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Abstract Slot structure is the equilibrium result of market demand side and slot resource supply side, while slot parameters reflect the operational support capacity of the aviation system. Time parameters reflect the operational support capability of the aviation system. Time structure should not only reflect changes in market demand, but also meet the constraints of operational efficiency. Constructing a reasonable 18–24 h timetable profile for busy airports that meets normal expectations for declared capacity and seasonal scheduling is a challenge in civil aviation slot management. This study utilizes historical data on airport flights and weather conditions to establish a regression prediction model for the time structure using K-means clustering and partial least squares regression. Additionally, ensemble learning is employed to forecast flight delay levels. The findings demonstrate that random forest yields favorable results in regression and prediction tasks, allowing for the integration of upper (good weather) and lower (severse weather) limits of the time profile with delay predictions as time parameter intervals. Consequently, the flights falling within these intervals achieve an average delay level of less than 15 min which meets the expectations of normal flight.

Seed coat color affects the appearance and commodity quality of mung beans (Vigna radiata L.). The substances that affect mung bean seed coat color are mainly flavonoids, which have important medicinal value. Mapping the seed coat color gene in mung beans would facilitate the development of new varieties and improve their value. In this study, an F2 mapping population consisting of 546 plants was constructed using Jilv9 (black seed coat) and BIS9805 (green seed coat). Using bulk segregated analysis (BSA) sequencing and kompetitive allele-specific PCR (KASP) markers, the candidate region related to seed coat color was finally narrowed to 0.66 Mb on chromosome (Chr.) 4 and included eight candidate genes. Combined transcriptome and metabolome analyses showed that three of the eight candidate genes (LOC106758748, LOC106758747, and LOC106759075) were differentially expressed, which may have caused the differences in flavonoid metabolite content between Jilv9 and BIS9805. These findings can provide a research basis for cloning the genes related to seed coat color and accelerate molecular marker-assisted selection breeding in mung beans.

Abstract Backgrounds Fat infiltration of skeletal muscle has been recognized as a common feature of many degenerative muscle disorders. Retinol binding protein 4 (RBP4) is an adipokine that has been demonstrated to be correlated with the presence and severity of sarcopenia in the elderly. However, the exact role and the underlying mechanism of RBP4 in muscle atrophy remains unclear. Methods Denervation‐induced muscle atrophy model was constructed in wild‐type and RBP4 knockout mice. To modify the expression of RBP4, mice were received intramuscular injection of retinol‐free RBP4 (apo‐RBP4), retinol‐bound RBP4 (holo‐RBP4) or oral gavage of RBP4 inhibitor A1120. Holo‐RBP4‐stimulated C2C12 myotubes were treated with siRNAs or specific inhibitors targeting signalling receptor and transporter of retinol 6 (STRA6)/Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) pathway. Fat accumulation, myofibre cross‐sectional area, myotube diameter and the expression of muscle atrophy markers and myogenesis markers were analysed. Results The expression levels of RBP4 in skeletal muscles were significantly up‐regulated more than 2‐fold from 7 days and sustained for 28 days after denervation. Immunofluorescence analysis indicated that increased RBP4 was localized in the infiltrated fatty region in denervated skeletal muscles. Knockout of RBP4 alleviated denervation‐induced fatty infiltration and muscle atrophy together with decreased expression of atrophy marker Atrogin‐1 and MuRF1 as well as increased expression of myogenesis regulators MyoD and MyoG. By contrast, injection of retinol‐bound holo‐RBP4 aggregated denervation‐induced ectopic fat accumulation and muscle atrophy. Consistently, holo‐RBP4 stimulation also had a dose‐dependent effect on the reduction of C2C12 myotube diameter and myofibre cross‐sectional area, as well as on the increase of Atrogin‐1and MuRF1 expression and decrease of MyoD and MyoG expression. Mechanistically, holo‐RBP4 treatment increased the expression of its membrane receptor STRA6 (>3‐fold) and promoted the phosphorylation of downstream JAK2 and STAT3. Inhibition of STRA6/JAK2/STAT3 pathway either by specific siRNAs or inhibitors could decrease the expression of Atrogin‐1 and MuRF1 (>50%) and decrease the expression of MyoD and MyoG (>3‐fold) in holo‐RBP4‐treated C2C12 myotube. RBP4 specific pharmacological antagonist A1120 significantly inhibited the activation of STRA6/JAK2/STAT3 pathway, ameliorated ectopic fat infiltration and protected against denervation‐induced muscle atrophy (30% increased myofibre cross‐sectional area) in mice. Conclusions In conclusion, our data reveal that RBP4 promotes fat infiltration and muscle atrophy through a STRA6‐dependent and JAK2/STAT3 pathway‐mediated mechanism in denervated skeletal muscle. Our results suggest that lowering RBP4 levels might serve as a promising therapeutic approach for prevention and treatment of muscle atrophy.

Abstract Background The Health and Medical Assistance Program for Poverty Alleviation is part of China’s targeted poverty elimination strategy, which aims to protect poor people’s right to health and prevent them from becoming trapped in or returning to poverty because of illness. Many tasks have been defined in this program, including raising the medical insurance level, providing a triage system, improving medical and health services, and enhancing people’s health. One pivotal aspect of this initiative involves equitable health resource allocation, a key measure aimed at bolstering medical and health services. This study aimed to analyze and compare health resource allocations in different counties in Northwest China after the implementation of the program. Methods The Gini coefficient quantifies the level of distributional equality, the Theil index assesses the sources of inequality, and the Health Resource Agglomeration Degree gauges the accessibility of health resources. Results 1) The health resource allocation distributed based on population(Gini Coefficient 0.35) among counties in Northwest China. 2) The contribution rate within non-impoverished counties is higher than that of impoverished counties, which means the inequality within non-impoverished counties. 3) The allocation of beds in medical institutions by area in non-impoverished counties was better than that in impoverished counties, and accessibility to health services for residents in non-impoverished counties was better than that in impoverished counties. Conclusion The analysis of health resource allocation among the five provinces in Northwest China revealed significant differences in equality among the five provinces in Northwest China, and the differences were mainly derived from the non-impoverished counties. Although the equality is gradually improving, the number of health resources in impoverished counties remain lower than that in non-impoverished counties.Subsequently, it is essential to ensure equitable distribution of healthcare resources while also taking into account their utilization and quality.

Abstract Visual adaptive devices have potential to simplify circuits and algorithms in machine vision systems to adapt and perceive images with varying brightness levels, which is however limited by sluggish adaptation process. Here, the avalanche tuning as feedforward inhibition in bionic two-dimensional (2D) transistor is proposed for fast and high-frequency visual adaptation behavior with microsecond-level accurate perception, the adaptation speed is over 104 times faster than that of human retina and reported bionic sensors. As light intensity changes, the bionic transistor spontaneously switches between avalanche and photoconductive effect, varying responsivity in both magnitude and sign (from 7.6 × 104 to −1 × 103 A/W), thereby achieving ultra-fast scotopic and photopic adaptation process of 108 and 268 μs, respectively. By further combining convolutional neural networks with avalanche-tuned bionic transistor, an adaptative machine vision is achieved with remarkable microsecond-level rapid adaptation capabilities and robust image recognition with over 98% precision in both dim and bright conditions.

Abstract Objective The objective of the present study was to explore the correlation between the advanced lung cancer inflammation index (ALI) and in‐hospital mortality among patients diagnosed with community‐acquired pneumonia (CAP). Methods Data from the Medical Information Mart for Intensive Care‐IV database were adopted to analyze the in‐hospital mortality of ICU patients with CAP. Upon admission to the ICU, fundamental data including vital signs, critical illness scores, comorbidities, and laboratory results, were collected. The in‐hospital mortality of all CAP patients was documented. Multivariate logistic regression (MLR) models and restricted cubic spline (RCS) analysis together with subgroup analyses were conducted. Results This study includes 311 CAP individuals, involving 218 survivors as well as 93 nonsurvivors. The participants had an average age of 63.57 years, and the females accounted for approximately 45.33%. The in‐hospital mortality was documented to be 29.90%. MLR analysis found that ALI was identified as an independent predictor for in‐hospital mortality among patients with CAP solely in the Q1 group with ALI ≤ 39.38 (HR: 2.227, 95% CI: 1.026–4.831, P = 0.043). RCS analysis showed a nonlinear relationship between the ALI and in‐hospital mortality, with a turning point at 81, and on the left side of the inflection point, a negative correlation was observed between ALI and in‐hospital mortality (HR: 0.984, 95% CI: 0.975–0.994, P = 0.002). The subgroup with high blood pressure showed significant interaction with the ALI. Conclusion The present study demonstrated a nonlinear correlation of the ALI with in‐hospital mortality among individuals with CAP. Additional confirmation of these findings requires conducting larger prospective investigations.

