A microarray data-based semi-kinetic method for predicting quantitative dynamics of genetic networks

BACKGROUND: Elucidating the dynamic behaviour of genetic regulatory networks is one of the most significant challenges in systems biology. However, conventional quantitative predictions have been limited to small networks because publicly available transcriptome data has not been extensively applied to dynamic simulation. RESULTS: We present a microarray data-based semi-kinetic (MASK) method which facilitates the prediction of regulatory dynamics of genetic networks composed of recurrently appearing network motifs with reasonable accuracy. The MASK method allows the determination of model parameters representing the contribution of regulators to transcription rate from time-series microarray data. Using a virtual regulatory network and a Saccharomyces cerevisiae ribosomal protein gene module, we confirmed that a MASK model can predict expression profiles for various conditions as accurately as a conventional kinetic model. CONCLUSION: We have demonstrated the MASK method for the construction of dynamic simulation models of genetic networks from time-series microarray data, initial mRNA copy number and first-order degradation constants of mRNA. The quantitative accuracy of the MASK models has been confirmed, and the results indicated that this method enables the prediction of quantitative dynamics in genetic networks composed of commonly used network motifs, which cover considerable fraction of the whole network

A simplified method for power-law modelling of metabolic pathways from time-course data and steady-state flux profiles

BACKGROUND: In order to improve understanding of metabolic systems there have been attempts to construct S-system models from time courses. Conventionally, non-linear curve-fitting algorithms have been used for modelling, because of the non-linear properties of parameter estimation from time series. However, the huge iterative calculations required have hindered the development of large-scale metabolic pathway models. To solve this problem we propose a novel method involving power-law modelling of metabolic pathways from the Jacobian of the targeted system and the steady-state flux profiles by linearization of S-systems. RESULTS: The results of two case studies modelling a straight and a branched pathway, respectively, showed that our method reduced the number of unknown parameters needing to be estimated. The time-courses simulated by conventional kinetic models and those described by our method behaved similarly under a wide range of perturbations of metabolite concentrations. CONCLUSION: The proposed method reduces calculation complexity and facilitates the construction of large-scale S-system models of metabolic pathways, realizing a practical application of reverse engineering of dynamic simulation models from the Jacobian of the targeted system and steady-state flux profiles

NMDAシグナルによる成熟脳内神経系前駆細胞の成長制御に関する神経薬理学的研究

取得学位：博士(薬学)，学位授与番号：博甲第552号，学位授与年月日：平成15年3月25日,学位授与年：200

The Role of Astrocytes in the Modulation ofK+-Cl−-Cotransporter-2 Function

Neuropathic pain is characterized by spontaneous pain, pain sensations, and tactile allodynia. The pain sensory system normally functions under a fine balance between excitation and inhibition. Neuropathic pain arises when this balance is lost for some reason. In past reports, various mechanisms of neuropathic pain development have been reported, one of which is the downregulation of K+-Cl−-cotransporter-2 (KCC2) expression. In fact, various neuropathic pain models indicate a decrease in KCC2 expression. This decrease in KCC2 expression is often due to a brain-derived neurotrophic factor that is released from microglia. However, a similar reaction has been reported in astrocytes, and it is unclear whether astrocytes or microglia are more important. This review discusses the hypothesis that astrocytes have a crucial influence on the alteration of KCC2 expression

COVID-19 and its impact on the national examination for pharmacists in Japan: An SNS text analysis.

The COVID-19 pandemic has created an extraordinary situation for undergraduate students. The aim of this study is to evaluate the impact of the COVID-19 pandemic on the national examination for pharmacists in Japan. In this study, we analyzed the content of Twitter to assess the impact of COVID-19 on the national exam, including psychological aspects. Tweets including the words "national examinations" and "pharmacists" were compiled from December 2020 to March 2021. ML-Ask, a python library, was used to evaluate the emotional register of the tweets on the basis of ten elements: Joy, Fondness, Relief, Gloom, Dislike, Anger, Fear, Shame, Excitement, and Surprise. The presence of COVID-19-related terms was clearly visible in tweets about the national examination of pharmacists between December 1st-and 15th, 2020. It was precisely during this period that the government had announced a strategy regarding national examinations, in the light of COVID-19. The analysis found that post December 16th, words associated with negative emotions were mainly related to the examination, but not to COVID-19. As a result of analyzing only infected areas, a relationship between employment and negative feeling was detected

Down-regulation of norepinephrine transporter function induced by chronic administration of desipramine linking to the alteration of sensitivity of local anesthetics-induced convulsions and the counteraction by co-administration with local anesthetics.

