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The bifunctional reactivity of three metal SNS (bis)amido complexes was computationally assessed by comparing the nucleophilicity of the M–Namido donor (Mn, Fe, Co). Hirshfeld charges identified the Mn–Namido donor as most nucleophilic and Fe as most electrophilic metal. Reaction energy profiles of a model bifunctional H2 activation showed Mn with the lowest reaction barrier (17 kcal mol−1), followed by Fe and Co (21 and 29 kcal mol−1).

Thermal rejuvenation was explored when Zr62Cu17Ni13Al8 metallic glass was rapidly heated to at least 100 K higher than its glass transition temperature at a heating rate of 60 K/s and then quenched into copper molds. The effect of the quenching temperature and the cooling rate on rejuvenation was evaluated using transmission electron microscopy images, differential scanning calorimetry, density measurements, and Vickers indents. This study suggests that the density of flow units is mainly affected by the final cooling rate rather than the quenching temperature.

Background/objectives Brain aging is a major risk factor for severe neurodegenerative diseases. Conversely, L-histidine and L-carnosine are known to exhibit neuroprotective effects. The aim of this study was to examine the potential for L-histidine, L-carnosine, and their combination to mediate anti-brain aging effects in neuronal cells subjected to D-galactose-induced aging. Materials/methods The neuroprotective potential of L-histidine, L-carnosine, and their combination was examined in a retinoic acid-induced neuronal differentiated SH-SY5Y cell line exposed to D-galactose (200 mM) for 48 h. Neuronal cell proliferation, differentiation, and expression of anti-oxidant enzymes and apoptosis markers were subsequently evaluated. Results Treatment with L-histidine (1 mM), L-carnosine (10 mM), or both for 48 h efficiently improved the proliferation, neurogenesis, and senescence of D-galactose-treated SH-SY5Y cells. In addition, protein expression levels of both neuronal markers (β tubulin-III and neurofilament heavy protein) and anti-oxidant enzymes, glutathione peroxidase-1 and superoxide dismutase-1 were up-regulated. Conversely, protein expression levels of amyloid β (1-42) and cleaved caspase-3 were down-regulated. Levels of mRNA for the pro-inflammatory cytokines, interleukin (IL)-8, IL-1β, and tumor necrosis factor-α were also down-regulated. Conclusions To the best of our knowledge, we provide the first evidence that L-histidine, L-carnosine, and their combination mediate anti-aging effects in a neuronal cell line subjected to D-galactose-induced aging. These results suggest the potential benefits of L-histidine and L-carnosine as anti-brain aging agents and they support further research of these amino acid molecules.

Background Patients with atrial fibrillation (AF) who initiated vitamin K antagonist (VKA) were at highest risk of stroke and bleeding in the first few months of therapy. Understanding of the temporal trend of clinical events in AF patients on non-VKA oral anticoagulant (NOAC) therapy should aid therapeutic decisions. Purpose To evaluate the temporal trend of clinical events in AF patients receiving edoxaban in routine clinical practice in the Global ETNA-AF program. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program evaluating the safety and effectiveness of edoxaban in patients from European and Asian countries. Thromboembolic, bleeding and death events were analysed separately for the 1st and 2nd year of the follow-up period, using a time-to-first-event estimation of cumulative incidence and annual rate via Kaplan-Meier method. Results A total of 27,617 patients were included in this analysis, 48.6% from Europe and 51.4% from Japan, Korea, and Taiwan. Baseline characteristics were consistent with typical AF population in real world studies (Table 1). Approximately 83% of patients received the recommended edoxaban dose. Annualized rates of ischaemic stroke and major bleeding (ISTH) were lower in the 2nd year than in the 1st year: ischaemic stroke 0.59% (95% CI, 0.50–0.70) vs 0.86% (95% CI, 0.75–0.98), p=0.015; major bleeding 0.87% (95% CI, 0.75–1.00) vs 1.15% (95% CI, 1.02–1.29), p=0.036. The trend toward lower rates of ischaemic stroke and major bleeding in the 2nd year was consistent across regions. All-cause mortality increased slightly from the 1st year to the 2nd year, which was not statistically significant and was not driven by cardiovascular (CV) mortality (Table 2). Conclusion In routine clinical practice in the Global ETNA-AF program, major bleeding and ischaemic stroke rates in >27,000 patients on edoxaban therapy declined from 1st year to 2nd year. Further analyses will investigate whether such trend is influenced by selection for healthier patients over time. Longer follow-up is needed to better understand long-term trends. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Table 1. Baseline characteristicsTable 2. Annualised clinical event rates

International audience; Experimental fission studies for reaction physics or nuclear spectroscopy can profit from fast, efficient, and radiation-resistant fission fragment (FF) detectors. When such experiments are performed in-beam in intense thermal neutron beams, additional constraints arise in terms of target-detector interface, beam-induced background, etc. Therefore, wide gap semi-conductor detectors were tested with the aim of developing innovative instrumentation for such applications. The detector characterization was performed with mass- and energy-separated fission fragment beams at the ILL (Institut Laue Langevin) LOHENGRIN spectrometer. Two single crystal diamonds, three polycrystalline and one diamond-on-iridium as well as a silicon carbide detector were characterized as solid state ionization chamber for FF detection. Timing measurements were performed with a 500-µm thick single crystal diamond detector read out by a broadband amplifier. A timing resolution of ∼10.2 ps RMS was obtained for FF with mass A = 98 at 90 MeV kinetic energy. Using a spectroscopic preamplifier developed at INFN-Milano, the energy resolution measured for the same FF was found to be slightly better for a ∼50-µm thin single crystal diamond detector (∼1.4% RMS) than for the 500-µm thick one (∼1.6% RMS), while a value of 3.4% RMS was obtained with the 400-µm silicon carbide detector. The Pulse Height Defect (PHD), which is significant in silicon detectors, was also investigated with the two single crystal diamond detectors. The comparison with results from α and triton measurements enabled us to conclude that PHD leads to ∼50% loss of the initial generated charge carriers for FF. In view of these results, a possible detector configuration and integration for in-beam experiments has been discussed.

