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Even though microbial photosensitive proteins have been used for optogenetics, their use should be optimized to precisely control second messengersin vivo. We exploitedGtCCR4andKnChR, cation channelrhodopsins from algae,BeGC1, a guanylyl cyclase rhodopsin from a fungus, and photoactivated adenylyl cyclases (PACs) from cyanobacteria (OαPAC) or bacteria (bPAC), to control cell functions in zebrafish. Optical activation ofGtCCR4 andKnChR in the hindbrain reticulospinal V2a neurons, which are involved in locomotion, immediately induced swimming behavior, whereas activation ofBeGC1 or PACs was achieved at a short latency.KnChR had the highest locomotioninducing activity of all the channelrhodopsins examined. Activation ofGtCCR4 andKnChR in cardiomyocytes induced cardiac arrest, whereas activation ofbPAC gradually induced bradycardia.KnChR activation led to an increase in intracellular Ca2+in the heart, suggesting that depolarization caused cardiac arrest. These data suggest that these optogenetic tools can be used to reveal the roles of second messengers in various cell types in vertebrates.Impact statementWe identified efficient and useful microbial channelrhodopsin, guanylyl cyclase rhodopsin, and photoactivated adenylyl cyclase that regulate neural activity and cardiac function in zebrafish.Major subject areasNeuroscience, Cell biologyResearch organismZebrafish (Danio rerio)

G protein-coupled receptors (GPCRs) transmit extracellular signals into the cell depending on the type of G protein. To analyze the functions of GPCR signaling, we developed optogenetic tools using animal G protein-coupled bistable rhodopsins that can be controlled into active and inactive states by light irradiation. We expressed Gq- and Gi/o-coupled bistable rhodopsins in hindbrain reticulospinal V2a neurons, which are involved in locomotion, or in cardiomyocytes of zebrafish. Light stimulation of the reticulospinal V2a neurons expressing Gq-coupled spider Rh1 resulted in an increase in the level of cytoplasmic Ca2+and evoked swimming behavior. Light stimulation of cardiomyocytes expressing the Gi/o-coupled mosquito Opn3, pufferfish TMT opsin, or lamprey parapinopsin induced cardiac arrest, and the effect was suppressed by treatment with pertussis toxin or barium, suggesting that Gi/o-dependent regulation of inward-rectifier K+channels controls cardiac function. These data indicate that these rhodopsins are useful for optogenetic control of GPCR-mediated signaling in neurons and cardiomyocytesin vivo.Impact statementAnimal G protein-coupled bistable rhodopsins can regulate Gq and Gi-mediated signaling in a light-dependent manner in neurons and cardiomyocytes, making them useful for analyzing roles of GPCR signalingin vivo.

When animals repeatedly receive a combination of neutral conditional stimulus (CS) and aversive unconditional stimulus (US), they learn the relationship between CS and US, and show conditioned fear responses after CS. They show passive responses such as freezing or panic movements (classical or Pavlovian fear conditioning), or active behavioral responses to avoid aversive stimuli (active avoidance). Previous studies suggested the roles of the cerebellum in classical fear conditioning but it remains elusive whether the cerebellum is involved in active avoidance conditioning. In this study, we analyzed the roles of cerebellar neural circuits during active avoidance in adult zebrafish,. When pairs of CS (light) and US (electric shock) were administered to wild-type zebrafish, about half of them displayed active avoidance. The expression of botulinum toxin, which inhibits the release of neurotransmitters, in cerebellar granule cells or Purkinje cells did not affect conditioning-independent swimming behaviors, but did inhibit active avoidance conditioning. Nitroreductase-mediated ablation of Purkinje cells in adult zebrafish also impaired active avoidance. Furthermore, the inhibited transmission of granule cells or Purkinje cells resulted in reduced fear-conditioned Pavlovian fear responses. Our findings suggest that the zebrafish cerebellum plays an active role in active avoidance conditioning. Significance Statement An animal can associate a neutral conditioned stimulus and an aversive unconditioned stimulus, and escape to avoid an aversive stimulus. This is called active avoidance conditioning and is essential for an animal’s survival. Although the amygdala and habenula nucleus are reportedly involved in active avoidance conditioning, the roles of other brain regions are largely unknown. We describe the roles of the cerebellum during active avoidance in adult zebrafish. The neurotoxin botulinum toxin-mediated inhibition of granule cells or Purkinje cells, or the ablation of Purkinje cells, suppressed active avoidance conditioning. Our findings indicate that the cerebellum plays a positive role in active avoidance conditioning.

