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Abstract Circulating tumor cells (CTCs) are precursors of distant metastasis in a subset of cancer patients. A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the foundation for therapeutic prevention of cancer metastasis. It remains elusive how CTCs evade immune surveillance and elimination by immune cells. In this study, we unequivocally identified a subpopulation of CTCs shielded with extracellular vesicle (EVs)-derived CD45 (termed as CD45+ CTCs) that resisted T cell attack. A higher percentage of CD45+ CTCs was found to be closely correlated with higher incidence of metastasis and worse prognosis in cancer patients. Moreover, CD45+ tumor cells orchestrated an immunosuppressive milieu and CD45+ CTCs exhibited remarkably stronger metastatic potential than CD45− CTCs in vivo. Mechanistically, CD45 expressing on tumor surfaces was shown to form intercellular CD45-CD45 homophilic interactions with CD45 on T cells, thereby preventing CD45 exclusion from TCR-pMHC synapse and leading to diminished TCR signaling transduction and suppressed immune response. Together, these results pointed to an underappreciated capability of EVs-derived CD45-dressed CTCs in immune evasion and metastasis, providing a rationale for targeting EVs-derived CD45 internalization by CTCs to prevent cancer metastasis.

Cancer immunotherapy, exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy, is revolutionizing cancer therapy. They induce long-term tumor regression and overall survival benefit in many types of cancer. With the advances in our knowledge about the tumor immune microenvironment, remarkable progress has been made in the development of small-molecule drugs for immunotherapy. Small molecules targeting PRR-associated pathways, immune checkpoints, oncogenic signaling, metabolic pathways, cytokine/chemokine signaling, and immune-related kinases have been extensively investigated. Monotherapy of small-molecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance. Here, we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

AbstractCatheter-related bloodstream infection (CRBSI) has become the bacterial infection of special concern considerably causing the prolonged hospitalization and the delayed clinical treatment. In this paper, silver nanoparticles (AgNPs) were stabilized in sodium polyethylene sulfonate (PVS) solution (PVS-Ag). Amphiphilic bio-carbon particles (ACPs) were synthesized from S. cerevisiae cells and employed as the matrix. Chitosan (CS) modification on ACPs (ACPs-CS) facilitated the PVS-Ag grafting with stability and efficiency. Results of morphologic analysis indicated that CS and PVS-Ag modification distinctly changed the morphological-structural properties of the ACPs surface. Surface potentials of ACPs, ACPs-CS and the obtained functionalized bio-carbon material (ACPs-CS-PVS-Ag) were −38.0 mV, +36.1 mV and −53.1 mV, respectively, revealing that the anionic groups enriched on the PVS-Ag surface had largely consumed the amino groups around the surface of ACPs-CS. Results from X-ray photoelectron spectroscopy (XPS) and thermogravimetric analysis (TGA) further demonstrated that AgNPs had successfully attached to the ACPs-CS surface. The anionic amphiphiles (ACPs-CS-PVS-Ag) exerted high blood-compatibility and bio-safety, especially the broad-spectrum antibacterial property at the microgram scale. In conclusion, the ACPs-CS-PVS-Ag assembly has potential value in the development of biomedical devices and/or implants for the safe-and-effective elimination of bacterial infections.

Anisotropic microstructures resulting from a well-ordered arrangement of filamentous extracellular matrix (ECM) components or cells can be found throughout the human body, including skeletal muscle, corneal stroma, and meniscus, which play a crucial role in carrying out specialized physiological functions. At present, due to the isotropic characteristics of conventional hydrogels, the construction of freeform cell-laden anisotropic structures with high-bioactive hydrogels is still a great challenge. Here, we proposed a method for direct embedded 3D cell-printing of freeform anisotropic structure with shear-oriented bioink (GelMA/PEO). This study focuses on the establishment of an anisotropic embedded 3D bioprinting system, which effectively utilizes the shear stress generated during the extrusion process to create cells encapsulating tissues with distinct anisotropy. In conjunction with the water-solubility of PEO and the in-situ encapsulation effect provided by the carrageenan support bath, high-precise cell-laden bioprinting of intricate anisotropic and porous bionic artificial tissues can be effectively implemented in one-step. Additionally, anisotropic permeable blood vessel has been taken as a representation to validate the effectiveness of the shear-oriented bioink system in fabricating intricate structures with distinct directional characteristics. Lastly, the successful preparation of muscle patches with anisotropic properties and their guiding role for cell cytoskeleton extension have provided a significant research foundation for the application of the anisotropic embedded 3D bioprinting system in the ex-vivo production and in-vivo application of anisotropic artificial tissues.

The gelatinization and retrogradation characteristics of wheat starch affect the eating quality of Chinese-style food. Rapid Visco Analyzer (RVA) parameters have been widely used as important indicators to evaluate and improve the quality of wheat starch. However, the genetic basis of RVA parameters remains to be further explored. In the present study, a natural population was genotyped using 90K single nucleotide polymorphism (SNP) arrays, and the RVA parameters of this population grown in five environments were evaluated. The results showed that 22,068 high-quality SNP markers were identified and distributed unequally on the chromosomes. According to the genetic distance, 214 wheat materials were divided into four groups. Except for the pasting temperature (PTT), six parameters followed a normal distribution. Based on the general linear model, 969 significant association SNPs were detected by genome-wide association studies (GWAS), and chromosomes 7A and 2B had the most associated SNPs. Breakdown viscosity (BV) was associated with the most SNPs (n = 238), followed by PTT (n = 186), peak viscosity (PV; n = 156), trough viscosity (TV; n = 127), and final viscosity (FV; n = 126). According to the average linkage disequilibrium (LD), 33 stable quantitative trait loci (QTLs) were identified for single parameters in multiple environments, of which 12 were associated with BV, followed by peak time (PT; n = 8) and PTT (n = 7). On the other hand, 67 pleiotropic QTLs were identified for multiple parameters. Three candidate genes—TasbeIIa, TasbeI, and TassIIa—were screened for phenotyping analysis. The grain width and the weight of the TasbeIIa and TaSSIIa knockout (KO) lines were significantly lower than those of the TasbeI KO lines and the control (CK). The KO lines had smaller endosperm cells, smaller A-type starch granules, and higher amylose content. The TasbeI KO lines showed normal RVA curves, while the TasbeIIa KO lines showed flat curves. However, the TaSSIIa lines failed to paste under the RVA temperatures. Conclusively, the SNPs/QTLs significantly associated with the RVA parameters and genetic resources with novel haplotypes could be used to improve the quality of wheat starch.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases and involves various pathogenic mechanisms, including oxidative stress and neuroinflammation. Niacin, an important cofactor in mitochondrial energy metabolism, may play a key role in the pathogenesis of PD. An in-depth exploration of the relationship between niacin and mitochondrial energy metabolism may provide new targets for the treatment of PD. The present study was designed to examine the association between dietary niacin intake and the risk of PD in US adults. Data from adults aged 40 years and older collected during cycles of the United States (US) National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018 were used. A multiple logistic regression model was used to analyze the relationship between dietary niacin intake and the risk of PD. Further linear tests using restricted cubic splines (RCS) were performed to explore the shape of the dose–response relationship. Subgroup stratification and interaction analyses were conducted according to years of education, marital status, smoking, and hypertension to evaluate the stability of the association between different subgroups. A total of 20,211 participants were included in this study, of which 192 were diagnosed with PD. In the fully adjusted multiple logistic regression model, dietary niacin intake was negatively associated with the risk of PD (OR: 0.77, 95%CI: 0.6–0.99; p = 0.042). In the RCS linear test, the occurrence of PD was negatively correlated with dietary niacin intake (nonlinearity: p = 0.232). In stratified analyses, dietary niacin intake was more strongly associated with PD and acted as an important protective factor in patients with fewer years of education (OR: 0.35, 95%CI: 0.13–0.93), married or cohabitating (OR: 0.71, 95%CI: 0.5–0.99), taking dietary supplements (OR: 0.6, 95%CI: 0.37 0.97), non-smokers (OR: 0.57, 95%CI: 0.39–0.85), those with hypertension (OR: 0.63, 95%CI: 0.63–0.95), coronary artery disease (OR: 0.77, 95%CI: 0.6–1), and stroke (OR: 0.75, 95%CI: 0.88–0.98), but the interaction was not statistically significant in all subgroups. Dietary niacin intake was inversely associated with PD risk in US adults, with a 23% reduction in risk for each 10 mg increase in niacin intake.

