flood control based on local priorities and sustainable urban development plans. However, to date, very few studies have examined the potential spatial mismatches in the “supply” and “demand” of SCC. This study presented the development of a framework to explore the supply–demand relationship based on a spatial multi-criteria evaluation of the existing SCC facilities, risk exposure, and socio-economic vulnerability. The feasibility and application of such a framework were successfully demonstrated in a field application in Guangzhou, China. The results indicated that most of the high-density areas in the city centres of Guangzhou were exposed to high risk with strong SCC demands. Furthermore, Liwan and Yuexiu districts exhibited SCC supply deficits, while SCC supply surpluses were observed in other central districts in Guangzhou. The findings of this study provided insight into the development of a generalised and replicable method that could be used to achieve a balance between the “supply” and “demand” of SCC for more participatory, strategic and multifunctional planning of SCC in various urban contexts.

Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe perimorbid cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, neither treatment with the mTOR inhibitor rapamycin alone nor dual treatment with lonafarnib plus rapamycin improved outcomes over that achieved with lonafarnib monotherapy.

The imbalance of gut microbiota has been confirmed to have a close pathological and physiological correlation with obesity and metabolic syndrome. Ramulus Mori (Sangzhi) Alkaloids (SZ-A) derived from twigs of mulberry was approved by the National Medical Products Administration of China in 2020 for the treatment of type 2 diabetes mellitus. In addition to its hypoglycemic effect, previous studies have confirmed that SZ-A also alleviates high-fat diet-induced obesity and non-alcoholic fatty liver disease and ameliorates obesity-linked adipose tissue metabolism and inflammation, indicating the potential of SZ-A to regulate obesity and metabolic syndrome. However, whether SZ-A can improve obesity and metabolic syndrome by regulating gut microbiota and its metabolism profiles remains unclear. The purpose of this study was to assess the effect of SZ-A on gut microbiota in obese mice and to explore the association among changes in gut microbiota, obesity, and lipid metabolism. The results showed that oral administration of SZ-A could significantly reduce body weight, fat mass, and the level of total cholesterol and low-density lipoprotein in serum in obese mice induced by a high-fat diet. Interestingly, SZ-A also regulated gut microbiota and changed the fecal metabolite composition of obese mice. Compared with the high-fat diet group, the ratio of Firmicutes to Bacteroides changed at the phylum level and the abundance of Bifidobacterium and Akkermansia muciniphila significantly increased at the genus level in the SZ-A group. The gut microbiota of the SZ-A group was reshaped and the relative abundance of microbial genes in bile acid metabolism and fatty acid metabolism were altered, which was consistent with the metabolomics results. Additionally, SZ-A greatly enriched the number of goblet cells and reduced inflammatory colon injury and pro-inflammatory macrophage infiltration induced by a high-fat diet in obese mice. In conclusion, SZ-A can alleviate obesity and metabolic syndrome by improving the gut microbiota and its metabolism profiles of obese mice induced by a high-fat diet.

ObjectiveCOQ8B nephropathy is a relatively rare autosomal recessive kidney disease characterized by proteinuria and a progressive deterioration of renal function, eventually leading to end-stage renal disease (ESRD). The objective is to study the characteristics and correlation between the genotype and the clinical phenotype of COQ8B nephropathy.MethodsThis is a retrospective study focusing on the clinical characteristics of seven COQ8B nephropathy patients diagnosed by gene sequencing. Basic clinical information, clinical manifestations, examinations, imaging, genomes, pathology, treatments, and prognosis of the patients were reviewed.ResultsOf the seven patients, two were male children and five were female children. The median age at the disease onset was 5 years and 3 months. The initial main clinical manifestations were proteinuria and renal insufficiency. Four patients had severe proteinuria, four had focal segmental glomerulosclerosis (FSGS) diagnosed by a renal biopsy, and two had nephrocalcinosis after an ultrasound was performed on them. There were no other clinical manifestations such as neuropathy, muscle atrophy, and so on in all of them. Their gene mutations were all exon variants, which were classified as heterozygous or homozygous variants by performing family verification analysis. Compound heterozygous variants were predominant in all, and all gene variants were inherited from their parents. One novel mutation, c.1465c>t, was found in this study. This gene mutation resulted from changes in the amino acid sequence, thus leading to an abnormal protein structure. Two patients with early diagnosis of COQ8B nephropathy presented with no renal insufficiency and were treated with oral coenzyme Q10 (CoQ10), and they maintained normal renal function. For the remaining five who were treated with CoQ10 following renal insufficiency, the deterioration of renal function could not be reversed, and they progressed to ESRD within a short time (median time: 7 months). A follow-up of these patients showed normal renal function with a CoQ10 supplement.ConclusionFor unexplained proteinuria, renal insufficiency, or steroid-resistant nephrotic syndrome, gene sequencing should be considered, in addition to renal biopsy, as early as possible. Timely diagnosis of COQ8B nephropathy and early supplementation of sufficient CoQ10 can help control the progression of the disease and significantly improve the prognosis.

Peripheral blood immune cells have different molecular characteristics at different stages of the whole lifespan. Knowledge of circulating immune cell types and states from children to centenarians remains incomplete. We profiled peripheral blood mononuclear cells (PBMCs) of multiple age groups with single-cell RNA sequencing (scRNA-seq), involving the age ranges of 1-12 (G1), 20-30(G2), 30-60(G3), 60-80(G4), and >110 years (G5). The proportion and states of myeloid cells change significantly from G1 to G2. We identified a novel CD8+CCR7+GZMB+ cytotoxic T cell subtype specific in G1, expressing naive and cytotoxic genes, and validated by flow cytometry. CD8+ T cells showed significant changes in the early stage (G1 to G2), while CD4+ T cells changed in the late stage (G4 to G5). Moreover, the intercellular crosstalk among PBMCs in G1 is very dynamic. Susceptibility genes for a variety of autoimmune diseases (AIDs) have different cell-specific expression localization, and the expression of susceptibility genes for AIDs changes with age. Notably, the CD3+ undefined T cells clearly expressed susceptibility genes for multiple AIDs, especially in G3. ETS1 and FLI1, susceptibility genes associated with systemic lupus erythematosus, were differentially expressed in CD4+ and CD8+ effector cells in G1 and G3. These results provided a valuable basis for future research on the unique immune system of the whole lifespan and AIDs.

Abstract Background Hereditary tyrosinemia type 1 (HT1) is a rare inherited metabolic disease characterized by severe liver and renal dysfunction. Early identification in affected children is critical for improved treatment options and prognosis. Methods In this study, we identified novel compound heterozygous mutations (NM_000137: c.657delC (p.K220Rfs*12) and c.607G>A (p.A203T)) in the fumarylacetoacetate hydrolase (FAH) gene in a family. We also characterized the clinical phenotype of the proband and verified the pathogenic effects of the mutations. Furthermore, we explored the pathogenic mechanism of renal injury through renal biopsy pathology and cell‐based in vitro assays. Our study aims to verify the association between novel fumarylacetoacetate hydrolase (FAH) variants and HT1, confirm the pathogenic effects of the mutations and explore the pathogenic mechanism of renal injury. Results We showed these FAH mutations were inherited in an autosomal recessive manner and resulted in abnormal FAH protein expression and dysfunction, leading to fumarylacetoacetate (FAA) accumulation. The proband also showed apparent renal injury, including glomerular filtration barrier dysfunction and abnormal tubular protein reabsorption. Conclusions These observations may provide deeper insights on disease pathogenesis and identify potential therapeutic approaches for HT1 from a genetic perspective. Similarly, we hope to provide valuable information for genetic counseling and prenatal diagnostics.