Spin Current as a Probe of the Z_{2}-Vortex Topological Transition in the Classical Heisenberg Antiferromagnet on the Triangular Lattice.

We have theoretically investigated transport properties of the classical Heisenberg antiferromagnet on the triangular lattice, in which a binding-unbinding topological transition of Z_{2} vortices is predicted to occur at a finite temperature T_{v}. It is shown by means of the hybrid Monte Carlo and spin-dynamics simulations that the longitudinal spin-current conductivity exhibits a divergence at T_{v}, while the thermal conductivity only shows a monotonic temperature dependence with no clear anomaly at T_{v}. The significant enhancement of the spin-current conductivity is found to be due to the rapid growth of the spin-current-relaxation time toward T_{v}, which can be understood as a manifestation of the topological nature of the free Z_{2} vortex whose lifetime gets longer toward T_{v}. The result suggests that the spin-current measurement is a promising probe to detect the Z_{2}-vortex topological transition, which has remained elusive in experiments.

Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer originating from rare populations of leukemia stem cells (LSCs). AML relapse after conventional chemotherapy is caused by a remaining population of drug-resistant LSCs. Selective targeting of the chemoresistant population is a promising strategy for preventing and treating AML relapse. Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 to maintain the stemness of LSCs. Here, we show that quiescent LSCs expressed the highest levels of enhancer of zeste (EZH) 1 and EZH2, the PRC2 catalytic subunits, in the AML hierarchy, and that dual inactivation of EZH1/2 eradicated quiescent LSCs to cure AML. Genetic deletion of Ezh1/2 in a mouse AML model induced cell cycle progression of quiescent LSCs and differentiation to LSCs, eventually eradicating AML LSCs. Quiescent LSCs showed PRC2-mediated suppression of Cyclin D, and Cyclin D-overexpressing AML was more sensitive to chemotherapy. We have developed a novel EZH1/2 dual inhibitor with potent inhibitory activity against both EZH1/2. In AML mouse models and patient-derived xenograft models, the inhibitor reduced the number of LSCs, impaired leukemia progression, and prolonged survival. Taken together, these results show that dual inhibition of EZH1/2 is an effective strategy for eliminating AML LSCs.

The Piccolo Intronic Single Nucleotide Polymorphism rs13438494 Regulates Dopamine and Serotonin Uptake and Shows Associations with Dependence-Like Behavior in Genomic Association Study.

Piccolo (PCLO) inhibits methamphetamine-induced neuropharmacological effects via modulation of dopamine (DA) uptake and regulation of the transport of synaptic vesicles in neuronal cells. Clinical studies have recently suggested that the single nucleotide polymorphism (SNP) rs13438494 in the intron 24 of the PCLO gene is associated with psychiatric disorder, in the meta-analysis of GWAS. Therefore, in this study, we attempted to evaluate the possible role of the PCLO SNP in the mechanisms of uptake of monoamines. To characterize rs13438494 in the PCLO gene, we constructed plasmids carrying either the C or A allele of the SNP and transiently transfected them into SH-SY5Y cells to analyze genetic effects on the splicing of PCLO mRNA. The C and A allele constructs produced different composition of the transcripts, indicating that the intronic SNP does affect the splicing pattern. We also transfected DA and serotonin (5-hydroxytryptamine; 5- HT) transporters into cells and analyzed their uptakes to elucidate the association to psychiatric disorders. In the cells transfected with the C allele, both the DA and 5-HT uptake were enhanced compared to the A allele. We also conducted a clinical study, in order to clarify the genetic associations. PCLO rs13438494 exhibits a relationship with the symptoms of drug dependence or related parameters, such as the age of first exposure to methamphetamine, eating disorders, tobacco dependence and fentanyl requirement. Our findings suggest that rs13438494 is associated with drug abuse and contributes to the pathogenesis of psychiatric disorders via modulation of neurotransmitter turnover.

Incubation of saccharin craving and within-session changes in responding for a cue previously associated with saccharin.

