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The purpose of this paper is to quickly and accurately perform the maximum power point tracking (MPPT) of a photovoltaic panel in accordance with the surrounding environment of variously changing photovoltaic systems. In this photovoltaic system, a power conversion system is configured with a differential power processing (DPP) structure to perform MPPT, and a method for improving this MPPT performance is proposed. MPPT is performed using the charging characteristics of the attached capacitor for voltage smoothing of the MPPT PV panel based on the proposed voltage reference model. The voltage reference model-based MPPT was applied to the proposed DPP structured photovoltaic system. Therefore, by enabling the expansion of the application of a high-efficiency photovoltaic system that has better power generation performance and can be adapted to various climate and temperature changes, a safer power generation system having less power loss was implemented to verify performance. It is also expected that by reducing the number of sensors in the system, annual maintenance costs will be reduced.

Complex and unsteady flow patterns occur around rotating rotor blades owing to the generation of shock waves at the blade tip and interference between the blade and tip wake when the blade rotates at high speeds, thereby resulting in specific noise characteristics. Furthermore, these noise characteristics cause noise pollution in private areas and degrade detectability of helicopters in military applications. Therefore, it is important to accurately analyze noise characteristics around rotor blades. In this study, a novel computational methodology with a chimera wake grid was proposed to efficiently and accurately predict high-speed impulsive (HSI) noise due to the shock wave at the blade tip. The proposed method enables accurate analysis of a complex flow region by overlapping a wake grid in the vicinity of shock waves. A 1/7-scaled UH-1H rotor blade was used to compare and verify the accuracy of HSI noise prediction and computational efficiency. The chimera grid method was applied to the present simulation for considering the blade motion and moving effects. A permeable surface for wrapping the surface of the physical blade was constructed to include quadrupole noise source generated from the control volume, thickness noise source, and loading noise source. Furthermore, the permeable Ffowcs Williams and Hawkings (FW–H) equations were used with the Kirchhoff approach to realize efficient far-field noise prediction. The proposed HSI noise analysis via chimera wake grid indicated that the strength of the shock wave is more precisely predicted, thereby resulting in improved prediction of the HSI noise. The proposed chimera methodology allows efficient noise prediction using a much coarser background grid system.

Two-dimensional molybdenum disulfide (MoS2) nanosheets have attracted great attention for electrochemical storage and conversion, but the scalable preparation of highly conductive and stable MoS2 n...

Flexible, thin, and lightweight supercapacitors have been regarded as important power sources for portable and wearable electronics; however, these are usually limited by relatively low areal or vo...

We report potentiometric performances of ion-to-electron transducer based on reduced graphene oxide (RGO) for application of all-solid-state potassium ion sensors. A large surface area and pore structure of RGO are obtained by a hydrothermal self-assembly of graphene oxide. The extensive electrochemical characterization of RGO solid contact at the interface of ion-selective membrane and gold electrode shows that the potassium ion-selective electrode based on RGO had a high sensitivity (53.34 mV/log[K+]), a low detection of limit (− 4.24 log[K+], 0.06 mM) a good potential stability, and a high resistance to light and gas interferences. The potentiometric K+-sensor device was fabricated by combining of screen-printed electrodes and a printed circuit board. The K+-sensor device accurately measures the ion concentration of real samples of commercial sports drinks, coke and orange juice, and then transfers the collected data to a mobile application through a Bluetooth module. The screen-printed ion sensors based on RGO solid contact show a great potential for real-time monitoring and point-of-care devices in human health care, water-treatment process, and environmental and chemical industries.

Juvenile Oncorhynchus mykiss (average weight: 22.3 g) were fed one of five selenomethionine diets (1.09, 8.79, 15.37, 30.79, or 61.58 mg Se/kg diet). After 4 weeks, hepatic catalase activity over 15.37 mg Se/kg diets was significantly decreased, and the glutathione peroxidase activity over 30.79 mg Se/kg diets was elevated compared to the controls. In the brain, the dopamine levels at 61.58 mg Se/kg diet and the serotonin levels over 15.37 mg Se/kg diets were significantly increased, whereas the 3,4-dihydroxyphenylacetic acid, homovanillic acid, and dopamine turnover, and the 5-hydroxyindoleacetic acid and serotonin turnover over 30.79 mg Se/kg diets were decreased. In muscle, the 3-nitrotyrosine level over 15.37 mg Se/kg diets, acetylcholine esterase activity over 30.79 mg Se/kg diets, and histological alterations over 8.79 mg Se/kg diets were increased. Our current results showed that selenomethionine disrupted dopamine and serotonin metabolism in the brain and damaged the neuromuscular system in skeletal muscle.

Most manganese oxide-based electrodes used for energy-storage applications suffer from poor ion and electron transport, particularly at high mass loadings and with thick electrodes. To counter this issue, 3D electrodes were developed; however, enhancing their areal and volumetric performance at high mass loadings is still a challenge. In this study, highly compact and 3D porous manganese dioxide and holey reduced graphene oxide (3D MnO2/HRGO) composite films were developed to ensure a high performance in supercapacitors at electrode thicknesses greater than 100 µm. The thick composite films were fabricated by the self-limiting deposition of MnO2 on 3D HRGO hydrogel scaffolds followed by capillary evaporation-induced drying. The 3D MnO2/HRGO electrodes optimized at a thickness of 216 μm showed outstanding specific areal and volumetric capacitances of 2.3 F cm−2 and 108.0 F cm−3 at 1 mA cm−2 and an impressive rate capability with a capacitance retention of 72.2% in the range of 1–40 mA cm−2. Furthermore, supercapacitors assembled with the 3D MnO2/HRGO electrodes with high mass loadings exhibited impressively high areal and volumetric energy densities of 149.7 μWh cm−2 and 2.8 mWh cm−3, respectively.

ObjectiveInterferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections.DesignWe explored the cellular targets of HBV in response to IFNs using proteome-wide screening.ResultsUsing LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5′-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22.ConclusionsWe verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system.

Activation of L-type voltage-dependent Ca2+ channels (VDCCL) by membrane stretch contributes to many biological responses such as myogenic contraction of arteries. However, mechanism for the stretch-induced VDCCL activation is unclear. In this study, we examined the hypothesis that caveolar remodeling and its related signaling cascade contribute to the stretch-induced activation of VDCCL in rat mesenteric arterial smooth muscle cells. The VDCCL currents were recorded with nystatin-perforated or with conventional whole-cell patch-clamp technique. Hypotonic (~230 mOsm) swelling-induced membrane stretch reversibly increased the VDCCL currents. Electron microscope and confocal imaging analysis revealed that both hypotonic swelling and cholesterol depletion by methyl-β-cychlodextrin (MβCD) similarly disrupted the caveolae structure and translocated caveolin-1 (Cav-1) from membrane to cytosolic space. Accordingly, MβCD also increased VDCCL currents. Moreover, subsequent hypotonic swelling after MβCD treatment failed to increase the VDCCL currents further. Western blotting experiments revealed that hypotonic swelling phosphorylated Cav-1 and JNK. Inhibitors of tyrosine kinases (genistein) and JNK (SP00125) prevented the swelling-induced facilitation of VDCCL currents. Knockdown of Cav-1 by small interfering RNA blocked both the VDCCL current facilitation by stretch and the related phosphorylation of JNK. Taken together, the results suggest that membrane stretch is transduced to the facilitation of VDCCL currents via caveolar structure-dependent tyrosine phosphorylation of Cav-1 and subsequent activation of JNK in rat mesenteric arterial myocytes.

Lipid rafts (LRs) play crucial roles in complex physiological processes, modulating innate and acquired immune responses to pathogens. The transmembrane C-type lectins human dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and its mouse homolog SIGN-R1 are distributed in LRs and expressed on splenic marginal zone (MZ) macrophages. The DC-SIGN-C1q or SIGN-R1-C1q complex could mediate the immunoglobulin (Ig)-independent classical complement pathway against Streptococcus pneumoniae. Precise roles of LRs during this complement pathway are unknown. Here we show that LRs are indispensable for accelerating the DC-SIGN- or SIGN-R1-mediated classical complement pathway against S. pneumoniae, thus facilitating rapid clearance of the pathogen. The trimolecular complex of SIGN-R1-C1q-C4 was exclusively enriched in LRs of splenic MZ macrophages and their localization was essential for activating C3 catabolism and enhancing pneumococcal clearance, which were abolished in SIGN-R1-knockout mice. However, DC-SIGN replacement on splenic MZ macrophage’s LRs of SIGN-R1-depleted mice reversed these defects. Disruption of LRs dramatically reduced pneumococcal uptake and decomposition. Additionally, DC- SIGN, C1q, C4, and C3 were obviously distributed in splenic LRs of cadavers. Therefore, LRs on splenic SIGN-R1+ or DC-SIGN+ macrophages could provide spatially confined and optimal bidirectional platforms, not only for usual intracellular events, for example recognition and phagocytosis of pathogens, but also an unusual extracellular event such as the complement system. These findings improve our understanding of the orchestrated roles of the spleen, unraveling a new innate immune system initiated from splenic MZ LRs, and yielding answers to several long-standing problems, including the need to understand the profound role of LRs in innate immunity, the need to identify how such a small portion of splenic SIGN-R1+ macrophages (S. pneumoniae, and the need to understand how LRs can promote the protective function of DC-SIGN against S. pneumoniae in the human spleen.

Lipid rafts (LRs) play crucial roles in complex physiological processes, modulating innate and acquired immune responses to pathogens. The transmembrane C-type lectins human dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and its mouse homolog SIGN-R1 are distributed in LRs and expressed on splenic marginal zone (MZ) macrophages. The DC-SIGN-C1q or SIGN-R1-C1q complex could mediate the immunoglobulin (Ig)-independent classical complement pathway against Streptococcus pneumoniae. Precise roles of LRs during this complement pathway are unknown. Here we show that LRs are indispensable for accelerating the DC-SIGN- or SIGN-R1-mediated classical complement pathway against S. pneumoniae, thus facilitating rapid clearance of the pathogen. The trimolecular complex of SIGN-R1-C1q-C4 was exclusively enriched in LRs of splenic MZ macrophages and their localization was essential for activating C3 catabolism and enhancing pneumococcal clearance, which were abolished in SIGN-R1-knockout mice. However, DC-SIGN replacement on splenic MZ macrophage’s LRs of SIGN-R1-depleted mice reversed these defects. Disruption of LRs dramatically reduced pneumococcal uptake and decomposition. Additionally, DC- SIGN, C1q, C4, and C3 were obviously distributed in splenic LRs of cadavers. Therefore, LRs on splenic SIGN-R1+ or DC-SIGN+ macrophages could provide spatially confined and optimal bidirectional platforms, not only for usual intracellular events, for example recognition and phagocytosis of pathogens, but also an unusual extracellular event such as the complement system. These findings improve our understanding of the orchestrated roles of the spleen, unraveling a new innate immune system initiated from splenic MZ LRs, and yielding answers to several long-standing problems, including the need to understand the profound role of LRs in innate immunity, the need to identify how such a small portion of splenic SIGN-R1+ macrophages (

Two-dimensional (2D) materials have been extensively studied as promising heterogeneous catalysts because of their high surface area, outstanding mechanical strength, and excellent chemical and thermal stability. Herein, we report an efficient and simple two-step strategy for the synthesis of 2D holey and ultrathin MnO2/graphene oxide nanosheets. As a 2D nanoporous support, holey graphene oxide (HGO) nanosheets are prepared by an oxidative etching method. The uniform and conformal deposition of MnO2 onto the HGO surface is performed by a solution-based self-limiting redox reaction, resulting in nanoporous MnO2/HGO nanosheets with a high surface area. The resulting MnO2/HGO shows outstanding catalytic performance for the glycolysis of polyethylene terephthalate (PET). A high conversion of PET (100%) and a high yield of a bis(hydroxyethyl) terephthalate (BHET) are achieved within a short reaction time of 10 min at a reaction temperature of 200 °C. Furthermore, the MnO2/HGO catalyst shows excellent recyclability for the glycolysis of PET; a BHET yield of 100% is obtained after 5 cycles.

Although previous studies have suggested that neuronal nitric oxide synthase (nNOS)-derived NO has neuroprotective effects on the development of Alzheimer’s disease (AD), the underlying molecular mechanisms are not fully elucidated. Here, we investigated whether and how disruption of nNOS dimerization contributes to the development of AD. No differences in synaptic number or expression of synaptic markers, including synaptophysin and postsynaptic density 95, were found in the cortex of 5 × FAD mice, which possess 5 familial AD mutations, at 6 months of age compared with control littermates. nNOS dimerization was disrupted in the 5 × FAD cortex, accompanied by an increase in reactive oxygen species (ROS) production. The subcellular distribution of cyclin-dependent kinase 5 (CDK5) shifted more diffusely toward a cytosolic compartment, but there was no change in total expression. Furthermore, the levels of p25, a CDK5 activator, increased significantly and it colocalized with nNOS in the 5 × FAD cortex. In silico analysis revealed that a new nNOS-specific GSP (glycine-serine-proline) motif was well-conserved across species at nNOS-Ser 293 , which is located ahead of the N-terminal hook. This motif was not present in the closely related isoform, endothelial NOS. Motif scan analysis also predicted that CDK5 can phosphorylate nNOS-Ser 293 with a high likelihood. An in vitro phosphorylation assay clearly showed that CDK5/p25 does indeed phosphorylate nNOS-Ser 293 . Finally, nNOS-S293D mutant, a phosphomimetic form of nNOS-Ser 293 , and nNOS-S293A mutant, a neutral form of nNOS-Ser 293 , significantly decreased nNOS dimerization and NO production. Taken together, our results demonstrate that nNOS dimers are disrupted in the 5 × FAD cortex, and nNOS-Ser 293 , a potential site of CDK5 phosphorylation, may be involved in the decrease in nNOS dimerization and NO production, and the development of AD.

Three-dimensional flows of Mach number 3 around a double-compression ramp with finite span have been investigated numerically. Shadowgraph visualisation images obtained in a supersonic wind tunnel are used for comparison. A three-dimensional Reynolds-averaged Navier–Stokes solver was used to obtain steady numerical solutions. Two-dimensional numerical results are also compared. Four different cases were studied: two different second ramp angles of $${30}^{\circ }$$ and $${45}^{\circ }$$ in configurations with and without sidewalls, respectively. Results showed that there is a leakage of mass and momentum fluxes heading outwards in the spanwise direction for three-dimensional cases without sidewalls. The leakage changed the flow characteristics of the shock-induced boundary layer and resulted in the discrepancy between the experimental data and two-dimensional numerical results. It is found that suppressing the flow leakage by attaching the sidewalls enhances the two-dimensionality of the experimental data for the double-compression ramp flow.

International audience; BACKGROUND & AIMS: Cytokines are key molecules implicated in the defense against virus infection. Tumor necrosis factor-alpha (TNF-alpha) is well known to block the replication of hepatitis B virus (HBV). However, the molecular mechanism and the downstream effector molecules remain largely unknown. METHODS: In this study, we investigated the antiviral effect and mechanism of p22-FLIP (FLICE-inhibitory protein) by ectopic expression in vitro and in vivo. In addition, to provide the biological relevance of our study, we examined that the p22-FLIP is involved in TNF-alpha-mediated suppression of HBV in primary human hepatocytes. RESULTS: We found that p22-FLIP, a newly discovered c-FLIP cleavage product, inhibited HBV replication at the transcriptional level in both hepatoma cells and primary human hepatocytes, and that c-FLIP conversion to p22-FLIP was stimulated by the TNF-alpha/NF-kappaB pathway. p22-FLIP inhibited HBV replication through the upregulation of HNF3beta but downregulation of HNF4alpha, thus inhibiting both HBV enhancer elements. Finally, p22-FLIP potently inhibited HBV DNA replication in a mouse model of HBV replication. CONCLUSIONS: Taken together, these findings suggest that the anti-apoptotic p22-FLIP serves a novel function of inhibiting HBV transcription, and mediates the antiviral effect of TNF-alpha against HBV replication

Physical inactivity and high-fat diet, especially high saturated fat containing diet are established risk factors for breast cancer that are amenable to intervention. High-fat diet has been shown to induce tumor growth and metastasis by alteration of inflammation but steady exercise has anti-tumorigenic effects. However, the mechanisms underlying the effects of physical activity on high-fat diet stimulated breast cancer initiation and progression are currently unclear. In this study, we examined how the intensity of physical activity influences high fat diet-stimulated breast cancer latency and progression outcomes, and the possible mechanisms behind these effects. Five-week-old female Balb/c mice were fed either a control diet or a high-fat diet for 8 weeks, and then 4T1 mouse mammary tumor cells were inoculated into the mammary fat pads. Exercise training occurred before tumor cell injection, and tumor latency and tumor volume were measured. Mice with a high-fat diet and low-intensity exercise (HFLE) had a longer tumor latency period, slower tumor growth, and smaller tumor volume in the final tumor assessment compared with the control, high-fat diet control (HFDC), and high-fat diet with moderate-intensity exercise (HFME) groups. Steady low- and moderate-intensity exercise had no effect on cell proliferation but induced apoptosis by activating caspase-3 through the alteration of Bcl-2, Bcl-xL, and Bax expression. Furthermore, steady exercise reduced M2 macrophage polarization in breast tumor tissue, which has been linked to tumor growth. The myokine, myostatin, reduced M2 macrophage polarization through the inhibition of the JAK-STAT signaling pathway. These results suggest that steady low-intensity exercise could delay breast cancer initiation and growth and reduce tumor volume through the induction of tumor cell apoptosis and the suppression of M2 macrophage polarization.

Hypertensive disorders of pregnancy (HDP) is major complication of maternal-fetal outcomes in obstetric field. Although HDP is mainly defined by high blood pressure, the information about the relationship between prehypertension (preHTN, 120-139mmHg and 80-89mmHg) and HDP development is limited. The objective of this study is to determine the usefulness of preHTN before 20 weeks gestation and uterine artery (UtA) Doppler velocimetry as a predictor of HDP. A total of 2039 singleton pregnant women who had received continuous prenatal care were included in this study. The participants were classified into 2 groups based on the highest blood pressure (BP) under 20 gestational weeks as defined by the Joint National Committee 7: Normotensive (n = 1816) and preHTN pregnant women (n = 223). All preHTN pregnant women were assessed using UtA Doppler velocimetry, and the numbers of preHTN assessments were recorded. The risk of HDP was assessed in the PreHTN groups through patient history and Doppler velocimetry. Compared to normotensive patients, a total of 223 preHTN patients had a higher risk of preeclampsia (OR: 2.3; CI: 1.2-4.3), gestational hypertension (OR: 3.3; CI: 2.0-5.4) and any HDP (OR: 3.0; CI: 2.0-4.5). In the preHTN group, 134 (60.1%) patients had preHTN measured at least twice and 89 (39.9%) patients had preHTN. The results showed that two or more preHTN measurements have high sensitivity for predicting HDP (OR: 1.9; CI: 1.0-3.1; sensitivity: 83.8%; specificity: 47.2%). Additionally, the combination of abnormal UtA Doppler velocimetry results and at least two preHTN measurements showed a high accuracy in predicting HDP (OR: 2.9; CI: 1.1-4.1; sensitivity: 67.6%; specificity: 98.4%). In conclusion, close BP monitoring and recording of every preHTN event are important for pregnant women with preHTN history, and UtA Doppler examination in those women during the 2nd trimester can be a further aid in determining the risk of HDP.

This article overall describes the development of histological method especially, cartilage and bone research in regenerative medicine. Kawamoto’s film method, which has been recently introduced into our laboratory, has been applied in various fields that make sectioning of hard tissues easier than the conventional method. Moreover, this method also does not require the time-consuming chemical fixation and/or decalcification process. Kawamoto method involves the use of the adhesive plastic film instead of a cover glass where the thin tissue sections are attached efficiently at low temperatures (-25°C). Furthermore, the histological method preserves the enzymatic activity in the fresh sections in comparison to that of chemically-treated tissue sections. In fact, we used this Kawamoto’s film method in one of our researches in which drug repositioning was employed for cartilage regeneration. Some of the Kawamoto-processed tissue sections are featured in this review article. Therefore, the application of this tissue preparation technique allowed effective and histological and histochemical studies within a shorter preparation time with ease and convenience. In the future, this Kawamoto method may offer further applications in the preparation of a more diverse tissues and samples not only in the preclinical but also in the clinical studies.

This research aims to find information level-based system for building information management about each design stage. Even though BIM model is built for the design aspect, it is difficult that the BIM data are utilized in the next process such as construction stage or analyzation stage. In order to accumulate building information and to reduce the leakage of building information, various researches and projects for exchanging information such as COBie and SPie are being undertaken in many countries. This research analyzes COBie, which is the de facto standard in US and UK, and suggests ways of adopting this format in the Korean construction practically. In addition, authors suggest the COBie-based new criteria and defines contents and roles in each stage for more effective application of the analyzed results. Pre-checking modules are also developed to validate the data extracted based on suggested Information-level in six stages of building design. Through the suggested criterion, managed information in each construction phase are verified explicitly and the accumulated information enables the Building Information Model to apply more in various design phases.

Immune tolerance at feto-maternal interfaces is a complex phenomenon. Although maternal decidual macrophages are well-known immune cells, little is known about fetal-derived macrophages (Hofbauer cells) within chorionic villi. Preeclampsia (PE) is a major cause of maternal mortality in the field of obstetrics, and the innate immunological role of maternal decidual macrophages is well known. In this study, we assessed the differential phenotypes and marker expression in fetal macrophages, known as dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN)-positive Hofbauer cells. We compared Hofbauer cell properties between normal and PE placenta chorionic villi and performed sequential staining of DC-SIGN, CD14, and CD68 to evaluate the existence of Hofbauer cells. Furthermore, to evaluate the immunological function of these cells, we stained the cells for CD163, a marker of immunoregulatory type 2 (M2) macrophages. Additionally, we examined the expression of the immunosuppressive cytokine interleukin (IL)-10, which is known to be produced by M2 macrophages. DC-SIGN+/CD14+, DC-SIGN+/CD68+, and CD163+/DC-SIGN+ cells were quantified based on photomicrographs. The results showed that CD14, CD163, DC-SIGN, and IL-10 levels were significantly downregulated in PE compared with normal. Additionally, CD163+/DC-SIGN+ Hofbauer cells were significantly less frequent in PE than in normal. DC-SIGN Hofbauer cells produced IL-10 at lower levels in the PE than in the normal. Thus, we speculate that fetal-derived Hofbauer cells may play an important role in normal pregnancy with immunosuppressive effects based on their M2 macrophage characteristics to maintain immune tolerance during pregnancy. Additionally, in PE, these functions were defective, supporting the roles of these macrophages in PE development.

Preconception exposure to EtOH through the paternal route may affect neurobehavioral and developmental features of offspring. This study investigates the effects of paternal exposure to EtOH before conception on the hyperactivity, inattention, and impulsivity behavior of male offspring in mice. Sire mice were treated with EtOH in a concentration range approximating human binge drinking (0-4 g/kg/day EtOH) for 7 weeks and mated with untreated females mice to produce offspring. EtOH exposure to sire mice induced attention deficit hyperactivity disorder (ADHD)-like hyperactive, inattentive, and impulsive behaviors in offspring. As a mechanistic link, both protein and mRNA expression of dopamine transporter (DAT), a key determinant of ADHD-like phenotypes in experimental animals and humans, were significantly decreased by paternal EtOH exposure in cerebral cortex and striatum of offspring mice along with increased methylation of a CpG region of the DAT gene promoter. The increase in methylation of DAT gene promoter was also observed in the sperm of sire mice, suggesting germline changes in the epigenetic methylation signature of DAT gene by EtOH exposure. In addition, the expression of two key regulators of methylation-dependent epigenetic regulation of functional gene expression, namely, MeCP2 and DNMT1, was markedly decreased in offspring cortex and striatum sired by EtOH-exposed mice. These results suggest that preconceptional exposure to EtOH through the paternal route induces behavioral changes in offspring, possibly via epigenetic changes in gene expression, which is essential for the regulation of ADHD-like behaviors.

Korean Red Ginseng (KRG) is an oriental herbal preparation obtained from Panax ginseng Meyer (Araliaceae). To expand our understanding of the action of KRG on central nervous system (CNS) function, we examined the effects of KRG on tissue plasminogen activator (tPA)/plasminogen activator inhibitor-1 (PAI-1) expression in rat primary astrocytes. KRG extract was treated in cultured rat primary astrocytes and neuron in a concentration range of 0.1 to 1.0 mg/mL and the expression of functional tPA/PAI-1 was examined by casein zymography, Western blot and reverse transcription-polymerase chain reaction. KRG extracts increased PAI-1 expression in rat primary astrocytes in a concentration dependent manner (0.1 to 1.0 mg/mL) without affecting the expression of tPA itself. Treatment of 1.0 mg/mL KRG increased PAI-1 protein expression in rat primary astrocytes to 319.3±65.9% as compared with control. The increased PAI-1 expression mediated the overall decrease in tPA activity in rat primary astrocytes. Due to the lack of PAI-1 expression in neuron, KRG did not affect tPA activity in neuron. KRG treatment induced a concentration dependent activation of PI3K, p38, ERK1/2, and JNK in rat primary astrocytes and treatment of PI3K or MAPK inhibitors such as LY294002, U0126, SB203580, and SP600125 (10 μM each), significantly inhibited 1.0 mg/mL KRG-induced expression of PAI- 1 and down-regulation of tPA activity in rat primary astrocytes. Furthermore, compound K but not other ginsenosides such as Rb1 and Rg1 induced PAI-1 expression. KRG-induced up-regulation of PAI-1 in astrocytes may play important role in the regulation of overall tPA activity in brain, which might underlie some of the beneficial effects of KRG on CNS such as neuroprotection in ischemia and brain damaging condition as well as prevention or recovery from addiction.

Liver regeneration after liver damage caused by toxins and pathogens is critical for liver homeostasis. Retardation of liver proliferation was reported in hepatitis B virus (HBV) X protein (HBx)-transgenic mice. However, the underlying mechanism of the HBx-mediated disturbance of liver regeneration is unknown. We investigated the molecular mechanism of the inhibition of liver regeneration using liver cell lines and a mouse model. The mouse model of acute HBV infection was established by hydrodynamic injection of viral DNA. Liver regeneration after partial hepatectomy was significantly inhibited in the HBV DNA-treated mice. Mechanism studies have revealed that the expression of urokinase-type plasminogen activator (uPA), which regulates the activation of hepatocyte growth factor (HGF), was significantly decreased in the liver tissues of HBV or HBx-expressing mice. The down-regulation of uPA was further confirmed using liver cell lines transiently or stably transfected with HBx and the HBV genome. HBx suppressed uPA expression through the epigenetic regulation of the uPA promoter in mouse liver tissues and human liver cell lines. Expression of HBx strongly induced hypermethylation of the uPA promoter by recruiting DNA methyltransferase (DNMT) 3A2. Conclusion: Taken together, these results suggest that infection of HBV impairs liver regeneration through the epigenetic dysregulation of liver regeneration signals by HBx. (Hepatology 2013;58:762–776)

Although the role of α-synuclein aggregation on Parkinson's disease is relatively well known, the physiological role and the regulatory mechanism governing the expression of α-synuclein are unclear yet. We recently reported that α-synuclein is expressed and secreted from cultured astrocytes. In this study, we investigated the effect of valproic acid (VPA), which has been suggested to provide neuroprotection by increasing α-synuclein in neuron, on α-synuclein expression in rat primary astrocytes. VPA concentrationdependently increased the protein expression level of α-synuclein in cultured rat primary astrocytes with concomitant increase in mRNA expression level. Likewise, the level of secreted α-synuclein was also increased by VPA. VPA increased the phosphorylation of Erk1/2 and JNK and pretreatment of a JNK inhibitor SP600125 prevented the VPA-induced increase in α-synuclein. Whether the increased α-synuclein in astrocytes is involved in the reported neuroprotective effects of VPA awaits further investigation.

Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections.We explored the cellular targets of HBV in response to IFNs using proteome-wide screening.Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, includingWe verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system.

Activation of L-type voltage-dependent Ca

J. Neurochem. (2012) 123, 226–238. Abstract Fragile X syndrome (FXS), the most common single genetic cause of mental retardation and autistic spectrum disease, occurs when FMR1 gene is mutated. FMR1 encodes fragile X mental retardation protein (FMRP) which regulates translation of mRNAs playing important roles in the development of neurons as well as formation and maintenance of synapses. To examine whether FMRP regulates cell viability, we induced apoptosis in rat primary cortical neurons with glutamate in vitro and with middle cerebral artery occlusion (MCAO) in striatal neurons in vivo. Both conditions elicited a rapid, but transient FMRP expression in neurons. This up-regulated FMRP expression was abolished by pre-treatment with PI3K and Protein Kinase B (Akt) inhibitors: LY294002, Akt inhibitor IV, and VIII. Reduced FMRP expression in vitro or in vivo using small hairpin Fmr1 virus exacerbated cell death by glutamate or MCAO, presumably via hypophosphorylation of Akt and reduced expression of B-cell lymphoma-extra large (Bcl-xL). However, over-expression of FMRP using enhanced green fluorescent protein (eGFP)-FMRP constructs alleviated cell death, increased Akt activity, and enhanced Bcl-xL production. The pro-survival role of Akt-dependent up-regulation of FMRP in glutamate-stimulated cultured neuron as well as in ischemic brain may have a clinical importance in FXS as well as in neurodegenerative disorders and traumatic brain injury.

Bax Inhibitor-1 (BI-1) is an evolutionally conserved apoptotic suppressor and belongs to the BI-1 family of proteins, which contain BI-1-like transmembrane domains. As their cellular functions and regulatory mechanisms remain incompletely understood, we compared their anti-apoptotic properties. Forced expression of BI-1 resulted in the most effective suppression of stress-induced apoptosis, compared with other family members, together with significant extracellular signal-regulated kinase (ERK)1/2 activation. BI-1-mediated ERK1/2 activation led to the suppression of mitochondria-mediated reactive oxygen species (ROS) production. Involvement of the ERK signaling pathway in BI-1-induced anti-apoptotic effects was confirmed by knockdown studies with ERK- or BI-1-specific siRNA. Moreover, we produced transgenic (TG) mice overexpressing BI-1, and the relationship between ERK1/2 activation and the suppression of ROS production or apoptosis was confirmed in mouse embryonic fibroblast (MEF) cells derived from these mice. Interestingly, we found that BI-1 TG mice showed splenomegaly and abnormal megakaryopoiesis. Taken together, our results suggest that BI-1-induced ERK1/2 activation plays an important role in the modulation of intracellular ROS generation and apoptotic cell death and may also affect autoimmune response.

Oroxylin A is a flavone isolated from a medicinal herb reported to be effective in reducing the inflammatory and oxidative stresses. It also modulates the production of brain derived neurotrophic factor (BDNF) in cortical neurons by the transactivation of cAMP response element-binding protein (CREB). As a neurotrophin, BDNF plays roles in neuronal development, differentiation, synaptogenesis, and neural protection from the harmful stimuli. Adenosine A2A receptor colocalized with BDNF in brain and the functional interaction between A2A receptor stimulation and BDNF action has been suggested. In this study, we investigated the possibility that oroxylin A modulates BDNF production in cortical neuron through the regulation of A2A receptor system. As ex-pected, CGS21680 (A2A receptor agonist) induced BDNF expression and release, however, an antagonist, ZM241385, prevented oroxylin A-induced increase in BDNF production. Oroxylin A activated the PI3K-Akt-GSK-3β signaling pathway, which is inhibited by ZM241385 and the blockade of the signaling pathway abolished the increase in BDNF production. The physiological roles of oroxylin A-induced BDNF production were demonstrated by the increased neurite extension as well as synapse formation from neurons. Overall, oroxylin A might regulate BDNF production in cortical neuron through A2A receptor stimulation, which promotes cellular survival, synapse formation and neurite extension.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by abnormal deposition of α-synuclein aggregates in many regions of the central and peripheral nervous systems. Accumulating evidence suggests that the α-synuclein pathology initiates in a few discrete regions and spreads to larger areas in the nervous system. Recent pathological studies of PD patients have raised the possibility that the enteric nervous system is one of the initial sites of α-synuclein aggregation and propagation. Here, we evaluated the induction and propagation of α-synuclein aggregates in the enteric nervous system of the A53T α-synuclein transgenic mice after injection of human brain tissue extracts into the gastric walls of the mice. Western analysis of the brain extracts showed that the DLB extract contained detergent-stable α-synuclein aggregates, but the normal brain extract did not. Injection of the DLB extract resulted in an increased deposition of α-synuclein in the myenteric neurons, in which α-synuclein formed punctate aggregates over time up to 4 months. In these mice, inflammatory responses were increased transiently at early time points. None of these changes were observed in the A53T mice injected with saline or the normal brain extract, nor were these found in the wild type mice injected with the DLB extract. These results demonstrate that pathological α-synuclein aggregates present in the brain of DLB patient can induce the aggregation of endogenous α-synuclein in the myenteric neurons in A53T mice, suggesting the transmission of synucleinopathy lesions in the enteric nervous system.

STUDY DESIGN Intended to investigate whether agmatine treatment reduces collagen scar area in mice subjected to spinal cord injury (SCI). OBJECTIVE The purpose of the present study is to demonstrate the protective effect of agmatine on complete transection SCI mice. SUMMARY OF BACK GROUND DATA: The deposition of collagen that occurs at the lesion site, during the SCI, was well known. Agmatine has been reported to exert neuroprotective effect in various stress models including central nervous system injuries. In the present investigation, we hypothesized that agmatine treatment could rescue the mice subjected to SCI. METHODS Complete SCI was made at the T9 level. Agmatine was dissolved in normal saline (100 mg/kg, Sigma, St. Louis, MO) and given intraperitoneally 5 minutes after complete transection daily for 4 weeks (agmatine-treated mice, n = 30). Controls received normal saline in the same manner (experimental control, n = 30). Surface righting reflex test, expression of bone morphogenetic protein-7 (BMP-7), TGFβ-2 (transforming growth factor β-2), and collagen scar area were measured and the results were compared with Mann-Whitney U test using SAS. RESULTS Agmatine treatment improved the surface righting reflex of mice at 4 weeks after SCI (P = 0.030). The collagen scar, physical barrier to axon regeneration, was noticeably diminished by agmatine treatment at 4 weeks after SCI (P = 0.001). The expression of BMP-7, which is considered both neuroprotective and neuroregenerative, was increased in agmatine treatment group compared with experimental control group in the early stages after SCI (P = 0.015 at 1 day after SCI; P = 0.010 at 3 days; P = 0.035 at 1 week; P = 0.826 at 2 weeks). The expression of TGFβ-2 correlated with the deposition of the collagen matrix at the lesion site was decreased with agmatine treatment at 1 and 2 weeks after SCI (P = 0.001 at 1 week; P = 0.002 at 2 weeks). Survival rate was found to be higher in agmatine treatment group than in the experimental control group for 4 weeks after SCI (P = 0.076). CONCLUSION These results suggest that agmatine treatment could support neuroregeneration by reducing the collagen scar area through decreasing the expression of TGFβ-2 and increasing the expression of BMP-7 after SCI. Especially, the improved surface righting reflex of agmatine-treated group proposes that agmatine treatment have the potency to facilitate functional recovery after SCI. However, the drug (agmatine) warrants further investigation in higher mammals.

Induced pluripotent stem (iPS) cells have been generated from various somatic cells; however, a major restriction of the technology is the use of potentially harmful genome-integrating viral DNAs. Here, without a viral vector, we generated iPS cells from fibroblasts using a non-viral magnetic nanoparticle-based transfection method that employs biodegradable cationic polymer PEI-coated super paramagnetic nanoparticles (NP). Our findings support the possible use of transient expression of iPS genes in somatic cells by magnet-based nanofection for efficient generation of iPS cells. Results of dynamic light scattering (DLS) analysis and TEM analyses demonstrated efficient conjugation of NP with iPS genes. After transfection, nanofection-mediated iPS cells showed ES cell-like characteristics, including expression of endogenous pluripotency genes, differentiation of three germ layer lineages, and formation of teratomas. Our results demonstrate that magnet-based nanofection may provide a safe method for use in generation of virus-free and exogenous DNA-free iPS cells, which will be crucial for future clinical applications in the field of regenerative medicine.

In the current investigation, the status of the septo­hippocampal cholinergic pathway and hippocampal mitogen­activated protein kinase (MAPK) signaling was examined in male Wistar rats with chronic cerebral hypoperfusion, which showed cognitive deficits based on assessment on a version of the Morris water maze. Chronic cerebral hypoperfusion was induced by bilateral common artery occlusion and maintained for 12 weeks until behavioral testing. Chronic cerebral hypoperfusion was shown to induce memory impairments and microglial activation in regions of white matter, including the fimbria of hippocampus. Choline acetyltransferase expression of the basal forebrain and expression of hippocampal MAPKs was decreased in rats with BCCAo compared to control rats. The results of this study suggest that cognitive decline induced by chronic cerebral hypoperfusion could be related to dysfunction of the basal forebrain cholinergic system and reduction of hippocampal MAPK activities.

The aims of the present study is to manufacture an injection mould with a pair of conformal cooling channels in each blade of the mould for a plastic fan part via laser-aided direct metal tooling (DMT) process to achieve both rapid and uniform cooling characteristics. The features of the design and the manufacturing process for the injection mould as well as the characteristics of the manufactured mould were discussed. Three-dimensional injection moulding analyses were performed to obtain a proper design of the conformal cooling channels. Injection moulding experiments were carried out to investigate the practical applicability of the fabricated mould and the influence of the cooling time on the qualities of the moulded product. The results of the experiments showed that a plastic fan part with superior qualities can be fabricated from the designed mould when the cooling time is 13 s. The efficiency of the designed mould was examined through a comparison of the product from the newly designed mould and that from a previously designed mould with linear cooling channels in terms of product qualities as well as the cooling and cycle times. The results of the comparison showed that the newly designed mould can remarkably reduce the positional error distributions and the eccentricity of the moulded product. In addition, it was shown that the cooling and cycle times of the designed mould can be shortened to 35.0 % and 25.7 % of those of the previously designed mould, respectively.

A new family of cytokine IL-32 has been implicated in pro-inflammatory immune responses several human diseases such as rheumatoid arthritis, inflammatory bowel diseases and vasculitis. In this study, we investigated the role of IL-32 in the inflammatory activation of cultured rat primary astrocytes. Treatment of IL-32 increased ROS production and augmented lipopolysaccharide-induced increased production of nitric oxide as well as the expression of iNOS. IL-32 also induced the expression of MMP-9 but not MMP-2 in rat primary astrocytes. The increased expression of these inflammatory mediators was accompanied by the increased mRNA expression encoding iNOS, MMP-9 and TNF-α. ERK1/2 and p38, two essential regulators of pro-inflammatory signaling in rat primary astrocytes were activated by IL-32 as evidenced by increased phosphorylation. The results from the present study suggest that IL-32 may play a role in the regulation of neuroinflammatory responses in several neurological disease conditions such as ischemia and Alzheimer's disease.

The objective of this study is to design the conformal cooling channels for the mould of a plastic drawer of a refrigerator by analysis of three-dimensional injection molding. In order to obtain the desired design of the conformal cooling channels, the influence of the diameter and the position of the conformal cooling channels on the moulding characteristics and the product qualities were quantitatively examined. From the results of the examination, an optimal design of the conformal cooling channels, which ensures uniform cooling and minimum potential deformation of the molded drawers, was estimated. By comparing the designed mould and a conventional mould with linear cooling channels from the viewpoints of the product qualities as well as cooling and cycle times, it was shown that the mould with conformal cooling channels can simultaneously improve the productivity of the injection moulding process and the product qualities.

Attention deficit hyperactivity disorder (ADHD) affects 4-12% of chool-age children worldwide and is characterized by three core symptoms: hyperactivity, inattention, and impulsivity. Although standard pharmacological treatments, such as methylphenidate and atomoxetine, are available, concerns about drug-induced psychological and cardiovascular problems, as well as growth retardation and sleep disturbances, highlight the continuing need for new therapeutic interventions. Using a neonatal hypoxia-induced hyperactivity model in rats, the potential positive role that oral administration of red ginseng extract may have in relation to the hyperactive phenotype was investigated. Hypoxia was induced in 2-day-old male Sprague-Dawley (SD) rat pups by placing them in a nitrogen chamber for 15 min. The neonatal hypoxia-induced rats showed a significant increase in hyperactivity phenotype, such as increased movement duration, movement distance, and rearing frequency, which was determined by monitoring their spontaneous locomotor activity using the Ethovision video tracking system. One week of oral treatment with red ginseng extract decreased the hyperactivity phenotype of the neonatal hypoxia-induced rats and increased the locomotor activity of the control rats. In the neonatal hypoxia-induced rats, expression of the norepinephrine transporter in the forebrain was increased, and red ginseng treatment partially prevented its up-regulation, while increasing its level in the control rats. Taken together, these results suggest that red ginseng extract decreased the neonatal hypoxia-induced hyperactivity phenotype, although it increased locomotor activity in normal animals.