Copper-Catalyzed Regioselective Coupling of Tosylhydrazones and 2-Pyridones: A Strategy for the Production of N-Alkylated Compounds.

The highly regioselective N-alkylation reaction of 2-pyridones was achieved through hydrazone chemistry, especially for substrates with bulky secondary alkyl groups. Described herein is a copper-catalyzed coupling reaction of pyridone derivatives with tosylhydrazones.

[Application of apparent diffusion coefficient in children aged 2-12 years with intellectual disability/global developmental delay who have normal conventional brain MRI findings].

OBJECTIVE: To study the value of fast spin-echo diffusion weighted imaging (TSE-DWI) apparent diffusion coefficient (ADC) in children aged 2-12 years with intellectual disability (ID)/global developmental delay (GDD) who have normal conventional brain MRI findings. METHODS: A total of 578 children with normal conventional brain MRI findings who met the diagnostic criteria for ID/GDD and 375 normal children were enrolled. Their imaging and clinical data were collected. All children underwent scanning with brain TSE-DWI sequence and routine sequence. ADC values of each brain region were compared between normal children with different ages, as well as between children with different degrees of ID/GDD in each age group. The influence of Adaptive Behavior Assessment System-II (ABAS-II) score on ADC values of each brain region was analyzed. RESULTS: For the normal children, the ADC values of the frontal and temporal white matter, the corpus callosum, the inner capsule, the centrum semiovale, the cerebellar dentate nucleus, the optic radiation, the thalamus, the lenticular nucleus, and the caudate nucleus gradually decreased with age (P<0.05). ADC values of the deep white matter, the shallow white matter, the deep gray matter nuclei, and the shallow gray matter increased with the increase in the degree of ID/GDD in the ID/GDD children aged 4-6 years (P<0.05). In the children with ID/GDD, the ADC values of the deep white matter, the shallow white matter, and the deep gray matter nuclei decreased with age (P<0.05). The ADC values of the children with ID/GDD decreased with the increase in ABAS-II score (P<0.05). CONCLUSIONS: ADC can reflect the subtle structural changes of brain regions in children with ID/GDD who have normal conventional brain MRI findings. It may be associated with social adaptation. It can provide an objective basis for the quantitative diagnosis of ID/GDD in children.

Quantum-level investigation of air decomposed pollutants gas sensor (Pd-modified g-C3N4) influenced by micro-water content.

In the electrical industry, there are many hazardous gases that pollute the environment and even jeopardize human health, so timely detection and effective control of these hazardous gases is of great significance. In this work, the gas-sensitive properties of Pd-modified g-C3N4 interface for each hazardous gas molecule were investigated from a microscopic viewpoint, taking the hazardous gases (CO, NOx) that may be generated in the power industry as the detection target. Then, the performance of Pd-modifiedg-C3N4 was evaluated for practical applications as a gas sensor material. Novelly, an unconventional means was designed to briefly predict the effect of humidity on the adsorption properties of this sensor material. The final results found that Pd-modified g-C3N4 is most suitable as a potential gas-sensitizing material for NO2 gas sensors, followed by CO. Interestingly, Pd-modified g-C3N4 is less suitable as a potential gas-sensitizing material for NO gas sensors, but has the potential to be used as a NO cleaner (adsorbent). Unconventional simulation explorations of humidity effects show that in practical applications Pd-modified g-C3N4 remains a promising material for gas sensing in specific humidity environments. This work reveals the origin of the excellent properties of Pd-modified g-C3N4 as a gas sensor material and provides new ideas for the detection and treatment of these three hazardous gases.

A rapid and accurate method for evaluating the degradation of pan-Akt in cells by PROTACs using NanoLuc luciferase.

Proteolysis targeting chimera (PROTAC) is a protein degradation technique that has been increasingly used in the development of new drugs in recent years. Akt is a classical serine/threonine kinase, and its role outside of the kinase has gradually gained attention in recent years, making it one of the proteins targeted by PROTACs. Currently, there are many methods used for the evaluation of intracellular protein degradation, but each has its own advantages or disadvantages. This study aimed to investigate the feasibility of evaluating the degradation of pan-Akt proteins in cells by PROTACs (MS21 and MS170) using the NanoLuc luciferase method. After conducting a thorough comparison between this method and the classical western blot assay in various cells, as well as testing the stability of the experiments between multiple batches, we found that NanoLuc luciferase is a highly accurate, stable, low-cost and easy-to-operate method for the evaluation of intracellular pan-Akt degradation by PROTACs with a short cycle time and high cellular expandability. Given the numerous advantages of this method, it is hypothesized that it could be extended to evaluate the degradation of more target proteins of PROTACs. In summary, the NanoLuc luciferase is a suitable method for early protein degradation screening of PROTAC compounds.

