Search

Reduced activation ferritic/martensitic (RAFM) steel, e.g., F82H, is the leading candidate structural material for fusion blanket. Of many blanket concepts, the water-cooled ceramic breeder blanket is an attractive concept because of its compactness and its compatibility with the technologies which using high-temperature water as coolant in conventional light water reactor. For tritium breeding, it is necessary to manage the corrosion of F82H by controlling not chemicals but hydrogen and oxygen in the cooling water. Understanding the effects of oxygen and hydrogen on corrosion property was therefore required for the blanket design. This work aims to investigate the corrosion behavior of F82H in high-temperature water with hydrogen added. Based on the results of the corrosion test, it is speculated that hydrogen addition expected no considerable change of the flow-accelerated corrosion (FAC). In contrast, it was found that the number of cycles to fracture was decreased in the high-temperature water in comparison to the fatigue test at room temperature in air. [ABSTRACT FROM AUTHOR]

Abstract SiC/SiC composites are promising structural candidate materials for various nuclear applications over the wide temperature range of 300–1000 °C. Accordingly, irradiation tolerance over this wide temperature range needs to be understood to ensure the performance of these composites. In this study, neutron irradiation effects on dimensional stability and mechanical properties to high doses (11–44 dpa) at intermediate irradiation temperatures (˜600 °C) were evaluated for Hi-Nicalon Type-S or Tyranno-SA3 fiber–reinforced SiC matrix composites produced by chemical vapor infiltration. The influence of various fiber/matrix interfaces, such as a 50–120 nm thick pyrolytic carbon (PyC) monolayer interphase and 70–130 nm thick PyC with a subsequent PyC (˜20 nm)/SiC (˜100 nm) multilayer, was evaluated and compared with the previous results for a thin-layer PyC (˜20 nm)/SiC (˜100 nm) multilayer interphase. Four-point flexural tests were conducted to evaluate post-irradiation strength, and SEM and TEM were used to investigate microstructure. Regardless of the fiber type, monolayer composites showed considerable reduction of flexural properties after irradiation to 11–12 dpa at 450–500 °C; and neither type showed the deterioration identified at the same dose level at higher temperatures (>750 °C) in a previous study. After further irradiation to 44 dpa at 590–640 °C, the degradation was enhanced compared with conventional multilayer composites with a PyC thickness of ˜20 nm. Multilayer composites have shown comparatively good strength retention for irradiation to ˜40 dpa, with moderate mechanical property degradation beginning at 70–100 dpa. Irradiation-induced debonding at the F/M interface was found to be the major cause of deterioration of various composites. [ABSTRACT FROM AUTHOR]

Abstract Lilly Laboratories cell porcine kidney 1 (LLC-PK1) cells transfected with human P-glycoprotein (LLC-PK1-P-gp) are widely used in transport assays to identify drug candidates that function as substrates of this efflux transporter. Endogenous transporters expressed in LLC-PK1 cells may complicate the interpretation of findings from P-gp-mediated transport assays. We investigated the impact of porcine breast cancer resistance protein (Bcrp) in P-gp-mediated transport assays in LLC-PK1 cells. Porcine Bcrp mRNA was detected in both LLC-PK1 wildtype (WT) and LLC-PK1-P-gp cells by quantitative RT-PCR. To investigate the activity and impact of porcine Bcrp, we conducted transport assays using 6 typical BCRP substrates in LLC-PK1 cells. Efflux ratios (ER) of the 6 BCRP substrates in LLC-PK1 WT cells were >2, and were reduced in the presence of the BCRP inhibitor Ko143. The efflux activities of the 6 BCRP substrates were confirmed using MDCKII cells transfected with human BCRP. Net ERs of prazosin and fluvastatin, dual substrates of P-gp and BCRP, determined by dividing ERs in LLC-PK1-P-gp cells by those in LLC-PK1 WT cells, were <2, but increased to >2 in the presence of Ko143. These results indicated that endogenous Bcrp in LLC-PK1 cells was involved in the transport of BCRP substrates and may interfere with the identification of P-gp substrates. [ABSTRACT FROM AUTHOR]

Abstract The R&D on SiC/SiC composites under the broader approach (BA) activities between Japan and the EU for fusion DEMO developed a fundamental database of mechanical (Task-1) and physical/chemical (Task-2) properties, with a primary target of the application of SiC/SiC composites as functional structure to be used in the dual coolant breeding blanket concept. This paper aims to summarize previous 10-years activities of the R&D of Japan and to provide the key deliverables toward the DEMO design. In Task-1, good creep and fatigue durability were first demonstrated. Besides, in-plane and inter-laminar strength anisotropy maps at elevated temperatures were comprehensively identified. In parallel, the irradiation effects of SiC materials were specifically determined as input parameters of the analytical model to provide for the irradiation-induced residual stresses. In Task-2, the apparent dose-dependence of the radiation-induced electrical conductivity and the indicative radiation-induced electrical degradation was identified by various irradiation sources. In addition, good gas confinement was identified. Furthermore, no accelerated corrosion for duration of 3000 h at below 1173 K was first demonstrated. With these achievements, it is suggested that the in-vessel component technology, e.g., material corrosion database development, activated corrosion product evaluation code development, compact module tests for validation of the key functions of the components, technology integration assessment for fusion nuclear tests, etc., should be further developed toward DEMO in near-term. [ABSTRACT FROM AUTHOR]

Abstract The lead-lithium (Pb-Li) alloy is considered as a coolant and a tritium breeder for fusion reactor blanket systems. One of the critical requirements in realization of the systems is the compatibility of silicon carbide (SiC) and its composites, as structural and/or functional materials of the blanket, with liquid Pb-Li flow at high temperatures. This study aims to clarify the corrosion process of high-purity SiC materials under flow condition of liquid Pb-Li for 3000 h at 700 and 900 °C, respectively, by using the rotating disc corrosion equipment. Furthermore, the effect of wall flow velocity on the compatibility was specifically evaluated. For that purpose the decrease rate (about 32–37%) of the wall flow velocity on disc type's sample by the dragging effect by fluidic viscosity was first calculated by numerical analysis of the rotating flow condition. The wall flow velocity dependence on the reaction layer's thickness was then evaluated for both high purity SiC and SiC/SiC composites. The test results show that the formation process of the surface reaction layer mainly depends on both the time required for the chemical reaction and the wall flow velocity in the initial stage but the reaction layer thickness tended to approach to the constant regardless of the wall flow velocity with increasing exposed time. In short, no accelerated corrosion was found for about 3000 h. It was also found that there was no significant difference of the temperatures between 700 and 900 °C. Finally the key corrosion mechanism, i.e., the reaction of oxide impurities, e.g., Li 2 O, in liquid Pb-Li with the Si-oxide layer over SiC, was identified. [ABSTRACT FROM AUTHOR]

