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.

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.

Swelling of nerve fibers associated with action potentials.

Swelling of nerve fibers during the action potential was demonstrated by three different methods. Generation of a propagated nerve impulse in a crab nerve produced an outward movement of 50 to 100 angstroms of the nerve surfce and a rise in swelling pressure on the order of 5 dynes per square centimeter. In squid giant axons, the amplitude of the observed outward movement of the surface was small.

Ion channels in plasmalemma of wheat protoplasts.

The patch-clamp technique was used to study passive movements of ions through the plasmalemma of wheat leaf protoplasts. This method overcomes the problems inherent in conventional electrophysiological study of plant cells. Changes in conductance were recorded in patches excised from the plasmalemma. Two types of patches were observed: (i) regions of low channel density, where discrete single-channel currents could be resolved and conductance ranged from 10 to 200 picosiemens and (ii) regions of high channel density, where single-channel currents could not be resolved and conductance was on the order of a few nanosiemens. The results indicate a striking similarity between animal and plant cell membranes in the basic phenomena of transport. Moreover, the approach used constitutes a new degree of refinement in the study of processes of regulation, pathology, and toxicity in plants.

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.

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.

Protective effect of vitamin E on spinal cord injury by compression and concurrent lipid peroxidation.

Studies were made on the influence of vitamin E on the effects of compression injury of the spinal cord associated with ischemia in rats. The motor disturbance induced by spinal cord injury was greatly reduced by vitamin E supplementation. After injury, the spinal cord evoked potentials showed greater recovery of both amplitude and latency in the vitamin E-supplemented group than in the control group. Spinal cord blood flow was promptly restored and remained normal after injury in the vitamin E-supplemented group, but was significantly decreased from 3 h after injury in the control group. Thiobarbituric acid (TBA)--reactive substances in the spinal cord was immediately increased by compression injury in both groups, and after injury it persisted at a high value for 24 h in the control group, but decreased within 1 h in the vitamin E-supplemented group. Pathological examination of the spinal cord showed less damage, such as bleeding and edema, in the vitamin E-supplemented group than in the control group. Vitamin E may have protective effects on the spinal cord by inhibiting damage induced by lipid peroxidation and/or by sustaining the blood flow by maintaining the normal metabolism of arachidonic acid.

Antibodies to synthetic peptides of the alpha1A subunit of the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome.

To search for antigenic sites in the molecular structure of alpha1A subunit of the voltage-gated calcium channel (VGCC) (P/Q-type) in the Lambert-Eaton myasthenic syndrome (LEMS), we studied by immunoprecipitation assay serum samples from 30 LEMS patients (16 with small cell lung carcinoma (SCLC), 20 disease controls (10 with SCLC without LEMS and 10 with myasthenia gravis), and 15 healthy controls. Synthetic peptide antigens corresponded to the extracellular region (S5-S6 linker region) of each of the four domains forming the alpha1 subunit of P/Q-type VGCC. In addition, we studied serum samples for anti-P/Q-type VGCC antibodies by using omega-conotoxin MVIIC-labeled extract of human cerebellum as an antigen. Among sera of 30 LEMS patients, nine samples (30%) (six with SCLC) were positive for antibodies to the domain IV S5-S6 linker peptide, and six samples (20%) (five with SCLC) were positive for antibodies to the domain II S5-S6 linker peptide. Only two of 15 antipeptide-positive sera were positive for both antibodies. Titers for antibodies to domain IV, as well as those for antibodies to domain II, correlated with those of anti-P/Q-type VGCC (human cerebellum extract) antibodies. The antipeptide antibody was present in only one of 20 disease controls, a patient with SCLC without LEMS. Our observations suggest two potential epitopes of LEMS antibodies.

Recombinant calcium channel is recognized by Lambert-Eaton myasthenic syndrome antibodies.

The authors studied sera from 36 patients with Lambert-Eaton myasthenic syndrome (LEMS) by immunoblots using the recombinant protein derived from the DNA sequence encoding for the domain III S5-S6 linker of the P/Q-type voltage-gated calcium channel al subunit. The results of 18 patients were positive for antibodies to this recombinant protein. The results of 2 of 10 patients with lung cancer without LEMS were also positive.

Cytotoxicity of a novel indoloquinone eo9 in hypoxic non-small-cell lung-cancer cell-lines.

