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Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P

Abstract Objective This study aimed to evaluate the long-term cost-effectiveness of conventional care (CC) and seven first-line targeted therapies marketed in China for the treatment of patients with ankylosing spondylitis (AS)–namely secukinumab, ixekizumab, infliximab, etanercept, adalimumab and golimumab and tofacitinib–from the perspective of the Chinese health care system. Methods The York model was structured as a 12-week decision tree leading into two Markov models. This study set 1 year as a recurring cycle and a lifetime timeframe for the model. Primary model outcomes included the costs in Chinese yuan (CNY), health outcomes in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of ¥89,358 (equal to the per capita gross domestic product in China in 2023) per QALY. Parameters in the York model were captured from network meta-analyses and literature including treatment response, short-term disease progression, patient functioning and long-term structural disease progression. Utilities are dependent on indicators such as the BASDAI score, the BASFI score, gender and age. Drug prices were analysed using the median price of the Chinese market from YAOZH net in the basic analysis. Costs and outcomes were discounted at 5.0%. We performed deterministic and probabilistic sensitivity analyses to investigate the robustness of the results. The prices of original drugs and generic drugs were used in the scenario analysis. Results Compared with CC, the ICER of golimumab was ¥104,217.4/QALY, which is between 1 and 3 times the GDP per capita, while the ICERs of the other six targeted therapies were less than ¥89,358/QALY. The specific economic rank of the targeted therapy was as follows: secukinumab > ixekizumab > tofacitinib > infliximab > etanercept > adalimumab > golimumab. Treatment response rates such as the BASDAI50, changes in the BASDAI/BASFI scores and the discounting rate were key model drivers. According to the scenario analysis, IL-17 inhibitors were still the most economical intervention when original drugs and generic drugs were used. Conclusion Targeted therapies are cost-effective treatments for AS. Overall, IL-17 inhibitors were the dominant treatment. The choice of the brand-new prices or generic drug prices can greatly affect economics.

Abstract The rising sentiment challenges of the metropolitan residents may be attributed to the extreme temperatures. However, nationwide real-time empirical studies that examine this claim are rare. In this research, we construct a daily extreme temperature index and sentiment metric using geotagged posts on one of China's largest social media sites, Weibo, to verify this hypothesis. We find that extreme temperatures causally decrease individuals' sentiment, and extremely low temperature may decrease more than extremely high temperature. Heterogeneity analyses reveal that individuals living in high levels of PM2.5, existing new COVID-19 diagnoses and low-disposable income cities on workdays are more vulnerable to the impact of extreme temperatures on sentiment. More importantly, the results also demonstrate that the adverse effects of extremely low temperatures on sentiment are more minor for people living in northern cities with breezes. Finally, we estimate that with a one-standard increase of extremely high (low) temperature, the sentiment decreases by approximately 0.161 (0.272) units. Employing social media to monitor public sentiment can assist policymakers in developing data-driven and evidence-based policies to alleviate the adverse impacts of extreme temperatures.

ABSTRACT Background Young lung cancer is a rare subgroup accounting for 5% of lung cancer. The aim of this study was to compare the causes of death (COD) among lung cancer patients of different age groups and construct a nomogram to predict cancer‐specific survival (CSS) in young patients with advanced stage. Methods Lung cancer patients diagnosed between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database and stratified into the young (18–45 years) and old (> 45 years) groups to compare their COD. Young patients diagnosed with advanced stage (IVa and IVb) from 2010 to 2015 were reselected and divided into training and validation cohorts (7:3). Independent prognostic factors were identified through the Fine‐Gray's test and further integrated to the competing risk model. The area under the receiver operating characteristic curve (AUC), consistency index (C‐index), and calibration curve were applied for validation. Results The proportion of cancer‐specific death (CSD) in young patients was higher than that in old patients with early‐stage lung cancer (p

Analcime plays a significant role in sandstone reservoirs as an authigenic diagenetic mineral in the Junggar Basin (northwestern China). However, the origin and controls on the reservoirs have received remarkably little attention. This study investigates the formation mechanism of analcime in the Middle Permian strata in the Jinan sag (southern Junggar Basin) through petrography and geochemistry. The results show that analcime is formed through early alkaline hydrolysis of volcanic materials under specific temperature and pressure conditions. The reservoir rocks primarily consist of various lithic sandstones, including volcanic debris such as basalt, andesite, and tuff. Analcime is characterized as rich in aluminium and poor in sodium, classified as low-silica analcime with a low Si-Al ratio (1.98–2.38). Furthermore, various other diagenetic minerals, such as glauconite, chlorite, albite, and calcite have been identified. The primary reservoir space chiefly consists of intragranular dissolved pores of analcime, while secondary pores are formed by intragranular pores of feldspar and lithic, along with some remaining intergranular pores. Cementation of analcime during early diagenesis changes primary pore structures and reduces reservoir properties. The low-silica analcime dissolves due to acidic pore fluids associated with three stages of oil and gas charging, transforming into albite and creating numerous secondary pores, thereby enhancing reservoir quality.

