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Abstract As a milestone in the exploration of topological physics, Fermi arcs bridging Weyl points have been extensively studied. Weyl points, as are Fermi arcs, are believed to be only stable when preserving translation symmetry. However, no experimental observation of aperiodic Fermi arcs has been reported so far. Here, we continuously twist a bi-block Weyl meta-crystal and experimentally observe the twisted Fermi arc reconstruction. Although both the Weyl meta-crystals individually preserve translational symmetry, continuous twisting operation leads to the aperiodic hybridization and scattering of Fermi arcs on the interface, which is found to be determined by the singular total reflection around Weyl points. Our work unveils the aperiodic scattering of Fermi arcs and opens the door to continuously manipulating Fermi arcs.

Bioabsorbable zinc (Zn)-based materials for bone defect repair have received increasing attention. Based on 3D printing technology, this study innovatively designed and manufactured pure Zn and Ti6Al4V porous scaffolds. The pore size of the scaffold was 700 μm and the porosity was 70%. Compared with the traditional Ti6Al4V scaffolds, it was found that the Zn scaffolds had a larger deformation, the ultimate compressive stress was 18 MPa, but the ultimate strain could exceed 20%, while Ti6Al4V was only 6%. The elastic modulus of the Zn scaffolds was also lower than that of Ti6Al4V, which was 0.25 GPa, which can meet bone repair requirements in the non-weight-bearing area. However, Zn scaffolds had better strain capacity and lower elastic modulus, so they had less stress-shielding effect on bone. Degradation experiments also proved that the Zn scaffold had good degradation performance. Further in vivo and in vitro experiments showed that the Zn scaffolds had better osteogenic ability than the Ti6Al4V scaffolds. The findings of our study underscore the potential of integrating pure Zn into 3D printed scaffolds for their application in orthopedic scenarios.

Circular RNAs (circRNAs) and small non-coding RNAs of the head-to-junction circle in the construct play critical roles in gene regulation and are significantly associated with breast cancer (BC). Numerous circRNAs are potential cancer biomarkers that may be used for diagnosis and prognosis. Widespread expression of circRNAs is regarded as a feature of gene expression in highly diverged eukaryotes. Recent studies show that circRNAs have two main biological modulation models: sponging and RNA-binding. This review explained the biogenesis of circRNAs and assessed emerging findings on their sponge function and role as RNA-binding proteins (RBPs) to better understand how their interaction alters cellular function in BC. We focused on how sponges significantly affect the phenotype and progression of BC. We described how circRNAs exercise the translation functions in ribosomes. Furthermore, we reviewed recent studies on RBPs, and post-protein modifications influencing BC and provided a perspective on future research directions for treating BC.

Abstract Background A consensus has not been reached on the value of prostate-specific antigen density (PSAD) as a predictor of biochemical recurrence of prostate cancer. This meta-analysis aimed to evaluate the association between PSAD and biochemical recurrence of prostate cancer after primary treatment. Methods Two authors systematically searched PubMed, Web of Science, and Embase databases (up to August September 10, 2023) to identify studies that assessed the value of pretreatment PSAD in predicting biochemical recurrence after primary treatment (radical prostatectomy or radiotherapy) of prostate cancer. A random effect model was used to pool adjusted hazard ratios (HR) with 95% confidence intervals (CI) for biochemical recurrence. Results Nine studies with 4963 patients were eligible for the meta-analysis. The reported prevalence of biochemical recurrence ranged from 4 to 55.1%. For patients with higher PSAD compared to those with low PSAD, the pooled HR of biochemical recurrence was 1.59 (95% CI 1.21–2.10). Subgroup analysis showed that the pooled HR of biochemical recurrence was 1.80 (95% CI 1.34–2.42) for patients who received radical prostatectomy, and 0.98 (95% CI 0.66–1.45) for patients who received radiotherapy. Conclusions Elevated pretreatment PSAD may be an independent predictor for biochemical recurrence of prostate cancer after radical prostatectomy. Determining PSAD could potentially improve the prediction of biochemical recurrence in patients with prostate cancer.

Abstract Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC50 values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

Conventional photodynamic therapy (PDT) approaches face challenges including limited light penetration, low uptake of photosensitizers by tumors, and lack of oxygen in tumor microenvironments. One promising solution is to internally generate light, photosensitizers, and oxygen. This can be accomplished through endogenous production, such as using bioluminescence as an endogenous light source, synthesizing genetically encodable photosensitizers in situ, and modifying cells genetically to express catalase enzymes. Furthermore, these strategies have been reinforced by the recent rapid advancements in synthetic biology. In this review, we summarize and discuss the approaches to overcome PDT obstacles by means of endogenous production of excitation light, photosensitizers, and oxygen. We envision that as synthetic biology advances, genetically engineered cells could act as precise and targeted “living factories” to produce PDT components, leading to enhanced performance of PDT.

Creep rupture tests were conducted on 67 thin-walled DD6 specimens, with thicknesses ranging from 0.35 mm to 1.50 mm, at temperatures of 760 °C, 850 °C, 980 °C, and 1100 °C, revealing a log-linear relationship between rupture lifetimes and specimen thicknesses. Micro-CT observations identified an inhomogeneous distribution of creep micropores around dendrites as a contributing factor to the thickness debit effect. Based on the reliability mathematical method, a possible explanation was proposed for the parabolic law relationship between rupture times and specimen thicknesses. In addition, a thickness debit characterization parameter (TDP) was derived to quantify the trend of creep property degradation as thickness decreases. The TDP equation effectively predicted the creep rupture lifetimes of DD6 thin-walled specimens mostly within a scatter band factor of 2.

Access to healthcare services using public transportation (PT-based healthcare accessibility) is a crucial aspect in achieving healthcare equity as it affects individuals’ ability to receive healthcare. Previous research has focused on the spatial features of healthcare accessibility. However, less attention has been given to its temporal characteristics, which can be influenced by transit schedules, multimodal connectivity, congestion, and other factors. This study proposes a framework to better understand the impacts of temporally varying PT-based healthcare accessibility on healthcare equity. A case study of Shanghai, China is used to illustrate the temporal variation of healthcare accessibility, with a focus on hourly inter- and intra-regional disparities. These disparities are captured using the Gini coefficient and Theil index. Additionally, the study introduces bivariate local Moran’s I to identify healthcare shortage areas and evaluate the spatial autocorrelation between population density and healthcare accessibility. The findings of this study reveal that the accessibility to healthcare services experiences significant fluctuations throughout the day, leading to temporal variations in healthcare equity. Subway service quality contributes more to temporal variations than bus service quality. The lowest point of such equity is reached when PT operates at its full capacity. On a spatial level, individuals residing in newly developed regions, which surround the historical urban core or recently planned city subcenters, tend to experience decreased accessibility to healthcare via public transportation. Consequently, it results in a heightened reliance on motorized transportation in these areas. These findings provide insights that can inform the design of PT accessibility-based strategies, healthcare improvement plans and inclusive housing policies, to address healthcare equity issues in metropolitan areas. By considering both spatial and temporal factors, we can better understand the complex relationships between transportation and healthcare accessibility to promote equitable access to healthcare services and foster social equity.

