Search

Abstract Background Immune checkpoint inhibitors (ICIs) have become the recommended first-line treatment for advanced non-small cell lung cancer (NSCLC) without driver gene mutations. However, data on the failure patterns of first-line ICIs monotherapy is limited, and the optimal strategy for subsequent treatment remains controversial. Methods Advanced NSCLC patients receiving first-line ICIs monotherapy at Guangdong Lung Cancer Institute between December 2017 and October 2021 were identified. The progressive sites were recorded to analyze failure patterns. Post-progression survival (PPS) was compared between different treatment regimens. Results A total of 121 patients receiving first-line ICIs monotherapy were identified, with a median progression-free survival of 8.6 months. Sixty-five patients had available imaging at diagnosis as well as progressive disease, with 56.9% showing oligoprogression. For those with progression in existing lesions, the most common sites were the liver (77.8%) and lung parenchyma (62.5%), while progression with new lesions frequently occurred in the liver (32.0%). Fifty patients with recorded subsequent treatment were included in the analysis of subsequent treatment patterns. Patients treated with anti-angiogenesis therapy could get better PPS (HR: 0.275, P = 0.013). Isolated oligoprogression occurred most often in the lung parenchyma and intracranial lesions. More than half of these patients continued immunotherapy after local treatment, with a 2.5-year PPS rate of 51.4%. Conclusion The liver was the most common site of progression on first-line ICIs monotherapy. Anti-angiogenesis-based therapy might be an optimal regimen at the time of progression. Patients with isolated oligoprogressive could still benefit from immunotherapy after local treatment.

Abstract The downregulation of Cadm4 (Cell adhesion molecular 4) is a prominent feature in demyelination diseases, yet, the underlying molecular mechanism remains elusive. Here, we reveal that Cadm4 undergoes specific palmitoylation at cysteine-347 (C347), which is crucial for its stable localization on the plasma membrane (PM). Mutation of C347 to alanine (C347A), blocking palmitoylation, causes Cadm4 internalization from the PM and subsequent degradation. In vivo experiments introducing the C347A mutation (Cadm4-KI) lead to severe myelin abnormalities in the central nervous system (CNS), characterized by loss, demyelination, and hypermyelination. We further identify ZDHHC3 (Zinc finger DHHC-type palmitoyltransferase 3) as the enzyme responsible for catalyzing Cadm4 palmitoylation. Depletion of ZDHHC3 reduces Cadm4 palmitoylation and diminishes its PM localization. Remarkably, genetic deletion of ZDHHC3 results in decreased Cadm4 palmitoylation and defects in CNS myelination, phenocopying the Cadm4-KI mouse model. Consequently, altered Cadm4 palmitoylation impairs neuronal transmission and cognitive behaviors in both Cadm4-KI and ZDHHC3 knockout mice. Importantly, attenuated ZDHHC3-Cadm4 signaling significantly influences neuroinflammation in diverse demyelination diseases. Mechanistically, we demonstrate the predominant expression of Cadm4 in the oligodendrocyte lineage and its potential role in modulating cell differentiation via the WNT-β-Catenin pathway. Together, our findings propose that dysregulated ZDHHC3-Cadm4 signaling contributes to myelin abnormalities, suggesting a common pathological mechanism underlying demyelination diseases associated with neuroinflammation.

Abstract Background There is growing evidence for a relationship between gut microbiota and hepatic encephalopathy (HE). However, the causal nature of the relationship between gut microbiota and HE has not been thoroughly investigated. Method This study utilized the large-scale genome-wide association studies (GWAS) summary statistics to evaluate the causal association between gut microbiota and HE risk. Specifically, two-sample Mendelian randomization (MR) approach was used to identify the causal microbial taxa for HE. The inverse variance weighted (IVW) method was used as the primary MR analysis. Sensitive analyses were performed to validate the robustness of the results. Results The IVW method revealed that the genus Bifidobacterium (OR = 0.363, 95% CI: 0.139-0.943, P = 0.037), the family Bifidobacteriaceae (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039), and the order Bifidobacteriales (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039) were negatively associated with HE. However, no causal relationship was observed among them after the Bonferroni correction test. Neither heterogeneity nor horizontal pleiotropy was found in the sensitivity analysis. Conclusion Our MR study demonstrated a potential causal association between Bifidobacterium, Bifidobacteriaceae, and Bifidobacteriales and HE. This finding may provide new therapeutic targets for patients at risk of HE in the future.

Despite translanguaging pedagogy gaining increasing popularity among researchers, studies on students' perceptions and experiences of translanguaging pedagogy in English for Academic Purposes (EAP) settings in China remain limited. This mixed methods research bridges this gap by shareing the findings of both questionnaires (1008) and follow-up interviews (34) from students enrolled on an EAP course at a Chinese university. Drawing on the concepts of translanguaging and co-learning, the paper reveals that the different translanguaging practices used by the teachers and students (as reported by students) in the EAP classroom helped to enhance student understanding and learning, classroom communication and motivation for learning. However, potential drawbacks are also noted, e.g. in how translanguaging is not conducive for creating a pure English learning environment and can reinforce some students' over-reliance on Chinese. The findings yield important implications for more careful and intentional pedagogical translanguaging design in EAP curriculum planning in China and beyond.

Abstract Purpose This study aimed to investigate clinical diagnostic values of mSEPT9 combined with NLR, PLR and LMR in CRC. Methods 329 subjects composed of 120 CRC patients, 105 polyps patients and 104 healthy participants were prospectively recruited. Clinicopathologic features were collected and analyzed. Plasma samples were collected for mSEPT9, NLR, PLR and LMR test. The sensitivity, specificity and AUC of each biomarker separately or in combination were estimated by the ROC curve. Results The levels of NLR, PLR and the PDR of mSEPT9 in CRC patients were significantly higher than those in non-CRC subjects, while LMR was the opposite. The PDR of mSEPT9 in CRC patients was significantly correlated with age, tumor size, tumor stage and M stage. ROC curve analysis demonstrated moderate diagnostic values of mSEPT9, NLR, PLR and LMR in CRC patients with AUC of 0.78 (Se = 0.68, and Sp = 0.89), 0.78 (Se = 0.68, and Sp = 0.83), 0.80 (Se = 0.68, and Sp = 0.81), and 0.77 (Se = 0.72, and Sp = 0.73), respectively. Moreover, combination of these four biomarkers dramatically enhanced the diagnostic accuracy of CRC (AUC = 0.92, Se = 0.90, and Sp = 0.87), especially for CRC patients with large tumors (AUC = 0.95) or distal metastasis (AUC = 0.95). Conclusion mSEPT9, NLR, PLR and LMR showed the potential to be reliable biomarkers for the diagnosis of CRC. And the combined application of these biomarkers further improved the diagnostic accuracy of CRC significantly.