Abstract Cryptosporidiosis is a worldwide zoonotic disease. Oxymatrine, an alkaloid extracted and isolated from the plant bitter ginseng, has been reported to have therapeutic effects on cryptosporidiosis. However, the underlying mechanism of its action remains unclear. In this study, we utilized network pharmacology and experimental validation to investigate the mechanism of oxymatrine in the treatment of cryptosporidiosis. First, the potential targets of drugs and diseases were predicted by TCMSP, Gene Cards, and other databases. Following the intersection of drug-disease targets, the DAVID database was used to implement the enrichment analysis of GO functions and KEGG pathways, and then the network diagram of "intersected target-KEGG" relationship was constructed. Autodock 4.2.6 software was used to carry out the molecular docking of core targets to drug components. Based on the establishment of a mouse model of cryptosporidiosis, the validity of the targets in the TNF/NF-κB signaling pathway was confirmed using Western blot analysis and Quantitative Rea-ltime-PCR. A total of 41 intersectional targets of oxymatrine and Cryptosporidium were generated from the results, and five core targets were screened out by network analysis, including RELA, AKT1, ESR1, TNF, and CASP3. The enrichment analysis showed that oxymatrine could regulate multiple gene targets, mediate TNF, Apoptpsis, IL-17, NF-κB and other signaling pathways. Molecular docking experiments revealed that oxymatrine was tightly bound to core targets with stable conformation. Furthermore, we found through animal experiments that oxymatrine could regulate the mRNA and protein expression of IL-6, NF-κB, and TNF-α in the intestinal tissues of post-infected mice through the TNF/NF-κB signaling pathway. Therefore, it can be concluded that oxymatrine can regulate the inflammatory factors TNF-α, NF-κB, and IL-6 through the TNF/NF-κB signaling pathway for the treatment of cryptosporidiosis. This prediction has also been validated by network pharmacology and animal experiments.

Abstract Hemangioma of infancy is the most common vascular tumor during infancy and childhood. Despite the proven efficacy of propranolol treatment, certain patients still encounter resistance or face recurrence. The need for frequent daily medication also poses challenges to patient adherence. Bleomycin (BLM) has demonstrated effectiveness against vascular anomalies, yet its use is limited by dose-related complications. Addressing this, this study proposes a novel approach for treating hemangiomas using BLM-loaded hyaluronic acid (HA)-based microneedle (MN) patches. BLM is encapsulated during the synthesis of polylactic acid (PLA) microspheres (MPs). The successful preparation of PLA MPs and MN patches is confirmed through scanning electron microscopy (SEM) images. The HA microneedles dissolve rapidly upon skin insertion, releasing BLM@PLA MPs. These MPs gradually degrade within 28 days, providing a sustained release of BLM. Comprehensive safety assessments, including cell viability, hemolysis ratio, and intradermal reactions in rabbits, validate the safety of MN patches. The BLM@PLA-MNs exhibit an effective inhibitory efficiency against hemangioma formation in a murine hemangioma model. Of significant importance, RNA-seq analysis reveals that BLM@PLA-MNs exert their inhibitory effect on hemangiomas by regulating the P53 pathway. In summary, BLM@PLA-MNs emerge as a promising clinical candidate for the effective treatment of hemangiomas. Graphical Abstract

Abstract Public health events (PHEs) have emerged as significant threats to human life, health, and economic growth. PHEs, such as COVID-19, have prompted a reevaluation for enhanced regular prevention and control (RPC). In this study, we focus on the core concept of prevention and control intensity (PCI), and establish a neoclassical economic growth model from the long-term and macro perspective to balance life protection and economic growth. The model construct the mechanism of PCI on economic growth through population dynamics and capital accumulation under the backdrop of RPC for PHEs. We find the conditions for PCI when the economy achieves steady state, and provides an algorithm establishing the optimal strategy that maximises per capita disposable income based on the optimal PCI and consumption. Simulation result quantifies an inverted U-shaped relationship between PCI and capital per capita, output per capita and consumption per capita in the steady state. The model suggests that, given the PHEs of inducing potential unemployment shock, it is worthwhile to combine the implementation of moderate PCI with coordinated policies of income distribution.

Abstract Topological phases in photonic systems have garnered significant attention, often relying on precise structural design for generating non-trivial topological phases. However, this dependency on fixed structures limits their adaptability. This study systematically explores incident angle-induced topological phase transitions in a one-dimensional photonic crystal (PC). Both TE and TM polarized modes undergo topological phase transitions at the same critical transition angles. Additionally, the TM-polarized mode undergoes a unique topological phase transition at the Brewster angle. When these two kinds of transition angles coincide, even if the band structure of the TM-polarized mode undergoes an open-close-reopen process, the topological properties of the corresponding bandgap remain unchanged. Based on theoretical analysis, we design the composite PCs comprising two interfaced PCs having common bandgaps but different topological properties. By tuning the incident angle, we theoretically and experimentally achieve TE-TM splitting of topological interface states in the visible region, which may have potential applications in optical communications, optical switching, photonic integrated circuits, and so on.

Abstract Background Non-pharmaceutical interventions (NPIs) have been widely utilised to control the COVID-19 pandemic. However, it is unclear what the optimal strategies are for implementing NPIs in the context of coronavirus vaccines. This study aims to systematically identify, describe, and evaluate existing ecological studies on the real-world impact of NPIs in containing COVID-19 pandemic following the roll-out of coronavirus vaccines. Methods We conducted a comprehensive search of relevant studies from January 1, 2021, to June 4, 2023 in PubMed, Embase, Web of science and MedRxiv. Two authors independently assessed the eligibility of the studies and extracted the data. A risk of bias assessment tool, derived from a bibliometric review of ecological studies, was applied to evaluate the study design, statistical methodology, and the quality of reporting. Data were collected, synthesised and analysed using qualitative and quantitative methods. The results were presented using summary tables and figures, including information on the target countries and regions of the studies, types of NPIs, and the quality of evidence. Results The review included a total of 17 studies that examined the real-world impact of NPIs in containing the COVID-19 pandemic after the vaccine roll-out. These studies used five composite indicators that combined multiple NPIs, and examined 14 individual NPIs. The studies had an average quality assessment score of 13 (range: 10–16), indicating moderately high quality. NPIs had a larger impact than vaccination in mitigating the spread of COVID-19 during the early stage of the vaccination implementation and in the context of the Omicron variant. Testing policies, workplace closures, and restrictions on gatherings were the most effective NPIs in containing the COVID-19 pandemic, following the roll-out of vaccines. The impact of NPIs varied across different time frames, countries and regions. Conclusion NPIs had a larger contribution to the control of the pandemic as compared to vaccination during the early stage of vaccine implementation and in the context of the omicron variant. The impact of NPIs in containing the COVID-19 pandemic exhibited variability in diverse contexts. Policy- and decision-makers need to focus on the impact of different NPIs in diverse contexts. Further research is needed to understand the policy mechanisms and address potential future challenges.

Abstract Background Sarcopenia is characterized by progressive loss of muscle mass and function due to aging. DNA methylation has been identified to play important roles in the dysfunction of skeletal muscle. The aim of our present study was to explore the whole blood sample‐based methylation changes of skeletal muscle function‐related factors in patients with sarcopenia. Methods The overall DNA methylation levels were analysed by using MethlTarget™ DNA Methylation Analysis platform in a discovery set consistent of 50 sarcopenic older adults (aged ≥65 years) and 50 age‐ and sex‐matched non‐sarcopenic individuals. The candidate differentially methylated regions (DMRs) were further validated by Methylation‐specific PCR (MSP) in another two independent larger sets and confirmed by pyrosequencing. Receiver operating characteristic (ROC) curve analysis was used to determine the optimum cut‐off levels of fibroblast growth factor 2 (FGF2)_30 methylation best predicting sarcopenia and area under the ROC curve (AUC) was measured. The correlation between candidate DMRs and the risk of sarcopenia was investigated by univariate analysis and multivariate logistic regression analysis. Results Among 1149 cytosine‐phosphate‐guanine (CpG) sites of 27 skeletal muscle function‐related secretary factors, 17 differentially methylated CpG sites and 7 differentially methylated regions (DMRs) were detected between patients with sarcopenia and control subjects in the discovery set. Further methylation‐specific PCR identified that methylation of fibroblast growth factor 2 (FGF2)_30 was lower in patients with sarcopenia and the level was decreased as the severity of sarcopenia increased, which was confirmed by pyrosequencing. Correlation analysis demonstrated that the methylation level of FGF2_30 was positively correlated to ASMI (r = 0.372, P

Abstract The rapid expansion of low‐voltage distributed photovoltaic (PV) systems with decentralized layouts poses significant data collection challenges. The scarcity of data amplifies prediction complexities, affecting the operational security and stability of distribution networks. To enhance predictive accuracy for distributed regional PV power generation, including unmonitored low‐voltage systems, this paper proposes a novel prediction approach that combines weight optimization and transfer learning. Firstly, to more accurately extrapolate from neighbouring monitored PV to estimate unmonitored PV outputs, a novel SSA‐MLP‐XGBoost model is proposed for monitored PV power plants, in which the hyperparameters of multilayer perceptron (MLP) and (extreme gradient boosting) XGBoost models are fine‐tuned using the sparrow search algorithm (SSA), and the optimized models are synergistically integrated to heighten prediction precision for monitored plants. Secondly, based on the predicted power curves of monitored PV power plants, a weight optimization model is presented to optimize the combined weights between unmonitored and monitored power stations. Furthermore, the power generation model from monitored facilities is transplanted to unmonitored plants for power generation estimation. Ultimately, the authors combine the weight optimization and transfer learning model to get more accurate and robust model. Validation across three regional distributed photovoltaic clusters demonstrates a noteworthy improvement in prediction accuracy—20%, 7.5%, and 25% for the respective clusters compared to the existing methods.

Abstract Objective About 10% of patients after cardiopulmonary bypass (CPB) would undergo acute liver injury, which aggravated the mortality of patients. Ac2-26 has been demonstrated to ameliorate organic injury by inhibiting inflammation. The present study aims to evaluate the effect and mechanism of Ac2-26 on acute liver injury after CPB. Methods A total of 32 SD rats were randomized into sham, CPB, Ac, and Ac/AKT1 groups. The rats only received anesthesia, and rats in other groups received CPB. The rats in Ac/AKT1 were pre-injected with the shRNA to interfere with the expression of AKT1. The rats in CPB were injected with saline, and rats in Ac and Ac/AKT1 groups were injected with Ac2-26. After 12 h of CPB, all the rats were sacrificed and the peripheral blood and liver samples were collected to analyze. The inflammatory factors in serum and liver were detected. The liver function was tested, and the pathological injury of liver tissue was evaluated. Results Compared with the sham group, the inflammatory factors, liver function, and pathological injury were worsened after CPB. Compared with the CPB group, the Ac2-26 significantly decreased the pro-inflammatory factors and increased the anti-inflammatory factor, improved liver function, and ameliorated the pathological injury. All the therapeutic effects of Ac2-26 were notably attenuated by the shRNA of AKT1. The Ac2-26 increased the GSK3β and eNOS, and this promotion was inhibited by the shRNA. Conclusion The Ac2-26 significantly treated the liver injury, inhibited inflammation, and improved liver function. The effect of Ac2-26 on liver injury induced by CPB was partly associated with the promotion of AKT1/GSK3β/eNOS.

Abstract Background Lip infantile hemangiomas tend to show less volumetric regression and are more susceptible to visible sequelae in the involuted stage. Some of them still require surgical management after propranolol therapy. This study aimed to evaluate the efficacy and safety of the Stepwise, Multi-Incisional, and Single-Stage (SMISS) approach applied to lip reduction for those with involuted lip hemangiomas. Methods A retrospective review was performed to evaluate patients with lip hemangioma who received previous propranolol treatment and underwent the aforementioned procedure. Demographic characteristics, lesion morphology, and medical history were reviewed. The Visual Analog Scale was applied to assess the postoperative appearance. Complications within 12 months postoperatively were recorded. Results A total of 18 patients with lip hemangioma were eligible. All patients received oral propranolol therapy before surgery, with treatment duration ranging from 6.0 to 23.0 months. Their age at surgery ranged from 2.5 to 9.0 years. The median Visual Analog Scale scores were 8.0, ranging from 4.0 to 10.0. No severe complications were reported. Conclusions This modified technique based on the SMISS approach has proven reliable and effective in improving the aesthetic outcome for involuted lip infantile hemangiomas. Practical surgical techniques still play an important part in the propranolol era.

We demonstrated herein an electrochemical dearomatizative alkylation of Katritzky salts, wherein Katritzky salts were harnessed as both radical acceptors and donors. A wide range of privileged dihydropyridine scaffolds was constructed with good to excellent yields. Cyclic voltammetry (CV) and electron paramagnetic resonance (EPR) results confirmed the key intermediates-dihydropyridine radicals and gram-scale reaction highlighted the practical and sustainable feature of the newly developed protocol.

Abstract Background Cardiopulmonary bypass (CPB) results in brain injury, which is primarily caused by inflammation. Ac2-26 protects against ischemic or hemorrhage brain injury. The present study was to explore the effect and mechanism of Ac2-26 on brain injury in CPB rats. Methods Forty-eight rats were randomized into sham, CPB, Ac, Ac/AKT1, Ac/GSK3βi and Ac/AKT1/GSK3βa groups. Rats in sham group only received anesthesia and in the other groups received standard CPB surgery. Rats in the sham and CPB groups received saline, and rats in the Ac, Ac/AKT1, Ac/GSK3βi and Ac/AKT1/GSK3βa groups received Ac2-26 immediately after CPB. Rats in the Ac/AKT1, Ac/GSK3βi and Ac/AKT1/GSK3βa groups were injected with shRNA, inhibitor and agonist of GSK3β respectively. The neurological function score, brain edema and histological score were evaluated. The neuronal survival and hippocampal pyroptosis were assessed. The cytokines, activity of NF-κB, S100 calcium-binding protein β(S100β) and neuron-specific enolase (NSE), and oxidative were tested. The NLRP3, cleaved-caspase-1 and cleaved-gadermin D (GSDMD) in the brain were also detected. Results Compared to the sham group, all indicators were aggravated in rats that underwent CPB. Compared to the CPB group, Ac2-26 significantly improved neurological scores and brain edema and ameliorated pathological injury. Ac2-26 reduced the local and systemic inflammation, oxidative stress response and promoted neuronal survival. Ac2-26 reduced hippocampal pyroptosis and decreased pyroptotic proteins in brain tissue. The protection of Ac2-26 was notably lessened by shRNA and inhibitor of GSK3β. The agonist of GSK3β recovered the protection of Ac2-26 in presence of shRNA. Conclusions Ac2-26 significantly improved neurological function, reduced brain injury via regulating inflammation, oxidative stress response and pyroptosis after CPB. The protective effect of Ac2-26 primarily depended on AKT1/ GSK3β pathway.

Abstract Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

Abstract Project Optimus is a US Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection and optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, and other stakeholders. Although there is much promise in this initiative, there are several challenges that need to be addressed, including multidimensionality of the dose optimization problem in oncology, the heterogeneity of cancer and patients, importance of evaluating long‐term tolerability beyond dose‐limiting toxicities, and the lack of reliable biomarkers for long‐term efficacy. Through the lens of Totality of Evidence and with the mindset of model‐informed drug development, we offer insights into dose optimization by building a quantitative knowledge base integrating diverse sources of data and leveraging quantitative modeling tools to build evidence for drug dosage considering exposure, disease biology, efficacy, toxicity, and patient factors. We believe that rational dose optimization can be achieved in oncology drug development, improving patient outcomes by maximizing therapeutic benefit while minimizing toxicity.

Abstract In this study, we investigated the codon bias of twelve mitochondrial core protein coding genes (PCGs) in eight Pleurotus strains, two of which are from the same species. The results revealed that the codons of all Pleurotus strains had a preference for ending in A/T. Furthermore, the correlation between codon base compositions and codon adaptation index (CAI), codon bias index (CBI) and frequency of optimal codons (FOP) indices was also detected, implying the influence of base composition on codon bias. The two P. ostreatus species were found to have differences in various base bias indicators. The average effective number of codons (ENC) of mitochondrial core PCGs of Pleurotus was found to be less than 35, indicating strong codon preference of mitochondrial core PCGs of Pleurotus. The neutrality plot analysis and PR2-Bias plot analysis further suggested that natural selection plays an important role in Pleurotus codon bias. Additionally, six to ten optimal codons (ΔRSCU > 0.08 and RSCU > 1) were identified in eight Pleurotus strains, with UGU and ACU being the most widely used optimal codons in Pleurotus. Finally, based on the combined mitochondrial sequence and RSCU value, the genetic relationship between different Pleurotus strains was deduced, showing large variations between them. This research has improved our understanding of synonymous codon usage characteristics and evolution of this important fungal group.

