IL-4 activates ULK1/Atg9a/Rab9 in asthma, NLRP3 inflammasomes, and Golgi fragmentation by increasing autophagy flux and mitochondrial oxidative stress.

During asthma, there is an intensification of pulmonary epithelial inflammation, mitochondrial oxidative stress, and Golgi apparatus fragmentation. However, the underlying mechanism remains largely unknown. Therefore, this study investigated the roles of ULK1, Atg9a, and Rab9 in epithelial inflammation, mitochondrial oxidative stress, and Golgi apparatus fragmentation. We found that ULK1 gene knockout reduced the infiltration of inflammatory cells, restored the imbalance of the Th1/Th2 ratio, and inhibited the formation of inflammatory bodies in the lung tissue of house dust mite-induced asthma mice. Moreover, we demonstrated that Atg9a interacted with ULK1 at S467. ULK1 phosphorylated Atg9a at S14. Treatment with ULK1 activator (LYN-1604) and ULK1 inhibitor (ULK-101) respectively promoted and inhibited inflammasome activation, indicating that the activation of inflammasome induced by house dust mite in asthma mice is dependent on ULK1. For validation of the in vivo results, we then used a lentivirus containing ULK1 wild type and ULK1-S467A genes to infect Beas-2b-ULK1-knockout cells and establish a stable cell line. The results suggest that the ULK1 S467 site is crucial for IL-4-induced inflammation and oxidative stress. Experimental verification confirmed that Atg9a was the superior signaling pathway of Rab9. Interestingly, we found for the first time that Rab9 played a very important role in inflammation-induced fragmentation of the Golgi apparatus. Inhibiting the activation of the ULK1/Atg9a/Rab9 signaling pathways can inhibit Golgi apparatus fragmentation and mitochondrial oxidative stress in asthma while reducing the production of NLRP3-mediated pulmonary epithelial inflammation.

Field-Free Spin-Orbit Torque-Induced Magnetization Switching in the IrMn/CoTb Bilayers with a Spontaneous In-Plane Exchange Bias.

Spin-orbit torque (SOT)-induced magnetization switching in ferrimagnetic materials is promising for application in a new generation of information storage devices. Here, we demonstrate SOT-induced field-free magnetization switching of the perpendicularly magnetized CoTb ferrimagnet layer in the IrMn/CoTb bilayer, in which the in-plane magnetic inversion symmetry is broken by a spontaneous in-plane exchange bias (IEB) established by isothermal crystallization of the IrMn layer. We obtain a significant SOT effective field acting on the CoTb layer and a large effective spin Hall angle in this system, derived by the second harmonic voltage measurement method. Moreover, the IrMn/CoTb bilayer demonstrates multistate magnetic switching behavior with different amplitudes of current pulses at zero field, which can mimic the synaptic weight updates in the neuromorphic network. These findings make the IrMn/CoTb bilayer with spontaneous IEB a promising candidate for potential applications in multilevel storage and neuromorphic computing.

Improved resistive switching performance and realized electric control of exchange bias in a NiO/HfO2 bilayer structure.

The fluctuation of switching parameters is unavoidable in conductive filaments (CFs)-type resistive switching (RS) devices, which restricts the application in resistive random-access memory. Here, we employed an uninsulated antiferromagnetic (AFM) NiO layer adhered to a well-insulating HfO2 layer to effectively suppress the RS fluctuation by achieving forming-free, narrower set voltage distribution, a more stable on/off ratio, and better endurance in comparison with single-HfO2-layer based RS devices. The conduction scaling behavior indicates that the NiO/HfO2 bilayer has a smaller scale parameter S0 (lateral dimension of the bottleneck for the CFs). Besides this, considering some preexisting conductive paths in the NiO layer, the electric fields and the formation/rupture of CFs can be highly localized, leading to reduced switching fluctuation and improved RS performance in the NiO/HfO2-based RS devices. Moreover, asymmetric I-V curves measured in a high resistance state (HRS) in positively and negatively biased regions and the electric modulation of exchange bias (EB) arising from the Co-NiO interfacial coupling are favorable for revealing the inherent mechanism for RS. The coexistence of RS and EB is also useful to the design of novel multifunctional memory devices.

Polydatin inhibits mitochondrial damage and mitochondrial ROS by promoting PINK1-Parkin-mediated mitophagy in allergic rhinitis.

