WDR45 mutation dysregulates iron homeostasis by promoting the chaperone-mediated autophagic degradation of ferritin heavy chain in an ER stress/p38 dependent mechanism.

Ferritin is the main iron storage protein that plays a pivotal role in the regulation of iron homeostasis. Mutations in the autophagy protein WD repeat domain 45 (WDR45) that lead to iron overload is associated with the human ß-propeller protein-associated neurodegeneration (BPAN). Previous studies have demonstrated that ferritin was decreased in WDR45 deficient cells, but the mechanism remains unclear. In this study, we have demonstrated that the ferritin heavy chain (FTH) could be degraded via chaperone-mediated autophagy (CMA) in ER stress/p38-dependent pathway. In HeLa cells, inducing the ER stress activated CMA, therefore facilitated the degradation of FTH, and increased the content of Fe2+. However, the increased CMA activity and Fe2+ as well as the decreased FTH by ER stress inducer were restored by pre-treatment with p38 inhibitor. Overexpression of a mutant WDR45 activated CMA thus promoted the degradation of FTH. Furthermore, inhibition of ER stress/p38 pathway resulted in reduced activity of CMA, which consequently elevated the protein level of FTH but reduced the Fe2+ level. Our results revealed that WDR45 mutation dysregulates iron homeostasis by activating CMA, and promotes FTH degradation through ER stress/p38 signaling pathway.

Island development suitability evaluation for supporting the spatial planning in archipelagic areas.

The study of island development suitability can provide important reference for island ecosystem-based management and sustainable development, as well as technical foundation for land development suitability evaluation and spatial planning in other areas. In this study, two typical China's archipelagos, namely, Miaodao Archipelago and Dongtou Archipelago, were selected to demonstrate the study. The carrying capacities of the three major development types, that is, ecological conservation, agricultural production, and urban construction, served as basic data; the controlling factors of island development suitability were identified in aspects of terrain, sea, and soil, and their influences on the three development types were separately measured in the two archipelagos and on different types of islands; and the island development suitability index (IDSI) was established for each of the three development types. Then, four schemes, namely, Schemes A-D, were designed based on the IDSIs and for purposes of free development, ecological conservation, agricultural production, and coordinated development, respectively, to conduct the island functional zoning, and the optimum scheme was finally selected. The results indicated that the influence natures and degrees of controlling factors showed distinct spatial heterogeneities across different archipelagos and across different types of islands within the same archipelago. Area proportions of the planned zones varied in different schemes for different purposes, and the optimum scheme was generated by assigning Schemes A, B, C, and D to the reclamation areas within the islands, the uninhabited islands, the sandy island, and the remaining islands, respectively. The present study validated two hypotheses: First, the factual influences of controlling factors on the land development suitability varied across different areas and might not be in accordance with the empirical cognitions. Second, the method of multiple schemes for different development purposes could contribute to solving the problem of disconnection of land development suitability with spatial planning.

Predictable Resistance and Overall Survival of Gemcitabine/Cisplatin by Platelet Activation Index in Non-Small Cell Lung Cancer.

BACKGROUND Gemcitabine/cisplatin (GP) resistance displays a negative role in treating advanced and metastatic non-small cell lung cancer (NSCLC). Several studies found that the association existed between platelets and cancer antigen 125 (CA125) with anticancer drugs. But the exact correlation between GP resistance and platelet activation index remains poorly understood. MATERIAL AND METHODS Pre-chemotherapy platelet activation index and CA125 were retrospectively evaluated in 169 advanced and metastatic NSCLC patients. All variables were screened by chi-square test and then evaluated by log-rank test. Survival curves were generated by Kaplan-Meier analysis. Univariate and multivariate survival analysis were performed by using Cox proportional hazards model. RESULTS The overall rate of GP resistance for NSCLC patients was 72.19%. Mean platelet volume (MPV) and plateletcrit (PCT) are negative predictors of GP resistance adenocarcinoma [Odds ratio (OR): 5.81, 95% confidence interval (CI): 1.082-31.195, P=0.004] and squamous cell carcinoma (PCT: R: 3.517, 95% CI: 1.087-11.387, P=0.036), respectively. But both were an independent factor associated with overall survival (OS). Moreover, only CA125 was a dependent factor associated with OS for squamous cell carcinoma [OS: hazard ratio (HR): 1.741, 95% CI: 1.002-3.024, P=0.049; GP resistance: OR: 4.862, 95% CI: 1.437-16.448, P=0.011]. CONCLUSIONS Platelet activation index will be a potential marker for predicting GP resistance. Besides, CA125 ≥16.9 could be used as a potential marker for predicting GP resistance and OS, which was more sensitive than CA125 ≥35 for squamous cell carcinoma.