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This note describes the construction of tetrasubstituted carbon stereocenters via palladium-catalyzed allylation of sp

Objective Dizziness is one of the most common symptoms in the general population. Patients with dizziness experience balance problems and anxiety, which can lead to decreased physical activity levels and participation in their daily activities. Moreover, recovery of vestibular function from vestibular injury requires physical activity. Although there are reports that decreased physical activity is associated with handicap, anxiety, postural instability and reduced recovery of vestibular function in patients with chronic dizziness, these data were collected by self-report questionnaires. Therefore, the objective data of physical activity and the relationships between physical activity, handicap, anxiety and postural stability in patients with chronic dizziness are not clear. The purpose of this research was to objectively measure the physical activity of patients with chronic dizziness in daily living as well as handicap, anxiety and postural stability compared to healthy adults. Additionally, we aimed to investigate the relationships between physical activity, handicap, anxiety and postural stability in patients with chronic dizziness. Methods Twenty-eight patients with chronic dizziness of more than 3 months caused by unilateral vestibular hypofunction (patient group) and twenty-eight age-matched community dwelling healthy adults (healthy group) participated in this study. The amount of physical activity including time of sedentary behavior, light physical activity, moderate to vigorous physical activity and total physical activity using tri-axial accelerometer, self-perceived handicap and anxiety using questionnaires, and postural stability were measured using computerized dynamic posturography. Results The results showed worse handicap, anxiety and postural stability in the patient group compared to the healthy group. Objective measures of physical activity revealed that the patient group had significantly longer time of sedentary behavior, shorter time of light physical activity, and shorter time of total physical activity compared to the healthy group; however, time of moderate to vigorous physical activity was not significantly different between groups. Moreover, there were correlations between physical activity and postural stability in the patient group, while there were no correlations between physical activity, handicap or anxiety in the patient group. Conclusion These results suggest that objectively measured physical activity of the patients with chronic unilateral vestibular hypofunction is lower compared to the healthy adults, and less active patients showed decreased postural stability. However, the details of physical activity and causal effect between physical activity and postural stability were not clear and further investigation is needed.

Direct catalytic C-C bond-forming addition to N-unprotected ketimines is an efficient and straightforward method of synthesizing N-unprotected tetrasubstituted amines that eliminates prior protection/deprotection steps and allows facile transformation of the products. Despite its advantages, however, N-unprotected ketimines have difficulties in C-C bond-forming reactions, and only a limited number of reactions and substrates are reported compared with their N-protected counterparts. Herein we report that N-unprotected trifluoromethyl ketimines are effective for C-C bond-forming reactions using Mannich-type reactions as a model case. We demonstrate that Lewis acid catalysis was effective for promoting reactions with various N-unprotected trifluoromethyl ketimines, and thiourea organocatalysis was effective for promoting highly enantioselective reactions with various carbonyl nucleophiles, providing direct access to various N-unprotected α- and/or β-tetrasubstituted amino acid esters. Furthermore, direct construction of vicinal tetrasubstituted chiral carbon stereocenters was achieved for the first time in a highly enantio- and diastereoselective manner. These results demonstrate the potential of N-unprotected ketimines as substrates applicable to many other addition reactions.

Background and Aims The aim of this study was to clarify whether dental floss clip (DFC) traction improves the technical outcomes of endoscopic submucosal dissection (ESD). Methods A superiority, randomized control trial was conducted at 14 institutions across Japan. Patients with single gastric neoplasm meeting the indications of the Japanese guidelines for gastric treatment were enrolled and assigned to receive conventional ESD or DFC traction-assisted ESD (DFC-ESD). Randomization was performed according to a computer-generated random sequence with stratification by institution, tumor location, tumor size, and operator experience. The primary endpoint was ESD procedure time, defined as the time from the start of the submucosal injection to the end of the tumor removal procedure. Results Between July 2015 and September 2016, 640 patients underwent randomization. Of these, 316 patients who underwent conventional ESD and 319 patients who underwent DFC-ESD were included in our analysis. The mean ESD procedure time was 60.7 and 58.1 minutes for conventional ESD and DFC-ESD, respectively ( P = .45). Perforation was less frequent in the DFC-ESD group (2.2% vs .3%, P = .04). For lesions located in the greater curvature of the upper or middle stomach, the mean procedure time was significantly shorter in the DFC-ESD group (104.1 vs 57.2 minutes, P = .01). Conclusions Our findings suggest that DFC-ESD does not result in shorter procedure time in the overall patient population, but it can reduce the risk of perforation. When selectively applied to lesions located in the greater curvature of the upper or middle stomach, DFC-ESD provides a remarkable reduction in procedure time.

