AMPK suppresses Th2 cell responses by repressing mTORC2

Allergic inflammation is a T helper 2 (Th2) cell-driven pathophysiological phenomenon, but the mechanism by which the metabolic cascade affects Th2 cell differentiation remains unclear. In this study, we investigated the roles of AMP-activated protein kinase (AMPK) and intracellular energy sensors in Th2 cell differentiation and the pathogenesis of allergic inflammation. Accordingly, T-cell-specific AMPK or Sirtuin 1 (Sirt1)-knockout mice were subjected to allergic inflammation, and their Th2 cell responses were investigated. The results demonstrated that inducing allergic inflammation in AMPK- and Sirt1-knockout mice increased Th2 cell responses and exacerbated allergic phenotypes. Furthermore, treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMPK, ameliorated allergic inflammation in mice. Mechanistically, our findings revealed that AMPK repressed mechanistic target of rapamycin complex 2 (mTORC2), which downregulated the expression of suppressor of cytokine signaling 5 (SOCS5) in CD4⁺ T cells. In addition, the loss of AMPK signaling reduced SOCS5 expression and increased interleukin-4-STAT6–GATA3 axis-mediated Th2 cell differentiation. Finally, the T-cell-specific deletion of Rictor, a member of mTORC2, in Sirt1^T-KO mice led to the reversal of allergic exacerbation to the level in control mice. Overall, our findings suggest that AMPK in CD4⁺ T cells inhibits the differentiation of Th2 cells by repressing mTORC2 and thus serves as a potential target for Th2 cell-associated diseases.Subject terms: Lymphocytes, Inflammation     

Preparation and Characterization of an Ancient Aminopeptidase Obtained from Ancestral Sequence Reconstruction for L-Carnosine Synthesis

As a biologically active peptide, L-carnosine has been widely used in the pharmaceutical, cosmetic and health care industries due to its various physiological properties. However, relatively little research is available regarding L-carnosine’s enzymatic synthesis function. In this study, a potential enzyme sequence with the function of carnosine synthesizing was screened out using the ancestral sequence reconstruction (ASR) technique. Identified with L-carnosine synthesis activity, this enzyme was further confirmed using autoproteolytic phenomenon via Western blot and N-terminal sequencing. After purification, the enzymatic properties of LUCA–DmpA were characterized. The melting temperature (T_m) and denaturation enthalpy (ΔH) of LUCA–DmpA were 60.27 ± 1.24 °C and 1306.00 ± 26.73 kJ·mol⁻¹, respectively. Circular dichroism (CD) spectroscopy results showed that this ancestral enzyme was composed of α-helix (35.23 ± 0.06%), β-sheet (11.06 ± 0.06%), β-turn (23.67 ± 0.06%) and random coil (32.03 ± 0.06%). The enzyme was characterized with the optimal temperature and pH of 45 °C and 9.0, respectively. Notably, LUCA–DmpA was also characterized with remarkable pH tolerance based on the observation of more than 85% remaining enzymatic activity after incubation at different pH buffers (pH = 6–11) for 12 h. Additionally, rather than being improved or inhibited by metal ions, its enzymatic activity was found to be promoted by introducing organic solvent with a larger log P value. Based on these homology modeling results, the screened LUCA–DmpA is suggested to have further optimization potential, and thereafter to be offered as a promising candidate for real industrial applications.     

Comparison on Protein Bioaccessibility of Soymilk Gels Induced by Glucono-δ-Lactone and Lactic Acid Bacteria

