Exploring Cognitive Diversity and Dynamics for Effective Language Memory Retention

Spaced repetition, key for long-term memory retention through optimized review schedules based on predicted memory retention, is increasingly vital for effective language learning. Traditional methods, however, often fail to account for individual cognitive variations and material difficulty, resulting in a lack of high adaptability and effectiveness. To address this, our study introduces the Multidimensional Cognition Regression (MCR) model. MCR incorporates the Difficulty Engineering (DE) module, which integrates both objective and subjective factors to evaluate the intricacy of the content. Moreover, MCR further leverages a variety of user memory and cognitive characteristics, combined with psychological insights and machine learning techniques, to predict the memory ``half-life" of material. This approach transcends methods like Half-Life Regression proven effective on Duolingo, reducing prediction errors demonstrated by lower Mean Absolute Error. Based on the predictive modeling of memory's halflife and corresponding biological memory patterns, we opt to schedule reviews at the juncture when the memory decays to its halflife point. Empirical validation in real-world settings showed enhanced retention efficiency

Discovery of Ureido-Based Apcin Analogues as Cdc20-specific Inhibitors against Cancer

Cdc20 is a promising drug target that plays an important role in the mid-anaphase process of cellular mitosis, and Apcin is the only reported core structure of the Cdc20-specific inhibitor. Some potent Apcin derivatives were obtained in our previous research, and a structure–activity relationship was determined. In this study, we designed and synthesized a series of ureido-based Apcin derivatives. The proliferation-inhibition experiments on four cancer-cell lines showed that ureido skeleton could promote the anti-proliferation activity of purine-substituted compounds, whereas the ureido analogues with pyrimidine substitutes showed no significant improvement in the inhibitory effect compared with the original ones. Further tests confirmed that ureido-based compounds can enhance the binding affinity to Cdc20 by increasing the levels of Cdc20 downstream proteins. Compound 27 revealed a remarkably antitumor activity pattern against Hela (IC50 = 0.06 ± 0.02 μM) and potent binding affinity to Cdc20. Moreover, compound 20 induced caspase-dependent apoptosis and cell-cycle arrest at the G2/M phase, and compound 27 induced caspase-dependent apoptosis and promoted microtubule polymerization. Finally, a molecular-docking simulation was performed for compounds 20 and 27 to predict the potential ligand–protein interactions with the active sites of the Cdc20 proteins

Design, Synthesis and Anti-fibrosis Activity Study of N1-Substituted Phenylhydroquinolinone Derivatives

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A Novel PDK1/MEK Dual Inhibitor Induces Cytoprotective Autophagy via the PDK1/Akt Signaling Pathway in Non-Small Cell Lung Cancer

In a preliminary study, we synthesized a series of new PDK1/MEK dual inhibitors. Antitumor activity screening showed that Compound YZT exerts a strong inhibitory action in A549 cells. However, the specific mechanism of YZT against non-small cell lung cancer (NSCLC) is largely unknown. This work confirmed the anti-proliferation and pro-apoptosis effects of YZT in NSCLC cells. Furthermore, YZT promotes autophagy and provokes complete autophagic flux in NSCLC cells. Notably, compared with YZT alone, the combination of YZT with the autophagy inhibitor chloroquine (CQ) or 3-methyladenine (3-MA) markedly strengthened the anti-proliferative and pro-apoptotic actions, suggesting that YZT-induced autophagy is cytoprotective. We further found that YZT-induced autophagy may exert a cytoprotective function by preserving the integrity of mitochondria and decreasing mitochondrial apoptosis. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that PDK1 is an upstream protein of the Akt/mTOR axis and western blotting verified that YZT induces autophagy by the PDK1/Akt/mTOR signaling axis. Finally, YZT plus CQ significantly enhanced the anticancer activities compared to YZT alone in an animal study and immunohistochemistry showed that the level of LC3 was increased by YZT, which is in line with the in vitro results. In short, our study provides reliable experimental basis for developing Compound YZT as a new chemotherapeutic drug candidate and suggests that combined administration of YZT with CQ is a potential therapy against NSCLC

A Novel PDK1/MEK Dual Inhibitor Induces Cytoprotective Autophagy via the PDK1/Akt Signaling Pathway in Non-Small Cell Lung Cancer