Abstract Accurate and timely data collection of material deterioration on the surfaces of architectural heritage is crucial for effective conservation and restoration. Traditional methods rely heavily on extensive field surveys and manual feature identification, which are significantly affected by objective conditions and subjective factors. While machine vision-based methods can help address these issues, the accuracy, intelligence, and systematic nature of material deterioration assessment for large-scale masonry towers with complex geometries still require significant improvement. This research focuses on the architectural heritage of masonry towers and proposes an intelligent assessment system that integrates an improved YOLOv8-seg machine vision image segmentation model with refined 3D reconstruction technology. By optimizing the YOLOv8-seg model, the system enhances the extraction capabilities of both detailed and global features of material deterioration in masonry towers. Furthermore, by complementing it with image processing methods for the global visualization of large-scale objects, this research constructs a comprehensive intelligent assessment process that includes "deterioration feature extraction—global visualization—quantitative and qualitative comprehensive assessment." Experimental results demonstrate that the intelligent assessment system significantly improves the performance of target feature extraction for material deterioration in masonry towers compared to existing methods. The improved model shows improvements of 3.39% and 4.55% in the key performance metrics of mAP50 and mAP50-95, respectively, over the baseline model. Additionally, the efficiency of global feature extraction and visualization of material deterioration increased by 66.36%, with an average recognition accuracy of 95.78%. Consequently, this system effectively overcomes the limitations and subjective influences of field surveys, enhancing the objectivity and efficiency of identifying and analyzing material deterioration in masonry towers, and providing invaluable data support for the subsequent preservation and restoration efforts.

AIM: To investigate the morphological characteristics of retinal vessels in patients with different severity of diabetic retinopathy (DR) and in patients with or without diabetic macular edema (DME). METHODS: The 239 eyes of DR patients and 100 eyes of healthy individuals were recruited for the study. The severity of DR patients was graded as mild, moderate and severe non-proliferative diabetic retinopathy (NPDR) according to the international clinical diabetic retinopathy (ICDR) disease severity scale classification, and retinal vascular morphology was quantitatively analyzed in ultra-wide field images using RU-net and transfer learning methods. The presence of DME was determined by optical coherence tomography (OCT), and differences in vascular morphological characteristics were compared between patients with and without DME. RESULTS: Retinal vessel segmentation using RU-net and transfer learning system had an accuracy of 99% and a Dice metric of 0.76. Compared with the healthy group, the DR group had smaller vessel angles (33.68±3.01 vs 37.78±1.60), smaller fractal dimension (Df) values (1.33±0.05 vs 1.41±0.03), less vessel density (1.12±0.44 vs 2.09±0.36) and fewer vascular branches (206.1±88.8 vs 396.5±91.3), all P

Abstract The Taklamakan and Gobi Desert (TGD) region has experienced a pronounced increase in summer precipitation, including high-impact extreme events, over recent decades. Despite identifying large-scale circulation changes as a key driver of the wetting trend, understanding the relative contributions of internal variability and external forcings remains limited. Here, we approach this problem by using a hierarchy of numerical simulations, complemented by diverse statistical analysis tools. Our results offer strong evidence that the atmospheric internal variations primarily drive this observed trend. Specifically, recent changes in the North Atlantic Oscillation have redirected the storm track, leading to increased extratropical storms entering TGD and subsequently more precipitation. A clustering analysis further demonstrates that these linkages predominantly operate at the synoptic scale, with larger contributions from large precipitation events. Our analysis highlights the crucial role of internal variability, in addition to anthropogenic forcing, when seeking a comprehensive understanding of future precipitation trends in TGD.

Mixed matrix membranes (MMMs) could combine the advantages of both polymeric membranes and porous fillers, making them an effective alternative to conventional polymer membranes. However, interfacial incompatibility issues, such as the presence of interfacial voids, hardening of polymer chains, and blockage of micropores by polymers between common MMMs fillers and the polymer matrix, currently limit the gas separation performance of MMMs. Ternary phase MMMs (consisting of a filler, an additive, and a matrix) made by adding a third compound, usually functionalized additives, can overcome the structural problems of binary phase MMMs and positively impact membrane separation performance. This review introduces the structure and fabrication processes for ternary MMMs, categorizes various nanofillers and the third component, and summarizes and analyzes in detail the CO2 separation performance of newly developed ternary MMMs based on both rubbery and glassy polymers. Based on this separation data, the challenges of ternary MMMs are also discussed. Finally, future directions for ternary MMMs are proposed.

Abstract Gene‐editing technology has become a transformative tool for the precise manipulation of biological genomes and holds great significance in the field of animal disease‐resistant breeding. Mastitis, a prevalent disease in animal husbandry, imposes a substantial economic burden on the global dairy industry. In this study, a regulatory sequence gene editing breeding strategy for the successful creation of a gene‐edited dairy (GED) goats with enhanced mastitis resistance using the ISDra2‐TnpB system and dairy goats as the model animal is proposed. This included the targeted integration of an innate inflammatory regulatory sequence (IRS) into the promoter region of the lysozyme (LYZ) gene. Upon Escherichia Coli (E. coli) mammary gland infection, GED goats exhibited increased LYZ expression, showing robust anti‐mastitis capabilities, mitigating PANoptosis activation, and alleviating blood‐milk‐barrier (BMB) damage. Notably, LYZ is highly expressed only in E. coli infection. This study marks the advent of anti‐mastitis gene‐edited animals with exogenous‐free gene expression and demonstrates the feasibility of the gene‐editing strategy proposed in this study. In addition, it provides a novel gene‐editing blueprint for developing disease‐resistant strains, focusing on disease specificity and biosafety while providing a research basis for the widespread application of the ISDra2‐TnpB system.