For the development of silicon carbide (SiC) materials for next-generation nuclear structural applications, degradation of material properties under intense neutron irradiation is a critical feasibility issue. This study evaluated the mechanical properties and microstructure of a chemical vapor infiltrated SiC matrix composite, reinforced with a multi-layer SiC/pyrolytic carbon–coated Hi-Nicalon TM Type S SiC fiber, following neutron irradiation at 319 and 629 °C to ∼100 displacements per atom. Both the proportional limit stress and ultimate flexural strength were significantly degraded as a result of irradiation at both temperatures. After irradiation at 319 °C, the quasi-ductile fracture behavior of the nonirradiated composite became brittle, a result that was explained by a loss of functionality of the fiber/matrix interface associated with the disappearance of the interphase due to irradiation. The specimens irradiated at 629 °C showed increased apparent failure strain because the fiber/matrix interphase was weakened by irradiation-induced partial debonding. [ABSTRACT FROM AUTHOR]

The acoustic emission (AE) technique was first applied to characterize the hot isostatic pressing (HIP) joint interface of reduced activation ferritic/martensitic (RAFM) steel and its applicability for the quality assurance was assessed. The preliminary evaluation identified the characteristic AE signal related to the cracking event at the HIP joint interface: loud and instantaneous AE, which is considered as a consequence of macro cracking. However it is very hard to detect any AE signals related to initial deformation prior to the maximum torque, e.g., yielding and work hardening. In contrast, it is clarified that the cumulative AE energy is closely related to the absorbed energy by torsion. Since it is recognized that the absorbed energy by torsion was dependent on the absorbed energy by Charpy impact test, a good correlation was eventually identified among them and this will be helpful in establishment of the AE technique for the quality assurance of the HIP joint interface. [ABSTRACT FROM AUTHOR]

Autophagy targets intracellular molecules, damaged organelles, and invading pathogens for degradation in lysosomes. Recent studies have identified autophagy receptors that facilitate this process by binding to ubiquitinated targets, including NDP52. Here, we demonstrate that the small guanosine triphosphatase Rab35 directs NDP52 to the corresponding targets of multiple forms of autophagy. The active GTP-bound form of Rab35 accumulates on bacteria-containing endosomes, and Rab35 directly binds and recruits NDP52 to internalized bacteria. Additionally, Rab35 promotes interaction of NDP52 with ubiquitin. This process is inhibited by TBC1D10A, a GAP that inactivates Rab35, but stimulated by autophagic activation via TBK1 kinase, which associates with NDP52. Rab35, TBC1D10A, and TBK1 regulate NDP52 recruitment to damaged mitochondria and to autophagosomes to promote mitophagy and maturation of autophagosomes, respectively. We propose that Rab35- GTP is a critical regulator of autophagy through recruiting autophagy receptor NDP52. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy and fibrosis in heart failure with preserved ejection fraction are associated with a pro-inflammatory state and reduced NO bioavailability. Effects on myocardial structural and molecular alterations were compared between Waon therapy (WT; repeated dry sauna therapy) and statin in hypertensive rats. Seven-week-old Dahl salt-sensitive rats were assigned to 4 groups: low-salt (LS) diet, high-salt (HS) diet, HS diet with oral fluvastatin (FL; 10 mg/kg/day for 4 weeks) starting from the age of 9 weeks, and HS diet with WT treatment in a far-infrared dry sauna (39 °C for 15 min followed by 34 °C for 20 min once daily for 4 weeks). HS rats developed left ventricular (LV) hypertrophy with preserved LV systolic function. WT reduced LV wall thickness and myocyte cross-sectional area along with decreased levels of myocardial ANP and BNP mRNA expression compared with HS rats. Reduction in LV fibrosis and increase in capillary density in WT animals were accompanied by reductions in myocardial levels of TGF-β1, MMP2, p22 and gp91 mRNA expression, and increases in myocardial levels of VEGF and HSP90 mRNA and phosphorylated eNOS protein. These effects were comparable between WT and FL animals. WT improves structural and molecular alterations in salt-induced hypertensive rats similarly to fluvastatin. [ABSTRACT FROM AUTHOR]

• Underwater acoustic emission (AE) was applied in failure evaluation of composites. • SiC/SiC composites with varied SiC fibers were irradiated to 30 dpa at 620–670°C. • Weibull statistics suggested no marked degradation of composite strength by irradiation. • No irradiation change of the AE onset (first matrix cracking) stress was demonstrated. Understanding the statistical properties of mechanical properties of non-irradiated and neutron-irradiated SiC/SiC composites is essential for component design. This study aims to evaluate the detailed damage accumulation behavior of composites focusing on two fracture parameters: proportional limit stress (PLS) and acoustic emission (AE) onset stress. The developmental underwater AE technique, which is benefit in non-contact in-situ failure monitoring method during mechanical testing and in handle of the irradiated material, was first applied to evaluate damage accumulation behavior. Two types of chemical vapor infiltration SiC/SiC composites were used: one reinforced with Hi-Nicalon Type-S SiC fiber and one reinforced with Tyranno-SA3 SiC fiber in the form of satin-woven 2D fabrics with pyrolytic carbon interface. Neutron irradiation in the High Flux Isotope Reactor at Oak Ridge National Laboratory reached a fluence of 30 dpa at a temperature of 620–670°C. Four-point flexural tests were conducted to evaluate post-irradiation strength. Weibull statistics did not suggest marked degradation of composite strength. Detailed failure behavior evaluated by AE demonstrated no irradiation-induced change of the AE onset stress (i.e., crack initiation equivalent stress). Failure probability analysis suggests that increasing the reliability of composites (i.e., the Weibull modulus rather than strength itself) is essential to expanding the design margin and benefiting from a probabilistic design approach. [ABSTRACT FROM AUTHOR]

Autophagy acts as a host-defense system against pathogenic microorganisms such as Group A Streptococcus (GAS). Autophagy is a membrane-mediated degradation system that is regulated by intracellular membrane trafficking regulators, including small GTPase Rab proteins. Here, we identified Rab30 as a novel regulator of GAS-containing autophagosome-like vacuoles (GcAVs). We found that Rab30, a Golgi-resident Rab, was recruited to GcAVs in response to autophagy induction by GAS infection in epithelial cells. Rab30 recruitment was dependent upon its GTPase activity. In addition, the knockdown of Rab30 expression significantly reduced GcAV formation efficiency and impaired intracellular GAS degradation. Rab30 normally functions to maintain the structural integrity of the Golgi complex, but GcAV formation occurred even when the Golgi apparatus was disrupted. Although Rab30 also colocalized with a starvation-induced autophagosome, Rab30 was not required for autophagosome formation during starvation. These results suggest that Rab30 mediates autophagy against GAS independently of its normal cellular role in the structural maintenance of the Golgi apparatus, and autophagosome biogenesis during bacterial infection involves specific Rab GTPases. [ABSTRACT FROM AUTHOR]

Over the past decade, significant progress has been made in the development of silicon carbide (SiC) composites, composed of near-stoichiometric SiC fibers embedded in a crystalline SiC matrix, to the point that such materials can now be considered nuclear grade. Recent neutron irradiation studies of Hi-Nicalon Type S SiC composites showed excellent radiation response at damage levels of 30–40 dpa at temperatures of 300–800 °C. However, more recent studies of these same fiber composites irradiated to damage levels of >70 dpa at similar temperatures showed a marked decrease in ultimate flexural strength, particularly at 300 °C. Here, electron microscopy is used to analyze the microstructural evolution of these irradiated composites in order to investigate the cause of the degradation. While minimal changes were observed in Hi-Nicalon Type S SiC composites irradiated at 800 °C, substantial microstructural evolution is observed in those irradiated at 300 °C. Specifically, carbonaceous particles in the fibers grew by 25% compared to the virgin case, and severe cracking occurred at interphase layers. [ABSTRACT FROM AUTHOR]

Nuclear-grade silicon carbide (SiC) composite material was examined for mechanical and thermophysical properties following high-dose neutron irradiation in the High Flux Isotope Reactor at a temperature range of 573–1073 K. The material was chemical vapor-infiltrated SiC-matrix composite with a two-dimensional satin weave Hi-Nicalon Type S SiC fiber reinforcement and a multilayered pyrocarbon/SiC interphase. Moderate (1073 K) to very severe (573 K) degradation in mechanical properties was found after irradiation to >70 dpa, whereas no evidence was found for progressive evolution in swelling and thermal conductivity. The swelling was found to recover upon annealing beyond the irradiation temperature, indicating the irradiation temperature, but only to a limited extent. The observed strength degradation is attributed primarily to fiber damage for all irradiation temperatures, particularly a combination of severe fiber degradation and likely interphase damage at relatively low irradiation temperatures. [ABSTRACT FROM AUTHOR]

Chronic neonatal blockade of N -methyl- d -aspartate (NMDA) receptors produces various abnormal behaviors in adulthood animals. This study investigated the effects of neonatal treatment chronically with MK-801 in rats on the preexposure-induced retardation of CS-US association, i.e. latent inhibition (LI), of two aversive classical conditioning tasks in adulthood. In conditioned taste aversion (CTA) using sucrose taste and LiCl, neonatal chronic MK-801 (0.4 mg/kg twice/day) treatment attenuated the inhibitory effect of sucrose preexposure on the aversive conditioning, although the treatment did not affect CTA conditioning itself. On the other hand, in conditioned emotional response (CER) using tone and electrical foot shock, rats neonatally treated with MK-801 showed the same degree of inhibitory effect of tone preexposure on the aversive conditioning compared with neonatally vehicle-treated rats, and also showed the same level of CER conditioning itself. Thus, the effect of chronic neonatal blockade of NMDA receptors on the LI of classical conditioning in adulthood was differentiated by the task employed. Results suggest that LI of CTA paradigm compared with that of CER is more sensitive to abnormal development after chronic neonatal blockade of NMDA receptors as an index of cognitive/attentional deficits caused by the treatment. [ABSTRACT FROM AUTHOR]

Autophagy plays a crucial role in host defence by facilitating the degradation of invading bacteria such as Group A S treptococcus ( GAS). GAS-containing autophagosome-like vacuoles ( GcAVs) form when GAS-targeting autophagic membranes entrap invading bacteria. However, the membrane origin and the precise molecular mechanism that underlies GcAV formation remain unclear. In this study, we found that Rab17 mediates the supply of membrane from recycling endosomes ( REs) to GcAVs. We showed that GcAVs contain the RE marker transferrin receptor ( TfR). Colocalization analyses demonstrated that Rab17 colocalized effectively with GcAV. Rab17 and TfR were visible as punctate structures attached to GcAVs and the Rab17-positive dots were recruited to the GAS-capturing membrane. Overexpression of Rab17 increased the TfR-positive GcAV content, whereas expression of the dominant-negative Rab17 form ( Rab17 N132 I) caused a decrease, thereby suggesting the involvement of Rab17 in RE- GcAV fusion. The efficiency of GcAV formation was lower in Rab17 N132 I-overexpressing cells. Furthermore, knockdown of Rabex-5, the upstream activator of Rab17, reduced the GcAV formation efficiency. These results suggest that Rab17 and Rab17-mediated REs are involved in GcAV formation. This newly identified function of Rab17 in supplying membrane from REs to GcAVs demonstrates that RE functions as a primary membrane source during antibacterial autophagy. [ABSTRACT FROM AUTHOR]

Understanding the cracking process of the composites is essential to establish the design basis for practical applications. This study aims to investigate the damage accumulation process and its anisotropy for nano-infiltration transient eutectic sintered (NITE) SiC/SiC composites by various characterization techniques such as the acoustic emission (AE), digital image correlation (DIC) and electrical resistivity (ER) measurements. Cracking behavior below the proportional limit stress (PLS) was specifically addressed. Similar to the other generic SiC/SiC composites, the 1st AE event was identified below the PLS for NITE SiC/SiC composites with a dependency of fabric orientation. The DIC results support that the primary failure mode depending on fiber orientation affected more than the other minor modes did. Detailed AE waveform analysis by wavelet shows a potential to classify the failure behavior depending on architecture. Cracking below the PLS is a potential concern in component deign but the preliminary ER measurements imply that the impact of cracking below the PLS on composite function was limited. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy is associated with increased oxidative stress and vascular endothelial dysfunction, which lead to coronary microangiopathy. We tested whether statin-induced redox imbalance improvements could ameliorate diabetic cardiomyopathy and improve coronary microvasculature in streptozotocin-induced diabetes mellitus (DM). Fluvastatin (10 mg/kg/day) or vehicle was orally administered for 12 weeks to rats with or without DM. Myocardial oxidative stress was assessed by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase subunit p22 and gp91 mRNA expression, and myocardial 8-iso-prostaglandin F (PGF) levels. Myocardial vascular densities were assessed using anti-CD31 and anti-α-smooth muscle actin (SMA) antibodies. Fluvastatin did not affect blood pressure or plasma cholesterol, but attenuated increased left ventricular (LV) minimum pressure and ameliorated LV systolic dysfunction in DM rats in comparison with vehicle (LV d P/d t, 8.9 ± 1.8 vs 5.4 ± 1.0 × 10 mmHg/s, P < 0.05). Myocardial oxidative stress increased in DM, but fluvastatin significantly reduced p22 and gp91 mRNA expression and myocardial PGF levels. Fluvastatin enhanced myocardial endothelial nitric oxide synthase (eNOS) protein levels and increased eNOS, vascular endothelial growth factor, and hypoxia-inducible factor-1α mRNA expression. CD31-positive cell densities were lower in DM rats than in non-DM rats (28.4 ± 13.2 vs 48.6 ± 4.3/field, P < 0.05) and fluvastatin restored the number (57.8 ± 18.3/field), although there were no significant differences in SMA-positive cell densities between groups. Fluvastatin did not affect cardiac function, oxidative stress, or vessel densities in non-DM rats. These results suggest that beneficial effects of fluvastatin on diabetic cardiomyopathy might result, at least in part, from improving coronary microvasculature through reduction in myocardial oxidative stress and upregulation of angiogenic factor. [ABSTRACT FROM AUTHOR]