Background Rostral ventrolateral medulla (RVLM) neuron hyperactivity raises sympathetic outflow, causing hypertension. MicroRNAs (miRNAs) contribute to diverse biological processes, but their influence on RVLM neuronal excitability and blood pressure (BP) remains widely unexplored. Methods and Results The RVLM miRNA profiles in spontaneously hypertensive rats were unveiled using RNA sequencing. Potential effects of these miRNAs in reducing neuronal excitability and BP and underlying mechanisms were investigated through various experiments. Six hundred thirty‐seven miRNAs were identified, and reduced levels of miR‐193b‐3p and miR‐346 were observed in the RVLM of spontaneously hypertensive rats. Increased miR‐193b‐3p and miR‐346 expression in RVLM lowered neuronal excitability, sympathetic outflow, and BP in spontaneously hypertensive rats. In contrast, suppressing miR‐193b‐3p and miR‐346 expression in RVLM increased neuronal excitability, sympathetic outflow, and BP in Wistar Kyoto and Sprague‐Dawley rats. Cdc42 guanine nucleotide exchange factor (Arhgef9) was recognized as a target of miR‐193b‐3p. Overexpressing miR‐193b‐3p caused an evident decrease in Arhgef9 expression, resulting in the inhibition of neuronal apoptosis. By contrast, its downregulation produced the opposite effects. Importantly, the decrease in neuronal excitability, sympathetic outflow, and BP observed in spontaneously hypertensive rats due to miR‐193b‐3p overexpression was greatly counteracted by Arhgef9 upregulation. Conclusions miR‐193b‐3p and miR‐346 are newly identified factors in RVLM that hinder hypertension progression, and the miR‐193b‐3p/Arhgef9/apoptosis pathway presents a potential mechanism, highlighting the potential of targeting miRNAs for hypertension prevention.

Particulate matter (PM), usually formed as aerosols suspended in atmosphere, is becoming a carrier of viruses and bacteria, accelerating the spread of respiratory diseases. Hence, air filtration devices are widely utilized for removing PM. In this study, a regenerated cellulose (RC) film was prepared with the properties of good mechanical strength, antibacterial, and highly efficient filtration (EF) properties, through cellulose dissolution and further crosslinking with P(AGE-DMDAAC)/ZnO. Results exhibited that the Young's modulus of the composite membrane was nearly 4.3 GPa. Additionally, the antibacterial performance against Escherichia coli and Staphylococcus aureus, was up to 99.89% and 99.67%, respectively. Meanwhile, RC composite filter exhibited a high PM 2.5 capture efficiency (over 99.91%). This study introduces an interesting approach to produce antibacterial films with the characteristics of notably good mechanical performance and high fine particle EF that can be utilized in a high humidity environment.

IntroductionNeutrophil extracellular traps (NETs) provide key innate immune mechanisms, and studies have shown innate immunity and adaptive immunity are directly linked to Parkinson’s disease (PD) pathology. However, limited research has been conducted on NETs in the context of PD.MethodsA differential analysis was implemented to acquire differentially expressed genes (DEGs) between PD and control as well as between high- and low-score groups determined by a gene set variation analysis (GSVA). Then, the genes within the critical module, obtained through a weighted gene co-expression network analysis (WGCNA), were intersected with the DEGs to identify the overlapping genes. Then, five kinds of algorithms in the protein–protein interaction (PPI) were performed to identify potential biomarkers. Subsequently, a nomogram for forecasting PD probability was created. An enrichment analysis and an immune infiltration analysis were performed on the identified biomarkers. qRT-PCR was performed to validate the expression trends of three biomarkers.ResultsWe revealed 798 DEGs between PD and control groups as well as 168 DEGs between high- and low-score groups obtained by differential analyses. The pink module containing 926 genes was identified as the critical module. According to the intersection of these gene sets, a total of 43 overlapping genes were screened out. Furthermore, GPR78, CADM3, and CACNA1E were confirmed as biomarkers. Moreover, we found that biomarkers mainly participated in pathways, such as the ‘hydrogen peroxide catabolic process’, and ‘cell cycle’; five kinds of differential immune cells between PD and control groups were identified. Finally, the qRT-PCR analysis demonstrated the up-regulation of GPR78, CADM3, and CACNA1E in the PD group.DiscussionOur study authenticated GPR78, CADM3, and CACNA1E as the biomarkers associated with PD. These findings provide an original reference for the diagnosis and treatment of PD.

Western postmodernism is a cultural trend of thought that emerged in the 1960s and 1970s. Its influence involves many fields, such as art, literature, philosophyand aesthetics, which indicates that a major change has taken place in the whole Western society, and also has a profound impact on contemporary culture and art. By analyzing the far-reaching influence of postmodernism on music and philosophy, this paper provided development strategies and suggestions for music and philosophy under the background of postmodernism. This paper studied the positive and negative effects of postmodernism on philosophy and music from two aspects: music and philosophy. The positive influence of postmodernism on philosophy and music is manifested in advocating equality, harmony between man and nature, innovation and critical spirit. Of course, the postmodernism trend of thought also has some negative effects, which should be viewed dialectically on its impact on music and philosophy. On the premise of encouraging innovation, respecting freedom and difference, self-confidence value should be established, so as to promote the further development of philosophy and music. Postmodernism is a cultural form in the later period of capitalism. In the field of music, it is necessary to not only adhere to the rebellion and openness brought by postmodernism, but also attach importance to the artistic value of music works to prevent the production and proliferation of vulgar music works. The influence of postmodernism on music and philosophy, studied in this paper, has important practical significance.

Background: Telomere shortening is strongly associated with cardiovascular aging and disease, and patients with shorter telomeres in peripheral blood leukocytes are at higher risk of cardiovascular diseases such as heart failure and atrial fibrillation (AF). Telomerase reverse transcriptase (TERT) maintains telomere length, and overexpression of TERT has been shown to reduce cardiomyocyte apoptosis and myocardial infarct size, and extend the lifespan of aged mice. However, the specific impact of TERT on the electrophysiology of cardiomyocytes remains to be elucidated. The aims of this study were to evaluate the role of TERT in Ca2+ homeostasis and mitochondrial function in atrial myocytes as well as the underlying mechanisms. Methods: TERT overexpressed and silenced HL-1 cells were constructed with lentiviruses, and the respective empty lentiviral vectors were used as negative controls. Then the patch clamp technique was used to record the electrophysiological characteristics such as cell action potential duration (APD) and L-type Ca2+ currents (ICa,L), flow cytometry was used to detect intracellular Ca2+ concentration and mitochondrial membrane potential (MMP), and the Seahorse assay was used to measure the oxygen consumption rate (OCR). Results: TERT silencing led to intracellular Ca2+ overload, shortened APD, decreased ICa,L current density, altered Ca2+ gating mechanism, decreased MMP and OCR, and increased reactive oxygen species (ROS), whereas TERT overexpression led to the reverse effects. Additionally, TERT silencing resulted in intracellular Ca2+ overload with decreased expression of the SERCA2a, CaV1.2, and NCX1.1, whereas TERT overexpression had opposing effects. Furthermore, we discovered that TERT could regulate the expression of p53 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The expression of PGC-1α was downregulated by the p53 agonist Tenovin-6 but upregulated by the p53 inhibitor PFTα. The effects of the PGC-1α inhibitor SR-18292 on intracellular Ca2+ and cell electrophysiology were similar to those of silencing TERT, whereas the PGC-1α agonist ZLN005 produced comparable outcomes to TERT overexpression. Conclusions: TERT silencing-induced Ca2+ overload and mitochondrial dysfunction may be one mechanism of age-related AF. Overexpression of TERT reduced the basis for arrhythmia formation such as AF, suggesting a favorable safety profile for TERT therapy. TERT regulated intracellular Ca2+ homeostasis and mitochondrial function through the p53/PGC-1α pathway. In addition, PGC-1α might be a novel target for AF, suggesting that intervention for AF should be not limited to abnormal cation handling.