Abstract Brominated flame retardants (BFRs) are a group of chemicals widely used in various applications to prevent or slow down the spread of fire. However, they have adverse effects on human health. There is a relative scarcity of population-based studies regarding BFRs, particularly their impact on the respiratory system. This study aimed to investigate the influence of BFRs on pulmonary function using data from the National Health and Nutrition Examination Survey. The study found that elevated serum concentrations of certain BFRs were associated with pulmonary ventilatory dysfunction. Adjusted analyses revealed positive correlations between PBDE47, PBDE183, and PBDE209 concentrations and ventilatory dysfunction. The analysis of mixed BFRs showed a positive relationship with pulmonary ventilation dysfunction, with PBDE47 making the most significant contribution. Our study demonstrates that both individual and combined BFRs exposure can lead to impaired pulmonary ventilation function. These findings provide evidence of the adverse effects of BFRs on lung function, emphasizing the importance of further investigating the potential health consequences of these compounds. Further large-scale longitudinal studies are needed to investigate this relationship in the future.

Abstract We introduce a computational approach for the design of target-specific peptides. Our method integrates a Gated Recurrent Unit-based Variational Autoencoder with Rosetta FlexPepDock for peptide sequence generation and binding affinity assessment. Subsequently, molecular dynamics simulations are employed to narrow down the selection of peptides for experimental assays. We apply this computational strategy to design peptide inhibitors that specifically target β-catenin and NF-κB essential modulator. Among the twelve β-catenin inhibitors, six exhibit improved binding affinity compared to the parent peptide. Notably, the best C-terminal peptide binds β-catenin with an IC50 of 0.010 ± 0.06 μM, which is 15-fold better than the parent peptide. For NF-κB essential modulator, two of the four tested peptides display substantially enhanced binding compared to the parent peptide. Collectively, this study underscores the successful integration of deep learning and structure-based modeling and simulation for target specific peptide design.

This paper proposed an efficient research method for high-dimensional uncertainty quantification of projectile motion in the barrel of a truck-mounted howitzer. Firstly, the dynamic model of projectile motion is established considering the flexible deformation of the barrel and the interaction between the projectile and the barrel. Subsequently, the accuracy of the dynamic model is verified based on the external ballistic projectile attitude test platform. Furthermore, the probability density evolution method (PDEM) is developed to high-dimensional uncertainty quantification of projectile motion. The engineering example highlights the results of the proposed method are consistent with the results obtained by the Monte Carlo Simulation (MCS). Finally, the influence of parameter uncertainty on the projectile disturbance at muzzle under different working conditions is analyzed. The results show that the disturbance of the pitch angular, pitch angular velocity and pitch angular of velocity decreases with the increase of launching angle, and the random parameter ranges of both the projectile and coupling model have similar influence on the disturbance of projectile angular motion at muzzle.

Magnetic graphene (Fe3O4@G) was synthesized as a magnetic solid phase extractor for the extraction and enrichment of organophosphorus pesticides in green tea by chemical coprecipitation method. Based on this, ultra high performance liquid chromatography tandem mass spectrometry method was developed for the determination of 19 organophosphorus pesticide residues in green tea. 40 mg adsorbent and 4 g sodium chloride were used in this experiment with the pH of sample solution at 7 for 20 min extraction time, 3.0 mL acetone desorption. The result showed that the prepared Fe3O4@G material had good stability and reusability with the linear correlation coefficients greater than 0.999 in the range of 5～500 μg/L. The limits of detection (LOD) and the limits of quantitation (LOQ) were 5.0～6.0 μg/kg and 15.0～20.0 μg/kg, respectively. The recoveries were between 61.2% and 94.9% with the relative standard deviations (RSD, n=6) in the range of 2.6%～10.2% when the samples were labeled at 20.0, 40.0 and 200.0 μg/kg. This method was safe and economy with a wide application range, easier control of pretreatment, less amount of organic solvent and reusable materials, which has a good application prospect in the enrichment and separation of pesticides in tea by the magnetic dispersion solid phase extraction technology.

