High-performance blue OLED using multiresonance thermally activated delayed fluorescence host materials containing silicon atoms.

We report three highly efficient multiresonance thermally activated delayed fluorescence blue-emitter host materials that include 5,9-dioxa-13b-boranaphtho[3,2,1-de]anthracene (DOBNA) and tetraphenylsilyl groups. The host materials doped with the conventional N7,N7,N13,N13,5,9,11,15-octaphenyl-5,9,11,15-tetrahydro-5,9,11,15-tetraaza-19b,20b-diboradinaphtho[3,2,1-de:1',2',3'-jk]pentacene-7,13-diamine (ν-DABNA) blue emitter exhibit a high photoluminescence quantum yield greater than 0.82, a high horizontal orientation greater than 88%, and a short photoluminescence decay time of 0.96-1.93 µs. Among devices fabricated using six synthesized compounds, the device with (4-(2,12-di-tert-butyl-5,9-dioxa-13b-boranaphtho[3,2,1-de]anthracen-7-yl)phenyl)triphenylsilane (TDBA-Si) shows high external quantum efficiency values of 36.2/35.0/31.3% at maximum luminance/500 cd m-2/1,000 cd m-2. This high performance is attributed to fast energy transfer from the host to the dopant. Other factors possibly contributing to the high performance are a T1 excited-state contribution, inhibition of aggregation by the bulky tetraphenylsilyl groups, high horizontal orientation, and high thermal stability. We achieve a high efficiency greater than 30% and a small roll-off value of 4.9% at 1,000 cd m-2 using the TDBA-Si host material.

Learning From Noisy Labels With Deep Neural Networks: A Survey.

Deep learning has achieved remarkable success in numerous domains with help from large amounts of big data. However, the quality of data labels is a concern because of the lack of high-quality labels in many real-world scenarios. As noisy labels severely degrade the generalization performance of deep neural networks, learning from noisy labels (robust training) is becoming an important task in modern deep learning applications. In this survey, we first describe the problem of learning with label noise from a supervised learning perspective. Next, we provide a comprehensive review of 62 state-of-the-art robust training methods, all of which are categorized into five groups according to their methodological difference, followed by a systematic comparison of six properties used to evaluate their superiority. Subsequently, we perform an in-depth analysis of noise rate estimation and summarize the typically used evaluation methodology, including public noisy datasets and evaluation metrics. Finally, we present several promising research directions that can serve as a guideline for future studies.

Erythroid Differentiation Regulator 1 Strengthens TCR Signaling by Enhancing PLCγ1 Signal Transduction Pathway.

Erythroid differentiation regulator 1 (Erdr1) has previously been reported to control thymocyte selection via TCR signal regulation, but the effect of Erdr1 as a TCR signaling modulator was not studied in peripheral T cells. In this report, it was determined whether Erdr1 affected TCR signaling strength in CD4 T cells. Results revealed that Erdr1 significantly enhanced the anti-TCR antibody-mediated activation and proliferation of T cells while failing to activate T cells in the absence of TCR stimulation. In addition, Erdr1 amplified Ca2+ influx and the phosphorylation of PLCγ1 in CD4 T cells with the TCR stimuli. Furthermore, NFAT1 translocation into nuclei in CD4 T cells was also significantly promoted by Erdr1 in the presence of TCR stimulation. Taken together, our results indicate that Erdr1 positively modulates TCR signaling strength via enhancing the PLCγ1/Ca2+/NFAT1 signal transduction pathway.

Characterization of metapopulation of Ellobium chinense through Pleistocene expansions and four covariate COI guanine-hotspots linked to G-quadruplex conformation.