Impaired skin wound healing in the elderly can lead to medical issues and increased mortality. Although l -histidine and l -carnosine are potent anti-aging amino acids, the wound healing effects of these amino acids in aging remain to be elucidated. Here, we investigated the regenerative potential of l -histidine and l -carnosine in in vitro and in vivo aging models. l -histidine (1 mM), l -carnosine (10 mM), or a combination improved proliferation, migration, senescence, and epithelial-mesenchymal transition (EMT) in d -galactose-induced aged keratinocytes. An in vivo mouse aging model was established with injection of d -galactose (s.c. 500 mg/kg) daily for eight weeks. Supplementation with l -histidine (2 g/L), l -carnosine (2 g/L), or a combination improved collagen and wound healing with EMT markers, E-cadherin, N-cadherin, and MMP-2. These effects were concomitant with reduced circulating levels of corticosterone and increased PI3K/Akt phosphorylation. These results suggest that l -histidine and l -carnosine have the potential to facilitate wound healing in aging skin.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background Age is a risk factor for ischemic stroke and bleeding in patients with atrial fibrillation (AF). The large dataset from the global prospective, noninterventional ETNA-AF program allows for analysis of the impact of age on clinical events in AF patients treated with edoxaban. Purpose Evaluate the safety and effectiveness of edoxaban by age subgroups and the impact of age on clinical events. Methods Baseline patient characteristics, thromboembolic and bleeding events, and mortality data were collected from patients with 2-year follow-up in ETNA-AF program and analyzed in defined age subgroups. Cox regression analysis was conducted using age as a continuous variable and clinical events as outcome variables. Results A total of 27,617 patients were categorized into four age subgroups: Conclusion Two-year follow-up data from the global ETNA-AF program support the use of edoxaban as a safe and effective treatment for AF patients across all age groups, including the very elderly, in routine clinical care. The impact of age on the risk of ICH was smaller than that of ischemic stroke and major bleeding.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background and Purpose The large global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program was designed to assess the safety and effectiveness of edoxaban, complementing randomized clinical trials. Methods ETNA collects data on patient characteristics and clinical events in unselected AF patients treated with edoxaban for stroke prevention, integrating data from prospective, noninterventional studies conducted in Europe, Japan, South Korea, and Taiwan. Results The 2-year follow-up analysis included 27,617 patients, the majority of whom (82.6%) received the recommended dose according to the local label. At baseline, the mean age was 73.6 ± 9.8 years and 58.1% were male. Half of the patients (50.5%) were 75 years or older. The CHA2DS2-VASc score was 3.3 ± 1.5, and the modified HAS-BLED score was 2.4 ± 1.1. The rate of ischemic stroke was 0.74%/yr, major bleeding 1.02%/yr, intracranial hemorrhage 0.29%/yr, and major gastrointestinal (GI) bleeding 0.51%/yr. All-cause mortality was 3.13%/yr, and cardiovascular (CV) mortality 1.45%/yr (see Table). Conclusion The rates of ischemic stroke and major bleeding events remained low globally and across regions during the two-year follow-up period in AF patients treated with edoxaban. Global(N = 27,617) Japan(N = 11,330) Korea/Taiwan(N = 2,870) Europe(N = 13,417) Age, mean (SD) 73.6 (9.8) 74.2 (10.1) 71.6 (9.5) 73.6 (9.5) Gender, male, % 58.1 59.4 60.2 56.6 Weight [kg], median (IQR) 69 (58, 81) 59 (51, 68) 65 (57, 73) 80 (70, 90) CrCL [mL/min], mean (SD) 68.7 (28.4) 63.9 (25.8) 63.4 (23.7) 74.4 (30.5) CHA2DS2-VASc, mean (SD) 3.3 (1.5) 3.5 (1.7) 3.1 (1.4) 3.2 (1.4) Mod. HAS-BLED≠, mean (SD) 2.4 (1.1) 2.4 (1.1) 2.3 (1.1) 2.5 (1.1) Edoxaban 60mg/30mg, % 53.5 / 46.5 27.6 / 72.4 48.8 / 51.2 76.4 / 23.6 2-year clinical events, N (%/year), [95% CI] Major Bleeding (ISTH) 477 (1.02) [0.93; 1.11] 188 (1.09) [0.94; 1.25] 51 (1.00) [0.74; 1.31] 238 (0.97) [0.85; 1.11] Intracranial Hemorrhage 135 (0.29) [0.24; 0.34] 68 (0.39) [0.30; 0.50] 17 (0.33) [0.19; 0.53] 50 (0.20) [0.15; 0.27] Major GI Bleeding 241 (0.51) [0.45; 0.58] 122 (0.70) [0.58; 0.84] 18 (0.35) [0.21; 0.55] 101 (0.41) [0.33; 0.50] Any Stroke 455 (0.97) [0.88; 1.06] 244 (1.41) [1.24; 1.60] 54 (1.06) [0.80; 1.38] 157 (0.64) [0.54; 0.75] Ischemic Stroke 347 (0.74) [0.66; 0.82] 179 (1.03) [0.89; 1.20] 43 (0.84) [0.61; 1.13] 125 (0.51) [0.42; 0.61] Hemorrhagic Stroke 99 (0.21) [0.17; 0.26] 67 (0.39) [0.30; 0.49] 9 (0.17) [0.08; 0.33] 23 (0.09) [0.06; 0.14] All-cause Death 1479 (3.13) [2.98; 3.30] 470 (2.70) [2.46; 2.96] 72 (1.40) [1.09; 1.76] 937 (3.80) [3.56; 4.05] CV Death 684 (1.45) [1.34; 1.56] 140 (0.80) [0.68; 0.95] 26 (0.50) [0.33; 0.74] 518 (2.10) [1.92; 2.29] ≠Excluding labile INR.

