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In this study, Aermet100 high-strength steel was fabricated using laser powder bed fusion (LPBF) technology. The influence of various process parameters on the surface quality and relative density of the samples was systematically examined. Additionally, the effects of the heat treatment process on the microstructure and mechanical properties of the material was investigated. The results indicate that the specimens were well-formed, achieving a relative density of 99.99% through an optimal combination of process parameters: a laser power of 220 W, scanning speed of 1000 mm/s, scanning rotation of 67°, and hatch spacing of 0.07 mm.The additively manufactured Aermet100 specimens exhibited ultrafine grains with an average size of 0.4 μm. Tempering of the as-built specimens at 482 °C for 2 h resulted in the highest strength and hardness. Grain refinement is identified as the primary factor contributing to the excellent combination of strength and ductility. Moreover, precipitation of secondary strengthening phases is attributed to hindering the movement of dislocations. The combined effects of fine grain strengthening, dislocation strengthening, and precipitation strengthening ultimately result in significant improvements in strength, reaching a maximum of 2064 MPa and an elongation of 8%.

Abstract Intervertebral disc degeneration (IDD), osteoarthritis (OA), and osteoporosis (OP) are common musculoskeletal disorders (MSDs) with similar age-related risk factors, representing the leading causes of disability. However, successful therapeutic development and translation have been hampered by the lack of clinically-relevant animal models. In this study, we investigated the potential suitability of the tree shrew, a small mammal with a close genetic relationship to primates, as a new animal model for MSDs. Age-related spontaneous IDD in parallel with a gradual disappearance of notochordal cells were commonly observed in tree shrews upon skeletal maturity with no sex differences, while age-related osteoporotic changes including bone loss in the metaphyses were primarily presented in aged females, similar to observations in humans. Moreover, in the osteochondral defect model, tree shrew cartilage exhibited behavior similar to that of humans, characterized by a more restricted self-healing capacity compared to the rapid spontaneous healing of joint surfaces observed in rats. The induced OA model in tree shrews was highly efficient and reproducible, characterized by gradual deterioration of articular cartilage, recapitulating the human OA phenotype to some degree. Surgery-induced IDD models were successfully established in tree shrews, in which the lumbar spine instability model developed slow progressive disc degeneration with more similarity to the clinical state, whereas the needle puncture model led to the rapid development of IDD with more severe symptoms. Taken together, our findings pave the way for the development of the tree shrew as a new animal model for the study of MSDs and aging.

Abstract Antivortices have potential applications in future nano-functional devices, yet the formation of isolated antivortices traditionally requires nanoscale dimensions and near-zero magnetocrystalline anisotropy, limiting their broader application. Here, we propose an approach to forming antivortices in multiferroic ε-Fe2O3 with the coalescence of misaligned grains. By leveraging misaligned crystal domains, the large magnetocrystalline anisotropy energy is counterbalanced, thereby stabilizing the ground state of the antivortex. This method overcomes the traditional difficulty of observing isolated antivortices in micron-sized samples. Stable isolated antivortices were observed in truncated triangular multiferroic ε-Fe2O3 polycrystals ranging from 2.9 to 16.7 µm. Furthermore, the unpredictability of the polarity of the core was utilized as a source of entropy for designing physically unclonable functions. Our findings expand the range of antivortex materials into the multiferroic perovskite oxides and provide a potential opportunity for ferroelectric polarization control of antivortices.

Abstract Introduction Cardiac arrest (CA), characterized by its heterogeneity, poses challenges in patient management. This study aimed to identify clinical subphenotypes in CA patients to aid in patient classification, prognosis assessment, and treatment decision-making. Methods For this study, comprehensive data were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) 2.0 database. We excluded patients under 18 years old, those not initially admitted to the intensive care unit (ICU), or treated in the ICU for less than 72 h. A total of 57 clinical parameters relevant to CA patients were selected for analysis. These included demographic data, vital signs, and laboratory parameters. After an extensive literature review and expert consultations, key factors such as temperature (T), sodium (Na), creatinine (CR), glucose (GLU), heart rate (HR), PaO2/FiO2 ratio (P/F), hemoglobin (HB), mean arterial pressure (MAP), platelets (PLT), and white blood cell count (WBC) were identified as the most significant for cluster analysis. Consensus cluster analysis was utilized to examine the mean values of these routine clinical parameters within the first 24 h post-ICU admission to categorize patient classes. Furthermore, in-hospital and 28-day mortality rates of patients across different CA subphenotypes were assessed using multivariate logistic and Cox regression analysis. Results After applying exclusion criteria, 719 CA patients were included in the study, with a median age of 67.22 years (IQR: 55.50-79.34), of whom 63.28% were male. The analysis delineated two distinct subphenotypes: Subphenotype 1 (SP1) and Subphenotype 2 (SP2). Compared to SP1, patients in SP2 exhibited significantly higher levels of P/F, HB, MAP, PLT, and Na, but lower levels of T, HR, GLU, WBC, and CR. SP2 patients had a notably higher in-hospital mortality rate compared to SP1 (53.01% for SP2 vs. 39.36% for SP1, P

Background: The tendon or ligament is attached to the bone by a triphasic but continuous area of heterogeneous tissue called the tendon-bone interface (TBI). The rapid and functional regeneration of TBI is challenging owing to its complex composition and difficulty in self-healing. The development of new technologies, such as decellularization, has shown promise in the regeneration of TBI. Several ex vivo and in vivo studies have shown that decellularized grafts and decellularized biomaterial scaffolds achieved better efficacy in enhancing TBI healing. However further information on the type of review that is available is needed. Aim of the review: In this review, we discuss the current application of decellularization biomaterials in promoting TBI healing and the possible mechanisms involved. With this work, we would like to reveal how tissues or biomaterials that have been decellularized can improve tendon-bone healing and to provide a theoretical basis for future related studies. Key scientific concepts of the review: Decellularization is an emerging technology that utilizes various chemical, enzymatic and/or physical strategies to remove cellular components from tissues while retaining the structure and composition of the extracellular matrix (ECM). After decellularization, the cellular components of the tissue that cause an immune response are removed, while various biologically active biofactors are retained. This review further explores how tissues or biomaterials that have been decellularized improve TBI healing.

This paper proposes a method for floor plan designs that combines shape grammar with Building Information Modeling (BIM) technology to create plan module libraries by using the mass modular housing project in ShanLiChenJia village as an example. The modular building is composed of several component modules, and shape grammar can manipulate their graphics and functions to enrich the combination relationship between component modules. The rule-making of the combination process can code the size relationship that affects the module form by adding space and size constraints. In the rule system of shape grammar, geometric dimensions, and functional attributes are first embedded in the shape graph. Then, the mapping relationship is established between the shape graph and the attributes of the modules. Finally, the BIM platform can establish the module library using Autodesk Revit. In addition, a spatial relationship in the scheme is selected in Revit software for generative experiments, which confirms the feasibility of shape grammar in generative design and spatial diversity of modular buildings.

