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Abstract The epidemic and outbreaks of influenza B Victoria lineage (Bv) during 2019–2022 led to an analysis of genetic, epitopes, charged amino acids and Bv outbreaks. Based on the National Influenza Surveillance Network (NISN), the Bv 72 strains isolated during 2019–2022 were selected by spatio-temporal sampling, then were sequenced. Using the Compare Means, Correlate and Cluster, the outbreak data were analyzed, including the single nucleotide variant (SNV), amino acid (AA), epitope, evolutionary rate (ER), Shannon entropy value (SV), charged amino acid and outbreak. With the emergence of COVID-19, the non-pharmaceutical interventions (NPIs) made Less distant transmission and only Bv outbreak. The 2021–2022 strains in the HA genes were located in the same subset, but were distinct from the 2019–2020 strains (P

Abstract Thyroid cancer is the most frequently observed endocrine-related malignancy among which anaplastic thyroid cancer (ATC) is the most fatal subtype. The synthesis of protein is active to satisfy the rapid growth of ATC tumor, but the mechanisms regulating protein synthesis are still unknown. Our research revealed that kinetochore protein NUF2 played an essential role in protein synthesis and drove the progression of ATC. The prognosis of patients with thyroid carcinoma was positively correlated with high NUF2 expression. Depletion of NUF2 in ATC cells notably inhibited the proliferation and induced apoptosis, while overexpression of NUF2 facilitated ATC cell viability and colony formation. Deletion of NUF2 significantly suppressed the growth and metastasis of ATC in vivo. Notably, knockdown of NUF2 epigenetically inhibited the expression of magnesium transporters through reducing the abundance of H3K4me3 at promoters, thereby reduced intracellular Mg2+ concentration. Furthermore, we found the deletion of NUF2 or magnesium transporters significantly inhibited the protein synthesis mediated by the PI3K/Akt/mTOR pathway. In conclusion, NUF2 functions as an emerging regulator for protein synthesis by maintaining the homeostasis of intracellular Mg2+, which finally drives ATC progression.

Abstract Fetal macrosomia is associated with maternal and newborn complications due to incorrect fetal weight estimation or inappropriate choice of delivery models. The early screening and evaluation of macrosomia in the third trimester can improve delivery outcomes and reduce complications. However, traditional clinical and ultrasound examinations face difficulties in obtaining accurate fetal measurements during the third trimester of pregnancy. This study aims to develop a comprehensive predictive model for detecting macrosomia using machine learning (ML) algorithms. The accuracy of macrosomia prediction using logistic regression, k-nearest neighbors, support vector machine, random forest (RF), XGBoost, and LightGBM algorithms was explored. Each approach was trained and validated using data from 3244 pregnant women at a hospital in southern China. The information gain method was employed to identify deterministic features associated with the occurrence of macrosomia. The performance of six ML algorithms based on the recall and area under the curve evaluation metrics were compared. To develop an efficient prediction model, two sets of experiments based on ultrasound examination records within 1-7 days and 8-14 days prior to delivery were conducted. The ensemble model, comprising the RF, XGBoost, and LightGBM algorithms, showed encouraging results. For each experimental group, the proposed ensemble model outperformed other ML approaches and the traditional Hadlock formula. The experimental results indicate that, with the most risk-relevant features, the ML algorithms presented in this study can predict macrosomia and assist obstetricians in selecting more appropriate delivery models.

Abstract As a new class of organic photocatalysts, polymer dots show a potential application in photocatalytic hydrogen peroxide production coupled with chemical oxidation such as methanol oxidation. However, the poor methanol oxidation ability by polymer dots still inhibits the overall photocatalytic reaction occurring in the neutral condition. In this work, an organic molecular catalyst 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl radical is covalently linked to a fluorene unit in a polymer skeleton, eventually enabling photocatalytic hydrogen peroxide production coupled with methanol oxidation in the neutral condition. By conducting various spectroscopic measurements, charge transfer between components in this molecular catalyst-immobilized polymer dots system is studied and found to be very efficient for hydrogen peroxide production coupled with alcohol oxidation. This work proves a strategy for designing polymer dots photocatalysts with molecular catalysts, facilitating their future development and potential applications in other fields such as water splitting, CO2 reduction, photoredox catalysis and photodynamic therapy.

Abstract Improvements in the polarization of environmentally-friendly perovskite ferroelectrics have proved to be a challenging task in order to replace the toxic Pb-based counterparts. In contrast to common methods by complex chemical composition designs, we have formed Mn-inlaid antiphase boundaries in Mn-doped (K,Na)NbO3 thin films using pulsed laser deposition method. Here, we observed that mono- or bi-atomic layer of Mn has been identified to inlay along the antiphase boundaries to balance the charges originated from the deficiency of alkali ions and to induce the strain in the KNN films. Thus, rectangular saturated polarization-electric field hysteresis loops have been achieved, with a significantly improved twice remanent polarization of 114 μC/cm2 with an applied electric field of 606 kV/cm, which can be comparable to that of the typical Pb-based thin films. Moreover, we directly see the Mn occupation at the A-site of KNN perovskite structure using atomic-scale microstructure and composition analysis. The Mn-inlaid antiphase boundary can further enrich the understanding of perovskite crystal structure and give more possibilities for the design and optimization of perovskite materials.

Microcirculatory disturbances are complex processes caused by many factors, including abnormal vasomotor responses, decreased blood flow velocity, vascular endothelial cell injury, altered leukocyte and endothelial cell interactions, plasma albumin leakage, microvascular hemorrhage, and thrombosis. These disturbances involve multiple mechanisms and interactions among mechanisms that can include energy metabolism, the mitochondrial respiratory chain, oxidative stress, inflammatory factors, adhesion molecules, the cytoskeleton, vascular endothelial cells, caveolae, cell junctions, the vascular basement membrane, neutrophils, monocytes, and platelets. In clinical practice, aside from drugs that target abnormal vasomotor responses and platelet adhesion, there continues to be a lack of multi-target drugs that can regulate the complex mechanistic links and interactions underlying microcirculatory disturbances. Natural products have demonstrated obvious positive therapeutic effects in treating ischemia/reperfusion (I/R)- and lipopolysaccharide (LPS)-induced microcirculatory disturbances. In recent years, numerous research papers on the improvement of microcirculatory function by natural products have been published in international journals. In 2008 and 2017, the first listed author of this review was invited to publish reviews in the journal of Pharmacology & Therapeutics on the improvement of microcirculatory disturbances and organ injury induced by I/R using Salvia miltiorrhiza ingredients and other natural components of compounded Chinese medicine, respectively. This review systematically summarizes the effects, targets of action, and mechanisms of natural products regarding improving I/R- and LPS-induced microcirculatory disturbances and tissue injury. Based on this summary, scientific proposals are suggested for the discovery of new drugs to improve microcirculatory disturbances in disease.

Abstract Purpose Osteosarcoma is a primary bone tumor lacking optimal clinical treatment options. Tumor-associated macrophages in the tumor microenvironment are closely associated with tumor development and metastasis. Studies have identified the macrophage receptor with collagenous structure (MARCO) as a specific receptor expressed in macrophages. This study aimed to investigate whether anti-MARCO mAb treatment can induce macrophage polarization in the tumor microenvironment and elicit anti-tumor effects. Methods THP-1 cells were treated with 20 ng/mL phorbol 12-myristate 13-acetate and 80 ng/mL interleukin-4 for 48 h to induce macrophage polarization to alternatively activated macrophages (M2). Enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, flow cytometry, and bioinformatic analyses were performed to evaluate macrophage polarization. The co-culture groups included a blank group, an M2 macrophage and U2OS co-culture group, and an anti-MARCO mAb-treated M2 macrophage group. Cell viability assays, cell scratch tests, apoptosis, and cell cycle analyses were performed to determine the effects of anti-MARCO mAb-treated macrophages on osteosarcoma cells. Results It was demonstrated that anti-MARCO mAb can drive macrophages toward classically activated macrophage (M1) polarization. Anti-MARCO mAb promoted the secretion of pro-inflammatory factors by macrophages, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta, interleukin-6 and interleukin-23. Studies on in vitro co-culture models have revealed that macrophages treated with anti-MARCO mAb can suppress the growth and migration of osteosarcoma cells, induce cell apoptosis, and inhibit cell cycle progression of osteosarcoma cells through M1 polarization of macrophages in vitro. Conclusion Anti-MARCO mAb treatment exerts anti-osteosarcoma effects by affecting macrophage polarization toward M1 macrophages, offering a potential new therapeutic approach for treating osteosarcoma.