Abstract: A silicon carbide fiber reinforced silicon carbide matrix (SiC/SiC) composite is a promising candidate for a fusion DEMO blanket. To develop design codes in practical use of them, strength anisotropy is an important issue to be clarified and therefore this study aimed to evaluate the failure behavior of the SiC/SiC composites to provide a strength map. For this purpose, detailed tensile, compressive and in-plane shear failure behaviors were evaluated by the acoustic emission (AE) technique for a plain–weave (P/W) chemically vapor-infiltration (CVI) SiC/SiC composite. The AE results distinguished damage accumulation processes by separately discussing localized variations of power within a time series by wavelet analysis. Of particular emphasis is that matrix cracking occurred prior to the proportional limit stress (PLS) by both tensile and compressive tests. This is because the rough-surface of SiC fibers resulted in the strong frictional stress at the fiber/matrix (F/M) interface, showing linearity in the stress–strain curve beyond the actual matrix cracking stress (i.e., possibly no sliding of the fibers at the F/M interface). In this paper, an updated failure envelope was provided by referring the true matrix cracking stresses as more realistic and reasonable failure criteria. [Copyright &y& Elsevier]

Background: Repeated low-temperature sauna (Waon) therapy relieves ischemic symptoms in patients with peripheral arterial disease. We investigated whether Waon therapy could improve myocardial perfusion in patients with ischemia related to chronic total occlusion (CTO) of coronary arteries. Methods: Twenty-four patients who had ischemia in the CTO-related area were examined. The severity of ischemia was quantified by thallium-201 myocardial perfusion scintigraphy with adenosine. The Waon group (n=16) was treated daily for three weeks with a 60°C far infrared-ray dry sauna bath for 15min and then kept in a bed covered with blankets for 30min. The control group (n=8) underwent myocardial perfusion scintigraphy twice with a three-week interval. Results: In the control group, neither summed stress score (SSS) nor summed difference score (SDS) of myocardial scintigraphy changed. However, Waon therapy improved both SSS (16±7 to 9±6, p<0.01) and SDS (7±4 to 3±2, p<0.01), and the improvement was greater in patients with higher SSS and SDS scores at the baseline. Waon therapy extended treadmill exercise time (430±185 to 511±192s, p<0.01) and improved flow-mediated dilation of the brachial artery (4.1±1.3 to 5.9±1.8%, p<0.05), but tended to decrease the number of circulating CD34-positive bone marrow-derived cells. Conclusions: Waon therapy improves CTO-related myocardial ischemia in association with improvement of vascular endothelial function. This therapy could be a complementary and alternative tool in patients with severe coronary lesions not suitable for coronary intervention. [ABSTRACT FROM AUTHOR]

Mobile genetic elements (MGEs) and genetic rearrangement are considered as major driving forces of bacterial diversification. Previous comparative genome analysis of Porphyromonas gingivalis, a pathogen related to periodontitis, implied such an important relationship. As a counterpart system to MGEs, clustered regularly interspaced short palindromic repeats (CRISPRs) in bacteria may be useful for genetic typing. We found that CRISPR typing could be a reasonable alternative to conventional methods for characterizing phylogenetic relationships among 60 highly diverse P. gingivalis isolates. Examination of genetic recombination along with multilocus sequence typing suggests the importance of such events between different isolates. MGEs appear to be strategically located at the breakpoint gaps of complicated genome rearrangements. Of these MGEs, insertion sequences (ISs) were found most frequently. CRISPR analysis identified 2,150 spacers that were clustered into 1,187 unique ones. Most of these spacers exhibited no significant nucleotide similarity to known sequences (97.6%: 1,158/1,187). Surprisingly, CRISPR spacers exhibiting high nucleotide similarity to regions of P. gingivalis genomes including ISs were predominant. The proportion of such spacers to all the unique spacers (1.6%: 19/1,187) was the highest among previous studies, suggesting novel functions for these CRISPRs. These results indicate that P. gingivalis is a bacterium with high intraspecies diversity caused by frequent insertion sequence (IS) transposition, whereas both the introduction of foreign DNA, primarily from other P. gingivalis cells, and IS transposition are limited by CRISPR interference. It is suggested that P. gingivalis CRISPRs could be an important source for understanding the role of CRISPRs in the development of bacterial diversity. [ABSTRACT FROM PUBLISHER]

Autophagy mediates the degradation of cytoplasmic contents in the lysosome and plays a significant role in immunity. Here we identified the small GTPases Rab9A and Rab23 as novel autophagy regulators during Group A streptococcus (GAS) infection. Rab9A was recruited to GAS-containing autophagosome-like vacuoles (GcAVs) after autophagosomal maturation and its activity was required for GcAV enlargement and eventual lysosomal fusion. GcAV enlargement appeared to be related to homotypic fusion of GcAVs with Rab9A. Rab23 was recruited to GAS-capturing forming autophagosomes. Knockdown of Rab23 expression decreased both LC3- and Atg5-positive GAS formation and caused the accumulation of LC3-positive structures that did not associate with intracellular GAS. It was suggested, therefore, that Rab23 is required for GcAV formation and is involved in GAS targeting of autophagic vacuoles. Furthermore, knockdown of Rab9A or Rab23 expression impaired the degradation of intracellular GAS. Therefore, our data reveal that the Rab9A and Rab23 GTPases play crucial roles in autophagy of GAS. However, neither Rab9A nor Rab23 were localized to starvation-induced autophagosomes. Not only Rab9A but also Rab23 was dispensable for starvation-induced autophagosome formation. These findings demonstrate that specific Rab proteins function at distinct steps during autophagy in response to GAS infection. [ABSTRACT FROM AUTHOR]

Abstract: Hot isostatic pressing (HIP) is a key technology used to fabricate a first wall with cooling channels for the fusion blanket system utilizing a reduced-activation ferritic/martensitic steel. To qualify the HIPped components, small specimen test techniques are beneficial not only to evaluate the thin-wall cooling channels containing the HIP joint but also to use in neutron irradiation studies. This study aims to develop the torsion test method with special emphasis on providing a reasonable and comprehensive method to determine interfacial shear properties of HIP joints during the torsional fracture process. Torsion test results identified that the torsion process shows yield of the base metal followed by non-elastic deformation due to work hardening of the base metal. By considering this work hardening issue, we propose a reasonable and realistic solution to determine the torsional yield shear stress and the ultimate torsional shear strength of the HIPped interface. Finally, a representative torsion fracture process was identified. [Copyright &y& Elsevier]

Abstract: A SiC/SiC composite is a candidate material for a demonstration fusion power reactor (DEMO). Identifying the inherent anisotropy of composites is required to predict axial/off-axial mechanical properties for various failure modes. This study evaluated crack propagation behavior by the various modes to provide strength anisotropy maps and we discussed a method to analytically predict this trend. The strength anisotropy maps identified for various fabric orientations clearly indicate that the composites failed in the mixed modes. Specifically, due to the axial anisotropy, five individual mode strengths such as tensile/compressive strengths in the axial/transverse directions, respectively, as well as the in-plane shear strength, are identified to become essential input parameters. With the analytical criterion based on the Tsai–Wu model, the strength anisotropy could satisfactorily be described. [Copyright &y& Elsevier]

