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The effect of Zn/Mg ratio on the microstructure and properties of Al-Zn-Mg-Cu alloys under single-step and double-step aging processes were investigated by using scanning electron microscopy (SEM), transmission electron microscopy (TEM), electron backscatter diffraction (EBSD), as well as hardness, room temperature tensile, and fracture toughness testing. During single-step aging, as the Zn/Mg ratio increases, the aging response of the alloys accelerates. However, the peak hardness and strength gradually decreased while the average size of precipitates increased. During double-step aging, as the secondary aging time increases, the strength and hardness of the alloys gradually decrease. Additionally, the higher the Zn/Mg ratio, the faster the strength and hardness decline. Under the T74 temper, the alloy with higher Zn/Mg ratios exhibits lower hardness and strength but better fracture toughness and larger precipitate sizes. A simple method was proposed to statistically determine the critical diameter size of GPII zone and η′ phase, which was approximately 4.47 nm. A strength model was developed to predict the yield strength of alloys, considering factors such as solid solution strengthening, grain boundary strengthening, and precipitation strengthening. The model demonstrates good predictive accuracy for both peak-aged and T74 temper alloys, providing valuable guidance for alloy design and microstructure regulation.

Background: In recent years, mRNA-based vaccines with promising safety and functional characteristics have gained significant momentum in cancer immunotherapy. However, stable immunological molecular subtypes of lung adenocarcinoma (LUAD) and novel tumor antigens for LUAD mRNA vaccine development remain elusive. Therefore, a novel approach is urgently needed to identify suitable LUAD subtypes and potential tumor antigens. Methods: The Cancer Genome Atlas (TCGA), the Genotype Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases were utilized to retrieve gene expression data. The LUAD Immunological Multi-Omics Classification (LIMOC) system was developed using seven machine learning (ML) algorithms by performing integrative immunogenomic analysis of single-cell and bulk tissue transcriptome profiling. Subsequently, a panel of approaches was applied to identify novel tumor antigens. Results: First, the LIMOC system was construct to identify three subtypes: LIMOC1, LIMOC2, and LIMOC3. Second, we identified CHIT1, LILRA4, and MEP1A as novel tumor antigens in LUAD; these genes were up-regulated, amplified, and mutated, and showed a positive association with APC infiltration, making them promising candidates for designing mRNA vaccines. Notably, the LIMOC2 subtype had the worst prognosis and could benefit most from mRNA immunization. Furthermore, we performed a comprehensive in silico screening of approximately 2000 compounds and identified Sorafenib and Azacitidine as potential subtype-specific therapeutic agents. Conclusions: Overall, our study established a robust LIMOC system and identified CHIT1, LILRA4, and MEP1A as promising tumor antigen candidates for development of anti-LUAD mRNA vaccines, particularly for the LIMOC2 subtype.

The application of traditional Al-Mg-Zn alloy in aerospace field is limited due to poor corrosion resistance for β-phase at grain boundaries and low strength for the lack of T phase. Here we propose a novel high Mg-containing Al-Mg-Zn-Si alloy with a novel alloying strategy of high Mg content combining with a suitable microalloying Si, obtaining small and densely precipitated nanoscale T’ phase in the matrix, co-existing T’ and η’ phases adjacent to grain boundary and T phase at grain boundary. The formation of GPT’ zone in the matrix is dramatically enhanced due to energetically favorable substitution of Al by Si and furtherly facilitates homogeneous growth of T’ phase by solute redistribution. η’ phase is transformed from T’ phase or evolved from GPIIη’ zone along grain boundary due to feasible thermodynamic condition of Mg-poor and Zn-rich domain by distinct Mg and Zn exsolution on grain boundary. The present alloying design makes it possible that differential precipitation behavior of T’ phase and T’ + η’ phases can simultaneously occur in the matrix and adjacent to grain boundary, the alloy has obviously advantaged overall performance over traditional Al-Zn-Mg-(Cu) alloys, which raises a new perspective for developing new high-performance lightweight aluminum alloys.

ABSTRACT: Mycoplasma synoviae (MS) is an essential pathogenic mycoplasma in poultry worldwide, posing a serious threat to the poultry industry's health. Timely detection is imperative for early diagnosis, prevention, and control of MS infection. Current laboratory methods for MS detection are generally complicated, time-consuming, and require sophisticated equipment. Therefore, a simple and rapid method is urgently needed. This study developed a novel real-time fluorescence-based recombinase-aided amplification (RF-RAA) technique for detecting MS nucleic acids, enabling target gene amplification within 20 min at 39°C. The RF-RAA outcomes are interpretable in 2 modalities: real-time fluorescence monitoring employing a temperature-controlled fluorescence detector or direct visual inspection facilitated by a portable blue light transilluminator. This method exhibits robust specificity, demonstrating no cross-reactivity with various common poultry pathogens, and achieves high sensitivity, detecting as low as 10 copies/μL for the standard plasmid. Seventy-one clinical samples of chicken throat swabs were detected by RF-RAA and real-time fluorescence quantitative polymerase chain reaction (qPCR) methods. The diagnostic coincidence rates of qPCR with RF-RAA (fluorescence monitoring) and RF-RAA (visual observation) were determined to be 100% and 97.2% (69/71), respectively. In conclusion, the RF-RAA method developed in this study provides a rapid and visually observable approach for MS detection, offering a novel technique to diagnosing MS infection, especially in resource-limited settings.

Peripheral blood mononuclear cells (PBMCs) were obtained from a patient diagnosed with Familial Hemiplegic Migraine Type 3, who carried a heterozygous A > C mutation in the SCN1A gene and reprogrammed using CytoTuneTM-iPS 2.0 Sendai Reprogramming Kit. The iPSC line maintained the mutation while expressing markers of pluripotency. Additionally, it exhibited a normal karyotype and demonstrated potential for in vitro differentiation into cells representing all three embryonic germ layers.

ABSTRACT: Fluoride is one of the essential trace elements for body. However, excessive fluoride poses a major threat to human and animal health. Fluorosis may cause pathological damage of the duodenum, but the underlying mechanism needs to be further studied. This study was to investigate the effects of long-term exposure to sodium fluoride (0, 500, 1,000, 2,000 mg/kg) on the duodenum of chickens. The results showed that after NaF exposure, intestinal epithelial cells were disarranged, necrotic or even exfoliated, goblet cells and mucus secretion were increased, and inflammatory response was induced in duodenal tissue. Oxidative stress, endoplasmic reticulum stress (ERs), and heat shock proteins (HSPs) are an adaptive response, however long-term, excessive changes are detrimental. Fluorosis activates ERs through IRE1, PERK and ATF6 pathways, increases the expression of HSP60, HSP70 and HSP90, and causes apoptosis and oxidative damage in duodenal tissue. In addition, fluorosis can activate the MAPK signaling pathway. This article can provide a reference for exploring the potential duodenal toxicity of sodium fluoride.