Abstract Compound warm extremes exert profound impacts on environment, health, and socioeconomics. Yang et al. (2024) indicated a shift or transition from warm‐dry extremes (WDEs), common in non‐ice‐covered areas, to warm‐wet extremes (WWEs) in ice‐covered zones. Utilizing ERA5 reanalysis data, this study determined the duration and frequency of WDEs and WWEs across ice‐covered and non‐ice‐covered regions. A comprehensive analysis uncovers the physical mechanisms responsible for the paradigm differences and attributes them to the weakening of land‐atmosphere interaction caused by ice‐cover, which inhibits soil moisture feedback and reduces the intensity and duration of warm events in ice‐covered areas. Both WDEs and WWEs are associated with high‐pressure systems (HPs). WDEs, situated directly beneath HPs, intensify due to adiabatic warming from subsidence motions. Conversely, WWEs, located beneath the poleward fringes of HPs, emerge from advective warming and moistening associated with poleward intrusions of warm‐moist air.

Zero-knowledge proof (ZKP) is a cryptographic primitive that enables a prover to convince a verifier that a statement is true, without revealing any other information beyond the correctness of the statement itself. Due to its powerful capabilities, its most practical type, called zero-knowledge Succinct Non-interactive ARgument of Knowledge (zkSNARK), has been widely deployed in various privacypreserving applications such as cryptocurrencies and verifiable computation. Although state-of-the-art zkSNARKs are highly efficient for the verifier, the computational overhead for the prover is still orders of magnitude too high to warrant use in many applications. This overhead arises from several time-consuming operations, including large-scale matrix-vector multiplication (MUL), number-theoretic transform (NTT), and especially the multi-scalar multiplication (MSM) which constitutes the largest proportion. Therefore, further efficiency improvements are needed. In this paper, we focus on comprehensive optimization of running time and storage space required by the MSM algorithm on GPUs. Specifically, we propose a novel, modular and adaptive parameter configuration technique—elastic MSM to enable us to adjust the scale of MSM according to our own wishes by performing a corresponding amount of preprocessing. This technique enables us to fully unleash the potential of various efficient parallel MSM algorithms. We have implemented and tested elastic MSM over three prevailing parallel Pippenger algorithms on GPUs. Across various preprocessing space limitations (across various MSM scales), our constructions achieve up to about 1.90×, 1.08× and 1.36× (2.58×, 1.39× and 1.91×) speedup versus three state-of-the-art parallel Pippenger algorithms on GPUs, respectively. From another perspective, elastic MSM could also be regarded as a preprocessing technique over the well-known Pippenger algorithm, which is modular and could be used to accelerate almost all the most advanced parallel Pippenger algorithms on GPUs. Meanwhile, elastic MSM provides an adaptive trade-off between the running time and the extra storage space needed by parallel Pippenger algorithms on GPUs. This is the first preprocessing technique to retain the improved MSM computation brought by preprocessing under varying storage space limitations. Specifically, across various preprocessing space limitations (across various MSM scales), our constructions achieve up to about 192× and 223× (159× and 174×) speedup versus two state-ofthe- art preprocessing parallel Pippenger algorithms on GPUs, respectively.

Background: In-stent neoatherosclerosis (ISNA) is identified as the primary cause of in-stent restenosis (ISR). The systemic immune inflammation index (SII), shows promise for predicting post-percutaneous coronary intervention (PCI) adverse cardiovascular events and is associated with coronary stenosis severity; however, its specific relationship with ISNA remains unclear. This study aimed to investigate the association between the SII and ISNA after drug-eluting stent (DES) implantation. Methods: This cross-sectional study included 195 participants with 195 ISR lesions who underwent optical coherence tomography (OCT)-guided PCI between August 2018 and October 2022. Participants were categorized based on the SII levels into Tertile 1 (SII 751.94, n = 65). Baseline Clinical, angiographic, and OCT characteristics were analyzed. The association of the SII with ISNA and thin-fibroatheroma (TCFA) was investigated using univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of the SII in detecting ISNA and TCFA. Results: Patients in Tertile 3 had a significantly higher incidences of ISNA and TCFA than did those in Tertile 1. Logistic regression analysis revealed the SII is an independent indicator of ISNA and TCFA in ISR lesions (P = 0.045 and P = 0.002, respectively). The areas under the ROC curves for ISNA and TCFA were 0.611 and 0.671, respectively. Conclusion: The SII is associated with ISNA and TCFA and may serve as an independent indicator in patients with ISR.

Summary: Myocardial remodeling (MR) following myocardial infarction (MI) contributes to heart failure. Inflammation is a key determinant in cardiac remodeling, with potential prognostic improvements by inhibiting inflammatory factors. Pattern recognition receptors, including interferon gamma-inducible protein-16 (IFI-16), play significant roles in this process, yet its specific involvement remains underexplored. This study investigates IFI-16’s role in initiating inflammation via the inflammasome and its direct interaction with galectin-3 protein post-MI. Elevated IFI-16 levels were observed in human and rat myocytes and a mouse MI model under hypoxic, nutrient-deprived conditions, correlating with increased inflammation-associated proteins. Suppression of IFI-16/IFI-204 using short hairpin RNA (shRNA) lentivirus or adeno-associated virus decreased inflammatory factor activation, thereby mitigating remodeling and enhancing cardiac function post-MI. Co-immunoprecipitation (coIP) and double-fluorescence staining confirmed IFI-16’s ability to interact directly with galectin-3. These findings underscore IFI-16’s critical role as a pro-inflammatory factor in post-MI MR, suggesting its inhibition as a potential therapeutic strategy.