In a preliminary study, we synthesized a series of new PDK1/MEK dual inhibitors. Antitumor activity screening showed that Compound YZT exerts a strong inhibitory action in A549 cells. However, the specific mechanism of YZT against non-small cell lung cancer (NSCLC) is largely unknown. This work confirmed the anti-proliferation and pro-apoptosis effects of YZT in NSCLC cells. Furthermore, YZT promotes autophagy and provokes complete autophagic flux in NSCLC cells. Notably, compared with YZT alone, the combination of YZT with the autophagy inhibitor chloroquine (CQ) or 3-methyladenine (3-MA) markedly strengthened the anti-proliferative and pro-apoptotic actions, suggesting that YZT-induced autophagy is cytoprotective. We further found that YZT-induced autophagy may exert a cytoprotective function by preserving the integrity of mitochondria and decreasing mitochondrial apoptosis. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that PDK1 is an upstream protein of the Akt/mTOR axis and western blotting verified that YZT induces autophagy by the PDK1/Akt/mTOR signaling axis. Finally, YZT plus CQ significantly enhanced the anticancer activities compared to YZT alone in an animal study and immunohistochemistry showed that the level of LC3 was increased by YZT, which is in line with the in vitro results. In short, our study provides reliable experimental basis for developing Compound YZT as a new chemotherapeutic drug candidate and suggests that combined administration of YZT with CQ is a potential therapy against NSCLC

A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G0/G1 phase and induces mitochondrial apoptosis in non-small cell lung cancer cells

Background A novel dual MEK/PDK1 inhibitor named 9za has been synthesized by our research team. Preliminary study showed that 9za possessed potent cytotoxicity and proapoptosis in non-small cell lung cancer (NSCLC) cells. Nevertheless, the precise underlying mechanism is vague. Methods In this work, we adopted the MTT assay, the Cell Cycle Detection Kit, and the JC-1 staining assay to detect the cell viability, the cell cycle distribution and the mitochondrial membrane potential (MMP), respectively. Cell apoptosis was measured by the morphology observation under a light microscope, Annexin V-FITC/propidium iodide (PI) apoptosis detection and the colorimetric TUNEL assay. Western blot was used to monitor the cell cycle-, apoptosis-related proteins and relevant proteins involved in the signaling pathways. Results The MTT assay demonstrated that 9za sharply decreased the viability of NSCLC cells. Cell cycle analysis revealed that low concentrations of 9za arrested the cell cycle at the G0/G1 phase , which was further confirmed by the decreased levels of Cyclin D1, cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6). Additionally, morphological observations, Annexin V-FITC/propidium iodide (PI) apoptosis analysis and TUNEL assays indicated that high concentrations of 9za induced cell apoptosis. Furthermore, the JC-1 staining assay revealed that the mitochondrial membrane potential was downregulated following 9za exposure. Western blot also showed that 9za markedly decreased the expression levels of total Bcl-2, Cytochrome C in the mitochondria and BCL2 associated X (BAX) in the cytoplasm. However, the levels of BAX in the mitochondria, Cytochrome C in the cytoplasm, active caspase-9, active caspase-3 and cleaved–PARP showed the opposite changes. Moreover, the dose-dependent decreased phosphorylation levels of PDK1, protein kinase B (Akt), MEK and extracellular signal regulated kinase 1/2 (ERK1/2) after 9za treatment verified that 9za was indeed a dual MEK/PDK1 inhibitor, as we expected. Compared with a single MEK inhibitor PD0325901 or a single PDK1 inhibitor BX517, the dual MEK/PDK1 inhibitor 9za could strengthen the cytotoxic and proapoptotic effect, indicating that the double blocking of the MEK and PDK1 signaling pathways plays stronger cell growth inhibition and apoptosis induction roles than the single blocking of the MEK or PDK1 signaling pathway in NSCLC cells. Our work elucidated the molecular mechanisms for 9za as a novel drug candidate against NSCLC

Design, Synthesis and Antifibrotic Activities of Carbohydrate- Modified 1-(Substituted aryl)-5-trifluoromethyl-2(1H) Pyridones

Pirfenidone, a pyridone compound, is an effective and novel antifibrotic agent. In this article, we describe the design, synthesis and activity evaluation of novel antifibrotic agents, 1-(substituted aryl)-5-trifluoromethyl-2(1H) pyridones modified with carbohydrate. Most of the title compounds exhibited comparable or better inhibitory activity than fluorofenidone. Notably, compound 19a demonstrated the highest cell-based inhibitory activity against NIH 3T3 (IC50 = 0.17 mM)