Improvement of PbSn Solder Reliability with Ge Microalloying-Induced Optimization of Intermetallic Compounds Growth.

PbSn solders are used in semiconductor devices for aerospace or military purposes with high levels of reliability requirements. Microalloying has been widely adopted to improve the reliability for Pb-free solders, but its application in PbSn solders is scarce. In this article, the optimization of PbSn solder reliability with Ge microalloying was investigated using both experimental and calculation methods. Intermetallic compounds (IMC) growth and morphologies evolution during reliability tests were considered to be the main factors of device failure. Through first-principle calculation, the growth mechanism of interfacial Ni3Sn4 was discussed, including the formation of vacancies, the Ni-vacancies exchange diffusion and the dominant Ni diffusion along the [1 0 0] direction. The doping of Ge in the cell increased the exchange energy barrier and thus inhibited the IMC development and coarsening trend. In three reliability tests, only 0.013 wt% Ge microalloying in Pb60Sn40 was able to reduce IMC thickness by an increment of 22.6~38.7%. The proposed Ge microalloying method in traditional PbSn solder could yield a prospective candidate for highly reliable applications.

A cholesterol-binding bacterial toxin provides a strategy for identifying a specific Scap inhibitor that blocks lipid synthesis in animal cells.

Lipid synthesis is regulated by the actions of Scap, a polytopic membrane protein that binds cholesterol in membranes of the endoplasmic reticulum (ER). When ER cholesterol levels are low, Scap activates SREBPs, transcription factors that upregulate genes for synthesis of cholesterol, fatty acids, and triglycerides. When ER cholesterol levels rise, the sterol binds to Scap, triggering conformational changes that prevent activation of SREBPs and halting synthesis of lipids. To achieve a molecular understanding of how cholesterol regulates the Scap/SREBP machine and to identify therapeutics for dysregulated lipid metabolism, cholesterol-mimetic compounds that specifically bind and inhibit Scap are needed. To accomplish this goal, we focused on Anthrolysin O (ALO), a pore-forming bacterial toxin that binds cholesterol with a specificity and sensitivity that is uncannily similar to Scap. We reasoned that a small molecule that would bind and inhibit ALO might also inhibit Scap. High-throughput screening of a ~300,000-compound library for ALO-binding unearthed one molecule, termed UT-59, which binds to Scap's cholesterol-binding site. Upon binding, UT-59 triggers the same conformation changes in Scap as those induced by cholesterol and blocks activation of SREBPs and lipogenesis in cultured cells. UT-59 also inhibits SREBP activation in the mouse liver. Unlike five previously reported inhibitors of SREBP activation, UT-59 is the only one that acts specifically by binding to Scap's cholesterol-binding site. Our approach to identify specific Scap inhibitors such as UT-59 holds great promise in developing therapeutic leads for human diseases stemming from elevated SREBP activation, such as fatty liver and certain cancers.

Construction and application of artificial lipoproteins using adiposomes.

Lipoproteins are complex particles comprised of a neutral lipid core wrapped with a phospholipid monolayer membrane and apolipoproteins on the membrane, which is closely associated with metabolic diseases. To facilitate the elucidation of its formation and dynamics, as well as its applications, we developed an in vitro system in which adiposomes, consisting of a hydrophobic core encircled by a monolayer-phospholipid membrane, were engineered into artificial lipoproteins (ALPs) by recruiting one or more kinds of apolipoproteins, for example, apolipoprotein (Apo) A-I, ApoE, ApoA-IV, and ApoB. In vitro and in vivo studies demonstrated the stability and biological activity of ALPs derived from adiposomes, which resembles native lipoproteins. Of note, adiposomes bearing ApoE were internalized via clathrin-mediated endocytosis following LDLR binding and were delivered to lysosomes. On the other hand, adiposomes bearing ApoA-IV mimicked the existing form of endogenous ApoA-IV and exhibited significant improvement in glucose tolerance in mice. In addition, the construction process was simple, precise, reproducible, as well as easy to adjust for mass production. With this experimental system, different apolipoproteins can be recruited to build ALPs for some biological goals and potential applications in biomedicine.

Physalin A alleviates intervertebral disc degeneration via anti-inflammatory and anti-fibrotic effects.