Repeated sauna treatment, known as Waon therapy, has been shown to improve cardiac function as well as exercise tolerance in patients with chronic heart failure. However, the underlying mechanisms of this therapy regarding these improvements remain to be elucidated. Forty-one patients with chronic heart failure (mean age 68.3 ± 13.5 years old) underwent Waon therapy 5 times a week for 3 weeks. Before and after treatment, a number of assessments were performed in all subjects: 6-minute walk test, echocardiography, determination of neurohumoral factors and number of circulating CD34+ cells, and a flow-mediated dilation (FMD) test of endothelial function. Cardiopulmonary exercise testing was also performed in 20 patients. Waon therapy increased the left ventricular ejection fraction (from 30.4 ± 12.6% to 32.5% ± 12.8%, p = 0.023) and reduced plasma levels of norepinephrine (from 400 ± 258 to 300 ± 187 pg/ml, p = 0.015) and brain natriuretic peptide (from 550 ± 510 to 416 ± 431 pg/ml, p = 0.035). Waon therapy increased the 6-minute walk distance (from 337 ± 120 to 379 ± 126 m, p <0.001) in association with an improvement in FMD (from 3.5 ± 2.3% to 5.5% ± 2.7%, p <0.001) and an increase in the number of circulating CD34+ cells (p = 0.025). Changes in 6-minute walk distance were correlated positively with those in the left ventricular ejection fraction and FMD and negatively with those in plasma levels of norepinephrine and brain natriuretic peptide levels. A multivariate analysis revealed that an increase in FMD was the only independent determinant of 6-minute walk distance improvement. Finally, Waon therapy significantly increased peak Vo 2, and this increase was also correlated with changes in FMD. In conclusion, repeated sauna therapy in patients with chronic heart failure improves exercise tolerance in association with improvement in endothelial function. [ABSTRACT FROM AUTHOR]

Abstract: A hot isostatic press (HIP) process is a key technology to fabricate a first wall with cooling channels of the blanket system utilizing a reduced-activation ferritic/martensitic (RAFM) steel such as F82H. A primary objective of this study is to characterize interfacial properties of HIPed F82H joints by torsion to identify the feasibility of this test method for the inspection of the HIPed F82H joints. It is apparent that the absorption energies of the HIP joints varied by the processing conditions, although the maximum shear strength was not much different. The fracture surface observation study indicated that the reduction of the absorption energy obtained in the torsion tests was primarily due to the oxide formed on the interface of the HIP joint. Of particular importance, these features were very consistent with the results of Charpy impact tests. Preliminary test results then suggest that the torsion test method with a miniature specimen has a potential to evaluate the shear properties of the HIPed joint interface. [Copyright &y& Elsevier]

Abstract: High purity chemically vapor-deposited (CVD) silicon carbide (SiC) and near-stoichiometric SiC fiber, chemically vapor-infiltrated (CVI) SiC matrix composite were evaluated following neutron irradiation to ∼28dpa at 300 and 650°C and to ∼41dpa at 800°C, respectively. The irradiated swelling, thermal conductivity, and elastic modulus indicated no additional changes in these properties at high fluences after saturation at low fluences. With a statistically meaningful sample population, no change in flexural strength of CVD SiC was observed after 300°C irradiation. A slight decrease in strength was observed after 650°C irradiation but was attributed to an experimental artifact; specifically, a reaction between samples and the capsule components. The Hi-Nicalon™ Type-S, CVI SiC composite retained the pre-irradiation strength and the non-linear fracture mode. The electrical resistivity measurement revealed a relatively minor effect of irradiation. Overall, irradiation-insensitivity of the high purity SiC ceramics and composite to neutron irradiation to doses 30–40dpa at temperatures 300–800°C was demonstrated. [Copyright &y& Elsevier]

Repeated sauna therapy (ST) increases endothelial nitric oxide synthase (eNOS) activity and improves cardiac function in heart failure as well as peripheral blood flow in ischemic limbs. The present study investigates whether ST can increase coronary vascularity and thus attenuate cardiac remodeling after myocardial infarction (MI). We induced MI by ligating the left coronary artery of Wistar rats. The rats were placed in a far-infrared dry sauna at 41°C for 15 min and then at 34&°C for 20 min once daily for 4 wk. Cardiac hemodynamic, histopathological, and gene analyses were performed. Despite the similar sizes of MI between the ST and non-ST groups (51.4 ± 0.3 vs. 51.1 ± 0.2%), ST reduced left ventricular (LV) end-diastolic (9.7 ± 0.4 vs. 10.7 ± 0.5 mm, P < 0.01) and end-systolic (8.6 ± 0.5 vs. 9.6 ± 0.6 mm, P < 0.01) dimensions and attenuated MI-induced increases in LV end-diastolic pressure. Cross-sectional areas of cardiomyocytes were smaller in ST rats and associated with a significant reduction in myocardial atrial natriuretic peptide mRNA levels. Vascular density was reduced in the noninfarcted myocardium of non-ST rats, and the density of cells positive for CD31 and for a-smooth muscle actin was decreased. These decreases were attenuated in ST rats compared with non-ST rats and associated with increases in myocardial eNOS and vascular endothelial growth factor mRNA levels. In conclusion, ST attenuates cardiac remodeling after MI, at least in part, through improving coronary vascularity in the noninfarcted myocardium. Repeated ST might serve as a novel noninvasive therapy for patients with MI. [ABSTRACT FROM AUTHOR]

The responses of sympathetic nerve activity to transient stress can be exaggerated in salt-sensitive (SS), hypertensive subjects. Cardiac and renal interstitial norepinephrine (iNE) levels during and after transient hypercapnia were investigated in conscious SS rats. Dahl SS and salt-resistant (SR) 6-wk-old rats were fed a high-salt diet, and at 12 wk iNE levels in the heart and kidney were determined using microdialysis with probes inserted in the left ventricular (LV) wall and kidney. A telemetry system determined blood pressure and heart rate (HR) in separate animals. After recovery from the operation, data were collected before, during, and after exposure to normoxic 10% CO2 for 25 min under unanesthetized conditions. The plasma NE concentrations at baseline did not differ between the two strains. Both cardiac and renal iNE levels were much higher in SS rats than in SR rats at baseline as well as during hypercapnic stress. After stress, the markedly increased iNE levels of SS rats were prolonged in the LV as well as in the kidney. During hypercapnic stress, HR decreased in both SS and SR rats, while sudden increases in HR immediately after the withdrawal from stress were followed by its slower reduction in SS rats compared with SR rats. In conclusion, transient hypercapnic stress causes exaggerated and prolonged elevation of iNE levels in the heart as well as in kidneys of SS animals. [ABSTRACT FROM AUTHOR]