The land snail Ellobium chinense (L. Pfeiffer, 1855) (Eupulmonata, Ellobiida, Ellobiidae), which inhabits the salt marshes along the coastal areas of northwestern Pacific, is an endangered species on the IUCN Red List. Over recent decades, the population size of E. chinense has consistently decreased due to environmental interference caused by natural disasters and human activities. Here, we provide the first assessment of the genetic diversity and population genetic structures of northwestern Pacific E. chinense. The results analyzed with COI and microsatellites revealed that E. chinense population exhibit metapopulation characteristics, retaining under the influence of the Kuroshio warm currents through expansion of the Late-Middle and Late Pleistocene. We also found four phylogenetic groups, regardless of geographical distributions, which were easily distinguishable by four unidirectional and stepwise adenine-to-guanine transitions in COI (sites 207-282-354-420: A-A-A-A, A-A-G-A, G-A-G-A, and G-G-G-G). Additionally, the four COI hotspots were robustly connected with a high degree of covariance between them. We discuss the role of these covariate guanines which link to form four consecutive G-quadruplexes, and their possible beneficial effects under positive selection pressure.

Effective reconstruction of functional organotypic kidney spheroid for in vitro nephrotoxicity studies.

Stable and reproducible kidney cellular models could accelerate our understanding of diseases, help therapeutics development, and improve nephrotoxicity screenings. Generation of a reproducible in vitro kidney models has been challenging owing to the cellular heterogeneity and structural complexity of the kidney. We generated mixed immortalized cell lines that stably maintained their characteristic expression of renal epithelial progenitor markers for the different lineages of kidney cellular compartments via the BMP7 signaling pathway from a mouse and a human whole kidney. These cells were used to generate functional and matured kidney spheroids containing multiple renal lineages, such as the proximal tubule, loop of Henle, distal tubules, and podocytes, using extracellular matrix and physiological force, named spheroid-forming unit (SFU). They expressed all apical and basolateral transporters that are important for drug metabolism and displayed key functional aspects of the proximal tubule, including protein endocytosis and increased gamma-glutamyltransferase activity, and cyclic AMP responded to external cues, such as parathyroid hormone. Following exposure, cells fluxed and took up drugs via proximal tubule-specific apical or basolateral transporters, and displayed increased cell death and expression of renal injury marker. Here, we developed a new differentiation method to generate kidney spheroids that structurally recapitulate important features of the kidney effectively and reproducibly using mixed immortalized renal cells, and showed their application for renal toxicity studies.

Progranulin attenuates liver fibrosis by downregulating the inflammatory response.

Progranulin (PGRN) is a cysteine-rich secreted protein expressed in endothelial cells, immune cells, neurons, and adipocytes. It was first identified for its growth factor-like properties, being implicated in tissue remodeling, development, inflammation, and protein homeostasis. However, these findings are controversial, and the role of PGRN in liver disease remains unknown. In the current study, we examined the effect of PGRN in two different models of chronic liver disease, methionine-choline-deficient diet (MCD)-induced non-alcoholic steatohepatitis (NASH) and carbon tetrachloride (CCl4)-induced liver fibrosis. To induce long-term expression of PGRN, PGRN-expressing adenovirus was delivered via injection into the tibialis anterior. In the CCl4-induced fibrosis model, PGRN showed protective effects against hepatic injury, inflammation, and fibrosis via inhibition of nuclear transcription factor kappa B (NF-κB) phosphorylation. PGRN also decreased lipid accumulation and inhibited pro-inflammatory cytokine production and fibrosis in the MCD-induced NASH model. In vitro treatment of primary macrophages and Raw 264.7 cells with conditioned media from hepatocytes pre-treated with PGRN prior to stimulation with tumor necrosis factor (TNF)-α or palmitate decreased their expression of pro-inflammatory genes. Furthermore, PGRN suppressed inflammatory and fibrotic gene expression in a cell culture model of hepatocyte injury and primary stellate cell activation. These observations increase our understanding of the role of PGRN in liver injury and suggest PGRN delivery as a potential therapeutic strategy in chronic inflammatory liver disease.

Ubiquitination of MAP1LC3B by pVHL is associated with autophagy and cell death in renal cell carcinoma.

