Demonstration of programmable light intensity of a micro-LED with a Hf-based ferroelectric ITZO TFT for Mura-free displays.

We demonstrate the programmable light intensity of a micro-LED by compensating threshold voltage variability of thin-film transistors (TFTs) by introducing a non-volatile programmable ferroelectric material, HfZrO2 (HZO) into the gate stack of the TFT. We fabricated an amorphous ITZO TFT, ferroelectric TFTs (FeTFTs), and micro-LEDs and verified the feasibility of our proposed current-driving active matrix circuit. Importantly, we successfully present the programmed multi-level lighting of the micro-LED, utilizing partial polarization switching in the a-ITZO FeTFT. We expect that this approach will be highly promising for the next-generation display technology, replacing complicated threshold voltage compensation circuits with a simple a-ITZO FeTFT.

Accelerated crystal structure prediction of multi-elements random alloy using expandable features.

Properties of solid-state materials depend on their crystal structures. In solid solution high entropy alloy (HEA), its mechanical properties such as strength and ductility depend on its phase. Therefore, the crystal structure prediction should be preceded to find new functional materials. Recently, the machine learning-based approach has been successfully applied to the prediction of structural phases. However, since about 80% of the data set is used as a training set in machine learning, it is well known that it requires vast cost for preparing a dataset of multi-element alloy as training. In this work, we develop an efficient approach to predicting the multi-element alloys' structural phases without preparing a large scale of the training dataset. We demonstrate that our method trained from binary alloy dataset can be applied to the multi-element alloys' crystal structure prediction by designing a transformation module from raw features to expandable form. Surprisingly, without involving the multi-element alloys in the training process, we obtain an accuracy, 80.56% for the phase of the multi-element alloy and 84.20% accuracy for the phase of HEA. It is comparable with the previous machine learning results. Besides, our approach saves at least three orders of magnitude computational cost for HEA by employing expandable features. We suggest that this accelerated approach can be applied to predicting various structural properties of multi-elements alloys that do not exist in the current structural database.

Metal@SiO2 Core-Shells with Self-Arrested Migrating Core.

Developing easy and customizable strategies for the directional structure modulation of multicomponent nanosystems to influence and optimize their properties are a paramount but challenging task in nanoscience. Here, we demonstrate highly controlled eccentric off-center positioning of metal-core in metal@silica core-shells by utilizing an in situ generated biphasic silica-based intraparticle solid-solid interface. In the synthetic strategy, by including Ca2+-ions in silica-shell and successive oxidative and reductive annealing at high temperature, a unique hairline-biphasic interface is evolved via the heat-induced concentric radial segregation of calcium silicate phase at the interior and normal silica phase at the exterior of core-shell, which can effectively arrest the outwardly migrating metal-core within rubbery calcium silicate phase, affording various eccentric core-shells, where core-positions are flexibly controlled by the annealing time and amounts of initially added Ca2+-ions. In the structure-property correlation study, the strategy allows fine-tuning of dipolar interaction-based blocking temperatures and magnetic anisotropies of different eccentric core-shells as the function of variable off-center distance of magnetic core without changing the overall size of nanoparticles. This work demonstrates the discovery and potential application of biphasic solid-solid media interface in controlling the heat-induced migration of metal nanocrystals and opens the avenues for exploiting the rarely studied high-temperature solid-state nanocrystal conversion chemistry and migratory behavior for directional nanostructure engineering.

Adiponectin Upregulates Filaggrin Expression via SIRT1-Mediated Signaling in Human Normal Keratinocytes.

