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ZFP91 positively regulates IL-1β production in macrophages and may be a potential therapeutic target to treat inflammatory-related diseases. We investigated whether this process is modulated by convallatoxin, which is a cardiac glycoside isolated from the traditional Chinese medicinal plant Adonis amurensis Regel et Radde.In vitro, the mechanisms by which convallatoxin inhibits ZFP91-regulated IL-1β expression were investigated using molecular docking, western blotting, RT-PCR, ELISA, immunofluorescence and immunoprecipitation assays.In vivo, mice liver injury was induced by an intraperitoneal injection of D-GalN and LPS, colitis was induced by oral administration of dextran sulfate sodium (DSS) in drinking water and peritonitis was induced by an intraperitoneal injection of alum.We confirmed that convallatoxin inhibited the release of IL-1β by down-regulating ZFP91. Importantly, we found that convallatoxin significantly reduced K63-linked polyubiquitination of pro-IL-1β regulated by ZFP91 and decreased the efficacy of pro-IL-1β cleavage. Moreover, convallatoxin suppressed ZFP91-mediated activation of the non-canonical cysteine-requiring aspartate protease-8 (caspase-8) inflammasome and MAPK signalling pathways in macrophages. Furthermore, we showed that ZFP91 promoted the assembly of the caspase-8 inflammasome complex, whereas convallatoxin treatment reversed this result. Mice in vivo studies further demonstrated that convallatoxin ameliorated D-GalN/LPS-induced liver injury, DSS-induced colitis and alum-induced peritonitis by down-regulating ZFP91.We show for the first time that convallatoxin-mediated inhibition of ZFP91 is an important regulatory event that prevents inappropriate inflammatory responses to maintain immune homeostasis. This mechanism provides new insight for the development of convallatoxin as a novel anti-inflammatory drug targeting ZFP91.This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

To elucidate the dynamic strain aging (DSA) mechanism that causes serrated flow in the tensile curves of an intercritical annealed steel with retained austenite (RA) and intercritical ferrite, the multi-aspect microstructural characterization and micromechanical deformation behavior were systematically investigated in this study. Our results demonstrate that the DSA phenomenon is dependent on the strain rate, deformation temperature, and strain. This is accompanied by deformation-induced martensitic transformation (DIMT) and the generation of crystallographic defects in nucleating and propagating Portevin-Le Chatelier bands. An increase in the deformation temperature and strain rate leads to an increase in the stacking fault energy of RA. This inhibits the growth of martensitic embryos and retards the kinetics of martensitic transformation of RA, consequently decreasing or suppressing the DSA phenomenon. Furthermore, neither the long-range diffusion model of carbon atoms nor the short-range diffusion model on the reorientation of C-Mn complexes could reasonably explain the DSA phenomenon in this study. Based on the in situ synchrotron X-ray diffraction results and established mathematical models stemming from the dislocation multiplication theory, the DSA could be attributed to the periodic instantaneous dislocation multiplication in constituent phases caused by burst DIMT.

The susceptibility to hydrogen embrittlement and diffusion behavior of hydrogen were evaluated in interstitial nitrogen-alloyed austenitic steel QN1803 and 304 and 316 L stainless steels. The amount of transformed martensite and the activation energy of hydrogen diffusion were revealed via electron backscattering diffraction and thermal desorption spectroscopy. The austenite stability of QN1803 during the deformation process was higher than that of 304 and 316 L. However, the hydrogen content of QN1803 was high because of the small grain size and low activation energy of hydrogen diffusion. For the stable QN1803 and 316 L austenitic steels, martensite had no evident harmful effect because of its discrete distribution. A planar dislocation slip was observed in QN1803 during deformation. Hydrogen charging enhanced dislocation mobility, leading to severe strain localization. Thus, the severe strain in QN1803 promoted microcracking.