3-Hydroxymethyl-5-aziridinyl-1-methyl-[1H-indole-4,7-dione]-prop-beta-en -alpha-ol (EO9) is a bioreductive anticancer agent active for non-small cell lung cancer (NSCLC) and structurally related to mitomycin C (MMC). DT-diaphorase (DTD) is regarded as a two electron reductase that plays an important role in the biotransformation of MMC to antitumor metabolites. To evaluate the role of DTD as a bioactivator of EO9 in NSCLC cell lines under oxic and hypoxic conditions, we examined the inhibitory effect of dicumarol which was regarded as a selective inhibitor of DTD on the sensitivity to EO9 in vitro. In this study, we used an MMC-resistant NSCLC cell line (PC-9/MC4) which was established from a PC-9 cell line as a parent cell line by continuous exposure to MMC in our laboratory. We reported previously that the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9 with decreased DTD activity. The IC50 value of PC-9 against EO9 was significantly increased by co-incubation with dicumarol under oxic conditions. EO9 was more cytotoxic against PC-9/MC4 than against PC-9 cells and the enhancement was impaired by tempol under hypoxic conditions. These findings suggest a suppressive role of DTD against one-electron reduction pathway in the bioactivation of EO9 under hypoxic conditions and EO9 may be more active against oxygen-deficient solid tumors especially in MMC-resistant NSCLC cells with low levels of DTD activity.

Stimulation of beta-adrenoceptor enhances sensitivity to cisplatin in non-small cell lung cancer cell lines.

Cisplatin is a key drug in chemotherapy for lung cancer. It has been reported that intracellular accumulation of cisplatin is an important step as a determinant for resistance to cisplatin, which may be modulated by Na+, K+-ATPase activity. And it has been reported that beta-adrenoceptor agonists modulate the Na+, K+-ATPase in some organs. In this study, the effects of a beta-adrenoceptor agonist and an antagonist on membrane Na+, K+-ATPase activity were evaluated using human non-small cell (NSCLC) lung cancer cell lines. In the NSCLC cell lines, sensitivity to cisplatin was improved by treatment with isoproterenol. Na+, K+-ATPase was activated and intracellular accumulation of cisplatin increased with the treatment. But the antagonist, propranolol, did not modulate sensitivity to cisplatin or Na+, K+-ATPase activity. These results suggest that beta-adrenoceptors may be one of the determinant for sensitivity to cisplatin in NSCLC, but endogenous catecholamine dose not play a role in the intracellular accumulation of cisplatin in these cell lines. Exogenous beta-adrenoceptor agonists may improve the antitumor effect of chemotherapy involving cisplatin.

Up-regulation of ICH-1L protein by thromboxane A2 antagonists enhances cisplatin-induced apoptosis in non-small-cell lung-cancer cell lines.

We evaluated the effect of thromboxane A2 (TXA2) blockade on cisplatin-induced apoptosis in non-small-cell lung cancer (NSCLC) cell lines. Cisplatin induced apoptosis in PC/9 and PC-9/CDDP in a dose-dependent manner. Treatment with specific TXA2 antagonist, calcium 5(Z)-1R,2S,3S,4S-7-[3-phenylsulfonylaminobicyclo[2,2,1]hept-2-yl]- 5-heptonoate hydrate (S-1452) and 5(Z-6-[(1R,2R,3R,4S)-3-(N-4-bromobenzenesulfonyl aminomethyl) bicyclo[2,2,1]heptane-2-yl]-hex-5-enoic acid (ONO-NT-126), enhanced the cisplatin-induced apoptosis in each cell line. Acetyl-L-aspartyl-glutamyl-valyl-aspart-1-aldehyde (Ac-DEVD-CHO) inhibited cisplatin-induced apoptosis and enhancement of the apoptosis by TXA2 blockade, but acetyl-L-tyrosyl-valyl-alanyl-aspart-1-aldehyde (Ac-YVAD-CHO) had no effect on the apoptosis. There was no difference in the interleukin-1beta-converting enzyme (ICE) protease protein expression in either cell line. Cysteine protease p32(CPP32) protein expression was lower in PC-9/CDDP but was not changed by S-1452, cisplatin, or cotreatment with cisplatin and S-1452. Ice and Ced-3 homolog (ICH-1L) expression was significantly lower in PC-9/CDDP and was up-regulated by S-1452 or ONO-NT-126. These data suggest that ICH-1L might play a critical role in cisplatin-induced apoptosis and that TXA2 blockade up-regulates ICH-1L protein expression. Overexpression of ICH-1L and treatment with cisplatin might result in an increase in apoptosis in NSCLC cell lines.

Modulation of sensitivity to mitomycin C and a dithiol analogue by tempol in non-small-cell lung cancer cell lines under hypoxia.

