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Atsushi Doi

Publications and source records attributed to Atsushi Doi.

30 records · Page 2Linked to original sources
PubMed2004

Constructing biological pathway models with hybrid functional Petri nets.

In many research projects on modeling and analyzing biological pathways, the Petri net has been recognized as a promising method for representing biological pathways. From the pioneering works by Reddy et al., 1993, and Hofestädt, 1994, that model metabolic pathways by traditional Petri net, several enhanced Petri nets such as colored Petri net, stochastic Petri net, and hybrid Petri net have been used for modeling biological phenomena. Recently, Matsuno et al., 2003b, introduced the hybrid functional Petri net (HFPN) in order to give a more intuitive and natural modeling method for biological pathways than these existing Petri nets. Although the paper demonstrates the effectiveness of HFPN with two examples of gene regulation mechanism for circadian rhythms and apoptosis signaling pathway, there has been no detailed explanation about the method of HFPN construction for these examples. The purpose of this paper is to describe method to construct biological pathways with the HFPN step-by-step. The method is demonstrated by the well-known glycolytic pathway controlled by the lac operon gene regulatory mechanism.

Adenosine Diphosphate↗
PubMed2003

Actions of noradrenaline on substantia gelatinosa neurones in the rat spinal cord revealed by in vivo patch recording.

To elucidate the mechanisms of antinociception mediated by the descending noradrenergic pathway in the spinal cord, the effects of noradrenaline (NA) on noxious synaptic responses of substantia gelatinosa (SG) neurones, and postsynaptic actions of NA were investigated in rats using an in vivo whole-cell patch-clamp technique. Under urethane anaesthesia, the rat was fixed in a stereotaxic apparatus after the lumbar spinal cord was exposed. In the current-clamp mode, pinch stimuli applied to the ipsilateral hindlimb elicited a barrage of EPSPs, some of which initiated an action potential. Perfusion with NA onto the surface of the spinal cord hyperpolarized the membrane (5.0-9.5 mV) and suppressed the action potentials. In the voltage-clamp mode (V(H), -70 mV), the application of NA produced an outward current that was blocked by Cs(+) and GDP-beta-S added to the pipette solution and reduced the amplitude of EPSCs evoked by noxious stimuli. Under the blockade of postsynaptic actions of NA, a reduction of the evoked and spontaneous EPSCs of SG neurones was still observed, thus suggesting both pre- and postsynaptic actions of NA. The NA-induced outward currents showed a clear dose dependency (EC(50), 20 microM), and the reversal potential was -88 mV. The outward current was mimicked by an alpha(2)-adrenoceptor agonist, clonidine, and suppressed by an alpha(2)-adrenoceptor antagonist, yohimbine, but not by alpha(1)- and beta-antagonists. These findings suggest that NA acts on presynaptic sites to reduce noxious stimuli-induced EPSCs, and on postsynaptic SG neurones to induce an outward current by G-protein-mediated activation of K(+) channels through alpha(2)-adrenoceptors, thereby producing an antinociceptive effect.

Adrenergic alpha-Agonists↗
PubMed2003

An unusual case of primary effusion lymphoma in a HIV-negative patient not pathogenetically associated with HHV8.

The development of an unusual case of primary pleural effusion in a 90-year-old human immunodeficiency virus (HIV)-negative Japanese woman with no identifiable tumor mass has been described. Pleural effusion specimens contained large diffuse lymphoma cells, with the phenotype and genotype of a B-cell lineage (positive for CD20, CD79a and clonal rearrangement of Ig heavy chain) and the c-myc gene rearrangement, but were negative for T-cell markers (CD45RO and CD3). The patient was negative for human herpes virus 8 (HHV8), Epstein-Barr virus (EBV) and hepatitis C virus (HCV), as well as human T-cell lymphotropic virus type-1 (HTLV-1). The patient died of respiratory failure 5 months after the diagnosis of primary effusion lymphoma (PEL), and an autopsy was performed. Autopsy findings revealed no evidence of tumor mass or bone marrow involvement of lymphoma cells. This case has been considered as a PEL in a HIV-, HHV8-, EBV- and HCV-negative patient. Although cytomorphology of lymphoma cells was classified as large-cell lymphoma in this case, it is interesting that the present case may represent an unusual subset of Burkitt-like disease because of clear B-cell phenotype and c-myc gene rearrangement.

Aged↗
PubMed2003

Biopathways representation and simulation on hybrid functional Petri net.

The following two matters should be resolved in order for biosimulation tools to be accepted by users in biology/medicine: (1) remove issues which are irrelevant to biological importance, and (2) allow users to represent biopathways intuitively and understand/manage easily the details of representation and simulation mechanism. From these criteria, we firstly define a novel notion of Petri net called Hybrid Functional Petri Net (HFPN). Then, we introduce a software tool, Genomic Object Net, for representing and simulating biopathways, which we have developed by employing the architecture of HFPN. In order to show the usefulness of Genomic Object Net for representing and simulating biopathways, we show two HFPN representations of gene regulation mechanisms of Drosophila melanogaster (fruit fly) circadian rhythm and apoptosis induced by Fas ligand. The simulation results of these biopathways are also correlated with biological observations. The software is available to academic users from http://www.GenomicObject.Net/.