Introduction: Insomnia is a chronic disease affecting a third of the global adult population. Hehuan Anshen Decoction (HHASD), an innovative formula derived from Traditional Chinese medicine, has demonstrated therapeutic efficacy in treating insomnia, however, the potential pharmacological mechanism underlying its anti-insomnia effects remains incompletely elucidated. This study aimed to explore the underlying mechanism of HHASD treatment in mice with insomnia induced by p-Chlorophenylalanine (PCPA). Methods: The active constituents of HHASD were analysed by means of UPLCHRMS. PCPA mice were administered HHASD orally for 7 days. The anti-insomnia phenotype of HHASD were assessed by behavioral tests, encompassing the open field test and pentobarbital sodium-induced sleep test, alongside the measurement of hypothalamic 5-HT levels. Then, we conducted an in-depth analysis of specific ferroptosis markers, considering biochemistry, genetics and morphology. Additionally, ferroptosis inhibitor RSL3 was used to observe the underlying mechanism of the effects of HHASD. Results: HHASD could effectively improve the insomnia behaviors induced by PCPA, resulting in increased movement trajectories, decreased sleep latency and prolonged sleep duration. Specifically, HHASD exerted a neuroprotective effect by enhancing the integrity of Nissl bodies in the hypothalamus of the PCPA mice. Mechanistic analysis revealed that HHASD could reverse the hypothalamic ferroptosis phenotype of insomnia mice by restoring the lowered levels of glutathione (GSH), inhibiting iron accumulation and elevated malondialdehyde (MDA), and mitigating mitochondrial cristae damage. Furthermore, HHASD enhanced the expression of SLC7A11 and GPX4 and reduced the ASCL4 in the hypothalamus, while the anti-insomnia effect of HHASD in the PCPA mice was eliminated by the GPX4 inhibitor RLS3. Conclusion: HHASD ameliorates insomnia-related behaviors and protects against neuronal damage by suppressing ferroptosis by regulation GPX4 signaling. This study is not only a valuable attempt to explore the potential mechanism of Traditional Chinese formula but also will provide a novel targeted therapy for the treatment strategy of insomnia.

Quantitative Magnetic Resonance Imaging (qMRI) offers precise measurements of the relaxation characteristics of microstructures, representing a cutting-edge method in non-destructive fruit analysis. This study aims to visualize information on changes in moisture status and distribution at the subcellular level of winter jujube. The 0.5 T nuclear magnetic imaging equipment was utilized to rapidly, non-invasively, and accurately capture the internal relaxation status of the sample with multiple-echo-imaging. By examining the signal and noise data, a simulated dataset was developed to tackle the optimization challenge of estimating parameters for the discrete relaxation model from the multiple-echo-imaging data, especially under conditions of low signal-to-noise ratio (SNR) and in the context of heteroscedastic noise. An optimal weighting factor and the T2NR truncation model have been identified to establish an effective experimental inversion strategy. Subsequently, multiple-echo-imaging can rapidly and stably yielded voxel-level maps under conditions of low signal-to-noise ratio. Utilizing this experimental approach, data from winter jujube was collected and analyzed, facilitating an exploration of water activity (T2 mapping) and associated water content (A2 mapping). Through analyzing winter jujube fruits across two maturity stages, this study elucidates the role of precise quantification and voxel-wise visualization in moisture status detection. The methodology presents an innovative approach for assessing internal moisture distribution in fruits.

We synthesized a core-shell resin structure with abundant architecture and excellent thermal stability through polymerization. Imidazole ionic liquid with varying carbon chain lengths was immobilized on the surface, resulting in the preparation of metal-free, halogen-free core-shell catalysts with different carbon chain lengths via HCO3- exchange. Characterization using FT-IR, XPS, and various techniques revealed the exceptional performance of our synthetic catalyst in terms of its internal structure. After extensive experimentation, we discovered that the synthesized catalyst exhibits dual functionality for epoxidation and CO2 cycloaddition reactions without requiring solvents or co-catalysts. The epoxidation system demonstrated remarkable conversion rates and selectivity while also exhibiting strong recyclability in heterogeneous reactions, according to kinetic parameters, the reaction order of styrene, TBHP and catalyst during epoxidation is approximately 1, the reference factor for this reaction was calculated to be 6.7×109 (L2·mol−2·min−1), with an activation energy of 48.9 kJ/mol obtained from analyzing reaction rates at different temperatures. In the CO2 cycloaddition reaction, our catalyst exhibited an advantage in catalyzing ring-opening reactions, achieving a conversion rate of 95 % for styrene oxide within six hours along with over 99 % selectivity towards cyclic carbonate formation. It is suggested that the epoxide reaction is carried out in steps, and it is inferred that the catalyst PS-ImC4HCO3 and TBHP are produced into peroxy intermediate active species TBA and HCO4, and the reaction between HCO4- and styrene is the determination step of the total reaction. The reaction rate constant k=0.009 of the absolute step is calculated based on the global optimization algorithm

Rationale and objectives: To investigate the relationship between the pericoronary adipose tissue CT mean attenuation (PCATMA) measurement and image reconstruction parameters (adaptive statistical iterative reconstruction-veo (ASIR-V) percentage, kernel, and slice thickness). Materials and methods: One hundred and ninety-eight consecutive patients underwent CT coronary angiography at 100 kilovoltage peak (kVp) (n = 102) and 120 kVp (n = 96) were included. All scans were reconstructed by three means: 1. with 11 different ASIR-V percentages, standard kernel and 0.625 mm; 2. with soft, standard, detail, and bone kernels, 60 % ASIR-V, and 0.625 mm; 3. at 0.625 mm and 1.25 mm slice thickness, standard kernel and 60 % ASIR-V. PCATMA of the three main coronary arteries was calculated using a dedicated software. Linear regression, analysis of variance (ANOVA), Friedman test, and paired t-test were used for statistical analysis. Results: Linear regression of pooled average data showed that the PCATMA was positively and linearly correlated with the ASIR-V percentage (all R squared >0.99). Regression analysis of individual data showed that most R squared were greater than 0.8 or 0.9, but their slope consisted of a relatively wide range. The difference of PCATMA among different kernels for each coronary artery reached statistically significant levels (P

Problems, such as toxic side effects and drug resistance of chemoradiotherapy, target therapy and immunotherapy accompanying the current anti-cancer treatments, have become bottlenecks limiting the clinical benefit for patients. Therefore, it is urgent to find promising anti-cancer strategies with higher efficacy and lesser side effects. Baicalein, a flavonoid component derived from the Chinese medicine scutellaria baicalensis, has been widely studied for its remarkable anti-cancer activity in multiple types of malignancies both at the molecular and cellular levels. Baicalein exerts its anti-tumor effects by inhibiting angiogenesis, invasion and migration, inducing cell apoptosis and cell cycle arrest, as well as regulating cell autophagy, metabolism, the tumor microenvironment and cancer stem cells with no obvious toxic side effects. The role of classic signaling pathways, such as PI3K/AKT/mTOR, MAPK, AMPK, Wnt/β-catenin, JAK/STAT3, MMP-2/-9, have been highlighted as the major targets for baicalein exerting its anti-malignant potential. Besides, baicalein can regulate the relevant non-coding RNAs, such as lncRNAs, miRNAs and circ-RNAs, to inhibit tumorigenesis and progression. In addition to the mentioned commonalities, baicalein shows some specific anti-tumor characteristics in some specific cancer types. Moreover, the preclinical studies of the combination of baicalein and chemoradiotherapy pave the way ahead for developing baicalein as an adjunct treatment with chemoradiotherapy. Our aim is to summary the role of baicalein in different types of cancer with its mechanisms based on in vitro and in vivo experiments, hoping providing proof for baicalein serving as an effective and safe compound for cancer treatment in clinic in the future.