A key control point in gene expression is the initiation of protein translation, with a universal stress response being constituted by inhibitory phosphorylation of the eukaryotic initiation factor 2α (eIF2α). In humans, four kinases sense diverse physiological stresses to regulate eIF2α to control cell differentiation, adaptation, and survival. Here we develop a computational molecular model of eIF2α and one of its kinases, the protein kinase R, to simulate the dynamics of their interaction. Predictions generated by coarse-grained dynamics simulations suggest a novel mode of action. Experimentation substantiates these predictions, identifying a previously unrecognized interface in the protein complex, which is constituted by dynamic residues in both eIF2α and its kinases that are crucial to regulate protein translation. These findings call for a reinterpretation of the current mechanism of action of the eIF2α kinases and demonstrate the value of conducting computational analysis to evaluate protein function.

PURPOSE: The purpose of this study was to investigate the effectiveness of cervicocephalic kinesthetic training on postural stability and neck joint position sense in healthy young adults. METHOD: 33 subjects were recruited for this study and randomly divided into training （n＝16） and control groups （n＝17）. The training group performed cervicocephalic kinesthetic training for 5 minutes per day for 10 days and the control group performed the same training but with eyes closed to eliminate visual feedback. All training sessions for both groups were performed under supervision. Pre and post cervical joint position sense and sensory organization testing （SOT） were measured on both groups. RESULT: Significant differences were found in cervical joint position sense and SOT condition 6 in the training group. No significant differences were found in SOT condition1-5 in both groups and cervical joint position in the control group. CONCLUSION: The improvements of postural stability and cervical joint position sense after 10 days of cervicocephalic kinesthetic training suggest that cervical joint position sense may may be beneficial for postural stability in healthy young adults.

Lanthanum trifluoromethanesulfonate is an effective single-component catalyst for synthesizing a variety of amides directly from esters and amines under mild conditions. Highly selective amidation of esters and amines, as well as catalyst-controlled amidation of esters, demonstrated the effectiveness of the catalyst system.

The reversible phosphorylation of proteins plays hugely important roles in a variety of cellular processes, such as differentiation, proliferation, and apoptosis. These processes are strictly controlled by protein kinases (phosphorylation) and phosphatases (de-phosphorylation). Here we provide a brief history of the study of protein phosphorylation, including a summary of different types of protein kinases and phosphatases. One of the most physiologically important serine/threonine phosphatases is PP2A. This review provides a description of the phenotypes of various PP2A transgenic mice and further focuses on the known functions of PP2A in bone formation, including its role in osteoblast differentiation and function. A reduction in PP2A promotes bone formation and osteoblast differentiation through the regulation of bone-related transcription factors such as Osterix. Interestingly, downregulation of PP2A also stimulates adipocyte differentiation from undifferentiated mesenchymal cells under the appropriate adipogenic differentiation conditions. In osteoblasts, PP2A is also involved in the ability to control osteoclastogenesis as well as in the proliferation and metastasis of osteosarcoma cells. Thus, PP2A is considered to be a comprehensive factor in controlling the differentiation and function of cells derived from mesenchymal cells such as osteoblasts and adipocytes.

Diethylenetriamine is effective for the direct cleavage of unactivated carbamates and ureas without additional reagents and catalysts. Various carbamates and ureas were cleaved to afford products in good yield, and the reactions were not affected by air or moisture. Unique chemoselective cleavage of carbamate and urea in the presence of amides was also achieved.

A green way to amino acids: α-Tetrasubstituted α-amino acid derivatives are formed in high yield and enantioselectivity by using a Rh-catalyzed enantioselective alkynylation of α-ketiminoesters. This reaction, which involves a proton transfer and can be conducted at room temperature, has high substrate scope (see scheme; Cbz = benzyloxycarbonyl, Fmoc = 9-fluorenylmethyloxycarbonyl).