Von Hippel Lindau (VHL) expression is significantly decreased in high-grade RCC, and autophagy, which is involved in tumor growth, invasion, differentiation, and metastasis, is activated in various human cancers. However, the relationship of autophagy and VHL in tumor progression remains controversial. Here, we showed that the expression levels of VHL and microtubule-associated protein 1 light chain 3B (MAP1LC3B, LC3B) were inversely correlated with various tumor grades of RCC tissues. pVHL was found to possess the LIR motif within a beta domain that interacted with MAP1LC3B and ubiquitinated it. The L101A VHL mutant failed to interact with MAP1LC3B, thereby failing to induce ubiquitination. MAP1LC3B-mediated autophagy was inhibited by functional pVHL and the ubiquitination of MAPLC3B was implicated in autophagy-induced cell death. We screened various autophagy inducers to determine the physiological function of the inhibition of LC3B-mediated autophagy by pVHL using VHL-deficient and VHL-expressing cell lines. MLN9708, a proteasome inhibitor, potently induced autophagy via the induction of MAP1LC3B and sensitized the cell to autophagy-mediated cell death in VHL-deficient and VHL-mutant (L101A) cells. In conclusion, our results showed that pVHL interacts with MAPL1LC3B and inhibits LC3B-mediated autophagy via MAP1LC3B ubiquitination. Furthermore, the activation of autophagy by the proteasome inhibitor MLN9708 induced cell death, indicating that MLN9708 can be used for VHL-deficient RCC therapy.

Stabilization of E2-EPF UCP protein is implicated in hepatitis B virus-associated hepatocellular carcinoma progression.

Hepatitis B virus (HBV) X protein (HBx) is associated with hepatocarcinogenesis. E2-EPF ubiquitin carrier protein (UCP) catalyzes ubiquitination of itself and von Hippel-Lindau protein (pVHL) for degradation and associates with tumor growth and metastasis. However, it remains unknown whether HBx modulates the enzyme activity of UCP and thereby influences hepatocarcinogenesis. Here, we show that UCP is highly expressed in liver tissues of HBx-transgenic mice, but not non-transgenic mice. UCP was more frequently expressed in HBV-positive liver cancers than in HBV-negative liver cancers. HBx binds to UCP specifically and serotype independently, and forms a ternary complex with UCP and pVHL. HBx inhibits self-ubiquitination of UCP, but enhances UCP-mediated pVHL ubiquitination, resulting in stabilization of hypoxia-inducible factor-1α and -2α. HBx and UCP stabilize each other by mutually inhibiting their ubiquitination. HBx promotes cellular proliferation and metastasis via UCP. Our findings suggest that UCP plays a key role in HBV-related hepatocarcinogenesis.

Proteogenomic Characterization of Human Early-Onset Gastric Cancer.

We report proteogenomic analysis of diffuse gastric cancers (GCs) in young populations. Phosphoproteome data elucidated signaling pathways associated with somatic mutations based on mutation-phosphorylation correlations. Moreover, correlations between mRNA and protein abundances provided potential oncogenes and tumor suppressors associated with patient survival. Furthermore, integrated clustering of mRNA, protein, phosphorylation, and N-glycosylation data identified four subtypes of diffuse GCs. Distinguishing these subtypes was possible by proteomic data. Four subtypes were associated with proliferation, immune response, metabolism, and invasion, respectively; and associations of the subtypes with immune- and invasion-related pathways were identified mainly by phosphorylation and N-glycosylation data. Therefore, our proteogenomic analysis provides additional information beyond genomic analyses, which can improve understanding of cancer biology and patient stratification in diffuse GCs.

Identification of Protein Markers Specific for Papillary Renal Cell Carcinoma Using Imaging Mass Spectrometry.

