Increasing evidence indicates that hyperuricaemia (HUA) is not only a result of decreased renal urate excretion but also a contributor to kidney disease. Na+-K+-ATPase (NKA), which establishes the ...sodium gradient for urate transport in proximal tubular epithelial cells (PTECs), its impairment leads to HUA-induced nephropathy. However, the specific mechanism underlying NKA impairment-mediated renal tubular injury and increased urate reabsorption in HUA is not well understood. In this study, we investigated whether autophagy plays a key role in the NKA impairment signalling and increased urate reabsorption in HUA-induced renal tubular injury. Protein spectrum analysis of exosomes from the urine of HUA patients revealed the activation of lysosomal processes, and exosomal expression of lysosome membrane protein 2 was associated with increased serum levels and decreased renal urate excretion in patients. We demonstrated that high uric acid (UA) induced lysosome dysfunction, autophagy and inflammation in a time- and dose-dependent manner and that high UA and/or NKA α1 siRNA significantly increased mitochondrial abnormalities, such as reductions in mitochondrial respiratory complexes and cellular ATP levels, accompanied by increased apoptosis in cultured PTECs. The autophagy inhibitor hydroxychloroquine (HCQ) ameliorated NKA impairment-mediated mitochondrial dysfunction, Nod-like receptor pyrin domain-containing protein 3 (NLRP3)-interleukin-1β (IL-1β) production, and abnormal urate reabsorption in PTECs stimulated with high UA and in rats with oxonic acid (OA)-induced HUA. Our findings suggest that autophagy plays a pivotal role in NKA impairment-mediated signalling and abnormal urate reabsorption in HUA-induced renal tubular injury and that inhibition of autophagy by HCQ could be a promising treatment for HUA.
The corrosion fatigue crack growth (FCG) behavior of the 316NG heat affected zone (HAZ) exposed to simulated pressurized water reactor (PWR) environment has been investigated. The results show that ...significant residual strains and lattice misorientations exist in the HAZ near the welding root. Z-phase precipitates are present in both the HAZ and annealed 316NG base metal. The FCG rate of the HAZ is much higher than that of the base metal. In PWR water, the corrosion FCG rate of the HAZ is strongly dependent on the cyclic loading frequency, but the effect of dissolved oxygen is negligible.
Artificial intelligence (AI) research began in theoretical neurophysiology, and the resulting classical paper on the McCulloch‐Pitts mathematical neuron was written in a psychiatry department almost ...80 years ago. However, the application of AI in digital neuropathology is still in its infancy. Rapid progress is now being made, which prompted this article. Human brain diseases represent distinct system states that fall outside the normal spectrum. Many differ not only in functional but also in structural terms, and the morphology of abnormal nervous tissue forms the traditional basis of neuropathological disease classifications. However, only a few countries have the medical specialty of neuropathology, and, given the sheer number of newly developed histological tools that can be applied to the study of brain diseases, a tremendous shortage of qualified hands and eyes at the microscope is obvious. Similarly, in neuroanatomy, human observers no longer have the capacity to process the vast amounts of connectomics data. Therefore, it is reasonable to assume that advances in AI technology and, especially, whole‐slide image (WSI) analysis will greatly aid neuropathological practice. In this paper, we discuss machine learning (ML) techniques that are important for understanding WSI analysis, such as traditional ML and deep learning, introduce a recently developed neuropathological AI termed PathoFusion, and present thoughts on some of the challenges that must be overcome before the full potential of AI in digital neuropathology can be realized.