Double-stranded RNA-dependent protein kinase (PKR) is one of the players in the cellular antiviral responses and is involved in transcriptional stimulation through activation of NF-κB. Treatment of the human osteosarcoma cell line MG63 with the protein phosphatase inhibitor okadaic acid stimulated the expression and phosphorylation of IκBα, as judged from the results of real-time PCR and western blot analysis. We investigated the functional relationship between PKR and signal transduction of NF-κB by establishing PKR-K/R cells that produced a catalytically inactive mutant of PKR. Phosphorylation of eIF-2α, a substrate of PKR, was not stimulated by okadaic acid in the PKR-K/R cells, whereas okadaic acid induced phosphorylation of eIF-2α in MG63 cells. Phosphorylation of NF-κB in MG63 cells was stimulated by okadaic acid; however, okadaic acid did not induce phosphorylation of NF-κB in the PKR-K/R cells. Finally, okadaic acid-induced apoptosis was inhibited in the PKR-K/R cells. Our results suggest that okadaic acid-induced phosphorylation of IκBα was mediated by PKR kinase activity, thus, indicating the involvement of this kinase in the control mechanism governing the activation of NF-κB and induction of apoptosis.

PURPOSE: The purpose of this study was to investigate muscle activation using electromyography （EMG）, postural control using computerized dynamic posturography （CDP） and spatioal body movements using accelerometery in different conditions in healthy young and older adults. METHOD: Nine healthy young adults and eight healthy older adults without history of neurological disease or falls participated in this study. Postural control was measured using the NeuroCom Equi-test CDP in 6 different conditions. Spatial body movements were measured by an accelerometer placed on the top of subject's head, sacrum and lateral knee joint. RESULTS: Compared to the young adults, healthy older adults had lower postural control scores in conditions 2, 5 and 6; spatial body movements were larger in forward-backward direction during condition 5 and in vertical direction during condition 6. EMG of Tibialis Anterior, Stenocreidmastoid and Rectus Abdominals in the older adults were more activated. CONCLUSION: Young adults were able to maintain better postural control with lower muscle activation compared to older adults.

We investigated the mechanism of transplacental macromolecular transport in rats on the nineteenth day of pregnancy using tracers, transmission electron microscopy and immunohistochemistry. The blood-placental barrier of full-term rat placentas was composed of a trilaminar layer of trophoblast cells that separates the fetal capillaries from the maternal blood spaces: a layer of cytotrophoblasts lining the maternal blood space and a bilayer of syncytiotrophoblast surrounding the fetal capillaries. Horseradish peroxidase, intravenously injected into the maternal circulation, was found in the maternal blood spaces, the interspaces between the cytotrophoblasts and the syncytiotrophoblast I, many pits and small vesicles in the syncytiotrophoblast I, vesicles of the syncytiotrophoblast II, fetal connective tissue and fetal capillaries. Intravenously injected ovalbumin was detected in the maternal blood spaces, a trilaminar layer and the fetal capillaries. Neonatal Fc receptor (FcRn), a receptor for IgG, was localized at the maternal side of the blood-placental barrier. These results show that the structure of the rat blood-placental barrier is quite similar to the human blood-placental barrier, and non-specific macromolecules and food allergens may penetrate through the blood-placental barrier of the full-term placenta from the maternal to fetal circulation mediated by FcRn.

Background and study aims: One of the major complications after endoscopic resection (ER) for large superficial esophageal squamous cell carcinoma (ESCC) is benign esophageal stricture, which can reduce quality of life even if ESCC achieves a cure without organ resection. Recently, steroid administration has been reported as a prophylactic treatment to prevent esophageal strictures. This retrospective study evaluated the stricture rate according to the different width of mucosal defects due to ER and compared it to that seen with prophylactic steroid administration. Patients and methods: Between June 2007 and December 2013, we enrolled patients with ESCC who had 3/4 or larger circumferential mucosal defects due to ER. In December 2009, steroid injections (triamcinolone acetonide 50 mg) into the ulcer bed due to ER were introduced. Beginning in November 2012, we commenced oral steroid administration (prednisolone 30 mg/day, tapered gradually for 8 weeks) in addition to steroid injection. Patients were classified into 3 groups according to the width of mucosal defect after ER (Group A, ≥ 3/4 and

Mechanistic studies and expansion of the substrate scope of direct enantioselective alkynylation of α-ketiminoesters catalyzed by adaptable (phebox)rhodium(III) complexes are described. The mechanistic studies revealed that less acidic alkyne rather than more acidic acetic acid acted as a proton source in the catalytic cycle, and the generation of more active (acetato-κ2O,O′)(alkynyl)(phebox)rhodium(III) complexes from the starting (diacetato)rhodium(III) complexes limited the overall reactivity of the reaction. These findings, as well as facile exchange of the alkynyl ligand on the (alkynyl)rhodium(III) complexes led us to use (acetato-κ2O,O′)(trimethylsilylethynyl)(phebox)rhodium(III) complexes as a general precatalyst for various (alkynyl)rhodium(III) complexes. Use of the (trimethylsilylethynyl)rhodium(III) complexes as precatalysts enhanced the catalytic performance of the reactions with an α-ketiminoester derived from ethyl trifluoropyruvate at a catalyst loading as low as 0.5 mol % and expanded the...