Abstract Background The primary pathogenic mechanism of schistosomiasis-associated liver fibrosis involves the deposition of schistosome eggs, leading to the formation of liver egg granulomas and subsequent liver fibrosis. Hepatic stellate cells are abnormally activated, resulting in excessive collagen deposition and fibrosis development. While specific long non-coding RNAs (lncRNAs) have been associated with fibrotic processes, their roles in schistosomiasis-associated liver fibrosis remain unclear. Methods Our previous research indicated that downregulating the ICOSL/ICOS could partially alleviate liver fibrosis. In this study, we established a schistosomiasis infection model in C57BL/6 and ICOSL knockout (KO) mice, and the liver pathology changes were observed at various weeks postinfection (wpi) using hematoxylin and eosin and Masson’s trichrome staining. Within the first 4 wpi, no significant liver abnormalities were observed. However, mice exhibited evident egg granulomas and fibrosis in their livers at 7 wpi. Notably, ICOSL-KO mice had significantly smaller pathological variations compared with simultaneously infected C57BL/6 mice. To investigate the impact of lncRNAs on schistosomiasis-associated liver fibrosis, quantitative real-time polymerase chain reaction (RT-qPCR) was used to monitor the dynamic changes of lncRNAs in hepatic stellate cells of infected mice. Results The results demonstrated that lncRNA-H19, -MALAT1, -PVT1, -P21 and -GAS5 all participated in liver fibrosis formation after schistosome infection. In addition, ICOSL-KO mice exhibited significantly inhibited expression of lncRNA-H19, -MALAT1 and -PVT1 after 7 wpi. In contrast, they showed enhanced expression of lncRNA-P21 and -GAS5 compared with C57BL/6 mice, influencing liver fibrosis development. Furthermore, small interfering RNA transfection (siRNA) in JS-1 cells in vitro confirmed that lncRNA-H19, -MALAT1, and -PVT1 promoted liver fibrosis, whereas lncRNA-P21 and -GAS5 had the opposite effect on key fibrotic molecules, including α- smooth muscle actin and collagen I expression. Conclusions This study uncovers that ICOSL/ICOS may play a role in activating hepatic stellate cells and promoting liver fibrosis in mice infected with Schistosoma japonicum by dynamically regulating the expression of specific lncRNAs. These findings offer potential therapeutic targets for schistosomiasis-associated liver fibrosis. Graphical Abstract

Abstract Quantifying the complexity of traffic scenarios not only provides an essential foundation for constructing the scenarios used in autonomous vehicle training and testing, but also enhances the robustness of the resulting driving decisions and planning operations. However, currently available quantification methods suffer from inaccuracies and coarse‐granularity in complexity measurements due to issues such as insufficient specificity or indirect quantification. The present work addresses these challenges by proposing a comprehensive entropy‐based model for quantifying traffic scenario complexity across multiple dimensions based on a consideration of the essential components of the traffic environment, including traffic participants, static elements, and dynamic elements. In addition, the limitations of the classical information entropy models applied for assessing traffic scenarios are addressed by calculating magnitude entropy. The proposed entropy‐based model is analyzed in detail according to its application to simulated traffic scenarios. Moreover, the model is applied to real world data within a naturalistic driving dataset. Finally, the effectiveness of the proposed quantification model is illustrated by comparing the complexity results obtained for three typical traffic scenarios with those obtained using an existing multi‐factor complexity quantification method.

Abstract Understanding the co-variability between the El Niño–Southern Oscillation (ENSO) and the background state in the tropical Pacific is critical for projecting future ENSO. The difficulty is rooted in a circular logic that the background state routinely defined by multi-decadal mean modulates, and is modulated by, ENSO. This circularity arises due to the asymmetry between El Niño and La Niña, resulting in a non-zero mean, referred to as the ENSO rectification effect. Here, we develop a method based on Box-Cox normalization to define the tropical Pacific background state and its associated anomalies, which removes the ENSO rectification effect and is referred to as the normalized mean state. The normalized mean state accurately quantifies ENSO-related anomalies, ENSO asymmetry, and the ENSO rectification effect. It is evident in both observations and model simulations that the normalized mean state has a clear asymmetric impact on the amplitude of ENSO. A warm background state weakens El Niño but strengthens La Niña through two key processes: the nonlinear response of precipitation to SST and oceanic zonal advection feedback. The normalized mean state successfully solves the circular reasoning fallacy resulting from ENSO asymmetry and offers a framework to study ENSO and tropical climate dynamics with far-reaching impacts on global climate.

Abstract Background The chemokine CX3CL1 has been reported to play an important role in optic nerve protection, but the underlying mechanism is still unclear. CX3CR1, the only receptor of CX3CL1, is specifically expressed on retinal microglia, whose activation plays a role in the pathological process of optic nerve injury. This study aimed to evaluate whether CX3CL1 exerts optic neuroprotection by affecting the activation of microglia by combining with CX3CR1. Methods A mouse model of distal optic nerve trauma (ONT) was used to evaluate the effects of the CX3CL1-CX3CR1 axis on the activation of microglia and survival or axonal regeneration of retinal ganglion cells (RGCs). The activation of microglia, loss of RGCs, and damage to visual function were detected weekly till 4 weeks after modeling. CX3CL1 was injected intravitreally immediately or delayed after injury and the status of microglia and RGCs were examined. Results Increases in microglia activation and optic nerve damage were accompanied by a reduced production of the CX3CL1-CX3CR1 axis after the distal ONT modeling. Both immediate and delayed intravitreal injection of CX3CL1 inhibited microglia activation, promoted survival of RGCs, and improved axonal regenerative capacity. Injection with CX3CL1 was no longer effective after 48 h post ONT. The CX3CL1-CX3CR1 axis promotes survival and axonal regeneration, as indicated by GAP43 protein and gene expression, of RGCs by inhibiting the microglial activation after ONT. Conclusions The CX3CL1-CX3CR1 axis could promote survival and axonal regeneration of RGCs by inhibiting the microglial activation after optic nerve injury. The CX3CL1-CX3CR1 axis may become a potential target for the treatment of optic nerve injury. Forty-eight hours is the longest time window for effective treatment after injury. The study is expected to provide new ideas for the development of targeted drugs for the repair of optic nerve.

Abstract Background Colorectal cancer (CRC) arises from complex interactions between host and environment, which include the gut and tissue microbiome. It is hypothesized that epigenetic regulation by gut microbiota is a fundamental interface by which commensal microbes dynamically influence intestinal biology. The aim of this study is to explore the interplay between gut and tissue microbiota and host DNA methylation in CRC. Methods Metagenomic sequencing of fecal samples was performed on matched CRC patients (n = 18) and healthy controls (n = 18). Additionally, tissue microbiome was profiled with 16S rRNA gene sequencing on tumor (n = 24) and tumor-adjacent normal (n = 24) tissues of CRC patients, while host DNA methylation was assessed through whole-genome bisulfite sequencing (WGBS) in a subset of 13 individuals. Results Our analysis revealed substantial alterations in the DNA methylome of CRC tissues compared to adjacent normal tissues. An extensive meta-analysis, incorporating publicly available and in-house data, identified significant shifts in microbial-derived methyl donor-related pathways between tumor and adjacent normal tissues. Of note, we observed a pronounced enrichment of microbial-associated CpGs within the promoter regions of genes in adjacent normal tissues, a phenomenon notably absent in tumor tissues. Furthermore, we established consistent and recurring associations between methylation patterns of tumor-related genes and specific bacterial taxa. Conclusions This study emphasizes the pivotal role of the gut microbiota and pathogenic bacteria in dynamically shaping DNA methylation patterns, impacting physiological homeostasis, and contributing to CRC tumorigenesis. These findings provide valuable insights into the intricate host-environment interactions in CRC development and offer potential avenues for therapeutic interventions in this disease.

