Giant Spin-Orbit Torque in Antiferromagnetic-Coupled Pt/[Co/Gd]N Multilayers with Suppressed Spin Dephasing and Robust Thermal Stability.

Manipulating magnetization via power-efficient spin-orbit torque (SOT) has garnered significant attention in the field of spin-based memory and logic devices. However, the damping-like SOT efficiency (ξDL) in heavy metal (HM)/ferromagnetic metal (FM) bilayers is relatively small due to the strong spin dephasing accompanied by additional spin polarization decay. Furthermore, the perpendicular magnetic anisotropy (PMA) originating from the HM/FM interface is constrained by the thickness of FM, which is unfavorable for thermal stability in practical applications. Consequently, it is valuable to develop systems that not only exhibit large ξDL but also balance thermal stability. In this work, we designed antiferromagnetic-coupled [Co/Gd]N multilayers, where staggered Co and Gd magnetic moments effectively suppress the spin dephasing and additional spin polarization decay. The ordered Co-Gd arrangements along the out-of-plane direction provide bulk PMA, endowing Pt/[Co/Gd]N high thermal stability. The SOT of Pt/[Co/Gd]N was systematically studied with N, demonstrating a significantly large ξDL of up to 0.66. The ξDL of Pt/[Co/Gd]N is greater than those of Pt/Co and Pt/ferrimagnetic alloys. This significant enhancement relies on the effective suppression of spin dephasing in [Co/Gd]N. Our work highlights that the antiferromagnetic-coupled [Co/Gd]N multilayer is a promising candidate for low-consumption and high-density spintronic devices.

NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth.

Calcium homeostasis is critical for cell proliferation, and emerging evidence shows that cancer cells exhibit altered calcium signals to fulfill their need for proliferation. However, it remains unclear whether there are oncogene-specific calcium homeostasis regulations that can expose novel therapeutic targets. Here, from RNAi screen, we report that adenosylhomocysteinase like protein 1 (AHCYL1), a suppressor of the endoplasmic reticulum (ER) calcium channel protein inositol trisphosphate receptor (IP3R), is selectively upregulated and critical for cell proliferation and tumor growth potential of human NRAS-mutated melanoma, but not for melanoma expressing BRAF V600E. Mechanistically, AHCYL1 deficiency results in decreased ER calcium levels, activates the unfolded protein response (UPR), and triggers downstream apoptosis. In addition, we show that AHCYL1 transcription is regulated by activating transcription factor 2 (ATF2) in NRAS-mutated melanoma. Our work provides evidence for oncogene-specific calcium regulations and suggests AHCYL1 as a novel therapeutic target for RAS mutant-expressing human cancers, including melanoma. IMPLICATIONS: Our findings suggest that targeting the AHCYL1-IP3R axis presents a novel therapeutic approach for NRAS-mutated melanomas, with potential applicability to all cancers harboring RAS mutations, such as KRAS-mutated human colorectal cancers.

Analysis and Optimization of Contact Material Ablation under the Cumulative Effect of the Number of Breakings of OLTC.

Vacuum on-load tap-changers (OLTC) for converter transformers have a much higher number of breakings than conventional circuit breakers. Contact ablation after several breakings will affect the stability and life of the device. This paper establishes the electromagnetic thermal multi-physical field coupling model of the vacuum interrupter for OLTC based on the finite element analysis method. The thermal field distribution of normal and ablative contact materials during the breaking process was analyzed. The key parameters affecting the contact temperature under the cumulative number of breakings are analyzed and the optimized design is completed. The simulation results show that the contact surface reaches a maximum temperature of 1390 K at 8 ms. There is a significant increase in the area of the high-temperature area on the contact surface. The possibility of re-ignition of the interrupter is increased. Based on the judgment matrix method, the key influencing parameters of the contact temperature rise are analyzed. The final parameters are selected as follows: contact material-CuCr8 alloy, contact seat thickness-2 mm, contact thickness-10 mm, and contact diameter-40 mm.

Developing Ecological Thresholds for Nitrogen and Phosphorus in the Haihe River Basin in China.

Many aquatic ecosystems are eutrophicated due to human inputs of nitrogen and phosphorus. Therefore, it is now considered important to establish nutrient criteria to prevent eutrophication. In this study, the water quality and biological data for 26 stations in the lower reaches of the Haihe River Basin were collected. The total nitrogen (TN) and total phosphorus (TP) ecological thresholds were derived from the threshold indicator taxa analysis (TITAN) and frequency distribution approach. The results showed that the TN threshold was 1.8 mg/L based on the TITAN and the TP threshold was 0.039 mg/L based on the frequency distribution approach. The TITAN also identified 29 indicator species of TN and 28 indicator species of TP. Based on these criteria, we found 73% sites with TN concentrations higher than the 1.8 mg/L. As for TP, 58% sites exceeded 0.039 mg/L. This study showed that most of the downstream areas of the Haihe River are subject to relatively serious disturbances. This finding could provide implications for identifying the water quality traits of and generating protection strategies for the Haihe River in Tianjin.

Discovery of Potent Antiallergic Agents Based on an o-Aminopyridinyl Alkynyl Scaffold.

Effective therapeutic agents are highly desired for immune-mediated allergic diseases. Herein, we report the design, synthesis, and structure-activity relationship of an o-aminopyridinyl alkyne series as novel orally bioavailable antiallergic agents, which was identified through phenotypic screening. Compound optimization yielded a highly potent compound 36, which effectively suppressed mast cell degranulation in a dose-dependent manner (IC50, 2.54 nM for RBL-2H3 cells; 48.28 nM for peritoneal mast cells (PMCs)) with a good therapeutic index. It also regulated the activation of FcεRI-mediated downstream signaling proteins in IgE/Ag-stimulated RBL-2H3 cells. In addition, 36 exhibited excellent in vivo pharmacokinetic properties and antiallergic efficacy in both passive systemic anaphylaxis (PSA) and house dust mite (HDM)-induced murine models of pulmonary allergic inflammation. Furthermore, preliminary analysis of the kinases profile identified Src-family kinases as potential targets for 36. Compound 36 may serve as a new valuable lead compound for future antiallergic drug discovery.

Understanding the effects of metal pre-exposure on the sensitivity of zebrafish larvae to metal toxicity: A toxicokinetics-toxicodynamics approach.

Organisms are increasingly tolerant to metal toxicity in the natural ecosystems, which did not match the results of the environmental risk assessment (ERA) of metals based on toxicity data from organisms in the laboratory. Studies have described the effects of pre-exposure to metals on metal toxicity tolerance in terms of the toxicokinetic (TK) process; however, the toxicodynamic (TD) process may be more susceptible to metal pre-exposure. Therefore, to determine whether pre-exposure to low concentrations of silver (Ag) or cadmium (Cd) affects the metal TK and TD processes of zebrafish (Danio rerio) larvae, we investigated four TK-TD model parameters that control tolerance and sensitivity to metal toxicity on the survival. Our results showed that the killing rate (ks) of larvae exposed to high Cd concentrations was significantly lower following pre-exposure to 10 µg/L Cd than that of larvaenot pre-exposed. However, the ks for high Ag concentrations was significantly higher in zebrafish larvae following pre-exposure to 2 µg/L Ag than in larvae not pre-exposed. In other words, a one-day pre-exposure to 2 µg/L Ag rendered the larvae more sensitive to Ag during a subsequent 4-day exposure to higher Ag concentrations, whereas a one-day pre-exposure to 10 µg/L Cd rendered the larvae more tolerance to Cd during a subsequent 4-day exposure to higher Cd concentrations. Our results further the current understanding of toxic metal tolerance mechanisms, both in TK and TD processes, and they will guide future laboratory studies to assess actual pre-exposure scenarios that occur in natural environments. Thus, our study can help reduce uncertainty in testing and improve ecological management concerning metal risk assessments.

Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes.

According to the binding mode of ABBV-744 with bromodomains and the cape space of HDAC, the novel selective HDAC/BRD4 dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. Evaluating the biomolecular activities through SARs exploration identified three kinds of selective dual inhibitors 41c (HDAC1/BRD4), 43a (pan-HDAC/BRD4) and 43d (HDAC6/BRD4(BD2)), whose target-related cellular activities in MV-4-11 cells were also confirmed. Significantly, the selective dual inhibitor 41c (HDAC1/BRD4) exhibited synergistic effects against MV-4-11 cells, which strongly induced G0/G1 cell cycle arrest and apoptosis, and the first HDAC6/BRD4(BD2) dual inhibitor was found. This study provides support for selective HDAC/BRD4 dual inhibitors as epigenetic probes based on pyrrolopyridone core for the future biological evaluation in different cancer cell lines.

GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes.

GPR52 is an orphan G protein-coupled receptor (GPCR) that has been recently implicated as a potential drug target of Huntington's disease (HD), an incurable monogenic neurodegenerative disorder. In this research, we found that striatal knockdown of GPR52 reduces mHTT levels in adult HdhQ140 mice, validating GPR52 as an HD target. In addition, we discovered a highly potent and specific GPR52 antagonist Comp-43 with an IC50 value of 0.63 µM by a structure-activity relationship (SAR) study. Further studies showed that Comp-43 reduces mHTT levels by targeting GPR52 and promotes survival of mouse primary striatal neurons. Moreover, in vivo study showed that Comp-43 not only reduces mHTT levels but also rescues HD-related phenotypes in HdhQ140 mice. Taken together, our study confirms that inhibition of GPR52 is a promising strategy for HD therapy, and the GPR52 antagonist Comp-43 might serve as a lead compound for further investigation.

A biological characteristic extrapolation of compound toxicity for different developmental stage species with toxicokinetic-toxicodynamic model.

Intraspecific difference in toxicity brings uncertainty to ecological risk assessment (ERA) and water quality criteria (WQC) of chemicals. Here, we compared intraspecies sensitivity to toxicants for Mesocyclops leuckarti of which toxicity data was obtained from published literatures, and zebrafish Danio rerio of which toxicity data was done in this study). Due to the internal concentration of chemicals not measured, simplified toxicokinetic-toxicodynamic (TK-TD) models were used, and we investigated whether TK-TD parameters estimated by Bayesian method might represent the differences in sensitivity between life-stages of 2 species. The results demonstrated that the difference in TK-TD parameters (background mortality m0, no effect concentration NEC, the killing rate ks, and the dominant rate kd) could represent the toxicity difference between life-stages of individual species. The TK-TD model could predict toxicity in individual species (Cyprinus carpio L., Enchytraeus crypticus, Folsomia candida, Hyalella Azteca) exposed to different chemical concentrations and successfully extrapolate toxicity between different life stages of Mesocyclops leuckarti and Danio rerio by scaling several TK-TD parameters. The modified TK-TD model on the extrapolation toxicity of chemicals between life stages for species could be useful for the ERA and for deriving and revising WQC for chemicals.

Adsorption and Gas Sensing Properties of the Pt3-MoSe2 Monolayer to SOF2 and SO2F2.

SF6 acts as an insulation gas in gas-insulated switchgear (GIS), which inevitably decomposes under partial discharge caused by insulation defects. This work is devoted to finding a new gas-sensing material for detecting two characteristic SF6 decomposition products: SOF2 and SO2F2. The platinum-cluster-modified molybdenum diselenide (Pt3-MoSe2) monolayer has been proposed as a gas sensing material. Based on first-principles calculations, the adsorption properties and the mechanism were studied by analyzing the adsorption structures, adsorption energy, charge transfer, density of states, and molecular orbitals. The adsorption ability of Pt3-MoSe2 to SO2F2 is stronger than that to SOF2 due to its chemisorption property. The obvious change of conductivity of the adsorption system during the gas adsorption process shows that Pt3-MoSe2 is sensitive to both of the gas molecules. In addition, the modest adsorption energy signifies that the gas adsorption process can be reversible, which confirms the feasibility of Pt3-MoSe2-based gas sensors. Our calculation suggests that Pt3-MoSe2-based gas sensors can be employed in GIS for partial discharge detection.

Novel Class of Colony-Stimulating Factor 1 Receptor Kinase Inhibitors Based on an o-Aminopyridyl Alkynyl Scaffold as Potential Treatment for Inflammatory Disorders.

