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It has been proposed that a plastic strain surface is reset to a point and re-evolves every cycle to correctly evaluate the plastic strain range under cyclic loading (Ohno et al., 2018b). This resetting scheme has the advantage of providing a definite value for the evolution parameter irrespective of the amounts of cyclic hardening, pre-straining, and ratcheting. In the present study, the resetting scheme was experimentally verified by performing the following three types of uniaxial cyclic tests of 316 stainless steel at 600 °C: constant strain range, gradual decrease, and step decrease tests. The gradual decrease tests, a new type of cyclic tests, had gradual strain range reduction with increasing number of cycles in the absence and presence of ratcheting such as found at notch roots. Thus, the effect of the strain range history on cyclic hardening was observed to be weaker than that due to stepwise decreasing the strain range. Using a constitutive model with the resetting scheme enabled good simulation of the cyclic hardening behavior in the gradual decrease tests. Cyclic softening after stepwise decreasing the strain range was also simulated well by extending the evolution equation of cyclic hardening.

BACKGROUND AND OBJECTIVE: Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are used either when conventional synthetic DMARDs are ineffective or when disease activity is high and with poor prognostic factors, based on various clinical guidelines. The purpose of this study was to investigate the prescribing trends of bDMARDs for patients with rheumatoid arthritis in Japan, and to clarify whether the pharmacological therapy of bDMARDs is administered based on guidelines.We conducted a descriptive epidemiological study from 2012 to 2018 using the JMDC Claims Database, a nationwide claims database, and described the annual changes based on the number of patients prescribed bDMARDs. Anti-rheumatic drugs were identified based on the Anatomical Therapeutic Chemical codes, including methotrexate, glucocorticoids, non-steroidal anti-inflammatory drugs and bDMARDs.From the database including 6,862,244 people, the data of 6407 patients with rheumatoid arthritis were extracted. The present study demonstrated that the proportion of patients prescribed bDMARDs was 1.0 per 1000 people, with those aged ≥ 65 years being the most common age group. The proportion of patients with rheumatoid arthritis who were prescribed bDMARDs increased significantly over time (p0.0001). Additionally, the concomitant proportions of methotrexate (p0.0001), non-steroidal anti-inflammatory drugs (p0.0001) and glucocorticoids (p = 0.0001) prescribed with bDMARDs decreased significantly over time.The increase in bDMARD monotherapy may be attributed to the new bDMARDs that have been launched sequentially; furthermore, physicians have come to recognise monotherapy as the mainstay of treatment. Future studies must accumulate evidence on the long-term efficacy and safety of bDMARDs.

In this paper, a new method for scaling the crack-tip stress distribution under small-scale yielding conditions is proposed and named the T-scaling method. This method enables identification of the different stress distributions for materials with different tensile properties but identical load in terms of K or J. Then, by assuming that the temperature dependence of a material is represented by the stress-strain relationship temperature dependence, a method to predict the fracture load at an arbitrary temperature from the already known fracture load at a reference temperature is proposed. This method is combined with the T-scaling method and the knowledge that the “fracture stress for slip induced cleavage fracture is temperature independent.” Once the fracture load is assumed, the fracture toughness Jc at the temperature under consideration can be evaluated by running elastic-plastic finite element analysis. Finally, the above-mentioned framework for predicting the Jc temperature dependence of a material in the ductile-to-brittle temperature region was validated for 0.55% carbon steel JIS S55C and reactor pressure vessel steel A533B. The proposed framework seems to be able to solve the problem faced by the master curve in the relatively high temperature region by requiring only tensile tests.

掲載に寄せて(福原裕二著), 北東アジアの海をめぐる国境漁業の現状(濱田武士著), 座談会「環(めぐ)りの海から北東アジアの諸課題を探求する」(濱田武士, 和田春樹, 岩下明裕, 西野正人, 安達二朗, 福原裕二), 講演＆座談会の開催とその記録の掲載にあたっては、JSPS科研費JP25285054の助成を得ています。また、平成28年度北東アジア地域学術交流研究助成金［共同プロジェクト研究助成事業］の助成を得ています。

Astrogliosis (i.e. glial scar), which is comprised primarily of proliferated astrocytes at the lesion site and migrated astrocytes from neighboring regions, is one of the key reactions in determining outcomes after CNS injury. In an effort to identify potential molecules/pathways that regulate astrogliosis, we sought to determine whether Rac/Rac-mediated signaling in astrocytes represents a novel candidate for therapeutic intervention following CNS injury. For these studies, we generated mice with Rac1 deletion under the control of the GFAP (glial fibrillary acidic protein) promoter (GFAP-Cre;Rac1flox/flox). GFAP-Cre;Rac1flox/flox (Rac1-KO) mice exhibited better recovery after spinal cord injury and exhibited reduced astrogliosis at the lesion site relative to control. Reduced astrogliosis was also observed in Rac1-KO mice following microbeam irradiation-induced injury. Moreover, knockdown (KD) or KO of Rac1 in astrocytes (LN229 cells, primary astrocytes, or primary astrocytes from Rac1-KO mice) led to delayed cell cycle progression and reduced cell migration. Rac1-KD or Rac1-KO astrocytes additionally had decreased levels of GSPT1 (G1 to S phase transition 1) expression and reduced responses of IL-1β and GSPT1 to LPS treatment, indicating that IL-1β and GSPT1 are downstream molecules of Rac1 associated with inflammatory condition. Furthermore, GSPT1-KD astrocytes had cell cycle delay, with no effect on cell migration. The cell cycle delay induced by Rac1-KD was rescued by overexpression of GSPT1. Based on these results, we propose that Rac1-GSPT1 represents a novel signaling axis in astrocytes that accelerates proliferation in response to inflammation, which is one important factor in the development of astrogliosis/glial scar following CNS injury.