Objective: To precisely assess preoperative osteoporosis in patients, a more precise method for evaluating osteoporosis is being developed to better guide the use of bone cement reinforced screws. Method: The retrospective analysis was conducted on patients who underwent posterior lumbar decompression and fusion internal fixation at Shanghai Tongren Hospital.The general information, bone mineral density assessment data, Fracture risk prediction rate(WHO Fracture Risk Assessment Tool (FRAX)), and whether to use cement reinforced screws were collected. Definition of combination method: T value ​3.5.The diagnostic rates of osteoporosis were compared between dual energy x-ray absorptiometry(DXA), Hounsfield Units(HU), Vertebral Bone Quality (VBQ), National Bone Health Alliance(NBHA), and combination methods, and the correlation between different methods was analyzed. Binary logistic regression was used to analyze the significant influencing factors of the use of cement-reinforced screws. Result: A total of 178 patients were enrolled in the study, aged 65.73 ​± ​14.43 years, 121 female, 57 male, Body Mass Index(BMI) was 22.88 ​± ​3.52, 57 (32.0%) used cement reinforced screws, and 14 (7.9%) had previous fracture history.The diagnostic rates of osteoporosis by DXA, HU, VBQ, NBHA and combination method were 22.5% (40/178), 47.2% (84/178), 56.2% (100/178), 64.0% (114/178) and 75.8% (135/178), respectively.HU, VBQ, NBHA, and combination methods were significantly different from DXA in the diagnosis rate of osteoporosis (P ​

Children’s study tables are an integral part of a child’s learning life. Consumers are often attracted to their styling when deciding on the use and purchase of a children’s study desk. This study focused on consumption preference for the styling of children’s study desks and delved into the factors that influence these preferences. An important aspect of this research is to understand how different shapes of children's desks influence consumer preferences through morphological analysis. The study breaks down these desks into six different parts based on morphological analysis: backplane, bookshelves, desktop, cabinet, drawer, and table legs. Through a hierarchical analysis (AHP) and pairwise comparisons, the study created a hierarchy of preferred morphological elements. The hierarchy ranked the importance of each element in influencing consumption preference, revealing the order of preference from backsplash to table legs. In addition, by integrating personal interviews and employing Qualitative Comparative Analysis (QCA), this study provides insights into the most preferred components – backplane and bookshelves. This integrated approach revealed a preference for desks with curved backsplashes and multi-tiered functional shelves, which was ultimately validated by successfully combining weighted rankings of specific component styles.

Abstract The central Sichuan Basin, located in western China, holds great significance in terms of hydrocarbon production, especially in relation to complex carbonate reservoirs, notably the Qixia Formation of the Middle Permian epoch. However, the comprehensive evaluation of this geological formation presents considerable challenges due to complex lithology, limited availability of reservoir property data at various scales, inadequacies in data integration, and the absence of a reliable reservoir ranking system for development decision making. Previous studies primarily relying on conventional data at the reservoir level, such as well logs and geological information, have proven insufficient in accurately characterizing the reservoir. This is especially evident without precise lithological information and detailed knowledge of microscale properties, which are crucial for effective reservoir evaluation. To address these challenges, this study integrates advanced technologies like X-ray diffraction, micro-CT and scanning electron microscope (SEM) techniques in digital drill cutting analysis at the microscale. A novel scoring system has been developed using a prominent component analysis (PCA) approach and an expert scoring system, which incorporates existing conventional well log data and digital cutting analysis. This scoring system has been validated using actual production data, thus establishing a robust evaluation methodology for assessing the exploration potential and optimizing development strategies for carbonate gas reservoirs in the Qixia Formation. The innovative approach, which incorporates parameters at both micro- and macroscales, holds promising potential in facilitating future exploration and development efforts.

Abstract Objectives The study aims to assess the effect of baseline glycated hemoglobin (HbA1c) levels on atrial fibrillation (AF) recurrence following cryoballoon ablation in patients with and without diabetes. Methods Consecutive AF patients receiving first cryoballoon ablation between April 2018 and April 2021 were included. AF recurrence and other clinical outcomes were recorded for a minimum of 12 months post-ablation, with regular assessments at 3, 6, and 12 months, followed by annual check-ups. The primary outcome was AF recurrence after ablation at longest follow-up. Multivariate Cox proportional hazards regression models were utilized to calculate the hazard ratio (HR) and 95% CI per standard deviation (SD) increase of baseline HbA1c level. Results 335 patients were included in the analysis. The mean age was 61.7 years, 61.8% were male. 12.8% had type 2 diabetes, and 81.7% of patients had paroxysmal AF. The median level of HbA1c was 5.3%, and the mean CHA2DS2-VASc score was 1.8. All cryoballoon ablation procedures, utilizing a 28-mm balloon, achieved successful pulmonary vein isolation. Over a median follow-up of 18 months, 105 patients (31.3%) experienced AF recurrence. In multivariate Cox proportional hazards analysis, a higher HbA1c level, persistent AF (HR 1.91, 95% CI 1.08 to 3.39, P = 0.026), alcohol consumption (HR 2.67, 95% CI 1.33 to 5.37, P = 0.006), and Nadir RSPV (HR 1.04, 95% CI 1.00 to 1.08, P = 0.005) were significant predictors of AF recurrence. Per-SD increase of HbA1c was associated with a 1.75-fold increase risk of AF recurrence (HR 1.75, 95% CI 1.39 to 2.21, P

Abstract Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Abstract Coronary chronic total occlusion (CTO) often occurs in patients with obstructive coronary artery disease, which remains one of the greatest challenges for interventional cardiologists. Coronary computed tomography angiography (CCTA) with its emerging post-processing techniques can provide a detailed assessment of CTO lesions before percutaneous coronary intervention (PCI), playing an important role in the clinical management of CTO PCI, from early diagnosis, pre-procedural outcome prediction, the crossing algorithm planning, intraprocedural guidance, and finally post-procedural assessment and follow-up. In addition, the feasibility of CT perfusion (CTP) in patients with CTO has been validated. Combined CCTA and CTP have the great potential to be the one-stop-shop imaging modality for assessing both anatomy and function of CTO lesions. This review aims to make radiologists understand the role of CCTA in the diagnosis and assessment of CTO lesions, thus assisting interventionalists in optimizing CTO PCI crossing strategies with the expertise of radiologists. Critical relevance statement The anatomical features of CTO on CCTA can reveal the complexity of CTO lesions and are associated with CTO PCI outcome, thus helping interventionalists optimize CTO PCI crossing strategies. Key points • CTO is the common lesion in invasive coronary angiography, and CTO PCI is technically difficult and its success rate is relatively low. • Length, collaterals, and attenuation-related signs can help distinguish CTO from subtotal occlusion. • The anatomical features of CTO lesions can help grade the difficulty of CTO PCI and predict procedural outcomes and long-term outcomes of CTO PCI. • The real-time fusion of CCTA with fluoroscopic angiography can be applied in highly complicated CTO lesions. • After CTO PCI, CCTA can help guide a second CTO PCI re-entry or follow up stent patency. Graphical Abstract