The development of new technologies for the separation, selection, and isolation of microparticles such as rare target cells, circulating tumor cells, cancer stem cells, and immune cells has become increasingly important in the last few years. Microparticle separation technologies are usually applied to the analysis of disease-associated cells, but these procedures often face a cell separation problem that is often insufficient for single specific cell analyses. To overcome these limitations, a highly accurate size-based microparticle separation technique, herein called "rotating magnetic chromatography", is proposed in this work. Magnetic nanoparticles, placed in a microfluidic separation channel, are forced to move in well-defined trajectories by an external magnetic field, colliding with microparticles that are in this way separated on the basis of their dimensions with high accuracy and reproducibility. The method was optimized by using fluorescein isothiocyanate-modified polystyrene particles (chosen as a reference standard) and then applied to the analysis of cancer cells like Hep-3B and SK-Hep-1, allowing their fast and high-resolution chromatographic separation as a function of their dimensions. Due to its unmatched sub-micrometer cell separation capabilities, RMC can be considered a break-through technique that can unlock new perspectives in different scientific fields, that is, in medical oncology.

The flow stress of high C-Mn austenitic steel is attributed to lattice friction, dynamic strain aging (DSA), mechanical twinning and forest hardening. However, it has not been clarified yet which mechanism quantitatively contributes most to the work hardening of 12.5Mn-1.1C steel. In this study, austenitic Hadfield steel (1.1 wt.% C and 12.5 wt.% Mn) was tensile tested at a strain rate of 10⁰ s− 1. The lattice friction was estimated by the Hall-Petch relationship. DSA effect was neglected because of the high strain rate of deformation. Twin plates characteristics and dislocation densities were estimated quantitatively at different strain levels (11, 18, 25, 38, and 55%). The deformed twin plates were studied by optical and transmission electron microscopies. Dislocation densities were estimated by analyzing the X-ray diffraction patterns using Rietveld analyses. A linear approach was utilized to model the flow stress during the plastic deformation, and it is found that the linear model is consistent with the experimental results. During the early stages of the plastic deformation, the mechanical twinning was the dominant deformation mechanism, and it was more effective to the flow stress than the forest hardening due to the enhancement of the twin nucleation process. However, with increasing the strain level, the thicknesses of the twinned plates were increased rather than the initiation of new twin plates, resulting in a reduced contribution by the mechanical twinning to the flow stress. On the other hand, increasing the dislocation densities with an increase in the strain level was detected, which resulted in an enhanced contribution by forest hardening to the flow stress more than the mechanical twinning.

This study examines the impact of communication on investors’ trading frequency based on a unique dataset drawn from a Chinese social trading platform. We find robust evidence that real-account portfolio owners on the platform trade more frequently under the influence of the comments posted by their leaders (the owners of portfolios they have followed). Moreover, portfolio owners are more sensitive to the quantity than to the tone of leaders’ comments. Finally, both trading frequency and leaders’ comments negatively impact portfolio owners’ future performance. Our findings support the notion that social interaction promotes active investment strategies.

The programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is abnormally expressed in cervical cancer cells. Moreover, PD-1/PD-L1 blockade reduces the apoptosis and exhaustion of T cells and inhibits the development of malignant tumors. Usnic acid is a dibenzofuran compound originating from Usnea diffracta Vain and has anti-inflammatory, antifungal, and anticancer activities. However, the molecular mechanism of its antitumor effects has not been fully elucidated. In this work, we first observed that usnic acid decreased the expression of PD-L1 in HeLa cells and enhanced the cytotoxicity of co-cultured T cells toward tumor cells. Usnic acid inhibited PD-L1 protein synthesis by reducing STAT3 and RAS pathways cooperatively. It was subsequently shown that usnic acid induced MiT/TFE nuclear translocation through the suppression of mTOR signaling pathways, and promoted the biogenesis of lysosomes and the translocation of PD-L1 to the lysosomes for proteolysis. Furthermore, usnic acid inhibited cell proliferation, angiogenesis, migration, and invasion, respectively, by downregulating PD-L1, thereby inhibiting tumor growth. Taken together, our results show that usnic acid is an effective inhibitor of PD-L1 and our study provide novel insights into the mechanism of its anticancer targeted therapy.