Athletes of skill-oriented sports (hereinafter referred to as “skilled athletes”), such as gymnasts and rhythmic gymnasts, have demonstrated better postural control than nonathletes. However, previous studies have mainly focused on single postural tasks and have not considered how skilled athletes use and allocate attentional resources during postural control. This research used the event-related potential (ERP) to explore the postural control performance of skilled athletes under cognitive processes and their utilization and allocation of attentional resources. A dual-task paradigm was used to simulate the actual situation in sports. 26 skilled athletes and 26 nonathletes were required to perform postural control and task-switching simultaneously. The results showed that skilled athletes demonstrated more postural control stability and a higher accuracy of task-switching than nonathletes in all dual tasks. Compared with nonathletes, they showed a stable enhanced N1 (electrodes: Oz, O1, and O2) amplitude during three postures. Moreover, larger N2 component on Fz, FCz, and Cz and theta band power was found in the frontal cortex (on Fz, FCz) of skilled athletes under feet together and single leg standing posture. The study illustrated that skilled athletes show greater frontal activation during dual tasks, which allows for more rational and flexible brain attentional resource input and allocation in cognitive processes, this may be due to long-term professional training, which enables them to have a higher level of automation of postural control and cognitive flexibility. This study’s results offer valuable insights into the interplay between postural control and multitasking in skilled athletes, and its outcomes carry significant implications for the training and assessment of athletes across various sports.

Introduction: Cinnabar is a commonly utilized mineral traditional Chinese medicine (TCM) in China. It has the functions of clearing the heart and calming the mind. However, there remains a dearth of pharmacological experiments on the metal elements of cinnabar on animal models. Therefore, this study aims to investigate the effects of cinnabar on neurotransmitter levels in p-chlorophenylalanine (PCPA) induced insomnia rats and the content of metal elements in plasma, heart, liver, spleen, lung and kidney of rats. Methods: Tissue hematoxylin and eosin (H&E) staining were used to assess the histological changes. The 5-HT and GABA in plasma and hypothalamus of rats were determined by enzyme-linked immunosorbent to evaluate the therapeutic effect. The content of metal elements in plasma, heart, liver, spleen, lung and kidney of rats was determined by ICP-MS. Results: After cured with cinnabar and its processed for fourteen days, the level of 5-HT in the plasma and hypothalamus increased (P

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3) influences cancer progression via participating in tumor aerobic glycolysis. In this study, we aimed to evaluate the prognostic significance of PFKFB3 in bladder cancer (BLCA) patients by analyzing a combination of publicly available databases, clinical patient data, and bladder tumor samples from our hospital. Single-cell and bulk RNA-seq data of bladder cancer, obtained from ENA, GEO, and TCGA databases, were utilized for our analysis. The results indicated that PFKFB3 mRNA expression was markedly elevated in bladder cancer compared to paired normal tissue. Furthermore, BLCA patients with high PFKFB3 expression exhibited a significantly worse prognosis (P

The screening and identification of drug metabolites in biological matrices is challenging, and ultra-high performance liquid chromatography-Q-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap MS) has become a powerful technological tool for drug metabolites analysis due to its high sensitivity. However, the spectral information contained in existing chemical standards and databases is very limited, and the UHPLC-Q-Exactive Orbitrap MS technique alone cannot satisfy the identification of complex and diverse metabolites. Therefore, there is an urgent need for a new strategy to achieve comprehensive drug metabolic profile. Based on this, we have innovatively constructed a “recursive tree” analysis strategy and bridged it with network pharmacology for elucidating the pharmacological mechanisms of drugs. In this paper, we investigated the overall metabolic profile of formononetin as an example and utilized the primary branching metabolites of formononetin as effective ingredients for the study of the anti-NAFLD mechanism. The results showed that a total of 131 metabolites (prototype drug included) were detected and identified. Among them, 106 metabolites were found in rats and 31 metabolites were found in liver microsomes. Glucose conjugation, demethylation, sulfation, glucuronidation, and their complex reactions were the major processes of formononetin biotransformation. Network pharmacology results screened 104 potential targets and 20 major signaling pathways. Their mechanisms may be additive and/or synergistic effects. In addition, the therapeutic effects of formononetin against NAFLD were investigated based on palmitic acid / oleic acid-induced HepG2 cells. In summary, the recursive tree analysis strategy provides a convenient method for the identification of metabolites, and its seamless integration with network pharmacology lays the foundation for studying the pharmacological activities of natural products.

Using aberration-corrected scanning transmission electron microscopy, a new fully coherent precipitate platelet designated X′′, with a flexible atomic layer FCC structure, was identified in a low Cu/Mg ratio Al-Cu-Mg-Ag alloy. The emergence of the X′′ phase is primarily attributed to the preferential segregation behavior of Mg and Cu atoms towards the {111}α Ag layers. The strengthening mechanism of the X′′ phase is principally driven by the coherency strengthening, yielding efficient reinforcement (99.8 MPa increment per 1 % volume fraction). After dislocation cutting, the X′′ phase maintains coherence with the matrix, minimizing local strain accumulation at the interface. The mechanical tests show that the alloy with the precipitated X′′ phase, despite its lower strength compared to the alloy with the precipitated Ω phase, exhibits superior ductility and work hardening. The study holds promising implications for designing novel Al-Cu-Mg-Ag alloys with a desirable strength-ductility balance.

TTMV::RARA is a recently reported fusion gene associated with acute promyelocytic leukemia (APL), caused by the integration of torque teno mini virus (TTMV) genomic fragments into the second intron of the RARA gene. Currently, there have been only six documented cases, with clinical presentations showing significant variability. Although initial responses to all-trans retinoic acid (ATRA) treatment may be observed in patients with TTMV::RARA-APL, the overall prognosis remains unfavorable among infrequent reported cases. This article presents a pediatric case that manifested as PML::RARA-negative APL with central nervous system involvement at onset. The patient experienced both intramedullary and extramedullary relapse one year after undergoing allogeneic hematopoietic stem cell transplantation. Upon identification as TTMV::RARA-APL and subsequent administration of two rounds of ATRA-based treatment, the patient rapidly developed multiple RARA ligand-binding domain mutations and demonstrated extensive resistance to ATRA and various other therapeutic interventions. Additionally, the patient experienced ARID1A mutant clone expansion and progressed MYC-targeted gene activation. This case represents the first documentation of extramedullary involvement at both the initial diagnosis and relapse stages, emphasizing the intricate clinical features and challenges associated with the rapid accumulation of multiple ATRA-resistant mutations in TTMV::RARA-APL, characterizing it as a distinct and complex sub-entity of atypical APL.