It remains unclear whether atherosclerosis in one vascular bed progresses in parallel with that in other vascular beds. We investigated serial changes in vessel wall areas (VWAs) in various vessels over 2 years of follow-up. Vessel wall areas in the thoracic descending aorta (TDA), common carotid artery (CCA), right (RCA), and left main trunk (LMT) of coronary artery were determined in 52 patients with coronary artery disease (CAD) using 64-slice multidetector computed tomography. Plasma levels of high-sensitivity CRP (hs-CRP) and matrix metalloproteinase (MMP)-9, as well as urinary 8-iso-prostaglandin F2α (PGF2α) were determined at the baseline. After the follow-up period, plaque progression in a specific vessel did not parallel that of other vessels, although changes in TDA-VWAs were weakly correlated with those of LMT-VWAs. Basal levels of hs-CRP, MMP-9, and PGF2α did not predict progression or regression of VWAs in any vessels. Multivariate analyses showed that LDL-cholesterol < 100 mg/dl and use of statin emerged as predictors of regressing VWAs in TDA ( p < 0.05 and p < 0.05, respectively) and LMT ( p < 0.05 and p = 0.13, respectively). Changes in soft plaques over 2 years paralleled those of VWAs in both coronary arteries. In conclusion, the progression or regression of atherosclerotic plaques is inhomogeneous among the vascular beds of patients with CAD. [ABSTRACT FROM AUTHOR]

Streptococcus pyogenes, one of the major human pathogens, is a unique species since it has acquired diverse strain-specific virulence properties mainly through the acquisition of streptococcal prophages. In addition, S. pyogenes possesses clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems that can restrict horizontal gene transfer (HGT) including phage insertion. Therefore, it was of interest to examine the relationship between CRISPR and acquisition of prophages in S. pyogenes. Although two distinct CRISPR loci were found in S. pyogenes, some strains lacked CRISPR and these strains possess significantly more prophages than CRISPR harboring strains. We also found that the number of spacers of S. pyogenes CRISPR was less than for other streptococci. The demonstrated spacer contents, however, suggested that the CRISPR appear to limit phage insertions. In addition, we found a significant inverse correlation between the number of spacers and prophages in S. pyogenes. It was therefore suggested that S. pyogenes CRISPR have permitted phage insertion by lacking its own spacers. Interestingly, in two closely related S. pyogenes strains (SSI-1 and MGAS315), CRISPR activity appeared to be impaired following the insertion of phage genomes into the repeat sequences. Detailed analysis of this prophage insertion site suggested that MGAS315 is the ancestral strain of SSI-1. As a result of analysis of 35 additional streptococcal genomes, it was suggested that the influences of the CRISPR on the phage insertion vary among species even within the same genus. Our results suggested that limitations in CRISPR content could explain the characteristic acquisition of prophages and might contribute to strain-specific pathogenesis in S. pyogenes. [ABSTRACT FROM AUTHOR]

Streptococcus pyogenes (group A streptococcus, GAS), one of the most common pathogens of humans, attaches and invades into human pharyngeal or skin epithelial cells. We have previously reported that induction of apoptosis is associated with GAS invasion, which induces mitochondrial dysfunction and apoptotic cell death. We demonstrate here that GAS-induced apoptosis is mediated by reactive oxygen species (ROS) production. Both the induction of apoptosis and ROS production markedly increased upon invasion of wild-type GAS strain JRS4 into HeLa cells; however, the apoptotic response was not observed in fibronectin-binding protein F1-disrupted mutant SAM1-infected cells. In Bcl-2-overexpressing HeLa cells (HBD98-2-4), the induction of apoptosis, ROS production and mitochondrial dysfunction were significantly suppressed, whereas the numbers of invaded GAS was not different between HeLa (mock cells) and the HeLa HBD98-2-4 cells. Whereas Rac1 activation occurred during GAS invasion, ROS production in GAS-infected cells was clearly inhibited by transfection with the Rac1 mutants (L37 or V12L37), but not by the dominant active mutant (V12L61) or by the dominant negative mutant (N17). These observations indicate that GAS invasion triggers ROS production through Rac1 activation and generated ROS induced mitochondrial dysfunction leading to cellular apoptosis. [ABSTRACT FROM AUTHOR]

This paper aims to evaluate fracture resistance of nanoinfiltration transient eutectic phase-sintered (NITE)–silicon carbide fiber-reinforced silicon carbide matrix (SiC/SiC) composites, using the single-edge notched bend (SENB) test and the double-notch tensile (DNT) test. Both SENB and DNT test results identified notch insensitivity of NITE–SiC/SiC composites. With the fact of notch insensitivity, unique proportional limit stress, and fracture strength were identified regardless of the presence of artificial notches. By applying the nonlinear fracture mechanics, micro- and macrocracking energies were separately estimated. Specifically, lower microcrack formation energy was identified compared with conventional low-stiffness composite system. Finally, superior crack resistance of NITE–SiC/SiC composites was clearly demonstrated. [ABSTRACT FROM AUTHOR]

The dehydration of 1,3-butanediol was investigated over CeO2–ZrO2 catalysts prepared by impregnation at temperatures of 325–375 °C. Pure CeO2 selectively catalyzed the dehydration of 1,3-butanediol to form 3-buten-2-ol and 2-buten-1-ol, while pure ZrO2, which was less active than pure CeO2, catalyzed the dehydration to 3-buten-1-ol. In the CeO2/ZrO2 catalyst in which CeO2 was supported on zirconia, the presence of a small amount of CeO2 suppressed the formation of 3-buten-1-ol and induced the dehydration of 1,3-butanediol to form 3-buten-2-ol and 2-buten-1-ol and the subsequent dehydrogenation of 3-buten-2-ol to form 3-buten-2-one and butanone. The activity would be related to the redox features of CeO2. The monoclinic phase of zirconia support decreased while the cubic CeO2 phase increased as CeO2 content was increased. In contrast, in the ZrO2/CeO2 catalyst in which ZrO2 was supported on cubic CeO2, only the cubic CeO2 phase was observed and ZrO2 species appeared in the form of a solid solution of CeO2–ZrO2 with fluorite structure. Regardless of zirconia loading, ZrO2 species did not affect the catalytic activity of ZrO2/CeO2, which was controlled by CeO2 species. [ABSTRACT FROM AUTHOR]

Abstract: Background: Ischemic preconditioning (IPC) reduced myocardial ATP depletion during sustained ischemia and has a powerful protective effect on the myocardium. The purpose of the present study was to clarify the effects of IPC on myocardial accumulation of fatty acid (FA) tracer and its intracellular metabolism. Methods: Myocardial ischemia-reperfusion (MI-R) injury was induced by the left coronary artery ligation for 15 min followed by reperfusion in Wistar rats. IPC was achieved with a single cycle of 5-minute coronary ligation followed by 5-minute reperfusion before MI-R. Three days after ischemia-reperfusion, FA metabolism was evaluated in rats with or without IPC using 131I- and 125I-15-(p-iodophenyl)-9-methylpentadecanoic acid (9MPA) and thin-layer chromatography. Results: IPC attenuated a reduction of 9MPA accumulation in ischemic region (IR). The metabolite fraction of 9MPA including both early and late metabolites was less in IR as compared to non-IR in rats without IPC. IPC increased the final metabolic product of 9MPA processed via α- and β-oxidation in both IR and non-IR. Conclusions: IPC accelerated fatty acid oxidation in both IR and non-IR. This alteration in fatty acid metabolism would inhibit an intracellular accumulation of detrimental fatty acid metabolites. [Copyright &y& Elsevier]