Since the emergence of proteomics methods, many proteins specific for renal cell carcinoma (RCC) have been identified. Despite their usefulness for the specific diagnosis of RCC, such proteins do not provide spatial information on the diseased tissue. Therefore, the identification of cancer-specific proteins that include information on their specific location is needed. Recently, matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) based imaging mass spectrometry (IMS) has emerged as a new tool for the analysis of spatial distribution as well as identification of either proteins or small molecules in tissues. In this report, surgical tissue sections of papillary RCC were analyzed using MALDI-IMS. Statistical analysis revealed several discriminative cancer-specific m/z-species between normal and diseased tissues. Among these m/z-species, two particular proteins, S100A11 and ferritin light chain, which are specific for papillary RCC cancer regions, were successfully identified using LC-MS/MS following protein extraction from independent RCC samples. The expressions of S100A11 and ferritin light chain were further validated by immunohistochemistry of human tissues and tissue microarrays (TMAs) of RCC. In conclusion, MALDI-IMS followed by LC-MS/MS analysis in human tissue identified that S100A11 and ferritin light chain are differentially expressed proteins in papillary RCC cancer regions.

Overexpression of miR-17 in gastric cancer is correlated with proliferation-associated oncogene amplification.

The molecular mechanism underlying microRNA (miR)-17 overexpression has not been clearly evaluated in gastric cancer. We aimed to evaluate the functional roles of miR-17 in gastric cancer and test its viability as a therapeutic target. We conducted comparative genomic hybridization and expression array analyses on human gastric cancer tissue samples, as well as evaluating the functional roles of miR-17 in gastric cancer cell lines and transgenic mice. miR-17 overexpression in gastric cancer patients was associated with copy number gain of proliferation-associated oncogenes such as MYC, CCNE1, ERBB2, and FGFR2. Copy number gain of MIR17HG gene (13q31.3) was rare, with an overall frequency of 2% in gastric cancers (1 of 51). miR-17 knockdown suppressed the monolayer and anchorage-independent growth of FGFR2-amplified KATO-III gastric cancer cells. mir-17-92 TG/TG mice overexpressing the mir-17-92 cluster under the villin promoter developed spontaneous benign tumors in the intestinal tract (log-rank P for tumor-free survival = 0.069). Taken together, miR-17 overexpression in gastric cancer was rarely associated with MIR17HG gene amplification, but correlated with proliferation-associated oncogene amplification. Therefore, miR-17-targeting approach may benefit patients with gastric cancers harboring proliferation-associated oncogene amplification.

Korean red ginseng (Panax ginseng) prevents obesity by inhibiting angiogenesis in high fat diet-induced obese C57BL/6J mice.

Adipose tissue growth and development are thought to be associated with angiogenesis and extracellular matrix remodeling. Because ginseng has been shown to inhibit angiogenesis and matrix metalloproteinase (MMP) activity, we hypothesized that adipose tissue growth and obesity can be regulated by Korean ginseng (Panax ginseng C.A. Meyer). Wild-type C57BL/6J mice were fed for 8 weeks with a low fat diet, a high fat diet (HFD), or HFD supplemented with 0.5% or 5% Korean red ginseng extract. We measured body weight, adipose tissue mass, food intake, MMP activity, and the expression of genes involved in angiogenesis and MMPs. Administering ginseng to HFD-induced obese mice produced reductions in body weight and adipose tissue mass compared with untreated counterparts. Ginseng treatment decreased blood vessel density and MMP activity in adipose tissues. Ginseng also reduced mRNA levels of angiogenic factors (e.g., VEGF-A and FGF-2) and MMPs (e.g., MMP-2 and MMP-9), whereas it increased mRNA levels of angiogenic inhibitors (e.g., TSP-1, TIMP-1, and TIMP-2) in adipose tissues. These results demonstrate that ginseng effectively reduces adipose tissue mass and prevents obesity in diet-induced obese mice and that this process may be mediated in part through the anti-angiogenic actions of ginseng.

Ginseng and Its Active Components Ginsenosides Inhibit Adipogenesis in 3T3-L1 Cells by Regulating MMP-2 and MMP-9.