Abstract Background Immune checkpoint inhibitors (ICIs) have demonstrated superior clinical efficacy in prolonging overall survival (OS) as the second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC), and were recommended by the guidelines. However, it remains uncertain which ICI is the most cost-effective. This study assessed the cost-effectiveness of ICIs as the second-line treatment for ESCC based on the perspective of the Chinese healthcare system. Methods A network meta-analysis (NMA) was performed to obtain the Hazard ratios (HRs) for indirect comparisons. A three-state Markov model with a 10-year time horizon was conducted to assess the cost-effectiveness. The state transition probabilities were calculated with Kaplan-Meier (KM) curves data from clinical trial and HRs from the NMA. Utilities and costs were derived from local charges or previously published studies. Univariate and probabilistic sensitivity analyses (PSA) were performed to examine model robustness. The results were assessed based on the total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results Five clinical trials (ATTRACTION-3, ESCORT, KEYNOTE-181, ORIENT-2, RATIONALE-302) with a total of 1797 patients were included in the NMA. The NMA showed that both camrelizumab and tislelizumab received relatively high rankings for progression-free survival (PFS) and OS. Compared with sintilimab, treatment with tislelizumab and camrelizumab gained 0.018 and 0.034 additional QALYs, resulting in incremental ICERs of $75,472.65/QALY and $175,681.9/QALY, respectively. Nivolumab and pembrolizumab produced lower QALYs and greater costs, suggesting that both were dominated in comparison to sintilimab. HRs and health state utilities were the most influential parameters in most univariate sensitivity analyses of paired comparisons. PSA results suggested that sintilimab had an 84.4% chance of being the most cost-effective treatment regimen at the WTP threshold of $38,223.34/QALY. In the scenario analysis, sintilimab would no longer be cost-effective, if the price of camrelizumab was assumed to decrease by 64.6% or the price of tislelizumab was assumed to decrease by 16.9%. Conclusions and relevance Among the five potential competing ICIs, sintilimab was likely to be the most cost-effective regimen as the second-line treatment for locally advanced or metastatic ESCC in China.

Precipitation and twinning strengthening mechanisms have been extensively investigated to improve the yield strength and ductility of face-centered cubic (FCC) multi-principle elements alloys (MPEAs). Compared with well-studied Al0.3CoCrFeNi in CoCrFeNi system, the microstructure and mechanical properties of a new designed CoCrNiFe0.62Al0.38 MPEA with lower Fe content were evaluated by transmission electron microscopy and tensile tests, respectively. Higher volume fraction of B2 nanoprecipitates and early deformation twining within FCC matrix were proposed to play key roles in improving the synergy strength and ductility of the AlCoCrFeNi system. The experimental results presented herein not only provide insight into how transition metal element affect precipitation and twining process of B2 phase reinforced FCC MPEAs, but also demonstrate useful guidance for the development of precipitation hardened CoCrFeNi system other than adjusting conventional elements such as Al, Ti, Ta, etc.

ObjectEstablish a clinical prognosis model of coronary heart disease (CHD) to predict 28-day mortality in patients with sepsis.MethodThe data were collected retrospectively from septic patients with a previous history of coronary heart disease (CHD) from the Medical Information Mart for Intensive Care (MIMIC)-III database. The included patients were randomly divided into the training cohorts and validation cohorts. The variables were selected using the backward stepwise selection method of Cox regression, and a nomogram was subsequently constructed. The nomogram was compared to the Sequential Organ Failure Assessment (SOFA) model using the C-index, area under the receiver operating characteristic curve (AUC) over time, Net reclassification index (NRI), Integrated discrimination improvement index (IDI), calibration map, and decision curve analysis (DCA).ResultA total of 800 patients were included in the study. We developed a nomogram based on age, diastolic blood pressure (DBP), pH, lactate, red blood cell distribution width (RDW), anion gap, valvular heart disease, peripheral vascular disease, and acute kidney injury (AKI) stage. The nomogram was evaluated using C-index, AUC, NRI, IDI, calibration plot, and DCA. Our findings revealed that this nomogram outperformed the SOFA score in predicting 28-day mortality in sepsis patients.

Pituitary neuroendocrine tumors (PitNETs) are a special class of tumors of the central nervous system that are closely related to metabolism, endocrine functions, and immunity. In this study, network pharmacology was used to explore the metabolites and pharmacological mechanisms of PitNET regulation by gut microbiota. The metabolites of the gut microbiota were obtained from the gutMGene database, and the targets related to the metabolites and PitNETs were determined using public databases. A total of 208 metabolites were mined from the gutMGene database; 1,192 metabolite targets were screened from the similarity ensemble approach database; and 2,303 PitNET-related targets were screened from the GeneCards database. From these, 392 overlapping targets were screened between the metabolite and PitNET-related targets, and the intersection between these overlapping and gutMGene database targets (223 targets) were obtained as the core targets (43 targets). Using the protein–protein interaction (PPI) network analysis, Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway and metabolic pathway analysis, CXCL8 was obtained as a hub target, tryptophan metabolism was found to be a key metabolic pathway, and IL-17 signaling was screened as the key KEGG signaling pathway. In addition, molecular docking analysis of the active metabolites and target were performed, and the results showed that baicalin, baicalein, and compound K had good binding activities with CXCL8. We also describe the potential mechanisms for treating PitNETs using the information on the microbiota (Bifidobacterium adolescentis), signaling pathway (IL-17), target (CXCL8), and metabolites (baicalin, baicalein, and compound K); we expect that these will provide a scientific basis for further study.

BackgroundSchistosomiasis is a relatively neglected parasitic disease that afflicts more than 250 million people worldwide, for which the control strategy relies mainly on mass treatment with the only available drug, praziquantel (PZQ). This approach is not sustainable and is a priority for developing novel drug candidates for the treatment and control of schistosomiasis.Methodologys/principal findingsIn our previous study, we found that DW-3-15, a kind of PZQ derivative, could significantly downregulate the expression of the histone acetyltransferase of Schistosoma japonicum (SjHAT). In this study, several commercially available HAT inhibitors, A485, C646 and curcumin were screened in vitro to verify their antischistosomal activities against S. japonicum juveniles and adults. Parasitological studies and scanning electron microscopy were used to study the primary action characteristics of HAT inhibitors in vitro. Quantitative real-time PCR was employed to detect the mRNA level of SjHAT after treatment with different HAT inhibitors. Our results demonstrated that curcumin was the most effective inhibitor against both juveniles and adults of S. japonicum, and its schistosomicidal effects were time- and dose dependent. However, A485 and C646 had limited antischistosomal activity. Scanning electron microscopy demonstrated that in comparison with DW-3-15, curcumin caused similar tegumental changes in male adult worms. Furthermore, both curcumin and DW-3-15 significantly decreased the SjHAT mRNA level, and curcumin dose-dependently reduced the SjHAT expression level in female, male and juvenile worms.ConclusionsAmong the three commercially available HATs, curcumin was the most potent against schistosomes. Both curcumin and our patent compound DW-3-15 markedly downregulated the expression of SjHAT, indicating that SjHAT may be a potential therapeutic target for developing novel antischistosomal drug candidates.

