Radial Spin Texture in Elemental Tellurium with Chiral Crystal Structure.

The chiral crystal is characterized by a lack of mirror symmetry and inversion center, resulting in the inequivalent right- and left-handed structures. In the noncentrosymmetric crystal structure, the spin and momentum of electrons are expected to be locked in the reciprocal space with the help of the spin-orbit interaction. To reveal the spin textures of chiral crystals, we investigate the spin and electronic structure in a p-type semiconductor, elemental tellurium, with the simplest chiral structure by using spin- and angle-resolved photoemission spectroscopy. Our data demonstrate that the highest valence band crossing the Fermi level has a spin component parallel to the electron momentum around the Brillouin zone corners. Significantly, we have also confirmed that the spin polarization is reversed in the crystal with the opposite chirality. The results indicate that the spin textures of the right- and left-handed chiral crystals are hedgehoglike, leading to unconventional magnetoelectric effects and nonreciprocal phenomena.

Large Variation of Dirac Semimetal State in Perovskite CaIrO_{3} with Pressure-Tuning of Electron Correlation.

The impact of electron correlation on the Dirac semimetal state is investigated for perovskite CaIrO_{3} in terms of the magnetotransport properties under varying pressures. The reduction of electron correlation with a pressure of 1 GPa enhances the Fermi velocity as much as 40%, but it reduces the mobility by an order of magnitude by detuning the Dirac node from the Fermi energy. Moreover, the giant magnetoresistance at the quantum limit due to the one-dimensional confinement of Dirac electrons is critically suppressed under pressure. These results indicate that the electron correlation is a crucial knob for controlling the transport of a correlated Dirac semimetal.

Strong-correlation induced high-mobility electrons in Dirac semimetal of perovskite oxide.

Electrons in conventional metals become less mobile under the influence of electron correlation. Contrary to this empirical knowledge, we report here that electrons with the highest mobility ever found in known bulk oxide semiconductors emerge in the strong-correlation regime of the Dirac semimetal of perovskite CaIrO3. The transport measurements reveal that the high mobility exceeding 60,000 cm2V-1s-1 originates from the proximity of the Fermi energy to the Dirac node (ΔE < 10 meV). The calculation based on the density functional theory and the dynamical mean field theory reveals that the energy difference becomes smaller as the system approaches the Mott transition, highlighting a crucial role of correlation effects cooperating with the spin-orbit coupling. The correlation-induced self-tuning of Dirac node enables the quantum limit at a modest magnetic field with a giant magnetoresistance, thus providing an ideal platform to study the novel phenomena of correlated Dirac electron.

Experimental Determination of the Topological Phase Diagram in Cerium Monopnictides.

Experimental determinations of bulk band topology in the solid states have been so far restricted to only indirect investigation through the probing of surface states predicted by electronic structure calculations. We here present an alternative approach to determine the band topology by means of bulk-sensitive soft x-ray angle-resolved photoemission spectroscopy. We investigate the bulk electronic structures of the series materials, Ce monopnictides (CeP, CeAs, CeSb, and CeBi). By performing a paradigmatic study of the band structures as a function of their spin-orbit coupling, we draw the topological phase diagram and unambiguously reveal the topological phase transition from a trivial to a nontrivial regime in going from CeP to CeBi induced by the band inversion. The underlying mechanism of the phase transition is elucidated in terms of spin-orbit coupling in concert with their semimetallic band structures. Our comprehensive observations provide a new insight into the band topology hidden in the bulk states.

Inhibition of malic enzyme 1 disrupts cellular metabolism and leads to vulnerability in cancer cells in glucose-restricted conditions.

Malic enzyme 1 (ME1) regulates one of the main pathways that provide nicotinamide adenine dinucleotide phosphate (NADPH), which is essential for cancer cell growth through maintenance of redox balance and biosynthesis processes in the cytoplasm. In this study, we found that ME1 inhibition disrupted metabolism in cancer cells and inhibited cancer cell growth by inducing senescence or apoptosis. In glucose-restricted culture conditions, cancer cells increased ME1 expression, and tracer experiments with labelled glutamine revealed that the flux of ME1-derived pyruvate to citrate was enhanced. In addition, cancer cells showed higher sensitivity to ME1 depletion in glucose-restricted conditions compared to normal culture conditions. These results suggest that in a low-glucose environment, where glycolysis and the pentose phosphate pathway (PPP) is attenuated, cancer cells become dependent on ME1 for the supply of NADPH and pyruvate. Our data demonstrate that ME1 is a promising target for cancer treatment, and a strategy using ME1 inhibitors combined with inhibition of glycolysis, PPP or redox balance regulators may provide an effective therapeutic option.

Acotiamide Hydrochloride, a Therapeutic Agent for Functional Dyspepsia, Enhances Acetylcholine-induced Contraction via Inhibition of Acetylcholinesterase Activity in Circular Muscle Strips of Guinea Pig Stomach.

Acotiamide is a first-in-class prokinetic drug approved in Japan for the treatment of functional dyspepsia. Given that acotiamide enhances gastric motility in conscious dogs and rats, we assessed the in vitro effects of this drug on the contraction of guinea pig stomach strips and on acetylcholinesterase (AChE) activity in stomach homogenate following fundus removal. We also investigated the serotonin 5-HT4 receptor agonist mosapride, dopamine D2 receptor and AChE inhibitor itopride, and representative AChE inhibitor neostigmine. Acotiamide (0.3 and 1 µM) and itopride (1 and 3 µM) significantly enhanced the contraction of gastric body strips induced by electrical field stimulation (EFS), but mosapride (1 and 10 µM) did not. Acotiamide and itopride significantly enhanced the contraction of gastric body and antrum strips induced by acetylcholine (ACh), but not that induced by carbachol (CCh). Neostigmine also significantly enhanced the contraction of gastric body strips induced by ACh, but not that by CCh. In contrast, mosapride failed to enhance contractions induced by either ACh or CCh in gastric antrum strips. Acotiamide exerted mixed inhibition of AChE, and the percentage inhibition of acotiamide (100 µM) against AChE activity was markedly reduced after the reaction mixture was dialyzed. In contrast, itopride exerted noncompetitive inhibition on AChE activity. These results indicate that acotiamide enhances ACh-dependent contraction in gastric strips of guinea pigs via the inhibition of AChE activity, and that it exerts mixed and reversible inhibition of AChE derived from guinea pig stomach.

Highly reversible capacity at the surface of a lithium-rich manganese oxide: a model study using an epitaxial film system.

Epitaxial films of Li2MnO3 were synthesized using pulsed laser deposition. A 12.6 nm film exhibited a high discharge capacity of over 300 mA h g(-1) following its fiftieth cycle and better stability than 29.8 and 47.8 nm films. The surfaces of such films are intrinsically active at the electrochemical interface.

Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer.

Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4-8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

Early use of allogeneic hematopoietic stem cell transplantation for infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia.

Sixty-two infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia (MLL-r ALL) were treated with the MLL03 protocol of the Japanese Pediatric Leukemia/Lymphoma Study Group: short-course intensive chemotherapy followed by early allogeneic hematopoietic stem cell transplantation (HSCT) within 4 months of the initial induction. The 4-year event-free survival and overall survival rates were 43.2% (95% confidence interval (CI)=30.7-55.1%) and 67.2% (53.8-77.4%), respectively. A univariate analysis showed younger age (<90 days at diagnosis), central nervous system disease and poor response to initial prednisolone therapy significantly associated with poor prognosis (P<0.05). In a multivariate analysis, younger age at diagnosis tended to be associated with poor outcome (hazard ratio=1.969; 95% CI=0.903-4.291; P=0.088). Although the strategy of early use of HSCT effectively prevented early relapse and was feasible for infants with MLL-r ALL, the fact that substantial number of patients still relapsed even though transplanted in their first remission indicates the limited efficacy of allogeneic HSCT for infants with MLL-r ALL. Considering the risk of severe late effects, indications for HSCT should be restricted to specific subgroups with poor risk factors. An alternative approach incorporating molecular-targeted drugs should be established.

Efficacy of azithromycin in preventing lethal graft-versus-host disease.

Acute graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation (BMT) is initiated by donor T lymphocytes that recognize histocompatibility antigens presented by recipient dendritic cells (DCs). Current approaches to reduce GVHD are focused on suppressing donor T lymphocyte responses to alloantigens. However, these strategies may be inadequate in the setting of allogeneic transplants (particularly histoincompatible transplants), may increase the risk of tumour relapse and are associated with high rates of opportunistic infections. We hypothesized that inhibition of recipient DCs might suppress GVHD. We recently demonstrated in vitro that azithromycin, a macrolide antibiotic, also acts as a nuclear factor (NF)-κB inhibitor of murine DCs and inhibits their maturation and functions, including allogeneic responses. We investigated whether azithromycin could prevent alloreactions in a murine histoincompatibility model. Oral administration of azithromycin to recipient mice for 5 days during major-histoincompatible BMT suppressed lethal GVHD significantly, whereas ex-vivo lymphocyte function was not affected by the drug. These data suggest that azithromycin has potential as a novel prophylactic drug for lethal GVHD.

Efficacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study.

AIMS: To evaluate the efficacy and safety of alogliptin added to metformin versus metformin monotherapy in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on metformin (500 or 750 mg/day) + diet/exercise. METHODS: In a randomized, double-blind trial, 288 patients with type 2 diabetes mellitus T2DM received either 12.5 or 25 mg alogliptin once daily + metformin or placebo + metformin for 12 weeks. Thereafter, 276 patients continued on one of the two alogliptin dosages + metformin in an open-label extension for 40 weeks. The primary efficacy endpoint in the randomized, double-blind phase was the change in HbA1c from baseline (week 0) to the end of treatment (week 12). The primary endpoint during the long-term extension phase was adverse events. RESULTS: After 12 weeks both dosages of alogliptin + metformin produced significantly greater changes from baseline in HbA1c than placebo (metformin monotherapy: with changes in LS means - 0.55 and - 0.64% vs. 0.22%, respectively; p < 0.0001). Incidences of adverse effects were comparable between groups, with no increases in hypoglycaemia. Over 52 weeks, there were no safety or tolerability concerns with alogliptin when added to metformin. CONCLUSIONS: Alogliptin 12.5 and 25 mg once daily was safe and effective when added to metformin (500 or 750 mg/day) in Japanese patients with inadequately controlled type 2 diabetes on metformin alone.

Widespread cortical and subcortical brain atrophy in Parkinson's disease with excessive daytime sleepiness.

Our aim was to determine regional brain atrophy in Parkinson's disease (PD) patients with excessive daytime sleepiness (EDS) using voxel-based morphometry (VBM). From 71 consecutive probable PD patients, nine non-demented and non-hallucinating patients with an Epworth Sleepiness Scale (ESS) ≥ 10 and 13 PD patients with an ESS ≤ 3 were selected as having EDS and as not having EDS, respectively. We also enrolled 22 healthy age- and sex-matched controls. Regional brain atrophy was assessed using VBM with 3-T magnetic resonance imaging. There was no difference in the dosage of dopaminergic drugs between PD patients with EDS and PD patients without EDS. PD patients with EDS showed marked atrophy in the gray matter of the frontal lobe, temporal lobe, occipital lobe, limbic lobe including the nucleus basalis of Meynert compared to controls (false discovery rate corrected p < 0.05). In contrast, PD patients without EDS did not show any significant difference in gray matter atrophy compared to controls (false discovery rate corrected p < 0.05). PD patients with EDS showed significant atrophy of the frontal lobe, temporal lobe, occipital lobe, limbic lobe including the nucleus basalis of Meynert compared to PD patients without EDS (uncorrected p < 0.001). PD patients with EDS, even without dementia and hallucination, showed significant gray matter atrophy compared to PD patients without EDS and controls.

Changes in beef sensory traits as somatic-cell-cloned Japanese black steers increased in age from 20 to 30 months.

Changes in sensory traits of longissimus muscle (LM) from 20-30-month-old cattle were investigated using somatic cell clones of Japanese black steers slaughtered at 20-, 25- and 30-months-old (n=3, 4 and 4 respectively). The fat content of LM samples at 20, 25 and 30 months were 23.7, 38.7 and 41.1%, respectively. Soluble collagen content and collagen solubility at 20 months was greater than at 25 and 30 months. In terms of sensory traits, initial tenderness and juiciness at 25 months was greater than at 20 months, and fattiness at 25 and 30 months was greater than at 20 months. These results demonstrate that the changes in physicochemical traits of beef accompanying the differences in slaughter age affect the sensory traits although the desirable effects of the sensory traits do not continue throughout the entire fattening period.

GPR40-induced insulin secretion by the novel agonist TAK-875: first clinical findings in patients with type 2 diabetes.