Abstract Reinforced concrete (RC) slabs are widely used in modern building structures due to their superior properties and ease of construction. However, their mechanical properties are limited by their punching shear strength in the connection region with the columns. Researchers have attempted to add steel reinforcement in the form of studs and randomly distributed fibers to concrete slabs to improve the punching strength. An additional strengthening method that consists of the application is a Fiber-Reinforced Polymer (FRP). However, current codes poorly calculate the punching shear strength of FRP-RC slabs. The aim of this study is to create a robust model that can accurately predict its punching shear strength, thus improving the analysis and design of composite structures with FRP-RC slabs. In this study, 189 sets of experimental data were collected and expanded using kernel density estimation (KDE), considering the small amount of data. Secondly, a punching shear strength prediction model for FRP-RC panels was constructed using XGBoost and compared with the model modeled by codes and researchers. Finally, a model explainability study was conducted using SHapley additive exPlanations (SHAP). The results show that kernel density estimation significantly improves the robustness and accuracy of XGBoost. The R-squared, standard deviation, and root mean square error of XGBoost on the training set are 0.99, 0.001, and 0.001, respectively. On the test set, the R-squared, standard deviation, and root mean square error are 0.96, 62.687, and 67.484, respectively. The effective depth of the FRP-RC slabs is the most important and proportional to the punching shear strength. This study can provide guidance for the design of FRP-RC slabs.

Abstract Background Coronary artery disease (CAD) has become a dominant economic and health burden worldwide, and the role of autophagy in CAD requires further clarification. In this study, we comprehensively revealed the association between autophagy flux and CAD from multiple hierarchies. We explored autophagy-associated long noncoding RNA (lncRNA) and the mechanisms underlying oxidative stress-induced human coronary artery endothelial cells (HCAECs) injury. Methods (1) Autophagy-related proteins including LC3, p62, Beclin1, ATG5, and ATG7 were immunohistochemical stained in coronary specimens; (2) The levels and function of autophagy in the HCAEC oxidative stress model were evaluated using western blot (WB), transmission electron microscopy (TEM), and mRFP-GFP-LC3 adenovirus transfection experiments; (3) The competing endogenous RNA (ceRNA) network of lncRNA LUCAT1/hsa-miR-6776-5p/LRRC25 axis was constructed and validated; (4) The expression levels of above autophagy-related RNAs in peripheral blood mononuclear cells (PBMCs) were verified by qPCR, and their diagnostic performance was subsequently analyzed using receiver operating characteristic (ROC) analysis. Results (1) The expression of LC3, Beclin1, ATG5, and ATG7 demonstrated a consistent decline whereas p62 expression exhibited an opposite increase as atherosclerosis progressed; (2) Autophagy levels was significantly elevated in HCAECs under oxidative stress, while inhibition of the initial stage of autophagy with 3-MA exacerbated cellular damage; (3) The lncRNA LUCAT1/hsa-miR-6776-5p/LRRC25 axis was established through bioinformatic prediction and validated by dual-luciferase reporter assay, which resulted in a significant decrease in autophagy levels in HCAECs; (4) In total, p62, ATG7, lncRNA LUCAT1 and LRRC25 were validated as robust diagnostic biomarkers for CAD. Conclusions Our results delineated the dynamic disruption of the autophagy landscape during the progression of human coronary atherosclerosis and identified the lncRNA LUCAT1/hsa-miR-6776-5p/LRRC25 axis, uncovered through transcriptomic profiling, as a protective mechanism against endothelial cell injury through autophagy activation. Furthermore, we recognized p62, ATG7, lncRNA LUCAT1, and LRRC25 as dependable autophagy-related diagnostic biomarkers in circulating PBMCs, correlating with CAD severity. Collectively, Our findings furnish novel insights into the intricate autophagy landscape at various levels of coronary atherosclerosis and propose potential diagnostic biomarkers, and a theoretical foundation for managing CAD patients.

Background and Aim: Machine learning based on clinical data and treatment protocols for better clinical decision-making is a current research hotspot. This study aimed to build a machine learning model on washed microbiota transplantation (WMT) for ulcerative colitis (UC), providing patients and clinicians with a new evaluation system to optimize clinical decision-making.MethodsPatients with UC who underwent WMT via mid-gut or colonic delivery route at an affiliated hospital of Nanjing Medical University from April 2013 to June 2022 were recruited. Model ensembles based on the clinical indicators were constructed by machine-learning to predict the clinical response of WMT after one month.ResultsA total of 366 patients were enrolled in this study, with 210 patients allocated for training and internal validation, and 156 patients for external validation. The low level of indirect bilirubin, activated antithrombin III, defecation frequency and cholinesterase and the elderly and high level of creatine kinase, HCO3- and thrombin time were related to the clinical response of WMT at one month. Besides, the voting ensembles exhibited an area under curve (AUC) of 0.769 ± 0.019 [accuracy, 0.754; F1-score, 0.845] in the internal validation; the AUC of the external validation was 0.614 ± 0.017 [accuracy, 0.801; F1-score, 0.887]. Additionally, the model was available at https://wmtpredict.streamlit.app.ConclusionsThis study pioneered the development of a machine learning model to predict the one-month clinical response of WMT on UC. The findings demonstrate the potential value of machine learning applications in the field of WMT, opening new avenues for personalized treatment strategies in gastrointestinal disorders.Trial registrationclinical trials, NCT01790061. Registered 09 February 2013 - Retrospectively registered, https://clinicaltrials.gov/study/NCT01790061

Compared with PELE with inert fillings such as polyethylene and nylon, reactive PELE (RPELE) shows excellent damage effects when impacting concrete targets due to the filling deflagration reaction. In present work, an analytical model describing the jacket deformation and concrete target damage impacted by RPELE was presented, in which the radial rarefaction and filling deflagration reaction were considered. The impact tests of RPELE on concrete target in the 592–1012 m/s were carried out to verify the analytical model. Based on the analytical model, the angle-length evolution mechanism of the jacket bending-curling deformation was revealed, and the concrete target damage was further analyzed. One can find out that the average prediction errors of the front crater, opening and back crater are 6.8%, 8.5% and 7.1%, respectively. Moreover, the effects of radial rarefaction and deflagration were discussed. It was found that the neglect of radial rarefaction overestimates the jacket deformation and concrete target damage, while the deflagration reaction of filling increases the diameter of the front crater, opening and back crater by 25.4%, 24.3% and 31.1%, respectively. The research provides a valuable reference for understanding and predicting the jacket deformation and concrete target damage impacted by RPELE.