The Lower Cretaceous Bashijiqike Formation, which is an important gas exploration target in the Kuqa Depression, Tarim Basin, China, is an excellent case illustrating the diagenesis and reservoir property variations of tight sandstone with burial depths ranging from 3500 m to 8000 m. Thus, integrated approaches incorporating thin-section petrographic characterization, mineral morphology and identification, X-ray diffraction analysis, reservoir property tests, and fluid inclusion analysis were applied to investigate the diagenesis and reservoir property variations of Bashijiqike sandstone with different burial depths. The main findings of this study were as follows. (1) Diagenesis of the Bashijiqike sandstone with a burial depth of less than 5000 m was mainly characterized by kaolinite, colloidal quartz, euhedral quartz, and the dissolution of feldspar, whereas diagenesis of the sandstone with a burial depth of more than 5000 m was primarily distinguished by albite, dolomite, calcite, illite, and chlorite. (2) The porosity and permeability rapidly decreased as the burial depth increased within the range of less than 5000 m, while they slowly decreased as the burial depth increased within the range of more than 5000 m, indicating that the reservoir properties have a nonlinear correlation with the burial depths ranging from 3500 m to 8000 m. (3) During the late stage of the Himalayan movement, the enhanced compaction of Bashijiqike sandstone with the increased burial depth resulted in a decrease in the number of intergranular pores, whereas the dissolution of feldspar and quartz led to the formation of secondary pores. Taken together, the findings of this study indicate that the Himalayan movement after the Neogene resulted in burial depth variations with regard to the studied sandstone, which represents the key controlling factor for both its diagenesis and its reservoir properties.

Accurate and effective building energy consumption prediction is an important basis for carrying out energy-saving evaluation and the main basis for building energy-saving optimization design. However, due to the influence of environmental and human factors, energy consumption prediction is often inaccurate. Therefore, this paper presents a building energy consumption prediction model based on an attention mechanism, time convolutional neural (TCN) network fusion, and a bidirectional gated cycle unit (BIGRU). First, t-distributed stochastic neighbor embedding (T-SNE) was used to preprocess the data and extract the key features, and then a BIGRU was employed to acquire past and future data while capturing immediate connections. Then, to catch the long-term dependence, the dataset was partitioned into the TCN network, and the extended sequence was transformed into several short sequences. Consequently, the gradient explosion or vanishing problem is mitigated when the BIGRU handles lengthy sequences while reducing the spatial complexity. Second, the self-attention mechanism was introduced to enhance the model's capability to address data periodicity. The proposed model is superior to the other four models in accuracy, with an mean absolute error of 0.023, an mean-square error of 0.029, and an coefficient of determination of 0.979. Experimental results indicate that T-SNE can significantly improve the model performance, and the accuracy of predictions can be improved by the attention mechanism and the TCN network.

Abstract Background China has implemented policies to make rare diseases more affordable. While previous studies evaluated overall affordability, few have examined affordability differences across regions and disease types. Given the vastness of China and varying medical policies across cities, this study assesses the affordability of rare diseases based on China’s First List of Rare Diseases (CFLRD), National Reimbursement Drug List (NRDL), and outpatient chronic and special disease policies in each prefecture. Method Six rare diseases were selected and the average annual treatment cost of all relevant drugs in NRDL was calculated for each disease. Based on the WHO/HAI standardized approach, the study analyzed 289 cities with outpatient chronic and special disease policies, measured the security levels by the actual reimbursement ratio of Basic Medical Insurance (BMI) and affordability by the ratio of individual expenses after reimbursement to the annual disposable income of urban residents in the province. The security levels and affordability differences across disease types and provinces were analyzed using the Mann-Whitney U test and the K-W test. Result The affordability of rare diseases varied significantly on the disease types and annual treatment cost. Diseases with an annual treatment cost below 100 000 yuan are affordable to all prefectures even with low reimbursement rates, while those with a higher treatment cost were not affordable in at least 80% of prefectures even though the reimbursement ratio is high. The affordability of the same disease varies significantly across provinces and municipalities. Outpatient chronic and special diseases insurance and critical illness insurance, and the inconsistencies between them, result in regional differences. Conclusion Although China has made progress in improving the affordability of rare diseases, significant differences persist between cities and diseases. The study suggests the optimization of the BMI system and explores independent funds and innovative insurance models to enhance the affordability of rare diseases, particularly those with extremely high treatment costs.

Abstract Objective To appraise the quality of guidelines on intravenous iodinated contrast media (ICM) use in patients with kidney disease, and to compare the recommendations among them. Methods We searched four literature databases, eight guideline libraries, and ten homepages of radiological societies to identify English and Chinese guidelines on intravenous ICM use in patients with kidney disease published between January 2018 and June 2023. The quality of the guidelines was assessed with the Scientific, Transparent, and Applicable Rankings (STAR) tool. Results Ten guidelines were included, with a median STAR score of 46.0 (range 28.5–61.5). The guidelines performed well in “Recommendations” domain (31/40, 78%), while poor in “Registry” (0/20, 0%) and “Protocol” domains (0/20, 0%). Nine guidelines recommended estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 as the cutoff for referring patients to discuss the risk-benefit balance of ICM administration. Three guidelines further suggested that patients with an eGFR < 45 mL/min/1.73 m2 and high-risk factors also need referring. Variable recommendations were seen in the acceptable time interval between renal function test and ICM administration, and that between scan and repeated scan. Nine guidelines recommended to use iso-osmolar or low-osmolar ICM, while no consensus has been reached for the dosing of ICM. Nine guidelines supported hydration after ICM use, but their protocols varied. Drugs or blood purification therapy were not recommended as preventative means. Conclusion Guidelines on intravenous ICM use in patients with kidney disease have heterogeneous quality. The scientific societies may consider joint statements on controversial recommendations for variable timing and protocols. Critical relevance statement The heterogeneous quality of guidelines, and their controversial recommendations, leave gaps in workflow timing, dosing, and post-administration hydration protocols of contrast-enhanced CT scans for patients with kidney diseases, calling for more evidence to establish a safer and more practicable workflow. Key points • Guidelines concerning iodinated contrast media use in kidney disease patients vary. • Controversy remains in workflow timing, contrast dosing, and post-administration hydration protocols. • Investigations are encouraged to establish a safer iodinated contrast media use workflow. Graphical Abstract