Background and Aims Biodegradable stents are reportedly effective for refractory benign esophageal strictures; however, little is known about their use in patients with refractory stricture after endoscopic submucosal dissection (ESD) or chemoradiotherapy (CRT) for esophageal cancer. This study aimed to evaluate the effectiveness of biodegradable stents for these patients. Methods Patients with refractory benign esophageal stricture with a dysphagia score (DS) of 2 or worse and for whom the passage of a standard size endoscope was not possible were eligible. The primary endpoint was the proportion of those who improved their DSs (% DS improved) at 12 weeks after stent placement, and the secondary endpoints were the proportion of those who improved their DSs at 24 weeks, dysphagia-free survival (DFS), and adverse events. Results Eighteen patients (men:women, 15:3; median age, 72 years; range, 53-80) were enrolled. Twelve patients improved their DS at 12 weeks (% DS improved, 66.7%; 90% CI, 44.6%-84.4%). Also, 8 of 11 patients (72.7%) after esophagectomy, 4 of 6 patients (66.7%) after ESD, and 3 of 4 patients (75%) after CRT improved at 12 weeks. Three patients who were treated with esophagectomy maintained their DS improvement at 24 weeks (% DS improved, 16.7%; 95% CI, 3.6%-41.4%). The median DFS was 14.1 weeks (95% CI, 13.0-19.0). One patient who had ESD and CRT developed an esophagobronchial fistula 3 months after stent placement. Conclusions Biodegradable stents are effective and tolerable for refractory benign esophageal strictures after treatment for esophageal cancer; however, long-term efficacy was limited, especially after ESD or CRT. (Clinical trial registration number: UMIN000008054.)

Microglia are derived from myelogenous cells and contribute to immunological and inflammatory responses in central nervous system. They play important roles not only in infectious diseases and inflammation after stroke, but also in psychiatric diseases such as schizophrenia. While recent studies suggest the significances of serum- and glucocorticoid-inducible kinases (SGKs) in other immune cells such as macrophages, T cells and dendritic cells, their role in microglia remains unknown. Here we, for the first time, report that SGK1 and SGK3 are expressed in multiple microglial cell lines. An SGK inhibitor, gsk650394, inhibits cell viability. In addition, lipopolysaccharide-induced expression of inflammatory regulators iNOS and TNFα was enhanced by gsk650394. Furthermore, translocation of NF-κB was enhanced by gsk650394. Taken together, these findings suggest that SGKs may play an important role in regulating microglial viability and inflammatory responses.

Mechanistic studies and expansion of the substrate scope of direct enantioselective alkynylation of α-ketiminoesters catalyzed by adaptable (phebox)rhodium(III) complexes are described. The mechanistic studies revealed that less acidic alkyne rather than more acidic acetic acid acted as a proton source in the catalytic cycle, and the generation of more active (acetato-κ(2)O,O')(alkynyl)(phebox)rhodium(III) complexes from the starting (diacetato)rhodium(III) complexes limited the overall reactivity of the reaction. These findings, as well as facile exchange of the alkynyl ligand on the (alkynyl)rhodium(III) complexes led us to use (acetato-κ(2)O,O')(trimethylsilylethynyl)(phebox)rhodium(III) complexes as a general precatalyst for various (alkynyl)rhodium(III) complexes. Use of the (trimethylsilylethynyl)rhodium(III) complexes as precatalysts enhanced the catalytic performance of the reactions with an α-ketiminoester derived from ethyl trifluoropyruvate at a catalyst loading as low as 0.5 mol % and expanded the substrate scope to unprecedented α-ketiminophosphonate and cyclic N-sulfonyl α-ketiminoesters.