Abstract We theoretically study the Goos-Hänchen (GH) and Imbert–Fedorov (IF) shifts of a reflected Gaussian beam from a hyperbolic metasurface composed of graphene grating based on topological insulators (TIs). Perturbations are generated on the surface of TIs by applying a thin magnetic film, resulting in a broken time-reversal symmetry. The GH and IF shifts are greatly enhanced as a result of the combined interaction of the graphene grating and the topological magnetoelectric effect (TME). In particular, even with the p-polarized incident beam near Brewster angles, the magnitude of IF shifts is increased by approximately two orders when compared to the case without graphene or a single layer of graphene. A critical frequency is identified when the propagation model in TIs transitions from a surface wave to a bulk wave, which leads to comparatively substantial GH shifts with high reflection. By adjusting the filling ratio, chemical potential and rotation angle of the graphene grating, the shift of GH and IF can be controlled. The dependence of the spatial shifts on the TME and the degree of anisotropy of the TI are also discussed. Our results may provide new possibilities for applications of the TI with the TME.

Abstract Distributing quantum entanglement between distant parties is a significant but difficult task in quantum information science, as it can enable numerous applications but suffers from exponential decay in the quantum channel. Quantum repeaters are one of the most promising approaches towards this goal. In a quantum repeater protocol, it is essential that the entanglement generation speed within each elementary link is faster than the memory decoherence rate, and this stringent requirement has not been implemented over a fiber of metropolitan scale so far. As a step towards this challenging goal, in this work we experimentally realize multiplexing-enhanced generation of heralded atom-photon quantum correlation over a 12 km fiber. We successively generate 280 pairs of atom-photon quantum correlations with a train of photonic time-bin pulses filling the long fiber, and read out the excited memory modes on demand with either fixed or variable storage time after successful heralding. With the multiplexing enhancement, the heralding rate of atom-photon correlation can reach 1.95 kHz, and the ratio between the quantum correlation generation rate to memory decoherence rate can be improved to 0.46 for a fiber length of 12 km. This work therefore constitutes an important step towards the realization of a large-scale quantum repeater network.

As a basic pathological feature at advanced stage of various kidney diseases, renal fibrosis (RF) is an important cause of kidney failure. It is characterized by an excessive accumulation of extracellular matrix (ECM), damage of renal tissue structure and loss of renal function. Regulated cell death (RCD) is closely correlated with RF since it involves a signaling cascade involving effector molecules. This review summarized the mechanism of RCD involved in the progression of RF and provided references for clinical treatment of RF.

A detrimental feedback loop between hypoxia and oxidative stress consistently drives macrophage polarization toward a pro-inflammatory M1 phenotype, thus persistently aggravating rheumatoid arthritis (RA) progression. Herein, an enzyme-catalyzed nanoplatform with synergistic hypoxia-relieving and reactive oxygen species (ROS)-scavenging properties was developed using bovine serum albumin-bilirubin-platinum nanoparticles (BSA-BR-Pt NPs). Bilirubin was employed to eliminate ROS, while platinum exhibited a synergistic effect in scavenging ROS and simultaneously generated oxygen. In mice RA model, BSA-BR-Pt NPs treatment exhibited superior effects, resulting in significant improvements in joint inflammation, cartilage damage, and bone erosion, compared to methotrexate, the most widely used antirheumatic drug. Mechanistically, RNA-sequencing data and experimental results elucidated that BSA-BR-Pt NPs induced a re-polarization of hypoxic M1 macrophages to M2 macrophages via switching glycolysis to oxidative phosphorylation through the inhibition of HIF-1α pathway. Collectively, this research for the first time elaborated the underlying mechanism of enzyme-catalyzed nanoplatform in orchestrating macrophage polarization, and identified a novel therapeutic strategy for RA and other inflammatory disorders.

Abstract To investigate the diagnostic value of intraoperative cytology and rapid immunocytochemistry in primary central nervous system lymphoma. 254 cases of lymphoma and 82 cases of non-lymphoma were collected from 2010 to 2023. Frozen section(FS) was using alone in 44 cases during 2010–2014, FS and intraoperative cytology(IC) were using in 251 cases during 2015 to 2022. Rapid immunocytochemical(RICC, CD20, GFAP) were using with FS + IC in 41 cases during 2021 to 2023. Method One: According to the results of archives, statistic the diagnostic accuracy of lymphoma during three time periods. Method Two: All cases were randomly renumbered, 4 neuropathologists compared the accuracy of independent histology and that of combining cytology. The archives showed the diagnostic accuracy of FS in PCNSL was 77.27%, FS + IC was 86.06%, FS + IC + RICC was 92.68%. The retrospective study demonstrated the diagnostic accuracy of FS was 79.76%, FS + IC was 87.33% and FS + IC + RICC was 92.68%. The positive predictive value, negative predictive value, sensitivity, specificity and accuracy of CD20 were 100%, 76.92%, 90.32%, 100% and 92.68%, respectively. The results of the paired χ2 test was no statistically significant difference (0.05

Abstract Ligand-protected metal nanoclusters provide an ideal platform for investigating photoredox catalysis. The central challenge is balancing their stability and catalytic activity. Here we show a photochemical reduction–oxidation cascade method for synthesizing an Au8Cu6 nanocluster, which features a robust structure and active surface. Photoredox catalytic activity of Au8Cu6 is developed for the functionalization of alkynes under oxidative conditions. Mechanism studies based on the precise structure reveal the catalytic process of the Au8Cu6 nanocluster. Oxidant-dependent selectivity of Au8Cu6 catalysis is developed for chemodivergent synthesis of mono- and di-functionalized products in high efficiency. The results will stimulate more research on metal nanocluster synthesis and catalysis.

Li metal batteries (LMBs) with LiNi0.8Mn0.1Co0.1O2 (NMC811) cathodes could release a specific energy of >500 Wh kg−1 by increasing the charge voltage. However, high-nickel cathodes working at high voltages accelerate degradations in bulk and at interfaces, thus significantly degrading the cycling lifespan and decreasing the specific capacity. Here, we rationally design an all-fluorinated electrolyte with addictive tri(2,2,2-trifluoroethyl) borate (TFEB), based on 3, 3, 3-fluoroethylmethylcarbonate (FEMC) and fluoroethylene carbonate (FEC), which enables stable cycling of high nickel cathode (LiNi0.8Co0.1Mn0.1O2, NMC811) under a cut-off voltage of 4.7 V in Li metal batteries. The electrolyte not only shows the fire-extinguishing properties, but also inhibits the transition metal dissolution, the gas production, side reactions on the cathode side. Therefore, the NMC811||Li cell demonstrates excellent performance by using limited Li and high-loading cathode, delivering a specific capacity >220 mA h g−1, an average Coulombic efficiency >99.6% and capacity retention >99.7% over 100 cycles.

This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5–59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8–31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.