This paper tries to articulate an indexical theory of pragmatics that can consistently cover not only (1) referential and (2) non-referential, social-indexical practices, but also (3) linguistic structure, or its metalinguistic (cross-linguistic) matrices, comprised of indexically anchored grammatical categories and distinctive features. Noting that all of the three domains (1)–(3), can be shown to be indexically organized and anchored onto the deictic center of communicative event, that is, on sociocultural, social-indexical interaction, I shall focus on articulating the deictically centered indexical organization of linguistic structure, or grammar. In so doing, I shall argue that not only social-indexical pragmatics, but also referential pragmatics and even grammar are anchored onto the deictic center of discursive interaction, which is, first and foremost, a sociocultural event. Consequently, theories of ‘language’, including both pragmatics and linguistics, must be ‘liberated’ from the reference- or semantics-centric perspectives; instead, they should start from ‘the bottom up’, from the deictic center of sociocultural interaction, i.e., ‘discourse’.

This paper tries to present a native grammarian’s view of Japanese, articulated in opposition to the analysis of the language based on the notions of ‘Western linguistics’ such as ‘subject’ and ‘tense’. Although Yamaguchi’s particular analysis, provided in section 2, is not shared by all native grammarians of Japanese, it does give an illustrative example of the perspectival stance, or ‘footing’, of a dominant school of National Language Studies ( koku-go-gaku ), of which Yamaguchi is a leading figure, towards language and culture. This ‘footing’, as seen in section 2, is characterized by its focus on ‘emic analysis’ and its espousal of nativism, which may be associated with nationalistic essentialism. As such, it gives us an opportunity to observe not only a different grammatical tradition, but also the irreducibly cultural , i.e., (social) pragmatic, dimension of grammatical (and pragmatic) analysis, centrally concerned with the (cross/sub)national identities and (cross/sub)disciplinary perspectives of grammarians, linguistics, and pragmaticists, as briefly suggested in section 1.

This paper tries to contextualize some of the major pragmatic theories of modern Anglo-American and Japanese societies in their socio-historic surrounds, identify them as modern linguistic ‘ideologies’, advance a socio-historic theory of pragmatics as an alternative, more (self-)critical ‘ideology’, and analyze the honorifics and honorification (deference entitlement) of the Modern Tokyo-standard variety of Japanese, as well as the native Japanese theories thereof, as ideologically mediated historic phenomena of modernity in such a critical framework.

This paper analyzes honorifics and deference entitlement in Modern Japanese along with the modern Japanese and Euro-American pragmatic theories thereof, as ideologically mediated social phenomena, in the critical–theoretical framework where they are contextualized to their socio-historic surrounds, inter alia to the modern socio-economic conditions giving rise to, but hidden behind, the modern pragmatic theories and the honorific phenomena analyzed by them.

R. Kopytko s'insurge contre le fait que le champ entier de l'epistemologie, notamment par rapport aux sciences humaines, repose sur une dichotomie entre rationalisme et empirisme. Kopytko defend ainsi un binarisme epistemologique reposant a la fois sur une approche rationaliste et empirique. Il retient ainsi la logique binaire de la raison primitive avancee par Levi-Strauss et la logique floue de l'empirisme instrumental. Ici, W. Koyama ne cherche pas a critiquer l'interpretation de Kopytko sur le recent developpement de la pragmatique mais essaie de montrer les limites historiques de sa matrice interpretative. En reponse, Kopytko montre les affinites qui existent entre eux malgre le fait que Koyama presente une vue radicale du non-cartesianisme en pragmatique et dans la philosophie de la science

This paper tries to advance a pragmatically-centered social theory of dialect and ‘dialectology’ (i.e., any knowledge, or ‘ideology’, about dialects). After discussing methodological issues, it will focus on ‘the Kyoto dialect’, and (1) analyze how the region of ‘Kyoto’ is pragmatically, culturally individuated; (2) provide a structural analysis of the local dialect, showing that it is not structurally individuated; and (3) relate how a native linguist has ideologically individuated the dialect in terms of the cultural (not structural) categories. In so doing, I shall try to articulate (a) how referential pragmatics, social-indexical pragmatics, linguistic structure, and linguistic ideologies are interrelated, and (b) how macro-social phenomena (linguistic structure and ‘sociolinguistic patterns’) can be related to referential and social-indexical pragmatics at the level of the micro-social speech event.

This obituary tries to represent the total vision of Jim McCawley's philosophy of practice, philosophy of language, linguistic theory, ‘syntactic’ theory, linguistic analyses and scientific practices, in all of which his individualism, relativism and critical rationalism were consistently manifested.

We report on a 54-year-old man with hepatocellular carcinoma (HCC) associated with a marked elevation of serum alkaline phosphatase (ALP) levels. Serum ALP was biochemically similar to that of universal (liver/bone/kidney) type. The noncarcinomatous area revealed typical micronodular cirrhosis due to excessive alcohol consumption. By histochemical staining, ALP activity was demonstrated diffusely within the cytoplasm of carcinoma cells. Immunohistochemical observation of the carcinoma cells excluded the intestinal or placental type of ALP. Tissue extracts from the carcinomatous area had much higher ALP activities than those from a noncarcinomatous area, which also showed characteristics of the universal type. The present HCC is the first reported to produce and excrete the universal type of ALP.

This entry articulates the relationships between pragmatics and semantics primarily in terms of their metatheoretical presuppositions, which are critically understood as sociohistorically contextualized ideologies. First, it explicates three methodological stances toward pragmatics and semantics – the componential (modular), perspectival (phenomenological), and critical sociological views – in relation to their sociohistorical contexts. Second, it critically reviews three approaches to the boundary setting vis-a-vis semantics, pragmatics, and extralinguistics (i.e., semanticism, complementarism, and pragmaticism) and relates them to the three methodological stances. Then, it succinctly describes the general historical shift of pragmatics from componentialism and semanticism to perspectivalism and complementarism and to critical pragmaticism.

This article articulates the status of phonetics and pragmatics in linguistics and in the broader matrix of communication, or semiotics. After reviewing how phonetics and pragmatics have been theorized in linguistics, it briefly describes how they are integrated with each other in the semiotic matrix of communication, centered around the discursive processes of presupposing contextualization, creative textualization, and decontextualizing stereotyping. Further, it illustrates how linguistic structure is indexically anchored on phonetics and pragmatics through distinctive features and grammatical categories, respectively. Finally, it succinctly explicates how phonetic and pragmatic variations may become decontextualized and endowed with social–indexical forces and then recontextualized to create discursive texts.

This article explicates the relationships between pragmatics and anthropology by describing the post-Kantian genealogies of the semantic and the social-scientific tradition, derived from neo-Kantians such as Frege and Boas, respectively. The Fregean semantic tradition has taken an empirical turn, resulting in today's cognitive linguistics and ‘pragmatics’; both are still undergoing a ‘drift’ from the logico-linguistic studies of semantic regularities to the sociohistoric studies of contextualized contingent actions and events (as in critical discourse analysis). Thus, the semantic tradition has been converging with the social-scientific tradition, including post-Boasian linguistic anthropology, which is centrally concerned with the historic (re)formations of identity and power in the sociocultural context of language use.

Proceedings of the Twenty-Third Annual Meeting of the Berkeley Linguistics Society: General Session and Parasession on Pragmatics and Grammatical Structure (1997)

B型劇症肝炎(感染源不明)の回復期に,黄疸を伴うSGPTの再上昇がみとめられ,非A・非B型急性肝炎が併発したと考えられた21歳女性例を報告した.B型劇症肝炎の極期(昏睡IV度の時期)には,血中免疫複合体と血中HBs抗原・抗体免疫複合体(ともにRaji細胞法)の出現をみとめたが,SGPTの再上昇の際には前者しか検出されず,また,HBs抗原のcpm値の再上昇もみとめられなかった.肝組織像では,B型劇症肝炎による昏睡出現後8日目の肝生検では,肝細胞の壊死はみとめられず,広汎性の肝細胞の水腫様腫大をみとめたのに比し,SGPTの再上昇時の肝生検では,亜小葉性の肝実質の脱落と肝実質内に著明な炎症細胞浸潤をみとめた.SGPTの再上昇の原因は,劇症肝炎の際に施行した輸血による非A・非B型急性肝炎と考えられた.