Continuous exposure to peritoneal dialysis fluids (PDFs) is associated with pathological responses such as persistent micro-inflammation, which leads to ultrafiltration failure. Pentraxin-3 (PTX3), a multifunctional soluble pattern recognition receptor, is produced at sites of inflammation by a wide range of cell types. This study investigates the in vivo expression of PTX3 in the peritoneal membrane of a rat continuous peritoneal dialysis (PD) model, as well as the effect of high glucose on the in vitro expression of PTX3.The expression of PTX3 was analyzed using RT-PCR, real-time PCR, immunohistochemistry and western blotting in a PD rat model receiving saline or conventional PDF containing 3.86% glucose for 8 weeks. The effects of high glucose on the expression of PTX3 were examined in cultured rat peritoneal mesothelial cells (RPMCs), mouse macrophage-like cells, and mouse fibroblasts.In a rat model of PD, eight-week instillation of the conventional PDF produced increased submesothelial thickening, followed by substantially enhanced PTX3 protein levels in the submesothelial layer of peritoneal membrane. PTX3 was detected in peritoneal mesothelial cells, macrophages and fibroblasts in the thickened submesothelial area. Glucose was found to induce PTX3 protein expression in RPMCs as well as macrophage-like cells and fibroblasts.Continuous exposure to conventional PDF induces PTX3 expression in the peritoneal membrane of rats. High glucose may be involved in the mechanism of PDF-induced local micro-inflammation in the peritoneum.

PURPOSE: The purpose of this study was to investigate the postural control on different conditions in health elder. METHOD: Twenty-four healthy older adults without history of neurological disease or falls participated in this study. Postural control was measured using the NeuroCom Equi-testR to examine the 6 different conditions; （1） eyes open with no movement of the support surface and visual surround, （2） eyes closed with no movement of support surface, （3） eyes open with a sway referenced visual surround and no movement of support surface, （4） eyes open with a sway referenced support surface and no movement of visual surround, （5） eyes closed with a sway referenced support surface, （6） eyes open with both a sway referenced support surface and a sway referenced visual surround. RESULT: The healthy elderly showed that postural control was unstable in condition 4 and 5 compared with condition 1 in static visual condition. Moreover, the postural control was unstable in condition 6 compared with condition 1 and 3 in dynamic visual situation. CONCLUSION: Vestibular and somatosensory systems were more important than visual system for maintaining the stable posture in healthy elderly.

The alpha subunit of eukaryotic initiation factor -2 (eIF-2alpha) is a molecule related to the first step of protein synthesis initiation in eukaryotes. eIF-2alpha is phosphorylated in response to a wide variety of stimuli, including viral infection, starvation, ischemia, and heat shock. Four mammalian eIF-2alpha kinases have been reported: PKR (double-stranded RNA dependent protein kinase), HRI (heme-regulated inhibitor), GCN2 (general control non-derepressible 2), and PERK (PKR-like endoplasmic reticulum kinase). Each kinase contains unique domains that recognize a different cellular stress and transmits the signals to eIF-2alpha. Hence, eIF-2alpha is considered to be a key molecule in integrated stress response. Understanding eIF-2alpha as a component of the integrated stress response may be helpful in revealing stress sitmulus and the responses to stress at the cellular level. This knowledge will contribute to the development of preventive and therapeutic approaches to stress mediated diseases.

A large number of recently launched pharmaceuticals and pharmaceutical candidates contain perfluoroalkyl groups because these moieties affect the physical properties and biological processing of organic molecules, while being stable to degradation.[1] For this reason, the introduction of trifluoromethyl groups into aryl halides by simple laboratory procedures is a major synthetic goal. Despite much effort to develop reactions that introduce trifluoromethyl groups into arene substrates, current methods are limited by some combination of high temperatures, high catalyst loadings, expensive reagents, catalysts, and ligands, low reactivity with electron-rich aromatic groups, and intolerance toward protic and electrophilic functional groups.[2–6] Methods to introduce longer perfluoroalkyl groups into aryl halides are even more limited.[7,8]

This paper describes a new technique for the design of 3-terminal regulators in which the output voltage level can be adjusted without additional terminals or extra off-chip components. This circuit restricts the increase in the number of terminal pins by using a pin as both a voltage supply output and a voltage setup input. The voltage setup information is introduced using a serial control signal from outside the chip. Using the intermediate voltage level between the supply voltage and the regulator output, the adjustment data in the internal nonvolatile memory are safely updated without noise disturbance. To input the setup information into the chip in a stable manner, we developed a new 1-wire serial interface which combines key pattern matching and burst signal detection. To ensure high reliability, we suggested a quantitative method for evaluating the influence of noise in our new interface using a simple model with superimposed random noise. Circuits additional to those for a conventional 3-terminal regulator, include a 1-wire serial communication circuit, a low-capacity non-volatile memory, and a digital to analog (D/A) converter. A test chip was developed using 0.35µm standard CMOS process, and there was almost no overhead to the conventional 3-terminal regulator in both chip area and power dissipation. In an on-board test with the test chip, we confirmed successful output voltage adjustment from 1.0V to 2.7V with approximately 6.5mV precision.