IntroductionAngong Niuhuang Wan (AGNHW), developed during the Qing dynasty (18th century) for the treatment of consciousness disturbances caused by severe infections, has been used to treat brain edema caused by ischemia‒reperfusion. However, it remains unclear whether AGNHW can ameliorate vascular-origin brain edema caused by lipopolysaccharides (LPS). This study explored the ameliorative effects of AGNHW on LPS-induced cerebrovascular edema in mice, as well as the potential underlying mechanisms.MethodsA cerebrovascular edema model was established in male C57BL/6N mice by two intraperitoneal injections of LPS (15 mg/kg), at 0 and 24 h. AGNHW was administered by gavage at doses of 0.2275 g/kg, 0.455 g/kg, and 0.91 g/kg, 2 h after LPS administration. In control mice, normal saline (NS) or AGNHW (0.455 g/kg) was administered by gavage 2 h after intraperitoneal injection of NS. The survival rate, cerebral water content, cerebral venous FITC-dextran leakage, Evans blue extravasation, and expression of vascular endothelial cadherin (VE-cadherin), zonula occludens-1 (ZO-1), claudin-5, phosphorylated caveolin-1 (CAV-1), and cytomembrane and cytoplasmic aquaporin 1 (AQP1) and aquaporin 4 (AQP4) were evaluated. The cerebral tissue phosphoproteome, blood levels of AGNHW metabolites, and the relationships between these blood metabolites and differentially phosphorylated proteins were analyzed.ResultsAGNHW inhibited the LPS-induced decrease in survival rate, increase in cerebral water content, decrease in VE-Cadherin expression and increase in phosphorylated CAV-1 (P-CAV-1). AGNHW treatment increased the expression of AQP4 on astrocyte membrane after LPS injection. AGNHW also inhibited the LPS-induced increases in the phosphorylation of 21 proteins, including protein kinase C-α (PKC-α) and mitogen-activated protein kinase 1 (MAPK1), in the cerebral tissue. Eleven AGNHW metabolites were detected in the blood. These metabolites might exert therapeutic effects by regulating PKC-α and MAPK1.ConclusionAGNHW can ameliorate cerebrovascular edema caused by LPS. This effect is associated with the inhibition of VE-Cadherin reduction and CAV-1 phosphorylation, as well as the upregulation of AQP4 expression on the astrocyte membrane, following LPS injection.

ABSTRACT The skin microbiome plays a pivotal role in human health by providing protective and functional benefits. Furthermore, its inherent stability and individual specificity present novel forensic applications. These aspects have sparked considerable research enthusiasm among scholars across various fields. However, the selection of specific 16S rRNA hypervariable regions for skin microbiome studies is not standardized and should be validated through extensive research tailored to different research objectives and targeted bacterial taxa. Notably, third-generation sequencing (TGS) technology leverages the full discriminatory power of the 16S gene and enables more detailed and accurate microbial community analyses. Here, we conducted full-length 16S sequencing of 141 skin microbiota samples from multiple human anatomical sites using the PacBio platform. Based on this data, we generated derived 16S sub-region data through an in silico experiment. Comparisons between the 16S full-length and the derived variable region data revealed that the former can provide superior taxonomic resolution. However, even with full 16S gene sequencing, limitations arise in achieving 100% taxonomic resolution at the species level for skin samples. Additionally, the capability to resolve high-abundance bacteria (TOP30) at the genus level remains generally consistent across different 16S variable regions. Furthermore, the V1-V3 region offers a resolution comparable with that of full-length 16S sequences, in comparison to other hypervariable regions studied. In summary, while acknowledging the benefits of full-length 16S gene analysis, we propose the targeting of specific sub-regions as a practical choice for skin microbial research, especially when balancing the accuracy of taxonomic classification with limited sequencing resources, such as the availability of only short-read sequencing or insufficient DNA.IMPORTANCESkin acts as the primary barrier to human health. Considering the different microenvironments, microbial research should be conducted separately for different skin regions. Third-generation sequencing (TGS) technology can make full use of the discriminatory power of the full-length 16S gene. However, 16S sub-regions are widely used, particularly when faced with limited sequencing resources including the availability of only short-read sequencing and insufficient DNA. Comparing the 16S full-length and the derived variable region data from five different human skin sites, we confirmed the superiority of the V1-V3 region in skin microbiota analysis. We propose the targeting of specific sub-regions as a practical choice for microbial research.

A small, nucleotide-binding domain, the ATP-cone, is found at the N-terminus of most ribonucleotide reductase (RNR) catalytic subunits. By binding adenosine triphosphate (ATP) or deoxyadenosine triphosphate (dATP) it regulates the enzyme activity of all classes of RNR. Functional and structural work on aerobic RNRs has revealed a plethora of ways in which dATP inhibits activity by inducing oligomerisation and preventing a productive radical transfer from one subunit to the active site in the other. Anaerobic RNRs, on the other hand, store a stable glycyl radical next to the active site and the basis for their dATP-dependent inhibition is completely unknown. We present biochemical, biophysical, and structural information on the effects of ATP and dATP binding to the anaerobic RNR from Prevotella copri. The enzyme exists in a dimer–tetramer equilibrium biased towards dimers when two ATP molecules are bound to the ATP-cone and tetramers when two dATP molecules are bound. In the presence of ATP, P. copri NrdD is active and has a fully ordered glycyl radical domain (GRD) in one monomer of the dimer. Binding of dATP to the ATP-cone results in loss of activity and increased dynamics of the GRD, such that it cannot be detected in the cryo-EM structures. The glycyl radical is formed even in the dATP-bound form, but the substrate does not bind. The structures implicate a complex network of interactions in activity regulation that involve the GRD more than 30 Å away from the dATP molecules, the allosteric substrate specificity site and a conserved but previously unseen flap over the active site. Taken together, the results suggest that dATP inhibition in anaerobic RNRs acts by increasing the flexibility of the flap and GRD, thereby preventing both substrate binding and radical mobilisation.

With the alterations in dietary structure and the augmentation of the human living standard, hyperuricemia (HUA) has emerged as a significant factor impacting contemporary human health. It has also been scientifically validated as an independent risk determinant for the progression of renal disease. Existing literature indicates that XCHD (Xiao Chai Hu Decoction) and YCSLS (Yinchen Siling San) possess a capability to ameliorate UA levels and fortify renal function, yet a comprehensive understanding of their mechanisms of action remains elusive. This investigation is designed to elucidate the therapeutic efficacy and mechanistic underpinnings of XCHD/YCSLS on the renal tissues of HUA-afflicted rats, with the objective of fortifying the evidence base to advocate its clinical application. Our preliminary findings substantiated that XCHD and YCSLS impede HUA progression through the inhibition of inflammatory and oxidative stress pathways. Further, we synthesized data from publicly accessible repositories to forecast interactions between XCHD, YCSLS, and their prospective targets in HUA, including the associated signaling pathways. This approach facilitated the identification of shared targets of XCHD/YCSLS, and HUA, and the subsequent correlation analysis of these targets employing KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) methodologies. The findings indicate that the TLR4/MYD88/NF-κB signaling constitutes one of the potential crucial conduits engaged in XCHD and YCSLS-induced HUA mitigation. In conclusion, the analysis of WB and IHC from HUA rat models corroborated that XCHD and YCSLS do indeed attenuate the expression of TLR4/MYD88/NF-κB, reinforcing the hypothesized pivotal role of the its signaling cascade in HUA. This warrants subsequent scholarly exploration.