Two kindreds of phosphofructokinase (PFK) deficiency associated with congenital nonspherocytic hemolytic anemia and mild myopathy were found in Japan. Both probands had jaundice, gallstones, and slight to moderate degree of exercise intolerance. They showed decreased level of red cell PFK activity and no increase of blood lactate in forearm ischemic exercise test. We studied these probands' red cell PFKs by partial purification and condensation. Muscle type isozyme of PFK in both cases was not demonstrable in starch gel electrophoresis and DEAE-Sephadex chromatography. The clinical symptoms are considered to be due to a defect of muscle type isozyme.

肝硬変の合併のないアルコール性肝障害で,肝性昏睡II度以上の肝不全を呈した6症例について臨床病理学的検討を行った.全例の血中HBs抗原は陰性で,大酒家である.肝性昏睡V度までが4例(死亡3例,生存1例),II度までが2例(生存)であった.肝組織像では,死亡例3例中2例は小葉全体に多数のアルコール硝子体を認める典型的なアルコール性肝炎であったが,他の1例には硝子体はなく,肝細胞の亜小葉性の壊死と著明なfoamy degenerationが認められるアルコール性肝炎であった.生存した3例は,蛍光抗体間接法および電子顕微鏡でもアルコール硝子体が認められず,炎症細胞浸潤もごくわずかであり,2例では強い肝内胆汁うっ滞と肝細胞の風船様変化を伴う肝線維症,他の1例は肝細胞の変化の乏しい肝線維症であった.重症のアルコール性肝障害でも組織学的には必ずしも典型的なアルコール性肝炎とは限らず,多彩な病理組織像を呈することを示した.

肝動脈塞栓術(transcatheter arterial embolization: TAE)後に肝細胞癌部およびその周辺領域がどのような形態学的変化をうけるのかを知る目的で,TAE後剖検しえた10例を対象に,病理組織学的に検討を加えた.TAEから剖検までの期間は12日～550日(平均170.4日),TAEの回数は1～5回(平均1.8回)であった.剖検では主腫瘍部にはいずれも大小の壊死巣がみられたが,1例を除いて全例に腫瘍細胞の残存と再発が認められた.談た,病理学的に,腫瘍の被膜内浸潤や門脈塞栓に対してTAEの効果を認めることができなかった.全症例の塞栓動脈は再疎通を示しており,さらに,剖検肝にバリウムを注入して軟線撮影を施行しえた3例においても腫瘍の栄養血管の新生と腫瘍濃染像が認められた.以上より,TAEで肝細胞癌部を完全壊死に陥らせ,とくに被膜内浸潤に至るまで効果をもたらすためには,栄養血管の再疎通を防止する方法をさらに考案する必要があると考えられた.

市販和漢薬(恵命我神散)による薬剤性肝障害の1例を報告する.症例は65歳女性.健胃薬として恵命我神散を約40日間服用後,食欲不振,両側大腿の斑状出血,黄疸が出現し,当科に入院した.入院時,黄疸と肝腫大を認め,生化学検査では総ビリルビン値,胆道系酵素およびGOT,GPTの上昇を認めた.第15病日に施行した肝生検組織所見は胆汁うっ滞型であった.恵命我神散に対するリンパ球刺激試験(lymphocyte stimulation test: LST)ではリンパ球刺激指数(lymphocyte stimulation index: LSI)は316%と陽性であったが,その組成生薬であるガジュツ,タクゴ,マコンブに対するLSTは,いずれも陰性であった.薬剤服用中止後,斑状出血,黄疸は速やかに消退し,総ビリルビン値,胆道系酵素も2ヵ月後に正常化した.