Cognitive impairment is a major complication of cerebral ischemia–reperfusion (CIR) injury and has an important impact on the quality of life of patients. However, the precise mechanisms underlying cognitive impairment after CIR injury remain elusive. In the current study, we investigated the role of interleukin 17 A (IL-17A) on CIR injury-induced cognitive impairment in wild-type and IL-17A knockout mice using RNA sequencing analysis, neurological assessments, Golgi–Cox staining, dendritic spine analysis, immunofluorescence assay, and western blot analysis. RNA sequencing identified 195 CIR-induced differentially expressed genes (83 upregulated and 112 downregulated), highlighting several enriched biological processes (negative regulation of phosphorylation, transcription regulator complex, and receptor ligand activity) and signaling pathways (mitogen-activated protein kinase [MAPK], tumor necrosis factor, and IL-17 signaling pathways). We also injected adeno-associated virus into the bilateral hippocampal CA1 regions of CIR mice to upregulate or downregulate cyclic AMP response element-binding protein. IL-17A knockout activated the extracellular signal-regulated kinase (ERK)/MAPK signaling pathway and further improved synaptic plasticity, structure, and function in CIR mice. Together, our findings suggest that IL-17A deficiency alleviates CIR injury by activating the ERK/MAPK signaling pathway and enhancing hippocampal synaptic plasticity.

The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rβ is translocated into the ER by β-arrestin2 (β-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2+ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2+ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr990 in HCC.

The content of Zn and Mg directly influences the microstructure characteristics of Al–Zn–Mg–Cu alloys. In the present study, the solidification phases of three as-cast Al–Zn–Mg–Cu alloys with different Zn/Mg ratio (1.5, 1.8 and 2.1 at.%, successively) were thoroughly investigated, and their evolutions during homogenizations were analyzed with the aid of optical microscopy (OM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). The results showed that serious dendritic segregation existed in the as-cast microstructures. In the as-cast alloys with three different Zn/Mg ratio, the secondary phases are represented by non-equilibrium intermetallic phases (Mg(Zn,Cu,Al)2 and Al2Cu) and precipitate MgZn2 phase. Thereinto, the Mg(Zn,Cu,Al)2 phase possessed a majority, which was determined through computational analysis of solidification processes. With the increase of Zn/Mg ratio, the amount of Mg(Zn,Cu,Al)2 phase continuously decreased, while the content of Al2Cu phase showed only minor variation. As the Zn/Mg ratio increased, the strength and hardness of the as-cast alloy gradually improved. The Zn/Mg ratio has a significant impact on the dissolution and transformation of the secondary phases during homogenization process. As the Zn/Mg ratio increased, the melting point of the as-cast eutectic gradually decreased. Additionally, due to the higher diffusion rate of Zn compared to Mg and Cu elements, the dissolution rate of the secondary phase increased accordingly. At relatively low temperatures (380, 410, and 440 °C), phase transformation from the Mg(Zn,Cu,Al)2 phase to the Al2CuMg phase occurred in all three alloys. However, phase transformation was only present in Low/Mid-Zn/Mg ratio alloys at 470 °C. These differences are attributed to the varying diffusion rates of Zn, Mg, and Cu elements during the homogenization process. The implementation of a two-stage homogenization process effectively addresses the issue of residual Al2CuMg phase in Low/Mid-Zn/Mg ratio alloys.

In this study, the effect of Sc content on the microstructural characteristics and phase evolution of an Al–Cu–Li alloy under as-cast and homogenization conditions was investigated. The results show the grain refinement effect was distinct when the content of Sc was 0.16 wt%. However, further increased in Sc content resulted in a limited decrease in grain size. Besides, In the 0.16Sc alloy, the flocculent phase with primary Al3(Sc,Zr) phase coexisting with W (Al8-xCu4+xSc) phase appeared, and in the 0.32Sc alloy, the additional blocky primary Al3(Sc,Zr) phase was observed. With the increased of Sc content, the proportion of primary Al3(Sc,Zr) and W phases gradually increased, and the number and size of Al2Cu and Ag-containing Al2CuMg phases at grain boundaries gradually decreased. Two different morphologies of the primary W phase, flocculent and long strip shaped, were revealed within the Sc-containing alloy. The formation of the core-shell structure formed by Al3(Sc,Zr) particles and W phase was generated by the peritectic-eutectic reaction (Liquid + Al3(Sc,Zr)→α-Al + W) and the long strip of W phase was generated by the eutectic reaction (Liquid→α-Al + Al2Cu + W). During the homogenization process, the Al2Cu and Ag-containing Al2CuMg phases were completely re-dissolved after the two previous stages of homogenization, and only a small amount of the spheroidal residual W phase persisted. A subsequent low temperature treatment was employed to allow the Sc atoms that had diffused into the Al matrix to precipitate as Al3(Sc,Zr) dispersoids, resulting in a higher number density of Al3(Sc,Zr) particles for more efficiently utilizing the Sc elements.

Insulin-like growth factor-1 receptor (IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers. However, targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings. Here, we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I. The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A. In response to ligands, IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250, opening the middle loop (Leu130‒Cys141) to the RING domain of MEX3A through the conformational changes of βarr2. The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I. The assay of the mutants βarr2Y64A and βarr2Y250A further confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A. The truncated-βarr2 and the peptide ATQAIRIF, which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes, thus blocking the IGF-1R-triggered RIG-I degradation. Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway. Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I. In summary, we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.

Summary: The enhanced use of protective materials and chemicals during the COVID-19 pandemic has probably increased river pollution, but the effects of country-specific measures on multiple pollutants in rivers worldwide are not well documented. Here, we use an updated, spatially explicit water quality model to estimate the effects of the increased use of hand soap (triclosan), personal protective equipment and packaging materials (plastics), painkillers (diclofenac), and reduced transportation (microplastics from car tires) on river pollution in 10,226 sub-basins worldwide. Model results indicate that, globally, COVID-19 measures increased river pollution with macroplastics by 56%, triclosan by 33%, and diclofenac by 50%. Notably, only microplastics from car tires decreased. We identified priority sub-basins and pollutants across the globe for which water pollution control strategies should consider the impacts of COVID-19 measures. For these sub-basins, our results can inform the development of strategies for ameliorating the impacts of measures taken during the COVID-19 pandemic. Science for society: Globally, river pollution is a growing concern, given its potential impacts on ecosystems. COVID-19 has likely compounded this pollution via an increased use of products such as masks, hand sanitizers, and painkillers. However, we do not have a clear understanding of pollutant types, at which locations pollution might have increased, or the extent of any increase. This hinders the development of pollution control strategies in the worst-affected river basins. Countries encouraged or enforced varying strategies to combat the pandemic; therefore, assessing the impact of these differing COVID-19 measures on river pollution requires models that capture country-specific strategies.