Printed circuit board (PCB) surface defect detection is an essential part of the PCB manufacturing process. Currently, advanced CCD or CMOS sensors can capture high-resolution PCB images. However, the existing computer vision approaches for PCB surface defect detection require high computing effort, leading to insufficient efficiency. To this end, this article proposes a local and global context-enhanced lightweight CenterNet (LGCL-CenterNet) to detect PCB surface defects in real time. Specifically, we propose a two-branch lightweight vision transformer module with local and global attention, named LGT, as a complement to extract high-dimension features and leverage context-aware local enhancement after the backbone network. In the local branch, we utilize coordinate attention to aggregate more powerful features of PCB defects with different shapes. In the global branch, Bi-Level Routing Attention with pooling is used to capture long-distance pixel interactions with limited computational cost. Furthermore, a Path Aggregation Network (PANet) feature fusion structure is incorporated to mitigate the loss of shallow features caused by the increase in model depth. Then, we design a lightweight prediction head by using depthwise separable convolutions, which further compresses the computational complexity and parameters while maintaining the detection capability of the model. In the experiment, the LGCL-CenterNet increased the mAP@0.5 by 2% and 1.4%, respectively, in comparison to CenterNet-ResNet18 and YOLOv8s. Meanwhile, our approach requires fewer model parameters (0.542M) than existing techniques. The results show that the proposed method improves both detection accuracy and inference speed and indicate that the LGCL-CenterNet has better real-time performance and robustness.

As satellite capabilities have evolved and new observation requirements have emerged, satellites have become essential tools in disaster relief, emergency monitoring, and other fields. However, the efficiency of satellite scheduling still needs to be enhanced. Learning and optimization are symmetrical processes of solving problems. Learning problem knowledge could provide efficient optimization strategies for solving problems. A knowledge-guided parallel hybrid local search algorithm (KG-PHLS) is proposed in this paper to solve time-dependent agile Earth observation satellite (AEOS) scheduling problems more efficiently. Firstly, the algorithm uses heuristic algorithms to generate initial solutions. Secondly, a knowledge-based parallel hybrid local search algorithm is employed to solve the problem in parallel. Meanwhile, data mining techniques are used to extract knowledge to guide the construction of new solutions. Finally, the proposed algorithm has demonstrated superior efficiency and computation time through simulations across multiple scenarios. Notably, compared to benchmark algorithms, the algorithm improves overall efficiency by approximately 7.4% and 8.9% in large-scale data scenarios while requiring only about 60.66% and 31.89% of the computation time of classic algorithms. Moreover, the proposed algorithm exhibits scalability to larger problem sizes.

Lightweight geopolymers have the advantages of a wide source of raw materials, chemical corrosion resistance, high mechanical strength and excellent durability, and are expected to replace traditional building insulation materials. In this paper, a green bio-based foaming agent with a small 1 h settlement distance, high average foaming multiple and low bleeding ratio was obtained by a Cetyltrimethylammonium Bromide/yeast solution. When the amount of Cetyltrimethylammonium Bromide is 0.50 wt%, the foam prepared by the yeast and Cetyltrimethylammonium Bromide solution exhibits the improved 1 h settlement distance, the large average foaming multiple, the small bleeding ratio and uniform foam size. Subsequently, a lightweight geopolymer based on metakaolin and fly ash (or silica fume) was successfully prepared by the bio-based foaming agent, and the effects of different foam content on the properties of the geopolymer, such as dry density, water absorption, thermal conductivity, compressive strength and morphology, were studied. With an increase in foam content, the dry density, thermal conductivity and compressive strength of the geopolymer gradually decrease, the water absorption increases, regardless of whether silica fume or fly ash are added. Herein, it is confirmed that the foaming agent based on yeast can be effectively used to prepare lightweight geopolymers, which can provide vast opportunities to turn into candidates for novel inorganic thermal insulation materials.

Abstract Immune checkpoint inhibitors (ICIs) have induced durable clinical responses in a subset of patients with colorectal cancer (CRC). However, the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies. Inflammation-related molecule A20 is closely related to cancer immune response, but the effect of A20 on “eat-me” signal and immunotherapy efficacy remains elusive. We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo. Higher A20 expression was associated with less infiltration of immune cells including CD3 (+), CD8 (+) T cells and macrophages in CRC tissues and also poorer prognosis. Gain- and loss-A20 functional studies proved that A20 could decrease the “eat-me” signal calreticulin (CRT) protein on cell membrane translocation via upregulating stanniocalcin 1 (STC1), binding to CRT and detaining in mitochondria. Mechanistically, A20 inhibited GSK3β phosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein. Our findings reveal a new crosstalk between inflammatory molecule A20 and “eat-me” signal in CRC, which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.

Abstract Background Immune checkpoint inhibitor (ICI) therapy has been used in various tumors. The biomarkers predictive of a response to ICI treatment remain unclear, and additional and combined biomarkers are urgently needed. Secreted factors related to the tumor microenvironment (TME) have been evaluated to identify novel noninvasive predictive biomarkers. Methods We analyzed 85 patients undergoing ICI therapy as the primary cohort. The associations between ICI response and all biomarkers were evaluated. A prediction model and a nomogram were developed and validated based on the above factors. Results Seventy-seven patients were enrolled in the validation cohort. In the primary cohort, the baseline serum levels of H3Cit, IL-8 and CRP were significantly higher in nonresponder patients. A model based on these three factors was developed, and the “risk score” of an ICI response was calculated with the formula: “risk score” = 3.4591×H3Cit + 2.5808×IL8 + 2.0045 ×CRP– 11.3844. The cutoff point of the “risk score” was 0.528, and patients with a “risk score” lower than 0.528 were more likely to benefit from ICI treatment (AUC: 0.937, 95% CI: 0.886–0.988, with sensitivity 80.60%, specificity 91.40%). The AUC was 0.719 (95% CI: 0.600-0.837, P = 0.001), with a sensitivity of 70.00% and specificity of 65.20% in the validation cohort. Conclusions A model incorporating H3Cit, IL-8 and CRP has an excellent prediction ability for ICI response; thus, patients with a lower “risk score” selectively benefit from ICI treatment, which may have significant clinical implications for the early detection of an ICI response.

Abstract Background Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been associated with the pathogenesis of stress-induced hypertension (SIH). Neuronal mitochondrial dysfunction is involved in many pathological and physiological processes. However, the impact of neuroinflammation on neuronal mitochondrial homeostasis and the involved signaling pathway in the RVLM during SIH are largely unknown. Methods The morphology and phenotype of microglia and the neuronal mitochondrial injury in vivo were analyzed by immunofluorescence, Western blot, RT-qPCR, transmission electron microscopy, and kit detection. The underlying mechanisms of microglia-derived tumor necrosis factor‐α (TNF-α) on neuronal mitochondrial function were investigated through in vitro and in vivo experiments such as immunofluorescence and Western blot. The effect of TNF-α on blood pressure (BP) regulation was determined in vivo via intra-RVLM microinjection of TNF-α receptor antagonist R7050. Results The results demonstrated that BP, heart rate (HR), renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE), and electroencephalogram (EEG) power increased in SIH rats. Furthermore, the branching complexity of microglia in the RVLM of SIH rats decreased and polarized into M1 phenotype, accompanied by upregulation of TNF‐α. Increased neuronal mitochondria injury was observed in the RVLM of SIH rats. Mechanistically, Sirtuin 3 (Sirt3) and p-AMPK expression were markedly downregulated in both SIH rats and TNF-α–treated N2a cells. AMPK activator A769662 upregulated AMPK–Sirt3 signaling pathway and consequently reversed TNF-α–induced mitochondrial dysfunction. Microinjection of TNF-α receptor antagonist R7050 into the RVLM of SIH rats significantly inhibited the biological activities of TNF-α, increased p‐AMPK and Sirt3 levels, and alleviated neuronal mitochondrial injury, thereby reducing c-FOS expression, RSNA, plasma NE, and BP. Conclusions This study revealed that microglia-derived TNF-α in the RVLM impairs neuronal mitochondrial function in SIH possibly through inhibiting the AMPK–Sirt3 pathway. Therefore, microglia-derived TNF-α in the RVLM may be a possible therapeutic target for the intervention of SIH.

IntroductionSenecavirus A (SVA) is a highly contagious virus that causes vesicular disease in pigs. At present, laboratory detection methods, such as virus isolation and polymerase chain reaction (PCR), required precision instruments and qualified personnel, making them unsuitable for point-of-care tests (POCT). Fortunately, the emergence of CRISPR/Cas system has provided new opportunities for fast and efficient pathogen detection.MethodsThis study successfully developed a precise and sensitive detection platform for diagnosing SVA by combining the CRISPR system with recombinase polymerase amplification (RPA). ResultsThe minimum detection limit of the assay was 10 copies of the SVA genome. Meanwhile, the assay demonstrated high specificity. To validate the effectiveness of this system, we tested 85 swine clinical samples and found that the fluorescence method had a 100% coincidence rate compared to RT-qPCR. DiscussionOverall, the RPA-CRISPR/Cas12a assay established in our study is a highly effective method for detecting SVA and holds great potential for practical applications in the resource-limited settings.

The secondary Bjerknes force (SBF) is the time-averaged interaction between two bubbles driven in a sound field. We derived a refined formula for the interaction force, incorporating the radial vibration and translational and deformational motions of the bubble. The coupling of pulsation, translation, and deformation enhances the interaction between bubbles but also weakens their stability, making it easier for bubbles to merge or break during motion. The effects of the coupling mode on the magnitude and direction of SBFs coupled with pulsation, translation, and deformation were numerically analyzed and studied. Under certain sound-field conditions, the SBF increased with increasing pressure amplitude, initial radius, and initial velocity, while decreased as the distance increased. In addition, the SBF irregularly increased with increasing frequency.

Fresh leaves of Echa 1 were fixed by roller, steam/hot air and light-wave, and the effects of the three fixation methods on the chemical characteristics of straight-shaped green teas (GTs) were studied by widely targeted metabolomic analysis. 1001 non-volatile substances was identified, from which 97 differential metabolites were selected by the criteria of variable importance in projection (VIP) > 1, p 1. Correlation analysis indicated that 14 taste-active metabolites were the major contributors to the taste differences between differently processed GTs. High-temperature fixation induces protein oxidation or degradation, γ-glutamyl peptide transpeptidation, degradation of flavonoid glycosides and epimerization of cis-catechins, resulting in the accumulation of amino acids, peptides, flavonoids and trans-catechins, which have flavor characteristics such as umami, sweetness, kokumi, bitterness and astringency, thereby affecting the overall taste of GTs. These findings provided a scientific basis for the directional processing technology of high-quality green tea.

Abstract Differential diagnosis of pulmonary nodules detected by computed tomography (CT) remains a challenge in clinical practice. Here, we characterize the global metabolomes of 480 serum samples including healthy controls, benign pulmonary nodules, and stage I lung adenocarcinoma. The adenocarcinoma demonstrates a distinct metabolomic signature, whereas benign nodules and healthy controls share major similarities in metabolomic profiles. A panel of 27 metabolites is identified in the discovery cohort (n = 306) to distinguish between benign and malignant nodules. The discriminant model achieves an AUC of 0.915 and 0.945 in the internal validation (n = 104) and external validation cohort (n = 111), respectively. Pathway analysis reveals elevation in glycolytic metabolites associated with decreased tryptophan in serum of lung adenocarcinoma vs benign nodules and healthy controls, and demonstrates that uptake of tryptophan promotes glycolysis in lung cancer cells. Our study highlights the value of the serum metabolite biomarkers in risk assessment of pulmonary nodules detected by CT screening.

Pear fruit senescence under high- and low-temperature conditions has been reported to be mediated by microRNAs. Long non-coding RNAs (lncRNAs), which can function as competing endogenous RNAs that interact with microRNAs, may also be involved in temperature-affected fruit senescence. Based on the transcriptome and microRNA sequencings, in this study, 3 330 lncRNAs were isolated from Pyrus pyrifolia fruit. Of these lncRNAs, 2 060 and 537 were responsive to high- and low-temperature conditions, respectively. Of these differentially expressed lncRNAs, 82 and 24 correlated to the mRNAs involved in fruit senescence under high- and low-temperature conditions, respectively. Moreover, three lncRNAs were predicted to be competing endogenous RNAs (ceRNAs) that interact with the microRNAs involved in fruit senescence, while one and two ceRNAs were involved in fruit senescence under high- and low-temperature conditions, respectively. A dual-luciferase assay showed that the interaction of an lncRNA with a microRNA disrupts the action of the microRNA on the expression of its target mRNA(s). Furthermore, four alternative splicing-derived lncRNAs interacted with miR172i homologies (Novel_88 and Novel_69) to relieve the repressed expression of their target and produce an miR172i precursor. Correlation analysis of microRNA expression suggested that Novel_69 is likely involved in the cleavage of the pre-miR172i hairpin to generate mature miR172i. Taken together, lncRNAs are involved in pear fruit senescence under high- or low-temperature conditions through ceRNAs and the production of microRNA.

In order to explore the differences of flavor characteristics among different cultivars (strains) of large-leaf yellow tea, the main tea tree varieties (strains) in Hubei Province were used as materials to process large-leaf yellow tea. The differences in sensory quality, taste and aroma components were analyzed, and chemometrics analysis was used to explore the relationship between taste-characteristic attributes and chemical compositions. The results showed that large-leaf yellow tea of B6-1 and 07-7-44 strains had the best total sensory scores with long-lasting roasting aroma and sweet floral fragrance, the large-leaf yellow tea of D12 and B6-1 strains had the higher contents of non-ester catechins and amino acids, while large-leaf yellow tea of D12, B6-1 and 07-7-44 strains had the lower ratio of tea polyphenols/amino acids, showed the characteristics of mellow and sweet aftertaste. Correlation analysis showed that taste score and total sensory score were significantly positively correlated with the contents of water extracts, amino acids and soluble sugars (P

Rostral ventrolateral medulla (RVLM) is thought to serve as a major vasomotor center that participates in controlling the progression of stress-induced hypertension (SIH). Circular RNAs (circRNAs) perform important functions in the regulation of diverse physiological and pathological processes. However, information concerning the functions of RVLM circRNAs on SIH remains limited. RNA sequencing was performed to profile circRNA expression in RVLMs from SIH rats, which were induced by electric foot shocks and noises. The functions of circRNA Galntl6 in reducing blood pressure (BP) and its potential molecular mechanisms on SIH were investigated via various experiments, such as Western blot and intra-RVLM microinjection. A total of 12,242 circRNA transcripts were identified, among which circRNA Galntl6 was dramatically downregulated in SIH rats. The upregulation of circRNA Galntl6 in RVLM effectively decreased the BP, sympathetic outflow, and neuronal excitability in SIH rats. Mechanistically, circRNA Galntl6 directly sponged microRNA-335 (miR-335) and restrained it to reduce oxidative stress. Reintroduction of miR-335 observably reversed the circRNA Galntl6-induced attenuation of oxidative stress. Furthermore, Lig3 can be a direct target of miR-335. MiR-335 inhibition substantially increased the expression of Lig3 and suppressed oxidative stress, and these favorable effects were blocked by Lig3 knockdown. CircRNA Galntl6 is a novel factor that impedes SIH development, and the circRNA Galntl6/miR-335/Lig3 axis represents one of the possible mechanisms. These findings demonstrated circRNA Galntl6 as a possibly useful target for the prevention of SIH.

In order to explore the correlation between mineral elements content and quality ingredients of flat green tea, ten representative flat green tea samples from five production areas (Dawu County, Hubei Province, Pan'an County, Zhejiang Province, She County, Anhui Province, Meitan County, Guizhou Province and Emeishan City, Sichuan Province) were collected. The content of nine mineral elements (Mg, K, Ca, P, Al, Mn, Fe, Zn, B) and five quality ingredients (water extracts, tea polyphenols, free amino acids, total soluble sugars, caffeine) were determined. Results showed that the mineral elements influenced each other and existed with synergistic or antagonistic effects. The water extracts content was significantly negatively correlated with the B content (P

In order to analyze the changes in the microbial community structure during the pile fermentation of Qingzhuan tea and their correlation with the formation of quality compounds in Qingzhuan tea, this study carried out metagenomic and metabolomic analyses of tea samples during the fermentation process of Qingzhuan tea. The changes in the expression and abundance of microorganisms during the pile fermentation were investigated through metagenomic assays. During the processing of Qingzhuan tea, there is a transition from a bacterial dominated ecosystem to an ecosystem enriched with fungi. The correlation analyses of metagenomics and metabolomics showed that amino acids and polyphenol metabolites with relatively simple structures exhibited a significant negative correlation with target microorganisms, while the structurally complicated B-ring dihydroxy puerin, B-ring trihydroxy galloyl puerlin, and other compounds showed a significant positive correlation with target microorganisms. Aspergillus niger, Aspergillus glaucus, Penicillium in the Aspergillaceae family, and Talaromyces and Rasamsonia emersonii in Trichocomaceae were the key microorganisms involved in the formation of the characteristic qualities of Qingzhuan tea.

In this study, near-infrared spectroscopy (NIRS) combined with a variety of chemometrics methods was used to establish a fast and non-destructive prediction model for the purchase price of fresh tea leaves. Firstly, a paired t-test was conducted on the quality index (QI) of seven quality grade fresh tea samples, all of which showed statistical significance (p < 0.05). Further, there was a good linear relationship between the QI, quality grades, and purchase price of fresh tea samples, with the determination coefficient being greater than 0.99. Then, the original near-infrared spectra of fresh tea samples were obtained and preprocessed, with the combination (standard normal variable (SNV) + second derivative (SD)) as the optimal preprocessing method. Four spectral intervals closely related to fresh tea prices were screened using the synergy interval partial least squares (si-PLS), namely 4377.62 cm−1–4751.74 cm−1, 4755.63 cm−1–5129.75 cm−1, 6262.70 cm−1–6633.93 cm−1, and 7386 cm−1–7756.32 cm−1, respectively. The genetic algorithm (GA) was applied to accurately extract 70 and 33 feature spectral data points from the whole denoised spectral data (DSD) and the four characteristic spectral intervals data (FSD), respectively. Principal component analysis (PCA) was applied, respectively, on the data points selected, and the cumulative contribution rates of the first three PCs were 99.856% and 99.852%. Finally, the back propagation artificial neural (BP-ANN) model with a 3-5-1 structure was calibrated with the first three PCs. When the transfer function was logistic, the best results were obtained (Rp2 = 0.985, RMSEP = 6.732 RMB/kg) by 33 feature spectral data points. The detection effect of the best BP-ANN model by 14 external samples were R2 = 0.987 and RMSEP = 6.670 RMB/kg. The results of this study have achieved real-time, non-destructive, and accurate evaluation and digital display of purchase prices of fresh tea samples by using NIRS technology.

Abstract Metastasis is the most prevalent cause of cancer deaths, and immunological components of the tumor microenvironment, especially tumor‐associated macrophages (TAMs), play a vital role in cancer metastasis. However, the underlying mechanisms of TAMs on non‐small‐cell lung cancer (NSCLC) metastasis remain largely unexplored. Herein, we demonstrated that M2‐like TAMs facilitate the migration and invasion of cancer cells in vitro and in vivo through intercellular delivery of M2‐like macrophage‐derived exosomes (M2‐exos). Importantly, we found that M2‐exos had considerably higher levels of integrin (ITG) αV and β3. The impact of M2‐like macrophage‐mediated invasion and migration of NSCLC cells was clearly decreased when ITG αVβ3 was blocked. Mechanistically, exosomal ITG αVβ3 produced from M2‐like macrophages successfully triggered the focal adhesion kinase signaling pathway in recipient cells, boosting the migratory and invasive abilities of NSCLC cells. Clinically, we found that metastatic NSCLC patients had greater ITG αV and β3 expression, which was associated with a worse prognosis. This study reveals a novel mechanism by which M2‐exos significantly increased NSCLC cell migration and invasion by delivering integrin αVβ3. Exosomal ITG αVβ3 can be used as a potential prognostic marker, and blocking ITG αVβ3 could be a viable treatment option for preventing tumor metastasis.

Background An enhanced understanding of larval ecology is fundamental to improve the management of locally depleted horseshoe crab populations in Asia. Recent studies in the northern Beibu Gulf, China demonstrated that nesting sites of Asian horseshoe crabs are typically close to their nursery beaches with high-density juveniles distributed around mangrove, seagrass and other structured habitats. Methods A laboratory Y-maze chamber was used to test whether the dispersal of early-stage juvenile tri-spine horseshoe crab Tachypleus tridentatus is facilitated by chemical cues to approach suitable nursery habitats. The juvenile orientation to either side of the chamber containing controlled seawater or another with various vegetation cues, as well as their movement time, the largest distance and displacement were recorded. Results The juveniles preferred to orient toward seagrass Halophila beccarii cues when the concentration reached 0.5 g l−1, but ceased at 2 g l−1. The results can be interpreted as a shelter-seeking process to get closer to the preferred settlement habitats. However, the juveniles exhibited avoidance behaviors in the presence of mangrove Avicennia marina and invasive saltmarsh cordgrass Spartina alterniflora at 2 g l−1. The juveniles also spent less time moving in the presence of the A. marina cue, as well as reduced displacement in water containing the S. alterniflora cue at 1 and 2 g l−1. These results may explain the absence of juvenile T. tridentatus within densely vegetated areas, which have generally higher organic matter and hydrogen sulfide. Conclusion Early-stage juvenile T. tridentatus are capable of detecting and responding to habitat chemical cues, which can help guide them to high-quality settlement habitats. Preserving and restoring seagrass beds in the intertidal areas should be prioritized when formulating habitat conservation and management initiatives for the declining horseshoe crab populations.

BackgroundAccurate assessment of the nature of enlarged retropharyngeal lymph nodes (RLN) of nasopharyngeal carcinoma (NPC) patients after radiotherapy is related to selecting appropriate treatments and avoiding unnecessary therapy. This study aimed to develop a non-invasive and effective model for predicting the recurrence of RLN (RRLN) in NPC.Materials and methodsThe data of post-radiotherapy NPC patients (N = 76) with abnormal enlargement of RLN who underwent endonasopharyngeal ultrasound-guided fine-needle aspirations (EPUS-FNA) were examined. They were randomly divided into a discovery (n = 53) and validation (n = 23) cohort. Univariate logistic regression was used to assess the association between variables (magnetic resonance imaging characteristics, EBV DNA) and RRLN. Multiple logistic regression was used to construct a prediction model. The accuracy of the model was assessed by discrimination and calibration, and decision curves were used to assess the clinical reliability of the model for the identification of high risk RLNs for possible recurrence.ResultsAbnormal enhancement, minimum axis diameter (MAD) and EBV-DNA were identified as independent risk factors for RRLN and could stratify NPC patients into three risk groups. The probability of RRLN in the low-, medium-, and high-risk groups were 37.5, 82.4, and 100%, respectively. The AUC of the final predictive model was 0.882 (95% CI: 0.782–0.982) in the discovery cohort and 0.926 (95% CI, 0.827–1.000) in the validation cohort, demonstrating good clinical accuracy for predicting the RRLN of NPC patients. The favorable performance of the model was confirmed by the calibration plot and decision curve analysis.ConclusionThe nomogram model constructed in the study could be reliable in predicting the risk of RRLN after radiotherapy for NPC patients.

Finance is a pillar industry of national governance. It also provides a solid guarantee for achieving the official Double Carbon target. The question of how to forefront the role of environmental governance in the reform of fiscal and taxation systems, whilst also motivating enterprises to enhance Environment in Environmental, Social, and Governance (EESG) considerations is worth investigating in depth. This study takes A-share listed companies in China from 2001 to 2020 as examples. The effect of Performance-Based Budgeting (PBB) reform on the EESG of these enterprises is empirically examined through quasi-natural experiments using a multi-time difference-in-difference model. We find that PBB significantly optimizes the EESG of the enterprises. The placebo test, the difference-in-difference method, and a series of other robustness tests all support this conclusion. Furthermore, it is suggested that the environmental governance effect of PBB is more significant in areas with heavy financial pressure and stronger government audit. The environmental governance effect of the PBB reform is significant for enterprises with government contracts, strong green innovation capabilities, or high financing constraints. The mechanism test is performed, and the results suggest that the influence mechanism of this environmental governance role lies in the fact that PBB has improved environmental protection subsidies and enhanced fiscal transparency. Through the economic consequences test, we find that enterprise EESG can bring economic benefits to enterprises, which is reflected in the improvement of enterprise return on total assets, price-to-book ratio, and total patent authorization. This study enriches literature on the economic consequences of PBB, and has significance in deepening current fiscal and tax system reform, vigorously optimizing the major strategy of carbon peak and carbon neutrality.