Abstract A flexible or planar eddy current probe with a differential structure can suppress the lift-off noise during the inspection of defects. However, the extent of the lift-off effect on differential probes, including different coil structures, varies. In this study, two planar eddy current probes with differential pickup structures and the same size, Koch and circular probes, were used to compare lift-off effects. The eddy current distributions of the probes perturbed by 0° and 90° cracks were obtained by finite element analysis. The analysis results show that the 90° crack can impede the eddy current induced by the Koch probe even further at relatively low lift-off distance. The peak-to-peak values of the signal output from the two probes were compared at different lift-off distances using finite element analysis and experimental methods. In addition, the effects of different frequencies on the lift-off were studied experimentally. The results show that the signal peak-to-peak value of the Koch probe for the inspection of cracks in 90° orientation is larger than that of the circular probe when the lift-off distance is smaller than 1.2 mm. In addition, the influence of the lift-off distance on the peak-to-peak signal value of the two probes was studied via normalization. This indicates that the influence becomes more evident with an increase in excitation frequency. This research discloses the lift-off effect of differential planar eddy current probes with different coil shapes and proves the detection merit of the Koch probe for 90° cracks at low lift-off distances.

Abstract The purpose of this study was to explore the diagnostic implications of ubiquitination-related gene signatures in Alzheimer's disease. In this study, we first collected 161 samples from the GEO database (including 87 in the AD group and 74 in the normal group). Subsequently, through differential expression analysis and the iUUCD 2.0 database, we obtained 3450 Differentially Expressed Genes (DEGs) and 806 Ubiquitin-related genes (UbRGs). After taking the intersection, we obtained 128 UbR-DEGs. Secondly, by conducting GO and KEGG enrichment analysis on these 128 UbR-DEGs, we identified the main molecular functions and biological pathways related to AD. Furthermore, through the utilization of GSEA analysis, we have gained insight into the enrichment of functions and pathways within both the AD and normal groups. Further, using lasso regression analysis and cross-validation techniques, we identified 22 characteristic genes associated with AD. Subsequently, we constructed a logistic regression model and optimized it, resulting in the identification of 6 RUbR-DEGs: KLHL21, WDR82, DTX3L, UBTD2, CISH, and ATXN3L. In addition, the ROC result showed that the diagnostic model we built has excellent accuracy and reliability in identifying AD patients. Finally, we constructed a lncRNA-miRNA-mRNA (competing endogenous RNA, ceRNA) regulatory network for AD based on six RUbR-DEGs, further elucidating the interaction between UbRGs and lncRNA, miRNA. In conclusion, our findings will contribute to further understanding of the molecular pathogenesis of AD and provide a new perspective for AD risk prediction, early diagnosis and targeted therapy in the population.

Abstract It is commonly assumed that gastrointestinal cancer is the most common form of cancer across the globe and is the leading contributor to cancer-related death. The intricate mechanisms underlying the growth of GI cancers have been identified. It is worth mentioning that both non-coding RNAs (ncRNAs) and certain types of RNA, such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), can have considerable impact on the development of gastrointestinal (GI) cancers. As a tumour suppressor, in the group of short non-coding regulatory RNAs is miR-34a. miR-34a silences multiple proto-oncogenes at the post-transcriptional stage by targeting them, which inhibits all physiologically relevant cell proliferation pathways. However, it has been discovered that deregulation of miR-34a plays important roles in the growth of tumors and the development of cancer, including invasion, metastasis, and the tumor-associated epithelial-mesenchymal transition (EMT). Further understanding of miR-34a’s molecular pathways in cancer is also necessary for the development of precise diagnoses and effective treatments. We outlined the most recent research on miR-34a functions in GI cancers in this review. Additionally, we emphasize the significance of exosomal miR-34 in gastrointestinal cancers.

Magnesium potassium phosphate cement (MKPC) and magnesium ammonium phosphate cement (MAPC) perform well as rapid repair materials, but the properties of their hydration products under NaCl attack (e.g., de-icing salt) are unknown. In this study, the synthesised magnesium phosphate cement (MPC) hydration products struvite and struvite-K were immersed in 5% and 15% NaCl solutions to study their phase and microstructural evolution. The results show that struvite partially dissolves in the pure water and NaCl solutions, without forming new crystalline hydrated products. However, in NaCl solutions, the morphology changes from scattered flakes to columnar structures. Struvite-K transforms into cattiite and hazenite (with higher strength) in the pure water and NaCl solutions, respectively, exhibiting flake-like morphology in pure water and clustered bloom morphology in NaCl solutions. The emergence of hazenite may contribute to MKPC displaying stronger resistance to NaCl corrosion compared to MAPC.

To address the low accuracy and stability when applying classical control theory in distribution networks with distributed generation, a control method involving flexible multistate switches (FMSs) is proposed in this study. This approach is based on an improved double-loop recursive fuzzy neural network (DRFNN) sliding mode, which is intended to stably achieve multiterminal power interaction and adaptive arc suppression for single-phase ground faults. First, an improved DRFNN sliding mode control (SMC) method is proposed to overcome the chattering and transient overshoot inherent in the classical SMC and reduce the reliance on a precise mathematical model of the control system. To improve the robustness of the system, an adaptive parameter-adjustment strategy for the DRFNN is designed, where its dynamic mapping capabilities are leveraged to improve the transient compensation control. Additionally, a quasi-continuous second- order sliding mode controller with a calculus-driven sliding mode surface is developed to improve the current monitoring accuracy and enhance the system stability. The stability of the proposed method and the convergence of the network parameters are verified using the Lyapunov theorem. A simulation model of the three-port FMS with its control system is constructed in MATLAB/Simulink. The simulation result confirms the feasibility and effectiveness of the proposed control strategy based on a comparative analysis.

Abstract Background Class III peroxidases (PODs) perform crucial functions in various developmental processes and responses to biotic and abiotic stresses. However, their roles in wheat seed dormancy (SD) and germination remain elusive. Results Here, we identified a wheat class III POD gene, named TaPer12-3A, based on transcriptome data and expression analysis. TaPer12-3A showed decreasing and increasing expression trends with SD acquisition and release, respectively. It was highly expressed in wheat seeds and localized in the endoplasmic reticulum and cytoplasm. Germination tests were performed using the transgenic Arabidopsis and rice lines as well as wheat mutant mutagenized with ethyl methane sulfonate (EMS) in Jing 411 (J411) background. These results indicated that TaPer12-3A negatively regulated SD and positively mediated germination. Further studies showed that TaPer12-3A maintained H2O2 homeostasis by scavenging excess H2O2 and participated in the biosynthesis and catabolism pathways of gibberellic acid and abscisic acid to regulate SD and germination. Conclusion These findings not only provide new insights for future functional analysis of TaPer12-3A in regulating wheat SD and germination but also provide a target gene for breeding wheat varieties with high pre-harvest sprouting resistance by gene editing technology.

Abstract Multi-modal combination therapy is regarded as a promising approach to cancer treatment. Combining chemotherapy and phototherapy is an essential multi-modal combination therapy endeavor. Ivermectin (IVM) is a potent antiparasitic agent identified as having potential antitumor properties. However, the fact that it induces protective autophagy while killing tumor cells poses a challenge to its further application. IR780 iodide (IR780) is a near-infrared (NIR) dye with outstanding photothermal therapy (PTT) and photodynamic therapy (PDT) effects. However, the hydrophobicity, instability, and low tumor uptake of IR780 limit its clinical applications. Here, we have structurally modified IR780 with hydroxychloroquine, an autophagy inhibitor, to synthesize a novel compound H780. H780 and IVM can form H780-IVM nanoparticles (H-I NPs) via self-assembly. Using hyaluronic acid (HA) to modify the H-I NPs, a novel nano-delivery system HA/H780-IVM nanoparticles (HA/H-I NPs) was synthesized for chemotherapy-phototherapy of colorectal cancer (CRC). Under NIR laser irradiation, HA/H-I NPs effectively overcame the limitations of IR780 and IVM and exhibited potent cytotoxicity. In vitro and in vivo experiment results showed that HA/H-I NPs exhibited excellent anti-CRC effects. Therefore, our study provides a novel strategy for CRC treatment that could enhance chemo-phototherapy by modulating autophagy.

