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Search Results: 1 - 10 of 1218 matches for " Keiko Doi "
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Inhibition of Phosphodiesterase-4 (PDE4) activity triggers luminal apoptosis and AKT dephosphorylation in a 3-D colonic-crypt model
Tsunoda Toshiyuki,Ota Takeharu,Fujimoto Takahiro,Doi Keiko
Molecular Cancer , 2012, DOI: 10.1186/1476-4598-11-46
Abstract: Background We previously established a three-dimensional (3-D) colonic crypt model using HKe3 cells which are human colorectal cancer (CRC) HCT116 cells with a disruption in oncogenic KRAS, and revealed the crucial roles of oncogenic KRAS both in inhibition of apoptosis and in disruption of cell polarity; however, the molecular mechanism of KRAS-induced these 3-D specific biological changes remains to be elucidated. Results Among the genes that were upregulated by oncogenic KRAS in this model, we focused on the phosphodiesterase 4B (PDE4B) of which expression levels were found to be higher in clinical tumor samples from CRC patients in comparison to those from healthy control in the public datasets of gene expression analysis. PDE4B2 was specifically overexpressed among other PDE4 isoforms, and re-expression of oncogenic KRAS in HKe3 cells resulted in PDE4B overexpression. Furthermore, the inhibition of PDE4 catalytic activity using rolipram reverted the disorganization of HCT116 cells into the normal physiologic state of the epithelial cell polarity by inducing the apical assembly of ZO-1 (a tight junction marker) and E-cadherin (an adherens junction marker) and by increasing the activity of caspase-3 (an apoptosis marker) in luminal cavities. Notably, rolipram reduced the AKT phosphorylation, which is known to be associated with the disruption of luminal cavity formation and CRC development. Similar results were also obtained using PDE4B2-shRNAs. In addition, increased expression of PDE4B mRNA was found to be correlated with relapsed CRC in a public datasets of gene expression analysis. Conclusions These results collectively suggested that PDE4B is upregulated by oncogenic KRAS, and also that the inhibition of PDE4 catalytic activity can induce both epithelial cell polarity and luminal apoptosis in CRC, thus highlighting the utility of our 3-D culture (3 DC) model for the KRAS-induced development of CRC in 3-D microenvironment. Indeed, using this model, we found that PDE4B is a promising candidate for a therapeutic target as well as prognostic molecular marker in CRC. Further elucidation of the signaling network of PDE4B2 in 3 DC would provide a better understanding of CRC in vivo.
Random Z(2) Higgs Lattice Gauge Theory in Three Dimensions and its Phase Structure
Shunsuke Doi,Ryosuke Hamano,Teppei Kakisako,Keiko Takada,Tetsuo Matsui
Physics , 2009,
Abstract: We study the three-dimensional random Z(2) lattice gauge theory with Higgs field, which has the link Higgs coupling $c_1 SUS$ and the plaquette gauge coupling $c_2 UUUU$. The randomness is introduced by replacing $c_1 \to -c_1$ for each link with the probability $p_1$ and $c_2 \to -c_2$ for each plaquette with the probability $p_2$. We calculate the phase diagram by a new kind of mean field theory that does not assume the replica symmetry and also by Monte Carlo simulations. For the case $p_1=p_2(\equiv p)$, the Monte Carlo simulations exhibit that (i) the region of the Higgs phase in the Coulomb-Higgs transition diminishes as $p$ increases, and (ii) the first-order phase transition between the Higgs and the confinement phases disappear for $p \ge p_c \simeq 0.01$. We discuss the implications of the results to the quantum memory studied by Kitaev et al. and the Z(2) gauge neural network on a lattice.