The potential toxicity and ecological risks of rare-earth nanoparticles in the environment have become a concern due to their widespread application and inevitable releases. The integration of hydroponics experiments, partial least squares structural equation modeling (PLS-SEM), and Transmission Electron Microscopy (TEM) were utilized to investigate the physiological toxicity, uptake and translocation of yttrium oxide nanoparticles (Y2O3 NPs) under different hydroponic treatments (1, 5, 10, 20, 50 and 100 mg·L−1 of Y2O3 NPs, 19.2 mg·L−1 Y(NO3)3 and control) in tomato (Lycopersicon esculentum) seedlings. The results indicated that Y2O3 NPs had a phytotoxic effect on tomato seedlings' germination, morphology, physiology, and oxidative stress. The Y2O3 NPs and soluble YIII reduced the root elongation, bud elongation, root activity, chlorophyll, soluble protein content and superoxide dismutase and accelerated the proline and malondialdehyde in the plant with increasing concentrations. The phytotoxic effects of Y2O3 NPs on tomato seedlings had a higher phytotoxic effect than soluble YIII under the all treatments. The inhibition rates of different levels of Y2O3 NPs in shoot and root biomass ranged from 0.2% to 6.3% and 1.0–11.3%, respectively. The bioaccumulation and translocation factors were less than 1, which suggested that Y2O3 NPs significantly suppressed shoot and root biomass of tomato seedlings and easily bioaccumulated in the root. The observations were consistent with the process of concentration-dependent uptake and translocation factor and confirmed by TEM. Y2O3 NPs penetrate the epidermis, enter the cell wall, and exist in the intercellular space and cytoplasm of mesophyll cells of tomato seedlings by endocytic pathway. Moreover, PLS-SEM revealed that the concentration of NPs significantly negatively affects the morphology and physiology, leading to the change in biomass of plants. This study demonstrated the possible pathway of Y2O3 NPs in uptake, phytotoxicity and translocation of Y2O3 NPs in tomato seedlings.

The invasion of Spartina alterniflora (S. alterniflora) has changed the carbon cycle process of local ecosystems. In order to clarify the effect of S. alterniflora invasion on coastal soil carbon pool in Northern Beibu Gulf, the distribution characteristics and influencing factors of soil organic carbon (SOC) and SOC storage (SOCS) at different intrusion stages were investigated and analyzed. The results showed that the SOC content in S. alterniflora wetlands (2.65–21.54 g/kg) was higher than that in mudflats (0.85–1.19 g/kg). SOC content in 0–20 cm depth was highest than that in 20–40 cm and 40–60 cm depth. The total SOCS increased by 72.11%, 78.45%, 77.56%, 80.42%, and 90.63% in 3a, 12a, 15a, 16–19a, and 26a compared with mudflats, respectively. S. alterniflora invasion increased SOC and SOCS both in surface soil and deep soil. SOCS increased rapidly during the initial stage of invasion, and remained in a relatively stable and continuous growth state after 12–15 years. The distributions and accumulation of SOC and SOCS were affected mainly by soil texture, soil bulk density, moisture content, total nitrogen and total phosphorus. The source of SOC from S. alterniflora was increasing with invasion ages and would be mainly input in 26a, while marine sources was mainly imported in other invasion ages. Our data indicated that S. alterniflora continuously enhances the SOC sequestration over the years in coastal wetland ecosystems.

Long-span steel structure trusses are widely used in factory buildings. However, with the increase in service time and dynamic load fatigue, transverse cracks at the bottom of the middle span and oblique deformation of the abdomen during the operation process may appear in a considerable part of long-span trusses with dynamic load. The U-shaped cracks at the bottom and belly, as well as the mid-span down deflection of the main truss, can also reduce the functionality of the factory building truss structure and limit the original crane load, thus affecting the normal safety and durability of the structure. Therefore, the principle of variable axial force cable system in the long-span factory building truss structure and 3D3S software modelling were applied. Analysing and studying the reinforcement method of large-span powerhouse trusses can provide practical experience for subsequent similar projects. In view of the above phenomenon, the large-span powerhouse trusses of Hongcheng Powerhouse No. 1 and No. 2, located in Tonglu, Zhejiang Province, were used as the research objects, and the variable axial force cable method was proposed to strengthen and lift the load. Considering the span of the powerhouse truss, a cable system with 22 m and a controlling force of 400 kN was proposed for Powerhouse 1, and a cable system with a variable axial force of 24 m was proposed for Powerhouse 2. The force model of large-span trusses was established by using the finite element method, which is commonly used to analyse the force of the truss. The influence of the reinforcement effect was analysed under two working conditions and compared from three aspects: stiffness, bearing capacity and stability. Furthermore, the phenomenon of uneven stress distribution was analysed. The stress distribution characteristics of each node were understood by simulating the most disadvantageous node plates with the greatest internal force before and after reinforcement.

Matching analysis is a key step in the process of verifying the adaptation of carbon-ceramic brake discs to high-speed trains’ braking system. Relevant research on matching analysis tends to be carried out only on a single parameter of the brake disc. Due to this lack of comprehensive analysis, a data-driven, parametric method is proposed to address the problem. We have summarised the matching parameters of carbon-ceramic brake discs in three dimensions: assembly interface, physical characteristics, and braking performance. The method is based on the feasibility of modelling the parameters, completing the analysis of non-modelled parameters through a comparative conformity check, and modelling parameters through a statistical analysis of the experimental data. Conformity comparison results show that the example carbon-ceramic brake disc is well suited to high-speed trains and is better matching than the example cast-steel brake discs in terms of mass and average frictional coefficient. Analysis of the simulated experimental data shows that under high-speed braking conditions, the maximum disc surface temperature and wear of the example carbon-ceramic disc is higher than that of the cast-steel disc, trains equipped with carbon-ceramic discs have shorter emergency braking distances and higher average braking deceleration, and the carbon-ceramic discs exhibit better matching performance.

There are problems associated with facial expression recognition (FER), such as facial occlusion and head pose variations. These two problems lead to incomplete facial information in images, making feature extraction extremely difficult. Most current methods use prior knowledge or fixed-size patches to perform local cropping, thereby enhancing the ability to acquire fine-grained features. However, the former requires extra data processing work and is prone to errors; the latter destroys the integrity of local features. In this paper, we propose a local Sliding Window Attention Network (SWA-Net) for FER. Specifically, we propose a sliding window strategy for feature-level cropping, which preserves the integrity of local features and does not require complex preprocessing. Moreover, the local feature enhancement module mines fine-grained features with intraclass semantics through a multiscale depth network. The adaptive local feature selection module is introduced to prompt the model to find more essential local features. Extensive experiments demonstrate that our SWA-Net model achieves a comparable performance to that of state-of-the-art methods with scores of 90.03% on RAF-DB, 89.22% on FERPlus, 63.97% on AffectNet.

Introducing the cloud platform operator (CPO) to manage all kinds of manufacturing services on the cloud service platform, the game strategy selection of the multiple participants in the cloud manufacturing alliance is one of current research hotspots of the cloud manufacturing mode. Based on the game theory, this article elaborates the multi-participants business collaboration process and proposes the game strategy selection framework of the multiple participants in the cloud manufacturing alliance. From the perspectives of the manufacturing resource demander (MRD), the manufacturing resource provider (MRP), and the CPO, the game types are analyzed, the benefit functions are established, the existences of game equilibria are proved, and their corresponding constraint conditions are obtained. Integrating the dominant game strategies of the multiple participants, the dominant combination strategies of the above three game equilibria are proposed and the intersection conditions of Nash equilibrium from the mixed perspective are obtained. A set of experimental data from the practical case is given to prove that the solution space of Nash equilibrium from the mixed perspective is not empty. This research provides the theoretical basis for the landing application of the cloud manufacturing mode and the technical support for the development of the cloud manufacturing service platform. It has the important academic value and the broad application prospects.