Hippeastrum, a highly diverse genus in the Amaryllidaceae family, is a valuable ornamental bulbous flowering plant. Somatic embryogenesis (SE) is an efficient method for mass production of Hippeastrum plantlets. Previous studies have been devoted to the in vitro propagation of Hippeastrum, but the SE and its regulatory networks are rarely reported. In this study, we established a direct SE method of Hippeastrum ‘Bangkok Rose’ using leaf bases as explants. MS supplemented with 1.00 mg · L−1 NAA +1.00 mg · L−1 KT + 0.25 mg · L−1 TDZ was the optimal medium for SE. Histological observations showed that the bipolar somatic embryo originated from the epidermal cell layer and underwent initiation, globular, scutellar and coleoptile stages. During SE, endogenous hormones of IAA, CTK, ABA, and SA were highly accumulated. Transcriptomic analysis revealed the genes encoding auxin biosynthesis/metabolic enzymes and efflux carriers were induced, while the auxin receptor of TIR1 and ARF transcriptional repressor of Aux/IAA were down-regulated and up-regulated, respectively, leading to suppression of auxin signaling. In contrast, cytokine signaling was promoted at the early stage of SE, as biosynthesis, transport, and signaling components were up-regulated. Various stress-related genes were up-regulated at the early or late stages of SE. Chromatin remodeling could also be dynamically regulated via distinct expression enzymes that control histone methylation and acetylation during SE. Moreover, key SE regulators, including WOXs and SERKs were highly expressed along with SE. Overall, the present study provides insights into the SE regulatory mechanisms of the Hippeastrum.

Abstract Implant-associated infections due to the formation of bacterial biofilms pose a serious threat in medical healthcare, which needs effective therapeutic methods. Here, we propose a multifunctional nanoreactor by spatiotemporal ultrasound-driven tandem catalysis to amplify the efficacy of sonodynamic and chemodynamic therapy. By combining piezoelectric barium titanate with polydopamine and copper, the ultrasound-activated piezo-hot carriers transfer easily to copper by polydopamine. It boosts reactive oxygen species production by piezoelectrics, and facilitates the interconversion between Cu2+ and Cu+ to promote hydroxyl radical generation via Cu+ -catalyzed chemodynamic reactions. Finally, the elevated reactive oxygen species cause bacterial membrane structure loosening and DNA damage. Transcriptomics and metabolomics analysis reveal that intracellular copper overload restricts the tricarboxylic acid cycle, promoting bacterial cuproptosis-like death. Therefore, the polyetherketoneketone scaffold engineered with the designed nanoreactor shows excellent antibacterial performance with ultrasound stimulation and promotes angiogenesis and osteogenesis on-demand in vivo.

ABSTRACTMetabolism reprogramming within the tumor microenvironment (TME) can have a profound impact on immune cells. Identifying the association between metabolic phenotypes and immune cells in lung adenocarcinoma (LUAD) may reveal mechanisms of resistance to immune checkpoint inhibitors (ICIs). Metabolic phenotypes were classified by expression of metabolic genes. Somatic mutations and transcriptomic features were compared across the different metabolic phenotypes. The metabolic phenotype of LUAD is predominantly determined by reductase-oxidative activity and is divided into two categories: redoxhigh LUAD and redoxlow LUAD. Genetically, redoxhigh LUAD is mainly driven by mutations in KEAP1, STK11, NRF2, or SMARCA4. These mutations are more prevalent in redoxhigh LUAD (72.5%) compared to redoxlow LUAD (17.4%), whereas EGFR mutations are more common in redoxlow LUAD (19.0% vs. 0.7%). Single-cell RNA profiling of pre-treatment and post-treatment samples from patients receiving neoadjuvant chemoimmunotherapy revealed that tissue-resident memory CD8+ T cells are responders to ICIs. However, these cells are significantly reduced in redoxhigh LUAD. The redoxhigh phenotype is primarily attributed to tumor cells and is positively associated with mTORC1 signaling. LUAD with the redoxhigh phenotype demonstrates a lower response rate (39.1% vs. 70.8%, p = 0.001), shorter progression-free survival (3.3 vs. 14.6 months, p = 0.004), and overall survival (12.1 vs. 31.2 months, p = 0.022) when treated with ICIs. The redoxhigh phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs.

Abstract Combinatorial optimization (CO) has a broad range of applications in various fields, including operations research, computer science, and artificial intelligence. However, many of these problems are classified as nondeterministic polynomial‐time (NP)‐complete or NP‐hard problems, which are known for their computational complexity and cannot be solved in polynomial time on traditional digital computers. To address this challenge, continuous‐time Ising machine solvers have been developed, utilizing different physical principles to map CO problems to ground state finding. However, most Ising machine prototypes operate at speeds comparable to digital hardware and rely on binarizing node states, resulting in increased system complexity and further limiting operating speed. To tackle these issues, a novel device‐algorithm co‐design method is proposed for fast sub‐optimal solution finding with low hardware complexity. On the device side, a piezoelectric lithium niobate (LiNbO3) microelectromechanical system (MEMS) oscillator network‐based Ising machine without second‐harmonic injection locking (SHIL) is devised to solve Max‐cut and graph coloring problems. The LiNbO3 oscillator operates at speeds greater than 9 GHz, making it one of the fastest oscillatory Ising machines. System‐wise, an innovative grouping method is used that achieves a performance guarantee of 0.878 for Max‐cut and 0.658 for graph coloring problems, which is comparable to Ising machines that utilize binarization.