Abstract Background Behaviors in captive animals, including changes in appetite, activity level, and social interaction, are often seen as adaptive responses. However, these behaviors may become progressively maladaptive, leading to stress, anxiety, depression, and other negative reactions in animals. Results In this study, we investigated the whole-genome sequencing data of 39 giant panda individuals, including 11 in captivity and 28 in the wild. To eliminate the mountain range effect and focus on the factor of captivity only, we first performed a principal component analysis. We then enumerated the 21,474,180 combinations of wild giant pandas (11 chosen from 28) and calculated their distances from the 11 captive individuals. The 11 wild individuals with the closest distances were used for the subsequent analysis. The linkage disequilibrium (LD) patterns demonstrated that the population was almost eliminated. We identified 505 robust selected genomic regions harboring at least one SNP, and the absolute frequency difference was greater than 0.6 between the two populations. GO analysis revealed that genes in these regions were mainly involved in nerve-related pathways. Furthermore, we identified 22 GO terms for which the selection strength significantly differed between the two populations, and there were 10 nerve-related pathways among them. Genes in the differentially abundant regions were involved in nerve-related pathways, indicating that giant pandas in captivity underwent minor genomic selection. Additionally, we investigated the relationship between genetic variation and chromatin conformation structures. We found that nucleotide diversity (θπ) in the captive population was correlated with chromatin conformation structures, which included A/B compartments, topologically associated domains (TADs) and TAD-cliques. For each GO term, we then compared the expression level of genes regulated by the above four factors (AB index, TAD intactness, TAD clique and PEI) with the corresponding genomic background. The retained 10 GO terms were all coordinately regulated by the four factors, and three of them were associated with nerve-related pathways. Conclusions This study revealed that giant pandas in captivity undergo short-term adaptation in nerve-related pathways. Furthermore, it provides new insights into the molecular mechanism of gene expression regulation under short-term adaptation to environmental change.

Abstract Background Chronic Achilles tendon ruptures (CATR) often require surgical intervention to restore function. Despite numerous treatment modalities available, the optimal management strategy remains controversial given the limited high-quality evidence available. This article aims to provide evidence-based guidelines for the surgical management of CATR through a comprehensive systematic review of the available data. The consensus reached by synthesizing the findings will assist clinicians in making informed decisions and improving patient outcomes. Methods A group of 9 foot surgeons in three continents was consulted to gather their expertise on guidelines regarding the surgical management of CATR. Following the proposal of 9 clinical topics, a thorough and comprehensive search of relevant literature published since 1980 was conducted for each topic using electronic databases, including PubMed, MEDLINE, and Cochrane Library, to identify relevant studies published until 1 October 2023. All authors collaborated in drafting, discussing, and finalizing the recommendations and statements. The recommendations were then categorized into two grades: grade a (strong) and grade b (weak), following the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) concept. Additionally, feedback from 21 external specialists, who were independent from the authors, was taken into account to further refine and finalize the clinical guidelines. Results Nine statements and guidelines were completed regarding surgical indications, surgical strategies, and postoperative rehabilitation protocol. Conclusion Based on the findings of the systematic review, this guideline provides recommendations for the surgical management of CATR. We are confident that this guideline will serve as a valuable resource for physicians when making decisions regarding the surgical treatment of patients with CATR.

Heavy metal contamination in water and soil presents a growing global issue that poses significant risks to environmental integrity and human well-being. Various heavy metals, including arsenic (As), lead (Pb), mercury (Hg), cadmium (Cd), and chromium (Cr), contaminate ecosystems. These metals enter the environment through both natural processes and human activities such as coal mining, leather production, metal processing, agriculture, and industrial waste disposal. With their high toxicity and tendency to accumulate in organisms, heavy metals induce oxidative stress in cells, resulting in organelle damage. This toxicity can lead to genetic mutations and histone alterations. Given the severe effects of heavy metals, urgent actions are required to eliminate them from polluted soil and water. While physicochemical techniques like membrane filtration, precipitation, oxidation, and reduction exist, they have limitations. Hence, there is a pressing need to devise environmentally friendly and cost-efficient approaches for heavy metal removal. This article examines heavy metal contamination in water and soil, its adverse impacts, and the cleanup of heavy metals using eco-friendly methods.

In this study, the dynamic changes of different anthocyanins in the processing of ‘Ziyan’ tea wine were investigated quantitatively. Results showed that six types of anthocyanins, namely petunidin, malvidin, pelargonidin, delphinidin, cyanidin and peonidin, as well as two co-pigmented substances, procyanidins and flavonoids, were detected in ‘Ziyan’ tea wine. As fermentation proceeded, the contents of petunidin, pelargonidin, delphinidin, cyanidin and peonidin decreased. Among them, petunidin, peonidin and pelargonidin showed a tendency of decreasing first, then increasing and finally decreasing, whereas delphinidin and cyanidin continued to decrease during fermentation. Variation trend of procyanidins and flavonoids was consistent with those of petunidin. Furthermore, metabolism of delphinidin, cyanidin and pelargonidin were main pathways responsible for the anthocyanin changes during ‘Ziyan’ tea wine processing. These findings suggested that the color of ‘Ziyan’ tea wine was achieved by the combination of various anthocyanins in different ratios and the co-pigmentation of procyanidins and flavonoids.

Background Fibroblast growth factor 21 (FGF21) has a protective effect against cardiovascular disease. However, the role of FGF21 in hypertension remains elusive.Methods Ten-week-old male C57BL/6 mice were randomly divided into normal-salt (NS) group, NS+FGF21 group, deoxycorticosterone acetate-salt (DOCA) group and DOCA+FGF21 group. The mice in NS group underwent uninephrectomy without receiving DOCA and 1% NaCl and the mice in DOCA group were subjected to uninephrectomy and DOCA-salt (DOCA and 1% NaCl) treatment for 6 weeks. At the same time, the mice were infused with vehicle (artificial cerebrospinal fluid, aCSF) or FGF21 (1 mg/kg) into the bilateral paraventricular nucleus (PVN) of mice.Results Here, we showed that FGF21 treatment lowered DOCA salt-induced inflammation and oxidative stress in the PVN, which reduced sympathetic nerve activity and hypertension. Mechanistically, FGF21 treatment decreased the expression of HNF4α and inhibited the binding activity of HNF4α to the promoter region of ACE2 in the PVN of DOCA salt-treated mice, which further up-regulated ACE2/Ang (1–7) signals in the PVN. In addition, ACE2 deficiency abolished the protective effect of FGF21 in DOCA salt-treated mice, suggesting that FGF21-mediated antihypertensive effect was dependent on ACE2.Conclusions The results demonstrate that FGF21 protects against salt-sensitive hypertension via regulating HNF4α/ACE2/Ang (1–7) axis in the PVN of DOCA salt-treated mice via multi-organ crosstalk between liver, brain and blood vessels.

ABSTRACTCAR-T cell therapy has emerged as a significant approach for the management of hematological malignancies. Over the past few years, the utilization of CAR-T cells in the investigation and treatment of solid tumors has gained momentum, thereby establishing itself as a prominent area of research. This descriptive study involved the retrieval of articles about CAR-T cell therapy for solid tumors from the Web of Science Core Collection (WoSCC) database. Subsequently, bibliometric analysis and knowledge map analysis were conducted on these articles. The field under consideration is currently experiencing a period of swift advancement, as evidenced by the escalating number of publications in this domain each year. The United States holds an indisputable position as the foremost leader in this particular field, with the University of Pennsylvania emerging as the most active institution. The authors with the highest citation frequency and co-citation frequency are Carl H. June and Shannon L. Maude, respectively. The research hotspots in this field mainly focus on five aspects. Additionally, 10 emerging themes were identified. This study undertakes a comprehensive, systematic, and objective analysis and exploration of the field of CAR-T cell treatment for solid tumors, utilizing bibliometric methods. The findings of this study are expected to serve as a valuable reference and enlightenment for future research endeavors in this particular domain.