Gypsum particleboard is attracting attention in the construction industry due to its excellent properties. However, the traditional raw materials for gypsum particleboard are facing a shortage of supply. In this study, we innovatively utilized bulk solid waste Phosphogypsum and Pennisetum giganteum for the first time to manufacture gypsum particleboard. This approach not only effectively addresses the issue of insufficient supply of traditional raw materials for gypsum particleboard but also provides a new pathway for the resource utilization of phosphogypsum. Through an orthogonal experimental design, we focused on optimizing the gypsum particleboard formulation, concentrating on factors such as density, the ratio of Pennisetum giganteum to gypsum (grass-plaster ratio), the ratio of water to gypsum (water-plaster ratio), and the size of the particles. The study determined that the optimal formulation parameters were a density of 1.2 g/cm³, a grass-plaster ratio of 0.20, a water-plaster ratio of 0.25, and a particle mesh number of 14. Under these conditions, the gypsum particleboard exhibited excellent performance, characterized by a static flexural strength of 6.5 MPa, a modulus of elasticity of 2010 MPa, an internal bond strength of 0.4 MPa, a 24-hour water-absorption thickness expansion rate of 2.2%, and an equilibrium moisture content of 1.6%, all meeting the American Society for Testing and Materials (ASTM) Standard D1037. These findings indicate that gypsum particleboards made with Pennisetum giganteum and phosphogypsum can perform comparably to those made with conventional materials. Additionally, a performance prediction model was established using Multiple Linear Regression Analysis (MLRA). The analysis revealed a significant linear relationship between the independent and dependent variables in the model, with the Analysis of Variance (ANOVA) significance levels being less than 0.05, demonstrating statistical significance. This result provides a theoretical basis for the future development of high-performance gypsum particleboard.

Abstract Soil salinity, the second most prominent cause of land degradation after soil erosion, has posed a persistent challenge to agriculture. Currently, approximately 1 billion hectares of Earth's land surface, equivalent to 7%, are affected by salinity. While biochar has proven effective in mitigating salinity stress, the specific role of deashed biochar in salinity mitigation has not been thoroughly explored. Therefore, this study was conducted to investigate the impact of four levels of deashed biochar (0%, 0.4%, 0.8%, and 1.2%) on the growth and physiological attributes of Fenugreek under both non-saline conditions (2.54 dS/m EC) and salinity stress conditions (5.46 dS/m EC). The results revealed a notable enhancement in various parameters under salinity stress. Compared to the control, the application of 1.20% deashed biochar led to a significant increase in shoot fresh weight (30.82%), root fresh weight (13.06%), shoot dry weight (17.43%), root dry weight (33.44%), shoot length (23.09%), and root length (52.39%) under salinity stress. Furthermore, improvements in internal CO2 concentration (9.91%), stomatal conductance (15.49%), photosynthetic rate (25.50%), and transpiration rate (10.46%) were observed, validating the efficacy of 1.20% deashed biochar in alleviating salinity stress. The study also demonstrated a significant decrease in the activities of oxidative stress markers such as peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), electrolyte leakage, and malondialdehyde (MDA). Simultaneously, there was an increase in the concentrations of essential nutrients, namely nitrogen (N), phosphorus (P), and potassium (K), in both shoot and root tissues. These findings collectively suggest that deashed biochar, particularly at a concentration of 1.20%, is recommended for achieving enhanced crop production under conditions of salinity stress.

Abstract The lower tropospheric subtropical circulation (SC) is characterized by monsoons and subtropical highs, playing an important role in global teleconnections and climate variability. The SC changes in a warmer climate are influenced by complex and region-specific mechanisms, resulting in uneven projections worldwide. Here, we present a method to quantify the overall intensity change in global SC, revealing a robust weakening across CMIP6 models. The weakening is primarily caused by global-mean surface warming, and partly counteracted by the direct CO2 effect. The direct CO2 effect is apparent in the transient response but is eventually dominated by the surface warming effect in a slow response. The distinct response timescales to global-mean warming and direct CO2 radiative forcing can well explain the time-varying SC changes in other CO2 emission scenarios. The declined SC implies a contracted monsoon range and drying at its boundary with arid regions under CO2-induced global warming.

With the rapid growth of Big Data, securing its storage has become crucial. This study proposes to enhance the secure storage of big data at rest in Hadoop by improving encryption algorithms. The Elliptic Curve Cryptography Algorithm (ECC) is upgraded by a parallel two-threaded approach for unstructured data. For structured data, enhance Paillier Homomorphic Encryption to support operations on ciphertexts. Experiments on datasets up to 4 G show that the modified ECC method reduces encryption time to 60 - 80 seconds, compared to 100 - 160 seconds for standard ECC, AES, and DES. It can also use shorter key lengths than RSA with comparable levels of security. Enhanced Paillier encryption uses large prime numbers to ensure the validity of the ciphertext. By combining these improved encryption techniques within a secure Hadoop framework, this research demonstrates an effective way to address vulnerabilities in Big Data storage.

Abstract Salinity stress adversely affects agricultural productivity by disrupting water uptake, causing nutrient imbalances, and leading to ion toxicity. Excessive salts in the soil hinder crops root growth and damage cellular functions, reducing photosynthetic capacity and inducing oxidative stress. Stomatal closure further limits carbon dioxide uptake that negatively impact plant growth. To ensure sustainable agriculture in salt-affected regions, it is essential to implement strategies like using biofertilizers (e.g. arbuscular mycorrhizae fungi = AMF) and activated carbon biochar. Both amendments can potentially mitigate the salinity stress by regulating antioxidants, gas exchange attributes and chlorophyll contents. The current study aims to explore the effect of EDTA-chelated biochar (ECB) with and without AMF on maize growth under salinity stress. Five levels of ECB (0, 0.2, 0.4, 0.6 and 0.8%) were applied, with and without AMF. Results showed that 0.8ECB + AMF caused significant enhancement in shoot length (~ 22%), shoot fresh weight (~ 15%), shoot dry weight (~ 51%), root length (~ 46%), root fresh weight (~ 26%), root dry weight (~ 27%) over the control (NoAMF + 0ECB). A significant enhancement in chlorophyll a, chlorophyll b and total chlorophyll content, photosynthetic rate, transpiration rate and stomatal conductance was also observed in the condition 0.8ECB + AMF relative to control (NoAMF + 0ECB), further supporting the efficacy of such a combined treatment. Our results suggest that adding 0.8% ECB in soil with AMF inoculation on maize seeds can enhance maize production in saline soils, possibly via improvement in antioxidant activity, chlorophyll contents, gas exchange and morphological attributes.

Abstract Maize cultivated for dry grain covers approximately 197 million hectares globally, securing its position as the second most widely grown crop worldwide after wheat. Although spermidine and biochar individually showed positive impacts on maize production in existing literature, their combined effects on maize growth, physiology, nutrient uptake remain unclear and require further in-depth investigation. That’s why a pot experiment was conducted on maize with spermidine and potassium enriched biochar (KBC) as treatments in Multan, Pakistan, during the year 2022. Four levels of spermidine (0, 0.15, 0.30, and 0.45mM) and two levels of potassium KBC (0 and 0.50%) were applied in completely randomized design (CRD). Results showed that 0.45 mM spermidine under 0.50% KBC caused significant enhancement in maize shoot length (11.30%), shoot fresh weight (25.78%), shoot dry weight (17.45%), root length (27.95%), root fresh weight (26.80%), and root dry weight (20.86%) over control. A significant increase in maize chlorophyll a (50.00%), chlorophyll b (40.40%), total chlorophyll (47.00%), photosynthetic rate (34.91%), transpiration rate (6.51%), and stomatal conductance (15.99%) compared to control under 0.50%KBC validate the potential of 0.45 mM spermidine. An increase in N, P, and K concentration in the root and shoot while decrease in electrolyte leakage and antioxidants also confirmed that the 0.45 mM spermidine performed more effectively with 0.50%KBC. In conclusion, 0.45 mM spermidine with 0.50%KBC is recommended for enhancing maize growth.

SARS-CoV-2 has been evolving into a large number of variants, including the highly pathogenic Delta variant, and the currently prevalent Omicron subvariants with extensive evasion capability, which raises an urgent need to develop new broad-spectrum neutralizing antibodies. Herein, we engineer two IgG-(scFv)2 form bispecific antibodies with overlapping epitopes (bsAb1) or non-overlapping epitopes (bsAb2). Both bsAbs are significantly superior to the parental monoclonal antibodies in terms of their antigen-binding and virus-neutralizing activities against all tested circulating SARS-CoV-2 variants including currently dominant JN.1. The bsAb1 can efficiently neutralize all variants insensitive to parental monoclonal antibodies or the cocktail with IC50 lower than 20 ng/mL, even slightly better than bsAb2. Furthermore, the cryo-EM structures of bsAb1 in complex with the Omicron spike protein revealed that bsAb1 with overlapping epitopes effectively locked the S protein, which accounts for its conserved neutralization against Omicron variants. The bispecific antibody strategy engineered from overlapping epitopes provides a novel solution for dealing with viral immune evasion.