Polydatin (PD), a natural product derived from Polygonum cuspidatum, has anti-inflammatory and antioxidant effects and has significant benefits in treating allergic diseases. However, its role and mechanism in allergic rhinitis (AR) have not been fully elucidated. Herein, we investigated the effect and mechanism of PD in AR. AR model was established in mice with OVA. Human nasal epithelial cells (HNEpCs) were stimulated with IL-13. HNEpCs were also treated with an inhibitor of mitochondrial division or transfected with siRNA. The levels of IgE and cellular inflammatory factors were examined by enzyme linked immunosorbent assay and flow cytometry. The expressions of PINK1, Parkin, P62, LC3B, NLRP3 inflammasome proteins, and apoptosis proteins in nasal tissues and HNEpCs were measured by Western blot. We found that PD suppressed OVA-induced epithelial thickening and eosinophil accumulation in the nasal mucosa, reduced IL-4 production in NALF, and regulated Th1/Th2 balance. In addition, mitophagy was induced in AR mice after OVA challenge and in HNEpCs after IL-13 stimulation. Meanwhile, PD enhanced PINK1-Parkin-mediated mitophagy but decreased mitochondrial reactive oxygen species (mtROS) production, NLRP3 inflammasome activation, and apoptosis. However, PD-induced mitophagy was abrogated after PINK1 knockdown or Mdivi-1 treatment, indicating a key role of the PINK1-Parkin in PD-induced mitophagy. Moreover, mitochondrial damage, mtROS production, NLRP3 inflammasome activation, and HNEpCs apoptosis under IL-13 exposure were more severe after PINK1 knockdown or Mdivi-1 treatment. Conclusively, PD may exert protective effects on AR by promoting PINK1-Parkin-mediated mitophagy, which further suppresses apoptosis and tissue damage in AR through decreasing mtROS production and NLRP3 inflammasome activation.

DEK deficiency suppresses mitophagy to protect against house dust mite-induced asthma.

DEK protein is highly expressed in asthma. However, the mechanism of DEK on mitophagy in asthma has not been fully understood. This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. PINK1-Parkin mitophagy, NLRP3 inflammasome, and apoptosis were examined after gene silencing or treatment with specific inhibitors (MitoTEMPO, MCC950, and Ac-DEVD-CHO) in house dust mite (HDM) or recombinant DEK (rmDEK)-induced WT and DEK-/- asthmatic mice and BEAS-2B cells. The regulatory role of DEK on ATAD3A was detected using ChIP-sequence and co-immunoprecipitation. rmDEK promoted eosinophil recruitment, and co-localization of TOM20 and LC3B, MFN1 and mitochondria, LC3B and VDAC, and ROS generation, reduced protein level of MnSOD in HDM induced-asthmatic mice. Moreover, rmDEK also increased DRP1 expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. These effects were partially reversed in DEK-/- mice. In BEAS-2B cells, siDEK diminished the Parkin, LC3B, and DRP1 translocation to mitochondria, mtROS, TOM20, and mtDNA. ChIP-sequence analysis showed that DEK was enriched on the ATAD3A promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models and interacted with DRP1, and siATAD3A could down-regulate DRP1 and mtDNA-mediated mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.

Comprehensive characterization of the chemical composition of Lurong dabu decoction and its absorbed prototypes and metabolites in rat plasma using UHPLC-Q Exactive Orbitrap-HRMS.

Lurong Dabu decoction (LRDBD) is an effective traditional Chinese Korean ethnic medicine prescription composed of eight herbs, which is used for treating asthma. However, its material basis has not been studied yet. Herein, the use of a new and highly sensitive UHPLC-Q Exactive Orbitrap-HRMS technique is proposed for the high-resolution and accurate identification of the material basis of LRDBD. We identified 122 compounds belonging to different groups in LRDBD. Among these, 23 ingredients produced by decoction were identified and compared with 8 single herb compounds. Moreover, 39 other significantly different compounds were identified. Additionally, 29 absorbed prototype components and 35 metabolites were identified in rat plasma. Half of the prototype components were originated from antler velvet, it has corroborated the compatibility theory of Sasang medicine. To the best of our knowledge, the material basis of LRDBD was characterized for the first time. Our findings provide basic data and a method for further discovering potential drug targets and revealing the action mechanism of LRDBD in asthma treatment.