Coupled channel approach to strangeness S = -2 baryon-bayron interactions in Lattice QCD
Kenji Sasaki,Sinya Aoki,Takumi Doi,Tetsuo Hatsuda,Yoichi Ikeda,Takashi Inoue,Noriyoshi Ishii,Keiko Murano
Physics , 2015, DOI: 10.1093/ptep/ptv144
Abstract: The baryon-baryon interactions with strangeness S = -2 with the flavor SU(3) breaking are calculated for the first time by using the HAL QCD method extended to coupled channel system in lattice QCD. The potential matrices are extracted from the Nambu-Bethe-Salpeter wave functions obtained by the 2+1 flavor gauge configurations of CP-PACS/JLQCD Collaborations with a physical volume of 1.93 fm cubed and with m_pi/m_K = 0.96, 0.90, 0.86. The spatial structure and the quark mass dependence of the potential matrix in the baryon basis and in the SU(3) basis are investigated.
Flows of a Rarefied Gas between Coaxial Circular Cylinders with Nonuniform Surface Properties  [PDF]
Toshiyuki Doi
Open Journal of Fluid Dynamics (OJFD) , 2019, DOI: 10.4236/ojfd.2019.91002
Abstract: Flows of a rarefied gas between coaxial circular cylinders with nonuniform surface properties are studied on the basis of kinetic theory. It is assumed that the outer cylinder is a diffuse reflection boundary and the inner cylinder is a Maxwell-type boundary whose accommodation coefficient varies in the circumferential direction. Three fundamental flows are studied: 1) a flow caused by the rotation of the outer cylinder (Couette flow), 2) a flow induced between the cylinders at rest kept at different temperatures (heat transfer problem), and 3) a flow induced by the circumferential temperature distribution along the cylindrical surfaces (thermal creep flow). The linearized ES-BGK model of the Boltzmann equation is numerically analyzed using a finite difference method. The time-independent behavior of the gas is studied over a wide range of the gas rarefaction degree, the radii ratio, and a parameter characterizing the distribution of the accommodation coefficient. Due to an effect of nonuniform surface properties, a local heat transfer occurs between the gas and the cylindrical surfaces in Couette flow; a local tangential stress arises in the heat transfer problem. However, the total heat transfer between the two cylinders in Couette flow and the total torque acting on the inner cylinder in the heat transfer problem vanish irrespective of the flow parameters. Two nondegenerate reciprocity relations arise due to the effect of nonuniform surface properties. The reciprocity relations among the above-mentioned three flows are numerically confirmed over a wide range of the flow parameters. The force on the inner cylinder, which also arises due to the effect of nonuniform surface properties in Couette flow and the heat transfer problems, is studied.
NSC-induced D-neurons are decreased in striatum of schizophrenia: Possible cause of mesolimbic dopamine hyperactivity  [PDF]
Keiko Ikemoto
Stem Cell Discovery (SCD) , 2012, DOI: 10.4236/scd.2012.22009
Abstract: Neural stem cell (NSC) hypofunction is an etiological hypothesis of schizophrenia. Although dopamine (DA) dysfunction is also a widely accepted hypothesis, molecular background of mesolimbic DA hyperactivity has not yet been well known. Here, the author proposes “D-cell hypothesis”, accounting for molecular basis of mesolimbic DA hyperactivity of schizophrenia, by NSC hypofunction and decrease of putative NSC-induced D-cells. The “D-cell” is defined as “non-monoaminergic aromatic L-amino acid decarboxylase (AADC)-containing cell”. D-cells produce trace amines, and also take up amine precursors and convert them to amines by decarboxylation. The author reported “dopa-decarboxylating neurons specific to the human striatum”, that is, “D-neurons” in the human striatum, and decrease of striatal D-neurons in patients with schizophrenia. Trace amine-associated receptor, type 1 (TAAR1), a subtype of trace amine receptors, having a quite number of ligands such as tyramine, β-phenylethylamine (PEA) and methamphetamine, has modulating functions on monoamine neurons. It has been known that reduced binding of ligands to TAAR1 receptors on DA terminal of DA neurons of the midbrain ventral tegmental area (VTA) increased firing frequency of VTA DA neurons. In brains of schizophrenia, NSC hypofunction in the subventricular zone of lateral ventricle may cause decrease of D-neurons in the striatum and nucleus accumbens, and may result in decrease of trace amine signals. Decrease of trace amine signals to TAAR1 on VTA DA neurons may increase firing frequency of VTA DA neurons, and may finally cause mesolimbic DA hyperactivity. Increased stimulation to DA D2 receptors of NSCs might suppress NSC proliferation, and may induce additional mesolimbic DA hyperactivity as well as D-cell decrease. This novel theory, “D-cell hypothesis”, possibly explains mesolimbic DA hyperactivity in pathogenesis of schizophrenia.