Baicalein, a nutritional phenolic bioactive small molecule present in the roots of Scutellaria baicalensis and Scutellaria lateriflora, shows promising therapeutic effects against a wide range of cancer cells. However, its potential binding with blood carrier proteins and its anticancer mechanisms have not been well investigated. In this study, the interaction between baicalein and immunoglobulin G (IgG) was analyzed by analyzing intrinsic fluorescence, ellipticity changes, as well as molecular docking. The anticancer effects of baicalein against a glioblastoma multiforme (GBM) cell line, U87MG, and one normal immortalized human astrocytes were assessed by MTT, real-time PCR, caspase assay, and western blot. It was shown that the fluorescence quenching mechanism of human IgG by baicalein was based on a static quenching, where one binding site was responsible for the formation of baicalein-IgG complex derived by the formation of hydrogen bonds and van der Waals forces. A molecular docking study indicated that tyrosine residues (Tyr 91 and Tyr 98) were mostly involved in the binding site of baicalein to IgG. The cellular assay demonstrated that baicalein induced U87MG cell line death with an IC50 concentration of 73.19 µM, whereas normal astrocytes depicted over 82.94% portion of viability at 100 µM baicalein. The Bax mRNA overexpression, Bcl-2 mRNA downexpression, as well as the elevation of caspase-9 and caspase-3 activities confirmed that baicalein could effectively trigger the apoptosis of U87MG cells. Moreover, it was explored that baicalein downregulated the expression of the Axl/STAT3 signaling pathway in the U87MG cells, which is responsible for cellular proliferation and growth. In conclusion, these data may provide useful information regarding the pharmaceutical application of baicalein.

Abstract Cancer metastasis is the leading cause of mortality in patients with hepatocellular carcinoma (HCC). To meet the rapid malignant growth and transformation, tumor cells dramatically increase the consumption of nutrients, such as amino acids. Peptide transporter 1 (PEPT1), a key transporter for small peptides, has been found to be an effective and energy‐saving intracellular source of amino acids that are required for the growth of tumor cells. Here, the role of PEPT1 in HCC metastasis and its underlying mechanisms is explored. PEPT1 is upregulated in HCC cells and tissues, and high PEPT1 expression is associated with poor prognosis in patients with HCC. PEPT1 overexpression dramatically promoted HCC cell migration, invasion, and lung metastasis, whereas its knockdown abolished these effects both in vitro and in vivo. Mechanistic analysis revealed that high PEPT1 expression increased cellular dipeptides in HCC cells that are responsible for activating the MAP4K4/G3BP2 signaling pathway, ultimately facilitating the phosphorylation of G3BP2 at Thr227 and enhancing HCC metastasis. Taken together, these findings suggest that PEPT1 acts as an oncogene in promoting HCC metastasis through dipeptide‐induced MAP4K4/G3BP2 signaling and that the PEPT1/MAP4K4/G3BP2 axis can serve as a promising therapeutic target for metastatic HCC.

Abstract Development of efficient, stable, and recyclable photocatalysts for organic synthesis is vital for transformation of traditional thermal organic chemistry into green sustainable organic chemistry. In this work, the study reports an electrostatic approach to assemble meso‐tetra (4‐sulfonate phenyl) porphyrin (TPPS)tetra (4‐sulfonate phenyl) porphyrin (TPPS) as a donor and benzyl viologen (BV) as an acceptor into stable and recyclable photocatalyst for an efficient organic transformation reaction – aryl sulfide oxidation. By use of the electrostatic TPPS‐BV photocatalysts, 0.1 mmol aryl sulfide with electron‐donating group can be completely transformed into aryl sulfoxide in 60 min without overoxidation into sulfone, rendering near 100% yield and selectivity. The photocatalyst can be recycled up to 95% when 10 mg amount is used. Mechanistic study reveals that efficient charge separation between TPPS and BV results in sufficient formation of superoxide which further reacts with the oxidized sulfide by the photocatalyst to produce the sulfoxide. This mechanistic pathway differs significantly from the previously proposed singlet oxygen‐dominated process in homogeneous TPPS photocatalysis.

Rice plays a crucial role in global food security, serving as a staple for more than half of the world's population. Rice blast, caused by the fungus Magnaporthe oryzae, is one of the most devastating fungal diseases, resulting in substantial economic losses in terms of rice yield and grain quality. The resistance provided by individual blast resistance genes tends to become ineffective within a few years of extensive agricultural use due to the rapid evolution of the fungus. Therefore, continuous efforts in resistance breeding in rice are required to enrich the pool of new resistance genes and alleles. A large-scale screening of new blast resistance alleles was conducted across 2000 rice accessions from major rice-producing areas in China. Field trials were employed in two rice uniform blast nurseries located in Enshi and Yichang. Approximately 153 rice accessions showed at least moderate resistance to the rice blast. Sequence-based allele mining was used to identify the allelic variants of major rice blast resistance genes at the Pi5 locus of chromosome 9. Six novel alleles were identified from 64 accessions. Field tests at five locations, including Enshi, Yichang, Lvtian, Taojiang, and Yaan, and greenhouse inoculation using 33 blast strains from Hubei, Hunan, Guangzhou, and Sichuan, were employed to verify the resistance of these six alleles. Three near-isogenic lines (types 2, 4, and 6) were constructed and inoculated with 31 blast isolates from Heilongjiang to evaluate their blast resistance. Furthermore, bulk segregant analysis was used to confirm that Pi5-type2 and Pi5-type6 are dominant alleles in the analyzed populations. These novel alleles expand the allelic series, enriching the genetic resources for rice blast resistance breeding programs, especially in the north of China. Furthermore, they provide valuable insights into the molecular interactions between rice and rice blast.

Overlapping protected areas, where the same land is designated as more than one type of protected area, is a widespread issue that complicates the management and effectiveness of the protected area network. Systematically assessing the extent of overlap, along with their effective integration, is crucial for enhancing the effectiveness of protected areas in meeting conservation objectives. We take the Qinghai- Xizang Plateau as a case study, conducting a quantitative assessment of the spatial relationships among six distinct categories of protected areas. We compare the efficacy of two scenarios aimed at integrating overlapping protected areas. Scenario 1 is based on the protection level and categories of protected area and Scenario 2 considers the conservation objectives in addition to Scenario 1. Our findings reveal that 240 (45.6%) protected areas on the Qinghai-Xizang Plateau experience overlap, encompassing about 6.6% of the total area of the protected areas. Notably, over 50% of geo-parks, scenic spots, and forest parks are affected by overlap. While both scenarios yielded comparable outcomes in terms of the overall number and area of integrated protected areas, they differed in their effectiveness across different categories. Compared to Scenario 1, Scenario 2 is more effective in 31 overlapping protected areas that match the conservation objectives. This study offers valuable insights and a reference for China and other nations grappling with the challenges of overlapping protected area designations, which will ultimately improve the efficiency of the protected area network.

Diabetic nephropathy (DN) is a common microvascular complication with limited effective interventions in diabetic patients. Linderae Radix is a traditional herbal tonic used to treat various kidney and metabolic diseases. In this study, we evaluated the efficacy and mechanism of the main bioactive components, sesquiterpene lactones in L. Radix (SLR), on DN. The results showed that treatment with SLR reduced the levels of apoptotic rates, ROS, TNF-α, IL-6, and IL-1β, but increased the activities of SOD and GSH-Px in high glucose-treated HK2 cells. Furthermore, SLR improved renal dysfunction but increased the activities of SOD and GSH-Px in the renal tissues of DN mice. Mechanistically, SLR upregulated the expressions of Nrf2 and HO-1 but downregulated NF-κB in high glucose-treated HK2 cells by targeting PPAR, which could be reversed by the PPARγ inhibitor SR202. Therefore, SLR improved DN by reducing oxidative stress, cell apoptosis, and inflammatory response through activating PPARγ/Nrf2 pathway.