Abstract Background This study aimed to explore the clinical value of 3D video-assisted thoracoscopic surgery in dissecting recurrent laryngeal nerve lymph nodes in patients undergoing minimally invasive esophagectomy. Methods A retrospective cohort study was conducted on 205 patients, including 120 males, who underwent esophagectomy from May 2018 to May 2020 in the Department of Thoracic Surgery at the Affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University. Perioperative parameters, including intraoperative blood loss, operation time, the number of dissected recurrent laryngeal nerve lymph nodes, the incidence and degree of postoperative recurrent laryngeal nerve injury, the volume of postoperative thoracic drainage, and postoperative complications, were compared between the 3D and 2D groups. Results There were no significant differences in the preoperative baseline data between these two groups (P > 0.05). The number of dissected recurrent laryngeal nerve lymph nodes in the 3D group was significantly higher than in the 2D group (P

Abstract Objective To investigate the structural abnormalities, genetic results, and postnatal clinical outcomes of fetuses with bovine aortic arch (Bovine Aortic Arch, BAA) to provide a basis for prenatal counseling and management. Methods A retrospective analysis was conducted on 216 fetuses diagnosed with bovine aortic arch through prenatal ultrasound screening at the First Affiliated Hospital of Anhui Medical University and the No.901 Hospital of the Joint Service of the People’s Liberation Army from January 2019 to February 2023. Their family history of genetic diseases, prenatal screening results, and postnatal follow-up data were collected. The fetuses were divided into an isolated BAA group (n = 192) and a non-isolated BAA group (n = 24). Chromosomal karyotyping and copy number variation (CNV) testing were conducted, and statistical analysis was performed using SPSS 22.0 software. Results Of the 216 fetuses with BAA, 192 were isolated BAA (88.89%), and 24 were non-isolated BAA (11.11%). Among the isolated BAA fetuses, only 1 case (0.52%) had chromosomal karyotype and pathogenic CNV abnormalities. Among the non-isolated BAA fetuses, 4 cases (16.67%) had chromosomal or CNV abnormalities, but the overall risk was low. The postnatal outcomes of isolated BAA fetuses were good (99.48%), while 79.17% of non-isolated BAA fetuses had good postnatal outcomes. Conclusion Most BAA fetuses are isolated, with a very low incidence of chromosomal abnormalities and pathogenic CNVs, and have good postnatal outcomes. The clinical value of isolated BAA is limited, and invasive prenatal diagnosis is not recommended for low-risk populations. Prenatal screening should focus on the risk of concurrent severe structural anomalies and chromosomal abnormalities.

The prediction of slope stability is considered as one of the critical concerns in geotechnical engineering. Conventional stochastic analysis with spatially variable slopes is time-consuming and highly computation-demanding. To assess the slope stability problems with a more desirable computational effort, many machine learning (ML) algorithms have been proposed. However, most ML-based techniques require that the training data must be in the same feature space and have the same distribution, and the model may need to be rebuilt when the spatial distribution changes. This paper presents a new ML-based algorithm, which combines the principal component analysis (PCA)-based neural network (NN) and transfer learning (TL) techniques (i.e. PCA–NN–TL) to conduct the stability analysis of slopes with different spatial distributions. The Monte Carlo coupled with finite element simulation is first conducted for data acquisition considering the spatial variability of cohesive strength or friction angle of soils from eight slopes with the same geometry. The PCA method is incorporated into the neural network algorithm (i.e. PCA-NN) to increase the computational efficiency by reducing the input variables. It is found that the PCA-NN algorithm performs well in improving the prediction of slope stability for a given slope in terms of the computational accuracy and computational effort when compared with the other two algorithms (i.e. NN and decision trees, DT). Furthermore, the PCA–NN–TL algorithm shows great potential in assessing the stability of slope even with fewer training data.

Abstract DNA methylation plays a significant role in regulating transcription and exhibits a systematic change with age. These changes can be used to predict an individual’s age. First, to identify methylation sites associated with biological age; second, to construct a biological age prediction model and preliminarily explore the biological significance of methylation-associated genes using machine learning. A biological age prediction model was constructed using human methylation data through data preprocessing, feature selection procedures, statistical analysis, and machine learning techniques. Subsequently, 15 methylation data sets were subjected to in-depth analysis using SHAP, GO enrichment, and KEGG analysis. XGBoost, LightGBM, and CatBoost identified 15 groups of methylation sites associated with biological age. The cg23995914 locus was identified as the most significant contributor to predicting biological age by calculating SHAP values. Furthermore, GO enrichment and KEGG analyses were employed to initially explore the methylated loci’s biological significance.

Abstract Background The aim of this study was to elucidate the critical role of autophagy-related gene aggregation in gastric cancer tumor microenvironment cells and to investigate their major roles in cellular functions. In particular, the expression of these genes in tumor-associated fibroblast subtypes was scrutinized in an attempt to explain their cell-subpopulation-specific roles in cell–cell communication and regulation of cellular functions. Methods In this study, single-cell RNA sequencing data were first analyzed in multiple steps, including data preprocessing, cell clustering, and cell classification. Cell subpopulations and gene expression patterns were identified and analyzed using unsupervised non-negative matrix factorization (NMF) techniques. The dynamic expression of autophagy-related gene aggregates in various cell types was deciphered by pseudotime trajectory analysis (PTA). Intercellular communication analysis was performed using the CellChat R software package, revealing the intricate communication patterns and exchange of key signaling molecules between cell subpopulations, and SCENIC analysis was used to identify gene regulatory networks and reveal the mechanisms behind cellular heterogeneity. Result Cell subpopulations associated with pan-apoptosis were identified by NMF decomposition and SCENIC analysis. Cell–cell communication analysis revealed intricate communication patterns and exchange of key signaling molecules between cell subpopulations. Dynamic expression of autophagy-related genes aggregated in the pseudotemporal trajectory of STAD was observed by PTA. In the fibroblast subtype, different ligand-receptor interactions and their key roles in immunomodulation were observed. Conclusion By deeply analyzing and comparing gene expression patterns within cellular subpopulations and intercellular communication, this study provides new insights into the role of pan-apoptosis-related genes in regulating immune responses and cellular functions in gastric cancer. These findings pave the way for further exploration of the role of these genes in tumorigenesis and immune regulation, as well as laying the foundation for potential therapeutic strategies.

Abstract Metamaterials are defined as artificially designed micro-architectures with unusual physical properties, including optical, electromagnetic, mechanical, and thermal characteristics. This study investigates the compressive mechanical and heat transfer properties of AlSi10Mg gradient metamaterials fabricated by Laser Powder Bed Fusion (LPBF). The morphology of the AlSi10Mg metamaterials was examined using an ultrahigh-resolution microscope. Quasi-static uniaxial compression tests were conducted at room temperature, with deformation behavior captured through camera recordings. The findings indicate that the proposed gradient metamaterial exhibits superior compressive strength properties and energy absorption capacity. The Gradient-SplitP structure demonstrated better compressive performance compared to other strut-based structures, including Gradient-Gyroid and Gradient-Lidinoid structures. With an apparent density of 0.796, the Gradient-SplitP structure exhibited an outstanding energy absorption capacity, reaching an impressive 23.57 MJ/m3. In addition, heat conductivity tests were performed to assess the thermal resistance of these structures with different cell configurations. The gradient metamaterials exhibited higher thermal resistance and lower thermal conductivity. Consequently, the designed gradient metamaterials can be considered valuable in various applications, such as thermal management, load-bearing, and energy absorption components.