Cooling Field Dependence of Exchange Bias in Mn-Doped Metal- Organic Framework [NH2(CH3)2][FeIIIFeII(HCOO)6].

Herein, an intriguing exchange bias (EB) effect manifesting itself from positive to negative with an increase in the cooling field (HFC) is reported in the single crystal of Mn-doped metal-organic framework (MOF) [NH2(CH3)2][FeIIIFeII(HCOO)6] (1) by finely tuning the exchange interactions between the magnetic ions. Note that the doping ratio of Mn relative to the total metal ions is about 15%. Negative magnetization and EB below the compensation temperature were both observed in 1, and the EB field (HE) changes its sign from positive to negative when HFC is larger than ∼10 kOe. The abnormal HFC dependence of EB can be interpreted explicitly by a combination of negative magnetization and couplings among the ions of Fe3+, Fe2+, and Mn2+ with varying the HFC. This work demonstrates a tunable EB in MOFs, in favor of designing novel magnetic devices.

Electric Control of Exchange Bias at Room Temperature by Resistive Switching via Electrochemical Metallization.

Electric field control of exchange bias (EB) plays an important role in spintronics due to its attractive merit of lower energy consumption. Here, we propose a novel method for electrically tunable EB at room temperature in a device with the stack of Si/SiO2/Ta/Pt/Ag/Mn-doped ZnO (MZO)/Pt/FeMn/Co/ITO by resistive switching (RS) via electrochemical metallization (ECM). The device shows enhanced and weakened EB when set at high-resistance state (HRS) and low-resistance state (LRS), respectively. For the device at LRS, the aberration-corrected scanning transmission electron microscopy (STEM) characterizations unambiguously reveal that the Ag filaments grow initially from the Ag anode and then elongate toward the ITO cathode. It is inferred that at LRS, a small portion of Ag filaments have passed through the MZO and the intervening thin Pt layer and extended into the FeMn layer. After applying reverse voltage, these Ag filaments are electrochemically dissolved and ruptured near the MZO/Pt interface. This is considered to be the main mechanism responsible for RS and switchable EB as well. This work presents a new strategy for designing low-power, nonvolatile magnetoelectric random access memory devices.

Strain Control of Phase Transition and Exchange Bias in Flexible Heusler Alloy Thin Films.

The practical applications for the distinctive functions of metamagnetic Heusler alloys, such as magnetic shape memory effect, various caloric effects, etc., strongly depend on the phase transition temperatures. Here, flexible Heusler alloy Ni-Mn-Sn films have been deposited on mica substrates by pulsed laser deposition with a Ti buffer layer. Clear ferromagnetic (FM) transition followed by the martensitic transformation at around room temperature and exchange bias (EB) with a blocking temperature of 70 K are observed. Under the application of both tensile and compressive strains by bending the mica substrates, all the characteristic temperatures of Ni-Mn-Sn films, including the FM transition temperature, martensitic transformation temperature, and blocking temperature of EB, are significantly increased by about 10 K. Furthermore, EB field and coercivity are both strongly strengthened, which is mainly caused by the simultaneous enhancement of FM and anti-FM Mn-Mn coupling because of their shortened separations by strain and verified by the Monte Carlo simulation results. The strain controlling for structural and magnetic properties provides efficient manipulation for Heusler alloy-based magnetic devices.

Large anisotropy of magnetic damping in amorphous CoFeB films on GaAs(001).

Amorphous CoFeB films grown on GaAs(001) substrates demonstrating significant in-plane uniaxial magnetic anisotropy were investigated by vector network analyzer ferromagnetic resonance. Distinct in-plane anisotropy of magnetic damping, with a largest maximum-minimum damping ratio of about 109%, was observed via analyzing the frequency dependence of linewidth in a linear manner. As the CoFeB film thickness increases from 3.5 nm to 30 nm, the amorphous structure for all the CoFeB films is maintained while the magnetic damping anisotropy decreases significantly. In order to reveal the inherent mechanism responsible for the anisotropic magnetic damping, studies on time-resolved magneto-optical Kerr effect and high resolution transmission electron microscopy were performed. Those results indicate that the in-plane angular dependent anisotropic damping mainly originates from two-magnon scattering, while the Gilbert damping keeps almost unchanged.