The growth and development of adipose tissue are believed to require adipogenesis, angiogenesis, and extracellular matrix remodeling. As our previous study revealed that ginseng reduces adipose tissue mass in part by decreasing matrix metalloproteinase (MMP) activity in obese mice, we hypothesized that adipogenesis can be inhibited by ginseng and its active components ginsenosides (GSs). Treatment of 3T3-L1 adipocytes with Korean red ginseng extract (GE) inhibited lipid accumulation and the expression of adipocyte-specific genes (PPARγ, C/EBPα, aP2, and leptin). GE decreased both the mRNA levels and activity of MMP-2 and MMP-9 in 3T3-L1 cells. These effects were further inhibited by total GSs (TGSs) and individual GSs. TGSs and individual GSs also significantly decreased MMP-2 and MMP-9 reporter gene activities in the presence of phorbol 12-myristate 13-acetate (PMA), the MMP inducer. Among the GSs, Rb1 most effectively inhibited MMP activity. In addition, PMA treatment attenuated the inhibitory actions of GE and GSs on adipogenesis. Moreover, GE and GSs reduced the expression of NF-κB and AP-1, the transcription factors of MMP-2 and MMP-9. These results demonstrate that ginseng, in particular GSs, effectively inhibits adipogenesis and that this process may be mediated in part through the suppression of MMP-2 and MMP-9. Thus, ginseng and GSs likely have therapeutic potential for controlling adipogenesis.

Compound K, a novel ginsenoside metabolite, inhibits adipocyte differentiation in 3T3-L1 cells: involvement of angiogenesis and MMPs.

Compound K, a novel ginsenoside metabolite formed by intestinal bacteria, is shown to inhibit angiogenesis and matrix metalloproteinase (MMP) activities. Since growth and development of adipose tissue are thought to require adipogenesis, angiogenesis, and extracellular matrix remodeling, we investigated whether compound K inhibits adipocyte differentiation and its potential mechanisms. Treatment of 3T3-L1 adipocytes with compound K inhibited lipid accumulation and expression of adipocyte-specific genes (i.e., PPARγ, leptin, aP2, and C/EBPα). Compound K decreased mRNA levels of angiogenic factors (i.e., VEGF-A and FGF-2) and MMPs (i.e., MMP-2 and MMP-9), whereas it increased mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2) in 3T3-L1 cells. MMP-2 and MMP-9 activities were also decreased in compound K-treated cells. These results demonstrate that compound K effectively inhibited adipogenesis and that this process may be mediated in part through changes in the expression of genes involved in angiogenesis and MMP system. Thus, by suppressing adipogenesis, compound K likely has therapeutic potential for the treatment of obesity and related disorders.

Development of chitosan-based ondansetron buccal delivery system for the treatment of emesis.

BACKGROUND: For the buccal drug delivery, chitosan (CS) can be used to improve drug absorption and reduce application frequency and drug amount. The aim of this study is to develop and evaluate mucoadhesive ondansetron buccal films for the treatment of emesis using CS as a mucoadhesive polymer. METHODS: The film prepared by solvent casting method was comprised of ondansetron (approximately 65 µg)-loaded mucoadhesive gels containing 1, 2 or 3% CS and impermeable backing layer. Rheological property of the gels, physiochemical properties of the films (weight, thickness, drug content, swelling ratio, adhesion time and mucoadhesive force) and in vitro ondansetron release profile from the films were determined to evaluate the formulation. The films containing 3% CS (diameter: 0.5 cm; thickness: 170 µm) was selected as the novel formulation, and were used for the in vivo study. Comparative pharmacokinetic studies of ondansetron with this film and oral solution were performed at the same dose in hamsters. RESULTS: The mean values of T(max) and C(max) of the film and oral solution were similar. However, the half-life, mean residence time and AUC(0-24 h) of the film were about 1.7, 1.4 and 2.0-fold higher than those of the oral solution, respectively. The film showed enhanced bioavailability and prolonged efficacy compared to the oral solution. CONCLUSIONS: The mucoadhesive ondansetron buccal film may be a potential alternative to the marketed oral formulation, parenterals and solid suppositories with better patient compliance and higher bioavailability for the treatment of emesis.