Abstract Accurate detection of asphalt pavement distress is crucial for road maintenance and traffic safety. However, traditional convolutional neural networks usually struggle with this task due to the varied distress patterns and complex background in the images. To enhance the accuracy of asphalt pavement distress identification across various scenarios, this paper introduces an improved model named SMG-YOLOv8, based on the YOLOv8s framework. This model integrates the space-to-depth module and the multi-scale convolutional attention mechanism, while optimizing the backbone’s C2f structure with a more efficient G-GhostC2f structure. Experimental results demonstrate that SMG-YOLOv8 outperforms the YOLOv8s baseline model, achieving P macro and mAP50 scores of 81.1% and 79.4% respectively, marking an increase of 8.2% and 12.5% over the baseline. Furthermore, SMG-YOLOv8 exhibits clear advantages in identifying various types of pavement distresses, including longitudinal cracks, transverse cracks, mesh cracks, and potholes, when compared to YOLOv5n, YOLOv5s, YOLOv6s, YOLOv8n, and SSD models. This enhancement optimizes the network structure, reducing the number of parameters while maintaining excellent detection performance. In real-world scenarios, the SMG-YOLOv8 model, when applied to image data collected from projects, achieves a P macro of 80.5% and an R macro of 86.2%. This result demonstrates its excellent generalization capability and practicality. The model provides significant technical support for the intelligent detection of pavement distress.

Abstract Background The urinary albumin to creatinine ratio (UACR) is associated with adverse cardiovascular outcomes, even when within the normal range. However, the potential modification of this effect by metabolic abnormalities remains unclear. This study explored whether metabolic abnormalities modify the association between normal-range UACR and cardiovascular mortality. Methods This cohort study included 27,298 U.S. adults from the National Health and Nutrition Examination Survey 1999–2018, with mortality follow-up through December 31, 2019. Normal UACR (

Immunotherapy is an important cancer treatment method that offers hope for curing cancer patients. While immunotherapy has achieved initial success, a major obstacle to its widespread adoption is the inability to benefit the majority of patients. The success or failure of immunotherapy is closely linked to the tumor's immune microenvironment. Recently, there has been significant attention on strategies to regulate the tumor immune microenvironment in order to stimulate anti-tumor immune responses in cancer immunotherapy. The distinctive physical properties and design flexibility of nanomedicines have been extensively utilized to target immune cells (including tumor-associated macrophages (TAMs), T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated fibroblasts (TAFs)), offering promising advancements in cancer immunotherapy. In this article, we have reviewed treatment strategies aimed at targeting various immune cells to regulate the tumor immune microenvironment. The focus is on cancer immunotherapy models that are based on nanomedicines, with the goal of inducing or enhancing anti-tumor immune responses to improve immunotherapy. It is worth noting that combining cancer immunotherapy with other treatments, such as chemotherapy, radiotherapy, and photodynamic therapy, can maximize the therapeutic effects. Finally, we have identified the challenges that nanotechnology-mediated immunotherapy needs to overcome in order to design more effective nanosystems.

Abstract Primary central nervous system lymphoma (PCNSL) is a rare and frequently fatal lymphoma subtype. The programmed death-1 (PD-1) pathway has emerged as a potential therapeutic target, but the effectiveness of PD-1 antibody sintilimab in combination with immunochemotherapy as a frontline treatment for PCNSL remains to be determined. In this phase 2 trial (ChiCTR1900027433) with a safety run-in, we included patients aged 18–70 with newly diagnosed PCNSL. Participants underwent six 21-day cycles of a SMTR regimen, which includes sintilimab (200 mg, Day 0), rituximab (375 mg/m2, Day 0), methotrexate (3.0 g/m2, Day 1 or 1.0 g/m2 for patients aged ≥65 years), and temozolomide (150 mg/m2/d, Days 1–5). Among 27 evaluable patients, the overall response rate (ORR) was 96.3% (95% confidence interval: 81–99.9%), with 25 complete responses. At a median follow-up of 24.4 months, the medians for duration of response, progression-free survival (PFS), and overall survival were not reached. The most common grade 3–4 treatment-related toxicities were increased levels of alanine aminotransferase (17.9%) and aspartate aminotransferase (14.3%). Additionally, baseline levels of interferon-α and the IL10/IL6 ratio in cerebrospinal fluid emerged as potential predictors of PFS, achieving areas under the curve of 0.88 and 0.84, respectively, at 2 years. Whole-exome sequencing revealed a higher prevalence of RTK-RAS and PI3K pathway mutations in the durable clinical benefit group, while a greater frequency of Notch and Hippo pathway mutations in the no durable benefit group. These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL, warranting further investigation.

Abstract Simultaneously improving the activity and stability of catalysts for anodic oxygen evolution reaction (OER) in proton exchange membrane water electrolysis (PEMWE) remains a notable challenge. Here, we report a chromium-doped ruthenium dioxide with oxygen vacancies, termed Cr0.2Ru0.8O2-x, that drives OER with an overpotential of 170 mV at 10 mA cm−2 and operates stably over 2000 h in acidic media. Experimental and theoretical studies show that the synergy of Cr dopant and oxygen vacancy induces an unconventional dopant-mediated hydroxyl spillover mechanism. Such dynamic hydroxyl spillover from Cr dopant to Ru active site changes the rate-determining step from OOH* formation to O2 formation and thus greatly improves the OER performance. Moreover, the Cr dopant and oxygen vacancy also play a crucial role in stabilizing surface Ru and lattice oxygen in the Ru-O-Cr structural motif. When assembled into the anode of a practical PEMWE device, Cr0.2Ru0.8O2-x enables long-term durability of over 200 h at an ampere-level current density and 60 degrees centigrade.

Abstract Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise.

Abstract Background The intricate interplay between genetics and immunology often dictates the host’s susceptibility to various diseases. This study explored the genetic causal relationship between natural killer (NK) cell-related traits and the risk of infection. Methods Single-nucleotide polymorphisms (SNPs) significantly associated with NK cell-related traits were selected as instrumental variables to estimate their genetic causal effects on infection. SNPs from a genome-wide association study (GWAS) on NK cell-related traits, including absolute cell counts, median fluorescence intensities reflecting surface antigen levels, and relative cell counts, were used as exposure instruments. Summary-level GWAS statistics of four phenotypes of infection were used as the outcome data. The exposure and outcome data were analyzed via the two-sample Mendelian randomization method. Results Each one standard deviation increase in the expression level of human leukocyte antigen (HLA)-DR on HLA-DR+ NK cells was associated with a lower risk of pneumonia (P

Abstract Background Multi-rooted teeth with extensive dental defects often face challenges in stability and biomechanical failure. High-performance polymer PEEK materials, with properties closer to dentin, show promise in reducing stress concentration and preserving tooth structure. This report aimed to explore the use of a highly retentive polyetheretherketone (PEEK) for manufacturing custom-made split post and core for the restoration of grossly destroyed endodontically treated molars. Clinical considerations A 40-year-old female patient presented with complaints of loss of tooth substance in the posterior mandibular tooth. This case involved the digital design and fabrication of PEEK split post and core to restore multirooted molar with insufficient dental tissue remnants. The restorations were evaluated over a 3-year follow-up using the World Federation criteria (FDI). The restoration was clinically evaluated through intraoral examination, radiographic assessment, and subjective patient satisfaction, and was deemed clinically good according to FDI criteria. Conclusion The outstanding mechanical properties of PEEK, coupled with the structure of the split post, provide an effective treatment option for weakened multirooted teeth. Simultaneously, the restoration configuration effectively addressed the challenge of varying postinsertion directions, and the interlocking mechanism between the primary and auxiliary posts enhanced the stability of the post and core.