Gallbladder and biliary diseases (GBDs) are one of the most common digestive diseases. The connections between GBDs and several organs other than the liver have gradually surfaced accompanied by the changes in people's diet structure and the continuous improvement of medical diagnosis technology. Among them, cholecardia syndrome that takes the heart as the important target of GBDs complications has been paid close attention. However, there are still no systematic report about its corresponding clinical manifestations and pathogenesis. This review summarized recent reported types of cholecardia syndrome and found that arrhythmia, myocardial injury, acute coronary syndrome and heart failure are common in the general population. Besides, the clinical diagnosis rate of intrahepatic cholestasis of pregnancy (ICP) and Alagille syndrome associated with gene mutation is also increasing. Accordingly, the underlying pathogenesis including abnormal secretion of bile acid, gene mutation, translocation and deletion (JAG1, NOTCH2, ABCG5/8 and CYP7A1), nerve reflex and autonomic neuropathy were further revealed. Finally, the potential treatment measures and clinical medication represented by ursodeoxycholic acid were summarized to provide assistance for clinical diagnosis and treatment.

Eupolyphaga sinensis Walker (ESW) is a traditional Chinese medicine formulation used to treat hyperlipidemia. However, the hypolipidemic effect of the active peptides from E. sinensis Walker (APE) is incompletely understood. We studied the hypolipidemic effect of APE and explored the impact of APE on the gut microbiota (GM) in rats suffering from hyperlipidemia. APE was prepared by enzymatic digestion, and its structure was characterized using various methods. The anti-hyperlipidemic activity of APE was assessed using a high-fat diet (HFD)-induced model in zebrafish and rats. In rats, HFD administration caused abnormalities of lipid metabolism and disturbances of the GM and amino acid (AA) profile in plasma. The abundance of bacteria of the phyla Firmicutes and Bacteroides was increased significantly (p

The spatial variability of river hydrochemistry in coal-grain composite areas is influenced by natural processes and human activities. However, there is little information thus far on the hydrochemical characteristics of river water and the spatial variability in coal–grain composite areas under the influence of multiple superimposed effects. In this study, river water samples (n = 31) were collected in a coal-grain composite area in the northern plain of Anhui Province (China). The main hydrochemical ions and stable isotopes (δ2H-H2O, δ18O-H2O, δ34S-SO42- and δ18O-SO42-) were then investigated. The objective was to analyze the spatial characteristics and controlling indicators of the main hydrochemical ions via multivariate statistical and isotope analysis methods. The values of δ34S-SO42- and δ18O-SO42- in river water ranged from 7.5 ‰ to 17.5 ‰ and from 4.4 ‰ to 10.7 ‰, respectively. According to the clustering analysis method, the river water samples were divided into two groups. Bayesian mixed model analysis indicated that the sources of SO42- in river water mainly included soil sulfate and mine drainage, with contribution proportions of 74.0 ± 3.1 % and 18.4 ± 4.1 % in River Group I, respectively, and 77.2 ± 3.0 % and 11.1 ± 5.1 % in River Group II, respectively. These results suggested that the controlling indicators of the spatial distribution characteristics of river hydrochemistry were natural processes (water–rock interactions) and human activities (coal mining, manure release and sewage discharge). The results could provide valuable information for regional water resource management, development, and similar coal–grain composite areas elsewhere.

Deep eutectic solvents (DES) doping is an important method to realize the preparation and modification of PEDOT:PSS films in aqueous solution, but there is no systematic research focusing on its action mechanism in polymerization process. A series of in-situ characterizations were conducted to investigate the effect of DES doping on properties and structure. The UV–Vis spectra indicated the DES doping can strengthen the π−π* stacking interaction and conjugation stabilization of PEDOT:PSS, and then lead to stronger photovoltaic conversion ability. The in situ FTIR spectra revealed the hydrogen bonds were incorporated into the polymer chain during polymerization process. The CV and SEM analysis results suggested that DES doping delayed passivation nucleation stage of PEDOT:PSS film in the thickness direction and remained a stable polymerization rate. The XPS spectra of S 2p proved DES doping decrease the interaction between PEDOT and PSS. Comprehensive experiments demonstrate that the structure-induced effects of DES can trigger structural reorganization in line conformation of PEDOT:PSS/DESs. It is structure-induced effects of DES that delays passivation nucleation stage in polymerization and improves the optical absorption contrast, maximum current density and some other properties efficently.

Since it may be employed to guide the production of high-quality plant protein as a partial substitute for animal protein using sono-physico-chemical effects, it is important to investigate the mixing of animal and plant protein in ultrasound (UID)-assisted processing systems. A study group of sono-physico-chemical processing with five distinct soy protein isolate (SPI)/ sarcoplasmic protein (SPN) ratios was developed in this work. The results showed that adding additional SPN to the mixed protein can increase its sono-physico-chemical impact, and this effect is greatest when the ratio of SPI to SPN is 1:3. The high SPN group's grafting rate rose from 39.13% to 55.26% in comparison to the high SPI content group. Quercetin (Que) may more readily modify SPN than SPI in the “dual protein” system used in this work, highlighting the critical function of plant protein in controlling the effects of UID-assisted processing in the “dual protein” system. Changes in apparent viscosity and microstructure are the primary parameters that affect the severity of sono-physico-chemical effects in SPI/SPN mixed protein systems, in addition to structural variables.

It is critical to increase the cooling channel's thermal-hydraulic performance for the sake of hot component safety and lowering power consumption during fluid transport. In this work, a hybrid V-shaped and spherical dimple structure is designed and numerically analysed to evaluate the heat transfer and fluid flow features in the rectangular cooling channel when the Reynolds number is 8500-50,000. The thermal-hydraulic performances of the cooling channel are compared with the spherical dimple only, the V-shaped dimple only, and the hybrid V-shaped and spherical dimple structure, and the effect of the spacing between the V-shaped dimple and spherical dimple in the hybrid V-shaped and spherical dimple structure on the fluid flow and heat transfer is also investigated. The findings show that the presence of longitudinal vortexes originating from the V-shaped dimple effectively eliminates the recirculation zone in the spherical dimple of the hybrid V-shaped and spherical dimple structure. Consequently, this leads to an improvement in heat transfer within the channel featuring the hybrid V-shaped and spherical dimple structure. Compared with spherical dimple only and V-shaped dimple only, the performance evaluation index of the hybrid V-shaped and spherical dimple structure under equal pumping power increases by up to 11.9% and 13.3%, respectively.

Difenoconazole (DFZ) is a classical triazole fungicide that causes immunosuppression in non-target organisms. Ferulic acid (FA) is a polyphenolic molecule found in nature that has antioxidant and anti-inflammatory activities. The purpose of this investigation was to see if FA could prevent DFZ-induced immunosuppression and to identify the potential mechanisms. Carp were exposed to 1/10 LC50 of DFZ as well as fed normal feed or feed containing dietary additive FA for 30 d. It was found that DFZ-induced immunosuppression could be improved by FA, as evidenced by upregulation of Hb, C3 and IgM and downregulation of LDH. It was then investigated that FA could ameliorate DFZ-induced splenic injury through p53-mediated apoptosis. At the same time, enhancing the levels of CAT, GSH and T-AOC in spleen and transcription levels Nrf2 signaling pathway related genes indicated that FA reduced oxidative damage caused by DFZ by blocking the Nrf2 signaling pathway. In addition, FA inhibited the inflammatory response triggered by TRAF/TAK1/NF-κB signaling pathway, downregulated the transcript levels of pro-inflammatory factors (il-1β, tnf-α, il-6) and the level of NLRP3 inflammasome (NRLP3, ASC, Caspase 1), and upregulated the transcript levels of anti-inflammatory factors (tgf-β1, il-10). In conclusion, the above results suggested that FA mediated TRAF/TAK1/NF-κB, Nrf2, and p53 pathways to attenuate DFZ-induced inflammation, oxidative stress, and apoptosis thereby enhancing the immune capacity of carp.