In this study, the competing mechanisms of carbon partitioning and concurrent pseudospinodal decomposition of supersaturated martensite, forming superlattice-ordered α″-Fe16C2, are elucidated in a quenching and partitioning (Q&P) steel containing high silicon based on various microstructural characterizations. Our results demonstrate that the fluctuation of carbon content caused by high-density dislocations and transformation residual stress in martensite may stimulate the pseudospinodal decomposition. Furthermore, the sluggish diffusion kinetics of silicon and nickel inhibits further transformation from α″-Fe16C2 to carbide precipitation. The experimental results provide new insights into the pseudospinodal decomposition and carbon redistribution mechanism during the carbon partitioning process.

Heterogeneous microstructures have been proposed to optimize the mechanical properties in the respect of strength and ductility synergy in many alloy systems. In this work, the multi-phase hetero-structured microstructure consisting of fine grains and coarse grains where the ferrite is embedded in the vicinity of the nano-grains was obtained by regulating the thermomechanical processing parameters. A yield strength of 1.2 GPa which is more than two times higher than the coarse grained counterpart with less uniform elongation loss is achieved in the multi-phase hetero-structured steel. The microscopic load transfer in this complex microstructure is investigated by the in situ high energy synchrotron X-ray diffraction. The persistent strain hardening is ascribed to the hetero-deformation induced stress associated with the joint activation of transformation-induced plasticity (TRIP) and twinning-induced plasticity (TWIP) effects. As a comparison, the single-phase hetero-structured steel exhibits little lower strength but higher uniform ductility.

In this study, we fabricated a super-hydrophilic (θ < 5°) hierarchical reticular porous structure on the surface of Ti–24Nb–4Zr–8Sn (Ti2448) by combining sandblasting, dual acid-etching, and alkali...

Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml. Compounds 8f and 9d showed the most potent inhibitory activities (MICs of 0.5–2 µg/ml). Furthermore, compounds 8b, 8d, 8f, 8k, 9b and 9e with antimicrobial activities were not cytotoxic to human gastric cancer cell lines (SGC-7901 and AGS) or a normal human liver cell line (L-02). Structure–activity relationship analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency and reducing the toxicity of the carbazole compounds. In vitro enzyme activity assays suggested that compound 8f binding to dihydrofolate reductase might account for the antimicrobial effect.

An ultrahigh damping capacity with internal friction close to 0.35 was detected over a large temperature range of 75 °C (from -40 to 35 °C) in Ti49.2Ni50.8 shape memory wires by adjusting the B2→R phase transformation through a low-temperature aging treatment. Microstructural analysis showed that the excellent damping performance is attributed to high-density nanodomains in the R phase, which are induced by short-range Ni segregation. These results are expected to further expand capacity for designing damping microstructure.

Q&P steels possessing a combination of ultra-high product of strength and tensile elongation (PSE) and superior impact toughness was obtained by tailoring the micromechanical deformation ability of retained austenite (RA) and martensite via low-temperature partitioning. Our results indicate that impact toughness is more susceptible to the heterogeneity of mechanical properties of constituent phases than its tensile mechanical properties. Through optimizing the difference between the constituent phases, the impact toughness can be improved significantly by the enhancement of micromechanical deformation ability of tempered martensite (TM) and corresponding alleviation of deformation incompatibility. Simultaneously, high PSE was preserved by using the deformation potential of RA and its transformation-induced plasticity effect. Load–unload–reload (LUR) tests were carried out to characterize the evolution of flow stress components and the influence of partitioning temperatures on the degree of deformation inhomogeneity between constituent phases during plastic deformation. Furthermore, the mechanical properties and micromechanical deformation ability of the constituent phases were quantitatively characterized using the nanoindentation technique, which indicates that degree of incompatible deformation is alleviated for steels partitioned at relatively high temperatures due to the enhancement of the deformation ability of TM. The underlying relationship between the dynamic transformation of metastable austenite based on the Olson and Cohen model, and high PSE was elucidated. As the partitioning temperature increases, the mechanical stability of RA increases, which is attributed to the synergistic effect of carbon partitioning and the improvement of compatible deformation capability of TM and RA, resulting in an excellent combination of concurrent ductility and impact toughness. Based on the above characterization and analysis, further investigation into the fractured morphology of impact and edge notched specimens was carried out to provide a comprehensive understanding of the damage and fracture mechanism, and to reveal the reasons for the improvement of mechanical properties. The nucleation position and propagation path of microvoids and microcracks depend on the deformation compatibility of constituent phases and the morphology of cementite in tempered martensite. The nucleation sites of microcracks and microvoids at the phase interface, due to stress concentration and dislocation pile-ups for incompatibility deformation of constituent phases, are substituted with nucleation sites at fractured cementite in TM with the increasing partitioning temperature.