Background: The incidence of intervertebral disc degeneration (IVDD) is a common degenerative disease with inflammation, decreased autophagy, and progression of fibrosis as its possible pathogenesis. Physalin A (PA) is a widely studied anti-inflammatory drug. However, its therapeutic effects on IVDD remain unexplored. Therefore, we aimed to explore the therapeutic potential of PA in IVDD progression. Materials and methods: In vivo, we investigated PA bioactivity using a puncture-induced IVDD rat model. IVDD signals and height changes were detected using X-ray, micro-CT, and MRI, and structural and molecular lesions using histological staining and immunohistochemistry of intervertebral disc sections. In vivo, interleukin-1 beta (IL-1ß) and TGF-ß1 were employed to establish inflammation fibrotic nucleus pulposus (NP) cells. The PA effect duration, concentration, influence pathways, and pathological changes in IVDD treatment were elucidated using western blotting, real-time PCR, and immunofluorescence. Results: PA exerted significant effects on IVDD remission due to anti-inflammation, fibrosis reduction, and autophagy enhancement. In vitro, PA improved inflammation by blocking the NF-κB and MAPK pathways, whereas it promoted autophagy via the PI3K/AKT/mTOR pathway and affected fibrotic progression by regulating the SMAD2/3 pathway. Moreover, PA improved the disc degeneration process in IVDD model. Conclusions: PA exhibited significant anti-inflammatory and anti-fibrotic effects and improved autophagy in vivo and in vitro IVDD models, thus effectively relieving IVDD progression, indicating it is a promising agent for IVDD treatment. The translational potential of this article: This study successfully reveals that PA, a natural bioactive withanolide, effectively relieved IVDD progression via inflammation inhibition, fibrosis reduction, and autophagy enhancement, indicating it is a promising agent for IVDD treatment.

Mulberroside A alleviates osteoarthritis via restoring impaired autophagy and suppressing MAPK/NF-κB/PI3K-AKT-mTOR signaling pathways.

Osteoarthritis (OA) is a trauma-/age-related degenerative disease characterized by chronic inflammation as one of its pathogenic mechanisms. Mulberroside A (MA), a natural bioactive withanolide, demonstrates anti-inflammatory properties in various diseases; however, little is known about the effect of MA on OA. We aim to examine the role of MA on OA and to identify the potential mechanisms through which it protects articular cartilage. In vitro, MA improved inflammatory response, anabolism, and catabolism in IL-1ß-induced OA chondrocytes. The chondroprotective effects of MA were attributed to suppressing the MAPK, NF-κB, and PI3K-AKT-mTOR signaling pathways, as well as promoting the autophagy process. In vivo, intra-articular injection of MA reduced the cartilage destruction and reversed the change of anabolic and catabolic-related proteins in destabilized medial meniscus (DMM)-induced OA models. Thus, the study indicates that MA exhibits a chondroprotective effect and might be a promising agent for OA treatment.

Inhibition of FAAH suppresses RANKL-induced osteoclastogenesis and attenuates ovariectomy-induced bone loss partially through repressing the IL17 pathway.

Fatty amide hydrolase (FAAH) is a key degradation enzyme of the endocannabinoid system, mainly responsible for the hydrolysis of arachidonic acid ethanolamine (AEA). Previous investigations have shown that FAAH is involved in a series of biological processes, such as inflammation, immune regulation, and transmembrane signal transduction of neurons. Endogenous cannabinoids and cannabinoid receptors have been reported to participate in the regulation of bone homeostasis by regulating the differentiation of osteoblasts and osteoclasts. We hypothesized that FAAH may play an important role in osteoclastogenesis based on the above evidence. The present study found that the FAAH expression was increased at both mRNA and protein levels during RANKL-induced osteoclastogenesis. Pharmacological and genetic inhibition of FAAH in bone marrow-derived macrophages (BMMs) inhibited osteoclastogenesis, F-actin ring formation, bone resorption, and osteoclast-specific gene expression in vitro. Moreover, intragastric administration of the FAAH inhibitor PF-04457845(PF) ameliorated ovariectomy (OVX)-induced bone loss in mice. Further investigation revealed that nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were inhibited by PF treatment and FAAH knockdown. RNAseq indicated that the IL17 pathway was blocked by PF, and administration of recombinant murine IL17 protein could partially restore osteoclastogenesis and activate NF-κB and MAPK pathways. To sum up, our findings demonstrate that targeting FAAH could be a promising candidate strategy for treating osteoclast-related diseases, especially osteoporosis.