ABSTRACTHigh-concentration protein formulation is of paramount importance in patient-centric drug product development, but it also presents challenges due to the potential for enhanced aggregation and increased viscosity. The analysis of critical quality attributes often necessitates the transfer of samples from their primary containers together with sample dilution. Therefore, there is a demand for noninvasive, in situ biophysical methods to assess protein drug products directly in primary sterile containers, such as prefilled syringes, without dilution. In this study, we introduce a novel application of water proton nuclear magnetic resonance (wNMR) to evaluate the aggregation propensity of a high-concentration drug product, Dupixent® (dupilumab), under stress conditions. wNMR results demonstrate a concentration-dependent, reversible association of dupilumab in the commercial formulation, as well as irreversible aggregation when exposed to accelerated thermal stress, but gradually reversible aggregation when exposed to freeze and thaw cycles. Importantly, these results show a strong correlation with data obtained from established biophysical analytical tools widely used in the pharmaceutical industry. The application of wNMR represents a promising approach for in situ noninvasive analysis of high-concentration protein formulations directly in their primary containers, providing valuable insights for drug development and quality assessment.

To study the acoustic radiation characteristics of forced vibration of granular assemblies, the acoustic radiation model of a single particle and the acoustic radiation model of granular assemblies are established. Combined with experimental verification, the variation law of radiated sound power in the process of forced vibration of granular assemblies is studied. The effects of vibration characteristics, material characteristics, mass characteristics, and distance characteristics on the acoustic radiation of forced vibration of granular assemblies are explored. The radiation range of radiated ultrasound in the process of forced vibration of granular assemblies is analyzed. The research results show that under the condition of forced vibration, the radiated sound power of the granular assemblies is obvious. The internal vibration of the granular assemblies will cause the granular particles to radiate the sound power of multiple frequencies outward. The granular particles will produce obvious ultrasonic sound power in the violent vibration state. The frequency of the sound wave will generally have a significant attenuation effect at 10 cm. Considering the relevant experimental research and engineering application of granular materials, the ultrasonic radiation characteristics should be analyzed to avoid the influence of ultrasonic radiation caused by its severe vibration.

BackgroundOnline health communities have given rise to a new e-service known as online medical consultations (OMCs), enabling remote interactions between physicians and patients. To address challenges, such as patient information overload and uneven distribution of physician visits, online health communities should develop OMC-oriented recommenders. ObjectiveWe aimed to comprehensively investigate what paradigms lead to the success of OMC-oriented recommendations. MethodsA literature search was conducted through e-databases, including PubMed, ACM Digital Library, Springer, and ScienceDirect, from January 2011 to December 2023. This review included all papers directly and indirectly related to the topic of health care–related recommendations for online services. ResultsThe search identified 611 articles, of which 26 (4.3%) met the inclusion criteria. Despite the growing academic interest in OMC recommendations, there remains a lack of consensus among researchers on the definition of e-service–oriented recommenders. The discussion highlighted 3 key factors influencing recommender success: features, algorithms, and metrics. It advocated for moving beyond traditional e-commerce–oriented recommenders to establish an innovative theoretical framework for e-service–oriented recommenders and addresses critical technical issues regarding 2-sided personalized recommendations. ConclusionsThis review underscores the essence of e-services, particularly in knowledge- and labor-intensive domains such as OMCs, where patients seek interpretable recommendations due to their lack of domain knowledge and physicians must balance their energy levels to avoid overworking. Our study’s findings shed light on the importance of customizing e-service–oriented personalized recommendations to meet the distinct expectations of 2-sided users considering their cognitive abilities, decision-making perspectives, and preferences. To achieve this, a paradigm shift is essential to develop unique attributes and explore distinct content tailored for both parties involved.

Traditional biomass boiler operations predominantly rely on manual control, with adjustments made based on operator experience. This approach not only demands considerable manpower but also leads to suboptimal resource utilization. Addressing the specific operational dynamics of biomass boilers, this study introduces a controller designed around the STM32 microcontroller. This device employs a modular architecture and incorporates cost-effective chips and peripheral components. To enhance energy efficiency and the overall user experience, the controller utilizes pulse width modulation pulse modulation alongside a fuzzy PID control strategy. Capable of toggling between manual and automatic modes for local operations, it also supports data logging directly on the device or in the cloud. Tailored to meet diverse user requirements, the controller facilitates remote monitoring and management. It employs a strategic control mechanism for various motors, ensuring precise hot water temperature measurements within the boiler and enabling data uploads to cloud platforms. This not only conserves energy and reduces labor costs but also promotes environmental sustainability and operational efficiency. Through ongoing refinement and rigorous testing, the controller has achieved a level of maturity that underscores its readiness for widespread implementation.

Mycotoxins are secondary metabolites produced during the growth, storage, and transportation of crops contaminated by fungi and are physiologically toxic to humans and animals. Aflatoxin, zearalenone, deoxynivalenol, ochratoxin, patulin, and fumonisin are the most common mycotoxins and can cause liver and nervous system damage, immune system suppression, and produce carcinogenic effects in humans and animals that have consumed contaminated food. Physical, chemical, and biological methods are generally used to detoxify mycotoxins. Although physical methods, such as heat treatment, irradiation, and adsorption, are fast and simple, they have associated problems including incomplete detoxification, limited applicability, and cause changes in food characteristics (e.g., nutritive value, organoleptic properties, and palatability). Chemical detoxification methods, such as ammonification, ozonation, and peroxidation, pollute the environment and produce food safety risks. In contrast, bioenzymatic methods are advantageous as they achieve selective detoxification and are environmentally friendly and reusable; thus, these methods are the most promising options for the detoxification of mycotoxins. This paper reviews recent research progress on common mycotoxins and the enzymatic principles and mechanisms for their detoxification, analyzes the toxicity of the degradation products and describes the challenges faced by researchers in carrying out enzymatic detoxification. In addition, the application of enzymatic detoxification in food and feed is discussed and future directions for the development of enzymatic detoxification methods are proposed for future in-depth study of enzymatic detoxification methods.

Liangshan Prefecture, located at the northeastern edge of the Hengduan Mountain System and within the southern section of the Sichuan-Yunnan tectonic belt in Sichuan Province, China, a region prone to landslides, collapses and debris flows due to its active tectonics, complex topography and significant river erosion. By analysing a dataset of environment factors and geological hazard catalogue, the research uses the Relief algorithm to identify critical influencing factors for each hazard type, selecting 10, 9 and 9 factors for landslides, collapses and debris flows, respectively. Five models are used to assess the vulnerability of these hazards: the Information Value model, the Evidence Weight model, the Logistic Regression model, and both the Evidence Weight-Logistic Regression and the Information Value-Logistic Regression coupled models. The effectiveness of these models is confirmed by confusion matrix and ROC curve analyses, with the combined models showing particularly high accuracy in assessing susceptibility. High risk zones were identified in specific areas and along major fault zones in Liangshan Prefecture. The research provides significant insights into the susceptibility of geological hazards in mountainous and canyon regions, offering a comprehensive approach that goes beyond the limitations of single model applications. This methodology not only provides more accurate and comprehensive results, but also serves as a fundamental reference for geological hazard mitigation and management in Liangshan Prefecture, potentially benefiting similar regions worldwide.