Abstract Background Patients with severe community-acquired pneumonia (sCAP) admitted to the intensive care unit (ICU) often exhibit muscle catabolism, muscle weakness, and/or atrophy, all related to an increased morbidity and mortality. However, the relationship between thoracic skeletal muscle mass and sCAP-related mortality has not been well-studied. Early recognition of sarcopenia in ICU patients with sCAP would benefit their prognosis. Methods A retrospective study was conducted in Taizhou Hospital of Zhejiang Province, involving 101 patients with sCAP admitted in the ICU between December 2022 and February 2023. We measured the cross-sectional aera of the pectoralis, intercostal, paraspinal, serratus, and latissimus muscles at the T4 vertebral level (T4CSA) using chest computed tomography. Discriminatory thresholds were established by performing receiver operating characteristic curve analysis, with a designated cutoff value of 96.75 cm2 for male patients. This cohort was classified into mortality and survival groups based on a 6-month post-admission outcome. Univariate and multifactorial logistic regression analyses were performed to validate the correlation between low thoracic skeletal muscle area and prognostic outcomes. Results The mean age of the patients was 75.39 ± 12.09 years, with an overall 6-month mortality of 73.27%. T4CSA of the 6-month survival group was significantly larger than that in the mortality group for overall cohort. The T4CSA in the survival group was significantly larger than that in the mortality group (104.29 ± 23.98cm2 vs. 87.44 ± 23.0cm2, p = 0.008). T4CSA predicted the 6-month mortality from sCAP in males with an AUC of 0.722 (95% confidence interval (CI), 0.582–0.861). The specificity and sensitivity were 71.4% and 71.1%, respectively, (p

Abstract Background Long non-coding RNAs (LncRNAs) have been implicated as critical regulators of cancer tumorigenesis and progression. However, their functions and molecular mechanisms in colorectal cancer (CRC) still remain to be further elucidated. Methods LINC00460 was identified by differential analysis between human CRC and normal tissues and verified by in situ hybridization (ISH) and qRT-PCR. We investigated the biological functions of LINC00460 in CRC by in vitro and in vivo experiments. We predicted the mechanism and downstream functional molecules of LINC00460 by bioinformatics analysis, and confirmed them by dual luciferase reporter gene assay, RNA immunoprecipitation (RIP), RNA pull-down, etc. Results LINC00460 was found to be significantly overexpressed in CRC and associated with poor prognosis. Overexpression of LINC00460 promoted CRC cell immune escape and remodeled a suppressive tumor immune microenvironment, thereby promoting CRC proliferation and metastasis. Mechanistic studies showed that LINC00460 served as a molecular sponge for miR-186-3p, and then promoted the expressions of MYC, CD47 and PD-L1 to facilitate CRC cell immune escape. We also demonstrated that MYC upregulated LINC00460 expression at the transcriptional level and formed a positive feedback loop. Conclusions The LINC00460/miR-186-3p/MYC feedback loop promotes CRC cell immune escape and subsequently facilitates CRC proliferation and metastasis. Our findings provide novel insight into LINC00460 as a CRC immune regulator, and provide a potential therapeutic target for CRC patients.

Abstract Background The chronic digestive condition gallstones is quite common around the world, the development of which is closely related to oxidative stress, inflammatory response and abnormalities of lipid metabolism. In the last few years, as a novel biomarker of lipid metabolism, the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) has garnered significant interest. However, its relationship with gallstones has not been studied yet. Methods 3,772 people, all under 50, were included in this study, and their full data came from the National Health and Nutrition Examination Survey (NHANES) database for the years 2017–2020. Information on gallstones was obtained through self-reported questionnaires. Smoothed curve fitting multifactorial logistic regression was utilized to evaluate the connection of NHHR with gallstone formation incidence. Subsequently, subgroup analysis and interaction tests were applied. Finally, to create a prediction model, logistic regression and feature screening by last absolute shrinkage and selection operator (LASSO) were used. The resulting model was displayed using a nomogram. Results In multivariate logistic regression that accounted for all factors, there was a 77% increase in the likelihood of gallstones for every unit rise in lnNHHR (OR 1.77 [CI 1.11–2.83]). Following NHHR stratification, the Q4 NHHR level was substantially more linked to the risk of gallstones than the Q1 level (OR 1.86 [CI 1.04–3.32]). This correlation was stronger in women, people under 35, smokers, abstainers from alcohol, non-Hispanic White people, those with excessively high cholesterol, people with COPD, and people without diabetes. After feature screening, a predictive model and visualized nomogram for gallstones were constructed with an AUC of 0.785 (CI 0.745–0.819), which was assessed by DCA to be clinically important. Conclusion In the group of people ≤ 50 years of age, elevated NHHR levels were substantially linked to a higher incidence of gallstones. This correlation was stronger in several specific groups such as females, under 35 years of age, smokers, and so on. Predictive models constructed using the NHHR have potential clinical value in assessing gallstone formation.

Abstract Background Leigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear. Methods Two unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants. Results We reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells. Conclusion Our results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.

Abstract Tripartite motif-containing 24 (TRIM24), also known as transcriptional intermediary factor 1α (TIF1α), is the founding member of TIF1 family. Recent evidence indicates that aberrant expression of TRIM24, functions as an oncogene, is associated with poor prognosis across various cancer types. TRIM24 exhibits a multifaceted structure comprising an N-terminal TRIM region with a RING domain, B-box type 1 and type 2 domains, and a coiled-coil region, as well as a C-terminal plant-homeodomain (PHD)-bromodomain. The bromodomain serves as a ‘reader’ of epigenetic histone marks, regulating chromatin structure and gene expression by linking associated proteins to acetylated nucleosomal targets, thereby controlling transcription of genes. Notably, bromodomains have emerged as compelling targets for cancer therapeutic development. In addition, TRIM24 plays specialized roles as a signal transduction molecule, orchestrating various cellular signaling cascades in cancer cells. Herein, we review the recent advancements in understanding the functions of TRIM24, and demonstrate the research progress in utilizing TRIM24 as a target for cancer therapy.