The purpose of the present study was to investigate the anti-inflammatory effects of a sugar isomer, leucrose (D-glucopyranosyl-α-(1–5)-D-fructopyranose) in a dextran sulfate sodium (DSS)-induced colitis mouse model and in RAW 264.7 macrophages. Colitis was induced in vivo with administration of two cycles of DSS (2.5%). Two groups of mice received an AIN-93G diet with 25% or 50% of the total sucrose content replaced with leucrose. This leucrose supplementation improved disease activity index (DAI) scores, colon length, histopathological damage, and myeloperoxidase (MPO) activity levels. In addition, the expression of pro-inflammatory mediators and cytokines decreased in the leucrose supplementation groups compared with the DSS alone treatment group. Furthermore, leucrose supplementation increased M2 macrophage polarization. Leucrose treatment suppressed IL-4-induced M2 polarization and increased JAK1/STAT6 phosphorylation in RAW264.7 cells. Taken together, these results indicate that leucrose exerts an anti-inflammatory effect by regulating M2 macrophage polarization via inflammatory cytokines and the JAK1/STAT6 signaling pathway.

Background The prevalence of atrial fibrillation (AF) and the need for appropriate anticoagulation increase with age. The benefit/risk profile of direct oral anticoagulants such as edoxaban in elderly population with AF in regular clinical practice is therefore of particular interest. Purpose Analyses of Global ETNA-AF data were performed to report patient characteristics, edoxaban treatment, and 1-year clinical events by age subgroups. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program conducted in Europe, Japan, Korea, Taiwan, and other Asian countries. Demographics, baseline characteristics, and 1-year clinical event data were analysed in four age subgroups. Results Of 26,823 patients included in this analysis, 50.4% were ≥75 years old and 11.6% were ≥85 years. Increase in age was generally associated with lower body weight, lower creatinine clearance, higher CHA2DS2-VASc and HAS-BLED scores, and a higher percentage of patients receiving the reduced dose of 30 mg daily edoxaban. At 1-year, rates of ISTH major bleeding and ischaemic stroke were generally low across all age subgroups. The proportion of intracranial haemorrhage within major bleeding events was similar across age groups. All-cause mortality increased with age more than cardiovascular mortality. Conclusion Data from Global ETNA-AF support the safety and effectiveness of edoxaban in elderly AF patients (including ≥85 years) in routine clinical care with only a small increase in intracranial haemorrhage. The higher all-cause mortality with increasing age is not driven by cardiovascular causes. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

The genetically encoded voltage indicators, ArcLight and its derivatives, mediate voltage dependent optical signals by intermolecular, electrostatic interactions between neighboring fluorescent proteins (FPs) via proton wires. A random mutagenesis event placed a negative charge on the exterior of the FP resulting in a greater than 10-fold improvement of the voltage-dependent optical signal. Repositioning this negative charge on the exterior of the FP reversed the polarity of voltage-dependent optical signals suggesting the presence of ‘hot spots’ capable of interacting with the negative charge on a neighboring FP thereby changing the fluorescent output. To explore the potential effect on the chromophore state, voltage-clamp fluorometry was performed with alternating excitation at 390 nm followed by excitation at 470 nm resulting in several mutants exhibiting voltage-dependent, ratiometric optical signals of opposing polarities. However, the kinetics, voltage ranges, and optimal FP fusion sites were different depending on the wavelength of excitation. These results suggest that the FP has external, electrostatic pathways capable of quenching fluorescence that are wavelength specific. ArcLight-derived GEVIs may therefore offer a novel way to map how conditions external to the β-can structure can affect the fluorescence of the chromophore and transiently manipulate those pathways via conformational changes mediated by whole cell voltage clamp.Statement of SignificanceArcLight-type GEVIs utilize proton pathways that send charge information outside of the FP to the internal chromophore enabling voltage induced conformational changes to affect fluorescence. These pathways are excitation wavelength specific suggesting that different external positions affect the protonated and deprotonated states of the chromophore.

