Multipole polaron in the devil's staircase of CeSb.

Rare-earth intermetallic compounds exhibit rich phenomena induced by the interplay between localized f orbitals and conduction electrons. However, since the energy scale of the crystal-electric-field splitting is only a few millielectronvolts, the nature of the mobile electrons accompanied by collective crystal-electric-field excitations has not been unveiled. Here, we examine the low-energy electronic structures of CeSb through the anomalous magnetostructural transitions below the Néel temperature, ~17 K, termed the 'devil's staircase', using laser angle-resolved photoemission, Raman and neutron scattering spectroscopies. We report another type of electron-boson coupling between mobile electrons and quadrupole crystal-electric-field excitations of the 4f orbitals, which renormalizes the Sb 5p band prominently, yielding a kink at a very low energy (~7 meV). This coupling strength is strong and exhibits anomalous step-like enhancement during the devil's staircase transition, unveiling a new type of quasiparticle, named the 'multipole polaron', comprising a mobile electron dressed with a cloud of the quadrupole crystal-electric-field polarization.

The prevalence of mental health problems in adults with intellectual disabilities in Japan, associated factors and mental health service use.

BACKGROUND: People with intellectual disabilities are more likely than people in the general population to experience life events associated with an increased risk of mental health problems. However, there has been little research in Japan on the prevalence of mental health problems in adults with intellectual disability (ID) or on associated factors and access to relevant services. METHODS: Informants completed the Japanese version of the Psychiatric Assessment Schedule for Adults with Developmental Disabilities Checklist, and questions on the use of mental health services, for 126 adults with ID living in Tokyo. RESULTS: A total of 23.8% of adults with ID had scores above the Psychiatric Assessment Schedule for Adults with Developmental Disabilities Checklist threshold score. Mental health problems were associated with age, gender and life events and not associated with the level of ID or living environment. Approximately 60% of participants with mental health problems were treated by psychiatrists and 6% of them received psychotherapy. CONCLUSION: In the present study, mental health problems occurred in adults with ID at similar frequencies as in previous studies. Adults with ID who experienced mental health problems tended to receive less psychological therapy than the general Japanese population experiencing such problems. This result may indicate poor provision of psychological services for people with intellectual disabilities in Japan.

Spin-orbit fluctuations in frustrated heavy-fermion metal LiV(2)O(4).

Spin fluctuations were studied over a wide momentum (ℏQ) and energy (E) space in the frustrated d-electron heavy-fermion metal LiV_{2}O_{4} by time-of-flight inelastic neutron scattering. We observed the overall Q-E evolutions near the characteristic Q=0.6 Å^{-1} peak and found another weak broad magnetic peak around 2.4 Å^{-1}. The data are described by a simple response function, a partially delocalized magnetic form factor, and antiferromagnetic short-range spatial correlations, indicating that heavy-fermion formation is attributable to spin-orbit fluctuations with orbital hybridization.

Prostaglandin F2α FP receptor inhibitor reduces demyelination and motor dysfunction in a cuprizone-induced multiple sclerosis mouse model.

Previously, we have demonstrated that prostamide/PGF synthase, which catalyzes the reduction of prostaglandin (PG) H2 to PGF2α, is constitutively expressed in myelin sheaths and cultured oligodendrocytes, suggesting that PGF2α has functional significance in myelin-forming oligodendrocytes. To investigate the effects of PGF2α/FP receptor signaling on demyelination, we administrated FP receptor agonist and antagonist to cuprizone-exposed mice, a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, glial activation, proinflammatory cytokine expression, and motor dysfunction. Administration of the FP receptor antagonist AL-8810 attenuated cuprizone-induced demyelination, glial activation, and TNFα expression in the corpus callosum, and also improved the motor function. These data suggest that during cuprizone-induced demyelination, PGF2α/FP receptor signaling contributes to glial activation, neuroinflammation, and demyelination, resulting in motor dysfunction. Thus, FP receptor inhibition may be a useful symptomatic treatment in multiple sclerosis.

Akt phosphorylation in human chondrocytes is regulated by p53R2 in response to mechanical stress.