IntroductionHigh-alkalinity water is a serious health hazard for fish and can cause oxidative stress and metabolic dysregulation in fish livers. However, the molecular mechanism of liver damage caused by high alkalinity in fish is unclear. MethodsIn this study, 180 carp were randomly divided into a control (C) group and a high-alkalinity (A25) group and were cultured for 56 days. High-alkalinity-induced liver injury was analysed using histopathological, whole-transcriptome, and metabolomic analyses. ResultsMany autophagic bodies and abundant mitochondrial membrane damage were observed in the A25 group. High alkalinity decreased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity and the total antioxidant capacity (T-AOC) and increased the malondialdehyde (MDA) content in liver tissues, causing oxidative stress in the liver. Transcriptome analysis revealed 61 differentially expressed microRNAs (miRNAs) and 4008 differentially expressed mRNAs. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that mammalian target of rapamycin (mTOR), forkhead box O (FoxO), mitogen-activated protein kinase (MAPK), and the autophagy signalling pathway were the molecular mechanisms involved. High alkalinity causes oxidative stress and autophagy and results in autophagic damage in the liver. Bioinformatic predictions indicated that Unc-51 Like Kinase 2 (ULK2) was a potential target gene for miR-140-5p, demonstrating that high alkalinity triggered autophagy through the miR-140-5p–ULK2 axis. Metabolomic analysis revealed that the concentrations of cortisol 21-sulfate and beta-aminopropionitrile were significantly increased, while those of creatine and uracil were significantly decreased. DiscussionThe effects of high alkalinity on oxidative stress and autophagy injury in the liver were analysed using whole-transcriptome miRNA-mRNA networks and metabolomics approaches. Our study provides new insights into liver injury caused by highly alkaline water.

Background and aimsThe American Heart Association (AHA) recently introduced the Life’s Essential 8 (LE8) to improve cardiovascular health (CVH). However, the association between LE8 and the risk of prediabetes or diabetes is not yet fully understood. Consequently, this study aims to assess the association between CVH, as evaluated by LE8, and the risk of prediabetes and diabetes.Methods and ResultsThis cross-sectional study encompassed 7,739 participants aged ≥20 years from the 2007-2018 National Health and Nutrition Examination Surveys (NHANES). The CVH of participants was evaluated using the LE8, combining four health behaviors and three health factors. Glucose metabolic status categories included normal glucose metabolism, prediabetes including isolated impaired fasting glucose, isolated impaired glucose tolerance, both IFG and IGT, and diabetes. The associations between CVH and prediabetes and diabetes were analyzed using logistic regression, linear regression, restricted cubic splines, and subgroup analyses. Among 7,739 participants, 1,949 had iIFG, 1,165 were diagnosed with iIGT, 799 were IFG+IGT, and 537 were diagnosed with diabetes. After multivariable adjustments, CVH scores were inversely associated with prediabetes and diabetes, with the most robust inverse association observed between IFG+IGT and CVH across all prediabetes subgroups. Of all CVH components not directly in the causal pathway, body mass index (BMI) had the most robust associations with prediabetes and diabetes. Subgroup analyses indicated that the negative correlation between CVH and prediabetes was stronger among those with university or higher education.ConclusionCVH, as defined by LE8, showed a significant negative association with prediabetes and diabetes.

Salinity is an important environmental factor that affects the health of aquatic animals, when salinity level above the tolerance threshold can pose a significant threat to the survival of aquatic animals. As a trace element necessary for animal growth, selenium participates in the body’s antioxidant reaction, and protect aquatic animals from oxidative stress damage. Biological methods for synthesizing selenium nanoparticles (bio-Se-NPs) from bacteria are safe, inexpensive, and accessible. Therefore, we synthesized selenium nanoparticles using Lactobacillus plantarum (probiotic) to study the growth, immune, antioxidant, and inflammatory responses of selenium-rich Lactobacillus plantarum (SL, a type of bio-Se-NPs) fed Cyprinus carpio under low-salinity (5 g/L salinity) and high-salinity (10 g/L salinity) stresses. Analyses revealed that the addition of SL at a concentration of 1 mg/kg significantly alleviated the growth inhibition caused by high-salinity stress. SL significantly alleviated salinity-induced liver tissue injury (numerous cytoplasmic vacuolations the accumulation, inflammatory cell infiltration, nuclear lysis, and some blood congestion). SL significantly alleviated the abnormal levels of serum ALT, AST, GGT and LDH caused by salinity stress, and improved lipid metabolism (TG, TC, LDL-C, HDL-C). SL can also regulates cytokines and antioxidant genes (TNF-α, iL-1β, iL-10, TGFβ-1, SOD, CAT, GPx1, and HO-1) through the NF-κB and Nrf-2 signaling pathways and thereby reduce the inflammatory response and increase the antioxidant level, and these effects attenuate salinity-mediated oxidative damage. In conclusion, our findings indicate that SL can significantly promote the growth and development of fish and alleviate the adverse effects of high-salinity stress and thus, SL can be a potential feed additive for alleviating oxidative stress and inflammatory responses.

For addressing the limitations of traditional elastic metamaterials in opening wide bandgaps below 100 Hz, a tunable pneumatic metamaterial plate with airbag local resonators is proposed. Utilizing the characteristics of airbags, such as small volume, large load-bearing capacity, easy stiffness adjustment, and the ability to provide multi-directional restoring forces, a structured low-stiffness local resonator with a certain load-bearing capacity is designed. By varying the gauge pressure of the airbag, the bandgap can be moved toward lower frequencies, thereby achieving a broad low-frequency vibration suppression capability for various wave propagations. The low-frequency vibration bandgap characteristics of the tunable pneumatic metamaterial are analyzed and verified by applying the finite element method. The results illustrate that this tunable pneumatic metamaterial can attenuate bending waves in the range of 22–121 Hz by adjusting the air pressure. Moreover, increasing the gauge pressure will not only shift the complete bandgap toward lower frequencies but also significantly expand the bandwidth of the complete bandgap. For instance, increasing the gauge pressure from 0 to 50 kPa reduces the opening frequency of the complete bandgap from 36 to 22 Hz while enhancing the relative bandwidth from 0.52 to 0.85. Extending from this, a parametric study was conducted to examine the impact of the structural parameters of airbag-type resonant units on bandgap evolution, summarizing the general principles for achieving wide low-frequency bandgaps. Finally, the bandgap characteristics of the tunable pneumatic metamaterial are confirmed through the frequency response function of a finite periodic structure.