Abstract Background The recent emergence of antibiotic-resistant strains of bacteria has increased the need to develop effective alternatives to antibiotics. Antimicrobial peptides have been considered as a promising product with several advantages. Results In this present study, we identified a novel cecropin from the armyworm, Mythimna separata (armyworm cecropin 1, AC-1) by transcriptome sequencing and multi-sequence alignment analysis. The AC-1 precursor comprised 63 amino acid residues, containing a conserved cleavage site of the signal peptide, Ala23-Pro24, while the mature AC-1 included 39 amino acid residues. Chemically synthesized AC-1 exhibited low hemolytic activity against chicken red blood cells, low cytotoxicity against swine testis cells, and effective antimicrobial activity against Salmonella, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa. Its antimicrobial activity against Salmonella remained after incubation for 1 h at 100 °C or in 250 mM NaCl, KCl, or MgCl2 solution, implying good thermal- and salt-resistant stabilities. The bactericidal effect of AC-1 on E. coli gradually increased with increasing AC-1 concentration, resulting in deformation, severe edema, cytolysis, cell membrane damage, and reducing intracellular electron density. Additionally, recombinant AC-1 protein expressed in E. coli was digested by enterokinase protease to obtain AC-1, which showed similar antimicrobial activity against E. coli to chemically synthesized AC-1. Conclusions This study identified a novel antimicrobial peptide that may represent a potential alternative to antibiotics.

Abstract Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies (Abs) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) Abs, are effective for patients with various cancers. However, low response rates to ICI monotherapies and even hyperprogressive disease (HPD) have limited the clinical application of ICIs. HPD is a novel pattern of progression, with an unexpected and fast progression in tumor volume and rate, poor survival of patients and early fatality. Considering the limitations of ICI due to HPD incidence, valid biomarkers are urgently needed to predict the occurrence of HPD and the efficacy of ICI. Here, we reviewed and summarized the known biomarkers of HPD, including tumor cell biomarkers, tumor microenvironment biomarkers, laboratory biomarkers and clinical indicators, which provide a potential effective approach for selecting patients sensitive to ICI cancer treatments.

Objectives: The World Health Organization proposed intrinsic capacity (IC) model to guide the implementation of person-centered care plan aimed at preserving or reserving functional ability, especially in frail older adults. We aimed to show the trajectory of IC and the overlap between IC impairment and frailty and investigate the correlation between IC domains and frailty status transitions.Method: Longitudinal observational study covering 230 community-dwelling older adults (mean age 84.0 ± 4.5 years) at baseline, and transition information at 2-year follow-up (n = 196). IC was measured by five domains: locomotion, cognition, vitality, psychological, and sensory. Frailty was defined by FRAIL Scale. IC and frailty status transitions were assessed. Logistic regression, odds ratios (OR) and 95% confidence interval (CI) were used for the analysis.Results: The prevalence of frailty was 23.0% and increased up to 41.8% over two years. Regarding frailty transitions, 38.3% of older adults progressed to more frailty status, and 8.6% regressed to lesser frailty status. The prevalence of IC impairment was 67.9% and increased to 81.6% over two years. Regarding IC transitions, 49.2% of adults with no IC impairment at baseline kept stable, and 50.8% developed new IC impairment. Among individuals with IC impairment at baseline, 57.9% worsened, and 13.5% improved. Importantly, IC impairment at baseline existed in 42.4% robust adults, 83.3% pre-frail adults, and 93.3% frail adults. 47.1% individuals who kept non-frail status within two years experienced IC worsened transition. Univariable analysis illustrated that new impaired locomotion, vitality, cognition, and sensory domains increased the risk of non-frail progressed to frail status. After adjusting for covariables, new impaired locomotion (OR = 3.625, 95% CI: 1.348–9.747) and vitality domains (OR = 3.034, 95% CI: 1.229–7.487) were associated with a higher possibility of non-frail progressed to frail status.Conclusion: IC impairment and frailty overlap and co-exist in older adults. IC impairment, especially new impairment in locomotion and vitality are associated with the transitions from non-frail to frail status. It is important that geriatricians tightly monitor IC trajectory and find the new impaired domains to take early action to minimize the public health burden of frailty.

Cancer cell-derived exosomes regulate tumor growth and progression. However, the effects of exosomes and its contents on head and neck squamous cell carcinoma (HNSCC) and its underlying mechanisms remain unclear. Here, we found HNSCC displayed a dysregulation of exosomes biogenesis. miR-185-3p was one of the most upregulated exosome-derived miRNAs in HNSCC. Functional assay showed that RAB25 is a direct downstream target of miR-185-3p. miR-185-3p/RAB25 signaling controlled tumor progression and correlated with disease prognosis. Targeting miR-185-3p/RAB25 significantly inhibited tumor growth and promoted drug response to chemotherapy. To conclude, the findings demonstrate exosomal miR-185-3p promotes tumor growth by mediating RAB25 that could be effectively targeted for HNSCC treatment.

Many catering merchants are currently adopting omnichannel sales methods. At a restaurant, customers can place their orders, and while waiting for the food to be completed, they can enjoy the restaurant’s service environment. Online customers, by placing orders on various apps, can skip the queue, increasing their utility by reducing the opportunity cost, but they cannot enjoy the restaurant’s service environment. For merchants, it is important to adequately address how to choose the optimal capacity to provide services to customers in different channels and obtain optimal profits based on the service environment. In this paper, we establish a stylized theoretical model to study the impact of the service environment on customers’ shopping behavior online and offline, and we study how merchants can formulate the optimal capacity. Our main results are as follows: First, improving the service environment was conducive to reducing the merchants’ safety capacity and could help them obtain higher profits. In short-term omnichannel operations, merchants obtained higher profits than in traditional offline single-channel operations. Improving the service environment increased profits, but the profit difference between short-term omnichannel and offline single-channel operations gradually decreased. Finally, in long-term operations, the process of online customers transferring to offline channels based on a high-quality service environment might be detrimental to merchants’ profits.

BackgroundPosttraumatic epilepsy (PTE) is a common sequela after traumatic brain injury (TBI), and identifying high-risk patients with PTE is necessary for their better treatment. Although artificial neural network (ANN) prediction models have been reported and are superior to traditional models, the ANN prediction model for PTE is lacking. ObjectiveWe aim to train and validate an ANN model to anticipate the risks of PTE. MethodsThe training cohort was TBI patients registered at West China Hospital. We used a 5-fold cross-validation approach to train and test the ANN model to avoid overfitting; 21 independent variables were used as input neurons in the ANN models, using a back-propagation algorithm to minimize the loss function. Finally, we obtained sensitivity, specificity, and accuracy of each ANN model from the 5 rounds of cross-validation and compared the accuracy with a nomogram prediction model built in our previous work based on the same population. In addition, we evaluated the performance of the model using patients registered at Chengdu Shang Jin Nan Fu Hospital (testing cohort 1) and Sichuan Provincial People’s Hospital (testing cohort 2) between January 1, 2013, and March 1, 2015. ResultsFor the training cohort, we enrolled 1301 TBI patients from January 1, 2011, to December 31, 2017. The prevalence of PTE was 12.8% (166/1301, 95% CI 10.9%-14.6%). Of the TBI patients registered in testing cohort 1, PTE prevalence was 10.5% (44/421, 95% CI 7.5%-13.4%). Of the TBI patients registered in testing cohort 2, PTE prevalence was 6.1% (25/413, 95% CI 3.7%-8.4%). The results of the ANN model show that, the area under the receiver operating characteristic curve in the training cohort was 0.907 (95% CI 0.889-0.924), testing cohort 1 was 0.867 (95% CI 0.842-0.893), and testing cohort 2 was 0.859 (95% CI 0.826-0.890). Second, the average accuracy of the training cohort was 0.557 (95% CI 0.510-0.620), with 0.470 (95% CI 0.414-0.526) in testing cohort 1 and 0.344 (95% CI 0.287-0.401) in testing cohort 2. In addition, sensitivity, specificity, positive predictive values and negative predictors in the training cohort (testing cohort 1 and testing cohort 2) were 0.80 (0.83 and 0.80), 0.86 (0.80 and 0.84), 91% (85% and 78%), and 86% (80% and 83%), respectively. When calibrating this ANN model, Brier scored 0.121 in testing cohort 1 and 0.127 in testing cohort 2. Compared with the nomogram model, the ANN prediction model had a higher accuracy (P=.01). ConclusionsThis study shows that the ANN model can predict the risk of PTE and is superior to the risk estimated based on traditional statistical methods. However, the calibration of the model is a bit poor, and we need to calibrate it on a large sample size set and further improve the model.