In the last ten years, there has been a notable rise in the study of metabolic abnormalities in cancer cells. However, compared to glucose or glutamine metabolism, less attention has been paid to the importance of lipid metabolism in tumorigenesis. Recent developments in lipidomics technologies have allowed for detailed analysis of lipid profiles within cancer cells and other cellular players present within the tumor microenvironment (TME). Traditional Chinese medicine (TCM) and its bioactive components have a long history of use in cancer treatments and are also being studied for their potential role in regulating metabolic reprogramming within TME. This review focuses on four core abnormalities altered by lipid reprogramming in cancer cells: de novo synthesis and exogenous uptake of fatty acids (FAs), upregulated fatty acid oxidation (FAO), cholesterol accumulation, which offer benefits for tumor growth and metastasis. The review also discusses how altered lipid metabolism impacts infiltrating immune cell function and phenotype as these interactions between cancer-stromal become more pronounced during tumor progression. Finally, recent literature is highlighted regarding how cancer cells can be metabolically reprogrammed by specific Chinese herbal components with potential therapeutic benefits related to lipid metabolic and signaling pathways.

The gas blast arc-extinguishing lightning protection gap is a new type of lightning protection device based on airflow active arc-extinguishing. This paper establishes an airflow and arc mathematical model for calculating and analyzing air flow and arc motion processes. Besides, the finite element software ANSYS 14.0 is employed for the arc-extinguishing simulation in the pressure field, interaction arc, and airflow processes. Accordingly, the test analysis effects of the arc-extinguishing gap lightning protection test are verified. High-speed cameras, recording oscillograph arc-extinguishing images, and arc waveforms are employed in the process to obtain the airflow response time and arc-extinguishing time effectively based on the data analysis. Comparing the actual results with the simulation results demonstrates the arc-extinguishing reliability and provides an effective scientific basis for its practical application.

Abstract Tumor‐derived exosomes are crucial for early non‐invasive and accurate tumor diagnosis in clinical diagnostics. The development of highly sensitive, simple, and intuitive exosome assays has sparked a research upsurge in clinical diagnostics. Here, we develop a bio‐responsive intelligent DNA hydrogel loaded with CRISPR/Cas12a for universal and ultrasensitive detection of the exosomes. The aptamer serves as the target response unit and switch, competitively disintegrating the region of the DNA linkers and then Cas12a/crRNA was released and activated, resulting in a high fluorescent intensity for exosome detection at the detection limit of 119 particles/μL. Moreover, a constructed colorimetric tube is made by loading a colorimetric filter membrane on the tube lid and intelligent DNA hydrogel on the tube bottom, which enables one‐pot portable colorimetric detection. Without the need for laboratory instruments and professionals, this strategy allows for naked eye detection with limit of detection as low as 104 particles/μL, and shows great applicability in distinguishing between healthy individuals, pretreatment patients, and post‐treatment patients after obtaining a testable analyte. In this study, an ultrasensitive detection platform for exosomes that enables one‐step sensing and dual signal output was introduced. The findings here suggest that this platform is a promising tool for the application of liquid biopsy based on exosomes in clinical diagnosis.

Study region: The mainstream reach from Zhongxian to Yunyang in the Three Gorges Reservoir. Study focus: In this study, the modified sequential extraction method (SEDEX) and diffusive gradients in thin films technique (DGT) were utilized to reveal geochemistry characteristics of sediment phosphorus (P) in a typical mainstream reach from Zhongxian (ZX) to Yunyang (YY) in the Three Gorges Reservoir (TGR). A hydrodynamic model was established for the study reach to clarify hydrodynamic characteristics in the pro-TGR and post-TGR periods and its effects on sediment deposition and P release. New hydrological insights for the region: Results illustrated that total phosphorus (TP) in the surface sediments was about 693.31–805.92 mg/kg, and inorganic phosphorus (IP) and organic phosphorus (OP) were 648–781 mg/kg and 23–45 mg/kg. Ca-bound P (Ca-P) made a major contribution (39.18–54.08%) to TP. Vertical distribution of labile P has a positive correlation with Fe(II) and S(-II), respectively, and labile P exhibited a synchronous change with Fe(II). Diffusion flux (Fd) of labile P was about 0.32–0.56 mg/(m2·d), and the sediment paid a role as P source during the sampling period. Affected by the operation of the TGR, velocity and sediment carrying capacity (S*) reduced significantly in the study reach. The velocity was about 1.0–3.0 m/s and 0.0–0.7 m/s, and S* ranged from 0–10 kg/m3 and 0–0.1 kg/m3 in the pro-TGR and post-TGR periods, respectively. A highlight of this work is that impacts of hydrodynamics on P mobility in a typical mainstream reach prone to deposition are systematically investigated by recreating the hydrodynamic processes in the pro-TGR and post-TGR periods.

Abstract Background Patients with chronic kidney disease (CKD) are at high risk of drug-related problems (DRPs) because of extensive comorbidities and pharmacokinetic changes. This study aimed to identify DRPs and possible contributing factors in hospitalized patients with CKD, and evaluate the efficacy of the clinical pharmacist services in detection and intervention of DRPs in a large general hospital in Zhejiang Province, eastern China. Methods With the approval of the Ethics Committee, patients with CKD admitted to the nephrology ward from January to December 2020 were enrolled in this prospective study. The clinical pharmacist identified and intervened the DRPs during hospitalization. The DRPs were classified using the Pharmaceutical Care Network Europe (PCNE) DRP classification system, and all data were statistically analyzed using Statistical Package for Social Science (SPSS) version 26.0. Results A total of 914 patients with CKD were included, with 463 DRPs observed among 420 (45.95%) participants; the average DRP per patient was 0.51 (standard deviation [SD], 0.60) before pharmacist intervention. Treatment safety accounted for the highest proportion of problems (43.84%), followed by treatment efficacy, accounting for 43.20%. Drug selection was the most common cause of DRPs (60.26%), and antibiotics and cardiovascular agents were the most common drugs associated with DRPs (32.84% and 28.66%, respectively). A total of 85.53% of pharmaceutical intervention recommendations were followed, and 84.23% of DRPs were completely resolved after intervention by the clinical pharmacist. The proportion of patients who experienced DRPs decreased to 7.77%, with an average of 0.08 (SD 0.28) DRPs during hospitalization after pharmacist’s intervention. Significant contributing factors for DRPs were CKD stage 4, number of comorbid diseases, number of prescribed medications, and hospitalization days in both the univariate and multivariate logistic regression models. Conclusion DRPs are common among hospitalized patients with CKD in China. CKD stage 4, the number of comorbidities, use of multiple prescription drugs, and extended length of hospital stay are contributing factors for DRPs. Even only one clinical nephrology pharmacist in the nephrology ward, clinical pharmacist can play an important role in facilitating the identification of DRPs in patients with CKD and assisting physicians resolve DRPs in this single center study in China.

Abstract Anaplastic thyroid carcinoma (ATC) was a rare malignancy featured with the weak immunotherapeutic response. So far, disorders of immunogenic cell death genes (ICDGs) were identified as the driving factors in cancer progression, while their roles in ATC remained poorly clear. Datasets analysis identified that most ICDGs were high expressed in ATC, while DE-ICDGs were located in module c1_112, which was mainly enriched in Toll-like receptor signalings. Subsequently, the ICD score was established to classify ATC samples into the high and low ICD score groups, and function analysis indicated that high ICD score was associated with the immune characteristics. The high ICD score group had higher proportions of specific immune and stromal cells, as well as increased expression of immune checkpoints. Additionally, TLR4, ENTPD1, LY96, CASP1 and PDIA3 were identified as the dynamic signature in the malignant progression of ATC. Notably, TLR4 was significantly upregulated in ATC tissues, associated with poor prognosis. Silence of TLR4 inhibited the proliferation, metastasis and clone formation of ATC cells. Eventually, silence of TLR4 synergistically enhanced paclitaxel-induced proliferation inhibition, apoptosis, CALR exposure and release of ATP. Our findings highlighted that the aberrant expression of TLR4 drove the malignant progression of ATC, which contributed to our understanding of the roles of ICDGs in ATC.

