Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, is highly expressed in the brain, but its function in the adult brain remains not well understood. In this study, we identify NLK as an interactor of huntingtin protein (HTT). We report that NLK levels are significantly decreased in HD human brain and HD models. Importantly, overexpression of NLK in the striatum attenuates brain atrophy, preserves striatal DARPP32 levels and reduces mutant HTT (mHTT) aggregation in HD mice. In contrast, genetic reduction of NLK exacerbates brain atrophy and loss of DARPP32 in HD mice. Moreover, we demonstrate that NLK lowers mHTT levels in a kinase activity-dependent manner, while having no significant effect on normal HTT protein levels in mouse striatal cells, human cells and HD mouse models. The NLK-mediated lowering of mHTT is associated with enhanced phosphorylation of mHTT. Phosphorylation defective mutation of serine at amino acid 120 (S120) abolishes the mHTT-lowering effect of NLK, suggesting that S120 phosphorylation is an important step in the NLK-mediated lowering of mHTT. A further mechanistic study suggests that NLK promotes mHTT ubiquitination and degradation via the proteasome pathway. Taken together, our results indicate a protective role of NLK in HD and reveal a new molecular target to reduce mHTT levels.
Background Triglyceride and glucose (TyG) index, triglyceride glucose-body mass (TyG-BMI) index, triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, and metabolic score for insulin resistance (METS-IR) are considered simple and reliable indicators of insulin resistance (IR). Although they have been associated with coronary artery disease (CAD), evidence supporting this is limited. Here, this is the first study to demonstrate the relationship between TyG-BMI index and CAD severity. The performance of the four non-insulin-based IR indexes in predicting CAD severity was explored. Methods We retrospectively analyzed 485 CAD patients between August 2020 and August 2021 in China, who were assigned into single- and multi-vessel CAD groups according to the coronary angiography (CAG) results. All patients were stratified into groups based on the tertiles of the TyG index, TyG-BMI index, TG/HDL-C ratio, and METS-IR. Results Patients in the multi-vessel CAD group had significantly higher TyG index, TyG-BMI index, TG/HDL-C ratio and METS-IR than those in the single-vessel CAD group. After adjusting for confounding factors, these four indicators were significantly associated with the risk of multi-vessel CAD. Notably, the highest tertile of TyG index, TyG-BMI index, TG/HDL-C ratio and METS-IR were significantly associated with the risk of multi-vessel CAD compared to participants in the lowest tertile. We also constructed receiver operating characteristic (ROC) curve, to assess CAD severity. The area under the curve (AUC) of the ROC plots was 0.673 (95% CI 0.620–0.726; P < 0.001) for TyG index, while those for the TyG-BMI index, TG/HDL-C ratio, and METS-IR were 0.704 (95% CI 0.652–0.755; P < 0.001), 0.652 (95% CI 0.597–0.708; P < 0.001), and 0.726 (95% CI 0.677–0.775; P < 0.001), respectively. Conclusions TyG-BMI index is not only significantly associated with CAD severity, but is also an independent risk factor for multi-vessel CAD. The TyG index, TyG-BMI index, TG/HDL-C ratio, and METS-IR could be valuable predictors of CAD severity. Among the four non-insulin-based IR indexes, METS-IR had the highest predictive value, followed by TyG-BMI index.
Architectural heritages, especially heritages of tourism, were destroyed in the process of urban reconstruction of China because of lacking protection from stakeholders. Therefore, there is an urgent need to identify the critical stakeholders to perform the responsibility of protection. The paper, focusing on architectural heritage of tourism, aims to identify the most important stakeholders for making them realize their critical roles in maintaining architectural heritages. Moreover, this paper also aims to evaluate the enthusiasm of stakeholders. As a result, the stakeholders with high importance and enthusiasm would be the critical stakeholders in maintaining architectural heritages. Thirteen stakeholders were selected through comprehensive literature review and the reality of China. A questionnaire survey was conducted with the qualified respondents in Mainland China. A five-point Likert scale and other statistical methods were used for achieving the results of evaluation. The findings demonstrated local government, central government, real estate development enterprise, expert groups, administration of architectural heritage protection, and construction company of architectural heritage are considered as the critical stakeholders for the sustainable development (SD) of architectural heritage of tourism. Finally, some helpful implications were introduced for improving the efficiency of participation and cooperation among all stakeholders.
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