Zeaxanthin augments CD8 effector T cell function and immunotherapy efficacy.

The detailed mechanisms underlying the regulatory significance of dietary components in modulating anti-tumor immunity remain largely unknown. Here, we apply a co-culture-based screening approach using a blood nutrient compound library and identify zeaxanthin (ZEA), a dietary carotenoid pigment found in many fruits and vegetables and known for its role in eye health, as an immunomodulator that enhances the cytotoxicity of CD8 T cells against tumor cells. Oral supplementation with ZEA, but not its structural isomer lutein (LUT), enhances anti-tumor immunity in vivo.

Functionally deficient UBOX5 variants and primary angle-closure glaucoma.

Primary angle-closure glaucoma is a major cause of irreversible blindness worldwide afflicting >20 million people. Through whole exome sequencing, we analysed the association between gene-based burden of rare, protein-altering genetic variants and disease risk in 4,667 affected individuals and 5,473 unaffected controls. We tested genes surpassing exome-wide significance (P < 2.

Design, synthesis, and biological evaluation of KDM5B degraders against hematologic malignancy cells.

Histone lysine-specific demethylase 5B (KDM5B) is frequently overexpressed in a wide range of tumors and is regarded as a promising target for drug development. Current drugs targeting KDM5B are primarily small-molecule inhibitors, which suffer from limitations such as poor selectivity and insufficient pharmacological efficacy. Targeted protein degradation (TPD) technology as an emerging drug development strategy has received extensive attention in recent years, that enables the catalytic elimination of the entire protein of interest, thereby disrupting both the enzymatic and non-enzymatic functions.

Discovery of potent anti-idiopathic pulmonary fibrosis (IPF) agents based on an o-aminopyridinyl alkynyl scaffold.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high mortality and limited treatment options. Targeting multiple kinase-driven pathological processes offers a promising strategy. Using epithelial-mesenchymal transition (EMT) phenotypic screening, we optimized a series of o-aminopyridinyl alkynyl compounds derived from CSF-1R relatively selective inhibitor, compound 1, through a structure-activity relationship (SAR) study, integrating liver and kidney cytotoxicity evaluations.

Giant Spin-Orbit Torque in Antiferromagnetic-Coupled Pt/[Co/Gd] 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 (ξ) 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.

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

Unlabelled: 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.

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.

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.

Discovery of Potent Antiallergic Agents Based on an -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 -aminopyridinyl alkyne series as novel orally bioavailable antiallergic agents, which was identified through phenotypic screening. Compound optimization yielded a highly potent compound , which effectively suppressed mast cell degranulation in a dose-dependent manner (IC, 2.

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- with an IC value of 0.

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.

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.

Adsorption and Gas Sensing Properties of the Pt-MoSe Monolayer to SOF and SOF.

SF 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 SF decomposition products: SOF and SOF. The platinum-cluster-modified molybdenum diselenide (Pt-MoSe) monolayer has been proposed as a gas sensing material.

Novel Class of Colony-Stimulating Factor 1 Receptor Kinase Inhibitors Based on an -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 IC values against CSF-1R without the inhibition of fibroblast growth factor receptors. One of the most promising hits, compound , potently inhibited CSF-1R kinase with an IC value of 0.

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 (k and elimination (k) rate constants were fitted using a one- and two-compartment first-order kinetic model, and bioconcentration factors (BCF) and 95% depuration times (t) for all tested chemicals were calculated, respectively.

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).

S-oxiracetam ameliorates ischemic stroke induced neuronal apoptosis through up-regulating α7 nAChR and PI3K / Akt / GSK3β 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.