A brand-new process with the combination of hot stamping and non-isothermal quenching and partitioning (Q&P) on a controlled servo press has been applied on a commercial QP980 steel to generate a microstructure of martensite and retained austenite. The results indicate that non-isothermal partitioning can be successfully carried out in this newly proposed novel hot stamping process. Compared to the conventional hot stamped steel, the total elongation can be increased from 12.5% to 14.6%, the uniform elongation can be increased by 19% (from 5.28% to 6.27%) and the product of strength and elongation can be enhanced by 9% (from 19.3 GPa% to 21.0 GPa%) for the steels treated by the new hot stamping plus non-isothermal Q&P process. These improved mechanical properties can be attributed to the increased fraction of retained austenite, as a result of the non-isothermal partitioning.

Encapsulated microstructures of austenite and co-precipitates were formed using a designed tempering and double partitioning (TDP) heat treatment based on the precipitation-induced localized austenite reversion in a medium manganese (Mn) steel. The retained austenite in TDP steel showed better mechanical stability due to the preferable coherency of austenite/ferrite interfaces and a greater capability of geometrically necessary dislocations (GNDs) accommodation. The outstanding cryogenic tensile mechanical properties were attributed to the heterogeneous capsule structure of the austenite in the TDP steel, in which the e-martensite transformation has been suppressed and the austenite were segmented by the α’-martensite during deformation.

Stent implantation has been a promising therapy for congenital heart disease (CHD) due to better efficacy. Compared to permanent metal stents, bioresorbable polymer stents have shown a great advantage in accommodating the vascular growth of pediatric patients, but the application is still limited due to inferior radial strength. Here, bioresorbable poly(p-dioxanone) (PPDO) sliding-lock stents for CHD treatment were fabricated by fused deposition modeling (FDM). The effects of FDM processing parameters, including nozzle temperature, bed temperature, layer thickness, and printing speed, on the mechanical properties of PPDO parts were investigated to optimize the processing condition to enhance the radial strength of stents. Finite element analysis (FEA) was also used to evaluate the mechanical properties of stents. PPDO sliding-lock stents fabricated under optimized FDM parameters showed radial strength of 3.315 ± 0.590 N/mm, superior to benchmark commercial metal stents. Radial strength curve and compression behavior of PPDO sliding-lock stents were investigated. Results of FEA exhibited that strut width, shape of the mesh cell and surface coverage ratio had an impact on the compression force of PPDO sliding-lock stents. PPDO sliding-lock stents fabricated with optimized FDM parameters show favorable mechanical performance and meet the requirement of CHD treatment.

The characterization of geometrically necessary dislocation (GND) is central to understanding the plastic deformation in materials. Currently, fast and accurate determination of GND density via Electron Backscatter Diffraction (EBSD) remains a challenge. Here, a multi-modal deep learning approach is proposed to predict GND density in terms of electron backscatter patterns (EBSPs) and dislocation configurations. The proposed multi-modal architecture consists of two separated convolutional neural network (CNN) processing streams. One CNN stream aims at extracting pattern shifts from EBSPs, and the other CNN stream focuses on learning suitable representations of dislocation configurations. We also introduce a specific data augmentation strategy termed neighboring pairs generating strategy for the GND prediction task. Taking the GND density from dictionary indexing-based analysis as the target property, high accuracy is achieved on several aluminum samples. Also, our networks are robust to various forms of noise, and the prediction speed is as fast as modern EBSD scanning rates, enabling real-time GND density analysis possible.