Adsorption removal of arsenic from aqueous solutions and groundwater by isomeric FeOOH.

FeOOH as a naturally abundant, relatively low-cost and effective adsorbent have been gradually valued in wastewater field rich in arsenic pollution, which can make for environmental remediation. In this study, FeOOH samples included Gth1/Gth2 as goethite, Aka1/Aka2 as akaganéite, and Lep as lepidocrocite, were prepared and used as adsorbents, and adsorption kinetic and isotherm experiments of As(III) were analyzed. Meanwhile, the effects of pH, adsorbent content, arsenic initial concentration and electrolyte solutions on adsorption processes were also discussed in detail to study adsorption behaviors and mechanism. The results showed that As(III) could be effectively adsorbed on goethite, akaganéite and lepidocrocite, the adsorption equilibrium achieved after 24 h. When As(III) concentration ranged in 40 mg/L, the saturated adsorption amounts (mg/g) calculated by the Langmuir equation were 12.3 (Gth1), 7.50 (Gth2), 6.29 (Aka1), 23.4 (Aka2), and 17.7 (Lep). The increase of adsorbent and adsorbate levels was favorable to improve the adsorption capacities of As(III) within a certain range. Removal efficiency of As(III) with Na2SO4 and NaH2PO4 as electrolyte reduced by about 10% and 30%, respectively. Therefore, the appropriate parameters in the adsorption process for investigation were isomeric FeOOH of 1.0 g/L, pH 7.0 and NaNO3 as electrolyte. In simulated groundwater filter system initially with 200 µg/L of arsenic species at about pH 7.0, arsenic removal strength for five FeOOH adsorbents (0.8 g) was Aka2 > Aka1 and Gth1 > Lep and Gth2. Some differences were present in the infrared (IR) spectra of arsenic-loaded and original isomeric FeOOH. These outcomes could give the aim at seeking high efficient materials for the purification of arsenic contaminated groundwater and put out the suggestion.

Glycogen Synthase Kinase 3ß inhibits BMSCs Chondrogenesis in Inflammation via the Cross-Reaction between NF-κB and ß-Catenin in the Nucleus.

Inflammation can influence the pluripotency and self-renewal of mesenchymal stem cells (MSCs), thereby altering their cartilage regeneration ability. Sprague-Dawley (SD) rat bone marrow mesenchymal stem cells (BMSCs) were isolated and found to be defective in differentiation potential in the interleukin-1ß- (IL-1ß-) induced inflammatory microenvironment. Glycogen synthase kinase-3ß (GSK-3ß) is an evolutionarily conserved serine/threonine kinase that plays a role in numerous cellular processes. The role of GSK-3ß in inflammation may be related to the nuclear factor-κB (NF-κB) signaling pathway and the Wnt/ß-catenin signaling pathway, whose mechanism remains unclear. In this study, we found that GSK-3ß can inhibit chondrogenesis of IL-1ß-impaired BMSCs by disrupting metabolic balance and promoting cell apoptosis. By using the inhibitors LiCl and SN50, we demonstrated that GSK-3ß regulates the chondrogenesis via the NF-κB and Wnt/ß-catenin signaling pathways and possibly mediates the cross-reaction between NF-κB and ß-catenin in the nucleus. Given the molecular mechanisms of GSK-3ß in chondrogenic differentiation in inflammation, GSK-3ß is a crucial target for the treatment of inflammation-induced cartilage disease.

Blood pressure mediated the effects of cognitive function impairment related to aluminum exposure in Chinese aluminum smelting workers.