The genetically encoded voltage indicators ArcLight and its derivatives mediate voltage-dependent optical signals by intermolecular, electrostatic interactions between neighboring fluorescent proteins (FPs). A random mutagenesis event placed a negative charge on the exterior of the FP, resulting in a greater than 10-fold improvement of the voltage-dependent optical signal. Repositioning this negative charge on the exterior of the FP reversed the polarity of voltage-dependent optical signals, suggesting the presence of “hot spots” capable of interacting with the negative charge on a neighboring FP, thereby changing the fluorescent output. To explore the potential effect on the chromophore state, voltage-clamp fluorometry was performed with alternating excitation at 390 nm followed by excitation at 470 nm, resulting in several mutants exhibiting voltage-dependent, ratiometric optical signals of opposing polarities. However, the kinetics, voltage ranges, and optimal FP fusion sites were different depending on the wavelength of excitation. These results suggest that the FP has external, electrostatic pathways capable of quenching fluorescence that are wavelength specific. One mutation to the FP (E222H) showed a voltage-dependent increase in fluorescence when excited at 390 nm, indicating the ability to affect the proton wire from the protonated chromophore to the H222 position. ArcLight-derived sensors may therefore offer a novel way to map how conditions external to the β-can structure can affect the fluorescence of the chromophore and transiently affect those pathways via conformational changes mediated by manipulating membrane potential.

Direct reprogramming is an efficient strategy to produce cardiac lineage cells necessary for cardiac tissue engineering and drug testing for cardiac toxicity. However, functional maturation of reprogrammed cardiomyocytes, which is of great importance for their regenerative potential and drug response, still remains challenging. In this study, we propose a novel electrode platform to promote direct cardiac reprogramming and improve the functionality of reprogrammed cardiac cells. Nonviral cardiac reprogramming was improved via a three-dimensional spheroid culture of chemically induced cardiomyocytes exposed to a small-molecule cocktail. A micropillar electrode array providing biphasic electrical pulses mimicking the heartbeat further enhanced maturation and electrophysiological properties of reprogrammed cardiac spheroids, leading to proper responses and increased sensitivity to drugs. On the basis of our results, we conclude that our device may have a wider application in the generation of functional cardiac cells for regenerative medicine and screening of novel drugs.

A single pulse of 2.0 to 3.5 kJ of input energy from a 450 mF capacitor was applied to a commercially pure Ti rod in a N2atmosphere. The surface of the Ti rod transformed from TiO2into titanium nitride in times as short as 159 msec, providing a bimodal morphology of the cross-section. A much higher value of hardness that was observed at the edge of the cross-section was attributed to nitrogen-induced solid-solution hardening that occurred during the electrical discharge process. The activation energy (Ea) for the diffusion process was estimated to be approximately 86.9 kJ/mol. Results show that the electrical discharge process is a possible potential method for the nitriding of Ti; advantages include a short processing time and control of the nitrided layer without dimensional changes.

A single pulse of 0.75-2.0 kJ/0.7g of atomized spherical Ti powders from 300 mF capacitor was applied to produce a microporous Ti implant compact by electro-discharge-sintering (EDS). A solid core in the middle of the compact surrounded by a microporous layer was found. X-ray photoelectron spectroscopy was employed to study the surface characteristics of the EDS Ti compact and it revealed that Ti, C and O were the main constituents on the surface with a smaller amount of N. The surface was lightly oxidized and was primarily in the form of TiO2resulting from the air oxidation during EDS processing. The lightly oxidized surface of the EDS compact also exhibited Ti nitrides such as TiN and TiON, which revealed that the reaction between air constituents and the Ti powders even in times as short as 128 msec.

Rapid heating blow molding is introduced as a thermoplastic molding process for bulk metallic glasses. Infrared heating allows the selective and quick heating of an object with precise control, providing the opportunity to achieve much lower viscosities than in conventional blow molding. These low viscosities enable short processing times, high strain rates, large strains, and good surface finishes even under a forming pressure as low as 105 ​Pa. This technology permits the blow molding of glassy metal sheets with a wide range of alloy compositions.

Background As populations age, prevalence of atrial fibrillation (AF) and ensuing need for oral anticoagulation increase. Benefits and risks of nonvitamin K antagonist oral anticoagulants such as edoxaban in the frail, elderly population with AF in regular clinical care is of special interest. Purpose Data from Global ETNA-AF capturing almost 2ehz745.1164 patients treated with edoxaban in Europe, Japan, and Korea/Taiwan, was analyzed to compare outcomes in patients Methods Global ETNA-AF is a multinational, multicentre, prospective, noninterventional program (EU: NCT02944019, Japan: UMINehz745.116417011, Korea/Taiwan: NCT02951039). Demographics, baseline characteristics, and 1-year outcome data were reported for 19416 patients classified into 3 age categories. Results At 1-year follow-up, rates of major bleeding (including intracranial haemorrhage [ICH]) and ischaemic stroke were generally low. All-cause and CV mortality increased with age; CV mortality was a minor proportion of all-cause mortality in all age groups. Rates of major bleeding and ischaemic stroke increased slightly with age, but to a lesser extent than all-cause and CV mortality. There was no increase in the rate of ICH with age. Conclusion Global data from this set of unselected patients support the use of edoxaban as a safe and effective treatment in elderly and very elderly patients with AF in regular clinical care. Acknowledgement/Funding Daiichi Sankyo