A review of experiments and models for the strain rate effect of NiTi Shape Memory Alloys (SMAs) is presented in this paper. Experimental observations on the rate-dependent properties, such as stress responses, temperature evolutions, and phase nucleation and propagation, under uniaxial loads are classified and summarized based on the strain rate values. The strain rates are divided into five ranges and in each range the deformation mechanism is unique. For comparison, results under other loading modes are also reviewed; however, these are shorter in length due to a limited number of experiments. A brief discussion on the influences of the microstructure on the strain-rate responses is followed. Modeling the rate-dependent behaviors of NiTi SMAs focuses on incorporating the physical origins in the constitutive relationship. Thermal source models are the key rate-dependent constitutive models under quasi-static loading to account for the self-heating mechanism. Thermal kinetic models, evolving from thermal source models, address the kinetic relationship in dynamic deformation.

In this study, the immunomodulatory effects and mechanism of action of a novel water-extracted Lonicera japonica polysaccharide (WLJP) on allergic rhinitis (AR) was investigated. For the efficacy of WLJP, behavioral symptoms (rubbing and sneezing), serum inflammatory factors, pathological damage, splenic T cell differentiation, gut microbiota imbalance, and protein analysis of the nasal mucosa and colon were assessed. WLJP and the NLRP3 inhibitor, CY-09, were co-evaluated in the AR model established using LPS + IFN-γ-induced THP-1 cells. The WLJP group showed decreased serum inflammatory factors, eosinophils, goblet cells, NLRP3 inflammasomes, splenic Th17 cell differentiation, and expression of IL-17, p-p65, and gut NLRP3 in the nasal mucosa while maintaining gut microbiota balance, repairing the mechanical barrier, and significantly improving AR behavioral symptoms. In vitro interaction analysis showed a significant interaction between CY-09 and WLJP. In conclusion, WLJP improves AR by repairing the gut barrier and inhibiting NLRP3 inflammasome-driven inflammation and the Th17 immune response.

Hepatocellular carcinoma results in a high risk of second primary malignancies and has prominent morbidity and mortality. There is a lack of effective treatment and prognosis is poor. Therefore, effective drugs need to be discovered. Carrimycin is a 16-member macrolide antibiotic with anticancer activity, and monomeric isovalerylspiramycin I is a main component. The aim of this study was to determine the anti-tumor effects of carrimycin and monomeric isovalerylspiramycin I on hepatocellular carcinoma through in vivo and in vitro experiments. In vitro, changes in cellular proliferation, migration, invasion, and apoptosis were analyzed by MTT, colony formation, EdU labeling, wound-healing, matrigel transwell invasion, and flow cytometric assays using SK-Hep1, Hep3B, SNU-354, SNU-387 hepatocellular carcinoma cell lines. Western blotting and RT-PCR were used to detect the effects of carrimycin and monomeric isovalerylspiramycin I on the expression levels of vascular endothelial growth factor (VEGF) and programmed death ligand 1 (PD-L1). Nude mice were subcutaneously transplanted with SK-Hep1 cells or C57BL/6J mice were orthotopically transplanted with hepatocarcinoma H22 cells. Tumor volume, pathological changes in tumor tissues, and the concentration of VEGF in mouse serum were measured after treatments. Carrimycin and monomeric isovalerylspiramycin I dose-dependently inhibited hepatocellular carcinoma cell viability, colony formation, and DNA replication. These agents markedly suppressed migration and invasion and promoted apoptosis of the cell lines. Western blotting and RT-PCR demonstrated that carrimycin and monomeric isovalerylspiramycin I reduced VEGF and PD-L1 protein and mRNA levels in a dose-dependent manner. In vivo studies further confirmed that carrimycin and monomeric isovalerylspiramycin I could significantly inhibit tumor growth, tumor histopathological alterations, and the concentration of VEGF in both mouse tumor models. These results show that carrimycin and monomeric isovalerylspiramycin I promoted apoptosis and inhibited proliferation, migration, and invasion of hepatocellular carcinoma cells. Therefore, our discovery suggests anti-tumor capacity for carrimycin and monomeric isovalerylspiramycin I and provides data on potential new drugs for inhibiting hepatocellular carcinoma.