In order to enhance the driving ability of autonomous vehicles on structured roads and enable them to plan safe and comfortable paths, we propose an obstacle avoidance path strategy for autonomous vehicles based on genetic algorithm. The use of Frenet-Serret enhances the adaptability of the algorithm in complex environments. In order to improve the generation and optimisation of obstacle avoidance trajectory, we establish an anti-collision model. When the vehicle faces a potential collision with an obstacle, the genetic algorithm quickly iterates and selects the first nine genes to generate the rough solution and convex space of the path. Combined with convex space, the quadratic programming method will numerically optimise the generated rough solution to generate an accurate path that satisfies the constraints. In addition, in order to ensure the safety and comfort in the process of obstacle avoidance, based on the dynamic constraints of the vehicle, the speed planning is used to determine the speed curve. We simulate in various scenarios involving moving obstacles. The real-time simulation based on the HIL platform proves that the proposed path planning strategy is effective in various driving scenarios.

Abstract Epstein-Barr virus (EBV) related post-transplant lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), for which no standard therapeutic means have been developed. Significant increase expression of natural killer group 2 member D ligands (NKG2DLs) was observed on B-lymphoblastoid cells of EBV-PTLD, indicating NKG2DLs as potential therapeutic targets for treatment of EBV-PTLD. In this study, the recombinant constructs of NKG2D CAR and IL-15/IL-15Rα-NKG2D CAR were generated with a retroviral vector and then transduced to human T cells to produce NKG2D CAR-T and IL-15/IL-15Rα-NKG2D CAR-T cells, respectively. B-lymphoblastoid cell lines (B-LCLs) and the xenografted mouse models were established to evaluate the efficacy of these CAR-T cells. IL-15/IL-15Rα-NKG2D CAR-T cells exhibited superior proliferation and antigen-specific cytotoxic effect compared to NKG2D CAR-T, as IL-15/IL-15Rα signaling promoted the expansion of less differentiated central memory T cells (TCM) and increased expression of CD107a and IFN-γ. Moreover, EBV DNA load was dramatically reduced, and 80% B-LCL cells were eliminated by IL-15/IL-15Rα-NKG2D CAR-T cells after co-culturing. In-vivo study confirmed that IL-15/IL-15Rα-NKG2D CAR-T cell therapy significantly enhanced antiviral efficacy in mice, as the serum load of EBV after IL-15/IL-15Rα-NKG2D CAR-T cell infusion was 1500 times lower than the untreated control (P

Ampakines are a class of orally available positive allosteric modulators of the AMPA-glutamate receptor (AMPAR) and have therapeutic implications for neurological/neuropsychiatric disorders in which AMPAR signaling is compromised. Low-impact ampakines are a distinct subclass of drugs that only modestly offset receptor desensitization and do not alter agonist binding affinity and thus lack the neurotoxicity and epileptogenic effects associated with other AMPAR modulators. In these studies, we describe the pre-clinical pharmacology of ampakine 1-(benzofurazan-5-ylcarbonyl)morpholine (CX717). CX717 modestly offsets desensitization in hippocampal patches and augments synaptic transmission in vivo. CX717 also enhances long-term potentiation in rats, which is crucial for learning and memory. CX717 enhances performance in the eight-arm radial maze and abrogates amphetamine-induced locomotor activity while being devoid of cataleptic activity in rats. CX717 also ameliorates alfentanil-induced respiratory depression in rats and is not toxic to cultured rat neurons. CX717 is active at doses of 0.3–10 mg/kg and lacked serious adverse events in safety studies in mice up to 2000 mg/kg. CX717 was also previously shown to be safe in humans and effective in reversing opiate-induced respiratory depression and hyperactivity and inattentiveness in adults with ADHD. These findings support the continued clinical investigation of CX717 in the treatment of ADHD, dementia, and opiate-induced respiratory depression.

BackgroundAbnormal thyroid hormone levels may occur in critical illness, which may have an interactive relationship with inflammatory reaction. At present, the relationship between triiodothyronine (T3)/thyroxine (T4) ratio and inflammatory indicators and all-cause mortality of stroke survivors is still unclear.MethodsWe obtained the relevant data of the respondents from 2007 to 2012 through the National Health and Nutrition Examination Survey (NHANES) database for statistical analysis. The ratio of T3/T4, a continuous variable, is transformed into three groups of classified variables, namely Q1, Q2 and Q3. The relationship between T3/T4 ratio and mortality was analyzed by Log-Rank test and K-M survival curve. Pearson correlation analysis was used to analyze the correlation between T3/T4 ratio and white blood cell (WBC), Neutrophil-to-Lymphocyte Ratio (NLR), systemic immune-inflammation index (SII) and neutrophil percentage-to-albumin ratio (NPAR). Cox univariate and multivariate analysis was used to identify independent risk factors for all-cause mortality in stroke survivors and a nomogram was drawn. Restricted cubic spline (RCS) curve was drawn to determine whether there was a linear relationship between T3/T4 ratio and mortality and the best cut-off value. Subgroup analysis showed the difference between the T3/T4 ratio and all-cause mortality among subgroups and a forest plot was drawn. The mediation effect analysis was used to analyze whether the ratio of T3/T4 could mediate the survival time through inflammatory indicators.ResultsAccording to the inclusion and exclusion criteria, a total of 267 people were included in the study, with a mortality rate of 49.06% (131/267), an average survival time of 111.22 ± 3.19 months, and a median survival time of 130 ± 11.27 months. The Log-Rank test and K-M survival curve showed that there were statistical differences among the Q1, Q2, and Q3 groups of the T3/T4 ratio (x2 = 16.32, p

BackgroundWhite matter hyperintensity (WMH) and brain atrophy, as imaging marker of cerebral small-vessel diseases (CSVD), have a high prevalence and strong prognostic value in stroke. We aimed to explore the association between lymphocyte count, a maker of inflammation, and WMH and brain atrophy in patients with acute ischemic stroke (AIS).MethodsA total of 727 AIS patients with lymphocyte count and brain magnetic resonance imaging data were enrolled. Participants were divided into four groups according to the quartiles of baseline lymphocyte counts. WMH is frequently divided into periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH). WMH was defined as Fazekas scale score ≥ 3; PVH was defined as periventricular Fazekas scale ≥2; DWMH was defined as deep Fazekas scale ≥2. Brain atrophy was defined as global cortical atrophy score ≥ 1. Multivariable logistic regression models were used to assess the association between lymphocyte count and WMH and brain atrophy.ResultsAmong 727 AIS, 517 (71.1%), 442 (60.8%), 459 (63.1%), 583 (80.2%) had WMH, PVH, DWMH and brain atrophy, respectively. After adjustment for potential covariates, the highest quartiles of lymphocyte counts were significantly associated with lower risk of WMH (adjusted odds ratio [aOR] 0.57, 95% confidence intervals [CI] 0.32–0.99), PVH (aOR 0.52, 95% CI 0.31–0.87), DWMH (aOR 0.53 95% CI 0.32–0.90) as well as brain atrophy (aOR 0.46, 95% CI 0.23–0.92) compared with the lowest quartiles of lymphocyte counts, respectively. Furthermore, a notable inverse association was observed between continuous lymphocyte counts and WMH, PVH, DWMH, and brain atrophy. Additionally, we found that the inverse association between baseline lymphocyte count and WMH was significant only in individuals with mild stroke.ConclusionIn patients with AIS, there was an independent and inverse association between the baseline lymphocyte count and both WMH and brain atrophy.