BACKGROUND: Filaggrin (FLG) is the major component of the epidermal granular layer and binds to and condenses the keratin cytoskeleton. FLG thus contributes to cell compaction and serves as a natural moisturizing factor by promoting unfolding and degradation into hygroscopic amino acids. Loss or downregulation of FLG has been shown to result in a weak stratum corneum, which causes water loss and increases the possibility of skin barrier-related seizure. Adiponectin (Acrp30) contributes to the functional recovery of somatic cells, including human normal epidermal keratinocytes (NHEKs). OBJECTIVE: To investigate the effect of Acrp30 in FLG expression and identifying its signal transduction mechanism. METHODS: Normal human keratinocytes were treated with Acrp30 and the levels of FLG were examined. Silent mating type information regulation 2 homolog (SIRT)-targeting siRNA and aryl hydrocarbon receptor nuclear translocator (ARNT)-targeting siRNA were used to identify the role of various signal transduction pathway components. RESULTS: Acrp30 upregulated SIRT1 and ARNT expression in NHEKs, resulting in increased FLG expression. Treatment with both SIRT1-targeting siRNA and ARNT-targeting siRNA blocked Acrp30 stimulation and silenced FLG expression. CONCLUSION: Adiponectin upregulates FLG expression through a SIRT1-mediated pathway. Our results suggest that Acrp30 is a promising agent for skin barrier permeability improvement.

Rapid Detection of Staphylococcus aureus and Methicillin-Resistant S. aureus in Atopic Dermatitis by Using the BD Max StaphSR Assay.

Eczematous lesions of atopic dermatitis (AD) patients are known to be a source of Staphylococcus aureus (SA) transmission and might be a reservoir for community-associated methicillin-resistant SA (MRSA). The BD Max StaphSR (BD-SR) is a fully automated, multiplex real-time PCR assay for the direct detection and differentiation of SA and MRSA from nasal swab samples. We evaluated the detection rates of SA and MRSA from skin lesions of outpatients with AD using the BD-SR assay, and determined the usefulness of the BD-SR assay. A total of 244 skin swab samples (skin lesions of 213 outpatients with AD and normal skin of 31 healthy controls) were tested directly by using the BD-SR assay. Of the 213 samples from patients with AD, 69 (32.4%) were positive for SA, 6 (8.7%) of which were positive for MRSA. Only 1 (3.2%) of 31 samples from healthy controls was positive for SA. The BD-SR assay is effective for the rapid detection of SA and MRSA from skin swab samples, which can provide important information for managing patients with AD and preventing the spread of MRSA.

Identification of novel candidate variants including COL6A6 polymorphisms in early-onset atopic dermatitis using whole-exome sequencing.

BACKGROUND: The prevalence of atopic dermatitis has increased over the last 10 years. Atopic dermatitis tends to run in families and commonly begins to manifest in childhood. The prevalence of atopic dermatitis is as high as 20% in children. Thus, early diagnosis and treatment of atopic dermatitis are important. Understanding its genetic basis is also needed to facilitate early detection. METHODS: To identify family-specific candidate genetic variants associated with early-onset atopic dermatitis in Koreans, we carried out whole-exome sequencing of three separate families with this condition. Additional validation was performed in 112 AD patients and 61 controls using Sanger sequencing. RESULTS: We focused on both common functional variants with a minor allele frequency higher than 1% and rare variants with a minor allele frequency less than 1%. The relevance of the respective variants was supported by a program that could predict whether the mutations resulted in damaged protein function. Fourteen overlapping genes were identified during exome sequencing. Three variants of the COL6A6 gene appeared in all three families and were in close proximity to atopic dermatitis-related loci on chromosome 3q21. The homozygous frequency for the rs16830494 minor allele (AA) and the rs59021909 (TT) allele and the rs200963433 heterozygous (CT) frequency were all higher in AD cases compared to controls in a population-based case-control study. CONCLUSION: Identifying family-specific COL6A6 polymorphisms and genetic variants of other candidate genes associated with AD using WES is a novel approach. Our study suggests that COL6A6 variants may be risk factors for atopic dermatitis. This study provides a genetic basis for early-onset AD diagnosis in Korean patients and the development of new therapies. TRIAL REGISTRATION: Trial registration number: IRB NO. C2008030 (133); Name of registry: The collection research of clinical data and patient blood to identify genetic and protein biomarker of atopic dermatitis; Date of registration: 09-July-2008. TRIAL REGISTRATION NUMBER: IRB NO. C2015258 (1716); Name of registry: The collection study of patient blood and clinical data for the development of the prognosis prediction and early diagnosis of atopic dermatitis; Date of registration: 15-jan-2016.

Correction: Adiponectin Suppresses UVB-Induced Premature Senescence and hBD2 Overexpression in Human Keratinocytes.

[This corrects the article DOI: 10.1371/journal.pone.0161247.].