Abstract The properties of two-dimensional covalent organic frameworks (2D COFs), including porosity, catalytic activity as well as electronic and optical properties, are greatly affected by their interlayer stacking structures. However, the precise control of their interlayer stacking mode, especially in a reversible fashion, is a long-standing and challenging pursuit. Herein, we prepare three 2D copper-organic frameworks, namely JNM-n (n = 7, 8, and 9). Interestingly, the reversible interlayer sliding between eclipsed AA stacking (i.e., JNM-7-AA and JNM-8-AA) and staggered ABC stacking (i.e., JNM-7-ABC and JNM-8-ABC) can be achieved through environmental stimulation, which endows reversible encapsulation and release of lipase. Importantly, JNM-7-AA and JNM-8-AA exhibit a broader light absorption range, higher charge-separation efficiency, and higher photocatalytic activity for sensitizing O2 to 1O2 and O2 •− than their ABC stacking isostructures. Consequently, JNM-8-AA deliver significantly enhanced photocatalytic activities for oxidative cross-coupling reactions compared to JNM-8-ABC and other reported homogeneous and heterogeneous catalysts.

Abstract Background Klotho is an anti-aging protein that has multiple functions and may play a key role in the pathogenesis and progression of chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). Fractional Exhaled Nitric Oxide (FeNO) is a non-invasive and novel biomarker that has the advantages of being simple, fast and reproducible. It can effectively assess the degree of airway inflammation in diseases such as asthma and COPD. Despite these insights, the relationship between serum Klotho levels and FeNO has not been explored yet. Methods Leveraging data from the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2012, we investigated the correlation between FeNO and serum Klotho levels. This association was scrutinized both as continuous variables and within quartile distributions, utilizing the Kruskal-Wallis H test. The correlation between the two variables was assessed through Spearman rank analysis. Employing survey weight-adjusted linear regression models, we gauged the strength of these associations. Results This study included 6,527 participants with a median FeNO level of 14.5 parts per billion (ppb). We found that FeNO levels varied significantly across different quartiles of Klotho protein (H = 7.985, P = 0.046). We also found a significant positive correlation between serum Klotho levels and FeNO levels in the whole population (Spearman’s rho = 0.029, P = 0.019). This correlation remained significant after adjusting for covariates such as age, gender, lung function, smoking status, alcohol use, BMI, cardiovascular disease (including hypertension, heart failure, coronary heart disease, and myocardial infarction), diabetes, inflammatory markers, serum vitamin D level and BUN (P

Abstract Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53.

Objective: Numerous studies have posited the involvement of serum uric acid (SUA) in the pathogenesis and progression of various cardiovascular diseases, particularly aortic aneurysms. However, the casual effect of SUA level on intracranial aneurysms (IAs) was rarely studied. Consequently, we aimed to explore the causal association between SUA and IAs using Mendelian randomization (MR) analysis. Methods: We conducted a two-sample MR analysis with SUA as the exposure variable and IAs as the outcome variable. Genome-wide association study (GWAS) datasets for SUA were acquired from the Open GWAS catalog, including 389,404 European and 129,405 East Asian individuals. The dataset for IAs was sourced from a meta-analysis of GWASs comprising 317,636 individuals across different ancestral populations (European: 7495 cases and 71,934 controls; East Asian: 3259 cases and 234,948 controls). The MR analyses were performed according to populations (European and East Asian) and IAs status [unruptured IAs (uIAs) or aneurysmal subarachnoid hemorrhage (aSAH)], respectively. The inverse variance weighted (IVW) method was employed as primary analysis to discern causal estimates. Results: Our findings revealed that an elevated genetically predicted SUA level (mg/dL) correlated with an increased risk of IAs among the European population (OR = 1.29 [95%CI:1.05–1.57], P = 0.013) and East Asian population (OR = 1.56 [95%CI: 1.27–1.92], P