BackgroundPost-stroke depression (PSD) is a well-established psychiatric complication following stroke. Nevertheless, the relationship between early-onset PSD and homocysteine (Hcy) or fibrinogen remains uncertain.MethodsAcute ischemic stroke (AIS) patients who met the established criteria were enrolled in this study. Early-onset PSD was diagnosed two weeks after the stroke. The severity of depressive symptoms was assessed by the Hamilton Depression Scale-17 items (HAMD-17), with patients scored ≥7 assigned to the early-onset PSD group. Spearman rank correlation analysis was employed to evaluate the associations between Hcy, fibrinogen, and HAMD scores across all patients. Logistic regression analysis was conducted to investigate the relationship between Hcy, fibrinogen, and early-onset PSD. Receiver operating characteristic curve (ROC) analysis was ASSDalso performed to detect the predictive ability of Hcy and fibrinogen for early-onset PSD.ResultsAmong the 380 recruited patients, a total of 106 (27.89%) patients were diagnosed with early-onset PSD. The univariate analysis suggested that patients in the PSD group had a higher admission National Institutes of Health Stroke Scale (NIHSS) score, modified Rankin Scale score (mRS), Hcy, and fibrinogen levels than patients in the non-PSD group (P

Summary: CD8+ T cells are rendered exhausted in tumor and chronic infection. Among heterogeneous exhausted T cells, a subpopulation of progenitor-like (Tpex) cells have been found important for long-term tumor or pathogen control and are also the main responders in immunotherapy. Using an RFP reporter mouse for the orphan nuclear receptor NR4A1, originally characterized as critical in T cell dysfunction, we discover that the reporter is highly expressed in Tpex cells in tumor and chronic infection. Enforced expression of Nr4a1 promotes Tpex cell accumulation, whereas tumor control is improved after Nr4a1 deletion, associated with increased effector function but decreased long-term maintenance of CD8+ T cells. Integrating chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis, NR4A1 is found to bind and promote the expression of Tpex-related genes, as well as suppress terminal differentiation-associated genes. This study therefore has identified a key role of NR4A1 in Tpex regulation and provides a promising target for immunotherapy.

The compressible multifunctional carbon aerogel is critical to the development of smart electronics, but it encounters considerable hurdles. Building pliable and completely conductive aerogels for piezoresistive pressure sensors is frequently impeded by the balancing act between elastic response and electric conductivity. This research presents the fabrication of conductive carbon aerogels that exhibit high flexibility and compressibility using a facile method of compositing hollow carbon nanofibers (HCNF) prepared via electrostatic spinning and freeze-drying. The combination of graphite and HCNF shows an ordered, interconnected porous structure consisting of a “layer pillar” skeleton with connected fibers. Due to its stable porous structure, the carbon aerogel has an ultra-low density (18.07 mg/cm3) with a compressive strain of up to 99 %. Under cyclic compression, this carbon aerogel exhibits excellent compressive resistance, stable linear piezoresistive response, ultra-high sensitivity (3.42 kPa−1), good reproducibility after 200 cycles, and ultra-fast response time (240 ms). These properties make it an ideal candidate for high-performance wearable pressure sensors for monitoring human motion. Thus, this work provides a highly flexible, lightweight, and robust multifunctional aerogel sensor that holds great promise for smart wearable sensing, medical devices, and smart robotics.

ObjectiveTo evaluate the incidence, outcome, and prognostic factors of prolonged mechanical ventilation (PMV) in children in Mainland China.MethodsA prospective study was conducted in 11 pediatric intensive care units (PICUs) from May 1, 2021, to April 30, 2022. All pediatric patients on mechanical ventilation meeting the criteria for PMV were included in the study.ResultsOut of 5,292 patients receiving mechanical ventilation, 278 children met the criteria for PMV (5.3%). After excluding case with incomplete data or lost to follow-up, the study included 250 patients. Among them, 115 were successfully weaned from mechanical ventilation, 90 died, and 45 were still on mechanical ventilation. The 6-month survival rate was 64%. The primary associated conditions of PMV were lower airway diseases (36%), central nervous system diseases (32%), and neuromuscular diseases (14%). The stepwise multiple logistic regression analysis indicated that the utilization of vasoactive agents and an elevated pediatric logistic organ dysfunction-2 (PELOD-2) score on the day of PMV diagnosis were significantly associated with an increased of PMV death. Specifically, the odds ratio (OR) for vasoactive agent use was 2.86; (95% CI: 0.15–0.84; P = 0.018), and for the PELOD-2 score, it was 1.37; 95% CI: 1.17–1.61; P

Background: The effects of metformin on atrial fibrillation (AF) in type 2 diabetes patients remain unclear. We aimed to explore the effects of metformin on AF, including new-onset AF and AF burden, in type 2 diabetes patients with pacemakers. Methods and results: This retrospective study included a total of 227 patients. Based on the presence of paroxysmal AF, the patients were divided into a paroxysmal AF group (n = 80) and a non-AF group (n = 147). In the non-AF group, a significant association was observed between metformin use and a lower risk of new-onset AF in multivariable Cox hazards models (hazard ratio [HR]: 0.36; 95 % confidence interval [CI]: 0.14–0.91; p = 0.0311*) when adjusted for age, sex, body mass index (BMI), drinking, smoking, left atrial dimension, creatinine, complications, and drugs. In the paroxysmal AF group, univariable analysis indicated no association between the AF burden and metformin use (p = 0.817). Furthermore, when adjusted for metformin use, age, sex, BMI, drinking, smoking, cardiovascular disease, myocardial infarction, heart failure, stroke, and ejection fraction in multivariable Cox hazards models, we found a lower proportion of major adverse cardiovascular events (MACEs) both in the total (HR: 0.28; 95 % CI: 0.1–0.82; p = 0.0202*) and the non-AF group (HR: 0.19; 95 % CI: 0.05–0.79; p = 0.0223*) compared to that in the AF group (HR: 0.31; 95 % CI: 0.02–4.41; p = 0.3879). Conclusion: In type 2 diabetes patients with pacemakers, metformin reduced the probability of new-onset AF instead of addressing the AF burden. Furthermore, metformin therapy decreased the incidence of MACEs in type 2 diabetes patients without AF.

Introduction: Biapenem is a carbapenem antibiotic widely used in Asia, can be used for the treatment of adults and children with infections due to susceptible bacteria. Although biapenem is utilized in the treatment of a diverse range of bacterial infections, current pharmacokinetic data in the context of septic populations remain limited. Consequently, our research aims to evaluate the pharmacokinetics and efficacy of biapenem within a septic population to optimize biapenem therapy.Methods: In this study, we characterized the pharmacokinetics of biapenem in septic patients using a population pharmacokinetic (PPK) approach. The clinical PK data to develop the PPK model were obtained from 317 septic patients admitted to Nanjing Drum Tower Hospital between 2018 and 2022. All patients were randomized to the modeling and validation cohorts at a 3:1 ratio, with PPK modeling and validation performed utilizing the NONMEM software.Results: The model found to best describe the available data was a two-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V2), and intercompartmental clearance (Q). A covariate analysis identified that creatinine clearance (CLCR) was a significant covariate influencing biapenem CL, while blood urea nitrogen (BUN) was a significant covariate influencing biapenem Q. Accoding to the clinical outcome analyses, 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT>MIC) is associated with favourable clinical outcomes. The PPK model was then used to perform Monte Carlo simulations to evaluate the probability of attaining 70% fT>MIC.Conclusions: A final PPK model of biapenem was established for patients with sepsis. The current daily dosage regimen of 1.2 g may insufficient to achieve 70% fT>MIC in septic patients. The dosage regimen of 600 mg every 6 h appears to be the optimal choice.

Precision medicine, characterized by the personalized integration of a patient’s genetic blueprint and clinical history, represents a dynamic paradigm in healthcare evolution. The emerging field of personalized anesthesia is at the intersection of genetics and anesthesiology, where anesthetic care will be tailored to an individual’s genetic make-up, comorbidities and patient-specific factors. Genomics and biomarkers can provide more accurate anesthetic protocols, while artificial intelligence can simplify anesthetic procedures and reduce anesthetic risks, and real-time monitoring tools can improve perioperative safety and efficacy. The aim of this paper is to present and summarize the applications of these related fields in anesthesiology by reviewing them, exploring the potential of advanced technologies in the implementation and development of personalized anesthesia, realizing the future integration of new technologies into clinical practice, and promoting multidisciplinary collaboration between anesthesiology and disciplines such as genomics and artificial intelligence.