Adiponectin Suppresses UVB-Induced Premature Senescence and hBD2 Overexpression in Human Keratinocytes.

Recent studies have revealed that adiponectin can suppress cellular inflammatory signaling pathways. This study aimed to elucidate the effect of adiponectin on the unregulated production of hBD2 in UVB-induced premature senescent keratinocytes. We constructed an in vitro model of premature senescent keratinocytes through repeated exposure to low energy UVB. After repeated low energy UVB exposure, there was significant generation of reactive oxygen species (ROS) and induction of senescence-associated markers, including senescence associated beta-galactosidase activity and expression of p16INK4a and histone H2AX. In addition, the present clinical study showed higher expression of hBD2 in sun-exposed skin of elderly group, and the overexpression of hBD2 was observed by c-Fos activation in vitro. Adiponectin has the ability to scavenge ROS and consequently inhibit MAPKs and SA-markers in UVB-exposed keratinocytes. An inhibitor study demonstrated that adiponectin downregulated hBD2 mRNA expression through suppression of the AP-1 transcription factor components c-Fos via inactivation of p38 MAPK. Collectively, the dysregulated production of hBD2 by the induction of oxidative stress was attenuated by adiponectin through the suppression of p38 and JNK/SAPK MAPK signaling in UVB-mediated premature senescent inducible conditions. These results suggest the feasibility of adiponectin as an anti-photoaging and anti-inflammatory agent in the skin.

Adiponectin corrects premature cellular senescence and normalizes antimicrobial peptide levels in senescent keratinocytes.

Stress-induced premature senescence or aging causes dysfunction in the human somatic system. Adiponectin (Acrp30) plays a role in functional recovery, especially with adenosine 3',5'-monophosphate (AMP)-activated protein kinase (AMPK) and silent mating type information regulation 2 homolog 1 (SIRT1). Acrp30 stimulation reduced the premature senescence positive ratio induced by hydrogen peroxide (H2O2) and restituted human ß-defensin 2 (hBD-2) levels in senescent keratinocytes. Acrp30 recovered AMPK activity in senescent keratinocytes and increased SIRT1 deacetylation activity. As a result, FoxO1 and FoxO3 transcription activity was recovered. Additionally, Acrp30 stimulation suppresses NFκB p65, which induces abnormal expression of hBD-2 induced by H2O2. In the present study, we have shown that Acrp30 reduces premature senescence and recovers cellular function in keratinocytes. These results suggest a role for Acrp30 as an anti-aging agent to improve impaired skin immune barriers.

Increased plasma levels of heat shock protein 70 associated with subsequent clinical conversion to mild cognitive impairment in cognitively healthy elderly.

BACKGROUND AND AIMS: Heat shock proteins (HSPs) have been regarded as cytoprotectants that protect brain cells during the progression of neurodegenerative diseases and from damage resulting from cerebral ischemia. In this study, we assessed the association between plasma HSP 70/27 levels and cognitive decline. METHODS: Among participants in the community-based cohort study of dementia called the Gwangju Dementia and Mild Cognitive Impairment Study, subjects without cognitive impairment at baseline, who then either remained without impairment (non-conversion group), or suffered mild cognitive impairment (MCI) (conversion group) (non-conversion group, N = 36; conversion group, N = 30) were analyzed. RESULTS: After a five to six year follow-up period, comparison of the plasma HSP 70 and HSP 27 levels of the two groups revealed that only the plasma HSP 70 level was associated with a conversion to MCI after adjustments for age, gender, years of education, follow-up duration, APOE e4, hypertension, and diabetes (repeated measure analysis of variance: F = 7.59, p = 0.008). Furthermore, an increase in plasma HSP 70 level was associated with cognitive decline in language and executive function (linear mixed model: Korean Boston Naming Test, -0.426 [-0.781, -0.071], p = 0.019; Controlled Oral Word Association Test, -0.176 [-0.328, -0.023], p = 0.024; Stroop Test, -0.304 [-0.458, -0.150], p<0.001). CONCLUSIONS: These findings suggest that the plasma HSP 70 level may be related to cognitive decline in the elderly.

Fisetin up-regulates the expression of adiponectin in 3T3-L1 adipocytes via the activation of silent mating type information regulation 2 homologue 1 (SIRT1)-deacetylase and peroxisome proliferator-activated receptors (PPARs).