OBJECTIVE: The p53 tumor-suppressor protein p53R2 is activated in response to various stressors that act on cell signaling. When DNA is damaged, phosphorylation of p53 at its Ser 15 residue induces p53R2 production. The role of p53R2 in chondrocytes remains poorly understood. In this study, we evaluated in chondrocytes, p53R2 expression and its regulation in response to mechanical stress. Furthermore, we investigated the function of p53R2 in relation to mechanotransduction. METHODS: Osteoarthritis (OA) cartilage obtained from total knee replacements and normal cartilage obtained from femoral neck fractures was used to measure p53R2 expression by using immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR). The OA chondrocytes were subjected to a high magnitude of cyclical tensile strain by using an FX-2000 Flexercell system. Next, sulfated glycosaminoglycan (sGAG) production was quantified in these cells. Protein expression of p53R2, and phosphorylation of Akt, p38MAPK, ERK1/2, and JNK was also detected using western blotting. Moreover, Akt phosphorylation was detected after transfecting the cells with p53R2-specific small interfering RNA (siRNA). RESULTS: Expression of p53R2 was significantly increased in OA chondrocytes and in chondrocytes after applying 5% tensile strain to the cells. However, Akt phosphorylation was down-regulated in OA chondrocytes after the strain, and was up-regulated after transfection of p53R2. sGAG protein as well as collagen type II and aggrecan mRNA was increased following transfection of p53R2-specific siRNA after 5% tensile strain. CONCLUSIONS: p53R2 could regulate matrix synthesis via Akt phosphorylation during chondrocyte mechanotransduction. Down-regulation of p53R2 may be a new therapeutic approach in OA therapy.

Some contributions to the application of LC-NMR, LC-MS, and LC-CD to the biosynthesis of isoquinoline alkaloids using callus cultures.

Hyphenated spectroscopic techniques in combination with a special extraction and work-up of plant calli cultures of Berberidaceae, Fumariaceae, and Papaveraceae families, e.g., enabled us to get deeper insight into the sequential biochemical conversions of precursors into simple isoquinoline- and protoberberine-alkaloids and their follow-up-products with different skeletons. Some new alkaloids of these types have been found.

The efficacy of oral beraprost sodium, a prostaglandin I2 analogue, for treating intermittent claudication in patients with arteriosclerosis obliterans.

AIM: This study aimed to evaluate the effect of oral beraprost sodium, a prostaglandin I2 analogue, on symptoms of intermittent claudication in patients with arteriosclerosis obliterans. The research design consisted of a before and after treatment study without comparison groups. The subjects comprised arteriosclerosis obliterans patients who experienced intermittent claudication. Furthermore, this study aimed to assess the mechanism of action of beraprost sodium via blood sampling and measurements of flow-mediated vasodilatation before and after treatment. METHODS: The study was performed prospectively in 7 patients with arteriosclerosis obliterans. Beraprost sodium (40 microg) was orally administered to 7 patients at study entry, followed by administration of 120 microg/day for 12 weeks. Blood sampling and measurements of flow-mediated vasodilatation were performed before and after treatment at study entry, 4 weeks, and 12 weeks after treatment. Treadmill exercise tests were performed three times at study entry, 4 weeks, and 12 weeks after treatment. The ankle-brachial index (ABI) was measured at rest and after exercise. RESULTS: Pain-free walking distances increased by 138% at 12 weeks after treatment. Maximum walking distances increased by 133%. The ABI was significantly increased at 4 weeks and 12 weeks after treatment at rest. Endothelin-1 levels tended to be decreased at 1 h after administration of 40 microg beraprost sodium. N(G),N(G)-dimethyl-L-arginine, nitrate ions, and flow-mediated vasodilatation. CONCLUSION: Beraprost sodium tended to decrease endothelin-1 levels and improved symptoms of intermittent claudication in patients with arteriosclerosis obliterans.

Excitation spectrum of PrOs(4)Sb(12) under a magnetic field.

The evolution of the magnetic excitation spectrum of the heavy fermion superconductor PrOs(4)Sb(12) was studied by inelastic neutron scattering on crossing the critical field H(c2) for superconductivity at low temperature. The peak positions in energy and the peak intensities of the modes of the triplet split by magnetic field confirm the known crystal field parameters for PrOs(4)Sb(12) in T(h) symmetry. A selective broadening of the lineshape occurs on increasing the magnetic field: the linewidth of the upper mode of the triplet increases while the one of the middle mode does not.

Long-term effect of intravenous immunoglobulin on anti-MuSK antibody-positive myasthenia gravis.