Abstract Background Patients with HBsAg-positive gastric cancer (GC) are a heterogeneous group, and it is not possible to accurately predict the overall survival (OS) in these patients. Methods We developed and validated a nomogram to help improve prediction of OS in patients with HBsAg-positive GC. The nomogram was established by a development cohort (n = 245), and the validation cohort included 84 patients. Factors in the nomogram were identified by univariate and multivariate Cox hazard analysis. We tested the accuracy of the nomograms by discrimination and calibration, and plotted decision curves to assess the benefits of nomogram-assisted decisions in a clinical context. Then we evaluated the risk in the two cohort. Results Significant predictors were age, tumor stage, distant metastases, gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. The nomogram had a concordance index (C-index) of 0.812 (95% CI 0.762–0.862), which was superior than the C-index of AJCC TNM Stage (0.755, 95% CI 0.702–0.808). The calibration plot in the validation cohort based on 5 predictors suggested good agreement between actual and nomogram-predicted OS probabilities. The decision curve showed that the nomogram in predicting OS is better than that of TNM staging system in all range. Moreover, patients were divided into three distinct risk groups for OS by the nomogram: low risk group, middle risk group and high risk group, respectively. Conclusion This nomogram, using five pre-treatment characteristics, improves prediction of OS in patients with HBsAg-positive gastric cancer. It represents an improvement in prognostication over the current TNM stage. To generalize the use of this nomogram in other groups, additional validation with data from other institutions is required.

Roasting is crucial for producing Yuan An yellow tea (YAYT) as it substantially affects sensory quality. However, the effect of roasting time on YAYT flavor quality is not clear. To investigate the effect of roasting time on the sensory qualities, chemical components, odor profiles, and metabolic profile of YAYTs produced with 13 min roasting, 16 min roasting, 19 min roasting, 22 min roasting, and 25 min roasting were determined. The YAYTs roasted for 22 min got higher sensory scores and better chemical qualities, such as the content of gallocatechin (GC), gallocatechin gallate (GCG), free amino acids, solutable sugar, meanwhile the lightness decreased, the hue of tea brew color (b) increased, which meant the tea brew got darker and yellower. YAYTs roasted for 22 min also increased the contents of key odorants, such as benzaldehyde, nonanal, β-cyclocitral, linalool, nerol, α-cedrol, β-ionone, limonene, 2-methylfuran, indole, and longiborneol. Moreover, non-targeted metabolomics identified up to 14 differentially expressed metabolites through pair-wise comparisons, such as flavonoids, phenolic acids, sucrose, and critical metabolites, which were the main components corresponding to YAYT roasted for 22 min. In summary, the current results provide scientific guidance for the production of high quality YAYT.

Peste des petits ruminants (PPR) is an acute and highly contagious disease in small ruminants that causes significant economic losses in developing countries. An increasing number of studies have demonstrated that both autophagy and apoptosis are important cellular mechanisms for maintaining homeostasis, and they participate in the host response to pathogens. However, the crosstalk between apoptosis and autophagy in host cells during PPRV infection has not been clarified. In this study, autophagy was induced upon virus infection in caprine endometrial epithelial cells (EECs), as determined by the appearance of double- and single-membrane autophagy-like vesicles, LC3-I/LC3-II conversion, and p62 degradation. We also found that PPRV infection triggered a complete autophagic response, most likely mediated by the non-structural protein C and nucleoprotein N. Moreover, our results suggest that autophagy not only promotes the replication of PPRV in EECs but also provides a potential mechanism for inhibiting PPRV-induced apoptosis. Inhibiting autophagosome formation by wortmannin and knocking down the essential autophagic proteins Beclin-1 and ATG7 induces caspase-dependent apoptosis in EECs in PPRV infection. However, inhibiting autophagosome and lysosome fusion by NH4Cl and chloroquine did not increase the number of apoptotic cells. Collectively, these data are the first to indicate that PPRV-induced autophagy inhibits caspase-dependent apoptosis and thus contributes to the enhancement of viral replication and maturity in host cells.

As a well-known example of “living fossil,” horseshoe crabs are ecologically significant macroinvertebrates in coastal and estuarine ecosystems. The tri-spine horseshoe crab, Tachypleus tridentatus, has been widely utilized for Tachypleus amebocyte lysate production and food consumption since the 1980s, which led to considerable population declines along the west coast of the Pacific Ocean. The declining horseshoe crab population is expected to have ecological and social impacts. Stock enhancement through captive rearing of juveniles is cited as an important alternative to repopulate the native T. tridentatus, which in turn supports sustainable resource utilization and research activities. The hatchery production techniques for this species have gradually developed following the mass culture efforts in Japan since the late 1980s. However, the previous studies have primarily concerned the feed types and husbandry conditions to maximize the growth and survival of the juveniles. Little is known about the practicability and effectiveness of releasing large numbers of hatchery-bred individuals through releasing programs. In this review, we (1) summarize the available captive breeding and rearing techniques, (2) discuss the release strategies that could potentially improve the survival of released juveniles, and (3) identify the future opportunities and challenges in establishing technical frameworks to support responsible stock enhancement programs for T. tridentatus. The information should benefit future horseshoe crab fisheries management efforts in the attempt to restore the severely depleted populations.

Background. Sudden cardiac death is a leading cause of death from coronary heart disease (CHD). The risk of sudden cardiac death (SCD) increases with age, and sudden arrhythmic death remains a major cause of mortality in elderly individuals, especially ventricular arrhythmias (VA). We developed a risk prediction model by combining ECG and other clinical noninvasive indexes including biomarkers and echocardiology for VA in elderly patients with CHD. Method. In the retrospective study, a total of 2231 consecutive elderly patients (≥60 years old) with CHD hospitalized were investigated, and finally 1983 patients were enrolled as the model group. The occurrence of VA within 12 months was mainly collected. Study parameters included clinical characteristics (age, gender, height, weight, BMI, and past medical history), ECG indexes (QTcd, Tp-e/QT, and HRV indexes), biomarker indexes (NT-proBNP, Myo, cTnT, CK-MB, CRP, K+, and Ca2+), and echocardiology indexes. In the respective study, 406 elderly patients (≥60 years old) with CHD were included as the verification group to verify the model in terms of differentiation and calibration. Results. In the multiparameter model, seven independent predictors were selected: LVEF, LAV, HLP, QTcd, sex, Tp-e/QT, and age. Increased HLP, Tp-e/QT, QTcd, age, and LAV were risk factors (RR > 1), while female and increased LVEF were protective factors (RR

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease-2019 (COVID-19), interacts with the host cell receptor angiotensin-converting enzyme 2 (hACE2) via its spike 1 protein during infection. After the virus sequence was published, we identified two potent antibodies against the SARS-CoV-2 receptor binding domain (RBD) from antibody libraries using a phage-to-yeast (PtY) display platform in only 10 days. Our lead antibody JMB2002, now in a Phase 1 clinical trial (ChiCTR2100042150), showed broad-spectrum in vitro blocking activity against hACE2 binding to the RBD of multiple SARS-CoV-2 variants, including B.1.351 that was reportedly much more resistant to neutralization by convalescent plasma, vaccine sera and some clinical-stage neutralizing antibodies. Furthermore, JMB2002 has demonstrated complete prophylactic and potent therapeutic efficacy in a rhesus macaque disease model. Prophylactic and therapeutic countermeasure intervention of SARS-CoV-2 using JMB2002 would likely slow down the transmission of currently emerged SARS-CoV-2 variants and result in more efficient control of the COVID-19 pandemic.