Time-dependent increases in cue-induced sucrose seeking after forced abstinence have been described in rats with a history of sucrose self-administration, suggesting sucrose craving "incubates". In the present study, we examined whether the incubation of craving generalizes to the artificial sweetener, saccharin. Thirty-one male Long-Evans rats lever pressed for 0.3% saccharin solution 1h/day for 10 days. On either Day 1 or 30 of forced abstinence, rats responded for 1h for presentation of a tone+light cue previously presented with every saccharin delivery during self-administration training. Rats responded more during this cue-reactivity test session following 30 vs. 1 day of forced abstinence ("incubation of craving"). This result is the first demonstration of the "incubation of saccharin craving" and suggests that a post-ingestive caloric consequence of self-administration is not a necessary condition for the development of incubation of sucrose craving. We also examined the time course (within-session decreases) of active-lever responding during the 1-h cue-reactivity test session. Rats in the Day 30 group responded more than rats in the Day 1 group from the beginning of the test session. In addition, within-session decreases in responding were shallower in slope in the Day 30 than the Day 1 group. These results indicate that "incubation of saccharin craving" enhances the persistence of seeking behavior.

Expansion of donor-reactive host T cells in primary graft failure after allogeneic hematopoietic SCT following reduced-intensity conditioning.

Graft rejection remains a major obstacle in allogeneic hematopoietic SCT following reduced-intensity conditioning (RIC-SCT), particularly after cord blood transplantation (CBT). In a murine MHC-mismatched model of RIC-SCT, primary graft rejection was associated with activation and expansion of donor-reactive host T cells in peripheral blood and BM early after SCT. Donor-derived dendritic cells are at least partly involved in host T-cell activation. We then evaluated if such an expansion of host T cells could be associated with graft rejection after RIC-CBT. Expansion of residual host lymphocytes was observed in 4/7 patients with graft rejection at 3 weeks after CBT, but in none of the 17 patients who achieved engraftment. These results suggest the crucial role of residual host T cells after RIC-SCT in graft rejection and expansion of host T cells could be a marker of graft rejection. Development of more efficient T cell-suppressive conditioning regimens may be necessary in the context of RIC-SCT.

Genome-wide association study identifies a potent locus associated with human opioid sensitivity.

Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.

Orbital order and Hund's rule frustration in Kondo lattices.

We analyze a microscopic origin of the Kondo effect-assisted orbital order in heavy-fermion materials. By studying the periodic two-orbital Anderson model with two local electrons, we show that frustration of Hund's rule coupling due to the Kondo effect leads to an incommensurate spiral orbital and magnetic order, which exists only inside the Kondo screened (heavy-electron) phase. This spiral state can be observed in neutron and resonant x-ray scattering measurements in U- and Pr-based heavy-fermion compounds, and realized in cold atomic gases, e.g., fermionic 173Yb.

Inhomogeneous superconducting States of mesoscopic thin-walled cylinders in external magnetic fields.

We theoretically investigate the appearance of spatially modulated superconducting states in mesoscopic superconducting thin-wall cylinders in a magnetic field at low temperatures. Quantization of the electron motion around the circumference of the cylinder leads to a discontinuous evolution of the spatial modulation of the superconducting order parameter along the transition line T(c)(H). We show that this discontinuity leads to the nonmonotonic behavior of the specific heat jump at the onset of superconductivity as a function of temperature and field. We argue that this geometry provides an excellent opportunity to directly and unambiguously detect distinctive signatures of the Fulde-Ferrell-Larkin-Ovchinnikov modulation of the superconducting order.

The function of platelet-derived growth factor in the differentiation of mouse tongue striated muscle.

OBJECTIVE: To determine the function of platelet-derived growth factor (PDGF) in the final differentiation phase of tongue striated muscle cells. MATERIALS AND METHODS: We analyzed the expressions of PDGF-A, -B, platelet-derived growth factor receptor (PDGFR)-α, and PDGFR-ß in mouse tongues between embryonic days (E) 11 and 15. Furthermore, we examined the effects of human recombinant PDGF-AB and the peptide antagonist for PDGFRs using an organ culture system of mouse embryonic tongue. Mouse tongues at E12 were cultured in BGJb medium containing human recombinant PDGF-AB for 4 days or the peptide antagonist for PDGF receptors for 8 days. RESULTS: PDGF-A, -B, PDGFR-α, and -ß were expressed in the differentiating muscle cells between E11 and 15. The human recombinant PDGF-AB induced increases in the mRNA expressions of myogenin and muscle creatine kinase (MCK) and the number of fast myosin heavy chain (fMHC)-positive cells, markers for the differentiation of muscle cells. On the other hand, the peptide antagonist for PDGFRs induced suppressions in the mRNA expressions of myogenin and MCK, and the number of fMHC-positive cells. Both the PDGF-AB and the antagonist failed to affect the expressions of cell proliferation markers. CONCLUSION: These results suggest that PDGF functions as a positive regulator in the final differentiation phase of tongue muscle cells in mouse embryos.