OBJECTIVES: Tumor-associated macrophages (TAMs) and tumor-associated fibroblasts (TAFs) are consisted of tumor microenvironment (TME), which are involved in cancer progression and metastasis. Interactions within TME induce M2 macrophage phenotype, TAMs, and activate TAFs. β-carotene (BC) is a well-known antioxidant and showed protective effects on several diseases, including cancers. The object of this study is to investigate the anti-colorectal cancer (CRC) effects of BC by controlling macrophage polarization and fibroblast activation. METHODS: TAMs were induced by treating with phorbol-12-myristate-13-acetate (PMA) and interleukin-4 (IL-4) in U937 cells and TAFs were induced by treating with transforming growth factor-β1 (TGF-β1) in CCD-18Co cells. To understand the effect of TME on cancer cells, HCT116 colon cancer cells were co-cultured with TAM or TAF conditioned media. The effects of BC on the expressions of cancer stem cells (CSCs) markers, epithelial-mesenchymal transition (EMT) markers along with invasion and migration were investigated. To confirm these results, the azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced colitis-associated CRC mice model was used. RESULTS: BC decreased M2 macrophage polarization with activating IL-6/STAT3 signaling pathways and suppressed the expressions of fibroblast activation markers and EMT markers. In addition, BC inhibited the expressions of TME-induced CSCs markers and EMT and suppressed cell invasion and migration. Furthermore, BC supplementation suppressed tumorigenesis and the expressions of M2 macrophage-associated markers, including CD206, Arg1, and Ym-1 as well as CSCs markers in vivo. CONCLUSIONS: BC suppressed CRC by regulating TAMs and TAFs in vitro and in vivo, which indicated the potential therapeutic effects of BC on inflammatory diseases. FUNDING SOURCES: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education and Brain Korea 21 Plus.

The advanced molybdenum-based rare process experiment (AMoRE) aims to search for neutrinoless double beta decay ($$0\nu \beta \beta $$0νββ) of $$^{100}$$100Mo with $$\sim 100\,\hbox {kg}$$∼100kg of $$^{100}$$100Mo-enriched molybdenum embedded in cryogenic detectors with a dual heat and light readout. At the current, pilot stage of the AMoRE project we employ six calcium molybdate crystals with a total mass of 1.9 kg, produced from $$^{48}$$48Ca-depleted calcium and $$^{100}$$100Mo-enriched molybdenum ($$^{48{{\text {depl}}}}\hbox {Ca}^{100}\hbox {MoO}_{4}$$48deplCa100MoO4). The simultaneous detection of heat (phonon) and scintillation (photon) signals is realized with high resolution metallic magnetic calorimeter sensors that operate at milli-Kelvin temperatures. This stage of the project is carried out in the Yangyang underground laboratory at a depth of 700 m. We report first results from the AMoRE-Pilot $$0\nu \beta \beta $$0νββ search with a 111 kg day live exposure of $$^{48{{\text {depl}}}}\hbox {Ca}^{100}\hbox {MoO}_{4}$$48deplCa100MoO4 crystals. No evidence for $$0\nu \beta \beta $$0νββ decay of $$^{100}$$100Mo is found, and a upper limit is set for the half-life of $$0\nu \beta \beta $$0νββ of $$^{100}$$100Mo of $$T^{0\nu }_{1/2} > 9.5\times 10^{22}~\hbox {years}$$T1/20ν>9.5×1022years at 90% C.L. This limit corresponds to an effective Majorana neutrino mass limit in the range $$\langle m_{\beta \beta }\rangle \le (1.2-2.1)\,\hbox {eV}$$⟨mββ⟩≤(1.2-2.1)eV.

Pulsatilla koreana Nakai, or pasque flower has been used as a medicinal plant for the treatment of amoebic dysentery, malaria, and internal hemorrhoids. The extract of Pulsatilla koreana Nakai, itself, has not been yet investigated for potential antiobesity effects. In this study, the antiobesity effect was evaluated on preadipocyte differentiation of Pulsatilla koreana Nakai extracted by 70 % ethanol in 3T3-L1 cells. Pulsatilla koreana Nakai ethanol extract at doses of 20 μg/ml significantly decreased lipid droplet accumulation, the expression of transcription factors, including CCAAT/enhancer-binding protein α, β, δ, peroxisome proliferator-activated receptor gamma and mRNA levels of fatty acid synthase. Moreover, Pulsatilla koreana Nakai ethanol extract also activated the phosphorylation of 5' adenosine monophosphate-activated protein kinase α. In conclusion, Pulsatilla koreana Nakai ethanol extract suppressed preadipocyte differentiation via down-regulation of CCAAT/enhancer-binding proteins, peroxisome proliferator-activated receptor gamma, and fatty acid synthase by phosphorylation of 5'-adenosine monophosphate-activated protein kinase α in adipocytes. This data suggested that Pulsatilla koreana Nakai ethanol extract be further explored as a new preventive and therapeutic agent against obesity.

A calcium molybdate ( $\text{CaMoO}_{4}$ ) crystal scintillator, with molybdenum enriched in $^{100}\text{Mo}$ and calcium depleted in $^{48}\text{Ca}$ ( $^{40}\text{Ca}{}^{100}\text{MoO}_{4}$ ), was developed by the Advanced Molybdenum based Rare process Experiment (AMoRE) collaboration to search for a neutrinoless double beta ( $0\nu \beta \beta $ ) decay of $^{100}\text{Mo}$ . We are planning to use about 10 kg of $^{40}\text{Ca}{}^{100}\text{MoO}_{4}$ crystals as cryogenic bolometers for the first phase of the experiment (AMoRE-I) at the Yang Yang underground laboratory (Y2L) in Korea. This experiment calls for an extremely low level of radioactive contamination in detectors, particularly by thorium, uranium, and radium decay chains. We measured scintillation properties and radioactive contamination of $\text{CaMoO}_{4}$ and $^{40}\text{Ca}{}^{100}\text{MoO}_{4}$ crystals at the Y2L. We also estimated the acceptable level of internal radioactive background using Monte Carlo simulation for the AMoRE-I.