D-Cell Hypothesis: Pathogenesis of Mesolimbic Dopamine Hyperactivity of Schizophrenia  [PDF]
Keiko Ikemoto
Journal of Behavioral and Brain Science (JBBS) , 2012, DOI: 10.4236/jbbs.2012.23048
Abstract: In the present article, the author proposes a new “D-cell hypothesis” for mesolimbic dopamine (DA) hyperactivity of schizophrenia, of which relevant molecular mechanism has not yet been known. The “D-cell” is defined as “the non-monoaminergic aromatic L-amino acid decarboxylase (AADC)-containing cell”. The D-cell contains AADC but not dopaminergic nor serotonergic. D-cells produce trace amines, and also take up amine precursors and convert them to amines by decarboxylation. The author reported “dopa-decarboxylating neurons specific to the human striatum”, that is, “D-neurons” in the human striatum, and preliminarily the number reduction of D-neurons in the striatum and nucleus accumbens of postmortem brains of patients with schizophrenia. Trace amine-associated receptor, type 1 (TAAR1), a subtype of trace amine receptors, having a large number of ligands, including tyramine, β-phenylethylamine (PEA), and methamphetamine, is a target receptor for the latest neuroleptic discovery. Recent studies have shown that the decreased stimulation of TAAR1 on cell membranes or nerve terminals of DA neurons in the midbrain ventral tegmental area (VTA) increased firing frequency of VTA DA neurons. In brains of schizophrenia, dysfunction of neural stem cells in the subventricular zone of lateral ventricle may cause reduction of the number of D-neurons in the striatum and nucleus accumbens, and may result in decrease of trace amine synthesis. The decrease of stimulation of TAAR1 on terminals of VTA DA neurons caused by trace amine reduction may increase firing frequency of VTA DA neurons, and may finally cause mesolimbic DA hyperactivity. This innovative theory, “D-cell hypothesis” might explain mesolimbic DA hyperactivity in pathogenesis of schizophrenia.
“D-cell hypothesis” of schizophrenia: possible theory for mesolimbic dopamine hyperactivity  [PDF]
Keiko Ikemot
World Journal of Neuroscience (WJNS) , 2012, DOI: 10.4236/wjns.2012.23021
Abstract: The author proposes a new “D-cell hypothesis” for mesolimbic dopamine (DA) hyperactivity of schizophrenia. The “D-cell” is defined as “non-monoaminergic aromatic L-amino acid decarboxylase (AADC)-containing cell”. D-cells produce trace amines, such as tyramine and β-phenylethylamine, and may also take up amine precursors and convert them to amines by decarboxylation. Trace amine-associated receptor, type 1 (TAAR1), a subtype of trace amine receptors, has a large number of ligands, including tyramine, β-phenylethylamine and methamphetamine, that influence on human mental states, and is now regarded to be a target receptor for novel neuroleptics. Recent studies revealed that the reduced stimulation of TAAR1 on DA neurons in the midbrain ventral tegmental area (VTA) increased firing frequency of VTA DA neurons. The author and her colleagues reported the decrease of D-neurons in the striatum and nucleus accumbens of postmortem brains of patients with schizophrenia. This may imply the decrease of trace amine synthesis, resulting the reduced stimulation of TAAR1 on terminals of midbrain VTA DA neurons, and may lead to mesolimbic DA hyperactivity in schizophrenia. The decrease of striatal D-neurons of postmortem brains of schizophrenia is supposed to be due to neural stem cell dysfunction in the subventricular zone of lateral ventricle. The decrease of striatal D-neurons and acts of TAAR1 signals on DA neurons-might explain mesolimbic DA hyperactivity of schizophrenia.