Anti-muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) patients show various responses to conventional immunosuppressive treatment and some patients are resistant to these therapies. We report a 50-year-old Japanese man with anti-MuSK antibody-positive MG, who showed no or poor response to various therapies, including plasmapheresis, corticosteroid, and tacrolimus. The patient was then treated with intravenous immunoglobulin (IVIG), and showed a good response that persisted over 20 months. The outcome of this case suggests that IVIG treatment may be an effective therapeutic option for anti-MuSK antibody-positive MG, with a potentially long-term effect.

Effects of chlorpromazine and trinitrophenol on the membrane motor of outer hair cells.

The motile activity of outer hair cells' cell body is associated with large nonlinear capacitance due to a membrane motor that couples electric displacement with changes in the membrane area, analogous to piezoelectricity. This motor is based on prestin, a member of the SLC26 family of anion transporters and utilizes the electric energy available at the plasma membrane associated with the sensory function of these cells. To understand detailed mechanism of this motile activity, we examined the effect of amphipathic ions, cationic chlorpromazine and anionic trinitrophenol, which are thought to change the curvature of the membrane in opposite directions. We found that both chemicals reduced cell length at the holding potential of -75 mV and induced positive shifts in the cells' voltage dependence. The shift observed was approximately 10 mV for 500 microM trinitrophenol and 20 mV for 100 microM cationic chlorpromazine. Length reduction at the holding potential and voltage shifts of the motile activity were well correlated. The voltage shifts of nonlinear capacitance were not diminished by eliminating the cells' turgor pressure or by digesting the cortical cytoskeleton. These observations suggest that the membrane motor undergoes conformational transitions that involve changes not only in membrane area but also in bending stiffness.

Effects of tarantula toxin GsMTx4 on the membrane motor of outer hair cells.

GsMTx4, a cationic hydrophobic peptide isolated from tarantula venom, is a specific inhibitor of stretch-activated channels (SACs). Here, we show that the toxin also affects the membrane motor of outer hair cells at low doses. The membrane motor of outer hair cells is based on prestin, a member of the SLC26 family of membrane proteins, and directly uses electrical energy available at the plasma membrane. It is considered to be an essential part of the "cochlear amplifier," which increases the sensitivity, tuning, and dynamic range of the mammalian ear. The toxin shifts the operating point of the motor. The saturating value of the voltage shift is (26 +/- 1) mV, capable of significantly reducing the performance of the cochlear amplifier. The dissociation constant is (3.1 +/- 0.6) microM, about five-fold higher than that for SACs.

N-Propargylamine protects SH-SY5Y cells from apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, through stabilization of mitochondrial membrane and induction of anti-apoptotic Bcl-2.

Propargylamine derivatives, rasagiline and (-)deprenyl, are anti-Parkinson agents and protect neurons from cell death as shown by in vivo and in vitro experiments. The studies on the chemical structure-activity relationship proved that the propargyl moiety is essentially required for the neuroprotective function. In this paper, neuroprotective activity of free N-propargylamine was studied using SH-SY5Y cells expressing only type A monoamine oxidase (MAO) against apoptosis induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. N-Propargylamine prevented apoptosis, whereas N-methylpropargylamine and propiolaldehyde did not. N-Propargylamine stabilized mitochondrial membrane potential and induced anti-apoptotic Bcl-2 at 1 microM-10 nM. N-Propargylamine inhibited MAO-A in competition to substrate with the apparent K(i) value of 28 microM, which was significantly higher than the concentration required for neuroprotection. It indicates that MAO inhibition is not prerequisite for the protective function of N-propargylamine. The anti-apoptotic function of N-propargylamine is discussed in terms of neuroprotection by propargylamines in neurodegenerative diseases, including Parkinson's disease.

Direct observation of quadrupolar excitons in the heavy-fermion superconductor PrOs4Sb12.

We report inelastic neutron scattering experiments performed to investigate the low energy magnetic excitations on single crystals of the heavy-fermion superconductor PrOs(4)Sb(12). The observed excitation clearly softens at a wave vector Q=(1,0,0), which is the same as the modulation vector of the field-induced antiferro-quadrupolar ordering, and its intensity at Q=(1,0,0) is smaller than that around the zone center. This result directly evidences that this excitonic behavior is derived mainly from nonmagnetic quadrupolar interactions. Furthermore, the narrowing of the linewidths of the excitations below the superconducting transition temperature indicates the close connection between the superconductivity and the excitons.