Objective: This systematic review was conducted to evaluate the efficacy and safety of continuous nursing care for the recovery of joint function in older adults with total hip or knee arthroplasty. Methods: Randomized controlled trials and cohort studies of continuous nursing in older patients after joint replacement were searched from the database of Cochrane Library, Web of Science, PubMed, and Embase from their establishment to October 25, 2023. After literature screening, two researchers completed data extraction, and the risk of bias was assessed using the Cochrane risk-of-bias tool. The risk analysis included in cohort studies was based on the Newcastle-Ottawa Scale (NOS). Results: The study included a total of 15 articles, comprising 34,186 knee and hip replacement patients. In this review, the effects of continuous nursing on the recovery of joint function of knee replacement and hip replacement in older adults were classified and discussed. Continuous nursing interventions targeted for total hip replacement could greatly increase the range of joint mobility, enhance muscle strength during hip movements like flexion, extension, and abduction, maintain joint stability, relieve pain, improve daily activities, and lower the risk of complications. For older patients with knee arthroplasty, continuous nursing programs could markedly improve knee motion range, joint flexion, joint stability, daily activities, and pain management. Despite the implementation of interventions, the incidence of complications caused by total knee replacement did not decrease. Out of all the studies reviewed, only one used a theoretical framework for interventions provided to patients during the postoperative period of hip arthroplasty. The overall quality of the included studies was very high. Conclusion: Continuous nursing can effectively improve the joint function of older patients after joint replacement. However, its effectiveness in terms of clinical outcomes, patient satisfaction, and medical cost of associated continuous nursing needs to be further clarified. In addition, continuous nursing has no significant advantage in the safety of postoperative complications and readmission rates in older adults after knee joint replacement. To enhance the efficacy and safety of continuous nursing effectively, it is crucial to refine the continuous nursing program in the future, thereby elevating the quality of nursing services.

Aiming at the frost heave characteristics of long-distance and large-section underground freezing projects in cities, the double-line tunnel of Shanghai Metro Line 18 undercrossing an operation station was select as an example,a three-dimensional numerical model was established by using finite element software based on the thermal-mechanical coupling equation. Combined with the physical parameters obtained from laboratory tests, the evolution law of frost heave displacement field of the project was studied, and the influence of measures such as the staggered peak freezing and the adjustment of brine temperature on the frost heave displacement field was explored. Under the experimental conditions, the results show that: ① the deformation of the station floor caused by frost heave which mainly occurs in the active freezing period. When the double-line tunnel is frozen at the same time, the vertical displacement of the station floor at 45days of freezing reaches 77.72% of the displacement at 90 days of freezing. ② When the freezing time reaches 90 days, compared with simultaneous freezing, the displacement of the station floor reduced by 7.7% under the condtion of staggered peak freezing. The superposition effect of frost heave in the same time period is effectively avoided, and the frost heave effect is reduced to a certain extent. ③ When the freezing time reaches 90 days, compared with simultaneous freezing, the displacement of the station floor reduced by 34.2% under the condtion of adjusting the brine temperature, it shown that the expansion rate and frost heave effect of frozen soil are effectively controlled. In engineering practice, measures such as staggered freezing and adjusting brine temperature are used together to control frost heave, and the maximum vertical deformation of the station floor is 25.41 mm. The deformation law of the station floor obtained by numerical simulation is basically consistent with the measured data, which effectively guided the construction of the project.

Abstract For a long time, hydrogen sulfide (H2S) has been considered a toxic compound, but recent studies have found that H2S is the third gaseous signaling molecule which plays a vital role in physiological and pathological conditions. Currently, a large number of studies have shown that H2S mediates apoptosis through multiple signaling pathways to participate in cancer occurrence and development, for example, PI3K/Akt/mTOR and MAPK signaling pathways. Therefore, the regulation of the production and metabolism of H2S to mediate the apoptotic process of cancer cells may improve the effectiveness of cancer treatment. In this review, the role and mechanism of H2S in cancer cell apoptosis in mammals are summarized.

Abstract All-small-molecule organic solar cells with good batch-to-batch reproducibility combined with non-halogen solvent processing show great potential for commercialization. However, non-halogen solvent processing of all-small-molecule organic solar cells are rarely reported and its power conversion efficiencies are very difficult to improve. Herein, we designed and synthesized a small molecule donor BM-ClEH that can take advantage of strong aggregation property induced by intramolecular chlorine-sulfur non-covalent interaction to improve molecular pre-aggregation in tetrahydrofuran and corresponding micromorphology after film formation. Tetrahydrofuran-fabricated all-small-molecule organic solar cells based on BM-ClEH:BO-4Cl achieved high power conversion efficiencies of 15.0% in binary device and 16.1% in ternary device under thermal annealing treatment. In contrast, weakly aggregated BM-HEH without chlorine-sulfur non-covalent bond is almost inefficient under same processing conditions due to poor pre-aggregation induced disordered π-π stacking, indistinct phase separation and exciton dissociation. This work promotes the development of non-halogen solvent processing of all-small-molecule organic solar cells and provides further guidance.

Abstract Background Because of the progress on the diagnosis and treatment for patients with breast cancer (BC), the overall survival of the patients has been improved. However, a number of BC patients cannot benefit from the existing therapeutic strategies as the essential molecular events triggering the development of BC are not well understood. Previous studies have shown that abnormal expression of zinc finger proteins is involved in the development of various malignancies, whereas it remains largely unclear on their significance during the progression of BC. In this study, we aimed to explore the clinical relevance, cellular function and underlying mechanisms of zinc finger protein 468 (ZNF468) in BC. Methods The clinical relevance of ZNF468 and TFAM was analyzed based on TCGA database. Overexpression or knockdown of ZNF468 and TFAM were performed by transfecting the cells with overexpression plasmids and siRNAs, respectively. Overexpression and knockdown efficacy was checked by immunoblotting. CCK-8, colony formation, transwell and apoptosis experiments were conducted to check the cellular function of ZNF468 and TFAM. The content of mtDNA was measured by the indicated assay kit. The effects of cisplatin on BC cells were detected by CCK-8 and colony formation assays. The regulation of ZNF468 on TFAM was analyzed by RT-qPCR, immunoblotting, dual luciferase activity and ChIP-qPCR assays. Results ZNF468 was overexpressed in BC patients and inversely correlated with their prognosis. Based on overexpression and knockdown assays, we found that ectopic expression of ZNF468 was essential for the proliferation, growth and migration of BC cells. The expression of ZNF468 also negatively regulated the sensitivity of BC cells to the treatment of cisplatin. Mechanistically, ZNF468 potentiated the transcription activity of TFAM gene via direct binding on its promoter. Lastly, we demonstrated that ZNF468 up-regulation of TFAM was important for the growth, migration and cisplatin resistance in BC cells. Conclusion Our study indicates that ZNF468 promotes BC cell growth and migration via transcriptional activation of TFAM. ZNF468/TFAM axis can serve as the diagnostic and therapeutic target, as well as the predictor of cisplatin effectiveness in BC patients.

Abstract Background Patients with colorectal cancer (CRC) with liver metastasis or drug resistance have a poor prognosis. Previous research has demonstrated that PPP2R1B inactivation results in the development of CRC. However, the role of PPP2R1B in CRC metastasis and drug resistance is unclear. Methods Venny 2.1 was used to determine the intersection between survival-related differentially expressed genes (DEGs) and liver metastasis-related DEGs according to RNA-seq data from The Cancer Genome Atlas (TCGA) and the GEO database (GSE179979). LC‒MS/MS and coimmunoprecipitation were performed to predict and verify the substrate protein of PPP2R1B. Gene Set Variation Analysis (GSVA) was subsequently utilized to assess pathway enrichment levels. The predictive performance of PPP2R1B was assessed by regression analysis, Kaplan–Meier (KM) survival analysis and drug sensitivity analysis. Immunohistochemistry (IHC), qRT-PCR and western blotting were performed to measure the expression levels of related mRNAs or proteins. Biological features were evaluated by wound healing, cell migration and invasion assays and CCK-8 assays. A mouse spleen infection liver metastasis model was generated to confirm the role of PPP2R1B in the progression of liver metastasis in vivo. Results According to bioinformatics analysis, PPP2R1B is significantly associated with liver metastasis and survival in CRC patients, and these findings were further verified via immunohistochemistry (IHC), qPCR and Western blotting. Pathway enrichment and LC‒MS/MS analysis revealed that PPP2R1B is negatively associated with the MAPK/ERK signalling pathway. Additionally, PD98059, a MAPK/ERK pathway inhibitor, inhibited EMT in vitro by reversing the changes in key proteins involved in EMT signalling (ZEB1, E-cadherin and Snail) and ERK/MAPK signalling (p-ERK) mediated by PPP2R1B. Oxaliplatin sensitivity prediction and validation revealed that PPP2R1B silencing decreased Oxaliplatin chemosensitivity, and these effects were reversed by PD98059 treatment. Moreover, PPP2R1B was coimmunoprecipitated with p-ERK in vitro. A negative correlation between PPP2R1B and p-ERK expression was also observed in clinical CRC samples, and the low PPP2R1B/high p-ERK coexpression pattern indicated a poor prognosis in CRC patients. In vivo, PPP2R1B silencing significantly promoted liver metastasis. Conclusions This study revealed that PPP2R1B induces dephosphorylation of the p-ERK protein, inhibits liver metastasis and increases Oxaliplatin sensitivity in CRC patients and could be a potential candidate for therapeutic application in CRC.