Animals↗
PubMed2003

Genomic Object Net: I. A platform for modelling and simulating biopathways.

Genomic Object Net (GON) 1.0 is a software package for creating models and simulations of biopathways. Its core architecture employs the notion of a hybrid functional Petri net with extension (HFPNe). HFPNe can seamlessly handle discrete and continuous objects and events while keeping the model components themselves simple. With the feature and graphical model editor, biopathways can be modelled intuitively and simulated on GON. The subsequent output of the simulation results can be evaluated in customised views on GON Visualizer by writing an XML file. Additionally, GON provides a tool to transform biopathway models in KEGG and BioCyc to the GON XML files for modelling and simulation. The tool avoids a lot of tedious work by users, enabling them to focus on the biological model.

Cell Physiological Phenomena↗
PubMed2002

Aconitine facilitates spontaneous transmitter release at rat ventromedial hypothalamic neurons.

The effects of aconitine, an Aconitum alkaloid, on spontaneous inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs respectively) were investigated in the mechanically dissociated rat ventromedial hypothalamic (VMH) neurons in which native presynaptic nerve terminals remained intact. Under current-clamp conditions, aconitine (3 x 10(-6) M) depolarized the neuron with generating the action potentials. The aconitine-induced depolarization was markedly suppressed in the presence of CNQX but it was facilitated in the presence of bicuculline, suggesting that release of excitatory and inhibitory neurotransmitters may be involved in the aconitine action in addition to its direct action on postsynaptic membrane. Under the voltage-clamp conditions, aconitine reversibly increased the frequency of spontaneous IPSC and EPSC frequency, but it did not alter their amplitude distribution. Tetrodotoxin (TTX, 3 x 10(-7) M) completely abolished the aconitine action on spontaneous IPSC frequency. Likewise removal of extracellular Na(+) completely suppressed the aconitine action. Both Ca(2+)-free external solution or addition of 10(-4) M Cd(2+) to normal solutions eliminated the facilitatory effect of aconitine on the IPSC frequency. Overall these results suggest that aconitine depolarizes the presynaptic membrane by activating voltage-dependent Na(+) channels. Increase of intraterminal Ca(2+) concentration via an activation of voltage-dependent Ca(2+) channels in turn enhances the spontaneous transmitter release from presynaptic nerve terminals. The presynaptic action of aconitine may play a crucial role for membrane excitability of rat VMH neurons.

Aconitine↗
PubMed2002

An electrophysiological study of muscarinic and nicotinic receptors of rat paratracheal ganglion neurons and their inhibition by Z-338.

1. To study the mechanisms involved in the action of Z-338, a newly synthesized gastroprokinetic agent, experiments were performed with the paratracheal ganglion cells acutely dissociated from 2-week-old Wistar rats. The effects of Z-338 on both nicotinic and muscarinic responses of the ganglion cells were studied by nystatin perforated patch recording configuration under the current- and voltage-clamp conditions. 2. Acetylcholine (ACh) or nicotine, and muscarine or oxotremorine-M (OX-M) induced membrane depolarization with rapid and slow time courses respectively, followed by repetitive generation of action potentials in the ganglion cell. Corresponding to the membrane depolarization induced by cholinergic agents, ACh induced biphasic inward currents with rapid and slow time courses under the voltage-clamp condition. Nicotine and muscarine or OX-M evoked inward currents with rapid and slow time courses, respectively. The rapid and slow inward currents were accompanied by increase and decrease in the membrane conductance, respectively. In addition, OX-M dose-dependently suppressed the M-type K(+) current evoked in response to hyperpolarizing voltage-steps from V(H) of -25 mV to -50 mV, indicating that the activation of muscarinic acetylcholine receptors inhibits M-type K(+) current, thus inducing inward current in the ganglion cell. 3. Z-338 competitively suppressed the inward currents induced by OX-M through M(1) ACh receptor, and uncompetitively suppressed the currents induced by nicotine. 4. The inhibitory actions of Z-338 on the membrane depolarization and corresponding inward currents mediated by M(1)-muscarinic and neuronal nicotinic ACh receptors in the isolated ganglion cells were discussed in relation to the inhibitory actions on autoreceptors in the parasympathetic nerve terminals, which would explain the gastroprokinetic actions of Z-338.

Animals↗
PubMed2002

Na(+)/Ca(2+) exchanger in GABAergic presynaptic boutons of rat central neurons.