OBJECTIVES: The aim of this study is to investigate the effects that the Al on blood pressure and the effect of hypertension in aluminum-induced cognitive impairment in electrolytic aluminum worker. METHODS: The study was conducted 392 male aluminum electrolytic workers in an aluminum plant of China. The concentration of alumina dust in the air of the electrolytic aluminum workshop is 1.07 mg/m3-2.13 mg/m3. According to the Permissible concentration-Time Weighted Average of alumina dust is 4 mg/m3, which does not exceed the standard. The blood pressure of the workers was measured. The plasma aluminum concentration of workers was determined by ICP-MS (Inductively Coupled Plasma Mass Spectrometry). Cognitive functions were measured using MMSE (Mini-Mental State Examination), VFT (Verbal Fluency Test), ATIME (Average Reaction Time), FOM (Fuld Object Memory Evaluation), DST (Digit Span Test), CDT (Clock Drawing Test) scales. Modified Poisson regression was used to analyze the risk of hypertension and cognitive impairment with different plasma aluminum concentrations. Generalized linear regression model was used to analyze the relationship between aluminum and cognitive function, blood pressure and cognitive function. Causal Mediation Analysis was used to analyze the mediation effect of blood press in aluminum-induced cognitive impairment. RESULTS: Plasma aluminum appeared to be a risk factor for hypertension (PR (prevalence ratio) = 1.630, 95 %-CI (confidence interval): 1.103-2.407), systolic blood pressure (PR = 1.578, 95 %-CI: 1.038-2.399) and diastolic blood pressure (PR = 1.842, 95 %-CI: 1.153-2.944). And plasma aluminum increased by e-fold, the scores of MMSE and VFT decreased by 0.630 and 2.231 units respectively and the time of ATIME increased by 0.029 units. In addition, generalized linear regression model showed that blood press was negatively correlated with the scores of MMSE and VFT. Finally, causal Mediation Analysis showed that hypertension was a part of the mediating factors of aluminum-induced decline in MMSE score, and the mediating effects was 16.300 % (7.100 %, 33.200 %). In addition, hypertension was a part of the mediating factors of aluminum-induced decline in VFT score, and the mediating effects was 9.400 % (2.600 %, 29.000 %) CONCLUSION: Occupational aluminum exposure increases the risk of hypertension and cognitive impairment. And hypertension may be a mediating factor of cognitive impairment caused by aluminum exposure.

Blood glucose mediated the effects of cognitive function impairment related to aluminum exposure in Chinese aluminum smelting workers.

OBJECT: To explore the effects of occupational aluminum exposure on workers' cognitive function and blood glucose concentration, and to analyze whether blood glucose concentration can mediate the cognitive changes caused by aluminum. METHOD: Our study recruited 375 workers from an aluminum factory in northern China. We collected the fasting elbow venous blood of the workers, measured their fasting blood glucose concentration (FBG), and used ICP-MS to determine plasma aluminum concentration (P-Al) as an indicator of internal exposure. The Montreal Cognitive Assessment (MoCA), was used to assess the cognitive function of workers. Generalized linear model was used to analyze the association of P-Al with cognitive function and blood glucose concentration, and the restricted cubic spline model was used to fit the dose-response relationship. We also conducted a mediation effect analysis. RESULT: We observed the dose-response relationship, that is, as the P-Al increased, sum of MoCA, visuospatial/executive, naming, language, and abstraction scores decreased, and the blood glucose concentration increased. For every e-fold increase in P-Al, sum of MoCA, visuospatial/executive, naming, language, and abstraction scores decreased by 0.328 points, 0.120 points, 0.059 points, 0.060 points, and 0.083 points, respectively, and FBG rose by 0.109 mmol/L. FBG has a significant mediating effect between P-Al and sum of MoCA (P for mediator=0.042), and it could explain 10.7% of the effect of cognitive level related to P-Al. CONCLUSION: Occupational aluminum exposure negatively affected the cognitive function of workers and positively affected FBG. FBG may partially explain the impact of occupational aluminum exposure on workers' cognitive function.

Mechanism by Which Aluminum Regulates the Abnormal Phosphorylation of the Tau Protein in Different Cell Lines.

Aluminum (Al) is an environmental neurotoxin to which humans are extensively exposed; however, the molecular mechanism of aluminum toxicity is unclear. Several studies have indicated that exposure to aluminum can cause abnormal phosphorylation of the tau protein. The purpose of this study was to investigate respectively the special molecular mechanism of abnormal regulation on synthesis and degradation of the tau protein induced by AlCl3 in cells of different species. The results of tau protein showed that the sites of abnormal tau phosphorylation induced by AlCl3 are Thr231, Ser262, and Ser396 in N2a cells. Meanwhile, the expressions of Thr181, Thr231, and Ser262 increased abnormally in SH-SY5Y cells. The result of the study showed that PP2A expression was high in N2a cells, while GSK-3ß and PP2A in SH-SY5Y cells were involved in the synthesis process of abnormal tau phosphorylation induced by AlCl3. In N2a cells, the ubiquitin-proteasome pathway (UPP) mainly regulated tau phosphorylation at Ser262 and Ser396. Meanwhile, in SH-SY5Y cells, the UPP mainly regulated tau phosphorylation at Thr231 and Ser396. In summary, the UPP is involved in the degradation of Tau that is abnormally phosphorylated induced by AlCl3, but this process is site-specific and differs in cells of different species.