Rac signaling affects numerous downstream targets; however, few studies have established in vivo levels. We generated mice with a single knockout (KO) of Rac1 (Keratin5 (K5)-Cre;Rac1flox/flox, Rac1-KO) and double KO of Rac1 and Rac3 (K5-Cre;Rac1flox/flox;Rac3−/−, Rac1/Rac3-DKO) in keratinocytes. Strikingly, Rac1-KO mice exhibited thinner dermal white adipose tissue, which was considerably further reduced in Rac1/Rac3-DKO mice. DNA microarray using primary keratinocytes from Rac1/Rac3-DKO mice exhibited decreased mRNA levels of Bmp2, Bmp5, Fgf20, Fgf21, Fgfbp1, and Pdgfα. Combinational treatment with BMP2 and FGF21 or BMP2 and FGF20 in culture medium, but not individual purified recombinant proteins, could differentiate 3T3-L1 fibroblasts into adipocytes, as could culture media obtained from primary keratinocytes. Conversely, addition of anti-BMP2 or anti-FGF21 antibodies into the culture medium inhibited fibroblast differentiation. Furthermore, combinational treatment with BMP2 and FGF21 promoted adipocyte differentiation only of rat primary white, but not brown, adipocyte precursors. Notably, brown adipogenesis by FGF21 was inhibited by BMP2. Thus, we proposed novel paracrine pathways from keratinocytes to intradermal pre-adipocytes, which function as Rac-dependent modulators of white adipogenesis, but also brown adipogenesis.

In this work, applicability of the modified Ritchie-Knott-Rice (RKR) failure criterion (which predicts the onset of cleavage fracture when the crack opening stress measured at four times the crack-tip opening displacement σ22d exceeds a critical value σ22c) is demonstrated for the test specimen with residual stress. This was done by comparing the results of the fracture toughness test and elastic-plastic finite element analysis results. 0.45 % carbon steel JIS S45C, whose tensile to yield stress ratio was equal to 1.5 was chosen as material for the test. SE(B) specimen of width 46 x thickness 23 mm, which complies the ASTM E1921 was used for the test. The residual stress was introduced to the crack-tip by mechanical pre-loading. The results showed that though scatter of the fracture toughness Jc was large, scatter of the critical value σ22c was very small. Thus, the modified RKR failure criterion has been shown to be applicable to the S45C SE(B) specimens of thickness 23 mm with residual stress by mechanical pre-loading. In addition, the J corresponding to the load that σ22d first reaches σ22c seemed to predict the lower bound toughness for the material and the specified specimen configuration.

NADPH oxidase (Nox) family proteins produce superoxide (O2 (⨪)) directly by transferring an electron to molecular oxygen. Dual oxidases (Duoxes) also produce an O2 (⨪) intermediate, although the final species secreted by mature Duoxes is H2O2, suggesting that intramolecular O2 (⨪) dismutation or other mechanisms contribute to H2O2 release. We explored the structural determinants affecting reactive oxygen species formation by Duox enzymes. Duox2 showed O2 (⨪) leakage when mismatched with Duox activator 1 (DuoxA1). Duox2 released O2 (⨪) even in correctly matched combinations, including Duox2 + DuoxA2 and Duox2 + N-terminally tagged DuoxA2 regardless of the type or number of tags. Conversely, Duox1 did not release O2 (⨪) in any combination. Chimeric Duox2 possessing the A-loop of Duox1 showed no O2 (⨪) leakage; chimeric Duox1 possessing the A-loop of Duox2 released O2 (⨪). Moreover, Duox2 proteins possessing the A-loops of Nox1 or Nox5 co-expressed with DuoxA2 showed enhanced O2 (⨪) release, and Duox1 proteins possessing the A-loops of Nox1 or Nox5 co-expressed with DuoxA1 acquired O2 (⨪) leakage. Although we identified Duox1 A-loop residues (His(1071), His(1072), and Gly(1074)) important for reducing O2 (⨪) release, mutations of these residues to those of Duox2 failed to convert Duox1 to an O2 (⨪)-releasing enzyme. Using immunoprecipitation and endoglycosidase H sensitivity assays, we found that the A-loop of Duoxes binds to DuoxA N termini, creating more stable, mature Duox-DuoxA complexes. In conclusion, the A-loops of both Duoxes support H2O2 production through interaction with corresponding activators, but complex formation between the Duox1 A-loop and DuoxA1 results in tighter control of H2O2 release by the enzyme complex.