The positive structure belts surrounding the Taibei Sag, Turpan-Hami Basin, have been the main targets for oil and gas exploration for years and are now left with remaining resources scattering in reservoirs adjacent to source rocks in the sag, where the Shuixigou Group with substantial oil and gas potential constitutes the primary focus for near-source exploration. Consequently, characterization of development and key controlling factors of reservoir space becomes a must for future exploration in the area. This study investigates the development traits, genesis, and controlling factors of the Xishanyao and Sangonghe formations in the Shengbei and Qiudong Sub-sags of the Taibei Sag with techniques such as cast thin-section observation, porosity and permeability tests, high-pressure mercury injection, and saturation fluid NMR analysis of reservoir rocks. The findings reveal that the Shuixigou Group in the Taibei Sag consists of lithic sandstone. Reservoirs in the group are mostly poor in terms of physical properties, with undeveloped primary pores dominated by intergranular dissolved pores as a result of a strong compaction. Comparative analysis of key controlling factors of the Sangonghe Formation reveals significant distinctions in sandstone particle size, sand body thickness, genesis and distribution, provenance location, and source rock type between the Qiudong area and Shengbei area. Vertically, the coal seams of the Xishanyao Formation exhibit heightened development with shallower burial depth and lower maturity compared to those of the Sangonghe Formation. Consequently, this environment fosters the formation of organic acids, which have a stronger dissolution effect on minerals to develop secondary dissolution pores, and ultimately resulting in better reservoir physical properties. Overall, the reservoirs within the Qiudong area of the Taibei Sag demonstrate superior characteristics compared to those in the Shengbei area. Furthermore, the reservoir physical properties of the Xishanyao Formation are better than those of the Sangonghe Formation. The research findings will provide valuable guidance for the exploration and development of lithological oil and gas reservoirs within the Taibei Sag.

Abstract Background Kirsten rat sarcoma (KRAS) and mutant KRASG12D have been implicated in human cancers, but it remains unclear whether their activation requires ubiquitination. This study aimed to investigate whether and how F-box and leucine-rich repeat 6 (FBXL6) regulates KRAS and KRASG12D activity in hepatocellular carcinoma (HCC). Methods We constructed transgenic mouse strains LC (LSL-Fbxl6 KI/+ ;Alb-Cre, n = 13), KC (LSL-Kras G12D/+ ;Alb-Cre, n = 10) and KLC (LSL-Kras G12D/+ ;LSL-Fbxl6 KI/+ ;Alb-Cre, n = 12) mice, and then monitored HCC for 320 d. Multiomics approaches and pharmacological inhibitors were used to determine oncogenic signaling in the context of elevated FBXL6 and KRAS activation. Co‑immunoprecipitation (Co-IP), Western blotting, ubiquitination assay and RAS activity detection assay were employed to investigate the underlying molecular mechanism by which FBXL6 activates KRAS. The pathological relevance of the FBXL6/KRAS/extracellular signal-regulated kinase (ERK)/mammalian target of rapamycin (mTOR)/proteins of relevant evolutionary and lymphoid interest domain 2 (PRELID2) axis was evaluated in 129 paired samples from HCC patients. Results FBXL6 is highly expressed in HCC as well as other human cancers (P

Abstract Background With the development of cancer precision medicine, a huge amount of high-dimensional cancer information has rapidly accumulated regarding gene alterations, diseases, therapeutic interventions and various annotations. The information is highly fragmented across multiple different sources, making it highly challenging to effectively utilize and exchange the information. Therefore, it is essential to create a resource platform containing well-aggregated, carefully mined, and easily accessible data for effective knowledge sharing. Methods In this study, we have developed “Consensus Cancer Core” (Tri©DB), a new integrative cancer precision medicine knowledgebase and reporting system by mining and harmonizing multifaceted cancer data sources, and presenting them in a centralized platform with enhanced functionalities for accessibility, annotation and analysis. Results The knowledgebase provides the currently most comprehensive information on cancer precision medicine covering more than 40 annotation entities, many of which are novel and have never been explored previously. Tri©DB offers several unique features: (i) harmonizing the cancer-related information from more than 30 data sources into one integrative platform for easy access; (ii) utilizing a variety of data analysis and graphical tools for enhanced user interaction with the high-dimensional data; (iii) containing a newly developed reporting system for automated annotation and therapy matching for external patient genomic data. Benchmark test indicated that Tri©DB is able to annotate 46% more treatments than two officially recognized resources, oncoKB and MCG. Tri©DB was further shown to have achieved 94.9% concordance with administered treatments in a real clinical trial. Conclusions The novel features and rich functionalities of the new platform will facilitate full access to cancer precision medicine data in one single platform and accommodate the needs of a broad range of researchers not only in translational medicine, but also in basic biomedical research. We believe that it will help to promote knowledge sharing in cancer precision medicine. Tri©DB is freely available at www.biomeddb.org , and is hosted on a cutting-edge technology architecture supporting all major browsers and mobile handsets.