Bortezomib is a classical proteasome inhibitor and previous researches have reported its roles of anti-oxidation and anti-inflammatory functions in various diseases. However, the role of Bortezomib ...in myocardial ischemia reperfusion injury (MIRI) is unclear. Thus, our research seeks to reveal the protective effects of Bortezomib pretreatment in the mice model of MIRI. First, by the optimization of Bortezomib concentration and pretreatment timepoints, we found that 0.5 mg/kg Bortezomib pretreatment 2 h before MIRI significantly attenuated pathological damage and neutrophil infiltration. Then we found that pretreatment with Bortezomib obviously increased myocardial systolic function ((left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS)) and decreased infarct size, as well as serum Troponin T levels. Meanwhile, Bortezomib pretreatment also remarkably augmented oxidative stress related protein levels of Superoxide dismutase Cu–Zn (SOD1), Catalase (CAT) and Glutathione (GSH), while reactive oxygen species (ROS) contents and Malonaldehyde (MDA) protein level were significantly reduced. Mechanistically, Bortezomib pretreatment significantly promoted nuclear translocation of transcriptional factor nuclear factor erythroid 2-related factor 2(Nrf2) and Heme Oxygenase 1(HO-1) expression. Interestingly, co-treatment with ML-385, a new type and selective Nrf2 inhibitor, counteracted antioxidative effects induced by Bortezomib pretreatment. In conclusion, Bortezomib pretreatment mitigates MIRI by inhibiting oxidative damage which is regulated by Nrf2/HO-1 signaling pathway.
•Low dose proteasome inhibitor Bortezomib alleviates MIRI in mice.•Low dose Bortezomib alleviates oxidative stress following MIRI.•The mechanisms of Bortezomib protection against MIRI involves activation of Nrf2/HO-1 anti-oxidative signaling pathway.
Regulatory T cells (Tregs) have been shown to attenuate the development and progression of atherosclerosis; however, the exact mechanism is still unclear. In our study, Tregs were adoptively ...transferred into ApoE−/− mice, and type 2 innate lymphoid cells (ILC2s) were expanded by the IL-2/Jes6-1 complex or depleted by anti-CD90.2 mAb in ApoE−/-Rag1−/− mice to study their effects on atherosclerosis. Then, Tregs were cocultured with ILC2s in vitro to analyze ILC2s number and IL-13 production. In vivo, ApoE−/-Rag1−/− mice were treated with activated Tregs with or without anti-CD90.2 mAb to explore whether Tregs reduced atherosclerosis through ILC2s. Finally, neutralizing antibodies and Transwell assay were used to investigate how Tregs regulate ILC2s. Our results show that both Tregs and ILC2s reduce atherosclerosis lesions and macrophage infiltration. Moreover, Tregs effectively expanded the number of ILC2s and increased their production of IL-13 in vivo and in vitro. Furthermore, the reductions in plaque size and macrophage infiltration by Tregs were partly reversed by anti-CD90.2 mAb. Mechanistically, our data reveal that IL-10, TGF-β and cell-cell contacts are required for Tregs-ILC2s regulation. These results show that Tregs may play a partial protective role against atherosclerosis by expanding the number of ILC2s and consequently increasing IL-13 production.
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•Tregs can modulate the number and function of type 2 innate lymphoid cells.•Tregs and type 2 innate lymphoid cells reduce atherosclerotic lesions.•Tregs protect from atherosclerosis partly through type 2 innate lymphoid cells.
Fatigue crack growth (FCG) in Z2CND18-12N austenitic stainless steel and its heat-affected zone (HAZ) in the Z2CND18-12N/16MND5 dissimilar metal weld joint has been investigated in room temperature ...air and 325°C water. The dependence of FCG rates on specimen orientation in room temperature air got somewhat evident as ΔK decreased to 13 MPa√m. However, for Z2CND18-12N steel, the influence of specimen orientation on the FCG in room temperature air and the corrosion fatigue crack growth (CFCG) in 325°C water was slight and negligible. A moderate increase in the FCG rate was observed for the Z2CND18-12N HAZ in room temperature air at a low ΔK = 13 MPa√m (near ΔK threshold), compared with its base metal. However, the CFCG rate difference between the Z2CND18-12N HAZ and its base metal was minor. The CFCG in the Z2CND18-12N in 325°C water (without the addition of H2) was consistent with a slip-oxidation-rupture mechanism and the oxide film on the corrosion fatigue crack tip mainly consisted of Fe3O4.
•Recovery of DMG from dimethylglycine hydrochloride by bipolar membrane electrodialysis.•The recovery ratio was 98% at low energy consumption and high current efficiency.•The BMED stack equipped with ...two compartment cell configurations (BP-A).•DMG macromolecules didn't cross membranes and there was almost no membrane fouling.
