The metabolic changes in melanoma cells that are required for tumor metastasis have not been fully elucidated. In this study, we show that the increase in glucose uptake and mitochondrial oxidative ...phosphorylation confers metastatic ability as a result of aryl hydrocarbon receptor nuclear translocator (ARNT) deficiency. In clinical tissue specimens, increased ARNT, pyruvate dehydrogenase kinase 1 (PDK1), and NAD(P)H quinine oxidoreductase-1 (NQO1) was observed in benign nevi, whereas lower expression was observed in melanoma. The depletion of ARNT dramatically repressed PDK1 and NQO1 expression, which resulted in an increase of ROS levels. The elimination of ROS using N-acetylcysteine (NAC) and inhibition of oxidative phosphorylation using carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and rotenone inhibited the ARNT and PDK1 deficiency-induced cell migration and invasion. In addition, ARNT deficiency in tumor cells manipulated the glycolytic pathway through enhancement of the glucose uptake rate, which reduced glucose dependence. Intriguingly, CCCP and NAC dramatically inhibited ARNT and PDK1 deficiency-induced tumor cell extravasation in mouse models. Our work demonstrates that downregulation of ARNT and PDK1 expression serves as a prognosticator, which confers metastatic potential as the metastasizing cells depend on metabolic changes.
Presenilin proteins (PS1 and PS2) represent the catalytic subunit of γ-secretase and play a critical role in the generation of the amyloid β (Aβ) peptide and the pathogenesis of Alzheimer disease ...(AD). However, PS proteins also exert multiple functions beyond Aβ generation. In this study, we examine the individual roles of PS1 and PS2 in cellular cholesterol metabolism. Deletion of PS1 or PS2 in mouse models led to cholesterol accumulation in cerebral neurons. Cholesterol accumulation was also observed in the lysosomes of embryonic fibroblasts from Psen1-knockout (PS1-KO) and
(PS2-KO) mice and was associated with decreased expression of the Niemann-Pick type C1 (NPC1) protein involved in intracellular cholesterol transport in late endosomal/lysosomal compartments. Mass spectrometry and complementary biochemical analyses also revealed abnormal N-glycosylation of NPC1 and several other membrane proteins in PS1-KO and PS2-KO cells. Interestingly, pharmacological inhibition of N-glycosylation resulted in intracellular cholesterol accumulation prominently in lysosomes and decreased NPC1, thereby resembling the changes in PS1-KO and PS2-KO cells. In turn, treatment of PS1-KO and PS2-KO mouse embryonic fibroblasts (MEFs) with the chaperone inducer arimoclomol partially normalized NPC1 expression and rescued lysosomal cholesterol accumulation. Additionally, the intracellular cholesterol accumulation in PS1-KO and PS2-KO MEFs was prevented by overexpression of NPC1. Collectively, these data indicate that a loss of PS function results in impaired protein N-glycosylation, which eventually causes decreased expression of NPC1 and intracellular cholesterol accumulation. This mechanism could contribute to the neurodegeneration observed in PS KO mice and potentially to the pathogenesis of AD.
Non-thermal atmospheric plasma (NTP) has shown its selective anticancer effects in many types of tumors in vitro and one of the main mechanisms is that the different increase of intracellular ROS in ...cancer and homologous normal cells. In this study, we report that NTP treatment reduces the proliferation in triple negative breast cancer (TNBC) and normal cell lines. Simultaneously, STAT3 pathway is inhibited by NTP effects. However, it is observed that normal cells MCF10A are more sensitive to ROS toxicity induced by NTP than cancer cells MDA-MB-231. When 5 mM of ROS inhibitor N-acetyl cysteine (NAC) is employed in NTP treatments, the proliferation of normal breast cells MCF10A recovers. Meanwhile, NTP effects remain significant inhibition of MDA-MB-231 cells. Our results further reveal that NTP can induce apoptosis in MDA-MB-231 cells through inhibiting interleukin-6 receptor (IL-6R) pathway. Moreover, the mechanism of NTP anti-cancer selectivity relates to constantly HER2/Akt activation induced by NTP especially in MCF10A cells but not in MDA-MB-231 cells. Therefore, these two different cell signaling pathways induced by NTP treatments in TNBC and homologous normal cells make NTP becoming a potential tool in future therapy.