Adiponectin, an adipokine, has been described as showing physiological benefits against obesity-related malfunctions and vascular dysfunction. Several natural compounds that promote the expression and secretion of adipokines in adipocytes could be useful for treating metabolic disorders. This study investigated the effect of fisetin, a dietary flavonoid, on the regulation of adiponectin in adipocytes using 3T3-L1 preadipocytes. The expression and secretion of adiponectin increased in 3T3-L1 cells upon treatment with fisetin in a dose-dependent manner. Fisetin-induced adiponectin secretion was inhibited by peroxisome proliferator-activated receptor (PPAR) antagonists. It was also revealed that fisetin increased the activities of PPARs and silent mating type information regulation 2 homologue 1 (SIRT1) in a dose-dependent manner. Furthermore, the up-regulation of adiponectin and the activation of PPARs induced by fisetin were prevented by a SIRT1 inhibitor. Fisetin also promoted deacetylation of PPAR γ coactivator 1 (PGC-1) and its interaction with PPARs. SIRT knockdown by siRNA significantly decreased both adiponectin production and PPARs-PGC-1 interaction. These results provide evidence that fisetin promotes the gene expression of adiponectin through the activation of SIRT1 and PPARs in adipocytes.

C-reactive protein inhibits survivin expression via Akt/mTOR pathway downregulation by PTEN expression in cardiac myocytes.

C-reactive protein (CRP) is one of the most important biomarkers for arteriosclerosis and cardiovascular disease. Recent studies have shown that CRP affects cell cycle and inflammatory process in cardiac myocytes. Survivin is also involved in cardiac myocytes replication and apoptosis. Reduction of survivin expression is associated with less favorable cardiac remodeling in animal models. However, the effect of CRP on survivin expression and its cellular mechanism has not yet been studied. We demonstrated that treatment of CRP resulted in a significant decrease of survivin protein expression in a concentration-dependent manner in cardiac myocytes. The upstream signaling proteins of survivin, such as Akt, mTOR and p70S6K, were also downregulated by CRP treatment. In addition, CRP increased the protein and mRNA levels of PTEN. The siRNA transfection or specific inhibitor treatment for PTEN restored the CRP-induced downregulation of Akt/mTOR/p70S6K pathway and survivin protein expression. Moreover, pretreatment with a specific p53 inhibitor decreased the CRP-induced PTEN expression. ERK-specific inhibitor also blocked the p53 phosphorylation and PTEN expression induced by CRP. Our study provides a novel insight into CRP-induced downregulation of survivin protein expression in cardiac myocytes through mechanisms that involved in downregulation of Akt/mTOR/p70S6K pathway by expression of PTEN.

The effect of soluble RAGE on inhibition of angiotensin II-mediated atherosclerosis in apolipoprotein E deficient mice.

BACKGROUND: The cross talk between RAGE and angiotensin II (AngII) activation may be important in the development of atherosclerosis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. In this study, we sought to determine the effect of sRAGE in inhibiting AngII-induced atherosclerosis in apolipoprotein E knockout mice (Apo E KO). METHODS AND RESULTS: 9 week old Apo E KO mice were infused subcutaneously with AngII (1 µg/min/kg) and saline for 4 weeks using osmotic mini-pumps. The mice were divided into 4 groups 1. saline infusion and saline injection; 2. saline infusion and sRAGE injection; 3. AngII infusion and saline injection; 4. AngII infusion and sRAGE injection. Saline or 0.5 µg, 1 µg, to 2 µg/day/mouse of sRAGE were injected intraperitoneally daily for 28 days. We showed that atherosclerotic plaque areas in the AngII-infused Apo E KO mice and markers of inflammation such as RAGE, ICAM-1, VCAM-1, and MCP-1 were increased in aorta compared to that of the Apo E KO mice. However, the treatment of 0.5 µg, 1 µg, and 2 µg of sRAGE in AngII group resulted in the dose-dependent decrease in atherosclerotic plaque area. We also demonstrated that sRAGE decreased RAGE expression level as well as inflammatory cytokines and cell adhesion molecules in AngII or HMGB1 treated-rat aorta vascular smooth muscle cells. CONCLUSION: The results demonstrated that partical blockade of RAGE activation by sRAGE prevent AngII -induced atherosclerosis. Therefore these results suggested that first, RAGE activation may be important in mediating AngII-induced atherogenesis, and second, AngII activation is a major pathway in the development of atherosclerosis. Taken together, results from this study may provide the basis for future anti- atherosclerotic drug development mediated through RAGE activation.