Fully oxidized poly(1-(N,N-dimethylamino)pyrrole)s (PDMAPyn+), which are synthesized through doping with anions with the same number of polymer units as the original pyrrole, have been proposed as candidates for molecular flat-band magnets from the theoretical calculations of Aoki and coworkers (Phys. Rev. B: Condens. Matter Mater. Phys., 2003, 68, 140403; Phys. Rev. B: Condens. Matter Mater. Phys., 2010, 82, 235127). Here we describe the synthesis of neutral forms of oligo(1-(N,N-dimethylamino)pyrrole)s (ODMAPys) from the dimer (2) to the dodecamer (12). The crystal structures of 2–6 (i.e., up to the hexamer) were determined by single crystal X-ray analysis. The chemical and electrochemical formation of their oxidized forms is also reported. Electrochemical measurements of the ODMAPys indicated that oligomers 4, 6, and 8 underwent 2e− oxidation, whereas 10 and 12 showed quasi-reversible 4e− oxidation. The oxidized forms maintained considerable chemical stability; 42+, 62+, 82+, 104+, and 124+ were isolated as SbCl6− salts. The neutral forms were colorless (λmax = 240–270 nm), whereas the oxidized forms exhibited strong blue color with λmax = 670–950 nm. EPR spectroscopy indicated that the dications 42+, 62+, and 82+ in the solid salts were intrinsically diamagnetic, but the tetracation of 104+ was paramagnetic at 4.4 K, which was supported by magnetic measurements. These physical properties of the ODMAPys are different from those common to polypyrroles, but consistent with their predicted unique electronic structures.

Although benzodiazepines (BZDs) are commonly prescribed for insomnia or anxiety, long-term use of BZDs causes serious adverse effects such as daytime drowsiness and cognitive decline. In the current study, we evaluated the predictors and preventers of long-term usage of BZDs from a retrospective survey by utilizing the 12-year prescription record of a university hospital. From the prescription data of 92,005 people, users of BZDs (n = 3,470, male = 39.2%, mean age = 60 ± 17.5) were analyzed. During this period, both the number of prescriptions (2722 in 2004 to 1019 in 2016) and the number of BZDs (1.73 in 2004 to 1.36 in 2016) gradually decreased, although more than half of the patients continued to take BZDs for over three years. High risk factors for long-term use of BZDs include elderly patients (>65 years old), high dosage (>5 mg diazepam per day), psychiatrist-prescribers, and users with polytherapy. Discontinuation is significantly found in users of hypnotic BZDs and alternative psychotropic medical drugs (including antipsychotics, serotonergic drugs, or newer types of sleep medicine). Future studies should focus on elucidating interventions that are more effective against long-term usage of BZDs.

In this paper, a new method for scaling the crack tip stress distribution under small scale yielding condition was proposed and named as T-scaling method. This method enables to identify the different stress distributions for materials with different tensile properties but identical load in terms of stress intensity factor (K) or J-integral (J). Then, a method to predict the fracture load at an arbitrary temperature from the already known fracture load at a reference temperature was proposed by assuming that the temperature dependence of a material is represented as the stress-strain relationship temperature dependence. This method was combined with the T-scaling method and the knowledge “fracture stress for slip induced cleavage fracture is temperature independent.” Once the fracture load is predicted, fracture toughness Jc at the temperature under consideration can be evaluated by running elastic-plastic finite element analysis. Finally, the above-mentioned framework to predict the Jc temperature dependency of a material in the ductile-to-brittle temperature region was validated for 0.55 % carbon steel JIS S55C. The proposed framework seems to have a possibility to solve the problem the master curve is facing in the relatively higher temperature region, by requiring only tensile tests.

In its resting state, Rho GDP-dissociation inhibitor (RhoGDI) α forms a soluble cytoplasmic heterodimer with the GDP-bound form of Rac. Upon stimulation, the dissociation of RhoGDIα from the RhoGDIα–Rac complex is a mandatory step for Rac activation; however, this mechanism is poorly understood. In this study, we examined how the cytoplasm/membrane cycles of the RhoGDI–Rac complex are regulated, as well as where RhoGDI dissociates from the RhoGDI–Rac complex, during FcγR-mediated phagocytosis. The negatively charged and flexible N terminus (25 residues) of RhoGDIα, particularly its second negative amino acid cluster possessing five negatively charged amino acids, was a pivotal regulator in the cytoplasm/membrane cycles of the RhoGDI–Rac complex. We also found that RhoGDIα translocated to the phagosomes as a RhoGDIα–Rac1 complex, and this translocation was mediated by an interaction between the polybasic motif in the C terminus of Rac1 and anionic phospholipids produced on phagosomes, such as phosphatidic acid, that is, by a phagosome-targeting mechanism of Rac1. Thus, we demonstrated that the targeting/accumulation of the RhoGDIα–Rac1 complex to phagosomes is regulated by a balance between three factors: 1) the negatively charged and flexible N-terminal of RhoGDIα, 2) the binding affinity of RhoGDIα for Rac1, and 3) anionic phospholipids produced on phagosomes. Moreover, we demonstrated that the mechanism of targeting/accumulation of the RhoGDIα–Rac1 complex is also applicable for the RhoGDIβ-Rac1 complex.

Phase diagrams of carbon dioxide (CO2)/tetramethoxysilane (TMOS) and CO2/tetraethoxysilane (TEOS) binary systems were measured. Liquid phase measurements were performed by observing the bubble point pressure with a synthetic method. Vapor phase measurements were conducted with a flow type apparatus. For the CO2/TMOS system, liquid phase lines were measured at temperatures from 313.2 to 393.2 K, and CO2 molar fractions from 0.15 to 0.85, and vapor phase lines were obtained at temperatures 313.2, 353.2 and 393.2 K and pressures up to 12 MPa. For the CO2/TEOS system, measurements were conducted only for liquid phase lines at temperatures from 313.2 to 373.2 K and CO2 molar fractions from 0.25 to 0.75. Phase behavior of these two systems was almost the same with each other. Experimental data were correlated with the Peng–Robinson equation of state (PR EoS), and the molecular interaction parameter kij and lij for both systems were determined. For large difference in the molecular size of CO2 and tetraalkoxysilanes, it was found that the lij could be negligible.

A flow-through constructed wetland (CW) has provided advanced treatment of wastewater with a complex matrix from a metal-processing plant. The main CW system (length 20 m, width 46 m, depth 0.3 m) was planted with aquatic plants such as Acorus gramineus, Cyperus alternifolius L., Iris pseudacorus, Lythrum anceps, Myosotis scorpioides, Phyla nodiflora L., and Zantedeschia aethiopica. During August–November 2007, the main CW system reduced total organic carbon concentrations from 5.7 to 1.2 mg/l, total nitrogen from 23.2 to 19.0 mg/l, and NH4+-N from 6.8 to 4.0 mg/l, on average, in physicochemically treated wastewater. Furthermore, CW reduced Fe concentrations significantly from 60 to 33 μg/l, Cu from 77 to 40 μg/l, Zr from 5.3 to 1.5 μg/l, Ag from 43 to 14 μg/l, Sn from 54 to 16 μg/l, and Au from 5.8 to 3.2 μg/l. For quantification and assessment of metal accumulation, A. gramineus and C. alternifolius were separately cultivated for 3 months in an experimental CW (length 10 m, width 1.25 m × 2 lanes, depth 0.3 m). The experimental CW showed low removals for most metals, probably because of lower plant density and the shorter HRT than the main CW. Bioconcentration factors (BCFs) of various metals such as Mn, Ni, Cu, Zn, In, Sm, Au, Pb, and Bi for both plants were 103–104. Generally, the metal with the higher concentration in water presented higher contents in plants. Both emergent plants commonly showed BCFs higher than >104 for Fe but lower than

OBJECTIVE Components of insulin/IGF-1 receptor–mediated signaling pathways in pancreatic β-cells have been implicated in the development of diabetes, in part through the regulation of β-cell mass in vivo. Studies in vitro have shown that the protein Ras homolog enriched in brain (Rheb) plays a key role as a positive upstream regulator of the mammalian target of rapamycin complex 1 (mTORC1) pathway in integrating inputs from nutrients and growth factors for cell growth. Our objective was to investigate the role of the mTORC1 pathway in the regulation of β-cell mass in vivo. RESEARCH DESIGN AND METHODS We generated transgenic mice that overexpress Rheb in β-cells. We examined the activation of the mTORC1 pathway and its effects on β-cell mass, on glucose metabolism, and on protection against hyperglycemia. RESULTS Immunoblots of islet extracts revealed that the phosphorylation levels of ribosomal protein S6 and eukaryotic initiation factor 4E binding protein 1, downstream effectors for mTORC1, were upregulated in transgenic β-cells. Immunostaining of the pancreatic sections with anti–phospho-S6 antibody confirmed upregulation of the mTORC1 pathway in β-cells in vivo. The mice showed improved glucose tolerance with higher insulin secretion. This arose from increased β-cell mass accompanied by increased cell size. The mice also exhibited resistance to hyperglycemia induced by streptozotocin and obesity. CONCLUSIONS Activation of the mTORC1 pathway by Rheb led to increased β-cell mass in this mouse model without producing obvious unfavorable effects, giving a potential approach for the treatment of β-cell failure and diabetes.

Subjects ranging in age from 50 to 89 years old, either with or without dementia were studied by both ELISA for anti-human T-cell lymphotropic virus type I (HTLV-I) gag 100-130 antibody and by cranial CT in order to clarify the relationship between HTLV-I infection and dementia. The frequency of anti-HTLV-I antibody was found to be significantly higher in the patients with dementia (24/130, 18.5%) than in those without dementia (11/139, 7.9%) (P=0.0169). Among the various types of dementia, HTLV-I seropositivity was found to be significantly associated with vascular dementia (11/48, 23%) (P= 0.0087), but not with Alzheimer type dementia. In addition, HTLV-I seropositivity was also associated with Babinski sign, and the severity of cerebral infarction, ventricular dilatation and periventricular lucency on CT. The presence of HTLV-I therefore appears to be one of the risk factors for vascular dementia in HTLV-I endemic areas.

SCA1 is a dominant spinocerebellar ataxia (SCA) and a multi-systemic syndrome caused by abnormal expansion of unstable CAG repeat in a novel gene located on chromosome 6p22-p23. We clinically studied 35 Japanese SCA1 patients who were assumed to have come from a common origin. The age at onset ranged from 15-63 years, and significantly correlated with CAG repeat units of mutant alleles. Ataxia was the initial symptom, and the majority of patients had a similar history of signs and symptoms. Nystagmus was at first minimal, later attenuated, and a slow saccade followed. Limb tendon reflexes were mostly hyperactive and depressed with the development of diffuse amyotrophy. The cardinal feature was ataxia-hyperreflexia-late slow saccade syndrome with terminal amyotrophy. Although the phenotype of SCA1 overlaps with those of other dominant SCAs, some facets of the neurological events differ from either SCA2 with ataxia-hyporeflexia-slow saccade syndrome, or early-onset Machado-Joseph disease with dystonia-bradykinesia-spasticity syndrome.

Though closed cell Al foams have extremely low density and high energy absorption performance, they are expected to improve the compressive strength and to clear the dynamic compression characteristics for much more practical application. In this research, the effects of density, test piece size and alloying (Al-10.0 mass%Zn-0.3 mass%Mg) on the uniaxial static and dynamic compressive strength was examined. Dynamic compressive strength were examined by the Split Hopkinson Pressure Bar (SHPB) method and the drop weight impact test device. As a result, the dynamic plateau stress of pure Al foams was about 1.3 times larger than the static one, and there was a scale effect of test pieces. The dynamic plateau stress of Al alloy foams was about 1.1 times larger than the static one, and there was less scale effect of test pieces for plateau stress because the cell walls of Al alloy foams tend to collapse owing to brittleness by alloying. The effect of the inner gas enclosed in cells on the dynamic response of pure Al foams by SHPB is also discussed. When providing inner gas vent holes, dynamic plateau stress decreased close to the static one. With Al foams, the increasing in dynamic plateau stress may be caused by the inner gas pressure rising under dynamic compressive conditions as well as influence of the strength and ductility of the cell wall. [doi:10.2320/matertrans.MRA2008487]

In this research, for the closed cell Al-Zn-Mg alloy foams which are fabricated by adding foaming agent to molten aluminum (direct aluminum foaming in melt), the effect of alloy contents and heat-treatment on the uniaxial static compression strength was examined. As a result, it was possible to achieve high compression strength by an increase in hardness and using appropriate alloy contents. The plateau region becomes longer, because the cell wall of Al-Zn-Mg alloy foams tends to incur brittle fracture by alloying. However, Al-Zn-Mg alloy foam with excessive alloy contents exhibits lower compression strength. There were few hardness improvements caused by heat treatment. Heat treatment did not cause improvement of compression strength. When the compression strength of Al foams is shown in relation to density and plateau stress, plateau stress of Al-10.0%Zn-0.3%Mg (mass%) alloy foam was about 1.7 times, and Al-10.0%Zn-1.0%Mg alloy foam was about 2 times higher than Al foam in density.

Closed cell porous Al has extremely low mass and provides high energy absorption performance. However, because of its low tensile strength, it has been expected to be used as porous Al filled members with a dense surface material, as well as to clarify its axial crushing performance. In this study, the effect of the axial crushing performance by porous Al filled members, the impact crushing test using several hollow forms and porous Al filling in different ways were examined, and FEM analysis was carried out. As a result, the energy absorption was increased about 1.6 times by press filling, and about 2.0 times by glue-press filling porous Al from the sum of individual one of hollow forms and porous Al; thus, the porous Al filled members provided the interaction effect. Based on the test result and the elastic-plastic FEM analysis in which the crushing behavior matched the test result, it was proved that the energy absorption was increased since the buckling transformation to inside forms was restrained. Moreover, porous Al penetrates inside transformation by glue-press filling and press filling porous Al, and accordingly the deformation resistance in the compression direction increased. This increase of the deformation resistance in the compression direction causes forms axisymmetric collapse mode, and the interaction effect of porous Al filled members can be expressed in as much that the form thickness apparently increases due to the effect of the mass of filling material. The estimate equation of the mean crushing stress as an index of the energy absorption well-matched the test result. Therefore, it was proved that the mass of filling material contributes as an additional thickness of forms. In addition, the interaction effect is decided by a filling method.

Recently, aluminum foams with more homogeneous pores are expected from the improvement of compression strength reliability. In this research, for the closed cell Al foams which are fabricated by adding foaming agent to molten aluminum (direct aluminum foaming in melt), the effect of pore control regarding viscosity, cooling rate and foaming agent size on the uniaxial static compression strength was examined. As a result, it is possible to make small and homogeneous pores by increase in viscosity, improvement in cooling rate and using a smaller foaming agent. However, Al foam with smaller a foaming agent became higher density as well as decreasing the pore size. The increment in the density of Al foam depends on the cell structure (thick cell walls and small pores). This is, the density increases with decreasing average pore diameter. Compression strength (plateau stress) of Al foams with small and homogeneous pores was improved. When the compression strength of Al foams is shown in relation to density and plateau stress, plateau stress was about the square of the increase in density.