Background: Research on intrahepatic cholestasis of pregnancy (ICP) has recently gained attention. However, no bibliometric analysis was performed in the ICP research field. Therefore, the present study aimed to use bibliometric analysis to analyze the current research hotspots and identify global research status in ICP to reference for future research directions. Methods: We comprehensively searched the Web of Science Core Collection (WoSCC) database from its inception to December 31, 2023. Articles and reviews related to ICP were downloaded as plain text file records. We used the VOSviewer and Citespace to perform the bibliometric analysis and visualization. The main bibliometric features were tabulated and calculated. Results: A total of 1092 documents, including 921 original articles and 171 reviews, were identified in WoSCC. These publications were published in 395 journals by 4751 authors from 1250 institutions and 61 countries/regions. The global publication numbers exhibited a gradual upward trend. China, the United States, and the United Kingdom were top contributors to scientific research on ICP. King's College London, London Imperial Coll Sci Technol & Med, and Sichuan University were the most productive institutions. Catherine Williamson had published the most papers and received the most total citations. The most productive journal was Journal of Maternal-Fetal & Neonatal Medicine. The most cited paper was Beuers et al. in the Journal of Hepatology (2009). Citation burst terms showed that “risk factors” and “perinatal outcomes” were hotspots. “Inflammation”, “risk factors”, “perinatal outcomes”, and “bile acid” have gained attention in more recent research. Conclusion: The present study comprehensively summarizes the global research status and research trends in ICP. Our study identifies hotspots, collaborative networks, and trends that will provide new insights and guidance for further research in the field.

In this study odour-less additive were added to modify the asphalt properties in order to reduce the asphalt flue gas produced during the application process.Three different brands of No. 70 asphalt were chosen as the base asphalt and different dosages of odour-less additive were added to prepare the odour-less asphalt. The effect of the odour-less additive on VOCs, CO, H2S, NO and SO2 were tested by a portable detector to determine the optimal dosage. Then, a gas chromatography was adopted to further analyze the effect of odour-less additive on the compounds in the VOCs. SEM was used to investigate the mechanism of odour-less asphalt. Finally, the effect of odour-less additive on the basic performance of asphalt and on the road performance of asphalt mixtures were analyzed. Research results indicate that the optimal dosage of odour-less additive for No.70 asphalt is 0.04%; The odour-less ratio of the total emissions of the five gases can reach up to 52.9%; Crude oil and the processing technology exert relative huge influence on the concentration of VOCs and the higher the concentration of the compound, the better the odour-less effect, and the odour-less ratio of ethanethiol can reach up to 73.7%. The odour-less asphalt inhibits the volatilization of small molecular substances by increasing the specific surface area of asphalt and improving the inter-molecular cohesion, thereby achieving the purpose of reducing asphalt flue gas; odour-less additive yields little effect on the performance of asphalt and asphalt mixtures.

Background: Tracheoesophageal fistula (TEF) remains a rare but significant clinical challenge, mainly due to the absence of established, effective treatment approaches. The current focus of therapeutic strategy is mainly on fistula closure. However, this approach often misses important factors, such as accelerating fistula contraction and fostering healing processes, which significantly increases the risk of disease recurrence. Methods: In order to investigate if Mesenchymal Stem Cells (MSCs) can enhance fistula repair, developed a TEF model in beagles. Dynamic changes in fistula diameter were monitored by endoscopy. Concurrently, we created a model of LPS-induced macrophage to replicate the inflammatory milieu typical in TEF. In addition, the effect of MSC supernatant on inflammation mitigation was evaluated. Furthermore, we looked at the role of TLR4/NF-κB pathway plays in the healing process. Results: Our research revealed that the local administration of MSCs significantly accelerated the fistula's healing process. This was demonstrated by a decline in TEF apoptosis and decrease in the production of pro-inflammatory cytokines. Furthermore, in vivo experiments demonstrated that the MSC supernatant was effective in suppressing pro-inflammatory cytokine expression and alleviating apoptosis in LPS-induced macrophages. These therapeutic effects were mainly caused by the suppression of TLR4/NF-κB pathway. Conclusion: According to this study, MSCs can significantly improve TEF recovery. They achieve this via modulating apoptosis and inflammatory responses, mainly by selectively inhibiting the TLR4/NF-κB pathway.

Summary: Bronchoscopic-assisted discrimination of lung tumors presents challenges, especially in cases with contraindications or inaccessible lesions. Through meta-analysis and validation using the HumanMethylation450 database, this study identified methylation markers for molecular discrimination in lung tumors and designed a sequencing panel. DNA samples from 118 bronchial washing fluid (BWF) specimens underwent enrichment via multiplex PCR before targeted methylation sequencing. The Recursive Feature Elimination Cross-Validation and deep neural network algorithm established the CanDo classification model, which incorporated 11 methylation features (including 8 specific to the TBR1 gene), demonstrating a sensitivity of 98.6% and specificity of 97.8%. In contrast, bronchoscopic rapid on-site evaluation (bronchoscopic-ROSE) had lower sensitivity (87.7%) and specificity (80%). Further validation in 33 individuals confirmed CanDo’s discriminatory potential, particularly in challenging cases for bronchoscopic-ROSE due to pathological complexity. CanDo serves as a valuable complement to bronchoscopy for the discriminatory diagnosis and stratified management of lung tumors utilizing BWF specimens.

Abstract Background Total joint replacement for osteoarthritis is one of the most successful surgical procedures in modern medicine. However, aseptic loosening continues to be a leading cause of revision arthroplasty. The diagnosis of aseptic loosening remains a challenge as patients are often asymptomatic until the late stages. MicroRNA (miRNA) has been demonstrated to be a useful diagnostic tool and has been successfully used in the diagnosis of other diseases. We aimed to identify differentially expressed miRNA in the plasma of patients with aseptic loosening. Methods Adult patients undergoing revision arthroplasty for aseptic loosening and age- and gender-matched controls were recruited. Samples of bone, tissue and blood were collected, and RNA sequencing was performed in 24 patients with aseptic loosening and 26 controls. Differentially expressed miRNA in plasma was matched to differentially expressed mRNA in periprosthetic bone and tissue. Western blot was used to validate protein expression. Results Seven miRNA was differentially expressed in the plasma of patients with osteolysis (logFC >|2|, adj-P |2|, adj-P

Abstract The pathogenesis of allergic asthma is similar to that of allergic rhinitis, with inflammation cells producing and releasing inflammatory mediators and cytokines closely related to CCR3.Based on the theory of "one airway, one disease", the use of CCR3 monoclonal antibody may have a similar effect on allergic rhinitis. However, there are few studies on CCR3 monoclonal antibody in allergic rhinitis. Therefore, the aim of this study was to investigate the effective concentration of CCR3 monoclonal antibody, to compare the effects of different methods of administration, and to examine the lung condition of allergic mice to investigate whether antibody treatment protects the lungs. In this study, we constructed a mouse model of allergic rhinitis and intraperitoneally injected different doses of CCR3 monoclonal antibody (5, 10, and 20 uL/mg) to observe its therapeutic effect: observing changes in tissue morphology of nasal mucosa, infiltration of inflammation, and using ELISA to detect changes in relevant inflammatory mediators and cytokines, studying the role of CCR3 mAb in inhibiting CCR3-related actions on the nasal mucosa of allergic rhinitis mice. Furthermore, In addition, the therapeutic effects of intraperitoneal injection (i.p.) and intranasal administration (i.n.) were studied on the basis of effective concentrations.