Necroptosis is a form of regulated programmed cell death that is mediated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting serine/threonine protein kinase-3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL); however, it is not known whether zinc finger protein 91 (ZFP91) is involved in this process. Here, we investigated ZFP91 as a potential mediator of necroptosis. Our mechanistic study demonstrates that ZFP91 promotes RIPK1-RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. ZFP91 stabilized RIPK1 to promote cell death by inducing RIPK1 de-ubiquitination. ZFP91 also significantly increased production of mitochondrial reactive oxygen species (ROS). Accumulation of ROS promoted RIPK3-independent necroptosis triggered by tumor necrosis factor (TNF). in vivo, ZFP91 knockdown alleviated TNFα-induced systemic inflammatory response syndrome (SIRS). These results provide direct evidence that ZFP91 plays an important role in the initiation of RIPK1/RIPK3-dependent necroptosis in vitro and in vivo. We discussed the potential of ZFP91 as a novel therapeutic target for necroptosis-associated diseases.

We discovered Elinvar effect in a severely cold worked Ti-50.8(at%)Ni thin belt that showed a modulus variation of less than 0.54GPa(∼1%) over a wide temperature range (−50 to 100 °C). Microstructural analysis showed an unraveled amorphous matrix dotted with nanosized crystallites, which demonstrated that the softening of the nanodomains in the retained nanosized crystallites and hardening of the amorphous matrix during cooling over wide temperature range can trigger the Elinvar effect.

This paper investigates the effects of global oil shocks on the returns and volatilities of Chinese commodities from 1997 to 2016. We identify the different causes of oil shocks by using a structur...

Ti–Ni based shape memory alloys are promising elastocaloric materials for solid-state refrigeration. In this paper, we made a comprehensive study on elastocaloric effect of a nanocrystalline Ti–44Ni–5Cu–1Al (at%) alloy exhibiting successive B2–B19–B19′ transformation. The maximum adiabatic temperature decrease by stress removal from 600 MPa is ΔTadi∼25 K with a small temperature distribution of ∼0.5 K. The value of ΔTadi is consistent with that calculated from strain-temperature relation. The effective working temperature window is ∼55 K, resulting in a high refrigeration capacity of RC = 4.2 kJ/kg. Material coefficient of performance reaches COP ∼9.6 when an Otto cycle is considered. The middle eigenvalue of the transformation matrix is λ2 ∼ 0.99, implying high lattice compatibility between the parent and martensite phases. These properties are related to the diffuse nature of successive B2–B19–B19’ martensitic transformation of this alloy.

The coupling effects between MX carbonitrides, M2X phase, M23C6 carbides, and the Laves phase and their influences on the mechanical properties during long-term aging at 650 °C were studied. Before aging for 40500 h, the subgrain size is mainly stabilized by M23C6 carbides, whose pinning effect gradually weakens with the coarsening during long-term aging. However, after aging for 40500 h, the volume fraction of nano-sized MX carbonitrides gradually increases and compensates for the loss of pinning effect from M23C6 carbides, working together with the M23C6 carbides to hinder the coarsening of the subgrain. The increase in the volume fraction of nano-sized MX carbonitrides from 40500 h to 49500 h, mainly resulting from the gradual dissolution of M2(C,N) carbonitrides, which not only contributes to the stability of the strength through the pinning effect and precipitation strengthening, but also benefits the ductility by suppressing the rapid coarsening of the Laves phase through the strong competition for Si between the Laves phase and MX. An unusual combination of stable strength and stable ductility in the later stages of long-term aging at 650 °C (approximately 9000 h) was achieved.