A new power system with new energy as the main body will be built. Wind power generation will become an important part of the new power system. Compared with onshore wind power, offshore wind power has become a research hotspot with the advantages of abundant wind resources, high utilization rate, close distance from power load, easy power transmission and consumption. However, with the large-scale offshore wind turbine capacity and the improvement of the proportion of wind power, its disadvantages of weak impact load resistance, weak grid friendliness, large volume and high cost are becoming increasingly prominent. In view of the above problems, this paper carries out the research on the design and modeling of double rotor double machine wind turbine generation system. The research contents include the designing the structure, analyzing the working principle, establishing the math model and proposing the control strategy. The system designed in this paper has the characteristics of strong impact load resistance, good power quality, high power grid stability and reliability, small volume, light weight and low cost.

When artificial intelligence technology erodes employees' professional knowledge, they tend to feel highly anxious, and turnover intention is created. This study aimed to test the impact of the perceived threat of artificial intelligence on turnover intention through perceived organizational support and the perceived value of artificial intelligence. The method and procedure were as follow: construct a theoretical framework and propose hypotheses - collect questionnaires through voluntary sampling - use a two-step approach to test the model. This study has some findings. Theoretically, this study proposes a conceptual model of artificial intelligence perception. The combination of technology threat avoidance, organizational support, and perceived value theories applies to the research background of this study. Methodologically, the relationship between the perceived threat of artificial intelligence, perceived organizational support, perceived value of artificial intelligence, and turnover intention variables was studied together for the first time, and the perceived value of artificial intelligence as a new significant mediator between perceived organizational support and turnover intention is discovered. Managementarily, when facing the threats of artificial intelligence to employees, hotel managers should emphasize organizational support, especially in finance, career, and adjustment. This study has important implications for luxury hotel management. First, hotel employees' perceptions of artificial intelligence are dual. Second, luxury hotel managers should consider perceived organizational support to be a key variable.

Terahertz (THz) absorbers with high absorptivity across a wide frequency band have attracted considerable interest. In this paper, we present the design of an ultra-broadband THz metamaterial absorber with high absorptivity based on a single-layer square silicon array and a silicon film backed with metallic gold. It is numerically demonstrated that the absorption exceeds 90% covering the frequency range of 0.62–8.75 THz (with an effective absorption bandwidth of 8.13 THz) when the conductivity of semiconductor (undoped silicon) is 600 S/m. Diffraction and impedance-matched induce strong absorption and the corresponding broad bandwidth. The proposed ultra-broadband THz absorber is polarization-insensitive at normal incidence. It can operate over a rather wide range of incidence angle up to 60 degrees for transverse magnetic (TM) terahertz wave. This work provides a way to achieving ultra-broadband terahertz absorption, which is very useful in the development of terahertz imaging, high sensitivity sensors and detection.

Narirutin, extracted from the dried ripe pericarp of Rutaceae orange and its cultivated varieties, is a dihydroflavone compound with various biological activities and pharmacological effects. So far as we know, the metabolism profiling of narirutin has been insufficient until now. In the present study, an efficient method was employed to perform rapid analysis and identification of narirutin metabolites by using ultra-high performance liquid chromatography quadrupole exactive orbitrap MS/MS (UHPLC-Q-Exactive Orbitrap MS/MS) combined with an analogous core recursion (ACR) analysis strategy. Firstly, according to the basic core structure of the dihydroflavonoid, the cleavage mode and fragmentation ions of narirutin were summarized. Secondly, based on the difference of the substituent groups, the fragment ions of narirutin were preliminarily inferred and verified by the secondary mass spectra of its standard compound. Thirdly, the fragment ions of narirutin in positive and negative ion modes were summarized to provide a basis for the identification of metabolites. Fourthly, candidate metabolites were accurately and tentatively identified according to the cleavage law of mass spectrometry, literature reports, comparison of reference substances, and especially the diagnostic fragment ion clusters (DFICs) and characteristic suggestive ions (CSIs) deduced preliminarily. Finally, a total of 46 metabolites (30 in vivo and 19 in vitro), including prototype drugs were identified based on the ACR analysis strategy, chromatographic retention behavior of metabolites, corresponding ClogP value and accurate molecular weight. Among them, 22 metabolites were discovered in rats plasma, 12 in urine, 4 in liver tissue, 19 in liver microsomes, respectively. Additionally, metabolites relative contents were also studied by extracted ion chromatography (EIC) method. Our result also illustrated that narirutin primarily underwent glucuronidation, sulfation, glutathione binding, deglycosylation, oxidation, reduction, methylation, hydroxylation, ring-opening and their composite reactions. A novel strategy was constructed to comprehensively elucidate the biotransformation pathways of narirutin in vitro and in vivo, and a systematic metabolic profile of narirutin was generated. This study provided a great reference for further understanding of the biotransformation pathways and guiding for clinical application of narirutin.

Background: Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. (AD) is a tall perennial herb named Baizhi in Chinese Medical Works. Its medicinal use was first recorded in Shennong's Classic of Material Medical, the first herbal monograph in ancient China. Aim of the review: This review systematically summarises and evaluates traditional applications, botany, chemistry, and pharmacology of AD. This review aims to support the researchers who would like to explore its further potential as a medical agent. Materials and methods: The information was collected from Web of Science (https://www.webofscience.com), PubMed (https://pubmed.ncbi.nlm.nih.gov), CNKI (https://kns.cnki.net), Dissertations, Chinese Pharmacopoeia, and Government documents. The keyword used in the literature search was Angelica dahurica. The chemical structures of the compounds in AD were obtained from either research articles or PubChem. The historical origin and ethnopharmacology of AD were reviewed in detail. In addition, relevant information was obtained from regional and global unpublished sources. The plant's name and its classifications were confirmed using the Medicinal Plant Name Service (http://mpns.kew.org) and Plants of the World Online (https://powo.science.kew.org). Results: Over time, AD has been used extensively for its medicinal uses. The bioactive chemical compound present in it is imperatorin (IMP). It has anti-inflammatory, analgesic, and other therapeutic effects, and it is used as a marker for the quality evaluation of AD. The most studied part of the plant is the root. The root contains coumarins and volatile oil. Modern science has found that AD has the ability to treat skin wounds, analgesic, anti-inflammatory, anti-tumor, anti-depressant, and antioxidant effects, etc. Conclusions: This paper presents a detailed comparative analysis of available resources, confirming the origin, traditional applications, and therapeutic uses of AD. Most importantly, it is widely welcomed as a therapeutic drug. The results of several studies showed that the chemical components of AD were more deeply involved in the central nervous system and histopathological mechanisms. Moreover, AD not only has medical effects but also can be used as food condiments and food accessories.