In this study, the protein bioaccessibility of soymilk gels produced by the addition of glu-cono-δ-lactone (GDL) and fermentation with lactic acid bacteria (LAB) was examined using an in vitro gastrointestinal simulated digestion model. The in vitro protein digestibility, soluble protein content, free amino acids contents, degree of hydrolysis, electrophoretic patterns, and peptide content were measured. The results suggested that acid-induced soymilk gel generated by GDL (SG) showed considerably reduced in vitro protein digestibility of 75.33 ± 1.00% compared to the soymilk gel induced by LAB (SL) of 80.57 ± 1.53% (p < 0.05). During the gastric digestion stage, dramatically higher (p < 0.05) soluble protein contents were observed in the SG (4.79–5.05 mg/mL) than that of SL (4.31–4.35 mg/mL). However, during the later intestinal digestion phase, the results were the opposite. At the end of the gastrointestinal digestion phase, the content of small peptides was not significantly different (p > 0.05) between the SL (2.15 ± 0.03 mg/mL) and SG (2.17 ± 0.01 mg/mL), but SL showed higher content of free amino acids (20.637 g/L) than that of SG (19.851 g/L). In general, soymilk gel induced by LAB had a higher protein bioaccessibility than the soymilk gel coagulated by GDL.     

Effect of Different Processing Methods on the Chemical Constituents of Scrophulariae Radix as Revealed by 2D NMR-Based Metabolomics

Scrophulariae Radix (SR) is one of the oldest and most frequently used Chinese herbs for oriental medicine in China. Before clinical use, the SR should be processed using different methods after harvest, such as steaming, “sweating”, and traditional fire-drying. In order to investigate the difference in chemical constituents using different processing methods, the two-dimensional (2D) ¹H-¹³C heteronuclear single quantum correlation (¹H-¹³C HSQC)-based metabolomics approach was applied to extensively characterize the difference in the chemical components in the extracts of SR processed using different processing methods. In total, 20 compounds were identified as potential chemical markers that changed significantly with different steaming durations. Seven compounds can be used as potential chemical markers to differentiate processing by sweating, hot-air drying, and steaming for 4 h. These findings could elucidate the change of chemical constituents of the processed SR and provide a guide for the processing. In addition, our protocol may represent a general approach to characterizing chemical compounds of traditional Chinese medicine (TCM) and therefore might be considered as a promising approach to exploring the scientific basis of traditional processing of TCM.     

Mesoporous sodium four-coordinate aluminosilicate nanoparticles modulate dendritic cell pyroptosis and activate innate and adaptive immunity

Pyroptosis is a programmed cell death widely studied in cancer cells for tumour inhibition, but rarely in dendritic cell (DC) activation for vaccine development. Here, we report the synthesis of sodium stabilized mesoporous aluminosilicate nanoparticles as DC pyroptosis modulators and antigen carriers. By surface modification of sodium-stabilized four-coordinate aluminium species on dendritic mesoporous silica nanoparticles, the resultant Na-^IVAl-DMSN significantly activated DC through caspase-1 dependent pyroptosis via pH responsive intracellular ion exchange. The released proinflammatory cellular contents further mediated DC hyperactivation with prolonged cytokine release. In vivo studies showed that Na-^IVAl-DMSN induced enhanced cellular immunity mediated by natural killer (NK) cells, cytotoxic T cells, and memory T cells as well as humoral immune response. Our results provide a new principle for the design of next-generation nanoadjuvants for vaccine applications.

Na-^IVAl-DMSN acts as both antigen carriers and modulators to “hyperactivate” dendritic cells (DCs) via potassium (K⁺) efflux dependent pyroptosis, eventually leading to enhanced adaptive and innate immunity.     

Phenothiazine-based covalent organic frameworks with low exciton binding energies for photocatalysis

Designing delocalized excitons with low binding energy (E_b) in organic semiconductors is urgently required for efficient photochemistry because the excitons in most organic materials are localized with a high E_b of >300 meV. In this work, we report the achievement of a low E_b of ∼50 meV by constructing phenothiazine-based covalent organic frameworks (COFs) with inherent crystallinity, porosity, chemical robustness, and feasibility of bandgap engineering. The low E_b facilitates effective exciton dissociation and thus promotes photocatalysis by using these COFs. As a demonstration, we subject these COFs to photocatalytic polymerization to synthesize polymers with remarkably high molecular weight without any requirement of the metal catalyst. Our results can facilitate the rational design of porous materials with low E_b for efficient photocatalysis.