This paper attempts to develop a unified model predictive control (MPC) method for integrated path planning and trajectory tracking of autonomous underwater vehicles (AUVs). To deal with the computational burden of online path planning, an event-triggered model predictive control (EMPC) method is introduced by using the environmental change as a triggering mechanism. A collision hazard function utilizing the changing rate of hazard as a triggering threshold is proposed to guarantee safety. We further give an illustration of how to calculate this threshold. Then, a Lyapunov-based model predictive control (LMPC) framework is developed for the AUV to solve the trajectory tracking problem. Leveraging a nonlinear integral sliding mode control strategy, we construct the contraction constraint within the formulated LMPC framework, thereby theoretically ensuring closed-loop stability. We derive the necessary and sufficient conditions for recursive feasibility, which are subsequently used to prove the closed-loop stability of the system. In the simulations, the proposed path planning and tracking control are verified separately and integrated and combined with static and dynamic obstacles.

ABSTRACT CONTEXT: Scrub typhus, caused by Orientia tsutsugamushi, has a wide range of clinical manifestations, including meningoencephalitis, acute renal failure, pneumonitis, myocarditis, and septic shock. However, there are no documented cases of scrub typhus with hypokalemia. In this report, we present a case of scrub typhus with hypokalemia and multiple organ failure syndrome, highlighting the importance of electrolyte imbalance in patients with scrub typhus. CASE REPORT: A 59-year-old woman presented to the emergency department with abdominal pain that had been present for 1 day. On admission, the physical examination and laboratory test results indicated that the patient had renal, liver, and circulatory failure, and hypokalemia. She developed meningitis and disseminated intravascular coagulation during hospitalization. She recovered with appropriate management, and was discharged on day 17. CONCLUSION: This report highlights the potential for atypical presentations of scrub typhus, including a previously undocumented association with hypokalemia. Although the contribution of hypokalemia to the patient’s clinical course remains uncertain, this case underscores the importance of considering electrolyte imbalance in the management of patients with scrub typhus. Further research is warranted to better understand the relationship between scrub typhus and electrolyte imbalance.

This study aimed to investigate whether and how nighttime warming (NW) influences the copper (Cu) bioaccumulation of wheat (Triticum aestivum L.) under Cu pollution. We examined plant growth, Cu concentration, and antioxidant enzymes of wheat after 6 months of Cu exposure (0, 100, 400, and 800 mg/kg) under NW. The results indicated that, NW of 1.54°C significantly promoted Cu translocation from root to shoot through an increasing root system under increased Cu treatments (p < 0.05). The Cu contents of grains were significantly increased by NW under 800 mg/kg Cu treatment (p < 0.05). NW decreased superoxide dismutase (SOD) activity under increased Cu treatments (p < 0.05). There were significantly negative correlations between biomass and Cu concentrations of the same part under NW (p < 0.05). The root biomass significantly increased by 51% in NW compared with nonnighttime warming (CK) (p < 0.05). These results provided evidence that wheat might respond to NW by altering their roots so that they were larger, thinner, and longer, suggesting that soil Cu translocation from root to shoot would be accelerated resulting from the expanded roots under elevated temperatures, and thus forewarned the food safety risks of climate change in agricultural ecosystem.

In this paper, we introduce a multi-modal sensor fusion system designed for biomedical engineering, specifically geared toward optimizing physical training by collecting detailed body movement data. This system employs inertial measurement units, flex sensors, electromyography sensors, and Microsoft's Kinect V2 to generate an in-depth analysis of an individual's physical performance. We incorporate a gated recurrent unit- recurrent neural network algorithm to achieve highly accurate body and hand motion estimation, thus surpassing the performance of traditional machine learning algorithms in terms of accuracy, precision, recall, and F1 score. The system's integration with the PICO 4 VR environment creates a rich, interactive experience for physical training. Unlike conventional motion capture systems, our sensor fusion system is not limited to a fixed workspace, allowing users to engage in exercise within a flexible, free-form environment.

Abstract Background The unilaterally extrapedicular approach is adopted increasingly to perform balloon kyphoplasty in treating osteoporotic lumbar fractures, which is intended to improve radiological and clinical efficacy. We compared the efficacy and safety of this method with a unilaterally transpedicular approach. Methods We conducted a single-center, randomized controlled trial enrolling participants with a one-level osteoporotic lumbar fracture in less than 1 month. Patients were randomly assigned to undergo kyphoplasty via either a unilaterally extrapedicular approach (treatment group) or a unilaterally transpedicular approach (control group). The primary outcome was the difference in change from baseline to 1 month in visual analog scale (VAS) scores between the two groups. Secondary outcome measures included vertebral height ratio, operation time, fluoroscopic times, hemoglobin loss, and cement leakage between groups. Data were analyzed by intention to treat principle. Results A total of 80 participants were assigned to the treatment group (n = 40) and control group (n = 40), with three and two patients lost to follow-up during 12 months in the two groups, respectively. At 1 month postoperatively, the treatment group showed a greater reduction in VAS score from baseline, compared with the control group (mean difference between groups = 0.63, 95%CI 0.19–1.06). There were no significant between-group differences in restoration in anterior, middle, and posterior vertebral body (P > 0.05). No significant differences were found in the rate of cement leakage and perioperative hemoglobin loss (P > 0.05). Conclusion Compared with balloon kyphoplasty via the unilaterally transpedicular approach in treating lumbar OVCFs, the unilaterally extrapedicular approach appears to be promising in achieving effective pain relief, adequate cement infusion, short operation time, less fluoroscopy exposure, and comparable risk of cement leakage and vessel injury. It is an alternative approach for lumbar OVCFs treated with kyphoplasty.