Rab18 binds PLIN2 and ACSL3 to mediate lipid droplet dynamics.

Lipid droplet (LD) is a vital organelle governing lipid homeostasis and Rab18 has been linked to lipid metabolism. However, the mechanisms of Rab18-mediated LD dynamics in myoblast cells remain elusive. Here, we report that Rab18 plays an important role in oleic acid (OA)-induced LD accumulation in mouse myoblast C2C12 cells. Rab18 was translocated from the endoplasmic reticulum (ER) to LDs during LD accumulation, which was regulated by perilipin 2 (PLIN2), a major LD protein. LD-associated Rab18 bound with the C terminus of PLIN2 and the LD localization of Rab18 was diminished when PLIN2 was depleted. Moreover, loss of function of Rab18 led to reduced triacylglycerol (TAG) level and fewer but larger LDs. In contrast, overexpression of Rab18 resulted in elevated TAG content and LD number. Furthermore, LD-associated Rab18 interacted with acyl-CoA synthetase long-chain family member 3 (ACSL3), which in turn promoted the LD localization of this protein. These data show that Rab18 interacts with PLIN2 and forms a complex with PLIN2 and ACSL3, which plays a critical role in LD accumulation and dynamics of myoblast cells.

Increased aluminum and lithium and decreased zinc levels in plasma is related to cognitive impairment in workers at an aluminum factory in China: A cross-sectional study.

BACKGROUND: Previous studies have shown that multiple imbalances of metal ions in the brain are closely associated with the neurodegenerative disorders. Our studies have shown that long-term working exposure to aluminum induces increased plasma aluminum levels and causes cognitive impairment in workers at aluminum factories. OBJECTIVE: To explore the levels of nine metals in plasma and the effect on cognitive function among in-service workers. METHODS: In this cross-sectional study, cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), which included seven subitems: executive/visuospatial abilities; naming; attention and calculation; language; abstract; recall; and orientation. The plasma levels of nine kinds of metals were measured by inductively coupled plasma-mass spectrometry (ICP-MS). A multivariate generalized linear regression model and Bayesian kernel machine regression (BKMR) were selected to estimate the relationship between metal plasma level and MoCA scores with adjustment for confounders. RESULTS: One hundred and eighty-seven workers participated in this study. In the multivariable generalized linear model, among these nine metals studied, five were related to the MoCA score: aluminum, lithium, cobalt, zinc and chromium. In the BKMR model, a significantly negative correlation between the plasma aluminum, lithium and the total MoCA score was observed. Moreover, for subitems on the MoCA scale, the plasma levels of lithium, aluminum, and zinc had a significant correlation with the executive/visuospatial abilities, naming, and orientation abilities, respectively. The log-transformation concentrations of plasma aluminum and lithium were negatively correlated with the executive/visuospatial abilities and naming abilities, respectively. The log-transformation plasma zinc concentration was positively correlated with orientation abilities. CONCLUSION: Based on the results, we determined that increased aluminum and lithium and decreased zinc levels in plasma were associated with the incidence of mild cognitive impairment (MCI) in workers at a Chinese aluminum plant.

Longitudinal study of the effects of occupational aluminium exposure on workers' cognition.

OBJECTIVE: To explore the effects of occupational aluminium(Al) exposure on workers' cognition through a longitudinal study. METHODS: The study population consisted of 276 workers in an Al factory. In 2014, we used inductively coupled plasma mass spectrometry (ICP-MS) to determine the plasma aluminium (P-Al) concentration of the workers, and a combined questionnaire to test the workers' cognitive function. Followed-up in 2016, the workers were tested again for cognitive function. Generalized linear regression was used to assess the association between P-Al concentration and cognitive scores, and multivariable logistic regression was used to assess the risk of cognitive decline caused by Al exposure. RESULTS: Generalized linear regression results showed that a non-significant association was found between the P-Al concentration and cognitive test scores (P > 0.05) in 2014. Two years later, each 10-fold increase in P-Al concentration was inversely associated with the score of Mini-Mental state examination (MMSE) (ß: -0.53, 95% CI: -0.86, -0.20) and Fuld object memory evaluation (FOME) (ß: -0.93, 95% CI: -1.62, -0.24). Each 10-fold increase in P-Al concentration was inversely associated with MMSE2016-2014 (ß: -0.38, 95% CI: -0.74, -0.01) and FOME2016-2014 (ß: -1.20, 95% CI: -1.95, -0.45). There was a statistically significant difference in the average annual rate of change of MMSE and FOME with the tertile of P-Al concentration increase (P < 0.05). The multivariable logistic regression results showed that as the P-Al concentration increased, the risk of a FOME score decline increased (Ptrend = 0.009). CONCLUSIONS: Continuous occupational Al exposure can damage workers' overall cognitive ability, especially episodic memory function.