Colony-stimulating factor 1 receptor (CSF-1R) is involved in inflammatory disorders as well as in many types of cancer. Based on high-throughput screening and docking results, we performed a detailed structure-activity-relationship study, leading to the discovery of a new series of compounds with nanomolar IC50 values against CSF-1R without the inhibition of fibroblast growth factor receptors. One of the most promising hits, compound 29, potently inhibited CSF-1R kinase with an IC50 value of 0.7 nM, while it showed no inhibition to the same family member FMS-like tyrosine kinase 3. Compound 29 displayed excellent anti-inflammatory effects against RAW264.7 macrophages indicated by significant inhibition against the activation of the CSF-1R pathway with low cytotoxicity. In addition, compound 29 exhibited strong in vivo anti-inflammatory efficacy alongside favorable drug characteristics. This novel compound 29 may serve as a new drug candidate with promising applications in inflammatory disorders.

Different factors determined the toxicokinetics of organic chemicals and nanomaterials exposure to zebrafish (Danio Rerio).

Little is known about how the chemical properties (molecular structure, such as the hydrophobic and hydrophilic end group for organic chemical, and particle size for nanomaterials (NMs)) quantitatively affect the toxicokinetics (TK) in organisms especially in short-term, single-species studies. A novel method based on a first-order one compartment TK model which described the monophasic uptake pattern and two-compartment TK model which adequately described the biphasic metabolism pattern was used to determine the bioconcentration and TK rate constants of organic compounds (n = 17) and nanomaterials (NMs, n = 7) in zebrafish. For both one and two compartment model, the uptake (kin) and elimination (kout) rate constants were fitted using a one- and two-compartment first-order kinetic model, and bioconcentration factors (BCF) and 95% depuration times (t95) for all tested chemicals were calculated, respectively. The results showed that there was significant difference in TK parameters kin, kout, and BCF between organic chemicals and nano metal oxides. For organic compounds, significant correlations were found between the kin and BCF and the octanol-water partition coefficient (Kow) and molecular mass. For nano metal oxides, there was a significant negative correlation between the kin or BCF and particle size, but a positive correlation between kin and Zeta potential of nanoparticles and also a significant positive correlation between kout and particle size or specific surface area. Those findings indicated that NMs particle size does matter in biological influx and efflux processes. Our results suggest that the TK process for organic compound and NMs are correlated by different chemical properties and highlight that the Kow, the absorption kin, metabolism k12 and k21, elimination rate kout, and all the parameters that enable the prediction and partitioning of chemicals need to be precisely determined in order to allow an effective TK modeling. It would therefore appear that the TK process of untested chemicals by a fish may be extrapolated from known chemical properties.

Design of a 1-Bit MEMS Gyroscope Using the Model Predictive Control Approach.

In this paper, a bi-level Delta-Sigma modulator-based MEMS gyroscope design is presented based on a Model Predictive Control (MPC) approach. The MPC is popular because of its capability of handling hard constraints. In this work, we propose to combine the 1-bit nature of the bi-level Delta-Sigma modulator output with the MPC to develop a 1-bit processing-based MPC (OBMPC). This paper will focus on the affine relationship between the 1-bit feedback and the in-loop MPC controller, as this can potentially remove the multipliers from the controller. In doing so, the computational requirement of the MPC control is significantly alleviated, which makes the 1-bit MEMS Gyroscope feasible for implementation. In addition, a stable constrained MPC is designed, so that the input will not overload the quantizer while maintaining a higher Signal-to-Noise Ratio (SNR).

S-oxiracetam ameliorates ischemic stroke induced neuronal apoptosis through up-regulating α7 nAChR and PI3K / Akt / GSK3ß signal pathway in rats.

Ischemic stroke, the main reason for severe disabilities in the world, is associated with a high incidence of sensorimotor and cognitive dysfunction. In this study, we use the middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and oxygen glucose deprivation/reoxygenation (OGD/R) model in fetal rat primary cortical neurons to investigate whether and how S-oxiracetam (S-ORC) protect brain injury from ischemic stroke. The results revealed that S-ORC reduced brain infarct size and lessened neurological dysfunction after stroke. Further study demonstrated that S-ORC diminished TUNEL positive cells, increased cell viability, decreased LDH activity, and inhibited cell apoptotic rate. Furthermore, S-ORC inhibited neuronal apoptosis by activating the PI3K/Akt/GSK3ß signaling pathway via α7 nAChR, which was evidenced by α7 nAChR siRNA. In conclusion, our findings strongly suggest that S-ORC could be used as an effective neuroprotective agent for ischemic stroke due to its effect in preventing neuronal apoptosis.