In this paper, a novel electrochemical sensing platform for the sensitive detection of interleukin 6 (IL-6) was designed and fabricated. A label-free aptasensor was fabricated by modifying the glassy carbon electrode (GCE) using a nanocomposite composed of carboxylated multi-walled carbon nanotubes (cMWCNTs), cobalt hexacyanoferrate (CoHCF) and gold nanoparticles (AuNPs). The nanocomposite improved electron transfer rate and increased intercalation of signaling molecules. Moreover, it also offers desirable capabilities for the immobilization of biomolecules. The cMWCNTs/CoHCF/AuNPs modified electrode showed good electrochemical characteristics and biocompatibility, thus achieving excellent sensor performance. The differential pulse voltammetry (DPV) was used to detect the peak current of CoHCF in the redox process. The peak current is proportional to the concentration of IL-6 on the electrode surface. Under optimal conditions, the proposed aptamer sensor exhibits a linear range from 0.5 pg/mL to 1000 pg/mL and has a low detection limit of 0.17 pg/mL. In addition, the IL-6 aptamer sensor has good selectivity, high stability, and satisfactory reproducibility, showing broad potential in clinical research and diagnostic applications.

Acute ischemic stroke (AIS) is a serious and life-threatening disease worldwide. Despite thrombolysis or endovascular thrombectomy, a sizeable fraction of patients with AIS have adverse clinical outcomes. In addition, existing secondary prevention strategies with antiplatelet and anticoagulant drugs therapy are not able to adequately decrease the risk of ischemic stroke recurrence. Thus, exploring novel mechanisms for doing so represents an urgent need for the prevention and treatment of AIS. Recent studies have discovered that protein glycosylation plays a critical role in the occurrence and outcome of AIS. As a common co- and post-translational modification, protein glycosylation participates in a wide variety of physiological and pathological processes by regulating the activity and function of proteins or enzymes. Protein glycosylation is involved in two causes of cerebral emboli in ischemic stroke: atherosclerosis and atrial fibrillation. Following ischemic stroke, the level of brain protein glycosylation becomes dynamically regulated, which significantly affects stroke outcome through influencing inflammatory response, excitotoxicity, neuronal apoptosis, and blood-brain barrier disruption. Drugs targeting glycosylation in the occurrence and progression of stroke may represent a novel therapeutic idea. In this review, we focus on possible perspectives about how glycosylation affects the occurrence and outcome of AIS. We then propose the potential of glycosylation as a therapeutic drug target and prognostic marker for AIS patients in the future.

A quantitative relationship between microstructure and tensile properties of Al–Zn–Mg–Cu alloys with various alloying degrees was investigated in this study. Three kinds of high strength Al–Zn–Mg–Cu alloys with little strength difference were used for the microstructural characteristic and statistical analysis. A strength model with high accuracy was established through the systematical calculation of strengthening theories, which was validated by the microstructure and ultimate tensile strength of a testing sample. The model gives the precise ratio of the contribution of precipitation hardening and even the component achieved from the bypass mechanism. Moreover, guidance on the regulation of precipitation phases was proposed from the strength model. It can be disclosed that the alloys will show the best strength when the precipitates of 7xxx series Al alloy are distributed near the right of critical radius, which is identified as 2.5 nm in this model.

Advanced aluminum-lithium alloys are the key structural materials urgently needed for the development of light-weighted aircraft in the aerospace field. In this study, we employ a machine learning approach accompanied by domain knowledge to realize the accelerated design of aluminum-lithium alloy with high specific modulus and specific strength by identifying an optimal combination of key features through a three-step feature filtering of datasets containing 145 alloys. The maximum specific modulus in the experimental alloys that screened from the predicted results increases by 4 % compared with the maximum specific modulus in the comparative dataset. The specific modulus of the designed alloy with the best comprehensive performance increased by 12.6 % compared with the widely used 2195-T8 alloy while maintaining a similar specific strength. Machine learning shows appealing feasibility and reliability in the field of materials design.

Neomangiferin (NMF) is an extremely special xanthone that could be simultaneously attributed to C-glycoside and O-glycoside with a variety of biological activities, such as anti-inflammatory, antitumor, antipyretic, and so on. So far as we know, the metabolism profiling has been insufficient until now. Herein, Drug Metabolite Cluster Centers (DMCCs)-based Strategy has been developed to profile the NMF metabolites in vivo and in vitro. Firstly, the DMCCs was proposed depending on literature-related and preliminary analysis results. Secondly, the specific metabolic rule was implemented to screen the metabolites of candidate DMCCs from the acquired Ultra High Performance Liquid Chromatography Quadrupole Exactive Orbitrap Mass Spectrometry (UHPLC-Q-Exactive Orbitrap MS) data by extracted ion chromatography (EIC) method. Thirdly, candidate metabolites were accurately and tentatively identified according to the pyrolysis law of mass spectrometry, literature reports, comparison of reference substances, and especially the diagnostic product ions (DPIs) deduced preliminarily. Finally, network pharmacology was adopted to elucidate the anti-inflammatory action mechanism of NMF on the basis of DMCCs. As a result, 3 critical metabolites including NMF, Mangiferin (MF) and Norathyriol (NA) were proposed as DMCCs, and a total of 61 NMF metabolites (NMF included) were finally screened and characterized coupled with 3 different biological sample preparation methods including solid phase extraction (SPE), acetonitrile precipitation and methanol precipitation. Among them, 32 metabolites were discovered in rat urine, 30 in rat plasma, 12 in rat liver, 9 metabolites in liver microsomes and 8 in rat faeces, respectively. Our results also illustrated that NMF primarily underwent deglucosylation, glucuronidation, methylation, sulfation, dihydroxylation and their composite reactions in vivo and in vitro. Additionally, network pharmacology analysis based on DMCCs revealed 85 common targets of disease-metabolites, and the key targets were TNF, EGFR, ESR1, PTGS2, HIF1A, IL-2, PRKCA and PRKCB. They exerted anti-inflammatory effects mainly through the pathways of inflammatory response, calcium-dependent protein kinase C activity, nitrogen metabolism, pathways in cancer and so on. In general, our study constructed a novel strategy to comprehensive elucidate the biotransformation pathways of NMF in vivo and in vitro, and provided vital reference for further understanding its anti-inflammatory action mechanism. Moreover, the established strategy could be generalized to the metabolism and action mechanism study of other natural products.

Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1–5. Surprisingly, unlike MLN4924, HA-1141 also triggers non-canonical endoplasmic reticulum (ER) stress and PKR-mediated terminal integrated stress response (ISR) to activate ATF4 at an early stage, and to inhibit protein synthesis and mTORC1 activity at a later stage, eventually leading to autophagy induction. Biologically, HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose. Taken together, our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress, leading to growth suppression of cancer cells.

The operation condition of wind turbine is complex with frequent load disturbances. However, the traditional rigid connection wind turbine has shortcomings in rejecting impact load disturbance. In this paper, a novel double rotor wind turbine generation system is proposed. Firstly, the concept design of the new system is carried out by adopting the technical route of ”double rotor machine + electrically excited synchronous generator”, and the main components and structural forms of the system are given. Then, the balance equations of speed, torque and power are derived based on the principles of kinematics and electrotechnics. Finally, the characteristics of the double rotor wind turbine generation system under different wind conditions are analyzed through simulation, where the anti-impact load capacity is evaluated. The simulation results show the superiority of the proposed novel double rotor wind turbine generation system.