Hydrazinolysis of unactivated amide bonds is significantly accelerated by the addition of ammonium salts. The reactions proceed at 50-70 °C to give amines with broad substrate scope that outperforms existing amide bond cleavage reactions. Application to peptide and amino sugar derivatives is also demonstrated.

Reexamination of heterocyclization of an enantiopure C2-symmetric bis-epoxide (7) with sodium sulfide is described. In addition to the reported processes leading to thiane (4a) and thiepane (6), another mode of cyclization was found to occur to a considerable extent, affording a symmetric dialkyl sulfide (5), and the structure of the main product reported (4a) has been revised. Conditions for the chemoselective formation of 6 were established, and effective transformation of 6 into 4 was accomplished by the modification of the processes.

The catalytic asymmetric aza-Morita-Baylis-Hillman reaction using unactivated methyl acrylate is described. A simple Lewis acidic metal catalyst, such as La(OTf)(3), was not suitable for the reaction, but rare earth metal alkoxide/linked-BINOL complexes possessing bifunctional Lewis acid and Brønsted base properties efficiently promoted the reaction in combination with an achiral nucleophilic organocatalyst. The combined use of a La(O-iPr)(3)/(S,S)-TMS-linked-BINOL complex with a catalytic amount of DABCO promoted the aza-Morita-Baylis-Hillman reaction of a broad range of N-diphenylphosphinoyl imines. Products from aryl, heteroaryl, and alkenyl imines were obtained in 67-99% yield and 81-95% ee. It is noteworthy that isomerizable alkyl imines could be employed as well, giving products in 78-89% yield and 94-98% ee. Initial rate kinetic studies as well as kinetic isotope effect experiments using alpha-deuterio-methyl acrylate support the importance of both the nucleophilicity of La-enolate and the Brønsted basicity of a La-catalyst for promoting the reaction.

INTRODUCTION AND METHODS: The purpose of this study was to investigate the effectiveness of gaze stability exercises on healthy young subjects. Subjects were randomly divided into experimental （n=28） and control groups （n=13）. The experimental group performed gaze stability exercise for three weeks and the control group did not. Pre and post body sway during quiet standing, standing with neck rotation, and dynamic visual acuity were measured on both groups. RESULTS: The results showed significant differences in body sway during standing with neck rotation and dynamic visual acuity in the experimental group （p

Catalytic asymmetric Michael reactions of a malonate to acyclic α,β-unsaturated N-acylpyrroles as ester equivalent acceptors are described. A La(O-iPr)3/(S,S)-linked-BINOL complex, which is suitable for Michael addition to cyclic enones, is not suitable for acyclic α,β-unsaturated N-acylpyrroles. A new (S,S)-Ph-linked-BINOL chiral ligand was developed to improve enantioselectivity, and a La(O-iPr)3/(S,S)-Ph-linked-BINOL complex with the addition of HFIP afforded Michael adducts in good yield and enantioselectivity (up to 96% ee).

The metamagnetic transition in FeRh thin films has been investigated via temperature-dependent x-ray-absorption fine-structure spectroscopy in order to gain correlations between magnetization and local electronic and geometric structures. According to the Fe and Rh $K$-edge x-ray-absorption near-edge structure (XANES), strong hybridization between Fe and Rh was revealed to exist. This Fe-Rh hybridization was observed to decrease during the phase transition from the antiferromagnetic (AFM) to ferromagnetic (FM) phases from the systematic change in the Fe $K$-edge XANES. In addition, only the Debye-Waller factor of the Fe-Fe pair in the AFM phase was observed to be considerably enhanced when compared with that in the FM phase, which was ascribed to local structural fluctuation inherent in the AFM phase. By considering the different features of the exchange interactions in Fe-Rh and Fe-Fe, this anomalous behavior is interpreted as being consistent with the recent theoretical study proposing the local fluctuations of spin and structure. Therefore, we consider that the local spin and Fe-Fe distance fluctuations play an important role in driving the metamagnetic transition, whereas the Fe-Rh hybridization correlates with the static stability of each magnetic phase.