We report the construction of phenothiazine-based covalent organic frameworks, which exhibited diverse structures, the feasibility of bandgap engineering, and unprecedented ultralow exciton binding energy of ∼50 meV for photocatalytic polymerization.     

Enantioselective Hydrogenation of Endocyclic Enones:the Solution to a Historical Problem

The enantioselective hydrogenation of endocyclic enones has been a historical problem for homogeneous catalysis.We herein report an efficient method to reduce e...     

Fixed-Time Leader-Following Consensus Tracking Control for Nonliear Multi-Agent Systems under Jointly Connected Graph

This paper researches the fixed-time leader-following consensus problem for nonlinear multi-agent systems (MASs) affected by unknown disturbances under the jointly connected graph. In order to achieve control goal, this paper designs a fixed-time consensus protocol, which can offset the unknown disturbances and the nonlinear item under the jointly connected graph, simultaneously. In this paper, the states of multiple followers can converge to the state of the leader within a fixed time regardless of the initial conditions rather than just converging to a small neighborhood near the leader state. Finally, a simulation example is given to illustrate the theoretical result.     

Solid Sampling Pyrolysis Adsorption-Desorption Thermal Conductivity Method for Rapid and Simultaneous Detection of N and S in Seafood

In this work, a rapid method for the simultaneous determination of N and S in seafood was established based on a solid sampling absorption-desorption system coupled with a thermal conductivity detector. This setup mainly includes a solid sampling system, a gas line unit for controlling high-purity oxygen and helium, a combustion and reduction furnace, a purification column system for moisture, halogen, SO₂, and CO₂, and a thermal conductivity detector. After two stages of purging with 20 s of He sweeping (250 mL/min), N₂ residue in the sample-containing chamber can be reduced to <0.01% to improve the device’s analytical sensitivity and precision. Herein, 100 s of heating at 900 °C was chosen as the optimized decomposition condition. After the generated SO₂, H₂O, and CO₂ were absorbed by the adsorption column in turn, the purification process executed the vaporization of the N-containing analyte, and then N₂ was detected by the thermal conductivity cell for the quantification of N. Subsequently, the adsorbed SO₂ was released after heating the SO₂ adsorption column and then transported to the thermal conductivity cell for the detection and quantification of S. After the instrumental optimization, the linear range was 2.0–100 mg and the correlation coefficient (R) was more than 0.999. The limit of detection (LOD) for N was 0.66 μg and the R was less than 4.0%, while the recovery rate ranged from 95.33 to 102.8%. At the same time, the LOD for S was 2.29 μg and the R was less than 6.0%, while the recovery rate ranged from 92.26 to 105.5%. The method was validated using certified reference materials (CRMs) and the measured N and S concentrations agreed with the certified values. The method indicated good accuracy and precision for the simultaneous detection of N and S in seafood samples. The total time of analysis was less than 6 min without the sample preparation process, fulfilling the fast detection of N and S in seafood. The establishment of this method filled the blank space in the area of the simultaneous and rapid determination of N and S in aquatic product solids. Thus, it provided technical support effectively to the requirements of risk assessment and detection in cases where supervision inspection was time-dependent.     

三点起爆形成尾翼EFP的数值模拟和实验研究

利用LS-DYNA软件对三点起爆形成尾翼EFP的过程进行了数值模拟,深入研究了爆轰波传播过程中的波形结构和强度的变化规律以及药型罩材料在复合爆轰波作用下驱动变形的特性和规律,加深了对三点起爆条件下药型罩形成带尾翼EFP机理的认识。在此基础上,设计了三点同步起爆装置和EFP装药进行实验。研究结果表明：设计的三点起爆装置作用可靠,满足三点起爆EFP装药的设计要求;形成的EFP弹形稳定,与计算结果吻合较好;尾翼EFP飞行过程中的速度降减小,稳定性提高。