Alterations of norepinephrine transporter (NET) function by chroninc inhibition of NET in relation to sensitization to seizures induce by cocaine and local anesthetics were studied. [3H]norepinephrine up take into hippocampus region but not cortex, striatum or amygdalae isolated from mice treated daily for 5 days with desipramine, an inhibitor of NET was significantly decreased. Daily treatment of cocaine increased [3H]norepinephrine uptake into hippocampus. The decrease in norepinephrine uptake induced by chronic desipramine treatment was reversed by co-administration of lidocaine, bupivacaine or tricaine with desipramine. Daily administration of desipramine increased the incidence of appearance of lidocaine-induced convulsions and decreased that of cocaine-induced convulsions. The changes in the convulsive sensitivity to lidocaine and cocaine induced by repeated administration of desipramine was reversed by co-administration of lidocaine with desipramine. These results suggest that down-regulation of hippocampal NET induced by chronic administration of desipramine may be relevant to desipramine-induced sensitization of lidocaine convulsions. Inhibition of Na+ channels by local anesthetics may regulate desipramine-induced down-regulation of NET function. While repeated administration of cocaine caused up-regulation of hipoccampal NET function. Cocaine kindling developed by repeated administration of cocaine may be due to the different mechanisms from those for desipramine-induced sensitization of lidocaine seizures

Glycinergic mediation of tactile allodynia induced by platelet-activating factor (PAF) through glutamate-NO-cyclic GMP signalling in spinal cord in mice

Our previous study showed that intrathecal (i.t.) injection of platelet-activating factor (PAF) induced tactile allodynia, suggesting that spinal PAF is a mediator of neuropathic pain. The present study further examined the spinal molecules participating in PAF-induced tactile allodynia in mice. I.t. injection of L-arginine, NO donor (5-amino-3-morpholinyl-1,2,3-oxadiazolium (SIN-1) or 3,3-bis(aminoethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18)) or cGMP analog (8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate; pCPT-cGMP) induced tactile allodynia. PAF- and glutamate- but not SIN-1- or pCPT-cGMP-induced tactile allodynia was blocked by an NO synthase inhibitor. NO scavengers and guanylate cyclase inhibitors protected mice against the induction of allodynia by PAF, glutamate and SIN-1, but not by pCPT-cGMP. cGMP-dependent protein kinase (PKG) inhibitors blocked the allodynia induced by PAF, glutamate, SIN-1 and pCPT-cGMP. To identify signalling molecules through which PKG induces allodynia, glycine receptor α3 (GlyR α3) was knocked down by spinal transfection of siRNA for GlyR α3. A significant reduction of GlyR α3 expression in the spinal superficial layers of mice treated with GlyR α3 siRNA was confirmed by immunohistochemical and Western blotting analyses. Functional targeting of GlyR α3 was suggested by the loss of PGE2-induced thermal hyperalgesia and the enhancement of allodynia induced by bicuculline, a GABAA receptor antagonist in mice after GlyR α3 siRNA treatment. pCPT-cGMP, PAF, glutamate and SIN-1 all failed to induce allodynia after the knockdown of GlyR α3. These results suggest that the glutamate-NO-cGMP-PKG pathway in the spinal cord may be involved in the mechanism of PAF-induced tactile allodynia, and GlyR α3 could be a target molecule through which PKG induces allodynia

Analgesic action of nicotine on tibial nerve transection (TNT)-induced mechanical allodynia through enhancement of the glycinergic inhibitory system in spinal cord

The activation of cholinergic pathways by nicotine elicits various physiological and pharmacological effects in mammals. For example, the stimulation of nicotinic acetylcholine receptors (nAChRs) leads to an antinociceptive effect. However, it remains to be elucidated which subtypes of nAChR are involved in the antinociceptive effect of nicotine on nerve injury-induced allodynia and the underlying cascades of the nAChR-mediated antiallodynic effect. In this study, we attempted to characterize the actions of nicotine at the spinal level against mechanical allodynia in an animal model of neuropathic pain, tibial nerve transection (TNT) in rats. It was found that the intrathecal injection of nicotine, RJR-2403, a selective 4 2 nAChR agonist, and choline, a selective 7 nAChR agonist, produced an antinociceptive effect on the TNT-induced allodynia. The actions of nicotine were almost completely suppressed by pretreatment with mecamylamine, a non-selective nicotinic antagonist, or dihydro- -erythroidine, a selective 4 2 nAChR antagonist, and partially reversed by pretreatment with methyllycaconitine, a selective 7 nAChR antagonist. Furthermore, pretreatment with strychnine, a glycine receptor antagonist, blocked the antinociception induced by nicotine, RJR-2403, and choline. On the other hand, the GABAA antagonist bicuculline did not reverse the antiallodynic effect of nicotine. Together, these results indicate that the 4 2 and 7 nAChR system, by enhancing the activities of glycinergic neurons at the spinal level, exerts a suppressive effect on the nociceptive transduction in neuropathic pain