This review explores the evolving landscape of blood biomarkers in the diagnosis of tuberculosis (TB), focusing on biomarkers derived both from the pathogen and the host. These biomarkers provide critical insights that can improve diagnostic accuracy and timeliness, essential for effective TB management. The document highlights recent advancements in molecular techniques that have enhanced the detection and characterization of specific biomarkers. It also discusses the integration of these biomarkers into clinical practice, emphasizing their potential to revolutionize TB diagnostics by enabling more precise detection and monitoring of the disease progression. Challenges such as variability in biomarker expression and the need for standardized validation processes are addressed to ensure reliability across different populations and settings. The review calls for further research to refine these biomarkers and fully harness their potential in the fight against TB, suggesting a multidisciplinary approach to overcome existing barriers and optimize diagnostic strategies. This comprehensive analysis underscores the significance of blood biomarkers as invaluable tools in the global effort to control and eliminate TB.

In this study, the effect of different acetylated distarch phosphate (ADSP) ratios (0, 1%, 2%, 3%, 4%, 5%) on the physicochemical characteristics and stability of the oyster sauce (OS) system was investigated. The texture, water state, interactions, rheological properties, microstructure, and stability of OS samples were analyzed through the texture analyser, low-field nuclear magnetic resonance (LF-NMR), particle diameter and zeta potential, fourier-transform infrared spectroscopy (FTIR), rheometer, and microscopes. The results revealed that the addition of ADSP improved the firmness, consistency, cohesiveness, and water-holding capacity of OS. Moreover, ADSP reduced the average particle size and zeta potential of OS, indicating that electrostatic and steric stabilization existed in the ADSP-OS system. The addition of ADSP enhanced the hydrogen bonding and decreased water mobility for OS system, processing a more continuous and smooth structure. All ADSP-OS samples were typical non-Newtonian fluids with shear-thinning characteristics. In addition, the non-significant instability index changes of ADSP-OS over the whole storage period confirmed the excellent long-term stabilization capability of OS prepared with ADSP. This study provides a theoretical basis for starch-based sauce products and contributes to the development of sauce products.

The western Pacific seamount area is abundant in both biological and mineral resources, making it a crucial location for international investigation of regional seabed resources. An essential stage in comprehending and advancing seamounts is gaining knowledge about the distribution characteristics and laws governing the seabed substrate. Deep-sea geological sampling is challenging because of the intricate nature of the deep-sea environment, resulting in increased difficulty in identifying and evaluating substrates. This study addresses the aforementioned issues by utilizing in-situ video footage obtained from the “Jiaolong” manned deep submersible and shipborne deep-water multibeam data. This data is used as a foundation for constructing a Western Pacific seamount areas substrate classification point set. Additionally, the paper introduces the mRMR-XGBoost substrate classification model. Substrate categorization in deep sea and mountainous regions has been successfully accomplished, yielding a classification accuracy of 92.5%. The classification experiments and box sampling results demonstrate that the mRMR-XGBoost substrate classification model proposed in this paper can efficiently use acoustic and optical data to accurately divide the substrate types in seamount areas, with better classification accuracy, when compared with commonly used machine learning models. It has a significant application value and the best classification effect on the two types of substrates: nodules and gravel substrates.

Guizhou Province has many multi-layer, thin-thick coal seams; however, complex geology, incomplete reservoir characterization, and sweet-spot selection technology prevent large-scale coalbed methane (CBM) development. This study evaluates the CBM reservoir properties within the Dahebian block using logging data, coal sample analysis, and well-testing data and develops a 3D static reservoir properties model to analyze their spatial and vertical propagation. A sweet spot evaluation model was established using a multi-level fuzzy method based on 9 parameters extracted from a 3D static reservoir properties model. The coal measure has 22 coal seams, and seams >2 m thick have 2 or 3 thin non-coal layers intercalated. Coal seams 1#, 7#, and 11# are thin to thick, deeply buried, widely distributed, and have high gas content and saturation. Undeformed and cataclastic coal predominates the coal seam 1# and 7#, whereas coal seam 11# is dominated by cataclastic and granulated coal. The southern and central parts of coal seam 7# and 11# have less tectonically deformed coal (TDC). Coal seams 1# and 7# have low permeability relative to seam 11# and are localized, while coal seams 11# have high permeability, are extensively distributed, and contain substantial gas concentrations. Comparative analysis of evaluation scores and CBM production statistics shows that high scores indicate sweet spots for CBM development. Sweet-spot potential was classified as high, medium, and low. Scattered sweet spots are found in single layers, while combined development (1# + 7#+11#) reveals a wider high-potential area in the south-central region. This area, featuring deep, thick coal seams, high permeability, gas saturation, reservoir pressure, and low TDC proportion, indicates significant development potential. This study validates CBM development statistics, identifies future development areas, and guides the development of geologically complex Guizhou CBM.

Summary: Facial infiltrating lipomatosis (FIL) is a congenital disorder. The pathogenesis of FIL is associated with PIK3CA mutations, but the underlying mechanisms remain undetermined. We found that the adipose tissue in FIL demonstrated adipocytes hypertrophy and increased lipid accumulation. All adipose-derived mesenchymal stem cells from FIL (FIL-ADSCs) harbored PIK3CA mutations. Moreover, FIL-ADSCs exhibited a greater capacity for adipogenesis. Knockdown of PIK3CA resulted in a reduction in the adipogenic potential of FIL-ADSCs. Furthermore, WX390, a dual-target PI3K/mTOR inhibitor, was found to impede PIK3CA-mediated adipogenesis both in vivo and in vitro. RNA sequencing (RNA-seq) revealed that the expression of transient receptor potential vanilloid subtype 1 (TRPV1) was upregulated after PI3K pathway inhibition, and overexpression or activation of TRPV1 both inhibited adipogenesis. Our study showed that PIK3CA mutations promoted adipogenesis in FIL-ADSCs and this effect was achieved by suppressing TPRV1. Pathogenesis experiments suggested that WX390 may serve as an agent for the treatment of FIL.

The incidence of ulcerative colitis (UC) is increasing each year, and its course is characterized by alternating remission-relapse; currently, there is no effective treatment for UC. Peptides produced from the hydrolysis of walnut proteins have physiological functions such as anti-inflammatory and antioxidant properties. The aim of this study was to analyze the preventive effect of walnut polypeptide (WP) on UC and to preliminarily screen bioactive peptides in WP. The results of in vitro experiments showed that WP was able to alleviate the LPS-induced inflammatory response by inhibiting M1 polarization in Raw 264.7 cells and thereby alleviating the LPS-induced inflammatory response. The results of in vivo experiments showed that dietary supplementation with 500 mg/kg WP significantly alleviated dextran sodium sulfate (DSS)-induced weight loss, colon shortening, and elevated DAI scores. WP treatment was able to suppress DSS-induced inflammatory responses in mice by inhibiting macrophage M1 polarization and NF-κB signaling pathway. WP intervention also helped maintain intestinal barrier integrity by promoting tight junction protein expression and mucus secretion. In addition, 16S rDNA sequencing showed that WP ameliorated gut microbial disorder induced by DSS, as evidenced by a decrease in the abundance of harmful bacteria (Erysipelatoclostridium, Helicobacter, and Parasutterella) and an increase in the abundance of beneficial bacteria (Flavonifractor, Anaerotignum, and Alistipes) after WP intervention. In conclusion, this study demonstrates that WP ameliorates DSS-induced colonic inflammation in mice by inhibiting inflammation, modulating the gut microbiota and repairing the intestinal barrier.