Caffeine and uric acid mediate glutathione synthesis for neuroprotection.

Several lines of epidemiological studies have indicated that caffeine consumption and plasma uric acid (UA) level were negatively correlated with the incidence of some neurodegenerative diseases. We report here a novel mechanism by which these purine derivatives increase neuronal glutathione (GSH) synthesis. Intraperitoneal injection of caffeine or UA into male C57BL/6 mice significantly increased total GSH levels in the hippocampus. Neither SCH58261, an adenosine A2A receptor antagonist, nor rolipram, a phosphodiesterase-4 inhibitor, increased GSH levels. Pretreatment with allopurinol, a drug to inhibit UA production, did not change the GSH level in the caffeine-treated mice. Hippocampal CA1 pyramidal neurons treated with caffeine or UA were resistant to oxidant exposure in the slice culture experiments. In experiments with the SH-SY5Y cell line, cysteine uptake was sodium-dependent and pretreatment with caffeine or UA increased cysteine uptake significantly as compared with the control conditions. Slice culture experiments using the hippocampus also showed increased cysteine and GSH contents after the treatment with caffeine or UA. Immunohistochemical analysis showed increased GSH levels in the hippocampal excitatory amino acid carrier-1 (EAAC1)-positive neurons of mice treated with caffeine or UA. These findings suggest that purine derivatives caffeine and UA induce neuronal GSH synthesis by promoting cysteine uptake, leading to neuroprotection.

Dermatophyte infections in Cairo, Egypt.

In this study, we examined dermatophyte infections in patients referred to the Department of Dermatology, EL-Houd El-Marsoud Hospital, Cairo, during March 2004 to June 2005. Of 506 patients enrolled in this investigation, 403 (79.6%) were clinically diagnosed as having dermatophytoses (age range 6-70 years; males 240; females 163). Species identification determined by observation of their macroscopic and microscopic characteristics was complemented with sequencing of the internal transcribed spacer ITS1-5.8S-ITS2 rDNA region. The most common dermatophyte infection diagnosed was tinea capitis (76.4%), followed by tinea corporis (22.3%) and tinea unguium (1.2%). The most frequently isolated dermatophyte species was Trichophyton violaceum, which accounted for most (71.1%) of all the recovered dermatophytes, followed by Microsporum canis (21.09%), Trichophyton rubrum (6.2%), and Microsporum boullardii (0.49%); both Epidermophyton floccosum and Trichophyton tonsurans were each only rarely isolated (0.24%).

Aflatoxin and ochratoxin A contamination of retail foods and intake of these mycotoxins in Japan.

A survey was undertaken of aflatoxin B1 (AFB1), B2 (AFB2), G1 (AFG1), G2 (AFG2), ochratoxin A (OTA), and fumonisin B1 (FB1), B2 (FB2) and B3 (FB3) contamination of various retail foods in Japan during 2004-05. The mycotoxins were analysed by high-performance liquid chromatography (HPLC), liquid chromatography/mass spectrometry (LC/MS) or high-performance thin-layer chromatography (HPTLC). Aflatoxins (AFs) were detected in ten of 21 peanut butter and in 22 of 44 bitter chocolate samples; the highest level of AFB1, 2.59 microg kg(-1), was found in peanut butter. Aflatoxin contamination was not observed in corn products (n = 55), corn (n = 110), peanuts (n = 120), buckwheat flour (n = 23), dried buckwheat noodles (n = 59), rice (n = 83) or sesame oil (n = 20). OTA was detected in 120 out of 192 samples of oatmeal, wheat flour, rye, buckwheat flour, raw coffee, roasted coffee, raisin, beer, wine and bitter chocolate, but not in rice or corn products. OTA levels in the positive samples were below 13 microg kg(-1). AFs and OTA intakes through the consumption of foods containing cacao were estimated using the data for mycotoxin contamination in bitter chocolate and those for the consumption of foods containing cacao in Japan.

Development of advanced-type multi-functional electronic personal dosemeter.