The tumor microenvironment (TME), consisting of stromal fibroblasts, immune cells, cancer cells and other cell types, plays a crucial role in cancer progression and metastasis. M2 macrophages and activated fibroblasts (AFs) modulate behavior of cancer cells in the TME. Since nutritional effects on cancer progression, including colorectal cancer (CRC), may be mediated by alterations in the TME, we determined the ability of β-carotene (BC) to mediate anti-cancer effects through regulation of macrophage polarization and fibroblast activation in CRC. The M2 macrophage phenotype was induced by treating U937 cells with phorbol-12-myristate-13-acetate and interleukin (IL)-4. Treatment of these M2 macrophages with BC led to suppression of M2-type macrophage-associated markers and of the IL-6/STAT3 signaling pathway. In separate experiments, AFs were induced by treating CCD-18Co cells with transforming growth factor-β1. BC treatment suppressed expression of fibroblast activation markers. In addition, conditioned media from BC-treated M2 macrophages and AF inhibited cancer stem cell markers, colon cancer cell invasiveness and migration, and the epithelial-mesenchymal transition (EMT). In vivo, BC supplementation inhibited tumor formation and the expression of M2 macrophage markers in an azoxymethane/dextran sodium sulfate-induced colitis-associated CRC mouse model. To our knowledge, the present findings provide the first evidence suggesting that the potential therapeutic effects of BC on CRC are mediated by the inhibition of M2 macrophage polarization and fibroblast activation.

Background/objectives Brain senescence causes cognitive impairment and neurodegeneration. It has also been demonstrated that curcumin (Cur) and hesperetin (Hes), both antioxidant polyphenolic compounds, mediate anti-aging and neuroprotective effects. Therefore, the objective of this study was to investigate whether Cur, Hes, and/or their combination exert anti-aging effects in D-galactose (Dg)-induced aged neuronal cells and rats. Materials/methods SH-SY5Y cells differentiated in response to retinoic acid were treated with Cur (1 μM), Hes (1 μM), or a combination of both, followed by 300 mM Dg. Neuronal loss was subsequently evaluated by measuring average neurite length and analyzing expression of β-tubulin III, phosphorylated extracellular signal-regulated kinases, and neurofilament heavy polypeptide. Cellular senescence and related proteins, p16 and p21, were also investigated, including their regulation of antioxidant enzymes. In vivo, brain aging was induced by injecting 250 mg/kg body weight (b.w.) Dg. The effects of supplementing this model with 50 mg/kg b.w. Cur, 50 mg/kg b.w. Hes, or a combination of both for 3 months were subsequently evaluated. Brain aging was examined with a step-through passive avoidance test and apoptosis markers were analyzed in brain cortex tissues. Results Cur, Hes, and their combination improved neuron length and cellular senescence by decreasing the number of β-gal stained cells, down-regulated expression of p16 and p21, and up-regulated expression of antioxidant enzymes, including superoxide dismutase 1, glutathione peroxidase 1, and catalase. Administration of Cur, Hes, or their combination also tended to ameliorate cognitive impairment and suppress apoptosis in the cerebral cortex by down-regulating Bax and poly (ADP-ribose) polymerase expression and increasing Bcl-2 expression. Conclusions Cur and Hes appear to attenuate Dg-induced brain aging via regulation of antioxidant enzymes and apoptosis. These results suggest that Cur and Hes may mediate neuroprotective effects in the aging process, and further study of these antioxidant polyphenolic compounds is warranted.

A quasiclassical trajectory method is used to study the temperature dependence of HBr + OH → Br + H2O using analytic forms of two-, three-, and four-body and long-range interaction potentials. Below 300 K, the reaction is attraction-driven and occurs through formation of a collision complex BrH···OH, which is sufficiently long-lived to enhance H atom tunneling. Strong negative temperature dependence of the complex-mode rate is found between 20 and 300 K, consistent with experimental data reported by various authors. Above 300 K, the reaction occurs primarily through a direct-reaction mechanism. The sum of the complex- and direct-mode rates is shown to describe the reaction over the wide range 20-2000 K. The primary kinetic isotope effect is nearly constant with the normal H reaction faster by a factor of ∼1.7 over the entire temperature range. The product energy distribution in vibration, rotation, and translation at 300 K is found to be 48, 8, and 44%, respectively. The 1:1 resonance leads to efficient flow of energy between the stretching modes. Less than a quarter of the H2O vibrational energy deposits in the bending mode through intramolecular flow from the two stretching modes.

Electrical discharge using a capacitance of 450 μF at 7.0 and 8.0 kJ input energies was applied to mechanical alloyed Ti5Si3powder without applying any external pressure. A solid bulk of nanostructured Ti5Si3with no compositional deviation was obtained in times as short as 159 μsec by the discharge. During an electrical discharge, the heat generated is the required parameter possibly to melt the Ti5Si3particles and the pinch force can pressurize the melted powder without allowing the formation of pores. Followed rapid cooling preserved the nanostructure of consolidated Ti5Si3compact. Three stepped processes during an electrical discharge for the formation of nanostructured Ti5Si3compact are proposed: (a) a physical breakdown of the surface oxide of Ti5Si3powder particles, (b) melting and condensation of Ti5Si3powder by the heat and pinch pressure, respectively, and (c) rapid cooling for the preservation of nanostructure. Complete conversion yielding a single phase Ti5Si3is primarily dominated by the solid-liquid mechanism.