We examined the mechanisms involved in the bioactivation of mitomycin C (MMC) and a newly developed MMC analogue: 7-N-(2-([2-(gamma-L-glutamylamino)ethyl]dithio)ethyl)mitomycin C, KW-2149, in non-small-cell lung cancer (NSCLC) cell lines under aerobic and hypoxic conditions. To investigate these mechanisms, we used MMC-resistant non-small-cell lung cancer cell lines (PC-9/MC4) that had been established in our laboratory from the parent PC-9 cell line by continuous exposure to MMC. We previously reported that the MMC-resistant cell line (PC-9/MC4) was poor in NAD(P)H dehydrogenase (quinone) activity and approximately 6-fold more resistant than the parent cells (PC-9) to MMC on 2-h exposure under aerobic conditions. In this study, the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9, the parent cell line, under aerobic conditions, and 5.2-fold more resistant under hypoxic conditions after 2-h exposure to MMC. However, on co-incubation with tempol, an inhibitor of the one-electron reduction pathway, the sensitivity of PC-9/MC4 to MMC was impaired under hypoxic conditions, but the impairment was not evident under aerobic conditions. KW-2149, the newly developed MMC analogue, was cytotoxic for both PC-9/MC4 and PC-9 cells, and the sensitivity of both cell lines to KW-2149 was not changed by exposure to hypoxic conditions or by coincubation with tempol. There were no significant differences in the intracellular uptake of MMC and the activities of cytosolic detoxification enzymes between the PC-9 and PC-9/MC4 cell lines. These results support the hypothesis that the one-electron reduction pathway plays a partial role in the bioactivation of MMC, but not of KW-2149, and that KW-2149 is excellent at circumventing resistance to MMC in NSCLC.

Atheroprotective effect of estriol and estrone sulfate on human vascular smooth muscle cells.

In patients with atherosclerosis, fibrosclerotic focuses are induced by multiplication of vascular smooth muscle cells (VSMC), and they are regulated by cytokines and regulators. There have been few reports about the atheroprotective effect of estriol (E(3)). Estrone sulfate (E(1)-S) is the predominant estrogen of conjugated equiline estrogens, which is commonly used in hormone replacement therapy, but it should be hydrolyzed by steroid sulfatase (STS) to enter the cells of target tissues. The purpose of this study was to detect STS in VSMC and to investigate whether E(3) and E(1)-S have atheroprotective effects like E(2). First, we detected the presence of STS mRNA in VSMC by in situ hybridization. We then examined the changes in the expression of mRNAs of cytokines, namely, PDGF-A chain, IL-1, IL-6 and TGF-beta, in VSMC, in the presence and absence of E(3) and estrogens. As a result, the expression of PDGF-A chain, IL-1 and IL-6 mRNAs was suppressed by E(3) (P<0.05 vs control) significantly like E(1)-S and E(2), but that of TGF-beta mRNA was not significantly affected by any estrogen. These results indicate that E(1)-S can be hydrolyzed by STS in VSMC, and that E(3) may regulate the cytokines by suppressing the production of mRNAs. It is suggested that there is a possibility of E(1)-S and E(3) having a direct effect on vessels in atherogenesis.

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.

Prenatal expression of inwardly rectifying potassium channel mRNA (Kir4.1) in rat brain.

The levels and cellular localization of the mRNA encoding the inwardly rectifying potassium ion channel Kir4.1 were investigated in the embryonic rat brain by Northern blots and in situ hybridization. This transcript was absent at embryonic day 13 (E13), whereas it was clearly present in E14-15 preparations, principally in the neuroepithelium of the cerebral cortex, thalamus, and hypothalamus. At later embryonic stages (E17-20), Kir4.1 mRNA levels increased and expanded to the mantle zone, such as the cortical plate, hippocampus, thalamus, and hypothalamus. The early appearance of Kir4.1 mRNA in various brain regions suggests an involvement of the channel in cell proliferation, migration and differentiation in the rat CNS.

Stretch sensitivity of the lateral wall of the auditory outer hair cell from the guinea pig.

The inner and outer hair cells of the mammalian hearing organ are mechano-transducer cells. Here we report evidence that the lateral wall of outer hair cells (OHCs) is a mechano-receptor. This mechano-sensitivity appears to complement that of the stereocilia. Patch clamping studies showed that stretching of the membrane patches by suction at the pipette activated potassium channels with 130 pS unit conductance specifically localized in the lateral wall. Application of an osmotic tension to the entire cell membrane under whole-cell recording produced a 10 mV hyperpolarization. The reversal potential and the magnitude of the macroscopic current under voltage clamp were consistent with the single-channel properties of stretch-activated potassium channels. The elongated cylindrical cell body of the OHC is optimally positioned in the cochlea to sense axial force due to the vibrations of the basilar membrane during sound stimulation. This sensitivity can explain the production of a predominantly hyperpolarizing response to sound stimuli, unique to the OHC. Coupled with voltage-dependent OHC motility, the stretch-activated channels may play an important role in producing a mechanical feedback, an indispensable element in cochlear tuning.