Abstract Gut microbiota plays a key role in insulin resistance (IR). Here we perform a case-control study of Chinese adults (ChiCTR2200065715) and identify that Parabacteroides distasonis is inversely correlated with IR. Treatment with P. distasonis improves IR, strengthens intestinal integrity, and reduces systemic inflammation in mice. We further demonstrate that P. distasonis-derived nicotinic acid (NA) is a vital bioactive molecule that fortifies intestinal barrier function via activating intestinal G-protein-coupled receptor 109a (GPR109a), leading to ameliorating IR. We also conduct a bioactive dietary fiber screening to induce P. distasonis growth. Dendrobium officinale polysaccharide (DOP) shows favorable growth-promoting effects on P. distasonis and protects against IR in mice simultaneously. Finally, the reduced P. distasonis and NA levels were also validated in another human type 2 diabetes mellitus cohort. These findings reveal the unique mechanisms of P. distasonis on IR and provide viable strategies for the treatment and prevention of IR by bioactive dietary fiber.

Abstract Metabolic reprogramming in malignant cells is a hallmark of cancer that relies on augmented glycolytic metabolism to support their growth, invasion, and metastasis. However, the impact of global adipose metabolism on tumor growth and the drug development by targeting adipose metabolism remain largely unexplored. Here we show that a therapeutic paradigm of drugs is effective for treating various cancer types by browning adipose tissues. Mirabegron, a clinically available drug for overactive bladders, displays potent anticancer effects in various animal cancer models, including untreatable cancers such as pancreatic ductal adenocarcinoma and hepatocellular carcinoma, via the browning of adipose tissues. Genetic deletion of the uncoupling protein 1, a key thermogenic protein in adipose tissues, ablates the anticancer effect. Similarly, the removal of brown adipose tissue, which is responsible for non-shivering thermogenesis, attenuates the anticancer activity of mirabegron. These findings demonstrate that mirabegron represents a paradigm of anticancer drugs with a distinct mechanism for the effective treatment of multiple cancers.

Abstract Salinity stress is one of the major hurdles in agriculture which adversely affects crop production. It can cause osmotic imbalance, ion toxicity that disrupts essential nutrient balance, impaired nutrient uptake, stunted growth, increased oxidative stress, altered metabolism, and diminished crop yield and quality. However, foliar application of osmoprotectant is becoming popular to resolve this issue in crops. These osmoprotectants regulate the cellular osmotic balance and protect plants from the detrimental effects of high salt concentrations. Furthermore, the role of arbuscular mycorrhizae (AMF) is also established in this regard. These AMF effectively reduce the salinity negative effects by improving the essential nutrient balance via the promotion of root growth. That’s why keeping in mind the effectiveness of osmoprotectants current study was conducted on cotton. Total of six levels of γ-Aminobutyric acid (GABA = 0 mM, 0. 5 mM, and 1 mM) and ectoine (ECT = 0 mM, 0.25 mM, and 0.5 mM) were applied as treatments in 3 replications. Results showed that 0.5 mM γ-Aminobutyric acid and ectoine performed significantly best for the improvement in cotton growth attributes. It also caused significant enhancement in K and Ca contents of the leaf, stem, bur, and seeds compared to the control. Furthermore, 0.5 mM γ-Aminobutyric acid and ectoine also caused a significant decline in Cl and Na contents of leaf, stem, bur, and seeds of cotton compared to control under salinity stress. A significant enhancement in chlorophyll contents, gas exchange attributes, and decline in electrolyte leakage validated the effectiveness of 0.5 mM γ-Aminobutyric acid and ectoine over control. In conclusion, 0.5 mM γ-Aminobutyric acid and ectoine have the potential to mitigate the salinity stress in cotton.

Intelligent pipeline inspection is necessary to operate submarine pipelines safely. At present, speed excursion and blockage are the challenges in the inspection of low-pressure gas pipelines. Accordingly, this study proposes a novel pneumo-electric hybrid-driven scheme to improve the traveling stability of inspection robots. To adapt to different working conditions, building blocks and CFD numerical simulation methods are used to study the throttling pressure control flow field of the robot. The results proved that the flow clearance had the most evident effect. The flow clearance was reduced from 30 to 5 mm, and the differential pressure of the prototype increased from 0.3 to 17 kPa. The skeleton diameter has a small effect on the differential pressure. The differential pressure increases as the gas velocity increases. By analyzing the prototype in different positions, it was found that the differential pressure of the prototype while passing the elbow decreased by 45% at 45°, which quantified the fluid-driven force gap of the prototype while passing through the elbow. Finally, by comparing the speed of prototype with that of fluid-driven pig, it is demonstrated that a pneumo-electric hybrid-driven scheme is an effective solution to the problem of unstable inspection operation of low-pressure gas pipelines.

The speed control of a pipeline inspection gauge (PIG) directly affects the quality of the comprehensive inspection of submarine pipelines. However, the mechanism of the gas flow behavior in a pipeline under the influence of a pig speed control valve is not well understood. In this study, the driving differential pressure of a pig was modeled based on the building block method and numerical simulations. For the first time, the influence of the pressure and flow rate of the gas in a pipeline on the torque of the speed control valve opening process was studied. The results show that when the opening angle of the speed control valve increased from 4.5° to 22°, the gas differential pressure reduced from 1325 to 73 kPa, realizing a 94.5% pressure reduction. In addition, the torque of the bypass valve increased from 7.7 to 2470 Nm during the closing process. The pressure and flow rate increases were directly correlated with increased torque. The established experimental system for torque measurement confirmed the numerical analysis results. By clarifying the law of torque variation, this study provides theoretical guidance for the structural design and control scheme of a pig speed control unit.

In this study, a high-efficiency superparamagnetic drug delivery system was developed for preclinical treatment of bladder cancer in small animals. Two types of nanoparticles with magnetic particle imaging (MPI) capability, i.e., single- and multi-core superparamagnetic iron oxide nanoparticles (SPIONs), were selected and coupled with bladder anti-tumor drugs by a covalent coupling scheme. Owing to the minimal particle size, magnetic field strengths of 270 mT with a gradient of 3.2 T/m and 260 mT with a gradient of 3.7 T/m were found to be necessary to reach an average velocity of 2 mm/s for single- and multi-core SPIONs, respectively. To achieve this, a method of constructing an in vitro magnetic field for drug delivery was developed based on hollow multi-coils arranged coaxially in close rows, and magnetic field simulation was used to study the laws of the influence of the coil structure and parameters on the magnetic field. Using this method, a magnetic drug delivery system of single-core SPIONs was developed for rabbit bladder therapy. The delivery system consisted of three coaxially and equidistantly arranged coils with an inner diameter of Φ50 mm, radial height of 85 mm, and width of 15 mm that were positioned in close proximity to each other. CCK8 experimental results showed that the three types of drug-coupled SPION killed tumor cells effectively. By adjusting the axial and radial positions of the rabbit bladder within the inner hole of the delivery coil structure, the magnetic drugs injected could undergo two-dimensional delivery motions and were delivered and aggregated to the specified target location within 12 s, with an aggregation range of about 5 mm × 5 mm. In addition, the SPION distribution before and after delivery was imaged using a home-made open-bore MPI system that could realistically reflect the physical state. This study contributes to the development of local, rapid, and precise drug delivery and the visualization of this process during cancer therapy, and further research on MPI/delivery synchronization technology is planned for the future.