Protective effect of survivin in Doxorubicin-induced cell death in h9c2 cardiac myocytes.

BACKGROUND AND OBJECTIVES: Apoptosis has been known to be an important mechanism of doxorubicin-induced cardiotoxicity. Survivin, which belongs to the inhibitor of apoptosis protein family, is associated with apoptosis and alteration of the cardiac myocyte molecular pathways. Therefore, we investigated the anti-apoptotic effect and cellular mechanisms of survivin using a protein delivery system in a doxorubicin-induced cardiac myocyte injury model. MATERIALS AND METHODS: We constructed a recombinant survivin which was fused to the protein transduction domain derived from HIV-TAT protein. In cultured H9c2 cardiac myocytes, TAT-survivin (1 µM) was added for 1 hour prior to doxorubicin (1 µM) treatment for 24 hours. Cell viability and apoptosis were evaluated by 2-(4,5-dimethyltriazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, caspase-3 activity, and terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay. We measured the expression levels of several apoptosis-related signal proteins. RESULTS: The survivin level was significantly reduced in a dose dependent manner up to 1 µM of doxorubicin in concentration. Purified recombinant TAT-survivin protein was efficiently delivered to H9c2 cardiac myocytes, and its transduction showed an anti-apoptotic effect, demonstrated by reduced caspase-3 activity and the apoptotic index, concomitantly with increased cell viability against doxorubicin injury. The phosphorylation of p38 mitogen-activated protein (MAP) kinase and the release of Smac from mitochondria were suppressed and the expression levels of Bcl-2 and cAMP response element-binding protein (CREB), the transcription factor of Bcl-2, were recovered following TAT-survivin transduction, indicating that survivin had an anti-apoptotic effect against doxorubicin injury. CONCLUSION: Our results suggest that survivin has a potentially cytoprotective effect against doxorubicin-induced cardiac myocyte apoptosis through mechanisms that involve a decrease in the phosphorylation of p38 MAP kinase, mitochondrial Smac release, and increased expression of Bcl-2 and CREB.

1-Deoxynojirimycin isolated from a Bacillus subtilis stimulates adiponectin and GLUT4 expressions in 3T3-L1 adipocytes.

We have demonstrated that 1-deoxynojirimycin (DNJ) isolated from Bacillus subtilis MORI could enhance the levels of adiponectin and its receptors in differentiated 3T3-L1 adipocytes, which has been shown to be effective in lowering blood glucose levels and enhancing insulin sensitivity. DNJ was not toxic to differentiated 3T3-L1 adipocytes for up to a concentration of 5 microM. In terms of expression levels of adiponectin and its receptors (AdipoR1 and AdipoR2), DNJ in concentrations as low as 0.5 microM elevated both mRNA and protein levels of adiponectin and transcript levels of AdipoR1 and AdipoR2. In addition, DNJ increased phosphorylation of 5' adenosine monophosphateactivated protein kinase (AMPK) in a statistically significant manner. Finally, treatment with DNJ resulted in increased mRNA expression of glucose transporter 4 (GLUT4), which encodes for a glucose transporter, along with a significant increase in glucose uptake into the adipocytes based on results of a 2-deoxy-D-[3H] glucose uptake assay. Our findings indicate that DNJ may greatly facilitate glucose uptake into adipose tissues by increasing the action of adiponectin via its up-regulated expression as well as its receptor genes. In addition, the glucose-lowering effects of DNJ may be achieved by an increased abundance of GLUT4 protein in the plasma membrane, as a consequence of the increased transcript levels of the GLUT4 gene and the activation of AMPK.

Effects of fisetin supplementation on hepatic lipogenesis and glucose metabolism in Sprague-Dawley rats fed on a high fat diet.