Rat Meynert neurons were acutely isolated using a dissociation technique that maintains functional GABAergic presynaptic boutons. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded under voltage-clamp conditions using whole cell patch-clamp recordings. Using the frequency of mIPSCs as a measure of presynaptic terminal excitability, the existence of a Na(+)/Ca(2+) exchanger (NCX) in these GABAergic nerve terminals was clearly demonstrated. Both the frequency and the amplitude of mIPSCs were unaffected by replacement of extracellular Na(2+). However, in this Na(+)-free external solution, ouabain could now induce a transient increase of mIPSCs frequency, which was not inhibited by adding Cd(2+) or cyclopiazonic acid but was inhibited by removing external Ca(2+). This indicates that this transient potentiation was dependent on external Ca(2+), but that this Ca(2+) influx was not via voltage-dependent Ca(2+) channels. KB-R7943, an inhibitor of NCX, at a concentration of 3 x 10(-6) M, reduced this transient increase of mIPSCs frequency without affecting mIPSCs amplitude and the response to exogenous GABA. These results demonstrate the existence of NCX in these GABAergic nerve terminals. In zero external Na(+), ouabain causes an accumulation of intraterminal Na(+) and a resultant influx of Ca(2+) through the reversed mode operation of NCX. However, under more physiological conditions, NCX may also operate in a forward mode and serve to maintain low intracellular [Ca(2+)] in nerve terminals.

Animals↗
PubMed2002

Diagnostic implications of modified treadmill and head-up tilt tests in exercise-related syncope: comparative studies with situational and/or vasovagal syncope.

BACKGROUND: The precise pathophysiological basis of exercise-related vasodepressor syncope is not well understood. PURPOSE: The diagnostic values of head-up tilt and modified treadmill tests with abrupt termination were tested in patients with exercise-related syncope and compared with those of patients with situational or vasovagal syncope. PATIENTS AND METHODS: Diagnostic accuracies of head-up tilt and modified treadmill exercise tests were examined in 44 patients with unexplained syncope (26 men, 18 women, aged 46 19 years) and in 20 control subjects. Results for 18 patients with syncope during exercise (short-distance dash [n=7], jogging [n=3], going up stairs [n=6], swimming [n=1] or cycling [n=1]), defined as exercise-related syncope, were compared with those for 26 patients with exercise-unrelated syncope (including situational [n=7] and vasovagal [n=14] syncope). RESULTS: No differences were found between the clinical backgrounds of subjects with and those without exercise-related syncope. Head-up tilt testing had good diagnostic sensitivities, specificities and accuracies in both exercise-related and exercise-unrelated groups (84% versus 77%, 84% versus 85%, 84% versus 80%, respectively). The corresponding values of modified treadmill tests in the two groups were 78% versus 19% (P<0.05), 95% versus 95% and 86% versus 52% (P<0.05), respectively. The results of exercise tests were of limited diagnostic value for exercise-unrelated syncope. Beta-blockade had good short term efficacy in subjects with exercise-related syncope (nine of 15, 60%) as well as in subjects with exercise-unrelated syncope (seven of 10, 70%). CONCLUSIONS: Modified treadmill exercise testing is thought to be useful for diagnosing exercise-related syncope.

Adolescent↗
PubMedDate not supplied

Revival of effective and safe high-dose mizoribine for the kidney transplantation.

We investigated whether high-dose Mizoribine (MIZ: a water-soluble anti-metabolite), 4-6 mg/kg/d was as effective and safe as mycophenolate mofetil (MMF) for patients after kidney transplantation. Between January 2001 and December 2005, 36 recipients at a stable phase more than one month passed after transplantation underwent conversion from MMF to MIZ, two from Azathioprine to MIZ, and two cases on MIZ from the beginning. There were 24-male and 16-female patients whose average age was 43.3 yr old and average weight was 54.0 kg. The types of transplantations were living donor renal transplantation 25, cadaveric renal transplantation 11, and simultaneous pancreas-kidney transplantation four examples. Of these, 33 patients were on Tacrolimus-based triple regimen and seven patients on Cyclosporine A base. The drugs used together with MIZ were basically the same as those before conversion. The reasons for conversion to MIZ were infection in 18 cases (45.0%), bone marrow suppression in nine cases (22.5%) and diarrhea in eight cases (20.0%), and post-transplant lymphoproliferative disorder in one case (2.5%). We initiated 4-6 mg/kg/d of MIZ divided twice a day depending on the serum creatinine (sCr) value of each patient. There was no big difference in the sCr value before and after MIZ administration in each individual patient, 1.79 +/- 1.37 and 1.65 +/- 1.30 mg/dL, respectively. A 12 h pharmaco-kinetic study of MIZ revealed that a peak value reached 2.87 microg/mL on average at three h (C3) followed by a slow decrease afterward. Acute rejection occurred in two cases and adverse effects were seen in five cases. The results of analysis of 349 points divided into three groups by renal function were as follows; poor renal function Group A revealed a trough level of 2.21 +/- 0.99 microg/mL and dosage 2.20 +/- 1.06 mg/kg, good renal function Group B had a trough level of 1.06 +/- 0.82 microg/mL and dosage 4.40 +/- 1.72 mg/kg, and excellent function Group C had a trough level of 0.92 +/- 0.55 microg/mL and dosage of 4.36 +/- 1.08 mg/kg. High-dose MIZ 4-6 mg/kg/d is an anti-metabolite having an equivalent immunosuppressive effect, fewer serious adverse events and good cost-effectiveness as MMF even for patients with prolonged hemodialysis period and declined digestive function in Japan.

Adolescent↗