A single pulse of 2.0 to 3.5 kJ of input energy from a 450 μF capacitor was applied in a low vacuum atmosphere to a commercially pure Ti rod. The electro-discharge process produced rapid temperature increases from 569 to 2516 °C in times as short as 159 μsec, depending on the input energy. The microstructure with equiaxed α grains was preserved after the electro-discharge regardless of applied input energy. At the same time, the original surface of Ti rod was modified by the electro-discharge into the form of primarily titanium oxycarbide from TiO2. A much higher value of hardness that was observed at the edge of the cross-section was thus attributed to carbon- and oxygen-induced solid-solution hardening that occurred during the electro-discharge process. From these results, it is concluded that the rapid formation of titanium oxycarbide on the Ti surface can be induced in times as short as 159 μsec by the electro-discharge process without changing its unique microstructure.

Essentials Antiangiogenic drugs are indicated as therapies for hereditary hemorrhagic telangiectasia. We interrogated the response to four antiangiogenic drugs for anemia and intestinal bleeding. Sorafenib and a pazopanib analog significantly improved while erlotinib worsened anemia. Some oral antiangiogenic drugs were effective in reducing intestinal bleeding. SummaryBackground Epistaxis and gastrointestinal (GI) tract hemorrhages are common symptoms of aged hereditary hemorrhagic telangiectasia (HHT) patients that result in anemia. Clinical as well as animal studies have suggested that vascular endothelial growth factor (VEGF) neutralizing antibodies lessen hemorrhage associated with adult-onset arteriovenous malformations (AVMs). Objectives The goal of this study is to evaluate potential therapeutic effects of oral delivery of four antiangiogenic tyrosine-kinase inhibitors (TKIs) in the development of adult-onset AVMs in a murine model of HHT. Methods An adult activin receptor-like kinase 1 (Alk1)-inducible knockout (iKO) model was utilized to evaluate the effect of oral administration of sorafenib, sunitinib, erlotinib and a pazopanib analog (GW771806) on hemoglobin level, GI hemorrhages and formation of wound-induced skin AVMs. Results and Conclusions Sorafenib and GW771806 significantly improved, yet erlotinib worsened, anemia and GI-bleeding in the Alk1-iKO model. However, none of these TKIs appeared to be effective for inhibiting the development of wound-induced skin AVMs. Taken together, these results suggest that oral delivery of antiangiogenic TKIs is selectively more effective for GI bleeding than mucocutaneous AVMs, and it may provide an experimental basis for selective therapeutic options depending on the symptoms of HHT.

A single pulse of 2·0–3·5 kJ of input energy from a 450 μF capacitor was applied to a Ti rod. The electrical discharge process can produce rapid temperature increases of Ti from 569 to 2398°C in times as short as 159 μs, depending on the input energy. With an input energy greater than 2·5 kJ, a β→α allotropic transformation occurred, showing a typical serrated morphology. At the same time, the original surface of Ti rod with TiO2 was modified into the form of primarily titanium oxycarbide. A much higher value of hardness that was observed at the edge of the cross-section was thus attributed to oxygen- and carbon-induced solid solution hardening during the electrical discharge process.

2·0 to 3·5 kJ of input energy as a single pulse from a 150 μF capacitor was applied to a 50% cold rolled Ti to induce rapid recrystallisation and surface modification. Using an input energy of 2·0 kJ, complete recrystallisation occurred over a period of 96 μs and the resulting microstructure was identical to that of a Ti before cold rolling. With an input energy of 2·5 kJ or higher, thermal oxycarburisation progressed by the formation of a titanium oxycarbide layer and the activation energy for the associated diffusion process was calculated to be 231 kJ mol−1. A much higher value of hardness that was observed at the edge of the cross section was attributed to oxygen and carbon induced solid solution hardening. Both the recrystallisation and surface modification processes depended on the amount of heat generated during an electro discharge, which could be manipulated by input energy and capacitance.

Dehydroascorbate reductase (DHAR, EC 1.8.5.1) helps to maintain redox pools of ascorbate (AsA) by recycling dehydroascorbate (DHA) to AsA. To investigate whether DHAR influences the acquired tolerance of rice plants to abiotic stresses, cDNA encoding DHAR (OsDHAR1) was isolated from rice and used to develop OsDHAR1-overexpressing transgenic rice plants regulated by a maize ubiquitin promoter. The incorporation and expression of the transgene was confirmed by polymerase chain reaction (PCR) and semi-quantitative reverse transcription PCR, real-time PCR, Western blot and enzyme activity. The overexpression of OsDHAR1 greatly increased the DHAR activity and the AsA/DHA ratio, following increase in AsA content and decrease in DHA content. In addition, the enzyme activity of monodehydroascorbate reductase, glutathione reductase and ascorbate peroxidase, which are related to the ascorbate–glutathione systems, was enhanced in the presence and the absence of salt stress in homozygous transgenic rice plants (OsDHAR1-OX1, -OX2) harbouring Ubi::OsDHAR1. In addition, OsDHAR1-expressing transgenic rice plants enhanced the redox state by reducing both hydroperoxide and malondialdehyde levels under salt and methyl viologen (MV) stress conditions, which led to better plant growth, ion leakage and quantum yield (Fv/Fm). Therefore, our results show that the overexpression of OsDHAR1 increases the adaptation of rice plants to salt stress, by maintaining the AsA pool, ion homoeostasis and redox homoeostasis. Finally, the findings of this study indicate that OsDHAR1 plays an important role in attenuating the deleterious effects of various abiotic stresses.