The modulatory effects of daily fisetin supplementation for 8 weeks on genes involved in hepatic lipogenesis and gluconeogenesis and hyperglycemia in rats fed a high fat (HF) diet were evaluated. Elevated levels of triglyceride (TG), along with hepatic TG content and glucose concentrations in a high fat diet group were found to be reduced by fisetin supplementation. The high fat diet significantly increased hepatic mRNA expressions of PPARγ, SREBP1C and SCD-1 genes in comparison to the control diet, which was subsequently reversed by supplementation with fisetin. In addition, fisetin supplementation significantly reduced hepatic mRNA abundance of FAS, ATPCL and G6Pase compared to the control group. Finally, epididymal mRNA abundance of GLUT4 was significantly increased by fisetin supplementation, compared to levels in the control and HF groups. Enhancement of GLUT4 expression by fisetin was further confirmed in differentiated 3T3-L1 adipocytes. Fisetin supplementation decreases cardiovascular risks by ameliorating hepatic steatosis and lowering circulating glucose concentrations.

Ubiquitin ligase CHIP induces TRAF2 proteasomal degradation and NF-κB inactivation to regulate breast cancer cell invasion.

Transcriptional factor nuclear factor-kappaB (NF-κB) plays a crucial role in human breast cancer cell invasion and metastasis. The carboxyl terminus of Hsc70-interacting protein (CHIP) is a U-box-type ubiquitin ligase that induces ubiquitination and proteasomal degradation of its substrate proteins. In this study, we investigated the role of CHIP in the NF-κB pathway in the invasion of MDA-MB-231 cells, a highly aggressive breast cancer cell line. We showed that overexpression of CHIP significantly inhibits the invasion of the MDA-MB-231 cells. The overexpression of CHIP suppressed expression of urokinase plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in MDA-MB-231 cells. Moreover, CHIP strongly inhibited the nuclear localization and the transcriptional activity of NF-κB. The activation of the IkappaB kinase complex (IKK) was also blocked by CHIP overexpression. Importantly, CHIP overexpression resulted in a significant decrease in the level of TNF receptor-associated factor 2 (TRAF2), an upstream key player in the NF-κB pathway. However, the level of TRAF2 was restored after treatment with a proteasome inhibitor, MG-132. Moreover, CHIP overexpression promoted the ubiquitination of TRAF2. We also found cell invasion significantly decreased in cells transfected with TRAF2 small interfering RNA (siRNA). In contrast, when CHIP expression was suppressed by siRNA in poorly invasive MCF-7 cells, cell invasion significantly increased in conjunction with enhanced NF-κB activation and TRAF2 levels. Taken together, these results suggest that CHIP regulates NF-κB-mediated cell invasion via the down-regulation of TRAF2.

C-reactive protein induces p53-mediated cell cycle arrest in H9c2 cardiac myocytes.

C-reactive protein (CRP) is one of the most important biomarker for cardiovascular diseases. Recent studies have shown that CRP affects cell survival, differentiation and apoptosis. However, the effect of CRP on the cell cycle has not been studied yet. We investigated the cell cycle alterations and cellular mechanisms induced by CRP in H9c2 cardiac myocytes. Flow cytometry analysis showed that CRP-treated H9c2 cells displayed cell cycle arrest in G0/G1 phase. CRP treatment resulted in a significant reduction in the levels of CDK4, CDK6 and cyclin D1 in a concentration-dependent manner. Interestingly, CRP caused an increase in the p53 accumulation and its phosphorylation on Ser15, leading to induce p21 upregulation. Treatment with a specific p53 inhibitor, PFT-α restored the levels of CDK4 and CDK6. A significant increase of ERK1/2 phosphorylation level was detected in CRP-treated cells. Furthermore, pretreatment of a specific ERK inhibitor resulted in decreased p53 phosphorylation and p21 induction. ERK inhibitor pretreatment induced significant restoration of protein levels of CDK4 and CDK6, leading to re-entry into the cell cycle. In addition, increased phosphorylation of p53 and ERK induced by CRP was considerably reversed by Fc gamma receptor IIIa (FcγRIIIa) knock-down using siRNA. FcγRIIIa siRNA transfection also restored the levels of cell cycle proteins. Our study has provided the first proposal on the novel insights into how CRP directly affects cell cycle in cells.