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Macroautophagy/autophagy is a catabolic process crucial for degrading cytosolic components and damaged organelles to maintain cellular homeostasis, enabling cells to survive in extreme extracellular environments. ENAH/MENA, a member of the Ena/VASP protein family, functions as a highly efficient actin elongation factor. In this study, our objective was to explore the role of ENAH in the autophagy process. Initially, we demonstrated that depleting ENAH in cancer cells inhibits autophagosome formation. Subsequently, we observed ENAH's colocalization with MAP1LC3/LC3 during tumor cell starvation, dependent on actin cytoskeleton polymerization and the interaction between ENAH and BECN1 (beclin 1). Additionally, mammalian ATG9A formed a ring-like structure around ENAH-LC3 puncta during starvation, relying on actin cytoskeleton polymerization. Furthermore, ENAH's EVH1 and EVH2 domains were found to be indispensable for its colocalization with LC3 and BECN1, while the PRD domain played a crucial role in the formation of the ATG9A ring. Finally, our study revealed ENAH-led actin comet tails in autophagosome trafficking. In conclusion, our findings provide initial insights into the regulatory role of the mammalian actin elongation factor ENAH in autophagy. Abbreviations: 3-MA 3-methyladenine; ABPs actin-binding proteins; ATG autophagy related; ATG9A autophagy related 9A; Baf A1 bafilomycin A1; CM complete medium; CytERM endoplasmic reticulum signal-anchor membrane protein; Cyto D cytochalasin D; EBSS Earl's balanced salt solution; ENAH/MENA ENAH actin regulator; EVH1 Ena/VASP homology 1 domain; EVH2 Ena/VASP homology 2 domain; GAPDH glyceraldehyde-3-phosphate dehydrogenase; Lat B latrunculin B; LC3-I unlipidated form of LC3; LC3-II phosphatidylethanolamine-conjugated form of LC3; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; mEGFP monomeric enhanced green fluorescent protein; mTagBFP2 monomeric Tag blue fluorescent protein 2; OSER organized smooth endoplasmic reticulum; PRD proline-rich domain; PtdIns3K class III phosphatidylinositol 3-kinase; WM wortmannin. [ABSTRACT FROM AUTHOR]

The optimal serum magnesium level of patients undergoing hemodialysis (HD) with cognitive impairment is still unclear. This study aimed to evaluate the association between serum magnesium levels and mild cognitive impairment among HD patients. This was a multicenter observational study. Patients undergoing hemodialysis from 22 dialysis centers in Guizhou Province, China were recruited into the study. HD patients were divided into five groups according to serum magnesium quintile. Cognitive function was measured with Mini Mental State Examination. The outcome was an incident mild cognitive impairment (MCI). Multivariate logistic regression analysis, restricted cubic spline and subgroup analysis were applied to explore the association of serum magnesium level with MCI. Among 3562 HD patients (mean age 54.3 years, 60.1% male), the prevalence of MCI was 27.2%. After adjusting for confounders, serum magnesium 0.41–0.83 mmol/L [odds ratios (OR) 1.55, 95% confidence interval (CI): 1.10–2.18] had a higher risk of MCI compared with serum magnesium of 1.19–1.45 mmol/L. A U-shaped association was identified between the serum magnesium and incident MCI (P for non-linearity = 0.004). The optimal range of magnesium level with the lowest risk of MCI was 1.12–1.24 mmol/L. As the serum magnesium level was lower than 1.12 mmol/L, the risk of MCI decreased by 24% per standard deviation (SD) increase in serum magnesium (OR 0.76, 95%CI: 0.62–0.93); when the serum magnesium level exceeds 1.24 mmol/L, a rise per SD increased the risk of MCI by 21% (OR = 1.20, 95%CI: 1.02–1.43). Subgroup analyses demonstrated that the associations were robust among individuals with low educational level, smoking, living alone, no working, and without hypertension or diabetes. Serum magnesium has a U-shaped association with MCI among HD patients. Both lower and higher serum magnesium can increase the risk of MCI for this population specifically. The optimal serum magnesium range with the lowest risk of MCI was 1.12–1.24 mmol/L. [ABSTRACT FROM AUTHOR]