Background: Several observational cohort studies suggested a close correlation between inflammatory bowel disease and erectile dysfunction. Nevertheless, whether there was a causal effect between them remained debatable. In this study, we aimed to detect the underlying causal links between genetically predicted inflammatory bowel disease and the risk of erectile dysfunction.Methods: A bidirectional Mendelian randomization (MR) study was performed to assess the causal link between inflammatory bowel disease and erectile dysfunction. Inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode, and simple mode were utilized to estimate the causality. The top single nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease cases (n = 25,800) and erectile dysfunction cases (n = 1,154) were extracted from the summary genome-wide association study (GWAS) data obtained from a publicly attainable database. MR-PRESSO global outlier test and MR-Egger regression were utilized to explore the horizontal pleiotropy and outlier instrumental variables. Cochran’s Q statistic was utilized to detect the heterogeneity.Results: In the forward MR study, the IVW approach demonstrated that genetically determined inflammatory bowel disease exhibited a suggestively causal association with an increased risk of erectile dysfunction (OR: 1.11, 95% CI: 1.02–1.21, p = 0.019), and also the genetically determined Crohn’s disease was found to be causally associated with an increased risk of erectile dysfunction (OR: 1.09, 95% CI: 1.02–1.17, p = 0.014). However, the MR analysis results showed no significant evidence supporting a causal effect of ulcerative colitis with erectile dysfunction (OR: 1.02, 95% CI: 0.92–1.14, p = 0.679). Furthermore, the reverse MR analysis showed no causal effects of genetically determined erectile dysfunction on inflammatory bowel disease. Additionally, sensitivity analysis demonstrated no pleiotropy and heterogeneity.Conclusion: Our MR analysis substantiated causal links of inflammatory bowel disease and Crohn’s disease on erectile dysfunction, which may further elucidate how inflammatory bowel disease impacted the initiation and development of erectile dysfunction, and facilitated the prevention and clinical management of inflammatory bowel disease in individuals with erectile dysfunction.

In order to quantitatively analyze the roughness of the bench floor during open-pit mine blasting, this study proposes a real-time measuring method for the three-dimensional terrain of the bench floor during the excavation process. Real-time monitoring is conducted at the boundary and discrete internal points of the workbench floor during electric shovel operation, utilizing real-time kinematic global navigation satellite system (RTK-GNSS) positioning technology. An improved convex hull algorithm is introduced to automatically extract the optimal boundary of discrete point clouds based on their spatial distribution characteristics. This study establishes a digital elevation model (DEM) using five interpolation algorithms for 3D terrain visualization simulation. Through cross-validation, a comparative analysis of the DEM accuracy, the simulation results of the ordinary kriging interpolation algorithm were found to be optimized. The optimized interpolation algorithm is applied to simulate the 3D terrain in the Dexing open-pit copper mine, and the relevant terrain parameters were calculated. This dataset can serve as a precise foundation for the real-time path planning of elevation blasting design and ground leveling operations.

IntroductionVillage clinics (VCs) are the foundation of the three-tiered health service system in China, delivering basic and routine outpatient services to citizens in rural China. VC technical efficiency and its convergence play a critical role in policy decisions regarding the distribution of health service resources in rural China.MethodsThis study measured VC technical efficiency (using the slacks-based measure model), its convergence (using the convergence model), and the factors that influence the convergence in Shanxi Province, China. Data were obtained from the Shanxi Rural Health Institute 2014–2018 Health Statistics Report, which involved 3,543 VCs.ResultsThe results showed that VC technical efficiency was low and differed by region. There was no α convergence in VC technical efficiency, but evidence of β convergence was found in Shanxi. The main factors that influence convergence were the building area of each VC (BA), proportion of government subsidies (PGS), and ratio of total expenditure to total income of each VC (RTETI).ConclusionThe government should increase investments in VCs and improve VC technical efficiency. Meanwhile, the government should be aware of and take measures to curb the inequity in VC technical efficiency among different regions and take suitable measures to curb this disparity.

ABSTRACTOutbreaks of acute respiratory viral diseases, such as influenza and COVID-19 caused by influenza A virus (IAV) and SARS-CoV-2, pose a serious threat to global public health, economic security, and social stability. This calls for the development of broad-spectrum antivirals to prevent or treat infection or co-infection of IAV and SARS-CoV-2. Hemagglutinin (HA) on IAV and spike (S) protein on SARS-CoV-2, which contain various types of glycans, play crucial roles in mediating viral entry into host cells. Therefore, they are key targets for the development of carbohydrate-binding protein-based antivirals. This study demonstrated that griffithsin (GRFT) and the GRFT-based bivalent entry inhibitor GL25E (GRFT-L25-EK1) showed broad-spectrum antiviral effects against IAV infection in vitro by binding to HA in a carbohydrate-dependent manner and effectively protected mice from lethal IAV infection. Although both GRFT and GL25E could inhibit infection of SARS-CoV-2 Omicron variants, GL25E proved to be significantly more effective than GRFT and EK1 alone. Furthermore, GL25E effectively inhibited in vitro co-infection of IAV and SARS-CoV-2 and demonstrated good druggability, including favorable safety and stability profiles. These findings suggest that GL25E is a promising candidate for further development as a broad-spectrum antiviral drug for the prevention and treatment of infection or co-infection from IAV and SARS-CoV-2.IMPORTANCEInfluenza and COVID-19 are highly contagious respiratory illnesses caused by the influenza A virus (IAV) and SARS-CoV-2, respectively. IAV and SARS-CoV-2 co-infection exacerbates damage to lung tissue and leads to more severe clinical symptoms, thus calling for the development of broad-spectrum antivirals for combating IAV and SARS-CoV-2 infection or co-infection. Here we found that griffithsin (GRFT), a carbohydrate-binding protein, and GL25E, a recombinant protein consisting of GRFT, a 25 amino acid linker, and EK1, a broad-spectrum coronavirus inhibitor, could effectively inhibit IAV and SARS-CoV-2 infection and co-infection by targeting glycans on HA of IAV and spike (S) protein of SARS-CoV-2. GL25E is more effective than GRFT because GL25E can also interact with the HR1 domain in SARS-CoV-2 S protein. Furthermore, GL25E possesses favorable safety and stability profiles, suggesting that it is a promising candidate for development as a drug to prevent and treat IAV and SARS-CoV-2 infection or co-infection.

Summary: Exhausted CD8+ T cells (Texs) are characterized by the expression of various inhibitory receptors (IRs), whereas the functional attributes of these co-expressed IRs remain limited. Here, we systematically characterized the diversity of IR co-expression patterns in Texs from both human oropharyngeal squamous cell carcinoma (OPSCC) tissues and syngeneic OPSCC model. Nearly 60% of the Texs population co-expressed two or more IRs, and the number of co-expressed IRs was positively associated with superior exhaustion and cytotoxicity phenotypes. In OPSCC patients, programmed cell death-1 (PD-1) blockade significantly enhanced PDCD1-based co-expression with other IR genes, whereas dual blockades of PD-1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) significantly upregulated CTLA4-based co-expression with other IR genes. Collectively, our findings demonstrate that highly diverse IR co-expression is a leading feature of Texs and represents their functional states, which might provide essential clues for the rational selection of immune checkpoint inhibitors in treating OPSCC.