Diagnostic Performance of 3D-NERVE as an Adjunct to Electromyography for the Assessment of Brachial Plexus Injury in Infants.

Objective: This study aimed to explore diagnostic performance of 3D-NERVE as an adjunct to electromyography for the assessment of brachial plexus injury in infants. Methods: Imaging of infants with brachial plexus injury using 3D-NERVE and/or 3D-STIR from 2019 to 2022 were reviewed. Images were evaluated between the 2 sequences for nerve-to-fat ratio, nerve-to-muscle ratio, muscle-to-fat ratio, fat suppression homogeneity, and display rate of brachial plexus branches. Results: This study included 37 infants who were referred for a clinical diagnosis of brachial plexus injury. A total of 21 infants accepted 3D-NERVE sequence scanning, and 16 infants accepted 3D-NERVE and 3D-STIR sequences scanning. The results of examination were generally consistent with electromyography. The 2 sequences were compared, yielding the following results. There were no pulsation artifacts (0/16), and 1 case with heterogeneous fat saturation (1/16) was seen on 3D-NERVE. There were no pulsation artifacts (0/16), and 5 cases with heterogeneous fat saturation (5/16) were seen on 3D-STIR. 3D-NERVE performed better (P < .05) for nerve-to-fat and nerve-to-muscle ratios compared with 3D-STIR, and no significant difference in the muscle-to-fat ratio (P > .05). The 3D-NERVE and STIR helped depict 100% (16/16) of the brachial roots and brachial plexus trunk. Brachial plexus bundles and brachial plexus branches were observed in 93.75% (15/16) and 68.75% (11/16) of the 3D-NERVE and 93.75% (15/16) and 62.5% (10/16) of the 3D-STIR, respectively. The differences were not statistically significant (P > .05). Conclusion: Nerve trauma was better visualized with the 3D-NERVE, which is an effective adjunct to electromyography for doctors to assess brachial plexus injury and consequently helps in better treatment planning.

Event-triggering load frequency control for multi-area power system based on random dynamic triggering mechanism and two-side closed functional.

By taking into account sampled-data mechanism and transmission delay, the novel event-triggering load frequency control (LFC) strategy involving random dynamic triggering algorithm (RDTA) is developed for multi-area power systems in this paper. Firstly, an improved multi-area LFC model considering sampling and transmission delay (STD) simultaneously is addressed. Secondly, a modified event-triggering mechanism (ETM) with RDTA is proposed, considering parameter disturbances and a dynamic adjustment mechanism of the triggering threshold. Thirdly, a more advanced Lyapunov-Krasovskii functional (LKF) is constructed, introducing the delay-dependent matrices, more variable cross terms and the two-sided closed functional. Furthermore, two less conservative stability criteria are obtained according to the designed approach. Finally, two multi-area LFC systems are presented to verify the progressiveness of the proposed approach.

Discovery of Clinical Candidate NTQ1062 as a Potent and Bioavailable Akt Inhibitor for the Treatment of Human Tumors.

Akt has emerged as an exciting target in oncology due to its critical roles in proliferation, survival, metabolism, metastasis, and invasion in tumor cells. Herein, we describe the discovery and optimization of a series of ATP-competitive Akt inhibitors that possess new chemical scaffolds and exhibit potent enzymatic activities and improved in vivo pharmacokinetic profiles. Remarkably, NTQ1062 (compound 22b) exhibited potent antitumor efficacies in vitro and in vivo, which was accomplished through the optimization of the hinge binder region and the linkage. Subsequent studies of NTQ1062 demonstrated that it possesses good oral pharmacokinetic characteristics and dose-dependent pharmacodynamic effects on downstream biomarkers. In addition, NTQ1062 exhibits a robust antitumor efficacy in xenograft models in which the PI3K-Akt-mTOR pathway was activated. Based on its ideal druglike properties, NTQ1062 is currently being evaluated in a phase I clinical trial for the treatment of advanced solid tumors (CTR20211999).

Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease.

Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compounds, exemplified by inhibitor 14, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concentrations that exceed those required for DLK inhibition in the brain.

Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12).

Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor 11, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.

Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models.

Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications.