1H-NMR investigation of the interaction between RNase T1 and a novel substrate analog, 2′-deoxy-2′-fluoroguanylyl-(3′–5′)uridine

AbstractThe interaction between RNase T1 and a non-hydrolysable substrate analog, 2′-deoxy-2′-fluoroguanylyl-(3′–5′)uridine (GfpU), was investigated using 1H-NMR spectroscopy. In the complex, the Gfp portion takes the syn form around the glycosidic bond and the 3′-endo form for the ribose moiety, similar to those found in 3′-GMP and 2′-deoxy-2′-fluoroguanosine 3′-monophosphate (Gfp). However, in contrast to the cases of these two inhibitors, the complex formation with GfpU at pH 6.0 was found to shift the His-40 C2 proton resonance of RNase T1 to high field as much as 1 ppm. At pH 6.0, this histidine residue appears to be unprotonated in the complex, but is protonated in the free enzyme (pKa of His-40 being 7.9). His-40, rather than Glu-58, is probably involved in the catalytic mechanism as a Lewis base, supporting the recent results from site-directed mutagenesis

Identification of lysophospholipid receptors in human platelets: the relation of two agonists, lysophosphatidic acid and sphingosine 1-phosphate

AbstractLysophosphatidic acid (LPA) and sphingosine 1-phosphate (Sph-1-P) are known as structurally related bio-active lipids activating platelets through their respective receptors. Although the receptors for LPA and Sph-1-P have been recently identified in various cells, the identification and characterization of ones in platelets have been reported only preliminarily. In this report, we first investigated the distinct modes of LPA and Sph-1-P actions in platelet activation and found that LPA functioned as a much stronger agonist than Sph-1-P, and high concentrations of Sph-1-P specifically desensitized LPA-induced intracellular Ca2+ mobilization. In order to identify the responsible receptors underlying these observations, we analyzed the LPA and Sph-1-P receptors which might be expressed in human platelets, by RT-PCR. We found for the first time that Edg2, 4, 6 and 7 mRNA are expressed in human platelets

Basic Consideration on Education for Severely- and Multi-handicapped Children : Returning to the Foundation of the Organization of Human Behaviour

The state and the developmental process of the severely- and multi-handicapped children were described. We divided them into two aspects; the function of the subject and the external world constructed by him. About the former, we investigated the system of the anticipation, the controll and the conffirmation of the behavior; about the latter, the construction of the postural space and the operational space

High-sensitivity quantitative analysis reveals the non-linear relationship between the dose and deposition of diphenylarsinic acid in the rat central nervous system following its subchronic exposure

In the year 2003, the residents of Kamisu, Japan, were exposed to pentavalent organic arsenic diphenylarsinic acid (DPAA[V]) via their normal drinking water. Following the exposure, they developed cerebellar and brainstem symptoms. Although the relatively high dose of DPAA(V) is assumed to have caused their symptoms, the relationship between the exposed dose of DPAA(V) and the level of their deposition in the central nervous system (CNS) remains unclear. Using liquid chromatography–tandem mass spectrometry, we examined the deposition of DPAA(V) and its pentavalent metabolites in the CNS tissues of Crl:CD(SD) rats following the administration of DPAA(V) for 28 days. We found that the concentrations of DPAA(V) in the CNS were very high, given a dose of 5.0 mg/kg/day. However, very low concentrations of DPAA(V) were detected at a dose of 0.3 or 1.2 mg/kg/day, suggesting the absence of a linear dose-response relationship between the dose and deposition of DPAA(V). We also found that this non-linear relationship was commonly observed in various non-CNS tissues, including the excretory system. Our study showed for the first time the exact relationship between the dose and tissue deposition of the organic arsenic following its subchronic administration

The Great Space Weather Event during February 1872 Recorded in East Asia

The study of historical great geomagnetic storms is crucial for assessing the possible risks to the technological infrastructure of a modern society, caused by extreme space-weather events. The normal benchmark has been the great geomagnetic storm of September 1859, the so-called "Carrington Event". However, there are numerous records of another great geomagnetic storm in February 1872. This storm, about 12 years after the Carrington Event, resulted in comparable magnetic disturbances and auroral displays over large areas of the Earth. We have revisited this great geomagnetic storm in terms of the auroral and sunspot records in the historical documents from East Asia. In particular, we have surveyed the auroral records from East Asia and estimated the equatorward boundary of the auroral oval to be near 24.3 deg invariant latitude (ILAT), on the basis that the aurora was seen near the zenith at Shanghai (20 deg magnetic latitude, MLAT). These results confirm that this geomagnetic storm of February 1872 was as extreme as the Carrington Event, at least in terms of the equatorward motion of the auroral oval. Indeed, our results support the interpretation of the simultaneous auroral observations made at Bombay (10 deg MLAT). The East Asian auroral records have indicated extreme brightness, suggesting unusual precipitation of high-intensity, low-energy electrons during this geomagnetic storm. We have compared the duration of the East Asian auroral displays with magnetic observations in Bombay and found that the auroral displays occurred in the initial phase, main phase, and early recovery phase of the magnetic storm.Comment: 28 pages, 5 figures, accepted for publication in the Astrophysical Journal on 31 May 201

Re-colonizing spaces of memorializing: the case of the Chattri Indian Memorial, UK

This article inspects the ways that spaces of war memorialization are organized and reorganized through official and unofficial meaning-making activities. It aims to contribute to the discussion of the ‘value’ of memorializing by examining a multifaceted space of remembrance and commemoration: the Chattri Indian Memorial built near Brighton, UK. The article brings postcolonial perspectives to explore how memorializing has been organized here, focusing on the activities of once-colonized people and the affective, embodied aspects of organizing practices. Built in 1921 to honour Indian soldiers who fought in WWI, the Chattri evolved from a colonial instrument to symbol and space for ethnic-Indian group activities. The study employed historical, visual and ethnographic methods to study the tangible monument and the changing nature of the memorializing activities carried out around the monument. Memorializing is conceptualized within three inter-related processes: colonizing, de-colonizing and re-colonizing to examine how forms and practices of memorialization constitute a values-laden organizing system

A Phase III Multicenter, Open-Label, One-Arm Study to Evaluate the Efficacy and Safety of Remifentanil Hydrochloride for Pediatric Subjects under General Anesthesia

レミフェンタニル塩酸塩は4-アニリドピペリジン誘導体で選択的μ-オピオイド受容体作動薬として，国内では，成人における「全身麻酔の導入及び維持における鎮痛」の効能・効果で汎用されているが，小児の適応はない。今回，小児におけるレミフェンタニル塩酸塩の有効性，安全性及び薬物動態を評価するため，挿管による気道確保及びオピオイド鎮痛薬による鎮痛を必要とする全身麻酔下での手術を行った1～15歳の小児患者80例を対象に，第Ⅲ相多施設単群非盲検試験を実施した。主要評価項目の皮膚切開時の刺激への反応は11.3％で，年齢区分（1～6歳，7～15歳）による明らかな差は認められなかった。本剤の使用に関連する有害事象は30.0％で，主な事象は心拍数減少であった。レミフェンタニルのクリアランスと年齢に明らかな傾向は認められなかった。レミフェンタニル塩酸塩は全身麻酔下の小児患者において，十分な鎮痛効果を認め，安全に使用可能であった。Remifentanil is a potent, selective, 4-anilidopiperidine µ- opioid receptor agonist not licensed for analgesia in the maintenance of general anesthesia in pediatric subjects in Japan.　A phase III trial was conducted to evaluate remifentanil for pediatric subjects in Japan.　This multicenter, open-label, one-arm study in pediatric subjects between 1 and 15 years of age receiving general anesthesia included 80 subjects.　Nine subjects (11.3%) showed response to skin incision, which was the primary endpoint, and no apparent difference in response rate was found according to age (1–6, and 7–15 years old).　Drug-related treatment emergent adverse events were found in 24 subjects (30.0%) with the most common event being heart rate decreased (26.3%).　Remifentanil was found to be effective and safe for analgesia in maintenance of general anesthesia for pediatric subjects

The identification and functional implications of human-specific "fixed" amino acid substitutions in the glutamate receptor family

<p>Abstract</p> <p>Background</p> <p>The glutamate receptors (GluRs) play a vital role in the mediation of excitatory synaptic transmission in the central nervous system. To clarify the evolutionary dynamics and mechanisms of the GluR genes in the lineage leading to humans, we determined the complete sequences of the coding regions and splice sites of 26 chimpanzee GluR genes.</p> <p>Results</p> <p>We found that all of the reading frames and splice sites of these genes reported in humans were completely conserved in chimpanzees, suggesting that there were no gross structural changes in humans after their divergence from the human-chimpanzee common ancestor. We observed low <it>K</it>_<it>A</it>/<it>K</it>_{<it>S </it>}ratios in both humans and chimpanzees, and we found no evidence of accelerated evolution. We identified 30 human-specific "fixed" amino acid substitutions in the GluR genes by analyzing 80 human samples of seven different populations worldwide. Grantham's distance analysis showed that <it>GRIN2C </it>and <it>GRIN3A </it>are the most and the second most diverged GluR genes between humans and chimpanzees. However, most of the substitutions are non-radical and are not clustered in any particular region. Protein motif analysis assigned 11 out of these 30 substitutions to functional regions. Two out of these 11 substitutions, D71G in <it>GRIN3A </it>and R727H in <it>GRIN3B</it>, caused differences in the functional assignments of these genes between humans and other apes.</p> <p>Conclusion</p> <p>We conclude that the GluR genes did not undergo drastic changes such as accelerated evolution in the human lineage after the divergence of chimpanzees. However, there remains a possibility that two human-specific "fixed" amino acid substitutions, D71G in <it>GRIN3A </it>and R727H in <it>GRIN3B</it>, are related to human-specific brain function.</p