A Bipolar membrane electrodialysis (BMED) was performed to achieve efficient production of N, N-dimethylglycine (DMG) from dimethylglycine hydrochloride. And the two-compartment cell configuration (BP-A) was used to avoid the amino acid macromolecules migrating through the membrane resulting in membrane fouling. Several experiment parameters including current density, initial dimethylglycine hydrochloride concentration and flow rate were discussed and compared. The results indicated that the optimal operation condition was at the current density of 50 A/m2, feed mole concentration of 0.3M and flow rate of 15L/h. Under the optimal condition, the energy consumption was 0.45 kWh/kg, the current efficiency was 65% and the recovery ratio for DMG reached 98% by calculation. In addition, the membrane fouling after experiments was conducted and further analyzed. It was observed that there was no appreciable change on the membrane during the BMED process by the SEM images and FTIR spectra. These results show that the harm of BMED process to membranes could be ignored. BMED method has the advantages of high purity, no by-products, low energy consumption and environmental friendliness. And this study can broaden the application of electrodialysis in the purification and preparation of macromolecular amino acids.
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Despite recent progress in hydrogel wound dressings, joint wound treatment remains an ongoing challenge due to their poor adhesive and stretchable properties. Herein, inspired by protein ...secretion-curing process of natural marine mussels, an adhesive nanofibrous hydrogel is developed via a sequential crosslinking strategy. Firstly, to avoid uncontrolled self-polymerization of dopamine (DA), DA grafted gelatin (GT) nanofibers are fabricated via electrospinning under pH value around 4. Further, the fibrous hydrogels are in-situ crosslinked under pH value of about 8 to strengthen the intermolecular interaction within fibers. The DA crosslinked GT fibrous hydrogels via Michael addition and Schiff base reaction exhibit superior adhesive and tensile properties which are 1.5 times and 3.1 times higher than those of GT fibrous hydrogels, respectively. The in vitro cytocompatibility tests and in vivo wound healing study further prove that GT grafted DA nanofibrous hydrogels are able to accelerate wound healing. Taken together, we demonstrate a simple and versatile strategy for generating adhesive and stretchable nanofibrous hydrogel, showing a great potential for joint wound care.
•Inspired by protein secretion-curing process of marine mussels, dopamine (DA) sequentially crosslinked gelatin (GT) (GT/EDC–NHS–DA) nanofibrous hydrogels was first developed.•GT/EDC–NHS–DA nanofibrous hydrogels possessed exceptional bio-adhesiveness ensuring close and stable wound contact.•GT/EDC–NHS–DA nanofibrous hydrogels possessed great tensile mechanical property allowing for 150° frequent facile bending.•GT/EDC–NHS–DA nanofibrous hydrogels promoted wound healing significantly with a wound healing ratio of 96% on postoperative day 15.
Polyvinyl alcohol/starch based composite membranes containing herbicide‐loaded metal‐organic‐framework (MOF‐5) was successfully synthesized by electrostatic spraying technique. Several main ...parameters affecting the adsorption of MOF‐5 were studied, including the initial concentration of the herbicide solution, adsorption time, and temperature. Under optimal conditions, herbicide‐loaded MOF‐5 was successfully synthesized and the main properties were characterized by Scanning Electron Microscopy (SEM), X‐Ray Diffraction (XRD), Fourier Transform Infrared Spectrometer (FTIR), Thermogravimetric Analysis (TG), and Brunauer‐Emmett‐Teller (BET), respectively. The results showed that the adsorption capacity of MOF‐5 at optimal conditions was 60.12wt%±0.61 % for atrazine. The sustained release effect of the AT@MOF‐5/PVA/ST composite membranes was reliable, and the cumulative release rate was about 50 % for 15 h. The release behaviour of AT from AT@MOF‐5/PVA/ST composite membranes was first dominated by the mechanism of Fickian diffusion and then by the mechanism of matrix erosion. The main advantages of agricultural herbicide film can be attributed to the eco‐friendly, biodegradable, and persistence of herbicide.
The purpose of this study is to investigate whether margin downregulations helped enhance the functions of index futures markets following the stock market crash in China in 2015. Using ...high-frequency trading data, we estimate the changes in the price discovery and volatility spillover relationships between the CSI 300 index and its futures. We find that reducing the margin ratio strengthens the lead role of futures in the lead-lag relationship and results in more volatility transmission from futures markets to the stock market. Furthermore, this paper shows that the expiration-day effect negatively influences the two functions.