Background The mitotic spindles are among the most successful targets of anti-cancer chemotherapy, and they still hold promise as targets for novel drugs. The anti-mitotic drugs in current clinical use, including taxanes, epothilones, vinca alkaloids, and halichondrins, are all microtubule-targeting agents. Although these drugs are effective for cancer chemotherapy, they have some critical problems; e.g., neurotoxicity caused by damage to neuronal microtubules, as well as innate or acquired drug resistance. To overcome these problems, a great deal of effort has been expended on development of novel anti-mitotics. Methods We identified novel microtubule-targeting agents with carbazole and benzohydrazide structures: N′-[(9-ethyl-9H-carbazol-3-yl)methylene]-2-methylbenzohydrazide (code number HND-007) and its related compounds. We investigated their activities against cancer cells using various methods including cell growth assay, immunofluorescence analysis, cell cycle analysis, tubulin polymerization assay, and tumor inhibition assay in nude mice. Results HND-007 inhibits tubulin polymerization in vitro and blocks microtubule formation and centrosome separation in cancer cells. Consequently, it suppresses the growth of various cancer cell lines, with IC50 values in the range 1.3–4.6 μM. In addition, HND-007 can inhibit the growth of taxane-resistant cancer cells that overexpress P-glycoprotein. Finally, HND-007 can inhibit HeLa cell tumor growth in nude mice. Conclusions and general significance Taken together, these findings suggest that HND-007 is a promising lead compound for development of novel anti-mitotic, anti-microtubule chemotherapeutic agents.

Optically active propargylic alcohols and propargylamines are highly useful and versatile building blocks. One of the most common approaches to these compounds is the catalytic asymmetric alkynylation of carbonyl compounds and imines. Various combinations of chiral ligands and metal catalysts have been examined and several highly efficient asymmetric catalysts have been developed so far. Although stoichiometric amounts of metal reagents were used for this type of reaction in the earliest stages of development, direct in situ generation of a metal alkynylide species from terminal alkynes with a catalytic amount of the metal reagent is currently a major interest in organic synthesis. This article summarizes catalytic asymmetric 1,2-alkynylation of aldehydes, ketones, aldimines and ketimines with respect to the use of either stoichiometric or catalytic amounts of metal reagents.

Catalytic asymmetric epoxidation of α-methyl α,β-unsaturated carboxylic acid derivatives was achieved using anilide as a template. The Pr(Oi-Pr)3-6,6′-Ph-BINOL complex (10 mol%) with a Ph3P(O) (30 mol%) additive promoted the epoxidation of anilides in up to 99% yield and 88% ee. For α-methyl-β-Ph α,β-unsaturated anilide, the Gd(Oi-Pr)3-6,6′-I-BINOL complex (10 mol%) with Ar3P(O) (30 mol%, Ar = 4-methoxyphenyl) was suitable, giving epoxide in 87% yield and 78% ee.

Nuclear factor-kappa B (NF-kappaB) is an essential transcription factor in the control of expression of genes involved in cell growth, differentiation, inflammation, and neoplastic transformation. Previously, we reported that okadaic acid (OA), which is a specific inhibitor of serine/threonine protein phosphatases, induced apoptosis in cells of human osteosarcoma cell line MG63. However, to date, it is not clear whether the phosphorylation status of NF-kappaB could be affected by the treatment with OA. In this report, we demonstrate that treatment of MG63 cells with OA enhanced the phosphorylation level of NF-kappaB, as judged from the results of Western blot analysis and a lambda protein phosphatase dephosphorylation assay. The phosphorylation level of NF-kappaB was enhanced in both time- and dose-dependent manners. In the cells treated with 100 nM OA for 3 h, consequential translocation of NF-kappaB from the cytosol to the nucleus occurred. Western blotting experiments with an anti-phospho-p65NF-kappaB antibody disclosed that the NF-kappaB was phosphorylated on serine 536. Furthermore, OA stimulated the transcriptional activity of NF-kappaB in MG63 cells, as judged from the results of a luciferase assay. Our findings indicate that OA elicit phosphorylation of NF-kappaB on serine 536 in MG63 cells, resulting in the translocation of phospho-NF-kappaB to the nucleus, thereby promoting transcriptional activity of genes.

Double-stranded RNA-dependent protein kinase (PKR) is a participant in the cellular antiviral response and phosphorylates the alpha-subunit of eukaryotic translation initiation factor 2alpha (eIF-2alpha) to block protein synthesis. Treatment of human osteosarcoma cell line MG63 cells with a serine and threonine protein phosphatase inhibitor, okadaic acid, at the concentration of 100 nM, but not at 20 nM, induced apoptosis. To investigate the functional relationship between phosphatases and apoptosis, we examined the phosphorylation levels of PKR and eIF-2alpha by Western blot analysis. During treatment of cells with it at the higher concentration (100 nM), okadaic acid increased the level of phosphorylated PKR in MG63 cells, this kinase phosphorylating eIF-2alpha. However, at the lower concentration (20 nM), okadaic acid did not affect the level of phosphorylated PKR. In the cells treated with 100 nM okadaic acid, activation of NF-kappaB also occurred. Even though inhibition of translation occurred simultaneously in MG63 cells, the expression of pro-apoptotic proteins Fas and Bax was not affected by 100 nM okadaic acid in these cells. We concluded that the inhibition of translation decreased anti-apoptotic protein expression, thus resulting in apoptosis. Our results also suggest that the inhibition of the protein phosphatase activity by okadaic acid induced apoptosis in MG63 cells through PKR and eIF-2alpha.