Higher output and compactness is becoming the norm for low speed diesel engines. The gripping torque of shrink-fit on semi-build up crankshaft can be raised by taking advantage of its high yield point in new cast steel “Throw Grade 5”. Instead, large oversized shrink-fit might induce higher residual stress in the pin fillet or overheating might cause decrease in the cold rolling effect in the pin fillet for short stroke crankshaft.In this paper, a shrink-fit test of the actual crankthrow was carried out for a large oversized shrink-fit. It was accomplished without any decrease of the cold rolling effect in pin fillet. Finally, in order to confirm to safety stress analysis on the crankshaft of a large engine with Throw Grade 5 was made taking the residual stress due to shrink-fit and cold rolling into account.

Apart from its unique lesion distribution pattern, the opticospinal form of multiple sclerosis (OSMS) is distinct among Japanese patients who satisfy the diagnostic criteria of MS. OSMS has been suggested to be strongly associated with HLA-DPB1*0501 in Japanese. However, association of DPB1*0301 with non-OSMS and lack of DPB1*0301 in OSMS were also reported. To verify the role of DPB1*0501 and DPB1*0301 in Japanese MS patients we determined the frequencies of these alleles in 26 patients with OSMS, 167 with non-OSMS and 156 normal subjects, who were all residents of Hokkaido, the northernmost island of Japan. All (100%) OSMS were negative for DPB1*0301 while 32 (19%) of the non-OSMS were positive for the allele. In DPB1*0301-negatives, the frequencies of DPB1*0501 in OSMS (85%) and non-OSMS (82%) were similar, but both were higher than in the controls (66%). In DPB1*0301-positives, the frequency of DPB1*0501 was low but similar in non-OSMS (12/32; 38%) and controls (6/14; 43%). Periventricular white matter lesions (PVL) were noted in 31 of 32 (97%) DPB1*0301-positive non-OSMS patients but in only 22 out of 135 (16%) DPB1*0301-negative non-OSMS patients and two out of 26 (8%) OSMS patients. Our findings indicate that DPB1*0501 plays an important role in the development of MS in general, but not in OSMS. The strong association of DPB1*0501 with OSMS may be due to the over-representation of the DPB1*0301 allele among individuals in the non-OSMS group. In addition, DPB1*0301 might be relevant to the development of periventricular lesions in Japanese patients with MS.

Effective, pharmacologic approaches to the treatment of cerebellar ataxia are lacking or inadequate. We recently reported preliminary evidence that tandospirone citrate (tandospirone), a 5-HT1A agonist, improved cerebellar ataxia in patients with Machado-Joseph disease (MJD). In the course of that study, we found that such treatment also alleviated the pain associated with cold sensations in the legs, insomnia, anorexia, and depression, all of which are thought to be mediated through activation of the 5-HT1A receptor. In this paper, we reviewed the few published clinical trials that involved the use of 5-HT1A receptor agonists for the treatment of cerebellar ataxia, and discussed the current theories regarding their mechanism of action. Cortical cerebellar atrophy (CCA) was reported, in a double-blind study, to be amenable to treatment with tandospirone. Other types of spinocerebellar degeneration (SCD) i.e., olivopontocerebellar atrophy (OPCA) and Machado-Joseph disease (MJD) have also been reported to respond to the drug, but these have been small studies. Responsive patients exhibited only mild ataxia. The doses of 5-HT1A agonists that have been used successfully ranged from 12.5 mg/day to 60 mg/day (or 1 mg/kg), and were well tolerated by most patients.

Acetogenin analogs in which the bis-adjacent THF ring was replaced with an enantioselectively synthesized 1,2-cyclopentanediol bis-ether skeleton were synthesized to obtain simplified mimics, and their inhibitory effect on mitochondrial NADH–ubiquinone oxidoreductase (complex I ) was examined. The results clearly demonstrate that the 1,2-cyclopentanediol bis-ether motif can substitute for the bis-THF ring while maintaining very potent inhibitory activity at the nanomolar level.

We investigated the polymorphisms of exon 1 (+49A/G) and promoter (-318C/T and -651C/T) regions of the CTLA-4 gene in 133 Japanese patients with conventional/classical multiple sclerosis (MS) and 156 healthy controls. Patients with optico-spinal MS (OSMS) or atypical clinical attacks were excluded from the study. There was no significant difference in the distribution of polymorphisms between patients and controls. Furthermore, there were no associations between polymorphisms and clinical characteristics, such as age at onset, disease prognosis, and HLA profiles. Our results suggest that CTLA-4 gene polymorphisms are neither conclusively related to susceptibility nor to the clinical characteristics of MS, especially in Japanese patients with conventional/classical form and clinical features identical to those of their counterparts in Western countries.

High strength cast steel, Throw Grade 5, has been developed for semi-built-up crankshafts to cover all current types of low speed diesel engines. Material test results with test pieces taken from a full-scale crankthrow are reported. Manufacturing approvals for this material have been taken from major classification societies. Prior to the application of this cast steel to an actual crankshaft, the crank pin fillet stresses at several points were measured in the workshop. The dynamic stress of each point, as analyzed with the finite element method, corresponds well with the measured data. Finally, application of this material to the crankshaft of an engine in a severe vibratory condition is introduced to show effective use of the material.