The water footprint (WF) is an essential indicator for assessing the pressure of human activities on freshwater resource utilization. The traditional WF model assumes that human water resource occupation comprises a green, blue, and grey WF, which can be linearly summed to the total WF. However, since there are two kinds of human demand for water resources, consumptive occupation and functional occupation, the relationship between them is not exclusive and does not have simple linear addition characteristics. The overlapping relationship between blue and grey WF has long been overlooked in the traditional WF calculation, resulting in a duplicate calculation of water requirement and exaggerating actual water resource demand. This study introduced a new index of blue-grey WF that deducted the overlapping portions of blue and grey WF, thereby calculating a region’s actual freshwater resource utilization. Northern Anhui, an arid region short of water resources with water pollution, was selected as a case study. The traditional WF calculation showed that the multi-year average WF of Northern Anhui was 3.44 × 1010 m3 from 2011 to 2020, with the grey, green, and blue WF accounting for 52.59 %, 27.63 %, and 19.78 %, respectively. The blue and grey WF overlapped each other and the blue WF can be fully covered by grey WF, resulting in a total blue-grey WF of 1.81 × 1010 m3, much lower than the sum of blue and grey WF. Based on the revised WF calculation model, the multi-year average WF of Northern Anhui was 2.76 × 1010 m3, decreased by 19.78 %, indicating a severe issue of duplicate calculation of blue and grey WF. The revised WF model could avoid the repeated calculation issues of water resources used by different functions. It provides a more reliable and accurate research method for regional water resources accounting and management decision-making.

IntroductionEnvironmental conditions play a prime role in the growth and development of plant species, exerting a significant influence on their reproductive capacity. Soybean is sensitive to high temperatures during flowering and seed developmental stages. Little is known about the combined environmental effect of temperature and CO2 on seed yield and quality and its future generation.MethodsA study was conducted to examine the effect of temperature (22/14°C (low), 30/22°C (optimum), and 38/30°C (high)), and CO2 (420 ppm (ambient; aCO2) and 720 ppm (elevated; eCO2)) on seed yield, quality, and transgenerational seedling vigor traits of soybean cultivars (DS25-1 and DS31-243) using Soil-Plant-Atmospheric-Research facility.ResultsA significant temperature effect was recorded among yield and quality attributes. At high-temperature, the 100-seed weights of DS25-1 and DS31-243 declined by 40% and 24%, respectively, over the optimum temperature at aCO2. The harvest index of varieties reduced by 70% when exposed to high temperature under both aCO2 and eCO2, compared to the optimum temperature at aCO2. The seed oil (- 2%) and protein (8%) content altered when developed under high temperature under aCO2. Maximum sucrose (7.5%) and stachyose (3.8%) accumulation in seeds were observed when developed under low temperatures and eCO2. When the growing temperature increased from optimum to high, the seed oleic acids increased (63%), while linoleic and linolenic acids decreased (- 28% and - 43%, respectively). Significant temperature and CO2 effects were observed in progenies with the highest maximum seedling emergence (80%), lesser time to 50% emergence (5.5 days), and higher seedling vigor from parents grown at low-temperature treatment under eCO2.DiscussionExposure of plants to 38/30°C was detrimental to soybean seed yield, and eCO2 levels did not compensate for this yield loss. The high temperature during seed developmental stages altered the chemical composition of the seed, leading to an increased content of monounsaturated fatty acids. The findings suggest that parental stress can significantly impact the development of offspring, indicating that epigenetic regulation or memory repose may be at play.

Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor is a highly aggressive malignant tumor that typically presents in bone and soft tissue. Primary ES of the intestine is relatively rare, which poses a challenge in distinguishing it from other primary tumors of the small intestine through imaging. This article details a case study of ES originating in the intestine. Computed tomography (CT) imaging suggested a small intestinal stromal tumor, and so the patient underwent resection of the small bowel and omental tumor. Pathology results confirmed the diagnosis of ES of the small intestine. Following surgery, the patient underwent six cycles of chemotherapy, and a follow-up positron emission tomography–CT revealed widespread dissemination of the disease with intraperitoneal metastasis, ultimately resulting in the death of the patient.

ObjectiveThis study aimed to develop and validate a survival prediction model and nomogram to predict survival in patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma undergoing treatment with anti-programmed cell death 1 receptor (PD-1). This model incorporates immune-related adverse events (irAEs) alongside common clinical characteristics as predictive factors.MethodA dataset comprising 255 adult patients diagnosed with advanced G/GEJ adenocarcinoma was assembled. The irAEs affecting overall survival (OS) to a significant degree were identified and integrated as a candidate variable, together with 12 other candidate variables. These included gender, age, Eastern cooperative oncology group performance status (ECOG PS) score, tumor stage, human epidermal growth factor receptor 2 (HER2) expression status, presence of peritoneal and liver metastases, year and line of anti-PD-1 treatment, neutrophil-to-lymphocyte ratio (NLR), controlling nutritional status (CONUT) score, and Charlson comorbidity index (CCI). To mitigate timing bias related to irAEs, landmark analysis was employed. Variable selection was performed using the least absolute shrinkage and selection operator (LASSO) regression to pinpoint significant predictors, and the variance inflation factor was applied to address multicollinearity. Subsequently, a Cox regression analysis utilizing the forward likelihood ratio method was conducted to develop a survival prediction model, excluding variables that failed to satisfy the proportional hazards (PH) assumption. The model was developed using the entire dataset, then internally validated through bootstrap resampling and externally validated with a cohort from another Hospital. Furthermore, a nomogram was created to delineate the predictive model.ResultsAfter consolidating irAEs from the skin and endocrine systems into a single protective irAE category and applying landmark analysis, variable selection was conducted for the prognostic prediction model along with other candidate variables. The finalized model comprised seven variables: ECOG PS score, tumor stage, HER2 expression status in tumor tissue, first-line anti-PD-1 treatment, peritoneal metastasis, CONUT score, and protective irAE. The overall concordance index for the model was 0.66. Calibration analysis verified the model’s accuracy in aligning predicted outcomes with actual results. Clinical decision curve analysis indicated that utilizing this model for treatment decisions could enhance the net benefit regarding 1- and 2-year survival rates for patients.ConclusionThis study developed a prognostic prediction model by integrating common clinical characteristics of irAEs and G/GEJ adenocarcinoma. This model exhibits good clinical practicality and possesses accurate predictive ability for overall survival OS in patients with advanced G/GEJ adenocarcinoma.

BackgroundGut microbiota has significant impact on the cardio-metabolism and inflammation, and is implicated in the pathogenesis and progression of atherosclerosis. However, the long-term prospective association between trimethylamine N-oxide (TMAO) level and major adverse clinical events (MACEs) in patients with coronary artery disease (CAD) with or without diabetes mellitus (DM) habitus remains to be investigated.MethodsThis prospective, single-center cohort study enrolled 2090 hospitalized CAD patients confirmed by angiography at Beijing Hospital from 2017-2020. TMAO levels were performed using liquid chromatography-tandem mass spectrometry. The composite outcome of MACEs was identified by clinic visits or interviews annually. Multivariate Cox regression analysis, Kaplan-Meier analysis, and restricted cubic splines were mainly used to explore the relationship between TMAO levels and MACEs based on diabetes mellitus (DM) habitus.ResultsDuring the median follow-up period of 54 (41, 68) months, 266 (12.7%) developed MACEs. Higher TMAO levels, using the tertile cut-off value of 318.28 ng/mL, were significantly found to be positive dose-independent for developing MACEs, especially in patients with DM (HR 1.744, 95%CI 1.084-2.808, p = 0.022).ConclusionsHigher levels of TMAO are significantly associated with long-term MACEs among CAD patients with DM. The combination of TMAO in patients with CAD and DM is beneficial for risk stratification and prognosis.

Triple negative breast cancer (TNBC) as the most aggressive molecular subtype of breast cancer is characterized by high cancer cell proliferation and poor patient prognosis. Abnormal lipid metabolism contributes to the malignant process of cancers. Study observed significantly enhanced cholesterol biosynthesis in TNBC. However, the mechanisms underlying the abnormal increase of cholesterol biosynthesis in TNBC are still unclear. Hence, we identified a member of the serine/threonine protein kinase family PKMYT1 as a key driver of cholesterol synthesis in TNBC cells. Aberrantly high-expressed PKMYT1 in TNBC was indicative of unfavorable prognostic outcomes. In addition, PKMYT1 promoted sterol regulatory element-binding protein 2 (SREBP2)-mediated expression of enzymes related to cholesterol biosynthesis through activating the TNF/ TNF receptor-associated factor 1 (TRAF1)/AKT pathway. Notably, downregulation of PKMYT1 significantly inhibited the feedback upregulation of statin-mediated cholesterol biosynthesis, whereas knockdown of PKMYT1 promoted the drug sensitivity of atorvastatin in TNBC cells. Overall, our study revealed a novel function of PKMYT1 in TNBC cholesterol biosynthesis, providing a new target for targeting tumor metabolic reprogramming in the cancer.