This study developed a drying method and a dryer that are optimized for shiitake mushrooms. They are mainly being cultivated and consumed as food and medicine in Korea, Japan, China, and Southeast Asia. They generally contain lots of moisture. For this reason, the use of a dryer causes problems such as decomposition and spoilage, and natural dry processing is preferred. To resolve these problems, various drying methods have been proposed (e.g. hot air drying, heat pump vacuum drying) but there has been a difficulty in maintaining a medium-temperature range of 30 to 40°C, the optimal temperature environments for retaining their main components. The study developed a 2-stage decompresses resistive heat pump dryer that can operate also in medium-temperature environments - existing decompresses heat pump dryers have been able to operate only in high-temperature environments. A dryer optimized for shiitake mushrooms that are being produced and distributed in large quantities was proposed, and the utility of the machine was proved through experiments.

An alternative energy technology to save power consumption in the steelmaking process was developed with supplementary oxygen injection in a new shaft electric arc furnace (EAF). The optimisation of oxygen injection for enhancing post-combustion was carried out to increase the preheating temperature of the scrap in the shaft using preheating simulation and trial tests. The conditions of oxygen injection from supersonic burners and an oxygen lance, and the appropriate injection distance between molten bath and oxygen lance, were established through fluid flow simulation and practical tests. In addition, the optimal conditions for supersonic burners and oxygen injection to enhance the post-combustion were deduced. From comparisons of the present and conventional results, it was found that the electric energy and operating time of the shaft EAF were decreased through practical improvements, resulting in energy savings and increase in productivity on the shaft EAF.

International audience; Production of neutron-rich nuclei around N = 126 by multinucleon transfer reactions has recently gained a renewal of interest both theoretically and experimentally. We are now advancing the KISS project at RIKEN to produce those nuclei by multinucleon transfer reactions and measure their lifetimes to investigate the astrophysical environments of the r-process. To investigate the relevance of the production mechanism, we performed measurements for the reaction system 136Xe + 198Pt, using the spectrometer VAMOS++ and the gamma-ray array EXOGAM at GANIL. Cross sections deduced from the measurements for neutron-rich nuclei around N = 126 show a modest enhancement when compared with the GRAZING calculations, indicating the advantage of the multinucleon transfer reactions as compared with fragmentation for production of N = 126 neutron-rich isotones. The possibility for production of neutron-rich nuclei around uranium beyond N = 126 by multinucleon transfer reactions is also discussed.

Despite many claims of good wear properties following total knee replacement (TKR) with an oxidised zirconium (OxZr) femoral component, there are conflicting clinical results. We hypothesised that there would be no difference in either the mid-term clinical and radiological outcomes or the characteristics of the polyethylene wear particles (weight, size and shape) in patients using an OxZr or cobalt-chrome (CoCr) femoral component. In all 331 patients underwent bilateral TKR, receiving an OxZr femoral component in one knee and a CoCr femoral component in the other. The mean follow-up was 7.5 years (6 to 8). Following aspiration, polyethylene wear particles were analysed using thermogravimetric methods and scanning electron microscopy. At the most recent follow-up, the mean Knee Society score, Western Ontario and McMaster Universities Osteoarthritis Index score, range of movement and satisfaction score were not significantly different in the two groups. The mean weight, size, aspect ratio and roundness of the aspirated wear particles were similar for each femoral component. Survivorship of the femoral, tibial and patellar components was 100% in both groups. In the absence of evidence of an advantage in the medium term we cannot justify the additional expense of an OxZr femoral component.

Scintillation properties and radioactive contamination of calcium molybdate scintillating crystals depleted in 48Ca and enriched in 100Mo (40Ca100MoO4 ) have been studied to prepare a 100Mo-based neutrinoless double beta decay experiment. The prospects of a neutrinoless double beta decay experiment using 40Ca100MoO4 crystals are discussed.

Thin films with tungsten trioxide (WO3) nanorods were fabricated by using an ArF pulsed laser deposition system. Because the ArF excimer laser operates at a very short wavelength of 193 nm, short enough to expect strong absorption of the photons in the semiconductor oxide targets, and because the clusters incoming to the substrates have high momentum, we could build thin films with good surface morphology. Highly homogeneous arrays of nanorods with sizes mostly in the range of 30–40 nm were observed. The absorbance response towards hydrogen (H2) gas was investigated for a WO3 film coated with 25-A-thick palladium (Pd). The Pd/WO3-nanorod thin films exhibited excellent gasochromic response when measured in the visible-NIR range (400–1000 nm). As low as 0.06% H2 concentration was clearly sensed. A significant reversible absorbance change and fast recovery (

Silicon dioxide film derived from polyphenylcarbosilane (PPCS) is being investigated for electronic ceramics and applications to dielectric materials. Polyphenylcarbosilane was heat treated under oxygen atmosphere to fabricate SiO2 film. The mechanical property and dielectric constant of the film were measured using a nanoindenter and a semiconductor parameter analyser with metal–insulator–semiconductor structure. The chemical behaviour and structure were analysed with an X-ray photoelectron spectrometer and a differential thermal analyser. From the results, the silicon oxide film was synthesised from PPCS due to proper heat treatment. Elastic modulus values of the fired PPCS film were from 8·9 to 27·9 GPa and hardness values of the fired PPCS film were from 0·47 to 2·29 GPa with increasing firing temperature. Change in mechanical properties is related to intermolecular binding strength in the film.