An advanced-type small, light, multi-functional electronic personal dosemeter has been developed using silicon semiconductor radiation detectors for dose management of workers at nuclear power plants and accelerator facilities. This dosemeter is 62 x 82 x 27 mm(3) in size and approximately 130 g in weight, which is capable of measuring personal gamma ray and neutron dose equivalents, Hp(10), simultaneously. The neutron dose equivalent can be obtained using two types of silicon semiconductors: a slow-neutron sensor (<1 MeV) and a fast-neutron sensor (>1 MeV). The slow neutron sensor is a 10 x 10 mm(2) p-type silicon on which a natural boron layer is deposited around an aluminium electrode. The fast neutron sensor is also a 10 x 10 mm(2) p-type silicon crystal on which an amorphous silicon hydride is deposited. The neutron energy response corresponding to the fluence-to-dose-equivalent conversion coefficient given by ICRP Publication 74 has been evaluated using a monoenergetic neutron source from 250 keV to 15 MeV at the Fast Neutron Laboratory of Tohoku University. As the result, the Hp(10) response to neutrons in the energy range of 250 keV and 4.4 MeV within +/-50% difference has been obtained.

Development of a neutron personal dose equivalent detector.

A new neutron-measuring instrument that is intended to measure a neutron personal dose equivalent, H(p)(10) was developed. This instrument is composed of two parts: (1) a conventional moderator-based neutron dose equivalent meter and (2) a neutron shield made of borated polyethylene, which covers a backward hemisphere to adjust the angular dependence. The whole design was determined on the basis of MCNP calculations so as to have response characteristics that would generally match both the energy and angular dependencies of H(p)(10). This new instrument will be a great help in assessing the reference values of neutron H(p)(10) during field testing of personal neutron dosemeters in workplaces and also in interpreting their readings.

Development of torsade de pointes caused by exacerbation of QT prolongation during clipping of cerebral artery aneurysm in a patient with subarachnoid haemorrhage.

We report the case of a 79-yr-old woman with subarachnoid haemorrhage (SAH) in whom torsade de pointes (TdP) caused by worsening the QT prolongation occurred during clipping of cerebral artery aneurysm. This patient shows a potential risk of occurrence of life-threatening tachyarrhythmia, TdP by prolonging the QT interval during surgery in patients with SAH even with no additional factors that predispose to TdP. Therefore, a proper monitoring of the QT interval is necessary as a predictor of TdP. When ventricular tachyarrhythmia occurs, recognition of TdP is important because antiarrhythmic drug therapy for TdP is different from that for ventricular tachyarrhythmias that is not TdP.

Regulation of STAT3-mediated signaling by LMW-DSP2.

Signal transducer and activator of transcription 3 (STAT3), which mediates biological actions in many physiological processes, is activated by cytokines and growth factors, and has been reported to be constitutively activated in numerous cancer cells. In this study, we examined whether low molecular weight-dual specificity phosphatase two (LMW-DSP2) is involved in the regulation of the interleukin 6 (IL-6)/leukemia inhibitory factor (LIF)/STAT3-mediated signaling pathway. IL-6/LIF-induced LMW-DSP2 expression in murine testicular or hepatoma cell lines, while LMW-DSP2 overexpression in 293T cells suppressed IL-6-induced phosphorylation and activation of STAT3. Furthermore, LMW-DSP2 suppressed the expression of IL-6-induced endogenous genes. In contrast, small-interfering RNA-mediated reduction of LMW-DSP2 expression enhanced IL-6-induced STAT3-dependent transcription. In fact, LMW-DSP2 interacted with STAT3 in vivo and endogenous LMW-DSP2 bound to STAT3 in murine testicular GC-1 cells. These results strongly suggest that LMW-DSP2 acts as a negative regulator of the IL-6/LIF/STAT3-mediated signaling pathway.

Aging and oxidative stress in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder, which may possibly be induced by oxidative stress. However, the age-related alteration of the endogenous antioxidant system is not well understood. To better understand this, we measured Cu/Zn-superoxide dismutase (SOD), glutathione peroxidase (GPx), and 4-hydroxynonenal (HNE)-conjugated GPx in cerebrospinal fluid of PSP patients by enzyme linked immunosorbent assay. A significant increase in the Cu/Zn-SOD level was detected in PSP group compared with controls. The levels of Cu/Zn-SOD and GPx in PSP group showed positive correlations with age. Two-thirds of total GPx was present as the HNE-conjugated form with positive correlation in PSP group. In conclusion, the endogenous antioxidant system of PSP patients appears to be activated with aging, however, it might be unable to function effectively because of conjugation with HNE.