The filling characteristic of rockfill is a non-ignorable engineering problem for high dams, and a reasonable control of compaction quality is the key to promoting the development of high dams. In this article, numerical and field tests were implemented to study the main problems affecting the compaction characteristics of large-size coarse-grained soil, namely determinations of the reasonable H0/dmax (the ratio of the compaction layer thickness to the maximum particle size) and the main influencing factors of minimum porosity. The macroscopic manifestations of the compaction characteristics were analyzed from the perspectives of energy, force chain, and particle breakage. The interaction between particles was explained by the 'filling effect' of fine particles, the 'wedging effect', and the 'wall effect' of coarse particles. It was found that the minimum porosity was not an inherent characteristic of rockfill, since the porosity and the corresponding degree of breakage were influenced by the compaction conditions. The value of H0/dmax meeting engineering practice was proposed, which can create favorable compaction conditions for obtaining the minimum porosity. Meantime, some suggestions were provided for obtaining the minimum porosity of large-size coarse-grained soil. The research results have an application reference value for the filling design and evaluation of high dams. [ABSTRACT FROM AUTHOR]

SmCo7-based permanent magnets with a TbCu7-type structure have excellent high-temperature performance. However, most of the previously reported SmCo7 nanocrystalline magnets were isotropic, which limited their application. So the preparation of anisotropic SmCo7 magnets with preferred texture is still a challenge. In this work, we prepared anisotropic SmCo6.8Hf0.2 nanocrystalline magnets by hot pressing and hot deformation method. EBSD results indicated that the {0001} orientation texture of the hot deformed magnet was remarkably preferred, which further improved the remanence. Subsequently, the structural evolution process was systematically characterized by TEM. It provides crucial insight for developing high-performance SmCo7-based magnets. Impact Statement: Up to now, most of the previously reported SmCo7 nanocrystalline magnets were isotropic, which limited their application. This work opens up new opportunities to create high-performance SmCo7-based nanostructured magnets. [ABSTRACT FROM AUTHOR]

Peritoneal dialysis (PD) patients have a high incidence of poor clinical outcomes, which is related to the inflammatory and nutritional status of this population. Platelet-to-albumin ratio (PAR), recently identified as a useful biomarker to monitor inflammation and nutrition, can predict a poor prognosis in various diseases. The aim of this study was to investigate the association between PAR and technique failure and mortality in PD patients. This single-center retrospective study enrolled 405 PD patients from 1 January 2011 to 31 December 2019 and collected complete demographic characteristics, clinical laboratory baseline data. The outcomes were technique failure and mortality. The associations between PAR and technique failure, death were analyzed by Cox proportional hazard models and competing risk regression models with kidney transplantation as a competing event. The areas under the curve (AUC) of receiver-operating characteristic analysis were used to determine the predictive values of PAR for technique failure and mortality. During a median follow-up period of 24.0 (range, 4.0–91.0) months, 139 (34.3%) PD patients experienced technique failure, 61 (15.1%) PD patients died. The patients with higher PAR levels had increased risk of technique failure and mortality. After adjustment for confounding factors, we found that high PAR levels were risk factor for both technique failure (subdistribution hazard ratio [SHR] 1.775; 95%CI, 1.157–2.720; p = 0.033] and mortality [SHR 3.710; 95%CI, 1.870–7.360; p < 0.001]. The predictive ability of PAR was superior to platelet and albumin based on AUC calculations for technique failure and mortality. PAR was a risk factor associated with technique failure and mortality in PD patients. [ABSTRACT FROM AUTHOR]