The reversible phosphorylation of proteins mediates cellular signals in eukaryotic cells. RNA interference inhibits the expression of genes and proteins in a sequence-specific manner and provides a tool to study the functions of target molecules. The effect of RNA interference on protein phosphatase isoforms in HEK-293 cells was examined. Protein phosphatase 1 delta (PP1delta) sequence-specific double-stranded RNA (dsRNA) inhibited mRNA and protein expression of the PP1delta. This RNA interference did not affect the expression of lphaand gamma1 isoforms of PP1. Transfection of antisense RNA specific for PP1delta also suppressed the expression of PP1delta. It was further demonstrated by an in vitro RNA cleavage assay that extracts of HEK-293 cells catalyzed the processing of dsRNA. This cell line had much stronger mRNA expression of Dicer, an RNase III-like enzyme, than did human osteoblastic MG63 cells. The present results show that RNA interference is a useful tool to distinguish between PP1 isoforms.

Full details of a direct catalytic asymmetric Mannich-type reaction of a hydroxyketone using a Et2Zn/(S,S)-linked-BINOL complex are described. By choosing the proper protective groups on imine nitrogen, either anti- or syn-beta-amino alcohol was obtained in good diastereomeric ratio, yield, and excellent enantiomeric excess using the same zinc catalysis. N-Diphenylphosphinoyl (Dpp) imine 3 gave anti-beta-amino alcohols in anti/syn = up to98/2, up to99% yield, and up to99.5% ee, while Boc-imine 4 gave syn-beta-amino alcohols in anti/syn = up to 5/95, up to99% yield, and up to99.5% ee. The high catalyst turnover number (TON) is also noteworthy. Catalyst loading was successfully reduced to 0.02 mol % (TON = up to 4920) for the anti-selective reaction and 0.05 mol % (TON = up to 1760) for the syn-selective reaction. The Et2Zn/(S,S)-linked-BINOL complex exhibited far better TON than in previous reports of catalytic asymmetric Mannich-type reactions. Mechanistic studies to clarify the reason for the high catalyst efficiency as well as transformations of Mannich adducts are also described.

Applications such as network server programs and distributed multimedia applications, in which system calls and input/output processing are frequently used, are highly dependent on the operating system. In evaluating the performance of such applications, the execution data for the application and the operating system must be acquired consistently. Conventionally, the performance of a program has mostly been examined through the occurrences of particular events, by means of the performance monitoring function provided by the CPU. The most frequent is the measurement of time based on the cumulative number of clocks in the CPU. In the present computer environment, these values vary depending on the measurement timing. In addition, in these methods, the information concerning the time of occurrence is not preserved when multiple events occur, and there is no means of analyzing the dependency among the events. It is thus difficult for the user to locate the reason for the variation of the value. In order to solve these problems, this paper considers memory access as the measure for performance evaluation. The “SURU” kernel level instruction tracer, the set of “SURU tools” that analyze the output data from TSURU, and the “SURU library” used to construct TSURU tools, are proposed. TSURU can acquire dynamic information such as the execution instruction sequence, the refer address, and the interrupt. Using the TSURU tools to analyze the data acquired by TSURU, the operation of the program under consideration can be traced, and the execution time and the page fault generation rate can be determined. Based on this result, the factors responsible for performance degradation can be analyzed, and the performance improvement obtainable by solving the problem can be estimated. With the TSURU library, the user can easily construct TSURU tools. © 2004 Wiley Periodicals, Inc. Electron Comm Jpn Pt 3, 87(12): 73–83, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjc.20131

Japanese Castle masonry walls constructed from the end of sixteen century to the middle of seventeen century hold a historical heritage in the construction culture and are famous worldwide for their uniqueness with mortar-less construction. Present investigations on these walls have shown bulging at various locations and the engineering evaluation on the wall stability needs to be urgently required. Based on this viewpoint, this paper presents the FEM analysis results on the stability and deformation behavior with parametric analyses on Osaka Castle masonry wall. It is found that the cobble plays a significant role in reducing the stresses of stone wall and that the masonry wall structure ratio adds stability by the arching effect action on the masonry wall.