Laminated composites have been extensively researched due to their excellent mechanical properties, but their application in superwetting fields has been rarely reported. In this work, the surfaces with extreme wettability were prepared based on laminated composites. The Ti6Al4V/304 stainless steel (304 SS) micro-laminated composites were fabricated by diffusion bonding the Ti6Al4V foils and 304 SS foils with the thickness of 10–50 μm in vacuum. The typical interfacial microstructure and the effect of diffusion temperature on the microstructure were investigated. The bonded interface of joints is mainly composed of β-Ti, Ti2Ni, FeTi, Fe2Ti, Fe–Cr from the Ti6Al4V side to the 304 SS. The effect of diffusion temperature on the microstructure was researched. Based on the prepared Ti6Al4V/304 SS micro-laminated composites, an array structure with micro grooves was fabricated through the simple chemical etching. The 304 SS foils were etched to form grooves, while Ti6Al4V foils still remained as bulges. Due to surface modification and rough morphology, the etched surfaces exhibited the excellent hydrophobicity. Increasing the width and depth of grooves and decreasing the width of bulges led to the higher water contact angles and improved hydrophobicity. The highest water contact angles of 148.3° has been achieved under the conditions of grooves with a width of 50 μm, a depth of 60 μm, and the bulges with a width of 10 μm. The surfaces exhibited nearly superhydrophobicity and performed self-cleaning property. The processing method of this work could expand the application of laminated composite in extreme wettability fields.

Introduction: CircRNAs are closely related to many human diseases; however, their role in acne remains unclear. This study aimed to determine the role of hsa_circ_0102678 in regulating inflammation of acne. Methods: First, microarray analysis was performed to study the expression of circRNAs in acne. Subsequently, RNase R digestion assay and fluorescence in situ hybridization assay were utilized to confirm the characteristics of hsa_circ_0102678. Finally, qRT-PCR, Western blotting analysis, immunoprecipitation, luciferase reporter assay, circRNA probe pull-down assay, biotin-labeled miRNA pull-down assay, RNA immunoprecipitation assay, and m6A dot blot assay were utilized to reveal the functional roles of hsa_circ_0102678 on inflammation induced by C. acnes biofilm in human primary keratinocytes. Results: Our investigations showed that the expression of hsa_circ_0102678 was significantly decreased in acne tissues, and hsa_circ_0102678 was a type of circRNAs, which was mainly localized in the cytoplasm of primary human keratinocytes. Moreover, hsa_circ_0102678 remarkably affected the expression of IL-8, IL-6, and TNF-α, which induced by C. acnes biofilm. Importantly, mechanistic studies indicated that the YTHDC1 could bind directly to hsa_circ_0102678 and promote the export of N6-methyladenosine-modified hsa_circ_0102678 to the cytoplasm. Besides, hsa_circ_0102678 could bind to miR-146a and sponge miR-146a to promote the expression of IRAK1 and TRAF6. Conclusion: Our findings revealed a previously unknown process by which hsa_circ_0102678 promoted keratinocyte inflammation induced by C. acnes biofilm via regulating miR-146a/TRAF6 and IRAK1 axis.

Recently, the world’s first plasma-propelled drone was successfully flown, demonstrating that plasma propulsion technology is suitable for drone flight. The research on plasma propulsion drones has sparked a surge of interest. This study utilized a proxy model and the NSGA-II multi-objective genetic algorithm to optimize the geometric parameters based on staggered thrusters that affect the performance of electroaerodynamics (EAD) thrusters used for solid-state plasma aircraft. This can help address key issues, such as the thrust density and the thrust-to-power ratio of solid-state plasma aircraft, promoting the widespread application of plasma propulsion drones. An appropriate sample set was established using Latin hypercube sampling, and the thrust and current data were collected using a customized experimental setup. The proxy model employed a genetically optimized Bayesian regularization backpropagation neural network, which was trained to predict the effects of variations in the geometric parameters of the electrode assembly on the performance parameters of the plasma aircraft. Based on this information, the maximum achievable value for a given performance parameter and its corresponding geometric parameters were determined, showing a significant increase compared to the sample data. Finally, the optimal parameter combination was determined by using the NSGA-II multi-objective genetic algorithm and the Analytic Hierarchy Process. These findings can serve as a basis for future researchers in the design of EAD thrusters, helping them produce plasma propulsion drones that better meet specific requirements.

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P 50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.