IntroductionTumor heterogeneity significantly complicates the selection of effective cancer treatments, as patient responses to drugs can vary widely. Personalized cancer therapy has emerged as a promising strategy to enhance treatment effectiveness and precision. This study aimed to develop a personalized drug recommendation model leveraging genomic profiles to optimize therapeutic outcomes.MethodsA content-based filtering algorithm was implemented to predict drug sensitivity. Patient features were characterized by the tumor microenvironment (TME), and drug features were represented by drug fingerprints. The model was trained and validated using the Genomics of Drug Sensitivity in Cancer (GDSC) database, followed by independent validation with the Cancer Cell Line Encyclopedia (CCLE) dataset. Clinical application was assessed using The Cancer Genome Atlas (TCGA) dataset, with Best Overall Response (BOR) serving as the clinical efficacy measure. Two multilayer perceptron (MLP) models were built to predict IC50 values for 542 tumor cell lines across 18 drugs.ResultsThe model exhibited high predictive accuracy, with correlation coefficients (R) of 0.914 in the training set and 0.902 in the test set. Predictions for cytotoxic drugs, including Docetaxel (R = 0.72) and Cisplatin (R = 0.71), were particularly robust, whereas predictions for targeted therapies were less accurate (R < 0.3). Validation with CCLE (MFI as the endpoint) showed strong correlations (R = 0.67). Application to TCGA data successfully predicted clinical outcomes, including a significant association with 6-month progression-free survival (PFS, P = 0.007, AUC = 0.793).DiscussionThe model demonstrates strong performance across preclinical datasets, showing its potential for real-world application in personalized cancer therapy. By bridging preclinical IC50 and clinical BOR endpoints, this approach provides a promising tool for optimizing patient-specific treatments.

IntroductionPrimary cilia play an important role in the development of cancer by regulating signaling pathways. Several studies have demonstrated that women with BRCA mutations have, on average, 50% fewer ciliated cells compared with general women. However, the role of tubal cilia loss in the development of epithelial ovarian cancer (EOC) remains unclear. Few specific studies have been found in linking HYDIN, a ciliary defect associated gene that encodes HYDIN axonemal central pair apparatus protein, which is involved in the transduction of Hedgehog (Hh) signal and is considered a cancer associated antigen, to ovarian cancer. Therefore, our study aimed to investigate the correlation between HYDIN gene mutations and tubal cilia loss in EOC.MethodsA whole exome sequencing (WES), immunohistochemistry (IHC), western blot, and reverse transcription quantitative (RT q) PCR were performed in 80 patients with EOC and 50 cases of non ovarian cancer to detect the mutations and expression of tubal ciliary marker, ciliary morphology, and abnormal rate.ResultsWe found that the incidence of tubal cilia loss was higher in EOC group with decreased expression of HYDIN compared with the control group (P

Summary: Faced with energy transition objectives, the ten countries of the Association of Southeast Asian Nations (ASEAN) have technology options to decarbonize power sector. This study investigates the hypothetical decarbonization pathways for ASEAN’s power sector. Here, we present an integrated power system capacity expansion model for ASEAN over 2018–2050. The results identify different pathways by strategically pursuing renewable energy, carbon capture and sequestration, and cross-border transmission. Transmission, while accounting for a marginal share in total cost (up to 0.5%), can reduce cumulative system costs by 11.9% and help achieve net-zero emissions. Across scenarios, generation infrastructure will require a cumulative investment equivalent to 29.6%–44.6% of ASEAN’s 2018 GDP (Gross Domestic Product). The investment requirements for the expansion plan, however, are unevenly distributed across countries, especially with the ambition to achieve a carbon-neutral power sector. Country-specific investments in decarbonization are a consideration for the region.

The ferulic acid (FA) / monoglyceride (MG) mixture could act as a gelator to structure sunflower oil at the gelator concentration (c) ≥ 4 % and the FA/MG ratios (r) of 0:100, 25:75, 50:50 and 75:25. The rectangular FA and needle-shaped MG crystals in the oleogel interlock with each other to form a 3D network, restricting the flow of oil. The gel strength and rheological performance of the oleogel were positively correlated with c and negatively correlated with storage temperature (t). Its gelation temperature was determined by c and r. Its β-carotene protective ability against ultraviolet irradiation was proportional to the FA concentration. The oleogel with r = 25:75, c = 5 % and t = 4 °C could partially substitute cocoa butter for chocolate production. With the increasing substitution rate (WCBS), the appearance, texture properties and enthalpy change of chocolate gradually deteriorated. But when WCBS ≤ 40 %, the oleogel had no significant effect on the sensory characteristics.

Salmonella typhimurium is a common cause of gastroenteritis, which infects animals and human. Protocatechuic acid has anti-inflammatory, immunoregulatory and anti-pathogenic effects, and is expected to be an effective choice for alleviating Salmonella infection and intestinal injury. A total of 180 1-d female, yellow-feathered chickens were randomly allocated into 3 treatment groups, the controls (Ctr), the Salmonella-challenged treatment (Sal) and the protocatechuic acid treatment (PA). Birds were fed a basal diet for 18 d, with birds in PA supplemented with 600 mg/kg protocatechuic acid. On 14 and 16 d, birds in Sal and PA were orally challenged with 109 CFU S. typhimurium, while birds in Ctr received an equal amount of PBS. The results showed that protocatechuic acid improved growth performance and jejunal structure in Salmonella-infected chickens (P < 0.05). In addition, protocatechuic acid suppressed (P < 0.05) the secretion of plasmal IgG, IL-1β, and IFN-β, and jejunal mucosal IL-6, IFN-β, complement protein 3 and 4. Mechanistically, the transcriptomic results showed that dietary protocatechuic acid inhibited acute inflammatory response and activated the signaling pathways of cytokine-cytokine receptor interaction, complement and coagulation cascades. Results of proteomic showed that protocatechuic acid inhibited the positive regulation of dendritic cell cytokine production and I-κB kinase/NF-κB signaling, as well as cytokine-cytokine receptor interaction and MAPK signaling pathways, and activated the mTOR signaling pathways. These results were critical to both suppressing the secretion of inflammatory cytokines and restoring the intestinal function. Dietary protocatechuic acid (600 mg/kg) was effective to alleviate Salmonella infection, as it suppressed the levels of cytokines and complement protein by inhibiting MAPK, I-κB kinase/NF-κB and enhancing the mTOR signaling pathway, thus offset the decline in weight loss and intestinal injury caused by infection.

ABSTRACT A rare case of ischemic stroke in a young adult demonstrating coexistence of moyamoya disease and carotid web in angiography was reported. Early recognition and prompt intervention should be stressed in individuals with cryptogenic stroke.