Bioconversion studies in cultured cells of Corydalis species.

Structural analysis of the metabolites of dopamine and salsolinol in cultured cells of Corydalis species was carried out using the combination of LC-MS and LC-NMR techniques. Metabolic pathways were clarified without the need to isolate the individual metabolites.

Tension sensitivity of prestin: comparison with the membrane motor in outer hair cells.

The membrane motor in outer hair cells undergoes conformational transitions involving charge displacement of approximately 0.8 e across the membrane and changes of approximately 4 nm(2) in its membrane area. Previous reports have established that the charge transfer in the membrane motor and that in prestin, a membrane protein in the plasma membrane of outer hair cells, are approximately equal. Here, we determine the membrane area changes based on its sensitivity to membrane tension. We found that prestin does undergo area changes and that the magnitude is approximately 1 nm(2), smaller than the value 4 nm(2) for outer hair cell motor. This result confirms that prestin is a protein that functions as a membrane motor based on piezoelectricity. The discrepancy in the magnitude could suggest a prestin-containing complex in outer hair cells.

Cooperative interaction as the physical basis of the negative stiffness in hair cell stereocilia.

A recent report confirmed that stiffness of the stereocilia can be negative, as predicted by the Howard-Hudspeth model. According to this model, the mechanotransducer channel's gating not only reduces the stereociliary stiffness, but can alter its sign as well. The basic assumptions of this model do not include cooperativity in channel gating. Here we consider two possible explanations for the observed negative stiffness. If the stereocilia have a special structure so that microscopic displacement can be imposed on each channel by controlling the bending of the bundle, negative stiffness can occur without channel cooperativity. If such a microscopic condition cannot be imposed by a macroscopic manipulation, an additional physical process, such as cooperativity in channel gating, is required to explain negative stiffness.

Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents.

Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts.

A two-state piezoelectric model for outer hair cell motility.

Recent studies have revealed that voltage-dependent length changes of the outer hair cell are based on charge transfer across the membrane. Such a motility can be explained by an "area motor" model, which assumes two states in the motor and that conformational transitions involve transfer of motor charge across the membrane and mechanical displacements of the membrane. Here it is shown that the area motor is piezoelectric and that the hair cell that incorporates such a motor in its lateral membrane is also piezoelectric. Distinctive features of the outer hair cell are its exceptionally large piezoelectric coefficient, which exceeds the best known piezoelectric material by four orders of magnitude, and its prominent nonlinearity due to the discreteness of motor states.

In vitro cytotoxicity of the protoberberine-type alkaloids.

In vitro cytotoxic activities of 24 quaternary protoberberine alkaloids related to berberine have been evaluated using a human cancer cell line panel coupled with a drug sensitivity database. Extending the alkyl chain at position 8 or 13 strongly influenced the cytotoxic activity, that is, relative lipophilicity as well as the size of the substituent affects cytotoxicity. The highest level of activity was observed in 8- or 13-hexyl-substituted derivatives of berberine. Structure-activity relationships are described.

Alzheimer's disease and estrogen.

The preventive effect of estrogen on Alzheimer's disease (AD) has become clear with epidemiological data. Therapeutic effects of estrogen have not yet been established. In this presentation, we report our new basic and clinical data. The estrogen receptor, (ER)alpha, and ERbeta mRNA were investigated in rat brain. Estradiol-17beta (E(2)) treatment following OVX reduced the levels of ERalpha mRNA in the hypothalamus. In the substantia innominata (SI), the number of choline acetyltransferase immunoreacive cells increased significantly in the estrogen treatment rat. The neurons in SI projecting to the forebrain cortex contained ERalpha. Increasing amounts of intracellular calcium, peroxidation, and apoptosis with amyloid beta were suppressed in neuronal cells from rat pheochromocytoma (PC12) cells with E(2). ERalpha cDNA transfected PC 12 cells elaborated more neurite-like processes with E(2). In clinics, we are currently preparing vaginal progesterone tablets, which essentially may concentrate in the endometrium to prevent endometrial cancer, with few general circulation of progesterone inviting less depression. The therapeutic effects of cyclic estrogen, such as its preventive effect, are suggested in these studies, at least on mild AD.