Deformable nanovesicles (DNVs) have been used in the buccal delivery of biomacromolecules due to their ability to enhance drug penetration. However, no breakthroughs have been made until now due to limited understanding of the factors affecting in vivo buccal delivery. In this study, we designed a series of DNVs, based on an insulin–phospholipid complex (IPC-DNVs), to investigate the influence of drug dose, buccal administration methods, and key quality characteristics of IPC-DNVs for buccal delivery. IPC-DNVs showed a non-linear dose–response relationship between 8 and 12 IU. There was no significant effect of drug delivery site (sublingual mucosa/buccal mucosa) or ligation time (15 or 30 min) on buccal absorption of IPC-DNVs. However, the area above the curve of reduction in blood glucose level overtime (AAC0–6h) for oral mucosa administration was significantly higher than that for buccal mucosa administration. Increasing the drug concentration in IPC-DNVs led to a decrease in AAC0–6h. This might be due to local leakage of DNVs, while squeezing through biological barriers with high concentration of insulin, thus hindering the subsequent delivery of DNVs. IPC-DNVs, measuring 80–220 nm in size, did not significantly affect AAC0–6h. However, when the size was increased to approximately 400 nm, AAC0–6h decreased, thus suggesting that IPC-DNVs with reasonable size were more effective. Additionally, increased deformability of IPC-DNVs might cause drugs to leak easily, thus reducing the promoting effect of buccal absorption. Our results clarified the effect of characteristics of IPC-DNVs on buccal delivery in vivo and provided meaningful support for the design of dosage form of DNVs. [ABSTRACT FROM AUTHOR]

Melanoma is among the most life-threatening cancers. The pathogenesis of melanoma has not been fully elucidated. Recently, dysregulated macroautophagy/autophagy has been found to play a critical but inconsistent role in modulating melanoma growth at different stages, with the regulatory mechanism unclear. The histone deacetylase SIRT6 (sirtuin 6) is a known autophagy regulator, and its involvement in cancer development has been reported. Therefore, we sought to determine the role of SIRT6 in melanoma growth and detect its possible link with autophagy in the current study. We initially observed that the expression of SIRT6 decreased in primary melanoma but increased in metastatic melanoma compared with melanocytic nevus. Notably, the expression of SIRT6 was significantly correlated with the expression of autophagy biomarkers including MAP1LC3/LC3 and SQSTM1/p62. Furthermore, SIRT6 suppressed the growth of primary melanoma but promoted metastatic melanoma development in an autophagy-dependent way in vitro. Moreover, SIRT6 exerted its regulation on melanoma growth via the IGF-AKT signaling pathway, and the intervention of AKT could partly reverse the effects of SIRT6 on melanoma growth by regulating autophagy. At last, we determined the effects of SIRT6 on melanoma development in vivo. Taken together, our findings demonstrate that the bimodal expression of SIRT6 at different melanoma stages plays a critical role in regulating melanoma growth through an autophagy-dependent manner, which indicates the potential of SIRT6 to be a biomarker and a therapeutic target in melanoma. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusionsOur research aimed to investigate the therapeutic effects of Tubastatin-A, a glucocorticoid receptor (GR) mitochondrial translocation inhibitor, and mitoquinone (MitoQ), an antioxidant, on attenuating dexamethasone (DEX)-induced macrophage apoptosis.We treated RAW264.7 macrophages with different combinations of DEX and either Tubastatin-A or MitoQ. Parameters such as mitochondrial GR translocation, mitochondrial reactive oxygen species levels, mitochondrial membrane potential, mitochondrial permeability transition pore opening, cytochrome C efflux to the cytosol, and apoptosis were subsequently evaluated in the different treatment groups via qRT–PCR, western blotting, and immunofluorescence assays.DEX intervention increased the translocation of GRs into the mitochondria, while reducing the expression of the mitochondrial gene MT-CO1 and the activity of mitochondrial respiratory chain complex IV in macrophages. In addition, DEX administration increased mtROS levels, mitochondrial permeability transition pore opening, and mitochondrial cytochrome C release in macrophages, which promoted their apoptosis. We found that Tubastatin-A inhibited mitochondrial GR translocation and reversed the DEX-induced increase in GR levels within the mitochondria. Furthermore, Tubastatin-A mitigated various mitochondrial changes induced by DEX, including reducing the efflux of mitochondrial cytochrome C and inhibiting macrophage apoptosis. Similarly, MitoQ exerted its effects on macrophage apoptosis by reducing mtROS levels through the mitochondrial pathway.The DEX-mediated translocation of GR into mitochondria disrupts the mitochondrial function of macrophages, which induces their apoptosis. By inhibiting mitochondrial translocation of GR and reducing mtROS levels, Tubastatin-A and MitoQ can effectively attenuate macrophage apoptosis, which has clinical implications for reducing the notable side effects associated with glucocorticoid use. [ABSTRACT FROM AUTHOR]