The purpose of this study was to investigate the longitudinal effects of perinatal exposure to dioxin on physical growth in a 3-year follow-up study. In 2015, 27 mother–infant pairs living in an ...electronic waste (e-waste) dismantling region and 35 pairs living in a control region were enrolled in the present study. Breast milk samples were collected at 4 weeks after birth. Physical growth, including weight, height, and head and chest circumferences, was measured at 6 months and 3 years of age. Dioxin levels in the breast milk were measured by gas chromatography/high-resolution mass spectrometry. Levels of 2,3,7,8-tetrachlorodibenzo-
p
-dioxin and toxic equivalency values in maternal breast milk of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCDDs/PCDFs were significantly higher in women residing in the e-waste dismantling region. In 3-year-old boys, inverse associations were found between height and PCDDs-TEQ. In girls, positive associations were found between height and 2,3,7,8-TetraCDD, PCDDs-TEQ, and PCDDs/PCDFs-TEQ, and for weight and PCDDs-TEQ and PCDDs/PCDFs-TEQ at 3 years of age. In this study, sex-specific differences were observed in children, in whom dioxin exposure decreased growth in boys but increased growth in girls during the first 3 years of life.
REPRESSOR OF SILENCING 1 (ROS1) is a DNA demethylation enzyme that was previously identified during a genetic screen for the silencing of both RD29A-LUC and 35S-NPTII transgenes on a T-DNA construct. ...Here we performed a genetic screen to identify additional mutants in which the 35S-NPTII transgene is silenced. We identified several alleles of ros1 and of the following components of the RNA-directed DNA methylation (RdDM) pathway: NRPD1 (the largest subunit of polymerase IV), RDR2, NRPE1 (the largest subunit of polymerase V), NRPD2, AGO4, and DMS3. Our results show that the silencing of 35S-NPTII in the RdDM pathway mutants is due to the reduced expression of ROS1 in the mutants. We also identified a putative histone acetyltransferase (ROS4) from the genetic screen. The acetyltransferase contains a PHD-finger domain that binds to unmethylated histone H3K4. The mutation in ROS4 led to reduction of H3K18 and H3K23 acetylation levels. We show that the silencing of 35S-NPTII and some transposable element genes was released by the ddm1 mutation but that this also required ROS4. Our study identifies a unique antisilencing factor, and reveals that the RdDM pathway has an antisilencing function due to its role in maintaining ROS1 expression.
The effects of temperature on the filtration efficiency and pressure drop of a dual‐layer granular bed filter were investigated in a hot dual‐layer granular bed filter with experimental dust. ...Enhanced higher filtration efficiency was obtained with higher filtration temperature, and the removal efficiency of ultrafine dust was also at a high level. Simultaneously, the total pressure drop maintained at an acceptable range. The results demonstrate that the dual‐layer granular bed has excellent prospects for application to low‐temperature coal pyrolysis.
The impact of temperature on the filtration efficiency and pressure drop of a dual‐layer granular bed filter in a hot dual‐layer granular bed filter with experimental dust was evaluated. Higher filtration temperatures improved the filtration efficiency and the removal efficiency of ultrafine dust. The dual‐layer granular bed has excellent potential for application to low‐temperature coal pyrolysis.
Introducing a coating shell between the filler and matrix is an effective way to reduce the dielectric loss of the particle/matrix dielectric composites. It found that besides the improvement in ...interface compatibility, there may be some other effects of the coating shell, such as the elimination of the dielectric mismatch. However, the specific mechanism is still unclear due to the absence of an effective model for the quantitative analysis of the relationship between core–shell structure and dielectric loss, hindering the progress of the dielectric composite design. Here, a phase-field model for simulating high-frequency, alternating-field polarization is employed to study the relationship between high-frequency polarization loss and the coating shell in the silicon dioxide coating boron nitride polytetrafluoroethylene-based (BN@SiO2/PTFE) composite. The results show that the dielectric mismatch makes the high-frequency polarization loss spatially localized and periodically time-variant. The reduction of polarization loss depends on the polarization loss of SiO2. To reduce the high-frequency dielectric loss of the composite, the coating shell should not only eliminate the dielectric mismatch, but its dielectric loss must also be lower than that of the core filler. Furthermore, the model provided in this work has the potential to extend the quantitative calculation of non-intrinsic polarization loss and conduction loss.
WeChat is one of the most popular social media mobile apps in China. WeChat was introduced to the course of Introduction to Human Health and Disease, as an instant interactive platform to enhance ...students' learning. Over a period of two years, a WeChat official account (OA) was set up and 157 push notifications were sent per semester. The push notifications included course notices, pre-class thought questions, after-class study materials, simulation exercises, teacher-student interactions, feedback and questions, and research progress relevant to the course. WeChat OA served as an active-learning teaching tool, accelerated further advancement of instant feedback and improvement in teaching activities, improved student-centered communication, and resulted in a high degree of student satisfaction.
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