We have synthesized Deltalac-acetogenins that are new acetogenin mimics possessing two n-alkyl tails without an alpha,beta-unsaturated gamma-lactone ring and suggested that their inhibition mechanism may be different from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. To elucidate the inhibition mechanism of Deltalac-acetogenins in more detail, we carried out wide structural modifications of original Deltalac-acetogenins and characterized the inhibitory action with bovine heart mitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THF rings and the stereochemistry around the hydroxylated bis-THF rings are important structural factors required for potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure (compound 7) appeared to be superior to that of the original Deltalac-acetogenins and equivalent to that of bullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complex I activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligand indicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors. The effects of compound 7 on superoxide production from complex I are also different from those of other complex I inhibitors. Our results clearly demonstrate that Deltalac-acetogenins are a novel type of inhibitor acting at the terminal electron-transfer step of bovine complex I.

We previously reported a patient with Machado-Joseph Disease (MJD) who had severe insomnia and a low serum melatonin (MLT) level, and whose insomnia was alleviated by oral MLT replacement therapy. The aims of this study were to examine whether patients with MJD are likely to have insomnia, and whether there is a relationship between the degree of insomnia and the serum MLT level among patients with MJD. This study included 8 patients with MJD. A 58-year-old-patient with cervical spondylosis was also included in this study to check the condition of the test room for sleeping. All patients filled out the Japanese version of Pittsburgh Sleep Quality Index (PSQI-J) questionnaire. We obtained blood samples at 12:00 and 24:00 hours to measure the MLT level. We checked the sleep condition of the patient once an hour and recorded the grade in sleep-logs: the grades of sleep condition were asleep, sleepy, or awake. Statistical analyses were performed to search for correlations between the PSQI score and the serum MLT level or actual sleep time using Spearman’s rank correlation coefficient. Seven of the 8 MJD patients had a total PSQI score of above 5.5 (cut-off level). The daytime MLT level (at 12:00 hours) was below 2.8 pg/mL in all 8 patients, whereas the mean night-time MLT level (at 24:00 hours) of the MJD patients (23.6 ± 17.5 pg/mL) was lower than that of the control patient (43.0 pg/mL) and also lower than the reported cut-off level among healthy people aged 30–50 years (55.5 pg/mL). There was a negative correlation between the total PSQI score and the serum MLT level among the MJD patients (P < 0.05). Our results show that a low serum MLT level may contribute to insomnia in patients with MJD.

Studies on the inhibition mechanism of acetogenins, the most potent inhibitors of complex I, are useful to elucidate the structural and functional features of the terminal electron-transfer step of this enzyme. We synthesized acetogenin mimics that possess two alkyl tails without a gamma-lactone ring, named Deltalac-acetogenin, and examined their inhibitory action on bovine heart mitochondrial complex I. Unexpectedly, the Deltalac-acetogenin carrying two n-undecanyl groups (compound 3) elicited very potent inhibition comparable to that of bullatacin. The inhibitory potency of compound 3 markedly decreased with shortening the length of either or both alkyl tails, indicating that symmetric as well as hydrophobic properties of the inhibitor are important for the inhibition. Both acetylation and deoxygenation of either or both of two OH groups adjacent to the tetrahydrofuran (THF) rings resulted in a significant decrease in inhibitory potency. These structural dependencies of the inhibitory action of Deltalac-acetogenins are in marked contrast to those of ordinary acetogenins. Double-inhibitor titration of steady-state complex I activity showed that inhibition of compound 3 and bullatacin are not additive, though the inhibition site of both inhibitors is downstream of iron-sulfur cluster N2. Our results indicate that the mode of inhibitory action of Deltalac-acetogenins differs from that of ordinary acetogenins. Therefore, Deltalac-acetogenins can be regarded as a novel type of inhibitor acting on the terminal electron-transfer step of complex I.

The presence of two hydroxy groups adjacent to the THF ring(s) is a common structural feature of natural acetogenins. To elucidate the role of each hydroxy group in the inhibitory action of acetogenins, we synthesized three acetogenin analogues which lack either or both of the hydroxy groups, and investigated their inhibitory activities with bovine heart mitochondrial complex I. Our results indicate that the presence of either of the two hydroxy groups sufficiently sustains a potent inhibitory effect.

長期継続的な酸性化ストレスにさらされる樹木の生理動態を監視するために，イオン交換繊維をコナラ樹幹の木部に挿入し，樹液中の主要無機イオンを継続捕集して分析を行う方法の適用性を検討した．その結 果，2～3月の休眠期から6～8月の成長期における気温上昇，日射量の変動に伴うコナラの活動が樹液中の陽イオン特に70～93％ のカリウムイオン及び13～4％ のカルシウムイオンの濃度変動と密接に関連することなどの知見が得られた．本法は改良により木部及び師部の樹液化学のモニタリングに適用可能である．