Cross-sectional study based on occupational aluminium exposure population.

To evaluate the different characteristics of cognitive impairment caused by occupational aluminium exposure at different ages, we surveyed 1660 workers in Shanxi Aluminium Plant, China, and assessed their cognitive function and plasma aluminium concentration. In multiple linear regression, the scores of the digit-span test (DST) and digit-span backward test (DSBT) were negatively correlated with plasma aluminium concentration when concentration reached 34.52 µg/L in younger group (＜40 years), while in the middle-aged group (≥40 years) only found when concentration reached 42.25 µg/L (ß<0, P < 0.05). In logistic regression, when plasma aluminum concentration reached 42.25µg/L, odds ratios (95 % confidence interval) were 1.695 (1.062-2.705) and 3.270 (1.615-6.620) for DST, 7.644 (3.846-15.192) and 15.308 (4.180-56.059) for DSBT in middle-aged group and younger group, respectively. These results showed that aluminium exposures were associated with cognitive impairment among aluminium-exposed workers, particularly for young workers who were more susceptible.

Identification of a degradation signal at the carboxy terminus of SREBP2: A new role for this domain in cholesterol homeostasis.

Lipid homeostasis in animal cells is maintained by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose proteolytic activation requires the cholesterol-sensing membrane protein Scap. In endoplasmic reticulum (ER) membranes, the carboxyl-terminal domain (CTD) of SREBPs binds to the CTD of Scap. When cholesterol levels are low, Scap escorts SREBPs from the ER to the Golgi, where the actions of two proteases release the amino-terminal domains of SREBPs that travel to the nucleus to up-regulate expression of lipogenic genes. The CTD of SREBP remains bound to Scap but must be eliminated so that Scap can be recycled to bind and transport additional SREBPs. Here, we provide insights into how this occurs by performing a detailed molecular dissection of the CTD of SREBP2, one of three SREBP isoforms expressed in mammals. We identify a degradation signal comprised of seven noncontiguous amino acids encoded in exon 19 that mediates SREBP2's proteasomal degradation in the absence of Scap. When bound to the CTD of Scap, this signal is masked and SREBP2 is stabilized. Binding to Scap requires an arginine residue in exon 18 of SREBP2. After SREBP2 is cleaved in Golgi, its CTD remains bound to Scap and returns to the ER with Scap where it is eliminated by proteasomal degradation. The Scap-binding motif, but not the degradation signal, is conserved in SREBP1. SREBP1's stability is determined by a degradation signal in a different region of its CTD. These findings highlight a previously unknown role for the CTD of SREBPs in regulating SREBP activity.

[Regulatory role of Ca MK-â ¡ and PP2A on hyperphosphorylated tau induced by Al Cl_3 in SH-SY5Y cells].