AIM: Free fatty acids act as signalling molecules for modulating insulin secretion, and their insulinotropic effects are glucose-dependent and mediated through G protein-coupled receptor 40 (GPR40). This mechanism is a potential target for new treatments for managing diabetes. In this study, we present the first clinical data for TAK-875, a novel highly selective, orally bioavailable GPR40 agonist, in Japanese patients with type 2 diabetes insufficiently controlled by diet or exercise therapy. METHODS: This was an exploratory phase II, multicentre, randomized, double-blind, parallel group study comparing the efficacy and tolerability of TAK-875 100 and 400 mg, and placebo, all administered once daily for 2 weeks. RESULTS: After 2 weeks of treatment, TAK-875 produced marked glucose lowering effects in a 75 g oral glucose tolerance test (OGTT) as evidenced by mean ± SE intergroup differences in plasma glucose AUC(0-3 h) of -12.98 ± 1.48 (p < 0.0001) and -8.12 ± 1.49 mmol·h/l (p < 0.0001), for TAK-875 400 mg vs. placebo and TAK-875 100 mg vs. placebo, respectively, and 2 h plasma glucose [-4.95 ± 0.71 (p < 0.0001) and -3.21 ± 0.71 mmol/l (p < 0.0001), respectively]. This was accompanied by a significant increase in insulin AUC(0-3 h) [34.68 ± 12.16 (p < 0.01) and 31.49 ± 12.20 (p < 0 · 05) µIU·h/ml, respectively]. Improvement in glycaemic profile was mirrored by a significant change in fasting plasma glucose [-2.37 ± 0·27 (p < 0.0001) and -1.88 ± 0.27 mmol/l (p < 0.0001), respectively]. No cases of hypoglycaemia were observed despite the significant reduction in plasma glucose. CONCLUSIONS: These exploratory findings provide evidence of the glucose-dependent insulinotropic potential of the GPR40 agonist TAK-875, and the promising clinical changes support future longer term clinical investigation.

The effect of azithromycin on the maturation and function of murine bone marrow-derived dendritic cells.

Dendritic cells (DCs) are professional antigen-presenting cells capable of initiating primary/adaptive immune responses and tolerance. DC functions are regulated by their state of maturation. However, the molecular pathways leading to DC development and maturation remain poorly understood. We attempted to determine whether inhibition of nuclear factor kappa B (NF-κB), which is one of the pivotal pathways underlying these processes, could induce immunophenotypic and functional changes in lipopolysaccharide-induced mature DCs derived from murine bone marrow. A comparative in vitro study of five clinically used drugs that are known to inhibit NF-κB demonstrated that azithromycin, a macrolide antibiotic, significantly inhibited expression of co-stimulatory molecules (CD40 and CD86) and major histocompatibility complex (MHC) class II by DCs. It also reduced Toll-like receptor 4 expression, interleukin-12 production and the allostimulatory capacity of DCs. These data suggest that azithromycin, as not only an NF-κB inhibitor but also an antibiotic, has potential as a novel drug for manipulation of allogeneic responses.

Anti-MuSK autoantibodies block binding of collagen Q to MuSK.

OBJECTIVE: Muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) accounts for 5%-15% of autoimmune MG. MuSK mediates the agrin-signaling pathway and also anchors the collagenic tail subunit (ColQ) of acetylcholinesterase (AChE). The exact molecular target of MuSK-immunoglobulin G (IgG), however, remains elusive. As acetylcholine receptor (AChR) deficiency is typically mild and as cholinesterase inhibitors are generally ineffective, we asked if MuSK-IgG interferes with binding of ColQ to MuSK. METHODS: We used 3 assays: in vitro overlay of the human ColQ-tailed AChE to muscle sections of Colq-/- mice; in vitro plate-binding assay to quantitate binding of MuSK to ColQ and to LRP4; and passive transfer of MuSK-IgG to mice. RESULTS: The in vitro overlay assay revealed that MuSK-IgG blocks binding of ColQ to the neuromuscular junction. The in vitro plate-binding assay showed that MuSK-IgG exerts a dose-dependent block of MuSK binding to ColQ by but not to LRP4. Passive transfer of MuSK-IgG to mice reduced the size and density of ColQ to ∼10% of controls and had a lesser effect on the size and density of AChR and MuSK. CONCLUSIONS: As lack of ColQ compromises agrin-mediated AChR clustering in Colq-/- mice, a similar mechanism may lead to AChR deficiency in MuSK-MG patients. Our experiments also predict partial AChE deficiency in MuSK-MG patients, but AChE is not reduced in biopsied NMJs. In humans, binding of ColQ to MuSK may be dispensable for clustering ColQ, but is required for facilitating AChR clustering. Further studies will be required to elucidate the basis of this paradox.