The herbal composition GGEx18 from Laminaria japonica, Rheum palmatum, and Ephedra sinica reduces obesity via skeletal muscle AMPK and PPARα.

CONTEXT: Since AMP-activated protein kinase (AMPK) activation in skeletal muscle of obese rodents stimulates fatty acid oxidation, it is reasonable to hypothesize that pharmacological activation of AMPK might be of therapeutic benefit in obesity. OBJECTIVE: To investigate the effects of the traditional Korean anti-obesity drug GGEx18, a mixture of three herbs, Laminaria japonica Aresch (Laminariaceae), Rheum palmatum L. (Polygonaceae), and Ephedra sinica Stapf (Ephedraceae), on obesity and the involvement of AMPK in this process. MATERIALS AND METHODS: After high fat diet-induced obese mice were treated with GGEx18, we studied the effects of GGEx18 on body weight, fat mass, skeletal muscle lipid accumulation, and the expressions of AMPK, peroxisome proliferator-activated receptor ά (PPARα), and PPARα target genes. The effects of GGEx18 and/or the AMPK inhibitor compound C on lipid accumulation and expression of the above genes were measured in C2C12 skeletal muscle cells. RESULTS: Administration of GGEx18 to obese mice for 9 weeks significantly (p < 0.05) decreased body and adipose tissue weights compared with obese control mice (p < 0.05). Lipid accumulation in skeletal muscle was inhibited by GGEx18. GGEx18 significantly (p < 0.05) increased skeletal muscle mRNA levels of AMPKα1 and AMPKα2 as well as PPARα and its target genes. Consistent with the in vivo data, GGEx18 inhibited lipid accumulation, and similar activation of genes was observed in GGEx18-treated C2C12 cells. However, compound C inhibited these effects in C2C12 cells. DISCUSSION AND CONCLUSION: These results suggest that GGEx18 improves obesity through skeletal muscle AMPK and AMPK-stimulated expression of PPARα and its target enzymes for fatty acid oxidation.

The Korean traditional medicine gyeongshingangjeehwan inhibits adipocyte hypertrophy and visceral adipose tissue accumulation by activating PPARalpha actions in rat white adipose tissues.

AIM OF THE STUDY: Gyeongshingangjeehwan (GGEx), which is a polyherbal drug composed of four medicinal plants, has traditionally been used as anti-obesity drug in Korean local clinics. Thus, we investigated the effects of GGEx on visceral adiposity and examined whether adipose peroxisome proliferator-activated receptor alpha (PPARalpha) activation is involved in this process. MATERIALS AND METHODS: After Obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats and differentiated 3T3-L1 adipocytes were treated with GGEx, we studied the effects of GGEx on not only visceral white adipose tissue (WAT) mass and adipocyte size, but also the expression of adipocyte marker and PPARalpha target genes. RESULTS: Administration of GGEx to obese rats for 8 weeks decreased visceral WAT weight by 30% and the size of adipocytes in mesenteric WAT by 31% without weight changes of other organs. Concomitantly, GGEx increased mRNA levels of PPARalpha target genes responsible for fatty acid beta-oxidation in mesenteric WAT whereas decreased mRNA expression of adipocyte markers, such as PPARgamma, aP2 and leptin. Serological studies demonstrated that plasma levels of free fatty acids and triglycerides as well as insulin and glucose were decreased following GGEx treatment. Consistent with the in vivo data, GGEx increased PPARalpha reporter gene activity and induced the mRNA expression of PPARalpha target genes involved in mitochondrial fatty acid beta-oxidation in 3T3-L1 cells. GGEx also inhibited triglyceride accumulation in these cells. CONCLUSION: These results suggest that GGEx promotes the reductions in visceral fat mass and adipocyte size in obese animals, and that this event may be mediated by adipose PPARalpha activation.