The transmission of manure- and wastewater-borne antibiotic-resistant bacteria (ARB) to plants contributes to the proliferation of antimicrobial resistance in agriculture, necessitating effective strategies for preventing the spread of antibiotic resistance genes (ARGs) from ARB in the environment to humans. Nanomaterials are potential candidates for efficiently controlling the dissemination of ARGs. The present study investigated the abundance of ARGs in hydroponically grown garlic (Allium sativum L.) following nano-CeO2 (nCeO2) application. Specifically, root exposure to nCeO2 (1, 2.5, 5, 10 mg L−1, 18 days) reduced ARG abundance in the endosphere of bulbs and leaves. The accumulation of ARGs (cat, tet, and aph(3’)-Ia) in garlic bulbs decreased by 24.2–32.5 % after nCeO2 exposure at 10 mg L−1. Notably, the lignification extent of garlic stem-disc was enhanced by 10 mg L−1 nCeO2, thereby accelerating the formation of an apoplastic barrier to impede the upward transfer of ARG-harboring bacteria to garlic bulbs. Besides, nCeO2 upregulated the gene expression related to alliin biosynthesis and increased allicin content by 15.9–16.2 %, promoting a potent antimicrobial defense for reducing ARG-harboring bacteria. The potential exposure risks associated with ARGs and Ce were evaluated according to the estimated daily intake (EDI). The EDI of ARGs exhibited a decrease exceeding 95 %, while the EDI of Ce remained below the estimated oral reference dose. Consequently, through stimulating physical and chemical defenses, nCeO2 contributed to a reduced EDI of ARGs and Ce, highlighting its potential for controlling ARGs in plant endosphere within the framework of nano-enabled agrotechnology.

Detecting faint and diminutive infrared targets devoid of clearly defined shape and texture details in intricate surroundings remains a formidable challenge within the domain of target detection. Current methodologies employing deep neural networks and pooling operations can easily cause small target loss, resulting in suboptimal detection outcomes. To address these issues, we design an innovative dynamic context-aware pyramid network. It comprises three core modules: dynamic context modulation (DCM), dynamic pyramid context (DPC), and shuffle attention fusion (SAF). Specifically, the DCM module is designed to adaptively capture diverse-scale information from input images, adapting to various target dimensions, and enhancing the feature representation capabilities crucial for effective target detection. Subsequently, the DPC module adaptively captures multiscale features and better utilizes contextual information by aggregating multiple DCM modules. This facilitates the retention of essential semantic information about small infrared targets within deeper network layers. Finally, through the designed SAF module, we facilitate the exchange of information within the same layer and establish correlations between different layers, ensuring the fusion of shallow spatial positional information and deep semantic information to enhance the overall detection performance. Furthermore, comprehensive ablation studies are conducted to substantiate the efficacy of the designed modules within the proposed network architecture. Simultaneously, we conducted a comparative analysis of the proposed network algorithm against several state-of-the-art methodologies for infrared small target detection, employing multiple evaluation metrics. The results consistently demonstrated the proposed model attains superior detection performance on the publicly available IRSTD-1 k, SIRST-Aug, and NUDT-SIRST datasets.

Job shop scheduling (JSS) aims to arrange the processing sequence of a series of operations to optimize the cost objective. The most common objective is to minimize the makespan without considering the flow time of materials between machines. However, in practical production scenarios, the material flow time directly affects the completion time of operations. Besides, facility layout (FL) is the premise of JSS. FL problem can be stated as assigning a range of production machines into the physical environment of the shop floor, which largely determines the time cost of material flow between machines. The result of FL will affect subsequent JSS. Therefore, the FL problem and the JSS problem naturally constitute a two-stage joint optimization problem. So far, the above-mentioned joint optimization problem is rarely studied in the literature because of the complexity of the problem. For this purpose, the joint optimization problem of FL and JSS is defined in this paper, called JSSFLP. Then, a hybrid heuristic evolutionary strategy (HHE) is proposed for solving the proposed JSSFLP. HHE consists of the meta-heuristic, the hyper-heuristic evolutionary algorithm, and the joint optimization mechanism (JOP), Among them, ant colony system (ACS), as a meta-heuristic algorithm, is used to solve the FL problem effectively, and genetic programming (GP), as a hyper-heuristic algorithm, is used to generate rule-based dispatching methods for JSS problem. Besides, JOP, as an adaptor, is designed to coordinate ACS and GP to solve JSSFLP cooperatively. Numerical experiments are conducted to demonstrate the feasibility and effectiveness of the proposed HHE and its component, respectively.

To address the challenges of low accuracy and poor robustness of traditional single prediction models for blast furnace molten iron temperature, a hybrid model that integrates the improved complete ensemble empirical mode decomposition with adaptive noise, kernel principal component analysis, support vector regression and radial basis functional neural network is proposed for precise and stable iron temperature prediction. First, the complete ensemble empirical mode decomposition is employed to decompose the time series of iron temperature, yielding several intrinsic mode functions. Second, kernel principal component analysis is used to reduce the dimensionality of the multi-dimensional key variables from the steel production process, extracting the major features of these variables. Then, in conjunction with the K-means algorithm, support vector regression is utilized to predict the first column of the decomposed sequence, which contains the most informative content, evaluated using the Pearson correlation coefficient method and permutation entropy calculation. Finally, radial basis function neural network is applied to predict the remaining time series of iron temperature, resulting in the cumulative prediction. Results demonstrate that compared to traditional single models, the mean absolute percentage error is reduced by 54.55%, and the root mean square error is improved by 49.40%. This novel model provides a better understanding of the dynamic temperature variations in iron, and achieves a hit rate of 94.12% within a range of ±5℃. Consequently, this work offers theoretical support for real-time control of blast furnace molten iron temperature and holds practical significance for ensuring the stability of blast furnace smelting and implementing intelligent metallurgical processes.

Ship detection in synthetic aperture radar (SAR) images is crucial in both civilian and military fields, offering extensive application prospects. Nonetheless, owing to the distinctive characteristics of SAR imaging, this task confronts numerous challenges. Specifically, ships with high aspect ratios, dense arrangements and small sizes in complex environments frequently yield in suboptimal positioning effects, consequently impacting detection performance. In response to the challenges in ship target detection, this article introduces a novel approach, termed Inner-alpha-CIOU (IA-CIOU), that relies on an enhanced intersection over union (IOU). Primarily, the method introduces Inner IOU, which effectively regulates generation of auxiliary bounding boxes through scale factor r. This ensures a better fit for dimensions of ship target frames, thereby enhancing target detection performance as well as expediting model convergence. Subsequently, this method introduces Alpha IOU, enhancing robustness of small-size ship targets in complex backgrounds by adjusting α. This allows the detector to achieve greater flexibility in ship regression accuracy. Following numerous experimental validations, proposed algorithm consistently outperforms on both SAR-Ship-Dataset, MSAR-1.0 dataset, and SAR ship detection dataset (SSDD) dataset. This groundbreaking innovation not only possesses immeasurable practical worth, but also introduces a fresh perspective together with enlightening insights for future research efforts.