BackgroundThe association between dietary zinc intake and epilepsy remains unclear. This study aimed to investigate the relationship between zinc intake from the diet and epilepsy, employing Mendelian randomization (MR) to explore potential causal links between zinc and epilepsy.MethodsThe cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2018. Among the 4,434 participants included, 1.5% (67/4,434) reported having epilepsy. Restricted cubic spline models and logistic regression models were employed to examine the relationships between dietary zinc intakes and epilepsy. Subsequently, a 2-sample Mendelian randomization (MR) analysis was conducted using the inverse variance weighted (IVW) approach as the primary analysis.ResultsIn the restricted cubic spline (RCS) analysis, the relationship between dietary zinc consumption and epilepsy displayed an L-shaped curve (nonlinear, p = 0.049). After multivariate adjustments, the adjusted odds ratios for epilepsy in T2 (5.0–11.0 mg/day) and T3 (≥11.0 mg/day) were 0.49 (95% confidence interval [CI]: 0.26–0.92, p = 0.026) and 0.60 (95% CI: 0.31–1.17, p = 0.132), respectively, compared to the lowest dietary zinc consumption tertile (T1, ≤5.0 mg/day). The IVW method indicated that genetically predicted zinc intake per standard-deviation increase was inversely associated with three types of epilepsy, including all types of epilepsy (OR = 1.06, 95% CI: 1.02–1.11, p = 0.008), generalized epilepsy (OR = 1.13, 95% CI: 1.01–1.25, p = 0.030), and focal epilepsy (documented hippocampal sclerosis) (OR = 1.01, 95% CI: 1.00–1.02, p = 0.025).ConclusionOur findings suggest that a daily zinc intake ranging from 5.0 to 11.0 mg is associated with the lowest risk of epilepsy. Furthermore, Mendelian randomization (MR) studies provide additional support for the existence of a causal relationship between zinc and epilepsy.

BackgroundPrevious studies suggest a link between diet-derived circulating antioxidants and epilepsy, but the causal relationship is unclear. This study aims to investigate the causal effect of these antioxidants on epilepsy.MethodsTo assess the causal link between dietary antioxidants and epilepsy risk, we conducted a two-sample Mendelian randomization (MR) analysis. This involved examining antioxidants such as zinc, selenium, α- and γ-tocopherol, vitamin A (retinol), vitamin C (ascorbate), and vitamin E (α-tocopherol). We utilized instrumental variables (IVs) which were genetic variations highly associated with these commonly used antioxidants. Exposure data were sourced from a comprehensive genome-wide association study (GWAS). We aggregated data from the International League Against Epilepsy (ILAE) Consortium sample, which included various types of epilepsy, as an outcome variable. Finally, we applied the inverse variance weighting method and conducted sensitivity analyses for further validation.ResultsBased on the primary MR estimates and subsequent sensitivity analyses, the inverse variance weighting (IVW) method revealed that a genetically predicted increase in zinc per standard deviation was positively associated with three types of epilepsy. This includes all types of epilepsy (OR = 1.06, 95% CI: 1.02–1.11, p = 0.008), generalized epilepsy (OR = 1.13, 95% CI: 1.01–1.25, p = 0.030), and focal epilepsy (documented hippocampal sclerosis) (OR = 1.01, 95% CI: 1.00–1.02, p = 0.025). However, there is no evidence indicating that other antioxidants obtained from the diet affect the increase of epilepsy either positively or negatively.ConclusionOur research indicates that the risk of developing epilepsy may be directly linked to the genetic prediction of zinc, whereas no such association was found for other antioxidants.

Individual tree detection and counting in unmanned aerial vehicle (UAV) imagery constitute a vital and practical research field. Vegetation remote sensing captures large-scale trees characterized by complex textures, significant growth variations, and high species similarity within the vegetation, which presents significant challenges for annotation and detection. Existing methods based on bounding boxes have struggled to convey semantics information about tree crowns. This paper proposes a novel deep learning network called VrsNet based on the density map information. The proposed work pioneers the segmentation and counting application by utilizing the semantic information of Gaussian contour. Besides, we sample and create the UAV vegetation remote sensing density dataset TreeFsc for experiments. In quantitative comparison across multiple datasets, the proposed method demonstrates high performance, with a 3.45 increase in MAE and a 4.75 increase in RMSE. Experiments demonstrate superior cross-region, cross-scale, and cross-species target detection capabilities of the proposed approach compared with the existing object detection methods. Our code and dataset are available at: https://github.com/luotiger123/VrsNet/tree/main/VrsNet.

Objective: An mRNA expression-based stemness index (mRNAsi) has been developed to characterize cancer stemness. However, the predictive value of mRNAsi-based signature in therapeutic resistance and immunotherapy in thyroid cancer (THCA) remains unclarified. This study evaluated and validated the role of mRNAsi in drug sensitivity, its relationship between mRNAsi and THCA clinical features and immunity based on bioinformatics. Methods: Based on transcriptome data of THCA patients from the Tumor Genome Atlas Project (TCGA) database, and expression data of multifunctional stem cell samples from the Progenitor Cell Biology Consortium (PCBC) databases, mRNAsi was calculated by the '' one class logistic regression (OCLR)'' method, Molecular subtypes of TCGA-THCA samples were identified with mRNAsi-related genes using ConsensusClusterPlus method. The gene mutation, clinical characteristics, immune characteristics, TIDE and drug sensitivity were compared among molecular subtypes. A prognostic model was designed with Lasso cox method. Modulation of malignant phenotype of THCA cell lines by model characterization genes is validated by CCK-8, flow cytometry. DNA methylation disorder in promoter region was analyzed between risk groups. The model was validated for survival in the internal Test dataset, while TCGA pan-cancer and immunotherapy datasets were further employed to validate the performance of this model. Results: We obtained a total of 78 stem cell samples, each containing the expression profile of 8087 mRNA genes. Based on mRNAsi, THCA was divided into 3 subtypes. Subtype C2 had the poorest prognosis and highest immune score, while subtype C3 had the best prognosis, lowest mRANsi and highest TIDE score. Patients in subtype C2 showed higher sensitivity to Cisplatin, Erlotinib, Paclitaxel, and Lapatinib. The prognostic signature was generated using 5 mRNAsi-related genes, which could predict prognosis for THCA. qRT-PCR results showed that the expression of 5 genes were various in Hth7 and KTC-1 cells, and inhibition CELSR3 expression increased percentage of apoptosis in Hth7 and KTC-1 cells. mRNAsi related DNA methylation sites were mainly enriched in tumor related pathways. Good performance of this model was validated in Test dataset, pan-cancer and immunotherapy datasets. Conclusion: This study identified three subtypes for classification and developed a prognostic model with mRNAsi-related genes, which provided great potential for prognosis and immunotherapy prediction.

Study region: Mihe River Basin, China. Study focus: The composite interaction of natural and anthropogenic factors has increased the complexity of hydrological variation and pollutant transformation in rivers, making it challenging to effectively analyze the spatial and temporal distribution characteristics of pollution sources. We combined two empirical models to quantitatively assess the spatial-temporal distribution of pollution sources in a high-flow variable river such as the Mihe River, providing a scientific basis and methodological support for watershed management. New regional hydrological insights: The findings show that: (1) The average nitrogen and phosphorus loading of the river during 2015–2021 were 13.08 × 103 and 38.03 t·a-1, respectively, exhibiting significant fluctuations with flow; (2) a load apportionment model (LAM) revealed that nonpoint sources were primary pollution sources for most of the period, and average contributions of nitrogen and phosphorus loading accounted for 81.7 and 99.6%, respectively; (3) an export coefficient model (ECM) revealed that nutrient loading was concentrated in the middle and lower reaches, which was highly consistent with the distribution of cropland and urban land. (4) The results of the two methods were consistent. However, LAM and ECM underestimate and overestimate total nutrient loading, respectively. Combining these two methods facilitates the accurate determine of spatial and temporal distribution of pollution sources in a high-flow variable river.