Why D-neuron? Importance in schizophrenia research  [PDF]
Keiko Ikemoto
Open Journal of Psychiatry (OJPsych) , 2012, DOI: 10.4236/ojpsych.2012.224055
Abstract: Recent pharmacological discovery on trace amine-associated receptor, type 1(TAAR1) has emphasized importance of trace amines in pathogenesis of psychoses, such as schizophrenia. TAAR1 has many ligands, including tyramine, β-phenylethylamine (PEA), amphetamines, and 3’-iodothyronamine. So-called D-neurons are putative producer of trace amines, endogenous ligands of TAAR1. The D-neuron is defined “the aromatic L-amino acid decarboxylase (AADC)-containing neuron, but not dopaminergic nor serotonergic”, i.e. not containing tyrosine hydroxylase nor tryptophan hydroxylase. AADC is an enzyme, also called dopa decarboxylase (DDC). The localization of D-neurons in the central nervous system has been specified into 15 groups, from the spinal cord (D1) to striatum (D15). We showed the decrease of D-neurons in D15 in postmortem brains of schizophrenia, where midbrain dopamine (DA) neurons are heavily innervated. Decrease of D-neurons may cause reduction of trace amines in the striatum, and may also decrease stimulation of TAAR1 on striatal terminals of ventral tegmental area (VTA) DA neurons. This might increase firing frequency of VTA DA neurons, and causes DA hyperactivity in the striatum and nucleus accumbens. In the present article, the author introduces the novel theory, “D-cell hypothesis”, for mesolimbic DA hyperactivity of schizophrenia. Some clinical and/or experimental evidences that support this hypothesis are mentioned. The D-neuron, as a trace amine producer, is a clue for elucidating pathogenesis of psychoses, as well as human mental functions. Thus, signal transduction of D-neurons should be investigated.
Altered Energy Homeostasis and Resistance to Diet-Induced Obesity in KRAP-Deficient Mice
Takahiro Fujimoto, Kyoko Miyasaka, Midori Koyanagi, Toshiyuki Tsunoda, Iwai Baba, Keiko Doi, Minoru Ohta, Norihiro Kato, Takehiko Sasazuki, Senji Shirasawa
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004240
Abstract: Obesity and related metabolic disorders have become leading causes of adult morbidity and mortality. KRAP (Ki-ras-induced actin-interacting protein) is a cytoskeleton-associated protein and a ubiquitous protein among tissues, originally identified as a cancer-related molecule, however, its physiological roles remain unknown. Here we demonstrate that KRAP-deficient (KRAP?/?) mice show enhanced metabolic rate, decreased adiposity, improved glucose tolerance, hypoinsulinemia and hypoleptinemia. KRAP?/? mice are also protected against high-fat diet-induced obesity and insulin resistance despite of hyperphagia. Notably, glucose uptake in the brown adipose tissue (BAT) in KRAP?/? mice is enhanced in an insulin-independent manner, suggesting that BAT is involved in altered energy homeostasis in KRAP?/? mice, although UCP (Uncoupling protein) expressions are not altered. Of interest is the down-regulation of fatty acid metabolism-related molecules, including acetyl-CoA carboxylase (ACC)-1, ACC-2 and fatty acid synthase in the liver of KRAP?/? mice, which could in part account for the metabolic phenotype in KRAP?/? mice. Thus, KRAP is a novel regulator in whole-body energy homeostasis and may be a therapeutic target in obesity and related diseases.
Extraction of Hadron Interactions above Inelastic Threshold in Lattice QCD
Sinya Aoki,Noriyoshi Ishii,Takumi Doi,Tetsuo Hatsuda,Yoichi Ikeda,Takashi Inoue,Keiko Murano,Hidekatsu Nemura,Kenji Sasaki
Physics , 2011, DOI: 10.2183/pjab.87.509
Abstract: We propose a new method to extract hadron interactions above inelastic threshold from the Nambu-Bethe-Salpter amplitude in lattice QCD. We consider the scattering such as $A+B\rightarrow C+D$, where $A,B,C,D$ are names of different 1-particle states. An extension to cases where particle productions occur during scatterings is also discussed.
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