Polar flagellated Pseudomonas aeruginosa PAO1 demonstrated extensive spreading growth in 2 days on 1.5% agar medium. Such spreading growth of P. aeruginosa PAO1 strains was absent on Luria–Bertani 1.5% agar medium, but remarkable on Davis minimal synthetic agar medium (especially that containing 0.8% sodium citrate and 1.5% Eiken agar) under aerobic 37 °C conditions. Analyses using isogenic mutants and complementation transformants showed that bacterial flagella and rhamnolipid contributed to the surface-spreading behavior. On the other hand, a type IV pilus-deficient pilA mutant did not lose the spreading growth activity. Flagella staining of PAO1 T cells from the frontal edge of a spreading colony showed unipolar and normal-sized rods with one or two flagella. Thus, the polar flagellate P. aeruginosa PAO1 T appears to swarm on high-agar medium by producing biosurfactant rhamnolipid and without differentiation into an elongated peritrichous hyperflagellate. [ABSTRACT FROM AUTHOR]

Abstract: The SiC layer integrity in the TRISO-coated gas-reactor fuel particle is critical to the performance, allowed burn-up, and hence intrinsic efficiency of high temperature gas cooled reactors. While there has been significant developmental work on manufacturing the fuel particles, detailed understanding of the effects of the complex in-service stress state combined with realistic materials property data under irradiation on fuel particle survival is not adequately understood. This particularly frustrates the modeling efforts that seek to improve fuel performance through basic understanding. In this work a compilation of non-irradiated and irradiated properties of SiC are provided and reviewed and analyzed in terms of application to TRISO fuels. In addition to a compilation and review of literature data, new data generated to fill holes in the existing database is included, specifically in the high-temperature irradiation regime. Another critical piece of information, the strength of the SiC/Pyrolytic carbon interface, was measured and is included, along with a formalism for its analysis. Finally, recommended empirical treatments of the data are suggested. [Copyright &y& Elsevier]

Abstract: Background: Elevated coagulative molecular markers could reflect the prothrombotic state in the cardiovascular system of patients with non-valvular atrial fibrillation (NVAF). A prospective, cooperative study was conducted to determine whether levels of coagulative markers alone or in combination with clinical risk factors could predict subsequent thromboembolic events in patients with NVAF. Methods: Coagulative markers of prothrombin fragment 1+2, D-dimer, platelet factor 4, and β-thromboglobulin were determined at the enrollment in the prospective study. Results: Of 509 patients with NVAF (mean age, 66.6±10.3 years), 263 patients were treated with warfarin (mean international normalized ratio, 1.86), and 163 patients, with antiplatelet drugs. During an average follow-up period of 2.0 years, 31 thromboembolic events occurred. Event-free survival was significantly better in patients with D-dimer level <150 ng/ml than in those with D-dimer level≧150 ng/ml. Other coagulative markers, however, did not predict thromboembolic events. Age (≧75 years), cardiomyopathies, and prior stroke or transient ischemic attack were independent, clinical risk factors for thromboembolism. Thromboembolic risk in patients without the clinical risk factors was quite low (0.7%/year) when D-dimer was <150 ng/ml, but not low (3.8%/year) when D-dimer was ≧150 ng/ml. It was >5%/year in patients with the risk factors regardless of D-dimer levels. This was also true when analyses were confined to patients treated with warfarin. Conclusions: D-dimer level in combination with clinical risk factors could effectively predict subsequent thromboembolic events in patients with NVAF even when treated with warfarin. [Copyright &y& Elsevier]

Tensile properties of Tyranno™-SA near-stoichiometric silicon carbide (SiC)-fiber–reinforced chemically vapor-infiltrated SiC-matrix composites with pyrolytic carbon interphases were experimentally studied. The influence of interphase thickness in a range of 60–300 nm on the tensile properties of the materials appeared to be generally minor. Thin interphase (<100 nm) did not have a significant deteriorating effect on composite properties, which has commonly been reported for conventional SiC-fiber composites. For very thin interphase (<60 nm) composites, a slight decrease in fracture strain and a substantial increase in interfacial sliding stress were noted. Increases in ultimate tensile strength and fracture strain were observed at a much thicker interphase (>600 nm) at the expense of composite stiffness. [ABSTRACT FROM AUTHOR]

Study objectives: The aim of this study was to investigate whether risk factors for embolism would promote thrombus formation in patients with nonvalvular atrial fibrillation (NVAF). Methods: Hemostatic markers for platelet activity (ie, platelet factor-4 and β-thromboglobulin [TG]), thrombotic status (ie, prothombin fragments 1 and 2), and fibrinolytic status (ie, d-dimer) were determined in 246 patients with NVAF (mean age, 66.1 years) and 111 control subjects without NVAF (68.3 years). Results: The β-TG level was higher in NVAF patients than in control subjects. D-dimer levels were higher in NVAF patients having risk factors (mean [± SE] d-dimer level, 158.6 ± 9.2 ng/mL) than in those without risk factors (mean d-dimer level, 92.1 ± 6.7 ng/mL; p < 0.01) and in control subjects (mean d-dimer level: control subjects with risk factors, 79.1 ± 10.3 ng/mL; control subjects without risk factors, 31.0 ± 7.4 ng/mL; p < 0.01). NVAF (odds ratio [OR], 3.94; 95% confidence interval [CI], 1.87 to 8.30; p = 0.0003) and age of ≥ 75 years (OR, 5.68; 95% CI, 2.87 to 11.23; p < 0.0001) emerged as predictors of elevated levels of d-dimer, and only NVAF (OR, 10.30; 95% CI, 5.67 to 18.72; p < 0.0001) emerged as a predictor of elevated levels of β-TG. Conclusions: NVAF patients whose conditions were complicated with risk factors for embolism could be in the prothrombotic state. Advanced age is a strong predictor of the prothrombotic state in NVAF patients. [ABSTRACT FROM AUTHOR]

Abnormalities in energy metabolism may play an important role in the development of hypertensive heart failure. However, the transition from compensated hypertrophy to heart failure is not fully understood in terms of energy metabolism. In Dahl salt-sensitive (DS) and salt-resistant (DR) rats, myocardial fatty acid and glucose uptake values were determined using 131I- or 125I-labeled 9-methylpentadecanoic acid (131I- or 125I-9MPA), and [14C]deoxyglucose ([14C]DG), fatty acid β-oxidation was identified using thin-layer chromatography, and insulin-stimulated glucose-uptake was observed using a euglycemic hyperinsulinemic glucose clamp. Six-week-old rats were fed a diet that contained 8% NaC1, which resulted in development of compensated hypertrophy in DS rats at 12 wk of age and ultimately led to heart failure by 18 wk of age. Uptake of [14C]DG increased markedly with age in the DS rats, whereas 131I-9MPA uptake was marginally but significantly increased only in animals aged 12 wk. The ratio of 125I-9MPA β-oxidation metabolites to total uptake in the DS rats was significantly lower (P < 0.05) at 12 (37%) and 18 (34%) wk compared with at 6 (45%) wk. Insulin increased [14C]DG uptake more than twofold in the DS rats at 6 wk, although this increase was markedly attenuated at 12 and 18 wk (11 and 8%, respectively). Our data suggest that in a hypertrophied heart before heart failure, fatty acid oxidation is impaired and the capacity to increase glucose uptake during insulin stimulation is markedly reduced. These changes in both glucose and fatty acid metabolism that occur in association with myocardial hypertrophy may have a pathogenic role in the subsequent development of heart failure. [ABSTRACT FROM AUTHOR]

Mouse PAT1 (putative anion transporter, CEFX, slc26a6), an orthologue of human SLC26A6, was recently identified at the intestinal brush-border membrane and shown to transport organic anions such as formate and oxalate, as well as inorganic ions. In this study, we conducted functional characterization of the uptake of formate by HEK293 cells transfected with PAT1. The uptake of formate by PAT1 was increased in the presence of an outwardly-directed Cl - gradient, whereas Na + had no effect, and the uptake was independent of pH. The Km of PAT1 for formate was 3.75 mM. Various organic acids exhibited a cis -inhibitory effect on the uptake of formate by PAT1. Furthermore, the uptake was increased by preloading with l -lactate, nicotinate, valproate and short-and medium-chain fatty acids, showing a trans -stimulatory effect. Thus, it was suggested that PAT1 transports organic acids as well as inorganic anions, demonstrating that it is involved in the intestinal absorption of anionic organic weak acids in the small intestine. [ABSTRACT FROM AUTHOR]

Objective. This study was performed to evaluate the effect of mutant alleles CYP2D6*2 and CYP2D6*10 on the pharmacokinetics of routinely administered metoprolol in middle-aged and elderly Japanese patients. Methods. We determined the genotypes of CYP2D6 in 34 patients aged from 56 years to 83 years, and analyzed the plasma concentration of metoprolol at steady state after repetitive administration. The pharmacokinetic parameters of metoprolol in individual patients were obtained from population estimates according to Bayes' theorem. Results. The plasma concentrations of metoprolol in the patients with CYP2D6*1/*1 (group 1a) were similar to those in the patients with CYP2D6*1/*2 (group 1b). The plasma concentrations in the patients with CYP2D6*1/*10 (group 2a) were also similar to those in the patients with CYP2D6*2/*10 (group 2b) but were higher than those in group 1 (group 1a plus 1b). The plasma concentrations of metoprolol in the patients with CYP2D6*10/*10 (group 3) were significantly higher than those in group 1 and group 2 (group 2a plus 2b). Mean values of oral clearance (in l/h/kg) in Groups 1, 2, and 3 were estimated to be 1.2, 1.0, and 0.49, respectively. These oral clearance values of metoprolol estimated in middle-aged and elderly Japanese patients were lower than those estimated in healthy young Chinese reported previously. Conclusion. The present study indicated that CYP2D6*10 is mainly responsible for the large pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients. In addition, the pharmacokinetics of repetitively administered metoprolol in middle-aged and elderly patients may be different from that of a single dose in younger patients. These results suggested that a lower dose of metoprolol may be used in middle-aged and elderly patients with CYP2D6*10. [ABSTRACT FROM AUTHOR]

: ObjectivesWe sought to evaluate the effects of various doses of guanethidine, a sympathoinhibitory drug, on ventricular function and survival in chronic heart failure (CHF) after myocardial infarction (MI) in rats.: BackgroundDirect inhibition of sympathetic outflow by a sympathoinhibitory drug might be an effective approach to therapy of CHF. However, recent clinical trials suggest that excessive suppression of sympathetic activity has an adverse effect on outcome. It remains unclear whether the beneficial effects of the sympathoinhibitory drug would be modified by its dosage.: MethodsThree doses of guanethidine (low-dose [LG], 1 mg/kg/day; medium-dose, 3 mg/kg/day; high-dose, 10 mg/kg/day) were administered via an osmotic mini-pump for 4 weeks. Hemodynamics, left ventricular (LV) diameters, plasma and myocardial norepinephrine (NE) levels, and survival were determined for four weeks after MI.: ResultsAs compared with MI rats receiving vehicle, LG suppressed LV dilation (9.2 ± 0.9 mm vs. 11.0 ± 0.8 mm, p < 0.05) and improved LV fractional shortening (25.0 ± 4.5% vs. 16.4 ± 4.7%, p < 0.05) in association with a reduction of plasma NE levels (520 ± 250 pg/ml vs. 1,000 ± 570 pg/ml, p < 0.05), but not with a significant reduction of noninfarcted myocardial NE levels (154 ± 71 ng/g vs. 207 ± 71 ng/g). Low-dose guanethidine reduced 24-h (6%) and 28-day mortality (6%), as compared with untreated MI rats (36% and 52%, respectively). High-dose guanethidine also reduced 24-h mortality (12%) but increased 28-day mortality (91%), in association with a depletion of myocardial NE. Medium-dose guanethidine had no beneficial effects on LV hemodynamics or long-term survival.: ConclusionsThese results indicate that the dosage of the sympathoinhibitory drug might be quite important for the treatment of CHF. [Copyright &y& Elsevier]

Examines the cardiac neuronal function and beta-receptor with a dual-tracer method of [131I]metaiodobenzylguanidine (MIBG) and [125I]iodocyanopindolol (ICYP) in rat heart failure after myocardial infarction (MI). Cardiac sympathetic neuronal alteration coupled with downregulation of beta-receptors in rat heart failure after MI; Autonomic nervous system.

Presents a study which examined the cardiac neuronal function and beta-receptor with a dual-tracer method of and idiosyncratically in rat heart failure after myocardial infarction. Methodology; Results and discussion; Conclusions.

This study examined the effect of knockout of KCNMA1 gene, coding for the BK channel, on cognitive and attentional functions in mice, with an aim to better understand its implications for human neurodevelopmental disorders. The study used the 3-choice serial reaction time task (3-CSRTT) to assess the learning performance, attentional abilities, and repetitive behaviors in mice lacking the KCNMA1 gene (KCNMA1 -/- ) compared to wild-type (WT) controls. Results showed no significant differences in learning accuracy between the two groups. However, KCNMA1 -/- mice were more prone to omitting responses to stimuli. In addition, when the timing of cue presentation was randomized, the KCNMA1 -/- showed premature responses. Notably, these mice also demonstrated a marked reduction in perseverative responses, which include repeated nose-poke behaviors following decisions. These findings highlight the involvement of the KCNMA1 gene in managing attention, impulsivity, and potentially moderating repetitive actions. • KCNMA1 gene knockout mice, lacking the BK channels, showed attentional deficits. • KO mice adapted to attention-related 3-CSRT task as accurately as WT mice. • KO mice increased task-cue omissions, which is interpreted as inattention. • Attentional load in this task increased impulsive responses of KO mice. • KO mice decreased repetitive nose-poke behaviors following choice. [ABSTRACT FROM AUTHOR]