Ulcerative colitis (UC) is a chronic and relapsing inflammatory disease of the intestine. Dysbiosis, especially the expansion of facultative anaerobic Enterobacteriaceae, maybe the main pathogenesis of UC. Gegen Qinlian decoction (GD), a traditional Chinese medicinal formula chronicled in the Shang Han Lun, is commonly used to treat UC and has shown an excellent effect on inducing disease remission. However, the role of GD in regulating gut microbiota has not been fully clarified. Herein, we investigated the potential effect of GD on inhibiting the expansion of Enterobacteriaceae and further explored the potential mechanism of this action. Our study demonstrated that GD remarkably reduced body weight loss of colitis mice, shortening of colon length, and inflammation of the colon. Peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling was inactivated in colitis colon tissue, and the abundance of Escherichia coli (E. coli, family of Enterobacteriaceae) in colonic contents and the concentration of lipopolysaccharide (LPS) in colonic tissue were significantly upregulated after DSS-treatment. Notably, GD administration can result in the activation of PPAR-γ and inactivation of iNOS, which lead to the reduction of nitrate, the inhibition of E. coli, and less production of LPS. Combined GD with PPAR-γ antagonist, the effect of GD on the treatment of UC was weakened, and effectless in inhibiting the expansion of Enterobacteriaceae. Therefore, GD ameliorates UC by preventing a dysbiotic expansion of potentially pathogenic E. coli by reducing nitrate levels in the lumen through activating PPAR-γ signaling.

Summary: Utilization of naturally occurring resources to construct functional catalytic materials is significantly important, and facile and environmental-benign strategies are highly desired to afford the materials having a specific structure and good catalytic activity. Herein, we reported an innovative deep eutectic solvent (DES)-assisted strategy to synthesize zirconium phytate with a thin nanosheet structure (denoted as Zr-Phy-DES) using plant-originated phytic acid (PhyA) as the renewable building block. This strategy was eco-friendly and adjustable owing to the designability of DESs. The Zr-Phy-DES as an acidic catalyst showed high activity on two important biomass transformations, i.e., dehydration of carbohydrates and Meerwein-Ponndorf-Verley reduction of ethyl levulinate. Interestingly, Zr-Phy-DES showed higher catalytic performance than the zirconium phytates prepared in ethylene glycol and N,N-dimethylformamide, confirming the advantage of DESs for preparing functional materials. Notably, the unique feature of this proposed strategy is that renewable catalysts are prepared in an environmental-benign solvent for efficiently catalyzing biomass transformation.

Proteases have a fundamental role in maintaining physiological homeostasis, but their dysregulation results in severe activity imbalance and pathological conditions, including cancer onset, progression, invasion, and metastasis. This striking importance plus superior biological recognition and catalytic performance of proteases, combining with the excellent physicochemical characteristics of nanomaterials, results in enzyme-activated nano-drug delivery systems (nanoDDS) that perform theranostic functions in highly specific response to the tumor phenotype stimulus. In the tutorial review, the key advances of protease-responsive nanoDDS in the specific diagnosis and targeted treatment for malignancies are emphatically classified according to the effector biomolecule types, on the premise of summarizing the structure and function of each protease. Subsequently, the incomplete matching and recognition between enzyme and substrate, structural design complexity, volume production, and toxicological issues related to the nanocomposites are highlighted to clarify the direction of efforts in nanotheranostics. This will facilitate the promotion of nanotechnology in the management of malignant tumors.

To meet the needs of the rapid development of education, there have been growing investments in the issue of university infrastructures. However, few studies have paid attention to the assessment and monetization of health risks in newly renovated teaching buildings. In this study, concentrations of the benzene series (BTEX) group were measured in five areas of three newly renovated teaching buildings. A total of 135 BTEX samples were collected using passive diffusion monitors and analyzed by GC–FID. Human health risk assessments were conducted by using probabilistic methods for four types of population exposure to BTEX. The results showed that the cancer risk of benzene accounted for most of the total in each group. There was over 90% probability of excess cancer risks in the areas within the tested buildings; and the non-cancer risks were all within the acceptable level. The health risks of men were greater than those of women, and those of teachers were higher than those of students. The model calculation results of Disability-Adjusted Life Year (DALY) and Willingness to Pay (WTP) indicated that the average price that society was willing to pay to offset the health damage caused in these newly renovated teaching buildings was 381.35 yuan/year. For the first time, this study highlights the health risks of newly built teaching buildings in universities, points out the urgent need to improve the control of BTEX sources in this type of indoor environment; moreover, it provides theoretical support for the society and occupational protection departments to compensate for the health damage to professionals.

In this work, the microstructure and mechanical properties of Mg–Al–Ca–Mn alloys with different Ca/Al ratios (0.2, 0.6 and 1.0) have been investigated. The results showed that with the increase of the Ca/Al ratios, the grain sizes of the alloys were significantly refined, and the morphologies and types of main second phases changed from a block Mg17Al12 phase to a semi-continuous Al2Ca (C15) phase and a continuous network (Mg, Al)2Ca (C36) phase. The extruded Mg–2.4Al–2.4Ca–0.6Mn alloy, which was consisted of dynamically recrystallized grains and undynamically recrystallized regions, possessed outstanding mechanical properties with the yield strength of 335.9 MPa, the ultimate tensile strength of 354.7 MPa and the elongation of 8.4%. This was mainly due to the resultant effects of grain refinement strengthening, secondary phases strengthening, texture strengthening and work hardening.

Summary: Pancreatic cancer is a deadly disease that accounts for approximately 5% of cancer deaths worldwide, with a dismal 5-year survival rate of 10%. Known genetic risk factors explain only a modest proportion of the heritable risk of pancreatic cancer. We conducted a whole-exome case-control sequencing study in 1,591 pancreatic cancer cases and 2,134 cancer-free controls of European ancestry. In our gene-based analysis, ATM ranked first, with a genome-wide significant p value of 1 × 10−8. The odds ratio for protein-truncating variants in ATM was 24, which is substantially higher than prior estimates, although ours includes a broad 95% confidence interval (4.0–1000). SIK3 was the second highest ranking gene (p = 3.84 × 10−6, false discovery rate or FDR = 0.032). We observed nominally significant association signals in several genes of a priori interest, including BRCA2 (p = 4.3 × 10−4), STK11 (p = 0.003), PALB2 (p = 0.019), and TP53 (p = 0.037), and reported risk estimates for known pathogenic variants and variants of uncertain significance (VUS) in these genes. The rare variants in established susceptibility genes explain approximately 24% of log familial relative risk, which is comparable to the contribution from established common susceptibility variants (17%). In conclusion, this study provides new insights into the genetic susceptibility of pancreatic cancer, refining rare variant risk estimates in known pancreatic cancer susceptibility genes and identifying SIK3 as a novel candidate susceptibility gene. This study highlights the prominent importance of ATM truncating variants and the underappreciated role of VUS in pancreatic cancer etiology.