Abstract It remains a major challenge to attribute heatwave’s lifecycle characteristics quantitatively to interwoven atmospheric and surface actions. By constructing a process-resolving, energetics-based attribution framework, here we quantitatively delineate the lifecycle of the record-breaking 2022 mega-heatwave over central-eastern China from a local energetics perspective. It is found that the cloudlessness induced radiative heating and atmospheric dynamics dominate the total energy buildup during the developing stage, while the land-atmosphere coupling and atmospheric horizontal advection act most effectively to sustain and terminate the heatwave, respectively. A reduction in anthropogenic aerosols provides a persistent positive contribution during the event, suggesting that pollution mitigation measures may actually increase the amplitudes of future heatwaves. With this framework, initial efforts are made to unravel culprits in a model’s sub-seasonal prediction of this mega-heatwave, demonstrating the framework’s potential for efficiently detecting the origins of climate extremes and quantitatively assessing the impacts of mitigation policies for sustainable development.

Anchor cable tension relaxation with time is a typical problem in the prestressed anchor cable structure used to reinforce slopes. In order to reasonably predict the tension relaxation of anchor cable, based on the interaction among the stable layer, anchor cable, slide mass and constraint components on the slope face in the anchor cable-slope system and the basic loading and deformation mechanism of the anchorage system, a four-body series rheological model composed of anchor cable, slide bed, slide body, and constraint components is established, in which the anchor cable and constraint components are simulated with Hooke body, the slide mass is simulated with Kelvin body or generalized Kelvin body, and the stable layer is simulated with generalized Kelvin body. The calculation equation of the anchor cable tension relaxation is accordingly derived. Some examples show that the error between the proposed value of cable tension relaxation and the observed results is smaller than those using the existing calculation methods. The maximum error of cable tension relaxation convergence value using the proposed method is about 11%, and the maximum error of the relaxation duration is about 10%. The relaxation rate of the anchor cable tension increases linearly with the diameter and elastic modulus of the anchor cable, and decreases nonlinearly with the increasing anchor hole spacing, the hysteresis elastic modulus and the viscosity coefficient (particularly in the initial stage) of the stable layer and slide mass. The instantaneous elastic modulus of the stable layer and the slide mass as well as the elastic modulus of the constraint components have little effect on the tension relaxation of the anchor cable. The proposed method can be used to quantitatively evaluate the anchor tension relaxation of slopes reinforced with prestressed anchor cables in practical engineering, which naturally allows to analyze the long-term stability of the anchored slopes.

Abstract Background To investigate the prevalence of euthyroid sick syndrome (ESS) and to evaluate the outcomes and risk factors associated with ESS among hospitalized patients with diabetic ketosis (DK) or diabetic ketoacidosis (DKA). Methods Laboratory and clinical data of 396 adult hospitalized DK/DKA patients with or without ESS were collected and analyzed. Spearman linear analysis and multivariable logistic regression analyses were used to evaluate correlated factors of thyroid hormones and risk factors of ESS. Results Most of the individuals were diagnosed with type 2 diabetes (359/396, 90.7%). The prevalence of ESS was 57.8% (229/396). Patients in ESS group were older and had a longer course of diabetes. Levels of thyroid hormones, serum lipids, and parameters reflecting acidosis were significantly decreased in ESS group. The proportion of patients with infection, acute renal injury and DKA was significantly higher in ESS group than in control group, accompanied by longer hospitalization stay and higher hospitalization costs. Free triiodothyronine positively correlates with albumin, eGFR, parameters reflecting acidosis and lipid profiles (All P

A new type of generator, a transgenerator, is introduced, which integrates the wind turbine and flywheel into one system, aiming to make flywheel-distributed energy storage (FDES) more modular and scalable than the conventional FDES. The transgenerator is a three-member dual-mechanical-port (DMP) machine with two rotating members (inner and outer rotors) and one stationary member (stator). The transgenerator–flywheel system is introduced with its configuration, transgenerator overview, flywheel operation principle and power management strategies, and control system. Simulations are performed in MATLAB 2023b/Simulink to verify the system viability, including control system verification and flywheel storage performance evaluation. The results show that the inner and outer rotors can be controlled independently with an accurate and fast control response, and the grid-side control works properly. The flywheel performs well, with considerable charging power and storage capacity.

Partial discharge (PD) is a localized discharge phenomenon in the insulator of electrical equipment resulting from the electric field strength exceeding the local dielectric breakdown electric field. Partial-discharge signal identification is an important means of assessing the insulation status of electrical equipment and critical to the safe operation of electrical equipment. The identification effect of traditional methods is not ideal because the PD signal collected is subject to strong noise interference. To overcome noise interference, quickly and accurately identify PD signals, and eliminate potential safety hazards, this study proposes a PD signal identification method based on multiscale feature fusion. The method improves identification efficiency through the multiscale feature fusion and feature aggregation of phase-resolved partial-discharge (PRPD) diagrams by using PMSNet. The whole network consists of three parts: a CNN backbone composed of a multiscale feature fusion pyramid, a down-sampling feature enhancement (DSFB) module for each layer of the pyramid to acquire features from different layers, a Transformer encoder module dominated by a spatial interaction–attention mechanism to enhance subspace feature interactions, a final categorized feature recognition method for the PRPD maps and a final classification feature generation module (F-Collect). PMSNet improves recognition accuracy by 10% compared with traditional high-frequency current detection methods and current pulse detection methods. On the PRPD dataset, the validation accuracy of PMSNet is above 80%, the validation loss is about 0.3%, and the training accuracy exceeds 85%. Experimental results show that the use of PMSNet can greatly improve the recognition accuracy and robustness of PD signals and has good practicality and application prospects.