Background We investigated the frequencies of the symptoms such as "ataxia, depression, insomnia, anorexia, and pain," that have been reported to be associated with 5-HT1A receptor, and the effect of tandospirone citrate (tandospirone: 5-HT1A agonist) in patients with Machado-Joseph disease (MJD). Methods Ten MJD patients received tandospirone (15-30 mg/d) for seven weeks. During that time, they were evaluated weekly using the Ataxia Rating Scale (ARS) and Total Length Traveled (TLT) by Stabilimetry tests, the Self-rating Depression Scale (SDS), which in addition to evaluating their level of depression, also evaluated their degree of insomnia and anorexia, and a pain questionnaire. Results Before tandospirone therapy, all patients displayed cerebellar ataxia, while insomnia, and leg pain was observed in 7 patients, depression in 6 patients, and anorexia was observed in 2 patients. In response to treatment, 7 of the 10 patients who were ataxic showed a reduction in their ARS, while 3 of 6 patients showed a reduction in their SDS, and 5 of 7 patients showed an alleviation of their insomnia and leg pain. Both of the affected patients showed a marked improvement in their anorexia. A stabilimetry test could be performed in 7 patients, 5 of whom showed a reduction in TLT. Conclusions Our data indicate that the patients with MJD are prone to manifest 5-HT1A receptor-associated symptoms, and tandospirone is a useful drug for these symptoms in patients with MJD, though a double-blind study is needed.

To investigate the frequency of positioning nystagmus in degenerative ataxic disorders, we examined downbeat positioning nystagmus (DPN) in 25 patients with spinocerebellar ataxia type 6 (SCA6) and 58 patients with other types of degenerative ataxia. DPN was observed in 21 of the 25 patients with SCA6 (84 %) versus only 3 of the 58 patients (5.2 %) with other types of degenerative ataxia, including multiple system atrophy, SCA1, SCA2, SCA3/Machado-Joseph disease, and non-SCA6 late-onset pure cerebellar ataxia. Our findings indicated that DPN is a distinct part of the clinical presentation of SCA6, showing that vestibular cerebellum is more affected in SCA6 than other types of degenerative ataxia.

Background: Oligoclonal IgG bands (OCB) are present in most patients with MS in Western countries; however, in Japanese MS patients, the OCB-positive rate is not as high. A relationship between immunogenetic backgrounds, namely, human leukocyte antigen (HLA) DR2 and DR4 positivity, and OCB production in MS patients from Hokkaido, the northernmost island of Japan, has been previously suggested by the authors.Objectives: To investigate the role of OCB in Japanese MS and to verify the interaction between immunogenetic backgrounds and OCB positivity.Methods: OCB, DR2(15), and DR4 positivity were studied in 45 patients with newly diagnosed MS. In addition to confirming the authors’ previous findings, the clinical and demographic features, MRI findings, OCB positivity, and DRB1*15 and DRB1*04 polymorphisms of an expanded data set of 99 MS patients were investigated by using multivariate analysis. Patients with opticospinal MS (OS-MS) were excluded from this study.Results: A relatively low OCB-positive rate (53.3%), HLA-DR15 association with OCB-positive MS (p = 0.0044), and DR4 association with OCB-negative MS (p = 0.0410) were confirmed. DR15 was not associated with OCB-negative MS. Demographic features, disease course, and disability were similar in the OCB-negative and OCB-positive group, whereas there was a preponderance of women in the OCB-positive group. An independent negative association of DRB1*0405 (p = 0.0021, adjusted odds ratio = 0.21) with OCB positivity was found.Conclusions: MS is heterogeneous in its association with HLA alleles, and based on the immunogenetic differences, the MS patients in this population include at least two HLA-related subpopulations with and without OCB.

Coal tar pitch-based coke powder with a fine mosaic texture was heat-treated with various concentrations of boron powder at 2900°C. Increasing the boron amount led to smaller d 002 and larger d 110 , and made the original fine texture coarser. Some small particles showed specific structures of polyhedrons, of which surfaces are 002 planes of graphite lattice, after heat treatment with boron. The size of the polyhedron increased with boron content. Boron concentration was lower at the surface than at the inner portions of particles for a powder heat-treated with a higher amount of boron, while it depended less on the depth for that heat-treated with a lower amount of boron. The formation mechanism of the polyhedron particle is discussed.

We investigated PvuII and XbaI polymorphism in the estrogen receptor gene (ERG) and HLA-DRB1*1501 positivity in 116 conventional multiple sclerosis (MS) patients and 101 healthy controls in a Japanese population. Logistic analysis revealed independent associations of [P] allele in the profiles for PvuII (p=0.0005, adjusted odds ratio (aOR)=3.17) and DRB1*1501 (p=0.0089, aOR=2.61) with conventional MS. Synergistic elevated risk of MS due to interaction between the [P] allele and HLA-DRB1*1501 allele was found among female patients (odds ratio=16.0; 95% CI=3.99-63.8, p

Tandospirone citrate (tandospirone) is an anti-anxiety drug that acts by combining with serotonin receptor (5-hydroxytryptamine-1 A [5-HT1A]). Recently, there have been a few reports of its potential role in the treatment of cerebellar ataxia. We report the first case of a patient with Machado-Joseph disease in which we successfully treated cerebellar ataxia. In addition, his leg pain, insomnia, anorexia, and depression, which are thought to be related to 5-HT1A receptors, were also remarkably alleviated by treatment with tandospirone.