OBJECTIVE: To explore the role of calcium/calmodulin-dependent protein kinase Ⅱ(CaMK-Ⅱ) and protein phosphatase-2 A(PP2 A) on hyperphosphorylation of tau induced by AlCl_3 in SH-SY5 Y cell. METHODS: SH-SY5 Y cells were assigned to the control group, AlCl_3 low, middle, high exposed groups(200, 400800 µmol/L Al~(3+)), KN93 intervention group(800 µmol/L Al~(3+)+0. 5 µmol/L KN93) and sphingosine intervention group(800 µmol/L Al~(3+)+5 nmol/L sphingosine). After 48 h of exposure and intervention, the viabilities of cells were measured by CCK-8 assay, the contents of CaMK-Ⅱ and PP2 A were determined by ELISA, and the expression of tau5 and phosphorylation of Thr-181, Thr-231, Ser-262 and Ser-396 were detected by Western-Blot. RESULTS: The viabilities of cells in AlCl_3 middle and high exposed groups were significantly lower than that of the control group(P<0. 05). Compared with the AlCl_3 high exposed group, the viabilities of cells in KN93 intervention group and sphingosine intervention group were significantly increased(P<0. 05), as well as the difference of the cell viability between sphingosine intervention group and the control group was not statistically significant. Compared with the control group, the contents of CaMK-Ⅱin AlCl_3 low, middle, high exposed groups were significantly increased(P<0. 05), while the contents of PP2 A in those groups were significantly decreased(P<0. 05). Compared with AlCl_3 high exposed group, the contents of CaMK-Ⅱ in KN93 intervention group and sphingosine intervention group were significantly decreased(P<0. 05), and PP2 A in those groups were significantly increased(P<0. 05). The expression of tau5 and phosphorylation of Thr-181, Thr-231, Ser-396 in AlCl_3 low, middle, high exposed group showed significantly higher than those of the control group(P<0. 05), while the phosphorylation of Ser-262 in AlCl_3 high exposed group showed significantly higher than that of the control group(P<0. 05). After intervention with KN93 and sphingosine, the expression of tau5, and phosphorylation of Thr-181, Thr-231, Ser-262, Ser-396 in KN93 intervention group and sphingosine intervention group were significantly lower than those of AlCl_3 high exposed group( P<0. 05), as well as compared with the control group, the phosphorylation of Ser-262 in KN93 intervention group and Thr-181, Thr-231 and Ser-396 in sphingosine intervention group were not statistical difference. CONCLUSION: AlCl_3 could increase the phosphorylation of Thr-181, Thr-231, Ser-262 and Ser396 in SH-SY5 Y cells, which mechanism may relate to the changes of CaMK-Ⅱand PP2 A. CaMK-Ⅱ mainly regulates the phosphorylation of Ser-262 induced by AlCl_3, while PP2 A mainly regulates the phosphorylation of Thr-181, Thr-231 and Ser-396 induced by AlCl_3. It is suggested that hyperphosphorylated tau protein induced by AlCl_3 is closely related to PP2 A.

Complexity drives speech sound development: Evidence from artificial language training.

Traditionally, learning is assumed to take place with exposure to simpler elements first followed by exposure to elements with increasing levels of difficulty. Recent reports suggest that exposure to complex elements leads to more widespread changes. However, whether learning via exposure to complex or to simple elements is more beneficial is a matter of ongoing debate. In the current study, using behavioral and electrophysiological measures, we aimed at understanding this by comparing subjects trained with complex speech sounds with those trained with simple speech sounds in a 5-day pseudoword-picture training paradigm. We found that though the subjects learned both complex and simple speech sounds to similar degrees, subjects who were trained with complex stimuli demonstrated more generalizations to novel complex and simple stimuli, whereas those trained with simple stimuli exhibited generalization only to simple but not to complex stimuli (Experiment 1). Along with behavioral measures, using mismatch negativity, we found that training with complex stimuli can lead to more extensive neural changes for both complex and simple stimuli as compared with training with simple stimuli (Experiment 2). In artificial language learning, learning with complex stimuli appears to be more effective than training with simple stimuli as far as generalization is concerned. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The Adrenal Lipid Droplet is a New Site for Steroid Hormone Metabolism.

Steroid hormones play essential roles for living organisms. It has been long and well established that the endoplasmic reticulum (ER) and mitochondria are essential sites for steroid hormone biosynthesis because several steroidogenic enzymes are located in these organelles. The adrenal gland lipid droplet (LD) proteomes from human, macaque monkey, and rodent are analyzed, revealing that steroidogenic enzymes are also present in abundance on LDs. The enzymes found include 3ß-hydroxysteroid dehydrogenase (HSD3B) and estradiol 17ß-dehydrogenase 11 (HSD17B11). Analyses by Western blot and subcellular localization consistently demonstrate that HSD3B2 is localized on LDs. Furthermore, in vitro experiments confirm that the isolated LDs from HeLa cell stably expressing HSD3B2 or from rat adrenal glands have the capacity to convert pregnenolone to progesterone. Collectively, these data suggest that LDs may be important sites of steroid hormone metabolism. These findings may bring novel insights into the biosynthesis and metabolism of steroid hormones and the development of treatments for adrenal disorders.