The clinical significance of serum antibodies against alcohol-altered rabbit hepatocytes was evaluated in 91 patients with alcoholic liver disease. Patients were divided into two groups according to the presence or absence of those antibodies at the time of first admission, and their clinical, biochemical, and histological findings were compared. In 38 seropositive patients, the total amount of ethanol consumption as well as serum activity of glutamate-oxaloacetate transaminase, serum levels of total bilirubin, gamma-globulin, IgG, and IgA were all significantly higher than in 53 seronegative patients. In addition, the extent of fibrosis, alcoholic hyalin, cholestasis, and lymphocytic and polymorpholeukocytic infiltrations in the liver were all significantly greater in the seropositive patients. Histological changes were compared in the 16 patients who continued to drink alcohol and who received repeated liver biopsies. Seven out of eight patients who were seropositive at the time of the first liver biopsy showed histological deterioration, whereas one of the eight seronegative patients showed a slight progression. These results suggest that the presence of serum antibodies against alcohol-altered liver cell membrane delineates a group of alcoholic patients with severe, advanced liver disease characterized by a tendency to progress with continued alcohol ingestion.

女性大酒家肝障害は,近年まれではなくなり,その臨床病理学的特徴が注目されているが,十分解明されていない.そこで,過去8年間に組織診断したアルコール性肝障害480例中にみられた女性大酒家肝障害25例(5.2%)について,病態の解析を試みた.女性例では,アルコール性肝炎,高度肝線維化,肝硬変といった進展した肝障害が全体の80%を占めた.また,女性大酒家肝障害では,更年期前の月経不順または無月経が52%に認められ,女性非アルコール性肝硬変(21例)における出現率(10%)より有意に高かった.男性のアルコール性肝硬変(45例)と比較すると,平均年齢,飲酒期間,積算飲酒総量はいずれも有意に低かった.以上より,女性大酒家は同量の飲酒でも短期間で高度肝障害発生の危険性が高く,月経異常を伴いやすい特徴がある.今後,女性ホルモンとアルコール性肝硬変発生との関係を生物学的に追求する必要が指摘できた.

The effects of procaine, Ca, Mg and K on the release of transmitter from the cholinergic sweat nerve endings in the forearm skin were studied. Sweating was visualized by the iodine-starch method of Wada and Takagaki. At a concentration of 10-7, intradermal injections of eserine did not produce a local sweating in a cool environment, but they became effective in eliciting sweat response on the injection wheals by entering a warm or hot environment. Local sweat responses to eserine in 10-6 and 10-5 were also intensified on exposure to heat. Procaine in 10-4 inhibited the sweat responses to eserine very probably by affecting the acetylcholine release from the sweat nerve endings. It was found that Ca ions contained in Krebs solution are important in the process of the acetylcholine release and excessive Ca facilitates this release. In contrast, Mg and K ions present in Krebs solution were without any effect. But, when Mg was in excess relative to Ca, it was observed that Mg antagonized the effect of Ca. The antagonism between Mg and Ca was demonstrated also in the case of spontaneous thermoregulatory sweating. The effect of Ca on the acetylcholine release seems to be antagonized by Mg in a ratio of approximately 1:2 in molality.

• A 32-year-old woman with asymptomatic primary biliary cirrhosis had autoimmune hemolytic anemia associated with reticulocytopenia and thrombocytopenia despite an intensely erythroid bone marrow. Her anemia was successfully treated with oral prednisolone and intravenous pulse methylprednisolone, with a rapid response of reticulocytosis and sustained erythrocytosis. Tiopronin therapy was later initiated and resulted in fever, rash, exacerbation of the liver disease, and positive direct and indirect antiglobulin tests. (Arch Intern Med1984;144:89-91)

Subkutane Einspritzung von Kalium- oder Natriumzyanid in die Zehenballen der Katze fuhrt uber einen Axonreflex zu merklichem Schwitzen. Dieser Effekt von Kaliumzyanid wird durch Procain und Atropin gehemmt, nicht aber durch Hexamethonium. Auch beim Menschen ruft intrakutan eingefuhrtes Natriumzyanid eine entsprechende Schweissabsonderung hervor.